A Novel NADH Model: Design, Synthesis, and its Chiral Reduction and Fluorescent Emission

Abstract

A novel chiral nicotinamide adenine dinucleotide hydrogen (NADH) model with C 3 symmetry was designed and synthesized. Hydrogens at the C-4 position of all dihydropyridine rings in the inner part of the bowl could transfer to the substrate with powerful enantioselectivity. This novel C 3 symmetrical NADH model is capable of fluorescence emission at 455 nm when excited at 390 nm.Keywords: chiral NADH model; enantioselectivity; fluorescence; magnesium(II); synthesis The coenzyme nicotinamide adenine dinucleotide hydrogen (NADH) is an important molecule in nature. Over the past several decades, NADH mimics have become one of the highlights of biochemistry and organic chemistry.[1] To the best of our knowledge, the dihydropyridine amido group is the key structure for NADH models.Kanomata [1f] designed and synthesized a bridged NADH model with an [n]A C H T U N G T R E N N U N G (2,5)pyridinophane (parapyridinophane) skeleton as a sterically-demanding side chain that induces high enantioselectivity. Kanomata believed that the oligomethylene chain bridging the 2-and 5-positions of a dihydronicotinoyl ring would behave as an "enzyme wall" that allows the substrates to approach from the opposite side exclusively. In the asymmetric reduction of methyl benzoylformate, mandelate was obtained with a high enantiomeric excess when a 1 molar ratio of magnesium was used.Generally, chemists had formerly designed NADH models according to three aspects: the first one was to control the stereoselectivity by changing the substitutent of the dihydronicotinamide with a view to form a remote sterically-demanding side chain.[2] The second aspect was to incorporate a substituent at the reaction center: the C-4 position of the dihydropyridine ring.[3] The third one was to design the specific conformation to obtain high stereoselectivity.[4] However, in the first situation the dihydronicotinamide unit needs to be modified significantly by introducing big chiral auxiliaries, a complicated ring or by changing the amide group to a chiral sulfinyl group. The second one suffered from loss of chirality at the C-4 position during the course of the model reduction reaction. The third one was particular and by far fewer models have been studied. Herein, a novel chiral NADH model compound 1 with C 3 -symmetry was designed and synthesized.Our model 1 has six chiral carbon centers. (1R,2R)-Diaminocyclohexane is introduced as chiral source to connect three identical pyridine-3,5-dicarbonyl groups into a large ring. Then three identical 1,4-dihydropyridine units are connected by the phenyl-1,3,5-trimethylene group to form model 1. Molecular modeling via molecular dynamics followed by energy minimization with Gaussian 03 shows that the bowl-shaped conformation shown in Figure 1 is the most stable one. The phenyl-1,3,5-trimethylene group is the "bottom" of the "bowl" and the rigidly defined concave cavity of the bowl can hold a metal ion in a fixed position relative to the 1,4-dihydropyridine. As a result, regulation of the stereoselective appro...

Rotational spectroscopy of methyl benzoylformate and methyl mandelate: structure and internal dynamics of a model reactant and product of enantioselective reduction

“…2 Over the years, numerous NADH mimics have been synthesized by organic chemists for use as enantioselective reducing agents in the laboratory. [7][8][9][10][11][12][13] Recently, this reaction was also used to characterize more unconventional enantioselective catalysts, including heterogeneous platinum-supported 14 and nano-confined 15 catalysts. [7][8][9][10][11][12][13] Recently, this reaction was also used to characterize more unconventional enantioselective catalysts, including heterogeneous platinum-supported 14 and nano-confined 15 catalysts.…”

Double Functional Group Transformations for Fluorescent Probe Construction: A Fluorescence Turn‐On Probe for Thioureas

“…2) When treated with thioureas, these two functional groups may undergo double functional group transformations to become the thiazole compounds 5 by the Hantzsch reaction. [7] Thus, we envisioned that the chemical transformation of the a-bromoketone to thiazole structure should inhibit both the fluorescence quenching processes and, thus, restore the intense fluorescence of the coumarin dye. In other words, we should observe a pronounced fluorescence turn-on signal, if probe 1 can be converted to thiazole compounds 5 by thioureas.…”

A Petal-type Chiral NADH Model: Design, Synthesis and its Asymmetric Reduction

“…3 ) Chiral NADH models with C 3 -symmetry. In our previous work, we have designed and synthesized the first C 3 symmetrical NADH model compound 4 with a special bowl-shaped conformation 18 .…”

“…Therefore, to design novel NADH models with symmetric structure and excellent enantioselectivity is a challenge for chemists. For the C 3 -symmetry models, it was shown that the three identical dihydropyridine units were connected to form a rigidly defined concave cavity which could encase and fix certain substrates to accomplish the biomimetic reduction with high yields and enantioselectivity 18 .…”

“…Here in, as part of our ongoing studies with regards to the development of new chiral NADH models 18 24 25 26 , we would like to report a synthesis of a novel petal-type chiral NADH model, which has six chair carbon centers. This new C 3 symmetrical NADH model shows better reactivity and enantioselectivity of asymmetric reduction of C=O bonds than the monomer portion with C 2 symmetry (compound 2 ).…”