An L-lactate dehydrogenase that requires coenzyme NADH catalyzes the enantioselective reduction of pyruvate to L-lactate in anaerobic glycolysis. As the first homochiral ansa-type NADH models, we designed the bridged NADH models 10a-c having a parapyridinophane structure for strictly mimicking the stereospecificity of hydrogen transfer in the biological asymmetric reduction with NADH. These models were synthesized in several steps from the corresponding bridged nicotinate 5 prepared by our novel pyridine-formation reaction of formyl-substituted (vinylimino)phosphorane 4 with methyl propiolate. The bridged NADH models 10a-c effected excellent biomimetic reduction at various temperatures in the presence of magnesium ion to achieve both the enantioselective and stereospecific reduction of the pyruvate analogues 12u-z into chiral lactate analogues 13u-z with 88-99% ee. The high enantioselectivity was almost completely dependent on the planar chirality of 10a-c but not on the nature of the substituents of their carbamoyl groups. The biomimetic reduction proceeded with retention of the planar chirality, showing that the bridged NADH models are useful for being recycled. An isotope experiment with the deuterated model (±)-10d confirmed the stereospecific hydrogen transfer, which is in good accordance with natural coenzyme characteristics. The model (S)-10c also exhibited good enantioselectivity for the reduction of activated ketones 14k-n into the corresponding chiral alcohols 15k-n with 79-89% ee. The simple bridged NADH model (S)-10c having both a primary carbamoyl group and a shielding bridge feigning an enzyme wall suggests a compact chemical miniature of a holoenzyme, coenzyme NADH linked dehydrogenase, in terms of the unique structure, high enantioselectivity, and recyclability.
ASJC Scopus subject areas
- Colloid and Surface Chemistry