A fundamentally new approach to enantioselective fluorination based on cinchona alkaloid derivatives/selectfluor combination [13]

Full text of DOI:10.1021/ja002732x

10728
J. Am. Chem. Soc. 2000, 122, 10728-10729
A Fundamentally New Approach to Enantioselective
Fluorination Based on Cinchona Alkaloid
Derivatives/Selectfluor Combination
Norio Shibata, Emiko Suzuki, and Yoshio Takeuchi*
Faculty of Pharmaceutical Sciences
Toyama Medical and Pharmaceutical UniVersity
Sugitani 2630, Toyama 930-0194, Japan
Figure 1.
Scheme 1. Fluorination of 1a by Quinine/Selectfluor
Combination
ReceiVed July 26, 2000
Several routes to chiral fluoro-organic compounds recently have
been developed.1 These include, for example, procedures for
diastereoselective fluorination2 of chiral organic compounds and
enantioselective alkylation3 of monofluoro-organic compounds.
A more elegant method for asymmetric introduction of a fluorine
substituent into a molecule involves agent-controlled enantio-
selective fluorination. In this process, fluorine is directly trans-
ferred enantioselectively to an achiral anion.4 Chiral sulfonamide-
type fluorinating agents have been developed for this purpose.5,6
However, these are far from ideal because of low chemical yield
and low optical purity of the fluorinated products. Furthermore,
the agents themselves are still relatively unavailable because their
preparation requires tedious and multistep procedures including
fluorination with toxic molecular fluorine or explosive gaseous
perchloryl fluoride.5 Due to these disadvantages, there is no report
of the use of these agents for asymmetric fluorination except the
original papers.5,6 We report herein a far more practical procedure
for agent-controlled enantioselective fluorination that is carried
out with commercially available agents. Thus, we have discovered
that fluorination of carbanions with Selectfluor occurs in a highly
enantioselective manner when done in the presence of cinchona
alkaloid derivatives, such as dihydroquinine 4-chlorobenzoate
(DHQB) or dihydroqunidine acetate (DHQDA) (Figure 1).
We first examined fluorination of (2-benzyl-3H-inden-1-yloxy)-
trimethyl-silane (1a) with quinine/Selectfluor combination7,8
prepared in situ from quinine and Selectfluor9 in MeCN at room
Table 1. Fluorination of Silyl Enol Ether 1 by DHQB/Selectfluor
Combination
entry
1
n
R
2
yield (%) ee (%)a configurationb
1
1a
1a
1b
1c
1d
1e
1f
1
1
1
1
2
2
2
Bn 2a
Bn 2a
Me 2b
99
86
93
99
94
71
95
89
91
54
73
42
67
71
R
R
R
R
R
R
S
2c
3
4
Et
Me 2d
Et 2e
Bn 2f
2c
5
6d
7
a Determined by HPLC analysis using a Chiralcel OB or OD. b The
absolute configuration of 2 was assigned on the basis of the HPLC
analysis using a Chiralcel compared with the authentic samples prepared
according to ref 6. c Fluorination was carried out at -80 °C in MeCN/
CH2Cl2 (3/4) for 48 h. d Fluorination was carried out at -50 °C in
MeCN/CH2Cl2 (3/4) for 12 h.
(1) (a) Enantiocontrolled Synthesis of Fluoro-organic Compounds;
Soloshonok, V. A., Eds.; John Wiley & Sons: Chichester, 1999. (b) Bravo,
P.; Resnati, G. Tetrahedron: Asymmetry 1990, 1, 661-692.
(2) (a) Welch, J. T.; Seper, K. W. J. Org. Chem. 1988, 53, 2991-2999.
(b) Ihara, M.; Kai, T.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc., Perkin
Trans. 1 1990, 2357-2358. (c) Davis, F. A.; Han, W. Tetrahedron Lett. 1992,
33, 1153-1156. (d) Davis, F. A.; Reddy, R. E. Tetrahedron: Asymmetry 1994,
5, 955-960. (e) Genet, J.-P.; Durand, J.-O.; Roland, S.; Savignac, M.; Jung,
F.; Tetrahedron Lett. 1997, 38, 69-72. (f) Enders, D.; Potthoff, M.; Raabe,
G.; Runsink, J. Angew. Chem., Int. Ed. Engl. 1997, 36, 2362-2364. (g)
McAtee, J. J.; Schinazi, R. F.; Liotta, D. C. J. Org. Chem. 1988, 53, 2161-
2167. (h) Davis, F. A.; Kasu, P. V. N. Tetrahedron Lett. 1998, 39, 6135-
6138.
(3) (a) Arai, S.; Oku, M.; Ishida, T.; Shioiri, T. Tetrahedron Lett. 1999,
40, 6785-6789. (b) Myers, A. G.; McKinstry, L.; Gleason, J. L. Tetrahedron
Lett. 1997, 38, 7037-7040.
(4) Davis, F. A.; Qi, H.; Sundarababu, G. In Enantiocontrolled Synthesis
of Fluoro-organic Compounds; Soloshonok, V. A., Eds.; John Wiley &
Sons: Chichester, 1999; pp 1-32.
(5) (a) Differding, E.; Lang, R. W. Tetrahedron Lett. 1988, 29, 6087-
6090. (b) Davis, F. A.; Han, W. Tetrahedron Lett. 1991, 32, 1631-1634. (c)
Davis, F. A.; Zhou, P.; Murphy, C. K.; Sundarababu, G.; Qi, H.; Han, W.;
Przeslawski, R. M.; Chen, B.-C.; Carroll, P. J. J. Org. Chem. 1998, 63, 2273-
2280.
(6) (a) Takeuchi, Y.; Suzuki, T.; Satoh, A.; Shiragami, T.; Shibata, N. J.
Org. Chem. 1999, 64, 5708-5711. (b) Takeuchi, Y.; Satoh, A.; Suzuki, T.;
Kameda, A.; Dohrin, M.; Satoh, T.; Koizumi, T.; Kirk, K. L. Chem. Pharm.
Bull. 1997, 45, 1085-1088.
temperature. We were encouraged to find that (R)-2-benzyl-2-
fluoroindanone (2a) was formed in 80% yield with 40% ee
(Scheme 1).
The preliminary result encouraged us to investigate other
systems in an attempt to improve enantioselectivity. After
screening several commercially available cinchona alkaloids10 as
our chiral source, we found that the DHQB/Selectfluor combina-
tion in MeCN at -20 °C effected the enantioselective fluorination
of 1a to furnish 2a with 89% ee (Table 1, entry 1). We also
investigated the fluorination of other silyl enol ethers 1b-f in
this system in order to determine generality of this reaction. As
can be seen by the results summarized in Table 1,11 the
corresponding 2-fluoroindanones 2a-c and 2-fluorotetralones
2d-f were obtained in high yields with moderate to high
enantiomeric excess (Table 1).
We next investigated the effectiveness of our system for the
enantioselective fluorination of acyclic esters, a much more
challenging problem. Chiral, nonracemic acyclic monofluoro
compounds have many applications, for example as chiral
(7) A quinine/Selectfluor combination was prepared as follows: A solution
of quinine (1.2 equiv) and Selectfluor (1.2 equiv) was stirred in dry MeCN in
the presence of molecular sieves 3 Å at room temperature for 1 h. The resultant
mixture was used as a quinine/Selectfluor combination without any treatment.
(8) Since quinine is a hydrate, the reaction was carried out in the presence
of molecular sieves 3 Å to remove water.
(10) Cinchona alkaloid (ee) (cf. reaction temperature: 0 °C); hydroquinine
4-chlorobenzoate (81%), hydroquinine (54%), hydroquinine 9-phenanthryl
ether (72%), hydroquinine 4-methyl-2-quinolyl ether (70%), (DHQD)2PHAL
(46%), (DHQ)2PYR (70%).
(11) Experimental procedure for the fluorination: see Supporting Informa-
tion.
(9) Selectfluor, see; Banks, R. E. J. Fluorine Chem. 1998, 87, 1-17.
10.1021/ja002732x CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/18/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 43, 2000 10729
Table 2. Enantioselective Fluorination of 4 with DHQDA/
Selectfluor Combination in MeCN/CH2Cl2 at -80 °C
Figure 2.
direct asymmetric syntheses. In addition, cyclic, active methylene
compounds such as 4e and 4f can be efficiently fluorinated with
high enantioselection (78-80% ee) (entries 7 and 8).11
It is very important to note that the cinchona alkaloid derivative
and Selectfluor must be mixed first for generating the combination
in situ before addition of substrates to achieve enantioselective
fluorination. For example, after a mixture of 4a and DHQDA
was stirred in MeCN/CH2Cl2 at room temperature for 1 h, addition
of Selectfluor at -80 °C gave racemic 3a in 76% yield. This
result gives useful information on the reaction mechanism of this
new fluorination procedure, since this seems to rule out the
involvement of a cinchona alkaloid-enolate complex. As a logical
alternative, it seems likely that the cinchona alkaloid must produce
an asymmetric environment around the fluorine atom.
Currently, we propose that this novel enantioselective fluorina-
tion reaction is mediated by a chiral N-fluoro species, NF-DHQB‚
BF4 and NF-DHQDA‚BF4, generated in situ by “fluorine trans-
fer”17 of the cinchona alkaloid by Selectfluor. This structure of
the species produced by the DHQB/Selectfluor combination was
presumed by 19F NMR spectroscopy, although further investiga-
tion for this structure is necessary (Figure 2).18
In conclusion, we have developed a practical enantioselective
fluorination reaction applicable to both cyclic and acyclic carbonyl
compounds using commercially or readily available cinchona
alkaloid derivatives and Selectfluor. A clearer understanding of
the mechanism by the alkaloid confers enantioselectivity to the
process will require more study. Indeed, we feel this novel
approach will provide principals and insights into the developing
area of enantioselective fluorination. For example, it should be
possible to develop the best chiral auxiliary for each target
compound simply by changing the OH protective group of
cinchona alkaloids. Our ongoing experiments are focused on
expanding applications in this manner, in isolation of the putative
NF-DHQB‚BF4 and NF-DHQDA‚BF4 in the solid-state, and in
clarification of the reaction mechanism of enantioselection. A
catalytic version of this fluorination reaction is also under
investigation.19
a Determined by HPLC analysis using a Chiralcel OB, OD, AS, or
AD. Configuration was not determined unless otherwise indicated.
b Fluorination was carried out by DHQB/Selectfluor combination in
MeCN at -20 °C. c The absolute configuration of 4a was assigned on
the basis of the HPLC analysis using a Chiralcel compared with the
authentic samples prepared according to ref 14. d Fluorination was
carried out by DHQB/Selectfluor combination in MeCN/CH2Cl2(3/4)
at -80 °C. Tol ) p-tolyl, Np ) 2-naphthyl, 4-iPr-Ph ) 4-isopropyl-
phenyl.
derivatizing agents,12 as chiral building blocks,1 and as synthetic
intermediates for fluorine-containing chiral liquid crystals.13
However, as a strategy to gain access to such compounds, agent-
controlled enantioselective fluorination of acyclic esters has
proven to be quite problematic when compared to results achieved
with cyclic ketones.5,6
Ethyl R-cyano-R-fluoro-tolyl acetate (3a),14 an efficient chiral
derivatizing agent, was selected as a target molecule. Fluorination
of ethyl R-cyano-tolyl acetate (4a) by the use of our DHQB/
Selectfluor/MeCN system at -20 °C to give (R)-3a with 29% ee
(Table 2, entry 1). When the reaction was carried out in MeCN/
CH2Cl2 (3/4) at -80 °C, the ee was increased to 51% (entry 2).
By again surveying a series of cinchona alkaloid derivatives, we
found that DHQDA was an excellent chiral auxiliary for fluorina-
tion of 4a, giving a dramatic improvement in ee to 87% with a
reversed (S)-enantioselection (entry 3). Fluorination of other
acyclic esters 4b-d using DHQDA/Selectfluor combination in
MeCN/CH2Cl2 provided products including chiral derivatizing
agents, 3b15 and 3c,16 with similar high enantiomeric excess.
Previously, chiral agents 3a-c had been prepared either by
separation of diastereomeric derivatives or by enzymatic
resolution,14-16 and this work represents the first examples of their
Acknowledgment. This work was partially supported by a Grant-
in-Aid for Scientific Research from the Ministry of Education, Science,
Sports and Culture of Japan. N.S. wishes to thank the Uehara Memorial
Foundation for support.
Supporting Information Available: Experimental details of enan-
tioselective fluorination of 4 and 1, details of 19F NMR studies of NF-
DHQB‚BF4. These material is available free of charge via the Internet at
http://pub.acs.org.
(12) Takeuchi, Y.; Takahashi, T. In Enantiocontrolled Synthesis of Fluoro-
organic Compounds; Soloshonok, V. A., Eds.; John Wiley & Sons: Chichester,
1999; pp 497-534.
(13) Kusumoto, T.; Hiyama, T. In Enantiocontrolled Synthesis of Fluoro-
organic Compounds; Soloshonok, V. A., Eds.; John Wiley & Sons: Chichester,
1999; pp 536-556.
(14) (a) Takeuchi, Y.; Konishi, M.; Hori, H.; Takahashi, T.; Kometani, T.;
Kirk, K. L. Chem. Commun. 1998, 365-366. (b) Takeuchi, Y.; Konishi, M.;
Hori, H.; Takahashi, T.; Kirk, K. L. Enantiomer 1999, 4, 339-344.
(15) Takahashi, T.; Fukushima, A.; Tanaka, Y.; Segawa, M.; Hori, H.;
Takeuchi, Y.; Burchardt, A.; Haufe, G. Chirality 2000, 12, 458-463.
(16) Takeuchi, Y., Itoh, N.; Note, H.; Koizumi, T.; Yamaguchi, K. J. Am.
Chem. Soc. 1991, 113, 6318-6320.
JA002732X
(17) Fluorine transfer was developed by Banks, see: Abdul-Ghani, M.;
Banks, R. E.; Besheesh, M. K.; Sharif, I.; Syvret, R. G. J. Fluorine Chem.
1995, 73, 255-257.
(18) The 254 MHz 19F NMR spectrum of Selectfluor and the combination
are available. See Supporting Information.
(19) The DHQB and DHQDA are recoverable by simple acidic/basic
extraction of the reaction mixture.