Enantioselective Organocatalytic Four-Atom Ring Expansion of Cyclobutanones: Synthesis of Benzazocinones

Article abstract of DOI:10.1002/anie.201810184

An enantioselective Michael addition– four-atom ring expansion cascade reaction involving cyclobutanones activated by a N-aryl secondary amide group and ortho-amino nitrostyrenes has been developed for the preparation of functionalized eight-membered benzolactams using bifunctional aminocatalysts. Taking advantage of the secondary amide activating group, the eight-membered cyclic products could be further rearranged into their six-membered isomers having a glutarimide core under base catalysis conditions without erosion of optical purity, featuring an overall ring expansion– ring contraction strategy.

Full text of DOI:10.1002/anie.201810184

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Enantioselective Organocatalytic Four-Atom Ring Expansion of
Cyclobutanones: Synthesis of Benzazocinones
Authors: Yirong Zhou, Yun-Long Wei, Jean Rodriguez, and Yoann
Coquerel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810184
Angew. Chem. 10.1002/ange.201810184
Link to VoR: http://dx.doi.org/10.1002/anie.201810184
http://dx.doi.org/10.1002/ange.201810184

10.1002/anie.201810184
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Organocatalytic Four-Atom Ring Expansion of
Cyclobutanones: Synthesis of Benzazocinones
Yirong Zhou,[a,b] Yun-Long Wei,[a] Jean Rodriguez,*,[a] and Yoann Coquerel*,[a]
Dedication ((optional))
Abstract: An enantioselective Michael addition / four-atom ring
expansion cascade reaction involving cyclobutanones activated by a
N-aryl secondary amide group and ortho-amino nitrostyrenes has
been developed for the preparation of functionalized eight-membered
benzolactams using bifunctional aminocatalysts. Taking advantage of
the secondary amide activating group, the eight-membered cyclic
products could be further rearranged into their six-membered isomers
having a glutarimide core under base-catalysis conditions without
erosion of optical purity, featuring an overall ring expansion / ring
contraction strategy.
described a rhodium(I)-catalyzed [4 + 2 + 2] cycloaddition using a
chiral phosphoramidite ligand,[4] while Dong and co-workers
developed
a rhodium(I)-catalyzed redox neutral annulative
hydroacylation employing a chiral diphosphine ligand.[5] Lately,
two organocatalytic approaches were reported relying on Lewis
base catalysis: Lu, Ullah and co-workers proposed a (4 + 4)
annulation based on allenes activation with a chiral phosphine
catalyst to afford azocines,[6] and the group of Romo used the
reactivity of catalytically generated a,b-unsaturated acyl
ammonium salts with a chiral tertiary amine catalyst in (5 + 3)
annulations.[7] Over the last two decades, organocatalytic
cascade reactions have established as a general and sustainable
strategy to rapidly access highly functionalized, structurally
diverse and complex molecules free from metal residues.[8]
Nevertheless, most of the established organocascades focus on
the preparation of energetically favorable five- and six-membered
rings. Otherwise, ring expansion strategies provide an appealing
way to prepare medium-sized rings from readily available small
Benzazocinones, that are eight-membered cyclic lactams fused
to a benzene ring, are privileged scaffolds that can be found in
various synthetic and natural products endowed with important
biological activities (Figure 1).[1,2] However, the construction of
medium-sized rings by organic synthesis is notoriously difficult
because of inherent unfavorable enthalpic and entropic factors,
as well as undesired transannular interactions.[1] Although steady
progresses have been made for the synthesis of medium-size
heterocycles, the direct synthesis of azocane derivatives remains
a largely unsolved issue,[3] especially when considering catalytic
enantioselective approaches. Actually, there has been only a
handful of examples of enantioselective syntheses reported on
this poorly-charted area of chemical space. The Rovis group
rings.[9] Herein we propose
a
direct enantioselective
organocatalytic synthesis of benzazocinones based on a Michael
addition / four-atom ring expansion cascade from activated
cyclobutanones and ortho-amino nitrostyrene derivatives using
bifunctional aminocatalysts [Scheme 1, b)]. The base-catalyzed
ring contraction of benzazocinone products into their six-
membered ring isomers having a glutarimide core with retention
of optical purity is also demonstrated.
Ph
OH
N
O
Ph
OH
N
H
H
O
O
N
a) previous work from acyclic precursors
R2
HN
O
H
R1
Rh(I)/L*
Lewis base*
acyclic
precursors
acyclic
precursors
O
N
O
ζ-clausenamide
balasubramide
OTBDMS
H
cycloaddition[4]
hydroacylation[5]
(4+4) annulation[6]
(5+3) annulation[7]
asporyzin A
OBn
optically
active
azocanes
O
BnO
OH
N
N
OH
O
H
b) this work: Michael addition / four-atom ring expansion organocascade
TBDPSO
O
O
benzazocine core of FR900482
sulpinine C
R2
R2
bifunctional
aminocatalyst*
O
O
NO2
Figure 1. Selected examples of benzazocinones in natural products and
R3
O
R1
+
N
N
bioactive molecules.
NH
H
N
H
R3
NO2
R1
O
Michael
R3
fragmentation
[a]
[b]
Dr. Y. Zhou, M. Y.-L. Wei, Prof. Dr. J. Rodriguez, Dr. Y. Coquerel
Aix Marseille Université, CNRS, Centrale Marseille, ISM2, 13397
Marseille, France
R2
R2
NO2
N
R3
O
N
E-mail: jean.rodriguez@univ-amu.fr
yoann.coquerel@univ-amu.fr
Dr. Y. Zhou
O
cyclization
NO2
NH
R1
NH
R1
Jiangxi Normal University, 330022, Nanchang, China
O
O
Supporting information for this article is given via a link at the end of
the document. It contains detailed experimental procedures, full
characterization data, details of the computational studies and single
crystal X-ray diffraction analysis data for 3b.
Scheme 1. Enantioselective approaches to azocane derivatives.
This article is protected by copyright. All rights reserved.

10.1002/anie.201810184
Angewandte Chemie International Edition
COMMUNICATION
Based on our previous work,[10] the cyclobutanone 1a
activated by a N-aryl secondary amide group at the b position and
the ortho-amino nitrostyrene derivative 2a were selected as the
prototypical substrates to test our hypothesis with the bifunctional
aminocatalyst OC1[11] in toluene, meta-xylene, or dichloroethane.
To our delight, the expected benzazocinone product 3a (dr = 4:1
to 5:1) was identified as the largely major product with 70% yield
in toluene and meta-xylene and 51% yield in dichloroethane, with
excellent enantioselectivities (Scheme 2). No Michael adduct or
respectively, in place of the N-3,5-bis(trifluoromethyl)benzyl group
found in OC2 gave only modest yields of 3a with complete loss of
the enantioselectivity. Catalyst OC7 derived from quinine is the
pseudo-enantiomer of catalyst OC2, and as such it delivered 3a
in similar yield but opposite and still excellent enantioselectivity.
With catalyst OC8, a diastereomer of OC2, the reaction afforded
only 26% yield of 3a as a nearly racemic product, indicating a
strong mismatch effect in this case. The replacement of the
squaramide double hydrogen-bond donor moiety by a thiourea in
OC10 or a urea in OC11, as well as the use of the so-called
Takemoto catalyst OC9 having a different chiral backbone, gave
the product 3a in only moderate yields and enantioselectivities.
Finally, catalyst OC12 having a missing N–H bond promoted the
reaction at a very slow rate (<10% conversion after 4 days).
Notably, the diastereoselectivity of the reaction is not much
affected by the nature of the catalyst, the product 3a being
systematically obtained as a ca. 5:1 mixture of the trans and cis
diastereomers, respectively.
NO2
CO2Et
+
O
OCn (5 mol%)
NO2
O
Boc
N
(R)
(S)
toluene (0.05 M)
22 ºC, 20–40 h
N
NH
H
N
H
O
CO2Et
Boc
(1.2 equiv)
O
1a
2a
3a
O
O
Et
O
O
O
O
N
H
(R)
N
H
H
N
N
N
H
(R)
(R)
(R)
(R)
F3C
H
(R)
N
H
N
H
N
H
N
H
F3C
F3C
H
MeO
MeO
CF3
With optimized reaction conditions in hand, we examined
the scope of this original transformation. The results are
summarized in Scheme 3. At first, a series of cyclobutanones 1
bearing different N-aryl secondary amide activating groups were
examined. All of them reacted smoothly with the ortho-amino
nitrostyrene 2a to afford the desired benzazocinone products 3b-
j and ent-3k in fair to good yields along with high to excellent
enantioselectivities. The absolute configuration of product 3b was
unambiguously determined to be (5S,6R) by X-ray diffraction
techniques (see Supporting Information),[13] which is consistent
with previous results.[10] In line with previous studies on
organocatalytic Michael additions with secondary b-
ketoamides,[10,14] substrates bearing a R1 electron-withdrawing
substituent systematically afforded better enantioselectivities,
which was attributed to the higher acidity of the secondary amide
N–H proton in these cases resulting in more compact and better-
defined transition states in the Michael addition step. As a scope-
limiting issue, the analog of 1 having a N-tert-butyl group in place
of the N-aryl substituent didn't react with nitrostyrene 2a using
catalyst OC1, while catalyst OC9 promoted only the
corresponding Michael addition at a slow rate without evidence
for any fragmentation.[10,15] The secondary amide N-aryl
substituent in 1 thus seems essential for the overall cascade to
proceed, probably a consequence of the higher acidity, and thus
higher electron-withdrawing character, of secondary N-aryl
amides compared to N-alkyl amides.[14a] Modifications of the
ortho-amino nitrostyrene substrate also proved possible as
illustrated by the introduction of an alkyl or a halogen substituent
on the phenyl ring in 3l and 3m, respectively, and by variations of
the carbamate protecting group in 3n-p, while maintaining high
levels of enantioselectivity. If all reactions proceeded with high to
excellent enantioselectivities, their diastereoselectivities were
found influenced by steric factors. For example, products 3b and
3j only differ by the position of the para- or meta-NO2 substituent
on the secondary amide phenyl ring and were obtained as 9:1 and
15:1 mixtures of diastereomers, respectively. Also, 3l is an ortho-
methylated analog of 3a on the fused benzo ring, which strongly
influenced the diastereoselectivity (5:1 dr for 3a vs >25:1 dr for 3l).
DFT calculations indicated a ca. 10 kJ mol-1 stabilization energy
for the trans diastereomers of 3a and 3l relative to their cis
isomers (see Supporting Information). Some degree of
N
CF3
CF3
OC1
N
N
70%, 5:1 dr, 96% ee
70%, 4:1 dr, 93% eea
51%, 5:1 dr, 93% eeb
OC2
80%, 5:1 dr, 94% ee
OC3
55%, 5:1 dr, 85% ee
O
O
F3C
O
O
O
O
N
H
N
H
N
H
(R)
(R)
(R)
(R)
(R)
(R)
N
H
N
H
MeO
N
H
N
H
N
H
N
H
F3C
F3C
MeO
MeO
CF3
N
Ph
N
N
OC4
71%, 6:1 dr, 96% ee
OC6
OC5
44%, 3:1 dr, 6% ee
30%, 3:1 dr, 9% ee
O
O
O
O
CF3
N
H
N
H
(S)
(S)
(S)
(R)
S
N
H
N
H
N
H
N
H
(R)
F3C
F3C
F3C
N
H
N
MeO
MeO
(R)
H
N
CF3
CF3
N
N
OC7
OC8
OC9
61%, 5:1 dr, –95% ee
26%, 5:1 dr, 2% ee
52%, 5:1 dr, 67% ee
CF3
CF3
CF3
S
O
S
N
N
H
N
H
(S)
(S)
(S)
(S)
(S)
N
N
F3C
N
F3C
N
O
F3C
N
(R)
H
H
H
H
H
H
MeO
MeO
MeO
N
N
N
OC10
68%, 6:1 dr, –81% ee
OC11
44%, 4:1 dr, –66% ee
OC12
<10% after 4 days
Scheme 2. Organocatalysts screening. Yields for isolated pure products. Dr
were determined by 1H NMR analysis of the crude reaction mixtures, and ee
were determined for the pure products by HPLC analyses on chiral stationary
phases. aReaction performed in meta-xylene. bReaction performed in 1,2-
dichloroethane.
hemiketal intermediate was detected in the crude reaction
mixtures. With the intention to optimize these results,
organocatalysts OC2–OC12 were screened for the same
reaction.[12] The results are listed in Scheme 2. It was found that
cinchonine and quinidine-derived squaramides OC1 and OC2 are
optimum for the synthesis of benzazocinone 3a in terms of
practicability, yield and enantioselectivity. Catalyst OC3, a
hydrogenated version of catalyst OC2, afforded the product in
significantly reduced efficiency and enantioselectivity, while
catalyst OC4, a sterically hindered version of catalyst OC2, gave
a comparable result than catalyst OC1. Catalysts OC5 and OC6
having a N-3,5-bis(trifluoromethyl)phenyl and a N-tert-butyl,
This article is protected by copyright. All rights reserved.

10.1002/anie.201810184
Angewandte Chemie International Edition
COMMUNICATION
R2
R3
O2N
NHBoc
H
NO2
O
O
NO2
OCn (2.5–5 mol%)
R2
NO2
R1
N
+
(6R)
(5S)
(R)
Boc
N
H
toluene (0.05 M)
22 ºC, 20–40 h
NH
R3
N
*
H
N
(6R)
(5S)
DBU (10 mol%)
O
H
N
O
N
O
R1
(1.2 equiv)
O
O
toluene/CH2Cl2 (2:1)
22 ºC, 12–48 h
1
2
3
O
R
NO2
3b: R = NO2, 9:1 dr, 99% ee
3e: R = H, 3:1 dr, 85% ee
3h: R = Br, 5:1 dr, 88% ee
3i: R = I, 5:1 dr, 90% ee
NO2
Boc
R
Boc
N
N
(6R)
(5S)
H
N
H
N
O
4b: 96%, 6:1 dr, 97% and 95% ee
4e: 65%, 2:1 dr, 83% and 84% ee
4h: 70%, 3:1 dr, 85% and 85% ee
4i: 70%, 2:1 dr, 85% and 85% ee
CF3
O
NO2
O
O
3c
3b
OC1: 64%, 6:1 dr, 96% ee
OC2: 64%, 5:1 dr, 92% ee
OC1: 66%, 9:1 dr, 99% ee
OC2: 74%, 6:1 dr, 96% ee
O2N
NBoc
H
R
NO2
H
NO2
NO2
R
Boc
Boc
N
Boc
O
N
N
(R)
H
(S)
O
N
H
O
O
N
H
N
F
O
N
N
CN
Boc
O
O
Boc
O
O
N
R
O
(5S)
O
3e
3f
N
(6R)
O
3d
NO2
OC1: 54%, 3:1 dr, 85% ee
OC2: 62%, 3:1 dr, 85% ee
OC1: 66%, 3:1 dr, 87% ee
OC2: 68%, 3:1 dr, 86% ee
N
OC2: 72%, 6:1 dr, 95% ee
NO2
NO2
NO2
NO2
Boc
Boc
Boc
N
N
N
H
H
H
O
O
O
N
Cl
N
Br
N
I
O2N
H
NHBoc
O
O
O
3g
3h
3i
NO2
(S)
Boc
OC1: 67%, 5:1 dr, 86% ee
OC2: 66%, 5:1 dr, 88% ee
OC1: 65%, 5:1 dr, 88% ee
OC2: 66%, 5:1 dr, 88% ee
OC2: 64%, 5:1 dr, 90% ee
N
*
(6S)
(5R)
DBU (10 mol%)
H
O
N
O
O
N
toluene/CH2Cl2
(2:1), 25 ºC, 48 h
CF3
O
Me
NO2
H
NO2
NO2
CF3
Boc
Boc
Boc
N
NO2
N
N
F3C
CF3
H
H
CF3
ent-3k: 10:1 dr, 97% ee
O
O
O
N
CO2Et
N
N
O
O
O
ent-4k: 71%, 3:1 dr, 96% and 97% ee
CF3
3j
ent-3k
3l
OC1: 64%, 15:1 dr, 94% ee
OC7: 85%, 10:1 dr, 97% ee
OC2: 82%, >25:1 dr, 95% ee
Scheme 4. Ring contraction of benzazocinones into glutarimides. The major
diastereomers are depicted, dr were determined by 1H NMR analysis of the
crude reaction mixtures, ee are reported for the major and minor diastereomers,
respectively, and were determined for the pure products by HPLC analyses on
chiral stationary phases. DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene.
Br
O
NO2
NO2
NO2
CF3
CF3
R
Cbz
N
N
Boc
O
N
H
H
H
O
N
O
O
N
NO2
N
CO2Et
O
O
O
3o, R = Bn,
3m
3n
OC1: 52%, 7:1 dr, 95% ee
3p, R = Et,
OC2: 33%, 4:1 dr, 88% ee
OC2: 50%, 8:1 dr, 99% ee
OC2: 54%, 6:1 dr, 94% ee
with substrate 3b (Table S1 in the Supporting Information)
allowed identifying DBU as a competent catalyst for the desired
transformation, which after optimization afforded the glutarimide
4b in good yield without significant erosion of optical purity but
some epimerization at the a position of the secondary amide.
Similarly, the benzazocinones 3e,h,i and ent-3k reacted with
DBU to afford the corresponding glutarimides 4e,h,i and ent-4k.
Scheme 3. Substrates scope. Reactions were performed on a 0.1–1.0 mmol
scale. Yields for isolated pure products. Dr were determined by 1H NMR analysis
of the crude reaction mixtures, and ee were determined for the pure products
by HPLC analyses on chiral stationary phases.
thermodynamic control of the diastereoselectivity could be
evidenced: 3k (the enantiomer of ent-3k) was prepared using
catalyst OC1 (70% yield, 10:1 dr, 83% ee) and chromatographic
techniques allowed us to obtain a sample of 3k enriched in the
minor diastereomer with dr = 2:1. This material was placed back
under the reaction conditions with 5 mol% OC1 in toluene.
Periodical monitoring of the mixture by 1H NMR analysis of
aliquots showed a slow conversion of the minor diastereomer into
the major one with dr = 3.6:1 after 20 h and dr = 7:1 after 50 h
without significant decomposition.
To further demonstrate the potential of this enantioselective
synthesis of benzazocinones, we examined their base-catalyzed
ring contraction into the corresponding glutarimides exploiting the
reactivity of the pendant N-aryl secondary amide group (Scheme
4). Notably, chiral glutarimide moieties are found in biologically
active natural and synthetic products including marketed drugs,[16]
but enantioselective methods for their synthesis remain
scarce.[7,17] A screening of archetypal Brønsted and Lewis bases
Mechanistically, this transformation may proceed by
a
thermodynamically-controlled transannular ring-rearrangement
involving the Brønsted base properties of the catalyst. A pure
sample of the minor diastereomer epi-ent-4k was obtained by
semi-preparative HPLC techniques and submitted back to the
reaction conditions, which afforded a 3:1 mixture of ent-4k and
epi-ent-4k. This experiment probed some degree of
thermodynamic control in the diastereoselectivity of the ring
rearrangement reaction, probably due to a DBU-catalyzed
epimerization at the imide enolisable position. DFT calculations
allowed a tentative assignment of the relative configuration in ent-
4k with a stabilization energy of 7.5 kJ mol-1 for the (R,S)
diastereomers depicted in Scheme 4 (see Supporting Information
for details). It is remarkable that glutarimides 4b,e,h,i and ent-4k
overall derive from the corresponding activated cyclobutanones 1
by an enantioselective ring expansion / ring contraction
approach.[18]
This article is protected by copyright. All rights reserved.

10.1002/anie.201810184
Angewandte Chemie International Edition
COMMUNICATION
[6]
[7]
[8]
H. Ni, X. Tang, W. Zheng, W. Yao, N. Ullah, Y. Lu, Angew. Chem. Int.
Ed. 2017, 56, 14222–14226.
In
summary,
an
enantioselective
synthesis
of
benzazocinones has been elaborated based on a Michael
addition / four-atom ring expansion cascade from activated
cyclobutanones and ortho-amino nitrostyrenes using bifunctional
G. Kang, M. Yamagami, S. Vellalath, D. Romo, Angew. Chem. Int. Ed.
2018, 57, 6527–6531.
Selected recent reviews and books on organocatalytic enantioselective
cascade reactions: a) Moyano A., Rios, R. Chem. Rev. 2011, 111, 4703–
4832; b) C. M. Marson, Chem. Soc. Rev. 2012, 41, 7712–7722; c) C. M.
R. Volla, I. Atodiresei, M. Rueping, Chem. Rev. 2014, 114, 2390–2431;
d) Y. Wang, H. Lu, P. Xu, Acc. Chem. Res. 2015, 48, 1832–1844; e) F.
Vetica, P. Chauhan, S. Dochain, D. Enders, Chem. Soc. Rev. 2017, 46,
1661–1674; f) Catalytic Cascade Reactions (Eds.: P. Xu, W. Wang),
John Wiley & Sons, Inc., Hoboken, NJ, 2013; g) Stereoselective multiple
bond-forming transformations in organic synthesis (Eds.: D. Bonne, J.
Rodriguez), John Wiley & Sons, Inc., Hoboken, NJ, 2015.
aminocatalysts. This newly developed approach allows
a
straightforward access to a class of molecules usually difficult to
synthesize in optically active form from readily available starting
materials under mild conditions. The benzazocinone products can
be further converted into functionalized glutarimide derivatives
without loss of the enantiomeric purity by a base-catalyzed ring
contraction.
[9]
Selected recent reviews on ring expansion synthetic strategies: a) E.
Leemans, M. D’hooghe, N. De Kimpe, Chem. Rev. 2011, 111, 3268–
3333; b) J. Christoffers, Catal. Today 2011, 159, 96–99; c) G. Fumagalli,
S. Stanton, J. F. Bower, Chem. Rev. 2017, 117, 9404–9432; d) J. R.
Donald, W. P. Unsworth, Chem. Eur. J. 2017, 23, 8780–8799. Selected
recent examples on ring expansion strategies: e) F. Behler, F. Habecker,
W. Saak, T. Klüner, J. Christoffers, Eur. J. Org. Chem. 2011, 4231–4240.
f) M. Penning, E. Aeissen, J. Christoffers, Synthesis 2015, 47, 1007–
1015; g) C. Kitsiou, J. J. Hindes, P. I'Anson, P. Jackson, T. C. Wilson, E.
K. Daly, H. R. Felstead, P. Hearnshaw, W. P. Unsworth, Angew. Chem.
Int. Ed. 2015, 54, 15794–15798; h) J. E. Hall, J. V. Matlock, J. W. Ward,
K. V. Gray, J. Clayden, Angew. Chem. Int. Ed. 2016, 55, 11153–11157;
i) R. Costil, Q. Lefebvre, J. Clayden, Angew. Chem. Int. Ed. 2017, 56,
14602–14606; j) T. C. Stephens, M. Lodi, A. M. Steer, Y. Lin, M. T. Gill,
W. P. Unsworth, Chem. Eur. J. 2017, 23, 13314–13318; k) R. Mendoza-
Sanchez, V. B. Corless, Q. N. N. Nguyen, M. Bergeron-Brlek, J. Frost, S.
Adachi, D. J. Tantillo, A. K. Yudin, Chem. Eur. J. 2017, 23, 13319–13322;
l) T. C. Stephens, A. Lawer, T. French, W. P. Unsworth, Chem. Eur. J.
2018, 24, 13947–13953; m) N. Wang, Q.-S. Gu, Z.-L. Li, Z. Li, Y.-L. Guo,
Z. Guo, X.-Y. Liu, Angew. Chem. Int. Ed. accepted article, DOI:
10.1002/anie.201808890.
Acknowledgements
Financial support from the Agence Nationale de la Recherche
(ANR-13-JS07-0002-01), Aix-Marseille Université, Centrale
Marseille, and the Centre National de la Recherche Scientifique
(CNRS) is gratefully acknowledged. Y. Z. thanks the National
Natural Science Foundation of China (no. 21602089) for support.
Y.-L. W. thanks the China Scholarship Council (no.
201508330296) for support. We thank Dr. Michel Giorgi (Aix-
Marseille Université) for the X-ray structural analysis, and Dr.
Nicolas Vanthuyne and Ms. Marion Jean (Aix-Marseille
Université) for HPLC methods.
Keywords: Synthetic methods • Organocatalysis • Medium-ring
compounds • Ring expansion • Ring contraction
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10.1002/anie.201810184
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COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
O
O
Yirong Zhou, Yun-Long Wei, Jean
Rodriguez,* Yoann Coquerel*
R2
O2N
NHR3
R2
R1
N
H
NO2
organocat.*
base
H
R3
O
(R)
+
N
(S)
(R)
(S)
NO2
H
N
4-to-8
8-to-6
R1
O
N
R1
O
Page No. – Page No.
R2
O
NH
R3
Enantioselective Organocatalytic
Four-Atom Ring Expansion of
Cyclobutanones: Synthesis of
Benzazocinones
A four-atom ring expansion strategy is developed for the organocatalytic
enantioselective synthesis of eight-membered ring benzolactams. A base-catalyzed
ring contraction of these medium-sized rings allowed the synthesis of glutarimides
with retention of the optical purity.
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