New advances in stereoselective Meyers' lactamization. Application to the diastereoselective synthesis of β-substituted oxazoloazepinones

Article abstract of DOI:10.1016/j.tetasy.2008.10.014

A stereoselective approach to the preparation of 7,5-fused bicyclic lactams based on Meyers' lactamization is presented. The lactamization step is conducted at 0 °C with 6-oxohexanoic acid 1 and with various chiral aminoalcohols in the presence of 2-fluoro-1-ethylpyridinium tetrafluoroborate (FEP) as an activating agent. Under these mild conditions, bicyclic lactams 2-4 were obtained in satisfactory yields and diastereoselectivities up to 95%. To account for the high level of diastereoselection, the mechanistic aspects of Meyers' lactamization were investigated by means of in situ infrared spectroscopy. Finally, the lactam enolate derived from 2 was subjected to reaction with various electrophiles, furnishing the corresponding β-substituted oxazoloazepinones 5-9 in good yields (up to 86%) and in moderate to excellent diastereoselectivities ranging from 27% to 95% de.

Full text of DOI:10.1016/j.tetasy.2008.10.014

Tetrahedron: Asymmetry 19 (2008) 2396–2401
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New advances in stereoselective Meyers’ lactamization. Application to the
diastereoselective synthesis of b-substituted oxazoloazepinones
*
*
Alexis Bouet, Sylvain Oudeyer , Georges Dupas, Francis Marsais, Vincent Levacher
UMR 6014 IRCOF, CNRS, Université et INSA de Rouen, BP 08, F 76131 Mont-Saint-Aignan Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective approach to the preparation of 7,5-fused bicyclic lactams based on Meyers’ lactamiza-
tion is presented. The lactamization step is conducted at 0 °C with 6-oxohexanoic acid 1 and with various
chiral aminoalcohols in the presence of 2-fluoro-1-ethylpyridinium tetrafluoroborate (FEP) as an activat-
ing agent. Under these mild conditions, bicyclic lactams 2–4 were obtained in satisfactory yields and dia-
stereoselectivities up to 95%. To account for the high level of diastereoselection, the mechanistic aspects
of Meyers’ lactamization were investigated by means of in situ infrared spectroscopy. Finally, the lactam
enolate derived from 2 was subjected to reaction with various electrophiles, furnishing the corresponding
b-substituted oxazoloazepinones 5–9 in good yields (up to 86%) and in moderate to excellent diastereo-
selectivities ranging from 27% to 95% de.
Received 1 September 2008
Accepted 14 October 2008
Available online 5 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
epinones by lactamization of an x-keto acid and (R)-phenylglycin-
ol. Alternatively, we had previously shown that 2-fluoro-1-
ethylpyridinium tetrafluoroborate (FEP) or Mukaiyama’s reagent
could advantageously replace conventional thermal conditions by
means of carboxylic acid activation, to afford 5,5- and 6,5-fused
bicyclic lactams with high diastereoselectivities under much
milder conditions.8 An axially chiral 7,5-fused bicyclic lactam, clo-
sely related to the circumdatin family of natural products, could be
Seven-membered nitrogen heterocycles are constituents of a
large number of compounds with interesting pharmacological
properties such as balanol, a potent inhibitor of the protein kinase
C enzyme, which has attracted a lot of synthetic efforts in the last
few years.1 The
c-secretase inhibitor LY411575 (IC50<1 nM in HEK
cells) discovered by researchers at Eli Lilly and presently studied
for potential use in the treatment of central nervous disorders
should also be mentioned.2 The azepine fragment is also encoun-
tered in stemoamide,3 a pyrroloazepine alkaloid isolated from
Stemona Tuberosa, the roots of which have been used in traditional
Asian folk medicine for the treatment of respiratory diseases
(Fig. 1).4 Among the various strategies already investigated for
the preparation of these biologically active products, only a few
report general methods for the construction of the seven-mem-
bered heterocyclic ring.
F
O
O
H
N
N
F
N
H
OH
O
LY411575
OH
To fill in this gap, Meyers attempted to extend the well-known
O
H
diastereoselective formation of 5,5- and 6,5-fused bicyclic lactams5
N
O
NH
to the construction of larger 7,5-fused bicyclic lactams from
x-keto
acids.6 Unfortunately, under routine cyclodehydration conditions,
both the yield and the diastereoselectivity were revealed to be
rather modest, likely due to a lack of rigidity of the larger seven-
membered ring. The limitation of Meyers’ methodology in con-
structing larger chiral 7,5-fused bicyclic lactams was also pointed
out more recently by Wünsch,7 who observed the total absence
of diastereoselectivity during the preparation of oxazolo[3]benzaz-
N
O
(+)-Balanol
H
H
O
OH
HO
H
O
O
HO
O
(-)-Stemoamide
HO2C
* Corresponding authors. Tel.: +33 (0) 235522496; fax: +33 (0) 235522962 (S.O.).
E-mail address: sylvain.oudeyer@insa-rouen.fr (S. Oudeyer).
Figure 1. Biological active compounds containing seven-membered nitrogen
heterocycles.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.014

A. Bouet et al. / Tetrahedron: Asymmetry 19 (2008) 2396–2401
2397
prepared under these new activation conditions, while classical
dehydrating conditions led mainly to the degradation of starting
material.9 Herein, we report a useful extension of these mild lacta-
mization conditions to the preparation of oxazoloazepinones
(Scheme 1). In addition, an evaluation of the potential of these
7,5-fused bicyclic lactams as chiral templates is reported during
the alkylation of the corresponding lactam enolates.
hydroxycyclohexanone dimer.10 The lactamization was then car-
ried out in dichloromethane at 0 °C in the presence of FEP, to afford
the desired 7,5-fused bicyclic lactam 2 in 60% yield. Interestingly,
the diastereoselectivity was found to be markedly influenced by
the sequence of the reagent addition. While disappointing results
(de = 10%) were obtained by adding (R)-phenylglycinol followed
by FEP to a solution of 6-oxohexanoic acid 1 and NEt3 (sequence
A), the diastereoselectivity could be significantly enhanced
(de = 80%) by first introducing the activating agent FEP followed
by (R)-phenylglycinol (sequence B). This result designates the for-
mation of the activated ester prior to the formation of the oxazol-
idine intermediate as a prerequisite for obtaining satisfactory
diastereoselectivities (Scheme 2).
Carboxylic acid activation by FEP
O
O
This work
de = ?
R2
O
N
O
4
R2=H
n= 4
To highlight the formation of various intermediates in the lacta-
mization process, sequences A and B were monitored by in situ
infrared spectroscopy (Figs. 2 and 3). Both sequences started with
the addition of NEt3 to a solution of 6-oxohexanoic acid 1 in dichlo-
romethane. Whereas the initial spectra of 6-oxohexanoic acid 1
showed two bands at 1710 cmꢀ1 and 1725 cmꢀ1 that are attributed
to the carboxylic and aldehyde functions, respectively, upon addi-
R1
R1
R1
R1
O
OH
H2N
O
toluene
N
N
N
O
R2
+
O
R2
O
R2
O
reflux
ref. 6
CO2H
R2
n= 2-4
n
tion of triethylamine a new absorbance appeared at 1370 cmꢀ1
,
n= 2, 3
High yield
High de
n=4
Modest yield
Low de
that is, associated with the formation of the corresponding carbox-
ylate salt. The disappearance of the aldehyde C@O stretch
(1725 cmꢀ1) after adding (R)-phenylglycinol, in conjunction with
the absence of any imine band (usually located near 1650 cmꢀ1),
suggested the rapid formation of the oxazolidine intermediate as
the main product. A quantitative 13C NMR experiment of a solution
of 6-oxohexanoic acid 1 and (R)-phenylglycinol in CDCl3 confirmed
the presence of the oxazolidine as a mixture of two diastereomers
with a slight diastereomeric enrichment of 57:43. Sequence A was
finally completed with the addition of FEP, to afford the desired
oxazoloazepinone 2 within a few minutes as indicated by the
appearance of a new band at 1650 cmꢀ1, that is, assigned to the
lactam C@O vibration. The NMR analysis of the crude product
showed a modest diastereoselectivity of 55:45 that is roughly the
same as the one measured in the oxazolidine intermediate. This
result suggests that the stereochemical outcome of the whole
lactamization process arises from the oxazolidine formation, which
may be considered as the stereodetermining step (Fig. 2).
In sequence B, FEP was first added to the carboxylate salt of 1 to
produce the activated ester as observed by the appearance of a new
absorbance at 1840 cmꢀ1 (Fig. 3). Upon addition of (R)-phenylgly-
cinol, an additional peak at 1650 cmꢀ1 appeared, revealing that lac-
tamization occurred within a few minutes. Subsequent 1H NMR
analysis of the crude product showed that the desired oxazoloaz-
epinone 2 was formed in up to 80% de. Unfortunately, no other
intermediates could be observed by in situ infrared spectroscopy
Scheme 1. Scope and limitation of Meyers’ bicyclic lactam formation under
dehydrating conditions.
2. Results and discussion
The required 6-oxohexanoic acid 1 was prepared in 80% yield by
a Baeyer–Villiger oxidation of the commercially available 2-
sequence A
Ph
O
OH
1) (R)-phenylglycinol/
O
N
NEt3 /CH2Cl2
2) FEP
O
yield = 60%
de =10%
O
O
H
OH
ref. 10
O
2
NaIO4
HO
H
4
THF/H2O
80%
Ph
1
O
N
1) FEP/NEt3 /CH2Cl2
yield = 60%
de =80%
O
2) (R)-phenylglycinol
H
2
sequence B
Scheme 2. FEP-promoted diastereoselective lactamization of 6-oxohexanoic acid 1.
Ph
Ph
Ph
sequence A
OH
O
HN
O
HN
H2N
+
-O
-O
O
O
4
4
H
(C)
1370 cm-1
H
1725 cm-1
de = 14% (determined by 13C NMR)
O
O
4
-O
Et3NH
H
(D)
FEP
Ph
1
1650 cm-1
(B)
NEt3
1725 cm-1
O
N
1710 cm-1
O
O
O
yield = 60%
de =10%
H
HO
H
4
2
1
Figure 2. Monitoring the lactamization process by in situ infrared spectroscopy (sequence A).

2398
A. Bouet et al. / Tetrahedron: Asymmetry 19 (2008) 2396–2401
Ph
N+
O
OH
Ph
O
O
1650 cm-1
Ph
1840 cm-1
HO
RO
1725 cm-1
Ph
N
H
O
4
H
O
O
OH
N
H2N
N+
O
H
O
Ph
Ph
4
(D)
H
O
HN
O
HN
+
2
O
RO
O
(C)
4
yield = 60%
de =80%
4
H
FEP
H
1725 cm-1
1370 cm-1
R =
O
O
N+
-O
H
4
Et3NH
1
1
(B)
1710 cm-1
NEt3
1725 cm-1
O
O
sequence B
HO
H
4
Figure 3. Monitoring the lactamization process by in situ infrared spectroscopy (sequence B).
due to the fast conversion of the activated ester into the desired
oxazoloazepinone 2. At this stage, two mechanisms were envi-
sioned to explain the formation of the oxazoloazepinone 2 from
the activated ester. The first involves the formation of the oxazol-
idine, which would subsequently react with the activated ester to
yield oxazoloazepinone 2 similarly to sequence A. Alternatively,
(R)-phenylglycinol may react first with the activated ester to fur-
center of the oxazoloazepinone 2 may be, however, reasonably
assigned as (S) by comparison with the literature data (Fig. 3).12
Although phenylglycinol is usually designated as the chiral
auxiliary of choice for synthetic applications on account of the
facile cleavage of the chiral appendage, (S)-tert-leucinol and
(S)-valinol were also considered in this study (Table 1). The
performances of (S)-tert-leucinol did not surpass those of (R)-phen-
ylglycinol, affording the oxazoloazepinone 3 in only 45% yield and
81% de (entries 1 and 2). The lactamization conducted with
(S)-valinol proceeded with a high diastereoselectivity, as only
one diastereomer could be detected on the 1H NMR spectra of
the crude product, however, at the expense of the yield not exceed-
ing 31% (entry 3). To complete this study, other reaction parame-
ters, such as temperature (ꢀ78 °C, 20 °C, or 40 °C) and solvents
(CH3CN, CHCl3, or DMF), were briefly examined during the forma-
tion of oxazoloazepinone 2 without any improvement of yield or
diastereoselectivity.
nish an
x-amido aldehyde. The diastereoselective lactamization
would then take place via the formation of an acyliminium species,
followed by the oxazolidine ring formation resulting from the pref-
erential attack of the alcohol on one face of the iminium. The
highly diastereoselective cyclisation of an
x-amido acetal into
oxazolo[3]benzazepinone reported by Wünsch11 is consistent with
this mechanistic scenario and argues in favor of the formation of an
x
-amido aldehyde as an intermediate. Attempts to determine the
relative configuration of the major diastereoisomer by NOESY
experiments failed. The stereochemistry at the N,O-acetal stereo-
With these new chiral oxazoloazepinones in hand, diastereo-
selective functionalization at C-6 of the oxazoloazepinone 2 was
then investigated (Table 2). Whereas alkylation of enolates derived
from 5,5- and 6,5-fused bicyclic lactams has already been exten-
sively exploited,5,13 it remains almost unexplored with 7,5-fused
bicyclic lactams,11 most likely due to the lack of general stereo-
Table 1
Lactamization of 6-oxohexanoic acid 1 with various aminoalcoholsa
Entry
Aminoalcohol
Lactam
Yieldb (%)
dec (%)
Ph
O
N
1
(R)-Phenylalaninol
60
80
O
Table 2
Alkylation of lactam enolate derived from oxazoloazepinone 2
H
2
Ph
Ph
Ph
1) LiHMDS (1.5 eq.)
THF, -78°C
O
H
O
O
H
t-Bu
N
N
N
O
O
O
H
O
O
+
2) Electrophile
(2.5 eq.)
THF, -78°C
N
2
(S)-tert-Leucinol
45
31
80
R
R
O
H
Exo
Endo
2
5-9
3
Entry
Electrophile
R
Product
Yield (%)
dea (%)
i-Pr
1
2
3
4
5
MeI
Me
5
6
7
8
9
73b
65
86
60
60
62
27
C6H5CH2Br
AllylBr
Ph2CO
Bn
N
3
(S)-Valinol
>95
CH2CH@CH2
C(OH)Ph2
N3
O
H
>95
>95
TrN3
>95d
c
4
Lactamization was conducted following the procedure B at 0 °C using com-
pound 1 (1 equiv), NEt3 (2 equiv), FEP (1.1 equiv), and aminoalcohol (1 equiv).
Diastereomeric excesses were determined by chiral GC and 1H NMR.
4 Equiv of LiHMDS was necessary to drive the reaction to completion.
Tr = triisopropyl-p-toluenesulfonyl.
a
a
b
c
b
Isolated yield.
Determined by 1H NMR and chiral GC.
Conversion determined by 1H NMR.
c
d

A. Bouet et al. / Tetrahedron: Asymmetry 19 (2008) 2396–2401
2399
selective access to these larger bicyclic lactams. A survey of the
literature revealed that while LDA provides rather poor yields dur-
ing the alkylation of various oxazolopiperidinones, much better
yields have been reached with comparable or higher level of dia-
stereoselectivity by using LiHMDS.13
isomer are given in square brackets. Gas chromatography was
performed on a Varian 3300 chromatograph fitted with a DB5
capillary column (l = 30 m, £ = 0.25 mm, df = 0.25
monitoring or on a Chirasil-Dex CBÒ chiral capillary column
(l = 25 m, £ = 0.25 mm, df = 0.25 m) for diastereomeric excesses
lm) for reaction
l
After optimization of the reaction conditions, treatment of oxa-
zoloazepinone 2 with LiHMDS at ꢀ78 °C in THF gave rise to the cor-
responding lactam enolate, which was subsequently trapped with
various electrophiles. In all cases, the reaction proceeded with
excellent conversions and isolated yields, ranging between 60%
and 86%. The diastereoselectivity was shown to be highly substrate
dependent, affording the b-substituted oxazoloazepinones 5–9 in
27–95% de. Whereas methyl iodide and benzyl bromide afforded
oxazoloazepinones 5 and 6 with very similar levels of diastereo-
selection (60% and 62%, respectively), allylbromide furnished oxa-
zoloazepinone 7 in only 27% de (entries 1–3). The more sterically
hindered benzophenone and triisopropyl-p-toluenesulfonylazide
led to high diastereoselectivities, providing oxazoloazepinones 8
and 9 in up to 95% de (entries 4 and 5). It should be noted that
although azidation of 2 occurred with complete conversion, we
did not succeed in the separation of the residual triisopropyl-p-tol-
uenesulfonylazide derivatives, used in excess, from the 6-azido-
oxazoloazepinone 9. All our efforts to determine the configuration
of the new stereocenter at C-6 of the various oxazoloazepinones 5–
9 by X-ray analysis and NOESY experiments failed. A preferential
endo-facial selectivity was observed by Wünsch during the diaste-
reoselective alkylation of an oxazolo[3]benzazepinone, which is
structurally closely related to our oxazoloazepinones.7,11 Although
the literature data strongly argue in favor of the preferential forma-
tion of the endo-diastereomer, it would be hazardous to conclude
on the configuration at C-6 in oxazoloazepinones 5-9. Indeed,
determination. EI-MS were performed on a GCQ Thermoquest
spectrophotometer coupled to a Finnigan-GCQ chromatograph
equipped with
£ = 0.25 mm, df = 0.25
a
DB5-MS capillary column (l = 25 m,
m). Other mass spectra (IC, FAB) were re-
l
corded on JEOL JMS AX-500 by the Mass Spectrometry Laboratory
at the University of Rouen. Elemental analysis was carried out at
the University of Rouen (Microanalytical Service Laboratory) on a
CARLO ERBA 1160. Optical rotation was measured at 20 °C in
CH2Cl2 or CHCl3 on a PERKIN–ELMER 341 micropolarimeter. All
reactions were carried out under an argon atmosphere, and were
monitored by thin-layer chromatography with Merck 60F-254 pre-
coated silica (0.2 mm) on aluminum. Flash chromatographies were
performed with SDS silica gel, 70–230 mesh (Merck). Preparative
layer chromatographies were performed with Merck 60 HF254
precoated silica on glass. The solvent systems were given v/v.
4.2. 6-Oxohexanoic acid 1
To
a solution of 2-hydroxycyclohexanone dimer (3.42 g,
30.0 mmol) in a 60% aqueous THF solution (300 mL) was added
sodium periodate (6.42 g, 30.0 mmol). The solution was stirred
for 10 h at room temperature. Thereafter, sodium periodate
(3.21 g, 15.0 mmol) was again added, and the solution was stirred
for an additional 6 h. The reaction mixture was diluted with AcOEt
(300 mL), and washed with brine. The organic phase was extracted
and dried over MgSO4. Flash chromatography of the residue
(eluent: ethylacetate/cyclohexane: 1/1) (stain reagent for TLC:
phosphomolybdic acid reagent) provided 6-oxohexanoic acid 1 as
a clear oil (3.12 g, 80%). 1H NMR 300 MHz, (CDCl3) d 9.65 (s, 1H);
2.22 (s, 2H); 2.12 (s, 2H); 1.43 (s, 4H). 13C NMR 75 MHz, (CDCl3)
whereas numerous literature reports mention
a preferential
endo-facial selectivity during the alkylation of 5,5-fused bicyclic
lactams,5 an exo-facial selectivity has also been reported in many
cases with 6,5-fused bicyclic lactams.13a–d
d 203.3; 179.4; 43.6; 33.9; 24.3; 21.6. IR
t
(cmꢀ1) (KBr): 3446;
2948; 1722; 1411. Anal. Calcd for C6H10O3: C, 55.37; H, 7.74; O,
36.88. Found: C, 55.25; H, 7.71; O, 36.81.
3. Conclusion
Meyers’ methodology was successfully applied to the stereose-
lective synthesis of new 7,5-bicyclic lactams. The lactamization
was conducted under mild conditions with 6-oxohexanoic acid 1
and with various chiral aminoalcohols in the presence of FEP as
activating agent. Oxazoloazepinones 2–4 were obtained in good
yields with diastereoselectivities of up to 95%. The sequence of
the reagent addition proved to be crucial in achieving good diaste-
reoselectivities. In an effort to gain insight into the difference in
the diastereoselectivity between sequences A and B, both lactami-
zation procedures were monitored by in situ infrared spectros-
copy. Lastly, to probe the synthetic potential of what can be
considered as new chiral templates for the stereoselective func-
tionalization of seven-membered ring heterocycles, alkylation of
the corresponding lactam enolates was investigated affording the
b-substituted oxazoloazepinones 5-9 in good yields and diastere-
oselectivities up to 95%.
4.3. (3R,9aRS)-Hexahydro-3-phenyloxazolo[3,2-a]azepin-5(6H)-
one 2 (procedure B)
To a solution of 6-oxohexanoic acid 1 (1.00 g, 7.68 mmol) in dry
CH2Cl2 (50 mL) at 0 °C was added triethylamine (2.16 mL,
15.5 mmol). Then, 2-fluoro-1-ethylpyridinium tetrafluoroborate
salt (FEP) (1.80 g, 8.45 mmol) was slowly added. The mixture was
stirred for 20 min at 0 °C after which (R)-phenylglycinol (1.05 g,
7.68 mmol) was added, and the resulting solution was stirred for
45 min at the same temperature. Water (50 mL) was added, and
the organic phase was extracted twice with CH2Cl2 (50 mL). After
drying over MgSO4, the combined organic layers were removed un-
der vacuum. The desired oxazoloazepinone 2 was obtained in 80%
de (measured by 1H NMR and GC analyses of the crude product).
Flash chromatography (AcOEt/cyclohexane 1/1) allowed us to iso-
late the pure (3R,9aS)-2 and a (3R,9aR)-enriched mixture of both
diastereomers in 60% yield (1.07 g). (3R,9aS)-2: white solid (mp:
132–133 °C). 1H NMR 300 MHz, (CDCl3) d 7.30–7.19 (HAr, 5H, m);
5.15 (H-3, 1H, d, J = 5.3 Hz); 5.08 (H-9a, 1H, d, J = 9.6 Hz); 4.11–
4.00 (H-2, 2H, m); 2.58 (H-6, 1H, dd, J = 14.9, 7.2 Hz); 2.30–2.19
(H-60 + H9, 2H, m); 1.99–1.95 (H-8, 1H, m); 1.86–1.80 (H-7, 1H,
m); 1.68–1.48 (H-90 + H-80 + H-70, 3H, m). 13C NMR 75 MHz, (CDCl3)
d 171.7 (C-5); 141.1 (CqAr); 128.5; 127.4; 126.7 (CHAr); 90.9 (C-9a);
72.7 (C-2); 60.0 (C-3); 38.7 (C-6); 34.7 (C-9); 26.6 (C-8); 23.3 (C-7).
4. Experimental
4.1. General methods
All solvents were dried according to the common methods and
were distilled before use. IR spectra were recorded on ELMER IRTF
1650 spectrometer. Melting points were determinated using WME
Kofler apparatus. 1H and 13C NMR spectra were recorded on a Bru-
ker 300 Avance (300 MHz). Chemical shifts are reported in d (ppm).
In the case of diastereomeric mixture, spectral data of the minor
IR
t
(cmꢀ1) (KBr): 3440; 2932; 2861; 1644; 1422. Anal. Calcd for
C14H17NO2: C, 72.70; H, 7.41; N, 6.06; O, 13.83. Found: C, 72.57;
H, 4.31; N, 6.19. ½a D20
ꢁ
¼ ꢀ59:1 (c 1.15, CH2Cl2). (3R,9aR)-2: 1H

2400
A. Bouet et al. / Tetrahedron: Asymmetry 19 (2008) 2396–2401
NMR (300 MHz, CDCl3) d [(3R,9aR)/(3R,9aS) mixture : 65/35] 7.30–
7.11 (HAr, 5H, m); 5.36 (H-9a, 1H, d, J = 9.6 Hz); 5.11–5.06 (H-3, 1H,
m); 4.24 (H-2, 1H, dd, J = 8.6, 6.2 Hz); 3.79 (H-2, 1H, dd, J = 8.8,
3.0 Hz); 2.42 (H-6, 1H, dd, J = 14.1, 7.2 Hz); 2.29–2.18 (H-6, 1H,
m); 1.98–1.45 (H-7 to H-9, 6H, m). 13C NMR (75 MHz, CDCl3) d
[(3R,9aR)/(3R,9aS) mixture : 65/35] 170.8 (C-5); 140.7 (CqAr);
128.6 ; 127.5 ; 126.3 (CHAr); 91.0 (C-9a); 72.4 (C-2); 60.2 (C-3);
38.5 (C-6); 34.7 (C-9); 26.2 (C-8); 23.1 (C-7).
dried over MgSO4, and concentrated to afford the crude product.
The diastereomeric excess was measured by 1H NMR and GC anal-
yses (de = 60%). Both diastereomers were separated by flash chro-
matography on silica gel (AcOEt/cyclohexane 20/80) in 73% yield
(41 mg). Under these chromatographic conditions, the minor dia-
stereoisomer was eluted before the major diastereomer. Com-
pound 5 (major diasteromer): white solid (mp: 74–76 °C). 1H
NMR (300 MHz, CDCl3) d 7.39–7.23 (HAr, 5H, m); 5.30–5.17 (H-
3 + H-9a, 2H, m); 4.14–4.05 (H-2, 2H, m); 2.95–2.86 (H-6, 1H,
m); 2.65–2.32 (H-9, 1H, m); 1.82–1.69 (H-7 + H-8 + H-9, 5H, m);
1.27 (CH3, 3H, d, J = 7.7 Hz). 13C NMR (75 MHz, CDCl3) d 174.2 (C-
5); 142.0 (CqAr); 128.8; 127.7; 127.0 (CHAr); 89.9 (C-9a); 72.9 (C-
2); 61.4 (C-3); 42.4 (C-6); 35.1 (C-9); 29.7 (C-7); 19.5 (C-8); 14.5
(CH3). EI-MS m/z 245; 148; 120; 119; 117; 104; 91; 77; 69; 55;
4.4. (3S,9aRS)-Hexahydro-3-tert-butyloxazolo[3,2-a]azepin-
5(6H)-one 3
The title compound was prepared according to procedure B
from 6-oxohexanoic acid 1 (185 mg, 1.42 mmol), triethylamine
(0.4 mL, 2.84 mmol), 2-fluoro-1-ethylpyridinium tetrafluoroborate
salt (FEP) (333 mg, 1.56 mmol), and (S)-tert-leucinol (166 mg,
1.42 mmol). The desired oxazoloazepinone 3 was obtained in 81%
de (measured by 1H NMR and GC analyses of the crude product).
Flash chromatography (cyclohexane/ethyl acetate 1/1) of the resi-
due provided compound 3 (134 mg, 45%) as an inseparable mixture
of diastereomers (3R,9aS)-3 and (3R,9aR)-3 in an 87/13 ratio.
(3R,9aS)-3 [chemical shift data of (3R,9aR)-3 appear in square bra-
kets]: 1H NMR 300 MHz, (CDCl3) d [5.10 (H-9a, 1H, m)]; 4.87 (H-9a,
1H, m); [4.20-4.18 (H-3, 1H, m)]; 4.00–3.95 (H-2, 2H, m); [3.85–
3.81 (H-2, 2H, m)]; 3.57 (H-3, 1H, dd, J = 9.0, 6.2 Hz); 2.60 (H-6,
1H, dd, J = 15.8, 7.3 Hz); 2.56-1.40 (H-6 to H9 + [H-6 to H9],
7H + [8H], m); 0.95–0.80 (CH3 + [CH3], 9H + [9H], s). 13C NMR
75 MHz, (CDCl3) d 175.0, [173.4] (C-5); 91.5, [91.2] (C-9a); 67.5,
[66.2] (C-2); 64.6, [63.8] (C-3); 39.5, [38.7] (C-6); [36.4], 35.5 (C-
tBu); 34.2, [30.0] (C-9); 27.6, [27.4] (CH3); 27.2, [25.9], 23.9,
[23.3] (C-7 and C-8). CI-MS m/z 212 (M+H+). HR-MS calcd for
C12H21NO2 (MH)+ m/z 212.1634, found: 212.1650.
41. IR
m
(cmꢀ1) (KBr) 3030; 2919; 1634; 1497; 1461; 1423;
1386; 1092; 711. HR-MS calcd for C15H20NO2 (MH)+ m/z
246.1494, found: 246.1511. ½a D20
¼ ꢀ22:6 (c 1.15, CHCl3). Com-
ꢁ
pound 5 (minor diasteromer): glassy solid. 1H NMR (300 MHz,
CDCl3) d 7.42–7.24 (HAr, 5H, m); 5.22–5.20 (H-3 + H-9a, 2H, m);
4.18–4.08 (H-2, 2H, m); 2.34–2.17 (H-6 + H-9, 2H, m); 2.03–1.97
(H-8, 1H, m); 1.80–1.48 (H-7 + H-8 + H-9, 4H, m); 1.15 (CH3, 3H,
d, J = 6.8 Hz). 13C NMR (75 MHz, CDCl3) d 173.9 (C-5); 141.6 (CqAr);
128.9; 127.8; 127.2 (CHAr); 90.8 (C-9a); 72.7 (C-2); 60.7 (C-3); 41.0
(C-6); 35.0 (C-9); 32.5 (C-7); 26.8 (C-8); 18.3 (CH3). HR-MS calcd
for C15H20NO2 (MH)+ m/z 246.1494, found: 246.1487.
½
a 2D0
ꢁ
¼ ꢀ60:0 (c 0.2, CHCl3).
4.7. (3R,6R,9aS)- and (3R,6S,9aS)-6-benzyl-3-phenyl-2,3,6,7,8,9-
hexahydrooxazolo[3,2-a]azepin-5(9aH)-one 6
According to general procedure
(3R,9aS)-2 (49 mg, 0.21 mmol), LiHMDS (0.318 mL, 0.318 mmol)
and benzyl bromide (66 L, 0.687 mmol) furnish 6 The diastereo-
C from oxazoloazepinone
l
4.5. (3S,9aR)-Hexahydro-3-iso-propyloxazolo[3,2-a]azepin-
5(6H)-one 4
isomeric excess (de = 62%) was measured by 1H NMR and GC anal-
yses from the crude product. Flash chromatography (AcOEt/
cyclohexane 10/90) furnished a mixture of diastereomers in a 84/
16 ratio (44 mg, 65%). Compound 6 (84/16 diastereoisomeric ra-
tio): 1H NMR (300 MHz, CDCl3) [chemical shift data of the minor
diastereomer appear in square brakets] d 7.36–7.11 (HAr and
[HAr], 20H, m); 5.23–5.01 (H-3 + H-9a and [H-3 + H-9a], 4H, m);
4.05–3.99 (H-2 and [H-2], 4H, m); [3.28–3.24 (H-6, 1H, m)];
3.05–1.31 (other H and [other H], 17H, m). 13C NMR (75 MHz,
CDCl3) d [173.1], 174.2 (C-5); 141.9, [141.4], [140.9], 139.0 (CqAr);
[129.8], 129.3, 129.0, [128.9], 128.8, [128.7], [127.9], 127.8,
[127.2], 127.1, 126.9, [126.5] (CHAr); [90.8], 89.9 (C-9a); 72.9,
[72.8] (C-2); 61.6, [60.7] (C-3); 49.8, [48.1] (C-6); [37.7], [34.9],
34.9, 34.6 (CH2-benzyl + C-9); [28.8], 25.8 (C-7); [26.9], 19.7 (C-
The title compound was prepared according to procedure B
from 6-oxohexanoic acid 1 (446 mg, 3.42 mmol), triethylamine
(1.0 mL, 6.84 mmol), 2-fluoro-1-ethylpyridinium tetrafluoroborate
salt (FEP) (803 mg, 3.77 mmol), and (S)-valinol (353 mg,
3.42 mmol). The desired oxazoloazepinone 4 was obtained in up
to 95% de (measured by 1H NMR and GC analyses of the crude
product). Flash chromatography (cyclohexane/ethyl acetate 1/1)
of the residue provided compound 4 (205 mg, 31%) as a colorless
oil. 1H NMR 300 MHz (CDCl3) d 5.90 (H-9a, 1H, d, J = 8.3 Hz);
3.96–3.88 (H-2, 2H, m); 3.63 (H-3, 1H, dd, J = 8.9, 6.0 Hz); 2.54
(H-6, 1H, dd, J = 15.2, 7.5 Hz); 2.24–1.77 (5H, m); 1.51–1.45 (3H,
m); 0.87 (CH3, 3H, d, J = 5.3 Hz); 0.85 (CH3, 3H, d, J = 5.3 Hz). 13C
NMR 75 MHz, (CDCl3) d 172.9 (C-5); 90.7 (C-9a); 67.8 (C-2); 62.2
(C-3); 39.1 (C-6); 35.1 (C-9); 30.9 (C-10); 27.0 (C-8); 23.7 (C-7);
19.8, 18.9 (CH3). EI-MS m/z 197; 154; 114; 95; 67. HR-MS calcd
for C11H19NO2 (MH)+ m/z 197.1416, found: 197.1414.
8); 14,5 (CH3). IR
m
(cmꢀ1) (neat) 3438; 2932; 2866; 1638; 1495;
1453; 751; 714; 699. HR-MS calcd for C21H24NO2 (MH)+ m/z
322.1807, found: 322.1816.
4.8. (3R,6R,9aS)- and (3R,6S,9aS)-6-allyl-3-phenyl-2,3,6,7,8,9-
hexahydrooxazolo[3,2-a]azepin-5(9aH)-one 7
4.6. (3R,6R,9aS)- and (3R,6S,9aS)-6-methyl-3-phenyl-
2,3,6,7,8,9-hexahydrooxazolo[3,2-a]azepin-5(9aH)-one 5
According to general procedure
(3R,9aS)-2 (50 mg, 0.22 mmol), LiHMDS (0.324 mL, 0.324 mmol)
and allyl bromide (47 L, 0.543 mmol) afforded 7. The diastereo-
C from oxazoloazepinone
4.6.1. General procedure C for the alkylation of
oxazoloazepinone (3R,9aS)-2
l
meric excess (de = 27%) was measured by 1H NMR and GC analyses
from the crude product. Flash chromatography (AcOEt/cyclohex-
ane 30/70) allowed us to isolate the pure major diastereomer
and a minor-enriched mixture of both diastereomers in 86%
(51 mg). The major diastereomer was eluted before the minor dia-
stereomer. Compound 7 (major diastereomer): colorless oil. 1H
To a precooled (ꢀ78 °C) solution of oxazoloazepinone (3R,9aS)-
2
(1 equiv, 0.2 mmol) in THF (5 mL), LiHMDS (1 M in THF,
1.5 equiv) was added dropwise. After stirring the solution at
L, 0.687 mmol) was added,
ꢀ78 °C for 1 h, methyl iodide (43
l
and stirring was continued until complete consumption of the
starting lactam. The reaction mixture was quenched by the addi-
tion of brine (10 mL), and the resulting mixture was extracted with
ethyl acetate (2 ꢂ 10 mL). The combined organic extracts were
NMR (300 MHz, CDCl3) d 7.36–7.18 (HAr, 5H, m); 5.82–5.70 (CHallyl
,
1H, m); 5.17–5.14 (H-3 + H-9a, 2H, m); 5.01–4.96 (CH2allyl, 2H, m);
4.11–4.01 (H-2, 2H, m); 2.61–2.53 (CH2, 1H, m); 2.19–2.10 (H-

A. Bouet et al. / Tetrahedron: Asymmetry 19 (2008) 2396–2401
2401
7 + H-6, 2H, m); 2.04–1.93 (CH2, 1H, m); 1.77–1.71 (H-8, 1H, m);
1.68–1.57 (H-70 + H-9, 3H, m); 1.37–1.25 (H-80, 1H, m). 13C NMR
(75 MHz, CDCl3) d 173.0 (C-5); 141.4 (CqAr); 137.4 (CHallyl);
128.9; 127.8; 127.2 (CHAr); 117.0 (CH2allyl); 90.8 (C-9a); 72.8 (C-
2); 60.6 (C-3); 46.0 (C-6); 36.3 (CH2); 35.0 (C-7); 29.3 (C-8); 26.9
m). 13C NMR (75 MHz, CDCl3) d 166.7 (C-5); 140.8 (CqAr); 128.6,
127.7, 126.9 (CHAr); 89.4 (C-9a); 72.6 (C-2); 66.7 (C-6); 60.9 (C-
3); 34.4, 28.0, 18.8 (C-7, C-8 and C-9). ESI-MS m/z 273.4 (MH+).
IR
m
(cmꢀ1) (neat) 2098; 1652.
(C-9). IC-MS m/z 272.0. IR
m
(cmꢀ1) (neat) 3392; 2927; 2860;
Acknowledgments
1647;1455; 1418; 1091; 713. HR-MS calcd for C17H22NO2 (MH)+
m/z 272.1650, found: 246.1647. ½a D20
ꢁ
¼ ꢀ70:0 (c 0.3, CHCl3). Com-
We are grateful for financial support of this work by the Minis-
try of Research and Technology (MRT) and the région Haute-Nor-
mandie. A. Bouet thanks the MRT for a grant.
pound 7 (minor diastereomer): 1H NMR (300 MHz, CDCl3) d (ma-
jor/minor mixture : 56/44) 7.30–7.00 (HAr, 5H, m); 5.70–5.50
(CHallyl, 1H, m); 5.10–4.80 (H-3 + H-9a + CH2allyl, 4H, m); 4.00–
3.80 (H-2, 2H, m); 2.05–1.00 (H-6 to H-9 + CH2, 9H, m). 13C NMR
(75 MHz, CDCl3) d 172.9 (C-5); 141.9 (CqAr); 135.7 (CHallyl);
128.8; 127.7; 127.0 (CHAr); 117.4 (CH2allyl); 89.8 (C-9a); 72.9 (C-
2); 61.5 (C-3); 47.8 (C-6); 34.9 (CH2); 32.8 (C-7); 26.7 (C-9); 19.5
References
1. Trost, B. M.; Fandrick, D. R.; Brodmann, T.; Stiles, D. T. Angew Chem., Int. Ed.
2007, 46, 1623 and references cited therein.
2. Fuwa, H.; Okamura, Y.; Morohashi, Y.; Tomita, T.; Iwatsubo, T.; Fukuyama, T.;
Natsugari, H. Tetrahedron Lett. 2004, 45, 2323; Peters, J.-U.; Galley, G.; Jacobsen,
H.; Czech, C.; David-Pierson, P.; Kitas, E. A.; Ozmen, L. Bioorg. Med. Chem. Lett.
2007, 17, 5918; Fauq, A. H.; Simpson, K.; Maharvi, G. M.; Golde, T.; Das, P.
Bioorg. Med. Chem. Lett. 2007, 17, 6392.
(C-8). IC-MS m/z 272.0. IR
m
(cmꢀ1) (neat) 3464; 3066; 3031;
2954; 2862; 1645; 1491; 1448; 1419; 715.
4.9. (3R,6R,9aS)- or (3R,6S,9aS)-6-(hydroxydiphenylmethyl)-
3-phenyl-2,3,6,7,8,9-hexahydro-oxazolo[3,2-a]azepin-
5(9aH)-one 8
3. For total and formal syntheses of (ꢀ)-stemoamide see: Torsell, S.; Wanngren,
E.; Somfai, P. J. Org. Chem. 2007, 72, 4246; and references cited therein Bogliotti,
N.; Dalko, P. I.; Cossy, J. J. Org. Chem. 2006, 71, 9528.
4. Pilli, R. A.; Ferreira de Oliveira, M. C. Nat. Prod. Rep. 2000, 17, 117 and references
cited therein.
5. For leading references on chiral non-racemic bicylic lactams in synthesis, see:
Romo, D.; Meyers, A. I. Tetrahedron 1991, 46, 9503; Groaning, M. D.; Meyers, A.
I. Tetrahedron 2000, 56, 9843.
6. Meyers, A. I.; Downing, S. V.; Weiser, M. J. J. Org. Chem. 2001, 66, 1413.
7. Husain, S. M.; Fröhlich, R.; Wünsch, B. Tetrahedron: Asymmetry 2008, 19, 1613.
8. Penhoat, M.; Leleu, S.; Dupas, G.; Papamicaël, C.; Marsais, F.; Levacher, V.
Tetrahedron Lett. 2005, 46, 8385.
9. Penhoat, M.; Bohn, P.; Leleu, S.; Dupas, G.; Papamicaël, C.; Marsais, F.; Levacher,
V. Tetrahedron: Asymmetry 2006, 17, 281.
10. Floresca, R.; Kurihara, M.; Watt, D. S.; Demir, A. J. Org. Chem. 1993, 58, 2196.
11. Wirt, U.; Fröhlich, R.; Wünsch, B. Tetrahedron: Asymmetry 2005, 16, 2199; Wirt,
U.; Schepmann, D.; Wünsch, B. Eur. J. Org. Chem. 2007, 462.
According to general procedure
(3R,9aS)-2 (52 mg, 0.23 mmol), LiHMDS (0.337 mL, 0.337 mmol)
and benzophenone (103 mg, 0.563 mmol) afforded (54 mg,
C from oxazoloazepinone
8
60%) as a single diastereoisomer after flash chromatography
(CH2Cl2/cyclohexane from 40/60 to 90/10). Pale yellow solid (mp:
174–176 °C). 1H NMR (300 MHz, CDCl3) d 7.39–7.37 (HAr, 2H, m);
7.25–7.01 (HAr, 13H, m); 5.77 (OH, 1H, br s); 4.89–5.83 (H-3 + H-
9a, 2H, m); 3.89–3.86 (H-2, 2H, m); 3.43–3.39 (H-6, 1H, m);
2.29–2.21 (H-9, 1H, m); 2.15–2.04 (H-90, 1H, m); 1.80–1.71 (H-
8 + H-7, 3H, m); 1.40–1.34 (H-80, 1H, m). 13C NMR (75 MHz, CDCl3)
d 171.9 (C-5); 146.0, 144.8, 141.8 (CqAr); 128.9, 128.3, 127.8, 127.5,
127.4, 127.3, 126.6 (CHAr); 89.8 (C-9a); 81.3 (Cq); 73.2 (C-2); 61.4
(C-3); 53.7 (C-6); 30.5 (C-9); 24.0, 21.8 (C-7 and C-8). CI-MS m/z
OMe
OH
H
O
OMe
HCl (1%)
HN
H
414.0. IR
m
(cmꢀ1) (neat) 3336; 3029; 2953; 2869; 1617; 1493;
N
MeOH
1448; 756; 701. HR-MS calcd for C27H28NO3 (MH)+ m/z 414.2069,
O
found: 414.2083. ½a D20
ꢁ
¼ ꢀ37:5 (c 1.0, CHCl3).
O
High de
4.10. (3R,6R,9aS)- or (3R,6S,9aS)-6-azido-3-phenyl-2,3,6,7,8,9-
hexahydro-oxazolo[3,2-a]azepin-5(9aH)-one 9
12. The (S)-configuration at the new N,O-acetal stereocenter, obtained from (R)-
phenylglycinol, is in accordance with the diastereoselection observed during
the formation of 5,5-, 6,5- and 7,5-fused bicyclic lactams, see Refs. 5, 6, 8, 9 This
is also coherent with the diastereoselection observed during the formation of
According to general procedure
C from oxazoloazepinone
oxazolo[3]benzoazepinone by lactamization of
acidic conditions, see Ref. 11.
x-amido acetals under mild
(3R,9aS)-2 (50 mg, 0.22 mmol), LiHMDS (0.324 mL, 0.324 mmol)
and trisyl azide (100 mg, 0.324 mol) provided 9 as a single diaste-
reomer along with some residual trisyl azide derivatives which are
unseparable by flash chromatography (AcOEt/cyclohexane 5/95 to
30/70) 8 : 1H NMR (300 MHz, CDCl3) d 7.32–7.18 (HAr, 5H, m); 5.3
(H-9a, 1H, d, J = 9.4 Hz); 5.06 (H-3, 1H, d, J = 4.7 Hz); 4.31 (H-6, 1H,
d, J = 6.4 Hz); 4.13–4.00 (H-2, 2H, m); 2.30–1.60 (H-7 and/or H-8
and/or H-9, 4H, m); 1.21–1.16 (H-7 and/or H-8 and/or H-9, 2H,
13. (a) Amat, M.; Escolano, C.; Lozano, O.; Gomes-Esqué, A.; Griera, R.; Molins, E.;
Bosch, J. J. Org. Chem. 2006, 71, 3804; (b) Amat, M.; Escolano, C.; Llor, N.;
Lozano, O.; Gomez-Esqué, A.; Griera, R.; Bosch, J. Arkivoc 2005, 9, 115; (c) Amat,
M.; Llor, N.; Hidalgo, J.; Hernandez, A.; Bosch, J. Tetrahedron: Asymmetry 1996,
7, 977; (d) Amat, M.; Lozano, O.; Escolano, C.; Molins, E.; Bosch, J. J. Org. Chem.
2007, 72, 4431; (e) Micoin, L.; Varea, T.; Riche, C.; Chiaroni, A.; Quirion, J.-C.;
Husson, H. P. Tetrahedron Lett. 1994, 35, 2529; (f) Philippe, N.; Levacher, V.;
Dupas, G.; Duflos, J.; Quéguiner, G.; Bourguignon, J. Tetrahedron: Asymmetry
1996, 7, 417.