Synthesis of new chiral 6-carbonyl 2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a] pyridines

Article abstract of DOI:10.1021/jo051192p

The preparation of new chiral 6-carbonyl 2,3,8,8a-tetrahydro-7H-oxazolo[3, 2-a]pyridines by an efficient two-step procedure is described.

Full text of DOI:10.1021/jo051192p

Synthesis of New Chiral 6-Carbonyl
2,3,8,8a-Tetrahydro-7H-oxazolo[3,2-a]pyridines
Romain Noe¨l, Corinne Vanucci-Bacque´,
Marie-Claude Fargeau-Bellassoued, and
Ge´rard Lhommet*
Universite´ P. et M. Curie, Laboratoire de Chimie Organique,
UMR 7611, Equipe de Chimie des He´te´rocycles, 4 place
Jussieu, 75252 Paris Cedex 05, France
FIGURE 1.
SCHEME 1
lhommet@ccr.jussieu.fr
Received June 13, 2005
The preparation of new chiral 6-carbonyl 2,3,8,8a-tetrahy-
dro-7H-oxazolo[3,2-a]pyridines by an efficient two-step pro-
cedure is described.
Whereas piperidine â-enamino carbonyl substructures
have been prepared from â-enamino carbonyl substrates
either upon addition of acrylates (to provide unsaturated
δ-lactam products5) or by intramolecular alkylation,6 our
approach to the target bicyclic molecules 2 relied on the
condensation of (S)-phenylglycinol to tricarbonyl com-
pounds 3. The latter compounds were expected to be
easily obtained by reaction of active methylene com-
pounds 5 with R,â-unsaturated carbonyl derivatives 4
(Scheme 1). This approach allows the synthesis of vari-
ously substituted structures while sparing the chiral
auxiliary since the latter is introduced in the late stages
of the synthesis.
To illustrate the potential of this approach, we decided
to focus our work on 4a,b (R1 ) H or Me). The required
tricarbonyl compounds 3 were thus readily prepared by
reacting either acroleine 4a or methylvinyl ketone 4b
with a variety of commercially available substituted
â-dicarbonyl compounds 5 (Table 1). Michael reactions
of dicarbonyl compounds 5 with acrolein 4a were per-
formed on solid Al2O3 without solvent according to a
literature procedure7 to lead to the expected products in
In our continuing efforts aimed at the synthesis of
chiral polyfunctional heterocycles as precursors of natural
products, we recently reported the preparation of bicyclic
piperidine â-enamino esters 1 (Figure 1) by condensation
of (S)-phenylglycinol with ω-oxo alkynoates and/or â-keto
esters.1 We and others have demonstrated that such
compounds bearing an exocyclic double bond are inter-
esting precursors to access to enantiopure mono- and
disubstituted piperidine â-amino esters that in turn are
useful intermediates in the total synthesis of alkaloids.2
During the course of this work, we realized that our
strategy could be extended toward â-enamino carbonyl
derivatives 2 possessing an intracyclic double bond (6-
carbonyl 2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]pyridines)
(Figure 1). Indeed, we envisioned that these compounds
would give rise to enantiopure 3-hydroxy-2,6-disubsti-
tuted piperidines that constitute a large group of natural
products such as Cassia and Prosopis alkaloids.3 Due to
their important biological activity, these compounds have
attracted particular attention from many research groups.4
Herein, we wish to report the results of this program that
successfully afforded unsaturated bicyclic piperidines 2.
(1) David, O.; Calvet, S.; Chau, F.; Vanucci-Bacque´, C.; Fargeau-
Bellassoued, M.-C.; Lhommet, G. J. Org. Chem. 2004, 69, 2888-2891.
(2) (a) Munchhof, M. J.; Meyers, A. I. J. Am. Chem. Soc. 1995, 117,
5399-5400. (b) Calvet-Vitale, S.; Vanucci-Bacque´, C.; Fargeau-Bel-
lassoued M.-C.; Lhommet, G. Tetrahedron 2005, 61, 7774-7782.
(3) (a) Schneider, M. J. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Pergamon: New York, 1996; Vol.
10, pp 155-299. (b) Nadin, A. J. Chem. Soc., Perkin Trans. 1 1998,
3493-3513.
(4) (a) Jourdant, A.; Zhu, J. Tetrahedron Lett. 2001, 42, 3431-3434.
(b) Comins, D. L.; Sandelier, M. J.; Abad Grillo, T. J. Org. Chem. 2001,
66, 6829-6832. (c) Singh, R.; Ghosh, S. K. Tetrahedron Lett. 2002, 43,
7711-7715. (d) Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz, S. J. Org.
Chem. 2002, 67, 1982-1992. (e) Dransfield, P. J.; Gore, P. M..;
Shipman, M.; Slawin, A. M. Z. Chem. Commun. 2002, 150-151. (f)
Ma, D.; Ma, N. Tetrahedron Lett. 2003, 44, 3963-3965.
(5) For some examples, see: (a) Brunerie, P.; Ce´le´rier, J.-P.; Huche´,
M.; Lhommet, G. Synthesis 1985, 735-738. (b) Huizenga, R. H.; van
Wiltenburg, J.; Pandit, U. K. Tetrahedron Lett. 1989, 30, 7105-7106.
(c) Cook, G. R.; Beholz, L. G.; Stille, J. R. J. Org. Chem. 1994, 59, 3575-
3584. (d) Paulvannan, K.; Stille, J. R. J. Org. Chem. 1994, 59, 1613-
1620. (e) Cimarelli, C.; Palmieri, G. Tetrahedron 1998, 54, 915-926.
(f) Agami, C.; Dechoux, L.; Hebbe S.; Me´nard, C. Tetrahedron 2004,
60, 5433-5438.
(6) (a) Michael, J. P.; Gravestock, D. Synlett 1996, 981-9982. (b)
Michael, J. P.; Gravestock, D. J. Chem. Soc., Perkin Trans. 1 2000,
1919-1928. (c) Ma, D.; Pu, X.; Wang, J. Tetrahedron: Asymmetry 2002,
13, 2257-2260. (d) Ma, N.; Ma, D. Tetrahedron: Asymmetry 2003, 14,
1403-1406.
(7) (a) Ranu, B. C.; Bhar, S.; Sarkar, D. C. Tetrahedron Lett. 1991,
32, 2811-2812. (b) Ranu, B. C.; Bhar, S. Tetrahedron 1992, 48, 1327-
1332.
10.1021/jo051192p CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/01/2005
9044
J. Org. Chem. 2005, 70, 9044-9047

TABLE 1. Preparation of Tricarbonyl Compounds 3
TABLE 2. Preparation of Compounds 2
ratiof
(8aR)-2/ yieldg
entry
3
R1
H
R2
R3
product procedurea (8aS)-2
(%)
entry
4
5
R1
H
R2
R3
procedurea 3 (yield, %)e
1
2
3a
OMe Me
2a
2b
2c
2d
2e
2f
Ac
B
40:60
25:75
85:15
92:8
96
81
87
61
86
86
64h
26h
81h
91h
86
90
60
91
70
89
76
89
i
1
2
4a 5a
OMe Me
A
3a9 (60)
3b10 (95)
3c11 (64)
3d12 (90)
3e (37)
4b 5a Me OMe Me
Bb
A
3
3b Me OMe Me
Ab,d
B
3
4a 5b
H
Me
Me
Me
4
Ac
B
30:70
40:60
92:8
4
4b 5b Me Me
Bc
A
5
3c
H
Me
Me
Me
5
4a 5c
4b 5c Me
4a 5d
H
-(CH2)3-
-(CH2)3-
OEt Ph
6
Ab,c
B
6
Bd
A
3f13 (57)
3g14 (53)
3h15 (59)
3i (80)f
3j (59)
7
3d Me Me
7
H
8
92:8
Ac
B
33:67
13:87
75:25
90:10
34:64
12:88
8
4b 5d Me OEt Ph
4a 5e OMe CH2Cl
4b 5e Me OMe CH2Cl
Bb
A
9
3e
3f Me
3g
H
-(CH2)3-
-(CH2)3-
9
H
10
11
12
13
14
15
16
17
18
19
20
Ab,d
B
10
Bb
a Procedure A: Al2O3, 0 °C, 10 min. Procedure B: Ni(acac)2.
b Without solvent, 48 h, 40 °C. c Dioxane, 19 h, 95°C. d Benzene,
40 h, 80°C. e Yields refer to isolated compounds after column
chromatography. f Crude yield. 3i was used without purification
in the next step due to its instability.
H
OEt Ph
2g
6
Ad,e
B
3h Me OEt Ph
3i OMe CH2Cl
3j Me OMe CH2Cl
Ab,d
B
H
2i
Ac
B
45:55
40:60
Ab,c
B
moderate yields (Table 1, entries 1, 3, 5, 7, and 9).
Regarding the reactions of methylvinyl ketone 4b, the
use of Ni(acac)2 as a catalyst8 allowed the preparation of
the target compounds in good to excellent yields (Table
1, entries 2, 4, 6, 8, and 10).
i
a Procedure A: 4 Å molecular sieves. Procedure B: Zn(ClO4)2‚
6H2O, MgSO4, rt. b In the presence of p-TSA. c Reaction at room
temperature. d Reaction at reflux temperature. e Reaction con-
ducted in toluene. f The diastereomeric ratio were estimated by
NMR and/or GC. g Yields refer to isolated compounds after column
chromatography. h Compound 3 and amine were used in a 1:1.1
ratio. i Untractable mixture.
Compounds 3 were reacted with (S)-phenylglycinol
generally in CH2Cl2 according to two procedures (Table
2). In procedure A, we conducted the reaction in the
presence of 4 Å molecular sieves between room and reflux
temperature. In the particular case of the substrates 3
stemming from methylvinyl ketone (R1 ) Me, entries 3,
7, 11, 15, and 19), the presence of catalytic amounts of
p-TSA was necessary to achieve faster and cleaner
reactions. In procedure B, we performed the condensation
of (S)-phenylglycinol on compounds 3 in the presence of
catalytic amount of Zn(ClO4)2‚6H2O and MgSO4, as
recently reported for the condensation of amines with
â-ketoesters.16 In both cases, we had to optimize reaction
conditions in order to improve yields. Initially, we found
that conversion rates of expected compounds 2 were
drastically improved upon using 2 molar equiv of tricar-
bonyl compounds 3 for 1 equiv of the amine, rather than
using equimolar amounts of reactants. However, in a few
cases, the improved conversion rates did not translate
into better isolated yields due to our difficulties to
separate by column chromatography the excess of sub-
strate 3 from the products 2. In these cases, better
isolated yields were obtained by using 3 and (S)-phen-
ylglycinol in a 1:1.1 ratio (Table 2, entries 7-10).
Whatever the amount of 3 used in these various reac-
tions, it should be noted that the diastereomeric excesses
of compounds 2 were identical.
As reported in Table 2, the expected piperidines 2 were
obtained in all cases in good to excellent yields, except
when reacting tricarbonyl substrates 3h and 3j. In the
case of the diketone 3h (Table 2, entries 15 and 16), the
only product isolated after silica gel chromatography was
racemic cyclohexanone 617 (Scheme 2). Comparison of the
physical and spectroscopic data for this compound with
those reported in the literature17 allowed to attribute a
cis relative stereochemistry. This unexpected product was
generated upon hydrolysis on silica gel of 1-oxo-4-
azaspiro[4.5]decane 7 that was identified by NMR as the
major product in the crude reaction mixture (character-
istic quaternary carbon of the oxazolidine moiety at δ 95.5
ppm). We postulated that compound 7 was the result
of an intramolecular aldolisation of the intermediate
enamine formed upon addition of (S)-phenylglycinol on
the carbonyl of the methyl ketone (Scheme 2).
(8) Nelson, J. H.; Howells P. N.; DeLullo, G. C.; Landen, G. L. J.
Org. Chem. 1980, 45, 1246-1249.
(9) Molander, G. A.; Kenny, C. J. Am. Chem. Soc. 1989, 111, 8236-
8246.
(10) Gutzwiller, J.; Labler, L.; Meier, W.; Fu¨rst, A.; Eder, U.; Sauer,
G.; Wiechert, R. Helv. Chim. Acta 1978, 61, 2397-2406.
(11) Bartolli, G.; Bosco, M.; Bellucci, M. C.; Marcantoni, E.; Sambri,
L.; Torregiani, E. Eur. J. Org. Chem. 1999, 617-620.
(12) Christoffers, J. J. Chem. Soc., Perkin Trans. 1 1997, 3141-
3149.
(13) Sauer, G.; Eder, U.; Hoyer, G. A. Chem. Ber. 1972, 105, 2358-
2367.
(14) Grigg, R.; Thornton-Pett. M.; Yoganathan, G. Tetrahedron 1999,
55, 1763-1780.
(17) (a) Walker, G. N. J. Am. Chem. Soc. 1955, 77, 3664-3667. (b)
Sen, P. K.; Das, T.; Maiti, K.; Maiti, B.; Sarkar, A. K. J. Indian Chem.
Soc. 1999, 76, 583-587. (c) Herna´ndez-Ortega, S.; Jime´nez-Cruz F.;
R´ıos-Olivares H.; Rubio-Arroyo, M. Acta Crystallogr. 2001, C57, 425-
427.
(15) Yadav, J. S.; Geetha, V.; Subba Reddy, B. V. Synth. Commun.
2002, 32, 3519-3524.
(16) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.; Melchiorre,
P.; Sambri, L. Synlett 2004, 2, 239-242.
J. Org. Chem, Vol. 70, No. 22, 2005 9045

SCHEME 2
shifts at C-8a for 2a,c,e,g,i were, respectively, in the
range 4.78-4.98 and 87.7-88.5 ppm for the major
isomers and downfield in the range 5.23-5.07 and 89.1-
89.5 ppm for the minor isomers. These values allowed
us to assign the (8aS) absolute stereochemistry to the
major isomers, in line with what was previously reported
on similar oxazolidine piperidines.18 X-ray analysis per-
formed on the minor isomer of 2c confirmed its (8aR)
absolute stereochemistry. Moreover, no equilibrium be-
tween the two oxazolidine epimers at C-8a was detectable
in the NMR spectra. This lack of epimerization at C-8a
was probably as a consequence of the stabilizing effect
of the â-enamino carbonyl moiety as already mentioned
for analogous derivatives.18
Concerning the chloromethyl ketone 3j, reaction with
(S)-phenylglycinol only resulted in an untractable mix-
ture. This is probably due to side reactions on the
chloromethyl ketone moiety.
These two opposite results concerning the stereochem-
istry at C-8a can be explained if one suppose that the
first step of the process leading to compounds 2 depends
on the nature of the substituent R1 (Scheme 3). In the
case of aldehydes (R1 ) H), the reaction would start with
the initial condensation of (S)-phenylglycinol on the
aldehyde moiety to lead to a diastereomeric mixture of
oxazolidines A.1 Subsequent attack of the hemiaminal
nitrogen on the distal ketone group would give com-
pounds 2 as a mixture of epimers via iminium ions B1
and B2.
Concerning the ketones (R1 ) Me and R3 * Ph), the
observed high diastereoselectivities suggest that a dif-
ferent process has taken place. In this case, phenylgly-
cinol would initially react on the activated ketone of the
1,3-dicarbonyl moiety to lead to enamine C. Intra-
molecular cyclization would then afford transiently imi-
nium ion D as one of the two reactive conformations D1
and D2 that respectively would yield isomer (8aS)-2 and
(8aR)-2 (Scheme 3). Due to the strong steric interaction
between the phenyl group and the R3 substituent that
disfavors conformation D1, the intramolecular cyclization
occurs preferentially via intermediate D2, which accounts
for the preferred (8aR) diastereoselectivity. In contrast
with these results, formation of cyclohexanone 6 from 3h
(R1 ) Me and R3 ) Ph) shows that the condensation of
(S)-phenylglycinol first occurred on the methyl ketone
In the other cases, the expected piperidines 2 were
obtained as separable mixtures of diastereomers at C-8a
with poor diastereomeric excesses when using procedure
A. Better diastereoselectivities were generally observed
following procedure B, particularly for angular methyl-
containing compounds (Table 2, entries 4, 8, and 12). In
particular, X-ray data from the major isomers of oxa-
zolidine 2b and 2d that were isolated as crystalline
compounds allowed us to assign a (8aR) absolute stereo-
chemistry to both derivatives. The same stereochemistry
was attributed to the major isomer of compound 2f, based
on the comparison of NMR spectroscopic data. Indeed,
the 1H NMR chemical shifts of the angular methyl of the
major isomer of 2b, 2d, and 2f were, respectively, at 1.44,
1.45, and 1.48 ppm. These singlets appeared deshielded
compared to the corresponding one of the minor isomers
of 2b, 2d, and 2f at, respectively, 1.30, 1.29, and 1.33
ppm. This stereochemistry for the major isomers is in
agreement with what we previously obtained for the
synthesis of exocyclic â-enaminoesters 1.1
Regarding the hydrogen-angular compounds, the re-
verse diastereoselectivity was observed. Here again, the
configuration assignment of the two diastereoisomers
were based on NMR data. The 1H and 13C NMR chemical
SCHEME 3
9046 J. Org. Chem., Vol. 70, No. 22, 2005

General Procedure B. To a mixture of methyl vinyl ketone
4b (1 mmol) and compound 5 (1 mmol) was added Ni(acac)2 (0.01
mmol). The reaction mixture was stirred at 40 °C for 48 h and
then purified by silica gel column chromatography to yield pure
compound 3. In the case of compounds 3d and 3f where the use
of solvents was required (see Table 2), the latter was concen-
trated in vacuo prior to chromatography to give compounds 3.
General Experimental Procedure for the Preparation
of Compounds 2. General Procedure A. To a solution of
compounds 3 (1 mmol) in CH2Cl2 (10 mL) were added (S)-
phenylglycinol (2 mmol) and 4 Å molecular sieves (1 g). In the
case of substrates 3b,d,f,h,j, p-TSA (0.1 mmol) was equally
added. The reaction mixture was stirred at room temperature
for 24 h and then filtrated over a Celite pad, and the organic
layer was concentrated in vacuo. Column chromatography on
silica gel afforded the expected compounds 2.
(Scheme 2), due to the known reduced reactivity of the
benzoyl moiety compared to a methyl ketone.
In conclusion, we have developed an efficient access
to new oxazolidines 2 by a two-step sequence, featuring
a Michael reaction of symmetrical â-diketones or â-ke-
toesters with acrolein or methylvinyl ketone, followed by
the condensation of (S)-phenylglycinol on the resulting
tricarbonyl compounds. We believed that these highly
functionalized compounds that we obtained in high yields
will prove to be valuable intermediates for the synthesis
of polysubtituted piperidine alkaloids. Further work
along these lines, aimed at developing the synthetic
applications of these polyfunctional heterocycles is under
way in our laboratory.
General Procedure B. To a solution of compounds 3 (1
mmol) in CH2Cl2 (10 mL) were successively added (S)-phenyl-
glycinol (2 mmol), Zn(ClO4)2‚6H2O (0.05 mmol), and MgSO4 (0.3
mmol). The reaction mixture was stirred at room temperature
for 24 h and filtrated. The organic layer was concentrated in
vacuo, and column chromatography on silica gel afforded this
expected compounds 2.
Experimental Section
General Experimental Procedure for the Preparation
of Compounds 3. General Procedure A. Activated neutral
Brockman I alumina was previously activated at 100 °C for 2 h.
To an ice-cooled, stirred suspension of Al2O3 (10 g) was added
compound 5 (1 mmol). Acrolein 4a (1 mmol) was then added
dropwise, and the reaction mixture was stirred for 10 min at 0
°C. The latter was then filtrered over a Celite pad and thor-
oughly washed with AcOEt. The organic layer was concentrated
in vacuo. Purification by silica gel column chromatography
yielded pure compound 3.
Supporting Information Available: Characterization
data for all obtained compounds.1H and/or 13C NMR spectra
of compounds 3, 2, and 6. Tables of X-ray crystallographic data
for compounds (8aR)-2b, (8aR)-2c, and (8aR)-2d as well as
CIF files. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Wong, Y.-S.; Marazano, C.; Gnecco, D.; Ge´nisson, Y.; Chiaroni,
A.; Das, B. C. J. Org. Chem. 1997, 62, 729-733.
JO051192P
J. Org. Chem, Vol. 70, No. 22, 2005 9047