Meyers' bicyclic lactam formation under mild and highly stereoselective conditions

Article abstract of DOI:10.1016/j.tetlet.2005.09.154

New and mild conditions to prepare chiral bicyclic lactams in high yields and high diastereoselectivities are reported herein. This approach based on the activation of the carboxylic acid by means of Mukaiyama's reagent is an excellent alternative to Meye

Full text of DOI:10.1016/j.tetlet.2005.09.154

Tetrahedron
Letters
Tetrahedron Letters 46(2005) 8385–8389
MeyersÕ bicyclic lactam formation under mild and
highly stereoselective conditions
Mae¨l Penhoat, Stephane Leleu, Georges Dupas, Cyril Papamicae¨l,
Francis Marsais and Vincent Levacher*
Laboratoire de Chimie Organique Fine et He´te´rocyclique UMR 6014 IRCOF,CNRS,Universite ´ et INSA de Rouen,BP 08,
F-76131 Mont-Saint-Aignan Ce´dex,France
Received 6August 2005; revised 24 September 2005; accepted 26September 2005
Available online 11 October 2005
Abstract—New and mild conditions to prepare chiral bicyclic lactams in high yields and high diastereoselectivities are reported
herein. This approach based on the activation of the carboxylic acid by means of MukaiyamaÕs reagent is an excellent alternative
to MeyersÕ dehydrating conditions and provide the main advantage to work at lower temperature (40 °C). Higher diastereoselectiv-
ity was obtained with 5,7-bicyclic lactams (de = 82% instead of 44% under standard dehydrating conditions).
Ó 2005 Elsevier Ltd. All rights reserved.
MeyersÕ bicyclic lactams have proven to be helpful chiral
building blocks for the stereoselective construction of
optically pure nitrogen heterocycles.1 The classical pro-
cedure used for accessing these versatile chiral bicyclic
lactam templates consists of cyclodehydration of a c-,
d- or x-keto acid and a chiral amino alcohol by simply
heating the two in toluene overnight with azeotropic re-
moval of water (Fig. 1). These dehydrating conditions,
rather drastic, may prove to be incompatible with highly
functionalized substrates, limiting seriously the scope of
this methodology. Taking this limitation into account,
the search of further reaction conditions is highly
desirable.
A survey of the literature reveals that no alternative pro-
cedures based on the activation of the carboxylic acid
O
O
R'
OH
OH
R
OH
R
Classical Meyers'
dehydrating conditions
H2N
Toluene, reflux
n
n
O
NH
O
R'
O
R'
N
R
Activation
O
n
O
R'
O
LG
R
Approach based on an
activation of the carboxylic acid
OH
H2N
LG
R
n
O
NH
n
- Lower temperature!
- Reaction rate!
- Diastereoselectivity!
O
R'
LG: Leaving group
Figure 1. MeyersÕ bicyclic lactam formation.
Keywords: MeyersÕ bicyclic lactam; Thioester; MukaiyamaÕs reagent; (R)-Phenylglycinol.
*
Corresponding author. Tel.: +33 02 3552 2485; fax: +33 02 3552 2962; e-mail: vincent.levacher@insa-rouen.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.154

8386
M. Penhoat et al. / Tetrahedron Letters 46 (2005) 8385–8389
have been investigated to explore possible milder reaction
conditions. In this context, we recently speculated that
such an approach could provide a beneficial effect on
the reaction rate and may have some influence on the dia-
stereoselective outcome of this lactamization (Fig. 1).
As an alternative route to MeyersÕ methodology, it was
then envisaged to have access to the desired bicyclic
lactams by dehydration of the b-ketoamide-alcohol 4
intermediate (Scheme 1, route A).4 According to
MukaiyamaÕs procedure,5 levulinic acid 1a was reacted
with N-methyl-2-chloropyridinium iodide in the pres-
ence of triethylamine in dichloromethane at reflux to
generate the corresponding activated ester 3. (R)-Phen-
ylglycinol was subsequently introduced and the mixture
stirred at reflux for 3 days. At this stage, we could not
find in the crude reaction mixture any trace of the
expected b-ketoamide-alcohol 4, but found instead the
presence of the bicyclic lactam trans-2a, which was fur-
ther isolated in high yield as a single diastereoisomer
(Scheme 1, route b). It should be emphasized that the
same stereoselection as that expected from the classical
MeyersÕ conditions was observed. The formation of
The thioester group displays a good compromise be-
tween stability and reactivity so that it can be handled
and purified without particular precaution, while pre-
senting the advantage to react faster than its oxoester
analogue. Accordingly, keto-thioesters appeared to be
excellent candidates to lactamize under mild conditions.
Thioesters have been successfully used in native peptide
ligation.2 This process, based on a preliminary transeste-
rification step followed by a spontaneous intramolecular
acyl transfer, takes advantage of this good balance be-
tween reactivity and stability of the thioester group to
promote peptide bond formation under mild conditions.
By analogy, this entropic activation was expected to
promote the lactamization of the oxazolidine thioester
intermediate under mild conditions (Fig. 2).
1
the activated ester 3 was evidenced from a H NMR
study which allowed us to conclude that this intermedi-
ate 3 reacts with (R)-phenylglycinol to produce the oxaz-
olidine intermediate 5 faster than the expected b-
ketoamide-alcohol 4. Compared with the previous cycli-
zation conditions of levulinic acid 1a and (R)-phenylgly-
cinol (Table 1, entry 1 and 3), these new conditions
proved to be superior, yielding the bicyclic lactam at
lower temperature with excellent stereoselectivity
(Scheme 1).
The required c-keto-thioester 1b was easily prepared in
80% yield from levulinic acid 1a and thiophenol in the
presence of 2-fluoro-1-ethylpyridinium tetrafluoro-
borate (FEP)3 and diisopropylethylamine (DIEA). The
reactivity of the resulting thioester 1b was compared
with that of levulinic acid 1a during bicyclic lactam for-
mation in the presence of (R)-phenylglycinol. The reac-
tion was conducted at different temperatures, in various
solvents. The results of these experiments are summa-
rized in Table 1. The reaction rate was extremely slow
at room temperature, and this with no difference be-
tween 1a or 1b (entries 4–6). At higher temperature
(80 °C, entries 2 and 8) no difference in reactivity was
observed between 1a and 1b. Although thioesters failed
to provide any significant improvement in terms of reac-
tion rate, this approach is still of interest because of the
high stereoselectivity observed with these new cycliza-
tion precursors (Table 1).
These new and mild conditions6 were assessed in the lac-
tamization of 2-acetyl-benzoic acid 1d and 2-formyl-
benzoic acid 1c, two cyclization precursors already sub-
jected to lactamization in toluene under classical Dean–
Stark conditions.7 As can be appreciated from Scheme
2, we were pleased to find that the use of MukaiyamaÕs
reagent furnished comparable results to those obtained
under dehydrating conditions, giving rise to trans-2c
and trans-2d in high yields and high diastereoselectivi-
ties. The relative configuration of the newly created ste-
1
reogenic centre was established by comparison of H
NMR data with those previously reported by Allin
Thioester and native chemical Ligation of peptides
Peptide
NH
O
Peptide
O
NH
HN
R
Peptide
HS
SR
R
O
R
Trans-
S
acyl
transfer
HN
SH
+
thioesterification
H2N
O
H
N
O
H2N
Peptide
Peptide
NH
N
O
H
Peptide
Thioester and bicyclic lactam formation
O
R
O
O
R
O
RS
R
O
N
O
+
NH
Ph
RS
Ph
Ph
OH
H2N
Figure 2. Thioester-assisted both ligation of peptides and bicyclic lactam formation.

M. Penhoat et al. / Tetrahedron Letters 46 (2005) 8385–8389
Table 1. Bicyclic lactam formation with c-keto-thioester 1b and levulinic acid 1a
8387
O
OH
Me
NEt3/CH2Cl2/r.t./24h/
thiophenol
Ph
Ph
R
O
1a
O
O
OH
80%
H2N
Table 1
N
S
N+
Et
F
O
SPh
Me
-
BF4
Me
trans-2a-(S,R)
1b
O
Entry
Sub.
T (°C)
Reaction time (h)
Solvent
de (%)
Conv. (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
110
80
40
22
22
22
60
80
24
72
72
168
168
168
72
Toluene
CH3CN
CH2Cl2
CHCl3
CHCl3
CH3CN
CHCl3
100
100
100
—
—
—
100
90
40
—
—
—
60
90
100
100
72
CH3CN
O
Ph
route A
OH
N
H
(b)
dehydrating
conditions
O
4
O
O
O
Ph
R
O
(a)
OH
Me
N+
X-
N
S
O
O
Me
trans-2a-(S,R)
O
1a
3
O
O
single
diasteromer
Yield = 85%
(b)
O
H
N
N+
X-
route b
Me
Ph
5
Scheme 1. MeyersÕ bicyclic lactam formation by means of MukaiyamaÕs reagent. Reagents and conditions: (a) N-methyl-2-chloropyridinium iodide/
NEt3/CH2Cl2/15 min/reflux; (b) (R)-phenylglycinol/CH2Cl2/72 h/reflux.
set of experiments showed that the same level of stereo-
control and similar yields can be achieved at much lower
temperatures than those routinely reported in the litera-
ture (Scheme 2).
Toluene/reflux
Ref.7
Yield=95%
de>95%
Ph
R
O
N
R
COOH
COR
Ph
S
OH
In the hope of broadening the scope of this methodol-
ogy, we then turned our attention to the construction
of larger 5,7-fused bicyclic lactams. Although MeyersÕ
methodology has been widely used in the construction
of 5,5- and 5,6-fused bicyclic lactams, modest perfor-
mances in terms of stereoselection and yield were
obtained when extended to 5,7-fused bicyclic lactams
(Fig. 3a).8 We9 and others10 have recently reported a
highly stereoselective access to axially chiral 5,7-fused
bicyclic lactams by using MeyersÕ methodology. This
approach offers the advantage to control in a single step
a chiral centre and a biarylic chiral axis. As a result of
O
H2N
Yield=90%
de>95%
trans-2c: R=H
trans-2d: R= Me
1c: R = H
1d: R = Me
Mukaiyama's reagent
/CH2Cl2/NEt3/40 °C
Scheme 2. Bicyclic lactam formation from 1c and 1d under classical
conditions and by means of MukaiyamaÕs reagent.
et al.7 In both procedures, the same stereoselection lead-
ing to the trans-lactams was observed. This preliminary

8388
M. Penhoat et al. / Tetrahedron Letters 46 (2005) 8385–8389
R1
R1
R1
O
O
O
O
N
OH
R2
N
N
n
O
R2
O
R2
(a)
O
R2
Ref. 1,8
R1
O
n= 1, 2, 3
n=1, 2
High yield
High de
n=3
Modest yield
Low de
OH
H2N
R1
O
R
Ref. 9,10
COOR3
COR2
N
S
O
R2
(b)
High yield
medium to high de
aR
Figure 3. Scope and limitation of MeyersÕ methodology with: (a) aliphatic keto-carboxylic acids; (b) biaryl keto-carboxylic acids.
the presence of a biaryl unit, the higher stereoselectivity
and reactivity observed, with this class of substrates,
may be attributed to conformational restrictions during
the lactamization step (Fig. 3b).
formic acid 1e in 86% yield. Alternatively, ester 8 could
be prepared through a three-step sequence involving a
preliminary Suzuki cross-coupling between boronic acid
9 and bromo ester 6. The resultant biaryl ester 10 was
subsequently converted to the corresponding bromo
derivative 11 in 91% yield which was finally subjected
to Hass–Bender reaction conditions to yield the corre-
sponding aldehyde 8 in 82% yield (Scheme 3).
Although under classical dehydrating conditions these
substrates gave fairly good results, both the reactivity
and stereoselectivity were found to be profoundly influ-
enced by various factors such as the nature of R2 and R3
as well as the nature of the aminoalcohol.9,10 Of parti-
cular interest in this context is the case of 20-formylbi-
phenyl-2-carboxylic acid 1e, which has already been
reported to undergo lactamization under dehydrating
conditions and furnishing the corresponding lactam
with only medium diastereoselectivity.10 Accordingly,
we became interested in testing our new conditions with
1e to provide milder conditions while hoping to improve
the stereoinduction of the lactamization process. Two
different routes were investigated for the preparation
of the required formic acid 1e. The first route is based
on a Suzuki cross-coupling reaction between the com-
mercially available aryl bromide ester 6 and boronic acid
7. The resulting biarylic ester 8 obtained in near quanti-
tative yield was then hydrolyzed to furnish the desired
We next examined the lactamization of 20-formylbiphen-
yl-2-carboxylic acid 1e under classical dehydrating con-
ditions. A solution of 1e and (R)-phenylglycinol in
toluene with azeotropic removal of water was stirred
for 30 h. As expected, under these dehydrating condi-
tions the lactamization proceeded in rather modest dia-
stereoselectivity (de = 44%). The bicyclic lactam trans-
2e was isolated in a satisfactory yield of 69%. In con-
trast, when the lactamization was carried out under acti-
vated conditions, in the presence of MukaiyamaÕs
reagent, the bicyclic lactam trans-2e was formed in
somewhat higher yield and, more interestingly, with a
significant higher level of stereoinduction (de = 82%).
This example demonstrated that these new lactamiza-
tion conditions not only provided milder reaction condi-
B(OH)2
CHO
CO2R
CHO
7
(a)
95%
82%
(c)
"Hass-Bender"
reaction
CO2Et
Br
8: R=Et
(d)
86%
1e : R=H
B(OH)2
Me
6
CO2Et
Br
CO2Et
Me
9
(b)
(a)
91%
94%
11
10
Scheme 3. Reagents and conditions: (a) Pd(PPh3)4 (8%)/K2CO3/toluene/H2O/reflux; (b) NBS/AIBN/CCl4/reflux/6h; (c) EtONa/2-nitropropane/
EtOH/reflux/10 h; (d) NaOH/rt/24 h.

M. Penhoat et al. / Tetrahedron Letters 46 (2005) 8385–8389
8389
Toluene/reflux
Ph
Yield=69%
de =44%
Ph
O
O
R
O
R
N
R
N
Ph
COOH
CHO
O
H
S
+
OH
H
H2N
aS
aR
Yield=80%
de>82%
minor
trans-2e-(aR,S,R) syn-2'e-(aS,R,R)
major
1e
Mukaiyama's reagent
/CH2Cl2/NEt3/40˚C
Scheme 4. Preparation of 5,7-fused bicyclic lactam 2e under activated conditions by means of MukaiyamaÕs reagent.
C.; Bosch, J. J. Org. Chem. 2003, 68, 1919–1928; (f) Ennis,
M. D.; Hoffman, R. L.; Ghazal, N. B.; Old, D. W.;
Mooney, P. A. J. Org. Chem. 1996, 61, 5813–5817; (g)
Allin, S. M.; James, S. L.; Elsegood, M. R. J.; Martin, W.
P. J. Org. Chem. 2002, 67, 9464–9467.
tions, but also promoted higher diastereoselectivity in
certain cases (Scheme 4).
In summary new and mild conditions were developed to
have access to chiral bicyclic lactams in good yield and
high diastereoselectivity. In a first approach, although
thioesters proved to be moderately reactive, they dis-
played the same high level of stereoinduction as that ob-
served with oxoester analogues, demonstrating their
potential as new cyclization precursors in this stereo-
selective lactamization process. A second approach
based on the activation of the carboxylic acid function
by means of MukaiyamaÕs reagent revealed to be an
excellent alternative to MeyersÕ dehydrating conditions,
providing the main advantage to work at lower temper-
ature. These new conditions are particularly attractive
for cyclization precursors vulnerable to degradation.
Further investigations are presently in progress to
demonstrate the potential of these results in the stereo-
selective preparation of 5,7-fused bicyclic lactams of
biological interest.
2. (a) Coltart, D. M. Tetrahedron 2000, 56, 3449; (b) Yeo, D.
S. Y.; Srinivasan, R.; Chen, G. Y. J.; Yao, S. Q. Chem.
Eur. J. 2004, 10, 4664; (c) Kent, S. J. Peptide Sci. 2003, 9,
574.
3. Li, P.; Xu, J.-C. Tetrahedron 2000, 56, 8119.
4. This alternative approach was mainly motivated by
ThottathilÕs work which reported the condensation of
(S)-5-(hydroxymethyl)2-pyrrolidinone with benzaldehyde
under dehydrating conditions providing the corresponding
bicyclic lactam in high yield with total diastereoselectivity.
(a) Thottatil, J. K.; Moniot, J. L.; Mueller, R. H.; Wong,
M. K. Y.; Kissick, T. P. J. Org. Chem. 1986, 51, 3140–
3143; (b) Thottatil, J. K.; Przybyla, C.; Malley, M.;
Gougoutas, J. Z. Tetrahedron Lett. 1986, 27, 1533.
PhCHO/toluene
O
N
O
N
H
O
APTS/reflux
HO
Ph
5. (a) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975,
1163; (b) Saigo, K.; Usui, M.; Kikushi, K.; Shimada, E.;
Mukaiyama, T. Bull. Chem. Soc. Jpn. 1977, 50, 1863–1866;
(c) Mukaiyama, T. Angew. Chem.,Int. Ed. Engl. 1979, 10,
707–808.
Acknowledgements
´
We thank the CNRS, the region Haute-Normandie and
the CRIHAN, for financial and technical support.
6. Typical procedure for the preparation of bicyclic lactams by
means of MukaiyamaÕs reagent. To a solution of 2-
acetylbenzoic acid 1d (1.4 g, 8.75 mmol) in CH2Cl2
(50 mL) was added NEt3 (1.73 g, 17.2 mmol) and N-
methyl-2-chloropyridinium iodide (MukayamaÕs reagent)
(2.4 g, 9.4 mmol). The reaction mixture was heated at
reflux for 15 min. (R)-Phenylglycinol (1.18 g, 8.6mmol)
was added and the resulting solution was stirred at reflux
for a further 72 h and then cooled to room temperature.
The crude was filtered, CH2Cl2 was evaporated and the
residue was purified by flash chromatography on silica gel
(AcOEt/cyclohexane: 1/1) to afford trans-2d in 90% yield
(de >95%).
Supplementary data
Experimental procedures for compounds 1b,e, trans-
2a,c–e, 8, 10 and 11; spectroscopic data for all com-
1
pounds (including H and 13C NMR spectra). Supple-
mentary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2005.09.154.
References and notes
7. (a) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A.
M. Z. J. Chem. Soc.,Perkin Trans. 1 2000, 1715–1721; (b)
Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M.
Z. Tetrahedron Lett. 1999, 143–146.
8. Meyers, A. I.; Downing, S. V.; Weiser, M. J. J. Org. Chem.
2001, 66, 1413–1419.
9. Penhoat, M.; Levacher, V.; Dupas, G. J. Org. Chem. 2003,
68, 9517–9520.
10. Edwards, D. J.; Pritchard, R. G.; Wallace, T. W.
Tetrahedron Lett. 2003, 44, 4665–4668.
1. For leading references on chiral bicyclic lactams, see: (a)
Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997, 1–8;
(b) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56,
9843–9873; (c) Amat, M.; Canto, M.; Llor, N.; Ponzo, V.;
PeÕrez, M.; Bosch, J. Angew. Chem.,Int. Ed. 2002, 41, 335–
337; (d) Amat, M.; Canto, M.; Llor, N.; Escolano, C.;
Molins, E.; Espinosa, E.; Bosch, J. J. Org. Chem. 2002, 67,
5343–5351; (e) Amat, M.; Llor, N.; Hidalgo, J.; Escolano,