Stereoselective synthesis of beta-hydroxyallenes with multiple contiguous stereogenic centers via aldehyde addition to alpha-alkenyl-substituted zirconacyclopentenes.

A highly stereoselective methodology for the synthesis of beta-hydroxyallenes with multiple stereogenic centers including allenic axial chirality, as well as center chirality, via addition of alpha-alkenylzirconacyclopentenes to aldehyde is described. Remarkably, the reaction occurs with completely different chemoselectivity in comparison with the usual alkyl- or aryl-substituted zirconacyclopentenes; that means, the C-C bond formation occurred selectively at the alkenylic carbon substituted with phenyl or alkyl group, while in the latter cases, insertion of aldehydes into the alkyl-zirconium bond to afford seven-membered oxazirconacycles has usually been observed.

Generation of allenic/propargylic zirconium complexes and subsequent cross-coupling reactions: a facile synthesis of multisubstituted allenes.

The beta-alkoxide elimination reaction of propargylic ether with Negishi reagent leads to allenes and/or alkynes after hydrolysis. The product distribution is highly dependent on the substitution pattern of starting propargylic ethers; that is, aryl- or alkyl-substituted propargylic ethers favor the allene products, whereas TMS-substituted propargylic ethers afford alkynes. DFT calculations revealed that both the large steric effect and the beta-effect of the TMS group favor the alkyne products, reversing the selectivity. Subsequent coupling reactions of the allenic/propargylic zirconium intermediates with aryl iodides in the presence of Pd(PPh(3))(4)/CuCl provide a straightforward route for the synthesis of multisubstituted allenes.

Synthesis and Biological Evaluation of Macrocyclized Betulin Derivatives as a Novel Class of Anti-HIV-1 Maturation Inhibitors.

A macrocycle provides diverse functionality and stereochemical complexity in a conformationally preorganized ring structure, and it occupies a unique chemical space in drug discovery. However, the synthetic challenge to access this structural class is high and hinders the exploration of macrocycles. In this study, efficient synthetic routes to macrocyclized betulin derivatives have been established. The macrocycle containing compounds showed equal potency compared to bevirimat in multiple HIV-1 antiviral assays. The synthesis and biological evaluation of this novel series of HIV-1 maturation inhibitors will be discussed.