Harnessing the Power of the Asymmetric Grignard Synthesis of Tertiary Alcohols: Ligand Development and Improved Scope Exemplified by One-Step Gossonorol Synthesis

Abstract

A series of N-substituted cyclohexyl­diamino­phenolic ligands for the asymmetric Grignard synthesis of tertiary alcohols is reported. The 2,5-dimethylpyrrole-decorated ligand led to improved enantioselectivities and broadened the scope of the methodology. As an exemplar, we report an unprecedented highly selective one-step synthesis of gossonorol in 93% ee, also constituting the shortest formal syntheses of natural products boivinianin B and yingzhaosu C.

Iodine‐Catalyzed Double [4+2] Oxidative Annulations for the Synthesis of Bipyrazines from Ketones and Diamines by a Domino Strategy

“…ESI‐MS: m/z [M+H] + 317. The NMR data were identical in all respects to those previously reported [24] …”

“…13 1 Hz, 2H), 3.17 (t, J = 5.2 Hz, 4H), 3.03 (t, J = 5.2 Hz, 4H), 2.05-1.99 (m, 8H). 13 [21] Petroleum ether/ethyl acetate [24] Petroleum ether/ethyl acetate = 1:1; cis-7, yellow solid (100 mg, 32%); mp 131-132 °C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.44 (d, J = 7.4 Hz, 4H), 7.41-7.28 (m, 6H), 6.15 (s, 2H), 4.50 (dt, J = 13.5, 3.4 Hz, 1H), 2.76 (s, 1H), 1.87-1.76 (m, 1H), 1.68-1.57 (m, 1H), 1.54-1.39 (m, 2H), 1.13-1.04 (m, 4H). 13 The NMR data were identical in all respects to those previously reported.…”

“…2‐(2,5‐Diphenylpyrrol‐1‐yl)‐cyclohexylamine (7) [24] . Petroleum ether/ethyl acetate=1:1; cis ‐7 , yellow solid (100 mg, 32%); mp 131–132 °C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.44 (d, J =7.4 Hz, 4H), 7.41–7.28 (m, 6H), 6.15 (s, 2H), 4.50 (dt, J =13.5, 3.4 Hz, 1H), 2.76 (s, 1H), 1.87–1.76 (m, 1H), 1.68–1.57 (m, 1H), 1.54–1.39 (m, 2H), 1.13–1.04 (m, 4H).…”

Asymmetric addition of Grignard reagents to ketones: culmination of the ligand-mediated methodology allows modular construction of chiral tertiary alcohols

“…19 While most of the new ligands failed to improve the enantioselectivity of the process ( Table 3 , entries 1–5 and 8), the use of ( R , R )-L12 showed unprecedented enantiocontrol, delivering the product ( R )-3a in 89% ee ( Table 3 , entry 6). Taking into consideration the previously demonstrated positive effect exerted by replacing the N -dimethyl group of ligand L0 with N -pyrrole L0′, 12 we extended the investigation of ( R , R )-L12 to the N -pyrrole analogue ( R , R )-L12′ ( Table 3 , entry 7). 20 Thus, a range of substituted aryl Grignard reagents were reacted with functionalized phenones in the presence of ( R , R )-L12 and ( R , R )-L12′ ( Table 4 ).…”

“…To overcome these limitations, we designed a conceptually new N,N,O-tridentate ligand L0 derived from trans -1,2-diaminocyclohexane (1,2-DACH), which enabled the development of an effective ligand-mediated, single metal based approach to the asymmetric Grignard synthesis of chiral tertiary alcohols, via an operationally simple and cost-effective process ( Scheme 2 ). 11 Fine tuning of L0 led to the design of the N -pyrrole analogue L0′ 12 enhancing the stereoselectivity and broadening the scope to new classes of tertiary alcohols ( Scheme 2a ). The application of the asymmetric Grignard method to the synthesis of valuable targets provided new effective and step-economical entries to a range of challenging products, significantly shortening the previously established preparations, including: (i) natural products, e.g.…”