Abstract:
A synthesis plan for the marine toxin azaspiracid-1 is presented. Disconnection at the C₂₀-C₂₁ bond breaks the molecule into two halves: the C₁-C₂₀ fragment (ABCD-ring domain) and the C₂₁-C₄₀ fragment (EFGHI-ring domain). The synthesis of the C₂₁-C₄₀ fragment is described. The C₂₁-C₄₀ fragment was prepared in a convergent manner from three sub-fragments: the C₂₁-C₂₆ aldehyde A, the C₂₇-C₃₄ keto aldehyde B, and the C₃₅-C₄₀ enolsilane C. The synthesis of the three sub-fragments is described. In the construction of subfragments, special emphasis was placed on the application of Lewis acid catalyzed enantioselective reactions. The key step in the synthesis of aldehyde A is an enantioselective hetero-DielsAlder reaction catalyzed by a chiral bis(oxazoline) copper(II) complex. The key step in the synthesis of keto aldehyde B is an enantioselective Mukaiyama aldol reaction. Two variants of this reaction are described, one catalyzed by a chiral copper(II) complex, and one catalyzed by a chiral tin(II) complex. Enolsilane C was prepared by two different routes; the second-generation synthesis utilizes the same enantioselective hetero-DielsAlder reaction developed for the synthesis of aldehyde A. Enolsilane C was coupled to keto aldehyde B by a chelation-controlled Mukaiyama aldol reaction. Magnesium bromide diethyl etherate promoted the reaction with high diastereoselectivity. The product of this reaction was then coupled directly to aldehyde A by a boron-mediated aldol reaction to establish the carbon skeleton of the C₂₁-C₄₀ fragment. This monocyclic precursor was elaborated to the pentacyclic EFGHI-ring domain in seven steps. Because the relative configuration between the E-ring domain and FGHI-ring domain was not established in the structure elucidation of azaspiracid-1, the boron-mediated fragment coupling was performed with both enantiomers of E-ring aldehyde A. Each of these adducts was converted into the corresponding diastereomeric C₂₁-C₄₀ fragment. A discussion of the structural revision of azaspiracid-1 is included. The adaptation of our synthesis plan to accommodate the revised structure is described. A synthesis of the C₁₃-C₂₀ fragment required for the revised synthesis is presented. The currently published synthetic approaches to azaspiracid-1 are reviewed.
