Total Synthesis of Spongistatin 1: A Synthetic Strategy Exploiting Its Latent Pseudo‐Symmetry

Abstract

The spongistatins comprise an important family of architecturally complex marine macrolides that display extraordinary antitumor activities against a variety of human cancer cell lines. These unique natural products were isolated independently by Pettit, Kitagawa and Fusetani in 1993, [1] although the absolute structure remained unknown until confirmation by synthesis in 1997.[2] The spongistatin family includes 9 macrolides, all of which possess remarkable growth inhibition properties against the US National Cancer Institutes panel of sixty human cancer cell lines. Spongistatin 1 (1) was extremely potent against a subset of highly chemoresistant tumor types, with typical GI 50 values of 2.5-3.5 10 À1 m. Cell lines derived from human melanoma were also found to be especially sensitive to Spongistatin 1, [1f, h] the most active of this family of macrolides (Scheme 1).Spongistatin 1 (1) comprises a 42-membered macrolide ring, 24 asymmetric centers, a chlorodiene sidechain, two spiroketals (of which only one contains full anomeric stabilization) and two pyranyl units. The complex molecular architecture and exciting biological profile of these natural products have attracted significant interest resulting in total syntheses by six groups. [2][3] Our initial synthetic analysis for 1 was consistent with established endgame strategies and corresponded to a C1ÀC41(OH) macrolactonization and C28ÀC29 Wittig olefination, resulting in two advanced fragments (ABCD fragment 2 and EF fragment 3) and hence enabling a convergent approach to the target (Scheme 1). [2][3] Furthermore, we recognized the utility of the anti-selective aldol coupling demonstrated by the groups of Evans, [2a] Paterson, [3d] Heathcock [3f] and more recently Smith [3a] and Crimmins, [3e] to join the AB and CD units together to form the basis of fragment 2 in their total syntheses. Accordingly, we envisaged that appropriately protected AB aldehyde 4 and Scheme 1. Structure and retrosynthetic analysis of Spongistatin 1 (1). TES = triethylsilyl, TBS = tert-butyldimethylsilyl, PMB = p-methoxybenzyl.

Update 1 of: Macrolactonizations in the Total Synthesis of Natural Products

“…In 1982, Corey also described the use of Palomo's reagent BOP-Cl 578 (26) in the synthesis of aplasmomycin. 410 This methodology was then used in a synthetic approach to enetetraynes 579 Peptide-coupling reagents PyBroP 581 (27) and PyBOP 582 (28) have also been successfully used in the synthesis of macrolactones. The enediyne-bridged tricyclic core of dynemicin A 583 was obtained in 51% yield using a PyBroP-mediated macrolactonization followed by a transannular Diels−Alder reaction at room temperature (eq a in Scheme 40).…”

Recherche de substances naturelles à activité thérapeutique (2)

“…Pettit, est confirmée en 1998 par Y. Kishi après synthèse totale [37,38]. En 2005, M. Ball réduit le nombre d'étapes de la synthèse totale de la spongistatine 1 de 65 à 46 [39], et, en 2008, le protocole de synthèse totale établi par A.B. Smith III permet d'atteindre le gramme [40].…”

A new era for organic synthesis—highlights of the recent progress

“…Stephacidin A [171], Stephacidin B [172], Phakellstatin [173], Chartelline A [174], Vindorosine [175], β-Erythroidine [176], Ecteinascidin 743 [177], Weiwitindolinone A isonitrile [178], Batzelladin F [179], Gelsemine (racemate) [180], Stenine (racemate) [181], (−)-Eudistomin C [182], Halipeptin A [183−184], Amythiamicin D [185], Thiostrepton [186], Isocomplestatin [187], Colombiasin A and elisapterosin B [188], (+)-Leucascandrolide [189], Spongistatin [190], Azaspiracid-2/3 [191−194], Spinosyns A and D [195], Apoptolidinone [196], RK-397 [197], Brevetoxin B [198], Tetracycline [199], Littoralisone [200], Garsubellin A [201], (+)-Absinthin [202], Machaeriol D [203], Mycalamide A [204], Haterumalide NA/oocydin A [205], Kendomycin [206], and OSW-1 [207] (and analogues).…”