Synthesis of Cyclosporine. I. Synthesis of enantiomerically pure (2S,3R,4R,6E)‐3‐hydroxy ‐4‐methyl‐2‐methylamino‐6‐octenoic acid starting from tartaric acid

Abstract

Starting from R, R-( + )-tartaric acid, the synthesis of (2 S, 3 R, 4 R, 6 E)-3-hydroxy-4-methyl-2-methylamino-6-octenoic acid in 24 steps is reported. This novel amino acid is found in the cyclic undecapeptide cyclosporin A, isolated from the fungal strain Tolypocladium inflatum GAMS. Its stereospecific synthesis allowed, for the first time, the isolation and characterization of the new amino acid previously reported as the 'C-9amino acid' [I].In the (4 R)-4-butenyl-4-N-dimethyl-threonine 25 (MeBmt, in a simplified staggered projection (i) and in a Fischer projection (ii), MeNH-and OH-groups are in a threoconfiguration as it is the case in N-methyl+-threonine (iii) and the OHand CH,groups in an erythro-configuration; the double bond is trans (E)-configurated. The

Neolignan Skeletons and Benzodioxanes Through Chiral Aryl Alkyl Ether Formation

“…2) (Li and Helm 1996). Protection, reduction, and benzylation of diethyl L-tartrate 1 provided 2 in 71 % yield (Wenger 1983;Johansson and Samuelsson 1984;Takano et al 1986). Reductive ringopening of 2 and subsequent mesylation afforded 3 in 95 % yield (Takano et al 1986).…”

Cyclosporines: Biosynthesis and Beyond

“…The routine total solid-phase synthesis of cyclosporines is complicated by the difficulty of coupling N-methylated amino acids and is also limited by the lack of commercial availability of Bmt due to its difficult synthesis [125][126][127]. Wenger [78,125,128] from Sandoz Ltd. described the first total synthesis of the CsA molecule using a fragment-condensation technique.…”

“…Wenger [78,125,128] from Sandoz Ltd. described the first total synthesis of the CsA molecule using a fragment-condensation technique. Subsequently, the Sandoz team reported the solid-phase synthesis of CsA and several of its analogs [129].…”

Methods for the Chemical Synthesis of Noncoded α‐Amino Acids found in Natural Product Peptides

“…The first synthesis of MeBmt was reported by Wenger in 1983 as a 24-step linear route from tartaric acid [220]. Evans and Weber used a diastereoselective aldol method of synthesizing MeBmt that provided the amino acid in high optical purity (>99% d.e.)…”