Design of new axially chiral NADH mimics. Mechanistic investigation of the enantioselective hydride transfer

Article abstract of DOI:10.1016/S0040-4039(01)00805-X

This paper reports the design of a new axially chiral NADH model which relies on the configurational control around the C3-C=O chiral axis by means of a chiral relay installed on the cyclic structure. The conformational and configurational control of the

Full text of DOI:10.1016/S0040-4039(01)00805-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4613–4616
Design of new axially chiral NADH mimics. Mechanistic
investigation of the enantioselective hydride transfer
Jean-Luc Vasse, Georges Dupas, Jack Duflos, Guy Que´guiner, Jean Bourguignon and
Vincent Levacher*
Laboratoire de Chimie Organique Fine et He´te´rocyclique associe´ au CNRS, IRCOF-INSA,
rue Tenie`res B.P 08 F-76131 Mont Saint Aignan Cedex, France
Received 29 March 2001; accepted 15 May 2001
Abstract—This paper reports the design of a new axially chiral NADH model which relies on the configurational control around
the C3-CꢀO chiral axis by means of a chiral relay installed on the cyclic structure. The conformational and configurational control
of the lactam moiety was successfully achieved affording two conformational diastereoisomers (aS,S)-1 and (aR,S)-1 in a ratio of
95:5, respectively. Reduction of methyl benzoylformate with model 1 afforded (R)-methyl mandelate in up to 84% e.e. The
stereoselective synthesis of 4-deuterated model 1 allowed us to establish that this enantioselective reduction arises from the
migration of the syn-oriented hydrogen with regard to the carbonyl dipole. © 2001 Elsevier Science Ltd. All rights reserved.
It has been suggested for some time that the stereo-
specificity of the NADH coenzyme would originate partly
from the conformation adopted by the nicotinamide
moiety. In particular it has been demonstrated from X-ray
and NMR analyses of dehydrogenases with bond NADH
that a trans-conformation of the nicotinamide amide and
an out-of-plane orientation of carbonyl amide with
respect to the dihydropyridine ring is adopted in many
cases.1 This conformer was proposed as the active
conformation of the coenzyme during a reduction reac-
tion; the hydrogen to be transferred being syn-oriented
(Fig. 1). An out-of-plane CꢀO amide orientation gives rise
to a configurational element, namely, a chiral axis which
may have important implications in the stereospecific
hydrogen transfer. Many chiral models based on an
out-of-plane orientation of the CꢀO amide have been
reported to evaluate the role of this configurational
element on the stereoselectivity of hydride transfer.2
With a view to mimic this configurational feature, we wish
to report herein a new biomimetic chiral NADH model
1 bearing a chiral linking bridge to ensure both confor-
mational and configurational control of the resulting
lactam (Fig. 1).3
Substrate
Substrate
H
Hsyn
O
Hsyn
H
O
N
O
N
H
R1
Hsyn
O
H
H
MeO
MeO
4
N
R1
R1
R2
3
2
NH2
*
N
N
N
N
*
1
R2
Stabilisation
Configurational
control around the
C3-C=0 bond
by incorporation of a
stereogenic center
Conformational
control of the
carboxamide
Active conformation
of the coenzyme
Stereocontrol
Model 1: R1=i-Pr ; R2=Me
via ring closure
Figure 1. Biomimetic design of a new axially chiral NADH model based on conformational and configurational control of
atropisomeric lactam by means of a chiral linking bridge.
Keywords: NADH; atropisomeric lactam; asymmetric reduction; mechanism.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00805-X

4614
J.-L. Vasse et al. / Tetrahedron Letters 42 (2001) 4613–4616
(aR,S)-1 and (aS,S)-1. As shown in Fig. 2, interconver-
Staggered conformation
Eclipsed conformation
sion between both diastereomeric atropisomers (aR,S)-
1 and (aS,S)-1, sets the substituent at the chiral centre
(R2) either in an eclipsed or staggered conformation
with respect to the neighbouring N-R1 substituent.
According to this conformational analysis, we planned
to control this conformational equilibrium in favour of
the staggered conformation in consequence of steric
interactions between R1 and R2 encountered in the
eclipsed conformation. As a result of the isopropyl
steric hindrance, molecular modelling4 indicates that
model 1 (R1=i-Pr and R2=Me) would be a good
candidate to control this equilibrium in favour of
(aS,S)-1.
O
O
Hsyn
Hsyn
H
H
R1
R1
N
N
aR
aS
R2
H
R2
H
s
S
N
N
Model (aR,S)-1
Model (aS,S)-1
Figure 2. Conformational and configurational analysis of
model 1.
The conformational control of the carboxamide would
be ensured by the cyclic structure of the seven-mem-
bered lactam to maintain a trans-conformation of the
CꢀO amide. Molecular modelling of such seven-mem-
bered ring revealed that the dihydropyridine ring and
the CꢀO lactam display a dihedral angle of about 45°.
The flipping of the lactam ring induces the configura-
tional inversion at the C3–CꢀO conformational chiral
axis. The configurational control of this chiral axis is
based on the incorporation of a second chiral element
on the lactam moiety, to promote a dynamic resolution
process of a pair of conformational diastereoisomers
Model 1 was prepared according to a Friedlander strat-
egy between benzazepin-3,5-dione 6 and amino amine
75 as shown in Scheme 1. The required benzazepin-3,5-
dione 6 was obtained in 5 steps from (S)-h-methyl-
benzylamine in an overall yield of 20%. Upon treatment
of (S)-h-methylbenzylamine with acetone, the interme-
diate imine was subsequently reduced with sodium
borohydride to yield the desired amine 2 in 65% yield.
Condensation of acid chloride 3 afforded b-amide ester
4 in 79% yield. After hydrolysis of the b-amide ester 4,
the resulting b-amide acid 5 was treated with oxalyl
O
O
O
NH2
Me
N
HN
R
N
d
Me
a
b
Me
Me
O
65%
38%
79%
2
4: R=OEt
5: R=OH
6
96%
c
O
MeO
MeO
Tol
H H
O
N
MeO
MeO
N
MeO
MeO
N
g
e
NH2
Me
Me
99%
N
81%
7
N
95%
8
9
Model 1
f
Scheme 1. Synthesis of axially chiral model 1. Reagents and conditions: (a) acetone/reflux then NaBH4/MeOH/rt/2 h; (b) 3:
EtOOCCH2COCl/CH2Cl2/NEt3/rt/12 h; (c) KOH/EtOH/0°C/5 h; (d) (COCl)2/CH2Cl2/o DMF/rt then AlCl3/1 h/rt; (e) EtOH/few
drops of piperidine/reflux/12 h; (f) MeOTf (1.1 equiv.)/CH2Cl2/rt/2 h; (g) NaBH4 (1.5 equiv.)/EtOH/rt/2 h.
Figure 3. (a) Identification of the most stable atropisomer (aS,S)-1 by NOESY experiment; (b) molecular modelling (MM2,
PCMODEL version 7).

J.-L. Vasse et al. / Tetrahedron Letters 42 (2001) 4613–4616
4615
chloride to furnish the corresponding acid chloride.
Friedel–Craft cyclisation supplied the desired ben-
zazepin-3,5-dione 6 in 38% yield.6 The Friedlander con-
densation (Borsche modification)7 of 6 with the amino
imine 7 occurred smoothly under mild conditions to
provide the required benzazepino[4,5-b]quinolin-3-one
8 in 81% yield. After quaternisation with methyl tri-
fluoromethanesulfonate, the resulting quinolinium salt
9 obtained in 95% yield was involved in the regioselec-
tive reduction. Under classical conditions, namely, by
using sodium dithionite and sodium carbonate,8 model
1 was obtained along with substantial amount of
unidentified by-product. Contrary to all expectations,9
it later emerged that the use of sodium borohydride
resulted in regioselective reduction leading to model 110
in quantitative yield (Scheme 1).
An additional NOE was observed between the methyl
at the stereogenic centre and one of both diastereotopic
hydrogen at C-4 which confirms the occurrence of
(aS,S)-1 and more interestingly, allows to assign Hsyn
and Hanti with respect to the CꢀO lactam (Fig. 3).
This former information prompted us to investigate the
diastereoselective reduction of the quinolinium salt 9
with NaBD4 with intent to gain afterwards an experi-
mental evidence that the transferred hydrogen would be
syn-oriented with respect to the CꢀO lactam. Interest-
ingly, reduction of 9 with NaBD4 afforded in a quanti-
tative yield (4R)-1-d1 in 95% d.e. The high level of
diastereoselectivity and the sense of induced stereoselec-
tivity may be attributable to the out-of-plane orienta-
tion of the CꢀO lactam, which would exert a steric
control to favour attack of the deuteride equivalent on
the opposite face of quinolinium salt 9 (Scheme 2).
1
The H NMR spectrum of model 1 revealed the pres-
ence of both diastereomeric atropisomers (aS,S)-1 and
(aR,S)-1 in a ratio of 95:5 respectively. As it had been
anticipated from molecular modelling, undesirable
eclipsing interactions in (aR,S)-1 result in the flipping
of the lactam ring, the methyl at the chiral centre being
oriented away from the isopropyl substituent in the
resulting isomer (aS,S)-1. The stereochemistry of the
major conformational isomer (aS,S)-1 was assigned by
a NOESY NMR experiment as indicated in Fig. 3, i.e.
the NOE between the hydrogen at the stereogenic cen-
tre and the hydrogen at the N-isopropyl substituent.
With model (4R)-1-d1 in hand, we tested the reduction
of methyl benzoylformate in acetonitrile in the presence
of magnesium perchlorate. As shown in Scheme 3,
deuterated model (4R)-1-d1 afforded (R)-methyl man-
delate in up to 84% e.e. with no deuteride incorpora-
tion. The resulting quinolinium salt 9-d1 was recovered
in good yield and high deuterium content (Scheme 3).10
Although these results sustain the hypothesis that the
syn orientated hydrogen in model 1 would be preferen-
tially transferred, the observed migration of Hsyn with
model (4R)-1-d1 may be ascribed to an isotope effect as
well. To ascertain that the Hsyn transfer observed does
not originate from an isotope effect, we undertook the
diastereoselective reduction of 9-d1 with NaBH4 afford-
ing (4S)-1-d1 in up to 95% d.e. The reduction of methyl
benzoylformate with (4S)-1-d1 provided (R)-d1-methyl
mandelate in up to 84% e.e. and high deuterium con-
tent. This former experiment confirms that with model
(4S)-1-d1 the effective stereodifferentiation of the
diastereotopic C-4 hydrogens overrides an eventual iso-
tope effect. To the best of our knowledge, we report
herein the first experimental evidence which clearly
establishes the preferential transfer of H-4 syn over H-4
anti, with regard to the carbonyl dipole.11
"D-"
O
O
H
Hsyn
D
i-Pr
i-Pr
N
N
aS
(a)
aS
H
Me
H
Me
S
98%
S
N
+
N
TfO-
9
(4R)-1-d1
d.e.>95%
Scheme 2. Diastereoselective reduction of quinolinium salt 9
with NaBD4. Reagents and conditions: (a) NaBD4/EtOD/rt/
2 h.
Scheme 3. Asymmetric reduction of methyl benzoylformate with (4R)-1-d1 and (4S)-1-d1.

4616
J. -L. Vasse et al. / Tetrahedron Letters 42 (2001) 4613–4616
1989, 54, 1313–1320; (b) Buck, H. M. Recl. Trav. Chim.
-
(ClO4
)
-
(ClO4
)
OMe
O
Mg2+
Pays-Bas 1996, 115, 329–332; (c) Mikita, Y.; Hayashi,
K.; Mizukami, K.; Matsumoto, S.; Yano, S.; Yamazaki,
N.; Ohno, A. Tetrahedron Lett. 2000, 41, 1035–1038; (d)
Vekemans, J. A. J. M.; Boogers, J. A. F.; Buck, H. M. J.
Org. Chem. 1991, 56, 10–16; (e) Ohno, A.; Kashiwagi,
M.; Ishihara, Y. Tetrahedron 1986, 42, 961–973; (f) Ohno,
A.; Tsutsumi, A.; Kawai, Y.; Yamazaki, N.; Mikita, Y.;
Okamura, M. J. Am. Chem. Soc. 1994, 116, 8133–8137;
(g) Ohno, A.; Tsutsumi, A.; Yamazaki, N.; Okamura,
M.; Mikita, Y.; Fujii, M. Bull. Chem. Soc. Jpn. 1996, 69,
1679–1685.
O
(S)
N
O
Hsyn
H
Me
H
OMe
OMe
N
Figure 4. Proposed ternary complex model 1/Mg(ClO4)2/sub-
strate.
3. Simple NADH models are sensitive to electrophilic addi-
tion at the 5,6-double bond of the dihydropyridine ring.
To circumvent this problem we undertook the synthesis
of quinoline-type NADH models, less sensitive to side-
reactions. For previous work related to stable annelated
NADH models, see: (a) Dupas, G.; Levacher, V.; Bour-
guignon, J.; Que´guiner, G. Heterocycles 1994, 39, 405–
429; (b) Levacher, V.; Dupas, G.; Que´guiner, G.;
Bourguignon, J. Trends Heterocyclic Chem. 1995, 4, 293–
302; (c) Vitry, C.; Vasse, J.-L.; Dupas, G.; Levacher, V.;
Que´guiner, G.; Bourguignon, J. Tetrahedron 2001, 57,
3087–3098.
It is assumed that in the presence of magnesium per-
chlorate, the reduction takes place via the establishment
of a ternary complex (model/Mg2+/methyl benzoylfor-
mate). The transition state depicted in Fig. 4 is a
working hypothesis to account for the obtained
stereoinformation, namely, the preferential syn-oriented
hydrogen transfer and the formation of (R)-methyl
mandelate. The high degree of stereocontrol of this
reduction process suggests that an out-of-plane orienta-
tion of the CꢀO lactam provides a configurational
element enable to stereodifferenciate the two
diastereotopic hydrogens at C-4 and to stereodiscrimi-
nate both enantiotopic faces of methyl benzoylformate.
Consequently, this work strongly supports the hypothe-
sis that the stereospecific transfer of one of the
diastereotopic C-4 hydrogens of the coenzyme to a
prochiral substrate may originate from the configura-
tional control of this non permanent axial chirality
around C3-CꢀO bond upon complexation with
dehydrogenases.
4. The eclipsed conformation (aR,S)-1 was shown to be 3
kcal/mol less stable than the staggered conformation
(aS,S)-1 by MM2 calculations.
5. Porter, H. K. The Zinin reduction of nitroarenes. Org.
React. 1973, 20, 455–481.
6. For similar intramolecular Friedel–Craft acylations, see:
(a) Mamouni, A.; Da¨ıch, A.; Decroix, B. J. Heterocyclic
Chem. 1996, 33, 1251; (b) Da¨ıch, A.; Decroix, B. J.
Heterocyclic Chem. 1996, 33, 873.
7. (a) Borsche, W.; Ried, W. Liebigs Ann. Chem. 1943, 554,
269; (b) Borsche, W.; Barthenheier, J. Liebigs Ann. Chem.
1941, 548, 50.
References
8. Blankenhorm, G.; Moore, E. G. J. Am. Chem. Soc. 1980,
102, 1092.
9. Reduction of quinolinium salts with NaBH4 usually pro-
duces the corresponding dihydroquinolines as a mixture
of 1,2- and 1,4-regioisomers.
1. (a) Ecklund, H.; Samama, J. P.; Jones, T. A. Biochem-
istry 1984, 23, 5982; (b) Skarzynski, T.; Moody, P. C. E.;
Wonacott, A. J. J. Mol. Biol. 1987, 193, 171; (c)
8
Almarsson, O.; Bruice, T. C. J. Am. Chem. Soc. 1993,
10. 1H NMR data (CDCl3, 200 MHz, 20°C): Model (aS,S)-1
l 1.02 (3H, d, J=6.8 Hz), 1.26 (3H, d, J=7.2 Hz), 1.66
(3H, d, J=7.1 Hz), 3.12 (3H, s), 3.50 (1H, d, J=18.5
Hz), 3.87 (3H, s), 3.91 (3H, s), 4.30 (1H, d, J=18.5 Hz),
4.54 (1H, q, J=7.2 Hz), 5.11 (1H, hept, J=6.8 Hz), 6.56
(1H, s), 6.67 (1H, s), 7.15–7.40 (4H, m). Deuterated
quinolinium salt (aS,S)-9-d1 l 1.17 (3H, d, J=6.5 Hz),
1.27 (3H, d, J=7.0 Hz), 1.33 (3H, d, J=7.0 Hz), 4.07
(3H, s), 4.35 (3H, s), 4.64 (3H, s), 4.76 (1H, q, J=7.5
Hz), 5.11 (1H, hept, J=7.0 Hz), 7.37 (1H, s), 7.45–7.70
(4H, m), 7.86 (1H, s).
115, 2125–2138; (d) Wu, Y.-D.; Houk, K. N.; J. Org.
Chem. 1993, 58, 2043-2045. The trans and cis assignments
are related to the orientation of the CꢀO carboxamide
with respect to C-2 as depicted below:
.
2. (a) De Kok, P. M. T.; Bastiaansen, L. A. M.; van Lier, P.
M.; Vekemans, J. A. J. M.; Buck, H. M. J. Org. Chem.
11. Obika, S.; Nishiyama, T.; Tatematsu, S.; Miyashita, K.;
Imanishi, T. Tetrahedron 1997, 53, 3073–3082.
.