Highly enantioselective addition of enals to isatin-derived ketimines catalyzed by N-heterocyclic carbenes: Synthesis of spirocyclic γ-lactams

Article abstract of DOI:10.1021/ol302475g

An N-heterocyclic carbene (NHC)-catalyzed annulation reaction of isatin N-Boc ketimines and enals is developed for the synthesis of spirocyclic oxindole-γ-lactams bearing one quaternary chiral center in good yields and excellent stereoselectivities (up to

Full text of DOI:10.1021/ol302475g

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5412–5415
Highly Enantioselective Addition of Enals
to Isatin-Derived Ketimines Catalyzed by
N‑Heterocyclic Carbenes: Synthesis of
Spirocyclic γ‑Lactams
Hui Lv, Bhoopendra Tiwari, Junming Mo, Chong Xing, and Yonggui Robin Chi*
Division of Chemistry & Biological Chemistry, School of Physical & Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
robinchi@ntu.edu.sg
Received September 8, 2012
ABSTRACT
An N-heterocyclic carbene (NHC)-catalyzed annulation reaction of isatin N-Boc ketimines and enals is developed for the synthesis of spirocyclic
oxindole-γ-lactams bearing one quaternary chiral center in good yields and excellent stereoselectivities (up to >20:1 dr and 99% ee).
γ-Lactams are privileged scaffolds found in naturally
occurring and synthetic biologically active compounds.1
The synthesis of γ-lactams has therefore received consider-
able attention. Examples of the representative methods to
γ-lactams include transition metal-catalyzed cyclization,2
intramolecular carbenoid CÀH insertion,3 hypervalent
iodine-promoted intramolecular electrophilic cyclization,4
a Lewis acid-catalyzed imino Mukaiyama-Aldol reaction,5
ring expansion of β-lactams,6 and tandem Aza-Michael
initiated cyclization.7 In recent years, the organocatalytic
approaches have become increasingly attractive for γ-lactam
synthesis. Under N-heterocyclic carbene (NHC) catalysis,8
the addition of enals (via homoenolate intermediates) to
(1) (a) Bergann, R.; Gericke, R. J. Med. Chem. 1990, 33, 492. (b)
Gouliaev, A. H.; Senning, A. Brain Res. Rev. 1994, 19, 180. (c) Duan,
J. W.; Chen, L.; Wasserman, Z. R.; Lu, Z.; Liu, R.-Q.; Covington, M. B.;
Qian, M.; Hardman, K. D.; Magolda, R. L.; Newton, R. C.; Christ,
D. D.; Wexler, R. R.; Decicco, C. P. J. Med. Chem. 2002, 45, 4954. (d)
Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.; Jensen,
P. R.; Fenical, W. Angew. Chem., Int. Ed. 2003, 42, 355. (e) Okazaki, Y.;
Ishizuka, A.; Ishihara, A.; Nishioka, T.; Iwamura, H. J. Org. Chem.
2007, 72, 3830.
(2) (a) Masse, C. E.; Panek, J. S. Chem. Rev. 1995, 95, 1293. (b) Lee,
S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402. (c) Trend, R. M.;
Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. Angew. Chem., Int. Ed.
2003, 42, 2892. (d) Madec, D.; Prestat, G.; Martini, E.; Fristrup, P.; Poli,
G.; Norrby, P. O. Org. Lett. 2005, 7, 995. (e) Craig, D.; Hyland, C. J. T.;
Ward, S. E. Chem. Commun. 2005, 3439. (f) Umemura, S.; McLaughlin,
M.; Micalizio, G. C. Org. Lett. 2009, 11, 5402.
(3) (a) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911. (b)
Yoon, C. H.; Flanigan, D. L.; Chong, B. D.; Jung, K. W. J. Org. Chem.
2002, 67, 6582. (c) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003,
103, 2861. (d) Choi, M. K. W.; Yu, W. Y.; Che, C. M. Org. Lett. 2005, 7,
1081. (e) Zhou, C. Y.; Che, C. M. J. Am. Chem. Soc. 2007, 129, 5828.
(4) Tellitu, I.; Serna, S.; Herrero, M. T.; Moreno, I.; Domınguez, E.;
Martin, R. S. J. Org. Chem. 2007, 72, 1526.
ꢀ
(6) (a) Alcaide, B.; Martın-Cantalejo, Y.; Perez-Castells, J.; Sierra,
M. A.; Monge, A. J. Org. Chem. 1996, 61, 9156. (b) Brabandt, W. V.;
Kimpe, N. D. J. Org. Chem. 2005, 70, 3369. (c) Almendros, P. A.;
Cabrero, G.; Ruiz, M. P. Org. Lett. 2005, 7, 3981. (d) Park, J. H.; Ha,
J. R.; Oh, S. J.; Kim, J. A.; Shin, D. S.; Won, T. J.; Lam, Y. F.; Ahn, C.
Tetrahedron Lett. 2005, 46, 1755. (e) Li, G. Q.; Li, Y.; Dai, L. X.; You,
S. L. Org. Lett. 2007, 9, 3519.
(7) Comesse, S.; Sanselme, M.; Daıch, A. J. Org. Chem. 2008, 73,
5566.
(8) For selected reviews on NHC catalysis: (a) Enders, D.; Niemeier,
O.; Henseler, A. Chem. Rev. 2007, 107, 5606. (b) Marion, N.; Diez-
Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (c)
Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. Rev. 2008, 37, 2691. (d)
Phillips, E. M.; Chan, A.; Scheidt, K. A. Aldrichim. Acta 2009, 42, 55. (e)
Moore, J. L.; Rovis, T. Top. Curr. Chem. 2009, 291, 77. (f) Biju, A. T.;
Glorius, F. Acc. Chem. Res. 2011, 44, 1182. (g) Chiang, P. C.; Bode, J. W.
TCI MAIL 2011, 149, 2. (h) Nair, V.; Menon, R. S.; Biju, A. T.; Sinu,
C. R.; Paul, R. R.; Jose, A.; Sreekumar, V. Chem. Soc. Rev. 2011, 40,
5336. (i) Rong, Z. Q.; Zhang, W.; Yang, G. Q.; You, S. L. Curr. Org.
Chem. 2011, 15, 3077. (j) Vora, H. U.; Rovis, T. Aldrichimica Acta 2011,
44, 3. (k) Chiang, P. C.; Bode, J. W. Science of Synthesis: Asymmetric
Organocatalysis, Vol. 1; Georg Thieme Verlag: Verlag, 2012. (l) Grossman,
A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314. (m) Bugaut, X.;
Glorius, F. Chem. Soc. Rev. 2012, 41, 3511.
(5) Pohmakotr, M.; Yotapan, N.; Tuchinda, P.; Kuhakarn, C.;
Reutrakul, V. J. Org. Chem. 2007, 72, 5016.
r
10.1021/ol302475g
Published on Web 10/12/2012
2012 American Chemical Society

aldehyde-derived imines (aldimines) has provided facile
access to γ-lactams.9 In 2005, Bode and co-workers re-
ported an addition of enals to aldehyde-derived N-sulfony-
limines to afford racemic γ-lactams.9a The enantioselective
synthesis of γ-lactams from aldimines have also been
developed.9b,c Scheidt and co-workers used NHC in com-
bination with a Lewis acid cocatalyst to promote the
annulation of enals with hydrazones to afford γ-lactams
with high enantioselectivities (Scheme 1a).9b Rovis and co-
workers demonstrated highly enantioselective umpolung
reactions of enals with N-aryl R,β-unsaturated aldimines
usinga cooperative Brønsted acidcocatalyst(Scheme 1b).9c
Table 1. Optimization of Reaction Conditionsa
entry
cat.
base
DBU
solvent
yield (%)b
drc
eed
1
A
B
C
D
D
D
D
D
D
D
D
D
D
D
THF
THF
THF
THF
CH2Cl2
Et2O
toluene
THF
THF
THF
THF
THF
THF
THF
2
DBU
<10
39
3
DBU
4:1
99
99
99
99
99
99
95
99
99
99
99
99
4
DBU
83(81)e
41
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
>20:1
20:1
20:1
5
DBU
Scheme 1. Asymmetric Synthesis of γ-Lactams via NHC
Catalysis
6
DBU
59
7
DBU
74
8
KOtBu
KOAc
DIPEA
Et3N
19
9
89
10
11
12
13f
14g
23
24
Cs2CO3
Cs2CO3
Cs2CO3
87(83)e
35
48
a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), cat. (10 mol %),
base (20 mol %), 2 mL solvent, 24 h at rt. b NMR yield (1,3,5-trimethox-
ybenzene as internal standard). c Diastereomeric ratio of 3a, determined
via 1H NMR analysis of unpurified reaction mixtures. Absolute config-
urations of the products were determined via X-ray of 3l (see Figure 1 and
Supporting Information). d Enantiomeric excess of 3a, determined via
chiral-phase HPLC analysis. e Number in the parentheses is the isolated
f
yield based on 1a. In presence 4 A MS. g 5 mol % of D.
_
reactions using ketimine electrophiles are rare.12 Here
we disclose an efficient addition of enals to isatin-derived
ketimines to afford spirocyclic oxindole-γ-lactams with
high diastereo- and enantioselectivities (Scheme 1d; typi-
cally 99% ee and 20:1 dr).13
Our investigation began by using isatin N-Boc ketimine
1a and cinnamaldehyde 2a as model substrates (Table 1).
Imidazolium-based NHC precatalyst A, previously found
effective in enal activations,14 did not work in our reaction
(entry 1). We then evaluated triazolium-based NHC cata-
lysts, and found that achiral precatalyst B could lead to the
formation of desired lactam product 3a with low but
encouraging yield (typically less than 10% yield, entry 2).
We next quickly moved to identify chiral NHC catalysts
While the use of aldimine electrophiles has shown to
be quite successful, a switch to ketone-derived imines
(ketimines) becomes challenging. Compared to aldimines,
ketimines are typically less reactive, and control of enan-
tioselectivities for ketimines are often more difficult. In
2008, Bode and co-workers made an use of cyclic sulfonyl
ketimines for the synthesis of γ-lactams (Scheme 1c).10
Unfortunately, the control of stereoselectivities remained
difficult after considerable efforts (27 catalysts were eval-
uated, the best results are 73% ee and 6:1 dr).11 To the best
of our knowledge, highly enantioselective organocatalytic
(9) (a) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131. (b) Raup,
D. E. A.; Cardinal-David, B.; Holte, D.; Scheidt, K. A. Nat. Chem. 2010,
2, 766. (c) Zhao, X. D.; DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc.
2011, 133, 12466. (d) Nair, V.; Varghese, V.; Babu, B. P.; Sinu, C. R.;
Suresh, E. Org. Biomol. Chem. 2010, 8, 761.
(10) Rommel, M.; Fukuzumi, T.; Bode, J. W. J. Am. Chem. Soc.
2008, 130, 17266.
(13) During the preparation of this manuscript, Jiao and Ye et al.
reported an annulation of enals with isatin N-aryl imines. However, the
best reported ee is 74%, and it is very difficult to get good ee and dr at the
same time. Zhang, B.; Feng, P.; Sun, L. H.; Cui, Y. X.; Ye, S.; Jiao, N.
Chem.;Eur. J. 2012, 18, 9198.
(11) Zheng, P.; Gondo, C. A.; Bode, J. W. Chem. Asian J. 2011, 6,
614.
(12) (a) Yan, W.; Wang, D.; Feng, J.; Li, P.; Zhao, D.; Wang, R. Org.
Lett. 2012, 14, 2512. (b) Hara, N.; Nakamura, S.; Sano, M.; Tamura, R.;
Funahashi, Y.; Shibata, N. Chem.;Eur. J. 2012, 18, 9276.
(14) (a) Sohn, S. S.; Rosen, E. l.; Bode, J. W. J. Am. Chem. Soc. 2004,
126, 14370. (b) Glorius, F.; Burstein, C. Angew. Chem., Int. Ed. 2004, 43,
6205. (c) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem.
Soc. 2006, 128, 8736. (d) Nair, V.; Vellalath, S.; Poonoth, M.; Mohan,
R.; Suresh, E. Org. Lett. 2006, 8, 507.
Org. Lett., Vol. 14, No. 21, 2012
5413

changes on dr and ee (entry 13), suggesting the presence of
trace water in the solvent was beneficial for the catalytic con-
versions. Finally, we chose 10% catalyst D with Cs2CO3 in
THF as an optimal condition to evaluate the substrate scope.
As briefed in Scheme 2, a broad range of isatin-derived
N-Boc ketimines and enals that exhibit diverse electronic
and steric properties could readily participate in this reac-
tion under the optimized condition (Table 1, entry 12). The
N-protecting groups for the amide in the isatin ring had
very mild influence only on the reaction yields (Scheme 2,
3aÀc). Notably, the amide N-unprotected ketimine could
also react well (3d). Substitution patterns on both the
ketimines and enals affected the yields and selectivities of
the products to some extent. In general, ketimines with
electron-donating substituents (3e and 3f) could afford
spiro-γ-lactams in better yields and selectivities compared
to the one with Àwithdrawing substituents (3g). Similar
substitution effects were observed for β-aryl enals (3hÀl).
β-heteroaryl enal also worked well (3m). Significantly,
β-alkyl enals were also tolerated and gave the products in
good to moderate yields and excellent enantioselectivities
albeit, with relatively lower diastereoselectivities (3n and 3o).
Scheme 2. Substrate Scopea
Figure 1. X-ray crystal structure of 3l.
a Reaction conditions: Same as in Table 1, entry 12 at 40 °C (3a, 3b
and 3h at rt). b 1.0 Equiv of enal was added after 12 h.
The resulting N-Boc protected γ-lactam 3 could be easily
deprotected under acidic condition to afford the free γ-
lactam4inhighyield (eq1). Theabsoluteconfigurations of
all the spirocyclic oxindole-γ-lactam products 3 were un-
ambiguously assigned on the basis of X-ray crystallo-
graphic analysis of 3l (Figure 1).16
for enantioselective transformations. Aminoindanol-derived
catalysts (e.g., C and D, Table 1), initially pioneered by
Rovis,15 were found to induce >99% enantioselectiv-
ities (e.g., entries 3 and 4). A switch from NHC precatalyst
Cto D led toexcellent yield and draswell(entry 4). Further
evaluations with regards to solvents and bases indicated
that both THF and toluene (entries 4 and 7) could be used,
and DBU, KOAc and Cs2CO3 (entries 4, 9 and 12) be-
haved well as the bases. It is interesting to note that the
addition of molecular sieve led to deminished yield with no
In summary, we have developed a highly enantioselective
reaction using ketone-derived imines as the electrophiles.
(15) (a) Kerr, M. S.; de-Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc.
2002, 124, 10298. (b) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126,
8877. For the preparation of catalysts C and D, see: (c) Kobayashi, S.;
Kinoshita, T.; Uehara, H.; Sudo, T.; Ryu, I. Org. Lett. 2009, 11, 3934.
Leeper et al. introduced the first aminoalcohol derived triazolium
catalysts, see: (d) Knight, R. L.; Leeper, F. J. J. Chem. Soc., Perkin
Trans. 1 1998, 1891.
(16) CCDC 892219 contains the supplementary X-ray crystallo-
graphic data. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
datarequest/cif.
5414
Org. Lett., Vol. 14, No. 21, 2012

This catalytic protocol allows for a rapid construction of
spirocyclic oxindole-γ-lactams with excellent diastereo-
and enantioselectivities. Further investigation into using
other sterically demanding and stereochemically challen-
ging electrophiles for stereoselective reactions is being
pursued in our laboratory.
(NRF), Singapore Economic Development Board (EDB),
GlaxoSmithKline (GSK) and Nanyang Technological
University (NTU) and Dr. Y. Li and Dr. R. Ganguly
(NTU) for X-ray structure.
Supporting Information Available. Experimental proce-
dures and spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the generous financial
supports from Singapore National Research Foundation
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
5415