Organocatalytic asymmetric synthesis of chiral fluorinated quaternary carbon containing β-ketoesters

Article abstract of DOI:10.1039/b900777f

Organocatalytic enantioselective conjugate addition of α- fluoroketoesters to nitroolefins efficiently catalyzed by a cinchona alkaloid-derivative affords versatile non-enolizable ketoesters by forming two consecutive fluorinated quaternary and tertiary c

Full text of DOI:10.1039/b900777f

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Organocatalytic asymmetric synthesis of chiral fluorinated quaternary
carbon containing b-ketoestersw
Hao Li, Shilei Zhang, Chenguang Yu, Xixi Song and Wei Wang*
Received (in College Park, MD, USA) 14th January 2009, Accepted 23rd February 2009
First published as an Advance Article on the web 12th March 2009
DOI: 10.1039/b900777f
Organocatalytic enantioselective conjugate addition of
a-fluoroketoesters to nitroolefins efficiently catalyzed by a
cinchona alkaloid-derivative affords versatile non-enolizable
ketoesters by forming two consecutive fluorinated quaternary
and tertiary chiral carbon centers with excellent enantioselectivity.
a fluorinated quaternary carbon center. However, to our
knowledge, the reaction has not been disclosed. It is expected
that the reactivity profile of the a-fluoroketoesters is different
to that of classic ketoesters. Moreover, the products resulting
from a conjugate addition reaction would generate fluorinated
quaternary carbon containing non-enolizable b-ketone esters,
which can be conveniently elaborated in organic synthesis and
could be potentially useful in drug discovery.11 Toward this
end, we disclose an unprecedented conjugate addition reaction
between a nucleophilic a-fluoroketoester and nitroolefins.
The process is efficiently promoted by a simple cinchona
alkaloid derivative with a remarkably low catalyst loading
(1 mol%). Significantly, the reaction affords the products
with a fluorine containing quaternary carbon center and an
adjacent chiral carbon center in high yields and with excellent
enantioselectivity.
The importance of fluorine-containing compounds has been
underlined by their broad applications in the areas of agri-
cultural, medicinal, and material chemistry.1 Statistic studies
reveal that ‘‘as many as 30–40% of agrochemical and 20% of
pharmaceuticals on market are estimated to contain fluorine.’’2 It
has been demonstrated that in many cases, the substitution of
hydrogen atom(s) with fluorine(s) in a biologically active
molecule can improve its properties such as potency and
bioavailability significantly as results of its distinctive
characteristics of the most electronegative element, highly
strong C–F bond and similar size to H atom. Nowadays, it
has become a general practice in drug design to incorporate
fluorine atom(s) into bioactive molecules to modulate their
biological properties. Accordingly, the selective fluorination of
organic compounds has been a fascinating topic in the recent
past.2,3
In our initial investigation, cinchona alkaloid quinine
derivatives are explored for the conjugate addition of
a-fluoroketoester 1 to trans-b-nitrostyrene 2a in CHCl3 with
1 mol% catalyst loading (Fig. 1 and Table 1).12 Gratifyingly,
the process proceeds smoothly to give the desired adduct 3a in
high yields and with moderate diastereoselectivity (Table 1).
The results indicate that a-fluoroketoesters are more active
nucleophiles than classic ketoesters. The enantioselectivity of
the reaction depends on the catalysts used (entries 1, 2, 9 and
10). Among these catalysts screened, catalyst II is superior to
others in terms of the observed selectivity of the reactions
(Table 1, entry 2). In this case, a high level of enantioselectivity
(97% and 97% for both diastereomers) is achieved. Accord-
ingly, we selected catalyst II for further optimization of
reactions conditions. Favorable aprotic and nonpolar solvents
were probed for the H-bonding mediated catalysis. The reac-
tions carried out in CHCl3 and Cl(CH2)2Cl afford higher ee
Construction of chiral quaternary carbons is a formidable
challenge in organic synthesis.4 However, the creation of chiral
fluorinated quaternary carbon centers is even more challen-
ging and only a handful of examples that mainly rely on metal
catalysis can be identified.3d,5 Moreover, the use of organo-
catalytic strategies for the preparation of fluorinated quaternary
carbon centers are more scarce. Based on the a-fluorination
of aldehydes using an electrophilic fluorinating agent,3e,6
Jørgensen and co-workers extended the strategy for an
asymmetric a-fluorination of a-branched aldehydes to produce
fluorinated quaternary centers.7 Shibata and coworkers
disclosed
a cinchona alkaloid catalyzed enantioselective
fluorination of allyl silanes, silyl enol ethers and oxindoles
with NSFI.8 Kim et al. have developed asymmetric fluorination
reactions using a phase-transfer catalyst as a promoter.9
It is established that ketoesters are effective nucleophiles
for organocatalyzed conjugate addition reactions.10 We
envisioned that the use of commercially available a-fluoro-
ketoesters as a nucleophile could produce compounds with
Department of Chemistry & Chemical Biology, University of
New Mexico, Albuquerque, NM 87131, USA.
E-mail: wwang@unm.edu; Fax: (+1) 505 277 2609;
Tel: (+1) 505 277 0756
w Electronic supplementary information (ESI) available: Experimental
and NMR data. CCDC 716267. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/b900777f
Fig. 1 Screened organocatalysts.
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Table 1 Organocatalytic enantioselective Michael reaction of methyl a-fluoromethyl ketoester (1) with trans-b-ntirostyrene (2a)a
Entry
Cat.
Solvent
t/h
Yieldb (%)
eec (%) A/B
dr A : Bd
1
2
3
4
5
6
7
8
9
10
I
CHCl3
CHCl3
CH2Cl2
Cl(CH2)2Cl
Toluene
Xylenes
Et2O
THF
CHCl3
CHCl3
24
24
24
24
48
48
24
24
24
24
94
95
97
97
92
92
96
92
92
94
93/95
97/97
96/94
97/96
92/91
90/91
87/88
90/88
88/82
70/81
1.6 : 1
2 : 1
3 : 1
3 : 1
1.8 : 1
2 : 1
3 : 1
2 : 1
2 : 1
2 : 1
II
II
II
II
II
II
II
III
IV
a
Reaction conditions: A mixture of 1a (0.10 mmol), 2 (0.105 mmol), and a catalyst (0.001 mmol) in a solvent (0.5 mL) was stirred at rt for a
b
c
specified period of time. Isolated yields. Determined by chiral HPLC analysis (Chiralpak AS-H); A corresponds to the major diastereoisomer.
d
1
Determined by H NMR.
values (entries 2 and 4), while a relatively better dr is obtained
in Cl(CH2)2Cl.
be tolerated. Both aromatic (entries 1–12) and aliphatic
(entry 13) systems can effectively participate in the process.
The electronic substitution nature on the aromatic rings of
nitroolefins 2 has apparently limited influence on the stereo-
chemical outcome. Electron-neutral (entry 1), withdrawing
(entries 2–5), donating (entries 6–10), and hetereoaromatic
(entries 11–12) systems undergo reactions smoothly. Probing
the steric effect on the enantioselectivity of the conjugate
addition processes reveals that such influence is also minimal
in terms of yield and enantioselectivity (entry 9). Moreover,
2-fluoromalonate ester can also serve as an effective nucleo-
phile for the conjugate addition process to give rise to a
With the optimized reaction conditions in hand, we turned
our attention to probing the generality of the conjugate
addition processes. As revealed in Table 2, the organocatalytic
enantioselective reactions served as an efficient and general
route for the preparation of the adducts with excellent levels of
enantioselectivity (94–99% ee) and in high yields (75–98%)
despite moderate drs (1.7–4 : 1). Importantly, two new stereo-
genic centers are created with forming a fluorine containing
quaternary carbon center and an adjacent chiral carbon
center. Significant structural variation of nitroolefins 2 can
Table 2 Catalyst II promoted enantioselective Michael reaction of methyl a-fluoromethyl ketoester (1) with trans-nitroolefins (2)a
Entry
R
3
t/h
Yieldb (%)
eec (%) A/B
dr A : Bd
1
2
3
4
5
6
7
8
9
10
11
12
13
14e
Ph
4-FC6H4
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
24
24
24
24
24
24
24
24
48
48
48
48
36
72
97
95
98
97
94
92
95
96
90
95
94
97
75
98
97/96
98/97
98/97
99/94
98/97
99/98
98/95
98/97
97/95
97/99
99/99
99/98
98/96
86
3 : 1
3 : 1
3 : 1
3.5 : 1
3.5 : 1
4 : 1
3 : 1
3 : 1
1.7 : 1
3 : 1
4 : 1
3.5 : 1
4 : 1
—
4-ClC6H4
4-BrC6H4
3-BrC6H4
4-MeC6H4
4-MeOC6H4
4-BnOC6H4
2-BnOC6H4
3,4-(OCH2O)C6H3
2-Furanyl
2-Thienyl
n-C5H11
2-ClC6H4
a
b
c
Reaction conditions: unless specified, see footnote a in Table 1. Isolated yields. Determined by chiral HPLC analysis (Chiralpak AS-H, or
Chiralcel OD-H); A corresponds to the major diastereoisomer. Determined by 1H NMR. Methyl 2-fluoromalonate used as nucleophile and
20 mol% catalyst used in CHCl3.
d
e
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3 For recent reviews, see: (a) K. Mikami, Y. Itoh and M. Yamanaka,
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Fig. 2 X-Ray crystallographic structure of 3n.
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product 3n in 98% yield and 86% ee. The absolute stereo-
configuration of the products was determined by single-crystal
X-ray structural analysis based on the product 3n (Fig. 2).13
In an exploratory study, we demonstrated that product 3c
can be conveniently converted to synthetically useful chiral
D1-pyrrolidine 4 by RANEYs-Ni mediated hydrogenation
with high efficiency (Scheme 1).14
6 (a) D. Enders and M. R. M. Huttl, Synlett, 2005, 991;
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K. A. Jørgensen, Chem.–Eur. J., 2006, 12, 6039.
Scheme 1 Transformation of 3c to chiral D1-pyrrolidine 4.
8 T. Ishimaru, N. Shibata, T. Horikawa, N. Yasuda, S. Nakamura,
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In conclusion, we have uncovered an unprecedented organo-
catalytic, enantioselective conjugate addition reaction of
a-fluoroketoester and nitroolefins. The process is efficiently
catalyzed by a readily available chiral cinchona alkaloid
derivative using as low as 1 mol%. Significantly, a fluorine
containing quaternary carbon center and an adjacent chiral
carbon center are created with an excellent level of enantio-
selectivity and in high yields in the conjugate addition process.
In principle, the strategy we have described can be extended to
other fluorinated nucleophilic reagents and Michael receptors.
This constitutes our future direction aimed at expanding
the scope of powerful organocatalytic processes for the
asymmetric synthesis of fluorine containing compounds.
Financial support for this work provided by the NSF
(CHE-0704015) is gratefully acknowledged. Thanks are
expressed to Dr Elieen N. Duesler for performing X-ray
analysis. The Bruker X8 X-ray diffractometer was purchased
via an NSF CRIF:MU award to the University of New
Mexico, CHE-0443580.
9 D. Y. Kim and E. J. Park, Org. Lett., 2002, 4, 545.
10 For selected examples using ketoesters as nucleophiles for
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11 See an example of non-enolizable ketoesters in the synthesis of
PDE4 inhibitor IC86518: P. J. Nichols, J. A. DeMattei,
B. R. Barnett, N. A. LeFur, T.-H. Chuang, A. D. Piscopio and
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13 See ESIw for details.
Notes and references
1 For reviews on applications of fluorinated compounds in medicinal
chemistry and drug discovery, see: (a) Biomedical Frontiers of
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J. T. Welch, ACS, Washington DC, 1996; (b) P. Kirsch, Modern
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14 D1-Pyrrolidines are useful building blocks in organic synthesis, see:
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4253; (b) J. M. Carney, P. J. Donoghue, W. M. Wuest, O. Wiest
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This journal is The Royal Society of Chemistry 2009
2138 | Chem. Commun., 2009, 2136–2138