Tetsuhide Kamijo

A stereoselective synthesis of cyclohexylnorstatine, the key component of a renin inhibitor

Abstract The title synthesis could be accomplished by employing the novel addition reaction of a Grignard reagent with an imine in the presence of cerium(III) chloride.

A stereoselective synthesis of the (2R, 3S)- and (2S, 3R)-3-amino-2-hydroxybutyric acid derivatives, the key components of a renin inhibitor and bestatin.

Abstract The title synthesis was achieved by featuring the [2+2]-cycloaddition reaction of benzyloxyketene with a chiral imine derived from methyl (R)- or (S)-mandelate, alcoholysis of the formed 3,4-cis disubstituted β-lactam under acidic conditions, and reductive removal obtained by the [2+2]-cycloaddition reaction employing achiral and chiral imines derived from benzylamine, p-anisidine, di-panisylmethylamine, and (S)-l-phenylethylamine were also reported. Stereoselectivity of the [2+2]-cycloaddition reaction could be explained by the initial formation of a zwitter-ionic intermediate and its subsequent conrotatory ring closure.

An efficient synthesis of methyl N-[2-(R)-(1-napthylmethyl)-3-(morpholinocarbonyl)propionyl]-(S)-histidinate, the key synthetic intermediate of renin inhibitors

Optically pure (R)-(1-naphthylmethyl)succinic acid could be efficiently prepared by a combination of optical resolution and racemization of the undesired enantiomer or by catalytic asymmetric reduction of (1-naphthylmethylene)succinic acid over a rhodium (I)-chiral phosphine complex. Highly chemoselective amide formation of di-4-nitrophenyl (R)-(1-naphthylmethyl)succinate with morpholine followed by coupling with methyl (S)-histidinate readily produced the title key synthetic intermediate.

A Novel Synthesis of Cyclohexylnorstatine Isopropyl Ester, the C-Terminal Component of a Renin Inhibitor

The title compound was produced diastereoselectively in racemic and optically active forms by employing the [2+2] cycloaddition reaction of an imine with benzyloxyketene followed by acidic alcoholysis of the formed 3,4-cis-disubstituted β-lactam with isopropanol

Design and synthesis of an orally potent human renin inhibitor containing a novel amino acid, cyclohexylnorstatine

An orally potent human renin inhibitor (1a) containing a novel amino acid, (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid named cyclohexylnorstatine, has been designed from the angiotensinogen transition-state and synthesized.

A practical synthesis of an orally potent renin inhibitor, isopropyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-{N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naphthyl)propionyl]-L-histidyl}aminobutyrate

The practical synthesis of an orally potent human renin inhibitor, isopropyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-{N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naphthyl)propionyl]-L-histidyl}-aminobutyrate, is presented. Optically pure cyclohexylnorstatine isopropyl ester (P1–P1′ moiety) was diastereoselectively and simply prepared from L-phenylalanine methyl ester. In a one-pot reaction, N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naphthyl)propionyl]-L-histidine methyl ester (P4–P2moiety) was conveniently hydrolysed, protected with a Boc group attached to the side-chain imidazole function, and coupled with the cyclohexylnorstatine ester to give the optically pure target renin inhibitor.