De Novo Formal Synthesis of (−)-Apicularen A via an Iterative Asymmetric Hydration Sequence

Abstract

A de novo approach to the formal total synthesis of the macrolide natural product (−)-apicularen A has been achieved in 18 steps from achiral starting materials.Both the absolute and relative stereochemistry of apicularen A were introduced by a Sharpless asymmetric dihydroxylation, a π-allyl-palladium catalyzed reduction, a stereoselective reduction and a base promoted transannulation to install the C-9 stereocenter.Since its isolation and structural determination by Jansen and co-workers, 1 apicularen A has attracted significant interest due to its extremely potent antitumor activity, apicularen A showed remarkable cytotoxicities against nine human cancer lines at quite low concentration (IC 50 ∼ 0.1-3 ng/mL). This activity persisted even with the multi-drug resistant line, KB-VI (IC 50 ∼ 0.4 ng/mL). 1b Recently, the mode of action for the apicularens was demonstrated to occur via the selective inhibition of the mammalian VATPases, 2 which are responsible for regulating the intracellular pH. Interestingly, while apicularen A and B were equipotent inhibitors of VATPases, apicularen A is ∼100 times more toxic to cancer cells. 1b This switch in activity controlled by glycosylation has peaked our interest in the synthesis of both apicularen A and B, as well as other glycosylated potential prodrugs.In addition to its fascinating biological activities, the structural novelty of apicularen A has also attracted the attention of the synthetic community. To date several total syntheses of apicularen A have been completed, 3 along with several formal total syntheses and various efforts to the unique bicyclic ring system. 4 While all of the previous syntheses of the apicularen A derived their asymmetry by a resolution or from the chiral pool, we were interested in a de novo asymmetric approach that would use asymmetric catalysis to install the four stereocenters in apicularen A from achiral starting materials. Herein we describe our successful efforts to implement this strategy for the de novo formal total synthesis of apicularen A.Retrosynthetically, we envisioned apicularen A (1) and apicularen B (2) as being derived from the known macrolide 3 and the amide side chain 4, which have been successfully used by Maier George.ODoherty@mail.wvu.edu. Supporting Information Available: Complete experimental procedures and spectral data for all new compounds can be found in the Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org. for the synthesis of 1 (Scheme 1). 5 In our strategy (Scheme 2), the macrolide 3 could be derived from macrolactone 5, which in turn could be obtained by cross metathesis of styrene 6 and alkene 7 . The homoallylic alcohol stereochemistry in the differentially protected tetraol 7 was planned to be introduced by the diastereoselective introduction of an allyl-group to the benzylidene-protected triol 8. 6 Previously we have been successful at preparing protected 3,5-dihydroxy esters from 2,4-dienoates. 6,7 Thus, we envisioned using this 4-step asy...

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