Total synthesis of (-)-mycalolide A
Total synthesis of (-)-mycalolide A
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DOI：
10.1021/ja994003r
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发表时间：
2000-02-16
影响因子：
15
通讯作者：
Panek, JS
中科院分区：
文献类型：
--
作者：
Liu, P;Panek, JS
In 1989 Fusetani and co-workers reported the isolation and planar structure of (-)-mycalolide A (1), a new secondary metabolite produced by a sponge of the genus mycale sp. 1 This macrolide belongs to a unique class of tris-oxazole containing natural products including ulapulides, 2 halichondramides, 3 and kabiramides, 4 which display a range of potent biological activities. Foremost among these is mycalolide A, which exhibits potent antifungal activity against a wide array of pathogenic fungi and cytotoxicity toward B-16 melanoma cells with IC50 values of 0.5-1.0 ng/mL. 1 Mycalolide A also specifically inhibits the actomyosin Mg2+-ATPase, 5 and serves as a novel actin depolymerizing agent which may find eventual applications in the pharmacological area for probing actin-mediated cell functions. 6 Recently we have established the relative and absolute stereochemistry of the mycalolides through a combination of chemical degradation, extensive 1H and 13C NMR analysis, and structural correlation experiments. 7 The unique structural features of these tris-oxazole containing macrolides have provided the motivation for the development of synthetic strategies toward these natural products. 8 In this communication, we report the first total synthesis of (-)-mycalolide A (1), which also confirms the relative and absolute stereochemical assignment of this natural product. 9 In planning our synthesis of mycalolide A, convergency was of course an essential component. Our second consideration was to extend the utility of chiral silane reagents in the area of acyclic stereocontrol, and to integrate the use of asymmetric catalysis with stoichiometric processes in assembling complex molecules. Retrosynthetic analysis of 1 led to fragments 2 and 3 through cleavage of the macrolide linkage and the C19-C20 olefin bond (Figure 1). In the synthetic direction, union of 2 and 3 via a Schlosser-Wittig reaction10 would be followed by macrocyclization. Further disconnection of 2 at the C6-C7 σ bond produced subunits 4 and 5, which served as our initial targets. It was envisioned that the stereogenic center of 4 could be accessed by a hydrolytic kinetic resolution (HKR) of terminal epoxide 6, 11 and the anti stereochemical relationship at the C8 and C9 in 5 would be established utilizing our chiral silane methodology. 12 Synthesis of subunit 4 (Scheme 1), was initiated by HKR of the racemic epoxide 6. 13 Thus,(()-6 was subjected to the resolution conditions as described by Jacobsen and co-workers, 11 providing (R)-6 of 99% ee in 94% yield. 14 Nucleophilic epoxide ring opening using higher order cuprate 9, 15 followed by stannane-iodine exchange and protection of the hydroxyl as its TBDPS ether, furnished 4 in four steps (64% overall). Construction of subunit 5 and introduction of the C8-C9 stereocenters (Scheme 2) required an anti selective crotylation with the tris-oxazole aldehyde 8. 8f In the presence of the bidentate Lewis acid TiCl4, the condensation between (S)-7 and 8 provided homoallylic alcohol 12 in 65% yield with high diastereoselectivity (anti/syn> 30: 1). This condensation proceeded presumably through a synclinal transition state, where TiCl4 simultaneously coordinates to the aldehyde carbonyl and the oxazole nitrogen to form a five-membered chelate, forcing a turnover of the transition state-controlled π-facial discrimination to deliver high anti selectivity. 16 Methylation of alcohol 12 (Ag2O/MeI), dihydroxylation of olefin 13 (OsO4/TMANO), and cleavage of the resulting diol (Pb (OAc) 4) completed the preparation of 5. The assembly of 2 was accomplished by a Kishi-Nozaki coupling17 between 4 and 5 (Scheme 3). Treatment of 4 and 5 with NiCl2-CrCl2 in …
