Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-09-23
2001-02-20
Oswecki, Jane C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S376100, C548S377100
Reexamination Certificate
active
06191283
ABSTRACT:
BACKGROUND OF THE INVENTION
There has been an increasing interest in optically active &bgr;-amino acids and peptides derived from them. Optically active &bgr;-amino acids include a number of naturally occurring substances in the free form with an interesting pharmacological profile. Functionalized &bgr;-amino acids are important segments of bioactive molecules. For example, Taxol™ contains the phenylisoserine side chain as its key pharmacophore, and compounds of cyclic &bgr;-amino acids make up the class of &bgr;-lactam antibiotics. Additionally, &bgr;-amino acids are components of peptidic natural products with a wide range of biological activity. Peptides consisting of &bgr;-amino acids have promising pharmaceutical use as orally active drugs since they are hydrolytically stable. Given the significance of the &bgr;-amino acids, development of new methodologies for their synthesis, especially for the stereoselective synthesis of chiral &bgr;-amino acids, is important.
Among the strategies for the synthesis of racemic &bgr;-amino acids is the conjugate addition of nitrogen nucleophiles to enoates. Other common approaches include diastereoselective additions in which the nitrogen nucleophile or the &agr;,&bgr;-unsaturated substrate is chiral. Typical examples include the Michael type addition of optically active lithium amides to &agr;,&bgr;-unsaturated esters, or additions of amines to chiral &agr;,&bgr;-unsaturated esters. These approaches however, require the use of stoichiometric amounts of expensive optically active reagents which limits their utility. A single example of chiral Lewis acid catalysis in the conjugate addition of amines to enoates has been reported, however, this method proceeds with only low to moderate selectivity (highest ee of 42%).
The current methods for the synthesis of chiral &bgr;-amino acids suffer from one or more of a number of disadvantages such as low yields, use of costly reagents, intricate purification steps or low enantiomeric excesses. Accordingly, in view of the potential pharmaceutical utility of &bgr;-amino acids and &bgr;-peptides there is a continuing need for methods which would permit the efficient, large scale preparation &bgr;-amino acids, especially in optically active form.
SUMMARY OF THE INVENTION
The present invention provides a method for the preparation of &bgr;-amino acid compounds through the conjugate addition of an amine nucleophile to an &agr;,&bgr;-unsaturated amide compound in the presence of a chiral Lewis acid complex. The chiral Lewis acid complex can be prepared from an azophilic metal salt and a chiral bisoxazolinylmethane ligand. The method provides a high yielding syntheses of &bgr;-amino acids and related derivatives from readily available starting materials and is amenable to large scale synthesis. Moreover, the present method yields these &bgr;-amino acid compounds in high enantiomeric excesses.
The method includes contacting the &agr;,&bgr;-unsaturated amide compound with an amine nucleophile in the presence of the chiral Lewis acid complex to form a chiral &bgr;-aminoamide. The method is typically carried out at room temperature or below in an organic solvent using catalytic or stoichiometric amounts of the chiral Lewis acid with respect to the &agr;,&bgr;-unsaturated amide compound.
The high enantiomeric excesses of the present method are believed in part to be related to a selective amidolysis of the minor enantiomer produced. The unique catalytic nature of the present method is based at least in part on the fact that the &agr;,&bgr;-unsaturated amide compound substrate is a better Lewis base than the &bgr;-amino acid compound product. Once a majority of the of the &agr;,&bgr;-unsaturated amide compound substrate is consumed, the minor enantiomer of the initially formed chiral &bgr;-aminoamide undergoes a faster rate of amidolysis with residual amine nucleophile to form a second &bgr;-aminoamide, thereby increasing the enantiomeric excess of the initially formed chiral &bgr;-aminoamide product.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method for the preparation of &bgr;-amino acids from &agr;,&bgr;-unsaturated amide compounds. The method involves contacting the &agr;,&bgr;-unsaturated amide compound with an amine nucleophile in the presence of an organic solvent and a chiral Lewis acid complex. The method is typically carried out at about room temperature (roughly 25° C.) or below. Temperatures of about −20° C. to about −80° C. are preferably employed in order to maintain a convenient reaction rate without substantially decreasing the yield or enantioselectivity. The reaction is typically carried out in an organic solvent which does not coordinate too strongly to the Lewis acid complex, e.g. a chlorinated organic solvent. Examples of suitable chlorinated organic solvents are methylene chloride, chloroform, or dichloroethane. Examples of other suitable organic solvents include ethers, such as methyl tert-butyl ether, aromatics, such as toluene, or acetonitrile. Preferably the organic solvent has a freezing point no more than about −100° C.
The reaction time necessary to carry out the present invention will vary depending on temperature, amine nucleophile, and chiral Lewis acid complex utilized. Typical reaction times range from 1.5 to 72 hours. Shorter or longer reaction times may be achieved by altering the reaction conditions.
In order to initiate amidolysis of the minor enantiomer thereby increasing the enantiomeric excess of the desired product, the present method typically employs a molar ratio of the amine nucleophile to the &agr;,&bgr;-unsaturated amide compound of about 0.5:1 to about 1.2:1. Preferably, a slight molar excess of the amine nucleophile is employed, e.g., a molar ratio to the &agr;,&bgr;-unsaturated amide compound of about 1.0:1 to about 1.2:1.
The present method is typically carried out with the chiral Lewis acid complex in a ratio of about 0.1:1 to about 1:1 with the &agr;,&bgr;-unsaturated amide compound. Preferably, the chiral Lewis acid complex is in a molar ratio with the &agr;,&bgr;-unsaturated amide compound of about 0.25:1 to about 0.40:1. The chiral Lewis acid complex typically if formed from a mixture of bisoxazolinylmethane ligand and azophilic metal salt in a molar ratio of at least about 1:1. Preferably the molar ratio of ligand to metal salt used to form the chiral Lewis acid complex is about 1:1 to about 1.1:1.
The Lewis acid complex employed in the present method typically is formed from a chiral bisoxazolinylmethane compound and a salt of an azophilic metal cation. As used herein such “azophilic metal cations” refer to those metal cations capable of coordination with nitrogen atoms of a ligand. The azophilic metal cation is preferably not too strongly azophilic to avoid selectively coordinating with the amine nucleophile in preference to the bisoxazolinylmethane compound. Examples of suitable azophilic metal cations include Zn
2+
, Mg
2+
, Sn
2+
, Sc
3+
, Y
3+
, and lanthanide cations. Preferably, the azophilic metal cation is Mg
2+
, Zn
2+
, Yb
3+
, Y
3+
, or Eu
3+
, with magnesium salts being particularly suitable. Included among suitable counterions are chlorine anion, bromine anion, iodine anion, and triflate anion. For economic and efficacy reasons, chloride and/or bromide counteranions are preferably used. Examples of particularly suitable azophilic metal salts include MgCl
2
and MgBr
2
. Another group of particularly suitable azophilic metal salts include the triflate salts of Mg
2+
, Zn
2+
, Yb
3+
, Y
3+
, and Eu
3+
.
The chiral Lewis acid complex employed in the present method is typically formed from a salt of an azophilic metal cation and a bisoxazolinylmethane compound. Examples of suitable bisoxazolinylmethane compounds include those substituted at any combination of the 4, 4′, 5, and 5′ positions to afford a chiral molecule. The substitution is typically such that symmetry of the molecule is maintained so as to avoid p
Jasperse Craig Peter
Liu Mei
Shay John Joseph
Sibi Mukund Prahalada Rao
Merchant & Gould P.C.
NDSU--Research Foundation
Oswecki Jane C.
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