Dual catalysis for enantioselective convergent synthesis of enantiopure vicinal amino alcohols

Abstract

Enantiopure vicinal amino alcohols and derivatives are essential structural motifs in natural products and pharmaceutically active molecules, and serve as main chiral sources in asymmetric synthesis. Currently known asymmetric catalytic protocols for this class of compounds are still rare and often suffer from limited scope of substrates, relatively low regio- or stereoselectivities, thus prompting the development of more effective methodologies. Herein we report a dual catalytic strategy for the convergent enantioselective synthesis of vicinal amino alcohols. The method features a radical-type Zimmerman-Traxler transition state formed from a rare earth metal with a nitrone and an aromatic ketyl radical in the presence of chiral N,N'-dioxide ligands. In addition to high level of enantio- and diastereoselectivities, our synthetic protocol affords advantages of simple operation, mild conditions, high-yielding, and a broad scope of substrates. Furthermore, this protocol has been successfully applied to the concise synthesis of pharmaceutically valuable compounds (e.g., ephedrine and selegiline).

Fig. 1

Retrosynthetic analysis and synthetic protocols of enantiopure vicinal amino alcohols. a The general protocols for synthesis of enantiopure vicinal amino alcohols and their derivatives. b Previous studies by Py and our group on SmI₂-mediated cross-coupling of nitrones with aldehydes/ketones may lead to homocoupling and reduction byproducts and are not ideally suitable for developing catalytic enantioselective variant. c Enantioselective reductive cross-coupling reaction of nitrones with aromatic aldehydes via the synergistic catalysis of chiral ligand-coordinated Lewis acid and photocatalyst was described. Through the radical-type Zimmerman–Traxler TS_II, vicinal hydroxyamino alcohols could be obtained exclusively with high stereoselectivity. This mild reaction is operationally simple with a wide array of nitrones and aromatic aldehydes

Fig. 2

Radical clock reactions. a The normal cross-coupling was observed without ring opening product from ketone 3. b The radical clock generated from well-designed radical clock precursor 4 was rearranged and added to nitrone 1f

Fig. 3

Proposed mechanism of this photocatalytic enantioselective reductive cross-coupling reaction. Relative Gibbs free energies (ΔG in kcal mol⁻¹ at 298 K) for key intermediates and transition states were computed at the SMD-B3LYP/DZP-level of theory

Fig. 4

Concise synthesis of (+)-ephedrine 6n and (−)-selegiline 8. A concise two-step synthesis of (1S,2-R)-(+)-ephedrine 6n and an efficient three-step preparation of (R)-(−)-selegiline 8 have been achieved both with 70% overall yield and 94% ee