Diastereoselective reactions at enantiomerically pure, sterically congested cyclohexanes as an entry to wailupemycins A and B: Total synthesis of (+)-wailupemycin B

Abstract

Wailupemycin A (1) and B (2) are polyketide natural products with a highly substituted cyclohexanone core. Three different routes for the syntheses of these compounds were pursued, which commenced from either (R)-(-)-carvone (ent-5) or (S)-(+)-carvone (5). In the first approach it was attempted to construct the skeleton of wailupemycin A from triol 19 (nine steps from ent-5; 19% yield) by a sequence of diastereoselective epoxidation, nucleophilic ring opening at C-13 and carbonyl addition at C-5. The synthetic plan failed at the stage of the carbonyl addition to aldehyde 27, which had been obtained in seven steps (18% yield) from triol 19. The second route included an epoxide ring opening at C-13 and a carbonyl addition at C-7 as key steps. It could have led to either wailupemycin A or B depending on the diastereoselectivity of the addition step. Starting from allylic alcohol 30 (six steps from ent-5; 59% yield) the cyclohexanone 28 was obtained in five steps (54% yield). Unfortunately, the carbonyl addition failed also in this instance. In the eventually successful third attempt the skeleton of wailupemycin B was built from cyclohexanone 43 (eight steps from 5; 53% yield) by highly diastereoselective carbonyl addition reactions at C-7 and C-12. The phenyl group at C-14 was introduced at a late stage of the synthetic sequence. Careful protecting group manipulation finally allowed for the total synthesis of (+)-wailupemycin B. The absolute and relative configuration of the natural product was unambiguously confirmed. The total yield of wailupemycin B amounted to 6 % over 23 steps starting from (S)-(+)-carvone (5). © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.