Altohyrtins total synthesis

TOTAL SYNTHESIS OF SPONGISTATIN 1 (ALTOHYRTIN A) A TALE OF TEN ALDOLS... 

This chapter attempts to recount some of the highs and lows encountered during the Paterson group s total synthesis of spongistatin 1/altohyrtin A, an extremely rare marine macrolide with a seductively complex structure in combination with displaying promising anticancer properties. We provide the reader with an emotional roller coaster ride through a project that spanned some 7 years, with early studies aimed at... 

Kary, P D, Roberts, S M, Watson, D J, Studies towards the total synthesis of altohyrtin A a convergent approach to the C38-C51 carbon framework. Tetrahedron Asymmetry, 10, 213-216, 1999. 

Total synthesis of altohyrtin A (spongistatin 1) Part 2. Angew. Chem. Int. Edit. Engl. 37, 192-196. 

In Section II, the synthetic strategies for macrolide synthesis are introduced and focus in particular on asymmetric synthesis of 1,3-diol, synthetic methodology for macrolactone, and glycosidation. In Section III, the total synthesis of selected macrolide antibiotics is introduced FK506 (tacrolimus 1), rapamycin (sirolimus 2), avermectins (3), altohyrtins (spongistatins 4), and epothilones (5) (Fig. 1). Several other synthesized macrolides are also illustrated. 

The first total synthesis of altohyrtin C (spongistatin 2 4b) was accomplished via diastereoselective aldol coupling of the C1-C15 AB and C16-C28 CD segments, Wittig coupling of the ABCD and the C29-C43 EF segments, addition of the C44-C51 side chain to the fully elaborated ABCDEF system, and the regiose-lective macrolactonization (Fig. 8). 

The first total synthesis of (+)-altohyrtin A (spongistatin T, 4a) by Kishi et al. was accomplished via Wittig coupling of the C1-C28 ABCD and C29-C51 EF... 

The ABCD segment 538 was then constructed (Scheme 76). The Julia coupling of 528 and 535 followed by methylenation afforded adduct 536. The AB spiroketal system was constructed by functional group manipulation to give 537, which was converted into ketoaldehyde 538 via protective group manipulation and oxidation. The spiroketal 539, which is a key intermediate for Kishi s total synthesis of altohyrtin A (4a), was also synthesized from 537. 

The completion of the total synthesis is described in Scheme 78. The Wittig reaction of 552 and 538 effected the coupling, and subsequent deprotection of TMS with KF afforded 41,42-dihydroxy carboxylic acid 553. Yamaguchi conditions effected macrolactonization of 553 in high yield and complete deprotection of the silyl groups afforded 4b and 554 in a ratio of 1 3. Treatment of (-)-23-epi-altohyrtin... 

Terauchi, T. Tanaka, T. Terauchi, T. Morita, M. Kimijima, K. Sato, I. Shoji, W. Nakamura, Y. Tsukada, T. Tsunoda, T. 2003. Formal total synthesis of altohyrtin C (spongistatin 2). Part 2 Construction of fuUy elaborated ABCD and EF fragments. Tetrahedron Lett. 44 7747-7751. 

Evans DA, Trotter BW, Coleman PJ, Cote B, Dias LC, Raja-pakse HA, Tyler AN. Enantioselective total synthesis of altohyrtin C (spongistatin 2). Tetrahedron 1999 55 8671-8726. 

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