U.S. patent application number 10/633760 was filed with the patent office on 2004-03-18 for combinatorial approach to chiral reagents or catalysts having amine or amino alcohol ligands.
This patent application is currently assigned to UNIVERSITY OF SOUTHERN CALIFORNIA, a California corporation. Invention is credited to Petasis, Nicos A..
Application Number | 20040053775 10/633760 |
Document ID | / |
Family ID | 22306137 |
Filed Date | 2004-03-18 |
United States Patent
Application |
20040053775 |
Kind Code |
A1 |
Petasis, Nicos A. |
March 18, 2004 |
Combinatorial approach to chiral reagents or catalysts having amine
or amino alcohol ligands
Abstract
Functionalized amine derivatives are prepared by reacting an
amine, a carbonyl derivative, and an organoboron compound under
mild conditions. Organoboronic acids (4) react with amines (2) and
alpha-hydroxy aldehydes (3) to give anti-alpha-amino alcohols (1)
with very high diastereoselectivities (>99% de). When optically
pure alpha-hydroxy aldehydes are used in this process, no
racemization occurs and the products are obtained with very high
enantioselectivities (>99% ee). The reaction also works with
unprotected glyceraldehyde to give the corresponding amino diol
derivatives, while unprotected carbohydrates give the corresponding
amino polyols. The chiral amino alcohol products of this process or
their derivatives, react further with metals or non-metals to give
adducts that are effective catalysts for a variety of asymmetric
reactions. Overall, the present invention relies on the facile
synthesis of the chiral amino alcohol ligands for the rapid
construction of combinatorial libraries of chiral catalysts. These
libraries can then be used to identify the most suitable catalyst
for a particular asymmetric transformation.
Inventors: |
Petasis, Nicos A.; (Hacienda
Heights, CA) |
Correspondence
Address: |
FISH & RICHARDSON P.C.
500 ARGUELLO STREET, SUITE 500
REDWOOD CITY
CA
94063
US
|
Assignee: |
UNIVERSITY OF SOUTHERN CALIFORNIA,
a California corporation
|
Family ID: |
22306137 |
Appl. No.: |
10/633760 |
Filed: |
August 4, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10633760 |
Aug 4, 2003 |
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09425498 |
Oct 22, 1999 |
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6602817 |
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60105489 |
Oct 23, 1998 |
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Current U.S.
Class: |
502/150 ;
502/152; 502/155; 502/161; 502/162; 502/167; 502/172; 536/55.3;
556/7 |
Current CPC
Class: |
B01J 2531/40 20130101;
B01J 2531/30 20130101; B01J 2219/00745 20130101; C07D 307/52
20130101; C07C 215/50 20130101; C07C 215/30 20130101; B01J 31/1805
20130101; B01J 2531/10 20130101; B01J 2219/00747 20130101; B01J
2219/00738 20130101; C40B 30/08 20130101; B01J 2531/20 20130101;
C07K 5/06026 20130101; C07C 229/36 20130101; B01J 2531/82 20130101;
B01J 2531/84 20130101; C07C 215/28 20130101; C07B 53/00 20130101;
C07B 2200/07 20130101; C40B 40/18 20130101; B01J 31/2243 20130101;
B01J 31/223 20130101 |
Class at
Publication: |
502/150 ;
502/162; 502/167; 502/161; 502/172; 502/152; 502/155; 556/007;
536/055.3 |
International
Class: |
B01J 031/00; C07H
005/04; C07F 005/02 |
Claims
What is claimed:
1. A process for preparing a chiral reagent or catalyst comprising
reacting a metal or metal derivative with one or more chiral amino
ligands.
2. The process according to claim 1 wherein the amino ligand is an
amino alcohol.
3. The process according to claim 2 wherein the metal or metal
derivative is reacted directly with the amino alcohol.
4. The process according to claim 2 wherein the metal or metal
derivative is reacted with the amino alcohol concurrent to
synthesis of the amino alcohol.
5. The process according to claim 2 wherein the amino alcohol is
prepared by a one-step reaction comprising: a) an organoboronic
acid; b) an amine; c) a compound selected from the group consisting
of an alpha-hydroxy aldehyde, an alpha-keto acid and a
carbohydrate.
6. The process according to claim 1 wherein the amino ligand is
prepared by the reaction of comprising: a) an organoboronic acid;
b) an amine; c) a compound selected from the group consisting of an
alpha-hydroxy aldehyde, an alpha-keto acid and a carbohydrate.
7. The process according to claim 6 wherein the amino ligand is
further modified prior to reaction with the metal or metal
derivative.
8. The process according to claim 1 wherein the chiral amino ligand
has an enantiomeric and/or diastereomeric purity of greater than
50%.
9. A process for preparing a combinatorial library of chiral
reagents or catalysts comprising reacting a metal or metal
derivative with one or more chiral amino ligands.
10. The process according to claim 9 wherein the amino ligand is an
amino alcohol.
11. The process according to claim 11 wherein the metal or metal
derivative is reacted directly with the amino alcohol.
12. The process according to claim 11 wherein the metal or metal
derivative is reacted with the amino alcohol concurrent to
synthesis of the amino alcohol.
13. The process according to claim 11 wherein the amino alcohol is
prepared by a one-step reaction comprising: a) an organoboronic
acid; b) an amine; c) a compound selected from the group consisting
of an alpha-hydroxy aldehyde, an alpha-keto acid and a
carbohydrate.
14. The process according to claim 9 wherein the amino ligand is
prepared by the reaction of comprising: a) an organoboronic acid;
b) an amine; c) a compound selected from the group consisting of an
alpha-hydroxy aldehyde, an alpha-keto acid and a carbohydrate.
15. The process according to claim 14 wherein the amino ligand is
further modified prior to reaction with the metal or metal
derivative.
16. The process according to claim 9 wherein the chiral amino
ligand has an enantiomeric and/or diastereomeric purity of greater
than 50%.
17. A combinatorial library of chiral reagents or catalysts
prepared according to claim 9.
18. The process according to claims 5 or 6 wherein at least one of
the organoboronic acid, the amine and/or the alpha-hydroxy
aldehyde, alpha-keto acid or monosaccharide is attached to a solid
support.
19. A process for producing a compound of formula M(L)n comprising
reacting a metal or metal derivative with one or more chiral amino
ligands, wherein M is an atom selected from the group consisting of
B, Li, Mg, Al, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr, Mo, Ru, Rh,
Pd, Ag, Re, Os, Ir, Pt, La, Ce and Yb; L is one or more same or
different ligands selected from the group consisting of chloro,
bromo, iodo, fluoro, oxo, hydroxy, hydroperoxy, alkoxy, aryloxy,
acyloxy, acetoacetyl, carboxy, nitro, amino, alkylamino,
dialkylamino, azido, carbonyl, alkyl, alenyl, dienyl, aryl,
triflate and arylsulfonyl; and n=1-6.
20. A compound produced by the process according to claim 19.
21. A combinatorial library produced by the process according to
claim 19.
22. The use of the compound according to claim 20 for the
preparation of an industrial chemical.
23. The use of the compound according to claim 20 for the
preparation of a pharmaceutical.
24. The use of the compound according to claim 20 for the
preparation of an agrochemical.
25. The process according to claim 1 wherein the chiral amino
ligand is selected from the group consisting of: 24wherein one or
more bonds exists among M and a heteroatom of the ligand; M=B, Li,
Mg, Al, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr, Mo, Ru, Rh, Pd, Ag,
Re, Os, Ir, Pt, La, Ce or Yb; and R.sup.1-R.sup.10=alkyl, alyl,
alkenyl, aryl, allenyl, or alkynyl group.
26. The process according to claim 9 wherein the chiral amino
ligand is selected from the group consisting of: 25wherein one or
more bonds exists among M and a heteroatom of the ligand; M=B, Li,
Mg, Al, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr, Mo, Ru, Rh, Pd, Ag,
Re, Os, Ir, Pt, La, Ce or Yb; and R.sup.1-R.sup.10=alkyl, alyl,
alkenyl, aryl, allenyl, or alkynyl group.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is based on U.S. Provisional Application
Serial No. 60/105,489, filed Oct. 23, 1998, incorporated herein by
reference in full.
FIELD OF THE INVENTION
[0002] This invention relates to the fields of organic synthesis,
asymmetric synthesis, catalysis, combinatorial catalysis,
organoboron chemistry, combinatorial chemistry and medicinal
chemistry. More specifically, the invention relates to methods for
preparing chiral amine or amino alcohols used to prepare chiral
reagents or catalysts which can be used for the synthesis of many
other molecules.
BACKGROUND OF THE INVENTION
[0003] Although many chiral reagents or catalysts containing chiral
amine or amino alcohol ligands and their methods of synthesis are
known, these often have limited effectiveness giving products with
high enantiomeric excess (% ee) only in certain cases. Most
synthetic routes to chiral amines or amino alcohols proceed with
low or mixed stereoselectivity, involve multiple steps, allow only
limited types of substituents, or require highly reactive
organometallics that involve cumbersome experimental conditions and
necessitate additional protection-deprotection steps.
[0004] Rather than rely on the identification of a globally
effective catalyst system, the present invention allows the facile
construction of stereochemically pure amine or amino alcohol
ligands that are subsequently used to form chiral reagents or
catalysts. These can be prepared either individually or as
combinatorial libraries and can be used to easily identify the most
suitable catalyst for a given transformation.
[0005] A key feature of the present invention is the construction
of amine or amino alcohol ligands in one or two steps and in high
enantiomeric and diastereomeric purity.
SUMMARY OF THE INVENTION
[0006] This invention relates to a practical and effective method
for the stereocontrolled synthesis of amines or amino alcohols for
the preparation of a large variety of chiral catalysts for
asymmetric synthesis. This process involves the one-step
combination of certain organoboron derivatives, including
organoboronic acids, organoboronates and organoborates with primary
or secondary amines and certain carbonyl derivatives, such as
.alpha.-keto acids, .alpha.-hydroxy aldehydes or carbohydrates.
This process constitutes a three-component reaction and is suitable
for the rapid generation of combinatorial libraries of amine or
amino alcohols. These products can be converted to chiral reagents
or catalysts via a subsequent reaction with an appropriate reagent,
which can be present as a fourth component or can be used in a
follow-up step.
[0007] The synthetic procedure is quite simple and works in a
variety of solvents, including water, ethanol, dichloromethane and
toluene. Product isolation is often very simple and can give fairly
pure products without the need for chromatography or distillation
of special significance is the fact that this process generates new
C--C bonds with very high stereoselectivity (up to more than 99% de
and 99% ee) when certain chiral components are used in the
reaction. Due to its operational simplicity and the fact that no
hazardous chemicals or special precautions are required, this
invention is suitable for the practical and convenient synthesis of
many types of amine or amino alcohol ligands, including
stereochemically pure derivatives. These molecules can then serve
as components of chiral reagents or catalysts which are useful for
the synthesis of a variety of chiral organic molecules. In this
manner, this invention is useful for the preparation of various
chemicals, pharmaceuticals and agrochemicals.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0008] Definitions:
[0009] An organoboron derivative, as defined herein, comprises a
compound having a boron atom connected to at least one alkyl,
allyl, alkenyl, aryl, allenyl or alkynyl group.
[0010] Alkyl groups of the present invention include
straight-chained, branched and cyclic alkyl radicals containing up
to about 20 carbons. Suitable alkyl groups may be saturated or
unsaturated. Further, an alkyl may also be substituted one or more
times on one or more carbons with substituents selected from the
group consisting of C1-C6 alkyl, C3-C6 heterocycle, aryl, halo,
hydroxy, amino, alkoxy and sulfonyl. Additionally, an alkyl group
may contain up to 10 heteroatoms or heteroatom substituents.
Suitable heteroatoms include nitrogen, oxygen, sulfur and
phosphorous.
[0011] Aryl groups of the present invention include aryl radicals
which may contain up to 10 heteroatoms. An aryl group may also be
optionally substituted one or more times with an aryl group or a
lower alkyl group and it may be also fused to other aryl or
cycloalkyl rings. Suitable aryl groups include, for example,
phenyl, naphthyl, tolyl, imidazolyl, pyridyl, pyrroyl, thienyl,
pyrimidyl, thiazolyl and furyl groups.
[0012] The term "combinatorial library" as used herein refers to a
set of compounds that are made by the same process, by varying one
or more of the reagents. Combinatorial libraries may be made as
mixtures of compounds, or as individual pure compounds, generally
depending on the methods used for identifying active compounds.
Where the active compound may be easily identified and
distinguished from other compounds present by physical and/or
chemical characteristics, it may be preferred to provide the
library as a large mixture of compounds. Large combinatorial
libraries may also be prepared by massively parallel synthesis of
individual compounds, in which case compounds are typically
identified by their position within an array. Intermediate between
these two strategies is "deconvolution", in which the library is
prepared as a set of sub-pools, each having a known element and a
random element. For example, using the process of the invention
each sub-pool might be prepared from only a single amine (where
each sub-pool contains a different amine), but a mixture of
different carbonyl derivatives (or organoboron reagents). When a
sub-pool is identified as having desired activity, it is
resynthesized as a set of individual compounds (each compound
having been present in the original active sub-pool), and tested
again to identify the compounds responsible for the activity of the
sub-pool.
[0013] The term "Metal" means any metal, metal derivative, or metal
substitute useful for performing the a reaction in order to
synthesize a reagant or catalyst. Examples include, but are not
limited to B, Li, Mg, Al, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr,
Mo, Ru, Rh, Pd, Ag, Re, Os, Ir, Pt, La, Ce and Yb.
[0014] General Description:
[0015] The first step of this invention involves a novel synthesis
of a chiral amine or amino alcohol ligand and the second step
involves the conversion of this amine or amino alcohol to a chiral
reagent or catalyst.
[0016] The first step is based on the use of organoboron compounds
in a C--C bond forming reaction where the electrophile is derived
from a carbonyl and an amine and the product is a new substituted
amine. There are many variations of this methodology involving
different organoboron, carbonyl and amine components. For the
purpose of illustration the following variations are described
here.
[0017] Synthesis of chiral amines: One aspect of the invention is a
process for generating chiral amine derivatives of formula (1) or a
combinatorial library of molecules of formula (1), by combining
compounds (2), (3) and (4): 1
[0018] where R.sup.1 and R.sup.2 are each independently selected
from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl,
acyl, carboxy, carboxamido, trialkylsilyl, aryldialkylsilyl,
diarylalkylsilyl, triarylsilyl, phosphinyl, and --YR, where Y is
selected from the group consisting of --O--, --NR.sub.a--, --S--,
--SO--, and --SO.sub.2--, and R and R.sub.a are each independently
selected from the group consisting of hydrogen, alkyl, aryl,
heteroaryl, and acyl, or R.sup.1 and R.sup.2 together form a
methylene bridge of 2 to 20 carbon atoms; and where R.sup.3 and
R.sup.4 are each independently selected from the group consisting
of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy, carboxy,
amino, alkylamino, dialkylamino, acylamino, carboxamido, thio,
alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl, and
heteroaryl; and where R.sup.5 is selected from the group consisting
of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and
allenyl; R.sup.6, R.sup.7 are selected from the group consisting of
hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro,
iodo, carboxy, amino, alkylamino, dialkylamino, acylamino,
carboxamido, thio, alkylthio, arylthio, acylthio, alkyl,
cycloalkyl, aryl, and heteroaryl, or together form a methylene
bridge of 3 to 7 atoms.
[0019] Following their formation, compounds of formula (1) can be
subsequently easily transformed to new derivatives. For example,
removing groups R.sup.1 and R.sup.2 can provide primary amines,
while joining two or more groups will result in the formation of
cyclic or polycyclic amines.
[0020] The multicomponent nature of the process described in this
invention allows the direct and rapid generation of combinatorial
libraries of individual products or mixtures of products, by
varying the desired substituents. Such libraries can be generated
either in solution or in the solid phase, upon attachment of one
substituent onto a solid support. For example, one may couple the
amine component (2) to a substrate through either R.sup.1 or
R.sup.2, and react the immobilized amine to a mixture of different
organoboron compounds (3), where R.sup.5 is a variety of different
groups) and individual or mixed carbonyl compounds (4) to produce a
mixture of bound products (1). Alternatively, the carbonyl compound
may be immobilized, and a mixture of organoboron compounds and
diverse amines added. Combinatorial libraries may be generated
either as individual compounds or as mixtures of compounds.
[0021] In another embodiment of the invention an organoboron
compound of formula (8) is combined with a preformed iminium
derivative (5), aminol (6), or aminal (7), prepared by the
combination of an amine (2) and a carbonyl compound (3), or by
other methods: 2
[0022] where R.sup.5 is selected from the group consisting of
alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl;
R.sup.6, R.sup.7 and R.sup.8 are selected from the group consisting
of hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro,
iodo, carboxy, amino, alkylamino, dialkylamino, acylamino,
carboxamido, thio, alkylthio, arylthio, acylthio, alkyl,
cycloalkyl, aryl, and heteroaryl, or together form a methylene
bridge of 3 to 7 atoms; X is a positive counter ion, and n is 0 or
1. Such reactions can take place directly or upon the addition of a
Lewis acid. In the case of fluoroborates (8),
R.sup.6=R.sup.7=R.sup.8=F) the reaction may be promoted by the
addition of a silyl derivative SiR.sup.9R.sup.10R.sup.11R.sup.12,
where R.sup.9 is selected from the groups consisting of: chloro,
bromo, iodo, alcoxy, acyloxy, triflate, alkylsulfonate or
arylsulfonate, while substituents R.sup.10, R.sup.11 and R.sup.12
are selected from the groups consisting of: alkyl, cycloalkyl,
aryl, alkoxy, aryloxy or chloro. A preferred R.sup.5 is an alkenyl
or aryl group leading to the formation of geometrically and
isomerically pure allylamines or benzylamines (2),
respectively.
[0023] Synthesis of chiral .alpha.-amino carbonyl derivatives: This
invention can be employed directly for the synthesis of chiral
.alpha.-amino acids or other .alpha.-amino carbonyl derivatives
(10) by combining an organoboron compound (4) with an amine (2) and
an .alpha.-dicarbonyl compound (9). 3
[0024] The reaction can proceed directly in a variety of solvents,
including water, alcohols, ethers, hydrocarbons, chlorinated
hydrocarbons and acetonitrile.
[0025] The stereochemistry of the product in these reactions can be
controlled by the use of a chiral amine, a chiral carbonyl compound
or a chiral organoboron derivative (L. Deloux et al., Chem. Rev.
(1993) 93:763). The use of chiral amines or similar amino alcohol
or amino acid derivatives can give products with a high degree of
diastereocontrol (up to 99.5% de). Removal of the chiral group
substituent can give the free amino acid with a high enantiomeric
excess (up to 99.5% ee).
[0026] The types of organoboron compounds that can be used in this
manner include compounds (4) that have R.sup.5 selected from the
group consisting of alkyl, allyl, cycloalkyl, aryl, heteroaryl,
alkenyl, alkynyl and allenyl, including substituted and
isomerically pure derivatives. The boron substituents R.sup.6 and
R.sup.7 which do not appear in the product (10), are selected from
the groups consisting of: hydroxy, alkoxy, aryloxy, heteroaryloxy,
chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino,
dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio,
acylthio, alkyl, cycloalkyl, aryl, heteroaryl, including
substituted and isomerically pure derivatives. Groups R.sup.6 and
R.sup.7 may be connected together to form a bridge of 3 to 7 atoms.
Substituents R.sup.3 in compound (9) are selected from the group
consisting of hydrogen, hydroxyl, alkoxy, amino, alkylamino,
dialkylamino, hydroxyamino, alkyl, cycloalkyl, aryl, hetero aryl,
including substituted and isomerically pure derivatives.
Substituents R.sup.4 in compound (9) are selected from the group
consisting of hydrogen, carboxy, alkyl, cycloalkyl, aryl., hetero
aryl, including substituted and isomerically pure derivatives.
Substituents R.sup.1 and R.sup.2 in amine (2) are selected from the
groups consisting of: alkyl, cycloalkyl, aryl, heteroaryl, hydroxy,
alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino,
dialkylamino, acylamino, carboxamido, alkylthio, arylthio,
acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl,
triarylsilyl, phosphinyl, alkylsulfonyl or arylsulfonyl, including
substituted and isomerically pure derivatives. Groups R.sup.1 and
R.sup.2 may be connected together to form a bridge of 2 to 20
atoms.
[0027] The reactants are combined in approximately equimolar
amounts in the solvent, and maintained at a temperature between
about 0.degree. C. and the reflux temperature of the solvent,
preferably between about 25.degree. C. and about 65.degree. C.,
until the reaction is complete. The course of the reaction may be
followed by any standard method, including thin-layer
chromatography, GC and HPLC. In general, the reaction is conducted
for about 1 to about 72 hours, preferably about 12 to about 24
hours. Product isolation usually gives fairly pure products without
the need for chromatography or distillation.
[0028] The products (10) of the invention can be subsequently
transformed to produce new derivatives. For example, if R.sup.3 is
hydroxyl, removing groups R.sup.1 and R.sup.2 can provide primary
amino acids, while joining two or more groups will result in the
formation of cyclic or polycyclic derivatives. A number of amine
components (2) can be used which include R.sup.1 and R.sup.2 groups
that can be easily removed in subsequent reactions. For example,
benzylamine derivatives can be cleaved by hydrogenation, while
others, such as the di(p-anisyl)methylamino group or the trityl
group, can be removed under acidic conditions which prevent facile
racemization.
[0029] The multicomponent nature of the process described in this
invention allows the direct and rapid generation of combinatorial
libraries of the products, by varying the desired substituents.
Such libraries can be generated either in solution or in the solid
phase, upon attachment of one substituent onto a solid support. In
this case at least one of the, groups R.sup.1 through R.sup.7 is a
polymeric material. For example, one may couple an amine (2) to a
substrate through either R.sup.1 or R.sup.2, and react the
immobilized amine with a mixture of different organoboron compounds
(4), where R.sup.5 is a variety of different groups) and individual
or mixed dicarbonyl compounds (9) to produce bound products (10).
Alternatively, the dicarbonyl compound may be immobilized, and a
mixture of organoboron compounds and diverse amines added.
Combinatorial libraries may be generated either as individual
compounds or as mixtures of compounds.
[0030] In order to improve the potential use of compounds (10) in
the synthesis of chiral reagents or catalysts, additional steps may
be carried out. For example, if compound (10) is an amino acid or
amino ester (R.sup.3=OH or OR) it can be converted to an amino
alcohol of formula (11) by reduction. Alternatively, if R.sup.3 in
compound (10) is an amino group, reduction will lead to a diamine
of formula (12). 4
[0031] Synthesis of chiral N-carboxymethyl amino acid derivatives:
The use of .alpha.-amino acid derivatives (13) as the amine
components in this process, can lead to N-carboxymethyl amino acid
products (14) with a very high degree of diastereocontrol. 5
[0032] Substituents R.sup.1 and R.sup.2 in the amino acid component
(13) are selected from the group consisting of alkyl, cycloalkyl,
aryl, hetero aryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl,
carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido,
alkyl thio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl,
diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl and
arylsulfonyl, including substituted and isomerically pure
derivatives. Groups R.sup.1 and R.sup.2 may also be connected to
other amino acid units (peptides) or may be connected together to
form a bridge of 2 to 20 atoms. Groups R.sup.8 and R.sup.9 are
selected from the group consisting of alkyl, cycloalkyl, aryl,
hetero aryl, acyl and carboxy, including substituted and
isomerically pure derivatives. Groups R.sup.8 and R.sup.9 may be
connected together or with other groups in (13), (9), or (4) to
form a bridge of 3 to 7 atoms. Substituents R.sup.3 and R.sup.4 in
compound (9) are each independently selected from the group
consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy,
carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido,
thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl, and
heteroaryl. The boron substitutent R.sup.5 in (4) is selected from
the group consisting of alkyl, cycloalkyl, aryl, heteroaryl,
alkenyl, alkynyl and allenyl. The boron substituents R.sup.6 and
R.sup.7 which do not appear in the products, are selected from the
group consisting of hydroxy, alkoxy, aryloxy, heteroaryloxy,
chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino,
dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio,
acylthio, alkyl, cycloalkyl, aryl and heteroaryl, including
substituted and isomerically pure derivatives.
[0033] In order to improve the potential use of compounds (14) in
the synthesis of chiral reagents or catalysts, additional steps may
be carried out. For example, different variations of compound (14)
can be converted to an amino diol of formula (15), a diamine
alcohol of formula (16) or a triamine of formula (17). 6
[0034] Synthesis of chiral 1,2-diamines and 1,2-amino alcohols: In
another embodiment of the invention an amine (2) and an organoboron
compound are reacted with carbonyl derivatives of the general
formula (18) to give products (19). 7
[0035] Groups R.sup.1 and R.sup.2 in the amine component (2) are
selected from the groups consisting of: alkyl, cycloalkyl, aryl,
hetero aryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl,
carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido,
alkyl thio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl,
diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl or
arylsulfonyl, including substituted and isomerically pure
derivatives. Groups R.sup.1 and R.sup.2 may be connected together
to form a bridge of 2 to 20 atoms. Groups R.sup.3 in compound (18)
are selected from the group consisting of hydrogen, alkyl,
cycloalkyl, aryl, and heteroaryl. Groups R.sup.3 in compound (18)
have at least one carbon atom and are attached to a group XH, where
X is selected from a group consisting of --O--, --NR.sub.a--,
--S--, and R.sub.a is independently selected from the group
consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, hydroxy,
alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, dialkylamino,
and acylamino. The boron substitutent R.sup.5 in compound (4) is
selected from the group consisting of alkyl, cycloalkyl, aryl,
heteroaryl, alkenyl, alkynyl and allenyl. The boron substituents
R.sup.6 and R.sup.7 which do not appear in the products, are
selected from the groups consisting of: hydroxy, alkoxy, aryloxy,
heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino,
alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio,
arylthio, acylthio, alkyl, cycloalkyl, aryl, heteroaryl, including
substituted and isomerically pure derivatives. Groups R.sup.6 and
R.sup.7 may be connected together to form a bridge of 3 to 7
atoms.
[0036] In one embodiment of the invention an amine (2) and an
organoboron compound (4) are reacted with 1-amino carbonyl
derivatives (20) to give directly 1,2-diamines (21). 8
[0037] Groups R.sup.1 and R.sup.2 in the amine component (2) are
selected from the groups consisting of: alkyl, cycloalkyl, aryl,
hetero aryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl,
carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido,
alkyl thio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl,
diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl or
arylsulfonyl, including substituted and isomerically pure
derivatives. Groups R.sup.1 and R.sup.2 may be connected together
to form a bridge of 2 to 20 atoms. Groups R.sup.3, R.sup.4 and
R.sup.8 in compound (20) are selected from the group consisting of
hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl. Groups R.sup.9
and R.sup.10 in compound (20) are selected from the group
consisting of alkyl, cycloalkyl, aryl, hetero aryl, hydroxy,
alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino,
dialkylamino, acylamino, carboxamido, alkyl thio, arylthio,
acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl,
triarylsilyl, phosphinyl, alkylsulfonyl and arylsulfonyl, including
substituted and isomerically pure derivatives. Groups R.sup.9 and
R.sup.10 may be connected with other groups in compounds (2), (20)
or (4) to form a bridge of 2 to 20 atoms. The boron substitutent
R.sup.5 in compound (4) is selected from the group consisting of
alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl.
The boron substituents R.sup.6 and R.sup.7 which do not appear in
the products, are selected from the group consisting of hydroxy,
alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo,
carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido,
thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl and
heteroaryl, including substituted and isomerically pure
derivatives. Groups R.sup.6 and R.sup.7 may be connected together
to form a bridge of 3 to 7 atoms.
[0038] The products (21) of the invention can be subsequently
transformed to produce new derivatives. For example, removing
groups R.sup.1 and R.sup.2 can provide primary amines, while
joining two or more groups will result in the formation of cyclic
or polycyclic derivatives. A number of amine components (2) can be
used which include R.sup.1 and R.sup.2 groups that can be easily
removed in subsequent reactions. For example, benzylamine
derivatives can be cleaved by hydrogenation, while others, such as
the di(p-anisyl)methylamino group or the trityl group, can be
removed under acidic conditions which prevent facile
racemization.
[0039] In another embodiment of the invention an amine (2) and an
organoboron compound are reacted with an .alpha.-hydroxy carbonyl
derivative (22) to give 1,2-amino alcohols (23). Compounds (22) can
also exist in a hemiacetal form, and can include carbohydrate
derivatives. The use of chiral derivatives (22) can form products
(23) with a very high degree of diastereocontrol (up to greater
than 99.5% de) and enantiocontrol diastereocontrol (up to greater
than 99.5% ee). 9
[0040] Groups R.sup.1 and R.sup.2 in the amine component (2) are
selected from the group consisting of alkyl, cycloalkyl, aryl,
hetero aryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl,
carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido,
alkyl thio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl,
diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl and
arylsulfonyl, including substituted and isomerically pure
derivatives. Groups R.sup.1 and R.sup.2 may be connected with other
groups in compounds (2), (22) or (4) to form a bridge of 2 to 20
atoms. Groups R.sup.3, R.sup.4 and R.sup.8 in compound (22) are
selected from the group consisting of hydrogen, alkyl, cycloalkyl,
aryl, and heteroaryl. The boron substitutent R.sup.5 in compound
(4) is selected from the group consisting of alkyl, cycloalkyl,
aryl, heteroaryl, alkenyl, alkynyl and allenyl. The boron
substituents R.sup.6 and R.sup.7 which do not appear in the
products, are selected from the groups consisting of: hydroxy,
alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo,
carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido,
thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl,
heteroaryl, including substituted and isomerically pure
derivatives. Groups R.sup.6 and R.sup.7 may be connected together
to form a bridge of 3 to 7 atoms.
[0041] An important feature of this variation is that when
optically pure alpha-hydroxy carbonyl compounds (22) are used, no
racemization occurs and the products (23) can be obtained as single
enantiomers, with greater than 99% ee
[0042] The products (23) of the invention can be subsequently
transformed to produce new derivatives. For example, removing
groups R.sup.1 and R.sup.2 can provide primary amines, while
joining two or more groups will result in the formation of cyclic
or polycyclic derivatives. A number of amine components (2) can be
used which include R.sup.1 and R.sup.2 groups that can be easily
removed in subsequent reactions. For example, benzylamine
derivatives can be cleaved by hydrogenation, while others, such as
the di(p-anisyl)methylamino group or the trityl group, can be
removed under acidic conditions which prevent facile racemization.
Also, the use of groups R.sup.5 in the organoboron component, such
as alkenyl or activated aryl or heteroaryl, followed by oxidative
cleavage gives new products where the R.sup.5 is a carbonyl group
(aldehyde, ketone or carboxylic acid). Alternatively, the use of
carbonyl components (22) having a group R.sup.4 or R.sup.8
consisting of a carbon atom attached to a hydroxyl group, as with
many carbohydrate derivatives, followed by oxidative diol cleavage
can produce new variations of compounds of the general formula
(10).
[0043] Synthesis of chiral reagents or catalysts: The second step
of this invention involves the reaction of a ligand derived from
the first step, for example a compound of formula (1), (10), (11),
(12), (14), (15), (16), (17), (19), (21), or (23) with a compound
(24) of the general formula M(L)n to give a new chiral reagent or
catalyst that contains one or more bonds among M and a heteroatom
of the ligand. 10
[0044] The atom M in formula (24) is selected from a group
consisting of Li, Mg, B, Al, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr,
Mo, Ru, Rh, Pd, Ag, Re, Os, Ir, Pt, La, Ce, Yb; where L is a ligand
selected from a group consisting of chloro, bromo, iodo, fluoro,
oxo, hydroxy, hydroperoxy, alkoxy, aryloxy, acyloxy, acetoacetyl,
carboxy, nitro, amino, alkylamino, dialkylamino, azido, carbonyl,
alkyl, alkenyl, dienyl, aryl, triflate, arylsulfonyl; where n is a
number selected from 0-6; and where all ligands L are the same or
different. Typical reagents of formula (24) include, but are not
limited to: ZnBr.sub.2, Ti(OR.sub.4), Zr(OR).sub.4, YbCl.sub.3,
CrCl.sub.2, WOCl.sub.4, FeCl.sub.2, RuCl.sub.2, CoCl.sub.2,
NiCl.sub.2, PdCl.sub.2, CuCl.sub.2, ZnCl.sub.2, AgOTf, BCl.sub.3,
AlCl.sub.3 etc.
[0045] The chiral reagents or catalysts derived during the second
step of this invention can be used in a large number of synthetic
processes for the preparation of a large variety chiral products.
These include: alkylations, aldol reactions, additions of
nucleophiles to aldehydes or ketones, additions of nucleophiles to
imine derivatives, Diels-Alder reactions, cycloadditions,
cyclopropanations, aziridinations, carbonyl reductions, alkene
hydrogenations, epoxidations, epoxide opening, etc.
[0046] Combinatorial catalysis: The facile synthesis of chiral
ligands and chiral catalysts with this invention, allows the rapid
preparation of large numbers of variants in the form of
combinatorial libraries of catalysts. Such libraries can then be
used to identify the optimum catalyst for any particular synthetic
transformation. Following the screening of the library of
catalysts, the most effective one can be easily prepared in large
quantities for scale-up.
[0047] Solid phase variations: When one of the three components
(organoboronic acid, amine, carbonyl) is attached to a solid
support, the resulting catalysts will also be attached to the solid
support. This variation allows the preparation of even larger
libraries via the usual pool and split approach.
[0048] Advantages and Improvements over Existing Technology
[0049] Although there are many known methods for the synthesis of
amine derivatives, due to the vital importance of these compounds
and the many shortcomings of existing methods, any conceptually new
and practical method in this are is of special significance. The
present method offers a number of advantages over existing methods:
Thus, this method is exceptionally environmentally friendly and
practical. The reactions can be done in water or aqueous solvents
at ambient temperature without using any toxic, hazardous or
corrosive materials, such as cyanides, isonitriles, strong acids,
strong bases, organotin, organocopper or other highly reactive
organometallic compounds. Also, the reaction does not require an
inert atmosphere, and can be done in the air. The present method
also involves a smaller number of synthetic steps than most
existing methods. All starting materials used in this type of
reaction are either commercially available or can be readily
prepared from commercially available reagents by a one-step
procedure.
[0050] The use of organoboron compounds, particularly boronic acids
and boronates, as nucleophilic components for amino acid and amine
synthesis is a new concept which offers a number of distinct
features, including the following:
[0051] 1. Organoboronic acids are often crystalline, easy to
prepare and easy to handle compounds that are stable in air and
water. They are also non toxic and non hazardous. Although the
synthesis and reactivity of these molecules has been studied
extensively, the present method is the first successful example of
their utilization in the synthesis of amines and amino acids.
[0052] 2. The present method is highly versatile, allowing a high
degree of structural variation in all of the reacting components.
The process is also a multi-component reaction, allowing the
one-pot construction of amine derivatives from several readily
available building blocks. For these reasons, this method is easily
applicable to the solid or liquid phase combinatorial
synthesis.
[0053] 3. The stereochemical control of the reaction can be
accomplished not only with the use of chiral amine and carbonyl
components but also with chiral organoboron derivatives. An
advantage of boron-based auxiliaries is that they can be easily
introduced and can be efficiently recycled after the reaction, thus
making this method especially attractive for large scale
applications.
[0054] 4. Due to the facile synthesis of alkenyl and aryl boron
derivatives, which proceed with complete control of geometry or
positional isomerism, the present method is uniquely capable of
furnishing isomerically pure products of this type.
[0055] 5. Of special significance is the ability to directly use
free amino acids in this reaction to give products of high
stereochemical purity.
[0056] Although amines and amino alcohols are common ligands for
many chiral catalysts, the processes described herein offer
numerous advantages including:
[0057] 1. Most of the existing methods cannot be adapted in a
combinatorial approach to catalyst optimization, due to the
required multi-step syntheses. While a number of combinatorial
approaches to catalyst development were reported, all of these
involve more elaborate sequential syntheses or chiral
building-block combinations.
[0058] 2. The present invention, involving a one-step
stereocontrolled synthesis of amino alcohols from readily available
starting materials, opens the way for the development of a
practical combinatorial catalyst synthesis involving these
well-established ligands.
[0059] 3. The fact that the present invention allows the
incorporation of multiple hydroxyl groups and other functionalities
without any extra protection--deprotection steps facilitates the
synthesis of some really complex chiral catalysts, that may be
effective, even though their structures may be difficult to
establish.
[0060] 4. Because aldehyde racemization does not occur under the
reaction conditions, relatively enantiomerically pure amino
alcohols can be obtained by using enantiomerically pure
alpha-hydroxy aldehydes, allowing for greater ease of recovery of
the desired product.
[0061] 5. By having one of the three components (organoboronic
acid, amine, carbonyl) attached to a solid support prior to the
reaction, the resulting catalysts will also be attached to the
support, in a single reaction step. This allows for potentially
faster screening of the compounds.
[0062] 6. The invention allows the preparation of potentially large
libraries of chiral catalysts with novel structures that may be
used to identify the most effective system for a particular
asymmetric transformation.
EXAMPLES
[0063] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how the processes of the present invention can be
performed, and are not intended to limit the scope of what the
inventors regard as their invention. Efforts have been made to
ensure accuracy with respect to numbers used (e.g. amounts,
temperature, etc.) but some experimental errors and deviations
should be accounted for. Unless indicated otherwise, parts are
parts by weight, molecular weight is weight average molecular
weight, temperature is in degrees centigrade, and pressure is at or
near atmospheric.
Example 1
[0064] 11
[0065] To a stirred solution of glyoxylic acid monohydrate (291 mg,
3.163 mmol) in dichloromethane (14 mL) was added
(S)(-)-2-phenylglycinol (434 mg, 3.163 mmol) in one portion. After
5 min (E)-2-phenylethenyl boronic acid (469 mg, 3.169 mmol) was
added and the reaction mixture was stirred vigorously at room
temperature for 12 hours. The precipitate was isolated by
filtration, washed with cold dichloromethane (15 mL) and acetone
(10 mL) and dried under vacuum to give the expected adduct (733 mg,
78% yield, >99% de, >99% ee). .sup.1H-NMR (360 MHz,
d.sub.6-DMSO) .delta. 7.2-7.5 (m, 10H), 6.54 (d, J=15.2 Hz, 1H),
6.20 (dd, J=15.2 Hz, 7.3 Hz, 1H), 3.84 (m, 1H), 3.64 (d, J=7.3 Hz,
1H), 3.45 (d, J=7.1 Hz, 2H). .sup.13-NMR (90 MHz, d.sub.6-DMSO)
.delta. 172.83, 139.79, 136.23, 131.07, 128.62, 128.34, 127.68,
127.51, 126.95, 126.38, 126.25, 65.97, 63.02, 60.96.
HRMS-CI(M.sup.++1) calcd 298.1365, obsd 298.1449. Anal. Calcd for
C.sub.18H.sub.19NO.sub.3: C, 72.71; H, 6.44; N, 4.71. Found: C,
72.27; H, 6.41 N, 4.69.
Example 2
[0066] 12
[0067] A mixture of L-phenylalanine (100 mg, 0.606 mmol), glyoxylic
acid monohydrate (56 mg, 0.608 mmol) and (E)-2-phenylethenyl
boronic acid (89 mg, 0.601 mmol) in methanol (8 mL) was stirred
vigorously for 24 hours. The precipitate was isolated by
filtration, washed with methanol (10 mL) and dried under vacuum to
give (E)-2-[(S)-N-(1'-carboxy-2'phenyl)-amino-4- -phenyl-3-butenoic
acid (160 mg, 82% yield, 99% de, 99% ee). .sup.1H NMR (360 MHz,
DMSO-d.sub.6) .delta. 7.18-7.45 (m, 10H), 6.58 (d, J=16.0 Hz, 1H),
6.10 (dd, J=16.0 Hz, 8.1 Hz, 1H), 3.91 (d, J=7.8 Hz, 1H), 3.45 (t,
J=6.4 Hz, 1H), 2.88 (m, 2H). .sup.13C NMR (90 MHz, DMSO-d.sub.6)
.delta. 174.9, 172.9, 138.0, 137.8, 136.1, 132.6, 129.4, 128.6,
127.7, 126.8, 126.4, 126.3, 61.7, 61.0, 59.6.
Example 3
[0068] 13
[0069] Alanine-proline (1,000 mg, 5.37 mmol), glyoxylic acid
monohydrate (544 mg, 5.91 mml) and 2-phenylethenyl boronic acid
(1,192 mg, 8 mmol) were vigorously stirred together in water (7 mL)
for 48 hours. The precipitate was filtered, washed with acetone
(2.times.10 mL) and dried to give a single crystalline product
(1,488 mg, 80% yield, >99% de, >99% e) the structure of which
was confirmed with X-ray crystallography. .sup.1H NMR (360 MHz,
DCl/D.sub.2O) .delta. 7.10-7.25 (br, 5H), 6.92 (d, J=15.6 Hz, 1H),
5.78 (dd, J=15.6 Hz, 9.8 Hz, 1H), 4.75 (d, J=9.8 Hz, 1H), 4.15 (q,
J=6.8 Hz, 1H), 3.84 (m, 1H), 3.20 (m, 2H), 1.58 (m, 2H), 1.41 (d,
J=6.8 Hz, 3H), 1.01-1.35 (m, 2H).
[0070] .sup.13C NMR (90 MHz, DCl/D.sub.2O) .delta. 174.2, 168.7,
168.2, 142.6, 133.4, 130.4, 129.3, 127.1, 114.7, 62.3, 59.4, 54.0,
47.4, 28.0, 24.0, 15.1. HRMS-CI calcd for
C.sub.18H.sub.22N.sub.2O.sub.5 (M+H.sup.+) 347.1528, found
347.1598. Anal. Calcd for C.sub.18H.sub.22N.sub.2O.sub.5: C, 62.42;
H, 6.40; N, 8.09. Found: C, 62.46; H, 6.41 N, 8.02.
Example 4
[0071] 14
[0072] 1-Naphthylboronic acid (110 mg, 0.64 mmol) and
(S)-5-phenyl-2,2-dimethyl-4-hydroxy-1,3-dioxolane (130 mg, 0.67
mmol) were dissolved in ethanol (5 mL). To this solution was added
dibenzylamine (126 mg, 0.64 mmol), the reaction was purged with
nitrogen, sealed and stirred at room temperature for 24, hours.
After the removal of volatiles, the residue was dissolved in
ethylacetate (100 mL) and extracted with 3 N NaOH (3.times.50 mL)
to remove unreacted boronic acid. Organic phase was dried over
sodium sulfate and evaporated. The residue was chromatographed on
silica gel using hexanes-ethylacetate (8:2) to yield pure product
as a white foamy powder (238 mg, 84% yield, >99% de and >99%
ee). [.alpha.].sub.D=+41.degree. (c=0.14, CH.sub.3OH); IR (KBr)
.delta. 3061, 2923, 1599, 1493, 1452, 1278, 1124, 1026, 965, 799,
781, 768 cm.sup.-1. .sup.1H NMR (360 MHz, CD.sub.3OD) .delta.
6.85-7.98 (m, 22H), 5.55 (d, J=9.2 Hz, 1H), 4.97 (d, J=9.2 Hz, 1H),
3.85 (d, J=14.2 Hz, 2H), 3.12 (d, J=14.2 Hz, 2H). .sup.13C NMR (90
MHz, CD.sub.3OD) .delta. 145.3, 141.1, 135.9, 135.4, 134.7, 129.9,
129.6, 129.2, 129.1, 128.9, 128.7, 128.6, 127.8, 127.3, 126.3,
125.9, 125.7, 75.8, 63.1, 55.4. HRMS-EI calcd. for
C.sub.32H.sub.30NO (M+H.sup.+) 444.2249, found 444.2285.
Example 5
[0073] 15
[0074] (R)-Glyceraldehyde (520 mg, ca. 75% in water, ca. 4.33 mmol)
was dissolved in EtOH (15 mL) and to this solution was added
aminodiphenylmethane (793 mg, 4.33 mmol), followed by
(E)-2-phenylethenyl boronic acid (652 mg, 4.4 mmol). The reaction
flask was sealed with plastic stopper and reaction mixture was
vigorously stirred for 24 hours at ambient temperature. After the
removal of volatiles, the residue was suspended in 6 N hydrochloric
acid (20 mL) and heated with vigorous stirring at 60 C for 1 hour.
After that time, the solution was cooled and filtered. The
precipitate on the filter was washed with cold water (2.times.10
mL), ethylacetate (3.times.20 mL) and dried. Obtained 1201 mg of
pure product (77% yield, >99% de, >99% ee). .sup.1H NMR (250
MHz, CD.sub.3OD) .delta.7.30-7.65 (m, 15H), 6.60 (d, J=16 Hz, 1H),
6.33 (dd, J=16 Hz, 8.5 Hz, 1H), 5.59 (s, 1H), 4.18 (m, 1H), 3.93
(dd, J=8.5 Hz, 3.0 Hz, 1H), 3.57 (dd, J=10.9 Hz, 5.6 Hz, 1H), 3.40
(dd, J=10.9 Hz, 7.6 Hz, 1H). .sup.13C NMR (63 MHz, C.sub.6D.sub.6)
.delta. 144.8, 143.3, 137.1, 134.0, 129.0, 128.8, 128.7, 128.1,
127.9, 127.7, 127.4, 127.3, 126.8, 74.2, 65.2, 64.0, 61.5. HRMS-CI
calcd. for C.sub.24H.sub.25NO.sub.- 2 (M+H.sup.+) 360.1885, found
360.1949.
[0075] The stereochemistry of the product was established as shown
16
[0076] below:
Example 6
[0077] 17
[0078] (D)-Ribose (158 mg, 1.05 mmol) was dissolved in EtOH (10 mL)
and to this solution was added N-benzylmethylamine (127 mg, 1.05
mmol), followed by (E)-2-phenylethenyl boronic acid (163 mg, 1.1
mmol). The reaction flask was sealed with a plastic stopper and the
reaction mixture was vigorously stirred for 24 hours at ambient
temperature. After the removal of volatiles, the residue was
redissolved in dichloromethane and purified by flash chromatography
on silicagel using dichloromethane-methanol (600:50) as the eluent
to obtain 278 mg of pure product (74% yield, >99% de). .sup.1H
NMR (360 MHz, CD.sub.3OD) .delta. 7.20-7.45 (m, 10H), 6.61 (d,
J=16.0 Hz, 1H), 6.33 (dd, J=16.0 Hz, 9.8 Hz, 1H), 3.98 (t, J=8.5
Hz, 1H), 3.65-3.88 (m, 5H), 3.58 (d, J=13.2 Hz, 1H), 3.49 (t, J=8.8
Hz, 1H), 2.25 (s, 3H). .sup.13C NMR (90 MHz, CD.sub.3OD) .delta.
138.9, 138.0, 137.8, 130.5, 129.6, 129.5, 128.8, 128.6, 127.6,
124.3, 77.2, 75.4, 71.4, 70.8, 64.1, 60.1, 37.9. HRMS-CI calcd. for
C.sub.21H.sub.27NO.sub.4 (M+H.sup.+) 358.1940, found 358.1987.
Example 7
[0079] 18
[0080] Prepared from (D)-xylose as in example 6 except that 2-furyl
boronic acid and phenylalanine were used and the reaction was run
for 48 hours in MeOH in 67% yield, >99% de, >99% ee. .sup.1H
NMR (360 MHz, CD.sub.3OD) .delta. 7.55-7.60 (br, 1H), 7.21-7.38 (m,
5H), 6.43 (br, 2H), 4.27 (m, 1H), 4.05 (m, 1H), 3.50-3.75 (m, 6H),
3.15 (m, 1H). .sup.13C NMR (90 MHz, CD.sub.3OD) .delta. 173.0,
145.3, 137.6, 130.6, 130.4, 130.0, 128.4, 113.5, 111.9, 72.9, 72.5,
71.6, 64.0, 63.0, 59.9, 37.0. HRMS-CI calcd. for
C.sub.18H.sub.23NO.sub.7 (M+H.sup.+) 366.1474, found 366.1553.
Example 8
[0081] 19
[0082] To the solution of salicylaldehyde (122 mg, 1 mmol) in ethyl
alcohol (7 mL) was added (S)-N-benzyl-1-phenylethylamine (211 mg, 1
mmol), followed by (E)-2-phenylethenyl boronic acid (148 mg, 1
mmol). The reaction flask was purged with argon, sealed and stirred
vigorously for 24 hours at ambient temperature. After the
evaporation of volatiles, the product was isolated by flash column
chromatography on silicagel using ethylacetate-hexanes (2:8) as the
eluent (315 mg, 75% yield, >99% de, >99% ee).
Example 9
[0083] The high degree of stereocontrol of this process of the
invention is illustrated in the following example. Thus, the final
amino alcohol was subjected to Mosher amide analysis, which
indicated a single enantiomer: 20
[0084] Some additional examples are shown in Table 1.
1TABLE 1 Reactions with disaccharides 21 22 23
* * * * *