Synthesis of chiral NADH analog based on proline template including thiourea and nicotinic acid moieties

Article abstract of DOI:10.1080/00397911.2010.505702

Chiral reductase-mimicking organic molecule built on proline template incorporating a covalently bound NADH mimic via thiourea, and related reducing agent Hantzsch dihydropyridine, was designed. A synthetic path was developed involving interlinking of chiral proline derivatives with thiourea and subsequent coupling reaction with nicotinoyl chloride. The structure of target compound was studied by x-ray, indicating a double H bond with thiourea hydrogens and oxygen O1 of benzylcarbamate fragment. The reduction of benzil and imines was performed. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.505702

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Synthesis of Chiral NADH Analog Based
on Proline Template Including Thiourea
and Nicotinic Acid Moieties
Gintautas Bagdžiūnas a , Matti Haukka b & Eugenijus Butkus a
a Department of Organic Chemistry, Vilnius University, Vilnius,
Lithuania
b Department of Chemistry, University of Joensuu, Joensuu, Finland
Published online: 29 Jun 2011.
To cite this article: Gintautas Bagdžiūnas , Matti Haukka & Eugenijus Butkus (2011) Synthesis of Chiral
NADH Analog Based on Proline Template Including Thiourea and Nicotinic Acid Moieties, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:17, 2517-2523, DOI: 10.1080/00397911.2010.505702
To link to this article: http://dx.doi.org/10.1080/00397911.2010.505702
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Synthetic Communications1, 41: 2517–2523, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.505702
SYNTHESIS OF CHIRAL NADH ANALOG BASED ON
PROLINE TEMPLATE INCLUDING THIOUREA AND
NICOTINIC ACID MOIETIES
1
2
1
ˇ
Gintautas Bagdziu¯nas, Matti Haukka, and Eugenijus Butkus
1Department of Organic Chemistry, Vilnius University, Vilnius, Lithuania
2Department of Chemistry, University of Joensuu, Joensuu, Finland
GRAPHICAL ABSTRACT
Abstract Chiral reductase-mimicking organic molecule built on proline template incorpor-
ating a covalently bound NADH mimic via thiourea, and related reducing agent Hantzsch
dihydropyridine, was designed. A synthetic path was developed involving interlinking of
chiral proline derivatives with thiourea and subsequent coupling reaction with nicotinoyl
chloride. The structure of target compound was studied by x–ray, indicating a double H
bond with thiourea hydrogens and oxygen O1 of benzylcarbamate fragment. The reduction
of benzil and imines was performed.
Keywords Enantioselective synthesis; NADH analog; proline; reduction
INTRODUCTION
A large number of NADH model compounds have been designed with the aim
of mimicking reduction process in vitro for development of new enantioselective
reducing agents during recent years.[1] Generally, chiral NADH models have been
designed by modifying the dihydropyridine ring or incorporating remote sterically
demanding side chains, or a substituent at the reaction center, the C4 position of
the dihydropyridine ring.[2] Herein, we report a synthesis of a chiral NADH model
compound based on a proline template including thiourea and nicotinic acid
Received May 22, 2010.
Address correspondence to Eugenijus Butkus, Department of Organic Chemistry, Vilnius
University, Naugarduko 24, LT-03225 Vilnius, Lithuania. E-mail: eugenijus.butkus@chf.vu.lt
2517

ˇ
G. BAGDZIUNAS, M. HAUKKA, AND E. BUTKUS
¯
2518
Figure 1. Multifunctional organocatalysts.
moieties. This approach may contribute to a development of new strategies for
asymmetric reductions of unsaturated organic compounds. Asymmetric reductions
have become an important goal of research carried out in both academic and indus-
trial laboratories because of a constantly increasing demand for enantiomerically
pure and biologically active substances.[3] Procuranti and Connon were the first to
demonstrate that multifunctional derivatives 1a–c (Fig. 1) based on (thio)ureas
and nicotinic acid moieties were efficient for the reduction of 1,2-diketones.[4]
Recently, novel urea and thiourea derivatives have been developed.[5] However,
chiral thioureas have not yet been explored as catalysts for asymmetric reduction
of prochiral ketones or imines using Hantzsch dihydropyridine ester.
The reduction of benzil (1,2-diphenyl-1,2-ethanedione, PhCOCOPh) by using
urea derivative 1b provided benzoin (2-hydroxy-2-phenylacetophenone) at almost
complete conversion yet with only 2% ee, and under different conditions enantio-
meric excess increased, though with a lesser conversion, proving the product racemi-
zation under the reaction conditions. Menche and Arikan reported on the reductive
amination of ketones and aldehydes with thiourea 2; however, subsequent work of
Zhang and Schreiner revealed that thiourea does not catalyze the formation of imi-
nes though catalyzes its reduction.[6] They developed catalyst 3 (Fig. 1), which was
more efficient for the reduction of aldimines compared to thiourea 2.
RESULTS AND DISCUSSION
We report the synthesis of a chiral coenzyme NADH model based on a chiral
thiourea analog built on proline as a chiral organic Lewis acid and involving the nic-
otinic acid moiety. The general synthesis of the target compound is presented in
Scheme 1. The synthesis of chiral protected amines 7a and b starting from proline
protected with benzyl carbamate and tert-butyl carbamate groups 4a and b,
Scheme 1. Reagents and conditions: (a) (1) ClCO2Et, TEA, ꢀ15 ꢁC, (2) NaBH4, THF=H2O, 0 ꢁC; 5a
(76%), 5b (80%); (b) (1) TsCl, TEA, THF, Rt, (2) NaN3, DMF, 80 ꢁC; 6a (80%), 6b (78%); (c) 7a: Pd=
C, H2 (1 atm.), MeOH, Rt (97%), 7b: Zn, NH4Cl, EtOH=H2O (3:1), Rt (90%).

NADH ANALOG BASED ON PROLINE TEMPLATE
2519
respectively, was accomplished following reported procedures.[7] Compounds 4a and
b were converted into alcohols 5a and b via a two-step sequence including the acti-
vation of acid with ethyl chloroformate and the following reduction with sodium
borohydride. The azides 6a and b were synthesized from alcohols 5a and b in two
steps by an activation of the latter with 4-toluenesulfonyl chloride[8] and following
substitution with sodium azide. The azide 6a protected with tert-butyl carbamate
group was converted into amine 7a by reduction using palladium on carbon as a
catalyst.[9] Meanwhile, a benzyl carbamate protected azide 6b was reduced with zinc
in the presence of ammonium chloride[10] because 6b was not stable at conditions
used for the reduction of 6a (Scheme 1).
The amines 7a and b were coupled with thioureas 8a and b using an elaborate
procedure by mixing amines and appropriate isothiocyanate in dry dichloromethane.
The deprotection of the benzyl carbamate group was unsuccessful using several
methods (viz. by palladium on carbon as a catalyst in methanol, and under the same
conditions in acetic acid, as well as by mixing with BF3 ꢂ Et2O and PhSH at room
temperature,[11] either with trimethylsilyl iodide in acetonitrile[12]). The Boc protected
derivative 8a, however, was deprotected smoothly with in situ–generated hydrogen
chloride[13] in excellent yield (94%), affording product 9.[14]
A coupling reaction between amine 9 and nicotinic acid chloride was
accomplished with 4-dimethylaminopyridine and N,N-diisopropylethylamine to
afford 10 in 63% yield.
The structure of 8b was studied by x-ray analysis, obtaining single crystals from
ethanol. It should be noticed that the crystal structure of 8b (Fig. 2) showed a double
Figure 2. Thermal ellipsoid plot (50% probability level) of 8b with the hydrogen bonds (dashed line) to the
closest neighboring molecule. One of the CF3 groups is positionally disordered over two sites: only one of
these is shown. Hydrogen bonds (A, ꢁ): N1–H1N 0.97(3), H1N O1# 1.98(3), N1 O1# 2.911(2), N1–H1N
˚
1
1
O1# 160(2), N2–H2N 0.86(2), H2N O1# 2.08(2), N2 O1# 2.910(2), N2–H2N O1# 160(2). #: x þ 2, y ꢀ 2,
ꢀz þ 2.

ˇ
¯
G. BAGDZIUNAS, M. HAUKKA, AND E. BUTKUS
2520
H bond with thiourea hydrogens and oxygen O1 of the benzylcarbamate fragment.
˚
The distances N1 O1# and N2 O1# are 2.911(2) A and 2.910(2), respectively (#:
1
1
x þ 2, y ꢀ 2, ꢀz þ 2). Because of the intermolecular hydrogen bonding, the molecules
of 8b form 1D chains in the direction of the a axis.
The synthesized NADH model 10 was examined in the catalytic reduction of
benzil by using sodium dithionite as coreductant under the same conditions pre-
viously developed.[4] In contrast, it was found that catalyst 10 under these conditions
afforded benzoin, though in poor yield, whereas at higher temperature (50 ꢁC) the
yield of benzil reduction product increased to 20–30%. However, the product race-
mization occurred under the reaction conditions. It should be mentioned that the
reduction under the same conditions with sodium dithionite entirely could not be
ignored.[15]
Further, reduction of imines 11, 12, and 13 using Hantzsch dihydropyridine ester
with 8b was performed under conditions developed by Menche. The reductions were
carried out in dichloromethane at 60 ꢁC in a Schlenk flask. However, the reduction of
11 and 12 did not proceed under these conditions, and only ca 10% conversion was
1
achieved with the substrate 13 after 120 h as estimated by H NMR spectroscopy.
In conclusion, we have synthesized a reductase-mimicking chiral NADH ana-
log built on proline framework incorporating a covalently bound thiourea with
related reducing agent, Hantzsch dihydropyridine. The reduction of benzil and imi-
nes 11–13 was performed by recycling the catalyst 10 in situ using sodium dithionite
under basic conditions: however, the reduction products were obtained with rather
poor conversion (ca. 30%). This could be explained by the modest catalytic reaction
cycles (turnover number was estimated to be ca. 4) and also a nonselective reduction
of nicotine acid moiety (change of 1,4-dihydropyridine to an inactive 1,2-dihydro
form). The practical exploration of the developed system is complicated because
of the eventual racemization of products under the reaction conditions. Further
modification of the NADH analogs is in progress.
EXPERIMENTAL
Melting points were determined on a Gallenkamp apparatus and are not cor-
rected. Infrared (IR) spectra were recorded in KBr pellets on a Perkin-Elmer Spec-
trum BX spectrometer. Proton and carbon nuclear magnetic resonance spectra were
recorded in CDCl3, d6-acetone, and dimethylsulfoxide (d6-DMSO) on a Varian
XL300 spectrometer, and chemical shifts are reported in parts per million relative
to tetramethylsilane (TMS) as an internal standard. The mass spectra (positive ion
EI) were measured on a dual-sector mass spectrometer using direct inlet. Thin-layer
chromatography (TLC) was carried out on Kieselgel 60 F254 (Merck) sheets coated

NADH ANALOG BASED ON PROLINE TEMPLATE
2521
with silica gel, and Kieselgel 60 silica gel (0.040–0.063 mm, Merck) was used for col-
umn chromatography. Optical rotations were measured on a polarimeter Polamat-A
(Carl Zeiss) at 546 nm.
Toluene and tetrahydrafuran (THF) were distilled from sodium benzophe-
none. Dichloromethane, chloroform, and acetonitrile were distilled from CaH2.
Dimethylformamide (DMF) was dried over CaH2 and distilled under reduced
pressure.
(S)-1-(3,5-Bis(trifluoromethyl)phenyl)-3-(tert-butyloxycarbonyl and
Carbobenzyloxy Pyrrolidin-2-ylmethyl)thiourea (8a and b)
3,5-Bis(trifluoromethyl)phenyl isothiocyanate (87 ml, 0.48 mmol) was added to
a stirred solution of 7a (100 mg, 0.50 mmol) or 7b (220 mg, 0.94 mmol) in dry CH2Cl2
(10 ml) at room temperature. The reaction mixture was stirred for 12 h under argon.
Removing the solvent in vacuo afforded the crude product purified by column chro-
matography [petroleum ether=ethyl acetate (5:1)]. Removing the solvent in vacuo
afforded a white solid.
17
Compound 8a. Yield 160 mg (74%). ½aꢃ546 ¼ ꢀ54:2ꢁ (1.90, chloroform); mp
1
55–57 ꢁC; IR (KBr, cmꢀ1): n 3250, 1665, 1623, 1543, 1278; H NMR (300 MHz,
CDCl3, ppm) d 8.99 (bs, 1H), 8.28 (s, 2H), 7.77 (s, 1H), 3.92–3.79 (m, 1H),
3.57–3.32 (m, 3H), 3.00 (bs, 1H), 2.20–1.81 (m, 2H), 1.49 (s, 9H), 1.31–1.24 (m,
2H); 19F NMR (280 MHz, CDCl3, ppm) d ꢀ 63.36; 13C NMR (100 MHz, d6-acetone,
ppm) d 180.4, 156.4, 140.3, 131.8, 125.0, 121.6, 117.9, 57.5, 53.4, 47.5, 46.7, 30.8,
28.4, 24.0; HRMS (EI) 471.1415 (C19H23F6N3O2S requires 471.1415).
17
Compound 8b. Yield 400 mg (89%). ½aꢃ546 ¼ ꢀ34:0ꢁ (2.55, chloroform);
mp 125–126 ꢁC; IR (KBr, cmꢀ1): n 3343, 1654, 1628, 1553, 1276; 1H NMR
(300 MHz, d6-acetone, ppm) d 8.85 (bs, 1H), 8.40 (m, 2H), 7.76 (s, 1H), 7.42–7.36
(m, 5H), 5.16 (s, 2H), 7.17–4.05 (m, 1H), 3.96–3.50 (m, 5H), 2.13–1.95 (m, 4H);
19F NMR (280 MHz, d6-acetone, ppm) d 63.27; 13C NMR (100 MHz, d6-acetone,
ppm) d 181.7, 156.4, 142.2, 137.4, 131.1, 128.6, 127.9, 123.8, 123.1, 117.0, 66.8,
57.6, 49.5, 46.9, 23.9, 23.0; HRMS (EI) 505.1259 (C22H21F6N3O2S requires
505.1259).
(S)-1-(3,5-Bis(trifluoromethyl)phenyl)-3-(pyrrolidin-2-
ylmethyl)thiourea Hydrochloride (9)
A solution of 8a (440 mg, 0.97 mmol) in 10 ml dry CH2Cl2 was cooled to 0 ꢁC
and 0.46 ml (9.7 mmol) MeOH and 0.69 ml (9.7 mmol) AcCl were added under
argon. The mixture was stirred at room temperature for 24 h, and the precipitate
was filtered and washed with petroleum ether to yield a white solid 9 (370 mg,
1
94%). H NMR (300 MHz, d6-DMSO, ppm) d 9.21 (bs, 1H), 8.94 (bs, 1H), 8.73
(bs, 1H), 8.34 (s, 2H), 7.81 (s, 1H), 3.86–3.84 (m, 3H), 3.25–3.20 (m, 2H),
2.16–1.60 (m, 4H); 19F NMR (280 MHz, d6-DMSO, ppm) d ꢀ61.91.

ˇ
¯
G. BAGDZIUNAS, M. HAUKKA, AND E. BUTKUS
2522
Compound 10
A solution of 140 mg (0.34 mmol) of hydrochloride 9, 73 mg (0.41 mmol) of
nicotinoyl chloride hydrochloride, and 10 mg (0.082 mmol) DMAP in 10 ml dry
CH2Cl2 was cooled to 0 ꢁC. Then 0.24 ml (1.4 mmol) disopropylethyl amine
(DIPEA) was added, and the mixture was stirred at room temperature 24 h under
argon. Upon completion, the reaction was quenched with a saturated solution of
NaHCO3. The organic layer was then diluted with CH2Cl2 and was washed with
water and brine. The combined organic layer was dried over Na2SO4. Filtration
and evaporation of the solvent provided the crude product, which was purified
by column chromatography (ethyl acetate), and evaporation of solvent in vacuo
17
afforded a white solid 10 (100 mg, 63%), mp 68–70 ꢁC. ½aꢃ546 ¼ ꢀ43:6 (1.15, acet-
1
one); H NMR (300 MHz, d6-acetone, ppm) d 9.71 (bs, 1H), 8.81–8.84 (m, 1H),
8.70–8.72 (m, 1H), 8.34 (s, 2H), 7.98–8.10 (m, 1H), 7.74 (s, 1H), 7.48–7.51 (m,
1H), 4.50–4.63 (m, 1H), 3.45–4.16 (m, 4H), 3.42 (bs, 1H), 1.91–2.40 (m, 4H);
19F NMR (280 MHz, acetone-d6, ppm) d 63.82; 13C NMR: (100 MHz, acetone-d6,
ppm) d 181.7, 169.0, 151.2, 148.6, 142.2, 135.1, 131.5, 123.8, 123.4, 122.9, 116.9,
57.3, 50.4, 46.9, 25.0, 24.8; HRMS (EI) 476.1106 (C20H18F6N4OS requires
476.1106).
Reduction of Benzil Using 10
In a flask with a stirring bar, Na2CO3 (30 mg, 0.30 mmol), Na2S2O4 (50 mg,
0.30 mmol), and a catalytic amount of 10 (5 mg, 0.0075 mmol) were dissolved in
water (1.0 ml). Subsequently, a solution of the benzil (30 mg, 0.15 mmol) in acetoni-
trile (2 ml) was added via syringe under argon. The resulting solution was vigorously
stirred in a closed vessel over 72 h at 50 ꢁC. The reaction mixture was distilled with
distilled water and extracted with ethyl acetate. The combined organic layer was
dried over Na2SO4. Filtration and evaporation of the solvent provided the crude
product, which was purified by column chromatography (petroleum ether and ethyl
acetate), and removing the solvent in vacuo afforded benzoin (10 mg, 31%).
Reduction of Imines 11–13
A solution of imines 11–13 (0.15 mmol) in DCM (2 ml) was treated with the
Hantzsch ester (HEH) (76 mg, 0.30 mmol) and a catalytic amount 8b (8 mg,
0.015 mmol), and the mixture was stirred in a closed vessel 120 h at 60 ꢁC under Ar.
Crystallographic Data
Crystallographic data (excluding structure factors) for the structures in this
article have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 736779. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: þ44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).

NADH ANALOG BASED ON PROLINE TEMPLATE
2523
ACKNOWLEDGMENT
This work was supported by Nordforsk via the Nordic-Baltic Network in
Crystal Engineering and Supramolecular Materials.
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