Conjugate Boration of β,β‐Disubstituted Unsaturated Esters: Asymmetric Synthesis of Functionalized Chiral Tertiary Organoboronic Esters

Abstract

Catalytic conjugate addition of a boron nucleophile (M-B) to unsaturated carbonyl substrates [1] has emerged as a novel synthetic tool to afford b-boryl carbonyl compounds, [2] an important class of organoboron compounds. While several important and efficient methodologies for conjugate boration have been developed, [3] the asymmetric conjugate boration of b,b-disubstituted a,b-unsaturated esters is especially challenging because of the low reactivity and poor enantioselectivity exhibited by these substrates. The lower reactivity of b,b-disubstituted a,b-unsaturated esters, compared to enones [1b, j] and b-monosubstituted substrates, is due to the inherently lower electrophilicity and greater steric bulkiness at the reaction site. As is often practiced with catalysts to address this type of challenge, the development of a more efficient catalytic system to enhance reactivity and enantioselectivity is required. In this communication, we describe a highly efficient catalytic system for the asymmetric conjugate boration of b,b-disubstituted a,b-unsaturated esters that produces tertiary organoboron compounds with a quaternary boron-substituted carbon center [4] and ester functional group. We also report the successful application of these organoboranes as carbon nucleophiles in a rhodiumcatalyzed addition reaction.Recently, Shibasaki and co-workers reported an efficient copper-catalyzed asymmetric conjugate boration of b-substituted cyclic enones in DMSO solvent.[5] However, in light of a major difficulty, the ketoQenol isomerization of b-borylated C-bound Cu ester enolate intermediates in copper-catalyzed borations, compared with enones, [6] we predicted and observed that b,b-disubstituted a,b-unsaturated esters would not be efficiently converted to products under the same conditions (CuPF 6 A C H T U N G T R E N N U N G (CH 3 CN) 4 , LiOtBu, (R,R)-QuinoxP, DMSO, RT).[7] Inclusion of proton accelerators [1c] seemed necessary to promote the conversion of the enolate intermediate to borylated product. Since we have observed greatly enhanced catalytic activity of copper-mediated nucleophiles through coordination with select ligands, [1c, 8] we started our investigation of the conjugate boration of b,b-disubstituted a,b-unsaturated esters with diboron (1) by screening ligands and proton sources. For the initial screening, we chose (E)-ethyl-3-phenylbut-2-enoate (2 a) as a model substrate (Table 1).A large difference in catalytic activity was observed depending on the chiral ligand employed. Josiphos and BINAP led to very poor conversions, while chiral phosphine ligands with a short tether between the two phosphines showed comparable reaction conversions (entries 3-5). The optimal ligand was determined to be MeDuphos, which resulted in complete conversion to the product with excellent [a]Entry Ligand Additive (2 equiv)Conv.[%][b]

Mechanism of NHC-Catalyzed Conjugate Additions of Diboron and Borosilane Reagents to α,β-Unsaturated Carbonyl Compounds

“…Also important are Si-containing organic molecules, entities that have significantly impacted the art of chemical synthesis. Accordingly, development of reliable catalytic enantioselective processes that generate C–B 1,2,3,4,5,6,7 or C–Si 8,9 bonds remains a compelling goal of research in modern chemistry. One area of activity relates to boryl and silyl conjugate addition (BCA and SCA, respectively) reactions that are facilitated by different transition metal species, 10 and in particular Cu-based chiral complexes.…”

Synthesis of Chiral Tertiary Boronic Esters by Oxime‐Directed Catalytic Asymmetric Hydroboration

“…For example, Tang recently described a remarkable rhodium-catalyzed reaction of α-arylenamides with B 2 (pin) 2 to provide the first enantioselective synthesis of chiral tertiary α-aminoboronic esters. [11] Shibasaki, [12] Hoveyda, [13] and Yun [14] independently developed asymmetric conjugate additions of B 2 (pin) 2 to unsaturated esters, ketones, and thioesters. Hoveyda also developed an efficient copper-catalyzed S N 2′ substitution of allylic carbonates by B 2 (pin) 2 .…”

Asymmetric Catalytic Borylation of α,β-Unsaturated Acceptors

“…Simultaneously, Yun and co-workers reported in 2010 an enantioselective β-borylation of β,β-disubstituted esters catalyzed by a bisphosphine (L10)-Cu complex, overcoming the reactivity limitation of their previous L1-Cu catalyst [24]. Enantioselective borylation by (L10)-Cu catalyst proceeded at room temperature with high enantioselectivity (Scheme 10).…”