Peptides in which the --CONH-- linkage has been replaced by the --COCH.sub.2 -- isosteric moiety are known as ketomethylene pseudopeptides.sup.1 having known utility. For example, such ketomethylene pseudopeptides may be useful an antibiotics, antibiotic enhancers or enzyme inhibitors. Further, this structural modification has been used to make peptide-like molecules with improved metabolic stability..sup.2 This structural motif has been employed for the preparation of numerous enzyme inhibitors,.sup.3 and have even been found as a natural product..sup.4 There have been a number of ingenious methods developed for the preparation of this important class of compounds. By far the most common approach to the synthesis of this class of peptide isosteres is to ignore the issue of absolute stereochemistry..sup.5 There are reports of possible solutions to the question of the absolute configuration of the N-terminal optically active center..sup.6 There is a singular report of a successful approach to the preparation of ketomethylene pseudopeptides with absolute stereocontrol at both asymmetric centers..sup.7
Inhibitor molecules based on the ketomethylene isostere have been found to be potent inhibitors of ACE (angiotensin converting enzyme),.sup.2 Substance P,.sup.3b carboxypeptidase A,.sup.3c carboxypeptidase A,.sup.3c and HIV protease..sup.8
The preparation of optically active alpha-amino ketones by dehydrogenation of racemic alpha-amino ketones and hydrogenation using an asymmetric hydrogenation catalyst is disclosed for dehydroketomethylene pseudopeptides having an aromatic substituent adjacent the keto group in U.S. Pat. No. 4,277,420; East German Application Nos. 280,527; 280,528; 280,529; 240,372 described in corresponding Derwent Abstract Numbers 90-36220/49, 90-362221/49, 90-36222/49, 87-057083/09, respectively.
Additional references directed to optically pure optically active intermediates include:
U.S. Pat. No. 4,912,221; PA1 EP Application No. 90307750.1; PA1 U.S. Pat. No. 4,906,773; PA1 U.S. Pat. No. 4,916,252; PA1 U.S. Pat. No. 4,316,847; PA1 EP Application No. 89403599.7; PA1 Japanese Number 3002152A described in WPI Acc No. 91-048825; PA1 German Appl. No. 140-036 described in Derwent Abstract No. 34661C/20. PA1 J. Am. Chem. Soc. 1977(August 31), 99;17 pp. 594652; PA1 J. Am. Chem. Soc. 1977(September 6), 94:18 pp. 6429-33; PA1 Synthesis 1979(May) pp.350-2; and PA1 Chem. Ber. 1981, 114, pp.1137-49. PA1 R.sub.1 is hydrogen, alkyl, lower cycloalkyl, or Ar wherein Ar is an aromatic group, preferably CH.sub.2 Ar, including, particularly, unsubstituted or substituted phenylmethyl; PA1 R.sub.2 is CH.sub.2 R.sub.9 wherein R.sub.9 is PA1 R.sub.3 is ##STR2## PA1 (1) hydrogen; PA1 (2) alkyl of from 1 to 6 carbons optionally substituted by one or two hydroxyl, chloro or fluoro; PA1 (3) cycloalkyl of from 3 to 7 ring carbons; PA1 (4) Ar.sub.4 which is a group such as phenyl, or phenyl substituted by one to three substituent(s) consisting of PA1 (5) Ar.sub.5 which is tolyl; PA1 (6) Ar.sub.6 which is tolyl substituted by one to three substituents consisting of PA1 (7) Ar.sub.7 which is a group optionally attached through a CH.sub.2 and is naphthyl or naphthyl substituted by one to three substituents consisting of PA1 (8) Ar.sub.8 which is a group such as indol-3-yl, indol-2-yl, or imidazoly-4-yl or indol-3-ylmethyl, indol-2-ylmethyl or imiadzol-4-ylmethyl (preferably unsubstituted or substituted phenyl or indol-3-yl); PA1 (9) NHA wherein A is PA1 (10) R.sub.12 (R.sub.13 R.sub.14 C).sub.m V wherein V is O or NH and R.sub.12 (R.sub.13 R.sub.14 are independently as defined above; PA1 (11) N(R.sub.11).sub.2 wherein R.sub.11 is independently as defined above; PA1 (12) NR.sub.15 R.sub.16 wherein R.sub.15 and R.sub.16 are joined to form a 4 to 6 membered saturated nitrogen containing heterocycle which is (a) azetidinyl, (b) pyrrolidinyl, (c) piperidinyl, or (d) morpholinyl; PA1 (13) R.sub.17 OCH.sub.2 O wherein R.sub.17 is PA1 (14) R.sub.17 OCH.sub.2 CH.sub.2 OCH.sub.2 wherein R.sub.17 is independently as defined above; PA1 (15) alkyl of from two to six carbons optionally substituted with R.sub.21 where in R.sub.21 is independently as defined above; PA1 (16) alkenyl of from two to six carbons optionally substituted with R.sub.21 where in R.sub.21 is independently as defined above;
Disclosure for a rhodium di (1R, 2R)- or (1S, 2S)-bis(phenyl-4-methoxyphenylphosphino)ethane (Rh DiPAMP) catalyst and its use as an enantioselective hydrogenation catalyst is exemplified in each of the following:
The present process takes advantage of the very practical method for the preparation of optically active succinates.sup.9 as a key component for a modified Dakin-West reaction. This protocol effectively introduces the C-terminal optically active center with the appropriate D- or L-amino acid absolute configuration at C-2. The Dakin-West reaction does not however offer a method for the control of the N-terminal optically active center at C-5. In an effort to control both asymmetric centers of a ketomethylene pseudopeptide, the present invention provides a method for the dehydrogenation/asymmetric hydrogenation of certain ketomethylene pseudopeptides. The invention is a novel synthetic method for the preparation of this class of peptide isostere in which both asymmetric centers are fixed with known absolute configuration. The present method permits the introduction of the C-5 optically active center with very high optical purity. In addition, since the absolute configuration of the C-5 center is induced by the absolute configuration of the asymmetric catalyst ligand, it is possible to make either typical antipode independently by the appropriate choice of ligand absolute configuration.
The flexibility of our synthesis permits the synthesis of very unique analogues of .alpha.-amino ketones that have improved biological properties relative to molecules available by more demanding syntheses. The literature is replete with examples of novel amino acid side chains designed to impart improved biological properties to these molecules.
USPTO Backgrounds
USPTO Backgrounds