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A highly efficient and practical means has been developed which enables compounds of the formula: wherein R1 is lower alkoxy, lower alkylamino, di-(loweralkyl) amino, or the monovalent radical A--NR3, wherein A is lower alkyl or A is R4 R5 NC(O)CH2 wherein, for example, R4 is hydrogen or alkyl and R5 is hydrogen, alkyl or a substituted alkyl, or R5 is R6 R7 N-Alk wherein R6 and R7 each is hydrogen or lower alkyl and Alk is a divalent alkyl radical; R3 is, for example, benzyl, alkyl or a substituted alkyl; and R2 is, inter alia, alkyl, cycloalkyl, 1H-imidazol-4-yl, 4-thiazolyl or 2-amino-4-thiazolyl; to be prepared through the kinetic resolution of a compound of the formula:wherein R1 is as defined herein, R2 is as defined herein, and B is lower alkyl. These compounds are useful intermediates in the synthesis of renin inhibiting compounds.
This article refer to the following
J. Chem. Soc. Perkin Trans, 1, 1990, pp. 1441-1445, "Asymmetric Synthesis of (R)-and (S)-4-(Substituted Benzyl)dihydrofuran-2(3H)-ones: An Application of theRuthenium-binap+Complex-catalysed Asymmetric Hydrogenation ofAlkylidenesuccinic Acids", L. Shao et al.
Journal of the American Chemical Society, 90:13, Jun. 19, 1968, pp. 3495-3502, "Absolute Steric Course of Hydrolysis by .alpha.-Chymotrypsin. Esters of .alpha.-Benzylsuccinic, .alpha.-Methyl-.beta.-phenylpropionic, and .alpha.-Methylsuccinic Acids(cas:110-15-6)", S.G. Cohen and A. Milovanovic.
EXAMPLE
2(R)-{(2-(1,1-dimethylethoxycarbonyl)amino-4-thiazolyl)methyl}-1,4-butanedioic Acid 4-(1,1-Dimethylethyl) Ester The amino group of the racemic 2(R,S)-{(2-amino-4-thiazolyl)methyl}-1,4-butanedioic acid 4-(1,1-dimethylethyl) 1-methyl ester from Example 5 was protected as a t-butyl carbamate group using (Boc)2 O and a suitable base in THF. Purification by silica chromatography gave the desired racemic 2(R,S)-{(2-(1,1-dimethylethyloxycarbonyl)amino-4-thiazolyl)-methyl}-1,4-bu tanedioic acid 4-(1,1-dimethylethyl) 1-methyl ester:1 H NMR (400MHz, CDCl3) δ8.85 (bs, 1H), 6.55 (s, 1H), 3.66 (s, 3H), 3.17 (m, 1H), 3.05 (m, 1H), 2.84 (m, 1H), 2.57 (m, 1H), 2.41 (m, 1H), 1.6 (s, 9H), 1.4 (s, 9H); MS (FAB) m/z 401.1 (MH)+ ; HRMS (FAB) Calcd. for (MH)+, 401.17462. Found 401.17570.
The racemic compound from above was submitted to a kinetic resolution using Subtilisin Carlsberg following the procedure of Example 2E. The title compound was obtained with 82.5% ee (analysis performed by HPLC using a chiral column (Condition A) after derivatization of an aliquot with diazomethane to give the corresponding methyl ester) and 35.5% yield. The methyl ester derivative was characterized: 1 H NMR (400 MHz, CDCl3) δ8.85 (bs, 1H), 6.55 (s, 1H), 3.66 (s, 3H), 3.17 (m, 1H), 3.05 (m, 1H), 2.84 (m, 1H), 2.57 (m, 1H), 2.41 (m, 1H), 1.6 (s, 9H), 1.4 (s, 9H); MS (FAB) m/z 401.1 (MH)+ succinic acids(cas:110-15-6)
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