Chiral biomimetic NADH models in the benzo[b]-1,6-naphthyridine series. A novel class of stable, reactive and highly enantioselective NADH mimics

Article abstract of DOI:10.1016/S0040-4020(03)00706-3

The preparation of a new class of tricyclic models 1 based on a Friedl?nder reaction between chiral piperidine-2,4-diones 2 and azomethine 3 is reported. Alkylation of the lactam allowed to install various pendant arms on the chiral cyclic inducer. The so-obtained mimics 1a,d,f,g,h,k were involved in the reduction of methyl benzoylformate to furnish methyl mandelate in 4-87% ee (R). The presence of a coordinating pendant arm proved to be essential to reach optimum results in terms of enantioinduction. Asymmetric reduction of 2-benzoylpyridine with mimics 1d,f,g produced α-phenyl-2-pyridinemethanol in 30-84% ee (R).

Full text of DOI:10.1016/S0040-4020(03)00706-3

Tetrahedron 59 (2003) 4911–4921
Chiral biomimetic NADH models in the
benzo[b]-1,6-naphthyridine series. A novel class of stable,
reactive and highly enantioselective NADH mimics
*
Jean-Luc Vasse, Vincent Levacher, Jean Bourguignon and Georges Dupas
´ ´ ´
Laboratoire de Chimie Organique Fine et Heterocyclique associe au CNRS,
´
IRCOF-INSA. B.P. 08 F-76131 Mont Saint Aignan Cedex, France
Received 4 February 2003; revised 18 March 2003; accepted 18 April 2003
¨
Abstract—The preparation of a new class of tricyclic models 1 based on a Friedlander reaction between chiral piperidine-2,4-diones 2 and
azomethine 3 is reported. Alkylation of the lactam allowed to install various pendant arms on the chiral cyclic inducer. The so-obtained
mimics 1a,d,f,g,h,k were involved in the reduction of methyl benzoylformate to furnish methyl mandelate in 4–87% ee (R). The presence of
a coordinating pendant arm proved to be essential to reach optimum results in terms of enantioinduction. Asymmetric reduction of
2-benzoylpyridine with mimics 1d,f,g produced a-phenyl-2-pyridinemethanol in 30–84% ee (R). q 2003 Elsevier Science Ltd. All rights
reserved.
1. Introduction
stereoselectivities.5 Biomimetic reductions are usually
performed in the presence of magnesium perchlorate. This
metal salt is involved in the formation of a ternary complex
mimic/Mg2þ/substrate activating both partners of the
reduction. A detailed NMR study of these models (II) in
the presence of magnesium perchlorate highlighted the
formation of a chelate between the alcohol chain and the
CvO lactam.5c In our continuous effort to develop this
biomimetic chemistry, we have linked the stability of
annulated models (I) and the good stereoselectivity of
model (II) to report herein the synthesis of a new chiral
NADH quinoline-type models 1 (Fig. 1). Some aspects of
this work have been briefly reported recently.6
Considerable effort has been devoted to elucidating the
stereospecificity of NADH coenzyme in biological
reduction processes. In the past two decades, the design
and synthesis of biomimetic NADH models has largely
contributed to define the role played by the nicotinamide
moiety of the coenzyme in the stereospecificity of biological
redox processes.1 Although some of these models exhibit
high performance in terms of enantioselectivity,2 most of
them did not find application in asymmetric reduction due to
their poor stability. Indeed, simple NADH mimics undergo
numerous parasites reactions which limit seriously the
perspective to regenerate these reagents. To improve
the stability of these reagents we developed, with success,
the synthesis of annulated NADH models (I).3 The second
important aim from the outset of this work was to develop
highly stereoselective NADH models. To this end, various
models (II) bearing aminoalcohols as chiral auxiliaries were
prepared and displayed high stereoselectivities during the
reduction of methyl benzoylformate.4 The chiral cyclic
inducer of models (II) was designed to examine the role of a
syn orientation of the carbonyl moiety on the stereochemical
outcome of biomimetic reductions. Although the good
performances of these models is thought to arise partly from
the syn orientation of the carbonyl group, the presence of the
complexing alcohol function at the exocyclic nitrogen
substituent has been shown to be essential to achieve high
Figure 1. New chiral annulated NADH mimics 1.
2. Results and discussion
2.1. Design of the tricyclic models-type 1
These biomimetic NADH models-type 1 are composed of
three modules. Module A protects the reagent against
electrophilic attacks on the 5,6-enamine double bond,
encountered with simple NADH models (I). As a result of
this protection, the reducing properties of annulated NADH
¨
Keywords: Friedlander reaction; enantioinduction; asymmetric reduction;
biomimetic NADH models.
*
Corresponding author. Tel.: þ33-2-35-52-24-85; fax: þ33-2-35-52-29-
62; e-mail: vincent.levacher@insa-rouen.fr
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00706-3

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J.-L. Vasse et al. / Tetrahedron 59 (2003) 4911–4921
Figure 2. (a) Design of a new tricyclic model 1. (b) Conformational
analysis of the stereocontrolling element (module C).
models are significantly altered. To overcome this side
effect, the electron donating methoxy groups on module A
are expected to restore the reactivity of the reagent. The
active part of the model (module B) is annulated by a second
module C to ensure the stereocontrol of reduction (Fig. 2(a)).
A straightforward conformational analysis prompted us to
install the chirality on the cyclic module C. As a
consequence of strong eclipsing interactions with the
neighboring N-alkyl substituent R2, we anticipated that R1
would adopt a pseudo-axial position (Fig. 2(b)). This
hypothesis is supported by molecular modeling7 and is
consistent with conformational analysis of 2-substituted-
3,4-dihydroisoquinoline-1-ones previously reported in the
literature.8 We reasoned that, in pseudo-axial position, R1
would exert a good stereodifferentiation of both dia-
stereotopic faces of the tricyclic model 1. In addition, the
design of this new chiral cyclic inducer C, offers the
possibility to install various substituents R2 to sharpen
the role of the alcohol function, on the origin of the
stereoselectivity with the previously reported NADH
models II.
Scheme 2. Synthesis of the piperidine-2,4-diones 2. Reagents and
conditions: (a) THF/2788C; (b) H2/Pd(OH)2; (c) ClCOCH2COOEt/NEt3/
CH2Cl2; (d) NaOMe/THF.
7a,b in excellent yields. Dieckmann cyclization furnished
the required chiral piperidine-2,4-diones 2a,b in 70 and
75%, respectively.
In a first attempt to prepare the desired benzo[b]-1,6-
naphthyridines 8a and 8b, piperidine-2,4-diones 2a and 2b
were reacted with 3,4-dimethoxy ortho-aminobenzalde-
hyde.11 Whatever the reaction conditions used, the cycliza-
tion products 8a and 8b were obtained in modest yield
(,20%) along with large amounts of unidentified products.
The major limitation of this procedure lies with the ease at
which ortho-aminobenzaldehydes undergo self-conden-
sation. To circumvent this problem we made use of the
Borsche modification12 employing arylimine 311 instead of
3,4-dimethoxy ortho-aminobenzaldehyde. The main advan-
tage of this procedure is to dispose large amounts of stable
azomethine 3 and to scale up the preparation of 8a and 8b to
a multi-gram scale in good yield. Thus, piperidine-2,4-
diones 2a and 2b reacted with azomethine 3 in the presence
of piperidine in refluxing ethanol to give 8a and 8b in 68 and
78% yields, respectively. Oxidative cleavage of 8a and 8b
in the presence of CAN afforded the corresponding
benzo[b]-1,6-naphthyridines 9a and 9b in 69 and 60%
yield, respectively (Scheme 3).
2.2. Synthesis of the tricyclic models-type 1
¨
Our synthetic approach is based on a Friedlander-type
reaction between piperidine-2,4-diones 2 and Schiff base 3
of the corresponding o-aminobenzaldehyde (Scheme 1).
An examination of the literature relating to the preparation
of piperidine-2,4-diones reveals that asymmetric synthesis
of this class of compounds bearing a stereogenic center at C-
6 has been rarely reported.9 We undertook to develop a
Dieckmann cyclization of compounds 7a,b intermediates,
easily accessible via diastereoselective conjugated addition
of (R)-lithium amide 4 to methyl crotonate or methyl
cinnamate (Fig. 3). Following this strategy, b-amino esters
5a,b are obtained in 69 and 72% yields, respectively, in up
to 95% de in both cases (Scheme 2). According to literature
reports, the absolute configuration of the newly created
stereogenic center was assigned as (S).10 Selective reductive
cleavage of the chiral auxiliary afforded b-aminoesters 6a,b
in 94 and 84% yields which were subsequently condensed
with ethyl malonyl chloride to produce b-(acylamino)esters
Alkylation of lactams 9a and 9b allowed to install a wide
choice of substituents, offering the opportunity to investi-
gate the influence of the N-substituent on the performance
of these models. According to a literature procedure,13
alkylation of lactams 9a,b is performed in DMSO in the
¨
Scheme 1. Retrosynthesis of the tricyclic models-type 1: Friedlander
approach.
Scheme 3. Reagents and conditions: (a) piperidine/EtOH/reflux;
(b) CAN/CH3CN/H2O.

J.-L. Vasse et al. / Tetrahedron 59 (2003) 4911–4921
4913
Table 1. Reagents and conditions: (a) RX/KOH/DMSO; (b) NaOH
Table 2. Reagents and conditions: (a) TfOMe/CH2Cl2; (b) Na2S2O4/Na2-
CO3
Entry
Compound
R2X
PhCH2Br
CH2vCHCH2Br
CH2vCHCH2Br
MeOCH2CH2I
AcO(CH2)3I
Product
Yield (%)
1
2
3
4
5
9a
9a
9b
9a
9a
10a: R1¼Me
10b: R1¼Me
10c: R1¼Ph
10d: R1¼Me
10e: R1¼Me
92
95
97
89
73
Entry
Compound
R2, R1
PhCH2, Me
(CH2)2OMe, Me
(CH2)3OH, Me
(CH2)2OH, Me
(CH2)2OH, Ph
Product
Yielda (%)
1
2
3
4
5
6
10a
10d
10f
10g
10h
10k
1a
1d
1f
1g
1h
1k
95
98
90
81
90
91
(CH2)2PO(OEt)2, Me
a
Overall yield (10!1).
procedure was developed from 10a,d,f,g,h,k, providing
models 1 with comparable overall yields (Table 2).
2.3. Reduction of methyl benzoylformate with NADH
mimics 1a,d,f,g,h,k
Models 1a,d,f,g,h,k were involved in the asymmetric
reduction of methyl benzoylformate in the presence of
magnesium perchlorate in acetonitrile at room temperature.
This metal salt, involved in the formation of a ternary
complex mimic/Mg2þ/substrate, activates both partners of
the reduction. The enantioselectivities observed ranged
from 4 to 87% (R) and in 90% yield in most cases. It is
interesting to note that quinolinium perchlorate salts could
be cleanly recovered and subsequently reduced in high
yield. The so-recycled NADH mimics could be used in a
second reduction process to give methyl mandelate with
comparable yields without erosion of the enantioinduction.
As can be seen from Table 1, the presence of an additional
binding element on the lactam chain (R2) appears to be
crucial to attain high level of asymmetric induction. While
1a afforded methyl mandelate in 4% ee (Table 3, entry 1),
all other models 1d,f,g,h,k, bearing an additional coordinat-
ing site, yielded methyl mandelate in 71–87% ee (Table 3,
entries 2–6). Lastly, comparison of the performance of 1g
and 1h reveals that changing the substituent R1 did not result
in any further improvement in the enantioselection (Table 3,
entries 4 and 5).
Scheme 4. Reagents and conditions: (a) OsO4/THF–H2O/NaIO4 then
NaBH4; (b) TsCl/NEt3/CH2Cl2; (c) NaI/acetone; (d) NaPO(OEt)2/THF.
presence of KOH to give 10a-e in 73–97% yields (Table 1).
Treatment of 10b,c with osmium tetroxide, followed by
reduction of the intermediate aldehyde with sodium
borohydride afforded the corresponding alcohols 10g,h, in
72% yield in both cases (Scheme 4).
The good affinity of the magnesium ion for the phosphonate
function prompted us to incorporate a phosphonate chain.
To this end, treatment of 10g with p-toluenesulphonyl
chloride afforded 10i in 59% yield which was cleanly
converted into the iodo derivative 10j in 80% yield by
treatment with sodium iodide in acetone. Many attempts to
introduce a phosphonate chain by means of Arbuzov
reaction failed, leading in most cases to the starting
material. Alternatively, the phosphonate chain could be
introduced by reacting 10j with diethylphosphite sodium
salt affording 10k, however, with a modest yield of 30%
(Scheme 4).14
2.4. Conformational analysis and mechanistic aspect of
the stereoselective hydrogen transfer
A detailed NMR study throws light on the conformation
adopted by the chiral cyclic inducer. As expe0cted,
measurement of the coupling constants between H-3 and
the two H-40 protons, demonstrated that R1 adopts a pseudo-
axial position in 8a and 8b. The same set of coupling
constants was observed in model 1a, indicating that the
methyl group occupies a pseudo-axial position as well.
Further support for this assignment came from a NOESY
experiment of 8a, showing a strong dipolar interaction
Quaternization of 10a,d,f,g,h,k with methyl trifluoro-
methanesulfonate afforded the corresponding quinolinium
salts 11a,d,f,g,h,k in nearly quantitative yield. Subsequent
regioselective reduction of the former quinolinium salts
with sodium dithionite gave the desired models 1a,d,f,g,h,k
in 81–98% yields. Alternatively, a simplified one pot

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J.-L. Vasse et al. / Tetrahedron 59 (2003) 4911–4921
Table 3. Reduction of methyl benzoylformate with models 1a,d,f,g,h,g.
Reagents and conditions: (a) Mg(ClO4)2/CH3CN/rt/24 h; (b) Na2S2O4/
Na2CO3/rt
Table 4. Reduction of 2-benzoylpyridine with NADH mimics 1d,f,g.
Reagents and conditions: (a) Mg(ClO4)2/CH3CN/rt/24 h
Entry
Compound
R2, R1
Yield (%)
e.e. (R) (%)
1
2
3
1d
1f
1g
(CH2)2OMe, Me
(CH2)3OH, Me
(CH2)2OH, Me
90
95
85
30
84
35
Entry Compound
R2, R1
PhCH2, Me
(CH2)2OMe, Me
(CH2)3OH, Me
(CH2)2OH, Me
(CH2)2OH, Ph
Yield (%) e.e. (R) (%)
1
2
3
4
5
6
1a
1d
1f
1g
1h
1k
95
98
90
81
90
91
4
71
81
86
84
87
2.5. Reduction of 2-benzoylpyridine with NADH mimics
1d,f,g
(CH2)2PO(OEt)2, Me
To further explore the potential of these new biomimetic
models 1, we next investigated the reduction of 2-benzoyl-
pyridine. Asymmetric reduction of diarylketones remains
poorly explored and only few papers deal with the
stereoselective preparation of a-phenyl-2-pyridine-
methanol.16 Under the same conditions, i.e. in acetonitrile
in the presence of magnesium perchlorate, a-phenyl-2-
pyridinemethanol was obtained in 75–90% yield and in
30–84% ee. While the best enantioselectivity (ee¼84%) is
reached with model 1f (Table 4, entry 2), it decreased
strongly (30–35% ee) when the coordinating pendant arm
(R2) turned out to be shorter (Table 4, entries 1 and 3).
between R1 (CH3) and H-40 equatorial. Molecular model-
ing5 confirms this finding and shows a dihedral angle (a) of
about 158 (Fig. 4(a)). As a result of the preferential
stabilization of R1 in pseudo-axial conformation, the
carbonyl lactam slightly oriented out-of-plane of the
dihydroquinoline, would in turn promote the complexation
of magnesium ion on one face of models 1. According to
this scenario, the lactam carbonyl would act as a ‘chiral
relay’ in the diastereofacial discrimination of both faces of
the model to promote Hsyn transfer.15 Although this chiral
relay may induce the stereodiscrimination of the two
diastereotopic H-4, the poor performance of 1a (Table 3,
entry 1) discloses that incorporation of a second binding site
(R2) is necessary to ensure the stereodifferentiation of both
faces of MBF. One can assume that this supplementary
binding site participates with the lactam carbonyl in the
formation of a chelate as illustrated in Figure 4(b). These
considerations led us to propose the ternary complex
depicted in Figure 4(b) which accounts for the formation
of (R)-methyl mandelate.
Comparison of the sign of the specific rotation value with
literature data reveal that (R)-a-phenyl-2-pyridinemethanol
was obtained in all cases. By analogy to the ternary complex
proposed for the reduction of MBF (Fig. 4(b)), one could
anticipate the sense of induction during the reduction of
2-benzoylpyridine. Indeed, the ketone displays two binding
sites, as in MBF, which would coordinate magnesium ions
as outlined in Figure 5.
Figure 5. Reduction of 2-benzoylpyridine with models 1: proposed ternary
complex.
3. Conclusion
We have reported with success the preparation of a new
class of NADH quinoline-type models 1 which rely on a
¨
Friedlander reaction between chiral piperidine-2,4-diones 2
and an o-aminobenzaldehyde derivative. Various coordinat-
ing pendant arms could be introduced on the lactam nitrogen
to probe the influence of a supplementary binding site on the
Figure 4. (a) Conformational analysis of the chiral cyclic inducer in 8a and
8b. (b) Binding sites for magnesium ion and proposed ternary complex
Model/Mg2þ/MBF.

J.-L. Vasse et al. / Tetrahedron 59 (2003) 4911–4921
4915
enantioselectivity of these new biomimetic models 1. We
could conclude that the cyclic chiral inducer (C) would
participate in the stereodifferentiation of both diastereotopic
faces of the mimics 1, whereas the complexing chain proved
to be essential to ensure the stereodifferentiation of both
prochiral faces of the substrate. The possibility to install
various pendant arms (R2) offers the opportunity, to some
extent, to tune the stereoselectivity of the model to a given
substrate. The screening of these various mimics, allowed to
select 1k, as the most efficient model towards the reduction
of methyl benzoylformate. Methyl mandelate was obtained
in 87% ee (R). In the case of 2-benzoylpyridine, the best
level of asymmetric induction is attained with model 1f
affording a-phenyl-2-pyridinemethanol in 84% ee (R).
ammonium chloride (10 mL) was added at 2508C. The
aqueous layer was extracted with diethylether. The organic
phase was dried (MgSO4) and evaporated under vacuum.
The crude product was purified by flash chromatography
(SiO2/diethylether–cyclohexane 1:5) to give 5a in 69%
yield as a colorless liquid. 1H NMR d 1.15 (3H, d,
J¼6.6 Hz), 1.37 (3H, d, J¼6.9 Hz), 2.13 (1H, dd, J¼14.2,
7.6 Hz), 2.38 (1H, dd, J¼14.2, 6.5 Hz), 3.45 (1H, q,
J¼7.3 Hz), 3.51 (3H, s), 3.67 (2H, s), 3.82 (3H, s), 3.90
(1H, q, J¼6.9 Hz), 6.88 (2H, d, J¼8.6 Hz), 7.36–7.21 (7H,
m). 13C NMR d 18.32, 26.77, 39.81, 48.63, 49.50, 51.19,
55.09, 56.90, 113.41, 126.44, 127.63, 127.81, 129.32,
133.26, 144.13, 158.27, 172.59. IR (neat): 2970, 1736,
1511, 1250, 1036, 702 cm21. HRMS (FAB): calcd for
C21H28NO3 [(MþH)þ]: 342.2069. Found: 342.2065.
4.1.3. Methyl (3S,aS)-3(N-p-methoxybenzyl-N-a-
methylbenzyl)amino-3-phenylpropanoate (5b). Accord-
ing to the procedure used to prepare 5a from trans-
methylcinnamate (1.78 g, 11 mmol), butyllithium in hexane
(4 mL, 2.5 M, 10 mmol) and 4 (2.4 g, 10 mmol). Purifi-
cation by flash chromatography (SiO2/diethylether–cyclo-
hexane 1:9) afforded 5b in 72% yield as a colorless oil. 1H
NMR d (200 MHz, CDCl3) 1.24 (3H, d, J¼6.9 Hz), 2.59
(1H, dd, J¼14.9, 9.0 Hz), 2.73 (1H, dd, J¼14.9, 6.1 Hz),
3.50 (3H, s), 3.63 (1H, d, J¼14.4 Hz), 3.74 (1H, d,
J¼14.4 Hz), 3.81 (3H, s), 4.04 (1H, q, J¼6.8 Hz), 4.47
(1H, dd, J¼9.0, 6.1 Hz), 6.85 (2H, d, J¼8.6 Hz), 7.23 (2H,
d, J¼8.6 Hz), 7.27–7.46 (10H, m). 13C NMR (50 MHz,
CDCl3) d 15.59, 37.34, 49.85, 51.31, 55.07, 56.20, 58.79,
113.44, 126.65, 127.06, 127.68, 127.86, 127.95, 128.13,
129.06, 133.02, 141.68, 143.99, 158.27, 172.11. IR (neat)
2950, 2838, 1737, 1611, 1511, 1452, 1249, 1170, 1035, 760,
735, 701 cm21. HRMS (FAB): calcd for C26H30NO3
[(MþH)þ] 404.2226. Found: 404.2234.
4. Experimental
4.1. General methods
The infra-red spectra were recorded on a Beckmann IR 4250
1
spectrometer. The H and 13C NMR spectra were recorded
on a 200 MHz Bruker apparatus. Spectra were recorded in
deuteriochloroform or in hexadeuteriodimethylsulfoxide
(DMSO-d6). Chemical shift are given in ppm with TMS
or HMDS as internal reference. Chemicals were purchased
from Aldrich Co. and Janssen Co. and, unless otherwise
stated, were used without further purification. Flash
chromatography was performed with silica 60 (70–230
mesh from Merck) and monitored by thin layer chromato-
graphy (TLC) with silica Plate (Merck, Kieselgel 60 F254).
The following compounds were prepared by literature
methods: 3,4-dimethoxy ortho-aminobenzaldehyde,11 6-(p-
tolylaminomethylidene)-3,4-dimethoxyaniline 3.11
4.1.1. (S)-N-p-Methoxybenzyl-1-phenylethylamine (4). A
solution of (S)-1-phenylethylamine (20 g, 165.2 mmol) and
p-anisaldehyde (22.45 g, 165.2 mmol) in methanol
(100 mL) was stirred at room temperature for 2 h. Sodium
borohydride (5 g, 129 mmol) was slowly added to the
solution at 08C. The solution was stirred at room
temperature for 2 h. Methanol was evaporated, the residue
was diluted with water and extracted with CH2Cl2
(3£100 mL). The combined organic layers were dried
(MgSO4) and evaporated to give 4 as a colorless liquid
(96%). The crude product is pure enough to be used in the
4.1.4. Methyl (3S)-3-(N-p-methoxybenzyl)amino
butyrate (6a). A mixture of b-amino ester 5 (6.82 g,
20 mmol), 20% Pd(OH)2/C (1.75 g, 2.5 mmol) and con-
centrated HCl (4.8 mL) in methanol (100 mL) was stirred
under 1 atm of hydrogen overnight at room temperature.
The mixture was then filtered through a plug of celite. The
methanol was evaporated under vacuum and the resultant
acidic aqueous layer was neutralized with 10% aqueous
K2CO3. Extraction with CH2Cl2 (3£50 mL), drying
(MgSO4) and evaporation of the solvent gave 6 in 94%
1
1
yield as a yellow oil. H NMR (200 MHz, CDCl3) d 1.17
next step without further purification. H NMR (200 MHz,
(3H, d, J¼6.4 Hz), 2.41 (1H, dd, J¼15.4, 6.2 Hz), 2.56 (1H,
dd, J¼15.4, 6.6 Hz), 2.81 (1H, s), 3.17 (1H, sept, J¼6.4 Hz),
3.67 (3H, s), 3.75 (2H, d, J¼7.4 Hz), 3.79 (3H, s), 6.86 (2H,
d, J¼8.6 Hz), 7.26 (2H, d, J¼8.6 Hz). 13C NMR (50 MHz,
CDCl3) d 20.29, 41.20, 49.41, 50.78, 51.32, 55.65, 110.84,
111.16, 119.95, 132.82, 147.79, 148.78, 172.62. IR (neat)
3327, 2954, 1732, 1514, 1248, 825 cm21. HRMS (FAB):
calcd for C13H20NO3 [(MþH)þ] 238.1443. Found:
238.1437.
CDCl3) d 1.39 (3H, d, J¼6.5 Hz), 3.57 (1H, d, J¼15.9 Hz),
3.64 (1H, d, J¼15.9 Hz), 3.83 (1H,q, J¼6.5 Hz), 3.85 (3H,
s), 6.89 (2H, d, J¼8.4 Hz), 7.23 (2H, d, J¼8.4 Hz), 7.40–
7.25 (5H, m). 13C NMR (50 MHz, CDCl3) d 24.80, 51.34,
55.56, 57.69, 114.06, 127.01, 127.21, 128.77, 129.60,
133.08, 145.93, 158.85. IR (neat) 3323, 2960, 2931, 2834,
1611, 1513, 1453, 1246, 1174, 1114, 1035, 822, 762,
701 cm21. MS (EI, 70 eV): 241.
4.1.2. Methyl (3S,aS)-3-(N-p-methoxybenzyl-N-a-
methylbenzylamino) butyrate (5a). A solution of n-butyl-
lithium in hexane (8.52 mL, 2.5 M, 21.3 mmol) was added
to a solution of 4 (5.1 g, 21.3 mmol) in THF (15 mL) at 08C.
The solution was cooled at 2708C and trans-methylcroto-
nate (2.56 g, 25.6 mmol) was added dropwise. After stirring
for 30 min at 2708C, a saturated aqueous solution of
4.1.5. Methyl (3S)-3-(N-p-methoxybenzylamino)-3-
phenylpropanoate (6b). According to the above procedure
used to prepare 6a from b-amino ester 5b (8.05 g,
20 mmol). Amino ester 6b was obtained in 84% yield as a
yellow oil. 1H NMR (200 MHz, CDCl3) d 2.00 (1H, broad),
2.63 (1H, dd, J¼15.6, 5.5 Hz), 2.75 (1H, dd, J¼15.6,

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J.-L. Vasse et al. / Tetrahedron 59 (2003) 4911–4921
8.5 Hz), 3.49 (1H, d, J¼12.9 Hz), 3.62 (1H, d, J¼12.9 Hz),
3.65 (3H, s), 3.81 (3H, s), 4.12 (1H, dd, J¼8.5, 5.5 Hz), 6.86
(2H, d, J¼8.6 Hz), 7.20 (2H, d, J¼8.6 Hz), 7.29–7.37 (5H,
m). HRMS (FAB): calcd for C18H22NO3 [(MþH)þ]
300.1600. Found: 300.1605.
17.9 mmol) in dry THF (25 mL) was added compound 7a
(5.0 g, 14.9 mmol). After refluxing for 2 h, THF was
evaporated under vacuum to give a slightly yellow solid.
After addition of 6N HCl (6 mL) at room temperature, the
resulting suspension was heated at reflux for 2 h. After
cooling, the solution was neutralized with aqueous 10%
Na2CO3 (pH¼8). The aqueous phase was extracted with
CH2Cl2 (3£30 mL) and the combined organic phases were
dried (Na2SO4). Evaporation of CH2Cl2 under vacuum gave
2a as a white solid in 70% yield after recrystallization in
ethanol. 1H NMR (200 MHz, CDCl3) d 1.19 (3H, d,
J¼6.7 Hz), 2.46 (1H, dd, J¼15.9, 2.5 Hz), 2.65 (1H, dd,
J¼15.9, 5.8 Hz), 3.38 (2H, m), 3.74 (1H, m), 3.80 (3H, s),
4.04 (1H, d, J¼14.7 Hz), 5.25 (1H, d, J¼14.7 Hz), 6.88 (2H,
d, J¼8.7 Hz), 7.23 (2H, d, J¼8.7 Hz). 13C NMR (50 MHz,
CDCl3) d 19.84, 46.50, 47.13, 48.04, 48.81, 55.63, 114.55,
129.11, 129.81, 159.60, 166.36, 204.21. IR (neat) 2969,
4.1.6. Methyl (3S)-3-(N-p-methoxybenzylamino-N-
ethoxycarbonylacetyl)-3-butyrate (7a). To
a stirred
solution of ethyl malonyl chloride (4.98 g, 37.0 mmol) in
CH2Cl2 (40 mL) was added dropwise a solution of b-amino
ester 6a (8.77 g, 37.0 mmol) and triethylamine (7.48 g,
37.0 mmol) in CH2Cl2 (40 mL). The stirring was continued
for an additional 4 h. After addition of water (100 mL), the
organic layer was washed with water (3£20 mL) and with
10% aqueous K2CO3 (2£20 mL). The organic phase was
dried (MgSO4) and evaporated under vacuum. The resultant
crude product was purified by chromatography (SiO2/
cyclohexane–EtOAc 7:3) affording 7a as a yellow oil in
86% yield. Compound 7a is obtained as a mixture of two
rotamers which interconvert by rotation about the amide
2907, 1654, 1556, 1492, 1356, 1237, 1027 cm21
.
Mp¼1428C. Anal. calcd for C14H17NO3: C, 68.00; H,
6.93; N, 5.66. Found: C, 67.84; H, 6.91 N, 5.62.
1
N–CvO bond. H NMR (200 MHz, CDCl3) d 1.22 (1.5H,
d, J¼6.8 Hz), 1.24 (1.5H, d, J¼6.9 Hz), 1.27 (1.5H, t,
J¼7.1 Hz) 1.32 (1.5H, t, J¼7.2 Hz), 2.35 (0.5H, dd, J¼15.5,
6.2 Hz), 2.54 (0.5H, dd, J¼15.5, 7.8 Hz), 2.58 (0.5H, dd,
J¼15.5, 7.3 Hz), 2.82 (0.5H, dd, J¼15.6, 6.9 Hz), 3.39 (1H,
s), 3.89 (0.5H, d, J¼15.8 Hz), 3.64 (0.5H, d, J¼15.8 Hz),
3.57 (1.5H, s), 3.66 (1.5H, s), 3.78 (1.5H, s), 3.81 (1.5H, s),
4.18 (1H, q, J¼7.1 Hz), 4.23 (1H, q, J¼7.1 Hz), 4.39 (0.5H,
d, J¼15.3 Hz), 4.65 (0.5H, d, J¼15.3 Hz), 4.46 (1H, s), 4.42
(0.5H, m), 4.59 (0.5H, m), 6.81 (1H, d, J¼8.6 Hz), 6.90 (1H,
d, J¼8.5 Hz), 7.15 (1H, d, J¼8.6 Hz), 7.18 (1H, d,
J¼8.5 Hz). 13C NMR (50 MHz, CDCl3) d 13.36, 16.30,
20.29, 21.80, 41.00, 41.90, 43.99, 44.50, 45.73, 51.74,
52.10, 53.06, 53.91, 54.03, 57.44, 57.52, 63.60, 63.68,
115.98, 116.51, 129.74, 130.50, 130.98, 132.84, 160.70,
161.31, 168.96, 169.85, 170.22, 173.30, 174.07. IR (neat)
4.1.9. (6S)-6-Phenyl-1-p-methoxybenzylpiperidine-2,4-
dione (2b). According to the above procedure used to
prepare 2a from compound 7b (1.97 g, 5.3 mmol) and
sodium methoxide (0.37 g, 6.6 mmol). Compound 2b was
obtained in 75% yield as a colorless oil, after purification by
1
flash chromatography (SiO2/EtOAc–cyclohexane 1:5) H
NMR (200 MHz, CDCl3) d 2.77 (1H, d, J¼12.8 Hz), 2.86
(1H, dd, J¼12.8, 2.9 Hz), 3.31 (1H, d, J¼20.4 Hz), 3.46
(1H, d, J¼20.4 Hz), 3.61 (1H, d, J¼14.6 Hz), 3.77 (3H, s),
4.75 (1H, dd, J¼5.1, 3.9 Hz), 5.59 (1H, d, J¼14.6 Hz), 6.84
(2H, d, J¼8.5 Hz), 7.06 (2H, dd, J¼7.6, 1.6 Hz), 7.15 (2H,
d, J¼8.5 Hz), 7.29–7.40 (3H, m). IR (neat) 2934, 1731,
1651, 1513, 1246, 1176, 1032, 733, 700 cm21. Anal. calcd
for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C, 73.66;
H, 6.02; N, 4.46.
2992, 2954, 1738, 1650, 1514, 1248, 1176, 1033 cm21
.
HRMS (FAB): calcd for C18H26NO6 [(MþH)þ] 352.1760.
4.1.10. (3S)-2-p-Methoxybenzyl-3-methyl-7,8-di-
methoxy-1-oxo-1,2,3,4-tetrahydrobenzo[b]-1,6-
naphthyridine (8a). A mixture of piperidin-2,4-dione 2a
(4.39 g, 17.8 mmol), Schiff base 3 (5.04 g, 18.7 mmol) and a
few drops of piperidine in ethanol (60 mL) was stirred at
room temperature for 24 h. The solvent was evaporated and
the crude product was purified by flash chromatography
(SiO2/EtOAc–cyclohexane 3:7) to give 2.66 g (68%) of 8a
as a beige solid. 1H NMR (200 MHz, CDCl3) d 1.18 (3H, d,
J¼6.6 Hz), 2.98 (1H, dd, J¼16.1, 1.9 Hz), 3.41 (1H, dd,
J¼16.1, 5.9 Hz), 3.80 (3H, s), 3.85 (m, 1H); 4.02 (3H, s),
4.03 (3H, s), 4.09 (1H, d, J¼14.6 Hz), 5.48 (1H, d,
J¼14.6 Hz), 6.89 (2H, d, J¼8.5 Hz), 7.16 (1H, s), 7.31
(2H, d, J¼8.5 Hz), 7.38 (1H, s), 8.74 (1H, s). 13C NMR
(50 MHz, CDCl3) d 18.80, 38.57, 48.08, 50.28, 55.61,
56.50, 56.57, 106.51, 107.53, 114.43, 121.32, 123.06,
129.73, 130.08, 135.45, 146.89, 150.11, 154.38, 154.38,
159.41, 163.56. IR (neat) 2966, 2933, 1644, 1504,
1249 cm21. Anal. calcd for C23H24N2O4: C, 70.39; H,
6.16; N, 7.14. Found: C, 70.34; H, 6.23; N, 7.04.
Found 352.1743.
4.1.7. Methyl (3S)-3-(N-p-methoxybenzyl-N-ethoxy-
carbonylacetylamino)-3-phenyl-propanoate
(7b).
According to the procedure used to prepare 7a from 6b
(4.0 g, 15 mmol), triethylamine (2.29 mL, 16.5 mmol) and
ethyl malonyl chloride (2.48 g, 16.5 mmol). Compound 7b
was obtained in 94% yield as a mixture of two rotamers. 1H
NMR (200 MHz, CDCl3) d 1.25 (1.8H, t, J¼7.2 Hz), 1.29
(2H, t, J¼7.6 Hz), 2.90 (2H, m), 3.38 (1H, s), 3.51 (1H, s),
3.59 (1.8H, s), 3.76 (3H, s), 3.86 (1.2H, s), 4.11–4.43 (2.4H,
m), 4.39 (0.6H, d, J¼7.0 Hz), 5.03 (0.4H, d, J¼6.5 Hz),
5.28 (0.4H, t, J¼7.3 Hz), 6.20 (0.6H, t, J¼7.7 Hz), 6.74–
6.81 (2H, m), 6.92 (1.2H, d, J¼8.5 Hz), 7.01 (0.8H, d,
J¼8.4 Hz), 7.26–7.32 (5H, m). 13C NMR (50 MHz, CDCl3)
d 171.44, 171.30, 168.26, 167.93, 167.82, 159.40, 158.95,
138.57, 138.02, 130.76, 129.42, 129.20, 129.02, 128.40,
127.85, 127.22, 114.58, 114.11, 61.95, 61.85, 57.92, 55.68,
55.64, 55.06, 52.29, 48.76, 45.89, 42.54, 42.08, 37.65,
36.78, 14.48. IR (neat) 2934, 1731, 1651, 1513, 1246, 1176,
1032, 733, 700 cm21. HRMS (FAB): calcd for C23H28NO6
[(MþH)þ] 414.1917. Found: 414.1923.
4.1.11. (3S)-2-p-Methoxybenzyl-7,8-dimethoxy-1-oxo-3-
phenyl-1,2,3,4-tetrahydrobenzo[b]-1,6-naphthyridine
(8b). According to the above procedure used to prepare 8a
from piperidine-2,4-dione 2b (1.73 g, 5.6 mmol) and Schiff
base 3 (1.51 g, 5.6 mmol). Compound 8b was obtained in
4.1.8. (6S)-1-(p-Methoxybenzyl)-6-methyl-piperidin-2,4-
dione (2a). To a solution of sodium methoxide (0.97 g,

J.-L. Vasse et al. / Tetrahedron 59 (2003) 4911–4921
4917
78% yield after purification by flash chromatography (SiO2/
1
EtOAc–cyclohexane 1:3). H NMR (200 MHz, CDCl3) d
chromatography (SiO2/EtOAc–cyclohexane 3:7) to give
10a in 92% yield as a thick oil. 1H NMR (200 MHz, CDCl3)
d 1.19 (3H, d, J¼6.6 Hz), 2.99 (1H, dd, J¼16.0, 2.0 Hz),
3.46 (1H, dd, J¼16.0, 5.8 Hz), 3.86 (1H, qdd, J¼6.6, 5.8,
2.0 Hz), 4.03 (3H, s), 4.04 (3H, s), 4.10 (1H, d, J¼14.9 Hz),
5.56 (1H, d, J¼14.9 Hz), 7.17 (1H, s), 7.29–7.38 (6H,
m), 8.75 (1H, s). 13C NMR (50 MHz, CDCl3) d 163.32,
154.05, 154.03, 149.77, 146.55, 137.70, 135.15, 128.72,
128.36, 127.96, 122.71, 120.88, 107.14, 106.18, 56.59,
56.51, 50.63, 48.73, 38.58, 18.85. Anal. calcd for
C22H22N2O3: C, 72.91; H, 6.12; N, 7.73. Found: C, 72.85;
H, 6.20; N, 7.63.
3.23 (1H, dd, J¼16.1, 1.8 Hz), 3.66 (1H, d, J¼14.6 Hz),
3.78 (1H, dd, J¼16.1, 7.2 Hz), 3.71 (3H, s), 3.88 (3H, s),
3.92 (3H, s), 4.77 (1H, dd, J¼6.8, 1.8 Hz), 5.78 (1H, d,
J¼14.6 Hz), 6.78 (2H, d, J¼8.6 Hz), 6.97 (2H, d,
J¼8.6 Hz), 7.05–7.18 (7H, m), 8.71 (1H, s); 13C NMR
(50 MHz, CDCl3) d 39.77, 48.44, 55.70, 56.56, 56.60,
57.71, 106.55, 107.64, 114.55, 121.71, 123.13, 126.61,
128.16, 129.24, 129.29, 129.76, 135.37, 139.87, 147.05,
150.22, 153.28, 154.48, 159.57, 164.74. IR (neat) 2925,
1648, 1502, 1249, 1154, 1031, 1010, 849, 737, 700 cm21
.
Anal. calcd for C28H26N2O4: C, 73.99; H, 5.77; N, 6.16.
Found: C, 74.02; H, 5.69; N, 6.02.
4.1.15. (3S)-2-Allyl-3-methyl-7,8-dimethoxy-1-oxo-
(10b).
1,2,3,4-tetrahydrobenzo[b]-1,6-naphthyridine
4.1.12. (3S)-7,8-Dimethoxy-3-methyl-1-oxo-1,2,3,4-tetra-
hydrobenzo[b]-1,6-naphthyridine (9a). A solution of
CAN (3.29 g, 6 mmol) in H2O–MeCN (1:9) (20 mL) was
added dropwise to a solution of 8a (0.78 g, 2 mmol) in
H2O–MeCN (1:9) (15 mL) at room temperature. The
mixture was stirred vigorously for 5 h, then diluted with
NaOH (2N, 12 mL). After stirring for 30 min, the mixture
was filtered. The filtrate was extracted with CH2Cl2
(4£20 mL). The resultant organic phase was dried over
MgSO4, filtered and evaporated. The residue was solubil-
ized in CH2Cl2 (5 mL). After addition of Et2O (45 mL), 9a
precipitates as white needles (0.375 g, 69%). 1H NMR
(200 MHz, CDCl3) d 1.42 (3H, d, J¼6.4 Hz), 3.05 (1H, dd,
J¼15.9, 10.0 Hz), 3.32 (1H, dd, J¼15.9, 4.6 Hz), 3.95–4.05
(1H, m), 4.03 (3H, s), 4.05 (3H, s), 5.97 (1H, s, broad), 7.14
(1H, s), 7.39 (1H, s), 8.69 (s, 1H). 13C NMR (50 MHz,
CDCl3) d 21.95, 39.39, 46.39, 56.00, 56.13, 105.95, 107.12,
120.10, 122.50, 134.91, 146.61, 149.74, 154.20, 155.04,
165.53. IR (neat): 3201, 3065, 1709, 1649, 1515, 1432,
1408, 1384, 1309, 1277, 998 cm21. Mp 2148C. Anal. calcd
for C15H16N2O3: C, 66.16; H, 5.92; N, 10.29. Found: C,
66.03; H, 5.81; N, 10.26.
According to the general procedure (A) used for the
preparation of 10a using allyl bromide as an electrophile
(173 mL, 2 mmol). Compound 10b was obtained in 95%
yield as a yellow solid. 1H NMR (200 MHz, CDCl3) d 1.19
(3H, d, J¼6.6 Hz), 3.04 (1H, dd, J¼16.0, 2.0 Hz), 3.53 (1H,
dd, J¼16.0, 6.0 Hz), 3.64 (1H, ddt, J¼15.3, 6.9, 1.4 Hz),
3.91 (1H, quint-t, J¼6.4, 2.0 Hz), 4.00 (3H, s), 4.02 (3H, s),
4.82 (1H, ddt, J¼15.3, 4.8, 1.7 Hz), 5.23 (1H, dd, J¼17.1,
1.3 Hz), 5.28 (1H, dd, J¼10.0, 1.3 Hz), 5.91 (1H, dddd,
J¼17.1, 10.0, 1.4, 1.7 Hz), 7.13 (1H, s), 7.36 (1H, s), 8.67
(1H, s). 13C NMR (50 MHz, CDCl3) d 18.94, 31.06, 47.95,
50.55, 56.29, 56.36, 106.25, 107.32, 117.61, 121.10, 122.83,
133.76, 146.67, 149.92, 154.20, 154.23, 163.05. IR (neat)
3369, 3264, 2967, 2933, 1650, 1505, 1253 cm21. Anal.
calcd for C18H20N2O3: C, 69.21; H, 6.45; N, 8.97. Found: C,
69.12; H, 6.50; N, 8.86.
4.1.16. (3S)-2-Allyl-3-phenyl-7,8-dimethoxy-1-oxo-
1,2,3,4-tetrahydrobenzo[b]-1,6-naphthyridine
(10c).
According to the general procedure (A) used for the
preparation of 10a from compound 9b (0.33 g, 1 mmol)
and allyl bromide as an electrophile (173 mL, 2 mmol).
Compound 10c was obtained in 97% yield as yellow oil. 1H
NMR (200 MHz, CDCl3) d 3.84 (1H, dd, J¼16.2, 6.8 Hz),
3.39 (1H, dd, J¼16.2, 2.0 Hz), 3.33 (1H, dd, J¼15.3,
7.4 Hz), 3.96 (3H, s), 3.98 (3H, s), 4.96–5.27 (4H, m), 5.91
(1H, m), 7.04–7.27 (7H, m), 8.75 (1H, s). Anal. calcd for
C23H22N2O3: C,73.78; H, 5.92; N, 7.48. Found: C, 73.75; H,
5.85; N, 7.35.
4.1.13. (3S)-7,8-Dimethoxy-1-oxo-3-phenyl-1,2,3,4-tetra-
hydrobenzo[b]-1,6-naphthyridine (9b). According to the
above procedure used to prepare 9a from 8b (0.61 g,
1.33 mmol), CAN (2.19 g, 4 mmol). Compound 9b was
obtained in 60% yield as white needles after recrystalliza-
tion in ethanol. 1H NMR (200 MHz, CDCl3) d 3.46 (2H, m),
4.03 (6H, s), 5.00 (1H, t, J¼7.2 Hz), 6.32 (1H, s broad), 7.14
(1H, s), 7.36–7.39 (6H, m), 8.73 (1H, s). 13C NMR
(50 MHz, CDCl3) d 40.41, 55.17, 56.03, 56.16, 105.99,
107.17, 120.15, 122.59, 126.19, 128.31, 128.98, 135.00,
140.54, 146.76, 149.82, 154.28, 154.39, 165.80. IR (neat)
3175, 3056, 1675, 1603, 1497, 1425, 1249 cm21. Mp
2388C. Anal. calcd for C20H18N2O3: C,71.84; H, 5.43; N,
8.38. Found: C, 71.73; H, 5.30; N, 8.27.
4.1.17. (3S)-2-(2-Methoxyethyl)-3-methyl-7,8-di-
methoxy-1-oxo-1,2,3,4-tetrahydrobenzo[b]-1,6-
naphthyridine (10d). According to the general procedure
(A) used for the preparation of 10a using 2-iodo-1-
methoxyethane (0.74 g, 2 mmol) as an electrophile. Com-
pound 10d was obtained in 89% yield as a yellow solid after
purification by flash chromatography (SiO2/EtOAc–cyclo-
1
hexane 4:1). H NMR (200 MHz, CDCl3) d 1.17 (3H, d,
4.1.14. General procedure A: (3S)-2-benzyl-3-methyl-
7,8-dimethoxy-1-oxo-1,2,3,4-tetrahydrobenzo[b]-1,6-
naphthyridine (10a). To a solution of powdered KOH
(0.224 g, 4 mmol) in DMSO (2 mL) was added 9a (0.272 g,
1 mmol) and benzyl bromide (238 mL, 2 mmol). After
stirring for 1 h at room temperature the mixture was poured
into water (20 mL) and extracted with CH2Cl2 (3£20 mL).
The combined organic extracts were washed with water
(5£10 mL), dried over MgSO4 and filtered. The solvent was
evaporated and the crude product was purified by flash
J¼6.7 Hz), 3.00 (1H, dd, J¼16.0, 2.0 Hz), 3.18 (1H, ddd,
J¼13.8, 7.1, 5.2 Hz), 3.36 (3H, s), 3.52–3.68 (3H, m), 3.99
(3H, s), 4.01 (3H, s), 4.04 (1H, m), 4.23 (1H, dt, J¼14.0,
4.4 Hz), 7.15 (1H, s), 7.39 (1H, s), 8.68 (1H, s); 13C NMR
(50 MHz, CDCl3) d 19.20, 38.41, 46.36, 53.02, 56.51,
56.60, 59.38, 71.88, 106.55, 107.53, 121.04, 123.04, 135.14,
146.81, 150.12, 154.39, 154.69, 163.58. IR (neat) 3374,
2936, 2832, 1644, 1601, 1506, 1254 cm21. Anal. calcd for
C18H22N2O4: C,65.44; H, 6.71; N, 8.48. Found: C, 65.37; H,
6.53; N, 8.31.

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J.-L. Vasse et al. / Tetrahedron 59 (2003) 4911–4921
4.1.18. (3S)-2-(3-Propyl acetate)-3-methyl-7,8-di-
methoxy-1-oxo-1,2,3,4-tetrahydrobenzo[b]-1,6-
naphthyridine (10e). According to the general procedure
(A) used for the preparation of 10a using 3-iodo-propyl-
acetate (0.74 g, 2 mmol) as electrophile. Compound 10e
was obtained in 65% yield as a colorless oil after flash
chromatography (SiO2/EtOAc–cyclohexane 4:1). 1H NMR
(200 MHz, CDCl3) d 1.22 (3H, d, J¼6.6 Hz), 2.07 (3H, s),
2.08 (2H, m), 3.02–3.14 (2H, m), 3.58 (1H, dd, J¼16.0,
6.0 Hz), 3.90 (1H, t, J¼5.5 Hz), 4.02 (3H, s), 4.04 (3H, s),
4.20 (2H, t, J¼6.2 Hz), 4.22 (1H, m), 7.14 (1H, s), 7.38 (1H,
s), 8.67 (1H, s); 13C NMR (50 MHz, CDCl3) d 18.90, 20.87,
27.61, 38.08, 43.07, 51.72, 56.03, 56.11, 62.07, 106.04,
107.03, 120.80, 122.58, 134.72, 146.39, 149.69, 153.75,
153.96, 163.12, 170.95. IR (neat) 2968, 1732, 1634, 1504,
1253, 753 cm21. Anal. calcd for C20H24N2O5: C, 64.50; H,
6.50; N, 7.52. Found: C, 64.25; H, 6.58; N, 7.39.
1258 cm21. Mp1978C. Anal. calcd for C17H20N2O4: C, 64.54;
H, 6.37; N, 8.85. Found: C, 64.22; H, 6.18; N, 8.69.
4.1.21. (3S)-2-(2-Hydroxyethyl)-3-phenyl-7,8-di-
methoxy-1-oxo-1,2,3,4-tetrahydrobenzo[b]-1,6-
naphthyridine (10h). According to the above procedure
used to prepare 10g from 10c (0.35 mg, 1.08 mmol),
osmium tetraoxide (4 wt% solution in water, 0.705 mL,
0.115 mmol), sodium periodate (0.70 g, 3.24 mmol),
sodium borohydride (81 mg, 2.15 mmol). Compound 10h
was obtained in 72% yield as a white solid after purification
1
by chromatography (SiO2/EtOAc–EtOH 99:1). H NMR
(200 MHz, CDCl3) d 3.25 (1H, ddd, J¼14.2, 6.2, 4.7 Hz),
3.29 (1H, dd, J¼16.2, 2.3 Hz), 3.87 (2H, m), 3.94–4.00
(7H, m), 4.21 (1H, ddd, J¼14.2, 5.7, 4.3 Hz), 5.06 (1H, dd,
J¼6.8, 2.3 Hz), 7.04–7.25 (7H, m), 8.70 (1H, s). 13C NMR
(50 MHz, CDCl3) d 39.29, 50.56, 56.04, 56.08, 60.93,
62.07, 106.03, 107.10, 120.92, 122.51, 125.96, 127.78,
128.75, 134.53, 139.46, 146.59, 149.76, 152.68, 154.08,
165.85. Anal. calcd for C22H22N2O4: C, 69.83; H, 5.86; N,
7.40. Found: C, 69.75; H, 5.82; N, 7.33.
4.1.19. (3S)-2-(3-Hydroxypropyl)-3-methyl-7,8-di-
methoxy-1-oxo-1,2,3,4-tetrahydrobenzo[b]-1,6-
naphthyridine (10f). To a stirred solution of 10e (0.32 g,
0.87 mmol) in ethanol (5 mL) was added a solution of KOH
(63 mg, 1.1 mmol) in ethanol (5 mL). After stirring for
30 min, the mixture was poured into water (10 mL). After
extraction with dichloromethane, the combined organic
layers were dried (MgSO4), filtered and evaporated to afford
4.1.22. (3S)-2-(2-Chloroethyl)-3-methyl-7,8-dimethoxy-
1-oxo-1,2,3,4-tetrahydrobenzo[b]-1,6-naphthyridine
(10i). To a stirred solution of 10g (2.0 g, 6.3 mmol) in
CH2Cl2 (20 mL) and triethylamine (900 mL, 6.9 mmol) was
added dropwise a solution of p-toluenesulphonyl chloride
(1.32 g, 6.9 mmol) in CH2Cl2 (20 mL). After stirring for
8 h, water (20 mL) was added. After phase separation, the
organic layer was washed with water (10 mL) dried over
MgSO4 and evaporated under vacuum. The crude product
was purified by chromatography (SiO2/cyclohexane–
EtOAc 7:3) to obtain 10i as a yellow solid (42%). 1H
NMR (200 MHz, CDCl3) d 1.23 (3H, d, J¼6.7 Hz), 3.07
(1H, dd, J¼16.1, 1.5 Hz), 3.24 (1H, ddd, J¼17.2, 8.8,
5.6 Hz), 3.70 (1H, dd, J¼16.1, 5.9 Hz), 3.83 (2H, m), 4.03
(3H, s), 4.05 (3H, s), 4.08 (1H, m), 4.51 (1H, dt, J¼13.8,
4.7 Hz), 7.15 (1H, s), 7.40 (1H, s), 8.67 (1H, s). 13C NMR
(50 MHz, CDCl3) d 18.90, 37.78, 42.38, 48.47, 53.43,
56.05, 56.15, 106.03, 107.10, 120.56, 122.54, 134.71,
146.54, 149.75, 153.96, 154.08, 163.41. Anal. calcd for
C17H19ClN2O3: C, 60.99; H, 5.72; N, 8.37. Found: C, 60.75;
H, 5.55; N, 8.18.
1
10f (98%) as a white solid. H NMR (200 MHz, CDCl3) d
1.24 (3H, d, J¼6.7 Hz), 1.88 (2H, m), 3.07 (1H, dd, J¼16.0,
2.0 Hz), 3.31 (1H, dt, J¼14.1, 5.3 Hz), 3.58 (1H, dd,
J¼16.0, 5.3 Hz), 3.62 (2H,m), 3.90 (1H, m), 4.01 (3H, s),
4.04 (3H, s), 4.19 (1H, ddd, J¼14.0, 9.2, 4.6 Hz), 7.13 (1H,
s), 7.37 (1H, s), 8.65 (1H, s). 13C NMR (200 MHz, CDCl3) d
18.93, 30.66, 37.97, 42.06, 51.53, 56.01, 56.10, 58.09,
106.00, 106.95, 120.34, 122.53, 134.83, 146.37, 149.75,
153.60, 154.08, 164.21. HRMS (FAB): calcd for
C18H23N2O4 [(MþH)þ]: 331.1658. Found: 331.1655.
4.1.20. (3S)-2-(2-Hydroxyethyl)-3-methyl-7,8-di-
methoxy-1-oxo-1,2,3,4-tetrahydrobenzo[b]-1,6-
naphthyridine (10g). To a stirred solution of 10b (0.36 g,
1.15 mmol) in THF–H2O (1:1) (18 mL) was added osmium
tetraoxide (4 wt% solution in water, 0.705 mL,
0.115 mmol), giving initially a clear solution which
darkened rapidly. The solution was stirred for 15 min, at
which time sodium periodate (0.747 g, 3.45 mmol) was
added in one portion affording a white precipitate. After 1 h,
methanol (9 mL) was added, the mixture was cooled at 08C,
and sodium borohydride (0.086 g, 2.3 mmol) was added in
one portion. The resultant black mixture was vigorously
stirred at 08C for 30 min and then poured into a saturated
NaHCO3 aqueous solution (30 mL). The aqueous phase was
extracted with CH2Cl2 (4£30 mL), the combined organic
phases were dried over Na2SO4 and concentrated to give
after flash chromatography (SiO2/EtOAc–EtOH 95:5) the
4.1.23. (3S)-2-(2-Iodoethyl)-3-methyl-7,8-dimethoxy-1-
oxo-1,2,3,4-tetrahydrobenzo[b]-1,6-naphthyridine (10j).
A solution of 10i (723 mg, 2.16 mmol) and sodium iodide
(1 g, 6.5 mmol) in dry acetone (15 mL) was heated to reflux
for 16 h. Filtration of sodium chloride and evaporation of
the solvent afforded a slightly yellow solid. The crude
product was dissolved in dichloromethane and washed with
saturated aqueous Na2SO3. The organic phase was dried
(Na2SO4) and evaporation of the solvent furnished 10i in
85% yield as a yellow solid. 1H NMR (200 MHz, CDCl3) d
1.23 (3H, d, J¼6.7 Hz), 3.09 (1H, dd, J¼16.0, 1.5 Hz),
3.24–3.56 (4H, m), 3.73 (1H, dd, J¼16.0, 5.9 Hz), 4.03
(3H, s), 4.05 (3H, s), 4.52 (1H, ddd, J¼13.4, 6.9, 3.9 Hz),
7.15 (1H, s), 7.39 (1H, s), 8.67 (1H, s). 13C NMR (50 MHz,
CDCl3) d 18.98, 26.76, 37.97, 49.10, 52.88, 56.05, 56.15,
106.04, 107.11, 120.53, 122.56, 125.36, 134.77, 146.58,
1
desired compound 10g (0.261 g, 72%) as a white solid. H
NMR (200 MHz, CDCl3) d 1.24 (3H, d, J¼6.8 Hz), 3.05
(1H, dd, J¼16.0, 1.8 Hz), 3.41 (1H, ddd, J¼14.1, 6.2,
3.8 Hz), 3.65 (1H, dd, J¼16.0, 6.0 Hz), 3.97 (2H, m), 4.00
(1H, m), 4.02 (3H, s), 4.04 (3H, s), 4.15 (1H, ddd, J¼14.1,
6.2, 3.8 Hz), 7.14 (1H, s), 7.39 (1H, s), 8.67 (1H, s). 13C
NMR (50 MHz, CDCl3) d 19.00, 38.01, 50.27, 53.45, 56.02,
5611, 62.57, 106.02, 107.05, 120.44, 122.51, 134.72, 146.53,
149.74, 153.75, 154.09, 164.88. IR (neat) 3193, 1649, 1506,
153. 88, 154.09, 163.25. IR (neat) 1650, 1499, 1254 cm21
.
HRMS: calcd for C17H19IN2O3 (Mþ): 426.0440. Found:
426.0437.

J.-L. Vasse et al. / Tetrahedron 59 (2003) 4911–4921
4919
4.1.24. (3S)-2-(2-Ethyl-diethylphosphonate)-3-methyl-
7,8-dimethoxy-1-oxo-1,2,3,4-tetrahydrobenzo[b]-1,6-
naphthyridine (10k). To a suspension of NaH (24 mg,
1 mmol) in THF (5 mL) was added dropwise a solution of
diethylphosphite in THF (5 mL) at 08C. The solution was
stirred for 30 min at room temperature. A solution of 10j
(213 mg, 0.5 mmol) in THF (5 mL) was added. The mixture
was stirred for a further 6 h, then quenched with water
(5 mL). The aqueous layer was extracted with CH2Cl2. The
organic phases were dried over MgSO4, filtered and
evaporated. The crude product was purified by chromato-
graphy (SiO2/EtOAc–EtOH 98:2) to obtain 10k as a
naphthyridinium triflate (11f). According to the general
procedure (B) used to prepare 11a from 10f (330 mg,
1 mmol). Tetrahydrobenzo-naphthyridium salt 11f was
1
obtained as yellow solid in a quantitative yield. H NMR
(200 MHz, CDCl3) d 1.21 (3H, d, J¼6.6 Hz), 1.80 (2H, m),
3.25–3.95 (7H, m), 3.94 (3H, s), 4.24 (3H, s), 4.57 (3H, s),
7.35 (1H, s), 7.64 (1H, s), 9.21 (1H, s). 19F NMR d 278.76.
13C NMR (50 MHz, CD3OD) d 161.59, 160.48, 155.40,
153.31, 143.08, 140.72, 126.10, 123.23, 109.74, 99.86,
60.27, 58.10, 57.98, 51.87, 44.41, 40.16, 34.92, 32.01,
19.78. HRMS (FAB): calcd for C19H25N2O4 (Mþ):
345.1814. Found 345.1812.
1
colorless oil (30%). H NMR (200 MHz, CDCl3) d 1.23
(3H, d, J¼6.6 Hz), 1.34 (6H, q, J¼6.8 Hz), 2.30 (2H, m),
3.05 (1H, d, J¼16.0 Hz), 3.33 (1H, m), 3.63 (1H, dd,
J¼16.0, 6.0 Hz), 3.95 (1H, m) 4.03 (3H, s), 4.05 (3H, s),
4.14 (4H, qd, J¼7.1, 8.0 Hz), 4.34 (1H, m), 7.14 (1H, s),
7.39 (1H, s), 8.66 (1H, s). 31P NMR d 29.38. 13C NMR
(50 MHz, CDCl3) d 16.25 (d, J¼2.5 Hz), 16.37 (d,
J¼1.9 Hz), 19.05, 24.87 (d, J¼138 Hz), 38.04, 41.25,
52.38, 56.01, 56.10, 61.71 (d, J¼6.5 Hz), 106.00, 107.06,
120.58, 122.51, 134.53, 134.70, 146.47, 149.69, 153.89,
153.99, 163.13. HRMS: calcd for C21H29N2O6P (Mþ):
436.1763. Found: 436.1760.
4.1.28. (3S)-2-(2-Hydroxyethyl)-3,5-dimethyl-7,8-
dimethoxy-1-oxo-1,2,3,4-tetrahydrobenzo[b]-1,6-
naphthyridinium triflate (11g). According to the general
procedure (B) used to prepare 11a from 10g (316 mg,
1 mmol). Tetrahydrobenzo-naphthyridium salt 11g was
1
obtained as a yellow solid in quantitative yield. H NMR
(200 MHz, CDCl3) d 1.25 (3H, d, J¼6.5 Hz), 3.17 (1H, m),
3.55 (1H, d, J¼18.4 Hz), 3.78 (3H, m), 4.08 (3H, s), 4.21
(3H, s), 4.25 (1H, m), 4.49 (3H, s), 7.46 (1H, s), 7.59 (1H, s),
9.14 (1H, s). 13C NMR (50 MHz, CDCl3) 160.21, 159.47,
154.75, 152.29, 142.20, 139.64, 124.74, 122.83, 108.45,
99.11, 61.15, 58.26, 57.22, 51.74, 49.25, 40.52, 34.45,
20.28. HRMS (FAB): calcd for C18H23N2O4 (Mþ):
331.1658. Found 331.1645.
4.1.25. General procedure (B): (3S)-2-benzyl-3,5-
dimethyl-7,8-dimethoxy-1-oxo-1,2,3,4-tetrahydrobenzo-
[b]-1,6-naphthyridinium triflate (11a). To a solution of
10a (362 mg, 1 mmol) in CH2Cl2 (5 mL), was added a
solution of methyl trifluoromethane sulfonate (180 mg,
1.1 mmol) in CH2Cl2 (5 mL) under nitrogen atmosphere.
The solution was stirred for 1 h, the solvent was evaporated
to give tetrahydrobenzo-naphthyridium salt 11a as a yellow
solid in a quantitative yield. 1H NMR (200 MHz, CDCl3) d
1.13 (3H, d, J¼6.6 Hz), 3.54 (1H, dd, J¼18.0, 3.6 Hz), 3.65
(1H, dd, J¼18.0, 6.3 Hz), 3.94 (1H, m), 4.00 (3H, s), 4.14
(3H, s), 4.16 (1H, d, J¼15.0 Hz), 4.45 (3H, s), 5.36 (1H, d,
J¼15.0 Hz), 7.32 (5H, m), 7.42 (1H, s), 7.69 (1H, s), 9.30
(1H, s). 13C NMR (50 MHz, CDCl3,) d 19.31, 34.13, 40.41,
48.53, 49.10, 56.69, 57.99, 99.07, 107.75, 121.92, 124.36,
127.85, 127.94, 128.89, 136.14, 139.48, 141.98, 151.95,
153.37, 159.27, 159.52. HRMS (FAB): calcd for
C23H25N2O3 (Mþ): 377.1865. Found: 377.1862.
4.1.29. (3S)-2-(2-Hydroxoxyethyl)-5-methyl-7,8-
dimethoxy-1-oxo-3-phenyl-1,2,3,4-tetrahydrobenzo[b]-
1,6-naphthyridinium triflate (11h). According to the
general procedure (B) used to prepare 11a from 10h
(378 mg, 1 mmol). Tetrahydrobenzo–naphthyridium salt
11h was obtained as a yellow solid in a quantitative yield.
1H NMR (200 MHz, CDCl3) d 3.01 (2H, m,), 3.63 (2H, m),
3.99 (3H, s), 4.12 (3H, s), 4.15 (2H, m), 4.34 (3H, s), 5.42
(1H, m), 7.20–7.30 (5H, m), 7.66 (1H, s), 8.03 (1H, s), 9.43
(1H, s). 19F NMR d 278.74. HRMS (FAB): calcd for
C23H25N2O4 (Mþ): 393.1814. Found 393.1816.
4.1.30. (3S)-2-(2-Ethyl-diethylphosphonate)-3,5-
dimethyl-7,8-dimethoxy-1-oxo-1,2,3,4-tetrahydrobenzo-
[b]y1,6-naphthyridinium triflate (11k). According to the
general procedure (B) used to prepare 11a from 10k
(436 mg, 1 mmol). Tetrahydrobenzo-naphthyridium salt
4.1.26. (3S)-2-(2-Methoxyethyl)-3,5-dimethyl-7,8-
dimethoxy-1-oxo-1,2,3,4-tetrahydrobenzo[b]-1,6-
naphthyridinium triflate (11d). According to the general
procedure (B) used to prepare 11a from 10d (330 mg,
1 mmol). Tetrahydrobenzo-naphthyridium salt 11d was
1
11k was obtained as yellow solid in quantitative yield. H
NMR (200 MHz, CDCl3) d 1.25–1.39 (9H, m), 2.22 (2H,
m), 3.30 (1H, m), 3.65 (1H, dd, J¼17.9, 2.4 Hz), 3.96–4.26
(13H, m), 4.59 (3H, s), 7.37 (1H, s), 7.72 (1H, s), 9.20 (1H,
s). 19F NMR d 278.72. Anal. calcd for C22H32N2O6P: C,
58.53; H, 7.14; N, 6.20. Found: C, 58.43; H, 7.23; N, 6.24.
1
obtained as yellow solid in a quantitative yield. H NMR
(200 MHz, CDCl3) d 1.23 (3H, d, J¼6.7 Hz), 3.22 (1H, m),
3.30 (3H, s), 3.57 (2H, m), 3.62 (1H, dd, J¼17.8, 2.5 Hz),
3.82 (1H, dt, J¼17.8, 6.0 Hz), 4.02 (3H, s), 4.12 (1H, m),
4.18 (3H, s), 4.22 (1H, m), 4.56 (3H, s), 7.34 (1H, s), 7.65
(1H, s), 9.15 (1H, s). 13C NMR (50 MHz, CDCl3) d 19.97,
34.46, 40.90, 46.16, 51.49, 57.11, 58.50, 59.375, 71.19,
99.62, 108.09, 122.58, 124.71, 139.88, 142.08, 152.39,
154.11, 159.67, 159.72. 19F NMR d 278.76. Mp 2088C.
HRMS (FAB): calcd for C19H25N2O4 (Mþ): 345.1814.
Found: 345.1812.
4.1.31. General procedure (C): (3S)-2-benzyl-3,5-
dimethyl-7,8-dimethoxy-1-oxo-1,2,3,4,5,10-hexahydro-
benzo[b]-1,6-naphthyridine (1a). To a solution of tetra-
hydrobenzo-naphtyridinium salt 11a (378.5 mg, 1 mmol) in
water (15 mL), were added in one portion sodium dithionite
(174 mg, 1 mmol) and sodium carbonate (106 mg, 1 mmol).
After stirring for 1 h under a nitrogen atmosphere, Na2S2O4
(174 mg, 1 mmol) and Na2CO3 (106 mg, 1 mmol) were
added. After stirring for 1 h, Na2S2O4 (174 mg, 1 mmol)
was added and stirring was continued for an additional 1 h.
The aqueous phase was extracted with CH2Cl2 (3£20 mL),
4.1.27. (3S)-2-(2-Hydroxypropyl)-3,5-dimethyl-7,8-
dimethoxy-1-oxo-1,2,3,4-tetrahydrobenzo[b]-1,6-

4920
J.-L. Vasse et al. / Tetrahedron 59 (2003) 4911–4921
the combined organic layers were dried over Na2SO4 and
evaporated under vacuum to give 1a in 95% yield as a red
oil. NMR (200 MHz, CDCl3) d 1.29 (3H, d, J¼6.5 Hz), 2.13
(1H, d, J¼16.0 Hz), 2.50 (1H, dd, J¼15.6, 4.5 Hz), 3.14
(3H, s), 3.43 (1H, m), 3.60 (1H, d, J¼18.5 Hz), 3.84 (1H, d,
J¼18.5 Hz), 3.86 (3H, s), 3.87 (3H, s), 4.11 (d, 1H,
J¼15 Hz), 5.44 (d, 1H, J¼15 Hz), 6.42 (1H, s), 6.68 (1H, s),
7.31 (5H, m). HRMS (FAB): calcd for C23H27N2O3
[(MþH)þ]: 379.2022. Found: 379.2018.
4.1.36. (3S)-2-(2-Ethyl-diethylphosphonate)-3,5-
dimethyl-7,8-dimethoxy-1-oxo-1,2,3,4,5,10-hexahydro-
benzo[b]-1,6-naphthyridine (1k). According to the general
procedure C from 11k (452 mg, 1 mmol) affording 1k
(91%) as a red oil. 1H NMR (200 MHz, CDCl3) d 1.23 (3H,
d, J¼6.7 Hz), 1.33 (6H, q, J¼6.2 Hz), 2.05 (2H, m), 2.35
(1H, dd, J¼16.4, 1.8 Hz), 2.87 (1H, dd, J¼16.4, 5.8 Hz),
3.07 (1H, m), 3.21 (3H, s), 3.58 (1H, d, J¼18.9 Hz), 3.63–
3.83 (2H, m), 3.86 (3H, s), 3.88 (3H, s), 4.02–4.18 (5H, m),
6.42 (1H, s), 6.63 (1H, s). 31P NMR d 30.14. HRMS (FAB):
calcd for C22H34N2O6P [(MþH)þ]: 453.2155. Found:
453.2150.
4.1.32. (3S)-2-(2-Methoxyethyl)-3,5-dimethyl-7,8-
dimethoxy-1-oxo-1,2,3,4,5,10-hexahydrobenzo[b]-1,6-
naphthyridine (1d). According to the general procedure
(C) from 11d (346 mg, 1 mmol) affording 1d as an orange
solid in 98% yield. 1H NMR (200 MHz, CDCl3) d 1.22 (3H,
d, J¼6.5 Hz), 2.34 (1H, dd, J¼16.1, 2.5 Hz), 2.88 (1H, dd,
J¼14.1, 5.9 Hz), 2.99 (1H, ddd, J¼14.2, 6.8, 5.8 Hz), 3.21
(3H, s), 3.35 (3H, s), 3.54 (2H, dd, J¼6.1, 4.7 Hz), 3.62 (1H,
m), 3.69 (1H, m), 3.78 (1H, m), 3.84 (3H, s), 3.88 (3H, s),
4.10 (1H, dt, J¼14.1, 4.6 Hz), 6.43 (1H, s), 6.65 (1H, s). 13C
NMR (50 MHz, CDCl3) d 18.39, 25.83, 32.32, 33.45, 50.93,
56.68, 56.75, 59.30, 72.49, 98.61, 99.08, 113.01, 116.14,
134.91, 145.02 (2C), 147.86, 166.02. HRMS (FAB): calcd
for C19H27N2O4 [(MþH)þ]: 347.1971. Found: 347.1968.
4.1.37. One pot procedure for the preparation of NADH
models 1 from compounds 10. To a stirred solution of 10
(1 mmol) in CH2Cl2 (5 mL) was added a solution of methyl
trifluoromethane sulfonate (180 mg, 1.1 mmol) in CH2Cl2
(5 mL). After stirring under nitrogen for 1 h at room
temperature, a solution of sodium dithionite (174 mg,
1 mmol) and sodium carbonate (106 mg, 1 mmol) in water
(15 mL) were added. After stirring for 1 h under nitrogen
atmosphere, Na2S2O4 (174 mg, 1 mmol) and Na2CO3
(106 mg, 1 mmol) were added in one portion. After stirring
for 1 h, Na2S2O4 (174 mg, 1 mmol) was added and stirring
was continued for an additional 1 h. The aqueous phase was
extracted with CH2Cl2 (3£20 mL), the combined organic
layers were dried over Na2SO4 and evaporated under
vacuum to give the corresponding model 1 in 81–98%
yield (see Table 2).
4.1.33. (3S)-2-(3-Hydroxypropyl)-3,5-dimethyl-7,8-
dimethoxy-1-oxo-1,2,3,4,5,10-hexahydrobenzo[b]-1,6-
naphthyridine (1f). According to the general procedure (C)
from 11f (346 mg, 1 mmol) affording 1f (90%) as a pink
solid. 1H NMR (200 MHz, CDCl3) d 1.27 (3H, d,
J¼6.5 Hz), 1.58–1.89 (2H, m), 2.29 (1H, dd, J¼16.3,
3.4 Hz), 2.81 (1H, dd, J¼16.3, 6.6 Hz), 3.14 (1H, dt,
J¼14.6, 1.8 Hz), 3.22 (3H, s), 3.52–3.76 (5H, m), 3.84 (3H,
s), 3.88 (3H, s), 4.08 (1H, dt, J¼14.6, 1.8 Hz), 4.52 (1H,
broad), 6.44 (1H, s), 6.63 (1H, s). HRMS (FAB): calcd for
C19H27N2O4 [(MþH)þ]: 347.1971. Found: 347.1973.
4.1.38. General procedure for the reduction of methyl
benzoylformate with NADH mimics 1a,d,f,g,h,k. In a
flask, flushed with argon, were introduced model 1
(1 mmol), acetonitrile (3 mL), methyl benzoylformate
(142 mL, 1 mmol) and magnesium perchlorate (224 mg,
1 mmol). The resulting solution was stirred at room
temperature for 24 h in the dark. After addition of water
(10 mL), the organic solvent was evaporated under reduced
pressure and the resulting aqueous phase was extracted with
CH2Cl2 (3£10 mL). After drying (MgSO4) and evaporation
of CH2Cl2, the residue was chromatographed on silica gel
(eluent Et2O–cyclohexane 2:1). Yield: 81–98%. Enantio-
meric excesses were determined by HPLC analysis using a
Chiralcel OD (250£4.6 mm; 10 mm). Chromatographic
conditions: injection: 20 ml (0.5 mg of methyl mandelate
in 10 mL of hexane). Eluent: hexane–2-propanol 90:10.
Flow rate: 1 mL/min. Pressure: 300 psi. Temperature: 228C.
UV detection: l¼235 nm. Retention time: 9.2 min [(S)-
enantiomer] and 14.8 min [(R)-enantiomer].
4.1.34. (3S)-2-(2-Hydroxyethyl)-7,8-dimethoxy-3,5-
dimethyl-1-oxo-1,2,3,4,5,10-hexahydrobenzo[b]-1,6-
naphthyridine (1g). According to the general procedure C
from 11g (332 mg, 1 mmol) affording 1g (81%) as an
1
orange solid. H NMR (200 MHz, CDCl3) d 1.24 (3H, d,
J¼6.5 Hz), 2.37 (1H, dd, J¼15.7, 2.6 Hz), 2.90 (1H, dd,
J¼15.7, 6.6 Hz), 3.17 (1H, m), 3.20 (3H,s), 3.63 (1H, m),
3.66 (1H, m), 3.69 (1H, m), 3.78 (2H, m), 3.83 (3H, s), 3.86
(3H, s), 3.87 (1H, m), 6.42 (1H, s), 6.61 (1H, s). HRMS
(FAB): calcd for C18H25N2O4 [(MþH)þ]: 333.1814. Found
333.1812.
4.1.35. (3S)-2-(2-Hydroxyethyl)-7,8-dimethoxy-5-
methyl-1-oxo-3-phenyl-1,2,3,4,5,10-hexahydrobenzo[b]-
1,6-naphthyridine (1h). According to the general pro-
cedure C from 11h (394 mg, 1 mmol) affording 1h (90%) as
4.1.39. General procedure for the reduction of 2-ben-
zoylpyridine with NADH mimics 1d,f,g. Model 1
(1 mmol), acetonitrile (3 mL), 2-benzoylpyridine (183 mg,
1 mmol) and magnesium perchlorate (224 mg, 1 mmol)
were introduced in a flask flushed with argon. The resulting
solution was stirred at room temperature for 24 h in the dark.
After addition of water (10 mL), the organic solvent was
evaporated under reduced pressure and the resulting
aqueous phase was extracted with CH2Cl2 (3£10 mL).
After drying (MgSO4) and evaporation of CH2Cl2, the
residue was purified by flash chromatography (SiO2/
EtOAc–cyclohexane 1:4) affording 2-(a-hydroxybenzyl)-
pyridine in 75–90% yield as a beige solid. 1H NMR
1
an orange solid. H NMR (200 MHz, CDCl3) d 2.71 (1H,
dd, J¼16.1, 4.3 Hz), 3.01 (1H, dt, J¼14.3, 4.7 Hz), 3.04
(3H, s), 3.09 (1H, ddt, J¼16.1, 7.1, 1.4 Hz), 3.53–3.71 (4H,
m), 3.76–3.81 (7H, m), 4.66 (1H, dd, J¼7.4, 4.3 Hz), 6.26
(1H, s), 6.53 (1H, s), 7.10–7.25 (5H, m). 13C NMR
(50 MHz, CDCl3) d 25.78, 33.42, 34.17, 50.41, 56.64,
56.71, 60.23, 63.37, 98.58, 99.30, 112.94, 115.90, 127.13,
128.40, 129.28, 134.33, 140.92, 144.85, 145.29, 147.88,
169.64. HRMS (FAB): calcd for C23H27N2O4 [(MþH)þ]:
395.1971. Found: 395.1973.

J.-L. Vasse et al. / Tetrahedron 59 (2003) 4911–4921
4921
7. PCMODELw 7.0 implementation of MM2 force-field.
CERIUS 2w, MSI CVFF force-field.
(200 MHz, CDCl3) d 5.40 (1H, s, broad, D2O exchange-
able), 5.77 (1H, s), 7.15–7.27 (2H, m), 7.30–7.43 (5H, m),
7.63 (1H, td, J¼7.6, 1.7 Hz), 8.57 (1H, dt, J¼4.7, 1.4 Hz).
IR (CHCl3) 3119, 1594, 1050, 756, 696 cm21. Enantiomeric
excesses were determined by HPLC analysis using a
Chiralcel OD (250£4.6 mm; 10 mm). Chromatographic
conditions: injection: 20 ml [0.5 mg of 2-(a-hydroxy-
benzyl)pyridine in 10 mL of hexane]. Eluent: hexane–2-
propanol 98:2. Flow rate: 1 mL/min. Pressure: 61 psi.
Temperature: 198C. UV detection: l¼230 nm. Absolute
configuration was determined by comparison with the sign
of the optical rotation known in literature.16a
8. (a) Schultz, A. G.; Kirincich, S. J.; Rahm, R. Tetrahedron Lett.
1995, 36, 4551–4554. (b) Derdau, V.; Snieckus, V. J. Org.
Chem. 2001, 66, 1992–1998.
¨
9. (a) Waldmann, H.; Braun, M.; Drager, M. Tetrahedron:
Asymmetry 1991, 2, 1231. (b) Davies, F.; Chao, B.; Fang, T.;
Szewczyk, J. M. Org. Lett. 2000, 2, 1041–1043. (c) Murray,
P. J.; Starkey, I. D. Tetrahedron Lett. 1996, 37, 1875–1878.
(d) Leflemme, N.; Dallemagne, P.; Rault, S. Tetrahedron Lett.
2001, 42, 8997–8999. (e) Kawecki, R. Tetrahedron 2001,
8385–8390.
10. (a) Davies, S. G.; Ichihara, O. Tetrahedron Lett. 1998, 39,
6045–6048. (b) Davies, S. G.; Ichihara, O. Tetrahedron:
Asymmetry 1991, 2, 183–186.
Acknowledgements
´
11. Vitry, C.; Vasse, J.-L.; Levacher, V.; Dupas, G.; Queguiner,
G.; Bourguignon, J. Tetrahedron 2001, 57, 3087.
12. Cheng, C. C.; Yan, S. J. The Friedlander Synthesis of
Quinolines Organic Reactions; Wiley: New York, 1982;
Vol. 28. pp 37–202.
´
We thank the CNRS, the region Haute Normandie and the
CRIHAN for technical and financial support.
13. Johnstone, R. A. W.; Rose, M. E. Tetrahedron 1979, 35, 2169.
14. At this stage of the synthesis, it was important to make sure
that deprotection and alkylation steps are performed under
non-racemizing conditions. To this end, oxidative cleavage of
rac-8a, followed by alkylation of the resulting lactam rac-9a
with allyl bromide furnished rac-10b. The enantioseparation
of rac-10b by chiral HPLC allowed us to conclude that no
racemization occurs when the same deprotection–alkylation
sequence is achieved starting from (S)-8a. Chromatographic
conditions: Chiralcel OD (250£4.6 mm, 10 mm), injection:
20 ml (0.5 mg of rac-10b in 10 mL of hexane); Eluent:
heptane/2-propanol: 80/20; Flow rate: 1 mL/min. Pressure:
455 psi. Temperature: 18.58C. UV detection: l¼230 nm.
Retention time: 13.25 min [(R)-enantiomer] and 15.64 min
[(S)-enantiomer].
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