Reports: G1
48092-G1 Catalytic Enantioselective Halogenation of Olefins
The goal of the proposal is to develop methods for the enantioselective construction of carbon-halogen bonds (C-X) through addition of halogens and nucleophiles to different substituted alkenes. We have originally proposed two different types of catalysts for the halogenation reactions. One is nucleophilic catalyst and the other is metal catalyst. We have mainly focused on the nucleophilic catalysts in the past year.
Halogen-promoted addition of nucleophiles to alkenes is one of the most fundamental reactions in chemistry and is widely used in organic synthesis. Among all halocyclizations, halolactonization is arguably the most versatile since the resulting lactone can easily be elaborated. We examined various substituted olefins for bromolactonization reactions and found that alkynyl substituted olefin underwent regio- and diastereoselective syn-1,4-bromolactonization in the presence of a number of nucleophilic catalysts. Although a broad range of diastereomeric ratios was observed, all of the catalysts except HMPA favored the syn-addition. Amine catalysts were more selective than others and DABCO afforded essentially one diastereomer (dr > 20:1 based on NMR analysis of the crude mixture). The 1,4-syn-addition occurred selectively over 1,2-anti-addition for most enynes. In contrast to 1,2-anti-addition to alkenes, where two adjacent stereogenic centers are created, 1,4-syn-addition across conjugated enynes can produce a stereogenic center and an axially chiral allene simultaneously. Enynes with Z- and E-configurations yielded products with complementary stereochemistry for the newly generated stereogenic center and axially chiral allene. Di-, tri-, and even tetra-substituted allenes can be prepared together with a five- or six-membered lactone from this enyne bromolactonization reaction efficiently and selectively.
Our preliminary study has demonstrated that 20 mol % cinchonidine catalyst can induce 58% ee and still retain high diastereoselectivity (dr > 20:1) for a conjugated cis-enyne. We are currently modifying the catalysts to improve the enantioselectivity and retain the high regio- and diastereoselectivity for the 1,4-syn-bromolactonization of the alkynyl substituted alkenes. In the future, we will expand the substrate scope of the bromolactonization to other substituted alkenes and expand the reaction scope of the halogenation to other nucleophiles and electrophiles.
