One-Pot Catalytic Enantio- and Diastereoselective Syntheses ofanti-,syn-cis-Disubstituted, andsyn-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 ≥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.

Stereoselective Synthesis of β-Hydroxy Enamines, Aminocyclopropanes, and 1,3-Amino Alcohols via Asymmetric Catalysis

“…Upon combining CF 3 CH 2 OZnCH 2 I with zinc β-alkoxy enamine intermediates, we were pleased to see formation of the desired cyclopropyl amines as a single diastereomer, although the yields were moderate. As we have observed with other systems,19,64,65 the cyclopropanation proceeds in low to moderate yield in the presence of the triethylborane, a byproduct formed in the transmetalation of the β-amino vinyl group from boron to zinc (Scheme 6). To achieve high yields the triethyborane was removed from the reaction mixture before the cyclopropanation step.…”

“…Our approach to the catalytic enantio- and diastereoselective synthesis of amino cyclopropyl carbinols is based on our prior efforts involving the diastereoselective directed cyclopropanation of allylic alcohols 19, 64, 65. At the outset of this study, however, it was not clear how the nitrogen of the enamine would impact the reactivity of the double bond toward cyclopropanation or if it would affect the diastereoselectivity.…”

Tandem catalytic enantio‐ and diastereoselective synthesis of cyclopropyl alcohols using aryl aldehydes

“…First, the use of zinc carbenoid species with different electronic properties was studied (Table ). It is known that electron withdrawing additives, such as CF 3 CO 2 H, CF 3 CH 2 OH, and phenol derivatives, can generate more reactive zinc carbenoids of the type Y–ZnCH 2 I (Y is the conjugate base of the acids listed above). Marginal improvement in the cyclopropanation conversion was observed, in particular with use of CF 3 CH 2 OH (entry 2).…”

“…Recently, we reported a tandem catalytic enantio‐ and diastereoselective synthesis of cyclopropyl alcohols starting from achiral reagents, thus eliminating the need for isolation of enantioenriched allylic alcohols . Our general strategy involved catalytic enantioselective carbonyl additions to aldehydes followed by diastereoselective cyclopropanation of the resulting allylic zinc alkoxide intermediates (Scheme ).…”

Katalytische asymmetrische Synthese von Allylalkoholen und Allylalkohol‐Derivaten und deren Anwendung in der organischen Synthese

“…Allerdings ermöglichte die Verwendung der Divinylzink‐Reagentien 151 als Nucleophile die Bildung der Epoxyalkohole 152 mit exzellenter Diastereoselektivität (Schema ) 98c. Von Walsh wurden auch verwandte, hoch stereoselektive Eintopfverfahren zur Herstellung von syn ‐Vinylcyclopropylalkoholen und anti‐ Cyclopropylalkoholen entwickelt 144b…”