Diastereo- and Enantioselective Conjugate Addition of α-Ketoesters to Nitroalkenes Catalyzed by a Chiral Ni(OAc)₂ Complex under Mild Conditions

Abstract

A highly efficient, catalytic, diastereo- and enantioselective conjugate addition of alpha-ketoesters to nitroalkenes has been devised. The reaction was applicable to various substrates. Notably, the combination of endogenous and exogenous bases was effective, allowing a small amount of the catalyst (0.1-1 mol % Ni) to promote the reaction efficiently. The synthetic utility of this reaction was demonstrated in the synthesis of substituted pyrrolidine derivatives, whose stereochemistry is closely related to biologically important natural products such as kainic acid.

Practical Total Syntheses of Acromelic Acids A and B

“…To address this issue, we examined the reaction of α-ketoester 7a. 40,43) The Ni-catalyzed reaction between 16 and 7a produced the desired product 28 quantitatively with excellent stereoselectivity (dr=20 : 1, 91% ee). Subsequent hydrogenation with Raney Ni also proceeded smoothly, but a 1 : 2 mixture of 29a and b were isolated after protection with a Cbz group at the secondary amine.…”

“…In contrast, we planned to use methoxy picolinic acid ester as a pyridone precursor to improve the efficiency of the syntheses, even though the reaction of a pyridine substrate might be challenging, since such heterocyclic compounds tend to affect key catalytic and stereoselective reactions. As a part of our research program on kainoid chemistry, [40][41][42][43] we herein describe the details of practical and scaleable total syntheses of acromelic acids A (1) and B (2).…”

“…Thus, a crucial step of the total synthesis would be stereoselective coupling between nitroalkene 6 and α-ketoester 7, which we expected to achieve by the use of a Ni-catalyzed asymmetric reaction. 40) Nitroalkene 6 would be synthesized from the corresponding pyridylaldehyde and nitromethane via Henry reaction and subsequent dehydration. Since 1 and 2 differ only in the substitution pattern on the pyridone ring, divergent synthesis of both regioisomeric pyridylaldehydes from the same compound is another key feature of the total synthesis.…”

“…Firstly, asymmetric conjugate addition of α-ketoester 7a with nitroalkene 15 was examined, since this reaction worked well in our previous 4-(2-methoxyphenyl)-2-carboxy-3-pyrrolidineacetic acid (MFPA) synthesis. 40) Although nitroalkene 15 had a Lewis-basic pyridine ring that potentially interferes with the Ni catalyst, the desired reaction proceeded smoothly without siginificant side reactions in the presence of 5 mol% of Ni(OAc) 2 -diamine catalyst 20 (Table 1, entry 1). In place of 7a, we next examined the reaction of 7b with the same oxidation state at the C4 side chain in 1 and 2.…”

“…The next task was inversion of the stereochemistry at the C-2 position. Since t-BuOK-promoted inversion gave the excellent results in our previous synthesis of MFPA, [40][41][42][43] the same condition was applied to N-Cbz-protected 23. However, treatment with t-BuOK resulted in marked decomposition of the substrate (vide infra).…”