Synthesis of the ABCD Ring System of Azaspiracid

Controlling influences in bisspiroketal formation: synthesis of the ABC ring system of azaspiracid

“…7a Nicolaou later reported the same stereochemical outcome on their related, D ring functionalized systems. 5 This cisoidal arrangement allows for placement of central furan oxygen in the anomeric (or pseudo-anomeric) positions with respect to both pyran rings.…”

Structural Revision and Total Synthesis of Azaspiracid‐1, Part 2: Definition of the ABCD Domain and Total Synthesis

“…Its attempted synthesis (Scheme ) was met with unexpected, but nevertheless, path‐pointing observations. Thus, substrate 9 was prepared from building blocks3 6 , 7 , and 8 according to our previously reported route,3 with the appropriate modification of building block 7 to accommodate the new stereochemical requirement at C14 in subtarget 4 . The intermediate 9 was then subjected to deprotection–cyclization cascade conditions 3.…”

“…Thus, substrate 9 was prepared from building blocks3 6 , 7 , and 8 according to our previously reported route,3 with the appropriate modification of building block 7 to accommodate the new stereochemical requirement at C14 in subtarget 4 . The intermediate 9 was then subjected to deprotection–cyclization cascade conditions 3. Interestingly, however, the major product formed in this double spiroketalization process ( 9 → 10 ) was that with the opposite stereochemistry at C13 from the one proposed in the C14‐ epi target intermediate 4 .…”

“…Compound 5 was synthesized stereoselectively as shown in Scheme . Thus, starting with the ketophosphonate 6 derived from L ‐malic acid (natural), and following our previously described route,3 intermediate 13 was prepared in 12 steps in good overall yield. To accommodate the requirements of the new subtarget 5 , a substantially modified sequence from 13 to 5 had to be developed.…”

Azaspiracid poisoning, the food-borne illness associated with shellfish consumption

“…The strategy of Nicolaou et al was to prepare key synthetic precursors, C1-C20, C21-C27 and C28-C40, and to link these segments with controlled relative stereochemistries (Nicolaou et al 2003a, b). There have been many other approaches to the synthesis of key structural elements of AZA1, especially the ABCD ring system and the C26-C40 (FGHI ring system) tetracyclic common domain (Carter and Weldon 2000, Aiguade et al 2001a, b, Carter and Graves 2001, Dounay and Forsyth 2001, Nicolaou et al 2001a, b, Carter et al 2002a, b, Sasaki et al 2003, Ishikawa and Nishiyama, 2004a.…”