1168
S. Purser et al.
CLUSTER
Selectfluor® in acetonitrile at room temperature. No fluor- Table 3 Synthesis of Compounds 24–29
inated products were formed under these conditions. The
starting material was consumed to give a complex reac-
tion mixture. Similarly, the fluorination of the tert-
butyldimethylsilyl-protected precursor (+)-17 was not
successful and led to unidentified products, a result sug-
gesting that deprotection took place under these condi-
tions to release the corresponding unprotected allylsilane,
a class of substrate found unsuitable for subsequent fluo-
rination. In contrast, the protected silanes (±)-18 and (+)-
19–23 were successfully converted into the corresponding
allylic fluorides when the reactions were performed in
acetonitrile in the presence of Selectfluor® (1.1 equiv) and
sodium bicarbonate (1.2 equiv). The reactions were com-
pleted within 72 hours (Table 3). All electrophilic fluo-
rodesilylations proceeded with full transposition of the
double bond to afford cyclopentene or cyclohexene rings
with the endocyclic double bond flanked by a fluorine
substituent and the protected alcohol. The yields ranged
from 56% to 90% and the level of diastereocontrol was
consistently very good to excellent. In most cases, only
one diastereomer was detected by 1H NMR and 19F NMR
of the crude reaction mixtures. The level of diastereocon-
trol is not affected by the substituents on the silyl group or
the ring size. In contrast, the protecting group of the sec-
ondary alcohol is important. Benzoyl-protected hydroxy-
allylsilanes (+)-20–23 led to complete diastereocontrol
(dr >98:2), whereas the corresponding acetyl-protected
allylsilanes (±)-18 and (+)-19 gave two diastereomeric
products in a ratio of 94:6 and 92:8, respectively. As
hypothesized, the use of cyclic syn-allylsilanes gave pre-
dominantly the fluorinated products resulting from an anti
approach of Selectfluor® with respect to the silyl group.
Within experimental error, the enantiomeric excesses of
the fluorinated products mirrored those measured for the
starting allylsilanes.
SiMe2R1
OR3
Selectlfuor® (1.1 equiv)
OR3
( )
n
NaHCO3 (1.2 equiv),
MeCN, r.t., 72 h
F
( )
n
Entry Starting R1
material
R3
n
Product Yield
(%)
dr
eeb
c
1
2
3
4
5
6
( )-18
(+)-19
(+)-20
(+)-21
(+)-22
(+)-23
Ph
Me
Ph
Ac
Ac
Bz
Bz
Bz
Bz
2
2
2
2
1
1
( )-24
(+)-25
(+)-26
(+)-27
(+)-28
(+)-29
69
90
75
75
56
79
94:6a
92:8a
–
c
–
>98:2 77
>98:2 83
>98:2 80
>98:2 86
Me
Ph
Me
a Inseparable mixture of diastereomers by column chromatography.
b The ee determined by chiral HPLC.
c The ee could not be determined by chiral HPLC.
S.; Nishida, T.; Yamada, D.; Nagaki, A.; Yoshida, J. J. Am.
Chem. Soc. 2004, 14338. (e) Fernandes, R. A.; Yamamoto,
Y. J. Org. Chem. 2004, 735. (f) Evans, D. A.; Aye, Y.; Wu,
J. Org. Lett. 2006, 2071. (g) Nair, V.; Dhanya, R.; Vidya,
N.; Devipriya, S. Synthesis 2006, 107. (h) Conchon, E.;
Gelas-Mialhe, Y.; Remuson, R. Tetrahedron: Asymmetry
2006, 1253. (i) Friestad, G. K.; Korapala, C. S.; Ding, H.
J. Org. Chem. 2006, 281.
(2) (a) For a recent review on the importance of fluorine in
biological and medicinal chemistry, see a special issue of:
ChemBioChem 2004, 5. (b) Bégué, J.-P.; Bonnet-Delpon,
D. J. Fluorine Chem. 2006, 992. (c) Kirk, K. L. J. Fluorine
Chem. 2006, 1013. (d) Isanbor, C.; O’Hagan, D. J. Fluorine
Chem. 2006, 303. (e) Smart, B. J. Fluorine Chem. 2001, 3.
(3) (a) Gouverneur, V.; Greedy, B. Chem. Eur. J. 2002, 766.
(b) Tredwell, M.; Gouverneur, V. Org. Biomol. Chem. 2006,
26.
(4) (a) Greedy, B.; Paris, J.-M.; Vidal, T.; Gouverneur, V.
Angew. Chem. Int. Ed. 2003, 3291. (b) Thibaudeau, S.;
Gouverneur, V. Org. Lett. 2003, 4891. (c) Thibaudeau, S.;
Fuller, R.; Gouverneur, V. Org. Biomol. Chem. 2004, 1110.
(d) Tredwell, M.; Tenza, K.; Pacheco, M. C.; Gouverneur,
V. Org. Lett. 2005, 4495. (e) Giuffredi, G.; Bobbio, C.;
Gouverneur, V. J. Org. Chem. 2006, 5361.
In conclusion, we have developed an efficient approach to
enantioenriched fluorinated carbocycles featuring an en-
docyclic allylic fluoride functional group, by electrophilic
fluorodesilylation of the corresponding allylsilanes. For
the syn-allylsilanes under investigation, the chirality
transfer upon fluorination was highly efficient and pro-
ceeded preferentially anti with respect to the silyl group.
The use of these novel fluorinated building blocks in the
synthesis of biologically important targets is under way in
our laboratory and will be reported in due course.
(5) (a) Purser, S.; Odell, B.; Claridge, T. D. W.; Moore, P. R.;
Gouverneur, V. Chem. Eur. J. 2006, 9176. (b) For the
synthesis of 3, see: Carter, M. J.; Fleming, I.; Percival, A. J.
Chem. Soc., Perkin Trans. 1 1981, 2415.
(6) (a) Heo, J.-N.; Micalizio, G. C.; Roush, W. R. Org. Lett.
2003, 1693. (b) Heo, J.-N.; Holson, E. B.; Roush, W. R. Org.
Lett. 2003, 1697. For sequential allyltitanation–ring-closing
metathesis see: (c) de Fays, L.; Adam, J.-M.; Ghosez, L.
Tetrahedron Lett. 2003, 7197. (d) Adam, J.-M.; de Fays, L.;
Laguerre, M.; Ghosez, L. Tetrahedron 2004, 7325.
(7) The synthesis of butenal is not trivial. For a multistep
sequence, see: Crimmins, M. T.; Kirincich, S. J.; Wells, A.
J.; Choy, A. L. Synth. Commun. 1998, 3675.
Acknowledgment
We thank the EPSRC and AstraZeneca for generous financial
support (S.P.).
References and Notes
(1) (a) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997,
2063. (b) Sarkar, T. K. In Science of Synthesis; Fleming, I.,
Ed.; Georg Thieme Verlag: Stuttgart, 2002, 837.
(8) Reuter, J. M.; Sinha, A.; Salomon, R. G. J. Org. Chem. 1978,
43, 2438.
(c) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 2763. (d)Suga,
Synlett 2007, No. 7, 1166–1168 © Thieme Stuttgart · New York