Construction of cis-azadecalone units via novel intermolecular Diels-Alder reaction

Article abstract of DOI:10.1016/S0040-4039(02)00068-0

N-Methoxycarbonyl-5-ethoxycarbonyl-2,3-dihydropyridin-4-one 1 reacts under thermal or Lewis acid-catalysed conditions with trimethylsilyloxybutadienes to give cis-azadecalones via a formal [4+2] cycloaddition.

Full text of DOI:10.1016/S0040-4039(02)00068-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1645–1648
Construction of cis-azadecalone units via novel intermolecular
Diels–Alder reaction
Hamid Dhimane,* Ste´phane Meunier, Corinne Vanucci-Bacque´ and Ge´rard Lhommet*
Laboratoire de Chimie des He´te´rocycles, associe´ au CNRS, Universite´ Pierre et Marie Curie, UMR 7611, 4, Place Jussieu,
F-75252 Paris cedex 05, France
Received 13 November 2001; revised 7 January 2002; accepted 8 January 2002
Abstract—N-Methoxycarbonyl-5-ethoxycarbonyl-2,3-dihydropyridin-4-one 1 reacts under thermal or Lewis acid-catalysed condi-
tions with trimethylsilyloxybutadienes to give cis-azadecalones via a formal [4+2] cycloaddition. © 2002 Elsevier Science Ltd. All
rights reserved.
Alkaloids containing the 1-azadecalin moiety are abun-
dant in nature and many exhibit significant biological
activities.1 Our interest in the development of new
strategies for the synthesis of such units prompted us to
consider a new approach relying on Diels–Alder reac-
tion of N-methoxycarbonyl-2,3-dihydropyridin-4-ones
as dienophiles. To the best of our knowledge, there is
no reported example of such intermolecular cycloaddi-
tions.2 Herein, we report our results concerning the
implementation of this strategy to access highly func-
tionalised octahydroquinoline skeletons.
Scheme 1.
Preliminary attempts showed that N-methoxycarbonyl-
2,3-dihydropyridin-4-one was inert as the dienophile,3
under various conditions. Therefore, we decided to
explore the behaviour of a dihydropyridone bearing at
C5 an alkoxycarbonyl substituent, that was expected to
heating compound 1 in the presence of less electron rich
dienes (isoprene, 2,3-dimethyl-1,3-butadiene, furan, 2-
enhance the reactivity of the enamine moiety as a
trimethylsilyloxyfuran, 1- and 2-trimethylsilyloxy-1,3-
dienophile.4
butadienes) did not yield any cycloadduct, even after 5
days of reaction.
Substrate 1, readily prepared from the commercially
available 3-ethoxycarbonyl-piperid-4-one hydrochlo-
We next examined the Lewis acid catalysed version of
ride,5 was first reacted under thermal conditions, with
these cycloadditions. The use of BF3–OEt2, TiCl4,
Danishefsky’s diene in toluene, at 130°C (sealed tube),
TMSOTf and Et2AlCl did not give any satisfactory
overnight. After purification on silica gel, desilylated
result. Isoprene and 2,3-dimethylbutadiene were shown
adduct 2 was isolated as a 80/20 diastereomeric mixture
(vide infra) in 85% overall yield (Scheme 1). However,
to be unreactive, whereas trimethylsilyloxy-butadienes
polymerised in most cases. However, 1,4-addition com-
pounds 3 and 4 (Fig. 1) were isolated following reaction
Keywords: dihydropyridone; cyclocondensation; stereoselective; Lewis
acid; octahydroquinoline.
* Corresponding authors. Present address (H.D.): Laboratoire de
Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR
of 1 with furan and 2-trimethylsilyloxyfuran, respec-
tively (27–78% yields),6 as previously reported in the
case of some enones.7
8601, Universite´ Rene´ Descartes, UFR Biome´dicale, 45 rue des
Saints-Pe`res, 75270 Paris, France; e-mail: hamid.dhimane@
biomedicale.univ-paris5.fr
We then turned our attention towards Lewis acids
derived from scandium copper
(Sc(OTf)3),8
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00068-0

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H. Dhimane et al. / Tetrahedron Letters 43 (2002) 1645–1648
the same experiment was conducted in the presence of
an excess of the diene, 5a was isolated as the major
product (68%), along with 6 (7%) and 1 (4%). These
results suggested an isomerisation of the kinetic
diastereoisomer 5b into the thermodynamic one 5a
either by successive retro-Mukaiyama/Mukaiyama
reactions (via the silylated enol of 6) or retro Diels–
Figure 1.
Alder/Diels–Alder reactions. The formation of
1
stemmed either from retro-Mukaiayama/retro-Michael
or from retro-Diels–Alder processes. Moreover, in
order to ascertain the relative stereochemistry of the
thermodynamic isomer 5a, the latter was transformed
in two steps into the corresponding crystalline benzoate
7a (Scheme 2), the configuration of which was secured
by X-ray analysis.12
(Cu(OTf)3),9 bismuth (BiCl3 and Bi(OTf)3)10 and ytter-
bium (Yb(OTf)3).11 Under these conditions, unactivated
dienes led to similar failures to those reported above. In
contrast, trimethylsilyloxybutadienes afforded, in most
cases, the corresponding cycloadducts (Table 1).
With the exception of BiCl3 which was totally ineffi-
cient (entry 3), reaction of 1 in the presence of these
Lewis acids with 1-trimethylsilyloxy-1,3-butadiene
afforded the expected cycloadducts 5a and/or 5b, along
with the monocyclic enal 6 (Scheme 2). The diastereose-
lectivity of 5 was highly dependant on the nature of the
Lewis acid employed (entries 1–5). The best chemical
yield in cycloadduct (5a and 5b) was obtained with
Yb(OTf)3, as the catalyst in refluxing CH2Cl2, for 24 h
(entry 5). Noteworthy in the latter case was the obser-
vation that a prolonged reaction time above 48 h
resulted in the obtention of only one diastereomer 5a
(entry 6).
2-Trimethylsilyloxy-1,3-butadiene was then reacted
with dienophile 1 in the presence of various Lewis
acids, among which only Sc(OTf)3, Cu(OTf)2 and
Yb(OTf)3 efficiently catalysed the expected cycloaddi-
tion (entries 7, 8 and 11). In all cases, azadecalone 8
was isolated (after acidic treatment) as a single
stereomer. Once again, the cis-configuration of this
compound was assigned based on X-ray data12 (Scheme
3).
As far as Danishefsy’s diene was concerned, the only
interesting results were obtained with BiCl3 and
Yb(OTf)3. In the former case (entry 14), three com-
pounds were identified in the crude mixture: desilylated
cycloadduct 2, enone 9 (resulting from 2 after elimina-
tion of methanol), along with a trace of phenol 10
(Scheme 3). Compound 2 was isolated as a mixture of
two diastereomers, in a ratio different from the one
obtained above. Attempts to isolate enone 9 by silica
gel chromatography mainly resulted in the obtention of
phenol 10, through retro-Michael and subsequent retro-
Formation of enal 6 is believed to result from the
protodesilylation of the Mukaiyama’s retroaldolisation
product of cycloadducts 5. Indeed, when submitted to
an overnight reflux in CH2Cl2 in the presence of
Yb(OTf)3, a purified diastereomeric mixture of 5a and
5b (30:70) mainly yielded enal 6 (38%) along with a
trace of 5a (7%) and substrate 1 (10%). Moreover, when
Table 1.
Entry
Diene
Lewis acid (equiv.)
Temp. (time)
Products (yield)a
1
2
3
4
5
6
Sc(OTf)3 (0.05)
Cu(TOf)3 (0.1)
BiCl3 (0.1)
Bi(OTf)3 (0.1)
Y(OTf)3 (0.05)
Y(OTf)3 (0.05)
−78 to 0°C (5 h)
rt (4 h)
rt
rt (5 h)
Reflux (24 h)
Reflux (48 h)
5a+5b (44%) [86:14]b 6 (34%)
5a+5b (35%) [57:43]b 6 (7%)
–
c
5a (46%) 6 (32%)
5a+5b (78%) [55:45]b 6 (7%)
5a (64%) 6 (16%)
7
8
9
10
11
Sc(OTf)3 (0.05)
Cu(TOf)3 (0.1)
BiCl3 (0.1)
Bi(OTf)3 (0.1)
Y(OTf)3 (0.05)
−78°C to rt (5 h)
rt (24 h)
rt
rt
8 (56%)
8 (56%)
c
–
–
c
Reflux (20 h)
8 (64%)
c
12
13
14
15
16
Sc(OTf)3 (0.05)
Cu(TOf)3 (0.1)
BiCl3 (0.1)
Bi(OTf)3 (0.1)
Y(OTf)3 (0.05)
rt
–
–
d
0°C (4 h)
rt (12 h)e
rt
2 (26%) 8 (50%) 10(15%)
c
–
rt (15 min)e
8 (56%) 10 (18%)
a Isolated yields.
b Diastereomeric ratio as estimated by 1H NMR and GC.
c No reaction was observed.
d Unreacted starting material was recovered. Only trace of 4-hydroxyacetophenone resulting from the dimerisation of the diene was isolated.
e Products isolated after submission of the crude reaction mixture to catalytic hydrogenation.

H. Dhimane et al. / Tetrahedron Letters 43 (2002) 1645–1648
1647
Scheme 2.
the crude reaction mixture was subjected to catalytic
hydrogenation prior to purification. This enable us to
isolate compounds 2, 10 and a ketone, whose spectro-
scopic data were in full agreement with compound 8,
previously obtained from 2-trimethylsilyloxy-1,3-buta-
diene (Table 1). This result led us to attribute a cis
junction to both diastereomers of 2, these isomers being
epimers at the stereogenic centre bearing the methoxy
group.
Finally, a very fast reaction was observed in the pres-
ence of Yb(OTf)3 as the catalyst, mainly yielding ketone
8 and phenol 10 after hydrogenation (entry 16). Of note
was the absence of methoxylated derivative 2 in the
reaction mixture.
In these preliminary studies, we have established the
feasibility of intermolecular Diels–Alder cyclocondensa-
tions between N-methoxycarbonyl-2,3-dihydropyridin-
4-one and trimethylsilyloxybutadienes which allows the
construction of highly functionalised cis-fused
azadecalones, a frequent central core of a variety of
alkaloids.13 Further work aimed at exploiting the syn-
thetic potentialities of this methodology is currently
underway.
Scheme 3.
Claisen type reactions followed by aromatisation. For-
mation of phenol 10 has already been reported in the
case of oxo-analogues.2 To prevent this degradation,

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H. Dhimane et al. / Tetrahedron Letters 43 (2002) 1645–1648
7. Similar results were reported previously for furan: (a) Liu,
References
H.; Ulibarri, G.; Browne, E. Can. J. Chem. 1992, 70,
1545–1554; (b) Satake, Y; Tadano, K. J. Carbohydr. Chem.
1997, 16, 441–447. For 2-trimethylsilyloxyfuran: (c) Kita-
jima, H.; Ito, K.; Katsuki, T. Tetrahedron 1997, 53,
17015–17028.
1. (a) Daly, J.; Garraffo, M.; Spande, T. In Alkaloids:
Chemical and Biochemical Perspectives; Pelletier, S. W.,
Ed. Alkaloids from amphibian skins; Pergamon, 1999; Vol.
13, pp. 1–161; (b) Blumenkopf, T. A.; Heathcock, C. H.
In Alkaloids: Chemical and Biochemical Perspective; Pel-
letier, S. W., Ed. Synthesis of Lycopodium alkaloids;
Wiley: New York, 1985; Vol. 3, pp. 185–240.
8. Kobayashi, S. Synlett 1994, 689–701.
9. Brunel, J. M.; Del Campo, B.; Buono, G. Tetrahedron Lett.
1998, 39, 9663–9666.
10. Garrigues, B.; Gonzaga, F.; Robert, H.; Dubac, J. J. Org.
Chem. 1997, 62, 4880–4882.
11. Danishefsky, S.; Bednarski, M. Tetrahedron Lett. 1984, 24,
721–724.
12. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 173235 (7a) and CCDC
173236 (8). Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
2. While we were engaged in this study, a similar approach
was described with dihydropyrones as dienophiles: Chen,
D.; Wang, J.; Totah, N. J. Org. Chem. 1999, 64, 1776–1777.
3. A similar absence of reactivity has been previously reported
in a related case. See reference 15 in: Wenkert, E.; Moeller,
P.; Piettre, S. J. Am. Chem. Soc. 1988, 110, 7188–7194.
4. Moreover, this added functionality would allow the intro-
duction of a chiral auxiliary.5
5. For the preparation of compound 1 and its chiral menthyl
derivatives which have previously been examined as
Michael acceptors, see: Brocherieux-Lanoy, S.; Dhimane,
H.; Vanucci-Bacque´, C.; Lhommet, G. Synlett 1999, 4,
405–408.
13. Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2000,
122, 4583–4592.
6. Compound 4 was isolated as 1/1 mixture of diastereomers.