Total synthesis and structural elucidation of azaspiracid-1. Synthesis-based analysis of originally proposed structures and indication of their non-identity to the natural product

Abstract

The key building blocks (6, 7, and 8) for the intended construction of the originally proposed structures of azaspiracid-1, a potent marine-derived neurotoxin, were coupled and the products elaborated to the targeted compounds (1a,b) and their C-20 epimers (2 and 3). The assembly of the three intermediates was accomplished by a dithiane-based coupling reaction that united the C₁-C₂₀ (7) and C₂₁-C₂₇ (8) fragments, followed by a Stille-type coupling which allowed the incorporation of the C₂₈-C₄₀ fragment (6) into the growing substrate. Neither of the final products (1a,b) matched the natural substance by TLC or ¹H NMR spectroscopic analysis, suggesting one or more errors in the originally proposed structure for this notorious biotoxin.