Synthetic studies on altohyrtins (spongistatins): Synthesis of the C1C14 (AB) spiroacetal portion

The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: the AB-spiroacetal segment

“…The mixture was extracted with EtOAc (4 × 15 mL), the combined extracts were dried (Na 2 SO 4 ) and concentrated in vacuo to yield the title compound (924 mg, 100%), as a colourless oil: R f : 0. 1.45 (1H, d, J = 13.7 Hz, 8-CH a H b ), 1.14 (3H, s, 9-CCH 3 ), 1.13 (3H, d, J = 6.7 Hz, 14-CCH 3 ), m,Si(CH(CH 3 ) 2 ) 3 ), 0.90 (9H, s, SiC(CH 3 ) 3 ), 0.04 (3H, s, SiCH 3 ), 0.03 (3H, s, SiCH 3 ); 13 C NMR: d (100.6 MHz,CDCl 3 ) 173.2,147.6,111.4,98.7,68.8,67.8,64.8,63.9,62.4,46.3,42.8,42.7,41.8,41.3,40.9,38.5,29.8,25.8,18.1,18.0,16.8,12. To a solution of the acid from the above procedure (3.02 g, 4.81 mmol), 2,2,2-trichloroethanol (0.554 mL, 5.77 mmol, 1.2 eq.) and DMAP (cat.)…”

“…2, and established that the altohyrtins and spongistatins had identical structures. Subsequent total syntheses have been reported by the Smith, 8 Paterson, 9 Crimmins 10 and Heathcock 11 groups, in addition to a formal total synthesis by Nakata and co-workers 12 and numerous synthetic approaches by other groups. 13 In this series of four papers, we provide a full account of our studies in this area leading to a highly stereocontrolled total synthesis of altohyrtin A/spongistatin 1, as well as access to novel structural analogues for biological evaluation.…”

Synthesis of the C16−C28 Spiroketal Subunit of Spongistatin 1 (Altohyrtin A): The Pyrone Approach

“…Since the CD spiroketal of spongistatin is an equatorial−axial spiroketal, thermodynamic control results in a mixture of the diaxial and equatorial−axial spiroketals in approximately equal ratios, depending on the reaction conditions. One exception is the apparent kinetic formation of a 6.5:1 ratio in favor of the axial−equatorial spiroketal observed by Heathcock 6a…”

“…We recently reported the preparation of the C1−C13 spiroketal (AB) subunit of the potent antitumor agent spongistatin 1 (altohyrtin A) 1 . Several other approaches to the AB spiroketal, CD spiroketal, 6a,e,g, and EF fragments 8 have been reported, and recently the first total syntheses of altohyrtins A 9 and C 10 were described.…”

An Aldol Approach to the Synthesis of the EF Fragment of Spongistatin 1

“…The activity of the spongistatins correlates well with the class of microtubule interactive antimitotics . The unique structures, the unprecedented biological activity, and the limited supply of the spongistatins have prompted substantial effort toward their total synthesis. − Several laboratories have reported progress toward the synthesis of the spongistatins, and three independent total syntheses have been documented. The total syntheses by Evans 20 and Kishi 21 served to confirm the structures of spongistatin 2 (altohyrtin C, 2 ) and spongistatin 1 (altohyrtin A, 1 ), respectively, and a recent report from the Smith group described the most recent synthesis of spongistatin 2, as well as a formal synthesis of spongistatin 1 …”