An “Aprotic” Tamao Oxidation/Syn-Selective Tautomerization Reaction for the Efficient Synthesis of the C(1)–C(9) Fragment of Fludelone

Abstract

An efficient synthesis of the C(1)–C(9) fragment of fludelone has been developed. The key step is a tandem silylformylation-crotylsilylation/Tamao oxidation sequence that establishes the C(5) ketone, the C(6), C(7), and C(8) stereocenters, and the C(9) alkene in a single operation from a readily accessed starting material. The stereochemical outcome at C(6) depends critically on the development of an “aprotic” Tamao oxidation, which leads to a reversal in the intrinsic diastereoselectivity observed using “standard” Tamao oxidation conditions.

Dirhodium(II)‐Mediated Alkene Epoxidation with Iodine(III) Oxidants

“…tert ‐Butyl[(3,3‐dimethyloxiran‐2‐yl)methoxy]dimethylsilane (2j): Prepared according to the general procedure for epoxidation using 1j (40.0 mg, 200 µmol) as the starting material. After purification by flash chromatography on silica gel (9.5:0.5 petroleum ether/AcOEt), 2j was obtained as a colorless oil (32.4 mg, 75 %).…”

Synthesis and Evaluation of a Linkable Functional Group-Equipped Analogue of the Epothilones

“…Given that one of the primary intended benefits of the secondgeneration stepwise sequence was to allow for high levels of diastereoselectivity in the crotylation event, we decided to evaluate the first-generation tandem and one-pot version of the sequence (Figure 3b). This was carried out according to our previous report 18 and produced 10 as the major product of a 7:1.3:1 mixture of diastereomers in 44% combined yield from 4. Though due to the added steric hindrance of the C(6)-4chlorobutyl group this sequence, too, proceeded with reduced efficiency relative to the version with the C(6)-methyl substrate, it also proceeds in just two pots, and because of this extraordinary step-economy, we were able to rapidly produce multigram quantities of 10 using this route.…”

“…Guided by the high-resolution structure of epothilone A bound in the taxane binding site (Figure 2b), we applied the methyl extension approach 16 to design the C(6)-4-azidobutyl epothilone B analogue 3 and synthesized it using our previously developed routes to the C(1)−C(9) fragment of the epothilones 18,19 and Danishefsky's fragment coupling and end-game strategies. 22,23,25 Amides 20 and 21 were then produced and evaluated in an in vitro cell growth inhibition assay and found to be approximately equipotent with epothilone B.…”

“…We have developed two conceptually related syntheses of the C(1)–C(9) fragment of the epothilone family of natural products , based on our silylformylation/crotylsilylation/Tamao oxidation methodology we developed for the step-economical and efficient syntheses of complex polyketide fragments. The requisite starting material for the synthesis of the C(6)-4-azidobutyl analogue, homopropargyl alcohol 4 , was prepared using our recently reported synthesis (see the Supporting Information file for details), and we began by examining our second-generation approach in which the three parts of the sequence were carried out in a stepwise fashion (Figure a) .…”

“…(a) Synthesis of the C(1)–C(9) fragment of the epothilones with a 4-chlorobutyl group installed at C(6) using our second generation approach (ref ). (b) Synthesis of the C(1)–C(9) fragment of the epothilones with a 4-chlorobutyl group installed at C(6) using our first generation approach (ref ).…”