Convergent stereospecific synthesis of LL-Z1640-2 (or C292), hypothemycin and related macrolides. Part 2

Resorcylic acid lactones as new lead structures for kinase inhibition

“…More satisfactory results were obtained by Sellès and Lett for their macrolactonization-based approach to the hypothemycin/LL-Z1640-2 macrocycle (Scheme 8) [36]. In contrast to the intramolecular setting, the intermolecular Suzuki reaction between the aryl bromide 20 and the vinyl-borane derived in situ from acetylene 29 proceeded very efficiently and provided the coupling product in 76% yield.…”

“…Esterification of alcohol 30 with carboxylic acid 21 in the presence of DCC proceeded smoothly and furnished the desired macrocyclization substrate 35 in 76% yield (Scheme 7) [36]. Unfortunately, the intramolecular Suzuki reaction with the vinyl-borane derived from 35 gave the desired macrolactone 36 only in low yield as part of complex reaction mixtures (15% under the optimized conditions shown for Scheme 7).…”

“…Conversion of 40 into LL-Z1640-2 (1) was accomplished in 74% yield with TosOH/DCM/MeOH at rt for 3.5 h. Virtually no isomerization of the C7 0 /C8 0 double bond was observed under these conditions and the remainder of the material was recovered unchanged (23% yield of recovered starting material). The final transformation of LL-Z1640-2 (1) into hypothemycin (2) was severely hampered by the low reactivity of the C1 0 /C2 0 double bond and could only be achieved in 17% yield with MCPBA/NaHCO 3 (30% of starting material recovered, Scheme 8) [36]. However, as had been predicted by Sellès and Lett at the outset of their work [35], the epoxidation reaction was highly stereoselective (and also regioselective) and provided hypothemycin (2) as the only isolable epoxide isomer.…”

“…(vii) pTsOH (0.5 equiv), DCM/MeOH 1/1, 3.5 h, 76%. (viii) MCPBA/NaHCO 3 (3 equiv), À20 / 0 C, 4 h, then pH 7 work-up, 17%[35,36]. 9.…”

Recent progress regarding the bioactivities, biosynthesis and synthesis of naturally occurring resorcinolic macrolides

“…For example, the Lett group reported synthetic routes for a series of RALs, such as radicicol (1), monocillin I (6) [109] , LL-Z1640-2 (3), and hypothemycin (4) [110] . In 2004, a modular synthesis of pochonin C (20) was presented by the group of Winssinger [111] ; then, concise syntheses of pochonin A (18) [112] and radicicol analog A (11) [113] were reported by the same group.…”