Nickel-catalyzed electrophiles-controlled enantioselective reductive arylative cyclization and enantiospecific reductive alkylative cyclization of 1,6-enynes

Abstract

Transition metal-catalyzed asymmetric cyclization of 1,6-enynes is a powerful tool for the construction of chiral nitrogen-containing heterocycles. Despite notable achievements, these transformations have been largely limited to the use of aryl or alkenyl metal reagents, and stereoselective or stereospecific alkylative cyclization of 1,6-enynes remains unexploited. Herein, we report Ni-catalyzed enantioselective reductive anti-arylative cyclization of 1,6-enynes with aryl iodides, providing enantioenriched six-membered carbo- and heterocycles in good yields with excellent enantioselectivities. Additionally, we have realized Ni-catalyzed enantiospecific reductive cis-alkylative cyclization of 1,6-enynes with alkyl bromides, furnishing chiral five-membered heterocycles with high regioselectivity and stereochemical fidelity. Mechanistic studies reveal that the arylative cyclization of 1,6-enynes is initiated by the oxidative addition of Ni(0) to aryl halides and the alkylative cyclization is triggered by the oxidative addition of Ni(0) to allylic acetates. The utility of this strategy is further demonstrated in the enantioselective synthesis of the antiepileptic drug Brivaracetam.

Fig. 1. Transition metal-catalyzed functionalization/cyclization of 1,6-enynes.

a Bioactive molecules containing chiral 2-pyrrolidone and 1,2,3,6-tetrahydropyridine skeletons. b Enantioselective cyclization of 1,6-enynes via carbometallation/cyclization/elimination pathway.

Fig. 2. Asymmetric reductive cyclization of 1,6-enynes.

a Enantiospecific allylic substitution with organometallic reagents. b Enantioselective or enantiospecific reductive cross-coupling of alkyl halides. c Enantioselective or enantiospecific reductive cyclization of 1,6-enynes (this work).

Fig. 3. Reaction scope of asymmetric reductive arylative cyclization.

The reactions were performed on a 0.2 mmol scale under the conditions in Table 1, entry 1.

Fig. 4. Reaction scope of asymmetric reductive alkylative cyclization.

The reactions were performed on a 0.1 mmol scale under the conditions in Table 2, entry 13.

Fig. 5. Effect of alkene geometry on stereochemical outcome.

The proposed mechanism is presented in the figure.

Fig. 6. Synthetic transformations and applications.

a Modification of biologically active molecules. b Synthetic transformations. c Application to the enantioselective synthesis of the antiepileptic drug Brivaracetam.

Fig. 7. Mechanistic investigations.

a Reductive cyclization of 1,7-enynes. b Reductive cyclization of alkenyl iodides. c Crossover experiment. d Stoichiometric experiment with aryl-Ni(II) complexes. e Quench of alkenylnickel intermediates. f Radical trapping experiment. TEMPO tetramethylpiperidine oxide. g Stoichiometric experiment with Ni(0). h Ring opening reaction. i Ring, closing reaction.

Fig. 8. Proposed Mechanism.

a Proposed carbometallation pathway for the enantioselective reductive trans-arylative cyclization. b Proposed allylic oxidative addition pathway for the enantiospecific reductive cis-alkylative cyclization.