Organocatalytic enantioselective γ-aminoalkylation of unsaturated ester: Access to pipecolic acid derivatives

Article abstract of DOI:10.1021/ol402358k

The direct γ-carbon functionalization of α,β-unsaturated esters via N-Heterocyclic Carbene (NHC) catalysis is disclosed. This catalytically generated nucleophilic γ-carbon undergoes highly enantioselective additions to hydrazones. The resulting δ-lactam products can be readily transformed to optically enriched pipecolic acid derivatives.

Full text of DOI:10.1021/ol402358k

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Organocatalytic Enantioselective
γ‑Aminoalkylation of Unsaturated Ester:
Access to Pipecolic Acid Derivatives
Jianfeng Xu, Zhichao Jin, 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 August 17, 2013
ABSTRACT
The direct γ-carbon functionalization of R,β-unsaturated esters via N-Heterocyclic Carbene (NHC) catalysis is disclosed. This catalytically
generated nucleophilic γ-carbon undergoes highly enantioselective additions to hydrazones. The resulting δ-lactam products can be readily
transformed to optically enriched pipecolic acid derivatives.
R,β-Unsaturated carbonyl compounds are common
synthetic building blocks, of which the carbonyl, R-, and
β-carbons are used as reactive sites. The γ-carbons of such
unsaturated compounds, on the other hand, are typically
less reactive. It is expected that a direct use of the γ-carbons
should provide new opportunities for efficient access to
useful molecules. Therefore, considerable efforts havebeen
drawn to the development of asymmetric catalytic methods
for the activation of γ-carbons of unsaturated carbonyl
compounds.1 These methods normally use preformed silyl
dienolates as substrates or use transition metals as catalysts.
Representative examples include the vinylogous aldol reac-
tions reported by Carreira,2 Evans,3 Denmark,4 and
Campagne;5 the vinylogous Mannich reactions reported
by Hoveyda,6 Shibasaki,7 and Nakamura;8 and the vinylo-
gous Michael addition reactions reported by MacMillan9
and Trost.10 In 2006, Jorgensen and co-workers disclosed
ꢀ
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10, 2319. (b) Shepherd, N. E.; Tanabe, H.; Xu, Y.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 3666.
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MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051. (c) Simmons,
B.; Walji, A. M.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2009, 48,
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Reddy, Y. V. Eur. J. Org. Chem. 2012, 865. (b) Jensen, K. L.; Dickmeiss,
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Rassu, G. Chem. Rev. 2000, 100, 1929. (b) Martin, S. F. Acc. Chem. Res.
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r
10.1021/ol402358k
XXXX American Chemical Society

the γ-addition of R,β-unsaturated aldehydes to azodicar-
boxylates via dienamine organocatalysis.11 This dienamine
chemistry12 has then been further advanced by the groups of
Melchiorre,13 Christmann,14 Chen,15 and Vicario.16 With
N-heterocyclic carbenes (NHCs)17 or cinchona alkaloids
as catalysts, Peters18 and Ye19 groups have activated the
γ-carbons of vinyl ketenes.20 This nice ketene-based ap-
proach, proven to be successful in a number of interesting
reactions, is somewhat limited by the unstable nature of the
ketene substrates.21
Scheme 1. NHC-Catalyzed γ-Activation of R,β-Unsaturated
Esters
Stable carboxylic esters are readily available, inexpen-
sive, and easy to handle. Asymmetric catalytic strategies
that can directly functionalize carboxylic esters (the carbo-
nyl, R-, β-, and γ-carbons, etc.) will provide useful solu-
tions for organic synthesis. Under a larger program of
organocatalytic ester activation, we developed the catalytic
conversion of saturated R-aryl acetic esters as NHC-
bounded enolate intermediates that led to R-functionalization
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Table 1. Condition Optimization
€
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entry
base
yield (%)a
erb
1
ꢀ, 1.5 equiv K2CO3
ꢀ
ꢀ
2
A, 1.5 equiv K2CO3
43
59
40
83
74
77
52
81
78
ꢀ
3
B, 1.5 equiv K2CO3
ꢀ
4
C, 1.5 equiv K2CO3
96:4
99:1
99:1
99:1
99:1
99:1
99:1
5
D, 1.5 equiv K2CO3
6
E, 1.5 equiv K2CO3
7
D, 1.0 equiv K2CO3
8
D, 0.5 equiv K2CO3
9c
10c
D (10 mol %), 1.5 equiv K2CO3
D (5 mol %), 1.5 equiv K2CO3
a Isolated yield based on 2a. b Enantiomeric ratio of 3a, determined
via chiral phase HPLC analysis; absolute configuration of the major
enantiomer was assigned based on X-ray structure of 3g (see Scheme 2
and Supporting Information). c 0.15 mmol (1.5 equiv) of 1a was used.
of saturated esters and an unusual β-sp3 carbon activation
of saturated esters.22 Concurrently, we set to activate R,β-
unsaturated esters via NHC organic catalysts for new
reactions. Very recently, we realized an organocatalytic
formal LUMO β-sp2 carbon activation of R,β-unsaturated
esters.23 Here we report the first direct organocatalytic
γ-carbon activation of R,β-unsaturated esters (Scheme 1).
The key steps involve addition of the NHC catalyst to the
(20) For indirect oxidative NHC method to generate similar vinyl
enolate intermediate, see: (a) Mo, J.; Chen, X.; Chi, Y. R. J. Am. Chem.
Soc. 2012, 134, 8810. (b) Chen, X.; Yang, S.; Song, B.-A.; Chi, Y. R.
Angew. Chem., Int. Ed. 201310.1002/anie.201305861.
(21) Tidwell, T. T. Ketenes, 2nd ed., John Wiley & Sons, Hoboken, NJ,
2006.
(22) (a) Hao, L.; Du, Y.; Lv, H.; Chen, X.; Jiang, H.; Shao, Y.; Chi,
Y. R. Org. Lett. 2012, 14, 2154. (b) Hao, L.; Chan, W. C.; Ganguly, R.;
Chi, Y. R. Synlett 2013, 24, 1197. (c) Fu, Z.; Xu, J.; Zhu, T.; Leong,
W. W. Y.; Chi, Y. R. Nat. Chem. 201310.1038/nchem.1710. (d) For
relevant work from Lupton, see: Ryan, S. J.; Candish, L.; Lupton, D. W. J.
Am. Chem. Soc. 2009, 131, 14176. (e) Candish, L.; Lupton, D. W. Org.
Lett. 2010, 12, 4836. (f) Candish, L.; Lupton, D. W. Org. Biomol. Chem.
2011, 9, 8182. (g) Candish, L.; Lupton, D. W. Chem. Sci. 2012, 3, 380. (h)
Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42, 4906.
(23) Cheng, J.; Huang, Z.; Chi, Y. R. Angew. Chem., Int. Ed. 2013, 52,
8592.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Scope of Reactionsa
Scheme 3. Reactions Using γ-Alkyl and β,β0-Dialkyl
Substituted R,β-Unsaturated Esters as Substrate
Key results of our initial studies using R,β-unsaturated
ester 1a and hydrazone 2a as model substrates are briefed
in Table 1. In the absence of the NHC catalyst, no
formation of product 3a was observed (Table 1, entry 1).
When triazolium-based NHC catalyst A was used, 3a was
obtained in 43% isolated yield (entry 2). Replacing the
phenyl group on the NHC catalyst with a mesityl substituent
led to 3a with an improved 59% yield (entry 3). We next
moved to chiral triazolium-based NHC catalysts and found
L-leucine derived catalysts C29 and D30 could afford 3a in
good yields and 96:4 and 99:1 er respectively (entries 4ꢀ5).
Aminoindanol derived catalyst E31 could also catalyze the
reaction to give 3a with similar er but lower yield (entry 6).
Further studies (entries 7ꢀ10) showed that 5 mol % NHC D
was enough to afford 3a with 78% yield and 99:1 er.
a Reaction for 24 h for 3aꢀi; 48 h for 3jꢀq (except 3k and 3p). b 24 h.
Having established an optimal protocol for this reaction
(Table 1, entry 10), we then examined the scope of the
R,β-unsaturated esters bearing a β-aryl and a β0-methyl
substituent (Scheme 2, 3aꢀi). Both electron-withdrawing
(3b, 3c) and electron-donating (3d) substituents on the
β-phenyl group were tolerated. Replacing the β-phenyl
group with naphthyl (3e), heteroaryl (3fꢀh), or vinyl
substituents were all well tolerated. The scope of the
hydrazones was also studied (Scheme 2, 3jꢀq) by using
1a as a model ester substrate. Various aryl substituents of
the hydrazones all worked well, giving products with
moderate to good yields and excellent er.
We next studied the ester substrate (4) bearing a sub-
stituent at the γ-carbon (Scheme 3, eq 1). The desired
trisubstitutedδ-lactam product(5) could be obtained in 9:1
dr and 99:1 er, albeit with relatively low yield. In this case, a
stronger base (Cs2CO3) was used and the reaction was
ester substrate to form R,β-unsaturated ester intermediate I,
followed by γ-CH deprotonation to form vinyl enolate inter-
mediate II bearing a nucleophilic γ-carbon. The vinyl enolate
intermediate II then undergoes nucleophilic additions to
hydrazones to form optically enriched δ-lactam products.
δ-Lactams are important precursors for bioactive pipecolic
acid and other piperidine derivatives, such as local anesthetic
ropivacaine,24 HIV protease inhibitor palinavir,25 thrombin
inhibitor argatroban,26 antitumor antibiotic tetrazomine,27
and best selling pharmaceuticals such as paroxetine.28 In the
present work, we converted δ-lactam 3a to its corresponding
chiral 4-phenyl substituted pipecolic ester and acid through
simple reduction and hydrolysis steps.
(24) Pacella, E.; Collini, S.; Pacella, F.; Piraino, D. C.; Santamaria,
V.; De Blasi, R. A. Eur. Rev. Med. Pharmacol. Sci. 2010, 14, 539.
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D.; Clouette, C.; Vaillancourt, M.; Cohen, E.; Pargellis, C.; Yoakim, C.;
Anderson, P. C. Antimicrob. Agents Chemother. 1997, 41, 965.
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van de Waterbeemd, H. J. Med. Chem. 1994, 37, 3889.
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Lett. 2009, 11, 3934.
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Org. Lett., Vol. XX, No. XX, XXXX
C

eqs 2ꢀ3). The standard conditions (Table 1, entry 10) used
above gave low conversion here. Further studies found
thatwithCs2CO3 asthebaseand 1,4-dioxaneasthe solvent
at 40 °C, the corresponding δ-lactam product (7a, 7b)
could be obtained with moderate to good yields and er’s
(eqs 2ꢀ3).
Scheme 4. Transformation of 3a to Pipecolic Acid Derivatives
The optically enriched δ-lactam product 3a obtained in
our studies could be readily transformed to chiral pipecolic
acid and its derivatives, as illustrated in Scheme 4.
A postulated catalytic cycle is illustrated in Scheme 5.
The addition of NHC to R,β-unsaturated ester 1a forms
intermediate I. Intermediate I then undergoes γ-deproto-
nation toaffordvinyl enolate intermediate II. Nucleophilic
γ-carbon addition of II to hydrazone 2a eventually form δ-
lactam product 3a and regenerates the NHC catalyst.
In summary, we have developed the first NHC-catalyzed
direct activation of the γ-carbons of R,β-unsaturated esters
that undergo addition to hydrazones in a highly efficient and
stereoselective manner to give δ-lactams. These lactam pro-
ducts could be easily transformed to optically enriched pipe-
colic acid derivatives using simple transformations. Further
studies to extend this catalytic protocol to γ,γ-disubstituted
esters, and other electrophiles are being pursued in our
laboratory.
Scheme 5. Postulated Catalytic Cycle
Acknowledgment. We thank the generous financial sup-
ports from Singapore National Research Foundation
(NRF), Singapore Economic Development Board (EDB),
GlaxoSmithKline (GSK), Nanyang Technological Univer-
sity(NTU) andDr. Y. Li(NTU) andDr. 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.
carried out for 48 h (eq 1). β,β0-Dialkyl substituted R,β-
unsaturated esters (6a, 6b) were also examined (Scheme 3,
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX