Efavirenz is manufactured worldwide, and its asymmetric synthesis requires a complex organometallic approach, while an organocatalytic approach is far less efficient. The first highly enantioselective approach is disclosed for the synthesis of Efavirenz under nonmetal organocatalysis with up to 93% ee for the Merck intermediate and 91% ee for the Lonsa intermediate using novel alkynyl cinchona catalysts.

Ether way: the cinchona-alkaloid-catalyzed title reaction was achieved in high yields with high to excellent ee values for the first time, and affords key intermediates for the biologically important 2 having a trifluoromethylated all-carbon quaternary chiral center. Ether-type catalysts (1) are more efficient in this transformation than the conventional hydroxy analogues.

Scheme 1. Asymmetric aerobic epoxidation of b-trifluoromethyl-b,bdisubstituted enones 1 by a methylhydrazine/base/cinchona alkaloid system. MTBE = methyl tert-butyl ether.

Fluoroform (HCF3, HFC-23) is a side product in the manufacture of polytetrafluoroethylene (Teflon). Despite its attractive properties, taming HCF3 for trifluoromethylation is quite problematic owing to its low acidity and the lability of the naked trifluoromethyl carbanion generated from HCF3. Herein we report the organic-superbase-catalyzed trifluoromethylation of ketones and arylsulfonyl fluorides by HCF3. The reactions were carried out by using a newly developed “superbase organocatalyst system” consisting of catalytic amounts of P4-tBu and N(SiMe3)3. A series of aryl and alkyl ketones were converted into the corresponding α-trifluoromethyl carbinols in good yields under the organocatalysis conditions in THF. The superbase organocatalytic system can also be applied to the trifluoromethylation of arylsulfonyl fluorides for biologically important aryl triflones in THF or DMF in good yields. Protonated P4-tBu, H[P4-tBu]+, is suggested to be crucial for the catalytic process. This new catalytic methodology using HCF3 is expected to expand the range of synthetic applications of trifluoromethylation.

The difluoromethylation of terminal alkynes through the use of fluoroform as a source of difluorocarbene is described. The choice of solvents and bases was found to be crucial for the transformation. A series of terminal alkynes 1 were nicely converted into the corresponding difluoromethyl alkynes 2 using potassium tert-butoxide in n-decane in moderate to good yields. Functional groups such as methoxy, dimethylamino, and bromo as well as phenyl, heteroaryl, and sterically demanding naphthyl were well tolerated under the reaction conditions. One-step transformations of difluoromethyl alkynes 2 to difluoromethylated isoxazoles 3 and 1,2,3-triazoles 4 were also achieved.