Concise Substrate-Controlled Asymmetric Total Syntheses of Dioxabicyclic Marine Natural Products with 2,10-Dioxabicyclo-[7.3.0]dodecene and 2,9-Dioxabicyclo[6.3.0]undecene Skeletons

We report a completely substrate-controlled approach
to the asymmetric
total synthesis of representative dioxabicyclic bromoallene marine
natural products with either a 2,10-dioxabicyclo[7.3.0]­dodecene or
2,9-dioxabicyclo[6.3.0]­undecene skeleton from commercially available
glycidol as a common starting material. The former include (−)-isolaurallene
(1), the enantiomeric form of natural (+)-neolaurallene
(2), and (+)-itomanallene A (3c), and the
latter are (+)-laurallene (4) and (+)-pannosallene (5a). In addition, our first syntheses of 3c and 5a established the structure and absolute stereochemistry
of both natural products. Our general approach to establish the α,α′-relative
stereochemistry of the medium-ring (oxonene or oxocene) and tetrahydrofuran,
respectively, involved the judicious pairing of our protecting-group-dependent
intermolecular amide enolate alkylation (either chemoselective chelation-controlled
or dianion alkylation) with either our intramolecular amide enolate
or nitrile anion alkylation. Remarkable selectivity was achieved through
the use of the appropriate alkylation steps, and this approach offered
us optional access to any of these dioxabicyclic bromoallene marine
natural products. In addition, a computational analysis was performed
to investigate conformational effects on the rate of oxonene formation
via RCM, a key step in these approaches. The results suggested an
alternative rationale for reactivity based on the avoidance of eclipsing
torstional interactions in the AS2-type ring conformation.