Enantioselective Synthesis of All‐Carbon Quaternary Stereogenic Centers by Catalytic Asymmetric Conjugate Additions of Alkyl and Aryl Aluminum Reagents to Five‐, Six‐, and Seven‐Membered‐Ring β‐Substituted Cyclic Enones

Abstract

Dedicated to Professor Elias J. CoreyCatalytic asymmetric conjugate addition (ACA) reactions of carbon-based nucleophiles to b,b-disubstituted enones present an efficient approach to enantioselective synthesis of allcarbon quaternary stereogenic centers [1] that reside adjacent to synthetically versatile enolates [Eq. (1)]. In spite of recent advances involving catalytic ACA reactions of alkyl metal (mostly dialkyl zinc) reagents, [2][3][4][5] a number of critical shortcomings remain unaddressed. One noteworthy challenge concerns transformations of b-substituted cyclopentenones, processes that are often less efficient [6,7] (vs. reactions of larger rings) but can deliver products that may be used in enantioselective syntheses of a variety of biologically active natural products.[8] Previously reported approaches, involving zinc-based reagents, are only effective with five-memberedring substrates when the enone bears an additional activating substituent.[4] Additions of trialkyl aluminum reagents to bsubstituted cyclopentenones catalyzed by chiral copper phosphoramidites have been shown to proceed in three cases. In only a single instance, however, is high selectivity observed (ACA with Et 3 Al; 96.5:3.5 e.r., 93 % ee).[5a] Herein, we disclose an efficient set of protocols for catalytic ACA reactions of alkyl and aryl aluminum reagents with a range of unactivated b-substituted cyclic enones, including cyclopentenones. Reactions, promoted in the presence of a chiral bidentate N-heterocyclic carbene (NHC) copper complex (5 mol %), are efficient (up to 97 % yield) and highly selective (up to > 99: < 1 e.r., greater than 98 % ee). In the case of transformations involving additions of aryl units, the requisite aluminum-based reagents are prepared in situ from commercially available dimethylaluminum chloride and the corresponding aryl lithium compounds.We began our investigations by examining the ability of NHC complexes 1-4 (Scheme 1), previously developed in our laboratories, [9] to promote ACA of trialkyl aluminum reagents to cyclic enones. As the main objective of these studies is reactions of b-substituted cyclopentenones, we selected 6 a to serve as the representative substrate (Table 1). Our focus on aluminum-based reagents [10] is partly due to the higher reactivity as well as the significantly lower cost of this class of alkylating agents (vs. dialkyl zinc reagents).Through an initial screening study (Table 1), we established that the first two generations of aryloxide-containing NHC copper complexes derived from 1 and 2[9a-b] do not Scheme 1. Air-stable chiral NHC silver(I) complexes that serve as precursors to the corresponding copper-based catalysts.

Catalytic SN2′‐ and Enantioselective Allylic Substitution with a Diborylmethane Reagent and Application in Synthesis

“…Matters improved with the NHC-Cu species derived from sulfonate-containing 10 (entry 7), which afforded 3a with 76% S N 2′ selectivity and 97:3 enantiomeric ratio (e.r.). Based on the finding that 4a is produced by a ligand-free Cu catalyst (entry 1), we used the crystalline and air-stable dimeric Ag complex 11a [6] , one of a set of complexes found to exchange ligands with exceptional efficiency; [16] the branched isomer 3a was thus formed in 95:5 S N 2′:S N 2 selectivity and 97:3 e.r. (entry 8, Table 1).…”

Catalytic enantioselective synthesis of quaternary carbon stereocentres

“…Hoveyda and coworkers reported the use of Cu/Ag–NHC catalyst for the conjugate addition of alkyl- and arylaluminum intermediates to conjugated enones (e.g., the synthesis of 56 , Fig. 6b), 42 as well as the addition of silicon-containing vinylaluminum intermediates. 43 The addition of arylzinc reagents can also be accomplished using a structurally related Cu/Ag–NHC catalyst generated from silver complex 62 , as exemplified in the formation of ent - 55 (Fig.…”

“…b , The addition of a trialkylaluminum compound to 54 to form cyclohexanone 56 . 42 Tf, trifluorosulfonyl; i -Bu, isobutyl; THF, tetrahydrofuran; Ph, phenyl; NHC, N -heterocyclic carbene. c , The addition of an arylzinc compound to 54 to form the enantiomer of cyclohexanone 55 .…”

Creation of Quaternary Stereogenic Centers via Copper-Catalyzed Asymmetric Conjugate Addition of Alkenyl Alanes to α,β-Unsaturated Cyclic Ketones

“…This finding shows that alkenylalanes possess the same levels of stability as previously observed for arylalanes. 7 Before testing the optimized conditions for different substrates we wanted to check if the addition of lithium salts and variations in the t-BuLi/Me 2 AlCl ratio would have an influence on the reaction ( Table 5). …”