Asymmetric 1,4-functionalization of 1,3-enynes via dual photoredox and chromium catalysis

Abstract

The merger of photoredox and transition-metal catalysis has evolved as a robust platform in organic synthesis over the past decade. The stereoselective 1,4-functionalization of 1,3-enynes, a prevalent synthon in synthetic chemistry, could afford valuable chiral allene derivatives. However, tremendous efforts have been focused on the ionic reaction pathway. The radical-involved asymmetric 1,4-functionalization of 1,3-enynes remains a prominent challenge. Herein, we describe the asymmetric three-component 1,4-dialkylation of 1,3-enynes via dual photoredox and chromium catalysis to provide chiral allenols. This method features readily available starting materials, broad substrate scope, good functional group compatibility, high regioselectivity, and simultaneous control of axial and central chiralities. Mechanistic studies suggest that this reaction proceeds through a radical-involved redox-neutral pathway.

Fig. 1. Catalytic asymmetric 1,4-functionalization of 1,3-enynes.

a Transition-metal catalyzed asymmetric 1,4-functionalization of 1,3-enynes. b This work: radical 1,4-functionalization of 1,3-enynes by dual photoredox and chromium catalysis. Rad alkyl radical precursors.

Fig. 2. The importance of chiral allenols.

Bn benzyl, TBS tert-butyldimethylsilyl, Me methyl, TIPS triisopropylsilyl, Et ethyl, Tol p-methylphenyl, t-Bu tert-butyl, Boc tert-butoxylcarbonyl.

Fig. 3. The scope of aldehydes in the 1,4-functionalization of 1,3-enynes.

^a2.0 equiv of DHP ester and 2.0 equiv of 1,3-enyne were used. i-Pr isopropyl, Bpin boronic acid pinacol ester, Ac acetyl.

Fig. 4. The scope of DHP esters and 1,3-enynes in the 1,4-functionalization of 1,3-enynes.

^a4-(tert-butyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile was used as radical precursor. ^b3.0 equiv of corresponding 1,3-enyne were used. ^cThe yield is for allenol product, and the minor regioisomer refers to the propargylation product from the 1,2-functionalization. TMS trimethylsilyl, TES triethylsilyl.

Fig. 5. Exploration of other radical precursors and representative synthetic applications.

a RBF₃K as the radical precursor. b Redox-active ester as the radical precusor. c Desilylation and cyclization. NBS N-bromosuccinimide.

Fig. 6. Mechanistic investigations.

a Radical trapping experiment. b Light on/off and quantum yield mearsurement. c The Stern–Volmer plot. d Proposed mechanism for the 1,4-functionalizaton of 1,3-enynes.