Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
1999-09-14
2004-02-17
Baker, Maurie Garcia (Department: 1639)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
C435S007100, C435S091500, C435S091500, C436S501000, C530S333000, C530S334000, C502S007000, C502S150000
Reexamination Certificate
active
06693168
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to chiral cyanoamines and methods of preparation.
BACKGROUND OF THE INVENTION
Recent research in the area of chiral catalysis has illustrated the ability to transform prochiral, inexpensive materials into optically pure, valuable chemicals. Chiral amino acids, amino alcohols, and diamines have been used in the synthesis of pharmaceuticals, diagnostics, and materials. With the exception of natural amino acids, which may be isolated from fermentation or hydrolysis of proteins, these materials are often time consuming and costly to manufacture.
One previously known route to prepare amino acids is the Strecker synthesis, a modified Mannich reaction in which a carbonyl-containing compound (either a ketone or aldehyde) is condensed with ammonia (or another amine) to form an imine component, which subsequently reacts with sodium cyanide to form a cyanoamine, which can then be hydrolyzed to yield an amino acid. This method works for aliphatic and aromatic carbonyl components. However, this method provides only racemic products in the absence of a chiral reagent. While chiral amino acids have been made using the Strecker methodology, these methods have generally depended upon the use of a chiral amine to form the imine component. The necessity of using a chiral reagent in stoichiometric quantity often makes such methods quite expensive.
SUMMARY OF THE INVENTION
The present invention relates to chiral catalysts that can be used to transform chemically compatible imines to optically enriched cyanoamines, to the application of such catalysts to the synthesis of optically enriched cyanoamines, and to the preparation of optically enriched amino acids, optically enriched amino alcohols, or optically enriched diamines.
In general, catalysts useful in the methods of the invention have the structure (Formula I):
where U, V, W, X, Y, and Z can each be, independently, hydrogen, a substituted or unsubstituted alkyl group (which can be straight- or branched chain, or may be cyclic), an aryl group (including heteroaryl), an aralkyl group, an alkaryl group, or a heterocyclic group; Ar is a substituted or unsubstituted aryl group or hydroxyalkyl group; R
1
is an alkyl group (e.g., lower alkyl), an aryl group, or a heterocyclic group; R
2
and R
3
are each, independently, hydrogen, an alkyl group (e.g., lower alkyl, an aryl group, or a heterocyclic group; M is a metal ion (including a proton, a main group metal ion, or a transition metal ion); L is a counterion; and n is an integer, e.g., an integer from 1 to 3. In certain embodiments, Y and Z are both hydrogen. In other embodiments, one, some, or all of U, V, W, X, Y, and Z are independently selected from side chain moieties of naturally occurring or synthetic amino acids.
Catalysts of the invention can be prepared by combining one equivalent of a metal ion with a ligand of Formula I, such that a catalyst complex is formed.
In one aspect, the invention provides catalysts for the asymmetric synthesis of amino acids using tripeptide-based complexes.
The invention also features methods for determining the optimal catalyst for the transformation of an imine described by the structure (1) of Scheme 2 (infra) to an optically enriched cyanoamine when that structure is described by the complex formed between M(L)
n
and the ligand.
In addition, the invention features a synthetic route to both enantiomers of tert-leucine in an optically enriched form, and a synthetic route to either enantiomer of any unnatural amino acid in an optically enriched form.
The invention also provides a synthetic route to all diastereomers of an amino acid with a chiral side chain in optically enriched form.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
DETAILED DESCRIPTION
The present invention relates to catalysts useful for promoting the formation of chiral, non-racemic cyanoamines, to combinatorial libraries (arrays) of such catalysts, to the use of an array of catalysts for selecting catalysts for the synthesis of chiral materials, and to the use of such catalysts for preparation of optically enriched materials.
A catalyst is a material that facilitates a desired outcome for a specific reaction and is not consumed (or is regenerated) in the course of the reaction by mechanistic pathways. The term “catalyst” may be applied to a metal, a ligand-metal complex, or to a ligand alone that performs the desired transformation.
Reactants or materials that are termed “chemically compatible” are those reactants or materials that do not undesirably impede or prevent a desired reaction from occurring, e.g., by destroying or interfering with the catalyst, ligand, metal or any other component of the reaction. Thus, reactants or materials that would cause an undesired outcome or prevent the desired transformation from occurring are incompatible and are not preferred for use in the methods described herein.
As will be appreciated by the skilled artisan, “chirality” refers to the innate handedness of a molecule. A chiral material is “optically enriched”, when the material is present in non-racemic form, i.e., when an excess of one enantiomer is present over the complimentary (antipodal) enantiomer. Optical enrichment is commonly expressed as enantiomeric excess, i.e., the excess of one enantiomer over its antipode. An enantiomeric excess of 100% indicates optical purity, i.e., the absence of one enantiomer. In preferred embodiments, reactions according to the invention can provide optically enriched, and preferably substantially optically pure products. In certain embodiments, the methods of the invention can provide a desired product (e.g., a cyanoamine) in at least 50% enantiomeric excess, more preferably at least about 60%, 70%, 80%, 90%, 95%, or 99% enantiomeric excess.
“Prochiral” refers to planar or achiral material that can react in a chiral environment to provide a chiral product.
The term “metal,” as used herein, includes a proton, a main-group metal atom or ion, a transition metal atom or ion, or any other metal atom or ion that can be used to form an active catalyst according to the invention. Metals present as components of catalysts of the invention are generally present in ionic, rather than elemental, forms (e.g., titanium in the +4 oxidation state). Exemplary metals include titanium, zirconium, vanadium, chromium, cobalt, nickel, copper, zinc, and manganese. The term “counterion” refers to any chemically compatible species used for charge balance. Exemplary counterions include halide (e.g., chloride, fluoride, bromide, or iodide), hydroxide, halite, alkoxide, boron halide, sulfate, phosphate, or other salt-forming anions.
A “library” is a collection of compounds (e.g., as a mixture or as individual compounds) synthesized from various combinations of one or more starting components (e.g., a combinatorial library). At least some of the compounds must differ from at least some of the other compounds in the library. A library can, for example, include 5 to 10, 50, 100, 1,000, 10,000, 50,000, or even 100,000 or more different compounds (i.e., not simply multiple copies of the same compounds, although some compounds in the library may be duplicated or represented more than once). Each of the different compounds, whether they have a different basic structure or
Dzierba Carolyn
Hoyeyda Amir
Krueger Clinton A.
Kuntz Kevin
Snapper Marc L.
Baker Maurie Garcia
Fish & Richardson PC
The Trustees of Boston College
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