Copper-Catalyzed Enantioselective Synthesis of trans-1-Alkyl-2-substituted Cyclopropanes via Tandem Conjugate Addition−Intramolecular Enolate Trapping

Abstract

Cu-TolBINAP-catalyzed conjugate addition of Grignard reagents to 4-chloro-α,β-unsaturated esters, thioesters, and ketones leads to 4-chloro-3-alkyl-substituted thioesters and ketones in up to 84% yield and up to 96% ee upon protonation of the corresponding enolates at low temperature. Tandem conjugate addition-enolate trapping, however, yields trans-1-alkyl-2-substituted cyclopropanes in up to 92% yield and up to 98% ee. The versatility of this reaction is illustrated by the formation of key intermediates for the formal syntheses of cascarillic acid and grenadamide.

Copper‐Catalyzed Asymmetric Conjugate Addition of Dimethylzinc to Acyl‐N‐methylimidazole Michael Acceptors: a Powerful Synthetic Platform

“…Binap-type atropoisomeric ligands were first evaluated. Initial experiments with Binap [11] highlighted the potential of Me 2 Zn in these reactions to achieve good conversions and 1,4-regioselectivity at room temperature, albeit with only modest enantioselectivities up to 26 %. Control experiments showed that both ligand and metal are essential:noc onversion could be observed in the absence of Scheme 1.…”

“…Theu se of more reactive organometallic reagents such as Me 3 Al or MeMgBr [12] led only to racemic 1,4-product 2a or amixture of 1,2/1,4 adducts,respectively (see SI). When other atropoisomeric classical ligands such as tol-binap, [11] Segphos, [13] difluorphos, [14] and phosphoramidites [15] were used, unsatisfying enantioselectivities were observed that did not exceed 70 %. Higher selectivity was observed with Josiphos L1a [16] (87 % ee)w hereas less than 5% ee was observed with the structural isomer L1b (Scheme 2; Table 1, entries 1-3).…”

Diastereoselective Mannich Reaction of Chiral Enolates Formed by Enantioselective Conjugate Addition of Grignard Reagents

“…[8] These enolates also open epoxides [9] or take part in cross-coupling [10] or cyclopropanation reactions. [11] Chiral metal enolates can also be trapped intramolecularly to form cycles. [12] This was realized by another conjugate addition [13] or a nucleophilic displacement of a remote halogen atom.…”

“…[12] This was realized by another conjugate addition [13] or a nucleophilic displacement of a remote halogen atom. [11] Intramolecular enolate trapping is also useful for Rh-catalyzed additions, although these reactions typically run without a chiral ligand. [14] Hayashi developed an intermolecular enantioselective version of rhodium enolate trapping in the aldol reaction.…”

Cyclopropane Compatibility with Oxidative Carbocation Formation: Total Synthesis of Clavosolide A

“…The synthesis of the cyclopropane-containing subunit (Scheme 5) employed Feringa’s elegant asymmetric 1,4-addition protocol 12 as the key step. Conjugate addition of MeMgBr to chloro enone 14 , prepared in one step from allyl chloride and acetyl chloride, 13 in the presence of CuI and ( R )-tolylBINAP provided a chloro enolate that could either be warmed to generate cyclopropane 15 directly or quenched at low temperature and subjected to base to effect the cyclopropanation in >90% ee.…”