A novel stereocontrolled synthesis of enantiopure bicyclic lactams

Article abstract of DOI:10.1016/S0040-4039(03)01209-7

A study on the reactivity of 3,4-dihydro-2-pyridones 9, derived from (S)-phenylglycinol, toward different bases is presented. Using a catalytic amount of bases, the cis bicyclic lactams were obtained with excellent diastereoselectivities.

Full text of DOI:10.1016/S0040-4039(03)01209-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5311–5313
A novel stereocontrolled synthesis of enantiopure bicyclic lactams
Claude Agami, Luc Dechoux* and Se´verine Hebbe
Laboratoire de Synthe`se Asyme´trique (UMR 7611), Universite´ P. et M. Curie, 4 place Jussieu, 75005 Paris, France
Received 20 February 2003; revised 12 May 2003; accepted 12 May 2003
Abstract—A study on the reactivity of 3,4-dihydro-2-pyridones 9, derived from (S)-phenylglycinol, toward different bases is
presented. Using a catalytic amount of bases, the cis bicyclic lactams were obtained with excellent diastereoselectivities. © 2003
Elsevier Science Ltd. All rights reserved.
As regards the enantioselective synthesis of polysubsti-
tuted piperidines,1 chiral non-racemic bicyclic lactams,2
derived from homochiral b-amino alcohols, are com-
monly considered as most useful starting materials. In
these syntheses, the bicyclic ring system is usually gen-
erated by cyclocondensation of d-oxoacid derivatives
with suitable b-amino alcohols. Amat et al. recently
These original bicyclic lactams allowed an efficient
access to piperidines 4 and 5 substituted at C-3 on the
piperidines. A problem in this approach was the lack of
stereoselectivity during the formation of the bicyclic
lactams. In all experiments, these compounds were
obtained in the form of two epimers 2 and 3, differing
by the configuration of the carbon bearing the carbonyl
group.
described an alternative procedure involving
a
diastereoselective oxidation of a (R)-phenylglycinol-
derived 2-pyridone and its subsequent conversion into
an enantiopure trihydroxypiperidine.3 Gnecco et al.
described a similar cyclisation starting from a (R)-
phenylglycinol-derived 3,4-dihydro-2-pyridone.4
Here we wish to present a new strategy towards
advanced precursor lactams 2 and 3, which can be used
for the synthesis of cis and trans 2,3-disubstituted pipe-
ridines. This strategy is based on a study of the cycliza-
tion of 3,4-dihydro-2-pyridones 9 bearing an internal
hydroxyl function. To our knowledge, such an internal
Michael addition on b-enaminoesters has not been
reported so far.
In a previous paper, we described the synthesis of chiral
non-racemic disubstituted piperidines5 4 and 5 from
respectively chiral bicyclic lactams 2 and 3.6 These
compounds were obtained by aza-annulation7 of b-
enaminoesters 1 derived from (S)-phenylglycinol with
acryloyl chloride (Scheme 1).
In order to prepare substrates 9 (Scheme 2) by an
aza-annulation process, condensation of TBDMS-pro-
Scheme 1.
Keywords: b-enaminoesters; bicyclic lactams; 3,4-dihydro-2-pyridones; oxazolidines; aza-annulation.
* Corresponding author. E-mail: dechoux@ccr.jussieu.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01209-7

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C. Agami et al. / Tetrahedron Letters 44 (2003) 5311–5313
Scheme 2. Reagents and conditions: (i) imidazole 2.5 equiv., TBDMSCl 1.2 equiv., CH2Cl2; (ii) methylpropiolate or b-ketoesters,
MeOH or EtOH; (iii) acryloyl chloride, THF; (iv) HF·pyridine, THF.
tected (S)-phenylglycinol with b-ketoesters (R=alkyl)
or methylpropiolate (R=H) yielded b-enaminoesters 7
which were used unpurified in the next step.
methylpropiolate. In neutral and acidic media, dihy-
dropyridones 9 were stable. Intramolecular Michael
addition were then performed in basic media using
LiHMDS, NaHMDS and KHMDS as bases, in THF
at 0°C. Thereafter, the reaction mixtures were treated
with an aqueous saturated ammonium chloride solution
and extracted with dichloromethane. The results are
presented in Table 1.
The aza-annulation reaction was performed by adding
1.2 equiv. of acryloyl chloride derivatives to b-enam-
inocarbonyl compounds 7 in THF at room tempera-
ture. The cyclization with acryloyl chloride was
successful and yielded good amounts of the expected
TBDMS-protected 3,4-dihydro-2-pyridones 8. Depro-
tection of compounds 8 with HF·pyridine worked prop-
erly and excellent yields of compounds 9 were obtained.
In all the experiments where R=alkyl (substrates
9a,b,d) bicyclic lactams were formed quantitatively. The
reactions were completed within 2 h. Study of the
stereoselectivity of the newly formed stereocenter on the
oxazolidine ring showed that only a cis configuration
At this stage the alcohols 9 were purified by chromato-
graphy on silica gel. The overall yield with R=alkyl
was higher than 80%, but it was only 45% with sub-
strate 9c (R=H) due to the poor yield of the condensa-
tion step between the protected (S)-phenylglycinol and
1
for the oxazolidine ring could be detected in the H
NMR spectrum of the crude product. This is in agree-
ment with our previous experiments on the reaction of
b-enaminoesters 1 with acryloyl chloride (Scheme 1).5
Table 1. Cyclization of 3,4-dihydro-2-pyridones 9

C. Agami et al. / Tetrahedron Letters 44 (2003) 5311–5313
5313
Scheme 3.
When 0.5 equiv. of base was used, the metal cation of
the base employed during intramolecular Michael addi-
tion had a dramatical effect on the stereoselectivity of
the reaction (entries 1–3). The best selectivity was
obtained with the less reactive base (LiHMDS, entry 1).
It is noteworthy that when an excess of LiHMDS was
used such as in entry 4 the conversion was low (57%).
A large increase in the diastereoselectivity of the 2 h
reaction was observed when a catalytic amount of bases
(10%) was used (entries 5–7). A total diastereoselectiv-
ity was observed with KHMDS when the reaction was
stopped after 1 h (entry 8).
enolate 11 abstracts an acidic hydrogen on alcohol 9.
Protonation takes place from the less crowded endo
diastereoface (anti to R and Ph). Upon exhaustion of
the acidic hydrogen in the medium, (after 1–2 h with
0.1 equiv. of base), epimerization takes place, due to
the abstraction of the hydrogen a to the amidic func-
tion.8 This equilibration is even faster when 0.5 equiv.
of bases are used.
In summary, we have found an easy and efficient route
to chiral non-racemic cis bicyclic lactams 2 in five steps,
starting from (S)-phenylglycinol. Complete diastereo-
control allows easy purification of compounds 2. The
overall yield, when R=alkyl, are >80%. This protocol
has allowed the synthesis of 10 g of bicyclic lactam 2a,
with 83% overall yield and one purification by chro-
matography on silica gel of the 3,4-dihydro-2-pyridone
9.
When KHMDS (0.5 equiv.) was used (entry 3), the
reaction was thermodynamically controlled, since it
appears that when cis stereomer 2a was exposed to 0.5
equiv. of KHMDS, the ratio of the diastereomers 2a
and 3a was approximately equivalent to the ratio
obtained in entry 3 (52/48). Thus, under kinetic control
(1–2 h reaction with 0.1 equiv. of base), cis bicyclic
lactams 2 were obtained with high diastereoselectivity.
References
1. For recent applications, see: (a) Amat, M.; Canto, M.;
Llor, N.; Ponzo, V.; Perez, M.; Bosch, J. Angew. Chem.,
Int. Ed. 2002, 41, 335; (b) Amat, M.; Perez, M.; Llor, N.;
Bosch, J. Org. Lett. 2002, 4, 2787; (c) Amat, M.; Canto,
M.; Llor, N.; Escolano, C.; Molins, E.; Espinosa, E.;
Bosch, J. J. Org. Chem. 2002, 67, 5343; (d) Allin, S. M.;
Vaidya, D. G.; James, S. L.; Allard, J. E.; Smith, T. A. D.;
McKee, V.; Martin, W. P. Tetrahedron Lett. 2002, 43,
3661; (e) Amat, M.; Perez, M.; Llor, N.; Bosch, J.; Lago,
E.; Molins, E. Org. Lett. 2001, 3, 611.
The cyclization was extended to substrates 9b–d, using
0.1 equiv. of NaHMDS as standard conditions. The
same stereoselectivity was observed in favor of the cis
stereomers 2b–d. Changing methyl ester to ethyl ester
did not modify the d.e. (entry 9). On the contrary, a
reaction starting from 9c was not complete, since only
40% conversion was obtained (entry 10). In this case,
the resulting enolate 11 formed by Michael addition
was expected to be less stable than the intermediate
alcoholate 10 (Scheme 3). Starting from substrate 9d,
partial epimerisation was observed after 2 h (entry 11).
When the reaction was quenched after 40 minutes, the
stereoselectivity was total (entry 12).
2. For reviews, see: (a) Groaning, M. D.; Meyers, A. I.
Tetrahedron 2000, 56, 9843; (b) Meyers, A. I. Brengel, G.
P. Chem. Commun. 1997, 1.
3. Amat, M.; Llor, N.; Huguet, M.; Molins, E.; Espinosa, E.;
Bosch, J. Org. Lett. 2001, 3, 3257.
Absolute configurations of the cis lactams 2 and trans
lactams 3 were deduced from the stereochemistry of
4. Teran, J. L.; Gnecco, D.; Galindo, A.; Juarez, J.; Bernes,
S.; Enriquez, R. G. Tetrahedron: Asymmetry 2001, 12, 357.
5. Agami, C.; Dechoux, L.; Me´nard, C.; Hebbe, S. J. Org.
Chem. 2002, 67, 7573.
1
compounds 2a and 3a already established by NOE H
NMR experiments and X-ray analysis. It was observed
that the chemical shift of the proton a to the ester
moiety in the major cis lactam diastereoisomers 2 was
found up field (2.6–2.7 ppm) from that of trans isomers
3 (3.1–3.2 ppm).
6. Agami, C.; Dechoux, L.; Hebbe, S. Tetrahedron Lett.
2002, 43, 2521.
7. (a) Hickmott, P. W.; Sheppard, G. J. Chem. Soc. C 1971,
1358; (b) Hickmott, P. W.; Sheppard, G. J. Chem. Soc. C
1971, 2112.
Rationalization of the stereochemical outcome in
intramolecular Michael addition is presented in Scheme
3. Following addition of alcoholate 10, the resulting
8. When the reaction was quenched after 12 h with MeOD,
the a-amidic position was partially deuterated.