Organocatalytic atroposelective synthesis of axially chiral styrenes

Abstract

Axially chiral compounds are widespread in biologically active compounds and are useful chiral ligands or organocatalysts in asymmetric catalysis. It is well-known that styrenes are one of the most abundant and principal feedstocks and thus represent excellent prospective building blocks for chemical synthesis. Driven by the development of atroposelective synthesis of axially chiral styrene derivatives, we discovered herein the asymmetric organocatalytic approach via direct Michael addition reaction of substituted diones/ketone esters/malononitrile to alkynals. The axially chiral styrene compounds were produced with good chemical yields, enantioselectivities and almost complete E/Z-selectivities through a secondary amine-catalysed iminium activation strategy under mild conditions. Such structural motifs are important precursors for further transformations into biologically active compounds and synthetic useful intermediates and may have potential applications in asymmetric synthesis as olefin ligands or organocatalysts.

Figure 1. Background introduction of axially chiral styrenes and our strategy.

(a) The existing approaches for atroposelective synthesis of axially chiral biaryls and styrenes. (b) Our strategy for atroposelective synthesis of axially chiral styrenes.

Figure 2. Computed rotation barriers of several styrenes and their corresponding half-life.

The above computed rotation barriers along the axial C-CAr bond and their corresponding t_1/2 (25 °C) were estimated by SMD M06-D3/6-31+G*//M06-D3/6-31G* method. (See the computational details and Supplementary Figs 1–4).

Figure 3. Preparative synthesis of 3y and 3n.

(a) Preparative synthesis of 3y under the corresponding standard conditions. (b) Gram-scale preparation of 3n.

Figure 4. Versatile chemical transformations of axially chiral 3n and 3y.

(a) Synthetic transforamtion of enantioenriched 3n. (b) Synthesis of diene via simple trasformation of 3y.