Organocatalytic asymmetric synthesis of 3-difluoroalkyl 3-hydroxyoxindoles

Article abstract of DOI:10.1039/c2cc17140f

We report the first example of highly enantioselective organocatalytic synthesis of 3-difluoroalkyl substituted 3-hydroxyoxindoles. The total synthesis of the difluoro analogue of convolutamydine E was achieved by this method.

Full text of DOI:10.1039/c2cc17140f

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COMMUNICATION
Organocatalytic asymmetric synthesis of 3-difluoroalkyl
3-hydroxyoxindoleswz
Yun-Lin Liua and Jian Zhou*ab
Received 17th November 2011, Accepted 16th December 2011
DOI: 10.1039/c2cc17140f
We report the first example of highly enantioselective organocatalytic
synthesis of 3-difluoroalkyl substituted 3-hydroxyoxindoles. The total
synthesis of the difluoro analogue of convolutamydine E was achieved
by this method.
The selective introduction of fluoroalkyl groups has become a
powerful strategy to modulate the pharmacological properties
of compounds in drug design.1 In this context, the incorporation
of difluoroalkyl unit is of current interest,2 since the gem-difluoro-
methylene group can influence the properties of its neighboring
Scheme 1 Dramatic difluorine effects.
groups, and increase the lipophilicity, metabolic stability and
bioavailability of the compounds.3 For example, eflornithine4a
and gemcitabine4b are rationally designed drugs. Given that
3-substituted 3-hydroxyoxindoles are widely present in bioactive
natural products and drugs and the C3 substituents greatly
influence their biological activities,5 we are interested in the catalytic
synthesis of enantioenriched 3-difluoroalkyl 3-hydroxyoxindoles.6,7
Surprisingly, while much progress has been made in the
trifluoro- and monofluoromethylation reactions,1c–e catalytic
asymmetric difluoromethylation remains a challenge.2a,8 No
successful catalytic asymmetric addition of difluoroalkyl-
containing nucleophiles to aldehydes or ketones has been
reported.8 The addition of TMSCF2SO2Ph or TMSCF2SePh to
carbonyl compounds was independently pioneered by Hu et al.8a
and Shibata et al.1f (with up to 64% ee). Alternatively, Bandini
et al.8b and Ma et al.8c tried the addition of CH3NO2 or indole to
a-CF2H aryl ketones, with excellent ee for limited examples.
In this context, the challenge was possibly due to the
dramatic difluorine effects on the reactivity. For example, we
found that a thiourea catalyst could catalyze the Strecker
reaction of acetophenone derived ketoimines alone using
TMSCN, but could not catalyze that of a-CF2H ketoimines.8f
While Zhao et al. reported that bifunctional catalyst 3
promoted the aldol reaction of isatin 1a and acetophenone 2
well (Scheme 1),5d we found that it could not catalyze the
reaction of isatin 1a and a-CF2H ketone 5a. In addition, we
also observed that the deprotonation of ketone 5b by NaH
to react with TMSCl selectively afforded silyl enol ether 6 at
ꢀ78 or 0 1C, and no difluoroenoxysilane 7a was detected by
NMR analysis. Accordingly, the identification of an effective
method to enable easily available difluoroalkyl-containing
reagents for reaction design would give an impetus in this
field. Here, we report that nitrogen based Lewis bases could
effectively activate difluoroenoxysilanes 79 for a highly enantio-
selective synthesis of 3-difluoroalkyl 3-hydroxyoxindoles.
Although difluoroenoxysilane 7 is a versatile synthon for
difluoro compounds, its application in asymmetric catalysis
was rare.8d,e The only successful example was a phosphoric
acid catalyzed Mannich reaction of 7 and aryl aldimines
developed by Akiyama et al.8e Since Lewis acid catalyzed
reactions of 7 and aldehydes suffered from high catalyst
loading or low efficiency,9a–c we focused on the use of organo-
catalysts for reaction development. After optimization (see
ESIz), cinchona alkaloid derived bifunctional (thio)urea
catalysts 3, 9, 1010 turned out to be promising for the reaction
of silyl enol ether 7b and isatin 1b, using CH2Cl2 as the solvent
at 0 1C (entries 1–3, Table 1), and quinine derived urea catalyst
10 could afford product 8a in 91% yield with 80% ee (entry 3).
The reaction possibly proceeded via the dual activation of both
isatin 1b by urea11 part of the catalyst and silyl enol ether 7b by
the tertiary amine moiety as a Lewis base for the activation of
trimethylsilyl nucleophiles.12 As is demonstrated, thiourea 11
could not catalyze this reaction (entry 4), but DMAP 12 could
catalyze efficiently to give product 8a in 95% yield (entry 5),
and the combination of 11 and 12 could afford product 8a in
11% ee (entry 6). Further optimization revealed that THF was
the optimal solvent (entry 7). Then the evaluation of substrate
a Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal University,
3663N, Zhongshan Road, Shanghai 200062, P. R. China.
E-mail: jzhou@chem.ecnu.edu.cn; Fax: +86-21-6223-4560
b State Key Laboratory of Elemento-organic Chemistry,
Nankai University, Tianjin 300071, P. R. China
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
details and spectral data. See DOI: 10.1039/c2cc17140f
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1919–1921 1919

Table 1 Condition optimizations
isolated as a 7k/DMF mixture in a ratio of 1 : 0.3. This impure
7k reacted with isatin 1b under the standard reaction conditions
to afford the desired product 8q in 65% ee with 27% yield.
Unfortunately, DMF was found to have negative effect on both
the reactivity and enantioselectivity.
Entrya
Cat.
Solvent
Time/d
Yieldb (%)
eec (%)
The thus obtained enantioenriched adducts were versatile
building blocks for a variety of fluorinated compounds. For
example, the reductive cyclization of product 8a readily
afforded the fluorinated 3a-hydroxyfuroindoline 13 in 75%
yield and 5 : 1 dr, without loss of enantioselectivity.
1
2
3
4
5
6
7
3
9
10
11
12
11 + 12
10
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
3
3
3
3
1
3
3
85
86
91
—
95
94
93
79d
73
80
—
—
11
94
a
b
c
On a 0.10 mmol. Isolated yield. Determined by chiral HPLC
d
analysis. Opposite enantiomer.
We further tried the synthesis of difluoro analogues of
convolutamydines A–E (Scheme 2),13 whose bioactivity was greatly
affected by the C3 side chains. For example, convolutamydine A
exhibited potent inhibitory activity on the differentiation of HL-60
human promyelocytic leukaemia cells at 0.1 mg mLꢀ1 activity, but
Table 2 Substrate scopea–c
convolutamydine B at 12.5 mg mLꢀ1 13a,b
The synthesis of
.
their difluoro analogues would be interesting to modulate their
properties for drug discovery.
Quinidine derived catalyst 3 was used for the reaction of
isatin 1j and 7c since the configuration of convolutamydines is
R. Product 8r was obtained in 76% yield with 90% ee (99% ee
after one recrystallization). The Baeyer–Villiger oxidation of 8r
gave 14 in 85% yield without loss of ee. By choosing the correct
reduction condition, the 3a-hydroxyfuroindoline 15 could
be obtained in 78% yield and 92% ee in two steps from 8r,
and difluoro analogue of convolutamydine E 16 could be
readily prepared in 52% yield with 98% ee (2 steps from 8r).
Compounds 13 and 15 can be potentially used for the synthesis
of the difluoro analogues of (+)-madindoline.14
It should be noted that our result is the first example of
organocatalytic asymmetric synthesis of tertiary alcohols via
the addition of trimethylsilyl enol ethers to ketones.15 In
addition, highly enantioselective Mukaiyama-aldol reaction
catalyzed by a bifunctional chiral nitrogen-based uncharged
Lewis base is unprecedented.11 All the known Lewis base
catalyzed protocols relied on the use of chiral salts such as
a
b
On a 0.25 mmol. Isolated yield. Determined by HPLC analysis.
c
scope with respect to both difluoroenoxysilanes and electro-
philes was carried out by running the reaction in THF at 0 1C,
with 10 mol% of catalyst 10 (Table 2).
Different aryl substituted difluoroenoxysilanes 7b–i gave
corresponding products 8a–h in high yield with excellent ee.
Only 2-thienyl substituted enol ether 7j provided product 8i in
moderate yield with 88% ee. A variety of substituted isatins
worked well to give the desired adducts 8j–p in excellent ee
with high yield. Unfortunately, a-aliphatic substituted difluoro-
enoxysilanes could not be prepared as ‘‘pure’’ compounds9a (for
details, see ESIz). For example, difluoroenoxysilane 7k was
Scheme 2 Synthesis of difluoro analogues of A–E.
c
1920 Chem. Commun., 2012, 48, 1919–1921
This journal is The Royal Society of Chemistry 2012

(c) L. Liu, S. Zhang, F. Xue, G. Lou, H. Zhang, S. Ma, W. Duan
and W. Wang, Chem.–Eur. J., 2011, 17, 7791; (d) Q. Guo,
M. Bhanushali and C.-G. Zhao, Angew. Chem., Int. Ed., 2010,
49, 9460; (e) K. Aikawa, S. Mimura, Y. Numata and K. Mikami,
Eur. J. Org. Chem., 2011, 62; (f) K. Zheng, C. Yin, X. Liu, L. Lin and
X. Feng, Angew. Chem., Int. Ed., 2011, 50, 2573; (g) L. Yin, M. Kanai
and M. Shibasaki, Angew. Chem., Int. Ed., 2011, 50, 7620; (h) K. Shen,
X. Liu, L. Lin and X. Feng, Chem. Sci., 2011, DOI: 10.1039/c1sc00544h.
6 For our efforts in this area: (a) Y.-L. Liu, B.-L. Wang, J.-J. Cao,
L. Chen, Y.-X. Zhang, C. Wang and J. Zhou, J. Am. Chem. Soc.,
2010, 132, 15176; (b) M. Ding, F. Zhou, Y.-L. Liu, C.-H. Wang,
X.-L. Zhao and J. Zhou, Chem. Sci., 2011, 2, 2035; (c) Z.-Y. Cao,
Y. Zhang, C.-B. Ji and J. Zhou, Org. Lett., 2011, 13, 6398;
(d) Z.-Q. Qian, F. Zhou, T.-P. Du, B.-L. Wang, M. Ding,
X.-L. Zhao and J. Zhou, Chem. Commun., 2009, 6753;
(e) F. Zhou, M. Ding, Y.-L. Liu, C.-H. Wang, C.-B. Ji,
Y.-Y. Zhang and J. Zhou, Adv. Synth. Catal., 2011, 353, 2945.
7 For reaction of 3-prochiral oxindoles with electrophilic fluorinating
reagents or ethyl trifluoropyruvate: (a) N. Shibata, J. Kohno, K. Takai,
T. Ishimaru, S. Nakamura, T. Toru and S. Kanemasa, Angew. Chem.,
Int. Ed., 2005, 44, 4204; (b) Y. Hamashima, T. Suzuki, H. Takano,
Y. Shimura and M. Sodeoka, J. Am. Chem. Soc., 2005, 127, 10164;
(c) S. Ogawa, N. Shibata, J. Inagaki, S. Nakamura, T. Toru and
M. Shiro, Angew. Chem., Int. Ed., 2007, 46, 8666. For 3-CF3-3-
hydroxyoxindole from chiral synthon, see: (d) S. Ogawa, N. Iida,
E. Tokunaga, M. Shiro and N. Shibata, Chem.–Eur. J., 2010, 16, 7090.
8 (a) C. Ni, F. Wang and J. Hu, Beilstein J. Org. Chem., 2008, 4, DOI:
10.3762/bjoc.4.21; (b) M. Bandini, R. Sinisi and A. Umani-Ronchi,
Chem. Commun., 2008, 4360; (c) J. Nie, G.-W. Zhang, L. Wang,
A. Fu, Y. Zheng and J.-A. Ma, Chem. Commun., 2009, 2356. For
synthesis of chiral amines with an a-difluoroalkyl group: (d) Z. Yuan,
Y. Wei and M. Shi, Chin. J. Chem., 2010, 28, 1709; (e) W. Kashikura,
K. Mori and T. Akiyama, Org. Lett., 2011, 13, 1860; (f) Y.-L. Liu,
T.-D. Shi, F. Zhou, X.-L. Zhao, X. Wang and J. Zhou, Org. Lett.,
2011, 13, 3826; (g) M.-W. Chen, Y. Duan, Q.-A. Chen, D.-S. Wang,
C.-B. Yu and Y.-G. Zhou, Org. Lett., 2010, 12, 5075.
9 (a) H. Amii, T. Kobayashi, Y. Hatamoto and K. Uneyama, Chem.
Commun., 1999, 1323; (b) F. Chorki, F. Grellepois, B. Crousse,
M. Ourevitch, D. Bonnet-Delpon and J.-P. Begue, J. Org. Chem.,
2001, 66, 7858; (c) Z.-L. Yuan, Y. Wei and M. Shi, Tetrahedron, 2010,
66, 7361; (d) Y. Guo and J.-M. Shreeve, Chem. Commun., 2007, 3583.
10 For reviews on cinchona alkaloids, see: (a) S. K. Tian, Y. Chen,
J. Hang, L. Tang, P. McDaid and L. Deng, Acc. Chem. Res., 2004,
37, 621; (b) S. J. Connon, Chem. Commun., 2008, 2499; (c) C. Palomo,
M. Oiarbide and R. Lopez, Chem. Soc. Rev., 2009, 38, 632; (d) E. M.
O. Yeboah, S. O. Yeboah and G. S. Singh, Tetrahedron, 2011,
67, 1725; (e) T. Marcelli and H. Hiemstra, Synthesis, 2010, 1229.
11 For reviews on Brønsted acid catalysis, see: (a) T. Akiyama, Chem.
Rev., 2007, 107, 5744; (b) A. G. Doyle and E. N. Jacobsen, Chem.
Rev., 2007, 107, 5713; (c) Z. Zhang and P. R. Schreiner, Chem. Soc.
Rev., 2009, 38, 1187; see for examples: (d) L. Ratjen, P. Garcia-
Garcia, F. Lay, M. E. Beck and B. List, Angew. Chem., Int. Ed., 2011,
50, 754; (e) J. D. McGilvra, A. K. Unni, K. Modi and V. H. Rawal,
Angew. Chem., Int. Ed., 2006, 45, 6130; (f) W. Zhuang, T. B. Poulsen
and K. A. Jørgensen, Org. Biomol. Chem., 2005, 3, 3284.
Scheme 3 Proposed transition states.
quaternary ammonium salts11c,d and carboxylate-ammonium
salts,11e with counter anions as anionic Lewis base catalysts to
activate trimethylsilyl enol ethers.
Based on the absolute configuration of the product 8, a
plausible mechanism was proposed for the observed enantio-
facial control of this reaction. As shown in Scheme 3, the
activation of difluoroenoxysilane 7 by the tertiary amine in the
quinine urea catalyst backbone forms a reactive pentacoordinate
silicate12a,b to react with isatin 1 which was activated by the urea
part of the catalyst 10 through H-bonding interaction. The
bifunctional catalysis was supported by the results shown in
Table 1 (entries 4–6). Among the two possible orientations, the
isatin was organized to avoid the unfavorable interaction
between the isatin benzene ring and the enolate, which made
the attack of the enolate from the Re face of the isatin favorable
to afford the S-enantiomer as the major product.5d
In conclusion, we have developed a highly enantioselective
synthesis of 3-difluoroalkyl 3-hydroxyoxindoles. Most importantly,
the identification of nitrogen-based Lewis bases as effective catalysts
to activate difluoroenoxysilane 7 would offer the premise of a
straightforward method for the catalytic asymmetric construction
of stereogenic carbon centers featuring a difluoroalkyl group.
The financial support from the NSFC (20902025, 21172075),
Innovation Program of SMEC (12ZZ046), Shanghai Pujiang
Program (10PJ1403100), and the 973 program (2011CB808600)
is highly appreciated.
Notes and references
1 For reviews, see: (a) L. Hunter, Beilstein J. Org. Chem., 2010, 6, DOI:
10.3762/bjoc.6.38; (b) D. O’Hagan, Chem. Soc. Rev., 2008, 37, 308;
(c) J. Nie, H.-C. Guo, D. Cahard and J.-A. Ma, Chem. Rev., 2011,
111, 455; (d) G. Valero, X. Company and R. Rios, Chem.–Eur. J.,
2011, 17, 2018; (e) D. Cahard, X. Xu, S. Couve-Bonnaire and
X. Pannecoucke, Chem. Soc. Rev., 2010, 39, 558; (f) N. Shibata,
S. Mizuta and H. Kawai, Tetrahedron: Asymmetry, 2008, 19, 2633.
2 (a) J. Hu, W. Zhang and F. Wang, Chem. Commun., 2009, 7465;
(b) M. J. Tozer and T. F. Herpin, Tetrahedron, 1996, 52, 8619;
(c) G. K. S. Prakash, J. Hu, T. Mathew and G. A. Olah, Angew.
Chem., Int. Ed., 2003, 42, 5216; (d) Y. Li and J. Hu, Angew. Chem.,
Int. Ed., 2007, 46, 2489; (e) P. V. Ramachandran, A. Tafelska-
Kaczmarek and K. Sakavuyi, Org. Lett., 2011, 13, 4044.
12 (a) S. E. Denmark and G. L. Beutner, Angew. Chem., Int. Ed.,
2008, 47, 1560; (b) J. Gawronski, N. Wascinska and J. Gajewy,
Chem. Rev., 2008, 108, 5227; (c) T. Ooi and K. Maruoka, Acc.
Chem. Res., 2004, 37, 526; (d) M. Horikawa, J. Busch-Petersen and
E. J. Corey, Tetrahedron Lett., 1999, 40, 3843; (e) R. P. Singh,
B. M. Foxman and L. Deng, J. Am. Chem. Soc., 2010, 132, 9558.
13 (a) Y. Kamano, H.-P. Zhang, Y. Ihihara, H. Kizu, K. Komiyama
and G. R. Pettit, Tetrahedron Lett., 1995, 36, 2783; (b) Y. Kamano,
A. Kotake, H. Hashima, I. Hayakawa, H. Hiraide, H. Zhang,
H. Kizu, K. Komiyama, M. Hayashi and G. R. Pettit, Collect. Czech.
Chem. Commun., 1999, 64, 1147; for the first example of total
synthesis of convolutamydine E, see: (c) N. Hara, S. Nakamura,
N. Shibata and T. Toru, Chem.–Eur. J., 2009, 15, 6790.
3 (a) C. Pesenti and F. Viani, ChemBioChem, 2004, 5, 590;
(b) J. A. Erickson and J. I. McLoughlin, J. Org. Chem., 1995,
60, 1626; (c) D. B. Damon and D. J. Hoover, J. Am. Chem. Soc.,
1990, 112, 6439.
14 T. Hirose, T. Sunazuka, T. Shirahata, D. Yamamoto, Y. Harigaya,
¯
I. Kuwajima and S. Omura, Org. Lett., 2002, 4, 501.
4 (a) P. Bey, F. Gerhart, V. V. Dorsselaer and C. Danzin, J. Med.
Chem., 1983, 26, 1551; (b) N. M. F. S. A. Cerqueira,
P. A. Fernandes and M. J. Ramos, Chem.–Eur. J., 2007, 13, 8507.
5 (a) F. Zhou, Y.-L. Liu and J. Zhou, Adv. Synth. Catal., 2010, 352, 1381;
(b) S. Peddibhotla, Curr. Bioact. Compd., 2009, 5, 20; Also see:
15 (a) T. Mukaiyama, Angew. Chem., Int. Ed., 2004, 43, 5590;
(b) S. Adachi and T. Harada, Eur. J. Org. Chem., 2009, 3661;
(c) M. Bella and T. Gasperi, Synthesis, 2009, 1583; For the only example
of addition of trichlorosilyl enolates to ketones, see: (d) S. E. Denmark,
Y. Fan and M. D. Eastgate, J. Org. Chem., 2005, 70, 5235.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1919–1921 1921