Total Synthesis of Erythronolide A

Abstract

Abstract The enantiospecific total synthesis of erythronolide A (1) through (9S)-9-deoxo-9-hydroxyerythronolide A (2) from the chiral C1–C6, C7–C9, and C10–C13 synthetic segments is described. The C10–C13 segment, (3R,4R,5R)-5-O-benzyl-2-iodo-3,4-O-isopropylidene-4-methyl-1-heptene-3,4,5-triol (11) was synthesized in 16 steps and an 8.3% overall yield from d-ribose. The C7–C9 segment, (S)-(+)-2-(2-bromo-1-methylethyl)-1,3-dioxolane (47) was prepared from methyl (S)-(+)-3-hydroxy-2-methylpropionate in 8 steps and a 49% overall yield. The coupling of the Grignard reagent, prepared from magnesium and 47, and the C1–C6 segment, 3,5,7-tri-O-benzyl-1,4,6-trideoxy-4,6-di-C-methyl-keto-l-ido-2-heptulose (13), afforded 5,7,9-tri-O-benzyl-2,3,6,8-tetradeoxy-2,4,6,8-tetra-C-methyl-l-threo-l-ido-nonose ethylene acetal (48) and its C4-epimer in 79% and 8% yields, respectively. 5,7,9-Tri-O-benzyl-4-O-t-butyldimethylsilyl-2,3,6,8-tetradeoxy-2,4,6,8-tetra-C-methyl-l-threo-l-ido-nonose (12), derived from 48, was subjected to coupling reaction with the lithium reagent prepared from 11 to afford about 5:1 excess of the “Cram” product 50. The homogeneous hydrogenation of 50 with [ClRh(Ph3P)3] gave 1,3,5,13-tetra-O-benzyl-6-O-t-butyldimethylsilyl-2,4,7,8,10,14,15-heptadeoxy-11,12-O-isopropylidene-2,4,6,8,10,12-hexa-C-methyl-d-arabino-d-gluco-l-ido-pentadecitol (54) and its C10-epimer in 41% and 7% yields from 12, respectively. The conversion of 54 to 2 was accomplished by a sequence of reactions including the Corey–Nicolaou lactonization method in a 17% overall yield. Selective 3,5-O-benzylidenation of 2 followed by PCC oxidation and debenzylidenation gave 1 in 52% yield.