γcarbon Activation through N-Heterocyclic Carbene/Bronsted Acids Cooperative Catalysis: A Highly Enantioselective Route to γlactams

Article abstract of DOI:10.1021/acs.orglett.5b01827

A carbon activation method that operates through N-heterocyclic carbene/Bronsted acid cooperative catalysis for highly enantioselective synthesis of γlactams is reported. The protocol allows the challenging remote carbon control of regioselectivity and en

Full text of DOI:10.1021/acs.orglett.5b01827

Letter
pubs.acs.org/OrgLett
γ‑Carbon Activation through N‑Heterocyclic Carbene/Brønsted Acids
Cooperative Catalysis: A Highly Enantioselective Route to δ‑Lactams
Yonglong Xiao,†,‡,§ Jinxin Wang,‡,§ Wenjing Xia,† Shuangjie Shu,† Shenchao Jiao,† Yu Zhou,*,†
and Hong Liu*,†
†CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences 555 Zuchongzhi
Road, Shanghai 201203, P. R. China
‡China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China
S
* Supporting Information
ABSTRACT: A γ-carbon activation method that operates
through N-heterocyclic carbene/Brønsted acid cooperative
catalysis for highly enantioselective synthesis of δ-lactams is
reported. The protocol allows the challenging remote γ-carbon
control of regioselectivity and enantioselectivity through
introduction of an appropriate γ-leaving group in the enals.
The reaction offers good yields and excellent enantioselectiv-
ities, and the resulting cyclic products can be easily converted into high-value drug-like derivatives.
Scheme 1. NHC-Catalyzed Lactams through γ-Carbon
Activation of Enals
C−H activation via N-heterocyclic carbene (NHC) catalysis
has attracted widespread attention for the rapid synthesis of
novel heterocycles.1 However, the most significant challenge is
to control reaction site selectivity.2 The activation of enals by
NHC generally offers homoenolate,3 enolate,4 or acyl anion
equivalents5 as the nucleophiles. Current studies have mainly
involved activation of the α- or β-carbon of carbonyl
compounds. Activation of the γ-carbon still remains a
significant challenge and has not been thoroughly investigated,
with only a few pioneering studies having been reported
involving γ-carbon activation that constructs intriguing
heterocycles.1a,2,6 The heterocyclic lactam motif represents a
significant portion of chemical space and is widespread in
synthetic biologically active molecules and natural products.1b,7
Such molecules are commonly obtained through cyclodehydra-
tion reactions of amino acids,8 Beckmann rearrangement of
cycloketones,9 or intramolecular cyclization of amides possess-
ing an alkene,10 alkyne,11 or allene group.12 However, it is often
difficult for these methods to impart good enantioselectivity.
Recently, there have been some reports studying the feasibility
for the enantioselective synthesis of lactams via NHC
catalysis,1b,13 but most of these protocols are limited to the
preparation of γ-lactams.13 The activation of enal γ-carbons to
prepare δ-lactams still faces significant barriers, with frequent
difficulty in obtaining good chemoselectivity (reactive position
selectivity) due to the presence of some competitive reaction
intermediates, such as homoenolate, enolate, or acyl anion
intermediates. On the other hand, the fact that chiral auxiliaries
may be relatively remote from the γ-carbon of enals makes
stereocontrol difficult.2 In 2013, Ye et al. reported a pioneering
NHC organocatalytic γ-carbon activation of enals, with γ-
leaving groups, to generate [4 + 2] annulation products
(Scheme 1a).6b However, this protocol requires a substituent in
the γ-position of the enal to stabilize the dienolate intermediate
generated during the activation. We envisioned that introducing
an appropriate leaving group at the γ-position of an enal might
generate a stable γ-unsubstituted homoenolate intermediate,
which could then react with an imine to give intriguing δ-
lactams (Scheme 1b). The key step would involve addition of
the NHC catalyst to the enal substrate I to form the γ-
unsubstituted homoenolate intermediate III following elimi-
nation of the γ-leaving group (Scheme 2). The γ-carbon of
dienolate intermediate III would then undergo nucleophilic
addition to the imine to eventually form the δ-lactam via a
Mannich reaction and subsequent cyclization. The overall
hypothesized pathway may be considered a similar process to
that found in the NHC-mediated activation of α,β-unsaturated
aldehydes.6b,14
Experimentally, we set out to achieve γ-carbon activation to
prepare the target δ-lactam using the enal 1 as a model
substrate and imine 2a as a model electrophile. The key results
of extensive studies are summarized in Table 1. Initially,
Cs2CO3 was selected as a base, and four different triazolium
Received: June 25, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01827
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Letter
was feasible. Accordingly, a variety of alternative bases were
investigated. The results demonstrated that the desired
products were observed with NaH, K2CO3, and PhCOONa
as the base, whereas no product could be detected in the
presence of DBU (Table 1, entries 5−8). We next explored the
influence of different solvents, with only a trace of the desired
product being found in CH3OH and no product being
observed in THF and dimethyl ether (Table 1, entries 9−
11). Some pioneering work from Scheidt and his colleagues has
indicated that cooperative catalysis by carbenes and Lewis acids
can achieve greater selectivity and more efficient reactivity than
either mode individually; in such cooperative catalysis, an
optimal Lewis acid catalyst can activate the electrophile by
lowering the energy of the lowest unoccupied molecular orbital
(LUMO) for the overall productive reaction.1c,2,15 Based on
these findings, two distinct Lewis acidic magnesium(II) and
scandium(III) salts were used, and a higher selectivity and more
efficient reactivity were obtained (Table 1, entries 12−13).
Further studies showed that the addition of a Bronsted acid (2-
Br-PhCOOH) could offer a better result, giving a 72% yield and
a 94% ee (Table 1, entries 14−15).5c In addition, some lithium
salts, such as LiBr and LiBF4, were evaluated. However, good
results were not obtained in the model reaction (Table 1,
entries 16−17).
Scheme 2. Postulated Catalytic Cycle
NHC precatalysts were screened in CH2Cl2 solvent (Table 1,
entries 1−4). Surprisingly, the process delivered the desired
Mannich adduct (3a) in a moderate yield of 36% and a high
enantioselectivity of 91% ee when the NHC precatalyst D was
used (Table 1, entry 4). This proof-of-principle result clearly
revealed that activation of the γ-carbon of enal, including a γ-
leaving group as a nucleophile using the NHC organocatalyst,
With the optimized catalysis conditions identified, a variety
of imines were investigated as potential substrates. The results
are summarized in Scheme 3. First, we explored a series of
a
Table 1. Optimization of the Reaction Conditions of Synthesis of 3a
b
c
entry
catalyst
base
solvents
additive
yield (%)
ee (%)
d
1
A
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
−
−
−
−
91
71
−
72
78
−
2
B
−
3
C
D
D
D
D
D
D
D
D
D
D
D
D
D
D
trace
36
45
−
24
27
−
4
5
6
DBU
7
K2CO3
8
PhCOONa
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
13
14
15
16
17
CH3OCH3
CH3OH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
−
−
trace
43
41
64
72
29
46
92
87
92
94
94
94
92
Sc(OTf)3
Mg(OTf)2
4-Br-PhCOOH
2-Br-PhCOOH
LiBr
LiBF4
a
Reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), catalyst A−D (0.02 mmol), base (0,2 mmol), solvent (2−3 mL), at 0 °C for 24 h under Ar
b
c
protection. Additive (0.1 mmol). Enantiomeric excess of 3a determined via chiral phase HPLC analysis; absolute configuration of the major
enantiomer was assigned on the basis of X-ray structure of 3k (see Figure S1 in the Supporting Information). No desired product found.
d
B
DOI: 10.1021/acs.orglett.5b01827
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Letter
substrates also gave the annulation products in good yields
(3o−3s, 63%−78%) and high enantioselectivities (83%−99%).
The S configuration of 3k was determined by X-ray analysis
(Figure S1 in the Supporting Information).
Scheme 3. Enantioselective Mannich Reactions with 4-(4-
Nitrophenoxy)but-2-enal
a
The cyclic products from this novel strategy can be easily
converted into high-value derivatives,16 thereby leveraging the
utility of the overall process (Scheme 4).17 For example, under
Scheme 4. Synthetic Transformations of 3a
different reaction temperatures, we found that cyclic product 3a
can be reduced to the long-chain amide 6a and the saturated δ-
lactams 4a and 5a. The saturated δ-lactam 5a is not only an
intriguing pharmacophore18 but also a known intermediate for
the synthesis of piperidine 8a, which is widely observed in
synthetic biologically active molecules and natural products,
such as the local anesthetic ropivacaine,19 the thrombin
inhibitor argatroban,20 the HIV-protease inhibitor palinavir,21
and the antitumor antibiotic tetrazomine,22 along with top-
selling pharmaceuticals that include paroxetine (a disubstituted
piperidine).23 The alkyl amide 6a has been widely used in the
material dye industry24 and pharmaceutical industry.25 In
addition, the δ-lactam 4a can be converted into the chiral
amino alcohol 7a in 72% yield with 93% ee;1b this compound is
generally used as a basic building block.
In summary, we have developed a highly effective catalytic
system for the enantioselective construction of a diverse array
of δ-lactams in good yields and with excellent enantioselectiv-
ities. The challenge of attaining high enantioselectivity at the
remote γ-carbon of an enal was achieved by introducing an
appropriate γ-leaving group. The reaction tolerates different
kinds of imines. The resulting cyclic products can be easily
converted into high-value derivatives, such as δ-lactams,
piperidines, amino alcohols, and alkyl amides, thereby broad-
ening the utility of the overall process. The widely available
substrates, excellent enantioselectivity, mild reaction conditions,
and wide reaction scope make this γ-carbon activation strategy
potentially useful for the synthesis of biologically active
molecules or natural products.
a
Reaction conditions: 1 (0.1 mmol), 2a ∼ 2s (0.2 mmol), catalyst D
(0.02 mmol), Cs2CO3 (0.2 mmol), additive (2-bromobenzoic acid, 0.1
mmol), DCM (2−3 mL), at 0 °C for 24 h under Ar protection. 4-(p-
Methylphenoxy)but-2-enal is also tested, but no desired product is
b
c
observed. The CCDC number of 3k is CCDC1024375.
imine substrates in which R1 was a methyl group (3a−3n).
Electron- donating, electron-withdrawing, and halogen groups
on the phenyl ring of R2 were tolerated and offered the desired
annulation products in good yields (3a−3k, 46−81%) with
excellent enantioselectivities (90−98%). Fused aromatic groups
(1-naphthyl and 2-naphthyl) and a heterocyclic group (2-
thioenyl) also gave excellent results, with 74−82% yields and
93−96% ee values (3l−3n). We further investigated the
tolerance of the process by varying the R1 group; the diversified
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01827.
Crystallographic data (CIF)
C
DOI: 10.1021/acs.orglett.5b01827
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Organic Letters
Detailed experimental procedures; spectral data for all
Letter
(12) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Org. Lett.
2007, 9, 2473.
(13) (a) Raup, D. E.; Cardinal-David, B.; Holte, D.; Scheidt, K. A.
Nat. Chem. 2010, 2, 766. (b) Phillips, E. M.; Reynolds, T. E.; Scheidt,
K. A. J. Am. Chem. Soc. 2008, 130, 2416.
new compounds (PDF)
AUTHOR INFORMATION
■
(14) Zhao, Y. M.; Cheung, M. S.; Lin, Z.; Sun, J. Angew. Chem., Int.
Corresponding Authors
Ed. 2012, 51, 10359.
*E-mail: zhouyu@simm.ac.cn.
*E-mail: hliu@mail.shcnc.ac.cn.
Author Contributions
§Y.X. and J.W. contributed equally.
(15) (a) Cardinal-David, B.; Raup, D. E. A.; Scheidt, K. A. J. Am.
Chem. Soc. 2010, 132, 5345. (b) Dugal-Tessier, J.; O’Bryan, E. A.;
Schroeder, T. B. H.; Cohen, D. T.; Scheidt, K. A. Angew. Chem., Int.
Ed. 2012, 51, 4963. (c) Cohen, D. T.; Cardinal-David, B.; Scheidt, K.
A. Angew. Chem., Int. Ed. 2011, 50, 1678. (d) Cohen, D. T.; Cardinal-
David, B.; Roberts, J. M.; Sarjeant, A. A.; Scheidt, K. A. Org. Lett. 2011,
13, 1068.
Notes
The authors declare no competing financial interest.
(16) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471.
(17) (a) Guijarro, D.; Pablo, O.; Yus, M. J. Org. Chem. 2013, 78,
3647. (b) Fenical, W.; Jensen, P. R.; Palladino, M. A.; Lam, K. S.;
Lloyd, G. K.; Potts, B. C. Bioorg. Med. Chem. 2009, 17, 2175.
(c) Perez-Faginas, P.; Aranda, M. T.; Garcia-Lopez, M. T.; Francesch,
A.; Cuevas, C.; Gonzalez-Muniz, R. Eur. J. Med. Chem. 2011, 46, 5108.
(18) (a) Horrocks, P.; Fallon, S.; Denman, L.; Devine, O.; Duffy, L.
J.; Harper, A.; Meredith, E. L.; Hasenkamp, S.; Sidaway, A.; Monnery,
D.; Phillips, T. R.; Allin, S. M. Bioorg. Med. Chem. Lett. 2012, 22, 1770.
(b) Atigadda, V. R.; Brouillette, W. J.; Duarte, F.; Ali, S. M.; Babu, Y.
S.; Bantia, S.; Chand, P.; Chu, N.; Montgomery, J. A.; Walsh, D. A.;
Sudbeck, E. A.; Finley, J.; Luo, M.; Air, G. M.; Laver, G. W. J. Med.
Chem. 1999, 42, 2332. (c) Kim, H. M.; Hong, S. H.; Kim, M. S.; Lee,
C. W.; Kang, J. S.; Lee, K.; Park, S. K.; Han, J. W.; Lee, H. Y.; Choi, Y.;
Kwon, H. J.; Han, G. Bioorg. Med. Chem. Lett. 2007, 17, 6234.
(d) Hoye, A. T.; Wipf, P. Org. Lett. 2011, 13, 2634.
(19) Timponi, C. F.; Oliveira, N. E.; Arruda, R. M. P.; Meyrelles, S.
S.; Vasquez, E. C. Basic Clin. Pharmacol. Toxicol. 2006, 98, 518.
(20) Lewis, B. E.; Wallis, D. E.; Berkowitz, S. D.; Matthai, W. H.;
Fareed, J.; Walenga, J. M.; Bartholomew, J.; Sham, R.; Lerner, R. G.;
Zeigler, Z. R.; Rustagi, P. K.; Jang, I. K.; Rifkin, S. D.; Moran, J.;
Hursting, M. J.; Kelton, J. G. Circulation 2001, 103, 1838.
(21) Reeder, M. R.; Anderson, R. M. Chem. Rev. 2006, 106, 2828.
(22) Suzuki, K.; Sato, T.; Morioka, M.; Nagai, K.; Abe, K.;
Yamaguchi, H.; Saito, T.; Ohmi, Y.; Susaki, K. J. Antibiot. 1991, 44,
479.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Grants 21021063,
91229204, 81302633, and 81025017), National S&T Major
Projects (2012ZX09103101-072, 2012ZX09301001-005,
2013ZX09507-001, and 2014ZX09507002-001), Sponsored
by Program of Shanghai Subject Chief Scientist (Grant
12XD1407100), supported by State Key Laboratory of
Bioorganic Chemistry.
REFERENCES
■
(1) (a) Wang, M.; Huang, Z.; Xu, J.; Chi, Y. R. J. Am. Chem. Soc.
2014, 136, 1214. (b) Cheng, J.; Huang, Z.; Chi, Y. R. Angew. Chem.,
Int. Ed. 2013, 52, 8592. (c) Raup, D. E.; Cardinal-David, B.; Holte, D.;
Scheidt, K. A. Nat. Chem. 2010, 2, 766. (d) Mo, J.; Shen, L.; Chi, Y. R.
Angew. Chem., Int. Ed. 2013, 52, 8588.
(2) Mo, J.; Chen, X.; Chi, Y. R. J. Am. Chem. Soc. 2012, 134, 8810.
(3) (a) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52,
6205. (b) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004,
126, 14370. (c) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am.
Chem. Soc. 2006, 128, 8736. (d) Zhao, X.; DiRocco, D. A.; Rovis, T. J.
Am. Chem. Soc. 2011, 133, 12466. (e) Fang, X.; Jiang, K.; Xing, C.;
Hao, L.; Chi, Y. R. Angew. Chem., Int. Ed. 2011, 50, 1910.
(4) (a) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
8418. (b) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A.
Angew. Chem., Int. Ed. 2007, 46, 3107. (c) Fang, X.; Chen, X.; Chi, Y.
R. Org. Lett. 2011, 13, 4708.
(23) Uzunova, V.; Sheline, Y.; Davis, J. M.; Rasmusson, A.; Uzunov,
D. P.; Costa, E.; Guidotti, A. Proc. Natl. Acad. Sci. U. S. A. 1998, 95,
3239.
(24) Tamura, T.; Tsukiji, S.; Hamachi, I. J. Am. Chem. Soc. 2012, 134,
2216.
(5) (a) DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2011, 133, 10402.
(b) Fang, X.; Chen, X.; Lv, H.; Chi, Y. R. Angew. Chem., Int. Ed. 2011,
50, 11782. (c) Liu, G.; Wilkerson, P. D.; Toth, C. A.; Xu, H. Org. Lett.
2012, 14, 858.
(25) Kaise, H.; Shimokawa, J.; Fukuyama, T. Org. Lett. 2014, 16, 727.
(6) (a) Shen, L. T.; Shao, P. L.; Ye, S. Adv. Synth. Catal. 2011, 353,
1943. (b) Chen, X. Y.; Xia, F.; Cheng, J. T.; Ye, S. Angew. Chem., Int.
Ed. 2013, 52, 10644.
(7) (a) Brouillette, W. J.; Atigadda, V. R.; Luo, M.; Air, G. M.; Babu,
Y. S.; Bantia, S. Bioorg. Med. Chem. Lett. 1999, 9, 1901. (b) Aminov, R.
I. Environ. Microbiol. 2009, 11, 2970. (c) Drawz, S. M.; Bonomo, R. A.
Clin. Microbiol. Rev. 2010, 23, 160.
(8) (a) Amat, M.; Canto, M.; Llor, N.; Bosch, J. Chem. Commun.
2002, 5, 526. (b) King, F. D.; Caddick, S. Org. Biomol. Chem. 2012, 10,
3244. (c) Esquivias, J.; Gomez-Arrayas, R.; Carretero, J. C. Angew.
Chem., Int. Ed. 2007, 46, 9257. (d) Cheemala, M. N.; Knochel, P. Org.
Lett. 2007, 9, 3089.
(9) (a) Furuya, Y.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc.
2005, 127, 11240. (b) Boero, M.; Ikeshoji, T.; Liew, C. C.; Terakura,
K.; Parrinello, M. J. Am. Chem. Soc. 2004, 126, 6280. (c) Jiang, Y.;
Huang, J.; Wang, W.; Glaser, R.; Hunger, M.; Marthala, V. R. J. Am.
Chem. Soc. 2006, 128, 14812.
(10) Salvador-Gonzalez, A.; Gomez-Arrayas, R.; Rodriguez-Rivero,
M.; Carretero, J. C. Org. Lett. 2008, 10, 4335.
(11) Wang, Y. F.; Toh, K. K.; Ng, E. P.; Chiba, S. J. Am. Chem. Soc.
2011, 133, 6411.
D
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