Catalytic Enantioselective Synthesis of Lactams through Formal [4+2] Cycloaddition of Imines with Homophthalic Anhydride

Article abstract of DOI:10.1002/anie.201612148

An amide-thiourea compound, operating through a novel ion pairing mechanism, is an efficient organocatalyst for the asymmetric reaction of homophthalic anhydride with imines. N-aryl and N-alkyl imines readily undergo formal [4+2] cycloaddition to provide lactams with high levels of enantio- and diastereoselectivity. The nature of the key chiral ion pair intermediate was elucidated by DFT calculations.

Full text of DOI:10.1002/anie.201612148

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201612148
German Edition: DOI: 10.1002/ange.201612148
Organocatalysis
Catalytic Enantioselective Synthesis of Lactams through Formal [4+2]
Cycloaddition of Imines with Homophthalic Anhydride
Claire L. Jarvis, Jennifer S. Hirschi, Mathew J. Vetticatt,* and Daniel Seidel*
Abstract: An amide-thiourea compound, operating through
a novel ion pairing mechanism, is an efficient organocatalyst
for the asymmetric reaction of homophthalic anhydride with
imines. N-aryl and N-alkyl imines readily undergo formal
[4+2] cycloaddition to provide lactams with high levels of
enantio- and diastereoselectivity. The nature of the key chiral
ion pair intermediate was elucidated by DFT calculations.
Owing to the utility of the lactam products, numerous
combinations and variations of the imine and anhydride
structures have been explored.[6] Significant efforts have been
devoted to rendering these reactions asymmetric.[7] However,
a catalytic enantioselective variant has remained elusive.[8,9]
Here we present an asymmetric ion pairing approach that
provides the first solution to this long-standing challenge.
Different mechanisms have been proposed for the title
reaction, including an iminolysis pathway and a concerted
[4+2] cycloaddition.[6,10] The perhaps most plausible mecha-
nism for the reaction of homophthalic anhydride 1 with
simple imines is shown in Figure 2. Imine and homophthalic
Formal [4+2] cycloadditions of enolizable anhydrides and
imines, first disclosed by Castagnoli, provide a powerful
platform for the preparation of valuable lactams (Figure 1).[1]
Figure 1. Access to pharmacophores through the reaction of enolizable
Figure 2. Proposed mechanism and ion pairing concept for enantiose-
anhydrides and imines.
lective catalysis.
While early reports focused on succinic anhydride and acyclic
imines, this chemistry was later expanded by Cushman and
Haimova to include homophthalic anhydrides (e.g., 1) and
dihydroisoquinolines,[2] thereby enabling the synthesis of
a number of tetrahydroprotoberberine alkaloids such as
(+)-canadine.[3] Small molecules with the same structural
motif have been investigated as antimalarials (e.g.,
(+)-SJ733)[4] and as anti-cancer agents, among others.[5]
anhydride 1 are thought to form the hydrogen-bonded
ion pair 2 in equilibrium. Ion pair 2, which depending on
the degree of proton transfer may also be considered as
a complex of the imine with the enol form of the anhydride,
undergoes a stereodetermining Mannich addition. The result-
ing intermediate 3 then engages in intramolecular aminolysis
of the anhydride to form the lactam product. This scenario
is supported by recent computational studies on closely
related reactions of imines with a-cyanosuccinic anhydride,[11]
and is consistent with the relatively high acidity of 1
(pKa = 8.15).[12]
[*] C. L. Jarvis, Prof. Dr. D. Seidel
Department of Chemistry and Chemical Biology, Rutgers
The State University of New Jersey
Piscataway, NJ 08854 (USA)
E-mail: seidel@rutchem.rutgers.edu
Homepage: http://seidel-group.com/
Since classic modes of substrate activation appeared
unsuitable, we conceived of a new anion binding/ion pairing
approach in order to render this reaction catalytic enantio-
selective (Figure 2).[13–15] Our concept is based on the notion
Dr. J. S. Hirschi, Prof. Dr. M. J. Vetticatt
Department of Chemistry, Binghamton University
Binghamton, NY 13902 (USA)
that
a
hydrogen-bonding (HB)[16] catalyst, which itself
remains neutral throughout the reaction, can confer enantio-
selectivity by simultaneously interacting with an anionic
nucleophile and a cationic electrophile. Specifically, we
envisioned that the interaction of a chiral thiourea catalyst
E-mail: vetticatt@binghamton.edu
Homepage: http://www.vetticattgroup.com/
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201612148.
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with homophthalic anhydride 1 would result in increased
substrate acidity via complex 4. This in turn would lower the
barrier for ion pair formation, thereby enabling the gener-
ation of chiral ion pair 5. Viewed from a different perspective,
the presence of an anion receptor is expected to increase the
equilibrium concentration of any ion pair intermediate.
Interaction of the iminium ion in 5 with a secondary hydro-
gen-bonding acceptor site on the catalyst would contribute to
the creation of a well-defined ion pair that is set up for an
enantioselective Mannich addition step.
We initiated our survey with benzaldehyde-derived N-
PMP imine and 1 (Table 1). In the absence of any catalyst,
product 6a was formed in 33% yield after 18 h (entry 1,
reaction incomplete). The Nagasawa catalyst 7a,[17] previously
shown to be an efficient anion-binding catalyst,[14b] provided
product 6a in good yield, excellent d.r., and moderate ee
(entry 2). Amide-thiourea catalyst 7b[14c] provided significant
improvements with regard to ee (entry 3). Unexpectedly,
application of Brønsted acid catalyst 7c[14g] resulted in further
improvements (entry 4). However, the carboxylic acid func-
tionality of 7c apparently plays no role in the catalytic
process, since the corresponding esters performed equally
well or better (entries 5–7). The most electron-deficient ester
catalyst 7 f gave the most favorable result (entry 7). This
prompted us to evaluate other electron-withdrawing groups
ortho to the amide group, in the absence or presence of other
electron-withdrawing groups (entries 8–13). Amide-thiourea
7h emerged as the superior catalyst with regard to selectivity
and activity, providing product 6a in excellent yield and d.r.,
and 88% ee following a reaction time of just one hour
(entry 9). Interestingly, all three regioisomeric catalysts (7b,
7k and 7l) were significantly less active and selective. As
anticipated, bifunctional catalysts containing basic sites
capable of deprotonating 1, as exemplified by the Takemoto
catalyst (7m),[18] provided poor results (entry 14). Replace-
ment of the catalyst amide moiety for sulfonamide proved
unfruitful (compare catalysts 7b and 7n, entries 3 and 15).
Finally, product 6a was obtained with 90% ee in a reaction
conducted at À408C (entry 16). A range of other solvents and
parameters were evaluated but did not result in any further
improvements.[19]
Table 1: Optimization of the reaction conditions.[a]
The scope of the reaction was found to be relatively broad
(Scheme 1). Different N-aryl groups on the imine were well-
tolerated (products 6b–6e). However, an N-benzylimine
provided lower ee values and poor diastereoselectivity (6 f).
On the other hand, product 6g, which has an N-tBu group,
was formed with excellent ee. Imines derived from a range of
aromatic aldehydes, bearing electronically diverse substitu-
ents in different ring positions, were readily accommodated.
Imines derived from heterocyclic aldehydes also performed
well, although a slight reduction in ee was noted for furan-
containing product 6o. An improved result could be obtained
upon switching the PMP group to tBu (product 6p). An a,b-
unsaturated imine species was also tested under these
reaction conditions to provide product 6q in excellent ee.
Product 6q was formed in competition with the correspond-
ing 3,4-cycloaddition product[20] (not shown), which was
obtained in racemic form.[19] Imines derived from aliphatic
aldehydes also participated in the title reaction. With the
exception of N-benzyl product 6 f, all of the lactams were
obtained predominantly as the kinetic cis products. While the
diastereoselectivity was often found to be high, lower d.r.
values may be due to epimerization of the initially formed
products to their corresponding trans isomers, which is a well-
known process.[6a]
Entry
Catalyst
t [h]
Yield [%]
d.r.
ee [%]
1
2
3
4
5
6
7
8
–
18
15
21
22
29
42
20
3
33
72
87
70
73
78
87
69
94
81
84
84
58
46
48
85
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
10:1
>19:1
>19:1
10:1
>19:1
>19:1
6:1
–
7a
7b
7c
7d
7e
7 f
7g
7h
7i
7j
7k
7l
7m
7n
7h
35
70
74
73
81
81
80
88
70
71
82
64
17
59
90
The lactam products could be readily modified. Removal
of the N-tBu group in 6g resulted in the formation of product
8 with excellent ee [Eq. (1)].[21] Importantly, no epimerization
was noted under these conditions. Epimerization of 8 to 9 was
9
1
10
11
12
13
14
15
16[b]
16
20
20
18
120
19
41
>19:1
>19:1
[a] Yields are given for chromatographically purified compounds. The ee
values were determined by HPLC analysis; see the Supporting Infor-
mation for details. [b] The reaction was performed at À408C.
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To obtain insight into the mechanism of the reaction, we
studied the dependence of product ee on catalyst ee. No
nonlinear effects were noted, which is suggestive of a rate-
limiting step that involves only one catalyst unit.[19] The
organization of the proposed rate- and stereo-determining
Mannich addition transition state (Figure 2) for the reaction
of 1 and N-phenyl benzimine catalyzed by 7h was investigated
using B3LYP-GD3[22]/6-311 + G** PCM[23] (diethyl ether)//
B3LYP/6-31G* calculations as implemented by Gaus-
sian09.[24] Consistent with our hypothesis, the reacting ion
pair benefits from bifunctional stabilization through H-
bonding interactions with the catalyst structure. Analysis of
the lowest-energy transition structure leading to the major
(S,S) enantiomer of product 6d (SS-TSMannich, Figure 3)
Figure 3. Lowest-energy transition structures leading to the major and
minor enantiomers of product 6d. All distances are in ꢀ and some
hydrogen atoms have been removed for clarity. C gray, O red, N blue,
S yellow, F green, H cyan.
À
reveals the following key characteristics: 1) C C bond
formation is relatively early (2.30 ꢀ); 2) the enolate of 1 is
bound to the catalyst through two strong H-bonding inter-
actions with the thiourea NH groups (1.88 ꢀ and 2.20 ꢀ); and
3) protonated imine is directed to the re face of this catalyst-
bound enolate through a strong H-bonding interaction with
the carbonyl oxygen of the amide moiety of the catalyst
(1.91 ꢀ). The corresponding transition structure leading to
the minor (R,R) enantiomer (RR-TSMannich, Figure 3) benefits
from very similar H-bonding interactions but is higher in
energy (DDG° = 2.0 kcalmolÀ1) than SS-TSMannich. This energy
difference is consistent with the 90% experimental ee
obtained for this reaction. We are currently investigating
the complete free-energy profile and exact origin of the
enantio- and diastereoselectivity of this reaction using
experimental and computational approaches. The results of
these investigations will be reported in due course.
Scheme 1. Substrate scope.
achieved in good yield upon exposure to DBU, albeit with
some loss in ee [Eq. (2), unoptimized]. Under similar
conditions, epimerization of 6a provided 10 [Eq. (3)].
In summary, we have developed the first catalytic
enantioselective reactions of an enolizable anhydride with
a range of simple imines. This formal [4+2] cycloaddition
reaction represents a rare case of asymmetric ion pairing
catalysis in which a neutral catalyst simultaneously interacts
with an anionic nucleophile and a cationic electrophile that
subsequently combine without generating byproducts.
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[10] a) M. Cushman, E. J. Madaj, J. Org. Chem. 1987, 52, 907; b) J.
Kaneti, S. M. Bakalova, I. G. Pojarlieff, J. Org. Chem. 2003, 68,
6824.
[11] a) O. Pattawong, D. Q. Tan, J. C. Fettinger, J. T. Shaw, P. H.-Y.
Cheong, Org. Lett. 2013, 15, 5130; b) M. J. Di Maso, K. M.
Snyder, F. De Souza Fernandes, O. Pattawong, D. Q. Tan, J. C.
Fettinger, P. H.-Y. Cheong, J. T. Shaw, Chem. Eur. J. 2016, 22,
4794.
Acknowledgements
This material is based upon work supported by the National
Science Foundation under CHE -1565599. We thank Dr. Tom
Emge (Rutgers University) for crystallographic analysis.
[12] N. Mofaddel, N. Bar, D. Villemin, P. L. Desbꢈne, Anal. Bioanal.
Chem. 2004, 380, 664.
Conflict of interest
[13] Selected reviews on anion binding/ion pairing catalysis: a) J.
Lacour, V. Hebbe-Viton, Chem. Soc. Rev. 2003, 32, 373; b) J.
Lacour, D. Moraleda, Chem. Commun. 2009, 7073; c) Z. Zhang,
P. R. Schreiner, Chem. Soc. Rev. 2009, 38, 1187; d) S. Beckendorf,
S. Asmus, O. G. MancheÇo, ChemCatChem 2012, 4, 926; e) E. P.
ꢉvila, G. W. Amarante, ChemCatChem 2012, 4, 1713; f) R. J.
Phipps, G. L. Hamilton, F. D. Toste, Nat. Chem. 2012, 4, 603;
g) P. A. Woods, A. D. Smith, Supramolecular Chemistry: From
Molecules to Nanomaterials 2012, 4, 1383; h) J.-F. Briꢈre, S.
Oudeyer, V. Dalla, V. Levacher, Chem. Soc. Rev. 2012, 41, 1696;
i) M. Mahlau, B. List, Angew. Chem. Int. Ed. 2013, 52, 518;
Angew. Chem. 2013, 125, 540; j) K. Brak, E. N. Jacobsen, Angew.
Chem. Int. Ed. 2013, 52, 534; Angew. Chem. 2013, 125, 558; k) D.
Seidel, Synlett 2014, 783; l) N. H. Evans, P. D. Beer, Angew.
Chem. Int. Ed. 2014, 53, 11716; Angew. Chem. 2014, 126, 11908;
m) N. Busschaert, C. Caltagirone, W. Van Rossom, P. A. Gale,
Chem. Rev. 2015, 115, 8038.
The authors declare no conflict of interest.
Keywords: anion binding · asymmetric catalysis ·
hydrogen bonding · ion pairing · organocatalysis
[1] a) N. Castagnoli, J. Org. Chem. 1969, 34, 3187; b) N. Castagnoli,
M. Cushman, J. Org. Chem. 1971, 36, 3404.
[2] a) M. Cushman, J. Gentry, F. W. Dekow, J. Org. Chem. 1977, 42,
1111; b) M. A. Haimova, N. M. Mollov, S. C. Ivanova, A. I.
Dimitrova, V. I. Ognyanov, Tetrahedron 1977, 33, 331.
[3] a) K. Iwasa, Y. P. Gupta, M. Cushman, J. Org. Chem. 1981, 46,
4744; b) K. Iwasa, Y. P. Gupta, M. Cushman, Tetrahedron Lett.
1981, 22, 2333.
[14] Selected examples from our group: a) M. Ganesh, D. Seidel, J.
Am. Chem. Soc. 2008, 130, 16464; b) C. K. De, E. G. Klauber, D.
Seidel, J. Am. Chem. Soc. 2009, 131, 17060; c) E. G. Klauber,
C. K. De, T. K. Shah, D. Seidel, J. Am. Chem. Soc. 2010, 132,
13624; d) C. K. De, D. Seidel, J. Am. Chem. Soc. 2011, 133,
14538; e) C. K. De, N. Mittal, D. Seidel, J. Am. Chem. Soc. 2011,
133, 16802; f) N. Mittal, D. X. Sun, D. Seidel, Org. Lett. 2012, 14,
3084; g) C. Min, N. Mittal, D. X. Sun, D. Seidel, Angew. Chem.
Int. Ed. 2013, 52, 14084; Angew. Chem. 2013, 125, 14334; h) N.
Mittal, D. X. Sun, D. Seidel, Org. Lett. 2014, 16, 1012; i) C. Min,
C.-T. Lin, D. Seidel, Angew. Chem. Int. Ed. 2015, 54, 6608;
Angew. Chem. 2015, 127, 6708; j) N. Mittal, K. M. Lippert, C. K.
De, E. G. Klauber, T. J. Emge, P. R. Schreiner, D. Seidel, J. Am.
Chem. Soc. 2015, 137, 5748; k) C. Zhao, S. B. Chen, D. Seidel, J.
Am. Chem. Soc. 2016, 138, 9053.
[4] a) M. B. Jimꢁnez-Dꢂaz, D. Ebert, Y. Salinas, A. Pradhan, A. M.
Lehane, M.-E. Myrand-Lapierre, K. G. OꢃLoughlin, D. M.
Shackleford, M. Justino de Almeida, A. K. Carrillo et al., Proc.
Natl. Acad. Sci. USA 2014, 111, E5455; b) D. M. Floyd, P. Stein,
Z. Wang, J. Liu, S. Castro, J. A. Clark, M. Connelly, F. Zhu, G.
Holbrook, A. Matheny, M. S. Sigal, J. Min, R. Dhinakaran, S.
Krishnan, S. Bashyum, S. Knapp, R. K. Guy, J. Med. Chem. 2016,
59, 7950.
[5] a) M. A. Cinelli, P. V. N. Reddy, P.-C. Lv, J.-H. Liang, L. Chen, K.
Agama, Y. Pommier, R. B. van Breemen, M. Cushman, J. Med.
Chem. 2012, 55, 10844; b) T. X. Nguyen, M. Abdelmalak, C.
Marchand, K. Agama, Y. Pommier, M. Cushman, J. Med. Chem.
2015, 58, 3188; c) M. Chatterjee, A. Hartung, U. Holzgrabe, E.
Mueller, U. Peinz, C. Sotriffer, D. Zilian (Julius-Maximilians-
Universitꢄt Wꢅrzburg, Germany), WO2015185114A1, 2015,
p. 38.
[15] Examples of anion-binding catalysis: a) M. Kotke, P. R.
Schreiner, Tetrahedron 2006, 62, 434; b) M. Kotke, P. R.
Schreiner, Synthesis 2007, 779; c) I. T. Raheem, P. S. Thiara,
E. A. Peterson, E. N. Jacobsen, J. Am. Chem. Soc. 2007, 129,
13404; d) S. J. Zuend, E. N. Jacobsen, J. Am. Chem. Soc. 2009,
131, 15358; e) R. S. Klausen, E. N. Jacobsen, Org. Lett. 2009, 11,
887; f) R. R. Knowles, S. Lin, E. N. Jacobsen, J. Am. Chem. Soc.
2010, 132, 5030; g) A. R. Brown, W.-H. Kuo, E. N. Jacobsen, J.
Am. Chem. Soc. 2010, 132, 9286; h) R. P. Singh, B. M. Foxman, L.
Deng, J. Am. Chem. Soc. 2010, 132, 9558; i) R. R. Knowles, E. N.
Jacobsen, Proc. Natl. Acad. Sci. USA 2010, 107, 20678; j) H. Xu,
S. J. Zuend, M. G. Woll, Y. Tao, E. N. Jacobsen, Science 2010,
327, 986; k) J. A. Birrell, J.-N. Desrosiers, E. N. Jacobsen, J. Am.
Chem. Soc. 2011, 133, 13872; l) Z. Zhang, K. M. Lippert, H.
Hausmann, M. Kotke, P. R. Schreiner, J. Org. Chem. 2011, 76,
9764; m) S. Lin, E. N. Jacobsen, Nat. Chem. 2012, 4, 817; n) Y.
Wang, T.-Y. Yu, H.-B. Zhang, Y.-C. Luo, P.-F. Xu, Angew. Chem.
Int. Ed. 2012, 51, 12339; Angew. Chem. 2012, 124, 12505;
o) A. G. Schafer, J. M. Wieting, T. J. Fisher, A. E. Mattson,
Angew. Chem. Int. Ed. 2013, 52, 11321; Angew. Chem. 2013, 125,
11531; p) A. Borovika, P.-I. Tang, S. Klapman, P. Nagorny,
Angew. Chem. Int. Ed. 2013, 52, 13424; Angew. Chem. 2013, 125,
13666; q) V. Kumar, S. Mukherjee, Chem. Commun. 2013, 49,
11203; r) Q. Zhao, J. Wen, R. Tan, K. Huang, P. Metola, R. Wang,
E. V. Anslyn, X. Zhang, Angew. Chem. Int. Ed. 2014, 53, 8467;
[6] a) M. Gonzꢆlez-Lꢇpez, J. T. Shaw, Chem. Rev. 2009, 109, 164;
b) M. Krasavin, D. Dar’in, Tetrahedron Lett. 2016, 57, 1635.
[7] Examples of asymmetric variants (through the use of enan-
tioenriched starting materials, chiral auxiliaries, or resolutions):
a) R. D. Clark, M. Souchet, Tetrahedron Lett. 1990, 31, 193;
b) M. Cushman, J. K. Chen, J. Org. Chem. 1987, 52, 1517; c) Y.
Vara, T. Bello, E. Aldaba, A. Arrieta, J. L. Pizarro, M. I.
Arriortua, X. Lopez, F. P. Cossio, Org. Lett. 2008, 10, 4759;
d) D. Q. Tan, A. Younai, O. Pattawong, J. C. Fettinger, P. H.-Y.
Cheong, J. T. Shaw, Org. Lett. 2013, 15, 5126; e) J. Liu, Z. Wang,
A. Levin, T. J. Emge, P. R. Rablen, D. M. Floyd, S. Knapp, J. Org.
Chem. 2014, 79, 7593. See also reference [3].
[8] A moderately enantioselective and mechanistically distinct
variant with N-sulfonylimines has recently been reported: S. A.
Cronin, A. Gutierrez Collar, S. Gundala, C. Cornaggia, E.
Torrente, F. Manoni, A. Botte, B. Twamley, S. J. Connon, Org.
Biomol. Chem. 2016, 14, 6955.
[9] Mechanistically distinct enantioselective catalytic reactions of
aldehydes and ketones with enolizable anhydrides: a) C. Cor-
naggia, F. Manoni, E. Torrente, S. Tallon, S. J. Connon, Org. Lett.
2012, 14, 1850; b) F. Manoni, C. Cornaggia, J. Murray, S. Tallon,
S. J. Connon, Chem. Commun. 2012, 48, 6502; c) C. Cornaggia, S.
Gundala, F. Manoni, N. Gopalasetty, S. J. Connon, Org. Biomol.
Chem. 2016, 14, 3040.
4
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Angewandte
Communications
Chemie
Angew. Chem. 2014, 126, 8607; s) Y. Gu, Y. Wang, T.-Y. Yu, Y.-
Chem. 2011, 2209; j) D. Parmar, E. Sugiono, S. Raja, M.
M. Liang, P.-F. Xu, Angew. Chem. Int. Ed. 2014, 53, 14128;
Angew. Chem. 2014, 126, 14352; t) M. Zurro, S. Asmus, S.
Beckendorf, C. Mꢅck-Lichtenfeld, O. G. MancheÇo, J. Am.
Chem. Soc. 2014, 136, 13999; u) O. Garcꢂa MancheÇo, S. Asmus,
M. Zurro, T. Fischer, Angew. Chem. Int. Ed. 2015, 54, 8823;
Angew. Chem. 2015, 127, 8947; v) J. M. Wieting, T. J. Fisher,
A. G. Schafer, M. D. Visco, J. C. Gallucci, A. E. Mattson, Eur. J.
Org. Chem. 2015, 525; w) J. Wen, R. Tan, S. Liu, Q. Zhao, X.
Zhang, Chem. Sci. 2016, 7, 3047; x) D. D. Ford, D. Lehnherr,
C. R. Kennedy, E. N. Jacobsen, J. Am. Chem. Soc. 2016, 138,
7860; y) D. D. Ford, D. Lehnherr, C. R. Kennedy, E. N. Jacobsen,
ACS Catal. 2016, 6, 4616.
Rueping, Chem. Rev. 2014, 114, 9047; k) T. J. Auvil, A. G.
Schafer, A. E. Mattson, Eur. J. Org. Chem. 2014, 2633.
[17] a) Y. Sohtome, A. Tanatani, Y. Hashimoto, K. Nagasawa,
Tetrahedron Lett. 2004, 45, 5589; b) Y. Sohtome, N. Takemura,
R. Takagi, Y. Hashimoto, K. Nagasawa, Tetrahedron 2008, 64,
9423.
[18] T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125,
12672.
[19] See the Supporting Information for details.
[20] A. Georgieva, E. Stanoeva, S. Spassov, M. Haimova, N.
De Kimpe, M. Boelens, M. Keppens, A. Kemme, A. Mishnev,
Tetrahedron 1995, 51, 6099.
[16] Selected reviews on hydrogen-bonding catalysis: a) P. R.
Schreiner, Chem. Soc. Rev. 2003, 32, 289; b) Y. Takemoto, Org.
Biomol. Chem. 2005, 3, 4299; c) M. S. Taylor, E. N. Jacobsen,
Angew. Chem. Int. Ed. 2006, 45, 1520; Angew. Chem. 2006, 118,
1550; d) S. J. Connon, Chem. Eur. J. 2006, 12, 5418; e) A. G.
Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713; f) T.
Akiyama, Chem. Rev. 2007, 107, 5744; g) X. Yu, W. Wang,
Chem. Asian J. 2008, 3, 516; h) P. M. Pihko, Hydrogen Bonding
in Organic Synthesis, Wiley-VCH, Weinheim, 2009; i) S.
Schenker, A. Zamfir, M. Freund, S. B. Tsogoeva, Eur. J. Org.
[21] R. Fu, B. Zhao, Y. Shi, J. Org. Chem. 2009, 74, 7577.
[22] a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648; b) S. Grimme, J.
Antony, S. Ehrlich, H. Krieg, J. Chem. Phys. 2010, 132, 154104.
[23] J. Tomasi, B. Mennucci, R. Cammi, Chem. Rev. 2005, 105, 2999.
[24] M. J. Frisch et al. Gaussian09, revisionD.01; Gaussian, Inc.:
Wallingford, CT, 2013.
Manuscript received: December 14, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Organocatalysis
C. L. Jarvis, J. S. Hirschi, M. J. Vetticatt,*
D. Seidel*
&&& — &&&
Catalytic Enantioselective Synthesis of
Lactams through Formal [4+2]
Cycloaddition of Imines with
Homophthalic Anhydride
Get it together: An amide-thiourea com-
pound, operating through a novel ion
pairing mechanism, is an efficient orga-
nocatalyst for the asymmetric reaction of
homophthalic anhydride with imines. N-
aryl and N-alkyl imines readily undergo
the formal [4+2] cycloaddition to provide
lactams with high levels of enantio- and
diastereoselectivity. The nature of the key
chiral ion pair intermediate was eluci-
dated by DFT calculations.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!