Highly enantio- and diastereoselective one-pot methods for the synthesis of halocyclopropyl alcohols.
The lack of methods for the stereoselective transfer of functionalized carbenoids is one of the most significant deficiencies of Simmons-Smith cyclopropanation reactions. Outlined herein are one-pot methods for the catalytic asymmetric synthesis of halocyclopropyl alcohols with up to four stereogenic centers from achiral starting materials. The first method involves asymmetric alkyl addition to a conjugated enal to generate an allylic alkoxide followed by tandem diastereoselective iodo-, bromo-, or chlorocyclopropanation to furnish halocyclopropyl alcohols. Enantioselectivities in these processes range from 89-99%, and dr's of >20:1 were achieved with all substrates optimized. The second method consists of an asymmetric vinylation of a saturated or aromatic aldehyde followed by a diastereoselective iodocyclopropanation to produce iodocyclopropyl alcohols with enantioselectivities between 86 and 99% and dr's of >20:1. These complementary methods enable the efficient synthesis of a variety of halocyclopropyl alcohols in one-pot procedures. Preliminary efforts to functionalize iodocyclopropanes involve reaction with an excess of LiCu(n-Bu)(2) to generate the cyclopropyl cuprate. This intermediate can be quenched with allyl bromides to generate the allylated cyclopropyl alcohols without loss of enantio- or diastereoselectivity.
Kim
Hun Young
HY
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, USA.
Salvi
Luca
L
Carroll
Patrick J
PJ
Walsh
Patrick J
PJ
D000438:Alcohols / Q000138:chemical synthesis* / Q000737:chemistry; D000478:Alkylation; D003521:Cyclopropanes / Q000737:chemistry*; D054879:Halogenation; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013237:Stereoisomerism; D014753:Vinyl Compounds / Q000737:chemistry
D000438:Alcohols; D003521:Cyclopropanes; D014753:Vinyl Compounds; C030797:cyclopropane