Asymmetric access to the smallest enolate intermediate via organocatalytic activation of acetic ester

Article abstract of DOI:10.1021/ol402877n

An NHC-catalyzed activation of acetic esters to afford enolate intermediates is disclosed. The catalytically generated triazolium enolate intermediates serve as two-carbon nucleophiles that undergo highly enantioselective reactions with enones and α,β-uns

Full text of DOI:10.1021/ol402877n

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Asymmetric Access to the Smallest
Enolate Intermediate via Organocatalytic
Activation of Acetic Ester
Shaojin Chen,† Lin Hao,† Yuexia Zhang, Bhoopendra Tiwari, 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 October 6, 2013
ABSTRACT
An NHC-catalyzed activation of acetic esters to afford enolate intermediates is disclosed. The catalytically generated triazolium enolate
intermediates serve as two-carbon nucleophiles that undergo highly enantioselective reactions with enones and R,β-unsaturated imines to give
R-unsubstituted δ-lactones and lactams, respectively.
The asymmetric catalytic generation of chiral enolates
and their equivalents via metal1 or organic molecule-based
catalysts2 is a basic strategy in organic synthesis. Chiral
enolate equivalents from acetic esters and their derivatives,
the smallest enolate intermediates, have attracted much
attention as two-carbon nucleophilic building blocks in
synthesis. Under organic catalysis, several approaches
have been developed for the catalytic generation of chiral
enolate intermediates from acetaldehyde and its derivatives
(Scheme 1). With a chiral amine catalyst, the List, Hayashi,
and Maruoka groups reported the use of acetaldehyde as
two-carbon building blocks via enamine intermediates
(Scheme 1a).3 With cinchona alkaloid catalysts, the groups
of Wynberg and Nelson successively reported the activation
of acetyl chloride to generate enolate intermediates that
underwent reactions with aldehydes to afford β-lactones
(Scheme 1b).4 N-Heterocyclic carbenes (NHC)5ꢀ8 have
also been utilized in the catalytic generation of enolate
from acetaldehyde derivatives. Bode and co-workers used
† These authors contributed equally.
(1) For selected examples, see: (a) Thorhauge, J.; Johannsen, M.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 1998, 37, 2404. (b) Yoshikawa,
N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem.
Soc. 1999, 121, 4168. (c) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000,
122, 12003. (d) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem.
Soc. 2002, 124, 11240. (e) Evans, D. A.; Downey, C. W.; Hubbs, J. L.
J. Am. Chem. Soc. 2003, 125, 8706.
(4) (a) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104,
166. (b) Wynberg, H.; Staring, E. G. J. J. Org. Chem. 1985, 50, 1977. (c)
Zhu, C.; Shen, X.; Nelson, S. G. J. Am. Chem. Soc. 2004, 126, 5352. (d)
Xu, X.; Wang, K.; Nelson, S. G. J. Am. Chem. Soc. 2007, 129, 11690.
(5) R,β-Unsaturated enals are not suitable substrates for the genera-
tion of R-unsubstituted enolates (e.g., acetic enolates). (a) He, M.;
Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418. (b)
Burstein, C.; Tschan, S.; Xie, X. L.; Glorius, F. Synthesis 2006, 2418. (c)
Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew. Chem.,
Int. Ed. 2007, 46, 3107. (d) Wadamoto, M.; Phillips, E. M.; Reynolds,
T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 10098. (e) Li, Y.;
Wang, X. Q.; Zheng, C.; You, S. L. Chem. Commun. 2009, 5823. (f)
Kaeobamrung, J.; Kozlowski, M. C.; Bode, J. W. Proc. Natl. Acad. Sci.
U.S.A. 2010, 107, 20661. (g) Fang, X. Q.; Chen, X. K.; Chi, Y. R. Org.
Lett. 2011, 13, 4708. (h) Fu, Z.; Sun, H.; Chen, S.; Tiwari, B.; Li, G.; Chi,
Y. R. Chem. Commun. 2013, 49, 261.
(2) For selected examples, see: (a) List, B.; Lerner, R. A.; Barbas,
C. F., III. J. Am. Chem. Soc. 2000, 122, 2395. (b) Sakthivel, K.; Notz, W.;
Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260. (c)
Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
6798. (d) Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790. (e) Hayashi, Y.;
Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji, M.; Sakai, K. Angew.
Chem., Int. Ed. 2003, 42, 3677. (f) Tang, Z.; Jiang, F.; Yu, L.; Cui, X.;
Gong, L.; Mi, A.; Jiang, Y.; Wu, Y. J. Am. Chem. Soc. 2003, 125, 5262.
€
(g) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 44,
ꢀ
861. (h) Rueping, M.; Sunden, H.; Hubener, L.; Sugiono, E. Chem.
Commun. 2012, 48, 2201.
(3) (a) Yang, J.; Chandler, C.; Stadler, M.; Kampen, D.; List, B.
ꢀ ^
Nature 2008, 452, 453. (b) Garcıa-Garcıa, P.; Ladepeche, A.; Halder, R.;
List, B. Angew. Chem., Int. Ed. 2008, 47, 4719. (c) Hayashi, Y.; Itoh, T.;
Aratake, S.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47, 2082. (d)
Hayashi, Y.; Itoh, T.; Ohkubo, M.; Ishikawa, H. Angew. Chem., Int. Ed.
2008, 47, 4722. (e) Kano, T.; Yamaguchi, Y.; Maruoka, K. Angew.
Chem., Int. Ed. 2009, 48, 1838.
(6) Lupton has studied NHC-catalyzed activation of enol ether to
generate substituted enol as a nucleophile; see: (a) Ryan, S. J.; Candish,
L.; Lupton, D. W. J. Am. Chem. Soc. 2009, 131, 14176. (b) Candish, L.;
Lupton, D. W. Org. Lett. 2010, 11, 4836.
r
10.1021/ol402877n
XXXX American Chemical Society

the application side, acetic esters can be an ideal choice as
they are stable and readily available.
Scheme 1. Generation of Two-Carbon Enolate Intermediates
Table 1. Optimization of NHC Catalyzed Annulation of Acetic
Ester with Chalconea
yield
(%)b
ee
(%)c
entry
condition
1
2
3
4
5
6
7
30 mol % A, 2.0 equiv of DBU, THF
30 mol % A, 2.0 equiv of DBU, CH2Cl2
30 mol % A, 2.0 equiv of DBU, CH3CN
30 mol % A, 2.0 equiv of Cs2CO3, CH3CN
30 mol % A, 2.0 equiv of Et3N, CH3CN
20 mol % A, 1.5 equiv of DBU, CH3CN
10 mol % A, 2.0 equiv of DBU, CH3CN
69
94
99
96
98
n.d.
98
96
80
99
30
trace
92d
88
R-chloroacetaldehyde bisulfite adducts as enolate precur-
sors for enantioselective reactions with enones to afford
lactones.9 Scheidt reported an internal redox transforma-
tion of R-aryloxyacetaldehyde to form an enolate inter-
mediate for Mannich reactions.10
a Reaction conditions: 1a (0.10 mmol), 2a (0.05 mmol), A(10ꢀ30 mol %),
base, solvent (0.5 mL), rt. b Yield of 3a was estimated via 1H NMR
analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as
an internal standard. c The ee of 3a was determined via chiral phase
HPLC analysis. d Isolated yield after SiO2 column chromatography.
We are interested in the use of esters as substrates as they
are stable, readily available, and inexpensive. Built on our
success with the usual and unusual activationsofesters and
R,β-unsaturated esters,11 here we report that an acetic ester
can be a suitable precursor for a two-carbon enolate
intermediate (Scheme 1c). As illustrated in Scheme 1c, an
acetic ester reacts with an NHC catalyst to produce inter-
mediate I, which on deprotonation generates enolate
intermediate II. This catalytically generated enolate II
undergoes enantioselective reaction with various electro-
philes (see the Supporting Information for detailed
mechanism). Esters are challenging substrates in part
because of the lower acidity of the R-CH, when compared
to the corresponding acetaldehyde and acetyl chloride. On
We started by using acetic ester 1a, prepared from acetic
acid and 4-nitrophenol,11a as the two-carbon enolate pre-
cursor. When chalcone 2a was the electrophile, aminoin-
danol-derived catalyst A12 was found as an effective
catalyst to give product 3a in 69% yield and 94% ee in
THF (Table 1, entry 1). CH2Cl2 was also a suitable solvent
while CH3CN performed the best (entries 2ꢀ3). The use of
Cs2CO3 gave a much lower yield (entry 4), and Et3N was
not an effective base (entry 5). We then found that the use
of 20 or 10 mol % of NHC precatalyst A was sufficient to
give good yields and excellent ee’s (entries 6ꢀ7).
(7) NHC-catalyzed activation of R-chloroaldehydes: (a) Reynolds,
N. T.; deAlaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 9518. (b)
Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 16406. (c) He,
M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088. (d) Vora,
H. U.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 2860. (e) Yang, L.; Wang,
F.; Chua, P. J.; Lv, Y.; Zhong, L.; Zhong, G. Org. Lett. 2012, 14, 2894. (f)
Jian, T. Y.; Sun, L. H.; Ye, S. Chem. Commun. 2012, 48, 10907.
(8) NHC-catalyzed activation of ketenes: (a) Duguet, N.; Campbell,
C. D.; Slawin, A. M. Z.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1108.
(b) Huang, X. L.; He, L.; Shao, P. L.; Ye, S. Angew. Chem., Int. Ed. 2009,
48, 192. (c) Jian, T. Y.; He, L.; Tang, C.; Ye, S. Angew. Chem., Int. Ed.
2011, 50, 9104. For examples of acid activation: (d) Belmessieri, D.;
Morrill, L. C.; Simal, C.; Slawin, A. M. Z.; Smith, A. D. J. Am. Chem.
Soc. 2011, 133, 2714. (e) Morrill, L. C.; Lebl, T.; Slawin, A. M. Z.; Smith,
A. D. Chem. Sci. 2012, 3, 2088. (f) Simal, C.; Lebl, T.; Slawin, A. M. Z.;
Smith, A. D. Angew. Chem., Int. Ed. 2012, 51, 3653. (g) Morrill, L. C.;
Douglas, J.; Lebl, T.; Slawin, A. M. Z.; Fox, D. J.; Smith, A. D. Chem.
Sci. 2013, 4, 4146.
Scheme 2. Reaction Condition for R,β-Unsaturated Imines
(9) He, M.; Beahm, B. J.; Bode, J. W. Org. Lett. 2008, 10, 3817.
(10) (a) Kawanaka, Y.; Phillips, E. M.; Scheidt, K. A. J. Am. Chem.
Soc. 2009, 131, 18028. (b) Phillips, E. M.; Wadamoto, M.; Roth, H. S.;
Ott, A. W.; Scheidt, K. A. Org. Lett. 2009, 11, 105.
(11) (a) Hao, L.; Du, Y.; Lv, H.; Chen, X.; Jiang, H.; Shao, Y.; Chi,
Y. R. Org. Lett. 2012, 14, 2154. (b) Fu, Z.; Xu, J.; Zhu, T.; Leong,
W. W. Y.; Chi, Y. R. Nat. Chem. 2013, 5, 835. (c) Cheng, J.; Huang, Z.;
Chi, Y. R. Angew. Chem., Int. Ed. 2013, 52, 8592. (d) Hao, L.; Chen, S.;
Xu, J.; Tiwari, B.; Fu, Z.; Li, T.; Lim, J.; Chi, Y. R. Org. Lett. 2013, 4956.
(e) Xu, J.; Jin, Z.; Chi, Y. R. Org. Lett. 2013, 5028.
(12) For selected reactions using this type of catalyst: (a) Kerr, M. S.;
deAlaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298. (b) Kerr,
M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876. (c) Chiang, P. C.;
Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc. 2007, 129, 3520. Also
see refs 5a and 7c.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Examples of the R,β-Unsaturated Ketonesa
Scheme 4. Examples of the R,β-Unsaturated Iminesa
a Reaction condition: 1a (0.10 mmol), 2 (0.05 mmol), B (0.015 mmol),
DBU (0.075 mmol), THF (0.5 mL). Reported yields are isolated yields
based on 2. Enantiomeric excesses were determined via chiral phase
HPLC. b 50 mg of 4 A MS were added; without 4 A MS, 5i was obtained
in 55% yield with 98% ee, and 5j in 52% yield with 98% ee.
substrates to give the corresponding enol lactone products
with good yields and excellent ee (Scheme 3, 3aꢀo). For
example, replacing the β- or carbonyl phenyl group with a
bulkier naphthyl substituent was well-tolerated in this
reaction (3b, 3c). Placing a methyl, Br, or Cl substituent
on either of the phenyl groups of chalcone had little
influence on the reaction yield or enantioselectivity
(3dꢀk). Heteroarylsubstituentsworkedfine aswell, except
when the β-phenyl unit was replaced with a furan ring,
causing the product (3n) to be obtained with a reduced
yield and ee (62% yield, 90% ee). The use of a β-alkyl
enone could also give the product with an excellent ee,
albeit with a low yield (3o, 36% yield).14 The absolute
configurations of the lactone products were estimated
based on X-ray crystal structure analysis of 3j.15
a Reaction conditions: 1a (0.20 mmol), 2 (0.10 mmol), A (0.02 mmol),
DBU (0.15 mmol), MeCN (1.0 mL). Reported yields are isolated yields
based on 2. Enantiomeric excesses were determined via chiral phase
HPLC.
After identifying chalcone as an effective electrophile
(Table 1), we moved to examine the use of R,β-unsaturated
imine 4a as another substrate to react with acetic ester 1a
(Scheme 2a). Interestingly, with the NHC precatalyst A
used above, much lower yields (e.g., <20%) of lactam
product 5a were obtained after testing several conditions
(Scheme 2a, NHC = A). Additional studies revealed that
amino alcohol derived catalyst B13 could catalyze this reac-
tion of an ester and R,β-unsaturated imine with a good yield
and 99% ee (Scheme 2a, NHC = B). It is worth noting that
NHC catalyst B could also mediate the reaction between the
acetic ester and enone to give lactone in excellent yield, albeit
with a slightly dropped 89% ee (Scheme 2b).
Examples of R,β-unsaturated imines used in the reac-
tions are shown in Scheme 4. Inall the reactions, the lactam
products were obtained in moderate to good yields with
98ꢀ99% ee. For the unsaturated imine substrates with an
The scope of the enone substrate was then explored.
Essentially, various chalcone-type enones were effective
(14) Raising the reaction temperature to 40 °C gave the product 3o in
27% yield with 98% ee. At 60 °C, the product was obtained in 24% yield
with 97% ee.
(15) CCDC 921945 (3j) and CCDC 921945 (5j) contain the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(13) For selected reactions using this type of catalyst: (a) Phillips,
E. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 2416.
(b) Cohen, D. T.; Cardinal-David, B.; Roberts, J. M.; Sarjeant, A. A.;
Scheidt, K. A. Org. Lett. 2011, 13, 1068. (c) Piel, I.; Steinmetz, M.;
Hirano, K.; Frohlich, R.; Grimme, S.; Glorius, F. Angew. Chem., Int.
Ed. 2011, 50, 4983. Also see refs 5d and 10a.
€
Org. Lett., Vol. XX, No. XX, XXXX
C

utility of the lactone and lactam products (Scheme 5).
Treatment of lactone 3a with meta-chloroperoxybenzoic
acid (mCPBA) gave an unstable epoxide product that
rearranged under acidic conditions to form butyrolactones
6 (and 60) that bear an important core structure found in
many biologically active natural products.16 Reduction of
5a using diisobutylaluminium hydride (DIBAL-H) af-
forded hemiaminal 7 in good yield. The adduct 7 could
be further transformed to piperidine 8 as a single isomer.
At a low temperature (ꢀ78 °C), the hemiaminal product 7
could be selectively reduced to form tetrahydropyridine 9
in good yield.17 Oxidation of the enamide functionalityof9
using RuCl3/NaIO4 afforded protected γ-amino acid 10,
which is useful in constructing peptide mimetics.18
Scheme 5. Synthetic Utility of the Lactone and Lactam Products
In summary, we have developed an NHC-catalyzed
generation of enolate intermediates from simple acetic
ester substrates. These enolate intermediates as two-carbon
building blocks readily underwent highly enantioselec-
tive reactions with R,β-unsaturated ketones and imines.
These reactions afforded R-unsubstituted δ-lactones
and lactams that were difficult to prepare using other
methods. Further mechanistic exploration and synthetic
application of this smallest ester enolate intermediate
are in progress.
electron-withdrawing Cl/Br substituent, the addition of a
molecular sieve could slightly improve the reaction yields
(5i, 5j), because these imine substrates could undergo
hydrolysis by the trace water present in the reaction. Under
this condition, alkyl substituted imines (R1 and/or R2 as
alkyl) were not suitable substrates. The absolute config-
urations of the lactam products were estimated based on
X-ray crystal structure analysis of 5j.15
Acknowledgment. We thank Singapore National Re-
search Foundation (NRF), Singapore Economic Develop-
ment Board (EDB), GlaxoSmithKline (GSK), and Nanyang
Technological University (NTU) for the generous financial
support and Dr. Y. Li (NTU) and Dr. R. Ganguly (NTU)
for the X-ray structure.
With the protocol for the asymmetric [4 þ 2] annulation
reaction established, we proceeded to explore the synthetic
(16) (a) Zhu, Y.; Shu, L.; Tu, Y.; Shi, Y. J. Org. Chem. 2001, 66, 1818.
(b) Bandichhor, R.; Nosse, B.; Reiser, O. Top. Curr. Chem. 2005, 243, 43.
(c) Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K. Angew. Chem., Int.
Ed. 2009, 48, 9426. (d) Li, Y.; Pattenden, G. Nat. Prod. Rep. 2011, 28,
429. (e) Lee, S.; Jang, J. H.; Hwang, G.-S.; Ryu, D. H. J. Org. Chem.
2013, 78, 770.
(17) Han, B.; Li, J.; Ma, C.; Zhang, S.; Chen, Y. Angew. Chem., Int.
Ed. 2008, 47, 9971.
(18) (a) Gao, M.; Wang, D.; Zheng, Q.; Wang, M. J. Org. Chem. 2006,
71, 9532. For a comprehensive review on peptide mimetics, see: (b) Seebach,
D.; Beck, A. K.; Bierbaum, D. J. Chem. Biodiversity 2004, 1, 1111.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX