Angewandte
Chemie
DOI: 10.1002/anie.200800717
Fluorination
Cinchona Alkaloid Catalyzed Enantioselective Fluorination of Allyl
Silanes, Silyl Enol Ethers, and Oxindoles**
Takehisa Ishimaru, Norio Shibata,* Takao Horikawa, Naomi Yasuda, Shuichi Nakamura,
Takeshi Toru, and Motoo Shiro
The enantioselective incorporation of fluorine into organic
molecules has been extensively exploited because chiral
À
functional groups with a C F unit have attractive properties
for pharmaceutical and materials applications.[1] The first
results on catalytic enantioselective fluorination were
reported by Togni et al. in 2000 for the reaction of b-keto
esters using TiIV/TADDOL catalysts.[2a] Since then, several
methods for the catalytic enantioselective fluorination of 1,3-
dicarbonyl compounds and related substrates have been
developed.[2,3] The enantioselective fluorination of aldehydes
catalyzed by proline and its analogues is also a recent topic in
this field.[4] However, a major limitation of this methodology
Scheme 1. Cinchona alkaloid catalyzed enantioselective fluorination.
is that ketones are poor substrates. Thus, the construction of
compounds containing a chiral quaternary carbon center with
a fluoro substituent remains problematic, with the exception
of the examples reported by Jørgensen et al.[4e]
In 2000 we developed combinations of cinchona alkaloids
and Selectfluor, that is, N-fluoroammonium salts of cinchona
alkaloids, as enantioselective fluorinating reagents,[5a] and
similar reagents were also independently reported by Cahard
et al.[6a] The advantage of these reagents is that a wide range
of substrates including silyl enol ethers, 1,3-dicarbonyl com-
pounds, lactones, oxindoles, dipeptides, and allyl silanes can
BOC=tert-butyloxycarbonyl.
and silyl enol ethers undergo efficient enantioselective
fluorodesilylation with N-fluorobenzenesulfonimide (NFSI)
and a catalytic amount of a bis-cinchona alkaloid in the
presence of excess base to provide the corresponding
fluorinated compounds with a F-substituted quaternary
carbon center with enantioselectivities up to 95% ee. Fur-
thermore, we demonstrate that the methodology can be
effectively extended to the catalytic enantioselective fluori-
nation of oxindoles. The X-ray crystal structure of the bis-
be effectively fluorinated in
a
highly enantioselective
cinchona
alkaloid
dihydroquinine(2,5-diphenyl-4,6-
manner.[6] The asymmetric fluoro semipinacol rearrangement
pyrimidinediyl diether) ((DHQ)2PYR) is also disclosed for
the first time.
of allylic alcohols is also induced by this combination.[6i]
However, this methodology requires
a
stoichiometric
We started by attempting a catalytic version of the
stoichiometric enantioselective fluorodesilylation of allyl
silane 1a described by Gouverneur et al.[6h] (Table 1). Using
a catalytic amount of (DHQ)2PYR and 1.2 equiv of Select-
fluor as the fluorination reagent in CH3CN at 08C, 1a was
converted to allylic fluoride 2a in 46% yield as a racemate
(entry 1, Table 1). We assume that an initial transfer fluori-
nation from Selectfluor to (DHQ)2PYR did not proceed since
Selectfluor reacts more readily with allyl silane 1a than with
the cinchona alkaloid. We next used NFSI as a fluorinating
reagent. Although (R)-2a was produced in 62% yield, the
enantioselectivity was only 19% ee (entry 2, Table 1). To our
great delight, the addition of K2CO3 dramatically improved
the enantioselectivity to 85% ee (entry 3, Table 1), and the
enantioselectivity of 2a was further enhanced to 91–94% ee
by the use of a large excess of K2CO3 (entries 4–7, Table 1).
Solvents also had a considerable effect on the enantioselec-
tivity (entries 8–10, Table 1). The configuration of 2a was
determined to be R by comparing the optical rotation and
HPLC data with the literature values.[6h] It should be
mentioned that the same selectivity for (R)-2a was observed
for the stoichiometric reaction reported by Gouverneur
et al.[6h]
amount of the cinchona alkaloid, and the catalytic version
of the reaction has not been very successful.[7] Herein we
disclose the first successful catalytic enantioselective fluori-
nation based on cinchona alkaloids (Scheme 1). Allyl silanes
[*] T. Ishimaru, Prof. N. Shibata, T. Horikawa, N. Yasuda,
Dr. S. Nakamura, Prof. T. Toru
Department of Applied Chemistry, Graduate School of Engineering
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
Fax: (+81)52-735-5442
E-mail: nozshiba@nitech.ac.jp
Dr. M. Shiro
Rigaku Corporation
3-9-12 Matsubara-cho, Akishima
Tokyo 196-8666 (Japan)
[**] Support was provided by KAKENHI (19390029) and by a Grant-in-
Aid for Scientific Research on the Priority Area “Advanced Molecular
Transformations of Carbon Resources” from the Ministry of
Education, Culture, Sports, Science and Technology Japan
(19020024).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2008, 47, 4157 –4161
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4157