Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
1997-06-27
2001-05-15
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C548S532000, C548S533000, C549S058000, C549S075000, C549S076000, C549S480000, C560S029000, C562S441000, C562S443000, C562S444000, C562S450000, C562S457000, C564S321000, C564S355000, C564S384000, C564S389000, C564S391000, C564S471000
Reexamination Certificate
active
06232467
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the fields of organic synthesis, organoboron chemistry, medicinal chemistry and combinatorial chemistry. More specifically, the invention relates to methods for preparing amines and amino acids using organoboron compounds.
BACKGROUND OF THE INVENTION
A variety of amines and amino acids (1-8) are of particular interest for the preparation of many types of compounds that are of interest to chemical, agrochemical, biotechnology and pharmaceutical industries. In particular there is a need for a method which allows the production of novel combinatorial libraries of amines and amino acids and is also suitable for the large scale preparation of such compounds.
&agr;-Amino acids (3) constitute a major class of naturally occurring molecules and have important and diverse biological functions. (G. C. Barrett, Ed., “Chemistry and Biochemistry of the Amino Acids”, Chapman and Hall, London, (1985)). Nearly a thousand naturally occurring amino acids are known and their number is constantly increasing. Besides their profound biological role as constituents of proteins, amino acids have been extensively used in organic synthesis as convenient and versatile precursors to many other target molecules.
Although there are many known methods for the synthesis of amino acids (R. M. Williams, “Synthesis of Optically Active &agr;-Amino Acids”, Pergamon Press, Oxford, (1989); R. M. Williams,
Aldrichim. Acta
(1992) 25:11; R. O. Duthaler,
Tetrahedron
(1994) 50:1539), most of these have a number of drawbacks including the use of toxic or hazardous reagents, the need for anhydrous or anaerobic conditions, the cumbersome isolation procedures, the requirement for multiple reaction steps, the limited applicability to certain substitution patterns, and difficulty in controling stereochemistry or isomeric purity.
In addition to the need to develop practical synthetic routes to the natural amino acids, for which there is a large and growing market, there is also an increasing demand for new methods to prepare diverse non-natural derivatives. Such compounds can serve as building blocks in combinatorial peptide synthesis and for the development of enzyme inhibitors, peptidomimetics and other bioactive molecules (G. M. Coppola and H. F. Schuster, “Asymmetric Synthesis: Construction of Chiral Molecules Using Amino Acids”, Wiley-Interscience, New York, (1987)). Amino acids with unusual side chains or with conformationally restricted backbones are of great interest due to their potential ability for highly selective receptor binding.
The valuable role of amines and amino acids in a variety of commercial applications requires practical and efficient methods for their preparation. This type of synthetic technology should have two important features, both of which are characteristic of the present invention: At the research and development stage, it is highly desirable to employ methods that allow the rapid production of a diverse array of molecules having many types of structural modifications, allowing the facile preparation of combinatorial libraries. Also, once a commercial product is identified, the required methodology for its large scale preparation should be characterized by high efficiency, low cost, facile isolation and purification, and low environmental hazards.
Known methods of multicomponent synthesis include the Strecker amino acid synthesis which involves the addition of cyanide to the adduct of a carbonyl compound and an amine to form aminonitriles, which can be hydrolyzed to amino acids. Another related method is the Ugi multicomponent reaction (I. Ugi et al.
Endeavour
(1994) 18:115), which involves the use of isonitriles for the formation of adducts which can be hydrolyzed to peptide derivatives.
The use of organoboron derivatives for the synthesis of substituted amines and amino acids in a multicomponent fashion as described herein, has no precedent in the literature. Although I have previously reported preliminary results on the use of (E)-alkenyl boronic acids for the synthesis of (E)-allylamines from amines and paraformaldehyde (N. A. Petasis et al.,
Tetrahedron Lett
. (1993) 34:583), this initial stepwise procedure involves high temperatures and rather harsh conditions which are quite limited in scope due to the decomposition of the starting materials and intermediates. Thus, while the reported method can be used for the preparation of simple allylamines, it is not suitable for the synthesis of more substituted allylamines or amino acids, which have to be derived from aldehydes and ketones other than paraformaldehyde, or from other types of boronic acids.
From the mechanistic point of view, the chemistry covered by this invention resembles a boron-directed Mannich reaction. While the conventional Mannich reaction is known (E. F. Kleinman et al.,
Comprehensive Organic Synthesis
(1991) 4:893; H. Heaney,
Comprehensive Organic Synthesis
(1991) 4:953; M. Tramontini and L. Angiolini, “Mannich Bases: Chemistry and Uses”, CRC Press, Boca Raton, (1994)), the use of relatively stable organoboron compounds to deliver various organic groups in a directed and stereocontrolled manner is not reported. The only types of boron-based reagents that are known to add to imines are the highly reactive allylic boranes and allylic boronates (W. R. Roush,
Comprehensive Organic Synthesis
(1991) 2:1; E. F. Kleinman et al.,
Comprehensive Organic Synthesis
(1991) 4:975; Y. Yamamoto et al.,
Chem. Rev
. (1993) 93:2207). However, despite an apparent similarity among allylic organoboron compounds with the corresponding alkenyl, aryl or alkyl derivatives, there is a significant difference in their reactivity. Thus, the “Grignard-like” addition of allylic nucleophiles to carbonyl-derived electrophiles involves a cyclic six-membered transition state. This mode of action, however, is not possible with other organoboron compounds, such as the ones utilized herein.
Among the compounds of interest are &bgr;,&ggr;-unsaturated-&agr;-amino acids (3, R
3
or R
4
=alkenyl), which have found numerous applications as synthetic intermediates and as mechanism-based suicide enzyme inhibitors, particularly of enzymes that metabolize amino acids, such as decarboxylases, transaminases or aminotransferases (L. Havlicek et al.,
Collect. Czech. Chem. Commun
. (1991) 56:1365).
Another important class of amino acids is the aryl glycines (3, R
3
or R
4
=aryl), which is found in many glycoptide and &bgr;-lactam antibiotics (R. M. Williams et al.,
Chem. Rev
. (1992) 92:889). The synthesis of such amino acids by other methods is often hampered by their facile epimerization and the difficulty to control stereochemistry and isomerism.
N-carboxymethyl amino acid or peptide derivatives, i.e. compounds of the general formula 5, are especially valuable as peptidomimetics and have been used in several enzyme inhibitors (C. J. Blankley et al.,
J. Med. Chem
. (1987) 30:992; J. Krapcho et al.,
J. Med. Chem
. (1988) 31:1148). Among the most notable is enalaprilat 9 (the active ingredient in the drug vasotec) and lisinopril (10), which are potent inhibitors of angiotensin-converting enzyme (ACE) used clinically for the treatment of hypertension (I. M. Wilde et al.,
Pharmaeconomics
(1994) 6:155). Similar compounds have also been considered as inhibitors of metalloproteinases (K. Chapman et al.,
J. Med. Chem
. (1993) 36:4293) with a potential use against cancer, arthritis and other diseases.
Other compounds of ineterest include substituted amines (1) and particularly allylic or benzylic amines (2), 1,2-diamines (6), 1,2-amino alcohols (7) and &agr;-amino aldehyde derivatives (8), all of which are very common components of a variety of bioactive molecules, including inhibitors of proteases and other enzymes, which are used as pharmaceuticals or agrochemicals. Among the compounds of the general formula 8 are those having additional hydroxyl groups within R
4
or R
8
which include various amino sugar derivatives (R. W. Jeanloz, “The Amino Sugars”, Academic Press, New York, (1969) exemp
Petasis Nicos A.
Zavialov Ilia A.
Fish & Richardson P.C.
Raymond Richard L.
University of Southern California
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