A formal total synthesis of the cytotoxic macrolide amphidinolide E is reported. The strategic steps are three Julia-Kocienski reactions (J-K), for the formation of the C5-C6, C9-C10, and C17-C18 double bonds, a Suzuki-Molander C21-C22 bond formation reaction, and a Kita-Trost macrolactonization. The "instability" of the two dienic systems and of the stereocenter at C2 (allylic methine, α to the carboxy group) and the protecting groups at C17-OH and C18-OH have posed difficult challenges. Each Julia-Kocienski olefination has been systematically optimized to provide the highest possible E/Z ratios.
ABSTRACT:The use of the 2-(4-methylphenylsulfonyl)ethenyl (Tosvinyl, Tsv) group for the protection of the NH group of a series of imides, azinones (including AZT), inosines, and cyclic sulfonamides has been examined. The Tsv-protected derivatives are obtained in excellent yields by conjugate addition to tosylacetylene (ethynyl p-tolyl sulfone). The stereochemistry of the double bond can be controlled at will: with only 1 mol % of Et 3 N or with catalytic amounts of NaH the Z stereoisomers are generated almost exclusively, while the E isomers are obtained using a stoichiometric amount of DMAP. Analogous phenylsulfonylvinyl-protected groups (with the Besvinyl or Bsv group instead of Tsv) are obtained stereospecifically by reaction with (Z)-or (E)-bis(phenylsulfonyl)ethene. For lactams and oxazolidinones, this last method is much better. The Tsv and Bsv groups are stable in the presence of non-nucleophilic bases and to acids. They can be removed highly effectively via a conjugate addition-elimination mechanism using pyrrolidine or sodium dodecanethiolate as nucleophiles.
We describe catalytic asymmetric C–C formation using terminal alkyl-metal nucleophiles generated from internal olefins through a ‘chain-walking’ isomerization mechanism. Hydrometallation of internal olefins with the Schwartz reagent gives the least hindered alkyl-zirconocene after thermal (60°C in THF) isomerization. After switching the solvent from THF to dichloromethane, the alkyl-zirconocenes can be used in copper-catalyzed asymmetric conjugate additions. Addition to a variety of cyclic α,β-unsaturated species were achieved in modest (22–50 %) yield with high (84–92 % ee) enantioselectivity. This work demonstrates that remote C–H functionalization coupled with asymmetric C–C bond formation is possible, but the present procedures are limited in terms of yield and olefin scope.
Additions of lactams, imides, (S)-4-benzyl-1,3-oxazolidin-2-one, 2-pyridone, pyrimidine-2,4-diones (AZT derivatives), or inosines to the electron-deficient triple bonds of methyl propynoate, tert-butyl propynoate, 3-butyn-2-one, Npropynoylmorpholine, or N-methoxy-N-methylpropynamide in the presence of many potential catalysts were examined. DABCO and, secondly, DMAP appeared to be the best (highest reaction rates and E/Z ratios), while RuCl 3 , RuClCp*(PPh 3 ) 2 , AuCl, AuCl(PPh 3 ), CuI, and Cu 2 (OTf) 2 were incapable of catalyzing such additions. The groups incorporated (for example, the 2-(methoxycarbonyl)ethenyl group that we name MocVinyl) serve as protecting groups for the above-mentioned heterocyclic CONH or CONHCO moieties. Deprotections were accomplished via exchange with good nucleophiles: the 1-dodecanethiolate anion turned out to be the most general and efficient reagent, but in some particular cases other nucleophiles also worked (e.g., MocVinyl-inosines can be cleaved with succinimide anion). Some structural and mechanistic details have been accounted for with the help of DFT and MP2 calculations.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.