Efficient and Stereoselective Access to the Polyol Fragment C9−C16 of Ansamycin Antibiotics

Abstract

Efficient synthesis of the fragment C9-C16 bearing the anti,syn stereotriad of ansamycin antibiotics is described. Key steps for controlling the configuration of the three stereogenic centers involve a stereoselective Reformatsky-type reaction followed by a diastereoselective reduction of a beta-ketosulfoxide.

Synthesis of Pyridines from Ketoximes and Terminal Alkynes via C–H Bond Functionalization

“…24 The remaining oximes, 1d and 1e were prepared from the common Weinreb amide intermediate 2,2-diethoxy- N -methoxy- N -methylpropanamide prepared from 2,2-diethoxypropionic acid ethyl ester. 25 …”

Synthesis of an Advanced Fragment of (+)-Trienomycinol

“…Finally en route to trienomycinol, the optimized crosscoupling conditions were applied to the reaction between the eastern and western parts 6 and 5b bearing the primary iodine. The substrate 5b was easily synthesized from the already reported methyl ester 5a 15 using the reaction sequence described for the synthesis of the model 15, that is, reduction of the ester with DIBAL-H followed by chlorina-…”

“…The anti, syn stereotriad C11-C13 was constructed via a stereoselective Reformatsky-type reaction followed by the reduction of the β-ketosulfoxide. 15 In this paper, we describe the synthesis of the eastern part 6 of (+)-trienomycinol (1), a common advanced intermediate of trienomycin's family. The stereogenic center C3 essential for the biological activity of trienomycinol would…”

“…NMR (300 MHz, CDCl 3 ): δ = 5.67 [t, J = 17.4 Hz, C(CH 3 )=CHCH 2 I, 1 H], 4.49 (td, J = 8.4 and 4.5 Hz, CHOTBDMS, 1 H), 3.94 [d, J = 10.5 Hz, C(CH 3 )=CHCH 2 I, 2 H], 2.04 [s, 3 H, C(CH 3 )=CHCH 2 I], 1.68-1.57 (m, 2 H, CH 2 CHOTBDMS), 1.41-1.26 [m, 6 H, (CH 2 ) 3 CH 2 CHOTBDMS], 1.14-1.10 (m, 3 H, CH 3 ), 0.89 (s, 9 H, t-C 4 H 9 ), 0.08 and 0.02 [2 s, 6 H, Si(CH 3 ) 2 t-Bu].Preparation of Compound 5b Starting from 5a (Scheme 6) (-)-(Z)-3{(4R,5S,6S)-2,2-Di-tert-butyl-6-[2-(tert-butyldimethylsilyloxy)ethyl]-5-methyl-1,3,2-dioxasilinan-4-yl}but-2-en-1-olStarting from ester 5a15 (65 mg, 0.134 mmol, 1 equiv) the same procedure as described for the preparation of compound 12 was used. The crude product was purified by column chromatograph (SiO 2 , CH 2 Cl 2 ) to afford the corresponding alcohol (49 mg, 0.108 mmol, 81%) as a colorless oil; R f = 0.33 (CH 2 Cl 2 ); [α] D 20 -18 (c = 0.5, CHCl 3…”

Recent advances in the diastereoselective Reformatsky-type reaction

“…25,26 Further reduction of the Reformatsky adducts with DIBAL-H or DIBAL-H/Yb(OTf) 3 afforded with high diastereoselectivity the syn,syn stereotriad 30 or the syn,anti stereotriad 31, present in many natural products. 27 The removal or transformation of the chiral sulfoxide allowed us to apply this methodology to the total synthesis of biologically active molecules 28,29 (see Section 4.5).…”