N-methyl-(R)-3-(tert-butyl)-sulfinyl-1,4-dihydropyridine: A novel NADH model compound

Article abstract of DOI:10.3390/12030415

We have synthesized a novel chiral NADH model compound, N-methyl-(R)-3-(tert-butyl)-sulphinyl-1,4-dihydropyridine with high enantioselectivity and used it in the reduction of methyl benzoylformate, producing (S)-methyl mandelate in 95% ee. The absolute st

Full text of DOI:10.3390/12030415

Molecules 2007, 12, 415-422
molecules
ISSN 1420-3049
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Full Paper
N-Methyl-(R)-3-(tert-Butyl)-Sulfinyl-1,4-Dihydropyridine: A
Novel NADH Model Compound
Kun Xie 1, You-Cheng Liu 1,2,*, Yi Cui 1, Jian-Ge Wang 3, Yao Fu 1 and Thomas C.W. Mak 4
1
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026,
P.R. China; E-mails: wilma@mail.ustc.edu.cn, vinsonyi@mail.ustc.edu.cn, fuyao@ustc.edu.cn
2
College of Chemistry, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
3
Department of Chemistry, Luoyang Normal University, Luoyang, Henan, 471022, P.R. China; E-
mail: wang_jiange@126.com
4
Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong
Kong SAR, P.R. China; E-mail: tcwmak@cuhk.edu.hk
* Author to whom correspondence should be addressed; E-mail: ycliu@ustc.edu.cn,
Received: 25 February 2007; in revised form: 7 March 2007 / Accepted: 7 March 2007 /
Published: 12 March 2007
Abstract: We have synthesized a novel chiral NADH model compound, N-methyl-(R)-3-
(tert-butyl)-sulphinyl-1,4-dihydropyridine with high enantioselectivity and used it in the
reduction of methyl benzoylformate, producing (S)-methyl mandelate in 95% ee. The
absolute structure of its precursor, 3-(tert-butyl)sulfinyl pyridine, was determined by X-
ray analysis.
Keywords: NADH model compound, chiral, sulfoxide, dihydropyridine, synthesis.
Introduction
Since Ohno and coworkers reported the first example of asymmetric reduction of ketones with a
coenzyme NADH model compound in 1975 [1], numerous efforts have been made to construct other
models mimicking such asymmetric reduction [2]. Most of the model compounds reported consist of 3-
carbonylated (e.g. amide or ester) 1,4-dihydropyridines with a chiral group attached far from the C(4)
reaction center, which often result in products of relatively low optical purity [3]. Model compounds

Molecules 2007, 12
416
possessing a sulfinyl group as a chiral inducer, on the other hand, have proved to be highly efficient,
allowing for the asymmetric reduction of various prochiral substrates with a high level of
stereospecificity [4-6]. To the best of our knowledge, thus far only three such chiral sulfoxides have
been reported as coenzyme NADH models (Figure 1).
Figure 1. The structures of three chiral sulfoxide coenzyme NADH model compouds.
O
S
O
S
O
S
H
H
H
H
H
H
R
R
Tol
Tol
Tol
N
R
N
Me
N
R = CH2Ph, n-Pr, Me
R=H or OMe
Me
Me
The precursor used to make these three chiral sulfoxides is (S)-menthyl-p-toluenesulfinate,
synthesized from p-toluenesufonyl chloride and (−)-menthol in 4 steps (Scheme 1) [7].
Scheme 1. Preparation of (S)-menthyl-p-toluenesulfinate.
O
S
O
S
Zn, Na2CO3
H3C
H3C
O−Na+
H3C
Cl
O
O
S
SOCl2/benzene
0 oC
Cl
(−)menthol/pyridine/
ether, room temp.
O
S
H3C
O
menthyl
crystallization
from acetone/HCl
O
−20 oC
S
O
p-tolyl
(S)-menthyl-p-toluenesulfinate
The total yield of the reaction sequence was rather low. Besides, the chiral auxiliary is fixed to be
the p-tolylsufinyl group. In the present investigation, we have designed a novel chiral NADH model,
which possesses a tert-butylsulfinyl group at the C(3) position in place of the traditional p-tolylsufinyl
group. The tert-butylsulfinyl moiety has proven to be a good chiral auxiliary, which has found
extensive use both in academics and industry [8]. It is well known that the tert-butyl group has a large
steric hindrance and consequently the C(4) prochiral hydrogen atoms in the dihydropyridine nucleus
are expected to be diastereomerically distinguished by the neighboring chiral tert-butylsulfinyl group
and the formal hydride transfer from the model compound to the carbonyl substrate should be highly
enantioselective. Herein we wish to report the synthesis of the novel chiral NADH model compound:

Molecules 2007, 12
417
N-methyl-(R)-3-(tert-butyl)-sulfinyl-1,4-dihydropyridine and its use in the asymmetric reduction of
methyl benzoylformate.
Results and Discussion
The synthesis of N-methyl-(R)-3-(tert-butyl)-sulfinyl-1,4-dihydropyridine can be represented by
the following scheme (Scheme 2).
Scheme 2. Asymmetric synthesis of N-methyl-(R)-3-(tert-butyl)-sulphinyl-1,4-dihydropyridine.
H
N
HO
H
N
i. SOCl2, Et3N,
THF, -78 oC
N
O
S
MeO
O
MeO
ii. t-BuMgCl
N
(-)-Quinine
(Rs)-1
O
S
iii. 3-PyMgBr
N
(Rs)-2 >99%ee
O
H
H
iv. CH3I, CHCl3
v. PNAH, MeOH
S
N
Me
(Rs)-3
The first goal of the synthesis was to find a good sulfinyl transfer reagent for preparing optical pure
R-tert-butanesulfinate. After reviewing the literature, we adopted a reported method [9] for the
preparation of a quinine derivative of tert-butanesulfinate. The experiment must be carried out in the
complete absence of oxygen and water, and the tert-butyl magnesium chloride (1.0M in THF) must be
freshly prepared.
Secondly, the displacement of the quinine auxiliary with the 3-pyridyl group was examined.
Following the literature [10], 3-pyridylmagnesium bromide was prepared. In order to maintain the
enantiomeric purity of the sulfinyl group, we cooled the 3-pyridylmagnesium bromide to -78°C and
tert-butylsulfinate added to it. To our surprise, the anticipated product was not obtained. However,
when the reaction was carried out at room temperature, 3-(tert-butyl)sulfinyl pyridine (2) was
obtained. By decreasing the concentration of reactants in the reaction mixture, the stereoselectivity of
the reaction could be increased from 88% ee to >99% ee. The stereochemistry of 2 was fully
determined by X-ray crystallographic analysis, and the absolute configuration of the molecular
skeleton was unambiguously established to be R (Figure 2) with a Fleck parameter of 0.09(8).

Molecules 2007, 12
Figure 2. ORTEP atoms labeled and drawn as 30% thermal ellipsoids for compound 2.
418
In the following step, the quaternization of compound 2 met with some difficulties. When the
reaction of 2 with benzyl bromide was carried out at 60 °C overnight according to the literature [4b],
the conversion was only about 50%. After continued heating for 2 days, the result was still
unsatisfactory. When compound 2 was heated in a toluene bath at 60 °C for two days for comparison,
the enantiomeric excess of compound 2 decreased from >99% to 90% and some byproducts were
obtained. We then tried to react compound 2 with methyl triflate according to the known method [6],
and the reaction was monitored by TLC analysis. After reaction for 30 min, nearly 100% conversion
was achieved, but the product was not the expected one, as its 1H-NMR spectrum showed no signal for
the tert-butyl group. Finally, we succeeded in quaternization of compound 2 by reaction with excess
methyl iodide at room temperature for 48 h. The product was used for further reaction after
evaporation under reduced pressure without additional purification.
Initial attempts to reduce the quarternary pyridinium salt by the usual method with
Na2S2O4/Na2CO3 [11] failed. The reaction mixture obtained was quite complex and it was difficult to
separate the product. We then tried to use N-benzyl-1,4-dihydronicotinamide (BNAH) and N-propyl-
1,4-dihydronicotinamide (PNAH) as the reducing reagent and obtained the desired product in moderate
yields. The latter gave a more satisfactory yield (80%) of N-methyl-(Rs)-3-(tert-butyl)-sulfinyl-1,4-
dihydropyridine (3) than the former route (yield 50%).
The enantioselectivity of compound 3 was assessed by the reduction of methyl benzoylformate
(Scheme 3). For comparison with the known models bearing a chiral sulfinyl group at C(3), model
compound 3 was tested under standard conditions, i.e. in the presence of magnesium perchlorate in
acetonitrile [4a, 6 ]. Under these conditions, (S)-methyl mandelate was obtained in 80% yield and
>95% ee, indicating that compound 3 was an efficient model of coenzyme NADH.
Scheme 3. Asymmetric reduction of methyl benzoylformate with model (Rs)-3.
O
HO
Ph
H
(Rs)-3
CO2Me
Ph
CO2Me
Mg(ClO4)2
MeCN
S >95% ee

Molecules 2007, 12
Experimental
General
419
Unless otherwise specified, all reagents were obtained from commercial sources and used without
further purification. THF was distilled from benzophenone/Na. Reactions were carried out under dry
Ar. tert-Butyl magnesium chloride (1M in THF) and iso-propyl magnesium chloride (2M in THF)
1
were purchased from Aldrich. Anhydrous quinine and 3-bromopyridine were supplied by ABCR. H-
13
NMR and C-NMR were recorded on Bruker AC-300 FT (1H: 300 MHz, 13C: 75.46 MHz) or Bruker
AV-400FT (1H: 400 MHz, 13C: 100 MHz) instruments using TMS as internal reference. The chemical
shifts (δ) and coupling constants (J) were expressed in ppm and Hz respectively. IR spectra were
recorded on a Perkin-Elmer, 2000FTIR, and [α]D on WZZ-2 polarimeter. Chiral HPLC was performed
on Waters 600E series instrument equipped with a 2487 dual absorbance UV detector. Chiralcel OD-H
and Chiralcel OB-H columns were purchased from Daicel Chemical Industries. High-resolution mass
spectra (HRMS) were determined on a Micromass GCT-MS mass spectrometer. Melting points were
measured on X-4 digital microscope melting point apparatus of Beijing Tech Instrument Co., Ltd.
3-(tert-Butyl) sulfinyl pyridine (2)
The quinine derivative of tert-butanesulfinate (Rs)-1 was prepared in 80% yield according to the
literature [9]. Bromine-magnesium exchange of 3-bromopyridine was achieved by a reported method
[10], except that the volume of the solvent (THF) was increased five-fold. iPrMgCl (10 mmol) was
added to 3-bromopyridine (0.96 mL, 10 mmol) in THF (50 mL) at room temperature. After stirring for
1 h, the solution of 1 (1M, 5 mmol) was added. The reaction mixture was stirred at ambient
temperature for 18 hours and then quenched with saturated aqueous NH4Cl solution. Extraction with
EtOAc (3 x 30 mL), drying over Na2SO4 and column chromatography on silica gel (eluent: EtOAc-
petrolum ether = 4:1) gave (Rs)-2 as a light yellow solid in 75% yield (>99% ee), which was
recrystallized from EtOAc-petroleum ether to give colorless needles, mp 92 °C; [α]22D +109.7o (c=
0.012, CHCl3); IR (KBr): 3038, 1571, 1039 cm-1; 1H-NMR (CDCl3, 300 MHz) δΗ (ppm): 1.19 (9H, s),
7.47 (dd, J = 4.9 and 7.9 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H,), 8.71 (2H, m); 13C-NMR (CDCl3, 75 MHz)
δC(ppm): 22.71 (CH3), 56.38 (C), 123.738 (CH), 134.063 (CH), 136.971 (C-S), 147.618 (CH), 152.124
(CH); Anal. Calcd. for C9H13NOS: C.58.98, H. 7.149, N. 7.642. Found: C. 59.01, H. 7.066, N. 7.30.
Figure 3. Resolution of compound 2 by HPLC with OB-H chiral stationary phase.
Retention Time
10.166
Area
Area%
99.67
0.33
Height
3988266
18897
134925083
443812
12.142

Molecules 2007, 12
420
Enantiomeric excess was determined by HPLC analysis (Figure 3) using a Chiracel OB-H column
(0.46 cm Φ x 25 cm; 10 µm particle size). Chromatographic conditions: injection: 10 µL; eluent:
hexane-2-propanol=70: 30; flow rate: 0.5 mLmin-1; temperature: 25 °C; UV detection: λ = 254 nm; tR
= 10.166 min [(R)-enantiomer] and 12.142 min [(S)-enantiomer].
X-ray crystal structure determination of compound 2
A colorless platelet crystal of 2 with approximate dimensions of 0.40 x 0.19 x 0.11 mm, mounted
on a fiberglass, was used for the X-ray study. All measurements were made on a Bruker Apex II CCD
area diffractometer with graphite monochromated Mo-Kα radiation. The structure was solved by direct
methods (SHELXS-97) and expanded using Fourier techniques (SHELXL-97). The nonhydrogen
atoms were refined anisotropically. H atoms were treated as riding, with C-H = 0.93 Å and with
Uiso(H) = 1.2Ueq(C,). The final cycle of full-matrix least-squares refinement was based on 1863
observed reflections and 113 variable parameters and converged with unweighted and weighted
agreement factors of R = 0.0292 and Rw = 0.0631. Crystal data: C9H13NOS, M = 183.26, crystal
system: orthorhombic, space group: P212121 (#19). Lattice parameters: a = 6.2116(9) Å, b = 6.2116(9)
Å, c = 16.310(2) Å, V = 1007.0(2) Å3, Z = 4, Dcalc = 1.209 Mg/m3. CCDC-630911 contains the
supplementary crystallographic data for this complex. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
(Rs)-1-Methyl-3-(tert-butyl)-sulfinyl-1,4-dihydropyridine (3)
A solution of 2 (100 mg, 0.55 mmol) and methyl iodide (0.1 mL, 1.65 mmol) in CHCl3 (4 mL) was
stirred in the dark at room temperature for 48 h. Removal of solvent and unreacted CH3I using a rotary
evaporator gave crude (Rs)-1-methyl-3-(tert-butylsulfinyl)pyridinium iodide (180 mg). It was treated
with PNAH (125 mg, 0.825 mmol) in methanol (8 mL), and the mixture was stirred under an Ar
atmosphere at room temperature in the dark for 6 h. Removal of solvent and purification by column
chromatography (eluent: EtOAc-petrolum ether-triethylamine = 10:15:2) afforded (Rs)-3 as a light
yellow oil which turned into a white solid after standing at ambient temperature (88 mg, 80% yield).
1
[α]18D +89.29o (c= 0.0014, CHCl3); H-NMR (CDCl3, 400 MHz) δΗ (ppm): 1.24 (s, 9H), 2.92 (s, 3H),
3.06, 3.15 (dm, J = 20 Hz, 2H), 4.58 (m, 1H), 5.69 (dq, J = 7.84 Hz, 1H), 6.32 (d, J = 0.64 Hz, 1H);
13C-NMR (CDCl3, 100 MHz) δC(ppm): 21.177 (CH2), 23.981 (CH3), 40.648 (CH3), 55.978 (C), 99.859
(CH), 105.346 (C), 130.650 (CH), 138.639 (CH); HRMS: 199.1031 (calcd. for C10H17NOS: 199.1031);
Anal. Calcd. for C10H17NOS: C. 60.26; H. 8.597; N. 7.028. Found: C. 60.08; H. 8.561; N. 6.786.
Reduction of methyl benzoylformate with (Rs)-3
Under Ar atmosphere, compound 3 (20 mg, 0.1 mmol), dry MeCN (2 mL), methyl
benzoylformate(14 µL, 0.1 mmol) and Mg(ClO4)2 (22.4 mg, 0.1 mmol) were successively introduced
into the flask. The resulting mixture was stirred at r.t. for 24h in the dark. After evaporation of the
solvent, the residue was purified by chromatography on silica gel (eluent: EtOAc-petrolum ether = 1:5)

Molecules 2007, 12
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to give (S)-methyl mandelate, yield 70%. Enantiomeric excess was determined by HPLC analysis
(Figure 4) using a Chiracel OD-H column (0.46 cm Φ x 25 cm; 10 µm particle size). Chromatographic
conditions: injection: 10 µL; eluent: hexane-2-propanol = 90:10; flow rate: 1 mL min-1; temperature:
25 °C; UV detection: λ= 235 nm; tR = 7.182 min [(S)-enantiomer] and 14.684 min [(R)-enantiomer].
Figure 4. Resolution of methyl mandelate with OD-H chiral stationary phase.
Retention Time
7.182
Area
Area%
97.55 1102298
2.45 16954
Height
19194245
4827771
14.684
Supplementary Material
Supplementary material file: http://www.mdpi.org/molecules/papers/12030415sm.pdf
Acknowledgements
Support from National Natural Science Foundation of China (Grant No. 20072036) and
Specialized Research Fund for the Doctoral Program of Higher Education of China is gratefully
acknowledged.
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Sample Availability: Samples of the compounds are available from the authors.
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