New Solutions to the C‐12,13 Stereoproblem of Epothilones B and D; Synthesis of a 12,13‐Diol‐Acetonide Epothilone B Analog

Abstract

Keywords: Microtubule stabilizing agent (MSAA) / Antitumor drugs / Ring-closing metathesis / Silicon tether / Epoxide formation / Stereoselective synthesis New approaches are described to the synthesis of epothilone B and a 12,13-diol-acetonide derivative. Specifically the (12Z) double bond is formed quantitatively by a silicon-tethered ring-closing metathesis (RCM) reaction with 85 % selecEpothilone B (1) [1] shows outstanding microtubule binding affinities and cytotoxity against tumor cells and multiple drug resistant tumor cell lines.[2] The role of 1 as a potential paclitaxel successor has initiated intense interest in its synthesis, resulting in numerous total syntheses of 1 and numerous derivatives thereof. [3] A central issue in most syntheses of epothilone B, in particular when aiming for the larger scale, has been the introduction of a 12R,13R-configured trisubstituted epoxide. The standard solution of this problem is the synthesis of the deoxy precursor, epothilone D (2) with a 12,13-(Z) double bond, which is epoxidized to give epothilone B in the last step of the sequence (Scheme 1). Alternatively, the 12,13-epoxide has been introduced with high stereocontrol relatively early, and has then been carried through the sequence to furnish 1 directly. [4] In both variants, the key step is an aldol addition of an enolate 4 or 6 ("southern fragment") to an aldehyde 3 or 5 ("northern fragment"). We report contributions to both variations and furthermore, the synthesis of a 12,13-diol derivative 7 will be described in detail.[5]For a stereocontrolled synthesis of the (12Z) double bond in a "northern fragment" such as 3 a surprisingly wide variety of approaches have been reported among which Danishefsky's B-alkyl Miyaura-Suzuki coupling [6] has found particularly widespread application, notwithstanding the low overall yield of 33 %.[7] Alternatively, Wittig [8] or Still-Gennari [9] carbonyl olefinations, organometallic additions to alkynols, [10] allylstannane-carbonyl addition, [11] allylic rearrangement [12] or the functionalization of nerol [3d] have also been used to solve the problem.[ Our approach was to enforce the (Z) geometry of the 12,13-olefin by incorporating it into a relatively small ring, with a maximum ring size of 8 (Scheme 2). Hence, the lactone 10 could be envisaged as a suitable precursor of 3. Following literature precedence, [13] 10 could be generated through a [3.3]-sigmatropic rearrangement of the ketene acetal 11, which was to be prepared from the carbonate 12 by a Tebbe olefination or from ortho-acetal 13 by a ClaisenJohnson protocol.In fact, the known aldehyde 14 [8,9] was converted into a 60:40 diastereomeric mixture of diols 15 (Scheme 3). Treatment with triphosgene furnished the cyclic carbonate 12, again as a 60:40 mixture of isomers. However, all attempts to convert 12 into 11 with Tebbe's reagent failed. Thus, the 15a/b mixture was heated with triethyl orthoacetate and a catalytic amount of amberlyst 15. Three products were isolated: ortho-acetal 13 (22 %) as a pure dias...

Highly Diastereoselective α-Hydroxylation of Fox Chiral Auxiliary-Based Amide Enolates with Molecular Oxygen

“…Chiral induction by auxiliaries, chiral oxidizing reagents, chiral catalysts, chiral phase transfer catalysts, and enzymes has also been reported. Furthermore, it appears in the literature that the most standard method extensively used in recent years is the oxidation of oxazolidinone-based chiral amide enolates with Davis’ oxaziridine . Intriguingly, the very attractive oxidation with molecular oxygen has not yet been developed for the synthesis of enantiopure compounds by mean of chiral auxiliaries-based methods.…”

Direct asymmetric syntheses of chiral aldehydes and ketones via N-acyl chiral auxiliary derivatives including chiral Weinreb amide equivalents

“…[34][35][36] This methodology has been utilised widely in the total syntheses of natural products and target syntheses of compounds of biological significance. [37][38][39][40][41][42][43][44][45][46][47][48] For example, Romanski and Jurczak employed the 1,3-dipolar cycloaddition of N-acryloyl sultam 33 in a synthesis of the 5a-reductase inhibitor (S)-dihydroyashabushiketol 38. N-Acryloyl sultam 33 was treated with oxime 34 and NCS to give 35 initially in >92 : 8 dr, and 54% yield and >99 : 1 dr after recrystallisation from i PrOH.…”

Muscarine, imidazole, oxazole and thiazole alkaloids

“…Recently, several reviews focusing on the biology and chemistry of epothilones have been published, [249][250][251] and many synthetic studies towards the total synthesis of epothilones have been carried out. [252][253][254][255] In order to improve aqueous solubility and in vivo antitumor activity, a great many epothilone analogs have been synthesized. By replacing the C15 thiazolyl side chain with a substituted thiazole, six analogs (442a,b, 443a-c and 444) of (E)-9,10-didehydroepothilone D 441 have been prepared and evaluated.…”