U.S. patent application number 14/173243 was filed with the patent office on 2014-08-14 for processes of enantioselectively forming an aminoxy compound and an 1,2-oxazine compound.
This patent application is currently assigned to Nanyang Technological University. The applicant listed for this patent is Nanyang Technological University. Invention is credited to Pei Juan CHUA, Min LU, Bin TAN, Guofu ZHONG, Di ZHU.
Application Number | 20140228564 14/173243 |
Document ID | / |
Family ID | 44560583 |
Filed Date | 2014-08-14 |
United States Patent
Application |
20140228564 |
Kind Code |
A1 |
ZHONG; Guofu ; et
al. |
August 14, 2014 |
PROCESSES OF ENANTIOSELECTIVELY FORMING AN AMINOXY COMPOUND AND AN
1,2-OXAZINE COMPOUND
Abstract
Disclosed is a process of enantioselectively forming an aminoxy
compound of Formula (3) ##STR00001## In formula (3) R.sup.1 is one
of an aliphatic group and an alicyclic group. R.sup.2 is one of
hydrogen, an aliphatic group, an alicyclic group, an aromatic
group, an arylaliphatic group and an arylalicyclic group. R.sup.3
is one of hydrogen, halogen, hydroxyl, and an aliphatic group with
a main chain having 1 to about 10 carbon atoms. The respective
aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic
groups of R.sup.1, R.sup.2, and R.sup.3 comprise 0 to about 3
heteroatoms independently selected from the group consisting of N,
O, S, Se and Si. The process includes contacting a carbonyl
compound of Formula (1) ##STR00002## and a nitroso compound of
Formula (2) ##STR00003## in the presence of a chiral catalyst. The
chiral catalyst is a compound of Formula (IX) ##STR00004##
Inventors: |
ZHONG; Guofu; (Singapore,
SG) ; LU; Min; (Singapore, SG) ; ZHU; Di;
(Singapore, SG) ; CHUA; Pei Juan; (Singapore,
SG) ; TAN; Bin; (Singapore, SG) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Nanyang Technological University |
Singapore |
|
SG |
|
|
Assignee: |
Nanyang Technological
University
Singapore
SG
|
Family ID: |
44560583 |
Appl. No.: |
14/173243 |
Filed: |
February 5, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12782709 |
May 18, 2010 |
8680335 |
|
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14173243 |
|
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|
61180353 |
May 21, 2009 |
|
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|
61241157 |
Sep 10, 2009 |
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Current U.S.
Class: |
544/63 |
Current CPC
Class: |
C07C 239/20 20130101;
C07D 265/02 20130101 |
Class at
Publication: |
544/63 |
International
Class: |
C07D 265/02 20060101
C07D265/02 |
Claims
1-12. (canceled)
13. A process of enantioselectively forming an 1,2-oxazine compound
of Formula (13) ##STR00110## wherein R.sup.2 is one of hydrogen, an
aliphatic group, and an alicyclic group, comprising 0 to about 3
heteroatoms independently selected from the group consisting of N,
O, S, Se and Si, R.sup.3 is one of hydrogen, halogen, OR.sup.6, an
aliphatic group with a main chain having 1 to about 10 carbon atoms
and 0 to about 3 heteroatoms independently selected from the group
consisting of N, O, S, Se and Si, and R.sup.8 is one of hydrogen,
NO.sub.2, CN, C(R.sup.40)O, COOR.sup.40, and CONR.sup.40R.sup.41,
an aliphatic group, an alicyclic group, an aromatic group, an
arylaliphatic group and an arylalicyclic group, comprising 0 to
about 3 heteroatoms independently selected from the group
consisting of N, O, S, Se and Si, wherein R.sup.40 and R.sup.41 are
independent from one another one of hydrogen, an aliphatic group,
an alicyclic group, an aromatic group, an arylaliphatic group and
an arylalicyclic group, comprising 0 to about 3 heteroatoms
independently selected from the group consisting of N, O, S, Se and
Si, and Z is one of NO.sub.2, CN, C(R.sup.42)O, COOR.sup.42, and
CONR.sup.42R.sup.43, wherein R.sup.42 and R.sup.43 are independent
from one another one of hydrogen, an aliphatic group, an alicyclic
group, an aromatic group, an arylaliphatic group and an
arylalicyclic group, comprising 0 to about 3 heteroatoms
independently selected from the group consisting of N, O, S, Se and
Si, the process comprising contacting a carbonyl compound of
Formula (11) ##STR00111## and a nitroso compound of Formula (2)
##STR00112## in the presence of a chiral catalyst, the catalyst
being a compound of Formula (IX) ##STR00113## wherein R.sup.4 and
R.sup.5 are independently one of COOH and ##STR00114## Y is one of
CHOH, O, S, Se, CH.sub.2, CHOH, CHSH and CHSeH, thereby forming a
reaction mixture, and allowing the carbonyl compound of Formula (1)
and the nitroso compound of Formula (2) to react in the reaction
mixture, thereby allowing the formation of the 1,2-oxazine compound
of Formula (13).
14. The process of claim 13, wherein the carbonyl compound of
Formula (1) and the nitroso compound of Formula (2) are allowed to
react at a temperature below 25.degree. C.
15. The process of claim 14, wherein the temperature is selected in
the range from about -80.degree. C. to about 0.degree. C.
16. The process of claim 13, wherein the carbonyl compound of
Formula (1) and the nitroso compound of Formula (II) are allowed to
react for a period of time selected in the range from about 15
minutes to about 48 hours.
17. The process of claim 13, wherein the reaction mixture is formed
in a dipolar aprotic solvent.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application makes reference to and claims the benefit
of priority of an application for "Organocatalytic Enantioselective
.alpha.-Aminoxylation of Aldehydes and its Application for the
Synthesis of Chiral 1,2-Diols, and
.alpha.-Aminoxylation/Aza-Michael Reactions for the Synthesis of
Functionalized Tetrahydro-1,2-Oxazines" filed on May 21, 2009 with
the United States Patent and Trademark Office, and there duly
assigned Ser. No. 61/180,353. This application further makes
reference to and claims the benefit of priority of an application
for "Processes Of Enantioselectively Forming An Aminoxy Compound
And An 1,2-Oxazine Compound" filed on Sep. 10, 2009 with the United
States Patent and Trademark Office, and there duly assigned Ser.
No. 61/241,157. The contents of said applications filed on May 21,
2009 and Sep. 10, 2009 are incorporated herein by reference for all
purposes in their entirety.
FIELD OF THE INVENTION
[0002] The present invention provides a process of
enantioselectively forming an aminoxy compound and an 1,2-oxazine
compound.
BACKGROUND OF THE INVENTION
[0003] The presence of optically active .alpha.-hydroxylcarbonyl
moieties as well as 1,2-diols in many biologically active natural
products motivated numerous research into finding new routes to
provide better stereocontrol for these synthetically useful
synthons. Asymmetric .alpha.-hydroxylation of enolates and the
Sharpless asymmetric dihydroxylation of olefins are some methods to
synthesize these compounds. The year 2000 saw a renaissance of
organocatalysis, and since then organocatalysis has emerged as an
extremely useful tool for the preparation of enantiomerically pure
compounds. Operational simplicity, availability and the
non-toxicity of the organic catalysts compared to the corresponding
transition-metal species, as well as its high efficiencies and
selectivities attained in many organocatalytic transformations made
this methodology very attractive for the formation of
enantiomerically pure compounds.
[0004] In 2003, Zhong (Angew. Chem., Int. Ed. (2003) 42, 4247),
MacMillan (S. P. Brown et al., J. Am. Chem. Soc. (2003) 125, 10808)
and Hayashi (Y. Hayashi et al., Tetrahedron Lett. (2003) 44, 8293)
independently reported the direct proline-catalyzed
.alpha.-aminoxylation of aldehydes with nitrosobenzene and the
usefulness of this reaction was demonstrated in the synthesis of
several biologically active compounds (S. P. Kotkar et al.,
Tetrahedron: Asymmetry (2007) 18, 1795; S. P. Kotkar et al.,
Tetrahedron: Asymmetry (2007) 18, 1738; S. P. Kotkar & A.
Sudalai, Tetrahedron Lett. (2006) 47, 6813; S. V. Narina & A.
Sudalai, Tetrahedron Lett. (2006) 47, 6799; S. G. Kim & T. H.
Park, Tetrahedron Lett. (2006) 47, 6369; Sousuke Hara et al.,
Tetrahedron Lett. (2006) 47, 1081; I. K. Mangion & D. W. C.
MacMillan, J. Am. Chem. Soc. (2005) 127, 3696). Though the scope of
the abovementioned reaction has been quickly extended to that of
ketones (Y. Hayashi et al., Angew. Chem., Int. Ed. (2004) 43, 1112;
A. Bogevig et al., Angew. Chem., Int. Ed, (2004) 43, 1109) after
the first report, there was little development in new
organocatalysts (T. Kano et al., Chem. Lett. (2008) 37, 250; Y.
Hayashi, et al., Adv. Synth. Catal. (2004) 346, 1435; H. Sunden et
al., Tetrahedron Lett. (2005) 46, 3385; W. Wang et al., Tetrahedron
Lett. (2004) 45, 7235; N. Momiyama et al., Proc. Natl. Acad. Sci.
USA (2004) 101, 5374) or environmentally friendly reaction
protocols (D. Font et al., Org. Lett. (2007) 9, 1943; H.-M. Guo et
al., Green Chem. (2006) 8, 682).
[0005] Recently, demand has increased for innovative and
imaginative synthetic methodologies to improve efficiency and
sustainability such as simplicity, atom economy, reduced chemical
wastage and energy usage, safety, and environment friendliness.
[0006] Accordingly, it is a further object of the present invention
to provide a synthesis route to .alpha.-hydroxycarbonyl- and/or
1,2-dihydroxy compounds under conditions that are a lower burden to
the environment than currently available methods.
[0007] Tetrahydro-1,2-oxazine derivatives occur frequently in
biologically active compounds (Uchida, I., et al., J. Am. Chem.
Soc. (1987) 109, 4108; Terano, H.; et al., J. Antibiot. (1989) 42,
145; Yu, Q.-S, et al., J. Med. Chem. (2002) 45, 3684; Katoh, T., et
al., Tetrahedron (1997) 53, 10229; Judd, T. C., & Williams, R.
M., Angew. Chem., Int. Ed. (2002) 41, 4683; Suzuki, M., et al.,
Angew. Chem. Int. Ed. (2002) 41, 4686) and are valuable synthetic
intermediates (Pulz, R., et al., Org. Lett. (2002) 4, 2353;
Tishkov, A. A., et al., Synlett (2002) 863; Buchholz, M.; Reissig,
H.-U. Eur. J. Org. Chem. (2003) 3524; Al-Harrasi, A., &
Reissig, H.-U., Angew. Chem. Int. Ed. (2005) 44, 6227; Carson, C.
A., & Kerr, M. A., Angew. Chem. Int. Ed. (2006) 45, 6560). Not
only do they have the potential to act as therapeutic agents and
chiral building blocks, they also possess synthetic utility through
reductive N--O bond cleavage to form highly functionalized
1,4-amino alcohols which can be found in a number of bioactive
natural products.
[0008] The nitroso function is recognized as a unique source to
prepare nitrogen- and oxygen-containing molecules. Various
catalytic asymmetric reactions exploiting the unique properties of
nitroso compounds (Palomo, C., et al., Angew. Chem. Int. Ed. (2007)
46, 8054), such as aminoxylation, oxyamination, and nitroso
Diels-Alder reactions, have recently been developed. Nevertheless,
only two general routes for tetrahydro-1,2-oxazines have so far
been used including the addition of nitrones to activated
cyclopropanes (M. P. Sibi, et al., J. Am. Chem. Soc. (2005) 127,
5764-5765) and the sequential nitroso aldol/Michael addition of
cyclic enones reported by Yamamoto et al. (Yamamoto, Y, et al., J.
Am. Chem. Soc. (2004) 126, 5962-5963; Momiyama, N, et al., J. Am.
Chem. Soc. (2007) 129, 1190-1195). The substrate scope for these
two examples is limited, and the development of a practical,
asymmetric synthetic procedure to access enantiopure functionalized
tetrahydro-1,2-oxazines from acyclic starting materials is highly
desirable.
[0009] Accordingly, it is a further object of the present invention
to provide a process that allows a simple formation of
tetrahydro-1,2-oxazine compounds with potentially high enantio- and
diastereoselectivity.
SUMMARY OF THE INVENTION
[0010] In a first aspect the invention relates to a process of
enantioselectively forming an aminoxy compound of Formula (3)
##STR00005##
In formula (3) R.sup.1 is one of an aliphatic group, an alicyclic
group, an aromatic group, an arylaliphatic group and an
arylalicyclic group. The respective aliphatic, alicyclic, aromatic,
arylaliphatic or arylalicyclic group includes 0 to about 3
heteroatoms independently selected from the group consisting of N,
O, S, Se and Si. R.sup.2 is one of hydrogen, an aliphatic group and
an alicyclic group. The respective aliphatic or alicyclic group
includes 0 to about 3 heteroatoms independently selected from the
group consisting of N, O, S, Se and Si. In some embodiments one of
R.sup.1 and R.sup.2 defines an aliphatic, aromatic or arylaliphatic
bridge that is linked to the respective other moiety of R.sup.2 and
R.sup.1. Accordingly, R.sup.1 and R.sup.2 may in some embodiments
define one common cyclic structure. R.sup.3 is one of hydrogen,
halogen, hydroxyl and an aliphatic group with a main chain having 1
to about 10 carbon atoms. The process includes contacting a
carbonyl compound of Formula (1)
##STR00006##
and a nitroso compound of Formula (2)
##STR00007##
in the presence of a chiral catalyst. The moieties R.sup.1, R.sup.2
and R.sup.3 in these formulas are as defined above. The chiral
catalyst is a compound of Formula (IX)
##STR00008##
In this formula (IX) R.sup.4 is one of COOH
##STR00009##
and Y in formula (IX) is one of CHOH, O, S, Se, CH.sub.2, CHOH,
CHSH and CHSeH. The reaction of the process is carried out in an
aqueous solution in the presence of a phase transfer catalyst.
[0011] In a further aspect the invention provides a process of
enantioselectively forming an aminoxy compound of Formula (4)
##STR00010##
In formula (4) R.sup.1 is one of an aliphatic group, an alicyclic
group, an aromatic group, an arylaliphatic group and an
arylalicyclic group. The respective aliphatic, alicyclic, aromatic,
arylaliphatic or arylalicyclic group includes 0 to about 3
heteroatoms independently selected from the group consisting of N,
O, S, Se and Si. R.sup.2 in formula (4) is one of hydrogen, an
aliphatic group and an alicyclic group. The respective aliphatic or
alicyclic, group includes 0 to about 3 heteroatoms independently
selected from the group consisting of N, O, S, Se and Si. In some
embodiments one of R.sup.1 and R.sup.2 define an aliphatic or
arylaliphatic bridge that is linked to the respective other moiety
of R.sup.2 and R.sup.1. Accordingly, R.sup.1 and R.sup.2 may in
some embodiments define one common cyclic structure. R.sup.3 is one
of hydrogen, halogen, hydroxyl and an aliphatic group with a main
chain having 1 to about 10 carbon atoms. The process includes
contacting a carbonyl compound of Formula (1)
##STR00011##
and a nitroso compound of Formula (2)
##STR00012##
in the presence of a chiral catalyst. The moieties R.sup.1, R.sup.2
and R.sup.3 in these formulas are as defined above. The chiral
catalyst is a compound of Formula (V)
##STR00013##
In this formula (V) R.sup.4 is one of COOH and
##STR00014##
Y in formula (V) is one of CHOH, O, S, Se, CH.sub.2, CHOH, CHSH and
CHSeH. The reaction of the process is carried out in an aqueous
solution in the presence of a phase transfer catalyst.
[0012] In yet a further aspect the invention provides a process of
enantioselectively forming an 1,2-oxazine compound of Formula
(13)
##STR00015##
In Formula (XIII) R.sup.2 is one of hydrogen, an aliphatic group
and an alicyclic group. The respective aliphatic or alicyclic,
group includes 0 to about 3 heteroatoms independently selected from
the group consisting of N, O, S, Se and Si. R.sup.3 is one of
hydrogen, halogen, OR.sup.6, an aliphatic group with a main chain
having 1 to about 10 carbon atoms. In Formula (13) R.sup.8 is one
of hydrogen, NO.sub.2, CN, C(R.sup.40)O, COOR.sup.40, and
CONR.sup.40R.sup.41, an aliphatic group, an alicyclic group, an
aromatic group, an arylaliphatic group and an arylalicyclic group.
The respective aliphatic, alicyclic, aromatic, arylaliphatic or
arylalicyclic group includes 0 to about 3 heteroatoms independently
selected from the group consisting of N, O, S, Se and Si. Moieties
R.sup.40 and R.sup.41 are independent from one another one of
hydrogen, an aliphatic group, an alicyclic group, an aromatic
group, an arylaliphatic group and an arylalicyclic group. The
respective aliphatic, alicyclic, aromatic, arylaliphatic or
arylalicyclic group includes 0 to about 3 heteroatoms independently
selected from the group consisting of N, O, S, Se and Si. In
Formula (13) Z is one of NO.sub.2, CN, C(R.sup.42)O, COOR.sup.42,
and CONR.sup.42R.sup.43. Moieties R.sup.42 and R.sup.43 are
independent from one another one of hydrogen, an aliphatic group,
an alicyclic group, an aromatic group, an arylaliphatic group and
an arylalicyclic group. The respective aliphatic, alicyclic,
aromatic, arylaliphatic or arylalicyclic group includes 0 to about
3 heteroatoms independently selected from the group consisting of
N, O, S, Se and Si. The process includes contacting a carbonyl
compound of Formula (11)
##STR00016##
and a nitroso compound of Formula (2)
##STR00017##
in the presence of a chiral catalyst. The moieties R.sup.2, R.sup.3
and R.sup.8 in these formulas are as defined above. The chiral
catalyst is a compound of Formula (IX)
##STR00018##
In this formula (IX) R.sup.4 is one of COOH and
##STR00019##
Y in formula (IX) is one of CHOH, O, S, Se, CH.sub.2, CHOH, CHSH
and CHSeH. By contacting carbonyl compound and the nitroso compound
in the presence of the chiral catalyst a reaction mixture is
formed. The carbonyl compound of Formula (1) and the nitroso
compound of Formula (2) are allowed to react in the reaction
mixture. Thereby the formation of the 1,2-oxazine compound of
Formula (13) is allowed to occur.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The invention will be better understood with reference to
the detailed description when considered in conjunction with the
non-limiting examples and the accompanying drawings.
[0014] FIG. 1A illustrates the reaction of a carbonyl compound of
Formula (1) with a nitroso compound of Formula (2) in the formation
of an aminoxy compound of Formula (3). The reaction is catalysed by
a chiral compound in the L form. FIG. 1B illustrates the reaction
of a carbonyl compound of Formula (1) with a nitroso compound of
Formula (2) in the formation of an aminoxy compound of Formula (4).
The reaction is catalysed by a chiral compound in the D form.
[0015] FIG. 2A illustrates a process that includes as a first step
the reaction of a carbonyl compound of Formula (11) with a nitroso
compound of Formula (2) in the formation of an 1,2-oxazine compound
of Formula (13). The reaction is catalysed by a chiral compound in
the L form. The depicted process includes a further step in which
the carbonyl group of the 1,2-oxazine compound of Formula (13) is
reduced, thereby forming 1,2-oxazine compound (14). If desired the
1,2-oxazine compound may be cleaved to yield an amine (15), which
is a 1,2-diol. FIG. 2B illustrates the corresponding process where
in the first step a chiral compound in the D form is used,
resulting the formation of an 1,2-oxazine compound of Formula
(16).
[0016] FIG. 3A shows an illustrative embodiment of the process
depicted in FIG. 2A. Each of moieties Z and R.sup.8 is in this
example an ester group. The 1,2-oxazine compound of Formula (13)
formed accordingly carries two ester groups. FIG. 3B illustrates
the corresponding process where in the first step a chiral compound
in the D form is used, thus defining an embodiment of the process
depicted in FIG. 2B. FIG. 3C depicts a further illustrative
embodiment of the process depicted in FIG. 2A. Moiety Z is in this
example a nitro group, so that an 1,2-oxazine compound of Formula
(33) is formed.
[0017] FIG. 4 illustrates the catalyst screening in the reaction
between a carbonyl compound of formula Ia and a nitroso compound of
formula 2a in the formation of an aminoxy compound of formula 9a.
Conditions: Nitrosobenzene (0.3 mmol), propanal (3 equiv), catalyst
(30 mol %), tetrabutylammonium bromide (2 equiv) and water (0.10
mL) were added at 0.degree. C. and then warmed to rt (23.degree.
C.) unless otherwise stated. a: Isolated yields. b: Determined by
chiral phase HPLC.
[0018] FIG. 5 illustrates the optimisation of reaction conditions
of the reaction depicted in FIG. 4, using catalyst IXd. Conditions:
Nitrosobenzene (0.3 mmol), propanal (3 equiv), catalyst (20 mol %),
tetrabutylammonium bromide (2 equiv) and water (0.10 mL) were added
at 0.degree. C. and stirred at rt (23.degree. C.) unless otherwise
stated. a: Isolated yields. b: Determined by chiral phase HPLC. c:
10 mol % of VI. d: 30 mol % of VI. e: No Bu.sub.4NBr added. f: 1
equiv Bu.sub.4NBr added. g: 1 equiv propanal added. h: 2 equiv
propanal added.
[0019] FIG. 6 illustrates the generality of reaction of
.alpha.-aminoxylation in the presence of water. Conditions:
Nitrosobenzene (0.3 mmol), propanal (3 equiv), catalyst (20 mol %),
tetrabutylammonium bromide (2 equiv) and water (0.10 mL) was added
at 0.degree. C. and stirred at rt (23.degree. C.) unless otherwise
stated. a: Isolated yields. b: Determined by chiral phase HPLC. c:
Nitrosotoluene was used instead of nitrosobenzene.
[0020] FIG. 7A depicts further examples of catalysts the use of
which is contemplated. R.sup.1, R.sup.1' and R.sup.1'' are
independently selected moieties as defined for R.sup.1 in the
description. In (IXg) and (IXh) n is an integer from 1 to about
20.
[0021] FIG. 7B illustrates by means of a scheme the synthesis of
chiral for tetrahydro-1,2-oxazines LII. a) Enantioselective
organocatalytic tetrahydro-1,2-oxazine synthesis by a C--O/C--N
sequence. b) Enamine-catalyzed .alpha.-aminoxylation versus Michael
addition. c) Aza-Michael addition versus nucleophilic attack on the
C.dbd.O group and subsequent asymmetric protonation.
EWG=electron-withdrawing group.
[0022] FIG. 8 illustrates the screening of reaction conditions of
an organocatalytic domino .alpha.-aminoxylation/aza-Michael
reaction of the invention yielding an aminoxy compound 33a.
Reaction conditions: 2a (1.0 equiv; 1 M), 31a (1.5 equiv), and
catalyst IX at room temperature (23.degree. C.) in the indicated
solvent. a: Yield of isolated product. b: Determined by chiral HPLC
analysis. c: Determined by .sup.1H NMR methods. d: Used 3 equiv of
31a. e: Reaction was conducted at 0.degree. C. f: Reaction was
conducted at -20.degree. C. g: 0.1 M of 2a. h: Added 1.0 equiv of
TEAB. i: In situ reduction was performed using NaBH.sub.4 to
provide the corresponding alcohol. n.d.=not determined.
[0023] FIG. 9 illustrates an analysis of the substrate scope of the
organocatalytic domino .alpha.-aminoxylation/aza-Michael reactions.
Reaction conditions: 2a (1.0 equiv; 0.1 m), 31a (3.0 equiv), TEAB
(1.0 equiv), and IXa (5 mol %) at -20.degree. C. in CH.sub.3CN. a:
Yield of isolated product. b: Determined by chiral HPLC analysis.
c: Determined by .sup.1H NMR methods.
[0024] FIG. 10 shows the X-ray crystal structure of 33d. The
crystal structure has been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition number:
CCDC 670447.
[0025] FIG. 11 depicts data of preliminary mechanistic
investigations on the catalysis of the aza-Michael addition step.
Reaction conditions: 47 (1.0 equiv, 0.1 m), 48 (1.0 equiv), and the
corresponding catalyst at room temperature in CH.sub.3CN. a:
Determined by .sup.1H NMR methods. TBS=tert-butyldimethylsilyl;
n.r.=no reaction.
[0026] FIG. 12A illustrates the DFT-calculated lowest energy
transition state for the aza-Michael addition/protonation in
CH.sub.3CN (see also the examples below). FIG. 12B depicts
schematically the transition state as confirmed by DF
calculations.
[0027] FIG. 13 depicts a catalyst and Solvent Screening in a tandem
aminoxylation/aza-Michael reaction using an aldehyde 21a with a
dicarboxyl moiety as the carbonyl compound. In all cases, 0.2 equiv
of catalyst was used in 0.1 M of nitrosobenzene solution. a:
Isolated yields. b: Ee and dr determined by HPLC employing a Daicel
Chiracel AS-H column. c: 2 equiv of PTC added, PTC)
tetraethylammonium bromide.
[0028] FIG. 14 illustrates identified optimized conditions for the
tandem aminoxylation/aza-Michael reaction. Conditions:
nitrosobenzene (0.1 mmol) was added to the solution of aldehyde and
catalyst in 1 mL of CH.sub.3CN at -78.degree. C., then stirred at
various temperatures. a: Equiv is mol ratio of
aldehyde/nitrosobenzene. b: Catalyst loading=proline/nitrobenzene.
c: Isolated yields. d: Ee and dr determined by HPLC employing a
Daicel Chiracel AS-H column. e: Reduction in situ was performed to
provide the corresponding alcohol. Dr was determined by .sup.1H
NMR.
[0029] FIG. 15 depicts the synthesis of hydrazine derivative 50i,
to analyse the stereochemistry of the tandem
aminoxylation/aza-Michael reaction.
[0030] FIG. 16 depicts an analysis of the reaction scope of the
tandem aminoxylation/Aza-Michael Addition based on an aldehyde 21a
with a dicarboxyl moiety. Conditions: Nitrosobenzene (0.1 mmol) and
L-proline (0.01 mmol) were added to the solution of aldehyde (0.3
mmol) in 1 mL of CH.sub.3CN at -78.degree. C., then stirred at
-20.degree. C.: Isolated yields. b: Ee and dr determined by HPLC
employing a Daicel Chiracel AS-H or AD-H column (see the Examples
below).
[0031] FIG. 17 depicts the X-ray crystal structure of 50i.
[0032] FIG. 18 depicts an HPLC spectrum of obtained compound 9a (A)
in comparison to a racemic mixture thereof (B).
[0033] FIG. 19A depicts the transition state for N--H adding to the
C.dbd.C bond in the course of the reaction in the gas phase, and
FIG. 19B the transition state for N--H adding to the C.dbd.C bond
in CH.sub.3CN solution.
[0034] FIG. 20 depicts a HPLC spectrum of a racemic mixture of
compound 33a (A) in comparison to the obtained product 33a (B).
[0035] FIG. 21 depicts a HPLC spectrum of a racemic mixture of
compound 33c (A) in comparison to the obtained product 33c (B).
[0036] FIG. 22 depicts a HPLC spectrum of a racemic mixture of
compound 33d (A) in comparison to the obtained product 33d (B).
[0037] FIG. 23 depicts a HPLC spectrum of a racemic mixture of
compound 33e (A) in comparison to the obtained product 33e (B).
[0038] FIG. 24 depicts a HPLC spectrum of a racemic mixture of
compound 33f (A) in comparison to the obtained product 33f (B).
[0039] FIG. 25 depicts a HPLC spectrum of a racemic mixture of
compound 33g (A) in comparison to the obtained product 33g (B).
[0040] FIG. 26 depicts a HPLC spectrum of a racemic mixture of
compound 33h (A) in comparison to the obtained product 33h (B).
[0041] FIG. 27 depicts a .sup.1H NMR spectrum of compound 33j.
[0042] FIG. 28 depicts a .sup.13C NMR spectrum of compound 33j.
[0043] FIG. 29 depicts a HPLC spectrum of a racemic mixture of
compound 33j (A) in comparison to the obtained product 33j (B).
[0044] FIG. 30 depicts a HPLC spectrum of a racemic mixture of
compound 33k (A) in comparison to the obtained product 33k (B).
[0045] FIG. 31 depicts a HPLC spectrum of a racemic mixture of
compound 33l (A) in comparison to the obtained product 33l (B).
[0046] FIG. 32 depicts a HPLC spectrum of a mixture of compound 33m
(A) in comparison to the obtained product 33m (B).
[0047] FIG. 33 depicts a HPLC spectrum of a mixture of compound 33n
(A) in comparison to the obtained product 33n (B).
[0048] FIG. 34 depicts a HPLC spectrum of a mixture of compound 33o
(A) in comparison to the obtained product 33o (B).
[0049] FIG. 35 depicts a HPLC spectrum of a mixture of compound 33p
(A) in comparison to the obtained product 33p (B).
[0050] FIG. 36 depicts a HPLC spectrum of a mixture of compound 33q
(A) in comparison to the obtained product 33q (B).
[0051] FIG. 37 a representation of the crystal data of compound 33d
(deposition number: CCDC 670447)
[0052] FIG. 38 depicts an HPLC spectrum of a racemic mixture of
compound 23a.
[0053] FIG. 39 depicts an HPLC spectrum of obtained compound
23a.
[0054] FIG. 40 depicts an HPLC spectrum of a racemic mixture of
compound 23b.
[0055] FIG. 41 depicts an HPLC spectrum of obtained compound
23b.
DETAILED DESCRIPTION OF THE INVENTION
[0056] The invention provides a process that involves forming a
2-aminoxy carbonyl compound. A 2-aminoxy carbonyl compound is
typically rather labile and will therefore generally within weeks,
days, hours or minutes--depending on the temperature and other
conditions under which it is stored--be further processed in
organic synthesis. Nevertheless, if suitable inert conditions are
maintained, a 2-aminoxy carbonyl compound can be stored for
extended periods of time. A simple further processing step often
referred to in the following is the conversion to the corresponding
2-aminoxy alcohol. Using the process of the invention this
conversion can be conveniently carried out in situ.
[0057] The 2-aminoxy carbonyl compound is of one of the general
formulae (3) and (4):
##STR00020##
Whether a 2-aminoxy carbonyl compound of formula (3) or of formula
(4) is obtained, is determined by the catalyst used (see below).
The 2-aminoxy alcohol is of one of the general formulae (9) and
(29):
##STR00021##
In formulae (3), (4), (9) and (29) R.sup.1 is one of an aliphatic
group, an alicyclic group, an aromatic group, an arylaliphatic
group and an arylalicyclic group.
[0058] The term "aliphatic" means, unless otherwise stated, a
straight or branched hydrocarbon chain, which may be saturated or
mono- or poly-unsaturated and include heteroatoms. The term
"heteroatom" as used herein means an atom of any element other than
carbon or hydrogen. An unsaturated aliphatic group contains one or
more double and/or triple bonds (alkenyl or alkinyl moieties). The
branches of the hydrocarbon chain may include linear chains as well
as non-aromatic cyclic elements. The hydrocarbon chain, which may,
unless otherwise stated, be of any length, and contain any number
of branches. Typically, the hydrocarbon (main) chain includes 1 to
5, to 10, to 15 or to 20 carbon atoms. Examples of alkenyl radicals
are straight-chain or branched hydrocarbon radicals which contain
one or more double bonds. Alkenyl radicals generally contain about
two to about twenty carbon atoms and one or more, for instance two,
double bonds, such as about two to about ten carbon atoms, and one
double bond. Alkynyl radicals normally contain about two to about
twenty carbon atoms and one or more, for example two, triple bonds,
such as two to ten carbon atoms, and one triple bond. Examples of
alkynyl radicals are straight-chain or branched hydrocarbon
radicals which contain one or more triple bonds. Examples of alkyl
groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, nonyl, decyl, the n isomers of these radicals, isopropyl,
isobutyl, isopentyl, sec-butyl, tert-butyl, neopentyl, 3,3
dimethylbutyl. Both the main chain as well as the branches may
furthermore contain heteroatoms as for instance N, O, S, Se or Si
or carbon atoms may be replaced by these heteroatoms.
[0059] The term "alicyclic" may also be referred to as
"cycloaliphatic" and means, unless stated otherwise, a non-aromatic
cyclic moiety (e.g. hydrocarbon moiety), which may be saturated or
mono- or poly-unsaturated. The cyclic hydrocarbon moiety may also
include fused cyclic ring systems such as decalin and may also be
substituted with non-aromatic cyclic as well as chain elements. The
main chain of the cyclic hydrocarbon moiety may, unless otherwise
stated, be of any length and contain any number of non-aromatic
cyclic and chain elements. Typically, the hydrocarbon (main) chain
includes 3, 4, 5, 6, 7 or 8 main chain atoms in one cycle. Examples
of such moieties include, but are not limited to, cyclopentyl,
cyclohexyl, cycloheptyl, or cyclooctyl. Both the cyclic hydrocarbon
moiety and, if present, any cyclic and chain substituents may
furthermore contain heteroatoms, as for instance N, O, S, Se or Si,
or a carbon atom may be replaced by these heteroatoms. The term
"alicyclic" also includes cycloalkenyl moieties that are
unsaturated cyclic hydrocarbons, which generally contain about
three to about eight ring carbon atoms, for example five or six
ring carbon atoms. Cycloalkenyl radicals typically have a double
bond in the respective ring system. Cycloalkenyl radicals may in
turn be substituted. Examples of such moieties include, but are not
limited to, cyclohexenyl, cyclooctenyl or cyclodecenyl.
[0060] In contrast thereto, the terms "aromatic" and "aryl" mean an
at least essentially planar cyclic hydrocarbon moiety of conjugated
double bonds, which may be a single ring or include multiple
condensed (fused) or covalently linked rings, for example, 2, 3 or
4 fused rings. The term aromatic also includes alkylaryl.
Typically, the hydrocarbon (main) chain includes 5, 6, 7 or 8 main
chain atoms in one cycle. Examples of such moieties include, but
are not limited to, cyclopentadienyl, phenyl, napthalenyl-,
[10]annulenyl-(1,3,5,7,9-cyclodecapentaenyl-), [12]annulenyl-,
[8]annulenyl-, phenalene (perinaphthene), 1,9-dihydropyrene,
chrysene (1,2-benzophenanthrene). An example of an alkylaryl moiety
is benzyl. The main chain of the cyclic hydrocarbon moiety may,
unless otherwise stated, be of any length and contain any number of
heteroatoms, as for instance N, O and S. Such a heteroaromatic
moiety may for example be a 5- to 7-membered unsaturated
heterocycle which has one or more heteroatoms from the series O, N,
S. Examples of such heteroaromatic moieties (which are known to the
person skilled in the art) include, but are not limited to,
furanyl-, thiophenyl-, naphtyl-, naphthofuranyl-,
anthrathiophenyl-, pyridinyl-, pyrrolyl-, quinolinyl,
naphthoquinolinyl-, quinoxalinyl-, indolyl-, benzindolyl-,
imidazolyl-, oxazolyl-, oxoninyl-, oxepinyl-, benzoxepinyl-,
azepinyl-, thiepinyl-, selenepinyl-, thioninyl-, azecinyl-,
(azacyclodecapentaenyl-), diazecinyl-,
azacyclododeca-1,3,5,7,9,11-hexaene-5,9-diyl-, azozinyl-,
diazocinyl-, benzazocinyl-, azecinyl-, azaundecinyl-,
thia[11]annulenyl-, oxacyclotrideca-2,4,6,8,10,12-hexaenyl- or
triazaanthracenyl-moieties.
[0061] The term "arylaliphatic" means a hydrocarbon moiety, in
which one or more aromatic moieties are substituted with one or
more aliphatic groups. Thus the term "arylaliphatic" also includes
hydrocarbon moieties, in which two or more aryl groups are
connected via one or more aliphatic chain or chains of any length,
for instance a methylene group. Typically, the hydrocarbon (main)
chain includes 5, 6, 7 or 8 main chain atoms in each ring of the
aromatic moiety. Examples of arylaliphatic moieties such as
alkylaryl moieties include, but are not limited, to
1-ethyl-naphthalene, 1,1'-methylenebis-benzene,
9-isopropylanthracene, 1,2,3-trimethyl-benzene,
4-phenyl-2-buten-1-ol, 7-chloro-3-(1-methylethyl)-quinoline,
3-heptyl-furan, 6-[2-(2,5-diethyl-phenyl)ethyl]-4-ethyl-quinazoline
or, 7,8-dibutyl-5,6-diethyl-isoquinoline.
[0062] The term "arylalicyclic" means a hydrocarbon moiety in which
an alicyclic moiety is substituted with one or more aryl group.
Three illustrative example of an arylalicyclic moiety are
"phenylcyclohexyl", "phenylcyclopentyl" or "naphthylcyclohexyl". In
typical embodiments an arylalicyclic moiety has a main chain of
more than about 10 carbon atoms. In some embodiments an
arylalicyclic moiety has a main chain of up to about 30 carbon
atoms.
[0063] Each of the terms "aliphatic", "alicyclic", "aromatic",
"arylaliphatic" and "arylalicyclic" as used herein is meant to
include both substituted and unsubstituted forms of the respective
moiety. Substituents my be any functional group, as for example,
but not limited to, amino, amido, azido, carbonyl, carboxyl, cyano,
isocyano, dithiane, halogen, hydroxyl, nitro, organometal,
organoboron, seleno, silyl, silano, sulfonyl, thio, thiocyano,
trifluoromethyl sulfonyl, p-toluenesulfonyl, bromobenzenesulfonyl,
nitrobenzenesulfonyl, and methanesulfonyl.
[0064] In formulae (3), (4), (9) and (29) R.sup.2 is one of
hydrogen, an aliphatic group and an alicyclic group. The aliphatic
and alicyclic groups of R.sup.1 and R.sup.2 may have a main chain
of about 1 to about 30 carbon atoms, such as 2 to about 30 carbon
atoms or 2 to about 25 carbon atoms, including about 1 to about 20
carbon atoms, about 2 to about 20 carbon atoms, about 3 to about 20
carbon atoms, about 1 to about 15 carbon atoms, about 2 to about 15
carbon atoms, about 1 to about 10 carbon atoms, about 2 to about 10
carbon atoms or about 1 to about 10 carbon atoms, such as 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20
carbon atoms. The respective aliphatic, alicyclic, aromatic or
arylaliphatic moiety of R.sup.1, R.sup.2 or R.sup.3 may have 0 to
about 5 heteroatoms, such as 0 to about 4 or 0 to about 3, e.g. 0,
1, 2, 3, 4 or 5 heteroatoms. A respective heteroatom may be
independently selected one of N, O, S, Se and Si.
[0065] R.sup.3 in formulae (3), (4), (9) and (29) is one of
hydrogen, hydrogen, halogen (e.g. F, Cl, Br or I), hydroxyl and an
aliphatic group. Where R.sup.3 is an aliphatic group it has a main
chain of 1 to about 10 carbon atoms, such as 1 to about 8 carbon
atoms, 2 to about 10 carbon atoms, 3 to about 10 carbon atoms or 1
to about 5 carbon atoms, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10
carbon atoms. Further, such an aliphatic or alicyclic group may
have 0, 1, 2 or 3 heteroatoms independently selected from the group
consisting of N, O, S, Se and Si
[0066] R.sup.3 in formulae (3), (4), (9) and (29) may be bonded to
any position of the aromatic ring relative to the nitrogen atom,
e.g. in ortho, meta or para position. The same applies to R.sup.3
in aromatic rings of other compounds named herein, such as formulae
(2), (4), (13), (14), (15), (25) or (33).
[0067] In the present process of the invention a contacting a
carbonyl compound of Formula (1) is provided:
##STR00022##
In formula (1) R.sup.1 and R.sup.2 are independently selected
moieties as defined above.
[0068] Further, a nitroso compound of Formula (2) is provided:
##STR00023##
In formula (2) R.sup.3 is as defined above. Further, a chiral
catalyst is provided. The chiral catalyst is in some embodiments a
compound of Formula (IX)
##STR00024##
R.sup.4 in formula (IX) may be a carboxyl group or the moiety
##STR00025##
Y in formula (IX) is one of CHOH, O, S, Se, CH.sub.2, CHOH, CHSH
and CHSeH. Accordingly, a catalyst of formula (IX) may for example
be one of the following compounds:
##STR00026##
[0069] The chiral catalyst is in some embodiments a compound of
Formula (V)
##STR00027##
R.sup.4 in formula (V), R.sup.5 in formula (VI) and Y in formula
(V) are as defined above (see for formulae (IX) and (X)). In
embodiments where a catalyst of Formula (IX) is employed, a product
of formula (3) is obtained. In embodiments where a catalyst of
Formula (V) is employed, a product of formula (4) is obtained.
[0070] The reaction of the carbonyl compound of Formula (1) and the
nitroso compound of Formula (2) is allowed to start by contacting
these two compounds in the presence of the chiral catalyst of
Formula (IX) or of Formula (V). Hence the reaction generally starts
once all the three compounds are brought in contact with each
other. A reaction mixture may be formed upon contacting the
carbonyl compound of Formula (1) and the nitroso compound of
Formula (2) in the presence of the chiral catalyst of Formulae (V)
or (IX). The reaction mixture may be formed at any temperature at
which the three compounds, i.e. the two reactants of formulae (1)
and (2) and the catalyst are at least essentially stable enough to
undergo an aminoxylation reaction. The present process of the
invention is carried out in an aqueous solution. Accordingly the
reaction mixture is typically formed at a temperature from about
0.degree. C. to about 100.degree. C., including from about
0.degree. C. to about 80.degree. C., from about 10.degree. C. to
about 80.degree. C., from about 20.degree. C. to about 80.degree.
C., from about 30.degree. C. to about 80.degree. C., from about
20.degree. C. to about 50.degree. C., from about 30.degree. C. to
about 50.degree. C. or from about 5.degree. C. to about 30.degree.
C., such as ambient temperature, e.g. about 18.degree. C. The
carbonyl compound of Formula (1) and the nitroso compound of
Formula (2) are allowed to react in the reaction mixture at a
temperature from about 5.degree. C. to about 100.degree. C., such
as from about 10.degree. C. to about 80.degree. C., from about
20.degree. C. to about 80.degree. C., from about 20.degree. C. to
about 60.degree. C., from about 30.degree. C. to about 60.degree.
C., from about 20.degree. C. to about 40.degree. C., from about
10.degree. C. to about 30.degree. C. or from about 10.degree. C. to
about 25.degree. C., including at or below about ambient
temperature, e.g. at or below about 18.degree. C.
[0071] The carbonyl compound of Formula (1) and the nitroso
compound of Formula (2) are allowed to react in the reaction
mixture for a period of time sufficient to allow the formation of a
product of Formula (3) or of formula (4), respectively. In some
embodiments the occurrence of the respective product is monitored
using a suitable spectrometric and/or chromatographic technique. In
some embodiments the reaction is allowed to proceed for a
predetermined period of time. Such a predetermined period of time
may for instance be based on optimization experiments carried out
in advance. In some embodiments the carbonyl compound of Formula
(1) and the nitroso compound of Formula (2) are allowed to react
for a period of time selected in the range from about 10 minutes to
about 48 hours, such as from about 15 minutes to about 24 hours,
from about 15 minutes to about 16 hours or from about 15 minutes to
about 12 hours, such as e.g. about 1, about 2, about 3, about 4,
about 5, or about 6 hours.
[0072] The present process is carried out in the presence of a
phase transfer catalyst. Examples of a suitable phase transfer
catalyst include, but are not limited to, a quaternary ammonium
salt, a quaternary phosphonium salt, a polyethylene glycol and a
crown ether. Examples of a quaternary ammonium salt include, but
are not limited to, tetra-n-butylammonium bromide,
methyltrioctylammonium chloride, benzyltributylammonium bromide,
benzyltributylammonium chloride, benzyltributylammonium iodide,
benzyltriethylammonium iodide, benzyl-trimethylammonium bromide,
benzyltripropylammonium chloride, (2-bromoethyl)trimethylammonium
bromide, 2-chloroethyl)trimethylammonium chloride,
(3-bromopropyl)trimethylammonium bromide,
(2-aminoethyl)trimethylammonium chloride,
(3-carboxypropyl)trimethylammonium chloride,
(3-chloro-2-hydroxypropyl)trimethylammonium chloride,
(4-nitrobenzyl)-trimethylammonium chloride,
(5-bromopentyl)trimethylammonium bromide,
(vinylbenzyl)trimethylammonium chloride, acetylcholine chloride,
acetylcholine iodide, benzalkonium chloride,
benzyldimethyl(2-hydroxyethyl)ammonium chloride, Benzethonium
chloride, Betaine hydrochloride, Carbamoylcholine chloride,
benzyldimethyloctylammonium chloride, benzyldimethyldecylammonium
chloride, benzyldimethyldodecylammonium chloride,
benzyldimethylhexadecylammonium chloride,
benzyldimethylstearylammonium chloride,
benzyldodecyldimethylammonium bromide,
bis(triphenylphosphoranylidene)ammonium chloride,
Cetyltrimethylammonium chloride, Cetyltrimethylammonium
hydrogensulfate, Domiphen bromide, Choline chloride,
diallyldimethylammonium chloride, didecyldimethylammonium bromide,
didodecyldimethylammonium bromide, dihexadecyldimethylammonium
bromide, dimethyldioctadecylammonium bromide,
dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride,
methyltrioctadecylammonium bromide, methyltrioctylammonium iodide,
tetradodecylammonium chloride, tetrabutylammonium acetate,
tetramethylammonium acetate, tetrabutylammonium benzoate,
tetraethylammonium trifluoroacetate, tetrabutylammonium
difluorotriphenylsilicate, tetrabutylammonium fluorosulfate,
tetrabutylammonium methanesulfonate, tetrabutylammonium
nonafluorobutanesulfonate, tetrabutylammonium nitrite,
tetramethylammonium hydrogenphthalate, tetraoctylammonium hydrogen
sulphate, 1,1-dimethyl-4-phenylpiperazinium iodide,
1,1'-dibenzyl-4,4'-bipyridinium dichloride,
1,2,3-trimethylimidazolium methyl sulphate,
1,3-didecyl-2-methylimidazolium chloride,
3-(2-hydroxyethyl)thiazolium bromide,
3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride,
5-(2-Hydroxyethyl)-3,4-dimethylthiazolium iodide or Dequalinium
chloride. Examples of a quaternary phosphonium salt include, but
are not limited to, tetrabutylphosphonium bromide,
tetrabutylphosphonium chloride, tetraoctylphosphonium bromide,
tetraphenylphosphonium bromide, tetrabutylphosphonium
hexafluorophosphate, tetrabutylphosphonium methanesulfonate,
tetraethylphosphonium bromide, tetraethylphosphonium
tetrafluoroborate, tributyl-tetradecylphosphonium chloride,
tributylhexadecylphosphonium bromide, trihexyltetradecylphosphonium
bromide, 1,12-dodecanediylbis(tributylphosphonium)dibromide,
benzyltriphenylphosphonium chloride,
bis[tetrakis(hydroxymethyl)phosphonium]sulphate,
butyltriphenylphosphonium bromide, dimethyldiphenylphosphonium
iodide, methyltriphenoxyphosphonium iodide,
ethyltriphenylphosphonium bromide, trimethylphenylphosphonium
iodide and
tetrakis[tris(dimethylamino)phosphoranylidenamino]phosphonium
chloride.
[0073] As already mentioned, the present reaction of the present
process of the invention is carried out in an aqueous solution. So
far .alpha.-aminoxylation is usually carried out in organic
solvents such as acetonitrile (Y. Hayashi, et al., Tetrahedron
Lett. (2003) 44, 8293; A. Cordova, et al., Chem. Eur. J. (2004) 10,
3673), chloroform (S. P. Brown, et al., J. Am. Chem. Soc. (2003)
125, 10808), dichloromethane (D. B. Ramachary & I. C. F.
Barbas, Org. Lett. (2005) 7, 1577), dimethylformamide (S.-G. Kim
& T.-H. Park, Tetrahedron Lett. (2006) 47, 9067) and
dimethylsulfoxide (G. Zhong, Angew. Chem., Int. Ed. (2003) 42,
4247; M. Lu, et al., Angew. Chem., Int. Ed., (2008) 47, 10187; D.
Zhu, et al., Org. Lett. (2008) 10, 4585; G. Zhong & Y. Yu, Org.
Lett. (2004) 6, 1637; G. Zhong, Chem. Commun. (2004) 606; X. Zhu,
et al., J. Mol. Biol. (2004) 343, 1269; B. Tan, et al., Org. Lett.
(2008) 10, 2437; B. Tan, et al., Org. Lett. (2008) 10, 3425; S. K.
David, et al., Chem. Commun. (2006) 3211; H. Sunden, et al.,
Tetrahedron Lett. (2005) 46, 3385; W. Wang, et al., Tetrahedron
Lett. (2004) 45, 7235). The use of such solvents contributes to the
organic waste, whereas the process of the invention provides a more
environmentally friendly protocol. Water, no doubt, is the most
inexpensive and environmentally benign solvent. Further advantages
that accompany the use of water as a solvent are an acceleration of
reaction rates and enhancement of reaction selectivities;
elimination of tedious protection-deprotection processes for
certain acidic-hydrogen containing functional groups and the
recycling of water-soluble catalysts after separation from
water-insoluble organic products.
[0074] As explained above, the obtained carbonyl compound of
formula (3) or of formula (4) may be further reduced to the
corresponding 2-aminoxy alcohol of formula (9) or of formula (29),
respectively, for example as disclosed by Zhong (Angew. Chem. Int.
Ed (2003) 42, 4247-4250). Catalytic hydrogenation using a suitable
catalyst such as Adam's catalyst may be used to cleave the O--N
bond of the aminoxy compound (9) or (29), thereby yielding a diol
of formula (8) or (38), respectively (ibid.)
##STR00028##
[0075] In a further aspect of the invention a process is provided,
in which a 1,2-oxazine compound of Formula (13) is formed.
##STR00029##
In the 1,2-oxazine compound of Formula (13) R.sup.2 and R.sup.3 are
as defined above (see formulae (3), (4), (9) and (29)). R.sup.8 is
one of hydrogen, NO.sub.2, CN, C(O)R.sup.40, COOR.sup.40, and
CONR.sup.40R.sup.41, an aliphatic group, an alicyclic group, an
aromatic group, an arylaliphatic group and an arylalicyclic group.
Where R.sup.8 is an aliphatic, an alicyclic, an aromatic, an
arylaliphatic or an arylalicyclic group it may include 0, 1, 2 or
about 3 heteroatoms. Such a heteroatom may be independently
selected from the group consisting of N, O, S, Se and Si. A
respective aliphatic, alicyclic, aromatic, arylaliphatic or
arylalicyclic group may have 1 to about 20 carbon atoms, about 2 to
about 20 carbon atoms, about 3 to about 20 carbon atoms, about 1 to
about 15 carbon atoms, about 2 to about 15 carbon atoms, about 1 to
about 10 carbon atoms, about 2 to about 10 carbon atoms or about 1
to about 10 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
[0076] Where R.sup.8 is C(O)R.sup.40, COOR.sup.40, or
CONR.sup.40R.sup.41 the moieties R.sup.40 and R.sup.41 are
independent from one another one of hydrogen, an aliphatic group,
an alicyclic group, an aromatic group, an arylaliphatic group and
an arylalicyclic group. A respective aliphatic, alicyclic,
aromatic, arylaliphatic or arylalicyclic group may have 1 to about
20 carbon atoms, about 2 to about 20 carbon atoms, about 3 to about
20 carbon atoms, about 1 to about 15 carbon atoms, about 2 to about
15 carbon atoms, about 1 to about 10 carbon atoms, about 2 to about
10 carbon atoms or about 1 to about 10 carbon atoms, such as 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20
carbon atoms. Further, such an aliphatic, alicyclic, aromatic,
arylaliphatic or arylalicyclic group may have 0, 1, 2 or 3
heteroatoms independently selected from the group consisting of N,
O, S, Se and Si.
[0077] Z in Formula (13) is one of NO.sub.2, CN, C(O)R.sup.42,
COOR.sup.42, and CONR.sup.42R.sup.43. The moieties R.sup.42 and
R.sup.43 are independent from one another one of hydrogen, an
aliphatic group, an alicyclic group, an aromatic group, an
arylaliphatic group and an arylalicyclic group. A respective
aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic
group may have 1 to about 20 carbon atoms, about 2 to about 20
carbon atoms, about 3 to about 20 carbon atoms, about 1 to about 15
carbon atoms, about 2 to about 15 carbon atoms, about 1 to about 10
carbon atoms, about 2 to about 10 carbon atoms or about 1 to about
10 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19 or 20 carbon atoms. Further, such an
aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic
group may have 0, 1, 2 or 3 heteroatoms independently selected from
the group consisting of N, O, S, Se and Si.
[0078] The process of forming a 1,2-oxazine compound of Formula
(13) includes providing a carbonyl compound of Formula (11):
##STR00030##
In Formula (11) R.sup.2 and R.sup.8 are as defined above. The
process further includes providing a nitroso compound of Formula
(2), as defined above. Further, a chiral catalyst is provided. The
chiral catalyst is a compound of Formula (IX) or of Formula (X), as
already defined above. The reaction of the carbonyl compound of
Formula (11) and the nitroso compound of Formula (2) is allowed to
start by contacting these two compounds in the presence of the
chiral catalyst of Formula (IX) or of Formula (X). Hence the
reaction generally starts once all the three compounds are brought
in contact with each other. The carbonyl compound of Formula (11)
is contacted with a nitroso compound of Formula (2) in the presence
of the chiral catalyst of Formula (IX) or of Formula (X). Thereby a
reaction mixture is formed. The reaction mixture may be formed at
any temperature at which the three compounds, i.e. the two
reactants of formulae (11) and (2) and the catalyst are at least
essentially stable enough to undergo an aminoxylation reaction. The
reaction mixture may for instance be formed at a temperature from
about -180.degree. C. to about 200.degree. C., including from about
-120.degree. C. to about 200.degree. C., from about -80.degree. C.
to about 200.degree. C., from about -180.degree. C. to about
150.degree. C., from about -120.degree. C. to about 160.degree. C.,
from about -80.degree. C. to about 140.degree. C., from about
-80.degree. C. to about 100.degree. C., from about -80.degree. C.
to about 60.degree. C. or from about -80.degree. C. to about
30.degree. C., such as at about -70.degree. C., at about
-20.degree. C., at about 0.degree. C. or at ambient temperature,
e.g. about 18.degree. C.
[0079] The reaction of the present process of the invention is
generally carried out in the liquid phase. Any solvent may be used,
as long as the compounds used dissolve therein sufficiently.
Solvents used may be polar or non-polar liquids, including aprotic
non-polar liquids. Examples of non-polar liquids include, but are
not limited to mineral oil, hexane, heptane, cyclohexane, benzene,
toluene, dichloromethane, chloroform, carbon tetrachloride, carbon
disulfide, dioxane, diethyl ether, diisopropylether, methyl propyl
ketone, methyl isoamyl ketone, methyl isobutyl ketone,
cyclohexanone, isobutyl isobutyrate, ethylene glycol diacetate, and
a non-polar ionic liquid. Examples of a non-polar ionic liquid
include, but are not limited to, 1-ethyl-3-methylimidazolium
bis[(trifluoromethyl)sulfonyl]amide bis(triflyl)amide,
1-ethyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]amide
trifluoroacetate, 1-butyl-3-methylimidazolium hexafluorophosphate,
1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide,
1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide,
trihexyl(tetradecyl)phosphonium bis[oxalate(2-)]borate,
1-hexyl-3-methyl imidazolium
tris(pentafluoroethyl)trifluorophosphate,
1-butyl-3-methyl-imidazolium hexafluorophosphate,
tris(pentafluoroethyl)trifluorophosphate,
trihexyl(tetradecyl)phosphonium,
N''-ethyl-N,N,N',N'-tetramethylguanidinium,
1-butyl-1-methylpyrroledinium
tris(pentafluoroethyl)trifluorophosphate,
1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide,
1-butyl-3-methyl imidazolium hexafluorophosphate,
1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide and
1-n-butyl-3-methylimidazolium. Exemplary aprotic non-polar liquids
include hexane, heptane, cyclohexane, benzene, toluene, pyridine,
dichloromethane, chloroform, carbon tetrachloride, carbon
disulfide, dioxane, diethyl ether, diisopropylether, ethylene
glycol monobutyl ether and tetrahydrofuran.
[0080] Examples of a polar solvent include, but are not limited to,
dioxane, diethyl ether, diisopropylether, ethylene glycol monobutyl
ether, tetrahydrofuran, methyl propyl ketone, methyl isoamyl
ketone, methyl isobutyl ketone, cyclohexanone, isobutyl
isobutyrate, ethylene glycol diacetate, and a polar ionic liquid.
Examples of a polar ionic liquid include, but are not limited to,
1-ethyl-3-methylimidazolium tetrafluoroborate,
N-butyl-4-methylpyridinium tetrafluoroborate,
1,3-dialkylimidazolium-tetrafluoroborate,
1,3-dialkylimidazolium-hexafluoroborate,
1-ethyl-3-methylimidazolium bis(pentafluoroethyl)phosphinate,
1-butyl-3-methylimidazolium
tetrakis(3,5-bis(trifluoromethylphenyl)borate, tetrabutyl-ammonium
bis(trifluoromethyl)imide, ethyl-3-methylimidazolium
trifluoromethanesulfonate, 1-butyl-3-methylimidazolium
methylsulfate, 1-n-butyl-3-methylimidazolium ([bmim])octylsulfate,
and 1-n-butyl-3-methylimidazolium tetrafluoroborate.
[0081] A polar protic solvent that may be used can be a solvent
that has, for example, a hydrogen atom bound to an oxygen atom as
in a hydroxyl group or a nitrogen as in an amine group. More
generally, any molecular solvent which contains dissociable
H.sup.+, such as hydrogen fluoride, is called a protic solvent. The
molecules of such solvents can donate an H.sup.+ (proton). The
examples of polar solvents named above with the exception of ionic
liquids are aprotic solvents. In some embodiments the solvent used
in the reaction of the present process of the invention is an
aprotic polar liquid. In some embodiments the solvent used is a
polar protic solvent. Examples of polar protic solvents include,
but are not limited to, water, an alcohol or a carboxylic acid.
Examples of an alcohol include, but are not limited to, methanol,
ethanol, 1,2-ethanediol (ethylene glycol), 1,3-propanediol
(.beta.-propylene glycol), 1,2-propanediol, n-propanol,
iso-propanol, n-butanol, iso-butanol, tert-butanol, 2-butanol,
2,3-butanediol (dimethylethylene glycol), 2-methyl-1,3-propanediol,
1-pentanol (amyl alcohol), 2-pentanol, 2-methyl-3-butanol,
3-methyl-1-butanol (iso-pentanol), 3-pentanol (sec-amyl alcohol),
2,4-pentanediol (2,4-amylene glycol), 4-methyl-1,7-heptanediol,
1,9-nonanediol, cyclohexanol, propoxymethanol and 2-ethoxyethanol
(ethylene glycol ethyl ether). As four illustrative examples of a
carboxylic acid may serve acetic acid, propionic acid, valeric acid
and caproic acid. In one embodiment of the present invention water
may be used. Various protic ionic liquids may be tested for their
suitability as a solvent for carrying out a method of the
invention. Protic ionic liquids are formed through the combination
of a Bronsted acid and Bronsted base (see Greaves, T. L., &
Drummond, C. J., Chem. Rev. (2008) 108, 206-237).
[0082] The carbonyl compound of Formula (11) and the nitroso
compound of Formula (2) may be allowed to react in the reaction
mixture at any desired temperature, including at a temperature from
about -200.degree. C. to about 200.degree. C., depending on the
boiling point of the solvent selected. The reaction may for example
be allowed to proceed at a temperature in the range from about
-120.degree. C. to about 180.degree. C., from about -100.degree. C.
to about 180.degree. C., from about -80.degree. C. to about
200.degree. C., from about -80.degree. C. to about 170.degree. C.,
from about -80.degree. C. to about 120.degree. C. or from about
-80.degree. C. to about 100.degree. C., such as at about
-70.degree. C., at about -20.degree. C., at about -10.degree. C. or
at about 0.degree. C., including at or below about ambient
temperature, e.g. at or below about 18.degree. C. or at or below
25.degree. C.
[0083] By allowing the carbonyl compound of Formula (1) and the
nitroso compound of Formula (2) to react in the reaction mixture,
the formation of the 1,2-oxazine compound of Formula (13) is
allowed to occur. In some embodiments the occurrence of the
respective product is monitored using a suitable spectrometric
and/or chromatographic technique. In some embodiments the reaction
is allowed to proceed for a predetermined period of time. Such a
predetermined period of time may for instance be based on
optimization experiments carried out in advance. In some
embodiments the carbonyl compound of Formula (11) and the nitroso
compound of Formula (2) are allowed to react for a period of time
selected in the range from about 10 minutes to about 48 hours, such
as from about 15 minutes to about 48 hours, from about 15 minutes
to about 24 hours, from about 15 minutes to about 16 hours or from
about 15 minutes to about 12 hours, such as e.g. about 1, about 2,
about 3, about 4, about 5, or about 6 hours.
[0084] The reaction of the present process of the invention
provides a direct tandem .alpha.-aminoxylation/aza-Michael reaction
of carbonyl compounds such as aldehydes. The reaction is highly
diastereo- and enantioselective. In some embodiments it bears a
remote enemalonate as Michael acceptor at the 8-position for the
synthesis of functionalized tetrahydro-1,2-oxazines (THOs), among
which both C--O and C--N bonds can be formed in excellent
stereoselectivity. On a general basis this process provides a
useful tool in synthesis strategy as illustrated by an exemplary
use of an aldehyde with an 1,3-dicarboxyl moiety, nitrosobenzene
and L-proline as the catalyst, in the following general
illustration:
##STR00031##
[0085] As illustrated in FIG. 7B, on a general basis the structure
of a tetrahydro-1,2-oxazine could for instance be assembled by
using two reactions to form both the C--O and C--N bonds. For
example, a potential route could be the .alpha.-aminoxylation of
alkenal (9) with nitrosobenzene (2a) and subsequent nucleophilic
attack of the in situ generated amine on Michael acceptor (LI). As
can be taken from the various possible reaction routes and the
various stereochemical possibilities, the reaction of the process
of the invention surprisingly proceeds in a highly controlled
manner. Without being bound by theory it is believed that
aza-Michael addition and protonation take place in a concerted
manner by a preferred transition state.
[0086] In order that the invention may be readily understood and
put into practical effect, particular embodiments will now be
described by way of the following non-limiting examples.
EXEMPLARY EMBODIMENTS OF THE INVENTION
Example 1
.alpha.-Aminoxylation of Aldehydes
[0087] To probe the feasibility of the .alpha.-aminoxylation of
aldehydes in aqueous media and phase-transfer catalyst, we first
performed .alpha.-aminoxylation of propanal to nitrosobenzene in
the presence of L-proline IXa, tetrabutylammonium bromide and water
at 0.degree. C. and then warmed to room temperature. To our
disappointment, the yield obtained in this initial reaction was
rather low, despite the high enantioselectivity achieved. This
prompted us to screen more catalysts IXb-IXd, Xa and XL (FIG. 4,
entries 2-6). Among all the catalysts investigated, only
L-thiaproline IXd gave a higher yield than IXa. Although IXd took a
longer reaction time and gave a slightly lower enantioselectivity
than IXa, we believed that higher enantioselectivity could be
achieved with the optimization of reaction conditions. This is the
first instance where L-thiaproline IXd was used as a catalyst in
.alpha.-aminoxylation. The use of IXd will potentially reduce much
hassle for stereoselective reactions as it is commercially
available.
[0088] For the optimisation of reaction condition, we first
investigated the effect of catalyst loading on the reaction (FIG.
5, entries 1-3). Highest yield and enantioselectivity were obtained
when 20 mol % of catalyst was used. The results of the reaction did
not improve when neat condition was used (FIG. 5, entry 4).
Screenings of various organic solvents revealed that chloroform and
dimethyl sulfoxide, preferred solvents for many
.alpha.-aminoxylation reactions, were not the best solvents when VI
was employed as catalyst (FIG. 5, entries 5-6). Although
acetonitrile gave comparable enantioselectivity, its lower yield
and longer reaction time made water the preferred choice of solvent
for this reaction (FIG. 5, entry 7). We discovered that 0.10 mL of
water is the optimum amount of water added to the system to attain
the highest yield and enantioselectivity achievable (FIG. 5,
entries 8-10). Both the yield and enantioselectivity dropped when
the amount of phase transfer catalyst was reduced (FIG. 5, entries
11-12). Similar trend was also observed with decreasing amounts of
propanal (FIG. 5, entries 13-14).
[0089] With optimal reaction conditions established, we probed the
scope of the reaction for a variety of aldehydes. The results are
summarized in FIG. 6. In the cases investigated, the
.alpha.-aminoxy alcohols were obtained in good to high yields
(74-88%) and excellent enantioselectivies (93->99%). The
L-thiaproline .alpha.-aminoxylation reaction between nitrosobenzene
and propanal was completed in 2 h with good yield (84%) and
excellent enantioselectivity (96%) (FIG. 6, entry 1). Not only
propanal, but linear chain aldehydes such as n-butanal, n-pentanal
and n-hexanal react with nitrosobenzene, affording .alpha.-aminoxy
alcohols in good yield with excellent enantioselectivities (FIG. 6,
entries 2-4). Branched aldehydes such as 3-methylbutanal are also
suitable substrates as it was also successfully converted to the
.quadrature.-aminoxy alcohols in good yield with excellent
enantioselectivity (FIG. 6, entry 5). Aldehydes containing an
aromatic moiety such as phenylacetaldehyde and 3-phenylpropanal
were successfully employed in this reaction (FIG. 6, entries 6 and
7). It is interesting to note that the reaction time for
phenylacetylaldehyde was significantly reduced. This may be due to
the activating effect of the benzene ring on the .alpha.-position
of the phenylacetylaldehyde. The introduction of a terminal double
bond on the aldehyde does not drastically affect the yield and
enantioselevitvity of the reaction (FIG. 6, entry 8). The reaction
also proceeded smoothly with protective groups such as benzyl
ethers and tert-butoxycarbonyl carbamates to afford the
.quadrature.-aminoxy alcohols in good yield with excellent
enantioselectivities (FIG. 6, entries 9-10). The scope of nitroso
compounds was briefly tested by replacing nitrosobenzene with
nitrosotoluene. When nitrosotoluene was treated with propanal under
the optimised conditions, the corresponding .alpha.-aminoxy alcohol
was obtained in 83% yield with an enantioselecitivity of 97%, which
is consistent with the results of nitrosobenzene.
Conclusions
[0090] In conclusion, L-thiaproline catalyzed .alpha.-aminoxylation
of aldehydes in aqueous media and phase-transfer catalyst afforded
the respective .alpha.-aminoxy alcohols in good to high yields
(74-88%) and excellent enantioselectivies (93->99%). This
reaction protocol may find potential use for industrial-scale
preparation due to its simple operation procedures, wide scope,
excellent enantioselectivities and environmental friendliness.
Further investigation on the application of L-thioproline in
asymmetric catalysis is in progress.
General Experimental Information
[0091] Analytical thin layer chromatography (TLC) was performed
using Merck 60 F254 precoated silica gel plate (0.2 mm thickness).
Subsequent to elution, plates were visualized using UV radiation
(254 nm) on Spectroline Model ENF-24061/F 254 nm. Further
visualization was possible by staining with basic solution of
potassium permanganate or acidic solution of ceric molybdate. Flash
chromatography was performed using Merck silica gel 60 with freshly
distilled solvents. Columns were typically packed as slurry and
equilibrated with the appropriate solvent system prior to use.
[0092] Proton nuclear magnetic resonance spectra (.sup.1H NMR) were
recorded on Bruker AMX 400 spectrophotometer (CDCl.sub.3 as
solvent). Chemical shifts for .sup.1H NMR spectra are reported as 6
in units of parts per million (ppm) downfield from SiMe.sub.4
(.delta. 0.0) and relative to the signal of SiMe.sub.4 (.delta.
0.0, singlet). Multiplicities were given as: s (singlet), d
(doublet), t (triplet), dd (doublets of doublet) or m (multiplets).
The number of protons (n) for a given resonance is indicated by nH.
Coupling constants are reported as a J value in Hz. Carbon nuclear
magnetic resonance spectra (.sup.13C NMR) are reported as 6 in
units of parts per million (ppm) downfield from SiMe.sub.4 (.delta.
0.0) and relative to the signal of chloroform-d (.delta. 77.03,
triplet).
[0093] Enantioselectivities were determined by High Performance
Liquid Chromatography (HPLC) analysis employing a Daicel Chirapak
AD-H (0.46 cm.times.25 cm), OD-H (0.46 cm.times.25 cm) or OJ-H
(0.46 cm.times.25 cm) column.
[0094] Optical rotations were measured in CHCl.sub.3 on a
Schmidt+Haensdch polarimeter (Polartronic MH8) with a 1 cm cell (c
given in g/100 mL). Absolute configuration of the products was
determined by comparison with compounds previously published.
[0095] Aldehydes 1i and 1j were prepared according to literature
procedures (preparation of 1i: Iyengar, R, et. al., J. of Org.
Chem. (2005) 70, 10645; preparation of 1j: More, J D, & Finney,
N S, Org. Lett. (2002) 4, 3001). The enantiomers used to determine
the ee values were synthesized with DL-proline as catalyst. All
other reagents were available from commercial sources and used
without further purification.
Typical Procedure for the .alpha.-aminoxylation of Aldehydes to
Nitrosobenzene in the Presence of Water
[0096] Water (0.10 mL) and tetrabutylammonium bromide (193.4 mg,
0.6 mmol) was added to a 5 mL drum vial containing nitrosobenzene 2
(32.1 mg, 0.3 mmol), corresponding aldehyde 1 (e.g. 1a) (0.9 mmol)
and a magnetic stirring bar. After stirring for 5 min at 0.degree.
C., L-thiaproline (8 mg, 0.06 mmol) was then added. The reaction
was first stirred at this temperature for about 10 min and then at
room temperature until the green solution turned yellow which
indicated complete consumption of the nitrosobenzene. As the
.alpha.-aminoxy aldehyde product is rather labile, isolation and
characterization was performed after conversion to the
corresponding .alpha.-aminoxy alcohol 9a by treatment of the
reaction mixture with NaBH.sub.4. The excess NaBH.sub.4 was
quenched by the addition of water and then extracted with
CH.sub.2Cl.sub.2 (3.times.30 ml). The combined organic extracts
were dried with Na.sub.2SO.sub.4 and concentrated in vacuo. The
crude oil was purified by flash column chromatography
(hexane/EtOAc=9/1.about.7/3) yielding pure .alpha.-aminoxy alcohols
9a.
[0097] Relative and absolute configurations of the products were
compared with the known .sup.1H NMR, chiral HPLC analysis, and
optical rotation values. The compounds in FIG. 6 as such have
previously been disclosed in the art.
[0098] In the following exemplary data on the formation of a series
of amineoxy compounds are provided. Following the foregoing
protocol products were obtained, isolated and characterized.
Experimental data of Compounds 9a-9k
(R)-2-(N-Phenylaminoxy)propan-1-ol (3a) [Hayashi, Y, et al., J.
Org. Chem. (2004) 69, 5966]
##STR00032##
[0100] .alpha.-Aminoxy alcohol 9a was prepared according to the
general procedure from propanal (0.07 mL, 0.9 mmol) to provide the
title compound as a pale yellow liquid (42.3 mg, 84% yield) after
flash column chromatography on silica gel
(hexane/EtOAc=9/1.about.7/3). Prepared according to the general
procedure to provide the title compound (96% yield).
[0101] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.29-7.25 (2H, m),
7.04-6.96 (3H, m), 4.16-4.08 (1H, m), 3.80-3.70 (2H, m), 2.56 (1H,
brs), 1.25 (3H, d, J=6.4 Hz).
[0102] .sup.13C-NMR (100 MHz, CDCl.sub.3) .delta. 148.5, 129.0,
122.4, 114.7, 80.0, 66.5, 15.4.
[0103] HPLC: Chiralpak AD-H (hexane/i-PrOH, 90/10, flow rate 1
mL/min, .lamda.=230 nm),
[0104] t.sub.R (minor)=10.6 min, t.sub.R (major)=12.1 min; 96%
ee.
[0105] [.alpha.].sub.D.sup.25=+2.9 (c=1.0, CHCl.sub.3).
(R)-2-(N-Phenylaminoxy)butan-1-ol (9b) [Hayashi, Y, et al., J. Org.
Chem. (2004) 69, 5966]
##STR00033##
[0107] .alpha.-Aminoxy alcohol 9b was prepared according to the
general procedure from butanal (0.08 mL, 0.9 mmol) to provide the
title compound as a pale yellow liquid (40.9 mg, 75% yield) after
flash column chromatography on silica gel
(hexane/EtOAc=9/1.about.7/3).
[0108] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.29-7.25 (2H, m),
7.07-6.96 (2H, m), 3.91-3.74 (3H, m), 2.67 (1H, brs), 1.78-1.53
(2H, m), 1.01 (3H, t, J=7.5 Hz).
[0109] .sup.13C-NMR (100 MHz, CDCl.sub.3) .delta. 148.4, 129.0,
122.4, 114.8, 85.3, 64.9, 22.9, 10.1.
[0110] HPLC: Chiralpak AD-H (hexane/i-PrOH, 90/10, flow rate 1
mL/min, .lamda.=230 nm),
[0111] t.sub.R (minor)=10.2 min, t.sub.R (major)=11.6 min; 98%
ee.
[0112] [.alpha.].sub.D.sup.23=+36.0 (c=1.0, CHCl.sub.3).
(R)-2-(N-Phenylaminoxy)pentan-1-ol (9c) [Hayashi, Y, et al., J.
Org. Chem. (2004) 69, 5966]
##STR00034##
[0114] .alpha.-Aminoxy alcohol 9c was prepared according to the
general procedure from pentanal (0.10 mL, 0.9 mmol) to provide the
title compound as a pale yellow liquid (46.0 mg, 79% yield) after
flash column chromatography on silica gel
(hexane/EtOAc=9/1.about.7/3).
[0115] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.28-7.15 (3H, m),
6.98-6.94 (2H, m), 3.94-3.91 (1H, m), 3.85-3.82 (1H, m), 3.75-3.71
(1H, m), 2.93 (1H, brs), 1.67-1.61 (1H, m), 1.54-1.33 (3H, m),
0.97-0.89 (3H, m).
[0116] HPLC: Chiralpak AD-H (hexane/i-PrOH, 90/10, flow rate 1
mL/min, .lamda.=230 nm),
[0117] t.sub.R (minor)=10.0 min, t.sub.R (major)=11.4 min; 97%
ee.
[0118] [.alpha.].sub.D.sup.23=+28.6 (c=1.0, CHCl.sub.3).
(R)-2-(N-Phenylaminoxy)hexan-1-ol (9d) [Cordova, A, et al., Chem.
Eur. J. (2004) 10, 3673]
##STR00035##
[0120] .alpha.-Aminoxy alcohol 9d was prepared according to the
general procedure from hexanal (0.11 mL, 0.9 mmol) to provide the
title compound as a pale yellow liquid (46.4 mg, 74% yield) after
flash column chromatography on silica gel
(hexane/EtOAc=9/1.about.7/3).
[0121] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.29-7.26 (2H,
m), 7.06-6.96 (3H, m), 3.98-3.92 (1H, m), 3.87-3.84 (1H, m),
3.79-3.72 (1H, m), 2.68 (1H, brs), 1.69-1.50 (1H, m), 1.47-1.30
(4H, m), 0.92 (3H, t, J=7.1 Hz).
[0122] .sup.13C NMR (100 MHz, CDCl.sub.3): 148.4, 129.0, 122.5,
114.9, 84.0, 65.4, 29.6, 27.9, 22.0, 14.0.
[0123] HPLC: Chiralpak AD-H (hexane/i-PrOH, 90/10, flow rate 1
mL/min, .lamda.=230 nm),
[0124] t.sub.R (minor)=9.5 min, t.sub.R (major)=11.4 min; 96%
ee.
[0125] [.alpha.].sub.D.sup.23=+22.5 (c=1.2, CHCl.sub.3).
(R)-3-Methyl-2-(N-phenylaminooxy)butan-1-ol (9e) (Cordova, A, et
al., Chem. Eur. J. (2004) 10, 3673)
##STR00036##
[0127] .alpha.-Aminoxy alcohol 9e was prepared according to the
general procedure from 3-methylbutanal (0.10 mL, 0.9 mmol) to
provide the title compound as a pale yellow liquid (44.8 mg, 76%
yield) after flash column chromatography on silica gel
(hexane/EtOAc=9/1.about.7/3).
[0128] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.30-7.26 (2H,
m), 7.03-6.99 (3H, m), 3.88-3.87 (2H, m), 3.76-3.74 (1H, m),
2.07-1.99 (1H, m), 1.05 (3H, d, J=6.9 Hz), 1.01 (3H, d, J=6.9
Hz).
[0129] .sup.13C NMR (100 MHz, CDCl.sub.3): 148.3, 129.0, 122.5,
115.0, 88.6, 63.6, 28.7, 18.7, 18.6.
[0130] HPLC: Chiralpak AD-H (hexane/i-PrOH, 90/10, flow rate 1
mL/min, .lamda.=230 nm),
[0131] t.sub.R (minor)=9.0 min, t.sub.R (major)=10.1 mins; 97%
ee.
[0132] [.alpha.].sub.D.sup.22=+33.4 (c=1.0, CHCl.sub.3).
(R)-2-Phenyl-2-(N-phenylaminooxy)ethanol (90 [Hayashi, Y, et al.,
J. Org. Chem. (2004) 69, 5966]
##STR00037##
[0134] .alpha.-Aminoxy alcohol 9f was prepared according to the
general procedure from 2-phenylacetaldehyde (0.11 mL, 0.9 mmol) to
provide the title compound as a pale yellow liquid (53.5 mg, 78%
yield) after flash column chromatography on silica gel
(hexane/Ether=9/1.about.7/3).
[0135] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.39-7.31 (5H,
m), 7.28-7.20 (2H, m), 6.99-6.94 (3H, m), 5.00 (1H, dd, J=3.5, 8.1
Hz), 3.99-3.92 (1H, m), 3.83-3.78 (1H, m), 2.58 (1H, brs).
[0136] .sup.13C NMR (100 MHz, CDCl.sub.3): 147.9, 137.7, 129.0,
128.7, 128.5, 127.0, 122.5, 115.0, 86.4, 66.4.
[0137] HPLC: Chiralpak OD-H (hexane/i-PrOH, 95/5, flow rate 1
mL/min, .lamda.=230 nm),
[0138] t.sub.R (major)=25.8 mins, t.sub.R (minor)=30.2 min; 93%
ee.
[0139] [.alpha.].sub.D.sup.24=-85.5 (c=1.1, CHCl.sub.3).
(R)-3-Phenyl-2-(N-phenylaminooxy)propan-1-ol (3g) [Hayashi, Y, et
al., J. Org. Chem. (2004) 69, 5966]
##STR00038##
[0141] .alpha.-Aminoxy alcohol 9g was prepared according to the
general procedure from 3-phenylpropanal (0.12 mL, 0.9 mmol) to
provide the title compound as a pale yellow liquid (55.9 mg, 77%
yield) after flash column chromatography on silica gel
(hexane/Ether=9/1.about.7/3).
[0142] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.32-7.18 (6H,
m), 7.08 (1H, brs), 6.94 (1H, t, J=7.3 Hz), 6.82 (2H, d, J=8.0 Hz),
4.16-4.10 (1H, m), 3.85 (1H, d, J=11.8 Hz), 3.04 (1H, dd, J=6.8,
13.7 Hz), 2.84 (1H, dd, J=7.0, 13.7 Hz), 2.62 (1H, brs).
[0143] .sup.13C NMR (100 MHz, CDCl.sub.3): 148.3, 137.8, 129.4,
128.9, 128.5, 126.4, 122.3, 114.6, 85.0, 64.1, 36.4.
[0144] HPLC: Chiralpak OD-H (hexane/i-PrOH, 91/9, flow rate 1
mL/min, .lamda.=230 nm),
[0145] t.sub.R (major)=57.9 min, t.sub.R (minor)=62.4 min; >99%
ee.
[0146] [.alpha.].sub.D.sup.22=+55.2 (c=1.3, CHCl.sub.3).
(R)-2-(N-Phenylaminooxy)pent-4-en-1-ol (9h) (Cordova, A, et al.,
2004, supra)
##STR00039##
[0148] .alpha.-Aminoxy alcohol 3h was prepared according to the
general procedure from 4-pentenal (0.09 mL, 0.9 mmol) to provide
the title compound as a pale yellow liquid (51.0 mg, 88% yield)
after flash column chromatography on silica gel
(hexane/EtOAc=9/1.about.7/3).
[0149] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.29-7.26 (2H,
m), 7.06-6.96 (3H, m), 5.93-5.82 (1H, m), 5.18-5.11 (2H, m),
4.05-4.00 (1H, m), 3.87-3.75 (2H, m), 2.54-2.32 (3H, m), 1.66 (1H,
brs).
[0150] .sup.13C NMR (100 MHz, CDCl.sub.3): 148.3, 134.0, 129.0,
122.5, 117.8, 114.8, 83.3, 64.6, 34.6.
[0151] HPLC: Chiralpak AD-H (hexane/i-PrOH, 90/10, flow rate 1
mL/min, .lamda.=230 nm),
[0152] t.sub.R (minor)=10.5 min, t.sub.R (major)=12.5 min; 96%
ee.
[0153] [.alpha.].sub.D.sup.23=-22.9 (c=1.0, CHCl.sub.3).
(R)-4-(Benzyloxy)-2-(N-phenylaminooxy)butan-1-ol (new compound)
(9i)
##STR00040##
[0155] .alpha.-Aminoxy alcohol 9i was prepared according to the
general procedure from 4-(benzyloxy)butanal (0.16 mL, 0.9 mmol) to
provide the title compound as a pale yellow liquid (73.8 mg, 86%
yield) after flash column chromatography on silica gel
(hexane/EtOAc=9/1.about.7/3).
[0156] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.34-7.23 (6H,
m), 7.05 (1H, brs), 6.98-6.94 (3H, m), 4.54-4.52 (2H, m), 4.14-4.11
(1H, m), 3.93-3.87 (1H, m), 3.81-3.77 (1H, m), 3.66 (2H, t, J=5.7
Hz), 2.81 (1H, t, J=5.9 Hz), 2.06-1.89 (2H, m).
[0157] .sup.13C NMR (100 MHz, CDCl.sub.3): 148.3, 138.0, 129.0,
128.5, 127.8, 122.4, 116.1, 114.8, 81.5, 73.2, 66.7, 64.8,
30.3.
[0158] HPLC: Chiralpak AD-H (hexane/i-PrOH, 91/9, flow rate 1
mL/min, .lamda.=230 nm),
[0159] t.sub.R (minor)=18.8 min, t.sub.R (major)=24.1 min; 97%
ee.
[0160] [.alpha.].sub.D.sup.22=+15.5 (c=1.1, CHCl.sub.3).
[0161] HRMS (ESI) calcd for C.sub.17H.sub.21NO.sub.3, m/z 288.1600.
found 288.1599.
(R)-tert-Butyl 3-hydroxy-2-(N-phenylaminooxy)propylcarbamate (new
compound) (9j)
##STR00041##
[0163] .alpha.-Aminoxy alcohol 9j was prepared according to the
general procedure from tert-butyl-3-oxopropylcarbamate (0.16 mL,
0.9 mmol) to provide the title compound as a pale yellow liquid
(67.2 mg, 79% yield) after flash column chromatography on silica
gel (hexane/EtOAc=9/1.about.7/3).
[0164] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.32-7.24 (3H,
m), 6.98-6.94 (2H, m), 5.02 (1H, brs), 3.94-3.92 (1H, m), 3.80 (2H,
s), 3.50-3.36 (2H, m), 1.45 (9H, s).
[0165] .sup.13C NMR (100 MHz, CDCl.sub.3): 157.1, 148.3, 129.0,
122.4, 114.6, 82.4, 80.0, 61.3, 39.6, 28.3.
[0166] HPLC: Chiralpak OJ-H (hexane/i-PrOH, 95/5, flow rate 1
mL/min, .lamda.=230 nm),
[0167] t.sub.R (minor)=24.8 min, t.sub.R (major)=26.6 min; 93%
ee.
[0168] [.alpha.].sub.D.sup.22=-8.2 (c=1.3, CHCl.sub.3).
[0169] HRMS (ESI) calcd for C.sub.14H.sub.23N.sub.2O.sub.4, m/z
282.1658. found 282.1659.
(R)-2-(p-Toluidinooxy)propan-1-ol (new compound) (9k)
##STR00042##
[0171] .alpha.-Aminoxy alcohol 9k was prepared according to the
general procedure from propanal (0.07 mL, 0.9 mmol) and
nitrosotoluene (36.3 mg, 0.3 mmol) to provide the title compound as
a pale yellow liquid (45.0 mg, 83% yield) after flash column
chromatography on silica gel (hexane/EtOAc=9/1.about.7/3).
[0172] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.07 (2H, d,
J=8.1 Hz), 6.99 (1H, brs), 6.88 (2H, d, J=8.3 Hz), 4.13-4.07 (1H,
m), 3.78-3.68 (2H, m), 2.28 (3H, s), 1.22 (3H, d, J=6.5 Hz).
[0173] .sup.13C NMR (100 MHz, CDCl.sub.3): 145.8, 132.0, 129.5,
115.3 79.8, 66.6, 20.6, 15.4.
[0174] HPLC: Chiralpak AD-H (hexane/i-PrOH, 90/10, flow rate 1
mL/min, .lamda.=230 nm),
[0175] t.sub.R (minor)=10.9 min, t.sub.R (major)=12.4 min; 97%
ee.
[0176] [.alpha.].sub.D.sup.25=+5.5 (c=1.5, CHCl.sub.3).
[0177] HRMS (ESI) calcd for C.sub.10H.sub.16NO.sub.2, m/z 182.1181.
found 182.1181.
Example 2
Formation of Functionalized Tetrahydro-1,2-oxazines via
.alpha.-Aminoxylation of Aldehydes and Aza-Michael Reaction
[0178] Nitroalkenes are among the most reactive Michael acceptors
(for a review, see: Berner, O M, et al., Eur. J. Org. Chem. (2002)
1877-1894), so investigations were started by using 31a under the
previously established conditions (Zhong, G, Angew. Chem. Int. Ed.
(2003) 42, 4247-4250) (nitroalkenal 31a (1.5 equiv), nitrosobenzene
(1.0 equiv), and l-proline (20 mol %) in DMSO). The domino strategy
was facile at room temperature and was complete within 30 minutes
(FIG. 8). The course of the reaction was easily monitored by
observing the change in the colour of the solution from green to
orange. After the workup, pure tetrahydro-1,2-oxazine (THO) 33a was
isolated in 46% yield with 99% enantiomeric excess (ee) and a
diastereomeric ratio (d.r.) greater than 99:1 (FIG. 8, entry 1).
This reaction led to the first successful isolation of a stable
aldehyde after the .alpha.-aminoxylation, and the rare case of an
inactivated amine undergoing a conjugate addition with an aliphatic
nitroalkene with high stereoinduction (for selected examples of
diaseteroselective aza-Michael additions to nitroalkenes, see: a)
P. L. Southwick, J. E. Anderson, J. Am. Chem. Soc. (1957) 79,
6222-6229; b) A. Kamimura, A. Kadowaki, Y. Nagata, H. Uno,
Tetrahedron Lett. (2006) 47, 2471-2473; c) D. Enders, J. Wiedemann,
Synthesis (1996) 1443-1450; d) D. Lucent, P. Heyse, A. Gissot, T.
Le Gall, C. Mioskowski, Eur. J. Org. Chem. (2000) 3575-3579). A
preliminary screening indicated that the catalytic activity and the
asymmetric induction were dependent on the solvent. Excellent
enantio- and diastereoselectivities were obtained in polar,
protophilic solvents, such as DMSO and DMF (FIG. 8, entries 1 and
2). A halogenated solvent possessing a lower polarity was also
tolerated (FIG. 8, entry 4), whereas an ethereal solvent (THF) and
water had deleterious effects on the reactivity (FIG. 8, entries 5
and 6).
[0179] Among the solvents tested, polar, protophobic acetonitrile
was found to be best with respect to the chemical yield and optical
purity (FIG. 8, entry 3). It is also noteworthy that although IXa
proved to be an excellent catalyst in the aminoxylation,
pyrrolidine-based tetrazole IXb (a) N. Momiyama, H. Torii, S.
Saito, H. Yamamoto, Proc. Natl. Acad. Sci. USA (2004) 101,
5374-5378; b) A. J. A. Cobb, D. A. Longbottom, D. M. Shaw, S. V.
Ley, Chem. Commun. (2004) 1808-1809; c) A. Hartikka, P. I.
Arvidsson, Tetrahedron: Asymmetry (2004) 15, 1831-1834) induced
reaction with lower conversion (FIG. 8, entry 7). Performing the
reaction with a larger excess of 31a led to complete conversion,
and 33a was isolated in 59% yield (FIG. 8, entry 8). The
temperature effect on the transformation was also examined.
Notably, considerable side reactions can be detected at 0.degree.
C. (FIG. 8, entry 9), but suppression of the homodimerization was
accomplished at -20.degree. C. (FIG. 8, entry 10). To avoid making
intractable byproducts, the reaction mixture was diluted (FIG. 8,
entry 11).
[0180] Next, the effect of the catalyst loading was evaluated.
Remarkably, in the presence of tetraethylammonium bromide (TEAB)
(FIG. 8, entry 12) (The addition of a phase transfer catalyst (PTC)
such as TEAB greatly enhanced the solubility of L-proline, which
helped to make a homogeneous solution; this increase in the
catalyst concentration resulted in a positive effect on reactivity
of the substrates.) a catalyst loading as low as 0.5 mol % could be
used without any loss in the ee values or the d.r. numbers (FIG. 8,
entry 14). For operational convenience 5 mol % 1-proline, under
otherwise identical reaction times, ensured high levels of reaction
efficiency and enantioselectivity (FIG. 8, entry 13). Notably,
after the in situ reduction, the d.r. of the corresponding alcohol
significantly dropped to 90:10 (FIG. 8, entry 15), albeit the ee
value was not affected. This result implied that 1-proline played
an important role in diastereocontrol.
[0181] The scope of these transformations was furthermore explored
by using the optimized reaction conditions. The method was applied
to a variety of nitroalkenal substrates, and as shown in FIG. 9
different substituents were well-tolerated at the a position to the
nitro group. The R.sup.8 group of component 31 ranges from simple
to sterically demanding groups, as well as valuable functional
groups. Good yields were observed although there was some
fluctuation depending on the substituents. The variation of the
steric effects (FIG. 9, entries 4-8) or the electronic effects
(FIG. 9, entries 9-16) had only a small impact on the introduction
of the third chiral center, which was evidenced by the uniformly
high ee and d.r. values. Furthermore, this method was applicable to
various aromatic nitroso compounds; for example, 2-methyl-,
4-methyl- and 4-bromonitrosobenzene (FIG. 9, entries 2, 3, and 17).
The fact that the R.sup.8 and R' groups of precursors 31 and 2,
respectively, can be varied demonstrates the versatility of the
approach of the invention.
[0182] This domino reaction generates up to three stereogenic
centers and forms only one out of eight possible stereoisomers. The
origin of the high stereoselectivity derives from the
.alpha.-aminoxylation reaction, which is known to proceed with high
enantioselectivity (For mechanistic studies, see: a) S. P. Mathew,
H. Iwamura, D. G. Blackmond, Angew. Chem. (2004) 116, 3379-3383;
Angew. Chem. Int. Ed. (2004) 43, 3317-3321; b) P. H.-Y. Cheong, K.
N. Houk, J. Am. Chem. Soc. (2004) 126, 13912-13913; c) H. Iwamura,
D. H. Wells, Jr., S. P. Mathew, M. Klussmann, A. Armstrong, D. G.
Blackmond, J. Am. Chem. Soc. (2004) 126, 16312-16313.). This
selectivity is maintained in the second step by going through a
sterically favored transition state (see below). The relative and
absolute configurations of THO 33d were determined by .sup.1H NMR
nuclear Overhauser effect (NOE) experiments and X-ray
crystallography (FIG. 10) and compared with respective related
.alpha.-aminoxylations Mathew et al., 2004, supra; Cheong et al.,
2004, supra; Iwamura et al., 2004, supra; CCDC 670447 (33d)
contains the supplemantary crystallographic data. These data can be
obtained free of charge from The Cambdridge Crystallographic Data
Center via www.ccdc.cam.ac.uk/data request/cif. The X-ray crystal
structure of 33d showed the relative configuration. The absolute
configuration was assigned for the .alpha.-aminoxy carbon center as
R based on previous reports and mechanism studies.).
[0183] Since the aldehyde group and the .alpha.-methylnitro group
are trans and pointing away from each other in the crystal
structure of 33d, it is unlikely that 1-proline participates in the
reaction by covalent bond catalysis in the transition state of the
aza-Michael addition/protonation step. To get some mechanistic
insight into this domino reaction, a series of control experiments
were carried out (FIG. 11). We chose
O-(tert-butyldimethylsilyl)-N-phenylhydroxylamine (47) and
(E)-(4-nitrobut-3-enyl)benzene (48) as mimics of the in situ
generated amine substrate and the nitroalkenyl reactant,
respectively. In the absence of any catalyst, the reaction did not
proceed after 2 days at -20.degree. C. (FIG. 11, entry 1).
Elevating the temperature to room temperature provided similar
results (FIG. 11, entry 2), and when 1 equivalent of TEA was used
as a Lewis base in the reaction it proceeded sluggishly with a 31%
conversion. This experiment revealed that the tertiary amine itself
was not sufficient to enhance the reactivity of 47 (FIG. 11, entry
3). The introduction of a hydrogen-bond donor (For selected recent
reviews on hydrogen-bonding catalysis, see: a) A. D. Doyle, E. N.
Jacobsen, Chem. Rev. 2007, 107, 5713-5743; b) P. R. Schreiner,
Chem. Soc. Rev. 2003, 32, 289-296; c) P. M. Pihko, Angew. Chem.
Int. Ed. (2004) 43, 2062-2064; d) Y. Takemoto, Org. Biomol. Chem.
(2005) 3, 4299-4306; e) C. Bolm, T. Rantanen, I. Schiffers, L.
Zani, Angew. Chem. Int. Ed. (2005) 44, 1758-1763; f) T. Akiyama,
Chem. Rev. (2007) 107, 5744-5758; g) M. S. Taylor, E. N. Jacobsen,
Angew. Chem. Int. Ed. 2006, 45, 1520-1543; h) S. J. Connon, Angew.
Chem. Int. Ed. (2006) 45, 3909-3912; i) T. Marcelli, J. H. van
Maarseveen, H. Hiemstra, Angew. Chem. Int. Ed. (2006) 45,
7496-7504), 20 mol % of quinine, resulted in full conversion within
18 hours. These observations indicate that the aza-Michael addition
step is catalyzed by hydrogen-bonding interactions. Combined with
the fact that intermediates cannot be detected in the .sup.1H NMR
spectra recorded during the course of the reaction or upon product
isolation, a concerted mechanism is proposed. After the
.alpha.-aminoxylation step, the aza-Michael addition/protonation
(For timely examples on organocatalytic asymmetric protonation,
see: a) C. H. Cheon, H. Yamamoto, J. Am. Chem. Soc. (2008) 130,
9246-9247; b) D. Leow, S. Lin, S. K. Chittimalla, X. Fu, C.-H. Tan,
Angew. Chem. Int. Ed. (2008) 47, 5641-5645) proceeds in a
synergistic way and is assisted by a molecule of water which
participates in two hydrogen bonds; the hydrogen bonds are formed
between the water molecule and both the in situ generated amine
moiety and the nitro group (FIG. 12A). DFT calculations of the
lowest energy transition state also confirm this assumption.
[0184] In summary, a novel, practical, and enantio- and
diastereoselective domino reaction is provided for the synthesis of
functionalized THOs, based on the use of a simple amine catalyst.
The results disclosed herein demonstrate the ability to control the
regio- and stereochemistry of the reaction for the synthesis of
THOs from acyclic substrates. It is expected that
.alpha.-aminoxylation directed domino reactions will have great
potential in the field of organocatalysis. The reaction, which is
easy to perform, proceeds cleanly with complete stereocontrol and
does not require a change in the reaction conditions or adding
reagents. This invention is likely to be used in synthetic
applications, especially since the .alpha.-aminoxylation reaction
can be combined with existing domino methods. Applications of this
methodology to total syntheses and detailed mechanistic studies
will be described in due course.
General Experimental Information
[0185] Analytical thin layer chromatography (TLC) was performed
using Merck 60 F254 precoated silica gel plate (0.2 mm thickness).
Subsequent to elution, plates were visualized using UV radiation
(254 nm) on Spectroline Model ENF-24061/F 254 nm. Further
visualization was possible by staining with basic solution of
potassium permanganate or acidic solution of ceric molybdate.
[0186] Flash chromatography (FC) was performed using Merck silica
gel 60 with freshly distilled solvents. Columns were typically
packed as slurry and equilibrated with the appropriate solvent
system prior to use.
[0187] .sup.1H and .sup.13C NMR spectra were recorded on Bruker AMX
300, 400 and 500 spectrophotometers at ambient temperature as
noted. Chemical shifts for .sup.1H NMR spectra are reported as
.delta. in units of parts per million (ppm) downfield from
SiMe.sub.4 (.delta. 0.0) and relative to the signal of chloroform-d
(.delta. 7.2600, singlet). Multiplicities were given as: s
(singlet), d (doublet), t (triplet), dd (doublets of doublet) or m
(multiplets). The number of protons (n) for a given resonance is
indicated by nH. Coupling constants are reported as a J value in
Hz. Data for .sup.13C NMR are reported as .delta. in ppm downfield
from SiMe.sub.4 (.delta. 0.0) and relative to the signal of
chloroform-d (.delta. 77.00, triplet).
[0188] Enantioselectivities were determined by High performance
liquid chromatography (HPLC) analysis employing a Daicel Chirapak
AS-H column. Optical rotations were measured in CHCl.sub.3 on a
Schmidt+Haensch polarimeter (Polartronic MH8) with a 10 cm cell (c
given in g/100 mL). Absolute configuration of the products was
determined by comparison with compounds previously published.
[0189] High resolution mass spectrometry (HRMS) was recorded on
Finnigan MAT 95.times.P spectrometer.
[0190] Nitroalkanes 112a-c, nitrosobenzene 2a, 2-nitrosotoluene 2b,
D,L- and L-proline were purchased from Sigma-Aldrich of highest
purity and used without further purification. 5,5-Dimethoxypentanal
131, Nitroalkanes 112d-g, 1-bromo-4-nitrosobenzene 2c and
4-nitrosotoluene 2d were prepared according to literature
procedures [for the preparation of 5,5-dimethoxypentanal 131, see:
Aggarwal, V K, et al., Org. Lett. (2002) 4, 1227; for the
preparation of nitroalkane 31d, see: Kornblum, N, & Weaver, W
M, J. Am. Chem. Soc. (1958) 80, 4333; for the preparation of
nitroalkane 31e-g, see: Kodukulla, R P K, et al., Synth. Commun.
(1994) 24, 819; for the preparation of 1-bromo-4-nitrosobenzene 2c
and 4-nitrosotoluene 2d, see: Defoin, A, Synthesis (2004) 706]. The
racemic products used to determine the e.e. values were synthesized
using D,L-proline as catalyst.
Typical Procedure for the Preparation of Nitroalkenals
##STR00043##
[0191] Procedure A
[0192] A mixture of the corresponding nitroalkane 112 (80.0 mmol),
aldehyde 131 (16.0 mmol) and triethylamine (3.2 mmol) was stirred
at 0.degree. C. for 30 min and allowed to reach room temperature
(r.t.) for 6-24 h. The volatiles were removed by evaporation in
vacuo. The nitroaldol thus obtained as a mixture of diastereomers
was dissolved in anhydrous dichloromethane (32 mL) and cooled to
-70.degree. C. Methanesulfonyl chloride (19.0 mmol) was added
dropwise followed by dropwise addition of a solution of
N,N-diisopropylethylamine (39.0 mmol) in anhydrous dichloromethane
(8 mL), keeping the reaction mixture below -60.degree. C. The
mixture was stirred at -70.degree. C. for 2-3 h and then allowed to
reach r.t. The solution was washed with water, HCl 1N (a.q) and
brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated in
vacuo. The crude nitroalkene was dissolved in THF (60 mL) at
0.degree. C., followed by addition of HCl 2N (15 mL, a.q.).
[0193] The solution was stirred at 0.degree. C. for 30 min and
allowed to reach r.t. for 6-8 h. The mixture was extracted with
Et.sub.2O. The organic phase was combined, washed with saturated
NaHCO.sub.3 (a.q.), brine, and dried over anhydrous
Na.sub.2SO.sub.4. The volatiles were evaporated in vacuo and the
crude nitroalkenal was purified by FC (EtOAc/Hexane) to give the
pure product 31 as exclusively E isomer.
Procedure B
[0194] To a stirred solution of tetra-n-butylammonium fluoride
(TBAF) (1M in THF, 22.0 mmol) in THF (300 mL) at 0.degree. C., was
added the corresponding nitroalkane 112 (24.0 mmol) in THF (40 mL)
and, after 5 min, a solution of aldehyde 131 (16.0 mmol) in THF (80
mL). After stirring at 0.degree. C. for 0.5-4 h, the mixture was
poured onto saturated NaHCO.sub.3 (a.q.) and extracted with
Et.sub.2O. The organic extracts were then washed with brine, dried
over anhydrous Na.sub.2SO.sub.4, filtered through a short plug of
Celite and evaporated in vacuo. The nitroaldol thus obtained as a
mixture of diastereomers was dissolved in anhydrous dichloromethane
(32 mL) and cooled to -50.degree. C. Trifluoroacetic anhydride
(16.0 mmol) was added dropwise followed by dropwise addition of a
solution of N,N-diisopropylethylamine (24.0 mmol) in anhydrous
dichloromethane (8 mL), keeping the reaction mixture below
-40.degree. C. After the mixture was stirred at -50.degree. C. for
3-4 h, a solution of 1,8-diazabicycloundec-7-ene (DBU) (16.0 mmol)
in anhydrous dichloromethane (8 mL) was added in one portion and
the reaction mixture was allowed to reach r.t. The solution was
washed with water, HCl 1N (a.q) and brine, dried over anhydrous
Na.sub.2SO.sub.4 and evaporated in vacuo. The crude nitroalkene was
dissolved in THF (40 mL) at 0.degree. C., followed by addition of
HCl 2N (10 mL, a.q.). The solution was stirred at 0.degree. C. for
30 min and allowed to reach r.t. for 6-8 h. The mixture was
extracted with Et.sub.2O. The organic phase was combined, washed
with saturated NaHCO.sub.3 (a.q.), brine, and dried over anhydrous
Na.sub.2SO.sub.4. The volatiles were evaporated in vacuo and the
crude nitroalkenal was purified by FC (EtOAc/Hexane) to give the
pure product 31 as exclusively E isomer except 31d.
(E)-6-nitrohex-5-enal 31a
##STR00044##
[0196] Prepared according to the general procedure A from
nitromethane 112a (80 mmol) and 5,5-dimethoxypentanal 131 (16 mmol)
to provide the title compound as yellow oil (1.51 g, 66% yield)
after silica gel chromatography (EtOAc/Hexane).
[0197] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.81 (s, 1H,
CHO), 7.29-7.22 (m, 1H, CH.dbd.CHNO.sub.2), 7.01 (d, J=13.6 Hz, 1H,
CHNO.sub.2), 2.57 (t, J=7.2 Hz, 2H, CH.sub.2CHO), 2.35 (q, J=7.2
Hz, 2H, CH.sub.2CH), 1.88 (m, 2H, CH.sub.2CH.sub.2CH.sub.2).
[0198] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 200.8, 141.2,
141.1, 42.7, 27.6, 20.0.
(E)-6-nitrohept-5-enal 31b
##STR00045##
[0200] Prepared according to the general procedure A from
nitroethane 112b (80 mmol) and 5,5-dimethoxypentanal 131 (16 mmol)
to provide the title compound as yellow oil (1.58 g, 63% yield)
after silica gel chromatography (EtOAc/Hexane).
[0201] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.81 (s, 1H,
CHO), 7.11 (t, J=8.0 Hz, 1H, CH.dbd.C(CH3)NO2), 2.56 (t, J=7.2 Hz,
2H, CH.sub.2CHO), 2.30 (q, J=7.2 Hz, 2H, CH.sub.2CH), 2.18 (s, 3H,
CH.sub.3), 1.87 (m, 2H, CH.sub.2CH.sub.2CH.sub.2).
[0202] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 201.1, 148.4,
134.6, 42.9, 27.2, 20.7, 12.5.
(E)-6-nitrooct-5-enal 31c
##STR00046##
[0204] Prepared according to the general procedure A from
1-nitropropane 112c (80 mmol) and 5,5-dimethoxypentanal 131 (16
mmol) to provide the title compound as yellow oil (1.51 g, 55%
yield) after silica gel chromatography (EtOAc/Hexane).
[0205] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.82 (s, 1H,
CHO), 7.03 (t, J=8.0 Hz, 1H, CH.dbd.C(C.sub.2H.sub.5)NO.sub.2),
2.65-2.54 (m, 4H, CH.sub.2CHO+CH.sub.2CH.sub.3), 2.30 (q, J=7.2 Hz,
2H, CH.sub.2CH), 1.87 (m, 2H, CH.sub.2CH.sub.2CH.sub.2), 1.13 (t,
J=7.6 Hz, 3H, CH.sub.2CH.sub.3).
[0206] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 201.1, 153.9,
134.2, 42.9, 26.9, 20.9, 19.9, 12.7.
6-nitro-6-phenylhex-5-enal 31d
##STR00047##
[0208] Prepared according to the general procedure B from
1-(nitromethyl)benzene 112d (24 mmol) and 5,5-dimethoxypentanal 131
(16 mmol) to provide the title compound as yellow oil (E/Z=6.7/1)
(1.44 g, 41% yield) after silica gel chromatography
(EtOAc/Hexane).
[0209] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.83-9.74 (1H,
CHO), 7.49-7.26 (m, 5.13H, ArH+CH.dbd.C(Ph)NO.sub.2 (E)), 6.03 (t,
J=7.6 Hz, 0.87H, CH.dbd.C(Ph)NO2(Z)), 2.63-2.46 (m, 2H,
CH.sub.2CHO), 2.43-2.17 (m, 2H, CH.sub.2CH), 1.95-1.82 (m, 2H,
CH.sub.2CH.sub.2CH.sub.2).
[0210] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 201.4, 153.2,
131.2, 130.3, 129.8, 128.9, 128.6, 126.7, 126.3, 43.0, 27.7, 22.1,
21.0.
(E)-6-nitro-7-phenylhept-5-enal 31e
##STR00048##
[0212] Prepared according to the general procedure B from
1-(2-nitroethyl)benzene 112e (24 mmol) and 5,5-dimethoxypentanal
131 (16 mmol) to provide the title compound as yellow oil (1.49 g,
40% yield) after silica gel chromatography (EtOAc/Hexane).
[0213] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.77 (t, J=2 Hz,
1H, CHO), 7.34-7.18 (m, 6H, ArH+CH.dbd.C(CH.sub.2)NO.sub.2), 3.99
(s, 2H, CH.sub.2Ph), 2.56-2.52 (m, 2H, CH.sub.2CHO), 2.41 (q, J=7.6
Hz, 2H, CH.sub.2CH), 1.92-1.84 (m, 2H,
CH.sub.2CH.sub.2CH.sub.2).
[0214] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 201.0, 151.0,
136.3, 136.2, 128.8, 128.0, 127.0, 42.9, 32.0, 27.4, 20.8.
(E)-6-nitro-7-p-tolylhept-5-enal 31f
##STR00049##
[0216] Prepared according to the general procedure B from
1-methyl-4-(2-nitroethyl)benzene 112f (24 mmol) and
5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound
as yellow oil (1.38 g, 35% yield) after silica gel chromatography
(EtOAc/Hexane).
[0217] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.77 (s, 1H,
CHO), 7.24-7.07 (m, 5H, ArH+CH.dbd.C(CH.sub.2)NO.sub.2), 3.95 (s,
2H, CH.sub.2Ar), 2.53 (t, J=7H, CH.sub.2CHO), 2.39 (q, J=7.2 Hz,
2H, CH.sub.2CH), 2.33 (s, 1H, CH.sub.3Ar), 1.91-1.83 (m, 2H,
CH.sub.2CH.sub.2CH.sub.2).
[0218] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 201.1, 151.2,
136.6, 136.1, 133.3, 129.4, 127.9, 42.9, 31.6, 27.4, 21.0,
20.8.
(E)-7-(4-chlorophenyl)-6-nitrohept-5-enal 31g
##STR00050##
[0220] Prepared according to the general procedure B from
1-chloro-4-(2-nitroethyl)benzene 112g (24 mmol) and
5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound
as yellow oil (1.93 g, 45% yield) after silica gel chromatography
(EtOAc/Hexane).
[0221] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.79 (s, 1H,
CHO), 7.29-7.12 (m, 5H, ArH+CH.dbd.C(CH.sub.2)NO.sub.2), 3.95 (s,
2H, CH.sub.2Ar), 2.56 (m, 2H, CH.sub.2CHO), 2.41 (q, J=7.7 Hz, 2H,
CH.sub.2CH), 1.93-1.83 (m, 2H, CH.sub.2CH.sub.2CH.sub.2).
[0222] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 200.8, 150.6,
136.5, 134.8, 132.9, 129.4, 128.9, 42.9, 31.4, 27.4, 20.8.
(E)-7-(4-bromophenyl)-6-nitrohept-5-enal 31h
##STR00051##
[0224] Prepared according to the general procedure B from
1-bromo-4-(2-nitroethyl)benzene 112h (24 mmol) and
5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound
as yellow oil (2.15 g, 43% yield) after silica gel chromatography
(EtOAc/Hexane).
[0225] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 9.79 (s, 1H,
CHO), 7.49-7.06 (m, 5H, ArH+CH.dbd.C(CH.sub.2)NO.sub.2), 3.92 (s,
2H, CH.sub.2Ar), 2.57 (t, J=7.0 Hz, 2H, CH.sub.2CHO), 2.41 (q,
J=7.5 Hz, 2H, CH.sub.2CH), 1.93-1.84 (m, 2H,
CH.sub.2CH.sub.2CH.sub.2).
[0226] .sup.13C NMR (75 MHz, CDCl.sub.3): .delta. 200.9, 150.5,
136.6, 135.3, 131.9, 129.8, 120.9, 42.9, 31.5, 27.4, 20.8.
General Procedure for Domino Aminoxylation/Michael Reaction
##STR00052##
[0228] To a 25 mL vial equipped with a magnetic stir bar and
charged with tetraethylammonium bromide (TEAB) (105 mg, 0.5 mmol)
was added CH.sub.3CN (5.0 mL), followed by the appropriate alkenal
(1.5 mmol) and the solution was cooled to -20.degree. C. for 10 min
before nitrosobenzene (54 mg, 0.5 mmol) was added in one portion
upon at which time the solution became green. To this green
homogeneous solution was then added L-proline (3.0 mg, 0.025 mmol)
in one portion. The resulting solution was then stirred at
-20.degree. C. until the limited reactants was fully consumed and
the disappearance of green color in solution, resulting in a final
yellow or orange homogeneous solution. The reaction mixture was
quenched with half saturated aqueous NH.sub.4Cl solution, extracted
with EtOAc, dried over anhydrous Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The resulting residue was then purified by
FC (EtOAc/Hexane) to provide the title compounds.
Optimization of Reaction Conditions
1) Solvent Effect
##STR00053##
TABLE-US-00001 [0229] entry solvent time % yield.sup.b % e.e..sup.c
d.r..sup.d 1 DMSO 0.5 h 46 99 >99:1 2 DMF 0.5 h 44 99 >99:1 3
CH.sub.3CN 0.5 h 55 99 >99:1 4 CHCl.sub.3 0.5 h 53 98 >99:1 5
THF 24 h <20 n.d. n.d. 6 H.sub.2O 48 h <5 n.d. n.d. 7 NMP 0.5
h 54 98 >99:1 8.sup.e CH.sub.3CN 0.5 h 49 99 >99:1 .sup.a
Unless otherwise noted, reactions were conducted with 1.0 equiv of
nitrosobenzene 2a (1M), 1.5 equiv of nitroalkenal 31a and 20 mol %
.sub.L-proline at room temperature. .sup.bIsolated yield.
.sup.cDetermined by chiral HPLC analysis (Chiralcel AS-H).
.sup.dDetermined by .sup.1H NMR. .sup.ePyrrolidine-based tetrazole
was used as catalyst.
[0230] The catalytic activity and asymmetric induction showed
dependence on the solvent. Excellent enantio- and
diastereoselectivity could be achieved in highly polar and
protophilic solvents, such as DMSO, DMF, and NMP (entries 1, 2, 7).
Halogenated solvent possessing a similar but lower polarity was
also tolerated (entry 4), whereas less polar ethereal solvent, such
as THF and the most polar solvent water showed deleterious effect
on reactivity (entries 5, 6). Among the solvents tested, the highly
polar but protophobic acetonitrile was found to be the best with
respect to the catalytic activity and the asymmetric induction
(entry 3). In addition, it is also noteworthy that although proved
to be an excellent catalyst in aminoxylation, pyrrolidine-based
tetrazole induced reaction with lower conversion (entry 8).
2) Temperature Effect
##STR00054##
TABLE-US-00002 [0231] entry temperature time % yield.sup.b %
e.e..sup.c d.r..sup.d 1 r.t. 0.5 h 55 99 >99:1 2 0.degree. C.
0.5 h 59 99 >99:1 3 -20.degree. C. 1 h 63 >99 >99:1
4.sup.e -20.degree. C. 1 h 67 >99 >99:1 5.sup.e -40.degree.
C. 4 h 53 >99 >99:1 6.sup.e -60.degree. C. 48 h <5 n.d.
n.d. .sup.a Unless otherwise noted, reactions were conducted with
1.0 equiv of nitrosobenzene 2a (1M), 1.5 equiv of nitroalkenal 31a
and 20 mol % .sub.L-proline in CH.sub.3CN. .sup.bIsolated yield.
.sup.cDetermined by chiral HPLC analysis (Chiralcel AS-H).
.sup.dDetermined by .sup.1H NMR. .sup.e3.0 equiv of 31a was
used.
[0232] Considerable side reactions were detected when the reaction
was conducted at r.t. or at 0.degree. C. (entries 1, 2).
Suppression of the homodimerization byproducts was accomplished at
-20.degree. C. (entry 3), while further lowering the temperature
imparted a detrimental influence on reaction efficiency (entries 5,
6). Implementing excess of nitroalkenal 31a also contributed to
higher chemical yield (entry 3 vs entry 4).
3) Concentration Effect
##STR00055##
TABLE-US-00003 [0233] entry concentration of 4a time % yield.sup.b
% e.e..sup.c d.r..sup.d 1 1M 1 h 67 >99 >99:1 2 0.5M 4 h 69
>99 >99:1 3 0.2M 14 h 71 >99 >99:1 4 0.1M 24 h 73
>99 >99:1 5 0.05M 48 h 70 >99 >99:1 .sup.a Unless
otherwise noted, reactions were conducted with 1.0 equiv of
nitrosobenzene 2a, 3.0 equiv of nitroalkenal 31a and 20 mol %
.sub.L-proline in CH.sub.3CN at -20.degree. C. .sup.bIsolated
yield. .sup.cDetermined by chiral HPLC analysis (Chiralcel AS-H).
.sup.dDetermined by .sup.1H NMR.
[0234] Results revealed that lowering the concentration from 1 M to
0.1 M extensively suppressed the homodimerization of 2a, thus
improved the chemical yield of 33a (entries 1-4). However, further
decreased concentration only resulted in longer reaction time
(entry 5).
4) Survey of Additives
##STR00056##
TABLE-US-00004 [0235] entry additive time % yield.sup.b %
e.e..sup.c d.r..sup.d 1 TEAB 0.1 eq 22 h 73 >99 >99:1 2 TEAB
0.5 eq 19 h 78 >99 >99:1 3 TEAB 1 eq 14 h 90 >99 >99:1
4 TEAB 2 eq 12 h 89 >99 >99:1 5 TBAB 1 eq 15 h 82 >99
>99:1 6 TEAI 1 eq 16 h 80 >99 >99:1 7 TBAI 1 eq 16 h 81
>99 >99:1 8 none 24 h 73 >99 >99:1 .sup.a Unless
otherwise noted, reactions were conducted with 1.0 equiv of
nitrosobenzene 2a (0.1M), 3.0 equiv of nitroalkenal 31a and 20 mol
% .sub.L-proline in CH.sub.3CN at -20.degree. C. .sup.bIsolated
yield. .sup.cDetermined by chiral HPLC analysis (Chiralcel AS-H).
.sup.dDetermined by .sup.1H NMR. TBAB = tetra-n-butylammonium
bromide, TEAI = tetraethylammonium iodide, TBAI =
tetra-n-butyl-ammonium iodide.
[0236] The addition of phase transfer catalyst (PTC) such as TEAB
greatly enhanced the solubility of L-proline which helped to make a
homogeneous solution, thus presented positive effect on reactivity
by increasing catalyst concentration in the reaction medium. The
using of 1 equiv of TEAB was found to be the best option (entry 4),
either changing it to other PTCs (entries 6-8) or using other
equivalents (entries 1, 2, and 5) provided inferior results.
5) Survey of Catalyst Loading
##STR00057##
TABLE-US-00005 [0237] entry mol % of cat. time % yield.sup.b %
e.e..sup.c d.r..sup.d 1 20 14 h 90 >99 >99:1 2 10 18 h 90
>99 >99:1 3 5 24 h 90 >99 >99:1 4 1 30 h 73 >99
>99:1 5 0.5 48 h 65 >99 >99:1 .sup.a Unless otherwise
noted, reactions were conducted with 1.0 equiv of nitrosobenzene 2a
(0.1M), 3.0 equiv of nitroalkenal 31a, 1.0 equiv of TEAB and
.sub.L-proline in CH.sub.3CN at -20.degree. C. .sup.bIsolated
yield. .sup.cDetermined by chiral HPLC analysis (Chiralcel AS-H).
.sup.dDetermined by .sup.1H NMR.
[0238] Next, we surveyed the catalyst loading with L-proline.
Gratifyingly, we could decrease the catalyst loading to 0.5 mol %
without any loss of asymmetric induction (entry 5). In terms of
operational convenience, the use of 5 mol % L-proline ensures high
levels of reaction efficiency and enantioselectivity while
maintaining expedient reaction times (entry 3).
Substrate Scope
(3R,6R)-3-(nitromethyl)-2-phenylmorpholine-6-carbaldehyde 33a
##STR00058##
[0240] Prepared according to the general procedure from 31a (1.5
mmol) and nitrosobenzene (0.5 mmol) to provide the title compound
as yellow oil (113 mg, 90% yield) after silica gel chromatography
(EtOAc/Hexane).
[0241] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.75 (d, J=1.5 Hz,
1H, CHO), 7.38-7.09 (m, 5H, ArH), 4.82 (dd, J=12.5, 9.5 Hz, 1H,
CH.sub.2NO.sub.2), 4.52-4.49 (m, 2H, CH.sub.2NO.sub.2+CHCHO), 4.43
(dd, J=6.7, 1.0 Hz, 1H, CHN), 2.25-2.12 (m, 2H, CH.sub.2CHCHO),
2.12-2.06 (m, 2H, CH.sub.2CHN).
[0242] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 202.5, 147.3,
129.4, 123.8, 115.8, 82.4, 71.8, 57.7, 21.9, 18.5.
[0243] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=230 nm),
[0244] t.sub.R (major)=15.8 min, t.sub.R (minor)=50.2 min; >99%
ee.
[0245] [.alpha.].sub.D.sup.25=-213.7 (c=1.0, CHCl.sub.3).
[0246] HRMS (EI) calcd for C.sub.12H.sub.14O.sub.4N.sub.2, m/z
250.0948. found 250.0944.
(3R,6R)-3-(nitromethyl)-2-o-tolylmorpholine-6-carbaldehyde 33b
##STR00059##
[0248] Prepared according to the general procedure from 31a (1.5
mmol) and 2-nitrosotoluene (0.5 mmol) to provide the title compound
as yellow oil (105 mg, 79% yield) after silica gel chromatography
(EtOAc/Hexane).
[0249] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.75 (d, J=1.0 Hz,
1H, CHO), 7.35-7.12 (m, 4H, ArH), 4.82 (m, 1H, CH.sub.2NO.sub.2),
4.61 (m, 1H, CH.sub.2NO.sub.2), 4.46 (m, 1H, CHCHO), 3.97-3.94 (m,
1H, CHN), 2.22 (s, 3H, CH.sub.3Ar), 2.20-2.13 (m, 2H,
CH.sub.2CHCHO), 2.06-1.75 (m, 2H, CH.sub.2CHN).
[0250] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 202.4, 145.8,
131.4, 126.6, 126.1, 119.9, 82.7, 71.9, 57.8, 22.8, 18.7, 17.5.
[0251] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=220 nm),
[0252] t.sub.R (major)=14.0 min, t.sub.R (minor)=16.8 min; 97%
ee.
[0253] [.alpha.].sub.D.sup.25=-66.9 (c=0.8, CHCl.sub.3).
[0254] HRMS (EI) calcd for C.sub.13H.sub.16O.sub.4N.sub.2, m/z
264.1105. found 264.1099.
(3R,6R)-2-(4-bromophenyl)-3-(nitromethyl)morpholine-6-carbaldehyde
33c
##STR00060##
[0256] Prepared according to the general procedure from 31a (1.5
mmol) and 1-bromo-4-nitrosobenzene (0.5 mmol) to provide the title
compound as yellow oil (145 mg, 88% yield) after silica gel
chromatography (EtOAc/Hexane).
[0257] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.75 (s, 1H, CHO),
7.28 (dd, J=120, 8.4 Hz, 4H, ArH), 4.85-4.79 (m, 1H,
CH.sub.2NO.sub.2), 4.53-4.49 (m, 2H, CH.sub.2NO.sub.2+CHCHO), 4.42
(m, 1H, CHN), 2.29-2.14 (m, 2H, CH.sub.2CHCHO), 2.13-1.83 (m, 2H,
CH.sub.2CHN).
[0258] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 202.0, 146.4,
132.4, 117.5, 116.5, 82.5, 71.8, 57.6, 21.9, 18.4.
[0259] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=254 nm),
[0260] t.sub.R (major)=17.5 min, t.sub.R (minor)=44.9 min; >99%
ee.
[0261] [.alpha.].sub.D.sup.25=-65.0 (c=0.8, CHCl.sub.3).
[0262] HRMS (EI) calcd for C.sub.12H.sub.13BrO.sub.4N.sub.2, m/z
328.0053. found 328.0009; calcd for
C.sub.12H.sub.13BrO.sub.4N.sub.2, m/z 330.0033. found 330.0031.
(3R,6R)-3-((S)-1-nitroethyl)-2-phenylmorpholine-6-carbaldehyde
33d
##STR00061##
[0264] Prepared according to the general procedure from 31b (1.5
mmol) and nitrosobenzene (0.5 mmol) to provide the title compound
as yellow solid (99 mg, 75% yield) after silica gel chromatography
(EtOAc/Hexane).
[0265] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.66 (s, 1H, CHO),
7.37-7.01 (m, 5H, ArH), 5.38-5.33 (m, 1H, CHNO.sub.2), 4.54-4.53
(m, 1H, CHCHO), 4.27-4.25 (m, 1H, CHN), 2.23-2.04 (m, 2H,
CH.sub.2CHCHO), 2.03-1.72 (m, 2H, CH.sub.2CHN), 1.26 (d, J=7.0 Hz,
3H, CH.sub.3).
[0266] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 202.7, 148.7,
129.3, 122.3, 114.1, 83.2, 82.2, 61.1, 22.7, 19.2, 18.6.
[0267] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=230 nm), t.sub.R (major)=11.0 min, t.sub.R
(minor)=20.6 min; 99% ee.
[0268] [.alpha.].sub.D.sup.25=-46.8 (c=1.1, CHCl.sub.3)
[0269] HRMS (EI) calcd for C.sub.13H.sub.16O.sub.4N.sub.2, m/z
264.1105. found 264.1104.
(3R,6R)-2-(4-bromophenyl)-3-((S)-1-nitroethyl)morpholine-6-carbaldehyde
33e
##STR00062##
[0271] Prepared according to the general procedure from 31b (1.5
mmol) and 1-bromo-4-nitrosobenzene (0.5 mmol) to provide the title
compound as yellow oil (125 mg, 73% yield) after silica gel
chromatography (EtOAc/Hexane).
[0272] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.63 (s, 1H, CHO),
7.24 (dd, J=115, 8.8 Hz, 4H, ArH), 5.37-5.30 (m, 1H, CHNO.sub.2),
4.53 (m, 1H, CHCHO), 4.22 (m, 1H, CHN), 2.23-2.04 (m, 2H,
CH.sub.2CHCHO), 2.03-1.71 (m, 2H, CH.sub.2CHN), 1.27 (d, J=6.8 Hz,
3H, CH.sub.3).
[0273] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 202.1, 147.8,
132.2, 115.8, 114.8, 83.2, 82.1, 61.0, 22.5, 19.1, 18.7.
[0274] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=254 nm),
[0275] t.sub.R (major)=14.3 min, t.sub.R (minor)=22.9 min; 99%
ee.
[0276] [.alpha.].sub.D.sup.25=-44.2 (c=0.7, CHCl.sub.3).
[0277] HRMS (EI) calcd for C.sub.13H.sub.15BrO.sub.4N.sub.2, m/z
342.0210. found 342.0209; calcd for
C.sub.13H.sub.15BrO.sub.4N.sub.2, m/z 344.0189. found 344.0194.
(3R,6R)-3-((S)-1-nitropropyl)-2-phenylmorpholine-6-carbaldehyde
33f
##STR00063##
[0279] Prepared according to the general procedure from 31c (1.5
mmol) and nitrosobenzene (0.5 mmol) to provide the title compound
as yellow oil (95 mg, 68% yield) after silica gel chromatography
(EtOAc/Hexane).
[0280] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.66 (s, 1H, CHO),
7.37-7.00 (m, 5H, ArH), 5.21-5.15 (m, 1H, CHNO.sub.2), 4.53 (m, 1H,
CHCHO), 4.25 (m, 1H, CHN), 2.22-2.04 (m, 2H, CH.sub.2CHCHO),
2.03-1.72 (m, 2H, CH.sub.2CHN), 1.67-1.43 (m, 2H,
CH.sub.2CH.sub.3), 0.81 (t, J=7.6 Hz, 3H, CH.sub.2CH.sub.3).
[0281] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 202.7, 148.6,
129.3, 122.3, 114.0, 89.1, 83.2, 60.3, 25.5, 22.7, 19.2, 10.4.
[0282] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=230 nm),
[0283] t.sub.R (major)=8.7 min, t.sub.R (minor)=16.9 min; >99%
ee.
[0284] [.alpha.].sub.D.sup.25=-38.3 (c=0.8, CHCl.sub.3).
[0285] HRMS (EI) calcd for C.sub.14H.sub.18O.sub.4N.sub.2, m/z
278.1261. found 278.1263.
(3R,6R)-2-(4-bromophenyl)-3-((S)-1-nitropropyl)morpholine-6-carbaldehyde
33g
##STR00064##
[0287] Prepared according to the general procedure from 31c (1.5
mmol) and 1-bromo-4-nitrosobenzene (0.5 mmol) to provide the title
compound as yellow oil (107 mg, 60% yield) after silica gel
chromatography (EtOAc/Hexane).
[0288] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.62 (s, 1H, CHO),
7.23 (dd, J=160, 9.2 Hz, 4H, ArH), 5.18-5.13 (m, 1H, CHNO.sub.2),
4.53-4.52 (m, 1H, CHCHO), 4.22-4.19 (m, 1H, CHN), 2.23-2.15 (m, 2H,
CH.sub.2CHCHO), 2.05-1.71 (m, 2H, CH.sub.2CHN), 1.38-1.07 (m, 2H,
CH.sub.2CH.sub.3), 0.83 (t, J=7.6 Hz, 3H, CH.sub.2CH.sub.3).
[0289] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 202.2, 147.9,
132.2, 115.6, 114.6, 89.0, 83.3, 60.2, 25.6, 22.6, 19.1, 10.4.
[0290] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=254 nm),
[0291] t.sub.R (major)=10.2 min, t.sub.R (minor)=18.0 min; >99%
ee.
[0292] [.alpha.].sub.D.sup.25=-36.5 (c=0.7, CHCl.sub.3).
[0293] HRMS (EI) calcd for C.sub.14H.sub.17BrO.sub.4N.sub.2, m/z
356.0366. found 356.0359.
(3R,6R)-3-((S)-nitro(phenyl)methyl)-2-phenylmorpholine-6-carbaldehyde
33h
##STR00065##
[0295] Prepared according to the general procedure from 31d (1.5
mmol) and nitrosobenzene (0.5 mmol) to provide the title compound
as white solid (119 mg, 73% yield) after silica gel chromatography
(EtOAc/Hexane).
[0296] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.61 (s, 1H, CHO),
7.29-6.64 (m, 10H, ArH), 6.32 (m, CHNO.sub.2), 4.80-4.77 (m, 1H,
CHCHO), 4.58 (m, 1H, CHN), 2.32-2.19 (m, 2H, CH.sub.2CHCHO),
2.18-1.88 (m, 2H, CH.sub.2CHN).
[0297] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 202.8, 148.0,
131.0, 129.6, 129.1, 128.2 128.2, 121.7, 115.0, 88.9, 83.2, 61.8,
23.3, 19.2.
[0298] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=220 nm),
[0299] t.sub.R (major)=11.9 min, t.sub.R (minor)=30.2 min; >99%
ee.
[0300] [.alpha.].sub.D.sup.25=-66.5 (c=0.8, CHCl.sub.3).
[0301] HRMS (EI) calcd for C.sub.18H.sub.18O.sub.4N.sub.2, m/z
326.1261. found 326.1262.
(3R,6R)-3-((S)-1-nitro-2-phenylethyl)-2-phenylmorpholine-6-carbaldehyde
33i
##STR00066##
[0303] Prepared according to the general procedure from 31e (1.5
mmol) and nitrosobenzene (0.5 mmol) to provide the title compound
as white solid (85 mg, 50% yield) after silica gel chromatography
(EtOAc/Hexane).
[0304] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.70 (s, 1H, CHO),
7.40-6.98 (m, 10H, ArH), 5.50-5.44 (m, 1H, CHNO.sub.2), 4.58-4.57
(m, 1H, CHCHO), 4.31 (m, 1H, CHN), 2.88-2.75 (m, 2H, CH.sub.2Ar),
2.23-2.20 (m, 2H, CH.sub.2CHCHO), 2.09-1.76 (m, 2H,
CH.sub.2CHN).
[0305] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 202.6, 148.6,
135.2, 129.5, 128.8, 128.5 127.5, 122.7, 114.4, 88.7, 83.2, 60.7,
38.5, 22.7, 19.2.
[0306] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=230 nm),
[0307] t.sub.R (major)=11.2 min, t.sub.R (minor)=35.2 min; >99%
ee.
[0308] [.alpha.].sub.D.sup.25=-51.8 (c=0.7, CHCl.sub.3).
[0309] HRMS (EI) calcd for C.sub.19H.sub.20O.sub.4N.sub.2, m/z
340.1418. found 340.1419.
(3R,6R)-2-(4-bromophenyl)-3-((S)-1-nitro-2-phenylethyl)morpholine-6-carbal-
dehyde 33j
##STR00067##
[0311] Prepared according to the general procedure from 31e (1.5
mmol) and 1-bromo-4-nitrosobenzene (0.5 mmol) to provide the title
compound as white solid (138 mg, 66% yield) after silica gel
chromatography (EtOAc/Hexane).
[0312] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.67 (s, 1H, CHO),
7.49-6.99 (m, 9H, ArH), 5.47-5.41 (m, 1H, CHNO.sub.2), 4.58-4.56
(m, 1H, CHCHO), 4.28-4.25 (m, 1H, CHN), 2.89-2.77 (m, 2H,
CH.sub.2Ar), 2.23-2.19 (m, 2H, CH.sub.2CHCHO), 2.11-1.78 (m, 2H,
CH.sub.2CHN).
[0313] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 202.0, 147.6,
134.9, 132.4, 128.9, 128.5 127.6, 116.0, 115.1, 88.5, 83.3, 60.4,
38.5, 22.4, 19.0.
[0314] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=254 nm),
[0315] t.sub.R (major)=12.4 min, t.sub.R (minor)=29.4 min; 99%
ee.
[0316] [.alpha.].sub.D.sup.25=-31.3 (c=0.7, CHCl.sub.3).
[0317] HRMS (EI) calcd for C.sub.19H.sub.19BrO.sub.4N.sub.2, m/z
418.0523. found 418.0521.
(3R,6R)-3-((S)-1-nitro-2-p-tolylethyl)-2-phenylmorpholine-6-carbaldehyde
33k
##STR00068##
[0319] Prepared according to the general procedure from 31f (1.5
mmol) and nitrosobenzene (0.5 mmol) to provide the title compound
as white solid (83 mg, 47% yield) after silica gel chromatography
(EtOAc/Hexane).
[0320] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.70 (s, 1H, CHO),
7.39-6.86 (m, 9H, ArH), 5.47-5.41 (m, 1H, CHNO.sub.2), 4.57 (m, 1H,
CHCHO), 4.58 (m, 1H, CHN), 2.84-2.70 (m, 2H, CH.sub.2Ar), 2.29 (s,
1H, CH.sub.3Ar), 2.21-2.10 (m, 2H, CH.sub.2CHCHO), 2.08-1.75 (m,
2H, CH.sub.2CHN).
[0321] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 202.6, 148.6,
137.1, 132.1, 129.5, 128.4, 122.7 114.6, 114.4, 88.8, 83.2, 60.6,
38.1, 22.6, 21.0, 19.2.
[0322] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=220 nm),
[0323] t.sub.R (major)=10.2 min, t.sub.R (minor)=30.7 min; >99%
ee.
[0324] [.alpha.].sub.D.sup.25=-19.3 (c=0.7, CHCl.sub.3).
[0325] HRMS (EI) calcd for C.sub.20H.sub.22O.sub.4N.sub.2, m/z
354.1574. found 354.1578.
(3R,6R)-2-(4-bromophenyl)-3-((S)-1-nitro-2-p-tolylethyl)morpholine-6-carba-
ldehyde 33l
##STR00069##
[0327] Prepared according to the general procedure from 31f (1.5
mmol) and 1-bromo-4-nitrosobenzene (0.5 mmol) to provide the title
compound as white solid (97 mg, 45% yield) after silica gel
chromatography (EtOAc/Hexane).
[0328] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.66 (s, 1H, CHO),
7.48-6.87 (m, 8H, ArH), 5.43-5.37 (m, 1H, CHNO.sub.2), 4.57-4.55
(m, 1H, CHCHO), 4.26-4.24 (m, 1H, CHN), 2.85-2.72 (m, 2H,
CH.sub.2Ar), 2.30 (s, 1H, CH.sub.3Ar), 2.21-2.19 (m, 2H,
CH.sub.2CHCHO), 2.10-1.78 (m, 2H, CH.sub.2CHN).
[0329] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 202.1, 147.6,
137.3, 132.4, 131.7, 129.5 128.4, 116.0, 115.1, 88.6, 83.3, 60.4,
38.1, 22.4, 21.1, 19.0.
[0330] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=254 nm),
[0331] t.sub.R (major)=10.1 min, t.sub.R (minor)=21.9 min; >99%
ee.
[0332] [.alpha.].sub.D.sup.25=-16.6 (c=0.6, CHCl.sub.3).
[0333] HRMS (EI) calcd for C.sub.20H.sub.21BrO.sub.4N.sub.2, m/z
432.0679. found 432.0681.
(3R,6R)-3-((S)-2-(4-chlorophenyl)-1-nitroethyl)-2-phenylmorpholine-6-carba-
ldehyde 33m
##STR00070##
[0335] Prepared according to the general procedure from 31g (1.5
mmol) and nitrosobenzene (0.5 mmol) to provide the title compound
as white solid (146 mg, 78% yield) after silica gel chromatography
(EtOAc/Hexane).
[0336] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.70 (s, 1H, CHO),
7.40-6.91 (m, 9H, ArH), 5.47-5.41 (m, 1H, CHNO.sub.2), 4.57 (m, 1H,
CHCHO), 4.31 (m, 1H, CHN), 2.85-2.68 (m, 2H, CH.sub.2Ar), 2.22-2.11
(m, 2H, CH.sub.2CHCHO), 2.09-1.75 (m, 2H, CH.sub.2CHN).
[0337] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 202.4, 148.5,
133.7, 133.4, 129.9, 129.5, 129.0 122.8, 114.3, 88.6, 83.2, 60.7,
37.8, 22.7, 19.1.
[0338] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=220 nm),
[0339] t.sub.R (major)=12.3 min, t.sub.R (minor)=48.2 min; >99%
ee.
[0340] [.alpha.].sub.D.sup.25=-43.2 (c=0.7, CHCl.sub.3).
[0341] HRMS (EI) calcd for C.sub.19H.sub.19ClO.sub.4N.sub.2, m/z
374.1028. found 374.1048; calcd for
C.sub.19H.sub.19.sup.37ClO.sub.4N.sub.2, m/z 376.0998. found
376.0990.
(3R,6R)-2-(4-bromophenyl)-3-((S)-2-(4-chlorophenyl)-1-nitroethyl)morpholin-
e-6-carbaldehyde 33n
##STR00071##
[0343] Prepared according to the general procedure from 31g (1.5
mmol) and 1-bromo-4-nitrosobenzene (0.5 mmol) to provide the title
compound as white solid (179 mg, 78% yield) after silica gel
chromatography (EtOAc/Hexane).
[0344] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.66 (s, 1H, CHO),
7.50-6.93 (m, 8H, ArH), 5.47-5.38 (m, 1H, CHNO.sub.2), 4.57 (m, 1H,
CHCHO), 4.28 (m, 1H, CHN), 2.86-2.71 (m, 2H, CH.sub.2Ar), 2.23-2.09
(m, 2H, CH.sub.2CHCHO), 2.07-1.75 (m, 2H, CH.sub.2CHN).
[0345] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 201.9, 147.5,
133.6, 133.3, 132.5, 129.9 129.1, 115.8, 115.2, 88.4, 83.3, 60.4,
37.8, 22.5, 18.9.
[0346] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=254 nm),
[0347] t.sub.R (major)=14.6 min, t.sub.R (minor)=34.2 min; >99%
ee.
[0348] [.alpha.].sub.D.sup.25=-17.5 (c=1.2, CHCl.sub.3).
[0349] HRMS (EI) calcd for C.sub.19H.sub.18BrClO.sub.4N.sub.2, m/z
452.0133. found 452.0136.
(3R,6R)-3-((S)-2-(4-bromophenyl)-1-nitroethyl)-2-Phenylmorpholine-6-carbal-
dehyde 33o
##STR00072##
[0351] Prepared according to the general procedure from 31h (1.5
mmol) and nitrosobenzene (0.5 mmol) to provide the title compound
as white solid (157 mg, 75% yield) after silica gel chromatography
(EtOAc/Hexane).
[0352] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.68 (s, 1H, CHO),
7.39-6.82 (m, 9H, ArH), 5.45-5.37 (m, 1H, CHNO.sub.2), 4.55-4.54
(m, 1H, CHCHO), 4.28-4.26 (m, 1H, CHN), 2.83-2.63 (m, 2H,
CH.sub.2Ar), 2.21-2.15 (m, 2H, CH.sub.2CHCHO), 2.11-1.71 (m, 2H,
CH.sub.2CHN).
[0353] .sup.13C NMR (75 MHz, CDCl.sub.3): .delta. 202.4, 148.5,
134.2, 131.9, 130.2, 129.5, 122.8, 121.7, 114.3, 88.5, 83.2, 60.7,
37.8, 22.7, 19.1.
[0354] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=220 nm),
[0355] t.sub.R (major)=13.3 min, t.sub.R (minor)=49.1 min; >99%
ee.
[0356] [.alpha.].sub.D.sup.25=-26.7 (c=1.2, CHCl.sub.3).
[0357] HRMS (EI) calcd for C.sub.19H.sub.19BrO.sub.4N.sub.2, m/z
418.0523. found 418.0530.
(3R,6R)-2-(4-bromophenyl)-3-((S)-2-(4-bromophenyl)-1-nitroethyl)morpholine-
-6-carbaldehyde 33p
##STR00073##
[0359] Prepared according to the general procedure from 31h (1.5
mmol) and 1-bromo-4-nitrosobenzene (0.5 mmol) to provide the title
compound as white solid (34.8 mg, 70% yield) after silica gel
chromatography (EtOAc/Hexane).
[0360] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.66 (s, 1H, CHO),
7.50-6.87 (m, 8H, ArH), 5.44-5.38 (m, 1H, CHNO.sub.2), 4.57 (m, 1H,
CHCHO), 4.27 (m, 1H, CHN), 2.84-2.69 (m, 2H, CH.sub.2Ar), 2.22-2.18
(m, 2H, CH.sub.2CHCHO), 2.11-1.75 (m, 2H, CH.sub.2CHN).
[0361] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 201.9, 147.5,
133.8, 132.5, 132.0, 130.2, 121.7, 116.2, 115.8, 88.3, 83.3, 60.4,
37.9, 22.5, 18.9.
[0362] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=220 nm), t.sub.R (major)=15.1 min, t.sub.R
(minor)=32.7 min; 99% ee.
[0363] [.alpha.].sub.D.sup.25=-24.1 (c=1.3, CHCl.sub.3).
[0364] HRMS (EI) calcd for C.sub.19H.sub.18Br.sub.2O.sub.4N.sub.2,
m/z 495.9637. found 495.9641.
(3R,6R)-3-(nitromethyl)-2-p-tolylmorpholine-6-carbaldehyde 33q
##STR00074##
[0366] Prepared according to the general procedure from 31a (1.5
mmol) and 4-nitrosotoluene (0.5 mmol) to provide the title compound
as white solid (119 mg, 90% yield) after silica gel chromatography
(EtOAc/Hexane).
[0367] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.77 (d, J=1.0 Hz,
1H, CHO), 7.20-7.06 (m, 4H, ArH), 4.85-4.81 (m, 1H, CHNO.sub.2),
4.54-4.50 (m, 2H, CHNO.sub.2+CHCHO), 4.40-4.38 (m, 1H, CHN), 2.35
(s, 3H, ArCH.sub.3), 2.33-2.11 (m, 2H, CH.sub.2CHCHO), 2.10-1.85
(m, 2H, CH.sub.2CHN).
[0368] .sup.13C NMR (125 MHz, CDCl.sub.3): .delta. 202.6, 145.0,
133.5, 129.9, 116.0, 82.4, 71.9, 58.0, 22.0, 20.7, 18.6.
[0369] HPLC: Chiralpak AS-H (hexane/i-PrOH, 85/15, flow rate 1
mL/min, .lamda.=230 nm),
[0370] t.sub.R (major)=13.4 min, t.sub.R (minor)=33.8 min; >99%
ee.
[0371] [.alpha.].sub.D.sup.25=-227.5 (c=0.9, CHCl.sub.3).
[0372] HRMS (EI) calcd for C.sub.13H.sub.16O.sub.4N.sub.2, m/z
264.1105. found 264.1099.
Survey the Catalysis in the Michael Addition Step
##STR00075##
TABLE-US-00006 [0373] entry cat. (mol % ) temperature time %
yield.sup.b 1 none r.t. 48 h n. r. 2 none -20.degree. C. 96 h n. r.
3 TEA (100) r.t. 48 h 31 4 Quinine (20) r.t. 12 h 95 .sup.a Unless
otherwise noted, reactions were conducted with 1.0 equiv of 47
(1M), 1.0 equiv of 48 in CH.sub.3CN. .sup.bIsolated yield.
[0374] A control experiment was designed to investigate the second
Michael addition step by using 47 and 48 as mimics of the in situ
generated amine moiety and nitroalkene part respectively. Without
catalyst, the reaction did not proceed even after 2 days (entry 1);
for the case at -20.degree. C., similar result was obtained (entry
2). In the presence of 1 equiv of TEA as general base, the reaction
gave 31% of Michael product after 48 h (entry 3), which revealed
that tertiary amine itself was not efficient to enhance the
reactivity of this transformation. When we changed to a catalyst
with H bond donating ability such as Quinine, the reaction went on
smoothly, providing 49 in excellent yield (entry 8). These
observations implied that the second Michael addition step may be
promoted through H-bonding catalysis. Combined with the fact that
no intermediates can be detected by NMR experiments of reaction
mixture or isolated, we propose a concerted mechanism for this
tandem reaction: After the first aminoxylation step, which is known
to proceed with high enantio-selectivity; clearly this selectivity
is kept in the second step via a sterically favorable transition
state (vide infra), and the final protonation was actually
conducted in a concerted route assisted by a molecule of water
through double H-bonding with in situ generated amine and the nitro
group (cf. FIG. 12B). The proposed transition state is confirmed by
DFT calculations (vide infra).
Computational Details.
[0375] DFT calculations were carried out with the Gaussian 03
package.sup.5. The transition structures are fully optimized by
B3LYP.sup.6 method using 6-31G(d) basis set and have been confirmed
to be a saddle point by the harmonic frequencies calculations at
the same level of theory. Transition state geometries are also
optimized in CH.sub.3CN solution with PCM model (Cossi, M, et al.,
J. Chem. Phys. (2002) 117, 43-54) in Gaussian 03.
[0376] The calculated lowest energy transition state in gas phase
and CH.sub.3CN solution are shown in FIG. 19A and FIG. 19B
respectively.
Example 3
Formation of Functionalized Tetrahydro-1,2-oxazines Via
.alpha.-Aminoxylation of Aldehydes and Aza-Michael Reaction Using
Aldehydes with an .alpha.,.beta.-unsaturated 1,3-dicarboxyl
Moiety
[0377] Investigations were started using the previously established
conditions: nitrosobenzene (0.1 mmol, 1.0 equiv) and dimethyl
2-(5-oxopentylidene)malonate (0.12 mmol, 1.2 equiv) were added to
20 mol % L-proline in 1.0 mL of DMSO. The organocatalytic tandem
aminoxylation/aza-Michael reaction was facile at room temperature
and can be accomplished within 30 min. The reaction progress can be
easily monitored by observation of its color change from green to
orange. After workup, the desired cyclic product was isolated in
37% yield with excellent enantioselectivity (98% ee) and
diastereoselectivity (>99:1 dr) (FIG. 13, entry 1). Furthermore,
various catalysts and solvents were surveyed and summarized in FIG.
13. The reaction proceeded smoothly in the presence of pyrrolidinyl
tetrazole IXb or thiazolidine-4-carboxylic acid IXd to afford the
cycloadduct in a slightly lower yield and without any loss in the
ee and dr values (FIG. 13, entries 2 and 3). Unfortunately,
Jorgenson's catalyst IV cannot be employed in this reaction to
afford the corresponding .alpha.-aminoxylation/aza-Michael product.
L-Proline was chosen as the catalyst not only because it is
abundant and cheap, but more importantly because of its efficiency
among all the other investigated catalysts. The screening of
various solvents revealed that CH.sub.3CN is the best solvent as it
gave the highest yield (52%) and without any loss of enantio- or
diastereoselectivities (FIG. 13, entry 5). Halogenated solvent
CHCl.sub.3 (Table 1, entry 6) and highly polar and protophilic
solvents, such as DMF and NMP (FIG. 13, entries 7 and 8), gave
relatively lower yields (41-46%) whereas a less polar ethereal
solvent, such as THF (FIG. 13, entry 9), and the most polar solvent
water showed a deleterious effect on reactivity even after addition
of tetraethyl ammonium bromide as PTC and stirring for 24 h (FIG.
13, entry 11).
[0378] Having established the choice of catalyst, the reaction
temperatures were screened. It was observed that when the reaction
temperature decreased from room temperature to -20.degree. C. (FIG.
14, entries 1-3), the suppression of both side reaction and
homodimer formation led to an increase in yield (from 52% to 65%)
and without any loss in the ee and dr values. Increasing the
equivalence of aldehyde to nitrosobenzene from 1.2 to 3 equiv
increased the yield from 65% to 79% and at the same time decreased
the reaction time from 24 h to 13 h. (FIG. 14, entries 3-6).
Lastly, when the catalyst loadings were decreased from 20 to 5 mol
%, the highest yield was found when 10 mol % of L-proline was used
(FIG. 14, entries 6-8). In terms of operational convenience, 10 mol
% of L-proline ensured high levels of reaction efficiency and
enantioselectivity and was thus used in the next reaction. It is
also noteworthy that after in situ reduction, the dr of
corresponding alcohol product dropped significantly to 1:1 (FIG.
14, entry 9).
[0379] We further explored the generality of the reaction. The
optimized reaction condition was applicable for reactions of
various aromatic nitroso compounds 2a-h and some
2-(5-oxopentylidene) malonate derivatives 21a-g, to give moderate
to good yields (52-84%) in excellent ee values (92-99%) and dr
values (>99:1). The 2-methyl substituent in nitrosotoluene
introduced more steric hindrance in the Michael addition step and
this may account for the decrease in ee values (from 98% to 94% ee)
when compared to the other nitrosobenzene derivatives. We observed
that the substitutents in malonate also affected the yield of the
Michael adducts. Isopropyl substituent, being more sterically
hindered than propyl groups, generally gave low yields when
compared with that of propyl substituents (FIG. 16, entries 10-11,
16-17, and 20-21). The reason why dipentyl 2-(5-oxopentylidene)
malonate gave the worst result remains unknown (FIG. 16, entry
13).
[0380] To determine the stereochemistry of the tandem
aminoxylation/aza-Michael reaction, a (2,4-dinitrophenyl) hydrazine
derivative 50i of the aldehyde product 23i was synthesized (FIG.
15). The relative configuration of the (2,4-dinitrophenyl)
hydrazone 50i was then determined by X-ray crystallography (FIG.
17). The R configuration of the chiral center created by the
Michael addition was established by comparing it with the
sterogenic center generated by the aminoxylation step based on the
relative configuration of 4i and the known chemistry7 of the
aminoxylation.
[0381] In summary, the first highly diastereo and enantioselective
approach for the synthesis of these functionalized
tetrahydro-1,2-oxazines via an organocatalyzed asymmetric tandem
aminoxylation/aza-Michael reaction is presented. Further
applications of this functionalized THOs to other synthetically
useful transformations are underway.
General Experimental Information
[0382] Unless otherwise stated, all reagents were purchased from
commercial suppliers and used without further purification. All
solvents employed in the reactions were used directly without
further purification. Organic solutions were concentrated under
reduced pressure on Heidolph rotary evaporator. Reactions were
monitored by thin-layer chromatography (TLC) on silica gel
precoated glass plates (0.25 mm thickness, 60E-254, E. Merck).
Chromatograms were visualized by fluorescence quenching with UV
light at 254 nm or by staining using 2,4-dinitrophenyl hydrazine
(2,4-DNP) stains. Further visualization was possible by staining
with base solution of potassium permanganate. Flash column
chromatography was performed using silica gel 60 (particle size
0.040-0.063 mm) from Merck. Racemic products were catalyzed by
D,L-Proline.
[0383] IR spectra were recorded using FTIR Restige-21 (Shimadzu)
with neat oil samples.
[0384] High Resolution Mass (HRMS) spectra were obtained using
Finnigan MAT95XP GC/HRMS (Thermo Electron Corporation) for EI+;
QTOF perimer for ESI.sup.+ and ESL
[0385] Proton nuclear magnetic resonance spectra (.sup.1H NMR)
were. recorded on a Bruker Avance DPX300, Bruker AMX400 and AMX500
spectrophotometer (CDCl.sub.3 as solvent). Chemical shifts for
.sup.1H NMR spectra are reported as .delta. in units of parts per
million (ppm) downfield from SiMe.sub.4 (.delta. 0.0) and relative
to the signal of chloroform-d (.delta. 7.26, s). Multiplicities
were given as: s (singlet); d (doublet); t (triplet); q (quartet);
dd (doublets of doublet); dt (doublets of triplet); or m
(multiplets). The number of protons (n) for a given resonance is
indicated by nH. Coupling constants are reported as a J value in
Hz. Carbon nuclear magnetic resonance spectra (.sup.13C NMR) are
reported as .delta. in units of parts per million (ppm) downfield
from SiMe.sub.4 (.delta. 0.0) and relative to the signal of
chloroform-d (.delta. 77.0, t).
[0386] Enantioselectivities were determined by High performance
liquid chromatography (HPLC) analysis employing a Daicel Chiracel
OD-H or AS-H column at 25.degree. C. (in comparison with racemic
products). Optical rotations were measured in CHCl.sub.3 on a
Schmidt+Haensch polarimeter with a 1 cm cell (c given in g/l
mL).
[0387] Absolute configurations of the products were determined by
X-Ray crystallography together with comparison of NMR data.
General Procedure for the Preparation of Substrates
##STR00076##
[0388] 5,5-Dimethoxypentanal (Aggarwal, V. K.; Roseblade, S. J.;
Barrell, J. K.; Alexander, R. Org. Lett. (2002) 4, 1227-1229)
[0389] A 500 mL, three-necked, round-bottomed flask was fitted with
a glass frit to admit ozone, and a magnetic stirrer bar and was
charged with cyclopentene (6.8 g, 100 mmol), anhydrous
dichloromethane (250 mL) and anhydrous methanol (50 mL). The flask
was cooled to -78.degree. C. and ozone was bubbled through the
solution with stirring until a blue colour remained. Nitrogen was
passed through the solution until the blue colour was discharged
and then the cold bath was removed. The drying tube and ozone inlet
were replaced with a glass stopper and a rubber septum and PTsOH
monohydrate (1.47 g, 7.70 mmol, 10% w/w) was added. The solution
was allowed to warm to room temperature as it stirred under
nitrogen for 90 minutes.
[0390] Anhydrous sodium hydrogencarbonate (2.59 g, 30.8 mmol) was
added to the flask and the mixture was stirred for 15 minutes after
which time dimethyl sulfide (16 mL, 200 mmol) was added. After
stirring for 16 hours the heterogeneous mixture was concentrated in
vacuo. Dichloromethane (100 mL) was added and the mixture was
washed with water (75 mL). The aqueous layer was extracted with
dichloromethane (3.times.100 mL) and the combined organic layers
were dried (MgSO.sub.4), filtered and concentrated in vacuo. Column
chromatography (EtOAc/Hexane=15:85) on silica gel gave aldehyde as
a colorless oil (7.0 g, 48%). (.sup.1H NMR [300 MHz, CDCl.sub.3]
1.57-1.79 (4H, m), 2.44-2.52 (2H, m), 3.32 (6H, s,
2.times.OCH.sub.3), 4.37 (1H, t, J=5.6 Hz, CH(OMe).sub.2), 9.77
(1H, t, J=1.3 Hz, CHO).
General Procedure of the Knoevenagel Reaction (Tietze, L. F.;
Beifuss, U. Angew. Chem. Int. Ed. (1985) 97, 1067-1068)
[0391] To a stirred solution of 5,5-dimethoxypentanal (1.46 g, 10
mmol) and dimethyl malonate (1.45 g, 11 mmol) in anhydrous
methylene chloride (5 mL) were added piperidine (85 mg, 1 mmol) and
acetic acid (60 mg, 1 mol) at 0.degree. C., the mixture was stirred
at room temperature for 45 min, TLC monitored, after the completely
consumption of Aldehyde, the reaction mixture was evaporated in
vacuo, diluted with ether 50 mL, and washed twice with water (20
mL.times.2), the aqueous phases were extracted with ether (10
mL.times.3), the organic phases were successively washed with
saturated sodium bicarbonate solution (10 mL), water (10 mL), brine
(10 mL), and dried over anhydrous Na.sub.2SO.sub.4. After removed
the solvent, the crude product was purified on silica gel column or
directly used in next step. Obtained 1.0 g colorless oil, yield
42%.
General Procedure of Deprotection (Zhou, Gang; Hu, Qi-Ying; Corey,
E. J. Org. Lett. (2003) 5, 3979-3982)
[0392] To a solution of dimethyl
2-(5,5-dimethoxypentylidene)malonate (1.0 g, 3.84 mmol) in THF (20
mL) was added 2N HCl (4 mL). After stirring for 8 h at r.t., the
mixture was extracted with Et.sub.2O (3.times.50 mL). The organic
phase was combined, washed with aq. NaHCO.sub.3 solution
(3.times.10 mL), brine (2.times.10 mL), and dried (MgSO.sub.4). The
solvent was removed in vacuo, Column chromatography
(EtOAc:Hexane=10:90) on silica gel gave to give 0.7 g (83%) of
aldehyde as a colorless oil.
##STR00077##
[0393] Colorless oil, yield 36% (two step) after silica gel
chromatography (EtOAc/Hexane=15:85).
[0394] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 9.78 (t, J=1.2
Hz, 1H), 7.00 (t, J=8.0 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 2.53
(m, 2H), 2.36 (q, J=7.8 Hz, 2H), 1.86 (m, 2H)
[0395] .sup.13C NMR (75 MHz, CDCl.sub.3): .delta. 201.4, 165.7,
164.2, 148.7, 128.9, 52.4, 52.4, 42.7, 28.9, 20.5
[0396] HRMS (ESI+) calcd for C.sub.10H.sub.15O.sub.5.sup.+3,
[M+H].sup.+215.0919. found 215.0917.
##STR00078##
[0397] Colorless oil, yield 43% (two step) after silica gel
chromatography (EtOAc/Hexane=15:85).
[0398] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.79 (s, 1H),
6.95 (t, J=8.0 Hz, 1H), 4.22-4.35 (m, 4H), 2.49-2.54 (m, 2H), 2.37
(q, J=7.3 Hz, 2H), 1.85 (t, J=7.3 Hz, 2H), 1.29-1.76 (m, 6H)
[0399] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 201.4, 165.3,
163.8, 147.6, 129.7, 61.4, 42.8, 28.8, 20.5, 14.1, 14.1
[0400] HRMS (ESI+) calcd for C.sub.12H.sub.19O.sub.5.sup.+,
[M+H].sup.+243.1232. found 243.1229.
##STR00079##
[0401] Colorless oil, yield 42% (two step) after silica gel
chromatography (EtOAc/Hexane=15:85).
[0402] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.67 (t, J=2.4
Hz, 1H), 6.84 (t, J=8.0 Hz, 1H), 4.09 (t, J=6.6 Hz, 2H), 4.04 (t,
J=6.6 Hz, 2H), 2.41 (dt, J.sub.1=1.2 Hz, J.sub.2=14.7 Hz, 2H), 2.25
(q, J=7.5 Hz, 2H), 1.53-1.78 (m, 6H), 0.86 (q, J=7.5 Hz, 6H)
[0403] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 201.2, 165.3,
163.7, 147.4, 129.6, 66.8, 66.7, 42.7, 28.7, 21.8, 21.8, 20.4,
10.3, 10.2
[0404] HRMS (ESI+) calcd for C.sub.14H.sub.23O.sub.5.sup.+,
[M+H].sup.+271.1545. found 271.1547.
##STR00080##
[0405] Colorless oil, yield 41% (two step) after silica gel
chromatography (EtOAc/Hexane=15:85).
[0406] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.73 (s, 1H),
6.83 (t, J=15.9 Hz, 1H), 5.00-5.15 (m, 2H), 2.43-2.48 (m, 2H),
2.25-2.33 (m, 2H), 1.76-1.81 (m, 2H), 1.23 (d, J=7.2 Hz, 6H), 1.26
(d, J=7.2 Hz, 6H)
[0407] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 201.3, 164.9,
163.3, 146.5, 130.4, 68.9, 68.9, 42.8, 28.6, 21.7 (2C), 20.5
(2C)
[0408] HRMS (ESI+) calcd for C.sub.14H.sub.23O.sub.5.sup.+,
[M+H].sup.+271.1545. found 271.1550.
##STR00081##
[0409] Colorless oil, yield 45% (two step) after silica gel
chromatography (EtOAc/Hexane=15:85).
[0410] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.75 (t, J=2.4
Hz, 1H), 6.90 (t, J=15.9 Hz, 1H), 4.15-4.23 (m, 4H), 2.45-2.50 (m,
2H), 2.31 (q, J=7.5 Hz, 2H), 1.81-1.86 (m, 2H), 1.59-1.67 (m, 4H),
1.31-1.49 (m, 4H), 0.86 (q, J=7.5 Hz, 6H)
[0411] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 201.3, 165.4,
163.8, 147.5, 129.7, 65.2, 42.8, 30.5, 30.5, 28.8, 20.5, 19.0,
13.6, 13.6
[0412] HRMS (ESI+) calcd for C.sub.16H.sub.27O.sub.5.sup.+,
[M+H].sup.+299.1858. found 299.1857.
##STR00082##
[0413] Colorless oil, yield 47% (two step) after silica gel
chromatography (EtOAc/Hexane=15:85).
[0414] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 9.66 (s, 1H),
6.83 (t, J=8.0 Hz, 1H), 4.11 (t, J=6.6 Hz, 2H), 2.40 (t, J=7.1 Hz,
2H), 2.24 (q, J=7.1 Hz, 2H), 1.76 (m, 2H), 1.54-1.60 (m, 4H),
1.23-1.26 (m, 8H), 0.80-0.81 (m, 6H)
[0415] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. 201.2, 165.4,
163.7, 147.4, 129.7, 65.4, 65.4, 42.7, 28.7, 28.1, 28.1, 27.9,
27.9, 22.2, 20.4, 13.8
[0416] HRMS (ESI+) calcd for C.sub.18H.sub.31O.sub.5.sup.+,
[M+H].sup.+327.2171. found 327.2168.
##STR00083##
[0417] Colorless oil, yield 48% (two step) after silica gel
chromatography (EtOAc/Hexane=15:85).
[0418] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 9.65 (s, 1H),
6.82 (t, J=8.0 Hz, 1H), 4.10 (t, J=6.6 Hz, 2H), 4.06 (t, J=6.6 Hz,
2H), 2.39 (t, J=7.4 Hz, 2H), 2.23 (q, J=7.4 Hz, 2H), 1.72 (m, 2H),
1.51-1.61 (m, 4H), 1.13-1.28 (m, 12H), 0.76-0.79 (m, 6H)
[0419] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. 201.2, 165.3,
163.7, 147.4, 129.7, 65.4, 65.3, 42.7, 31.3, 28.7, 28.4, 28.4,
25.5, 25.4, 22.4, 22.4, 20.4, 13.9
[0420] HRMS (ESI+) calcd for C.sub.20H.sub.35O.sub.5.sup.+,
[M+H].sup.+355.2484. found 355.2485.
General Procedure for Synthesis of Nitrosobenzene Derivatives
(Defoin, A., Synthesis (2004)
##STR00084##
[0421] R'=3-Me, 4-Me, 3-Cl, 4-Cl, 4-Br, 4-OPh
[0422] To a stirred solution of aniline (10 mmol) in MeOH (3 mL)
were added H.sub.2O.sub.2 (5.5 mL, 40 mmol, 4 equiv) and H.sub.2O
(4.5 mL). Aniline precipitated as fine crystals and then MoO.sub.3
(144 mg, 1 mmol) and aqueous KOH solution (1 mL, 1 mmol) were added
and the solution stirred at 0.degree. C. The solution became brown
and then yellow with formation of a precipitate, pH value 3-3.5.
The reaction was monitored by .sup.1H NMR in CDCl.sub.3. After the
reaction finished, H.sub.2O (15 mL) was added and extracted with
DCM 50 mL.times.3, dried with anhydrous MgSO.sub.4, concentrated
and purified by column chromatography (EtOAc/Hexane=5:95) on silica
gel to give the nirosobenzene derivatives as a yellow solid.
##STR00085##
[0423] Prepared according to the general procedures as a yellow
solid, yield 67% after silica gel chromatography.
[0424] .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta.7.78 (d, J=6.5 Hz,
1H), 7.64 (s, 1H), 7.49-7.54 (m, 2H), 2.51 (s, 3H)
[0425] .sup.13C-NMR (125 MHz, CDCl.sub.3): .delta. 166.3, 139.5,
136.3, 129.1, 120.9, 119.1, 21.2
[0426] HRMS (EI+) calcd for C.sub.7H.sub.7NO, [M].sup.+ 121.0522.
found 121.0524.
##STR00086##
[0427] Prepared according to the general procedures as a yellow
solid, yield 61% after silica gel chromatography.
[0428] .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta. 8.06 (dt,
J.sub.1=1.4 Hz, J.sub.2=7.8 Hz, 1H), 7.69 (m, 1H), 7.61-7.64 (m,
2H)
[0429] .sup.13C-NMR (125 MHz, CDCl.sub.3): .delta. 165.1, 136.0,
135.0, 130.8, 121.5, 118.7
[0430] HRMS (EI+) calcd for C.sub.6H.sub.4ClNO, [M].sup.+ 140.9976.
found 140.9974.
[0431] The .sup.1H-NMR of 4-Me, 4-Cl, 4-Br nitosobenzenes are
consistent with literature (Defoin, 2004, supra) reported.
[0432] The .sup.1H-NMR of 4-OPh nitrosobenzene is consistent with
literature (Momiyama, N, et al., J. Am. Chem. Soc. (2007) 129,
1190-1195) reported.
General Procedure for the Tandem Aminoxylation-Michael Addition
reaction
[0433] In a 5 mL vial equipped with stirring bar, dimethyl
2-(5-oxopentylidene)malonate (63 mg, 0.3 mmol) was dissolved in 1
mL of CH.sub.3CN. The mixture was then cooled to -78.degree. C. for
5 min, L-Proline (1.2 mg, 0.01 mmol) and nitrosobenzene (10.7 mg,
0.1 mmol) was added in one portion. The resulted mixture was then
stirred at -20.degree. C. and monitored by TLC, after complete
consumption of the nitrosobenzene, the solvent was removed under
vacuum, 5 mL of H.sub.2O was added, and extracted with ethyl
acetate 10 mL three times. The combined organic layers were washed
with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated
under vacuum after filtration. Purification by flash column
chromatography (silica gel, Hexane/EtOAc) afforded the product 26
mg (84%). The ee value was measured by HPLC on a chiral phase HPLC:
Chiral-AS-H column, .lamda.=254 nm, i-PrOH/hexane=5:95, flow
rate=1.0 mL/min, t.sub.1=12.99 min (major), t.sub.2=13.72 min
(minor), 98% ee.
##STR00087##
[0434] Prepared according to the general procedure, got a colorless
oil, 27 mg, yield 84% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85).
[0435] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.68 (d, J=1.2
Hz, 1H), 7.25-7.31 (m, 2H), 7.09-7.12 (m, 2H), 6.98 (t, J=7.5 Hz,
2H), 4.49-4.60 (m, 2H), 4.28 (d, J=9.0 Hz, 1H), 3.66 (s, 3H), 3.10
(s, 3H), 2.02-2.18 (m, 3H), 1.78-1.80 (m, 1H)
[0436] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 203.1, 168.2,
167.5, 147.6, 128.6 (2C), 122.7, 116.0 (2C), 82.9, 59.1, 52.8,
52.2, 49.4, 23.8, 19.2
[0437] HRMS (ESI-) calcd for C.sub.16H.sub.18NO.sub.6.sup.-,
[M-H].sup.- 320.1134. found 320.1133.
[0438] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AS-H column (Hexane/1-propanol=95:5, 1
mL/min): t.sub.1=12.99 min (major), t.sub.2=13.72 min (minor).
[0439] (>98% ee) [.alpha.].sup.25.sub.D: -6.17 (c=0.51,
CHCl.sub.3).
##STR00088##
[0440] Prepared according to the general procedure, got a colorless
oil, 23 mg, yield 70% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85)
[0441] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.75 (s, 1H),
7.35 (d, J=7.8 Hz, 1H), 7.14-7.19 (t, J=6.6 Hz, 2H), 7.03-7.08 (m,
1H), 4.46-4.47 (m, 1H), 4.34-4.37 (m, 1H), 4.23-4.27 (m, 1H), 3.73
(s, 3H), 3.22 (s, 3H), 2.25 (s, 3H), 2.03-2.20 (m, 3H), 1.69-1.70
(m, 1H)
[0442] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 203.1, 168.3,
167.5, 146.3, 130.74 (2C), 125.9, 125.3, 119.6, 83.0, 58.3, 52.8,
52.3, 49.5, 23.6, 19.4, 17.6
[0443] HRMS (ESI-) calcd for C.sub.17H.sub.20NO.sub.6.sup.-,
[M-H].sup.- 334.1291. found 334.1291.
[0444] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AS-H column (Hexane/1-propanol=99:1,
1.0 mL/min): t.sub.1=17.02 min (minor), t.sub.2=19.42 min (major).
(94% ee)
[0445] [.alpha.].sup.25.sub.D: -10.57 (c=0.71, CHCl.sub.3)
##STR00089##
[0446] Prepared according to the general procedure, got a colorless
oil, 21 mg, yield 63% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85).
[0447] .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta. 9.69 (s, 1H),
7.18 (t, J=8.1 Hz, 1H), 6.93 (t, J=8.1 Hz, 2H), 6.81 (d, J=8.1 Hz,
1H), 4.56 (d, J=8.5 Hz, 2H), 4.51 (d, J=3.2 Hz, 1H), 4.28 (d, J=8.5
Hz, 1H), 3.77 (s, 3H), 3.14 (s, 3H), 2.35 (s, 3H), 2.04-2.15 (m,
3H), 1.78-1.80 (m, 1H)
[0448] .sup.13C-NMR (125 MHz, CDCl.sub.3): .delta. 203.2, 168.3,
167.5, 147.7, 138.4, 128.5, 123.5, 116.7, 113.3, 82.9, 59.1, 52.8,
52.1, 49.4, 23.8, 21.6, 19.3
[0449] HRMS (ESI-) calcd for C.sub.17H.sub.20NO.sub.6.sup.-,
[M-H].sup.- 334.1291. found 334.1295.
[0450] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AD-H column (Hexane/1-propanol=95:5,
1.0 mL/min): t.sub.1=14.90 min (minor), t.sub.2=18.17 min (major).
(98% ee)
[0451] [.alpha.].sup.25.sub.D: -59.13 (c=1.2, CHCl.sub.3)
##STR00090##
[0452] Prepared according to the general procedure, got a colorless
oil, 24 mg yield 73% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85).
[0453] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 9.64 (d, J=1.0
Hz, 1H), 7.07 (d, J=8.6 Hz, 2H), 6.98 (d, J=8.6 Hz, 2H), 4.45-4.48
(m, 2H), 4.22 (d, J=9.3 Hz, 1H), 3.73 (s, 3H), 3.12 (s, 3H), 2.26
(s, 3H), 2.00-2.09 (m, 3H), 1.74-1.78 (m, 1H)
[0454] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. 203.2, 168.3,
167.6, 145.3, 132.4, 129.1 (2C), 116.6 (2C), 82.9, 59.5, 52.8,
52.2, 49.5, 23.8, 20.6, 19.4
[0455] HRMS (ESI-) calcd for C.sub.17H.sub.20NO.sub.6.sup.-,
[M-H].sup.- 334.1291. found 334.1292.
[0456] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AS-H column (Hexane/1-propanol=95:5,
1.0 mL/min): t.sub.1=12.81 min (major), t.sub.2=17.86 min (minor).
(99% ee)
[0457] [.alpha.].sup.25.sub.D: -53.67 (c=1.2, CHCl.sub.3)
##STR00091##
[0458] Prepared according to the general procedure, got a colorless
oil, 23 mg, yield 65% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85).
[0459] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 9.65 (s, 1H),
7.16-7.21 (m, 2H), 6.92 (t, J=8.4 Hz, 2H), 4.55 (d, J=9.2 Hz, 2H),
4.50 (d, J=4 Hz, 1H), 4.26 (d, J=9.2 Hz, 1H), 3.75 (s, 3H), 3.18
(s, 3H), 2.05-2.15 (m, 3H), 1.77-1.79 (m, 1H)
[0460] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. 202.7, 168.0,
167.3, 148.8, 134.6, 129.6, 122.4, 115.8, 114.0, 83.1, 58.9, 52.9,
52.3, 49.3, 23.66, 19.0
[0461] HRMS (ESI-) calcd for C.sub.16H.sub.17ClNO.sub.6.sup.-,
[M-H].sup.- 354.0776. found 354.0772.
[0462] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AD-H column (Hexane/1-propanol=95:5,
1.0 mL/min): t.sub.1=17.73 min (minor), t.sub.2=27.99 min (major).
(98% ee)
[0463] [.alpha.].sup.25.sub.D: -11.79 (c=1.0, CHCl.sub.3)
##STR00092##
[0464] Prepared according to the general procedure, got a colorless
oil, 22 mg, yield 62% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85)
[0465] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 9.63 (s, 1H),
7.23 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 4.48-4.53 (m, 2H),
4.24 (d, J=9.2 Hz, 1H), 3.74 (s, 3H), 3.16 (s, 3H), 2.01-2.13 (m,
3H), 1.75-1.79 (m, 1H)
[0466] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. 202.8, 168.0,
167.4, 146.2, 128.6 (2C), 127.7, 117.4 (2C), 83.0, 59.1, 52.9,
52.3, 49.4, 23.7, 19.1
[0467] HRMS (ESI-) calcd for C.sub.16H.sub.17ClNO.sub.6.sup.-,
[M-H].sup.- 354.0776. found 354.0772.
[0468] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AS-H column (Hexane/1-propanol=95:5,
1.0 mL/min): t.sub.1=17.90 min (major), t.sub.2=26.08 min (minor).
(99% ee)
[0469] [.alpha.].sup.25.sub.D: -34.46 (c=1.1, CHCl.sub.3)
##STR00093##
[0470] Prepared according to the general procedure, got a colorless
oil, 29 mg, yield 72% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85).
[0471] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.65 (s, 1H),
7.40 (d, J=9.0 Hz, 2H), 7.01 (d, J=9.0 Hz, 2H), 4.50-4.56 (m, 2H),
4.26 (d, J=9.0 Hz, 1H), 3.73 (s, 3H), 3.18 (s, 3H), 2.05-2.16 (m,
3H), 1.70-1.80 (m, 1H)
[0472] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 202.7, 168.0,
167.4, 146.7, 131.5 (2C), 117.6 (2C), 115.2, 83.0, 59.0, 52.9,
52.3, 49.4, 23.7, 19.0
[0473] HRMS (ESI-) calcd for C.sub.16H.sub.17BrNO.sub.6.sup.-,
[M-H].sup.- 398.0239. found 398.0234.
[0474] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AS-H column (Hexane/1-propanol=95:5,
1.0 mL/min): t.sub.1=17.28 min (major), t.sub.2=19.42 min (minor).
(>99% ee)
[0475] [.alpha.].sup.25.sub.D: -26.52 (c=1.2, CHCl.sub.3).
##STR00094##
[0476] Prepared according to the general procedure, got a colorless
oil, 21 mg, yield 52% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85)
[0477] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 9.69 (s, 1H),
7.31 (t, J=8.0 Hz, 2H), 7.07-7.09 (m, 3H), 6.94-6.97 (m, 4H),
4.44-4.48 (m, 2H), 4.23 (d, J=9.2 Hz, 1H), 3.75 (s, 3H), 3.27 (s,
3H), 2.01-2.14 (m, 3H), 1.76-1.79 (m, 1H)
[0478] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. 202.9, 168.1,
167.5, 157.8, 152.5, 143.6, 129.7 (2C), 123.0 (2C), 119.5 (2C),
118.4, 118.2 (2C), 83.0, 60.0, 52.8, 52.4, 49.5, 23.9, 19.4
[0479] HRMS (ESI-) calcd for C.sub.22H.sub.22NO.sub.7.sup.-,
[M-H].sup.- 412.1396. found 412.1401.
[0480] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AS-H column (Hexane/1-propanol=95:5,
1.0 mL/min): t=22.85 min (major). (99% ee)
[0481] [.alpha.].sup.25.sub.D: -14.17 (c=1.0, CHCl.sub.3)
##STR00095##
[0482] Prepared according to the general procedure, got a colorless
oil, 25 mg, yield 73% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85)
[0483] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.69 (s, 1H),
7.27 (t, J=8.1 Hz, 2H), 7.12 (t, J=8.1 Hz, 2H), 6.96 (t, J=7.2 Hz,
1H), 4.58 (d, J=8.7 Hz, 1H), 4.49 (s, 1H), 4.18-4.25 (m, 3H), 3.51
(q, J=7.2 Hz, 2H), 2.06-2.14 (m, 3H), 1.82-1.84 (m, 1H), 1.28 (t,
J=7.2, 3H), 1.00 (t, J=7.2 Hz, 3H)
[0484] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 203.3, 167.9,
167.2, 147.8, 128.5 (2C), 122.7, 116.3 (2C), 82.9, 61.7, 61.4,
59.1, 49.9, 23.7, 19.3, 14.0, 13.6
[0485] HRMS (ESI-) calcd for C.sub.18H.sub.22NO.sub.6.sup.-,
[M-H].sup.- 348.1447. found 348.1446.
[0486] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AS-H column (Hexane/1-propanol=99:1,
1.0 mL/min): t.sub.1=7.09 min (major), t.sub.2=10.20 min (minor).
(99% ee)
[0487] [.alpha.].sup.25.sub.D: -66.57 (c=1.1, CHCl.sub.3)
##STR00096##
[0488] Prepared according to the general procedure, got a colorless
oil, 30 mg, yield 81% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85)
[0489] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.69 (s, 1H),
7.26-7.30 (m, 2H), 7.11-7.13 (m, 2H), 6.98 (t, J=7.5 Hz, 1H), 4.58
(d, J=8.7 Hz, 1H), 4.49 (s, 1H), 4.24 (d, J=9 Hz, 1H), 4.16 (t,
J=7.2 Hz, 2H), 3.41 (t, J=7.2 Hz, 2H), 2.06-2.14 (m, 3H), 1.82-1.84
(m, 1H), 1.64-1.72 (m, 4H), 1.40-1.42 (m, 2H) 0.92 (t, J=7.2, 3H),
0.86 (t, J=7.2, 3H)
[0490] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 203.3, 168.0,
167.3, 147.2, 128.5 (2C), 122.7, 116.3 (2C), 82.9, 67.3, 67.0,
59.1, 49.9, 23.7, 21.9, 21.8, 21.4, 19.3, 10.3, 10.2
[0491] HRMS (ESI-) calcd for C.sub.20H.sub.26NO.sub.6.sup.-,
[M-H].sup.- 376.1760. found 376.1758.
[0492] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AS-H column (Hexane/1-propanol=95:5,
1.0 mL/min): t.sub.1=7.43 min (major), t.sub.2=9.80 min (minor).
(99% ee)
[0493] [.alpha.].sup.25.sub.D: -38.28 (c=0.9, CHCl.sub.3)
##STR00097##
[0494] Prepared according to the general procedure, got a colorless
oil, 26 mg, yield 69% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85).
[0495] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.68 (s, 1H),
7.25 (t, J=7.8 Hz, 2H), 7.11 (d, J=7.8 Hz, 2H), 6.98 (t, J=14.7 Hz,
1H), 5.01-5.09 (m, 1H), 4.54 (d, J=8.1 Hz, 1H), 4.46 (s, 1H),
4.35-4.46 (m, 1H), 4.10 (d, J=5.4 Hz, 1H), 2.03-2.17 (m, 3H),
1.84-1.88 (m, 1H), 1.24 (d, J=6.3 Hz, 3H), 1.01 (d, J=6.3 Hz, 3H),
0.92 (d, J=7.2 Hz, 3H).
[0496] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 203.4, 167.5,
166.8, 148.0, 128.5 (2C), 123.0, 116.9 (2C), 82.9, 69.3, 69.2,
59.2, 50.4, 34.2, 23.6, 21.5, 21.3, 21.2, 19.5
[0497] HRMS (ESI-) calcd for C.sub.20H.sub.26NO.sub.6.sup.-,
[M-H].sup.- 376.1760. found 376.1758.
[0498] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AS-H column (Hexane/1-propanol=99:1,
1.0 mL/min): t.sub.1=6.76 min (minor), t.sub.2=7.64 min (major).
(99% ee)
[0499] [.alpha.].sup.25.sub.D: -23.10 (c=1.0, CHCl.sub.3)
##STR00098##
[0500] Prepared according to the general procedure, got a colorless
oil, 31 mg, yield 79% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85)
[0501] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.67 (s, 1H),
7.25 (t, J=7.5 Hz, 2H), 7.11 (d, J=7.5 Hz, 2H), 6.96 (t, J=7.5 Hz,
1H), 4.47-4.57 (m, 2H), 4.21 (d, J=9 Hz, 1H), 4.13 (t, J=13.2 Hz,
2H), 3.44 (t, J=13.2 Hz, 2H), 2.04-2.12 (m, 3H), 1.81-1.83 (m, 1H),
1.61-1.63 (m, 2H), 1.17-1.56 (m, 6H), 0.82-0.96 (m, 6H)
[0502] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 203.3, 168.0,
167.3, 147.8, 128.5 (2C), 122.7, 116.4 (2C), 82.9, 65.6, 65.3,
59.1, 49.9, 30.4, 30.1, 23.7, 19.3, 19.0, 18.9, 13.7, 13.6
[0503] HRMS (ESI-) calcd for C.sub.22H.sub.30NO.sub.6.sup.-,
[M-H].sup.- 404.2073. found 404.2072.
[0504] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AS-H column (Hexane/1-propanol=99:1,
1.0 mL/min): t.sub.1=7.30 min (major), t.sub.2=9.58 min (minor).
(99% ee)
[0505] [.alpha.].sup.25.sub.D: -37.25 (c=1.2, CHCl.sub.3)
##STR00099##
[0506] Prepared according to the general procedure, got a colorless
oil, 29 mg, yield 67% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85)
[0507] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 9.67 (s, 1H),
7.26 (t, J=8.0 Hz, 2H), 7.09 (d, J=8.0 Hz, 2H), 6.96 (t, J=8.0 Hz,
1H), 4.55 (d, J=8.7 Hz, 1H), 4.48 (d, J=4.0 Hz, 1H), 4.21 (d, J=8.7
Hz, 1H), 4.12 (t, J=6.6 Hz, 2H), 3.42 (t, J=6.6 Hz, 2H), 2.06-2.08
(m, 3H), 1.80-1.85 (m, 1H), 1.12-1.38 (m, 12H), 0.85-0.91 (m,
6H)
[0508] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. 203.4, 168.0,
167.3, 147.8, 128.5 (2C), 122.7, 116.3 (2C), 82.9, 65.9, 65.6,
59.1, 49.9, 28.1, 27.9, 27.8, 27.7, 23.7, 22.2, 19.3, 14.0
[0509] HRMS (ESI-) calcd for C.sub.24H.sub.34NO.sub.6.sup.-,
[M-H].sup.- 432.2390. found 432.2388.
[0510] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AS-H column (Hexane/1-propanol=95:5,
1.0 mL/min): t.sub.1=14.96 min (minor), t.sub.2=22.61 min (major).
(92% ee)
[0511] [.alpha.].sup.25.sub.D: -40.8 (c=1.2, CHCl.sub.3)
##STR00100##
[0512] Prepared according to the general procedure, got a colorless
oil, 32 mg, yield 71% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85)
[0513] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 9.67 (s, 1H),
7.26 (t, J=8.0 Hz, 2H), 7.10 (d, J=8.0 Hz, 2H), 6.96 (t, J=8.0 Hz,
1H), 4.47-4.56 (m, 2H), 4.21 (d, J=8.7 Hz, 1H), 4.12 (t, J=6.6 Hz,
2H), 3.42 (t, J=6.6 Hz, 2H), 2.04-2.11 (m, 3H), 1.81-1.85 (m, 1H),
1.56-1.63 (m, 2H), 1.19-1.38 (m, 14H), 0.85-0.91 (m, 6H)
[0514] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. 203.4, 168.0,
167.3, 147.8, 128.5 (2C), 122.7, 116.3 (2C), 82.9, 65.9, 65.6,
59.1, 49.9, 31.4, 28.3, 28.0, 25.5, 25.4, 23.73, 22.5, 19.3,
14.0
[0515] HRMS (ESI-) calcd for C.sub.26H.sub.38NO.sub.6.sup.-,
[M-H].sup.- 460.2704. found 460.2699.
[0516] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AD-H column (Hexane/1-propanol=98:2,
1.0 mL/min): t=5.10 min (major). (99% ee)
[0517] [.alpha.].sup.25.sub.D: -14.41 (c=0.7, CHCl.sub.3)
##STR00101##
[0518] Prepared according to the general procedure, got a colorless
oil, 26 mg, yield 73% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85)
[0519] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.74 (s, 1H),
7.35 (m, 1H), 7.11-7.15 (m, 2H), 7.02 (t, J=6.9 Hz, 1H), 4.43-4.45
(m, 1H), 4.11-4.27 (m, 4H), 3.52-3.65 (m, 2H), 2.22 (s, 3H),
2.03-2.09 (m, 3H), 1.68-1.71 (m, 1H), 1.26 (t, J=7.2 Hz, 3H), 1.00
(t, J=7.2 Hz, 3H)
[0520] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 203.2, 168.1,
167.1, 146.5, 130.7 (2C), 125.9, 125.3, 119.6, 83.0, 61.7, 61.4,
58.1, 49.9, 23.5, 17.7, 14.0, 13.7
[0521] HRMS (ESI-) calcd for C.sub.19H.sub.24NO.sub.6.sup.-,
[M-H].sup.- 362.1604. found 362.1599.
[0522] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AD-H column (Hexane/1-propanol=97:3,
1.0 mL/min): t.sub.1=12.72 min (major), t.sub.2=14.63 min (minor),
(>95% ee)
[0523] [.alpha.].sup.25.sub.D: -23.6 (c=1.1, CHCl.sub.3)
##STR00102##
[0524] Prepared according to the general procedure, got a colorless
oil, 28 mg, yield 72% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85)
[0525] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.74 (s, 1H),
7.34 (d, J=7.8 Hz, 1H), 7.03-7.15 (m, 2H), 7.04 (t, J=7.8 Hz, 1H),
4.44-4.46 (m, 1H), 4.12-4.29 (m, 2H), 4.04-4.11 (m, 2H), 3.45-3.54
(m, 2H), 2.23 (s, 3H), 2.05-2.17 (m, 3H), 1.62-1.72 (m, 1H),
1.38-1.45 (m, 2H), 0.92 (t, J=7.5 Hz, 3H), 0.819 (t, J=7.5 Hz,
3H)
[0526] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 203.2, 168.1,
167.2, 146.5, 130.7 (2C), 125.9, 125.3, 119.6, 83.0, 67.3, 67.0,
58.1, 49.9, 23.6, 21.8, 21.5, 17.7, 10.3, 10.2
[0527] HRMS (ESI-) calcd for C.sub.21H.sub.28NO.sub.6.sup.-,
[M-H].sup.- 390.1917. found 390.1916.
[0528] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AD-H column (Hexane/1-propanol=97:3,
1.0 mL/min): t.sub.1=13.77 min (minor), t.sub.2=17.06 min (major)
(98% ee)
[0529] [.alpha.].sup.25.sub.D: -8.58 (c=0.90, CHCl.sub.3)
##STR00103##
[0530] Prepared according to the general procedure, got a colorless
oil, 27 mg, yield 69% after silica gel chromatography, eluent
(EtOAc/Hexane=5:95-15:85)
[0531] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.75 (s, 1H),
7.33 (d, J=7.8 Hz, 1H), 7.12-7.13 (m, 2H), 7.03 (t, J=6.9 Hz, 1H),
5.04-5.10 (m, 1H), 4.40-4.44 (m, 2H), 4.23 (s, 2H), 2.23 (s, 3H),
2.03-2.14 (m, 3H), 1.71-1.73 (m, 1H), 1.24 (d, J=7.2 Hz, 3H), 1.23
(d, J=7.2 Hz, 3H), 0.99 (d, J=7.2 Hz, 6H), 0.98 (d, J=7.2 Hz,
3H).
[0532] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 203.4, 167.7,
165.7, 146.7, 130.7 (2C), 125.9, 125.3, 119.6, 83.0, 69.3, 69.0,
57.7, 50.1, 23.4, 21.6, 21.4, 21.4, 21.2, 17.7
[0533] HRMS (ESI-) calcd for C.sub.21H.sub.28NO.sub.6.sup.-,
[M-H].sup.- 390.1917. found 390.1916.
[0534] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AD-H column (Hexane/1-propanol=97:3,
1.0 mL/min): t.sub.1=8.34 min (minor), t.sub.2=9.77 min (major).
(>95% ee)
[0535] [.alpha.].sup.25.sub.D: -12.36 (c=0.90, CHCl.sub.3)
##STR00104##
[0536] Prepared according to the general procedure, obtained a
colorless oil, 29 mg, yield 71% after silica gel chromatography,
eluent (EtOAc/Hexane=5:95-15:85).
[0537] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.74 (s, 1H),
7.34 (d, J=7.8 Hz, 1H), 7.02-7.15 (m, 2H), 7.06 (t, J=8.1 Hz, 1H),
4.44-4.45 (m, 1H), 4.21-4.28 (m, 2H), 4.05-4.18 (m, 2H), 3.45-3.60
(m, 2H), 2.22 (s, 3H), 2.04-2.09 (m, 3H), 1.61-1.63 (m, 4H),
1.20-1.40 (m, 6H), 0.84-0.94 (m, 6H)
[0538] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta.203.2, 168.1,
167.2, 139.6, 130.7 (2C), 125.9, 125.7, 119.5, 83.0, 65.6, 65.3,
58.1, 49.8, 30.4, 30.1, 23.6, 19.32, 19.0, 19.0, 17.7, 13.7,
13.6
[0539] HRMS (ESI-) calcd for C.sub.23H.sub.32NO.sub.6.sup.-,
[M-H].sup.- 418.2230. found 418.2229.
[0540] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AD-H column (Hexane/1-propanol=97:3,
1.0 mL/min): t.sub.1=8.79 min (minor), t.sub.2=11.30 min (major).
(96% ee)
[0541] [.alpha.].sup.25.sub.D: -25.24 (c=0.71, CHCl.sub.3)
##STR00105##
[0542] Prepared according to the general procedure, obtained a
colorless oil, 28 mg, yield 67% after silica gel chromatography,
eluent (EtOAc/Hexane=5:95-15:85).
[0543] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.66 (s, 1H),
7.38 (d, J=9.0 Hz, 2H), 7.01 (d, J=9.0 Hz, 2H), 4.49-4.56 (m, 2H),
4.18-4.23 (m, 3H), 3.60 (q, J=7.2 Hz, 2H), 2.05-2.15 (m, 3H),
1.82-1.84 (m, 1H), 1.29 (t, J=6.9 Hz, 3H), 1.05 (t, J=6.9 Hz,
3H)
[0544] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 202.8, 167.7,
167.1, 146.9, 131.4 (2C), 117.9 (2C), 115.3, 83.0, 61.8, 61.6,
59.0, 49.8, 23.6, 19.1, 14.0, 13.6
[0545] HRMS (ESI-) calcd for C.sub.18H.sub.21BrNO.sub.6.sup.-,
[M-H].sup.- 426.0552. found 426.0557.
[0546] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AS-H column (Hexane/1-propanol=95:5,
1.0 mL/min): t.sub.1=8.99 min (major), t.sub.2=13.75 min (minor).
(99% ee)
[0547] [.alpha.].sup.25.sub.D: -26.52 (c=1.2, CHCl.sub.3).
##STR00106##
[0548] Prepared according to the general procedure, obtained a
colorless oil, 28 mg, yield 67% after silica gel chromatography,
eluent (EtOAc/Hexane=5:95-15:85).
[0549] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.64 (s, 1H),
7.36 (d, J=9.0 Hz, 2H), 6.99 (d, J=9.0 Hz, 1H), 4.47-4.54 (m, 2H),
4.14-4.22 (m, 3H), 3.47 (t, J=6.6 Hz, 2H), 2.35 (t, J=7.2 Hz, 2H),
2.05-2.08 (m, 3H), 1.81-1.86 (m, 1H), 1.64-1.70 (m, 4H), 0.92-0.98
(m, 6H)
[0550] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 202.8, 167.8,
167.2, 146.9, 137.3 (2C), 118.0 (2C), 115.3, 83.0, 67.4, 67.2,
59.0, 49.8, 31.6, 29.0, 23.6, 23.5, 21.8, 21.5, 19.2, 14.1, 10.3,
10.2
[0551] HRMS (ESI-) calcd for C.sub.20H.sub.25BrNO.sub.6.sup.-,
[M-H].sup.- 454.0866. found 454.0862.
[0552] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AS-H column (Hexane/1-propanol=95:5,
1.0 mL/min): t.sub.1=7.89 min (major), t.sub.2=12.31 min (minor).
(99% ee)
[0553] [.alpha.].sup.25.sub.D: -11.81 (c=1.1, CHCl.sub.3)
##STR00107##
[0554] Prepared according to the general procedure, obtained a
colorless oil, 30 mg, yield 67% after silica gel chromatography,
eluent (EtOAc/Hexane=5:95-15:85).
[0555] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.64 (s, 1H),
7.36 (d, J=9.0 Hz, 2H), 6.99 (d, J=9.0 Hz, 1H), 5.04-5.10 (m, 1H),
4.41-4.47 (m, 2H), 4.26 (s, 2H), 2.25 (s, 3H), 2.06-2.13 (m, 3H),
1.73-1.75 (m, 1H), 0.24 (d, J=7.2 Hz, 6H), 1.01 (d, J=7.2 Hz,
6H)
[0556] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 202.9, 167.3,
166.8, 147.0, 131.4 (2C), 118.4 (2C), 115.6, 83.0, 69.5, 69.4,
65.9, 59.0, 50.3, 23.5, 21.5, 21.3, 21.2, 19.3, 15.2
[0557] HRMS (ESI-) calcd for C.sub.20H.sub.25BrNO.sub.6.sup.-,
[M-H].sup.- 454.0866. found 454.0868.
[0558] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AD-H column (Hexane/1-propanol=97:3,
1.0 mL/min): t.sub.1=15.22 min (minor), t.sub.2=26.14 min (major).
(99% ee)
[0559] [.alpha.].sup.25.sub.D: -11.26 (c=0.7, CHCl.sub.3)
[0560] IR Spectra:
[0561] The infrared spectra were recorded using neat liquid samples
for all the tandem reaction products (23a-23v). All showed the
characteristic strong C.dbd.O stretches (1690-1745 cm.sup.-1) for
both aldehydes and carboxylic esters.
##STR00108##
[0562] Prepared according to the general procedure, obtained a
colorless oil, 34 mg, yield 71% after silica gel chromatography,
eluent (EtOAc/Hexane=5:95-15:85).
[0563] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.64 (s, 1H),
7.36 (d, J=9.0 Hz, 2H), 6.98 (d, J=9.0 Hz, 1H), 4.47-4.53 (m, 3H),
4.11-4.23 (m, 5H), 2.17-2.35 (m, 3H), 1.80-1.83 (m, 1H), 1.24-1.39
(m, 8H), 0.85-0.94 (m, 6H)
[0564] .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 202.9, 167.8,
167.2, 146.8, 131.4 (2C), 118.0 (2C), 115.5, 83.0, 65.7, 65.5,
59.0, 49.8, 30.4, 30.1, 23.6, 19.0, 18.9, 13.7
[0565] HRMS (ESI-) calcd for C.sub.22H.sub.29BrNO.sub.6.sup.-,
[M-H].sup.- 482.1180. found 482.1178.
[0566] The enantiomeric excess was determined by HPLC analysis
employing a Daicel Chiracel AD-H column (Hexane/1-propanol=90:10,
1.0 mL/min): t.sub.1=11.45 min (minor), t.sub.2=14.63 min (major).
(99% ee)
[0567] [.alpha.].sup.25.sub.D: -7.13 (c=1.1, CHCl.sub.3)
##STR00109##
[0568] .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 10.99 (s, 1H),
9.04 (d, J=2.6 Hz, 1H), 8.27 (dd, J.sub.1=2.4 Hz, J.sub.2=9.6 Hz,
1H), 7.85 (d, J=9.6 Hz, 1H), 7.60 (d, J=2.6 Hz, 1H), 7.24 (t, J=7.9
Hz, 2H), 7.07 (d, J=7.9 Hz, 2H), 6.96 (t, J=7.9 Hz, 1H), 4.93 (s,
1H), 4.51 (m, 1H), 4.20 (q, J=7.1 Hz, 2H), 4.09 (d, J=8.3 Hz, 1H),
3.51-3.62 (m, 2H), 2.20-2.34 (m, 2H), 2.09-2.14 (m, 1H), 1.93-1.97
(m, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.00 (t, J=7.1 Hz, 3H)
[0569] .sup.13C-NMR (100 MHz, CDCl.sub.3): .delta. 167.8, 167.3,
151.1, 147.7, 144.9, 138.2, 130.0, 129.2, 128.6, 123.4, 123.1,
117.3, 116.4, 61.7, 61.5, 59.3, 50.6, 29.7, 23.6, 22.8, 14.0,
13.6
[0570] The invention illustratively described herein may suitably
be practiced in the absence of any element or elements, limitation
or limitations, not specifically disclosed herein. Thus, for
example, the terms "comprising", "including," containing", etc.
shall be read expansively and without limitation. Additionally, the
terms and expressions employed herein have been used as terms of
description and not of limitation, and there is no intention in the
use of such terms and expressions of excluding any equivalents of
the features shown and described or portions thereof, but it is
recognized that various modifications are possible within the scope
of the invention claimed. Thus, it should be understood that
although the present invention has been specifically disclosed by
exemplary embodiments and optional features, modification and
variation of the inventions embodied therein herein disclosed may
be resorted to by those skilled in the art, and that such
modifications and variations are considered to be within the scope
of this invention.
[0571] The invention has been described broadly and generically
herein. Each of the narrower species and subgeneric groupings
falling within the generic disclosure also form part of the
invention. This includes the generic description of the invention
with a proviso or negative limitation removing any subject matter
from the genus, regardless of whether or not the excised material
is specifically recited herein.
[0572] Other embodiments are within the following claims. In
addition, where features or aspects of the invention are described
in terms of Markush groups, those skilled in the art will recognize
that the invention is also thereby described in terms of any
individual member or subgroup of members of the Markush group.
* * * * *
References