Lactam Derivative, Epiderstatin

Epiderstatin (48), having a unique alkylidene lactam, was isolated as a potent inhibitor of the signal transduction induced by epidermal growth factor in quiescent Balb/MK cells [44-46]. However, the activity was later found to be due to contaminating 13-acetoxycycloheximide 21 [47]. The (3S,5S)-absolute stereochemistry of 48 was established by X-ray analysis [48]. Dow's first synthesis also confirmed the relative stereochemistry [49] (Scheme 7).

Dimethyl glutarate (49) was converted to monothioglutarimides transand cis-50 as a 1 : 1 mixture. Glutarimide fragment 53 was derived from 51 [15] via diazo ketone 52. The mixture 50 was treated with NaH and condensed with 0.5 equivalents of 53, the S-alkylated intermediate 54 being rearranged [50], to give epiderstatin 48 and cis-48 as a 3 : 1 mixture. Treatment of the single isomer cz's-50 gave a 1: 3 mixture. They determined the relative stereochemistry based on these results. Ubukata et al. followed this method and resolved four stereoisomers by chiral HPLC [47].

Ubukata's synthesis [51] started with ammonolysis followed by Swern oxidation of (±)-55 [52] to give nitrile aldehyde 56. Wittig-Horner reaction of 56 with phosphonate 58 derived from glutarimide acetic acid 57 [27] gave 59. The nitrile was converted to amide 60, which was subjected to selenolac-tamization [53] to afford 61. Oxidation-elimination of the selenenide moiety gave 48 a diastereomeric mixture.

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