Convenient one-pot synthesis of chiral tetrahydropyridines via a multicomponent reaction

Article abstract of DOI:10.1055/s-2008-1067092

The multicomponent condensation of various β-dicarbonyl compounds, acrolein and (S)-2-phenylglycinol was found to provide a one-pot access to chiral 6-carbonyl-3-phenyl-2,3,8,8a-tet-rahydro-7H-[l,3]oxazolo[3,2-a]pyridines. The value of this methodology is illustrated by the short and efficient synthesis of (-)-lupinine.

Full text of DOI:10.1055/s-2008-1067092

1948
PAPER
Convenient One-Pot Synthesis of Chiral Tetrahydropyridines
via a Multicomponent Reaction
One-Pot Synthes
o
T
m
etrahydropyridinesain Noël, Marie-Claude Fargeau-Bellassoued, Corinne Vanucci-Bacqué, Gérard Lhommet*
Laboratoire de Chimie Organique, Equipe Chimie des Hétérocycles, CNRS, UMR 7611, Université Pierre & Marie Curie,
4 place Jussieu, 75005 Paris, France
Fax +33(1)44273056; E-mail: gerard.lhommet@upmc.fr
Received 11 March 2008
Route a
Abstract: The multicomponent condensation of various b-dicarbo-
nyl compounds, acrolein and (S)-2-phenylglycinol was found to
provide a one-pot access to chiral 6-carbonyl-3-phenyl-2,3,8,8a-tet-
rahydro-7H-[1,3]oxazolo[3,2-a]pyridines. The value of this meth-
odology is illustrated by the short and efficient synthesis of (–)-
lupinine.
O
NH2
Ph
O
O
O
R1
HO
5
R2
3
R1
R2
O
R3
O
R3
4
2
Key words: multicomponent reaction, tetrahydropyridines, oxazo-
lidine, asymmetric synthesis, alkaloids
Route b
O
O
R2
NH2
Ph
O
R1
R2
+
+
HO
R3
Substituted tetrahydropyridine intermediates have proved
to be useful for the preparation of various natural products
such as matrine,1 cytisine2 and tashiromine.3 For our
part, we have recently reported the preparation of chiral
6-carbonyl-3-phenyl-2,3,8,8a-tetrahydro-7H-[1,3]oxazo-
lo[3,2-a]pyridine derivatives 1 whose diastereoselective
controlled reduction enabled us to prepare enantiopure
‘all cis’ 2,6- and 2,3,6-substituted b-amino carbonyl pipe-
ridines.4 This approach allowed us to achieve the efficient
total synthesis of a 2,6-disubstituted 3-hydroxypiperidine,
(–)-deoxocassine.4 Compounds 1 were prepared accord-
ing to a two-step sequence5 featuring a Michael reaction
of symmetrical b-diketones or b-keto esters 2 with a,b-un-
saturated carbonyl compounds 3 (in particular, acrolein
R1
O
N
O
R3
Ph
2
3
5
1
Scheme 1
Ph
O
OH
N
Ph
O
N
N
O
N
HO
Ph
Ph
(–)-lupinine (6)
7
(2R,3R)-8j
and methyl vinyl ketone), followed by the condensation of Figure 1
a chiral amine, (S)-2-phenylglycinol (5), with the result-
ing tricarbonyl compounds 4 (Scheme 1, Route a). Fol-
In a preliminary study, we found that reactions with vari-
ous a,b-unsaturated carbonyl compounds 3 were only ef-
ficient in the case of acrolein (3a, R1 = H).8 Therefore, we
decided to focus our study on the preparation of tetrahy-
drooxazolopyridines 1 bearing an angular hydrogen atom
at C-8a (R1 = H).
lowing these results, we envisioned an alternative strategy
allowing the preparation of these complex compounds via
a one-pot multicomponent reaction (MCR).
Indeed, MCRs have recently emerged as a powerful tool
in organic synthesis due to their advantages such as time
and cost savings, atom economy and environmental
friendliness. Recent studies on MCRs between b-dicarbo-
nyl derivatives, a,b-unsaturated compounds and function-
alized amines6,7 have prompted us to report our results on
the preparation of target compounds 1 via a three-compo-
nent reaction involving compounds 2, 3 and (S)-2-phe-
nylglycinol (5) (Scheme 1, Route b). The value of the
resulting chiral tetrahydropyridines as precursors of natu-
ral products will be illustrated by the total enantioselective
synthesis of the quinolizidine alkaloid (–)-lupinine (6)
(Figure 1).
To evaluate the scope of our new MCR, we carried out the
reactions using various b-keto esters (R2 = OR) and b-
diketones (R2 = alkyl, phenyl) 2a–j whose R3 substituents
were either simple or functionalized alkyl groups or, alter-
natively, a phenyl moiety (Table 1). The corresponding
compounds were commercially available, except for com-
pounds 2d9 and 2f10 that were prepared by condensation of
the dianion of methyl acetoacetate with 1-bromo-3-chlo-
ropropane or 2-(2-bromoethyl)-1,3-dioxolane, respective-
ly.
We first investigated the condensation of b-keto ester 2a
(R2 = OMe, R3 = Me), acrolein (3a) and (S)-2-phenylgly-
cinol (5) (1.1:1.1:1 molar ratio) in toluene at room temper-
ature. Monitoring of the reaction by GC showed that, after
SYNTHESIS 2008, No. 12, pp 1948–1954
x
x.
x
x
.
2
0
0
8
Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1067092; Art ID: Z06408SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of Chiral Tetrahydropyridines
1949
Table 1 Preparation of Compounds 1 by the Multicomponent Reaction of 2, 3a and 5
O
O
O
R2
O
R2
NH2
Ph
toluene
4 Å MS
8a
8a
R2
+
+
+
HO
R3
N
R3
H
N
O
O
O
R3
Ph
(8aR)-1
Ph
(8aS)-1
2
3a
5
Entry
R2
R3
2
Time (h)
0.5c
24d
4c
Products 1 Yielda (%) Ratiob (8aR)-1:(8aS)-1
1
2
OMe
OEt
Me
n-Pr
2a
2b
2c
2d9
2e
2f10
2g
2h
2i
1a5
1b
1c5
1d
1a
57
40
58
41
29
39
19e
75
54
63
67:33
85:15
58:42
80:20
70:30
67:33
60:40
50:50
60:40f
70:30
3
OMe
OMe
OMe
OMe
OEt
CH2Cl
4
(CH2)3CH2Cl
24d
24d
24d
24d
1c
5
CH2CO2Me
6
(CH2)3CH(OCH2CH2O)
1f
7
Ph
1g5
1h5
1i5
1j
8
Me
Me
9
–(CH2)3–
24d
15d
10
Ph
Me
2j
a Isolated yields.
b Estimated by 1H NMR spectroscopy and GC.
c Reaction carried out at room temperature.
d Reaction carried out in refluxing toluene.
e Compound 4g was also obtained in 45% isolated yield.
f Ratio of (3aR)-1i:(3aS)-1i.
disappearance of the starting materials, the crude mixture yields. At this point, comparison of the MCR and the two-
was composed of the expected compound 1a along with step sequence was possible, since we had previously pre-
another derivative, which was identified (see below) as pared compounds 1a, 1h and 1i according to Scheme 1,
tricyclic compound 7 (Figure 1), in a 38:62 ratio. In con- Route a.5 Although condensation of (S)-2-phenylglycinol
trast, in the presence of 4-Å molecular sieves, which act with the appropriate tricarbonyl compounds 4 was partic-
as both a dehydrating agent and a Michael reaction pro- ularly efficient (86–96% isolated yield), it required two
moter,6 this reaction proceeded more rapidly (0.5 h) af- equivalents of reactants 4. In addition, the necessary iso-
fording the expected tetrahydropyridine 1a as the major lation of compounds 4 (37 to 64% isolated yield) lowered
product, with only a trace of byproduct 7 being detected the overall yield (34 to 57%). Overall, at least for these
in the crude mixture by GC. Compound 1a was thus iso- compounds, MCRs clearly appears more efficient than the
lated as a 67:33 mixture of two diastereomers at C-8a, in two-step procedure.
a good 57% overall isolated yield (Table 1, entry 1).
Screening of the reaction conditions (temperature, reac-
tion time, molar ratio) did not result in an improved yield
Noteworthy, the MCR of keto diester 2e only allowed the
isolation of compound 1a in low yield (Table 1, entry 5)
as a result of decarboxylation of the expected tetrahydro-
of compound 1a. We next examined the MCR of b-dicar-
pyridine product in refluxing toluene. Phenylketo ester 2g
bonyl derivatives 2b–j with acrolein and (S)-2-phenylgly-
was also atypical: reaction led to the expected compound
cinol in 1.1:1.1:1 molar ratio. The optimized reaction
1g in only 19% isolated yield, along with tricarbonyl de-
conditions are summarized in Table 1. As for b-keto ester
2a, MCRs with compounds 2c and 2h conducted at room
temperature rapidly led to the expected tetrahydropy-
ridines 1c and 1h (Table 1, entries 3 and 8); however,
completion of the reaction in the case of the other com-
pounds required an increase in both the reaction time and
the temperature (up to toluene reflux). In all cases, com-
pound 7 was detected as a trace in the crude reaction mix-
tures and compounds 1 were obtained as mixtures of two
diastereomers at C-8a,11 in moderate to good overall
rivative 4g5 (Scheme 1; R1 = H, R2 = OEt, R3 = Ph) that
was surprisingly obtained as the major product in 45%
isolated yield (Table 1, entry 7).12
Regarding the MCR with unsymmetrical b-diketone 2j
(Table 1, entry 10), the reaction turned out to be totally
regioselective as only one tetrahydropyridine 1j was iso-
lated. In order to unambiguously assign its structure, we
decided to perform its reduction. Treatment of compound
1j with in situ generated sodium triacetoxyborohydride13
Synthesis 2008, No. 12, 1948–1954 © Thieme Stuttgart · New York

1950
R. Noël et al.
PAPER
Route b
Route c
afforded piperidine 8j (Figure 1) in 86% yield as a single
isomer. Its stereochemistry was assigned to (2R,3R) by
analogy with the results previously obtained on similar
compounds.4 The 1H NMR signal of the methyl substitu-
ent of 8j (doublet at d = 0.75 ppm) confirmed the presence
of an aromatic ketone in 1j.
Route a
2a
2a
5
5
3a
(0.5 h)
3a
(4 h)
(99%)
(50%)
(4 h)
MeO2C
HN
Concerning the stereochemical outcome, the tetrahydro-
pyridines 1a–d,f–j were generally obtained as an insepa-
rable mixture of diastereomers at C-8a, with variable
diastereomeric excesses (1:1 to 85:15 ratio of isomers).
Based on NMR data in line with what has been previously
reported on similar oxazolidine derivatives,5 the (8aR) ste-
reochemistry was assigned to all the major isomers. Note-
worthy, the diastereoselectivities of compounds 1 were
opposite, depending on the procedure followed. Indeed,
when comparisons of the MCR and the two-step proce-
dure (Scheme 1, Route a) were possible (Table 1, entries
1, 3 and 7–9), we observed that the (8aS)-isomers were
major in the case of the step-by-step strategy.5 Whatever
the stereochemical outcome, the poor obtained diastereo-
selectivities of compounds 1 are of little importance since
we have shown4 that the stereochemistry at the C-8a cen-
ter has no influence on the stereochemistry of the products
obtained after further transformations such as reductions.
OHC
CO2Me
N
O
NH
O
HO
HO
Ph
Ph
10
Ph
4a
9
10'
5
(4 h)
3a
(3 h)
2a
(4 h)
(51%)
(36%)
(46%)
CO2Me
ratio (8aR)-1a/(8aS)-1a
Route a: 45:55
Route b: 90:10
N
O
Ph
1a
Route c: 66:34
Scheme 2
Ph
In order to rationalize the mechanisms involved in the
three-component reaction, we investigated the three dif-
ferent possible two-step sequences using b-keto ester 2a,
acrolein (3a) and (S)-2-phenylglycinol (5) as the starting
materials (Scheme 2). All reactions were carried out in
toluene at room temperature in the presence of 4-Å molec-
ular sieves and monitored by GC to follow the consump-
tion of the starting materials. First, compound 2a was
reacted with acrolein (3a) to give the tricarbonyl deriva-
tive 4a5 in 50% isolated yield. The latter was then reacted
with (S)-2-phenylglycinol (5) to give the target tetrahy-
dropyridine 1a in 51% isolated yield as two isomers in a
45:55 ratio (Scheme 2, Route a).
OH
N
3a
5
(36%)
7
10
10'
toluene
4 Å MS, 15 h
N
HO
Ph
Scheme 3
This mechanistic study showed that all possible pathways
yield the target tetrahydropyridine 1a and therefore none
can be ruled out. In the multicomponent process, the three
routes are likely to be in competition. In a related study,6a
the authors postulated that the reaction proceeded initially
via the Michael addition of the b-dicarbonyl compound to
the a,b-unsaturated carbonyl derivative (Scheme 2, Route
a) without any contribution from the other pathways. In
our case, occurrence of this pathway might be substantiat-
ed by the isolation of intermediate tricarbonyl compound
4g when aromatic keto ester 2g was used as the reactant
(Table 1, entry 7); however, the presence of 1,5-diazocane
7, detected as a trace in all three-component reaction mix-
tures, provides proof of the formation of intermediates 10
and/or 10¢. Therefore, we assume that Route c resulting
from the initial rapid reaction of (S)-2-phenylglycinol
with the aldehyde function of acrolein is highly competi-
tive. Moreover, the isolated overall yield and the diaste-
reomeric excess obtained according to this route for
compound 1a fit well with the results obtained for the
MCR (Table 1, entry 1).
We then condensed compound 2a with (S)-2-phenylglyci-
nol (5) and isolated the described enamino ester 914 in
quantitative yield. Reaction with acrolein (3a) gave rise to
1a in 36% isolated yield as a 90:10 mixture of isomers
(Scheme 2, Route b). Finally, (S)-2-phenylglycinol and
acrolein reacted instantaneously to give an intermediate
we could not isolate but that was supposed to consist of an
equilibrated mixture of enimine 10 and oxazolidine 10¢.
Subsequent addition of b-keto ester 2a gave rise to 1a in
46% overall isolated yield as a 66:34 mixture of isomers
(Scheme 2, Route c).
Evidence of the presence of 1-aza-1,3-butadiene 10 (or of
the corresponding oxazolidine 10¢) was obtained upon
prolonged reaction between (S)-2-phenylglycinol and ac-
rolein (15 h). In this case, we isolated 1,5-diazocane 7 in
36% yield as a mixture of three isomers in a 50:25:25 ra-
tio. The latter compound might stem from the
cyclodimerization15 of enimine 10 followed by the subse-
quent addition of the hydroxy groups to the resulting
enamine moieties (Scheme 3).
As an illustration of the efficiency of our methodology for
the rapid synthesis of natural products, we decided to car-
ry out the total synthesis of (–)-lupinine (6) (Figure 1), a
quinolizidine alkaloid extracted from Lupinus species.16
Synthesis 2008, No. 12, 1948–1954 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Chiral Tetrahydropyridines
1951
Thin-layer chromatography was performed on Merck precoated sil-
ica gel (60 F254) plates and column chromatography on silica gel
Gerudan SI 60 (40–60 mm) (Merck). Melting points are uncorrect-
ed. IR spectra were recorded on a Philips PU 9700 instrument. Gas
chromatography was performed on capillary Chrompack CP-SIL5
columns. Optical rotations were measured on a Perkin–Elmer 341
polarimeter. HRMS data were recorded on an LTQ-Orbitrap (Ther-
mo Scientific) mass spectrometer and are accurate to 4 ppm. NMR
spectra were recorded using a 250-MHz spectrometer (Bruker ARX
250). Chemical shifts (d) are expressed in ppm relative to TMS at
d = 0 ppm for 1H NMR spectra and to CDCl3 at d = 77.16 ppm for
13C NMR spectra.
The key step of our approach is the preparation of poly-
functional tetrahydropyridine 1k obtained by the MCR of
commercially available b-keto diester 2k, acrolein (3a)
and (S)-2-phenylglycinol (5) in 44% isolated yield as a
67:33 ratio of isomers, the major one being of (8aR) con-
figuration (Scheme 4). Enamino diester 1k was diastereo-
selectively reduced upon treatment with in situ generated
sodium triacetoxyborohydride in acetic acid,4,13 leading to
piperidine 8k in 92% isolated yield as a single isomer. By
analogy with some previously reported results,4 the ste-
reochemistry of 8k was assigned to (2R,3R). This absolute
stereochemistry was ultimately secured by the obtainment
of (–)-lupinine (see below). Hydrogenolysis in the pres-
Compounds 1a–d,f–k; General Procedure
A heterogenous mixture of acrolein (3a; 1.1 mmol), a dicarbonyl
ence of palladium(II) hydroxide on carbon as the catalyst, compound 2 (1.1 mmol), (S)-2-phenylglycinol (5; 1.0 mmol) and 4-
Å MS (10 g) in toluene (40 mL) was stirred at the appropriate tem-
followed by treatment with p-toluenesulfonic acid in re-
fluxing toluene, gave rise to the bicyclic lactam 11 in 86%
overall isolated yield. The double reduction of the ester
and amide functions with lithium aluminum hydride in re-
perature until disappearance of the starting materials, as determined
by GC. The mixture was filtered through a Celite® pad and the or-
ganic layer was concentrated under reduced pressure. Column chro-
matography on silica gel afforded the expected compound 1.
fluxing tetrahydrofuran afforded the expected compound
6 in 83% isolated yield. The spectroscopic data and the
Methyl (3S)-5-Methyl-3-phenyl-2,3,8,8a-tetrahydro-7H-
[1,3]oxazolo[3,2-a]pyridine-6-carboxylate (1a)5
From 2a (70 mL, 0.65 mmol), (S)-2-phenylglycinol (80 mg, 0.58
mmol), acrolein (45 mL, 0.65 mmol) and 4-Å MS (5.8 g) in toluene
(23 mL) at r.t. for 0.5 h was obtained 1a (91 mg, 57%) as a 67:33
mixture of two diastereomers that were not separated.
20
optical rotation of this compound {[a]D –21 (c 0.615,
EtOH)} were consistent with those reported in the litera-
20
ture for (–)-lupinine {[a]D20 –21.5 (c 0.36, EtOH)10, [a]D
–22 (c 0.71, EtOH)17}.
CO2Et
CO2Et
Ethyl (3S)-3-Phenyl-5-propyl-2,3,8,8a-tetrahydro-7H-[1,3]ox-
azolo[3,2-a]pyridine-6-carboxylate (1b)
NaBH(OAc)3
AcOH, MeCN
3a, 5
From 2b (95 mL, 0.60 mmol), (S)-2-phenylglycinol (74 mg, 0.54
mmol), acrolein (40 mL, 0.60 mmol) and 4-Å MS (5.4 g) in reflux-
ing toluene (22 mL) for 24 h was obtained 1b (68 mg, 40%) as an
85:15 inseparable mixture of two diastereomers.
O
( )3
N
( )3
O
4 Å MS, toluene
(44%; 67:33)
(92%)
CO2Et
CO2Et
Ph
1k
2k
Colorless solid; Rf = 0.22 (EtOAc–cyclohexane, 1:9).
IR (CHCl3): 1670 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C19H26NO3: 316.1907; found:
CO2Et
CO2Et
1) H2, Pd(OH)2/C
LiAlH4
6
( )3
N
N
2) PTSA, toluene
(86%)
316.1905.
THF
(83%)
HO
CO2Et
O
For (3S,8aR)-1b (major isomer, from a mixture):
Ph
1H NMR (250 MHz, CDCl3): d = 0.74 (t, J = 7.25 Hz, 3 H), 1.15–
1.60 (m, 3 H), 1.25 (t, J = 7.0 Hz, 3 H), 2.16–2.44 (m, 3 H), 2.70–
2.95 (m, 2 H), 3.76 (dd, J = 6.0, 8.75 Hz, 1 H), 4.10 (q, J = 7.0 Hz,
2 H), 4.42 (dd, J = 7.25, 8.75 Hz, 1 H), 4.90 (t, J = 6.5 Hz, 1 H), 5.04
(dd, J = 4.0, 9.75 Hz, 1 H), 7.20–7.40 (m, 5 H).
13C NMR (62.5 MHz, CDCl3): d = 14.3, 14.7, 21.2, 22.7, 26.7, 32.8,
59.0, 61.4, 73.9, 89.4, 94.3, 125.9, 127.9, 129.1, 142.2, 156.5,
168.2.
8k
11
Scheme 4
In conclusion, we have developed a novel, rapid access to
chiral, bicyclic functionalized tetrahydropyridines 1 by a
three-component reaction between acrolein (3a), (S)-2-
phenylglycinol (5) and various b-dicarbonyl compounds
2. This simple methodology allowed the concomitant for-
mation of four bonds and two stereogenic centers, leading
in good yields to the target compounds which constitute
valuable intermediates for the synthesis of alkaloids. An J = 7.0 Hz, 3 H), 4.20–4.28 (m, 2 H), 4.75 (dd, J = 2.5, 10.0 Hz, 1
illustration has been given by the total enantioselective
synthesis of (–)-lupinine that was achieved in five steps
and in 29% overall yield from commercially available ma-
terials. To our knowledge, this synthesis constitutes the
most rapid and efficient access to this alkaloid.
For (3S,8aS)-1b (minor isomer, characteristic signals from a mix-
ture):
1H NMR (250 MHz, CDCl3): d = 0.84 (t, J = 7.25 Hz, 3 H), 1.22 (t,
H), 4.82–4.88 (m, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 14.5, 22.3, 26.8, 33.3, 60.5, 74.6,
88.5, 93.9, 126.1, 127.8, 129.0, 143.5, 155.2, 168.3.
Methyl (3S)-5-(Chloromethyl)-3-phenyl-2,3,8,8a-tetrahydro-
7H-[1,3]oxazolo[3,2-a]pyridine-6-carboxylate (1c)5
From 2c (70 mL, 0.61 mmol), (S)-2-phenylglycinol (74 mg, 0.54
mmol), acrolein (40 mL, 0.61 mmol) and 4-Å MS (5.4 g) in toluene
(22 mL) at r.t. for 4 h was obtained 1c (96 mg, 58%) as a 58:42 in-
separable mixture of two diastereomers.
Unless otherwise specified, materials were purchased from com-
mercial suppliers and used without further purification. THF was
distilled from sodium/benzophenone ketyl immediately prior to use.
Synthesis 2008, No. 12, 1948–1954 © Thieme Stuttgart · New York

1952
R. Noël et al.
PAPER
Methyl (3S)-5-(4-Chlorobutyl)-3-phenyl-2,3,8,8a-tetrahydro-
7H-[1,3]oxazolo[3,2-a]pyridine-6-carboxylate (1d)
1-[(3S)-5-Methyl-3-phenyl-2,3,8,8a-tetrahydro-7H-[1,3]oxazo-
lo[3,2-a]pyridin-6-yl]ethanone (1h)5
From 2h (60 mL, 0.61 mmol), (S)-2-phenylglycinol (74 mg, 0.54
mmol), acrolein (40 mL, 0.61 mmol) and 4-Å MS (6 g) in toluene
(20 mL) at r.t. for 1 h was obtained 1h (105 mg, 75%) as a 50:50
mixture of two diastereomers that were not separated.
From 2d9 (124 mg, 0.65 mmol), (S)-2-phenylglycinol (80 mg, 0.58
mmol), acrolein (45 mL, 0.65 mmol) and 4-Å MS (5.8 g) in reflux-
ing toluene (23 mL) for 24 h was obtained 1d (83 mg, 41%) as an
80:20 inseparable mixture of two diastereomers.
Colorless solid; Rf = 0.20 (EtOAc–cyclohexane, 1:9).
IR (CHCl3): 1680 cm–1.
HRMS (ESI): m/z [M + Na]+ calcd for C19H24ClNO3Na: 372.1337;
found: 372.1333.
(1S)-1-Phenyl-1,2,3a,4,5,7,8,9-octahydro-6H-[1,3]oxazolo[3,2-
a]quinolin-6-one (1i)5
From 2i (73 mg, 0.65 mmol), (S)-2-phenylglycinol (80 mg, 0.58
mmol), acrolein (45 mL, 0.65 mmol) and 4-Å MS (5.8 g) in reflux-
ing toluene (23 mL) for 24 h was obtained 1i (85 mg, 54%) as a
60:40 inseparable mixture of two diastereomers.
For (3S,8aR)-1d (major isomer, from a mixture):
1H NMR (250 MHz, CDCl3): d = 1.40–1.75 (m, 4 H), 2.15–2.50 (m,
4 H), 2.66–2.92 (m, 2 H), 3.29–3.38 (m, 2 H), 3.63 (s, 3 H), 3.75
(dd, J = 6.5, 8.75 Hz, 1 H), 4.44 (t, J = 8.0 Hz, 1 H), 4.91 (t, J = 6.75
Hz, 1 H), 5.04 (dd, J = 4.0, 10.0 Hz, 1 H), 7.23–7.40 (m, 5 H).
13C NMR (62.5 MHz, CDCl3): d = 21.0, 26.2, 26.5, 30.0, 32.6, 44.6,
50.6, 61.4, 73.9, 89.4, 94.1, 125.9, 128.0, 129.2, 142.0, 156.2,
168.3.
[(3S)-5-Methyl-3-phenyl-2,3,8,8a-tetrahydro-7H-[1,3]oxazo-
lo[3,2-a]pyridin-6-yl](phenyl)methanone (1j)
From 2j (105 mg, 0.65 mmol), (S)-2-phenylglycinol (80 mg, 0.58
mmol), acrolein (45 mL, 0.65 mmol) and 4-Å MS (5.8 g) in reflux-
ing toluene (23 mL) for 15 h was obtained 1j (118 mg, 63%) as a
70:30 mixture of two diastereomers.
For (3S,8aR)-1j (major isomer):
For (3S,8aS)-1d (minor isomer, characteristic signals from a mix-
20
ture):
Colorless solid; mp 143 °C; [a]D +309 (c 0.875, CH2Cl2);
Rf = 0.27 (EtOAc–cyclohexane, 30:70).
1H NMR (250 MHz, CDCl3): d = 3.98–4.01 (m, 1 H), 4.26 (dd,
J = 6.5, 5.75 Hz, 1 H), 4.75 (dd, J = 2.5, 10.0 Hz, 1 H).
IR (CHCl3): 1540 cm–1.
13C NMR (62.5 MHz, CDCl3): d = 22.1, 25.7, 26.6, 30.3, 31.9, 42.7,
1H NMR (250 MHz, CDCl3): d = 1.49–1.68 (m, 1 H), 1.89 (s, 3 H),
2.25–2.32 (m, 1 H), 2.34–2.52 (m, 1 H), 2.64–2.78 (m, 1 H), 3.74
(dd, J = 7.50, 8.75 Hz, 1 H), 4.50 (dd, J = 7.50, 8.75 Hz, 1 H), 4.93
(t, J = 7.50 Hz, 1 H), 5.09 (dd, J = 4.00, 9.75 Hz, 1 H), 7.20–7.55
(m, 10 H).
13C NMR (62.5 MHz, CDCl3): d = 19.2, 23.3, 26.7, 61.7, 74.1, 89.7,
105.6, 125.7, 127.7, 127.9, 128.0, 129.1, 129.9, 140.9, 143.1, 152.9,
195.6.
60.5, 74.5, 88.4, 93.7, 126.0, 127.9, 129.0, 143.3, 155.0, 168.5.
Methyl (3S)-5-[3-(1,3-Dioxolan-2-yl)propyl]-3-phenyl-2,3,8,8a-
tetrahydro-7H-[1,3]oxazolo[3,2-a]pyridine-6-carboxylate (1f)
From 2f10 (140 mg, 0.65 mmol), (S)-2-phenylglycinol (80 mg, 0.58
mmol), acrolein (45 mL, 0.65 mmol) and 4-Å MS (5.8 g) in reflux-
ing toluene (23 mL) for 24 h was obtained 1f (85 mg, 39%) as a
67:33 inseparable mixture of two diastereomers.
HRMS (ESI): m/z [M + H]+ calcd for C21H22NO2: 320.1645; found:
320.1646.
Colorless solid; Rf = 0.27 (EtOAc–cyclohexane, 3:7).
IR (CHCl3): 1680 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C21H28NO5: 374.1967; found:
For (3S,8aS)-1j (minor isomer, characteristic signals from a mix-
ture):
374.1962.
1H NMR (250 MHz, CDCl3): d = 1.78 (s, 3 H), 4.02 (d, J = 8.75 Hz,
1 H), 4.29 (dd, J = 6.5, 8.5 Hz, 1 H), 4.83–4.92 (m, 2 H).
For (3S,8aR)-1f (major isomer, from a mixture):
1H NMR (250 MHz, CDCl3): d = 1.50–1.85 (m, 5 H), 2.15–2.40 (m,
3 H), 2.65–2.80 (m, 1 H), 2.96–3.09 (m, 1 H), 3.63 (s, 3 H), 3.72–
4.00 (m, 5 H), 4.43 (dd, J = 7.25, 8.75 Hz, 1 H), 4.66 (t, J = 4.25 Hz,
1 H), 4.90–4.95 (m, 1 H), 5.02 (dd, J = 3.75, 9.75 Hz, 1 H), 7.21–
7.39 (m, 5 H).
13C NMR (62.5 MHz, CDCl3): d = 21.0, 23.7, 26.5, 30.3, 33.6, 50.5,
61.1, 64.7, 73.7, 89.2, 93.9, 104.2, 125.7, 127.8, 129.0, 142.0,
156.3, 168.2.
13C NMR (62.5 MHz, CDCl3): d = 20.1, 24.2, 26.6, 61.3, 74.6, 88.8,
105.4, 126.0, 127.7, 127.9, 128.2, 129.1, 129.8, 142.4, 143.7, 151.8,
196.2.
Ethyl (3S)-5-(4-Ethoxy-4-oxobutyl)-3-phenyl-2,3,8,8a-tetrahy-
dro-7H-[1,3]oxazolo[3,2-a]pyridine-6-carboxylate (1k)
From 2k (290 mL, 1.37 mmol), (S)-2-phenylglycinol (171 mg, 1.25
mmol), acrolein (93 mL, 1.37 mmol) and 4-Å MS (12 g) in refluxing
toluene (50 mL) for 24 h was obtained 1k (212 mg, 44%) as a 67:33
inseparable mixture of two diastereomers.
For (3S,8aS)-1f (minor isomer, characteristic signals from a mix-
ture):
1H NMR (250 MHz, CDCl3): d = 4.25 (dd, J = 6.25, 8.5 Hz, 1 H),
4.70–4.76 (m, 2 H), 4.84–4.90 (m, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 22.0, 23.3, 30.7, 32.9, 60.3, 64.8,
74.5, 88.3, 93.6, 125.9, 127.7, 128.8, 143.2, 155.0, 168.4.
Colorless oil; Rf = 0.19 (EtOAc–cyclohexane, 15:85).
IR (CHCl3): 1735, 1680 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C22H30NO5: 388.2118; found:
388.2122.
For (3S,8aR)-1k (major isomer, from a mixture):
Ethyl (3S)-3,5-Diphenyl-2,3,8,8a-tetrahydro-7H-[1,3]oxazo-
lo[3,2-a]pyridine-6-carboxylate (1g)5
From 2g (165 mL, 0.96 mmol), (S)-2-phenylglycinol (119 mg, 0.87
mmol), acrolein (65 mL, 0.96 mmol) and 4-Å MS (9 g) in refluxing
toluene (25 mL) for 24 h were obtained 1g (57 mg, 19%) as a 60:40
inseparable mixture of two diastereomers, along with 4g5 (90 mg,
45%).
1H NMR (250 MHz, CDCl3): d = 1.14–1.28 (m, 6 H), 1.42–2.42 (m,
8 H), 2.67–2.80 (m, 1 H), 2.99–3.16 (m, 1 H), 3.74 (dd, J = 5.75, 8.5
Hz, 1 H), 3.97–4.15 (m, 4 H), 4.43 (dd, J = 7.25, 8.5 Hz, 1 H), 4.99–
5.99 (m, 2 H), 7.20–7.38 (m, 5 H).
13C NMR (62.5 MHz, CDCl3): d = 14.1, 14.5, 20.9, 24.2, 26.4, 29.8,
33.7, 58.7, 60.0, 60.7, 73.6, 89.0, 94.1, 125.7, 127.6, 128.9, 142.0,
155.3, 167.8, 173.3.
Synthesis 2008, No. 12, 1948–1954 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Chiral Tetrahydropyridines
1953
For (3S,8aS)-1k (minor isomer, characteristic signals from a mix-
ture):
1H NMR (250 MHz, CDCl3): d = 4.25 (dd, J = 6.25, 8.75 Hz, 1 H),
4.75 (dd, J = 2.25, 10.0 Hz, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 22.0, 23.7, 30.4, 58.7, 60.0, 60.1,
74.4, 88.2, 94.0, 126.0, 127.5, 128.6, 143.2, 154.1, 168.0, 173.5.
stirred for 36 h at reflux temperature, sat. NaHCO3 soln (10 mL)
was added and the aqueous layer was extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure. Purification of the crude product
by silica gel column chromatography (EtOAc) afforded compound
11 (169 mg, 86%) as a colorless oil.
[a]D20 +65 (c 1.31, MeOH); Rf = 0.15 (EtOAc).
(3S,9S)-3,9-Diphenyloctahydro-5H,11H-bis[1,3]oxazolo[3,2-
a:3¢,2¢-e][1,5]diazocine (7)
IR (CHCl3): 1730, 1645 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.26 (t, J = 7.0 Hz, 3 H), 1.51–
1.87 (m, 6 H), 1.92–2.14 (m, 2 H), 2.24–2.49 (m, 3 H), 2.63–2.69
(m, 1 H), 3.41–3.49 (m, 1 H), 4.10–4.19 (m, 2 H), 4.80–4.89 (m, 1
H).
13C NMR (62.5 MHz, CDCl3): d = 14.3, 19.4, 21.0, 27.7, 27.9, 32.8,
42.1, 44.5, 56.5, 60.4, 170.1, 172.7.
A heterogenous mixture of (S)-2-phenylglycinol (5; 74 mg, 0.54
mmol), acrolein (3a; 40 mL, 0.59 mmol) and 4-Å MS (6 g) in tolu-
ene (23 mL) was stirred at r.t. After 15 h, the mixture was filtered
through a Celite® pad and the organic layer was concentrated under
reduced pressure. Purification of the crude product by silica gel col-
umn chromatography (EtOAc–cyclohexane, 15:85) afforded 7 (34
mg, 36%) as a 50:25:25 inseparable mixture of three diastereomers.
HRMS (ESI): m/z [M + H]+ calcd for C12H20NO3: 226.1437; found:
226.1439.
Colorless oil; Rf = 0.09 (EtOAc–cyclohexane, 15:85).
1H NMR (250 MHz, CDCl3): d = 1.95–2.15 (m, 4 H), 2.50–2.65 (m,
1.5 H), 2.70–2.80 (m, 1 H), 2.97–3.15 (m, 1.5 H), 3.58–3.73 (m, 2
H), 3.80–3.88 (m, 1.5 H), 4.00–4.13 (m, 1.5 H), 4.20–4.30 (m, 2 H),
4.51 (t, J = 5.25 Hz, 0.5 H), 4.72 (dd, J = 1.5, 8.0 Hz, 0.5 H), 7.25–
7.49 (m, 10 H).
13C NMR (62.5 MHz, CDCl3): d = 30.9, 36.3, 38.0, 43.7, 46.9, 48.7,
69.3, 70.0, 71.4, 72.5 (2 signals), 73.0, 92.9, 95.6, 100.0, 127.5,
127.7, 128.0, 128.6, 128.7, 139.6, 140.0, 141.2.
(–)-Lupinine (6)10,17
To a soln of LiAlH4 (68 mg, 1.79 mmol) in anhyd THF (6 mL) was
added a soln of compound 11 (136 mg, 0.60 mmol) in anhyd THF
(6 mL). After being stirred at reflux temperature for 2 h, the reaction
mixture was cooled to 0 °C and sat. Na2SO4 soln was added until
gas evolution ceased. The mixture was filtered through a Celite®
pad and the organic layer was concentrated under reduced pressure.
Purification of the crude product by silica gel column chromatogra-
phy (1 N NH3 in EtOAc–cyclohexane, 80:20) afforded 6 (85 mg,
83%); [a]D20 –21 (c 0.615, EtOH).
HRMS (ESI): m/z [M + H]+ calcd for C22H27N2O2: 351.2067; found:
351.2065.
Ethyl (2R,3R)-2-(4-Ethoxy-4-oxobutyl)-1-[(1S)-2-hydroxy-1-
phenylethyl]piperidine-3-carboxylate (8k)
References
A soln of NaBH(OAc)3 was prepared by the portionwise addition of
NaBH4 (76 mg, 2 mmol) to glacial AcOH (1.15 mL, 20 mmol) in
MeCN (2.3 mL) at 0 °C. After H2 gas evolution had ceased (30
min), a soln of compound 1k (156 mg, 0.40 mmol) in MeCN (4 mL)
was added. After the mixture was stirred for 48 h at r.t., H2O (10
mL) was added and solid Na2CO3 was slowly added until pH 9. The
aqueous layer was extracted with CH2Cl2 (3 × 10 mL) and the com-
bined organic layers were dried (Na2SO4) and concentrated under
reduced pressure. Purification of the crude product by silica gel col-
umn chromatography (EtOAc–cyclohexane, 3:7) afforded (2R,3R)-
8k (145 mg, 92%) as a colorless oil.
[a]D20 –22 (c 2.58, MeOH); Rf = 0.20 (EtOAc–cyclohexane, 3:7).
IR (CHCl3): 3500, 1730 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.18 (t, J = 7.0 Hz, 3 H), 1.25 (t,
J = 7.0 Hz, 3 H), 1.32–1.79 (m, 8 H), 2.07–2.16 (m, 2 H), 2.16–2.36
(m, 1 H), 2.60–2.89 (m, 3 H), 3.09–3.17 (m, 1 H), 3.70–4.15 (m, 7
H), 7.25–7.39 (m, 5 H).
(1) Boiteau, L.; Boivin, J.; Liard, A.; Quiclet-Sire, B.; Zard, S.
Z. Angew. Chem. Int. Ed. 1998, 37, 1128.
(2) Botuha, C.; Galley, C. M. S.; Gallagher, T. Org. Biomol.
Chem. 2004, 2, 1825.
(3) Paulvannan, K.; Stille, J. R. J. Org. Chem. 1994, 59, 1613.
(4) Noël, R.; Vanucci-Bacqué, C.; Fargeau-Bellassoued, M.-C.;
Lhommet, G. Eur. J. Org. Chem. 2007, 476.
(5) Noël, R.; Vanucci-Bacqué, C.; Fargeau-Bellassoued, M.-C.;
Lhommet, G. J. Org. Chem. 2005, 70, 9044.
(6) (a) Simon, C.; Peyronel, J.-F.; Rodriguez, J. Org. Lett. 2001,
3, 2145. (b) Liéby-Muller, F.; Constantieux, T.; Rodriguez,
J. Synlett 2007, 1323.
(7) For a review on MCRs using b-dicarbonyl derivatives, see:
Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org.
Chem. 2004, 4957.
(8) The use of methyl vinyl ketone always led to intractable
mixtures, with only a trace of the expected tetrahydro-
pyridines.
(9) Calvet, S.; David, O.; Vanucci-Bacqué, C.; Fargeau-
Bellassoued, M.-C.; Lhommet, G. Tetrahedron 2003, 59,
6333.
(10) Agami, C.; Dechoux, L.; Hebbe, S.; Ménard, C. Tetrahedron
2004, 60, 5433.
13C NMR (62.5 MHz, CDCl3): d = 14.2, 14.4, 21.3, 22.5, 23.0, 25.6,
34.4, 42.1, 42.6, 57.2, 60.3, 63.2, 67.3, 128.1, 128.7, 140.3, 173.5,
174.0.
HRMS (ESI): m/z [M + H]+ calcd for C22H34NO5: 392.2431; found:
392.2432.
(11) The diastereomers were inseparable by column chromato-
graphy, except for compounds 1a and 1h.5
Ethyl (1R,9aR)-6-Oxooctahydro-2H-quinolizine-1-carboxylate
(11)
(12) Improved yield was obtained by the addition of 0.5 more
equivalents of (S)-2-phenylglycinol after reaction for 24
hours; under these conditions, the expected compound 1g
was isolated in 53% yield and the presence of compound 4g
was not detected.
(13) Cimarelli, C.; Palmieri, G. J. Org. Chem. 1996, 61, 5557.
(14) Agami, C.; Dechoux, L.; Ménard, C.; Hebbe, S. J. Org.
Chem. 2002, 67, 7573.
A soln of compound 8k (341 mg, 0.87 mmol) in EtOAc (9 mL) was
subjected to hydrogenation (1 atm) in the presence of Pd(OH)2/C
(68 mg) at r.t. for 15 h. The suspension was then filtered through a
Celite® pad and the organic layer was concentrated under reduced
pressure. The crude product was diluted with toluene (20 mL) and
PTSA (17 mg, 0.089 mmol) was added. After the mixture was
Synthesis 2008, No. 12, 1948–1954 © Thieme Stuttgart · New York

1954
R. Noël et al.
PAPER
(15) Banwell, M. G.; Crasto, C. F.; Easton, C. J.; Karoli, T.;
March, D. R.; Nairn, M. R.; O’Hanlon, P. J.; Oldman, M. D.;
Willis, A. C.; Yue, W. Chem. Commun. 2001, 2210.
(16) Kinghorn, A. D.; Balandrin, M. F. In Alkaloids: Chemical
and Biological Perspectives, Vol. 2; Pelletier, S. W., Ed.;
John Wiley & Sons: New York, 1984, 105.
(17) Ledoux, S.; Marchalant, E.; Célérier, J.-P.; Lhommet, G.
Tetrahedron Lett. 2001, 42, 5397.
Synthesis 2008, No. 12, 1948–1954 © Thieme Stuttgart · New York