New NADH models bearing a phosphonate or a chiral oxazaphospholidine oxide at the dihydropyridine ring

Article abstract of DOI:10.1016/S0040-4039(01)00027-2

Novel NADH models bearing a phosphonate at the 3-position of a stable 1,4-dihydroquinoline structure were successfully involved in the reduction of methyl benzoylformate. Asymmetric reduction of the former ketone with a NADH model bearing a chiral oxazaphospholidine oxide is reported affording methyl benzoylformate in 45% e.e.

Full text of DOI:10.1016/S0040-4039(01)00027-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1871–1873
New NADH models bearing a phosphonate or a chiral
oxazaphospholidine oxide at the dihydropyridine ring
Jean-Luc Vasse, Sophie Goumain, Vincent Levacher,* Georges Dupas, Guy Que´guiner and
Jean Bourguignon
Laboratoire de Chimie Organique Fine et He´te´rocyclique associe´ au CNRS, IRCOF-INSA, rue Tenie`res BP 08,
F-76131 Mont Saint Aignan Cedex, France
Received 28 November 2000; accepted 5 January 2001
Abstract—Novel NADH models bearing a phosphonate at the 3-position of a stable 1,4-dihydroquinoline structure were
successfully involved in the reduction of methyl benzoylformate. Asymmetric reduction of the former ketone with a NADH model
bearing a chiral oxazaphospholidine oxide is reported affording methyl benzoylformate in 45% e.e. © 2001 Elsevier Science Ltd.
All rights reserved.
The crucial role of NAD(P)H as coenzyme in biological
reductions has stimulated a great deal of interest in the
field of biomimetic organic chemistry.1 Numerous non
chiral and chiral NADH models were studied with a view
to developing new chemoselective and enantioselective
reducing agents. Most of these biomimetic models carry
an amide group at the 3-position of the 1,4-dihydropy-
ridine (model a in Scheme 1). Reduction of a substrate
is generally achieved in the presence of divalent metal
ions (most often Mg2+) which play a fundamental role
in the hydrogen mechanism transfer.2 In the past, NADH
models bearing a sulfinyl group instead of a carbonylated
derivative at the 3-position were described (model b in
Scheme 1).3 In models a or b, the main role of the CꢀO
or SꢀO bond is to stabilize the labile dihydropyridine
structure through their electron withdrawing character.
H
H
X
X
Models a: X=CONR2
Models b: X=SOR
Models c: X=PO(OR)2
O
OH
Mg2+
+
+
R2
R1
R2
R1
N
N
+
Me
Me
Scheme 1.
Tol
+
O
N
O
H H
O
MeO
MeO
P(OEt)2
MeO
MeO
MeO
MeO
P(OEt)2
P(OEt)2
(ii) (iii)
(i)
N
Me
NH2
N
Me
O
Me
Me
Model 3
1
2
OH
COOMe
yield=82%
(iv)
Scheme 2. Reagents and conditions: (i) Piperidine/EtOH/reflux/2.5 h (50%); (ii) MeOTf/CH2Cl2/rt/1 h (100%); (iii) Na2S2O4/
Na2CO3/EtOH (97%); (iv) methyl benzoylformate/Mg(ClO4)2/CH3CN/rt/24 h (82%).
Keywords: biomimetic reduction; coenzyme models; non chiral or chiral phosphonic acid derivatives.
* Corresponding author. Fax: +33 (0) 2 35 52 29 62.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00027-2

1872
J.-L. Vasse et al. / Tetrahedron Letters 42 (2001) 1871–1873
The phosphonate group is able to exhibit electronic
properties similar to CꢀO or SꢀO groups and possesses
a good affinity with magnesium ions which play a
fundamental role in reductions mediated with NADH
models. We wish to report herein the synthesis of a
novel generation of NADH models bearing this type of
substituent at the 3-position of a dihydropyridine ring
(model c in Scheme 1).4
elution order during a chromatographic separation to
those observed for similar compounds of known
configurations.8 Supporting evidence for this assign-
ment may be found from the NOESY spectrum of the
more polar diastereoisomer. It shows an NOE between
the C4(H) and the methyl connected to the phosphorus
atom (Scheme 3). Such a correlation is only consistent
with the isomer (2R,4S)-4. The next steps of this syn-
thesis were accomplished with the diastereoisomer
(2R,4S)-4, the only one which has been isolated prop-
erly in an enantiomerically pure form. Under the basic
conditions used for the formation of 2, Borsche con-
densation with oxazaphospholidine oxide (2R,4S)-4
and imine 1 led exclusively to the formation of tarry
material. To circumvent this problem, Borsche conden-
sation had to be performed under acidic conditions,
affording compound 6 in good yield. Finally, com-
pound 79 was obtained according to a classic route by
quaternization followed by regioselective reduction.
With model 7 in hands, reduction of methyl benzoylfor-
mate gave the corresponding (R)-methyl mandelate in
45% e.e.10
With a view to protecting the 5,6 double bond against
pernicious side reactions and with respect to previous
works in our group,5 we intended to synthesize an
annelated model in the quinoline series. For that pur-
pose, commercially available diethyl(2-oxopropyl)-
phosphonate was condensed with imine 1 derived from
2-amino-4,5-dimethoxybenzaldehyde according to the
Borsche modification of the Friedlander reaction6
affording quinoline 2.7 Quaternization followed by
regioselective 1,4-reduction gave the desired model 38 in
48% overall yield (Scheme 2). The resulting reagent 3
was successfully involved in the reduction of methyl
benzoylformate in the presence of Mg2+ ions providing
the corresponding methyl mandelate in 82% yield
(Scheme 2).
In summary this work describes the first biomimetic
reduction with an NADH model bearing a phosphonic
acid derivative. Although reagent 7 is not as effective as
models a or b in terms of enantioselectivity,11 the use of
an oxazaphospholidine oxide as chiral inductor corre-
sponds to the first asymmetric reduction with a NADH
model based on a chiral phosphorus. In models a or b,
the CꢀO or SꢀO groups seem to play a crucial role in
the stereospecific transfer of the hydride equivalent
mediated by a ternary complex substrate/Mg2+/model.
Studies showed that the transferred hydrogen is syn to
the CꢀO or SꢀO groups, which would adopt an out of
plane orientation with respect to the dihydropyridine
ring.12 The stereoselection of the reduction leading to
(R)-methyl mandelate is probably correlated with the
Given that a phosphonate group linked to a 1,4-dihy-
dropyridine structure is able to mediate a biomimetic
reduction, it was of interest to investigate the potential
of a chiral analog to promote an asymmetric reduction.
We turned our interest in the synthesis of chiral oxaza-
phospholidine oxide derivatives such as 7, readily avail-
able from a chiral aminoalcohol (Scheme 3). According
to a literature procedure,8 condensation of N-benzyl-
(S)-valinol with methyl phosphonic dichloride supplied
the oxazaphospholidine oxide 4 as a diastereoisomeric
mixture (ratio 55:45).9 The absolute configuration at
the phosphorus atom of both diastereoisomers (2S,4S)-
4 and (2R,4S)-4 were established by comparing their
Ph
Ph
Ph
4
O
2
Me
N
Me
O
N
O
HN
HO
(i) (ii)
(iii)
+
P
P
H
H
O
NOE
(2R, 4S)-4
(2S, 4S)-4
Ph
Ph
N
Ph
O
O
H
N
O
H
P
P
MeO
MeO
MeO
O
N
O
(v) (vi)
(iv)
O
P
N
Me
MeO
N
Me
Me
Me
O
5
7
6
OH
COOMe
yield=82%
e.e. =45%(R)
(vii)
Scheme 3. Reagents and conditions: (i) MeP(O)Cl2/NEt3/CH2Cl2; (ii) flash chromatography on silica gel i-PrOH/heptane: 1/9 as
eluent to separate both diastereoisomers (2S,4S)-4 (less polar) and (2R,4S)-4 (more polar); (iii) LDA/AcOEt/THF/−78°C (67%);
(iv) toluene/p-TSA (74%); (v) TfOMe/CH2Cl2/2 h (95%); (vi) Na2S2O4/Na2CO3/EtOH (91%); (vii) methyl benzoylformate/
Mg(ClO4)2/CH3CN/rt/24 h (82%).

J.-L. Vasse et al. / Tetrahedron Letters 42 (2001) 1871–1873
1873
necessary out of plane orientation of the PꢀO bond
owing to the steric hindrance between the oxazaphos-
pholidine structure and the methyl at the 2-position.
The mechanism of the enantioselective hydrogen trans-
fer with model 7 and with other similar models is under
progress.
J=16 Hz, 1H); 7.35 (s, 1H); 7.09 (s, 1H); 4.16 (m, 4H);
4.05 (s, 3H); 4.01 (s, 3H); 2.87 (s, 3H), 1.36 (t, J=7 Hz,
6H). Compound 3: 6.57 (s, 1H); 6.42 (s, 1H); 4.0 (m, 4H);
3.86 (s, 3H); 3.81 (s, 3H); 3.34 (d, J=7 Hz, 2H); 3.26 (s,
3H); 2.38 (s, 3H); 1.26 (t, J=7 Hz, 6H).
8. Katagiri, N.; Yamamoto, M.; Iwaoka, T.; Kaneko, C. J.
Chem. Soc., Chem. Commun. 1991, 1429.
9. Spectral data 1H NMR (CDCl3) compound (2R,4S)-4
(more polar): 7.38–7.19 (m, 5H); 4.32–3.95 (m, 4H); 3.21
(m, 1H); 2.00 (m, 1H); 1.41 (d, J=16 Hz, 3H); 0.93 (d,
J=7 Hz, 3H); 0.75 (d, J=7 Hz, 3H). Compound (2S,4S)-
4 (less polar): 7.52–7.42 (m, 2H); 7.37–7.27 (m, 3H);
4.13–3.81 (m, 4H); 3.03 (m, 1H); 1.80 (m, 1H); 1.40 (d,
J=16 Hz, 3H); 0.78 (d, J=7 Hz, 3H); 0.82 (d, J=7 Hz,
3H). Compound 5: 7.30–7.10 (m, 5H); 4.23–3.85 (m, 4H);
3.30–2.82 (m, 3H); 2.17 (s, 3H); 1.85 (m, 1H); 0.80 (d,
J=7 Hz, 3H); 0.64 (d, J=7 Hz, 3H). Compound 6: 8.50
(d, J=16 Hz, 1H); 7.25–6.90 (m, 7H); 4.42–4.05 (m, 4H);
3.96 (s, 3H); 3.90 (s, 3H); 3.55 (m, 1H); 2.62 (s, 3H); 2.20
(m, 1H); 1.00 (d, J=7 Hz, 3H); 0.75 (d, J=7 Hz, 3H).
Compound 7: 7.30 (m, 5H); 6.45 (s, 1H); 6.35 (s, 1H);
4.30–3.85 (m, 4H); 3.80 (s, 3H); 3.75 (s, 3H); 3.45 (m,
1H); 3.20 (m, 1H); 3.15 (s, 3H); 3.05 (m, 1H); 2.35 (s,
3H); 2.02 (m, 1H); 0.95 (d, J=7 Hz, 3H); 0.75 (d, J=7
Hz, 3H).
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were
briefly
described by: Razumov, A. I.; Liober, B. G.; Sokolov, M.
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tiomeric excesses. See the following examples.
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7. Spectral data 1H NMR (CDCl3) compound 2: 8.60 (d,
.