Atropoisomeric quinolinium salt promoting the access to both enantiomeric forms of methyl mandelate: a versatile NADH mimic.

Article abstract of DOI:10.1039/b207434f

Asymmetric reduction of methyl benzoylformate by a new NADH mimic is reported; depending on the hydride source used to reduce the NAD+ precursor, NADH mimics so obtained lead to an inversion of enantioselectivity, affording either (R)-methyl mandelate in

Full text of DOI:10.1039/b207434f

Atropoisomeric quinolinium salt promoting the access to both
enantiomeric forms of methyl mandelate: a versatile NADH mimic†
Jean-Luc Vasse, Vincent Levacher,* Jean Bourguignon and Georges Dupas
Laboratoire de Chimie Organique Fine et Hétérocyclique, I.R.C.O.F, 1, rue Tesnieres, Mont-Saint-Aignan,
France 76131. E-mail: Vincent.Levacher@insa-rouen.fr
Received (in Cambridge, UK) 30th July 2002, Accepted 28th August 2002
First published as an Advance Article on the web 10th September 2002
Asymmetric reduction of methyl benzoylformate by a new
NADH mimic is reported; depending on the hydride source
used to reduce the NAD+ precursor, NADH mimics so
obtained lead to an inversion of enantioselectivity, affording
either (R)-methyl mandelate in 88% ee or (S)-methyl
mandelate in 78% ee.
transferred to the substrate. In this series of NADH models, a
slow equilibrium between the two conformational diastereo-
isomers occurs. To enhance the reactivity of the pro-(S)-H (H in
model I, Scheme1), the reactivity of the pro-(R)-H (D in model
I, Scheme 1), should be blocked to allow only the transfer of the
pro-(S)-H after conformational interconversion of the seven-
membered ring. This could be achieved by introduction of a
methyl group at C-4 and diastereoselective reduction using an
appropriate hydride source. In this communication, we wish to
report the cis and trans introduction of the hydrogen at C-4 with
respect to the carbonyl group, and the results obtained in the
reduction of the methyl benzoylformate (MBF) using these two
mimics generated from one enantiopure quinolinium salt. (Fig.
2).
The development of versatile chiral systems that are able to
selectively form either enantiomer of a given product is a very
exiting challenge as sometimes only one enantiomer of the
required chiral auxiliary is readily available. In the enzymatic
reductions requiring NAD(P)H, it is known that depending on
the substrate associated with its oxidoreductase enzyme, the
pro-(R) or pro-(S) hydrogen is differentiated and stereospecif-
1
ically transferred to the substrate. It has been suggested that
The synthesis of the quinolinium salt 3 was carried out from
this specificity originated from the trans out-of-plane orienta-
quinoline 14 by addition of methyllithium to yield the
6
tion adopted by the amide function which exhibits the transfer
intermediate 1,4-dihydropyridine. Subsequent NCS oxidation
syn
2
of the H with respect to the carbonyl. Many chiral models
based on an out-of-plane orientation of the CNO amide have
been reported to evaluate the role of this configurational
of the 1,4-dihydropyridine followed by quaternisation of the
resulting quinoline 2 afforded the desired quinolinium salt
(aS,1S)- 3 in 81% overall yield from 1 (Scheme 2).
3
element on the stereochemistry of the hydride transfer. We
3
Reduction of the quinolinium salt 3 with BH ·THF complex
have previously reported this selective syn-hydrogen transfer
afforded NADH model 4 in 95% yield as a single stereoisomer
(d.e. > 95%) assigned as (aS,1S,4R)-4 by a NOESY experiment.
The high level of diastereoselection may be explained by
chelation-control between the lactam and the boron empty-p-
orbital which activates the cis adduct formation (Scheme 3).
The resulting reactive model (aS,1S,4R)-4 bearing the hydride
equivalent syn with respect to the carbonyl function leads to (R)-
methyl mandelate in 52% yield and an enantiomeric excess of
using labelled models I (Scheme 1).4
8
8% (Scheme 3, path A).
As previously reported with model I, trans introduction of
the hydrogen at C-4 was accomplished by NaBH reduction of
4b
4
Scheme 1 Experimental proof of the syn-hydrogen transfer to methyl
benzoylformate using labelled models I. Reagents and conditions: (i)
Mg(ClO ) /CH CN/rt.
4 2 3
quinolinium salt 3 resulting in a mixture of conformational
diastereoisomers (aS,1S,4S)-4 and (aR,1S,4S)-4. This partial
epimerisation of C-3–CNO chiral axis, not observed with model
In such series of models as I, a slow equilibrium between the
two conformational diastereoisomers (aS,S)-I and (aR,S)-I
occurs by flipping of the C-3–CNO chiral axis. This equilibrium
is biased towards (aS,S)-I as consequence of steric repulsions in
(aR,S)-I between the bulky isopropyl chain and the methyl
group (Fig. 1).
5
From the labelled study, we and others have shown that only
the syn-hydrogen with respect to the carbonyl group is
Fig. 1 Equilibrium between the two conformational diastereoisomers
(aS,S)-I and (aR,S)-I.
†
Electronic supplementary information (ESI) available: experimental. See
Fig. 2 Design of a new NAD+ mimic promoting the access to both
http://www.rsc.org/suppdata/cc/b2/b207434f/
enantiomeric forms of methyl mandelate.
2
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+
Scheme 3 Reversal of stereochemistry in the reduction of quinolinium salt 3. Access to (S) or (R)-methyl mandelate from the same NAD mimic 3.
clearly indicated that in (aR,1S,4S)-4, placing the hydride
equivalent syn with respect to the carbonyl lactam is the only
reactive conformation of the model.
To summarize, the control of the axial chirality in the seven-
+
membered fused ring in NAD mimic 3 allowed the ster-
eoselective introduction of a latent (R)-director or (S)-director
hydride equivalent at the C-4 position. The absolute ster-
eochemistry of the product could therefore be controlled by
choice of the appropriate primary hydrogen source. Finally,
these results open the way for further investigations of this class
of NADH models as molecular switches. Indeed, if one could
control the equilibrium between both conformational diaster-
eoisomers (aS,1S,4S)-4 and (aR,1S,4S)-4, in a predictable
manner, it would offer the opportunity to switch-on/off, on
demand, the reducing properties of these biconformational
chiral NADH mimics.
Scheme 2 Reagents and conditions: (i) MeLi/THF/240 °C/2 h; (ii) NCS/
MeOH/rt/1 h; (iii) TfOMe/CH Cl /2 h.
2
2
Notes and references
I, is likely due to steric repulsion between the carbonyl and the
methyl group at C-4 in the initially formed conformational
diastereoisomer (aS,1S,4S)-4. Nevertheless, as the absolute
configuration at C-4 is controlled by a trans introduction of the
hydride,4 the crude mixture was assessed in the reduction of
MBF, leading to (S)-methyl mandelate in 40% yield with an
enantiomeric excess of 78% (Scheme 3, path B). In the
1
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1
2
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4
mechanism depicted in Scheme 3, NaBH -mediated reduction
3
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of NAD+ mimic 3 results initially in the formation of the
unreactive conformer (aS,1S,4S)-4 which undergoes a con-
formational interconversion prior to reducing MBF into (S)-
methyl mandelate. This scenario is supported by a conforma-
tional study of the recovered quinolinium salt 3 by means of
NOESY experiments. In contrast to NADH mimics 4, their
oxidized forms (aS,1S)-3 and (aR,1S)-3 do not interconvert and
4
3
are configurationally stable for many days in CH CN at room
temperature. Consequently, one can consider that the reactive
conformation of mimic 4 is imprinted on the recovered
quinolium salt 3. As expected, reduction of MBF with
5
6
(aS,1S,4R)-4 affords the quinolinium perchlorate salt (aS,1S)-3
(path A), whereas the two conformational diastereoisomers
(aS,1S,4S)-4 and (aR,1S,4S)-4 lead to the exclusive formation of
the conformational diastereoisomer (aR,1S)-3 (path B). This
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