Methyl -statine from

Simvastatin is a semi-synthetic statin that is produced from the natural statin lovasta-tin7 Both are potent antihypercholesterolemic agents with simvastatin differing from lovastatin by just one additional methyl substituent residing on the 2-(5)-methylbutyrate side chain (Figure 1.6). 

P,y-Diamino analogues 49 of statine are prepared stereoselectively starting from the O-methyl hydroxamate derivative of N-protected statine. The reaction sequence involves the formation of a p-lactam intermediate obtained by internal cyclization under Mitsunobu conditions.184 Alternatively, direct amination of either a p-oxo ester 31 followed by reduction of the resulting enamine 50, 85 or by reduction of the corresponding ,p-unsaturated ester, 88 gives an enantiomeric mixture of the corresponding unprotected p-amine, which is protected by a carbamate prior to chromatographic separation (Scheme 20). 

Lovastatin was the first statin to be developed, and was isolated from the fungus Aspergillus terreus. It was launched in 1987 by Merck, Sharpe and Dohme (USA), and is a two-fold more potent methyl-homologue of mevastatin (Fig. 4.3). 

Boc-L-Leucinal 1s a useful chiral synthon in the preparation of the natural amino acid statine [S-(R, R )]-4-am1no-3-hydroxy-6-methylheptanoic acid (3S.4S). The procedure reported here Is based on the method of Fehrentz and Castro for the preparation of optically active Boc amino aldehydes from a-amino acids. It Is satisfactory on a kilogram scale. Boc-L-Leucinal has also been prepared by the reduction of Boc-L-leucine methyl ester with d1Isobutyl aluminum hydride or by oxidation of Boc-L-leucinolThe reaction conditions described here differ from those In the literature. The N-... 

Prompted by the success with lovastatin, Merck developed the semisynthetic statin simvastatin, which differs from the former by an additional methyl group in its side-chain. Pravastatin was the first statin to be marketed by Sankyo in 1989. It is obtained from mevastatin by microbial hydroxy-lation. The efficacy of these statins differs in patients very little from that of lovastatin. 

Epoxides, derived from alkenes, are important synthetic precursors to statine. Sharpless asymmetric epoxidation of 5-methyl-l-hexen-3-ol 6.173) gave 6.174... 

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