Copper-catalysed asymmetric reductive cross-coupling of prochiral alkenes

Abstract

Asymmetric construction of C(sp³)-C(sp³) bond with good stereocontrol of the two connecting carbon centres retaining all carbon or hydrogen substituents is a challenging target in transition metal catalysis. Transition metal-catalysed reductive coupling of unsaturated π-substrates is considered as a potent tool to expediently develop the molecular complexity with high atom efficiency. However, such an asymmetric and intermolecular process has yet to be developed fully. Herein, we report an efficient strategy to reductively couple two prochiral conjugate alkenes using a copper-catalysed tandem protocol in the presence of diboron. Notably, this transformation incorporates a wide range of terminal and internal enynes as coupling partners and facilitates highly diastereo- and enantioselective synthesis of organoboron derivatives with multiple adjacent stereocentres in a single operation.

Fig. 1. Overview of C(sp³)–C(sp³) bond formation.

a Asymmetric induction of the new C(sp³)–C(sp³) bond at both carbons. b Prior works (radical involved). c Copper-catalysed conjugate addition of chiral alkyl nucleophiles with α-heterofunctionality. d Copper-catalysed reductive coupling of two conjugate alkenes (this work).

Fig. 2. Optimisation of coupling reaction conditions.

All reactions were carried out in a 0.5 mmol scale using 1a (1.5 equiv.) and 2a (1.0 equiv.) under a N₂ atmosphere at 40 °C, unless otherwise noted. Yields of 3a are isolated and diastereomeric ratio of product 3a was determined via ¹H NMR analysis of the unpurified mixtures and was high (>98:2) in all cases. B₂pin₂ = Bis(pinacolato)diboron.

Fig. 3. Substrate scope of terminal enynes and alkylidene malonates.

Reactions were generally conducted in a 0.5 mmol scale using 1 (1.5 equiv.) and 2 (1.0 equiv.) at 0 °C (condition A) unless otherwise noted. Under condition B, 1 (1.0 equiv.) and 2 (2.0 equiv.) were used at 0 °C. a The reaction was carried out at 40 °C. b The reaction was carried out in methyl tert-butyl ether (MTBE) instead of THF. c 1.5 equiv. of 2 was used.

Fig. 4. Substrate scope of internal enynes.

Reactions were generally conducted in a 0.5 mmol scale using 4 (1.2 equiv.) and 2 (1.0 equiv.) with the L5-copper catalyst at 40 °C unless otherwise noted. a %ee was determined with 6 f. b MTBE was used as solvent.

Fig. 5. Mechanistic data and applications.

a Hammett plot (condition A). b Proposed catalytic cycle. c Large-scale synthesis & application. Reaction conditions: I. NaBO₃, H₂O/THF, rt. II. p-TSOH, benzene, rt. III. Pd/C, H₂, THF, rt. IV. NaCl, DMSO/H₂O, 160 °C. V. Vinylmagnesium bromide, I₂, THF, MeOH −78 °C. VI. Benzofuran, n-BuLi, NBS, THF, −78 °C.