Highly Enantioselective Reduction of α‐Methylated Nitroalkenes

Abstract

The enantioselective preparation of a-substituted nitroalkanes of type 1 is of high interest due to the use of the corresponding amines 2 in the synthesis of pharmaceuticals. [1] Representative examples for commercial drugs based on such amines are Tamsulosin and Selegiline (Scheme 1). Due to the lack of suitable enantioselective catalytic synthetic methodologies, these drugs are produced in a laborious fashion either by chiral resolution (at the final stage of a suitable amine) or by a reaction relying on a chiral auxiliary (used in stoichiometric amount and not recyclable). [1,2] An attractive alternative synthetic approach would be based on the enantioselective reduction of a-methylated nitroalkenes of type 5 as a key step. The concept of this process as well as its integration in the preparation of amines and related derivatives is shown in Scheme 2. The trans substrates 5 are easily accessible starting from economically attractive and readily available industrial chemicals (aldehydes, nitroethane), and methods have been reported for the final transformation of the nitro group into an amino group with retention of the absolute configuration. [3] However, hitherto reported processes for the enantioselective reduction of nitroalkenes 5 in the presence of chemocatalysts as well as enzymes only led to low to moderate and in a few cases good enantioselectivities. For instance, in the presence of metalcontaining hydrogenation catalysts maximum enantioselectivities of 58 % ee are obtained for the nitroalkanes 1. [4] Alternatively, due to the achievements in the enzymatic reduction of activated C=C bonds of a multitude of substrate classes, [5] the enantioselective reduction of a-methylated nitroalkenes 5 using ene reductases was also studied. [5,6] Despite intensive efforts, however, until recently such enzyme-catalyzed processes for these substrates have given only enantioselectivities of 0-48 % ee in most cases and 70 % ee at best. [6a-g] In a current study, the enantioselectivity has been increased up to 84 % ee.[6h] A range of reasons for this were identified, such as the high CH acidity and the resulting sensitivity of nitroalkanes 1 towards racemization, [7] as well as the general low enantioselectivity of enzymes in the reduction of substrates of type 5. [6] One difficulty may arise from the fact that the stereogenic center is not formed in the initial addition of the hydride, but in the subsequent protonation of the resulting carbanion; [8] the control of enantioselectivity in such asymmetric protonations is generally considered to be difficult. A further demanding task is avoiding the competing enzymatic Nef reaction, [9] which transforms nitroalkenes 5 into the corresponding ketones. Accordingly (and independent of the type of catalyst), the development of a highly enantioselective C = C reduction of nitroalkenes of type 5 is still regarded as a challenge. Herein we report the first highly enantioselective process for the reduction of amethylated trans-nitroalkenes 5 to provide nitroalkanes 1 with enantio...

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