Spirastrellolide E: synthesis of an advanced C(1)–C(24) southern hemisphere

Abstract

The synthesis of a C(1)-C(24) advanced southern hemisphere fragment towards the total synthesis of spirastrellolide E has been achieved. Highlights of the route include a highly convergent Type I Anion Relay Chemistry (ARC) tactic for fragment assembly, in conjunction with a directed, regioselective gold-catalyzed alkyne functionalization to generate the central unsaturated [6,6]-spiroketal.

Type II Anion Relay Chemistry: Conformational Constraints To Achieve Effective [1,5]-Vinyl Brook Rearrangements

“…6 Indeed, by employing a series of diverse dithiane ARC linchpins, a number of architecturally complex targets have been achieved, as demonstrated in synthetic ventures toward spirastrellolide E, 7 (−)-secu’amamine A, 8 rhizopodin, 9 enigmazole A, 10 and most recently mandelalide A. 11 …”

Synthesis of the Spirastrellolide A, B/C Spiroketal: Enabling Solutions for Problematic Au(I)-Catalyzed Spiroketalizations

“…While the reaction proceeded using the Echavarren catalyst (Table 1, entry 1), unfortunately, the yield was low (50% isolated yield) and it appeared that one diastereomer rapidly provided the product while the other sluggishly reacted and formed a mixture of 8 and [5,7]spiroketals. Use of simple AuCl provided the same results (entry 2).…”

Synthesis of a C(1)–C(23) Fragment for Spirastrellolide E: Development of a Mechanistic Rationale for Spiroketalization

“…Our early interest in the spirastrellolides resulted in approaches toward both advanced northern 4q and southern 8 hemispheres of the spirastrellolide family of macrolides. With these achievements, we turned to the evolution of our synthetic strategy with particular emphasis on scalability, in preparation for a total synthesis of spirastrellolide E. We recently described a streamlined approach to an advanced southern hemisphere fragment, 9 which significantly increased the overall yield while reducing the longest linear sequence by 14 steps. We report here additional significant refinements of our overall synthetic strategy, including a stereochemical rationale for the strategic level gold-catalyzed spiroketalization that now permits access to a C(1)–C(23) southern hemisphere that proceeds in 7% overall yield and provides more than 500 mg of the requisite southern hemisphere.…”

“…Synthetic analysis of 8 is outlined in Scheme 3 . Similar to our recently published approach to a C(1)–C(24) southern hemisphere, 9 we chose to utilize a directed gold-catalyzed spiroketalization 10 to build the unsaturated spiroketal core.…”

“… 9 , 11 Requisite 11 would be prepared via an Evans glycolate aldol reaction now with acrolein to install the key cis stereochemistry of the diol ( 17 , Scheme 4 ). Further manipulations of 17 were performed as previously described 9 (see Supporting Information ). Overall, the new alkyne synthesis proceeded in 22% yield, readily providing multigram amounts of 11 in one batch.…”