One-pot catalytic enantio- and diastereoselective syntheses of anti-, syn-cis-disubstituted, and syn-vinyl cyclopropyl alcohols

Abstract

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.

Scheme 1

Tandem Approaches to Enantio- and Diastereoenriched Cyclopropyl Alcohols

Figure 1

Structures of members of the oxylipin natural products, which contains both syn and anti cyclopropyl alcohol motifs

Scheme 2

Asymmetric Cyclopropanation of Dienols by Charette and Barrett.

Scheme 3

Synthesis of VCP's.

Scheme 4

Tandem Sequence to Afford anti-Cyclopropyl Alcohols with High Enantio- and Diastereoselectivity (Table 6).

Scheme 5

Two Routes to cis-Disubstituted Cyclopropyl Alcohols.

Scheme 6

Enantioselective Generation of (Z)-Allylic Alcohols in the Presence of TEEDA inhibitor.

Scheme 7

One-pot Synthesis of cis-Disubstituted Cyclopropyl Alcohols.

Figure 2

X-ray structure of the camphanic ester of compound 23.