Synthesis of Spirastrellolide A Fragments for Structure Elucidation

Abstract

A stereocontrolled synthesis of two diastereomeric C 1 -C 22 fragments of spirastrellolide A consistent with reported spectroscopic data has been achieved to aid in a complete configurational assignment of this structurally novel and potent antimitotic natural product. A highly convergent coupling of two enantiomeric C 1 -C 10 methyl ketone fragments with an enantiopure C 11 -C 22 spiroketal aldehyde produced the C 1 -C 22 fragments with a longest linear sequence of 13 steps from commercially available starting materials.Given our fascination with structurally novel bioactive natural products, we became interested in spirastrellolide A -a potent antimitotic macrolactone isolated from extracts of a Caribbean marine sponge by Andersen and coworkers. 1 A revised and more complete structure of spirastrellolide A was reported in a subsequent manuscript, which also included data related to its ability to potently inhibit protein phosphatase 2A (PP2A). 2 Although the relative stereochemistry within the C 3 -C 7 (cis) and the C 9 -C 24 fragments has been elucidated, the relative stereochemistry between these fragments remains uncertain. 2 As shown in Figure 1, we targeted two alternative C 1 -C 22 fragments 3 and 4 that represent the two diastereomers compatible with the published structural information. 3,4 These diastereomers in turn would be available through a substrate-controlled 1,3-anti Mukaiyama aldol reaction of enantiomerically pure spiroketal aldehyde 6 with the two enantiomeric cis-tetrahydropyranyl fragments 5 and ent-5, followed by a 1,3-anti-b-hydroxy ketone reduction. An added advantage of this convergent approach is that it allows for the synthesis of additional stereoisomers (C 9 , C 11 ) in the linker region connecting the cis-THP and the spiroketal fragments.The synthesis of the two enantiomeric cis-tetrahydropyranyl fragments 5 and ent-5 is shown in Scheme 1, and is based on a final Wacker oxidation of allyl-substituted tetrahydropyranyl derivative 9 to yield methyl ketone 5 in 70% yield. 5 Previously, we had reported the synthesis of compound 9, where the intermediate 8 was synthesized from 7 using Brown's B-allyl bis(4-isocaranyl)borane in 92% ee. 6,7 However, for the preparation of ent-8, we found Leighton's allyl silane reagent 10 8 to be operationally more practical, and also provided slightly better ee in comparison to B-allyl bis(2-isocaranyl)borane. 9,10 From ent-8 (92% ee), 11 the cis-substituted tetrahydropyran ent-5 was prepared according to the synthesis of 5.

Synthesis and Biological Evaluation of the Southern Hemisphere of Spirastrellolide A and Analogues

“…Protein phosphatases are recognized as potential targets in drug discovery for Parkinson’s disease, Alzheimer’s disease, and specifically tumor suppressors for blood cancers. − Due to these features, spirastrellolide is potentially a lead compound for anticancer therapeutics. This activity has inspired a significant amount of interest from the synthetic community resulting in elegant total syntheses − and synthetic strategies toward this natural product. − Despite its potency, a comprehensive biological evaluation of spirastrellolide A has not been undertaken, perhaps due to limited supplies from these studies or from natural sources. , Inspired by the eribulin work, we envisioned that SAR studies on simplified analogues of the marine macrolide spirastrellolide A might help identify the pharmacophore.…”