Simple access to highly functional bicyclic γ- and δ-lactams: Origins of chirality transfer to contiguous tertiary/quaternary stereocenters assessed by DFT

Article abstract of DOI:10.1002/chem.201405094

This paper describes the synthesis of both polysubstituted oxazolo-pyrrolidinones and -piperidinones by a domino process. The methodology is based on the reaction between hydroxyl halogenoamides and Michael acceptors, which leads efficiently to bicyclic lactams. The process is compatible with unsymmetrical electron-withdrawing groups on the Michael acceptor, which allows the formation of two contiguous and fully controlled tertiary and quaternary stereocenters. In the case of tetrasubstituted Michael acceptors, two adjacent quaternary stereocenters are formed in good yield. Starting from (R)-phenylglycinol derived amides results in the formation of enantioenriched bicyclic lactams in low to good yields and with high levels of stereo-selectivity, thus greatly increasing the scope and interest of this strategy. The origins of chirality transfer and diastereoselectivity were studied by DFT calculations and have been attributed to a kinetic control in one of the last two steps of the reaction sequence. This selectivity is dependent upon both the substituents on the Michael acceptor and the sodium cation chelation.

Full text of DOI:10.1002/chem.201405094

DOI: 10.1002/chem.201405094
Full Paper
&
Bicyclic Lactams
Simple Access to Highly Functional Bicyclic g- and d-Lactams:
Origins of Chirality Transfer to Contiguous Tertiary/Quaternary
Stereocenters Assessed by DFT
Ronan Le Goff,[a] Arnaud Martel,*[b] Morgane Sanselme,[c] Ata Martin Lawson,[a]
Adam Da¨ıch,[a] and Sꢀbastien Comesse*[a]
Dedicated to Dr. Cathy Kadouri on the occasion of her retirement
Abstract: This paper describes the synthesis of both poly-
substituted oxazolo-pyrrolidinones and -piperidinones by
a domino process. The methodology is based on the reac-
tion between hydroxyl halogenoamides and Michael accept-
ors, which leads efficiently to bicyclic lactams. The process is
compatible with unsymmetrical electron-withdrawing
groups on the Michael acceptor, which allows the formation
of two contiguous and fully controlled tertiary and quaterna-
ry stereocenters. In the case of tetrasubstituted Michael ac-
ceptors, two adjacent quaternary stereocenters are formed
in good yield. Starting from (R)-phenylglycinol derived
amides results in the formation of enantioenriched bicyclic
lactams in low to good yields and with high levels of stereo-
selectivity, thus greatly increasing the scope and interest of
this strategy. The origins of chirality transfer and diastereose-
lectivity were studied by DFT calculations and have been at-
tributed to a kinetic control in one of the last two steps of
the reaction sequence. This selectivity is dependent upon
both the substituents on the Michael acceptor and the
sodium cation chelation.
Introduction
Functionalized pyrrolidines, piperidines, and their correspond-
ing lactams are important N-heterocyclic structures, and they
are found in many biologically relevant compounds.[1] Nowa-
days, bicyclic lactams 1 are attractive scaffolds for the synthesis
of compounds that are based on such five- and six-membered
ring systems (Scheme 1).[2] These building blocks were first pre-
pared by Meyers through a stereocontrolled cyclodehydration
of a d- or g-keto acid/ester 2 and a chiral amino alcohol, such
as (R)-phenylglycinol 3, and they are still used as key inter-
mediates in current total syntheses. As these bicyclic lactams
are efficient templates for the synthesis of functionalized N-
Scheme 1. Meyers’ approach and our synthetic route to bicyclic lactams 1.
heterocycles, many alternative strategies for their preparation
have been developed in recent years[3] in conjunction with the
total synthesis of enantioenriched natural or synthetic prod-
ucts.[4]
[a] R. Le Goff, Dr. A. M. Lawson, Prof. A. Da¨ıch, Dr. S. Comesse
Laboratoire de Chimie, URCOM, EA 3221 - FR CNRS 3038
Universitꢀ du Havre, UFR Sciences et Techniques
25 rue Philippe Lebon, 76058 Le Havre cedex (France)
Fax: (+033)2-32-74-43-91
To this end, considerable effort has been focused on the ste-
reoselective functionalization of the lactam ring, and important
contributions in this field of research have been published by
Amat and Bosch.[5] These authors managed to synthesize poly-
substituted oxazolo-piperidinones that contained a tertiary or
quaternary stereocenter (R4 ¼R5) at the 5-position of the piperi-
dine ring[6] by a smart, dynamic kinetic resolution and desym-
metrization process.[7] However, Meyers’ methodology to
access such substituted bicyclic lactams presents two major
drawbacks that limit its scope: 1) it is restricted to prochiral, d-
oxo diesters, and 2) to the best of our knowledge, no example
of oxazolo pyrrolidinones has been described.
E-mail: sebastien.comesse@univ-lehavre.fr
[b] Prof. A. Martel
Team MSO, IMMM, UMR 6283, PRES LUNAM
Universitꢀ du Maine
Avenue O. Messiaen, 72085 Le Mans cedex 9 (France)
Fax: (+033)2-43-83-39-02
E-mail: arnaud.martel@univ-lemans.fr
[c] Dr. M. Sanselme
Laboratoire de Cristallographie, IRCOF, UPRES-EA 3233
’Universitꢀ de Rouen
1 rue Tesniꢁre 76821 (France)
Considering our interest in tandem/domino reactions,[8]
which are powerful tools for the formation of multiple bonds
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405094.
Chem. Eur. J. 2015, 21, 2966 – 2979
2966
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
in one synthetic operation,[9] we have recently reported a new
acid-free domino process for the synthesis of oxazolo-pyrrolidi-
nones or -piperidinones, which was optimized by an ab initio
study.[10] However, in this preliminary paper the scope of this
process was limited to simple substrates and no stereoselec-
tive approaches were described. Nevertheless, with the help of
a complementary DFT study the process was identified to pro-
ceed through a multistep sequence, which involved up to four
transition states. Herein, we present our findings on the diaste-
reoselective synthesis of bicyclic g- and d-lactams 1, in a one-
pot domino reaction from commercially available or easily syn-
thesized Michael acceptors 4 or 4’ and amido alcohols 5 A–D
(Schemes 1 and 2). This domino process is compatible with
and Cl were examined owing to the reactivity of the Michael
acceptors, which has been justified in our previous paper.[10] In-
itially, Michael acceptors that possessed symmetrical electron-
withdrawing groups (E=E’) were engaged. The results ob-
tained from the reactions of diethyl chloromethylene malonate
4a’ and commercially available ethoxymethylene malononitrile
4b have already been reported,[10] and these substrates react-
ed to give the desired bicyclic g-lactams 1aA[12] and 1bA in 67
and 70% yield, respectively (Table 1, entries 1 and 2). When
ethoxymethylene diphenylketone 4c was reacted with achiral
amide 5 A under conditions I, the domino process led to the
bicyclic lactam 1cA in 64% yield (Table 1, entry 3). The 1,3-in-
danedione derived Michael acceptor 4d proved to be very un-
stable in conditions I and II, and only conditions III led
to the formation of spiro-product 1dA, which was iso-
lated in a good yield (Table 1, entry 4). Our investiga-
tions then turned to a more challenging domino pro-
cess with substrates that contained unsymmetrical
electron-withdrawing groups (E¼E’), which would fur-
nish contiguous tertiary/quaternary stereocenters.
As observed with the other diester and diketone
substrates, conditions I proved to be the best reac-
tion conditions for the chlorinated Michael acceptor
4e’, but the product 1eA was obtained with a poor
60:40 diastereomeric ratio (d.r.) in 60% yield (Table 1,
entry 5). Fortunately, the reaction of commercially
available ethyl 2-cyano-3-ethoxyacrylate 4 f under the
same conditions led to the formation of 1 fA in
almost the same yield but this time with high levels
of diastereoselectivity (>98:2 d.r., Table 1, entry 6).
We then turned our attention to the less reactive Mi-
chael acceptor 4g’, which possessed both ester and
2-nitrophenyl functional groups and was synthesized in four
steps from the commercially available 2-nitrophenylacetic
acid.[13] However, regardless of which reaction conditions were
used, we observed both poor yields and no diastereoselectivity
for the bicyclic product 1gA (Table 1, entry 7).
The diastereoselective outcome of this domino process
could be explained by either specific chelation of the cation or
steric effects of the electron-withdrawing groups. The replace-
ment of the ketone in 4e’ by a 2-nitrophenyl functional group
in 4g’, which exhibits a similar level of steric hindrance but
very different chelating properties (Table 1, entries 5 vs. 7), led
to reduced levels of diastereoselectivity in the corresponding
product 1gA. This observation suggests that the steric effect
has a stronger influence on the diastereoselectivity than chela-
tion. Based on these results, we anticipated that the significant
steric difference between the nitrile functional group and the
2-nitrophenyl group should allow us to achieve high levels of
diastereoselectivity in the domino reaction of Michael acceptor
4h’ (Table 1, entries 7 vs. 8). This hypothesis was confirmed
under conditions I, which led to the formation of oxazolo-pyr-
rolidinone 1hA with an excellent >98:2 dr and in 78% yield
due to the higher activation of the nitrile group compared to
the ester moiety.
Scheme 2. Scope of the proposed methodology.
a wide variety of Michael acceptors, both symmetrical (E=E’)
and unsymmetrical (E¼E’). For the latter, this methodology
allows the formation of two contiguous stereogenic centers in
high dr and good yield. Notably, the construction of quaterna-
ry stereocenters that bear two electron-withdrawing groups,
which are unavailable by classical approaches, can be formed
through this process. Furthermore, this domino reaction is
compatible with chiral amido alcohols 5C and 5D, derived
from (R)-phenylglycinol, which enable the formation of enan-
tioenriched g- and d-lactams, respectively, with high levels of
diastereocontrol and, in some cases, double chirality transfer
(bottom part of Scheme 2). This diastereoselective process was
extended to a variety of structures and is rationalized by a DFT
study of the key transition states (TS).
Results and Discussion
The reactivity was first probed by using the achiral amide 5 A
with various Michael acceptors 4 (LG=OEt) and 4’ (LG=Cl)
that contain two electron-withdrawing groups (E=E’ or E¼E’,
Table 1).[11] For this purpose, three different conditions were
tested: NaH in THF at 08C (conditions I), K2CO3 in CH3CN
heated at reflux (conditions II), and Cs2CO3 in THF at room
temperature in the presence of molecular sieves (condition-
s III). Moreover, in certain cases both of the leaving groups OEt
The proposed mechanism for this domino reaction is a three
to four step process that starts from 4 or 4’ and 5 (see
Chem. Eur. J. 2015, 21, 2966 – 2979
www.chemeurj.org
2967
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Table 1. Direct access to racemic bicyclic lactams 1.
Entry Michael acceptor
1
Yield [%][a] and d.r.[c]
conditions[b]
4 or 4’
67[10]
I
1
2
3
–
Scheme 3. Proposed mechanism for the domino process.
70[10]
II
–
–
To confirm the hypothesis that it is predominately steric ef-
fects that govern the stereochemical outcome of the reaction,
a DFT study was performed to identify the main factors that in-
fluence the selectivity of this multistep sequence. The DFT cal-
culations were performed with Gaussian 09[14] at M06-2X/6-
311+G(d,p) by using the polarizable continuum model
(IEFPCM) for the description of THF as the solvent. The study
was first performed on Michael acceptors that contained both
nitrile and methyl ester functionalities. The methyl ester func-
tional group was chosen instead of the ethyl ester to limit the
number of possible conformations and subsequent CPU costs.
The counterion (Na+) was included in the model to make the
system neutral and to study the influence of its position in the
reaction sequence. For each intermediate, a full conformer
search was first performed by using Spartan’10[15] and the
most stable conformers were progressively optimized with in-
creasing levels.
64 I
4
78 III
–
5
6
60 I
59 I
60:40[d]
>98:2
Initially, the four TS of the sequence were resolved on
a model reaction that involved 5E (R1 =R2 =H) and 4i (E=
CO2Me, E’=CN) with a systematic search of the limited
number of possible conformers for each TS, and evaluation of
the potential positions of the cation close to the groups that
bear the negative charge. The first two steps of the sequence
involved an energy profile similar to the one previously calcu-
lated (see the Supporting Information, page7).[10] However,
compared to previous results, the use of Truhlar’s density func-
tional theory M06-2X[16] improved the energy calculation for
TS2 as expected for systems that involve hydrogen bonds and
dispersion interactions.[17]
7
8
17 I
78 I
50:50
>98:2
The favored TS2 leads to the formation of the most stable
intermediates Int2iE.1 and Int2iE.2. In addition, the pathway
to the previous intermediate Int1 (Scheme 3) is fully reversible
(see the Supporting Information, page7), which ensures the
preferential existence of these two stable intermediates by
placing the amido alcohol chain syn to the nitrile group. The
study was then focused on the last two steps of the sequence,
which control the diastereoselectivity of the reaction. The cor-
responding TS were calculated to examine the energy profile
of this part of the process (Scheme 4 and Figure 1). As expect-
ed, the pathways that involve TS3iE.1 and TS3iE.2, which are
derived from Int2iE.1 and Int2iE.2, respectively, are the pre-
ferred ones. However, TS3iE.3, which was derived from the
[a] Yields of isolated products. [b] Conditions I: NaH, THF, 08C; II: K2CO3,
CH3CN, heated at reflux; III: Cs2CO3, THF, molecular sieves, RT. [c] d.r. de-
termined by 1H NMR analysis of the crude reaction mixture. [d] d.r.=dia-
stereomeric ratio. The stereochemistry of the major diastereoisomer was
not determined.
Scheme 3 for a simplified mechanism).[10] After deprotonation
by the base, NaH in this case, an addition–elimination process
takes place between 5 and 4 or 4’, which leads to the inter-
mediate Int2. An aza-Michael addition of the resulting amidate
onto the double bond provides Int3 and a subsequent intra-
molecular nucleophilic substitution furnishes the bicyclic
adduct 1.
Chem. Eur. J. 2015, 21, 2966 – 2979
www.chemeurj.org
2968
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 4. Energy profile of the second part of the reaction sequence on
the model bicyclic lactam 1iE (7S*,7aS*). Gibbs free energies quoted in kcal
molꢀ1 at 298 K.
less probable intermediate Int2iE.3, was identified at approxi-
mately the same level of energy. These TS are all in the same
energy range and they are lower in energy than TS4, which
ensures a full reversibility of the first cyclization step. There-
fore, the selectivity of the complete sequence is largely related
to the last TS (TS4). The preferred conformation of all the tran-
sition states were studied by considering both the possible
chelation of the sodium cation with the nitrile, the ester, or the
carbonyl group of the amide, and the possible orientation of
the oxazolidine ring, which drives the configuration of the dia-
stereoisomer that is formed. Among the eight conformers of
TS4iE that were found, six appear in the same energy range,
and two (TS4iE.7 and TS4iE.8) are notably higher. The six
lowest energy TS display an optimal orientation of the oxazoli-
dine ring (f between 848 and 888, Table 2), which optimizes
the overlap of the s*CꢀO and s*CꢀN orbitals; whereas, TS4iE.7
and TS4iE.8 cannot benefit from the same stabilization. The
conformation that is adopted by the oxazolidine ring in these
TS (f=161.38 and f=167.58, Table 2) prevents any possible
contribution of the s*CꢀO orbital. In order to assess this hypoth-
esis, a Natural Bond Orbital (NBO) analysis was performed by
using NBO 6.0.[18] The second order perturbation theory analy-
sis on the NBO basis provided an estimation of the interaction
between the occupied p orbital at C(2) and the closest s* orbi-
tals. As expected, for TS4iE.7 and TS4iE.8 the contribution of
the s*CꢀO orbital is considerably reduced and the contribution
of the s*CꢀH orbital is not sufficient to counterbalance this
effect. The contribution of the three s* orbitals are summed in
the last column of Table 2 and this illustrates the contribution
of the overlap with the s* orbitals towards the stabilization of
the negative charge of the carbanion. The difference between
Figure 1. Geometry of the main intermediates and TS in the reaction be-
tween 4i and 5E to give 1iE.
the sum of the three orbital contributions in TS4iE.7 and
TS4iE.5 is 7.7 kcalmolꢀ1. Consequently, this can account for
the main contribution to the energy difference that exists be-
tween these two TS (7.9 kcalmolꢀ1).
The two lowest energy TS4iE conformers (TS4iE.1 and
TS4iE.2) place the sodium cation close to the bromine in
order to assist the departure of the leaving group; the cation
also chelates to the carbonyl of the amide (Figure 1). In addi-
tion to the stabilization from the electron-withdrawing groups,
chelation with the oxygen of the amide group also contributes
to stabilization of the negative charge of the carbanion by an
improved overlap of the s*CꢀO and s*CꢀN orbitals (Table 2, en-
tries 1 and 2). The lowest energy TS4iE conformer (TS4iE.1)
Chem. Eur. J. 2015, 21, 2966 – 2979
www.chemeurj.org
2969
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Table 2. Second order perturbation theory analysis of Fock matrix in NBO
basis
[a]
f
pC(2)!
pC(2)!
pC(2)!
S[c]
s*C(3)ꢀO(5)[b] s*C(3) ꢀN(6)[b] s*C(3) ꢀH(4)[b]
TS4iE.1
TS4iE.2
TS4iE.3
TS4iE.4
TS4iE.5
TS4iE.6
83.1 19.2
11.9
12.0
12.2
10.5
11.5
10.8
10.1
7.2
–
–
–
–
–
–
9.14
9.36
31.1
31.0
25.8
25.9
27.5
26.7
19.8
18.4
86.4 19.0
87.7 13.6
86.0 15.3
84.1 15.9
86.5 15.9
TS4iE.7 161.3
TS4iE.8 167.5
0.5
1.8
[a] H(4)-C(3)-C(2)-C(1) dihedral angle. [b] Second order perturbative esti-
mate of full p orbital at C(2) and s* interactions in kcalmolꢀ1. [c] Sum of
the stabilization energies associated with these interactions in kcalmolꢀ1
.
Scheme 5. Energy profile of the last steps of the reaction sequence with
amido alcohol 5A to give 1iA. Gibbs free energies quoted in kcalmolꢀ1 at
273 K.
lies sufficiently lower in energy than TS4iE.2 and TS4iE.6 such
that it induces a good level of diastereoselectivity in favor of
the adduct 1iE (7S*,7aS*) (Scheme 4). In this preferred TS, the
oxazolidine ring is located preferentially on the side of the ni-
trile group in order to minimize unfavorable steric interactions.
After excluding the least favored TS and the corresponding
intermediates, the second part of the reaction sequence was
studied with the amido alcohol 5 A that contained the more
realistic methyl groups as substituents (Scheme 5). For this
new energy profile that leads to 1iA, the Gibbs free energies
were calculated at 273 K in order to best describe the reaction
pathway that gives 1 fA (compare Scheme 5 and Table 1,
entry 6). The calculations showed a greater discrimination be-
tween the various TS and intermediates, which led to the
emergence of a single favorable pathway (Int2iA.1–TS3iA.1–
Int3iA.1–TS4iA.1). This favored reaction pathway, and there-
fore the resulting selectivity, is mainly kinetically controlled by
the steric interactions that occur in TS4 between the oxazoli-
dine ring, which bears the gem-dimethyl group, and the CN or
the bulkier ester group. The presence of real substituents, such
as the gem-dimethyl group, obviously has a significant effect
on the preferred conformation of Int3 and TS4 because of
steric repulsion between the oxazolidine ring and the ester
moiety. Therefore, the conformation that is preferentially
adopted by Int3iA.1 will place the oxazolidine ring on the side
of the nitrile group in order to reduce the steric interaction
(Figure 2). It should be noted that if TS4iA.1 is close in energy
to the previously described TS4iE.1, and places the sodium
cation in the same position, the energy of TS4 compared to
TS3 must be significantly lower (compare Schemes 4 and 5). In
addition to this significant modification of the energy gap at
TS4, some perturbations are also observed for TS3 with a redis-
tribution of the TS. For example, the TS that best corresponds
to the previously most stable TS3 conformer (TS3iE.1) is
TS3iA.3. Additionally, in the present case only three TS3 con-
formers could be obtained. All attempts to locate the missing
confomers by comparison with TS3iE during the optimization
Figure 2. Geometry of the main intermediates and TS in the reaction be-
tween 4i and 5A to give 1iA.
Chem. Eur. J. 2015, 21, 2966 – 2979
www.chemeurj.org
2970
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
process were unsuccessful due to a very flat energy profile,
which invariably led to the corresponding Int2 or Int3.
Table 3. Direct access to enantioenriched bicyclic lactams.
Next, the synthesis of the more interesting enantioenriched
g- and d-lactams from the (R)-phenylglycinol derivatives 5C
and 5D (Table 3) were investigated by employing the optimum
conditions for the domino process that were reported in
Table 1. Beginning with the diester Michael acceptor 4a’, the
oxazolo-pyrrolidinone 1aC was isolated in a good yield and
with excellent diastereomeric ratio (Table 3, entry 1). In addi-
tion, the chiral six-membered ring oxazolo-piperidinone 1aD
was also obtained using our strategy with >98:2 d.r. and an
acceptable yield (Table 3, entry 2). In this case, the poor reactiv-
ity of the b-chlorophenylglycinol derivative 5D led to prepon-
derant side reactions as a consequence of the survival of the
malonic carbanion that corresponds to Int3, as previously
demonstrated.[10] This led us to use the Michael acceptor 4a
that contains an ethoxy substituent, which is more stable and
therefore less prone to the formation of side products. The re-
action of Michael acceptor 4b also led to the formation of the
target bicyclic compound 1bC in 41% yield and an excellent
diastereomeric ratio (>98:2 d.r., Table 3, entry 3). The Michael
acceptor with two phenyl ketone groups 4c’ and the substrate
that is derived from 1,3-indanedione 4d both reacted to give
the corresponding lactams in satisfactory yields and with com-
plete diastereocontrol (Table 3, entries 4 and 5). As observed
with the achiral amide 5 A (Table 1, entry 5), the reaction be-
tween the keto–ester Michael acceptor 4e’ and the (R)-phenyl-
glycinol derivative 5C gave the product 1eC with a low diaste-
reomeric ratio but a good yield (Table 3, entry 6). Alternatively,
unsymmetrical Michael acceptors 4 f and 4h’ furnished the de-
sired bicyclic lactams 1 fC and 1hC with high levels of diaste-
reoselectivity (both >98:2 dr), which allowed the construction
of two contiguous stereocenters with total stereocontrol
(Table 3, entries 7 and 8).
Entry Michael acceptor
1
Yield [%][a] and d.r.[c]
conditions[b]
76
>98:2
1
I
59
2
3
4
>98:2
>98:2
>98:2
I[e]
41
II
61
I
64
III
5
>98:2
77
I
6
7
60:40[d]
The cis relationship between the phenyl group and the
C(7a)-hydrogen atom of the oxazolidine ring was confirmed by
X-ray structural analysis of the domino products 1aC and 1hC
(Figure 3). This analysis also proved the cis relationship be-
tween the C(7a)-hydrogen atom and the 2-nitrophenyl func-
tional group of the bicyclic lactam 1hC, which confirms that
the biggest substituent on the C(7) atom is preferentially locat-
ed on the side of this hydrogen atom.
60
I
>98:2
>98:2
53
I
8
To rationalize the double diastereoselectivity that is ob-
served with nitrile–ester Michael acceptor substrates, based on
previous results, the most reliable TS and intermediates were
calculated at M06-2X/6-311+G(d,p) level by using the polariza-
ble continuum model for the description of THF, and the Gibbs
free energies are given at 273 K (Scheme 6, Figure 4, and
Table 3, entry 7). The diastereoselectivity that is induced by the
phenyl group was studied together with the selectivity that is
induced by the last step of the sequence. The energy profile
shown in Scheme 6 suggests that the stereoselectivity of the
reaction sequence is mainly controlled in the last step. The
transfer of chirality from C(3) to C(7a) is controlled in the first
cyclization step via TS3; however, the calculated energy gap
between TS3iC.1a and TS3iC.2b (0.9 kcalmolꢀ1) fails to fully
explain the complete diastereocontrol that is observed in the
[a] Yields of isolated products. [b] Conditions I: NaH, THF, 08C; II: K2CO3,
CH3CN, heated at reflux; III: Cs2CO3, THF, molecular sieves, RT. [c] d.r. de-
termined by 1H NMR analysis of the crude mixture. [d] The stereochemis-
try of the major diastereoisomer was not determined. [e] 2.4 equiv of
NaH were used.
formation of 1 fC. In fact, this step was found to be fully rever-
sible as TS4iC.1b (10.8 kcalmolꢀ1) lies significantly higher in
energy than TS3iC.2b (8.3 kcalmolꢀ1). As a consequence, the
intermediate Int3iC.1a, which is consumed faster, can be re-
generated from Int3iC.1b through a reverse step to Int2. The
stereochemistry of the product is thus mainly controlled by
the kinetics of the last step of the sequence (TS4). The diaste-
Chem. Eur. J. 2015, 21, 2966 – 2979
www.chemeurj.org
2971
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
The stereoselectivity of the re-
action is strongly correlated to
the steric interactions that occur
between the oxazolidine ring
and the activating group of the
Michael acceptor in TS4.
A
simple study of this final TS in
the reaction sequence should
give the desired data on the dia-
stereocontrol of the reaction. For
example, the lack of diastereose-
lectivity that is observed with
the compounds that contain
electron-withdrawing
groups
Figure 3. Stick model plots of the crystal structures of 1aC and 1hC. ORTEP representation of compound 1aC,
only one molecule of the asymmetric unit (Z’=2) is displayed.
that possess a similar degree of
Scheme 6. Energy profile of the last two steps of the reaction sequence with
amido alcohol 5C to give 1iC. Gibbs free energies quoted in kcalmolꢀ1 at
273 K.
reoselectivity that is observed in the oxazolidine ring is mainly
a consequence of the placement of the phenyl ring in the
least sterically hindered position, which leads to a significant
energy gap between TS4iC.1a and TS4iC.1b. The other four
calculated TS4 conformers are significantly higher in energy,
corroborating the facts that the preferred lowest energy TS
conformers place the sodium cation in a position where it is
able to chelate to both the bromine atom and the carbonyl of
the amide group (energy gap of 3.1 kcalmolꢀ1 between
TS4iC.1a and TS4iC.2a), and that the oxazolidine ring lies on
the side of the nitrile group during the cyclization step (energy
gap of 3.7 kcalmolꢀ1 between TS4iC.1a and TS4iC.3a).
Figure 4. Geometry of the main intermediates and TS in the reaction be-
tween 4i and 5C to give 1iC.
Chem. Eur. J. 2015, 21, 2966 – 2979
www.chemeurj.org
2972
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
steric bulk, such as 1eA and 1gA (Table 1, entries 5 and 7), can
certainly be explained by the poor discrimination between the
two most plausible conformers in the last key step of the reac-
tion sequence. To this end, the TS4 conformers that lead to
both 1jA, which is analogous to 1eA (Table 1, entry 5) and
1kA, which is analogous to 1gA (Table 1, entry 7), were calcu-
lated at the same level as previously described (M06-2X/6-
311+G(d,p)) with IEFPCM model for the description of THF. As
before, the ethyl ester groups in 1eA and 1gA were replaced
by methyl ester groups in 1jA and 1kA to limit the number of
possible conformations of the ester moiety. The Gibbs free en-
ergies are given in kcalmolꢀ1 at 273 K.
Among the seven TS4jA conformers that were obtained,
the two most stable ones, TS4jA.1 and TS4jA.2, were separat-
ed by only 0.1 kcalmolꢀ1 and led to divergent diastereoisomers
(Scheme 7, Figure 5). The third conformer TS4jA.3 lies signifi-
cantly higher in energy. Interestingly, contrary to previous re-
sults, the sodium cation preferentially chelates the carbonyl
groups of the ester and the ketone. This can be explained by
the favorable chelation angle and the increased chelation abili-
ty of the carbonyl group compared to the nitrile group. The
very small energy difference that was calculated between
TS4jA.1 and TS4jA.2 explains the lack of diastereoselectivity
that is observed in the formation of 1jA and, consequently,
1eA (Table 1, entry 5). The poor selectivity, in this case, is relat-
ed to the absence of discrimination in the steric interactions
between the oxazolidine ring and either the ester or the
phenyl ketone groups. It is also important to notice that the
energy barrier is significantly higher in this case, which shows
the crucial role that is played by TS4.
Figure 5. Geometry of the main intermediates and TS in the reaction to give
1jA from Int3jA.
The favored TS4 conformations for the final step in the reac-
tion sequence was also studied for 1kA (TS4kA, Scheme 8,
Figure 6), the methyl ester analogue of 1gA. After DFT calcula-
tions, nine TS4kA conformations were obtained, among which
eight were very close in energy. As before, the two most stable
conformations, TS4kA.1 and TS4kA.2, were very close in
energy and led to divergent diastereoisomers, which can ex-
plain the total lack of diastereoselectivity that is observed for
1gA (Table 1, entry 7). These results demonstrate the possibili-
ty of predicting the stereocontrol of the reaction from the cal-
culation of the last TS conformers. In the most stable TS4 con-
formers that were calculated (TS4kA.1 and TS4kA.2), the
sodium cation was placed in a position close to the bromine
atom, as in TS4iE.1, TS4iA.1, and TS4iC.1 (Scheme 4–
Scheme 6). However, the energy difference with the other cal-
culated TS conformers is greatly reduced unlike in the previous
cases.
The study was then extended to the selective formation of
1hA (Table 1, entry 8). Six possible conformers of TS4 were
identified, with TS4hA.1 lying significantly lower in energy
than the others (Scheme 9, Figure 7), which explains the high
levels of diastereoselectivity that were observed in the reaction
Scheme 7. Energy profile of the last two steps of the reaction sequence
starting from amido alcohol 5A to give 1jA. Gibbs free energies quoted in
kcalmolꢀ1 at 273 K.
Chem. Eur. J. 2015, 21, 2966 – 2979
www.chemeurj.org
2973
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 8. Energy profile of the last two steps of the reaction sequence
starting from amido alcohol 5A to give 1kA. Gibbs free energies quoted in
kcalmolꢀ1 at 273 K.
of 1hA, in favor of the (7S*,7aS*) diastereoisomer. TS4hA.1 is
the TS4 conformer that displays the best conjugation of the ar-
omatic ring with the carbanion. In addition, the oxazolidine
ring lies on the side of the nitrile group, which is the site of
the least steric hindrance, and this further confirms that the
stereochemical outcome of the reaction is mainly controlled
by steric effects. Like with the other Michael acceptors that
possess at least one nitrile group, the most stable TS confor-
mer (TS4hA.1) places the sodium cation close to the bromine
atom, and the alternative TS are significantly higher in energy.
At this juncture, we turned our attention toward the more
sterically hindered, and thus most challenging, Michael accept-
ors that contain four substituents on the double bond
(Table 4). Once again, three sets of reaction conditions that
employ three different bases: Cs2CO3, K2CO3, or NaH, were
tested for this reaction; however, only the reactions that used
NaH led to the desired bicyclic lactams, with low to good
yields being observed. The first attempt, between 4l’ and 5 A,
was a failure and the desired product was never observed
(Table 4, entry 1). By replacing one of the ester groups with
a more reactive nitrile moiety, the lactam 1mA was obtained
in only 4% yield but in a good >98:2 diastereomeric ratio
(Table 4, entry 2). Thankfully, the more reactive dinitrile accept-
or 4n reacted smoothly and in a good 64% yield to give 1nA,
which has two contiguous quaternary centers (Table 4,
entry 3). The low yield (10%) attained in the case of 4o is
probably due to the acidity of the methyl protons on the CH3
moiety of this acceptor, which are not compatible with the
basic conditions used in this domino process (Table 4, entry 4).
Nevertheless, the chiral amido alcohol 5C reacted with 4n to
Figure 6. Geometry of the main intermediates and TS in the reaction to give
1kA from Int3kA.
furnish the enantioenriched lactam 1nC in an excellent >98:2
d.r. and 65% yield (Table 4, entry 5). Finally, this process was
also efficient for the formation of the spiro-compound 1pA,
which was obtained in 61% yield (Table 4, entry 6).
In the case of 1nC, the cis relationship between both phenyl
groups was determined by NOESY experiments with an NOE
being observed between the ortho-phenyl protons (Figure 8).
To explain the good selectivity that was observed in the
case of 1nC in favor of the (3R,7aS) diastereoisomer (Table 4,
entry 5), the TS conformers that correspond to the last two
steps of the reaction sequence were calculated at the same
level as previously described (M06-2X/6-311+G(d,p)) by using
the IEFPCM model for the description of THF (Scheme 10,
Figure 9). The Gibbs free energies of the energy profile are
Chem. Eur. J. 2015, 21, 2966 – 2979
www.chemeurj.org
2974
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 9. Energy profile of the two last steps of the reaction sequence
starting from amido alcohol 5A to give 1hA. Gibbs free energies quoted in
kcalmolꢀ1 at 273 K.
given in kcalmolꢀ1 at 273 K. In this case, the stereoselectivity
of the sequence was controlled by TS3, which governs the rel-
ative stereochemistry of the 3R and 7aS stereocenters of the
oxazolidine. Two TS3 and four TS4 conformers were obtained.
Interestingly, in this case, the TS4 conformers lie slightly lower
in energy than the corresponding TS3 conformers, which indi-
cates that the observed stereoselectivity is a consequence of
the kinetic control that is imparted by the first cyclization. The
presence of two nitrile groups allows complete discrimination
between the two usual positions that are occupied by the
sodium cation in favor of chelation with the carbonyl of the
amide and the bromine atom. Therefore, this selectivity is not
the sole consequence of steric effects, but it is also due to the
position of the phenyl ring of the phenylglycinol in TS3nC.2
(Figure 9), which reduces the ability of the sodium cation to be
complexed by the solvent. This contribution was partially
taken into account by the PCM solvent model.
Figure 7. Geometry of the main intermediates and TS in the reaction to give
1hA from Int3hA.
carbonyl, which enabled the b-
elimination of a phenyl sulfone
moiety after the domino process.
This hypothesis was confirmed by
the sole formation of d-lactam 1rB
from the reaction of 4r and 5B,
where no b-elimination was ob-
Figure 8. NOESY experiments
served (Table 5, entry 5). In order
to overcome this unwanted side
reaction, modified reaction condi-
for 1nC.
As demonstrated above, the domino process proved to be
sensitive to steric effects. In this context, substrates that con-
tained one or two bulky phenyl sulfones were then investigat-
ed in order to determine whether the final cyclization step
would be possible under the same reaction conditions
(Table 5). Only conditions I furnished the g-lactams 1qA and
1rA, which were both isolated in a low 33% yield but with
high levels of diastereoselectivity (>98:2 d.r., Table 5, entries 1
and 3). It was found that the lower yields attained in these
cases were partly due to the formation of unsaturated side
products 6 and 7. The formation of these side products was
due to the presence of an acidic proton in a-position of the
tions I’ were applied. Therefore, the reactions were carried out
at ꢀ208C with a substoichiometric amount of the base to give
the g-lactams 1qA and 1rA both with high selectivities
(Table 5, entries 2 and 4).[19] In addition, the diphenyl sulfone
derivative 4q’ furnished the corresponding lactam 1qA in
a better yield (78%, Table 5, entry 2). However, the more reac-
tive nitrile–phenyl sulfone Michael acceptor reacted to give
1rA with only 22% yield (Table 5, entry 4). In this case, the de-
sired reaction is in competition with the degradation of the
starting material 4r’; whereas, in most cases the domino pro-
cess is predominant and only a few side products can be ob-
served.
Chem. Eur. J. 2015, 21, 2966 – 2979
www.chemeurj.org
2975
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Table 4. Synthesis of bicyclic lactams 1 that bear two contiguous quater-
nary stereocenters.
Entry
1
Michael Acceptor
1
Yield [%][a]
n.d.
d.r.[b]
–
2
3
4
5
4
64
10
65
>98:2[c]
Scheme 10. Energy profile of the two last steps of the reaction sequence
starting from amido alcohol 5C to give 1nC. Gibbs free energies quoted in
kcalmolꢀ1 at 273 K.
–
–
>98:2
6
61
–
[a] Yields of isolated products. [b] d.r. determined by 1H NMR analysis of
the crude reaction mixture. [c] The stereochemistry of the major diaste-
reoisomer was not determined.
Under the modified conditions I’ (ꢀ208C), the lower temper-
ature led to preponderant side reactions, which were further
amplified by the high reactivity of the Michael acceptor
(Table 5, entry 2 vs. 3). Similarly, as shown above (Table 1, en-
tries 1 and 2) in the case of the reaction with the less reactive
amido alcohol 1B, the ethoxy substituted acceptor 4r was
used instead (Table 5, entry 5). The same behavior was ob-
served for amido alcohol 5C, which was derived from (R)-phe-
nylglycinol, for the formation of g-lactam 1qC (Table 5, en-
tries 6 and 7). It is worth highlighting that unsaturated com-
pounds, such as 6–8, are of interest from a synthetic point of
view[20] and efforts will be devoted to their direct access in the
near future.
Figure 9. Geometry of the main intermediates and TS in the reaction to give
1nC from Int3nC.
Chem. Eur. J. 2015, 21, 2966 – 2979
www.chemeurj.org
2976
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Experimental Section
Table 5. Competitive formation of the unsaturated products 6–8.
Synthesis of d- and g-lactams
Conditions I: Michael acceptor (4 or 4’, 1.2 mmol, 1.2 equiv) and N-
hydroxyalkyl a-bromoacetamide or b-chloropropanamide (5 A-D,
1.0 mmol, 1 equiv) were dissolved in freshly distilled THF (10 mL) at
RT Sodium hydride (48 mg, 60% suspension in mineral oil,
1.2 mmol, 1.2 equiv for 4; 96 mg, 60% suspension in mineral oil,
2.4 mmol, 2.4 equiv for 4’) was then added at 08C. The mixture
was stirred for 3 to 5 h and was then quenched carefully at 08C by
addition of a saturated aqueous solution of NH4Cl (10 mL). The
aqueous phase was extracted with EtOAc (3ꢂ10 mL), the organic
phases were combined, washed with brine, dried over MgSO4 and
solvent was removed under vacuum. The residue was then chro-
matographed on silica gel to afford the desired compound.
Entry Michael acceptor Temp. [8C][a]
1
Yield [%][b] 1:6–8[d]
1
2
0
ꢀ20
33
78
94:6
94:6
33[c]
22[c]
Conditions II: Michael acceptor (4 or 4’, 1.2 mmol, 1.2 equiv), N-hy-
droxyalkyl a-bromoacetamide or b-chloropropanamide (5 A–D,
1.0 mmol, 1 equiv), and potassium carbonate (152 mg, 1.1 mmol,
1.1 equiv) were dissolved in freshly distilled CH3CN (10 mL) and the
mixture was heated at reflux for 3 to 5 h. The resulting slurry was
filtered through a small pad of Celite 545 using CH2Cl2. The organic
phase was evaporated under vacuum and the residue was chroma-
tographed on silica gel to afford the desired compound.
3
4
0
79:21
92:8
ꢀ20
5
0
–
52[c]
18[c]
51[c]
Conditions III: Michael acceptor (4 or 4’, 1.5 mmol, 1.5 equiv), N-
hydroxyalkyl a-bromoacetamide or b-chloropropanamide (5 A-D,
1.0 mmol, 1 equiv), and cesium carbonate (152 mg, 1.2 mmol,
1.2 equiv) were dissolved in freshly distilled THF (10 mL) in the
presence of molecular sieves. The resulting mixture was stirred for
7 days and was then quenched by addition of a saturated aqueous
solution of NH4Cl (10 mL). The aqueous phase was extracted with
EtOAc (3ꢂ10 mL), the organic phases were combined, washed
with brine, dried over MgSO4, and solvent was removed under
vacuum. The residue was then chromatographed on silica gel to
afford the desired compound.
6
7
0
80:20
88:12
ꢀ20
[a] Conditions I: NaH, THF, 08C or ꢀ208C. [b] Yields of isolated products.
[c]>98:2 d.r. determined by 1H NMR analysis of the crude reaction mix-
ture. [d] Ratio determined by 1H NMR analysis of the crude reaction mix-
ture.
(ꢁ)-(7R,7aS)-Ethyl 7-cyano-hexahydro-3,3-dimethyl-5-oxopyrro-
lo[2,1-b]oxazole-7-carboxylate (1 fA): Obtained by reaction be-
tween 4 f and 5 A under conditions I and, after purification by
flash chromatography (EtOAc/cyclohexane, 50:50), 1 fA was isolat-
Conclusion
We have reported an efficient and highly diastereoselective
synthesis of Meyers’ bicyclic lactams by an acid-free domino
process in which functionalized bicyclic systems are obtained
from cheap, commercially available reagents. One break-
through of this approach, compared to the existing protocols,
is the formation of a tunable quaternary stereocenter at the 4-
position of pyrrolidinone. Using our strategy, six-membered bi-
cyclic d-lactams were obtained in usually good yields and with
high levels of diastereoselectivity. With the help of DFT calcula-
tions, the stereocontrol in the construction of the two contigu-
ous diastereomeric centers was explained by a combination of
steric and stereoelectronic effects that control the conforma-
tion in the final key steps. The role and the position of the
cation proved to be highly dependent on the nature of the
electron-withdrawing groups on the Michael acceptor. Interest-
ingly, the transfer of chirality from the amido alcohol to the
N,O-ketal or acetal carbon atom of the oxazolidine proved to
be controlled by either the first cyclisation step or surprisingly,
during the second cyclization. In other words, the stereochem-
istry of a stereogenic center that is formed through a domino
process is not necessarily controlled during its formation but
can also be controlled in a subsequent step of the reaction se-
quence. The total synthesis of heterocyclic alkaloids using this
methodology is currently under study.
1
ed as a colorless oil. Yield: 59%; H NMR (300 MHz, CDCl3): d=5.60
(s, 1H), 4.35 (q, J=7.1 Hz, 2H), 4.13 (d, J=8.4 Hz, 1H), 3.96 (d, J=
8.4 Hz, 1H), 3.29 (d, J=16.5 Hz, 1H), 3.03 (d, J=16.5 Hz, 1H), 1.65
(s, 3H), 1.38 (s, 3H), 1.37 ppm (t, J=7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=166.0, 165.3, 114.8, 94.0, 83.0, 64.2, 59.2, 51.3, 44.6, 24.8,
22.1, 13.9 ppm; IR (neat): n˜ =1744, 1710, 1392, 1246, 1041 cmꢀ1
;
HRMS (ESI): m/z calcd (%) for C12H17N2O4+: 253.1188 [M+H]+; found
253.1196.
(3R,8aS)-Diethyl 5-oxo-3-phenyltetrahydro-2H-oxazolo[3,2-a]pyr-
idine-8,8(3H)-dicarboxylate (1aC): Obtained by reaction between
4a’ and 5C under conditions I and, after purification by flash chro-
matography (EtOAc/cyclohexane, 50:50), 1aC was isolated as a col-
orless oil: Yield: 59%; [a]2D0 =ꢀ104.8 (c=0.73, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.37–7.24 (m, 5H), 5.45–5.40 (m, 1H), 5.43 (s,
1H), 4.43 (t, J=8.0 Hz, 1H), 4.33–4.21 (m, 4H), 3.92 (dd, J=8.4,
5.6 Hz, 1H), 2.60–2.49 (m, 1H), 2.55–2.35 (m, 2H), 2.24–2.18 (m,
1H), 1.31 (t, J=7.1 Hz, 3H), 1.27 ppm (t, J=7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=168.9, 167.9, 166.9, 139.5, 128.9, 127.8, 126.2,
88.2, 72.1, 62.4, 62.1, 58.0, 56.0, 28.8, 24.5, 14.1 ppm; IR (neat): n˜ =
1727, 1664, 1252, 1178, 1016, 700 cmꢀ1; HRMS (ESI): m/z calcd (%)
for C19H23NO6+Na+: 384.1423 [M+Na]+; found: 384.1418.
(3R,7S,7aS)-Ethyl 7-cyano-hexahydro-5-oxo-3-phenylpyrrolo[2,1-
b]oxazole-7-carboxylate (1 fC): Obtained by reaction between 4 f
and 5C under conditions I and, after purification by flash chroma-
Chem. Eur. J. 2015, 21, 2966 – 2979
www.chemeurj.org
2977
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
tography (EtOAc/cyclohexane, 20:80), 1 fC was isolated as a color-
less oil: Yield: 60%; [a]2D0 =ꢀ147.4 (c=0.38, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.42–7.32 (m, 3H), 7.29–7.27 (m, 2H), 5.67 (s,
1H), 5.33 (dd, J=7.0, 4.3 Hz, 1H), 4.66 (dd, J=8.6, 7.0 Hz, 1H), 4.39
(q, J=7.1 Hz, 2H), 4.21 (dd, J=8.6, 4.3 Hz, 1H), 3.49 (d, J=17.0 Hz,
1H), 3.14 (d, J=17.0 Hz, 1H), 1.40 ppm (t, J=7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=171.4, 165.5, 137.9, 129.1, 128.3, 125.9, 114.6,
(3R,7aS)-3-Phenyl-7-(phenylsulfonyl)-2,3-dihydropyrrolo[2,1-
b]oxazol-5(7aH)-one (8): Obtained as a side product from the
domino reaction between 4q’ and 5C and, after purification by
flash chromatography (EtOAc/cyclohexane, 30:70), 1 fA was isolat-
ed as a white solid: Yield: 7%; m.p. 1358C; [a]2D0 =ꢀ20.1 (c=0.23,
1
CHCl3); H NMR (300 MHz, CDCl3): d=8.02 (d, J=7.6 Hz, 2H), 7.74
(t, J=7.4 Hz, 1H), 7.62 (t, J=7.7 Hz, 2H), 7.44–7.20 (m, 5H), 6.76 (s,
1H), 5.90 (s, 1H), 4.94 (t, J=7.3 Hz, 1H), 4.72–4.57 (m, 1H),
4.05 ppm (dd, J=8.9, 7.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=
172.5, 157.9, 138.2, 138.0, 135.4, 135.1, 129.7, 129.1, 128.9, 128.3,
126.1, 91.4, 78.6, 58.1 ppm; IR (neat): n˜ =3093, 1702, 1325, 1150,
732, 719, 696, 682 cmꢀ1; HRMS (ESI): m/z calcd (%) for C18H16NO4S+:
342.0801 [M+H]+; found: 348.0793.
93.2, 75.2, 64.4, 57.9, 50.4, 42.9, 13.9 ppm; IR (neat): n˜ =1722, 1391,
1250, 1033, 698 cmꢀ1; HRMS (ESI): m/z calcd (%) for C16H17N2O4
301.1188 [M+H]+; found: 301.1195.
:
+
(3R,7S,7aS)-7-(2-Nitrophenyl)-5-oxo-3-phenylhexahydropyrro-
lo[2,1-b]oxazole-7-carbonitrile (1hC): Obtained by reaction be-
tween 4h’ and 5C under conditions I and, after purification by
flash chromatography (EtOAc/cyclohexane, 30:70), 1hC was isolat-
ed as a white solid: Yield: 53%; m.p. 1548C; [a]2D0 =ꢀ249.5 (c=
Acknowledgements
1
0.88, CHCl3); H NMR (300 MHz, CDCl3): d=7.89–7.85 (m, 2H), 7.69
(t, J=7.6 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.42–7.14 (m, 5H), 5.74 (s,
1H), 5.46–5.29 (m, 1H), 4.78 (t, J=7.7 Hz, 1H), 4.26 (dd, J=8.4,
4.0 Hz, 1H), 3.39 (d, J=16.7 Hz, 1H), 3.23 ppm (d, J=16.7 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=170.6, 149.3, 138.1, 133.8, 130.9,
130.5, 129.2, 128.4, 128.3, 126.2, 125.9, 117.1, 96.1, 76.0, 57.8, 49.5,
We thank the Fꢀdꢀration de Chimie: FR CNRS 3038 (INC3M),
the “rꢀseau CRUNCH”, ERDF funding (A-I chem channel - Inter-
reg IV4 program) and the URCOM laboratory for their financial
support. The authors are also grateful to the French “Ministꢃre
de l’Enseignement Supꢀrieur et de la Recherche” for the Grad-
uate Fellowship attributed to one of us, R.L.G. The authors also
wish to thank CRIHAN and IMMM for the use of their computa-
tion facilities. We thank Patricia Gangnery, Emmanuelle Mebold
and Magdalena Livadaris for HRMS analysis.
44.3 ppm; IR (neat): n˜ =2249, 1716, 1525, 1347, 721, 701 cmꢀ1
;
HRMS (ESI): m/z calcd (%) for C19H16N3O4+: 350.1141 [M+H]+;
found: 350.1133.
(3R)-5-oxo-3,7a-Diphenyltetrahydropyrrolo[2,1-b]oxazole-
7,7(7aH)-dicarbonitrile (1nC): Obtained by reaction between 4n
and 5C under conditions I and, after purification by flash chroma-
tography (EtOAc/cyclohexane, 20:80), 1nC was isolated as a white
solid: Yield: 65%; m.p. 1158C; [a]2D0 =ꢀ52.1 (c=0.70, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.58–7.54 (m, 2H), 7.51–7.48 (m, 3H),
7.25–7.15 (m, 3H), 7.08–7.05 (m, 2H), 5.30 (t, J=7.4 Hz, 1H), 4.94
(dd, J=9.0, 7.6 Hz, 1H), 4.20 (dd, J=9.0, 7.4 Hz, 1H), 3.59 (d, J=
16.4 Hz, 1H), 3.37 ppm (d, J=16.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d=169.2, 136.2, 134.6, 131.2, 129.4, 128.9, 128.5, 127.0,
126.3, 111.9, 111.3, 101.9, 76.2, 59.4, 44.8, 44.7 ppm; IR (neat): n˜ =
1728, 1337, 749, 697, 667 cmꢀ1; HRMS (ESI): m/z calcd (%) for
C20H16N3O2+: 330.1243 [M+H]+; found: 330.1241.
Keywords: bicyclic lactams
· DFT · diastereoselectivity ·
domino reactions · quaternary stereocenter
[1] For pyrrolidines, see: a) N. T. Jui, J. A. O. Garber, F. G. Finelli, D. W. C. Mac-
Millan, J. Am. Chem. Soc. 2012, 134, 11400–11403, and references there-
in; b) B. M. Trost, T. M. Lam, M. A. Herbage, J. Am. Chem. Soc. 2013, 135,
2459–2461; c) D. Enders, D. P. Gçddertz, C. BeceÇo, G. Raabe, Adv.
Synth. Catal. 2010, 352, 2863–2868, and references therein; for piperi-
dines, see: d) P. R. Krishna, B. K. Reddy, P. Srinivas, Tetrahedron 2012, 68,
841–845, and references therein; e) P. S. Watson, B. Jiang, B. Scott, Org.
Lett. 2000, 2, 3679–3681; for g- and d-lactams, see: f) N. A. Sorto, M. J.
Di Maso, M. A. MuÇoz, R. J. Dougherty, J. C. Fettinger, J. T. Shaw, J. Org.
Chem. 2014, 79, 2601–2610, and references therein.
[2] For a recent account, see: a) M. Amat, M. Pꢀrez, J. Bosch, Synlett 2011,
143–160; for a review, see: b) M. D. Groaning, A. I. Meyers, Tetrahedron
2000, 56, 9843–9876.
[3] See for example: a) N. Zill, A. Schoenfelder, N. Girard, M. Taddei, A.
Mann, J. Org. Chem. 2012, 77, 2246–2253; b) D. Kalaitzakis, T. Montag-
non, I. Alexopoulou, G. Vassilikogiannakis, Angew. Chem. Int. Ed. 2012,
51, 8868–8871; Angew. Chem. 2012, 124, 8998–9001; c) M. Enßle, S.
Buck, R. Werz, G. Maas, Beilstein J. Org. Chem. 2012, 8, 433–440; d) Z.
Jin, H. Huang, W. Li, X. Luo, X. Liang, J. Ye, Adv. Synth. Catal. 2011, 353,
343–348; e) Z. Jin, X. Wang, H. Huang, X. Liang, J. Ye, Org. Lett. 2011,
Modified conditions I: Chlorinated Michael acceptor (4’, 1.5 mmol,
1.5 equiv) and N-hydroxyalkyl a-bromoacetamide (5, 1.0 mmol,
1 equiv) were dissolved in freshly distilled THF (10 mL) and cooled
to ꢀ208C. Sodium hydride (80 mg, 60% suspension in mineral oil,
2.0 mmol, 2.0 equiv) was added and the mixture was stirred at
ꢀ208C for 4 h. The reaction was quenched carefully at ꢀ208C by
the addition of a saturated aqueous solution of NH4Cl (10 mL). The
aqueous phase was extracted with EtOAc (3ꢂ10 mL), the organic
phases were combined, washed with brine, dried over MgSO4 and
solvent was removed under vacuum. The residue was then chro-
matographed on silica gel to afford the desired compound.
(3R,7aS)-3-Phenyl-7,7-bis(phenylsulfonyl)tetrahydropyrrolo[2,1-
b]oxazol-5(6H)-one (1qC): Obtained by reaction between 4q’ and
5C under modified conditions I and, after purification by flash
chromatography (EtOAc/cyclohexane, 30:70), 1qC was isolated as
a white solid: Yield: 51%; m.p. 1968C; [a]2D0 =ꢀ87.8 (c=0.74,
ˇ
ˇ
13, 564–567; f) S. Cꢄhalovꢅ, G. Valero, J. Schimer, M. Humpl, M. Dracꢄn-
´
sky, A. Moyano, R. Rios, J. Vesely, Tetrahedron 2011, 67, 8942–8950; g) J.
Salvadori, E. Airiau, N. Girard, A. Mann, M. Taddei, Tetrahedron 2010, 66,
3749–3753; h) M. Weber, S. Jautze, W. Frey, R. Peters, J. Am. Chem. Soc.
2010, 132, 12222–12225; i) S. Dekeukeleire, M. D’hooghe, N. De Kimpe,
J. Org. Chem. 2009, 74, 1644–1649.
1
CHCl3); H NMR (300 MHz, CDCl3): d=8.15 (d, J=7.1 Hz, 2H), 8.12
[4] a) M. Mizutani, F. Inagaki, T. Nakanishi, C. Yanagihara, I. Tamai, C. Mukai,
Org. Lett. 2011, 13, 1796–1799; b) S. Sarkar, D. Schepmann, B. Wꢆnsch,
Tetrahedron: Asymmetry 2011, 22, 1411–1422; c) S. Sen, V. R. Potti, R.
Surakanti, Y. L. N. Murthy, R. Pallepogu, Org. Biomol. Chem. 2011, 9,
358–360; d) M. E. Jung, J. J. Chang, Org. Lett. 2010, 12, 2962–2965; e) Y.
Nakamura, A. M. Burke, S. Kotani, J. W. Ziller, S. D. Rychnovsky, Org. Lett.
2010, 12, 72–75.
(d, J=6.4 Hz, 2H), 7.83–7.62 (m, 6H), 7.48–7.31 (m, 3H), 7.22 (d, J=
7.1 Hz, 2H), 6.29 (s, 1H), 5.01 (t, J=6 Hz, 1H), 4.73 (t, J=7.7 Hz,
1H), 4.11 (dd, J=8.1, 5.4 Hz, 1H), 3.93 (d, J=18.0 Hz, 1H),
3.30 ppm (d, J=18.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=169.8,
138.1, 136.9, 135.9, 135.5, 135.2, 132.0, 130.8, 129.3, 129.0, 128.7,
128.2, 125.8, 93.0, 89.0, 76.4, 57.3, 39.8 ppm; IR (neat): n˜ =1713,
1333, 1315, 1149, 714, 683 cmꢀ1; HRMS (FI): m/z calcd (%) for
C24H21NO6S2+: 483.0810 [M]+ 483.0810,; found: 483.0838.
[5] a) F. Arioli, M. Pꢀrez, F. Subrizi, N. Llor, J. Bosch, M. Amat, J. Org. Chem.
2014, 79, 7740–7745; b) M. Amat, R. Ballette, S. Proto, M. Pꢀrez, J.
Chem. Eur. J. 2015, 21, 2966 – 2979
www.chemeurj.org
2978
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Bosch, Chem. Commun. 2013, 49, 3149–3151; c) M. Amat, C. Ramos, M.
Pꢀrez, E. Molins, P. Florindo, M. M. M. Santos, J. Bosch, Chem. Commun.
2013, 49, 1954–1956; d) M. Amat, L. Novꢄo, N. Llor, E. Molins, J. Bosch,
Org. Lett. 2012, 14, 210–213; e) M. Amat, V. Semak, C. Escolano, E.
Molins, J. Bosch, Org. Biomol. Chem. 2012, 10, 6866–6875; f) M. Amat, F.
Subrizi, V. Elias, N. Llor, E. Molins, J. Bosch, Eur. J. Org. Chem. 2012,
1835–1842.
[14] Gaussian 09, Revision B.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E.
Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Men-
nucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian,
A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O.
Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro,
M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Ko-
bayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyen-
gar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B.
Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,
O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin,
K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg,
S. Dapprich, A. D. Daniels, ꢈ. Farkas, J. B. Foresman, J. V. Ortiz, J. Cio-
slowski, D. J. Fox, Gaussian, Inc. Wallingford CT, 2009.
[6] a) M. Amat, G. Guignard, N. Llor, J. Bosch, J. Org. Chem. 2014, 79, 2792–
2802; b) M. Amat, E. Ghirardi, L. Navꢄo, R. Griera, N. Llor, E. Molins, J.
Bosch, Chem. Eur. J. 2013, 19, 16044–16049; c) M. Amat, O. Bassas, N.
Llor, M. Cantꢇ, M. Pꢀrez, E. Molins, J. Bosch, Chem. Eur. J. 2006, 12,
7872–7881; d) M. Amat, M. Cantꢇ, N. Llor, V. Ponzo, M. Pꢀrez, J. Bosch,
Angew. Chem. Int. Ed. 2002, 41, 335–338; Angew. Chem. 2002, 114,
345–348; an oxazolo-piperidinone bearing a quaternary stereocenter at
the 5-position of the piperidine ring was obtained by Padwa and co-
workers, in this case via a transient N-acyliminium ion, see: e) J. Boon-
sompat, A. Padwa, J. Org. Chem. 2011, 76, 2753–2761.
[7] a) S. Malaquin, M. Jida, J. Courtin, G. Laconde, N. Willand, B. Deprez, R.
Deprez-Poulain, Tetrahedron Lett. 2013, 54, 562–567; b) L. A. Tuan, G.
Kim, Tetrahedron Lett. 2010, 51, 2354–2355; c) M. D. Ennis, R. L. Hoff-
man, N. B. Ghazal, D. W. Old, P. A. Mooney, J. Org. Chem. 1996, 61,
5813–5817.
[8] a) R. Le Goff, A. M. Lawson, A. Da¨ıch, S. Comesse, Org. Biomol. Chem.
2013, 11, 1818–1821; b) I. Allous, S. Comesse, M. Sanselme, A. Da¨ıch,
Eur. J. Org. Chem. 2011, 5303–5310; c) M. Saber, S. Comesse, V. Dalla, A.
Da¨ıch, M. Sanselme, P. Netchita¨ılo, Synlett 2010, 2197–2201; d) S. Co-
messe, M. Sanselme, A. Da¨ıch, J. Org. Chem. 2008, 73, 5566–5569; e) F.
Pin, S. Comesse, M. Sanselme, A. Da¨ıch, J. Org. Chem. 2008, 73, 1975–
1978.
[15] Spartan’10, Wavefunction, Inc, Irvine, CA.
[16] Y. Zhao, D. Truhlar, Theor. Chem. Acc. 2008, 120, 215–241.
[17] L. A. Burns, A. V. Mayagoitia, B. G. Sumpter, C. D. Sherrill, The Journal of
Chemical Physics 2011, 134, 084107–084125.
[18] NBO 6.0., E. D. Glendening, J. K. Badenhoop, A. E. Reed, J. E. Carpenter,
J. A. Bohmann, C. M. Morales, C. R. Landis, F. Weinhold, Theoretical
Chemistry Institute, University of Wisconsin, Madison, 2013.
[19] All unsulfonated Michael acceptors that required conditions I were
tested with modified conditions I but no significant enhancements of
the yield and/or diastereoselectivity, in the case of keto/ester, were ob-
served.
[20] a) M. Amat, N. Llor, B. Checa, M. Pꢀrez, J. Bosch, ARKIVOC 2014, ii, 6–18;
b) L.-J. Jiang, B. Teng, J.-F. Zheng, J.-L. Ye, P.-Q. Huang, Tetrahedron 2010,
66, 172–175; c) M. N. Alberti, G. C. Vougioukalakis, M. Orfanopoulos, J.
Org. Chem. 2009, 74, 7274–7282; d) J. E. Resek, J. Org. Chem. 2008, 73,
9792–9794; e) F. Aydogana, A. S. Demira, Tetrahedron: Asymmetry 2004,
15, 259–265; f) C. Agami, A. Beauseigneur, S. Comesse, L. Dechoux, Tet-
rahedron Lett. 2003, 44, 7667–7669; g) S. M. Allin, S. L. James, W. P.
Martin, T. A. D. Smith, M. R. J. Elsegood, J. Chem. Soc. Perkin Trans.
1 2001, 3029–3036; h) A. I. Meyers, C. J. Andres, J. E. Resek, C. C. Wood-
all, M. A. McLaughlin, P. H. Lee, D. A. Price, Tetrahedron 1999, 55, 8931–
8952.
[9] For a recent review on stereocontrolled domino reactions, see: H. Pel-
lissier, Chem. Rev. 2013, 113, 442–524.
[10] S. Comesse, A. Martel, A. Da¨ıch, Org. Lett. 2011, 13, 4004–4007.
[11] One of the problems we envisioned in this case was the possible com-
petitive formation of morpholin-3-one or 1,4-oxazepan-3-one deriva-
tives by an intramolecular nucleophilic substitution of the alcoholate
onto the carbone that contains the bromine atom; however, we never
observed them.
[12] For all bicyclic lactams 1xY, the x refers to the Michael acceptor sub-
strate 4x or 4x’ and the Y refers to the amido alcohol 5Y substrate.
[13] Syntheses of both 2-nitrophenyl Michael acceptors are reported in the
Supporting Information.
Received: September 2, 2014
Published online on December 18, 2014
Chem. Eur. J. 2015, 21, 2966 – 2979
www.chemeurj.org
2979
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim