An investigation of the use of Cp 2 Zr(H)Cl (Schwartz's reagent) to reduce a variety of amides to the corresponding aldehydes under very mild reaction conditions and in high yields is reported. A range of tertiary amides, including Weinreb's amide, can be converted directly to the corresponding aldehydes with remarkable chemoselectivity. Primary and secondary amides proved to be viable substrates for reduction as well, although the yields were somewhat diminished compared to the corresponding tertiary amides. Results from NMR experiments suggested the presence of a stable, 18-electron zirconacycle intermediate that presumably affords the aldehyde upon water or silica gel workup. A series of competition experiments revealed a preference of the reagent for substrates in which the lone pair of the nitrogen is electron releasing and thus more delocalized across the amide bond by resonance. This trend accounts for the observed excellent selectivity for tertiary amides versus esters. Experiments regarding the solvent dependence of the reaction suggested a kinetic profile similar to that postulated for the hydrozirconation of alkenes and alkynes. Addition of panisidine to the reaction intermediate resulted in the formation of the corresponding imine mimicking the addition of water that forms the aldehyde.

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The rhodium-catalyzed tandem silylformylation-crotylsilylation reaction has been extended to include internal alkynes. Tamao oxidation of the initial product leads to the production of a substituted enol, which undergoes highly diastereoselective tautomerization. The resulting one-pot procedure fashions three new stereocenters, a ketone, and a terminal alkene from a butenyl group, a propynyl group, a silyl hydride, H 2 O 2 , and CO.As part of a program devoted to the development of efficient tandem reaction strategies for polyketide natural product synthesis we have reported the tandem intramolecular silylformylation-allyl(crotyl)silylation of alkynes which, following Tamao oxidation, provides access to β,β′-dihydroxyketones with good levels of 1,5-diastereoselection (Scheme 1). 1 In an effort to expand the scope of this methodology to include more heavily propionate-derived polyketide fragments the use of internal alkynes presented itself as an intriguing possibility. Assuming the rhodium-catalyzed silylformylation would tolerate such substrates, 2 the tandem crotylsilylation event would produce intermediates such as 1. Tamao oxidation 3 would then presumably generate an enol that upon tautomerization would generate an additional methylbearing stereocenter. 4 The ultimate utility of this method would of course depend on the levels of diastereoselectivity that could be achieved in the Tamao oxidation/tautomerization process. If successful, reactions of this type would represent a remarkable example of a complexity generating reaction, as a butenyl fragment, a propynyl fragment, and CO would be transformed in a one-pot process into stereochemically and functionally complex polypropionate arrays.The investigation commenced with achiral alcohol 2 in order to isolate the diastereoselectivity of the tautomerization event relative to the neighboring stereocenter(s). Silylation of 2 with 1,1-diallyl-N,N-diethylsilanamine 5 gave silane 3 in 85% yield (Scheme 2). When 3 was subjected to tandem silylformylation-allylsilylation/Tamao oxidation, keto diol 4 was indeed produced, with promising (4:1) diastereoselectivity albeit in only 46% yield. Examination of leighton@chem.columbia.edu. the reaction mixture revealed substantial amounts of an enone byproduct suggesting elimination during the Tamao oxidation. Use of KF in place of NaHCO 3 solved this problem and led to the isolation of 4 in 70% yield and 3:1 dr. When di-cis-crotylsilane 5 was prepared and subjected to the tandem reaction conditions, 6 was isolated in 63% yield and 7:1 dr. NIH Public AccessHaving established (1) that internal alkynes are well tolerated in the tandem silylformylationallylsilylation reaction, and (2) that useful levels of diastereoselectivity may be attained in the Tamao oxidation/tautomerization, we turned next to an examination of chiral homopropargylic alcohol starting materials. Silanes 7, 8, and 9 were prepared and subjected to the reaction conditions (Scheme 3). As shown, these substrates led to ketodiols 10, 11, and 12 with 6:1, 1...

An intramolecular copper-mediated reductive Castro-Stephens reaction furnished a key macrocyclic triene intermediate for the total synthesis of oximidine II. Herein we describe the total synthesis of the natural product as well as studies to deduce the mechanism of this unprecedented reaction.

The synthesis and biological evaluation of a novel paclitaxel photoaffinity probe is described. The synthesis involved the preparation of an azide-containing C13 side chain through a Staudinger cycloaddition followed by a lipase-mediated kinetic resolution to obtain the azetidinone in 99% ee. Coupling of the enantiopure side chain precursor to 7-TES-baccatin III and subsequent silyl ether deprotection afforded 3'-(4-azidophenyl)-3'-dephenylpaclitaxel, which was shown to be as active as paclitaxel in tubulin assembly and cytotoxicity assays.