Design and synthesis of cage-like NADH model molecule intermediate with multi-chiral centers

Article abstract of DOI:10.1080/00397911.2018.1557689

Studying NADH molecules is one of the most active areas in biomimetic research. It is important to design novel and efficient chiral NADH model molecules. Herein, a cage-like NADH model with multi-chiral centers was designed, and key intermediates have been synthesized. In this study, we found that pentafluorophenoxy group is an excellent leaving group for our synthetic route.

Full text of DOI:10.1080/00397911.2018.1557689

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Design and synthesis of cage-like NADH model
molecule intermediate with multi-chiral centers
Tong Zhang, Cui-Bing Bai, Yue-Hua Wu, Nai-Xing Wang, Bao-Cai Xu, Zhan Yan
& Yalan Xing
To cite this article: Tong Zhang, Cui-Bing Bai, Yue-Hua Wu, Nai-Xing Wang, Bao-Cai Xu,
Zhan Yan & Yalan Xing (2019) Design and synthesis of cage-like NADH model molecule
intermediate with multi-chiral centers, Synthetic Communications, 49:3, 410-416, DOI:
10.1080/00397911.2018.1557689
To link to this article: https://doi.org/10.1080/00397911.2018.1557689
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2019, VOL. 49, NO. 3, 410–416
https://doi.org/10.1080/00397911.2018.1557689
Design and synthesis of cage-like NADH model molecule
intermediate with multi-chiral centers
Tong Zhanga, Cui-Bing Baia, Yue-Hua Wua, Nai-Xing Wanga, Bao-Cai Xub,
Zhan Yana, and Yalan Xingc
aTechnical Institute of Physics and Chemistry & University of Chinese Academy of Sciences Chinese
b
Academy of Sciences, Beijing, China; School of Food and Chemical Engineering, Beijing Technology
c
and Business University, Beijing, China; Department of Chemistry, William Paterson University of New
Jersey, Wayne, NJ, USA
ABSTRACT
ARTICLE HISTORY
Received 5 November 2018
Studying NADH molecules is one of the most active areas in biomim-
etic research. It is important to design novel and efficient chiral
NADH model molecules. Herein, a cage-like NADH model with multi-
chiral centers was designed, and key intermediates have been syn-
thesized. In this study, we found that pentafluorophenoxy group is
an excellent leaving group for our synthetic route.
KEYWORDS
Cage-like; multi-chiral
centers; NADH; symmetry;
intermediate
GRAPHICAL ABSTRACT
Introduction
NADH is a very important coenzyme which plays a key role in glycolysis, fatty acid
metabolism, amino acid degradation and other metabolic processes. Therefore, studying
NADH coenzymes has attracted wide attention of biologists and chemists, and has
become one of the most active areas in biomimetic research.[1–8]
In organisms, coenzyme NADH and its oxidation state NADþ could reduce or oxi-
dize specific substances by supplying or capturing hydride under the catalysis of related
CONTACT Nai-Xing Wang
nxwang@mail.ipc.ac.cn
Technical Institute of Physics and Chemistry & University of
Chinese Academy of Sciences Chinese Academy of Sciences, Beijing 100190, China.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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411
enzymes, and provide necessary circular reactions for energy storage and release. Many
redox reactions and metabolic processes in organisms could not work without the par-
ticipation of NADH.[9] Due to the important role of coenzyme NADH in organisms,
biomimetic study about NADH is always a hot topic in biochemistry, organic chemistry,
physical chemistry and related fields.[10,11] In recent years, some model molecules have
been synthesized by biomimetic methods, and dihydropyridine amide group, which is
the active group in NADH, has been well investigated. Meanwhile, great progress has
been made in the study of hydride and electron transfer between oxidation and reduc-
tion states of model molecules.[12–22] Our group has also contributed valuable work and
reported several syntheses of novel NADH model molecules.[23,24]
In order to further study the reaction mechanism of chiral NADH model molecules
in asymmetric reactions and the catalyzed reactions with enzymes, we designed novel
chiral NADH model molecules, and key intermediates were synthesized.
Discussion
Because of the novelty and complexity of the target molecule structure, it is difficult to
explore and determine the synthetic route. However, on the basis of our previous work,
the synthetic route of target molecules was determined, and the key intermediates have
been synthesized (Scheme 1).
On the basis of our group’s previous research work, we improved the synthetic route
and replaced some raw materials which are difficult to prepare. The key intermediate
compounds 2–8 were synthesized and characterized.
In order to introduce chiral centers into the target molecule, we chose the commer-
cial available cyclohexanediamine as chiral source. With the help of tartaric acid, chiral
resolution was achieved and pure chiral cyclohexanediamine was obtained. In order to
preserve chiral cyclohexanediamine better, we transformed it to corresponding hydro-
chloride. (Boc)2O could selectively protect amino group of cyclohexanediamine under
base conditions and generate hydrochloride of compound 2 (Scheme 2).
Through esterification of pyridine 3,5-dicarboxylic acid and unilateral deesterification,
pyridine 3,5-dicarboxylic acid by unilateral protection was prepared. Then pyridine 3,5-
dicarboxylic acid reacted with compound 2 to provide compound 3. In order to carry
on the macrocyclic ring closure smoothly, we used the pentafluorophenol to react with
compound 3. And compound 4 with pentafluorophenoxy group was synthesized after
esterification (Scheme 3).
Considering that synthetic conditions of pure tribenzylamine are very harsh and diffi-
cult to control, we decide to replace it with trimethyl tribenzylamine as building block,
which has high yield. Through bromomethylation, azidation and Staudinger reaction,
intermediate 5 was obtained. This synthetic route is efficient and convenient, and the
yields of bromomethylation and azidation are very high (Scheme 4).
In this study, we found that pentafluorophenoxy group was an excellent leaving
group. Compound 6 should to be synthesized at room temperature to avoid racemiza-
tion. Initially we tried pyridinecarbonyl chloride to react with compound 5, but it did
not work and pure product could not be obtained. Then we tried methoxy group and
ethoxy group as leaving group, and it failed to react with compound 5 at room

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Scheme 1. Proposed synthetic route.
temperature. At last, we found compound 4 could smoothly react with compound 5
with help of leaving group pentafluorophenoxy to obtain key intermediate compound 6,
the key intermediate of the cage-like NADH model molecule which had multiple chiral
centers (Scheme 5). In addition, compound 6 could also be transformed to pedal-like
NADH model molecule.

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Scheme 2. Synthesis of compound 2.
Scheme 3. Synthesis of compound 3 and 4.
Scheme 4. Synthesis of compound 5.
According to the synthetic route we designed, intermediate compound 7 is a very
important in cyclization step. We used 1,3,5-trihydroxybenzene and chloroacetic acid to
react under base condition, and obtained tripod acid with flexible chain in one step.
Then compound 8 was synthesized with pentafluorophenyl group as the directing group

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Scheme 5. Synthesis of compound 6.
Scheme 6. Synthesis of compound 7 and 8.
(Scheme 6). Then we made great efforts for the final macrocyclic ring closure step and
spent more than two years, however, it did not work. It might be a bigger entropy
decrease and multi reaction cites that inhibited the ring closure, so now we still did not
get the desired cage-like model molecule. However, further studies are currently under
investigation and will be presented in a due time.
Conclusion
In conclusion, a novel cage-like NADH model with multi-chiral centers was designed,
and we have synthesized its key intermediates. In this study, we found that pentafluoro-
phenoxy group was an excellent leaving group. It might be a bigger entropy decrease
and multi reaction cites that inhibited the ring closure, so desired cage-like model mol-
ecule couldn’t be obtained. Further studies are currently under investigation and will be
presented in a due time.

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Experimental
General considerations: All reagents were commercially available and used without
1
extra purification. H and 13C NMR spectra (400 MHz or 100 MHz, respectively) were
recorded in CDCl3 with TMS as internal standard. HRMS were recorded by EI
(Supplementary material).
Synthesis of compound 6: CH2Cl2 solution containing compound 4 (0.57 g,
0.0018 mol) and trimethylamine was slowly adding to CH2Cl2 solution containing com-
pound 5 (3.17 g, 0.006 mol). The reactant was stirred at room temperature overnight
and monitored by TLC. When the reaction was over, solvent was removed by rotary
evaporator and the remaining was purified by column chromatography (CH2Cl2/
CH3OH ¼ 10/1) to obtain compound 6 in 35% yield.
Tri-tert-butyl-((1R,1’R,1’’R,2R,2’R,2’’R)-((5,5’,5’’-((((2,4,6-trimethylbenzene-1,3,5-
triyl)tris(methylene))tris(azanediyl)) tris(carbonyl))tris(nicotinoyl))tris(azanediyl))-
tris(cyclohexane-2,1-diyl))tricarbamate (compound 6): white solid (0.78 g,
1
0.00063 mol). H NMR (400 MHz, DMSO); d 9.03–9.01 (d, J ¼ 9.45 Hz, 6H), 8.72 (s,
3H), 8.51 (s, 3H), 8.42–8.40 (d, J ¼ 8.62 Hz, 3H), 6.67–6.65 (d, J ¼ 8.73 Hz, 3H), 4.59 (s,
6H), 3.72–3.70 (d, J ¼ 9.66 Hz, 3H), 3.38–3.36 (d, J ¼ 8.87 Hz, 3H), 2.43 (s, 9H), 1.78 (s,
6H), 1.66 (s, 6H), 1.31–1.19 (m, 41H); 13C NMR (100 MHz, DMSO); d 164.29, 163.76,
155.61, 150.28, 137.10, 134.13, 132.30, 129.87, 129.56, 129.51, 77.34, 53.73, 53.02, 31.73,
31.55, 28.04, 24.68, 24.45, 16.00; HRMS (ESI) m/z: [M þ Na]þ calcd for C66H90N12O12
1265.6693; found, 1265.6691.
Funding
Support for this research was provided by the National Natural Science Foundation of
China (21676003).
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