J. Tenenbaum, W. Morris, D. Custar
Jun 20, 2011
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0
Influential Citations
31
Citations
Journal
Angewandte Chemie
Abstract
Okilactomycin (1a) is a structurally interesting antitumor antibiotic that was isolated from Streptomyces griseoflavus in 1987.[1] In vitro studies have demonstrated that 1a exhibits significant antitumor and antiproliferative activity against both lymphoid leukemia L1210 cells and P388 leukemia cells with IC50 values of 216 nM and 89 nM, respectively.[1b] A closely related compound, chrolactomycin (1b), differs only in structure by the replacement of a methyl group with a methoxy moiety at the pyranone/lactone ring fusion and displays promising telomerase inhibition.[1c,d] In addition to their potent biological activity, these compounds posses a compact and intriguing architecture. The tricyclic core is characterized by a unique 6,5-fused tetrahydropyranone γ-lactone bicycle with a spiro fusion to a highly substituted cyclohexene. A strained deoxygenated dipropionate segment spans this unusual tricycle to generate a highly rigid tetracyclic topology. Despite the biological activity and structural complexity, there have been only limited reports on the synthesis of okilactomycin (1a) over the last two decades, namely from the laboratories of Takeda, Paquette, and Smith.[2] These synthetic efforts culminated in a total synthesis of unnatural enantiomer (−)-1 a and determination of the absolute configuration of the natural product by Smith et al. in 2007.[2d,e] There are no syntheses of chrolactomycin (1b) reported to date. We disclose herein a convergent synthesis of (−)-1 a utilizing a Prins-type Maitland–Japp cyclization strategy of two advanced fragments.