Synthesis of the C9-C21 Fragment of Geldanamycin via a Diastereoselective Substrate-Controlled Hydrogenation

Abstract

An Ir-catalyzed diastereoselective hydrogenation was employed to establish the stereogenic center at carbon atom C14 of a C9-C21 fragment of geldanamycin. The fragment was stereoselectively synthesized from D-mannitol in 18 steps.Geldanamycin (1, Scheme 1) was the first ansamycin antibiotic, which was isolated from a microorganism 2 but not from higher plants. It has received recently increased scientific attention because it was found to be a specific inhibitor of the heat shock protein 90 (Hsp90). 3 This activity has far reaching implications in particular relating to cancer therapy with Hsp90 being overexpressed in many tumor cells. 4 Despite the fact that geldanamycin itself is not a suitable drug candidate due to severe side effects, 5 synthetic access to it and its analogues is highly desirable as these compounds allow a chemical evaluation of Hsp90 binding. So far two total syntheses of geldanamycin (1) have been reported. 6 A considerable number of synthetic analogues have been prepared either by derivatization of the natural product 7 or by de novo synthesis. 8,9 Scheme 1 Retrosynthesis of geldanamycin (1) leading to the C 9 -C 21 fragment 2. Possible disconnections include carbonyl olefination (I), enantioselective allyl transfer (II), and ring-closing metathesis (III).Our own retrosynthetic plan to geldanamycin relies on the idea of a ring closure between C4 and C5 by metathesis (Scheme 1, step III). 9,10 The stereogenic centers at C6 and C7 are to be established by an enantioselective allyl transfer 9,11 (step II) and the double bond between C8 and C9 by carbonyl olefination (step I). 9 Fragment 2 results from this consideration as a suitable precursor with the amino group protected by a benzyloxycarbonyl (Z) group and the double bond serving as a protected aldehyde surrogate at C9. Prompted by recent advances in ansamycin syntheses 6,12 we disclose in this communication a new access to the C9-C21 skeleton of geldanamycin, which employs a diastereoselective substrate-controlled hydrogenation as the key step.The synthesis of the hydrogenation precursor 8 commenced with bissilyl ether 3 (TIPS = triisopropylsilyl), which was obtained by silylation (TIPSCl, imidazole, DMF, r.t., 4 h, 82%) from the corresponding literatureknown dimethoxytetraol, which in turn is accessible in three steps from D-mannitol. 13 Glycol cleavage was achieved with lead(IV) acetate to yield the protected D-glyceraldehyde, which was directly taken into an E-selective Wittig reaction with easily available 14 ylide 4 (dr: E/Z = 97:3). Reduction of the ester to the corresponding primary alcohol 5 was accomplished with LAH in almost quantitative yield (Scheme 2). Attempts to convert the resulting alcohol directly into bromide 6 failed. Allylic alcohol 5 was therefore converted into the respective mesylate fol-O O N H O O MeO OH MeO MeO geldanamycin (1) 15 9 O NH 2 4 Oi-Pr Oi-Pr NHZ MeO OTBDMS MeO C 9 -C 21 fragment (2) ΙΙ ΙΙΙ Ι 11 14 6Scheme 2 Synthesis of the hydrogenation precursor 8 starting from known D-mannitol-derived diol 3...