Synthesis of substituted prolines

Details Synthesis of substituted prolines Synthesis of substituted prolines

2000-05-05

2002-02-26

Solola, T. A. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06350882

ABSTRACT:

BACKGROUND OF THE INVENTION
Substituted prolines are widely used in biological activity studies of modified conformational constrained peptides (R. Sharma et al.,
J. Org. Chem
., Vol. 61, p. 202 (1996)). Several routes have been developed to synthesize these conformational constrained amino acid analogues (Sasaki et al.,
J. Org. Chem
., Vol. 62, p. 765, (1997); Karaoyan et al.,
Tetra. Lett
., Vol. 38, p. 85 (1997); Lorthios et al.,
Tetra. Lett
., Vol. 38, p. 89, (1997)). However, few of these routes are amenable to large-scale preparation.
Racemic 3-substituted prolines have been synthesized by condensation of diethyl acetylaminomalonate with the appropriate &agr;, &bgr;-unsaturated aldehyde, followed by reduction, saponification, decarboxylation, and hydrolysis. (D. A. Cox et al.,
J. Am. Chem. Soc
., Vol. 88, pg. 2019 (1996); O. Tiba et al.,
Polym. Sci., Part A: Polym. Chem
., Vol. 25, pg. 3437, (1987); J. Y. L. Chung et al.,
J. Org. Chem
., Vol. 55, p. 270 (1990)). Enantiopure 3-alkyl and 3-phenylprolines were obtained through separation of the diastereomeric amides by column chromatography, followed by hydrolysis. (J. Y. L. Chung et al.,
J. Org. Chem
.) This synthesis required many steps and the overall yields are low. The conjugated addition of stabilized carbanions, in the presence of alkali salts of proline as the catalyst, to &agr;, &bgr;-unsaturated aldehydes and ketones, has been reported to afford adducts of moderate to high enantiomeric excess (“ee”) (M. Yamaguchi et al.,
J. Org. Chem
., Vol. 61, p. 3520 (1996)).
Therefore, it is an object of this invention to provide a process for the synthesis of substituted prolines that is more efficient, and less time consuming.
It is also an object of this invention to provide a process for the synthesis of enantiopure substituted prolines that would not require the use of chromatography to separate the diastereomers.
It is a further object of this invention to provide a process for the synthesis of enantiopure substituted prolines that does not use expensive chiral auxiliary and produces a better yield.
SUMMARY OF THE INVENTION
The instant invention is directed to a practical process for the synthesis of substituted prolines. In particular, this invention is related to an improved, enantioselective process for the synthesis of trans 3-alkyl prolines.
DETAILED DESCRIPTION
The instant invention is directed to a process for synthesizing substituted prolines, in particular, optically pure substituted prolines. The process of the instant invention comprises the steps of:
a) adding an unsubstituted or substituted proline alkali salt and an alkali halide to a solution of dialkylacylamidomalonate; and
b) adding &agr;, &bgr; unsaturated aldehyde to produce an adduct.
In a further embodiment, the process of the instant invention comprises the steps of:
a) adding an unsubstituted or substituted proline alkali salt and an alkali halide to a solution of dialkylacylamidomalonate;
b) adding &agr;, &bgr; unsaturated aldehyde to produce an adduct; and
c) converting the adduct to provide a substituted proline.
In an embodiment of the instant invention, the steps of converting the adduct to a substituted proline comprise:
c) mixing the adduct with trialkylsilane in a solvent;
d) adding acid and aqueous base; and
e) isolating an N-acyl substituted proline.
In a further embodiment of the instant invention, the steps of converting the substituted proline to an optically pure substituted proline comprise:
f) mixing the N-acyl substituted proline with a chiral base;
g) isolating a salt of the chiral base and the N-acyl substituted proline as a crystalline solid;
h) adding aqueous base and acid; and
i) isolating an optically pure substituted proline.
A fourth embodiment of the instant invention comprises the steps of:
a) adding an unsubstituted or substituted proline alkali salt and an alkali halide to a solution of dialkylacylamidomalonate;
b) adding &agr;, &bgr; unsaturated aldehyde to produce an adduct;
c) mixing the adduct with trialkylsilane in a solvent;
d) adding an acid;
e) adding a basic solution to produce a first biphasic mixture;
f) adding a solvent and an acid to the aqueous layer of the first biphasic mixture to produce a second biphasic mixture;
g) adding aqueous base to the organic layer of the second biphasic mixture to produce a third biphasic mixture;
h) adding an acid to acidify the aqueous layer of the third biphasic mixture; and
i) isolating an N-acyl substituted proline.
A further embodiment of this fourth embodiment of the instant invention further comprises the steps of:
j) mixing the N-acyl substituted proline with a chiral base;
k) isolating a salt of the chiral base and the N-acyl substituted proline as a crystalline solid;
l) dissolving the salt in an aqueous base and a solvent to produce a fourth biphasic mixture;
m) adding an acid to acidify the aqueous layer of the fourth biphasic mixture; and
n) isolating an optically pure substituted proline.
A specific example of the process of the instant invention comprises the steps of:
a) adding proline lithium salt and CsF to a solution of diethylacetamidomalonate; and
b) adding trans-2-pentenal to produce an adduct.
A further embodiment of the specific example of instant invention comprises the steps of:
c) mixing the adduct with triethylsilane in toluene;
d) adding an inorganic acid;
e) adding a solution of Na
2
CO
3
to produce a first biphasic mixture;
f) adding toluene and HOAc to the aqueous layer of the first biphasic mixture to produce a second biphasic mixture;
g) adding aqueous NaOH to the organic layer of the second biphasic mixture to produce a third biphasic mixture;
h) adding an acid to acidify the aqueous layer of the third biphasic mixture;
i) isolating N-acetyl-trans-3-ethylproline.
A further embodiment of the specific example of the instant invention comprises the steps of:
j) mixing the N-acetyl-trans-3-ethylproline with (S)-&agr;-methylbenzylamine; and
k) isolating a salt of (S)-&agr;-methylbenzylamine and N-acetyl-3(R)-ethyl-2(R)-proline as a crystalline solid;
l) dissolving the salt in aqueous NaOH and MTBE to produce a fourth biphasic mixture;
m) adding an acid to acidify the aqueous layer of the fourth biphasic mixture; and
n) isolating optically pure (2R,3R)-3-ethylproline.
As used herein, the phrase“substituted proline” is intended to include a proline , substituted with 1 to 3 substituents selected from an alkyl, alkoxy, aryl, aralkyl, heteroalkyl, heteroaryl or heteroaralkyl group. As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having 1 to 6 carbon atoms, unless otherwise specified; “alkoxy” represents an alkyl group of 1 to 6 carbon atoms, unless otherwise indicated, attached through an oxygen bridge. “Heteroalkyl”, as used herein, is intended to refer to an alkyl chain, as described above, wherein 1 to 3 of the carbon atoms is replaced with a heteroatom, such as S, N, O and the like. “Halide”, as used herein, means fluoride, chloride, bromide or iodide. As used herein, “alkali” is intended to include all of the alkali metals, such as lithium, sodium, potassium, rubidium, cesium and francium.
As used herein, “aryl” is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
As used herein, the terms “substituted C
1
-C
6
alkyl” and “substituted C
1
-C
6
alkoxy” are intended to include the branch or straight-chain alkyl group of the specified number of carbon atoms, wherein the carbon atoms may be substituted with F, Cl, Br, I, CF
3
, N
3
, NO
2
, NH
2
, oxo, —OH, —O(C
1
-C
6
alkyl), S(O)
0-2
, (C
1
-C
6
alkyl)S(O)
0-2
—, (C
1
-C
6
alkyl)S(O)
0-2
(C
1
-C
6
alkyl)—, C
3
-C
20
cycloalkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, —C(O)NH, (C
1
-C
6
alkyl)C(O)NH—, H
2
N—C(NH)—, (C
1
-C
6
alkyl)C(O)—, —O (C
1
-C
6
alkyl)CF
3
, (C
1
-C
6
alkyl)OC(O)—, (C
1
-C
6

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