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Highly enantio- and diastereoselective one-pot methods for the synthesis of halocyclopropyl alcohols.

ABSTRACT: 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.

SUBMITTER: Kim HY

PROVIDER: S-EPMC2646170 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Highly enantio- and diastereoselective one-pot methods for the synthesis of halocyclopropyl alcohols.

Kim Hun Young HY Salvi Luca L Carroll Patrick J PJ Walsh Patrick J PJ

Journal of the American Chemical Society 20090101 3

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-, ...[more]

PMID: 19154172

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Project description:Highly enantio- and diastereoselective methods for the synthesis of a variety of cyclopropyl alcohols are reported. These methods represent the first one-pot approaches to syn-vinyl cyclopropyl alcohols, syn-cis-disubstituted cyclopropyl alcohols, and anti-cyclopropyl alcohols from achiral precursors. The methods begin with enantioselective C-C bond formations promoted by a MIB-based zinc catalyst to generate allylic alkoxide intermediates. The intermediates are then subjected to in situ alkoxide-directed cyclopropanation to provide cyclopropyl alcohols. In the synthesis of vinyl cyclopropyl alcohols, hydroboration of enynes is followed by transmetalation of the resulting dienylborane to zinc to provide dienylzinc reagents. Enantioselective addition to aldehydes generates the requisite dienyl zinc alkoxides, which are then subjected to in situ cyclopropanation to furnish vinyl cyclopropyl alcohols. Cyclopropanation occurs at the double bond allylic to the alkoxide. Using this method, syn-vinylcyclopropyl alcohols are obtained in 65-85% yield, 76-93% ee, and > 19:1 dr. To prepare anti-cyclopropanols, enantioselective addition of alkylzinc reagents to conjugated enals provides allylic zinc alkoxides. Because direct cyclopropanation provides syn-cyclopropyl alcohols, the intermediate allylic alkoxides were treated with TMSCl/Et(3)N to generate intermediate silyl ethers. In situ cyclopropanation of the allylic silyl ether resulted in cyclopropanation to form the anti-cyclopropyl silyl ether. Workup with TBAF affords the anti-cyclopropyl alcohols in one pot in 60-82% yield, 89-99% ee, and > or = 10:1 dr. For the synthesis of cis-disubstituted cyclopropyl alcohols, in situ generated (Z)-vinyl zinc reagents were employed in asymmetric addition to aldehydes to generate (Z)-allylic zinc alkoxides. In situ cyclopropanation provides syn-cis-disubstituted cyclopropyl alcohols in 42-70% yield, 88-97% ee, and > 19:1 dr. These one-pot procedures enable the synthesis of a diverse array of cyclopropyl alcohol building blocks with high enantio- and diastereoselectivities.

Dataset Information

Highly enantio- and diastereoselective one-pot methods for the synthesis of halocyclopropyl alcohols.

Publications

Highly enantio- and diastereoselective one-pot methods for the synthesis of halocyclopropyl alcohols.

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