Enantioselective N-Heterocyclic Carbene Catalyzed Cyclopentene Synthesis via the β-Azolium Ylide

Article abstract of DOI:10.1002/anie.201804271

Herein we report the cycloisomerization of electron-poor 1,5-dienes via the β-azolium ylide to give enantioenriched cyclopentenes. The reaction is mediated by a chiral N-heterocyclic carbene (NHC) catalyst, exploits readily available substrates, has good generality (17 examples), and displays excellent enantioselectivity (mostly >94:6). Studies demonstrating the viability of a related dynamic kinetic resolution are reported, as are those with alternate tethers and derivatizations.

Full text of DOI:10.1002/anie.201804271

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: Enantioselective N-heterocyclic carbene catalyzed cyclopentene
synthesis via the b-azolium ylide
Authors: Lydia Scott, Yuji Nakano, Changhe Zhang, and David W
Lupton
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804271
Angew. Chem. 10.1002/ange.201804271
Link to VoR: http://dx.doi.org/10.1002/anie.201804271
http://dx.doi.org/10.1002/ange.201804271

Angewandte Chemie International Edition
10.1002/anie.201804271
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
NHC catalysis
Enantioselective N-heterocyclic carbene catalyzed cyclopentene
synthesis via the azolium ylide**
Lydia Scott, Yuji Nakano, Changhe Zhang and David W. Lupton*
Abstract: Herein we report the cycloisomerization of electron-poor
1
,5-dienes via the azolium ylide to give enantioenriched
cyclopentenes. The reaction exploits readily available substrates,
has good generality (17-examples), and displays excellent
enantioselectivity (most > 94:6). Studies demonstrating the viability
of a related dynamic kinetic resolution are reported, as are those
with alternate tethers and derivatizations.
More than 45 years ago, work from Morita[1a] and
[
1b,c]
Baylis/Hillman
led to the discovery that simple conjugate
acceptors can couple with aldehydes using catalytic phosphine or
amine Lewis bases (eq. 1). Key mechanistic features of these, and
the related Rauhut-Currier reaction, [
1o,p]
involve 1,4-addition of the
Lewis base to give enolate 1, which is alkylated, and following
elimination of the catalyst, provides substituted products (i.e. 2).
Finer mechanistic detail, enantioselective variants, and more
sophisticated reaction designs, have since allowed these reactions to
[
1]
enter the lexicon of synthesis.
In 1962, Takashina and Price observed that acrylonitrile gives
hexamer 3 in the presence of triphenyl phosphine and ethanol (eq.
[
2a]
2
).
3
It was proposed that following 1,4-addition of the Ph P,
alcohol mediated tautomerization gives the novel phosphonium
ylide (i.e 45), which goes on to provide 3.[2] More recently, Fu
reported the N-heterocyclic carbene (NHC) catalyzed formation of
[
3]
cyclopentane 6, via the related azolium ylide 7 (eq. 3). This
[
4]
species, a type of deoxy-Breslow intermediate, is analogous to
adducts discovered by Enders in stoichiometric reactions of the
[
4a]
triphenyltriazolium carbene with conjugate acceptors.
While
reactions of the Breslow intermediate, the archetypal acyl anion
equivalent formed under NHC catalysis, continue to attract
[
5a,c]
significant attention,
azolium ylides (i.e. 7) have remained
[
6]
[7]
largely overlooked. Specifically, Matsuoka,
Glorius,
and
[
8]
Berkessel have studied the dimerization (and oligomerization) of
electron-poor olefins (i.e. eq. 4), Chen has exploited the azolium
ylide in polymerization catalysis,[ and we have developed a
moderately enantioselective (most <79:21 er) synthesis of aryl
9]
Scheme 1. Background and reaction design.
[
10]
propionates.
The unusual reactivity of the azolium ylide, combined with
the proximity of the chiral azolium to the site of bond formation, a
priori, make it well-suited to new enantioselective reaction designs.
To demonstrate this, we envisaged a synthesis of cyclopentenes,
exploiting the cycloisomerization of electron-poor 1,5-dienes (i.e. 8)
[]
Ms. Lydia Scott, Dr. Yuji Nakano, Dr. Changhe Zhang
Professor David W. Lupton*
School of Chemistry, Monash University
Clayton 3800, Victoria, AUSTRALIA
Fax: (+) 61 3 9905 4597
(
eq. 5). While cyclopentenes are found extensively in bioactive and
[
11]
natural products (Scheme 1),
their enantioselective synthesis is
E-mail: david.lupton@monash.edu
often more challenging than that of analogous cyclohexenes. Herein
we report studies that have led to the discovery of a highly
enantioselective (most > 94:6 er) route to cyclopentenes 9. The
reaction exhibits good generality (17-examples), while exploiting
readily accessible substrates and catalysts.
[
] The authors thank the Australian Research Council through the
Discovery (DP150101522 and DP170103567) programs for financial
support. DWL thanks Dr. Amanda E. Lee for copy-editing.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.
Reaction discovery commenced with the preparation of 1,5-
diene 8a. This was achieved by alkylation of the enamine of
1
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201804271
ethyl ester, sulfonyl ketone, and nitrile functionality. In all cases
high enantioselectivity (≥92:8 er) and acceptable yields were
achieved. Deletion of the R group was subsequently examined to
probe the role of Thorpe-Ingold rate enhancement. Gratifyingly, bis-
ethyl ester 9e, t-butyl/ethyl ester 9f, cyano/ethyl ester 9g, and
Weinreb amide/ethyl ester 9h all formed in 70-87% yield and in
isobutyraldehyde with bromomethylethylacrylate and Wittig
homologation of the resultant unpurified aldehyde.[12] With facile
access to the required substrate, the cycloisomerization was
[
4a,13]
1
examined with the Enders TPT catalyst A
and triazolylidene B.
most cases ≥ 93:7 er. Dimethyl cyclopentenes, bearing various E
While both were viable, the latter gave cyclopentene 9a in 99%
2
groups and both ethyl and methyl ester E groups, were also readily
yield (Table 1, entries 1 and 2). Oligomerization can plague
prepared. Thus, products 9a and i-k were formed in 81-88% yield
reactions of the azolium ylide and was not observed in either case. and high enantiopurity (all ≥94:6 er). In addition, cyclobutane 9l,
Studies into the enantioselective variant commenced with NHCs C
and D1 bearing the N-4-MeOC substituent, as exploited in other
Pleasingly, cyclopentene 9a formed
and cyclopentanes 9m and n were prepared in good yield and with
high enantioselectivity (88:12, 97:3 and 93:7 er respectively).
Finally, introduction of oxygen and nitrogen containing heterocycles
was examined. Thus, piperidine 9o and tetrahydropyran 9p were
prepared in good yields and high enantioselectivity (95:5 and 93:7
er).
6
H
4
[
3a,10]

azolium ylide reactions.
with moderate enantioenrichment in both cases (Table 1, entries 3
and 4). Further catalyst screening, with six NHCs bearing various N-
[
14]
substituents (D1-6),
in refluxing THF, using 1,5-diene 8b,
demonstrated that the least nucleophilic[14a] catalyst D6 gave
cyclopentene 9b in 73% yield and an 85:15 enantiomeric ratio
Table 2. Scope of the enantioselective cyclopentene synthesis.a-c
(
Table 1, entry 10). This selectivity was enhanced at lower
temperature, although the yield was compromised (Table 1, entry
1). However, at 40 C in the absence of salt by-products,[15]
cyclopentene 9b formed in 93% isolated yield and in a 97:3 er
Table 1, entry 12).
1
(
Table 1. Selected optimization studies.
entry
8
cat
T (°C)
solvent
yielda
erb
1
2
3
4
5
6
7
8
9
a
A





toluene
53
99
60
95
28
-
-
"
"
"
b
"
"
"
"
"
"
"
B
"
-
C
"
~68:32
72:28
80:20
-
D1
D1
D2
D3
D4
D5
D6
D6
D6c
"
THF

"
"
"
"
"
"
"

-
-

26
18
73
50
93
ND
ND
85:15
96:4
97:3

10
11
12

rt
40
[
a] Isolated yield [b] Enantiomeric ratio by HPLC over chiral stationary phases
c] NHC prepared with 40 mol% KHMDS and isolated from KBF and HMDS,
see experimental section.
[
4
a] NHC D6 generated with 40 mol% KHMDS and isolated from KBF and
[
4
HMDS [b] Isolated yield [c] Enantiomeric ratio determined by HPLC over chiral
stationary phases.
Reaction generality was examined through variation of the two
Next we envisioned exploiting the Brønsted basicity of the NHC to
allow the dynamic kinetic resolution of racemic 1,5-diene
substrates. When benzyl 1,5-diene 8q was exposed to the reaction
conditions, a 2:1 diastereomeric mixture of cyclopentene 9q formed
with 82% yield and high levels of enantiopurity (89:11 and 94:6 er)
1
2
Michael acceptor groups (E and E ) and the R substituents (Table
). Substrates were prepared, using the previously described
2
[17]
[
11]
procedure or, in the case of 8e-h, by Wittig reaction of a known
aldehyde precursor.
[
16]
The cycloisomerization proved robust, with
1
7 cyclopentenes 9a-q prepared in good yield and with high
(eq. 8). Resubjection of this mixture to the reaction conditions had
enantiopurity. Specifically, studies commenced by examining
little impact on stereochemical purity, indicating that the
diastereoselectivity likely arose from resolution prior to
1
variation in the E group to give spirocyclic decanes 9b-d containing
2
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201804271
cycloisomerization. To increase the effectiveness of the resolution
the reaction was repeated at elevated temperature. This gave the
expected product 9q in an increased 7:1 diastereomeric ratio, with
moderate reduction in enantiopurity.
While the Brønsted basicity of the NHC was advantageous in
the previous reaction this compromised enantioselectivity when aryl
linkers were examined in the substrate (i.e. 10). Specifically, diene
1
0 provided indene 11[18] as a racemic mixture under the standard
conditions. It was postulated that racemization occurred via the
aromatic indenyl anion. Lowering the temperature allowed indene
1
1
to be prepared in 85:15 er; however conversion was
compromised (eq. 9).
Next derivatizations were examined to probe the utility of the
products and determine the absolute configuration of the
cyclopentenes. Thus, diester 9e was converted to the known diacid
[
19]
1
3e
by exhaustive alkylation, followed by ester hydrolysis. In
addition, derivatization through complete reduction with DIBAL-H
afforded diol 14m, while reduction at sustained low temperatures
provided aldehyde 15m (eq. 10).
Preliminary mechanistic studies were undertaken to examine
the nature of the turn-over limiting step. Thus, the synthesis of
cyclopentene 9b was performed with the pseudo-racemic catalyst
mixture derived from ent-D1 and D6. The reaction was terminated
after around 30% conversion and the enantiopurity of 9b determined
to be 97:3 er (eq. 11); unchanged from the reaction with D6 alone
[
14a]
(Table 2). Since the D6 catalyst is less nucleophilic than ent-D6,
this result is inconsistent with either turn-over limiting 1,4-addition
of the catalyst (D6 + 8e16) or cyclization (i.e. 1718); steps that
would be expected to be accelerated by a highly nucleophilic
catalyst. Consistent with this result is turn-over limiting proton
transfer (i.e. 1617) and reversible 1,4-addition of the NHC. Thus,
a plausible mechanism for the cycloisomerization begins with the
reversible 1,4-addition of NHC D6 to 1,5-diene 8e to give enolate
1
6. To minimise steric interactions the enolate is likely oriented
such that Re protonation is hindered by the benzyl group. Thus, Si-
protonation followed by deprotonation gives azolium ylide 17,
with the enediamine oriented to minimise interactions with the t-
butyl group, while the none conjugated ethyl ester is oriented to
minimise interactions with the benzy group. Diastereoselective, and
ultimately enantiodetermining, cyclization with the conjugate
acceptor in a pseudo-equatorial position then provides cyclopentane
1
8. Consistent with stereoselective cyclisation via this conformation
is the reaction’s sensitivity to the size of the E group, with the
smaller nitrile group decreasing the enantioselectivity of the
cyclopentene synthesis compares to the ethyl ester (Table 2: 9b cf. d,
e cf. g, and m cf. n). Finally, protonation and elimination of the
catalyst gives cyclopentene 9e.
Scheme 2. Dynamic kinetic resolution, derivatizations, and mechanism.
The Breslow intermediate, derived from the 1,2-addition of
carbenes to aldehydes, remains the most influential species in NHC
[
5,20]
organocatalysis.
Beyond enabling direct acyl anion equivalent
Keywords: enantioselective catalysis • N-heterocyclic carbene •
1,4-addition • -azolium ylide • cyclopentene •
reactions, its subsequent rearrangement underpins a host of
[
5]
alternative transformations. In contrast, the azolium ylide is far
less developed. Although studies into the fundamental reactivity of
the azolium ylide have been reported in the last 12-years, further
work is required to allow it to gain general utility. This study is the
first to deliver a highly enantioselective reaction. In addition to
providing a concise approach to diverse cyclopentenes, it should
serve to support future studies in azolium ylide catalysis.
[
1] (a) K.-i., Morita, Z. Suzuki, H. Hirose, Bull. Chem. Soc. Jpn. 1968,
4
1, 2815; (b) A. B. Baylis, M. E. D. Hillman, Chem. Abstr. 1972, 77,
3
4174q; (c) Reaction of Acrylic Type Compounds with Aldehydes
and Certain Ketones. Ger. Offen. 2,155,113, 1972; For selected
mechanistic studies see: (d) J. S. Hill, N. S. Isaacs, J. Phys. Org.
Chem. 1990, 3, 285. (e) K. E. Price, S. J. Broadwater, H. M. Jung, D.
T. McQuade, Org. Lett. 2005, 7, 147. (f) K. E. Price, S. J.
Broadwater, B. J. Walker, D. T. McQuade, J. Org. Chem. 2005, 70,
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
3
980. (g) V. K. Aggarwal, S. Y. Fulford, G. C. Lloyd-Jones, Angew.
3
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201804271
Int. Ed. 2011, 50, 8412
[
8] O.-a. Rajachan, M. Paul, V. R. Yatham, J.-M. Neudörfl, K.
Kanokmedhakul, S. Kanokmedhakul, A. Berkessel, Tetrahedron
Lett. 2015, 56, 6537
Chem. Int. Ed. 2005, 44, 1706. (h) R. Robiette, V. K. Aggarwal, J.
N. Harvey, J. Am. Chem. Soc. 2007, 129, 15513; For selected
reviews on the MBH and aza-MBH see: (i) E. Ciganek, Org. React.
[
9] (a) Y. Zhang, E. Y.-X Chen, Angew. Chem. Int. Ed. 2012, 51, 2465;
(
1
b) M. Hong, E. Y.-X. Chen, Angew. Chem. Int. Ed. 2014, 53,
1900; see also: (c) W. N. Ottou, D. Bourichon, J. Vignolle, A.-L.
1
997, 51, 201; (j) G. Masson, C. Housseman, J. Zhu, Angew. Chem.
Wirotius, F. Robert, Y. Landais, J.-M. Sotiropoulos, K. Miqueu, D.
Taton, Chem. Eur. J. 2014, 20, 3989
Int. Ed. 2007, 46, 4614; (k) D. Basavaiah, B. S. Reddy, S. S.
Badsara, Chem. Rev. 2010, 110, 5447; (l) Y. Wei, M. Shi, Chem.
Rev. 2013, 113, 6659; (m) Y. C. Fan, O. Kwon, Chem. Commun.
[
[
10] Y. Nakano, D. W. Lupton Angew. Chem. Int. Ed. 2016, 55, 3135
11] Indoxamycin synthesis and reassignment see: (a) O. K. Jekker, E.
M. Carreira Angew. Chem. Int. Ed. 2012, 51, 3474; For necrodol
synthesis see: (b) R. T. Jacobs, G. I. Feutrill, J. Meinwald J. Org.
Chem. 1990, 55, 4051; For medellin A isolation see: (c) X.-Y. Chai,
J.-F. Sun, L.-Y. Tang, X.-W. Yang, Y.-Q. Li, H. Huang, X.-F. Zhou,
B. Yang, Y. Liu, Chem. Pharm. Bull. 2010, 58, 1391; for
vetrispirene reassignment see: (d) J. A. Marshall, N. H.; Andersen, P.
C. Johnson J. Am. Chem. Soc. 1967, 89, 2748, and references
therein; for a review on cyclopentenes see: (e) B. Heasley, Curr.
Org. Chem. 2014, 18, 641, and references therein.
2
013, 49, 11588; (n) H. Pellissier, Tetrahedron 2017, 73, 2831; for
reviews on the RC reaction see: (o) C. E. Aroyan, A. Dermenci, S. J.
Miller, Tetrahedron 2009, 65, 4069; (p) P. Xie, Y. Huang, Eur. J.
Org. Chem. 2013, 28, 6213
[
2] N. Takashina, C. C. Price, J. Am. Chem. Soc. 1962, 84, 489; for
more recent studies and discussions see: (b) C. D. Hall, N. Lowther,
B. R. Tweedy, A. C. Hall, G. Shaw, J. Chem. Soc. Perkin Trans. 2,
1
2
998, 2047; (c) S. N. Khong, Y. S. Tran, O. Kwon, Tetrahedron,
010, 66, 4760, and references therein.
[
[
3] (a) C. Fischer, S. W. Smith, D. A. Powell, G. C. Fu, J. Am. Chem.
Soc. 2006, 128, 1472; For a review discussing the 1,4-addition of
NHCs and subsequent chemistry see: (b) X.-Y. Chen, S. Ye Org.
Biomol. Chem. 2013, 11, 7991
[
[
[
12] See SI for a 3-step sequence with one purification.
13]D. Enders, K. Breuer, J. H. Teles, Helv. Chim. Acta. 1996, 79, 1217.
14] For a discussion on the impact of the N-substituent see: (a) A.
Levens, F. An, M. Breugst, H. Mayr, D. W. Lupton, Org. Lett.
4] The term deoxy-Breslow describes compounds with a formal double
bond to a carbon lacking an oxygen substituent, this include, but is
not limited to, the azolium ylide. For examples of various deoxy-
Breslow intermediates see: (a) D. Enders, K. Breuer, G. Raabe, J.
Runsink, J. H. Teles, J.-P. Melder, K. Ebel, S. Brode, Angew. Chem.
Int. Ed. Engl. 1995, 34, 1021; (b) C. E. I. Knappke, J.-M. Neudörfl,
A. J. von Wangelin, Org. Biomol. Chem. 2010, 8, 1695; (c) C. E. I.
Knappke, A. J. Arduengo (III), H. Jiao, J. Haijun, J.-M. Neudörfl, A.
J. von Wangelin, Synthesis, 2011, 3784; (d) R. N. Reddi, P. K,
Prasad, A. Sudalai, Angew. Chem. Int. Ed. 2015, 54, 14150; (e) M.
Schedler, N. E. Wurz, C. G. Daniliuc, F. Glorius, Org. Lett. 2014,
2
016, 18, 3566, and references therein. For examples of the impact
of the N-substiuent on reaction outcome: (b) M. S. Kerr, J. R. de
Alaniz, T. Rovis, J. Am. Chem. Soc. 2002, 124, 10298; (c) J. R. de
Alaniz, T. Rovis, J. Am. Chem. Soc. 2005, 127, 6284; (d) C. J.
Collett, R. S. Massey, O. R. Maguire, A. S. Batsanov, A. C.
O’Donoghue, A. D. Smith, Chem. Sci. 2013, 4, 1514.
[
15] For NHC generation see SI, for other reactions from our group
which show salt sensitivity see: (a) S. J. Ryan, L. Candish, D. W.
Lupton, J. Am. Chem. Soc. 2011, 133, 4694; (b) A. Levens, A.
Ametovski, D. W. Lupton, Angew. Chem. Int. Ed. 2016, 55, 16136.
16] R. Grigg, M. J. Dorrity, F. Heaney, J. F. Malone, S. Rajviroongit,
V. Sridharan, S. Surendrakumar, Tetrahedron 1991, 47, 8297.
17] For selected examples of NHC mediated reaction involving kinetic
resolution see: (a) D. T. Cohen, C. C. Eichman, E. M. Phillips, E. R.
Zarefsky, K. A. Scheidt, Angew. Chem. Int. Ed. 2012, 51, 7309; (b)
R. C. Johnston, D. T. Cohen, C. C. Eichman, K. A. Scheidt, P. H. Y.
Cheong, Chem. Sci. 2014, 5, 1974; (c) C. G. Goodman, J. S.
Johnson, J. Am. Chem. Soc. 2014, 136, 14698; (d) C. G. Goodman,
M. M. Walker, J. S. Johnson, J. Am. Chem. Soc. 2015, 137, 122; (e)
G. Zhang, S. Yang, X. Zhang, Q. Lin, D. K. Das, J. Liu, X. Fang, J.
Am. Chem. Soc. 2016, 138, 7932; (f) Z. Wu, F. Li, J. Wang, Angew.
Chem. Int. Ed. 2015, 54, 1629; (g) C. Zhao, F. Li, J. Wang, Angew.
Chem., Int. Ed. 2016, 55, 1820; (h) X. Chen, J. Z. M. Fong, J. Xu, C.
Mou, Y. Lu, S. Yang, B.-A. Song, Y. R. Chi, J. Am. Chem. Soc.
[
[
1
6, 3134; (f) A. Bhunia, S. Thorat, R. G. Gonnade, A. T. Biju, Chem.
Commun. 2015, 51, 13690; For studies into the properties of deoxy-
Breslow intermediate see: (g) A. Berkessel, S. Elfert, Adv. Synth.
Catal. 2014, 356, 571; (h) B. Maji, M. Horn, H. Mayr, Angew.
Chem. Int. Ed. 2012, 51, 6231; (i) B. Maji, H. Mayr, Angew. Chem.
Int. Ed. 2012, 51, 10408.
[
5] For selected reviews, on general NHC catalysis see: (a) D. Enders,
O. Niemeier, A. Henseler, Chem. Rev. 2007, 107, 5606; (b) M. N.
Hopkinson, C. Richter, M. Schedler, F. Glorius, Nature 2014, 510,
4
85; (c) D. M. Flanigan, F. Romanov-Michailidis, N. A. White, T.
Rovis, Chem. Rev. 2015, 115, 9307. For homoenolate chemistry see:
d) V. Nair, R. S. Menon, A. T. Biju, C. R. Sinu, R. R. Paul, A. Jose,
(
V. Sreekumar, Chem. Soc. Rev. 2011, 40, 5336; (e) R. S. Menon, A.
T. Biju, V. Nair, Beilstein J. Org. Chem. 2016, 12, 444. For acyl
azolium enolates see: (f) J. Douglas, G. Churchill, A. D. Smith,
Synthesis 2012, 44, 2295. For cascade catalysis see: (g) A.
Grossmann, D. Enders, Angew. Chem. Int. Ed. 2012, 51, 314. For
acyl anion chemistry see: (h) X. Bugaut, F. Glorius, Chem. Soc. Rev.
2
016, 138, 7212; (i) S. Mondal, S. Mukherjee, T. K. Das, R.
Gonnade, A. T. Biju, ACS Catal. 2017, 7, 3995; (j). Dong, M.
Frings, H. Cheng, J. Wen, D. Zhang, G. Raabe, C. Bolm, J. Am.
Chem. Soc. 2016, 138, 2166.
[
[
[
18] For preparation of indene 11 as a racemate see: A. V. Novikov, A.
R. Kennedy, J. D. Rainier, J. Org. Chem. 2003, 68, 993.
19] A. García Martínez, E. Teso Vilar, A. García Fraile, S. De La Moya
Cerero, B. Lora Maroto, Tetrahedron: Asymmetry. 2001, 12, 189.
20] (a) T. Ugai, S. Tanaka, S. Dokawa, J. Pharm. Soc. Jpn. 1943, 63,
2
012, 41, 3511. For applications in total synthesis see: (i) J.
Izquierdo, G. E. Hutson, D. T. Cohen, K. A. Scheidt, Angew. Chem.
Int. Ed. 2012, 51, 11686. For acyl anion free catalysis see: (j) S. J.
Ryan, L. Candish, D. W. Lupton, Chem. Soc. Rev. 2013, 42, 4906.
For acyl azolium catalysis: (k) S. De Sarkar, A. Biswas, R. C.
Samanta, A. Studer, Chem. Eur. J. 2013, 19, 4664; (l) C. Zhang, J.
F. Hooper, D. W. Lupton, ACS Catalysis 2017, 7, 2583. For
reactions with esters see: (m) P. Chauhan, D. Enders, Angew. Chem.
Int. Ed. 2014, 53, 1485. For cooperative catalysis see: (n) M. H.
Wang, K. A. Scheidt, Angew. Chem. Int. Ed. 2016, 55, 14912.
2
96; (b) R. Breslow, J. Am. Chem. Soc. 1958, 80, 3719.
[
6] (a) S.-i. Matsuoka, Y. Ota, A. Washio, A. Katada, K. Ichioka, K.
Takagi, M. Suzuki, Org. Lett. 2011, 13, 3722; (b) S.-i. Matsuoka, Y.
Tochigi, K. Takagi, M. Suzuki, Tetrahedron, 2012, 68, 9836; (c) S.-
i. Matsuoka, S, Namera, A. Washio, K. Takagi, M. Suzuki, Org.
Lett. 2013, 15, 5916; (d) T. Kato, Y. Ota, S.-i. Matsuoka, K. Takagi,
M. Suzuki, J. Org. Chem. 2013, 78, 8739; (e) T. Kato, S.-i.
Matsuoka, M. Suzuki, J. Org. Chem. 2014, 79, 4484; (f) S.-i.
Matsuoka, M. Nakazawa, M. Suzuki, Bull. Chem. Soc. Jpn. 2015,
8
8, 1093. S.-i. Matsuoka, N. Awano, M. Nakazawa, M. Suzuki,
Tetrahedron Lett. 2016, 57, 5707
[
7] A. T. Biju, M. Padmanaban, N. E. Wurz, F. Glorius, Angew. Chem.
4
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201804271
NHC Catalysis
Lydia Scott, Yuji Nakano, Changhe
Zhang and David W. Lupton*
_
_________ Page – Page
Enantioselective N-heterocyclic carbene
catalyzed cyclopentene synthesis via
the azolium ylide.
High five! A highly enantioselective synthesis of cyclopentenes has been
developed by cycloisomerization of electron poor 1,5-dienes. The reaction is viable
with chiral N-heterocyclic carbenes (NHCs), providing 16 cyclopentenes in good
yields (most ≥ 82% yield) and with high enantiopurity (most > 94:6 er). The reaction
proceeds via the azolium ylide, a relatively rare example of a conjugate acceptor
umpolung. Derivatizations and a related kinetic resolution are presented.
5
This article is protected by copyright. All rights reserved.