Aza-annulation of β-enaminolactones: application to the synthesis of enantiopure difunctionalized bicyclic lactams

Article abstract of DOI:10.1016/j.tetlet.2008.11.070

Diastereoselective aza-annulation of seven-membered β-enaminolactones 2 gives access to bicyclic heterocyles 5. Fragmentation of molecule 5a with lithium methoxide affords cis or trans bicyclic lactams 8 with excellent stereoselectivities.

Full text of DOI:10.1016/j.tetlet.2008.11.070

Tetrahedron Letters 50 (2009) 617–619
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Aza-annulation of b-enaminolactones: application to the synthesis
of enantiopure difunctionalized bicyclic lactams
*
Jeanne Alladoum, Valérie Toum, Séverine Hebbe, Catherine Kadouri-Puchot, Luc Dechoux
Université Pierre et Marie Curie-Paris 6 Laboratoire de Chimie Organique UMR 7611, Institut de Chimie Moléculaire FR 2769, 4 Place Jussieu, Case Courrier 47, 75005 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2008
Revised 17 November 2008
Accepted 18 November 2008
Available online 24 November 2008
Diastereoselective aza-annulation of seven-membered b-enaminolactones 2 gives access to bicyclic het-
erocyles 5. Fragmentation of molecule 5a with lithium methoxide affords cis or trans bicyclic lactams 8
with excellent stereoselectivities.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
b-Enaminoesters
Aza-annulation
Bicyclic lactams
Intramolecular Michael addition
The aza-annulation of b-enaminocarbonyl compounds with
acrylate derivatives, originally studied by Hickmott and Sheppard,1
is a convenient, efficient and now well-known route for the synthe-
sis of d-lactams, and has been used successfully in the synthesis of
various nitrogen heterocycles.2
Herein, we wish to present our first results concerning the aza-
annulationofb-enaminolactones 2. Toourknowledge, theaza-annu-
lation of enaminolactone derivatives has not yet been described.
Recently, we reported the enantioselective synthesis of orthog-
onally protected b-aminodiacids 3 by using b-enaminolactones 2.3
These compounds were prepared in two steps by condensation of
dimethyl acetonedicarboxylate with (R)-phenylglycinol 1 followed
by a one-pot procedure -lactonization and regioselective alkylation
in basic medium (Scheme 1) .
The aza-annulation of enaminolactones 2 (R = H, Me, Et, Bn) was
performed by adding 1 equiv of acryloyl chloride to a solution of 2
in THF. After 10 h, the reactions were quenched with a saturated
aqueous solution of sodium carbonate and extracted twice with
dichloromethane. The results are presented in Scheme 2.
Cyclization of compounds 2a and 2b did not lead to the ex-
pected bicyclic products 4a and 4b but with total regio- and excel-
lent stereoselectivity to bicyclic lactones 5a and 5b in good yields.4
The (R) absolute configuration of the newly created stereocentre in
product 5a was established by X-ray analysis.5 It is noteworthy
that the stereoselectivity for the formation of 5a decreased when
the reaction was left for more then one day under the reaction con-
ditions, that is, in acidic medium. After 5 days, the diastereomeric
excess reached only 60%.
The postulated mechanism is presented in scheme 3. The un-
ique formation of products 5 implies that there is an equilibration
between enaminolactones 2 and their isomers 6. It is noteworthy
that these regioisomers 6 were not detected in the 1H NMR spec-
trum of compounds 2. The aza-annulation is believed to proceed
via an initial 1,4-addition of the b-enaminoesters 7 to the
a,b-
unsaturated acid chloride followed by an intramolecular N-acyla-
tion.6 The observed stereochemistry corresponds to an attack of
acryloyl chloride in an anti orientation with respect to the phenyl
group on the Z isomer, an internal hydrogen bonding may stabilize
this Z configuration in compound 6 (Scheme 3).
Starting from compound 2b (R = Me), product 5b was obtained
with a total diastereocontrol and in almost the same yield.7,8 Nev-
ertheless, the aza-annulation did not work with more bulky sub-
stituents such as ethyl and benzyl as in compounds 2c and 2d,
respectively. In these cases, the starting materials were recovered
unchanged.
CO Me
2
CO Me
2
R
R
NH
2
HN
OH
Ph
H N
2
O
CO H
2
O
Ph
1
2
3
* Corresponding author. Tel.: +33 01 44 27 30 13; fax: +33 01 44 27 37 87.
E-mail address: dechoux@ccr.jussieu.fr (L. Dechoux).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.070

618
J. Alladoum et al. / Tetrahedron Letters 50 (2009) 617–619
CO2Me
CO2Me
CO2Me
R
R
O
5a R=H (yield=77%, d.e.>95%)
5b R=Me (yield=75%, d.e.>95%)
5c R=Et (yield=0%)
R
N
N
HN
O
O
5c R=Bn (yield=0%)
O
O
O
Ph
O
O
Ph
Ph
4
2
5
Scheme 2.
O
Cl
MeO
CO Me
2
CO Me
2
R
R
R
MeO C
2
O
R
O
HN
HN
Cl
N
O
O
O
HN
O
O
O
Ph
O
Ph
O
Ph
O
Ph
2
6
7
5
Scheme 3.
Next we examined the hydrogenation of enaminolactone 5a.
alcoholate 9a which then adds stereoselectively via a Michael addi-
tion on the resulting b-enaminoester giving cis-oxazolidine 8a.
Then, epimerization takes place, due to the abstraction of the pro-
Hydrogenation using Pd/C or Pd(OH)2 in methanol at 1 atm of
hydrogen left compound 5a unchanged. With the same catalyst
and under a hydrogen pressure of 40 atm, we observed the forma-
tion of a complex mixture of products arising from the opening of
the cyclic systems. With Raney Nickel in methanol and under
40 atm of hydrogen, we observed a fragmentation of the seven-
membered ring and the formation of oxazolidine 8a with total ste-
reocontrol but with low conversion. Such fragmentation was also
realized quantitatively using 1 equiv of MeOLi in different solvents
(THF, methanol or a mixture of THF/MeOH: 90:10). In aprotic sol-
vent, we observed only the epimerization of the starting enamino-
lactone 5a to form isomer 5a0. In pure methanol, the fragmentation
was observed but in lower yields and the reaction was not repro-
ducible. In contrast using 10% MeOH in THF, a mixture of cis and
trans lactams 8a,a0 were obtained (Scheme 4), the ratio depending
on reaction time.
Study of the relative configuration of the newly formed stereo-
centre on the oxazolidine ring in products 8a,a0 showed that only a
cis configuration for the oxazolidine ring could be detected in the
1H NMR spectrum of the crude product.9 This is in agreement with
our previous experiments on the intramolecular addition of alco-
holates to b-enaminoesters.10 The relative configuration on the
lactam ring was established by NOE 1H NMR experiments and, as
was already noted in our laboratory for similar structures,11 we ob-
ton
a to the ester function giving the thermodynamically more
stable epimer 8a0 (Scheme 5).
Actually, under kinetic control (when the reaction was
quenched with aqueous NH4Cl 1 min after addition of 1 equiv of
MeOLi to compound 5a), cis bicyclic lactam 8a was obtained with
good diastereoselectivity de = (94%), total conversion and excellent
yield (>90%).
Under thermodynamically controlled conditions, that is, 1 equiv
of MeOLi in THF/MeOH: 90:10 after 6 days at room temperature,
trans lactam 8a0 was obtained with good diastereoselectivity (8a0/
8a = 90:10). It is noteworthy that neither alcohol 9a nor alcohol
9a0 was detected in the 1H NMR of the crude mixtures even when
the reactions were followed by 1H NMR in deuterated THF.
We found exactly the same results in terms of diastereoselectiv-
ity when starting from epimer 5a0 (Scheme 5). These results sug-
gest that under these reaction conditions, there exists a rapid
equilibration between the two diastereoisomers enaminolactones
5a and 5a0, which then react rapidly to give compound 8a via ena-
minolactone 5a. In contrast, oxazolidine 8a0 which should arise
from direct opening of enaminolactone 5a0 is not observed under
kinetic control indicating that v2 ꢀ v1.
In summary, we have found an easy and efficient route to chiral
non-racemic cis bicyclic enaminolactone 5a,b in three steps, start-
ing from (R)-phenylglycinol. Complete diastereocontrol allows easy
purification of compounds 5. This protocol has allowed the synthe-
sis of 10 g of compound 5a, with 70% overall yield and one purifica-
tion by chromatography on silica gel. We showed the first results
concerning this new chiral scaffold 5a in the enantioselective
served that the chemical shift of the proton
a to the ester moiety in
the cis lactam diastereoisomers 8a was found up field (2.74 ppm)
from those of trans isomers 8a0 (3.75 ppm).11,12
The stereochemistry of this original fragmentation was then
examined. First, we have supposed that the first step is the addi-
tion of MeOLi to the lactone 5a and formation of an intermediate
CO2Me
CO Me
CO Me
2
2
H
MeOLi, THF, MeOH
CH CO Me
CH CO Me
2 2
2
2
+
O
N
O
N
N
O
O
O
O
Ph
Ph
O
Ph
5a
8a
8a'
Scheme 4.

J. Alladoum et al. / Tetrahedron Letters 50 (2009) 617–619
619
1657; (c) Kozikowski, A. P.; Campiani, G.; Sun, L. Q.; Wang, S.; Saxena, A.;
Doctor, B. P. J. Am. Chem. Soc. 1996, 118, 11357; (d) Benovsky, P.; Stille, J. R.
Tetrahedron Lett. 1997, 38, 8475; (e) Beholz, L. G.; Benovsky, P.; Ward, D. L.;
Barta, N. S.; Stille, J. R. J. Org. Chem. 1997, 62, 1033; (f) Danieli, B.; Martinelli, L.
M.; Passarella, D.; Silvani, A. J. Org. Chem. 1997, 62, 6519; g Benovsky, P.;
Stephenson, G. A.; Stille, J. R. J. Am. Chem. Soc. 1998, 120, 2493; (h) Hadden, M.;
Nieuwenhuyzen, M.; Potts, D.; Stevenson, P. J. J. Chem. Soc., Perkin Trans. 1 1998,
3437; (i) Cimarelli, C.; Palmieri, G. Tetrahedron 1998, 54, 915; (j) Agami, C.;
Dechoux, L.; Hebbe, S.; Ménard, C. Tetrahedron 2004, 60, 6433; (k) Escolano, C.;
Amat, M.; Bosch, J. Chem. Eur. J. 2006, 12, 8198 and references cited therein; (l)
Amat, M.; Llor, N.; Checa, B.; Pérez, M.; Bosch, J. Tetrahedron Lett. 2007, 48,
6722; (m) Amat, M.; Santos, M. M. M.; Gómez, A. M.; Jokic, D.; Molins, E.; Bosch,
J. Org. Lett. 2007, 9, 2907; (n) Amat, M.; Griera, R.; Fabregat, R.; Bosch, J.
Tetrahedron: Asymmetry 2008, 19, 1233; (o) Amat, M.; Griera, R.; Fabregat, R.;
Molins, E.; Bosch, J. Angew. Chem., Int. Ed. 2008, 47, 3348.
CO2Me
H
CO2Me
H
MeOLi, THF, MeOH
N
N
O
O
O
O
O
O
Ph
Ph
5a'
v2
5a
+ MeOLi
v1
3. Alladoum, J.; Dechoux, L. Tetrahedron Lett. 2005, 46, 8203.
CO2Me
H
CO2Me
H
4. Spectral analysis for compound 5a: white solid, 1H NMR (250 MHz, CDCl3): 2.13–
2.31 (m, 2H), 2.63–2.70 (m, 2H), 3.65 (t, 1H, J = 3.75 Hz), 3.75 (s, 3H), 4.45 (d,
1H, J = 13.75 Hz.), 4.73 (dd, 1H, J = 6.75 and 13.75 Hz), 5.19 (s, 1H), 6.18 (d, 1H,
J = 6.5 Hz), 7.16–7.30 (m, 5H). 13C NMR (63 MHz, CDCl3): 21.2, 28.6, 47.0, 53.0,
57.9, 66.5, 100.8, 125.7, 127.5, 128.5, 134.1, 143.8, 166.7, 168.4, 170.6. Mp:
N
N
O
O
O
O
164 °C; ½a 2D0
ꢂ20 (c 0.92; CHCl3). Anal. Calcd for C17H17NO5: C, 64.75; H, 5.43;
ꢁ
OMe
Ph
OMe
Ph
N, 4.44. Found : C, 64.69; H, 5.60; N, 4.29.
LiO
9a
5. Atomic coordinates, bond lengths and angles have been deposited at the
Cambridge Crystallographical Data Center with the deposition number CCDC
635512.
LiO
9a'
6. Agami, C.; Hamon, L.; Kadouri-Puchot, C.; Le Guen, V. J. Org. Chem. 1996, 61,
5736.
7. Absolute configuration on the newly created stereocentre was deduced from
the configuration of compound 5a.
Intramolecular
Michael Addition
- MeOLi
8. The reaction was performed on a mixture of the two epimers 2b.
9. Relative configurations of the cis lactams 8a and trans lactams 8a0 were
established by NOE 1H NMR experiments.
MeOLi
8a
8a'
10. Agami, C.; Dechoux, L.; Hebbe, S. Tetrahedron Lett. 2003, 44, 5311.
11. a Similar strong deshielding effects were already observed in another bicyclic
lactams: Ref. 2j.; (b) Agami, C.; Dechoux, L.; Ménard, C.; Hebbe, S. J. Org. Chem.
2002, 67, 7573; (c) Agami, C.; Dechoux, L.; Hebbe, S.; Ménard, C. Tetrahedron
Lett. 2002, 43, 2521.
Scheme 5.
12. Spectral analysis for compound 8a: Colorless oil, 1H NMR (250 MHz, CDCl3):
2.06–2.13 (m, 2H), 2.38–2.55 (m, 1H), 2.64–2.70 (m, 1H), 2.74 (t, 1H, J = 5 Hz),
2.78 (d, 1H, J = 15.75 Hz), 2.91 (d, 1H, J = 15.75 Hz), 3.48 (s, 3H), 3.71 (s, 3H),
4.04 (dd, 1H, J = 7.25 and 9.25 Hz), 4.50 (d, 1H, J = 8.5 Hz); 5.37 (t, 1H,
J = 7.75 Hz), 7.14–7.30 (m, 5H). 13C NMR (63 MHz, CDCl3): 19.5, 29.2, 38.4, 49.5,
synthesis of cis and trans bicyclic lactams 8a and 8a0 with good
diastereoselectivities.13 The stereochemistry of this new fragmen-
tation was studied allowing the efficient synthesis of both stereo-
isomers in good yields and stereoselectivities. These original
bicyclic lactams should allow an efficient enantioselective access
to various cis and trans 2,3-disubstituted piperidines.
51.5, 52.1, 58.5, 69.6, 93.1, 125.4, 127.1, 128.3, 138.7, 168.6, 169.1, 170.8. ½a D20
ꢁ
ꢂ68 (c 1.13; CHCl3). Anal. Calcd for C18H21NO6: C, 62.24; H, 6.09; N, 4.03.
Found: C, 61.23; H, 6.01; N, 3.90. Spectral analysis for compound 8a0: Colorless
oil, 1H NMR (250 MHz, CDCl3): 2.06–2.13 (m, 2H), 2.52–2.61 (m, 2H), 2.68 (d,
1H, J = 15 Hz), 2.87 (d, 1H, J = 14.75 Hz), 3.62 (s, 3H), 3.66 (s, 3H); 3.75 (t, 1H,
J = 4.5 Hz), 3.97 (dd, 1H, J = 7.75 and 8.75 Hz), 4.41 (d, 1H, J = 8.5 Hz); 5.36 (d,
1H, J = 8 Hz), 7.15–7.31 (m, 5H). 13C NMR (63 MHz, CDCl3): 19.7, 27.9, 41.4,
References and notes
43.4, 52.0, 59.0, 70.1, 93.6, 125.5, 127.4, 128.7, 139.3, 168.8, 169.8, 171.1. ½a D20
ꢁ
1. (a) Hickmott, P. W.; Sheppard, G. J. Chem. Soc. C 1971, 1358; (b) Hickmott, P. W.;
Sheppard, G. J. Chem. Soc. C 1971, 2112.
2. (a) Paulvannan, K.; Stille, J. R. Tetrahedron Lett. 1993, 34, 8197; (b) Agami, C.;
Kadouri-Puchot, C.; Le Guen, V.; Vaissermann, J. Tetrahedron Lett. 1995, 36,
ꢂ35 (c 0.91; CHCl3).
13. For reviews on byclic lactams see: (a) Groaning, M. D.; Meyers, A. I. Tetrahedron
2000, 56, 9843; (b) Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997, 1.