U.S. patent application number 16/176302 was filed with the patent office on 2019-05-02 for synthesis of boronate ester derivatives and uses thereof.
The applicant listed for this patent is Rempex Pharmaceuticals, Inc.. Invention is credited to Serge Henri Boyer, Scott J. Hecker, Petrus J. Hermsen, Gerardus K.M. Verzijl.
Application Number | 20190127396 16/176302 |
Document ID | / |
Family ID | 66245250 |
Filed Date | 2019-05-02 |
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United States Patent
Application |
20190127396 |
Kind Code |
A1 |
Boyer; Serge Henri ; et
al. |
May 2, 2019 |
SYNTHESIS OF BORONATE ESTER DERIVATIVES AND USES THEREOF
Abstract
Disclosed herein are methods for the preparation of boronate
derivatives in the synthesis of antimicrobial compounds and uses
thereof. Disclosed herein includes method of making a compound of
Formula (B) by reducing the ketone group of the keto-ester compound
of Formula (A), and the reduction can be performed using a
Ruthenium based catalyst system or using an alcohol dehydrogenase
bioreduction system.
Inventors: |
Boyer; Serge Henri; (San
Diego, CA) ; Hecker; Scott J.; (Del Mar, CA) ;
Verzijl; Gerardus K.M.; (Well, NL) ; Hermsen; Petrus
J.; (Horst, NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Rempex Pharmaceuticals, Inc. |
Lincolnshire |
IL |
US |
|
|
Family ID: |
66245250 |
Appl. No.: |
16/176302 |
Filed: |
October 31, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62580343 |
Nov 1, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 69/675 20130101;
C12P 41/002 20130101; C07C 67/31 20130101; C12P 9/00 20130101; C07F
5/025 20130101; C07F 5/04 20130101; C07C 67/31 20130101; C07C
69/675 20130101 |
International
Class: |
C07F 5/02 20060101
C07F005/02; C07C 69/675 20060101 C07C069/675; C07F 5/04 20060101
C07F005/04; C07C 67/31 20060101 C07C067/31; C12P 9/00 20060101
C12P009/00 |
Claims
1. A compound having the structure of Formula (I): ##STR00036##
wherein X is a halogen and m is an integer between 2 and 6.
2. The compound of claim 1, wherein X is Cl and m is 2.
3. (canceled)
4. A compound having the structure of Formula (II): ##STR00037## or
a salt thereof, wherein: X is a halogen, m is an integer between 2
and 6, each of R.sup.1a and R.sup.1b is independently selected from
the group consisting of an optionally substituted C.sub.1-C.sub.12
alkyl, optionally substituted C.sub.3-C.sub.8 cycloalkyl,
optionally substituted C.sub.2-C.sub.12 alkenyl, optionally
substituted C.sub.2-C.sub.12 alkynyl, optionally substituted aryl,
and optionally substituted heteroaryl, or R.sup.1a and R.sup.1b
together with intervening atoms optionally form a 5-7 membered
boron ester ring, and R.sup.2 is selected from the group consisting
of an optionally substituted C.sub.1-C.sub.12 alkyl, optionally
substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted
C.sub.2-C.sub.12 alkenyl, optionally substituted C.sub.2-C.sub.12
alkynyl, optionally substituted aryl, and optionally substituted
heteroaryl.
5. The compound of claim 4, wherein X is Cl and each of R.sup.1a
and R.sup.1b are a butyl group.
6-8. (canceled)
9. A method of making a compound of Formula (B), comprising the
steps of: reducing the ketone group of a compound of Formula (A):
##STR00038## to form a compound of Formula (B): ##STR00039##
wherein: X is a halogen, and m is 2 to 6.
10. The method of claim 9, wherein X is Cl and m is 2.
11. (canceled)
12. The method of claim 9, wherein the ketone group in the compound
of Formula (A) is reduced using a Ruthenium based catalyst.
13. The method of claim 12, wherein the Ruthenium based catalyst
has the structure of Formula (III): R.sup.3Ru(X.sup.1).sub.2 (III),
wherein: X.sup.1 is a halogen, benzene, cymene, or an acetyl (OAc)
group; and R.sup.3 is a ligand selected from the group consisting
of (S)-BINA, (R)-BINAP, (R)--H.sub.8-BINAP, (R)-SegPhos,
(R)-DM-SegPhos, (S)-SegPhos, (R)-tolyl-BINAP, (R)-xylyl-BINAP,
(S)-tolyl-BINAP, (S)-BINAPHANE, (S)-PhanePhos, JosiPhos-2-1,
(R)-SolPhos SL-A001-1, (S)-MeOBiPhep, (S)--P-Phos, and
(S)-(+)-DTBM-SEGPHOS.
14-18. (canceled)
19. The method of claim 9, comprising reducing the ketone group in
the compound of Formula (A) with an alcohol dehydrogenase
system.
20. The method of claim 19, wherein the alcohol dehydrogenase
system comprises a reduced nicotinamide adenine dinucleotide
(NADH), a reduced nicotinamide adenine dinucleotide phosphate
(NADPH), and an alcohol.
21-26. (canceled)
27. A method of making a compound of Formula (C), comprising:
reacting a boronate compound B(OR.sup.4a)(OR.sup.4b)(OR.sup.4c)
with a compound of Formula (B-1): ##STR00040## to form the compound
of Formula (C): ##STR00041## wherein: X is a halogen; m is an
integer between 2 and 6; R.sup.2 is selected from the group
consisting of an optionally substituted C.sub.1-C.sub.12 alkyl,
optionally substituted C.sub.3-C.sub.8 cycloalkyl, optionally
substituted C.sub.2-C.sub.12 alkenyl, optionally substituted
C.sub.2-C.sub.12 alkynyl, optionally substituted aryl, and
optionally substituted heteroaryl; R.sup.4a and R.sup.4b are
independently selected from the group consisting of an optionally
substituted C.sub.1-C.sub.12 alkyl, optionally substituted
C.sub.3-C.sub.8 cycloalkyl, optionally substituted C.sub.2-C.sub.12
alkenyl, optionally substituted C.sub.2-C.sub.12 alkynyl,
optionally substituted aryl, and optionally substituted heteroaryl,
or R.sup.4a and R.sup.4b together with intervening atoms optionally
form a 5-8 membered boron ester ring; and R.sup.4c is selected from
the group consisting of an optionally substituted C.sub.1-C.sub.12
alkyl, optionally substituted C.sub.3-C.sub.8 cycloalkyl,
optionally substituted C.sub.2-C.sub.12 alkenyl, optionally
substituted C.sub.2-C.sub.12 alkynyl, optionally substituted aryl,
and optionally substituted heteroaryl.
28. The method of claim 27, wherein X is Cl, m is 2, and R.sup.2,
R.sup.4a, and R.sup.4b are each independently a butyl group.
29-31. (canceled)
32. A method of making a compound of Formula (D), comprising:
reacting magnesium with a compound of Formula (C): ##STR00042## to
form a first reaction intermediate; and hydrolyzing the first
reaction intermediate to form the compound of Formula (D):
##STR00043## wherein: X is a halogen, m is an integer between 2 and
6, and R.sup.2 is selected from the group consisting of an
optionally substituted C.sub.1-C.sub.12 alkyl, optionally
substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted
C.sub.2-C.sub.12 alkenyl, optionally substituted C.sub.2-C.sub.12
alkynyl, optionally substituted aryl, and optionally substituted
heteroaryl, and each of R.sup.4a and R.sup.4b are independently
selected from the group consisting of an optionally substituted
C.sub.1-C.sub.12 alkyl, optionally substituted C.sub.3-C.sub.8
cycloalkyl, optionally substituted C.sub.2-C.sub.12 alkenyl,
optionally substituted C.sub.2-C.sub.12 alkynyl, optionally
substituted aryl, and optionally substituted heteroaryl, or
R.sup.4a and R.sup.4b together with intervening atoms optionally
form a 5-8 membered boron ester ring.
33. The method of claim 32, wherein X is Cl, m is 2, and R.sup.2,
R.sup.4a, and R.sup.4b are independently a butyl group.
34-36. (canceled)
37. The method of claim 32, wherein the compound of Formula (D) is
##STR00044##
38-40. (canceled)
41. A method of making a compound of Formula (E), comprising:
reducing the ketone group of a keto-ester compound of Formula
(A-1): ##STR00045## to form a compound of Formula (B-1):
##STR00046## reacting a boronate compound
B(OR.sup.4a)(OR.sup.4b)(OR.sup.4c) with the compound of Formula (B)
to form a compound of Formula (C): ##STR00047## reacting magnesium
with the compound of Formula (C) to form a first reaction
intermediate hydrolyzing the first reaction intermediate to form a
compound of Formula (D): ##STR00048## and reacting the compound of
Formula (D) with a complexing agent of Formula (CL); ##STR00049##
to form the compound of Formula (E): ##STR00050## wherein: X is a
halogen, m is an integer between 2 and 6, n is an integer between 0
and 6, Y' is O or N.sup.+R.sup.9R.sup.10; Y.sup.2 is O or
NR.sup.11; R.sup.2 is selected from the group consisting of an
optionally substituted C.sub.1-C.sub.12 alkyl, optionally
substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted
C.sub.2-C.sub.12 alkenyl, optionally substituted C.sub.2-C.sub.12
alkynyl, optionally substituted aryl, and optionally substituted
heteroaryl, each R.sup.5 and R.sup.6 are independently selected
from the group consisting of H, optionally substituted phenyl, and
optionally substituted C.sub.1-4 alkyl, or R.sup.5 and R.sup.6
together with the atom to which they are attached, form .dbd.O;
each R.sup.7 and R.sup.8 are independently selected from the group
consisting of H, optionally substituted phenyl, and optionally
substituted C.sub.1-4 alkyl, or R.sup.5 and R.sup.7 together with
the atom to which they are attached form an aryl or heteroaryl
ring; or R.sup.7 and R.sup.8 together with the atom to which they
are attached, form .dbd.O; and each R.sup.9, R.sup.10, and R.sup.11
are independently selected from the group consisting of H,
optionally substituted phenyl, and optionally substituted C.sub.1-4
alkyl.
42. The method of claim 41, wherein X is Cl, m is 2, and R.sup.2 is
a butyl group.
43-46. (canceled)
47. The method of claim 41, wherein the complexing agent of Formula
(CL) is NH.sub.2(CH.sub.2).sub.2OH.
48-49. (canceled)
50. The method of claim 41, further comprising reacting the
compound of Formula (E) with pinanediol to form a compound of
Formula (F): ##STR00051## protecting the hydroxy group of the
compound of Formula (F) with a PG group to form a compound of
Formula (G): ##STR00052## reacting the compound of Formula (G) with
n-butyllithium and dichloromethane to form a compound of Formula
(H): ##STR00053## reacting the compound of Formula (H) with an
LiN(SiR.sup.12).sub.2 to form a compound of Formula (J):
##STR00054## reacting the compound of Formula (J) with
R.sup.13--COCl to form a compound of Formula (K): ##STR00055## and
removing the PG group on the compound of formula (K) to form a
compound of formula (L): ##STR00056## wherein: PG is a hydroxy
protection group, R.sup.12 is optionally substituted phenyl or
optionally substituted C.sub.1-8 alkyl, and R.sup.13 is selected
from optionally substituted C.sub.1-8 alkyl, optionally substituted
C.sub.0-4 alkyl-C.sub.6-10 aryl, optionally substituted C.sub.0-4
alkyl-5-10 membered heteroaryl, optionally substituted C.sub.0-4
alkyl-C.sub.3-10 carbocyclyl, and C.sub.0-4 alkyl-4-10 membered
heterocyclyl.
51-53. (canceled)
54. The method of claim 50, wherein R.sup.13 is ##STR00057##
Description
INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/580,343, filed Nov. 1, 2017, the disclosure of
which is incorporated herein by reference in its entirety.
BACKGROUND
Field
[0002] The present application relates to certain compounds and to
methods for the preparation of certain compounds that can be used
in the fields of chemistry and medicine. More specifically, the
present application relates to intermediates and methods in the
synthesis of boronic acid antimicrobial compounds.
Description of the Related Art
[0003] Antibiotics have been effective tools in the treatment of
infectious diseases during the last half-century. From the
development of antibiotic therapy to the late 1980s there was
almost complete control over bacterial infections in developed
countries. However, in response to the pressure of antibiotic
usage, multiple resistance mechanisms have become widespread and
are threatening the clinical utility of anti-bacterial therapy. The
increase in antibiotic resistant strains has been particularly
common in major hospitals and care centers. The consequences of the
increase in resistant strains include higher morbidity and
mortality, longer patient hospitalization, and an increase in
treatment costs.
[0004] Various bacteria have evolved .beta.-lactam deactivating
enzymes, namely, .beta.-lactamases, that counter the efficacy of
the various .beta.-lactam antibiotics. .beta.-lactamases can be
grouped into 4 classes based on their amino acid sequences, namely,
Ambler classes A, B, C, and D. Enzymes in classes A, C, and D
include active-site serine .beta.-lactamases, and class B enzymes,
which are encountered less frequently, are Zn-dependent. These
enzymes catalyze the chemical degradation of .beta.-lactam
antibiotics, rendering them inactive. Some .beta.-lactamases can be
transferred within and between various bacterial strains and
species. The rapid spread of bacterial resistance and the evolution
of multi-resistant strains severely limits .beta.-lactam treatment
options available.
[0005] The increase of class D .beta.-lactamase-expressing
bacterium strains such as Acinetobacter baumannii has become an
emerging multidrug-resistant threat. A. baumannii strains express
A, C, and D class .beta.-lactamases. The class D .beta.-lactamases
such as the OXA families are particularly effective at destroying
carbapenem type .beta.-lactam antibiotics, e.g., imipenem, the
active carbapenems component of Merck's Primaxin.RTM. (Montefour,
K.; et al. Crit. Care Nurse 2008, 28, 15; Perez, F. et al. Expert
Rev. Anti Infect. Ther. 2008, 6, 269; Bou, G.; Martinez-Beltran, J.
Antimicrob. Agents Chemother. 2000, 40, 428, 2006, 50, 2280; Bou,
G. et al, J. Antimicrob. Agents Chemother. 2000, 44, 1556). This
has imposed a pressing threat to the effective use of drugs in that
category to treat and prevent bacterial infections. Indeed the
number of catalogued serine-based .beta.-lactamases has exploded
from less than ten in the 1970s to over 300 variants. These issues
fostered the development of five "generations" of cephalosporins.
When initially released into clinical practice, extended-spectrum
cephalosporins resisted hydrolysis by the prevalent class A
.beta.-lactamases, TEM-1 and SHV-1. However, the development of
resistant strains by the evolution of single amino acid
substitutions in TEM-1 and SHV-1 resulted in the emergence of the
extended-spectrum .beta.-lactamase (ESBL) phenotype.
[0006] New .beta.-lactamases have recently evolved that hydrolyze
the carbapenem class of antimicrobials, including imipenem,
biapenem, doripenem, meropenem, and ertapenem, as well as other
.beta.-lactam antibiotics. These carbapenemases belong to molecular
classes A, B, and D. Class A carbapenemases of the KPC-type
predominantly in Klebsiella pneumoniae but now also reported in
other Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter
baumannii. The KPC carbapenemase was first described in 1996 in
North Carolina, but since then has disseminated widely in the US.
It has been particularly problematic in the New York City area,
where several reports of spread within major hospitals and patient
morbidity have been reported. These enzymes have also been recently
reported in France, Greece, Sweden, United Kingdom, and an outbreak
in Germany has recently been reported. Treatment of resistant
strains with carbapenems can be associated with poor outcomes.
[0007] Another mechanism of .beta.-lactamase mediated resistance to
carbapenems involves combination of permeability or efflux
mechanisms combined with hyper production of beta-lactamases. One
example is the loss of a porin combined in hyperproduction of ampC
beta-lactamase results in resistance to imipenem in Pseudomonas
aeruginosa. Efflux pump over expression combined with
hyperproduction of the ampC .beta.-lactamase can also result in
resistance to a carbapenem such as meropenem.
[0008] Thus, there is a need for improved .beta.-lactamase
inhibitors and efficient methods for making these improved
.beta.-lactamase inhibitors.
SUMMARY
[0009] Some embodiments relate to a compound having the structure
of Formula (I):
##STR00001##
[0010] or a salt thereof, wherein X is a halogen and m is an
integer between 2 and 6.
[0011] Some embodiments relate to a compound having the structure
of Formula (II):
##STR00002##
[0012] or a salt thereof, wherein:
[0013] X is halogen,
[0014] m is an integer between 2 and 6,
[0015] each of R.sup.1a and R.sup.1b is independently selected from
the group consisting of an optionally substituted C.sub.1-C.sub.12
alkyl, optionally substituted C.sub.3-C.sub.8 cycloalkyl,
optionally substituted C.sub.2-C.sub.12 alkenyl, optionally
substituted C.sub.2-C.sub.12 alkynyl, optionally substituted aryl
and optionally substituted heteroaryl, or
[0016] R.sup.1a and R.sup.1b together with intervening atoms
optionally form a 5-7 membered boron ester ring, and
[0017] R.sup.2 is selected from the group consisting of an
optionally substituted C.sub.1-C.sub.12 alkyl, optionally
substituted C.sub.3-C.sub.5 cycloalkyl, optionally substituted
C.sub.2-C.sub.12 alkenyl, optionally substituted C.sub.2-C.sub.12
alkynyl, optionally substituted aryl and optionally substituted
heteroaryl.
[0018] Some embodiments relate to a method of making a compound of
Formula (B), comprising the steps of:
[0019] reducing the ketone group of the keto-ester compound of
Formula (A):
##STR00003##
[0020] to form a compound of Formula (B):
##STR00004##
[0021] wherein:
[0022] X is a halogen, and
[0023] m is an integer between 2 and 6.
[0024] Some embodiments relate to A method of making a compound of
Formula (C), comprising:
[0025] reacting a boronate compound
B(OR.sup.4a)(OR.sup.4b)(OR.sup.4c) with a compound of Formula
(B-1)
##STR00005##
[0026] to form the compound of Formula (C)
##STR00006##
[0027] wherein:
[0028] X is a halogen,
[0029] m is an integer between 2 and 6,
[0030] R.sup.2 is selected from the group consisting of an
optionally substituted C.sub.1-C.sub.12 alkyl, optionally
substituted C.sub.3-C.sub.5 cycloalkyl, optionally substituted
C.sub.2-C.sub.12 alkenyl, optionally substituted C.sub.2-C.sub.12
alkynyl, optionally substituted aryl and optionally substituted
heteroaryl, and
[0031] R.sup.4a and R.sup.4b are independently selected from the
group consisting of an optionally substituted C.sub.1-C.sub.12
alkyl, optionally substituted C.sub.3-C.sub.8 cycloalkyl,
optionally substituted C.sub.2-C.sub.12 alkenyl, optionally
substituted C.sub.2-C.sub.12 alkynyl, optionally substituted aryl
and optionally substituted heteroaryl, or
[0032] R.sup.4a and R.sup.4b together with intervening atoms
optionally form a 5-8 membered boron ester ring; and
[0033] R.sup.4c is selected from the group consisting of an
optionally substituted C.sub.1-C.sub.12 alkyl, optionally
substituted C.sub.3-C.sub.5 cycloalkyl, optionally substituted
C.sub.2-C.sub.12 alkenyl, optionally substituted C.sub.2-C.sub.12
alkynyl, optionally substituted aryl and optionally substituted
heteroaryl.
[0034] Some embodiments relate to a method of making a compound of
Formula (D), comprising:
[0035] reacting magnesium with a compound of Formula (C):
##STR00007##
[0036] to form a first reaction intermediate, and
[0037] hydrolyzing the first reaction intermediate to form the
compound of Formula (D):
##STR00008##
[0038] wherein:
[0039] X is a halogen,
[0040] m is an integer between 2 and 6, and
[0041] R.sup.2 is selected from the group consisting of an
optionally substituted C.sub.1-C.sub.12 alkyl, optionally
substituted C.sub.3-C.sub.5 cycloalkyl, optionally substituted
C.sub.2-C.sub.12 alkenyl, optionally substituted C.sub.2-C.sub.12
alkynyl, optionally substituted aryl and optionally substituted
heteroaryl, and
[0042] each of R.sup.4a and R.sup.4b are independently selected
from the group consisting of an optionally substituted
C.sub.1-C.sub.12 alkyl, optionally substituted C.sub.3-C.sub.8
cycloalkyl, optionally substituted C.sub.2-C.sub.12 alkenyl,
optionally substituted C.sub.2-C.sub.12 alkynyl, optionally
substituted aryl and optionally substituted heteroaryl, or
[0043] R.sup.4a and R.sup.4b together with intervening atoms
optionally form a 5-8 membered boron ester ring.
[0044] Some embodiments relate to a method of making a compound of
Formula (E), comprising
[0045] reducing the ketone group of a keto-ester compound of
Formula (A-1),
##STR00009##
[0046] to form a compound of Formula (B-1),
##STR00010##
[0047] reacting a boronate compound
B(OR.sup.4a)(OR.sup.4b)(OR.sup.4c) with the compound of Formula (B)
to form a compound of Formula (C),
##STR00011##
reacting magnesium with the compound of Formula (C) to form a first
reaction intermediate,
[0048] hydrolyzing the first reaction intermediate to form a
compound of Formula (D),
##STR00012##
[0049] reacting the compound of Formula (D) with a complexing agent
of Formula (CL)
##STR00013##
[0050] to form the compound of Formula (E):
##STR00014##
[0051] wherein:
[0052] X is a halogen,
[0053] m is an integer between 2 and 6,
[0054] n is an integer between 0 and 6,
[0055] Y.sup.1 is O or N.sup.+R.sup.9R.sup.10,
[0056] Y.sup.2 is O or NR.sup.11;
[0057] R.sup.2 is selected from the group consisting of an
optionally substituted C.sub.1-C.sub.12 alkyl, optionally
substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted
C.sub.2-C.sub.12 alkenyl, optionally substituted C.sub.2-C.sub.12
alkynyl, optionally substituted aryl and optionally substituted
heteroaryl, and
[0058] each R.sup.5 and R.sup.6 are independently selected from the
group consisting of H, optionally substituted phenyl and optionally
substituted C.sub.1-4 alkyl, or R.sup.5 and R.sup.6 together with
the atom to which they are attached, form .dbd.O;
[0059] each R.sup.7 and R.sup.8 are independently selected from the
group consisting of H, optionally substituted phenyl and optionally
substituted C.sub.1-4 alkyl, or R.sup.5 and R.sup.7 together with
the atom to which they are attached form an aryl or heteroaryl
ring; or R.sup.7 and R.sup.8 together with the atom to which they
are attached, form .dbd.0; and
[0060] each R.sup.9, R.sup.10, and R.sup.11 are independently
selected from the group consisting of H, optionally substituted
phenyl and optionally substituted C.sub.1-4 alkyl.
BRIEF DESCRIPTION OF THE DRAWINGS
[0061] FIG. 1 shows the bioreduction of Compound 1 using an alcohol
dehydrogenase system at pH 6.5 and pH 7.5.
[0062] FIG. 2 shows the bioreduction reaction progress with a
GDH/glucose regeneration system.
[0063] FIG. 3 shows the bioreduction reaction progress with an IPA
system.
[0064] FIG. 4 shows the effect of acetone on the reduction of
Compound 1.
[0065] FIG. 5 shows the effect of acetone removal on the reduction
reaction of Compound 1.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0066] Numerous references are cited herein. The references cited
herein, including the U.S. patents cited herein, are each to be
considered incorporated by reference in their entirety into this
specification.
[0067] Embodiments of the invention include, but are not limited
to, methods for the preparation of various compounds and
intermediates, and the compounds and intermediates themselves. In
some embodiments, one or more substituents, one or more compounds,
or groups of compounds can be specifically excluded in any one or
more of the methods or compounds as described more fully below.
[0068] Where the compounds disclosed herein have at least one
chiral center, they may exist as individual enantiomers and
diastereomers or as mixtures of such isomers, including racemates.
Separation of the individual isomers or selective synthesis of the
individual isomers is accomplished by application of various
methods which are well known to practitioners in the art. Unless
otherwise indicated, all such isomers and mixtures thereof are
included in the scope of the compounds disclosed herein.
Furthermore, compounds disclosed herein may exist in one or more
crystalline or amorphous forms. Unless otherwise indicated, all
such forms are included in the scope of the compounds disclosed
herein including any polymorphic forms. In addition, some of the
compounds disclosed herein may form solvates with water (i.e.,
hydrates) or common organic solvents. Unless otherwise indicated,
such solvates are included in the scope of the compounds disclosed
herein. Additionally, in some embodiments, the compounds disclosed
herein can form oligomers and other higher-order polymers.
[0069] The skilled artisan will recognize that some structures
described herein may be resonance forms or tautomers of compounds
that may be fairly represented by other chemical structures, even
when kinetically; the artisan recognizes that such structures may
only represent a very small portion of a sample of such
compound(s). Such compounds are considered within the scope of the
structures depicted, though such resonance forms or tautomers are
not represented herein.
[0070] Isotopes may be present in the compounds described. Each
chemical element as represented in a compound structure may include
any isotope of said element. For example, in a compound structure a
hydrogen atom may be explicitly disclosed or understood to be
present in the compound. At any position of the compound that a
hydrogen atom may be present, the hydrogen atom can be any isotope
of hydrogen, including but not limited to hydrogen-1 (protium) and
hydrogen-2 (deuterium). Thus, reference herein to a compound
encompasses all potential isotopic forms unless the context clearly
dictates otherwise.
Definitions
[0071] As used herein, abbreviations of the ligand are defined as
follows. [0072] (S)-BINA=(S)-Biphenylindanone A [0073]
(R)-BINAP=(R)-(+)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl
[0074]
(R)--H.sub.8-BINAP=(R)-(+)-2,2'-Bis(diphenylphospino)-5,5',6,6',7,7',8,8'-
-octahydro-1,1'-binaphthyl [0075]
(R)-SegPhos=(R)-(+)-5,5'-Bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole
[0076]
(R)-DM-SegPhos=(R)-(+)-5,5'-Bis[di(3,5-xylyl)phosphino]-4,4'-bi-1,-
3-benzodioxole [0077]
(S)-SegPhos=(S)-(-)-5,5'-Bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole
[0078]
(R)-tolyl-BINAP=(R)-(+)-2,2'-Bis(di-p-tolylphosphino)-1,1'-binapht-
hyl [0079]
(R)-xylyl-BINAP=(R)-(+)-2,2'-bis(di(3,5-xylyl)phosphino)-1,1'-b-
inaphthy [0080]
(S)-tolyl-BINAP=(S)-(-)-2,2'-p-tolyl-phosphino)-1,1'-binaphthyl
[0081]
(S)-BINAPHANE=(R,R)-1,2-Bis[(R)-4,5-dihydro-3H-binaphtho(1,2-c:2',1'-e)ph-
osphepino]benzene [0082]
(S)-PhanePhos=(S)-(+)-4,12-Bis(diphenylphosphino)-[2.2]-paracyclophane
[0083]
JosiPhos-2-1=(R)-1-[(SP)-2-(Diphenylphosphino)ferrocenyl]ethyldi-t-
ert-butylphosphine [0084] (R)-SolPhos
SL-A001-1=(R)-7,7'-Bis(diphenylphosphino)-3,3',4,4'-tetrahydro-4,4'-dimet-
hyl-8,8'-bi(2H-1,4-benzoxazine) [0085]
(S)-MeOBiPhep=(S)-(-)-2,2'-Bis(diphenylphosphino)-6,6'-dimethoxy-1,1'-bip-
henyl, [0086]
(S)--P-Phos=(S)-(-)-2,2',6,6'-Tetramethoxy-4,4'-bis(diphenylphosphino)-3,-
3'-bipyridine [0087]
(S)-(+)-DTBM-SEGPHOS=(S)-(+)-5,5'-Bis[di(3,5-di-tert-butyl-4-methoxypheny-
l)phosphino]-4,4'-bi-1,3-benzodioxole
[0088] "Solvate" refers to the compound formed by the interaction
of a solvent and a compound described herein or salt thereof.
Suitable solvates are pharmaceutically acceptable solvates
including hydrates.
[0089] The term "pharmaceutically acceptable salt" refers to salts
that retain the biological effectiveness and properties of a
compound and, which are not biologically or otherwise undesirable
for use in a pharmaceutical. In many cases, the compounds disclosed
herein are capable of forming acid and/or base salts by virtue of
the presence of amino and/or carboxyl groups or groups similar
thereto. Pharmaceutically acceptable acid addition salts can be
formed with inorganic acids and organic acids. Inorganic acids from
which salts can be derived include, for example, hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and
the like. Organic acids from which salts can be derived include,
for example, acetic acid, propionic acid, glycolic acid, pyruvic
acid, oxalic acid, maleic acid, malonic acid, succinic acid,
fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic
acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid, and the like.
Pharmaceutically acceptable base addition salts can be formed with
inorganic and organic bases. Inorganic bases from which salts can
be derived include, for example, sodium, potassium, lithium,
ammonium, calcium, magnesium, iron, zinc, copper, manganese,
aluminum, and the like; particularly preferred are the ammonium,
potassium, sodium, calcium and magnesium salts. Organic bases from
which salts can be derived include, for example, primary,
secondary, and tertiary amines, substituted amines including
naturally occurring substituted amines, cyclic amines, basic ion
exchange resins, and the like, specifically such as isopropylamine,
trimethylamine, diethylamine, triethylamine, tripropylamine, and
ethanolamine. Many such salts are known in the art, as described in
WO 87/05297, Johnston et al., published Sep. 11, 1987 (incorporated
by reference herein in its entirety).
[0090] As used herein, "C.sub.a to C.sub.b" or "C.sub.a-b" in which
"a" and "b" are integers refer to the number of carbon atoms in the
specified group. That is, the group can contain from "a" to "b",
inclusive, carbon atoms. Thus, for example, a "C.sub.1 to C.sub.4
alkyl" or "C.sub.1-4 alkyl" group refers to all alkyl groups having
from 1 to 4 carbons, that is, CH.sub.3--, CH.sub.3CH.sub.2--,
CH.sub.3CH.sub.2CH.sub.2--, (CH.sub.3).sub.2CH--,
CH.sub.3CH.sub.2CH.sub.2CH.sub.2--, CH.sub.3CH.sub.2CH(CH.sub.3)--
and (CH.sub.3).sub.3C--.
[0091] The term "halogen" or "halo," as used herein, means any one
of the radio-stable atoms of column 7 of the Periodic Table of the
Elements, e.g., fluorine, chlorine, bromine, or iodine, with
fluorine and chlorine being preferred.
[0092] As used herein, "alkyl" refers to a straight or branched
hydrocarbon chain that is fully saturated (i.e., contains no double
or triple bonds). The alkyl group may have 1 to 20 carbon atoms
(whenever it appears herein, a numerical range such as "1 to 20"
refers to each integer in the given range; e.g., "1 to 20 carbon
atoms" means that the alkyl group may consist of 1 carbon atom, 2
carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon
atoms, although the present definition also covers the occurrence
of the term "alkyl" where no numerical range is designated). The
alkyl group may also be a medium size alkyl having 1 to 9 carbon
atoms. The alkyl group could also be a lower alkyl having 1 to 4
carbon atoms. The alkyl group may be designated as "C.sub.1-4
alkyl" or similar designations. By way of example only, "C.sub.1-4
alkyl" indicates that there are one to four carbon atoms in the
alkyl chain, i.e., the alkyl chain is selected from the group
consisting of methyl, ethyl, propyl, iso-propyl, n-butyl,
iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include,
but are in no way limited to, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
[0093] As used herein, "alkoxy" refers to the formula --OR wherein
R is an alkyl as is defined above, such as "C.sub.1-9 alkoxy",
including but not limited to methoxy, ethoxy, n-propoxy,
1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and
tert-butoxy, and the like.
[0094] As used herein, "alkylthio" refers to the formula --SR
wherein R is an alkyl as is defined above, such as "C.sub.1-9
alkylthio" and the like, including but not limited to
methylmercapto, ethylmercapto, n-propylmercapto,
1-methylethylmercapto (isopropylmercapto), n-butylmercapto,
iso-butylmercapto, sec-butylmercapto, tert-butylmercapto, and the
like.
[0095] As used herein, "alkenyl" refers to a straight or branched
hydrocarbon chain containing one or more double bonds. The alkenyl
group may have 2 to 20 carbon atoms, although the present
definition also covers the occurrence of the term "alkenyl" where
no numerical range is designated. The alkenyl group may also be a
medium size alkenyl having 2 to 9 carbon atoms. The alkenyl group
could also be a lower alkenyl having 2 to 4 carbon atoms. The
alkenyl group may be designated as "C.sub.2-4 alkenyl" or similar
designations. By way of example only, "C.sub.2-4 alkenyl" indicates
that there are two to four carbon atoms in the alkenyl chain, i.e.,
the alkenyl chain is selected from the group consisting of ethenyl,
propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl,
buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl,
1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl,
buta-1,2-dienyl, and buta-1,2-dien-4-yl. Typical alkenyl groups
include, but are in no way limited to, ethenyl, propenyl, butenyl,
pentenyl, and hexenyl, and the like.
[0096] As used herein, "alkynyl" refers to a straight or branched
hydrocarbon chain containing one or more triple bonds. The alkynyl
group may have 2 to 20 carbon atoms, although the present
definition also covers the occurrence of the term "alkynyl" where
no numerical range is designated. The alkynyl group may also be a
medium size alkynyl having 2 to 9 carbon atoms. The alkynyl group
could also be a lower alkynyl having 2 to 4 carbon atoms. The
alkynyl group may be designated as "C.sub.2-4 alkynyl" or similar
designations. By way of example only, "C.sub.2-4 alkynyl" indicates
that there are two to four carbon atoms in the alkynyl chain, i.e.,
the alkynyl chain is selected from the group consisting of ethynyl,
propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and
2-butynyl. Typical alkynyl groups include, but are in no way
limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and
the like.
[0097] As used herein, "heteroalkyl" refers to a straight or
branched hydrocarbon chain containing one or more heteroatoms, that
is, an element other than carbon, including but not limited to,
nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl
group may have 1 to 20 carbon atom, although the present definition
also covers the occurrence of the term "heteroalkyl" where no
numerical range is designated. The heteroalkyl group may also be a
medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl
group could also be a lower heteroalkyl having 1 to 4 carbon atoms.
The heteroalkyl group may be designated as "C.sub.1-4 heteroalkyl"
or similar designations. The heteroalkyl group may contain one or
more heteroatoms. By way of example only, "C.sub.1-4 heteroalkyl"
indicates that there are one to four carbon atoms in the
heteroalkyl chain and additionally one or more heteroatoms in the
backbone of the chain.
[0098] As used herein, "alkylene" means a branched, or straight
chain fully saturated di-radical chemical group containing only
carbon and hydrogen that is attached to the rest of the molecule
via two points of attachment (i.e., an alkanediyl). The alkylene
group may have 1 to 20 carbon atoms, although the present
definition also covers the occurrence of the term alkylene where no
numerical range is designated. The alkylene group may also be a
medium size alkylene having 1 to 9 carbon atoms. The alkylene group
could also be a lower alkylene having 1 to 4 carbon atoms. The
alkylene group may be designated as "C.sub.1-4 alkylene" or similar
designations. By way of example only, "C.sub.1-4 alkylene"
indicates that there are one to four carbon atoms in the alkylene
chain, i.e., the alkylene chain is selected from the group
consisting of methylene, ethylene, ethan-1,1-diyl, propylene,
propan-1,1-diyl, propan-2,2-diyl, 1-methyl-ethylene, butylene,
butan-1,1-diyl, butan-2,2-diyl, 2-methyl-propan-1,1-diyl,
1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene,
1,2-dimethyl-ethylene, and 1-ethyl-ethylene.
[0099] As used herein, "alkenylene" means a straight or branched
chain di-radical chemical group containing only carbon and hydrogen
and containing at least one carbon-carbon double bond that is
attached to the rest of the molecule via two points of attachment.
The alkenylene group may have 2 to 20 carbon atoms, although the
present definition also covers the occurrence of the term
alkenylene where no numerical range is designated. The alkenylene
group may also be a medium size alkenylene having 2 to 9 carbon
atoms. The alkenylene group could also be a lower alkenylene having
2 to 4 carbon atoms. The alkenylene group may be designated as
"C.sub.2-4 alkenylene" or similar designations. By way of example
only, "C.sub.2-4 alkenylene" indicates that there are two to four
carbon atoms in the alkenylene chain, i.e., the alkenylene chain is
selected from the group consisting of ethenylene, ethen-1,1-diyl,
propenylene, propen-1,1-diyl, prop-2-en-1,1-diyl,
1-methyl-ethenylene, but-1-enylene, but-2-enylene,
but-1,3-dienylene, buten-1,1-diyl, but-1,3-dien-1,1-diyl,
but-2-en-1,1-diyl, but-3-en-1,1-diyl, 1-methyl-prop-2-en-1,1-diyl,
2-methyl-prop-2-en-1,1-diyl, 1-ethyl-ethenylene,
1,2-dimethyl-ethenylene, 1-methyl-propenylene,
2-methyl-propenylene, 3-methyl-propenylene,
2-methyl-propen-1,1-diyl, and 2,2-dimethyl-ethen-1,1-diyl.
[0100] The term "aromatic" refers to a ring or ring system having a
conjugated pi electron system and includes both carbocyclic
aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g.,
pyridine). The term includes monocyclic or fused-ring polycyclic
(i.e., rings which share adjacent pairs of atoms) groups provided
that the entire ring system is aromatic.
[0101] As used herein, "aryl" refers to an aromatic ring or ring
system (i.e., two or more fused rings that share two adjacent
carbon atoms) containing only carbon in the ring backbone. When the
aryl is a ring system, every ring in the system is aromatic. The
aryl group may have 6 to 18 carbon atoms, although the present
definition also covers the occurrence of the term "aryl" where no
numerical range is designated. In some embodiments, the aryl group
has 6 to 10 carbon atoms. The aryl group may be designated as
"C.sub.6-10 aryl," "C.sub.6 or C.sub.10 aryl," or similar
designations. Examples of aryl groups include, but are not limited
to, phenyl, naphthyl, azulenyl, and anthracenyl.
[0102] As used herein, "aryloxy" and "arylthio" refers to RO-- and
RS--, in which R is an aryl as is defined above, such as
"C.sub.6-10 aryloxy" or "C.sub.6-10 arylthio" and the like,
including but not limited to phenyloxy.
[0103] An "aralkyl" or "arylalkyl" is an aryl group connected, as a
substituent, via an alkylene group, such as "C.sub.7-14 aralkyl"
and the like, including but not limited to benzyl, 2-phenylethyl,
3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene
group is a lower alkylene group (i.e., a C.sub.1-4 alkylene
group).
[0104] As used herein, "heteroaryl" refers to an aromatic ring or
ring system (i.e., two or more fused rings that share two adjacent
atoms) that contain(s) one or more heteroatoms, that is, an element
other than carbon, including but not limited to, nitrogen, oxygen
and sulfur, in the ring backbone. When the heteroaryl is a ring
system, every ring in the system is aromatic. The heteroaryl group
may have 5-18 ring members (i.e., the number of atoms making up the
ring backbone, including carbon atoms and heteroatoms), although
the present definition also covers the occurrence of the term
"heteroaryl" where no numerical range is designated. In some
embodiments, the heteroaryl group has 5 to 10 ring members or 5 to
7 ring members. The heteroaryl group may be designated as "5-7
membered heteroaryl," "5-10 membered heteroaryl," or similar
designations. Examples of heteroaryl rings include, but are not
limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl,
thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,
pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl,
benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and
benzothienyl.
[0105] A "heteroaralkyl" or "heteroarylalkyl" is heteroaryl group
connected, as a substituent, via an alkylene group. Examples
include but are not limited to 2-thienylmethyl, 3-thienylmethyl,
furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl,
isoxazollylalkyl, and imidazolylalkyl. In some cases, the alkylene
group is a lower alkylene group (i.e., a C.sub.1-4 alkylene
group).
[0106] As used herein, "carbocyclyl" means a non-aromatic cyclic
ring or ring system containing only carbon atoms in the ring system
backbone. When the carbocyclyl is a ring system, two or more rings
may be joined together in a fused, bridged or spiro-connected
fashion. Carbocyclyls may have any degree of saturation provided
that at least one ring in a ring system is not aromatic. Thus,
carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls.
The carbocyclyl group may have 3 to 20 carbon atoms, although the
present definition also covers the occurrence of the term
"carbocyclyl" where no numerical range is designated. The
carbocyclyl group may also be a medium size carbocyclyl having 3 to
10 carbon atoms. The carbocyclyl group could also be a carbocyclyl
having 3 to 6 carbon atoms. The carbocyclyl group may be designated
as "C.sub.3-6 carbocyclyl" or similar designations. Examples of
carbocyclyl rings include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,
2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and
spiro[4.4]nonanyl.
[0107] A "(carbocyclyl)alkyl" is a carbocyclyl group connected, as
a substituent, via an alkylene group, such as "C.sub.4-10
(carbocyclyl)alkyl" and the like, including but not limited to,
cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl,
cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl,
cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl,
cyclohexylethyl, cycloheptylmethyl, and the like. In some cases,
the alkylene group is a lower alkylene group.
[0108] As used herein, "cycloalkyl" means a fully saturated
carbocyclyl ring or ring system. Examples include cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl.
[0109] As used herein, "cycloalkenyl" means a carbocyclyl ring or
ring system having at least one double bond, wherein no ring in the
ring system is aromatic. An example is cyclohexenyl.
[0110] As used herein, "heterocyclyl" means a non-aromatic cyclic
ring or ring system containing at least one heteroatom in the ring
backbone. Heterocyclyls may be joined together in a fused, bridged
or spiro-connected fashion. Heterocyclyls may have any degree of
saturation provided that at least one ring in the ring system is
not aromatic. The heteroatom(s) may be present in either a
non-aromatic or aromatic ring in the ring system. The heterocyclyl
group may have 3 to 20 ring members (i.e., the number of atoms
making up the ring backbone, including carbon atoms and
heteroatoms), although the present definition also covers the
occurrence of the term "heterocyclyl" where no numerical range is
designated. The heterocyclyl group may also be a medium size
heterocyclyl having 3 to 10 ring members. The heterocyclyl group
could also be a heterocyclyl having 3 to 6 ring members. The
heterocyclyl group may be designated as "3-6 membered heterocyclyl"
or similar designations. In preferred six membered monocyclic
heterocyclyls, the heteroatom(s) are selected from one up to three
of O, N or S, and in preferred five membered monocyclic
heterocyclyls, the heteroatom(s) are selected from one or two
heteroatoms selected from O, N, or S. Examples of heterocyclyl
rings include, but are not limited to, azepinyl, acridinyl,
carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl,
morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl,
piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl,
pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl,
1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl,
1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl,
trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl,
1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl,
oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl,
thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl,
tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl,
tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl,
dihydrobenzofuranyl, benzimidazolidinyl, and
tetrahydroquinoline.
[0111] A "(heterocyclyl)alkyl" is a heterocyclyl group connected,
as a substituent, via an alkylene group. Examples include, but are
not limited to, imidazolinylmethyl and indolinylethyl.
[0112] As used herein, "oxo" refers to .dbd.O.
[0113] As used herein, "acyl" refers to --C(.dbd.O)R, wherein R is
hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-7 carbocyclyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
and 5-10 membered heterocyclyl, as defined herein. Non-limiting
examples include formyl, acetyl, propanoyl, benzoyl, and acryl.
[0114] An "O-carboxy" group refers to a "--OC(.dbd.O)R" group in
which R is selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl, C.sub.6-10 aryl,
5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as
defined herein.
[0115] A "C-carboxy" group refers to a "--C(.dbd.O)OR" group in
which R is selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl, C.sub.6-10 aryl,
5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as
defined herein. A non-limiting example includes carboxyl (i.e.,
--C(.dbd.O)OH).
[0116] A "cyano" group refers to a "--CN" group.
[0117] A "cyanato" group refers to an "--OCN" group.
[0118] An "isocyanato" group refers to a "--NCO" group.
[0119] A "thiocyanato" group refers to a "--SCN" group.
[0120] An "isothiocyanato" group refers to an "--NCS" group.
[0121] A "sulfinyl" group refers to an "--S(.dbd.O)R" group in
which R is selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl, C.sub.6-10 aryl,
5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as
defined herein.
[0122] A "sulfonyl" group refers to an "--SO.sub.2R" group in which
R is selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl, C.sub.6-10 aryl, 5-10
membered heteroaryl, and 5-10 membered heterocyclyl, as defined
herein.
[0123] An "S-sulfonamido" group refers to a
"--SO.sub.2NR.sub.AR.sub.B" group in which R.sub.A and R.sub.B are
each independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered
heterocyclyl, as defined herein.
[0124] An "N-sulfonamido" group refers to a
"--N(R.sub.A)SO.sub.2R.sub.B" group in which R.sub.A and Rb are
each independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered
heterocyclyl, as defined herein.
[0125] An "O-carbamyl" group refers to a
"--OC(.dbd.O)NR.sub.AR.sub.B" group in which R.sub.A and R.sub.B
are each independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered
heterocyclyl, as defined herein.
[0126] An "N-carbamyl" group refers to an
"--N(R.sub.A)C(.dbd.O)ORB" group in which R.sub.A and R.sub.B are
each independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered
heterocyclyl, as defined herein.
[0127] An "O-thiocarbamyl" group refers to a
"--OC(.dbd.S)NR.sub.AR.sub.B" group in which R.sub.A and R.sub.B
are each independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered
heterocyclyl, as defined herein.
[0128] An "N-thiocarbamyl" group refers to an
"--N(R.sub.A)C(.dbd.S)ORB" group in which R.sub.A and R.sub.B are
each independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered
heterocyclyl, as defined herein.
[0129] A "C-amido" group refers to a "--C(.dbd.O)NR.sub.AR.sub.B"
group in which R.sub.A and R.sub.B are each independently selected
from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-7 carbocyclyl, C.sub.6-10 aryl, 5-10 membered
heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
[0130] An "N-amido" group refers to a
"--N(R.sub.A)C(.dbd.O)R.sub.B" group in which R.sub.A and R.sub.B
are each independently selected from hydrogen, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 carbocyclyl,
C.sub.6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered
heterocyclyl, as defined herein.
[0131] An "amino" group refers to a "--NR.sub.AR.sub.B" group in
which R.sub.A and R.sub.B are each independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-7 carbocyclyl, C.sub.6-10 aryl, 5-10 membered heteroaryl,
and 5-10 membered heterocyclyl, as defined herein. A non-limiting
example includes free amino (i.e., --NH.sub.2).
[0132] An "aminoalkyl" group refers to an amino group connected via
an alkylene group.
[0133] An "alkoxyalkyl" group refers to an alkoxy group connected
via an alkylene group, such as a "C.sub.2-8 alkoxyalkyl" and the
like.
[0134] As used herein, a substituted group is derived from the
unsubstituted parent group in which there has been an exchange of
one or more hydrogen atoms for another atom or group. Unless
otherwise indicated, when a group is deemed to be "substituted," it
is meant that the group is substituted with one or more
substitutents independently selected from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkenyl, C.sub.1-C.sub.6 alkynyl, C.sub.1-C.sub.6
heteroalkyl, C.sub.3-C.sub.7 carbocyclyl (optionally substituted
with halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, and C.sub.1-C.sub.6 haloalkoxy),
C.sub.3-C.sub.7-carbocyclyl-C.sub.1-C.sub.6-alkyl (optionally
substituted with halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkyl, and C.sub.1-C.sub.6 haloalkoxy),
5-10 membered heterocyclyl (optionally substituted with halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, and C.sub.1-C.sub.6 haloalkoxy), 5-10 membered
heterocyclyl-C.sub.1-C.sub.6-alkyl (optionally substituted with
halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, and C.sub.1-C.sub.6 haloalkoxy), aryl
(optionally substituted with halo, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, and
C.sub.1-C.sub.6 haloalkoxy), aryl(C.sub.1-C.sub.6)alkyl (optionally
substituted with halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkyl, and C.sub.1-C.sub.6 haloalkoxy),
5-10 membered heteroaryl (optionally substituted with halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, and C.sub.1-C.sub.6 haloalkoxy), 5-10 membered
heteroaryl(C.sub.1-C.sub.6)alkyl (optionally substituted with halo,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, and C.sub.1-C.sub.6 haloalkoxy), halo, cyano, hydroxy,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkoxy(C.sub.1-C.sub.6)alkyl (i.e., ether), aryloxy, sulfhydryl
(mercapto), halo(C.sub.1-C.sub.6)alkyl (e.g., --CF.sub.3),
halo(C.sub.1-C.sub.6)alkoxy (e.g., --OCF.sub.3), C.sub.1-C.sub.6
alkylthio, arylthio, amino, amino(C.sub.1-C.sub.6)alkyl, nitro,
O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido,
N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl,
cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl,
sulfonyl, and oxo (.dbd.O). Wherever a group is described as
"optionally substituted" that group can be substituted with the
above substituents.
[0135] It is to be understood that certain radical naming
conventions can include either a mono-radical or a di-radical,
depending on the context. For example, where a substituent requires
two points of attachment to the rest of the molecule, it is
understood that the substituent is a di-radical. For example, a
substituent identified as alkyl that requires two points of
attachment includes di-radicals such as --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH(CH.sub.3)CH.sub.2--, and the
like. Other radical naming conventions clearly indicate that the
radical is a di-radical such as "alkylene" or "alkenylene."
[0136] When two R groups are said to form a ring (e.g., a
carbocyclyl, heterocyclyl, aryl, or heteroaryl ring) "together with
the atom to which they are attached," it is meant that the
collective unit of the atom and the two R groups are the recited
ring. The ring is not otherwise limited by the definition of each R
group when taken individually. For example, when the following
substructure is present:
##STR00015##
and R.sup.1 and R.sup.2 are defined as selected from the group
consisting of hydrogen and alkyl, or R.sup.1 and R.sup.2 together
with the nitrogen to which they are attached form a heteroaryl, it
is meant that R.sup.1 and R.sup.2 can be selected from hydrogen or
alkyl, or alternatively, the substructure has structure:
##STR00016##
where ring A is a heteroaryl ring containing the depicted
nitrogen.
[0137] Similarly, when two "adjacent" R groups are said to form a
ring "together with the atoms to which they are attached," it is
meant that the collective unit of the atoms, intervening bonds, and
the two R groups are the recited ring. For example, when the
following substructure is present:
##STR00017##
and R.sup.1 and R.sup.2 are defined as selected from the group
consisting of hydrogen and alkyl, or R.sup.1 and R.sup.2 together
with the atoms to which they are attached form an aryl or
carbocyclyl, it is meant that R.sup.1 and R.sup.2 can be selected
from hydrogen or alkyl, or alternatively, the substructure has
structure:
##STR00018##
where A is an aryl ring or a carbocyclyl containing the depicted
double bond.
[0138] Wherever a substituent is depicted as a di-radical (i.e.,
has two points of attachment to the rest of the molecule), it is to
be understood that the substituent can be attached in any
directional configuration unless otherwise indicated. Thus, for
example, a substituent depicted as -AE- or
##STR00019##
includes the substituent being oriented such that the A is attached
at the leftmost attachment point of the molecule as well as the
case in which A is attached at the rightmost attachment point of
the molecule.
[0139] "Leaving group," or "LG," as used herein refers to any atom
or moiety that is capable of being displaced by another atom or
moiety in a chemical reaction. More specifically, in some
embodiments, "leaving group" refers to the atom or moiety that is
displaced in a nucleophilic substitution reaction. In some
embodiments, "leaving groups" are any atoms or moieties that are
conjugate bases of strong acids. Examples of suitable leaving
groups include, but are not limited to, tosylates and halogens.
Non-limiting characteristics and examples of leaving groups can be
found, for example in Organic Chemistry, 2d ed., Francis Carey
(1992), pages 328-331; Introduction to Organic Chemistry, 2d ed.,
Andrew Streitwieser and Clayton Heathcock (1981), pages 169-171;
and Organic Chemistry, 5th ed., John McMurry (2000), pages 398 and
408; all of which are incorporated herein by reference for the
limited purpose of disclosing characteristics and examples of
leaving groups.
[0140] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which the embodiments belong. Although
any methods and materials similar or equivalent to those described
herein can also be used in the practice or testing of the
embodiments, the preferred methods and materials are now described.
All publications mentioned herein are incorporated herein by
reference to disclose and describe the methods and/or materials in
connection with which the publications are cited.
Protecting Groups
[0141] In some circumstances, a chemical reaction may need to be
performed selectively at one reactive site in a multifunctional
compound. One such method that is useful for accomplishing such
selectivity is to temporarily block one or more reactive sites in
the multifunctional compound with a protective group. Such a method
is often referred to as "protecting" the functional group. Many
protecting groups are known in the art. See, e.g., Greene et al.,
Protective Groups in Organic Synthesis, Third Ed. (John Wiley &
Sons, Inc. 1999), herein incorporated by reference in its entirety;
Wutz et al., Greene's Protective Groups in Organic Synthesis,
Fourth Ed. (John Wiley & Sons, Inc. 2007), herein incorporated
by reference in its entirety. When more than one reactive site in a
multifunctional compound requires protecting, or when a compound is
prepared that will possess more than one protected functional
group, it is important to use orthogonal protecting groups.
Protecting groups are orthogonal if they are susceptible to
selective removal.
[0142] In some embodiments, it may be necessary to protect one or
more functional groups so as to prevent their interference in the
desired reaction. For example, it may be necessary to protect one
or more functional groups such as amines, carboxylic acids, and/or
hydroxyl groups.
[0143] Suitable protecting groups for protecting amines include:
carbamates such as alkyl carbamates including methyl, ethyl,
propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, neopentyl,
hexyl, heptyl, nonnyl, decanyl, and configurational isomers
thereof; 9-flurenylmethyl; 9-(2-sulfo)flurenylmethyl;
9-(2,7-dibromo)fluorenylmethyl;
17-tetrabenzo[a,c,g,i]flurenylmethyl; 2-chloro-3-indenylmethyl;
benz[f]inden-3-ylmethyl;
2,7-di-t-butyl[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl;
1,1-dioxobenzo[b]thiophene-2-ylmethyl; substituted ethyl carbamates
such as 2,2,2-trichloroethyl; 2-trimethyl silylethyl;
2-phenylethyl; 1-(1-adamantyl)-1-methylethyl; 2-chloroethyl;
1,1-dimethyl-2-haloethyl; 1,1-dimethyl, 2,2-dibromoethyl;
1,1-dimethyl-2,2,2-trichloroethyl; 1-methyl-1-(4-biphenylyl)ethyl;
1-(3,5-di-t-butylphenyl)-1-methylethyl; 2-(2'- and 4'-prydyl)ethyl;
N-(2-pivaloylamino)-1,1-dimethylethyl;
2-[(2-nitrophenyl)dithio]-1-phenylethyl;
2-(N,N-dicyclohexylcarboxamido)ethyl; t-butyl; 1-adamantyl;
2-adamantyl; vinyl; allyl; 1-isopropylallyl; cinnamyl;
4-nitrocinnamyl; 3-(3'-pyridyol)prop-2-enyl; 8-quinolyl;
N-hydroxypiperidinyl; alkydithio; benzyl; p-methoxybenzyl;
p-nitrobenzykl; p-bromobenzyl; p-chlorobenzyl; 2,4-dichlorobenzyl;
4-methyl sulfinylbenzyl; 9-anthrylmethyl; diphenylmethyl;
2-methylthioethyl; 2-methyl sulfonylethyl;
2-(p-toluenesulfonyl)ethyl; [2-(1,3-dithianyl)]methyl;
4-methylthiophenyl; 2,4-dimethylthiophenyl; 2-phosphonioethyl;
1-methyl-1-(triphenylphosphonio)ethyl; 1,1-dimethyl-2-cyanoethyl;
2-dansylethyl; 2-(4-nitrophenyl)ethyl; 4-phenylacetoxybenzyl;
4-azidobenzyl; 4-azidomethoxybenzyl; m-chloro-p-acyloxybenzyl;
p-(dihydroxyboryl)benzyl; 5-benzisoxazolylmethyl;
2-(trifluoromethyl)-6-chromonylmethyl; m-nitrophenyl;
3,5-dimethoxybenzyl; 1-methyl-1-(3,5-dimethoxyphenyl)ethyl;
a-methylnitropiperonyl; o-nitrobenzyl; 3,4-dimethoxy-6-nitrobenzyl;
phenyl(o-nitrophenyl)methyl; 2-(2-nitrophenyl)ethyl;
6-nitroveratryl; 4-methoxyphenacyl; 3',5'-dimethoxybenzoin;
phenothiazinyl-(10)-carbonyl derivatives;
N'-p-toluenesulfonylaminocarbonyl; N'-phenylaminothiocarbonyl;
t-amyl; S-benzyl thiocarbamate; butynyl; p-cyanobenzyl; cyclobutyl;
cyclohexyl; cyclopentyl; cyclopropylmethyl; p-dicyloxybenzyl;
diisopropylmethyl; 2,2-dimethoxycarbonylvinyl;
o-(N',N'-dimethylcarboxamido)benzyl;
1,1-dimethyl-3-(N',N'-dimethylcarboxamido)propyl;
1,1-dimethylpropynyl; di(2-pyridyl)methyl; 2-furanylmethyl;
2-iodoethyl; isobornyl; isobutyl; isonicotinyl;
p-(p'-methoxyphenylazo)benzyl; 1-methylcyclobutyl;
1-methylcyclohexyl; 1-methyl-1-cyclopropylmethyl;
1-methyl-1-(p-phenylazophenyl)ethyl; 1-methyl-1-phenylethyl;
1-methyl-1-(4'-pyridyl)ethyl; phenyl; p-(phenylazo)benzyl;
2,4,6-tri-t-butylphenyl; 4-(trimethylammonium)benzyl;
2,4,6-trimethylbenzyl; and other similar carbamates; amides,
including, but not limited to, formyl, acetyl, chloroacetyl,
trichloroacetyl, trifluoroacetyl, phenylacetyl, propionyl,
3-phenylpropionyl, 4-pentenoyl, picolinoyl, 3-pyridylcarboxamide,
benzoylphenylalanyl, benzoyl, p-phenylbenzoyl, amides whose
cleavage is induced by nitro group reduction, such as
o-nitrophenylacetyl, o-nitrophenoxyacetyl,
3-(o-nitrophenyl)propionyl, 2-methyl-2-(o-nitrophenoxy)propionyl,
3-methyl-3-nitrobutyryl, o-nitrocinnamoyl, o-nitrobenzoyl, and
3-(4-t-butyl-2,6-dinitrophenyl)-2,2-dimethylpropionyl; amides whose
cleavage is induced by release of an alcohol, such as
o-(benzoyloxymethyol)benzoyl, (2-acetoxymethyl)benzoyl,
2-[(t-butyldiphenylsiloxy)methyl]benzoyl,
3-(3',6'-dioxo-2',4',5'-trimethylcyclohexa-1',4'-diene-3,3-dimethylpropio-
nyl, and o-hydroxy-trans-cinnamoyl; amides whose cleavage is
induced by other chemical reactions, such as
2-methyl-2-(o-phenylazophenoxy)propionyl, 4-chlorobutyryl,
acetoacetyl, 3-(p-hydroxyphenyl)propionyl,
(N'-dithiobenzyloxycarbonylamino)acetyl, N-acetylmethionine, and
4,5-diphenyl-3-oxazolin-2-one; cyclic imide derivatives such as
N-phthaloyl, N-tetrachlorophthaloyl, N-4-nitrophthaloyl,
N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,
N-2,5-dimethylpyrrolylN-2,5-bis(triisopropylsiloxy)pyrrolyl,
N-1,1,4,4-tetramethyldisilylazacyclopentane adduct,
N-1,1,3,3-tetramethyl-1,3-disilaisoindolyl, 5-substituted
1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted
1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted
3,5-dinitro-4-pyridonyl, and 1,3,5-dioxazinyl; N-alkyl and N-aryl
derivatives, such as N-methyl, N-t-butyl, N-allyl,
N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl,
N-cyanomethyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl),
N-2,4-dimethoxybenzyl, N-2-azanorbornenyl, N-2,4-dinitrophenyl,
quaternary ammonium salts, N-benzyl, N-4-methoxybenzyl,
N-2,4-dimethoxybenzyl, N-2-hydroxybenzyl, N-diphenylmethyl,
N-bis(4-methoxyphenyl)methyl, N-5-dibenzosuberyl,
N-triphenylmethyl, N-(4-methoxyphenyl)duiphenylmethyl,
N-9-phenylfluorenyl, N-ferrocenylmethyl, and N-2-picolylamine
N'-oxide; imine derivatives, such as N-1,1-dimethylthiomethylene,
N-benzylidene, N-p-methoxybenzylidine, N-diphenylmethylene,
N-[(2-pyridyl)mesityl]methylene, N--(N',N'-dimethylaminomethylene),
N--(N',N'-dibenzylaminomethylene), N--(N'-t-butylaminomethylene),
N,N'-isopropylidene, N-p-nitrobenzylidene, N-salicylidene,
N-5-chlorosalicylidene,
N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene, and
N-t-butylidene; enamine derivatives, such as
N-(5,5-dimethyl-3-oxo-1-cyclohexenyl),
N-2,7-dichloro-9-fluorenylmethylene,
N-2-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl,
N-4,4,4-trifluoro-3-oxo-1-butenyl, and
N-1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl; and N-heteroatom
derivatives such as N-metal, N-borane, N-diphenylborinic acid,
N-diethylborinic acid, N-difloroborinic acid,
N,N'-3,5-bis(trifluoromethyl)phenylboronic acid,
N-[phenyl(pentacarbonylchromium-or-tungsten)]carbonyl, N-copper
chelates, N-zinc chelates, and 18-crown-6 derivatives, N--N
derivatives such as N-nitro, N-nitroso, N-oxide, and triazene
derivatives, N--P derivatives such as N-diphenylphosphinyl,
N-dimethylthiophosphinyl, N-diphenylthiophosphinyl,
N-dialkylphosphoryl, N-dibenzylphosphoryl, N-diphenylphosphoryl,
and iminotriphenylphosphorane derivatives, N--Si derivatives,
N-sulfenyl derivatives such as N-benzenesulfonyl,
N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl,
N-pentachlorobenzenesulfenyl, N-2-nitro-4-methoxybenzenesulfenyl,
N-triphenylmethyl sulfenyl,
N-1-(2,2,2-trifluoro-1,1-diphenyl)ethylsulfenyl, and
N-3-nitro-2-pyridinesulfenyl, and/or N-sulfonyl derivatives such as
N-p-toluenesulfonyl, N-benzenesulfonyl,
N-2,3,6-trimethyl-4-methoxybenzenesulfonyl,
N-2,4,6-trimethoxybenzenesulfonyl,
N-2,6-dimethyl-4-methoxybenzenesulfonyl,
N-pentamethylbenzenesulfonyl,
N-2,3,5,6-tetramethyl-4-methoxybenzenesulfonyl,
N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl,
N-2,6-dimethoxy-4-methylbenzenesulfonyl,
N-3-methoxy-4-t-butylbenzenesulfonyl,
N-2,2,5,7,8-pentamethylchroman-6-sulfonyl,
N-2-nitrobenzenesulfonyl, N-4-nitrobenzenesulfonyl,
N-2,4-dinitrobenzenesulfonyl, N-benzothiazole-2-sulfonyl,
N-methanesulfonyl, N-2-(trimethyl silyl)ethanesulfonyl,
N-9-anthracenesulfonyl,
N-4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonyl,
N-benzylsulfonyl, N-trifluoromethylsulfonyl, N-phenacylsulfonyl,
and N-t-butylsulfonyl.
[0144] Suitable protecting groups for carboxylic acids include:
esters such as enzymatically cleavable esters including heptyl,
2-N-(morpholino)ethyl, choline, (methoxyethoxy)ethyl, methoxyethyl;
alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl,
tert-butyl, sec-butyl, pentyl, neopentyl, hexyl, heptyl, nonnyl,
decanyl, and configurational isomers thereof; substituted methyl
esters such as 9-fluroenylmethyl, methoxymethyl, methylthiomethyl,
tetrahydropyranyl, teatrahydrofuranyl, methoxyethoxymethyl,
2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, pivaloyloxymethyl,
phenylacetoxymethyl, triisopropylsilylmethyl, cyanomethyl, acetol,
phencacyl, p-bromophenacyl, .alpha.-methylphenacyl,
p-methoxyphenacyl, desyl, carboamidomethyl,
p-azobenzenecarboxamidomethyl, N-phthalidimdomethyl; 2-substituted
ethyl esters such as 2,2,2-trichloroethyl, 2-haloethyl,
.omega.-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl,
1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl,
2-(p-toluenesulfonyl)ethyl, 2-(2'-pyridyl)ethyl,
2-(p-methoxyphenyl)ethyl, 2-(diphenylphosphino)ethyl,
1-methyl-1-phenylethyl, 2-(4-acetyl-2-nitrophenyl)ethyl,
2-cyanoethyl, 3-methyl-3-pentyl, dicyclopropylmethyl,
2,4-dimethyl-3-pentyl, cyclopentyl, cyclohexyl, allyl, methallyl,
2-methylbut-e-en-2-yl, 3-methylbut-2-(prenyl), 3-buten-1-yl,
4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, .alpha.-methylcinnamyl,
prop-2-ynyl, phenyl; 2,6-dialkylphenyl esters such as
2,6-dimethylphenyl, 2,6-diisopropylphenyl,
2,6-di-t-butyl-4-methylphenyl, 2,6-di-t-butyl-4-methoxyphenyl,
p-(methylthio)phenyl, pentafluorophenyl, benzyl; substituted benzyl
esters such as triphenylmethyl, diphenylmethyl,
bis(o-mitrophenyl)methyl, 9-anthrylmethyl,
2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyreneylmethyl,
2-(trifluoromethyl)-6-chromonylmethyl, 2,4,6-trimethylbenzyl,
p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,
2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl,
4-azidomethoxybenzyl,
4-{N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino}benzy-
l, piperonyl, 4-picolyl, polymer supported p-benzyl; silyl esters
such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl,
i-propyldimethylsilyl, phenyldimethylsilyl, di-t-butylmethylsilyl,
triisopropylsilyl; activated esters such as thiol esters; oxazoles;
2-alkyl-1,3-axazoline; 4-alkyl-5-oxo-1,3-oxazolidine;
2,2-bistrifluoromethyl-4-alkyl-5-oxo-1,3-oxazolidine;
5-alkyl-4-oxo-1,3-dioxolane; dioxanones; ortho esters;
pentaaminocobalt(III) complexes; and stannyl esters such as
triethylstannyl and tri-n-butylstannyl; amides such as
N,N-dimethyl, pyrrolidinyl, piperidinyl,
5,6-dihydrophenanthridinyl, o-nitroanilide, N-7-nitroindolyl,
N-8-nitro-1,2,3,4-tetrahydroquinolyl, 2-(2-aminophenyl)acetaldehyde
dimethyl acetal amide, and polymer supported p-benzenesulfonamide;
hydrazides such as N-phenyl, N,N'diisopropyl; and
tetraalkylammonium salts such as methyl, ethyl, propyl, isopropyl,
butyl, tert-butyl, sec-butyl, pentyl, neopentyl, hexyl, heptyl,
nonnyl, decanyl, and configurational isomers thereof.
[0145] Suitable protecting groups for hydroxyl groups include:
silyl ethers such as trimethylsilyl, triethylsilyl,
triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,
dimethylthexylsilyl, 2-norbornyldimethylsilyl, t-butyl-dimethyl
silyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl,
triphenylsilyl, diphenylmethylsilyl, di-t-butylmethylsilyl,
bis(t-butyl)-1-pyrenylmethoxysilyl, tris(trimethylsilyl)silyl:
sisyl; (2-hydroxystyryl)dimethylsilyl;
(2-hydroxystyryl)diisopropylsilyl, t-butylmethoxyphenyl silyl,
t-butoxydiphenyl silyl,
1,1,3,3-tetraisopropyl-3-[2-(triphenylmethoxy)ethoxy]disiloxane-1-yl,
fluorous silyl; C.sub.1-10alkyl ethers such as methyl, ethyl,
propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, neopentyl,
hexyl, heptyl, nonnyl, decanyl, and configurational isomers
thereof; substituted methyl ethers such as methoxymethyl,
methylthiomethyl, (phenyldimethylsilyl)methoxymethyl,
benzyloxymethyl, p-methoxybenzyloxymethyl,
[(3,4-dimethoxybenzyl)oxy]methyl, p-nitrobenzyloxymethyl,
o-nitrobenzyloxymethyl, [(R)-1-(2-nitrophenyl)ethoxy]methyl,
(4-methoxyphenoxy)methyl, guaiacolmethyl, t-butoxymethyl,
4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl,
2-cyanoethoxymethyl, 2,2,2-trichloroethoxymethyl,
bis(2-chloroethoxy)methyl, 2-(trimethyl silyl)ethoxymethyl,
methoxymethyl, O-Bis(2-acetoxyethoxy)methyl, tetrahydropyranyl,
fluorous tetrahydropyranyl, 3-bromotetrahydropyranyl,
tetrahydrothiopyranyl, 1-methoxycyclohexyl,
4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl,
4-methoxytetrahydrothiopyranyl S,S-dioxide,
1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,
1-(2-fluorophenyl)-4-methoxypiperidin-4-yl,
1-(4-chlorophenyl)-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl,
tetrahydrofuranyl, tetrahydrothiofuranyl, and
2,3,2a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl;
substituted ethyl ethers such as 1-ethoxyethyl,
1-(2-chloroethoxy)ethyl, 2-hyddroxyethyl, 2-bromoethyl,
1-[2-(trimethyl silyl)ethoxy]ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,
1-methyl-1-phenoxyethyl, 2,2,2-trichloroethyl,
1,1-dianisyl-2,2,2-trichloroethyl,
1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 1-(2-cyanoethoxy)ethyl,
2-trimethyl silylethyl, 2-(benzylthio)ethyl,
2-(phenylselenyl)ethyl, t-butyl, allyl, prennyl, cinnamyl,
2-phenallyl, propargy, p-chlorophenyl, p-methoxyphenyl,
p-nitrophenyl, 2,4-dinitrophenyl,
2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl; benzyl; substituted
benzyl ethers such as p-methoxybenzyl, 3,4-dimethoxybenzyl,
o-nitrobenzyl, p-nitrobenzyl, pentadienylnitrobenzyl,
pentadienylnitropiperonyl, halobenzyl, 2,6-dichlorobenzyl,
2,4-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl,
2,6-difluorobenzyl, fluorous benzyl, 4-fluorousalkoxybenzyl,
trimethylsilylxylyl, 2-phenyl-2-propyl (Cumyl), p-acylaminobenzyl,
p-azidobenzyl, 4-azido-3-chlorobenzyl, 2-trifluoromethylbenzyl,
4-trifluromethylbenzyl, p-(methyl sulfinyl)benzyl,
p-siletanylbenzyl, 4-acetoxybenzyl,
4-(2-trimethylsilyl)ethoxymethoxybenzyl, 2-napthylmethyl,
2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,
2-quinolinylmethyl, 6-methoxy-2-(4-methylphenyl)-4-quinolinemethyl,
1-pyrenylmethyl, diphenylmethyl, 4-methoxydiphenylmethyl,
4-phenyldiphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl,
triphenylmethyl, a-napthyldiphenylmethyl,
p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,
tri(p-methoxyphenyl)methyl,
4-(4'-bromophenacyloxy)phenyldiphenylmethyl, 4,4',4`
`-tris(4,5-dichlorophthalimidophenyl)methyl,
4,4',4''-tris(levulinoyloxyphenyl)methyl,
4,4',4''-tris(benzoyloxyphenyl)methyl,
4,4'-dimethoxy-3''-[N-imidazolylmethyl)]trityl,
4,4'-dimethoxy-3''-[N-imidazolylethyl)carbamoyl]trityl,
1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl,
4-(17-tetrabenzo[a,c,g,i]fluorenylmethyl)-4,4'-dimethoxytrityl,
9-anthryl, 9-(9-phenyl)xanthenyl, 9-phenylthioxanthyl,
9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl,
4,5-bis(ethoxycarbonyl)-[1,3]-dioxolan-2-yl, benzisothiazolyl
S,S-dioxido; C.sub.1-10alkyl esters such as formyl, acetyl,
propionyl, isopropionyl, butyryl, tert-butyryl, sec-butyryl,
pentanoyl, neopentanoyl, hexanoyl, heptanoyl, nonanoyl, decanoyl,
and configurational isomers thereof, esters such as benzoylformate,
chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,
methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,
p-chlorophenoxyacetate, phenylacetate, polymer supported
p-phenylacetate, diphenylacetate, bisfluorous chain type propanoyl,
nicotinate, 3-phenylpropionate, 4-pentenoate, 4-oxopentanoate,
4,4-(ethylenedithio)pentanoate,
5-[3-bis(4-methoxyphenyl)hydroxymethylphenoxy]levulinate,
pivaloate, 1-adamantoate, crotonate, 4-methoxycrotonate, benzoate,
p-phenylbenzoate, 2,4,6-trimethylbenzoate, picolinate, nicotinate,
4-bromobenzoate, 2,5-difluorobenzoate, p-nitrobenzoate,
2,6-dichloro-4-methylphenoxyacetate,
2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,
2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,
isobutyrate, monosuccinoate, 2-methyl-2-butenoate,
(E)-2-methyl-2-butenoate, (Z)-2-methyl-2-butenoate,
o-(methoxycarbonyl)benzoate, polymer supported p-benzoate,
a-naphthoate, nitrate, alkyl
N,N,N',N'-tetramethylphosphorodiamidate, 2-chlorobenzoate,
3',5'-dimethoxybenzoin, N-phenylcarbamate, borate,
dimethylphosphinothioyl, 2,4-dinitrophenylsulfenate, and
photolabile esters; carbonates, including methyl, methoxymethyl,
9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl,
1,1-dimethyl-2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,
2-(triphenylsulfonyl)ethyl, 2-(triphenylphosphonia)ethyl, isobutyl,
vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl,
3,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, and silyl
esters; carbonates cleaved by .beta.-elimination such as
2-dansylethyl, 2-(4-nitrophenyl)ethyl, 2-(2,4-dinitrophenyl)ethyl,
2-cyano-1-phenylethyl, S-benzyl thiocarbonate, 4-ethoxy-1-mapthyl,
and methyl dithiocarbonate, carbonates cleaved with assisted
cleavage such as 2-iodobenzoate, 4-azidobutyrate,
4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,
2-formylbenzenesulfonate, 2-(methylthiomethyoxy)ethyl,
4-(methylthiomethoxymethyl)butyrate,
2-(methylthiomethoxymethyl)benzoate,
2-(chloroacetoxymethyl)benzoate,
2-[(2-chloroacetoxy)ethyl]benzoate, 2-[2-(benzyloxy)ethyl]benzoate,
2-[2-(4-methoxybenzyloxy)ethyl]benzoate; and sulfonates such as
sulfate, allylsulfate, C.sub.1-10alkyl sulfonates such as methyl,
ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl,
neopentyl, hexyl, heptyl, nonnyl, decanyl, and configurational
isomers thereof, benzylsulfonate, tosylate, and
2-[(4-nitrophenyl)ethyl]sulfonate.
Protection and Deprotection Reactions
[0146] Reagents, solvents, and reaction conditions useful for
protecting amines, carboxylic acids, and alcohols are well-known in
the art. Likewise, reagents, solvents, and reaction conditions
useful for deprotecting amines, carboxylic acids, and alcohols are
well known in the art. See, e.g., Greene et al., Protective Groups
in Organic Synthesis, Third Ed. (John Wiley & Sons, Inc. 1999),
herein incorporated by reference in its entirety; Wutz et al.,
Greene's Protective Groups in Organic Synthesis, Fourth Ed. (John
Wiley & Sons, Inc. 2007), herein incorporated by reference in
its entirety. While references have been made to specific reagents,
solvents, and reaction conditions in the schemes described above,
it is readily envisioned that equivalent reagents, solvents, and
reaction conditions may be utilized to protect and deprotect
amines, carboxylic acids, and alcohols.
Intermediate Compounds
[0147] Some embodiments disclosed herein include intermediates in
the synthetic methods described herein, including a compound having
the structure of Formula (I) or (II) as described herein.
[0148] In some embodiments, X is Cl. In some embodiments, m is
2.
[0149] In some embodiments for the compounds of Formula (II), X is
a halogen, and
[0150] each of R.sup.1a and R.sup.1b is independently selected from
the group consisting of an optionally substituted C.sub.1-C.sub.12
alkyl, optionally substituted C.sub.3-C.sub.8 cycloalkyl,
optionally substituted C.sub.2-C.sub.12 alkenyl, optionally
substituted C.sub.2-C.sub.12 alkynyl, optionally substituted aryl
and optionally substituted heteroaryl, or R.sup.1a and R.sup.1b
optionally form a 5-7 membered boron ester ring with intervening
atoms, and R.sup.2 is selected from the group consisting of an
optionally substituted C.sub.1-C.sub.12 alkyl, optionally
substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted
C.sub.2-C.sub.12 alkenyl, optionally substituted C.sub.2-C.sub.12
alkynyl, optionally substituted aryl and optionally substituted
heteroaryl.
[0151] In some embodiments, X is Cl.
[0152] In some embodiments, each of R.sup.1a and R.sup.1b is a
butyl group. In some embodiments, R.sup.1a and R.sup.1b are both
n-butyl groups.
Methods of Preparation
[0153] Some embodiments relate to a method of making a compound of
Formula (B) by reducing the ketone group of the keto-ester compound
of Formula (A). In some embodiments, the reduction is performed
using a Ruthenium based catalyst system. In some embodiments, the
reduction is performed using an alcohol dehydrogenase bioreduction
system
[0154] In some embodiments, for the compound of Formula (A)-(C),
(A-1), and (B-1), X is Cl. In some embodiments, m is 2.
[0155] In some embodiments, the ketone group in the compound of
Formula (A) is reduced using a Ruthenium based catalyst.
[0156] In some embodiments, the Ruthenium based catalyst has the
structure of Formula (III):
R.sup.3Ru(X.sup.1).sub.2 (III),
[0157] wherein:
[0158] X.sup.1 is a halogen, benzene, cymene, or an acetyl (OAc)
group; and
[0159] R.sup.3 is a ligand selected from the group consisting of
(S)-BINA, (R)-BINAP, (R)--H.sub.8-BINAP, (R)-SegPhos,
(R)-DM-SegPhos, (S)-SegPhos, (R)-tolyl-BINAP, (R)-xylyl-BINAP,
(S)-tolyl-BINAP, (S)-BINAPHANE, (S)-PhanePhos, JosiPhos-2-1,
(R)-SolPhos SL-A001-1, (S)-MeOBiPhep, (S)--P-Phos, and
(S)-(+)-DTBM-SEGPHOS.
[0160] In some embodiments, X.sup.1 is a Cl or --OAc group.
[0161] In some embodiments, R.sup.3 is (R)-SegPhos.
[0162] In some embodiments, the Ruthenium based catalyst is
Ru(OAc).sub.2((R)-SegPhos).
[0163] In some embodiments, the Ruthenium based catalyst is
[NH.sub.2Me.sub.2][{RuCl((S)-SegPhos)}.sub.2(.mu.-Cl).sub.3] or
[NH.sub.2Me.sub.2][{RuCl((R)-DM-SegPhos)}.sub.2(.mu.-Cl).sub.3].
[0164] In some embodiments, the ketone group in the compound of
Formula (A) is reduced using Ru(OAc).sub.2((R)-SegPhos) and
methanol.
[0165] In some embodiments, the method described herein includes
reducing the ketone group in the compound of Formula (A) with an
alcohol dehydrogenase system.
[0166] In some embodiments, the alcohol dehydrogenase system
comprises a reduced nicotinamide adenine dinucleotide (NADH), a
reduced nicotinamide adenine dinucleotide phosphate (NADPH), and an
alcohol.
[0167] In some embodiments, the alcohol is isopropyl alcohol.
[0168] In some embodiments, the reduction is performed at a pH less
than about 8. In some embodiments, the reduction is performed at a
pH less than about 7.5. In some embodiments, the reduction is
performed at a pH less than about 7. In some embodiments, the
reduction is performed at a pH in the range of about 5 to 8, about
5.5 to 7.5, about 6 to 6.5. In some embodiments, the reduction is
performed at pH about 6.
[0169] In some embodiments, the method described herein includes
dividing and adding reaction reagents in two or more portions. In
some embodiments, the method described herein includes dividing and
adding the compound of Formula (A) into two or more portions.
[0170] In some embodiments, the method described herein includes
applying vacuum prior to adding a new portion of reaction reagents.
In some embodiments, the method described herein includes applying
vacuum prior to adding a new portion of the compound of Formula
(A).
[0171] In some embodiments, the resulted compound (B) has an
enantiomeric excess of more than 80%. In some embodiments, the
resulted compound (B) has an enantiomeric excess of more than 90%.
In some embodiments, the resulted compound (B) has an enantiomeric
excess of more than 92%, 94%, 95%, 96%, 97%, 98%, or 99%.
[0172] In some embodiments, R.sup.2, R.sup.4a and R.sup.4b are each
independently a butyl group. In some embodiments, R.sup.2 is a
t-butyl group and R.sup.4a and R.sup.4b n-butyl group. In some
embodiments, R.sup.2, R.sup.4a and R.sup.4b are each independently
optionally substituted C.sub.1-6 alkyl group.
[0173] Some embodiments relate to a method of making the compound
of Formula (B-1) by adding a boronate to the compound of formula
(C).
[0174] Some embodiments relate to a compound of making the compound
of formula (D) from the compound of Formula (C) using a Grignard
reagent. In some embodiments, the Grignard reagent is
magnesium.
[0175] In some embodiments, R.sup.2, R.sup.4a and R.sup.4b are
independently a butyl group. In some embodiments, R.sup.2 is a
t-butyl group, and R.sup.4a and R.sup.4b are n-butyl group.
[0176] In some embodiments, the compound of Formula (D)
[0177] is
##STR00020##
[0178] In some embodiments, the method described herein further
includes mixing ZnCl.sub.2 with magnesium to react with the
compound of Formula (C).
[0179] In some embodiments, the method described herein further
includes adding acid to hydrolyze the first reaction
intermediate.
[0180] In some embodiments, the method described herein further
includes adding dichloromethane to the reaction mixture after the
hydrolysis of the first reaction intermediate.
[0181] Some embodiments relate to a method of making the compound
of Formula (E) by reacting the compound of Formula (D) with the
complexing agent of Formula (CL).
[0182] In some embodiments, for the compound of Formula (D) and
(E), R.sup.2 is a butyl group. In some embodiments, R.sup.2 is a
t-butyl group.
[0183] In some embodiments, for the compound of Formula (D) and
(E), m is 2. In some embodiments, for the compound of Formula (CL)
and (E), n is 2.
[0184] In some embodiments, the compound of Formula (E) is
##STR00021##
In some embodiments, the complexing agent of Formula (CL) is
NH.sub.2(CH.sub.2).sub.2OH.
[0185] In some embodiments, the compound of Formula (E) has the
structure of Formula (E-1):
##STR00022##
[0186] In some embodiments, the method described herein further
includes reacting the compound of Formula (E) with pinanediol to
form a compound of Formula (F)
##STR00023##
[0187] protecting the hydroxy group of the compound of Formula (F)
with a PG group to form a compound of Formula (G),
##STR00024##
[0188] reacting the compound of Formula (G) with n-butyllithium and
dichloromethane to form a compound of Formula (H), and
##STR00025##
[0189] reacting the compound of Formula (H) with an
LiN(SiR.sup.12).sub.2 to form a compound of Formula (J)
##STR00026##
[0190] reacting the compound of Formula (J) with R.sup.13--COCl to
form a compound of Formula (K)
##STR00027##
[0191] removing the PG group on the compound of formula (K) to form
a compound of formula (L):
##STR00028##
[0192] wherein:
[0193] PG is a hydroxy protection group,
[0194] R.sup.12 is optionally substituted phenyl or optionally
substituted C.sub.1-8 alkyl, and
[0195] R.sup.13 is selected from optionally substituted C.sub.1-8
alkyl, optionally substituted C.sub.0-4 alkyl-C.sub.6-10 aryl,
optionally substituted C.sub.0-4 alkyl-5-10 membered heteroaryl,
optionally substituted C.sub.0-4 alkyl-C.sub.3-10 carbocyclyl, and
C.sub.0-4 alkyl-4-10 membered heterocyclyl.
[0196] In some embodiments, the compound of Formula (G) reacts with
the n-butyllithium and dichloromethane at a temperature lower than
-90.degree. C. to form the compound of Formula (H).
[0197] In some embodiments, the PG group is a
tert-Butyldimethylsilyl group.
[0198] In some embodiments, R.sup.2 is t-butyl group.
[0199] In some embodiments, R.sup.13 is
##STR00029##
[0200] In some embodiments, the compound of Formula (L) is
##STR00030##
[0201] The compounds disclosed herein may be synthesized by methods
described below, or by modification of these methods. Ways of
modifying the methodology include, among others, temperature,
solvent, reagents etc., known to those skilled in the art. In
general, during any of the processes for preparation of the
compounds disclosed herein, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry (ed. J. F. W. McOmie, Plenum Press, 1973); and P. G. M.
Green, T. W. Wutts, Protecting Groups in Organic Synthesis (3rd
ed.) Wiley, New York (1999), which are both hereby incorporated
herein by reference in their entirety. The protecting groups may be
removed at a convenient subsequent stage using methods known from
the art. Synthetic chemistry transformations useful in synthesizing
applicable compounds are known in the art and include e.g. those
described in R. Larock, Comprehensive Organic Transformations, VCH
Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for
Organic Synthesis, John Wiley and Sons, 1995, which are both hereby
incorporated herein by reference in their entirety. The routes
shown and described herein are illustrative only and are not
intended, nor are they to be construed, to limit the scope of the
claims in any manner whatsoever. Those skilled in the art will be
able to recognize modifications of the disclosed syntheses and to
devise alternate routes based on the disclosures herein; all such
modifications and alternate routes are within the scope of the
claims. Unless otherwise indicated, substituent variables in the
following schemes have the same definitions as elsewhere in this
application.
[0202] An exemplary but non-limiting general synthetic scheme for
preparing the intermediate compound of Formula
EXAMPLES
Example 1--Stability of Compound 1
[0203] The stability of Compound 1 was studied and it was found
that the keto ester of Compound 1 is very unstable in aqueous
environment. Upon incubation in phosphate buffer (pH=7.5) for 24
hours at 28.degree. C. less than 10% of the original amount of
Compound 1 remained. At the same time a significant increase of the
degradation product was observed.
##STR00031##
[0204] The stability of Compound 1 was also tested with the
bioreduction enzyme system. This test was performed by incubation
of 40 mM compound 1 at 28.degree. C. in phosphate buffer and
co-factors/co-factor regeneration system (NADH, NADPH, glucose/GDH
solution) at pH 6.5 and 7.5. The test results showed that Compound
1 was more stable at lower pH. However, decomposition still
occurred relatively fast at pH 6.5.
Example 2--Bioreduction of Compound 1 at Different pH
[0205] The reduction of Compound 1 was tested using an alcohol
dehydrogenase bioreduction system. This experiment was performed on
250 .mu.L scale using compound 1 at a concentration of 40 mM (about
1% w.t.). The bioreduction reaction was tested at pH 7.5 and pH
6.5.
[0206] When the reaction was performed at pH 6.5, approximately 85%
conversion was achieved within 2 hours. At pH 7.5 the performance
of the enzyme was not as good as at pH 6.5, i.e. significantly
lower levels of conversion were achieved. FIG. 1 shows the reaction
comparison of pH 6.5 and pH 7.5, and the conversion rate was
calculated based on the remaining amount of Compound 2
(product).
[0207] A sample from the experiment at pH 7.5 was freeze dried.
Compound 2 (product) was analyzed by chiral GC after being
converted to a corresponding trifluoroacetate. Based on this
analysis the enantiomeric excess of Compound was determined to be
at least 99%.
Example 3--Bioreduction of Compound 1 with Different Co-Factor
Regeneration System
[0208] Two different co-factor regeneration systems were tested,
i.e. the original GDH/glucose system as well as 2-propanol (IPA).
The experiments were performed on 2 mL scale at pH=6.5. The
experimental data showed that the GDH/glucose based system had
difficulties in producing more than 50-60 mM of Compound 2. The
reaction progress with the GDH/glucose system is shown in FIG. 2.
The reaction was fast but leveled off after approximately 4 hours.
This may be related to a pH effect, i.e. the co-factor regeneration
results in the formation of gluconic acid which may reduce the pH
to a level where the enzyme becomes deactivated. The data also
reflected the limited stability of the substrate, i.e. the decrease
of Compound 1 on average was higher than the amount of Compound 2
that was being formed.
[0209] The performance of the IPA-system was better, i.e. higher
concentrations of Compound 2 could be achieved. The reaction
progress of the IPA system is shown in FIG. 3. In this case the
reaction more or less stopped after 4 hours. The incomplete
conversion of Compound 1 might by due to the presence of acetone,
which was generated during the co-factor regeneration.
Example 4. Effect of Acetone on Bioreduction Reaction
[0210] The effect of acetone on the reduction was tested and the
result is shown in FIG. 4. Experiments were performed with 200 mM
of Compound 1 as starting materials, and one experiment had
additional acetone added while the other experiment did not. When
additional acetone was added to the reaction mixture, only 80 mM of
Compound 2 was obtained as compared to 120 mM in the absence of
additional acetone. The bioreduction of Compound 1 was hampered by
the acetone that was generated during the co-factor regeneration
process.
[0211] Two experiments were performed in parallel using 200 mM of
Compound 1. The first experiment was performed without any vacuum
applied whereas in the second experiment vacuum was applied (2
minutes 100 mbar every 20 minutes during the first 4 hours of the
reaction). The reactions were sampled, and the concentration of
Compound 2 formed and the remaining amount of Compound 1 were
determined by HPLC analysis. The conversion curves based on this
data are shown in FIG. 5. As shown in FIG. 5, the removal of
acetone increased the conversion rate of this bioreduction
reaction.
Example 5--Bioreduction of Compound 1 Preparation Scale
[0212] The reduction of Compound 1 was performed in a pH-stat
equipment using an alcohol dehydrogenase system. The starting
reagents included 1 mM NADH, 1 mM NADPH, 20% v/v IPA, 20% v/v CFE,
Buffer, and 0.1 mM KPi pH 6.5, and the final volume of the starting
reagents was 40 ml. The starting materials were stirrer speed at a
reaction temperature of 28.degree. C. Before adding compound 1 to
start the reaction, the pH was set to 6.0 using HCl. During the
reaction the pH was maintained constant by titration with 1M
NaOH.
##STR00032##
[0213] Reaction was started by adding 200 .mu.L of compound 1. A
new portion of 200 .mu.L Compound 1 was added every 20 min with a
total dosing time of 200 min and a total dosing amount of 2.1 g.
Before adding each new portion of Compound 1, vacuum (about 160
mbar) was applied for 1 min to remove the acetone in the reaction
mixture. After the total amount of Compound 1 was added, vacuum was
applied 3 times with a 20 min interval. Subsequently, vacuum was
applied once per hour for another 4 hours.
[0214] After an overnight incubation, the reduction product was
isolated by extraction with methyl tert-butyl ether (MTBE). First,
the reaction mixture was mixed with about 100 ml MTBE; and about 4
g Dicalite were then added to mixture. Filtration was performed
using a glass filter coated with Dicalite. The filtrate was
phase-separated and both phases (water and organic phase) as well
as the filter cake were analyzed. The water and organic phase were
analyzed after being diluted 1:5 with acetonitrile. The filter cake
was mixed with acetonitrile, centrifuged and the supernatant was
analyzed, and the results are shown in Table 1. Test A was
performed without taking any samples, while Test B was performed
with samples taking every 20 min. The enantiomeric excess of the
isolated alcohol was more than 99%.
TABLE-US-00001 TABLE 1 Bioreduction of Compound 1 to form Compound
2 obtained in two tests Test A Test B Yield (product/starting
substrate) 88.87 82.20 remaining substrate [%] 2.55 2.17 Product
loss in filter cake [%] 0.78 0.85 Mass balance 92.2 86.23 *based on
detection limit of 0.1 mg/ml
Example 6--Asymmetric Hydrogenation Solvent Screening
[0215] The asymmetric hydrogenation was performed at ambient
temperature with 25 bar H.sub.2 in a selection of solvents
including methanol, ethanol, IPA, ethyl acetate, DCM,
C.sub.6H.sub.5C.sub.1, DMF, and THF. The best performance was
achieved in methanol, in which case a high conversion to the
desired Compound 2 was achieved. The enantiomeric excess of the
obtained product was found to be 88%. In ethanol the reaction was
more sluggish and no full conversion was achieved. In addition, the
enantiomeric excess of Compound 2 was somewhat lower (82%). In the
other solvents (virtually) no conversion of Compound 1 could be
achieved.
Example 7--Asymmetric Hydrogenation Catalyst Screening
[0216] The asymmetric hydrogenation reactions were performed with
2.8 mmol (720 mg with an assay of 80% w.t.) Compound 1 in 4.2 ml of
solvent at 5 bar H.sub.2 and 25.degree. C. in a selection of
catalysts including A:Ru(OAc).sub.2((R)-BINAP); B:
Ru(OAc).sub.2((R)-SegPhos), C: Ru(OAc).sub.2((R)-SegPhos), D:
Ru(OAc).sub.2((R)-DM-SegPhos); E:
[NH.sub.2Me.sub.2][{RuCl((S)-SegPhos.RTM.)}.sub.2.mu.-Cl).sub.3];
F:
[NH.sub.2Me.sub.2][{RuCl((R)-DM-SegPhos.RTM.)}.sub.2.mu.-Cl).sub.3].
The reaction results are shown in Table 2.
TABLE-US-00002 TABLE 2 Catalyst screening results Catalyst catalyst
loading Solvent time (h) Assay yield (%) e.e (%) A 0.5 MeOH 4 91 95
B 0.5 4 40 94 C 0.5 MeOH 4 45 93 D 0.5 MeOH 4 10 88 A 0.5 IPA 17 1
-- C 0.5 IPA 17 -- -- D 0.5 MeOH 17 68 85 D 0.5 IPA 17 2 78 E 0.25
MeOH 17 88 85 F 0.25 MeOH 17 96 75 E 0.25 IPA 17 -- -- F 0.25 IPA
17 3 78 A.sup.a 0.5 MeOH 17 86 69 A.sup.b 0.5 MeOH 17 84 70 A.sup.a
0.5 IPA 17 -- -- A.sup.b 0.5 IPA 17 -- -- .sup.aIn the presence of
6 mol % HCl; .sup.bin the presence of 6 mol % HCl and 1% LiCl
[0217] As shown in Table 2, Ru(OAc).sub.2((R)-BINAP) showed the
best performance in the asymmetric hydrogenation of Compound 1.
That is remarkable as Noyori reported BINAP-Rucarboxylate complexes
to be completely ineffective in the hydrogenation of .beta.-keto
esters (JACS 1987, 109, 5856). The corresponding halogen complexes
were found to be much more active.
[0218] It was therefore speculated that the actual catalytic
species in the asymmetric hydrogenation of Compound 1 is not the
carboxylate complex, but rather the chloride complex which may be
formed in situ from Ru(OAc).sub.2((R)-BINAP) and HCl (released from
Compound 1). Alternatively, the HCl may promote enolisation of
Compound 1 in which case the reduction of Compound 1 actually
occurs via hydrogenation of the enol (C.dbd.C hydrogenation) and
not the ketone (C.dbd.O hydrogenation). This would match with the
fact that Ru(OAc).sub.2((R)-BINAP) is known to be a suitable
catalyst for the hydrogenation of olefins.
[0219] In addition to the catalyst listed in Table 2, 10 additional
catalysts RuBr.sub.2(Ligand) were synthesized and tested in the
hydrogenation of compound 1 in methanol at 25.degree. C. and 5 bar
H.sub.2. The results are shown in Table 3.
TABLE-US-00003 TABLE 3 Catalyst screening results Ligand e.e. (%)
(R)-tolyl-BINAP 83 (R)-xylyl-BINAP 74 (S)-tolyl-BINAP 81
(S)-BINAPHANE no conversion (S)-PhanePhos 61 JosiPhos-2-1 80
(R)-SolPhos SL-A001-1 83 (S)-MeOBiPhep 77 (S)-P-Phos 92
(S)-(+)-DTBM-SEGPHOS .RTM. 62
[0220] As shown in Table 3, BINAP and SegPhos.RTM. type of ligands
(table 6) are the most selective ligands in the hydrogenation of
Compound 1.
[0221] More Ru-based catalysts were tested in a range of solvents,
and the results were shown in Table 4. The base (triethylamine) was
added into one reaction mixture as a additive.
TABLE-US-00004 TABLE 4 Catalyst screening results in different
solvents H.sub.2 Catalyst Solvent (bar) Additive yield (%) e.e (%)
[RuCl.sub.2(benzene)].sub.2/(S)- DMF/MeOH (1.5:1) 5 none 2 97 BINAP
in DMF [RuCl.sub.2(benzene)].sub.2/(S)- DMF/MeOH (1.5:1) 5 none 14
97 BINAP in DMF [RuCl.sub.2(cymene)].sub.2/(S)- DMF/MeOH (1.5:1) 5
none 2 76 BINAP in DMF RuBr.sub.2((S)-BINAP) AcOH 5 none -- --
Ru(OAc).sub.2((R)-H.sub.8-BINAP) MeOH 5 none 91 91
Ru(OAc).sub.2((R)-SegPhos) MeOH 5 none 91 93 Ru(OAc).sub.2((R)-DM-
MeOH 5 none 68 84 SegPhos) [NH.sub.2Me.sub.2][{RuCl((S)- AcOH 5
none -- -- SegPhos .RTM.)}.sub.2(.mu.-Cl).sub.3]
([RuCl.sub.2(benzene)].sub.2/(R)- MeOH 5 none 96 88 BINAP)dmf
([RuCl.sub.2(cymene)].sub.2/(R)- MeOH 5 none 94 88 BINAP)dmf
RuCl.sub.2((S)-BINAP) in DMF DMF/MeOH (1.4:1) 5 none 226 --
RuCl.sub.2((S)-BINAP) in DMF DMF/MeOH (1.4:1) 25 none 26 96
RuCl.sub.2((R)-BINAP) MeOH 5 none 92 87 RuCl.sub.2((R)-BINAP) MeOH
5 Et.sub.3N 91 98 RuCl.sub.2((R)-BINAP) MeOH 5 none 92 87
RuCl.sub.2((R)-BINAP) TFE 5 none 2 -- RuCl.sub.2((S)-BINAP) in DMF
MeOH 5 none 91 87 RuCl.sub.2((S)-BINAP) in DMF MeOH 5 none 1 --
RuCl.sub.2((R)-BINAP) DCM/MeOH (1:3) 5 none 94 87
RuCl.sub.2((R)-BINAP) DCM/MeOH (1:1) 5 none 94 82
[0222] As shown in Table 4, the results clearly show that the
presence of triethylamine significantly improved the
enantioselectivity of the Ru(BINAP)Cl.sub.2 catalyzed hydrogenation
of Compound 2 (98% e.e. as compared to 87% in the absence of
base).
Example 8--Asymmetric Hydrogenation Catalyst Screening Additive
Effect
[0223] More catalysts were tested in the presence of
trimethylamine. The results are shown in Table 5.
TABLE-US-00005 TABLE 5 Catalyst screening results in the presence
of Et.sub.3N Time yield e.e Catalyst Solvent Additive.sup.[1] (h)
(%) (%) RuBr.sub.2((S)-BINAP) MeOH 8 92 97.0
[NH.sub.2Me.sub.2][{RuCl((S)-SegPhos .RTM.)}.sub.2(.mu.-Cl).sub.3]
MeOH 16 94 93.3 RuCl.sub.2((R)-BINAP) DMF/MeOH 16 3 97.5 (2.5:1.7)
RuCl.sub.2((S)-BINAP)dmf DMF/MeOH 16 2 97.4 (2.5:1.7)
RuCl.sub.2((R)-BINAP) MeOH LiCl 2 95 96.5 RuCl.sub.2((R)-BINAP)
MeOH ZnCl.sub.2 3 91 86.7 RuCl.sub.2((R)-BINAP).sup.[a] MeOH
ZnCl.sub.2 2 94 96.6 [NH.sub.2Me.sub.2][{RuCl((S)-SegPhos
.RTM.)}.sub.2(.mu.-Cl).sub.3] MeOH 18 26 98.2
Ru(OAc).sub.2(.RTM.-BINAP) MeOH 1.5 94 98.4
Ru(Oac).sub.2(.RTM.-BINAP) MeOH LiCl 1.5 94 98.3
RuCl.sub.2((R)-BINAP) MeOH (5% 7 137 91.6 v.v H.sub.2O)
Ru(OAc).sub.2((R)-BINAP) MeOH 1.5 96 98.3 Ru(OAc).sub.2((R)-BINAP)
MeOH/EtOH 2 95 98.3 (1:1) Ru(OAc).sub.2((R)-BINAP) MeOH/IPA 4.5 72
98.0 (1:1) Ru(OAc).sub.2((R)-DM-SegPhos) MeOH 18 96 98.6
Ru(OAc).sub.2((R)-SegPhos) MeOH 6.5 96 99.5
Ru(OAc).sub.2((R)-H8-BINAP) MeOH 4 97 98.9
Ru(OAc).sub.2((R)-T-BINAP) MeOH 2 97 97.7
Ru(OAc).sub.2((R)-DM-BINAP) MeOH 5 1 98.2 RuCl.sub.2((S)-BINAP)
MeOH 20 32 -- Ru(OAc).sub.2((R)-BINAP) EtOH/IPA 20 96 96.4 1:1
Ru(OAc).sub.2((R)-BINAP) MeOH/IPA 5 97.7 1:1 .sup.[1]equiv.
Relative to Ru; .sup.[2]Reaction time to full conversion or maximum
run time according to the hydrogen uptake curves. [3] Internal
standard not completely dissolved; full conversion. .sup.[a]no Et3N
was added.
[0224] The results listed in Table 5 show that the positive effect
exhibited by triethylamine is not limited to the BINAP-based
catalysts. The selectivity of the hydrogenation reaction was also
improved in the presence of this base in the SegPhos.RTM.-ligand
family. Application of Ru(OAc).sub.2((R)-SegPhos) in combination
with triethylamine provided Compound 2 in 96% yield and 99.5%
enantiomeric excess. With the antipode of the same catalyst
(S/C=200) the desired product 1 was obtained in 93% yield and 99.3%
enantiomeric excess.
[0225] Asymmetric hydrogenation at lower catalyst loading (S/C=500)
resulted in complete conversion within 15 hours and a marginally
lower selectivity (99% ee). At S/C=1000 the reaction was still not
complete after 20 hours and the selectivity dropped to 98% ee. This
suggests that application of a low catalyst loading may require
purification of Compound 1.
[0226] When the optically pure Compound 2 was used to make Compound
3, Compound 4, and Compound 5, no erosion of enantiomeric excess
occurred during the later steps. Therefore, asymmetric
hydrogenation of Compound 1 using Ru(OAc).sub.2((R)-SegPhos) as the
catalyst provided the desired hydroxy ester Compound 2 in excellent
yield and enantiomeric excess.
Example 9--Asymmetric Hydrogenation of Compound 1
[0227] The asymmetric hydrogenation was conducted with crude
Compound 1 having a purity of 80% (.sup.1H NMR). Crude Compound 1
(0.72 g, 2.8 mmol) was placed in a 5 mL vial and hexadecane (48
.mu.L) was added as the internal standard. In order to remove HCl
the vial was placed under vacuum for 0.25 hours. The mixture of
Compound 1 and internal standard was dissolved in methanol (4.2
mL), and 10 .mu.L of triethylamine was later added to form a
starting material.
[0228] Ru(OAc).sub.2((S)-SegPhos) (11.6 mg; S/C=200) was placed in
an Endeavor glass tube and subsequently the starting material was
added. The glass tube was placed in the Endeavor parallel reactor
and the reactor was closed under a flow of nitrogen gas followed by
inertisation with 5 cycles of N.sub.2 (3 bar). The nitrogen head
space was replaced by hydrogen by 5 cycles of H.sub.2 (25 bar). The
hydrogenations were carried out using 5 bar of H.sub.2 pressure at
25.degree. C.
[0229] IPC: A sample (50 .mu.L) was dissolved in DCM (1 mL). The
solution was analyzed by GC equipped with a HP 5 column. Oven:
80.degree. C. 3 min., 10.degree. C./min.fwdarw.300.degree. C.,
300.degree. C. 5 min.
[0230] Enantiomeric excess: A sample (10 .mu.L) was placed in a 1.5
mL vial and the solvent was removed by placing the sample in a
vacuum oven at ambient temperature. The residue was dissolved in
trifluoroacetic anhydride (TFAA) (100 .mu.L) and the mixture
diluted with DCM (1 mL). The solution was analyzed by chiral
GC.
[0231] Work-up: The reaction mixtures of several of these reactions
were pooled in a 250 mL Schlenk vessel. In order to avoid
transesterification, the methanol was subsequently removed in vacuo
at 20.degree. C. and the methanol was collected in a cold-trap
filled with liquid nitrogen. The residue was subjected to
distillation at <0.2 mbar starting at an oil bath temperature of
90.degree. C. which was slowly increased to 120.degree. C.
providing 5.52 g colorless liquid. The purity of the reduced
product was about 92.4 w %, the isolated yield corrected for its
purity was 87%, and the e.e. was 99.3%.
Example 10--Intramolecular Grignard Reaction
##STR00033##
[0233] When making alkylboronate compound 4 from Compound 3, the
zinc-insertion method resulted in the des-chloro compound after
aqueous work-up. Magnesium insertion resulted in one major product
(73 area % by means of GC-analysis). Addition of additives were
tested in the Grignard reaction. When LiCl and MgCl.sub.2 were
tested, their use resulted in significant levels of deschlorination
and side products. However, in the presence of two equivalents of
ZnCl.sub.2 a clean conversion to Compound 4 was achieved.
[0234] To test the effect of the additive, a 1.5 mL vial was placed
in the glove box, the additive and clear DMF Zn-adduct solution
(0.1 mL) and the mixture was allowed to stir for 15 minutes at
800.degree. C. (in case the additive was a solvent, pre-treatment
at 80.degree. C. was not performed). The mixture was cooled to
ambient temperature after which the (Pin)BOMe (33 .mu.L, 0.2 mmol)
was added. After addition of the borate ester the mixture was
heated overnight at elevated temperature. The complete reaction
mixture was treated with water (0.5 mL) and subsequently extracted
with DCM (1 mL). Part of organic phase (0.5 mL) was, diluted with
DCM (0.5 mL) and dried over Na.sub.2SO.sub.4. The DCM--was analyzed
by GC. Any remaining the Zn-adduct was detected as deschloro
compound 6.
##STR00034##
[0235] The effect of the ZnCl.sub.2 was tested at different
equivalence of the starting material Compound 3, and the results
are shown in Table 6.
TABLE-US-00006 TABLE 6 Effect of ZnCl.sub.2 on the Grignard
reaction Compound 4 ZnCl.sub.2 [equiv] t [h] 13 [area %] 11/12
[area %] [area %] 1.sup.[a] 1.5 12 <1 75 1 1.5 12 <1 76 0.5
1.5 20 <1 70 0.1 1.5 32 18 29 1.sup.[a,b] 2 5 <1 86 All
experiments at 0.05-0.1 mol scale, substrate concentration 0.1M
unless indicated otherwise. .sup.[a]experiment at 0.2M Compound 3.
.sup.[b]experiment at 0.5 mol scale
[0236] The effect of ZnCl.sub.2 as an additive was further tested
at several equivalence ratios with different amount of magnesium
used for the reaction, and the results are collected in table
7.
TABLE-US-00007 TABLE 7 Effect of ZnCl.sub.2 on the Grignard
reaction ZnCl.sub.2 Compound 4 Mg [equiv] [equiv] T [.degree. C.] t
[h] [%] 13 [area %] 1.6 0.5 80 1.25 54 3.9 1.6 0.5 25 40 65 3.8 1.6
0.5 25 19 63 4.2 40 +2 64 4.7 60 +2 69 3.9 80 +1 45 5.4 80 +17 1 --
1.6 1.0 25 21 37 -- 3.2 0.5 25 22 82 --
[0237] As shown in Table 7, the reaction proceeded smoothly at
ambient temperature using unactivated magnesium dust. In fact, at
elevated temperature the yield of the reaction dropped. An excess
of magnesium was required to achieve full conversion of the
substrate. In one reaction, Compound 4 was obtained in
approximately 80% yield (based on GC-analysis of Compound 5;
experiment at 0.5 mmol scale and 0.5M substrate concentration.
Example 11--Synthesis of Compound 5 Preparative Scale
##STR00035##
[0239] To a flame dried Schlenk flask containing B(O-nBu).sub.3 (Fw
230.15, 6.10 g, 26.5 mmol) was added the optically enriched hydroxy
ester Compound 2 (5.25 g; assay 92%; e.e. 99.3%, 23.1 mmol). The
mixture was allowed to stir under high vacuum (<0.2 mbar) for 2
hours at ambient temperature, while trapping the evaporated
n-butanol in liquid nitrogen.
[0240] The residue was dissolved in dry THF (40 mL), and
subsequently Mg (Fw 24.3, 2.13 g, 88 mmol) and ZnCl.sub.2 (Fw
136.30, 1.81 g, 13.3 mmol) was added. The mixture was stirred at
24.degree. C. for 24 hours (GC-analysis showed complete conversion
of the starting material).
[0241] The mixture was cooled to 5.degree. C. with an ice bath and
subsequently quenched with 1 N HCl (150 mL). Residual magnesium was
removed by filtration. Subsequently the filtrate was extracted with
MTBE (80 mL). After phase separation the water layer was extracted
with MTBE (2.times.33 mL). The combined organic phase was
concentrated in vacuo at 60.degree. C. Residual amounts of
1-butanol were removed by a stream of N.sub.2 providing 5.82 g of
crude Compound 4.
[0242] For complexation with ethanolamine (Fw 61.08, d 1.012), the
residue was dissolved in CH.sub.3CN (3.2 mL). Subsequently
ethanolamine (1.52 g; 25 mmol) was added. Slow addition of MTBE (19
mL) resulted in the precipitation of solid material accompanied by
some oily material. The mixture was stirred overnight and
subsequently diluted with heptane (19 mL). The precipitated
Compound 5 was isolated by filtration as a white solid (2.73 g;
11.2 mmol; 49% yield; ee 99.5%).
Example 12--Synthesis of Rac-Compound 5 (Intramolecular Approach,
0.8 g Scale)
[0243] To a flame dried Schlenk flask containing B(O-nBu).sub.3 (Fw
230.15, 905 mg, 3.93 mmol) was added hydroxy ester Compound 2
(assay 96%, 780 mg, 3.59 mmol). The mixture was allowed to stir
under high vacuum (0.05 mbar) for 45 minutes hour at ambient
temperature, while trapping the evaporated n-butanol in liquid
nitrogen.
[0244] In a second flame dried flask magnesium (298 mg; 12.3 mmol)
and ZnCl.sub.2 (254 mg; 1.869 mmol) was stirred in 7.5 ml of dry
THF. Subsequently, the content of the first flask was transferred
to the second flask and obtained reaction mixture was stirred for
20 hours at ambient temperature. According to GC-analysis this
mixture still contained a small amount (2 area %) of Compound
2.
[0245] The reaction mixture was transferred to a 100 mL conical
flask, cooled to 0.degree. C. and subsequently 15 mL of 1 N aqueous
HCl was slowly added. Stirring was continued while the mixture was
allowed to warm up to ambient temperature. This mixture was
extracted with
[0246] DCM (3.times.50 ml), the combined organic phases were dried
over Na.sub.2SO.sub.4 and subsequently concentrated in vacuo.
Residual amounts of DCM were removed by a stream of N.sub.2. 0.73 g
of Compound 4 was made. A sample of the crude Compound 4 (2.24 mg)
was dissolved in DCM (1 mL). Subsequently hexadecane (2.03 mg) and
pinanediol (8.59 mg) were added and the solution was analyzed by
GC. Based on the analysis of the pinanediol boronate adduct of the
product, the assay of the crude Compound 4 was determined to be 81
w %, which corresponds with a yield of 82%.
[0247] The crude Compound 4 was dissolved in dry 1,4-dioxane (3.6
ml) and subsequently ethanolamine (d:1.012, Fw: 61.08, 220 mg, 3.6
mmol) was added. In order to speed up the precipitation of Compound
5 the mixture was seeded with Compound 5 (2 mg). After 2.5 hours of
stirring, Compound 5 started to precipitate. Heptane (1.8 mL) was
added and the mixture was allowed to stir overnight. As a result
the mixture turned into a gel-like substance which was no longer
stirrable.
[0248] Filtration of the Compound 5 was therefore difficult. The
mixture was diluted with a couple of mL of heptane and transferred
to a filter. The mixture was filtered and washed with 1,4-dioxane
(2.times.2.5 mL). Washing was not easy, since the material was
sticky. After drying in air giving Compound 5 was obtained as an
off white solid (416 mg, 1.71 mmol, 48% yield). .sup.1H-NMR
spectrum is in agreement with reference sample. The overall yield
is uncorrected for losses due to sampling and technical losses.
Example 13. Synthesis of Rac-Compound 5 (Intramolecular Approach,
2.1 g Scale)
[0249] To a flame dried Schlenk flask containing B(OnBu).sub.3 (Fw
230.15, 2.42 g, 10.5 mmol) was added the hydroxy ester Compound 2
(2.10 g, 10 mmol). The mixture was allowed to stir under high
vacuum (0.05 mbar) for 75 minutes hour at ambient temperature,
while trapping the evaporated n-butanol in liquid nitrogen.
[0250] The residue was dissolved in dry THF (20 mL) and
subsequently Mg (Fw 24.3, 802 mg, 33 mmol) and ZnCl.sub.2 (Fw
136.30, 682 mg, 5 mmol) was added. The mixture was stirred at
24.degree. C. for 27 hours (GC-analysis showed complete conversion
of the starting material).
[0251] The reaction mixture was transferred to a 300 mL conical
flask. Residual amounts of reaction mixture were transferred by
rinsing with THF. The mixture was cooled to 5.degree. C. with an
ice bath and subsequently quenched with 1 N HCl (60 mL). The Mg did
not dissolve completely. Subsequently the mixture was extracted
with MTBE (32 mL). After phase separation the water layer was
extracted with MTBE (2.times.13 mL). The combined organic phase was
concentrated in vacuo at 60.degree. C. Residual amounts of
1-butanol were removed by a stream of N.sub.2 providing 2.05 g of
crude Compound 4.
[0252] For complexation with ethanolamine (Fw 61.08, d 1.012), the
residue was dissolved in CH.sub.3CN (1.3 mL) and MTBE (7.5 mL)
followed by the addition of ethanolamine (610 mg, 10 mmol). The
addition of ethanolamine was accompanied by immediate precipitation
of an off white solid. The mixture was allowed to stir over the
weekend. Compound 5 was filtered off, washed with MTBE (7.5 mL) and
dried giving Compound 5 in 1450 mg (6.0 mmol, 60%) isolated
yield.
* * * * *