Total Synthesis of the Z-Isomers of the Proposed and Revised Structures of Aspergillide B via an Iodocyclization and Ring-Closing Metathesis Strategy

Abstract

The synthesis of Z-isomers of both the proposed and revised structures of aspergillide B is described. A divergent route is employed that involves kinetically controlled ring-closing metathesis for the construction of a 14-membered macrocyclic ring, ester formation under Yamaguchi conditions, a Wacker-type oxidative cyclization for creation of the C4 stereogenic center and a previously reported diastereoselective isomerization-iodocyclization strategy for the construction of the 2,6-trans-disubstituted tetrahydropyran subunit.Kusumi and co-workers isolated aspergillides A-C from the marine derived fungus, Aspergillus ostianus strain 01F313, cultured in a potato-dextrose (1/2PD) medium containing bromine-modified artificial sea water, and thereby launched an exciting chapter in natural product synthesis. 1 These novel macrolides exhibit significant cytotoxic activity against mouse lymphocytic leukemia cells with LD 50 values ranging from 2-70 μg/mL. Structurally, the aspergillide macrolides bear a 14-membered lactone ring with 2,6-cis-or 2,6-trans-trisubstituted dihydro-or tetrahydropyran subunits and an E-alkene bond at C8-C9. Though the structures and stereochemistry were established on the basis of detailed NMR studies and by employing a modified Mosher's ester method, there were some discrepancies in the structures of aspergillides A and B. However, Kusumi and Uenishi assigned the corrected structures via X-ray crystallographic analysis of the benzoate ester derivatives, and by total synthesis. 2,3 The proposed and confirmed structures of aspergillides A and B are shown in Figure 1. Because of their potent cytotoxic activity and unique structural features, the aspergillides have attracted interest from the synthetic community. 2,4-6 Due to these structural ambiguities, we have focused our attention on the syntheses of the Z-isomers of both the enantiomers (revised and proposed) of aspergillide B. Our group has previously developed an efficient and novel iodocyclization strategy for the synthesis of trans-2,6-dihydropyrans, which are building blocks of many complex bioactive natural products. The versatility of this methodology has resulted in the synthesis of complex natural products such as the bicyclic core of (+)-sorangicin A, 7a the macrolactone core of leucascandrolide A, 7c the total synthesis of polyrachitides 7b and the formal total synthesis of cladosporin. 7d In continuation of our efforts toward the synthesis of pyran-containing complex natural products, herein, we report a divergent synthesis of the proposed and revised structures of aspergillide B, with cis-alkene geometry at C8-C9, by employing an iodocyclization and ring-closing metathesis (RCM) based strategy. In our retrosynthetic analysis (Scheme 1), we envisaged that the target molecules could be prepared from macrolactones 3 and 4, which in turn could be synthesized from dienes 7a and 7b, respectively, following ring-closing metathesis 8 and tert-butyldimethylsilyl ether deprotection. Dienes 7a or 7b could be obtained by coupling of acid 10...