Chemo-, Regio-, and Diastereoselective Synthesis of Functionalized Cyclopropanes by Cyclization of Dilithiated Nitriles with Epibromohydrin

Abstract

The cyclization of 1,1-dianions with epibromohydrin results in chemo-, regio-, and diastereoselective formation of functionalized hydroxymethyl cyclopropanes. [reaction: see text]

Diastereoselective One-Pot Knoevenagel Condensation/Corey–Chaykovsky Cyclopropanation

“…This observation can be rationalized by increased steric repulsion imparted by the aryl ring (relative to the nitrile) on the aldehyde derived side chain during 1,3-elimination of dimethylsulfoxide in the cyclopropanation of the intermediate acrylonitrile. This effect has previously been reported in the construction of similar cyclopropanes from cyanohydrins. , …”

“…This effect has previously been reported in the construction of similar cyclopropanes from cyanohydrins. 1,8 Construction of the pyrrolidine ring of (±)-bicifadine as described below also demonstrates the syn relationship between the nitrile group and aldehyde derived functionality. Minimal byproducts were observed in the crude reaction mixtures, with the mass balance of the low yielding reactions comprised of unreacted starting materials or degradation to unidentifiable products.…”

“…Trisubstituted aryl cyclopropylnitriles have found utility in organic synthesis as precursors to a wide variety of natural products, , biologically active compounds, , and important materials. , Current methodology to rapidly assemble these compounds primarily relies on addition/cyclization reactions between aryl acetonitriles and epihalohydrins , or 1,4-additions of aryl acetonitriles in anionic − or ylide − forms to Michael acceptors followed by a cyclization step. Additional approaches to access trisubstituted aryl cyclopropylnitriles include carbenoid chemistry − or the treatment of acrylonitriles with sulfur/sulfoxonium ylides , or photochemical conditions .…”

Stereocontrolled Synthesis of Trisubstituted Cyclopropanes: Expedient, Atom-Economical, Asymmetric Syntheses of (+)-Bicifadine and DOV21947

“…Similar transformations have been reported, although the protocols are not scalable and attempts to optimize the conditions have resulted in a poor yield and/or ee 4a. As a result, we decided to carry out a systematic investigation on this transformation to gain mechanistic insight and ultimately to arrive at an optimized, scaleable protocol.…”

Trimethylsilylacetonitrile (TMSAN)

“…TMSAN is usually used as a nucleophile, mainly in additions to a carbonyl group, 1 in order to obtain cyanomethylated adducts, or in nucleophilic substitution reactions, for example in the preparation of functionalized cyclopropanes. 2 …”