Asymmetric generation of fluorine-containing quaternary carbons adjacent to tertiary stereocenters: Uses of fluorinated methines as nucleophiles

Article abstract of DOI:10.1039/b823184b

Organocatalytic asymmetric Michael reactions of fluorinated nucleophiles with nitroolefins catalyzed by Cinchona alkaloid-derived thiourea catalysts generated the desired Michael products containing vicinal fluorinated quaternary and tertiary chiral cente

Full text of DOI:10.1039/b823184b

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Asymmetric generation of fluorine-containing quaternary carbons
adjacent to tertiary stereocenters: uses of fluorinated methines as
nucleophilesw
Xiao Han,a Jie Luo,a Chen Liuab and Yixin Lu*ab
Received (in Cambridge, UK) 24th December 2008, Accepted 11th February 2009
First published as an Advance Article on the web 26th February 2009
DOI: 10.1039/b823184b
Organocatalytic asymmetric Michael reactions of fluorinated
nucleophiles with nitroolefins catalyzed by Cinchona alkaloid-
derived thiourea catalysts generated the desired Michael
products containing vicinal fluorinated quaternary and tertiary
chiral centers with exceptional enantioselectivity.
Fig. 1 Construction of adjacent fluorinated quaternary tertiary
stereocenters.
Fluorinated compounds are of central importance in medicinal
chemistry.1 Substitution of a hydrogen atom or hydroxyl
fluorine-containing quaternary carbons adjacent to tertiary
stereocenters using fluorinated methines as nucleophiles.
Optically pure a-substituted a-fluorinated b-ketoesters are
important molecules, which are regarded as non-enolizable
b-ketoesters, and the presence of carbonyl and carboxylic acid
functional groups allows for facile synthetic manipulations.
To construct chiral acyclic a-fluorinated a-substituted
b-ketoesters9 adjacent to a tertiary stereocenter (Fig. 1), one
direct approach is to perform asymmetric fluorination on the
a-substituted b-ketoester. Up to the present time, an efficient
asymmetric organocatalytic fluorination of b-ketoester is yet
to be discovered, presumably due to the facile enol formation
and the subsequent competing non-stereoselective fluorination
reaction. We envisioned that employment of a fluorinated
nucleophile could be an easy solution, as the carbon–carbon
bond-forming reactions of this type of substrate are well-
established in the literature.10
group in biologically active molecules with a fluorine atom
often renders improved physiological properties to the drug
candidates. Thus it is not surprising that asymmetric synthesis
of organofluorine compounds has drawn much attention in
recent years.2
Construction of quaternary stereocenters is one of the most
challenging tasks in organic synthesis, and impressive progress
has been made in the past decade.3 Catalytic synthesis of chiral
fluorinated quaternary carbon centers poses a daunting
synthetic challenge, and a number of excellent approaches
based on metal catalysis appeared in the literature recently.4 In
contrast to the transition metal-based fluorination methods,
organocatalytic approaches for the preparation of fluorinated
quaternary centers are rather limited. The phase transfer
catalyst-promoted fluorination developed by Kim and Park
was the first organocatalytic example in the literature.5
Jørgensen et al. reported a direct a-fluorination of a-branched
aldehydes to access fluorinated quaternary centers.6 Recently,
Shibata and co-workers disclosed a bis-Cinchona alkaloid-
promoted enantioselective fluorination of allyl silanes, silyl
enol ethers and oxindoles.7
In our initial studies, a number of a-unsubstituted and
a-substituted b-ketoesters were selected as nucleophiles, and
their Michael additions to nitroolefins catalyzed by Cinchona
alkaloid-based thiourea bifunctional organocatalysts11 were
examined (Table 1). The a-unsubstituted b-ketoesters led to
the formation of the products with high enantioselectivity, but
virtually no diastereoselectivity was observed (entries 1–3).
Methyl substitution at the a-position did not improve the
diastereoselectivity (entry 4). The b-ketoesters with a-fluorine
atoms gave very promising results, and the ketone moieties in
the nucleophiles were important in stereochemical control.
While the methyl ketone led to the formation of low
diastereoselective products (entry 5), the combination of
phenyl ketone and a-fluorinated nucleophilic groups yielded
the desired products with moderate diastereoselectivity and
excellent enantioselectivity (entry 6). Different Cinchona
alkaloid-derived catalysts showed similar catalytic activities,
and trifluoromethyl-substituted thioureas worked slightly
better than the non-fluorinated counterparts (entries 7–11).
After solvent screening and lowering the reaction temperature
to ꢀ20 1C, we were able to prepare the desired adduct 3f with a
6 : 1 dr and 97% ee (entry 16).
We became interested in developing an organocatalytic
approach to access chiral fluorinated quaternary stereogenic
centers adjacent to tertiary stereocenters. Stereoselective
synthesis of vicinal quaternary and tertiary stereogenic centers
is a formidable challenge in organic synthesis, and highly
enantioselective methods to access these structural motifs
are scarce.8 To the best of our knowledge, enantioselective
construction of fluorinated quaternary carbons adjacent to
tertiary stereocenters is unknown in the literature. Herein, we
wish to report a Cinchona alkaloid-catalyzed construction of
a Department of Chemistry, National University of Singapore,
Singapore, Republic of Singapore. E-mail: chmlyx@nus.edu.sg;
Fax: +65-6779-1691; Tel: +65-6516-1569
b Medicinal Chemistry Program, Life Sciences Institute, National
University of Singapore, Singapore, Republic of Singapore
w Electronic supplementary information (ESI) available: Experimental
details, analytical data, HPLC chromatogram and NMR spectra of
products. See DOI: 10.1039/b823184b
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Table 1 Screening of organocatalysts for the asymmetric Michael
addition to nitroolefina
Table 2 Diastereoselective and enantioselective Michael addition of
a-fluorinated b-ketoester 1f to various nitroolefinsa
Entry
R
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
9
10
11e
12e
13
p-F-Ph
99
98
97
98
96
96
97
99
98
97
95
96
5 : 1
5 : 1
5 : 1
4 : 1
5 : 1
5 : 1
3 : 1
5 : 1
8 : 1
6 : 1
6 : 1
6 : 1
—
98
99
97
99
96
97
99
99
98
96
97
96
—
m-Br-Ph
p-Br-Ph
o-Cl-Ph
p-Me-Ph
p-OMe-Ph
o-CF3-Ph
p-CN-Ph
o-OMe-Ph
2-Thiophene
n-Butyl
Isobutyl
Cyclohexyl
f
—
Entry
Product
Catalyst
Solvent
drb
eec (%)
a
The reactions were performed with ketoester (0.05 mmol), nitroolefin
(0.05 mmol) and catalyst (0.005 mmol) in solvent (0.1 mL).
Diastereomers of 5a, 5b and 5e were separable by column chromato-
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
QD-1b
QD-1b
QD-1b
QD-1b
QD-1b
CD-1a
CD-1b
Q-1a
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH3Cl
1 : 1
1 : 1
2 : 3
2 : 3
3 : 2
4 : 1
5 : 1
4 : 1
5 : 1
4 : 1
5 : 1
5 : 1
2 : 1
4 : 1
2 : 1
6 : 1
82/92
85/85
88/88
93/94
91/90
ꢀ90
ꢀ94
ꢀ93
ꢀ94
91
94
91
92
92
88
97
graphy. Isolated yield. Determined by 1H NMR analysis of the
d
crude product. The ee value of the major diastereomer, determined
b
c
e
f
by chiral HPLC analysis. Reactions were run for 48 h. No reaction
after 48 h.
9
Q-1b
10
11
12
13
14
15
16d
QD-1a
QD-1b
QD-1b
QD-1b
QD-1b
QD-1b
QD-1b
Table 3 Asymmetric Michael addition of different a-fluorinated
b-ketoestersa
THF
CH2Cl2
Acetone
Toluene
a
The reactions were performed with ketoester (0.05 mmol), nitroolefin
(0.05 mmol) and catalyst (0.005 mmol) in solvent (0.1 mL) at room
temperature, unless otherwise specified. Yields were estimated by
1H NMR analysis of the crude product. For entries 1–4, the reactions
Entry
R/Ar/R0
Yieldb (%)
drc
eed (%)
were run for 12 h. Determined by 1H NMR analysis of the
b
1
2
3
4
5
6
7
8
p-OMe-Ph/Ph/Et
m-Cl-Ph/Ph/Et
m-Cl-Ph/p-F-Ph/Et
p-NO2-Ph/Ph/Et
p-NO2-Ph/p-Me-Ph/Et
p-NO2-Ph/m-Br-Ph/Et
p-CF3-Ph/Ph/Et
p-CF3-Ph/o-Cl-Ph/Et
t-Bu/p-Br-Ph/Et
97
98
97
98
96
98
97
96
90
90
65
4 : 1
4 : 1
4 : 1
4 : 1
3 : 1
4 : 1
3 : 1
3 : 1
97
96
96
97
96
97
95
95
97
98
98
c
crude product. The ee values of both diastereomers or the major
d
diastereomers, determined by chiral HPLC analysis. The reaction
was carried out at ꢀ20 1C.
The generality of the reaction was then examined, and the
results are summarized in Table 2. A wide range of aryl
and alkyl nitroolefins could be used as Michael acceptors. In
all the examples studied, quantitative yields and virtually
perfect enantioselectivities were achieved. Cyclohexylvinyl
benzene proved to be ineffective, presumably due to the steric
hindrance induced by the substituent (entry 13).
9e
10e
11f
19 : 1
19 : 1
2.5 : 1
t-Bu/p-OMe-Ph/Et
Ph/o-Cl-Ph/t-Bu
a
The reactions were performed with ketoester (0.05 mmol), nitroolefin
b
(0.05 mmol) and catalyst (0.005 mmol) in solvent (0.1 mL). Isolated
c
1
d
yield. Determined by H NMR analysis of the crude product. The
ee value of the major diastereomer, determined by chiral HPLC
e
analysis. Reactions were carried out at room temperature for
We next explored the effects of various ketone components
in the asymmetric induction (Table 3). Different aryl ketones
could be employed, generating the desired adducts with
moderate diastereoselectivity and excellent enantioselectivity
(entries 1–8). When tert-butyl ketone was utilized, very high
diastereoselectivity was attainable, and the enantioselectivity
of the Michael additions remained near perfect (entries 9
and 10). However, tert-butyl ester turned out to be less
effective; much longer reaction time was required to achieve
moderate chemical yield, and there was no improvement in
diastereoselectivity (entry 11).12
f
24 h. The reaction was run at room temperature for 48 h.
The conjugate addition adducts containing vicinal fluorinated
quaternary carbons and tertiary stereogenic centers can be
readily converted into synthetically useful chiral structural
scaffolds with three contiguous stereogenic centers (Scheme 1).
Reduction of the nitro group to amino functionality, followed by
reductive amination yielded highly substituted chiral pyrrolidine
10. Alternatively, selective reduction of ketone, subsequent nitro
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Scheme 1 Conversion of fluorinated Michael adduct to a chiral
pyrrolidine and lactam.
reduction and spontaneous cyclization led to the ready formation
of optically pure lactam 9.13
In summary, we have disclosed a highly enantioselective
organocatalytic generation of fluorinated quaternary stereogenic
centers adjacent to tertiary stereocenters, by employing
fluorine-containing methines as nucleophiles. We believe that
such an approach could complement the existing asymmetric
fluorination method to access a wide range of chiral fluorinated
molecules. Our results represent the first example in the
literature that a-fluorinated b-ketoesters were used as
nucleophiles, and highly functional, congested fluorinated
quaternary and chiral tertiary centers could be efficiently
constructed. Investigations to understand the origin of the
observed high enantioselectivity, and the full extension of the
scope of our approach employing fluorinated nucleophiles are
in progress in our laboratory, and will be reported in due
course.
5 D. Y. Kim and E. J. Park, Org. Lett., 2002, 4, 545.
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K. A. Jørgensen, Chem.–Eur. J., 2006, 12, 6039.
7 T. Ishimaru, N. Shibata, T. Horikawa, N. Yasuda, S. Nakamura,
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D. W. C. MacMillan, Proc. Natl. Acad. Sci. U. S. A., 2004, 101,
5482.
9 Chiral acyclic substituted b-ketoesters are rare in the literature. In
most cases, cyclic b-ketoesters were used as the substrates. For
selected examples, see ref. 8a, 10c and d.
10 For selective enantioselective organocatalytic reactions involving
b-ketoesters, see: (a) F. Wu, H. Li, R. Hong and L. Deng, Angew.
Chem., Int. Ed., 2006, 45, 947; (b) F. Wu, R. Hong, J. Khan, X. Liu
and L. Deng, Angew. Chem., Int. Ed., 2006, 45, 4301; (c) T. Okino,
Y. Hoashi, T. Furukawa, X. Xu and Y. Takemoto, J. Am. Chem.
Soc., 2005, 127, 119; (d) T. B. Poulsen, L. Bernardi, J. Aleman,
J. Overgaard and K. A. Jørgensen, J. Am. Chem. Soc., 2007, 129,
441.
We thank the National University of Singapore and the
Ministry of Education (MOE) of Singapore (R-143-000-
362-112) for generous financial support.
11 For a review on Cinchona alkaloid-based urea and thiourea
organocatalysts, see: S. J. Connon, Chem. Commun., 2008, 2499.
12 The extension of current methodology to a-fluorinated nitro esters
and a-fluorinated cyano esters was unsuccessful, no desired
products were formed under the same activation conditions.
13 For recent examples of constructing chiral pyrrolidines and lac-
tams, see: (a) T. A. Johnson, D. O. Jang, B. W. Slafer, M. D. Curtis
and P. Beak, J. Am. Chem. Soc., 2002, 124, 11689; (b) C. Najera,
M. G. Retamosa and J. M. Sansano, Angew. Chem., Int. Ed., 2008,
47, 6055.
Notes and references
1 For general reviews on fluorinated compounds in medicinal chem-
istry, see: (a) K. Muller, C. Faeh and F. Diederich, Science, 2007,
317, 1881; (b) K. L. Kirk, Org. Process Res. Dev., 2008, 12, 305.
2 For recent reviews, see: (a) K. Mikami, Y. Itoh and M. Yamanaka,
Chem. Rev., 2004, 104, 1; (b) V. A. Brunet and D. O’Hagan,
Angew. Chem., Int. Ed., 2007, 46, 1179; (c) G. K. S. Prakash and
P. Beier, Angew. Chem., Int. Ed., 2006, 45, 2172; (d) P. M. Pihko,
Angew. Chem., Int. Ed., 2006, 45, 544; (e) M. Oestreich, Angew.
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This journal is The Royal Society of Chemistry 2009
2046 | Chem. Commun., 2009, 2044–2046