Synthesis of novel enantiopure fluorinated building blocks from acyclic chiral allylsilanes

Article abstract of DOI:10.1021/ol0518535

(Chemical Equation Presented) Homochiral β-fluorinated γ,δ-unsaturated carboxylic acids with an allylic fluorinated stereogenic center are available from the corresponding enantiopure allylsilanes. The key step for introduction of the fluorine substituent

Full text of DOI:10.1021/ol0518535

ORGANIC
LETTERS
2005
Vol. 7, No. 20
4495-4497
Synthesis of Novel Enantiopure
Fluorinated Building Blocks from
Acyclic Chiral Allylsilanes
Matthew Tredwell, Kenny Tenza, Ma Carmen Pacheco, and
Ve´ronique Gouverneur*
UniVersity of Oxford, Chemistry Research Laboratory, 12 Mansfield Road,
OX1 3TA Oxford. U.K.
Veronique.gouVerneur@chem.ox.ac.uk
Received August 2, 2005
ABSTRACT
Homochiral
enantiopure allylsilanes. The key step for introduction of the fluorine substituent is an electrophilic fluorodesilylation reaction carried out in
the presence of Selectfluor. Reduction of the resulting -fluorinated pentenoic acid into the corresponding fluorinated alcohol was also performed
leading to the formation of an enantiopure second-generation fluorinated building block.
â-fluorinated γ,δ-unsaturated carboxylic acids with an allylic fluorinated stereogenic center are available from the corresponding
â
The extraordinary range of applications of fluorinated com-
pounds has stimulated the search for inventive and efficient
approaches to their synthesis.1 The incorporation of a fluorine
substituent R to a carbonyl group is now well established
with several reagent-based enantioselective fluorinations of
enolates or silyl enol ethers having been reported in the
literature.2 More recently, it has been found that transition-
metal complexes and small organic molecules are efficient
catalysts for the formation of enantioenriched R-fluorinated
carbonyl derivatives.3 By way of contrast, only a few syn-
thetic routes have been developed for the preparation of
homochiral fluorinated building blocks other than R-fluor-
inated carbonyl compounds. For example, a general meth-
odology for the preparation of enantiopure â-fluorinated γ,δ-
unsaturated carboxylic acids with a stereogenic fluorinated
allylic carbon has yet to be developed.4 As part of a research
program aimed at developing innovative methodologies for
the preparation of fluorinated compounds, we have reported
that nonaromatic organosilanes, such as vinylsilanes, allyl-
silanes and allenylmethylsilanes, react with 1-chloromethyl-
4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluorobo-
(3) (a) Ma, J.-A.; Cahard, D. Chem. ReV. 2004, 104, 6119-6146. (b)
Hintermann, L.; Togni, A. Angew. Chem., Int. Ed. 2000, 39, 4359-4362.
(c) Piana, S.; Devillers, I.; Togni, A.; Rothlisberger, U. Angew. Chem., Int.
Ed. 2002, 41, 979-982. (d) Hamashima, Y.; Yagi, K.; Takano, H.; Tamas,
L.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 14530-14531. (e) Ma, J.-
A.; Cahard, D. Tetrahedron: Asymmetry 2004, 15, 1007-1011. (f) Shibata,
N.; Ishimura, T.; Nagai, T.; Kohno, J.; Toru, T. Synlett 2004, 1703-1706.
(g) Enders, D.; Huttl, M. R. M. Synlett 2005, 991-993. (h) Bernardi, L.;
Jørgensen, K. A. Chem. Commun. 2005, 1324-1326. (i) Steiner, D. D.;
Mase, N.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2005, 44, 3706-3710.
(j) Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
8826-8828. (k) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjærsgaard,
A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703-3706.
(4) For alternative synthesis of enantioenriched â-fluorinated carboxylic
acids not featuring an allylic fluoride, see, for example: (a) Kollonitsch,
J.; Marburg, S.; Perkins, L. M. J. Org. Chem. 1979, 44, 771-777. (b)
Blackburn, G. M.; Rahid, A. J. Chem. Soc., Chem. Commun. 1988, 4, 317-
319. (c) Armone, A.; Cavicchioli, M.; Donadelli, A.; Resnati, G. Tetrahe-
dron: Asymmetry 1994, 5, 1019-1028. (d) Myers, A. G.; Barbay, J. K.;
Zhong, B. J. Am. Chem. Soc. 2001, 123, 7207-7219.
(1) (a) For a recent book on the synthesis, reactivity, and applications
of fluorocompounds, see: Modern Fluoroorganic Chemistry; Kirsch, P.,
Ed.; Wiley-VCH Verlag GmbH & Co. KgaA: Weinheim, 2004. (b) Hiyama,
T.; Shimizu, M. Angew. Chem., Int. Ed. 2005, 44, 214-231.
(2) (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. (d) Takeuchi, Y.; Suzuki, T.; Satoh, A.; Shiragami, T.;
Shibata, N. J. Org. Chem. 1999, 64, 5708-5711. (e) Shibata, N.; Liu, Z.;
Takeuchi, Y. Chem. Pharm. Bull. 2000, 48, 1954-1958. (f) Liu, Z.; Shibata,
N.; Takeuchi, Y. J. Org. Chem. 2000, 65, 7583-7587. (g) Cahard, D.;
Audouard, C.; Plaquevent, J.-C.; Roques, N. Org. Lett. 2000, 2, 3699-
3701. (h) Shibata, N.; Suzuki, E.; Takeuchi, Y. J. Am. Chem. Soc. 2000,
122, 10728-10729. (i) Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J. Am.
Chem. Soc. 2001, 123, 7001-7009.
10.1021/ol0518535 CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/27/2005

rate) (Selectfluor) to give structurally diverse fluorinated
compounds. Indeed, using this methodology for electrophilic
fluorination, fluoroalkenes, difluorinated amides, ethers or
alcohols, allylic fluorides and fluorodienes were made avail-
able.5 In this paper, we now report the first application of
electrophilic fluorodesilylation on acyclic homochiral allyl-
silanes to prepare enantiopure â-fluorinated R-substituted
carboxylic acids with an allylic monofluorinated stereogenic
center (Scheme 1).
product to elimination. However, before addressing such
matters, it was necessary to validate the feasibility of the
proposed synthetic scheme.
The asymmetric synthesis of two representative homochiral
allylsilanes 1 and 2 began with a diastereoselective decon-
jugative alkylation of the known acylated oxazolidinone7 3
with benzyl bromide or methyl iodide using a mixture of
THF in the presence of HMPA as the solvent system
(Scheme 2).
Scheme 1. Retrosynthetic Approach to Enantiopure
â-Fluorinated R-Substituted Carboxylic Acids
Scheme 2. Syntheses of Enantiopure Allylsilanes 1 and 2
These novel compounds are valuable synthetic intermedi-
ates as they provide numerous opportunities for subsequent
functional manipulation of the double bond or the carboxylic
acid group.6 In this paper, we also describe how these novel
homochiral fluorinated compounds were reduced to give
second-generation building blocks with two stereocenters,
one of them being fluorinated.
With benzyl bromide as the electrophile, this reaction gave
product 4 in 56% yield as a single diastereomer after purifi-
cation. It was assumed that the benzyl group of the chiral
auxiliary was shielding the â face of the Z-enolate and that
the alkylated compound was indeed formulated as 4. This
was proved unambiguously by X-ray analysis.8 Similarly,
the methylation of 3 provided, after purification, compound
5 as a single diastereomer with the configuration of the newly
formed stereocenter assigned by analogy with 4. Upon cross-
metathesis with three equivalents of allyltrimethylsilane in
the presence of 5 mol % of the second generation Grubbs
catalyst at reflux in DCM, the terminal double bond of 4
and 5 was functionalized to give the desired homochiral
allylsilanes 1 and 2 in 95% and 77% isolated yield,
respectively. Compound 1 was formed as the sole E-isomer,
but a mixture of E- and Z-isomers was formed for the methyl-
substituted allylsilane 2. We also prepared the enantiopure
allylsilane 6 released from the chiral auxiliary.8
The enantiopure chiral allylsilanes that we employed were
generated by a cross-metathesis coupling of allyltrimethyl-
silane with the corresponding enantiopure deconjugated
carboxylic acid derivative. To prepare these enantiopure
R-functionalized building blocks we opted to use Evans-type
oxazolidinones as the chiral auxiliaries. This approach raises
several points of interest such as whether the existing
stereocenters of the homochiral allylsilane will exert some
degree of stereocontrol in the fluorination step or whether
the key fluorinated intermediate will be subject to elimination
or epimerization upon cleavage of the chiral auxiliary.
Indeed, there is no precedent in the literature about the way
in which the presence of a stereocenter on the allylic carbon
not bearing the silyl group might control the diastereoselec-
tivity of electrophilic fluorination with a reagent such as
Selectfluor or on the sensitivity of the resulting â-fluorinated
We next studied the reactivity of these various allylsilanes
toward Selectfluor (Table 1).
The fluorodesilylation of allylsilane 1 with Selectfluor in
acetonitrile occurred smoothly at room temperature and
afforded the corresponding allylic fluorides anti-7 and syn-7
with an overall chemical yield of 95%. The two diastereo-
mers were formed as a roughly 1/1 mixture (Table 1, entry
1). Changing the reaction solvent or using additives did not
improve significantly the level of diastereocontrol (Table 1,
(5) (a) Gouverneur, V.; Greedy, B. Chem. Eur. J. 2002, 8, 766-771.
(b) Greedy, B.; Gouverneur, V. Chem. Commun. 2001, 233-234. (c)
Greedy, B.; Paris, J.-M.; Vidal, T.; Gouverneur, V. Angew. Chem., Int. Ed.
2003, 42, 3291-3294. (d) Thibaudeau, S.; Gouverneur, V. Org. Lett. 2003,
5, 4891-4893. (e) Pacheco, M. C.; Gouverneur, V. Org. Lett. 2005, 7,
1267-1270.
(6) For selected references on the reactivity of allylic fluorides, see: (a)
Thibaudeau, S.; Fuller, R.; Gouverneur, V. Org. Biomol. Chem. 2004, 2,
1110-1112. (b) Gree, D.; Vallerie, L.; Gre´e, R.; Toupet, L.; Washington,
I.; Pelicier, J.-P.; Villacampa, M.; Perez, J. M.; Houk, K. N. J. Org. Chem.
2001, 66, 2374-2381. (c) Davis, F. A.; Qi, H. Tetrahedron Lett. 1996, 37,
4345-4348. (d) Fujita, M.; Ishizuka, H.; Ogura, K. Tetrahedron Lett. 1991,
32, 6355-6358. (e) Prakesch, M.; Gre´e, D.; Gre´e, R. Acc. Chem. Res. 2002,
35, 175-181.
(7) (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1984,
106, 4261-4263. (b) Thom, C.; Kocienski, P. Synthesis 1992, 6, 582-
586.
(8) For details, see the Supporting Information.
4496
Org. Lett., Vol. 7, No. 20, 2005

Scheme 3. Synthesis of the â-Fluorinated Carboxylic Acids
Table 1. Fluorodesilylation of Enantiopure Allylsilanes 1, 2,
and 6
(Scheme 4). This alcohol could not be prepared from the
fluorinated intermediate syn-7 by direct reductive cleavage
of the chiral auxiliary, as a competitive elimination process
took place leading to the formation of the nonfluorinated
diene.
yield
ratio
entry allylsilane
conditions
MeCN
acetone, NaHCO3
MeCN, NaHCO3
acetone, NaHCO3,
LiCl
product (%) anti/syn
1
2
3
4
1
1
1
1
7
7
7
7
95
100a
100a
<50a
1.2:1
2:1
1.4:1
2:1
Scheme 4. Reduction of the â-Fluorinated Carboxylic Acid
syn-9 into the Corresponding Alcohol syn-10
5
6
2
6
MeCN
MeCN
8
9
82
61
1:1
1:1
a Conversion.
In summary, we have shown that the concept of electro-
philic fluorodesilylation can be applied to acyclic chiral
allylsilanes for the preparation of enantiopure R-substituted
â-fluorinated carboxylic acids featuring an allylic fluoride.
These compounds can be reduced to the corresponding fluori-
nated alcohols. These novel fluorinated building blocks are
difficult to obtain by other routes. The main limitation of
our strategy is the poor level of diastereocontrol for the
fluorodesilylation step. The existence of several reactive con-
formations for the starting chiral allylsilane is likely to be
responsible for this limitation. The presence of an additional
stereogenic center on the carbon bearing the silyl group
combined with the use of Z-allylsilane might allow for better
diastereoselectivity in the future. The synthesis of these more
elaborated allylsilanes and a study of their reactivity in the
presence of Selectfluor is currently ongoing in our laboratory.
entries 2-4). The two diastereomers anti-7 and syn-7 were
separated by careful column chromatography. Their relative
stereochemistry was determined unambiguously by X-ray
crystallography of the anti-7 isomer.8 Similarly, a high yield
of the desired â-fluorinated R-methylated carboxylic acid
derivative was obtained upon treatment of allylsilane 2 with
Selectfluor in acetonitrile, the latter process providing the
two separable diastereomers anti-8 and syn-8 in equal
amounts in an 82% overall yield (Table 1, entry 5). Upon
treatment with Selectfluor, allylsilane 6 afforded the two dia-
stereomeric â-fluorinated acids anti-9 and syn-9 as a 1/1 mix-
ture in 61% yield (Table 1, entry 6). These two â-fluorinated
acids could not be separated by SiO2 column chromatogra-
phy. These data suggested that the poor diastereocontrol ob-
served is not the result of a mismatch of the two stereogenic
centers remote from the reacting site in compounds 1 or 2.
The chiral auxiliary in the syn â-fluorinated carboxylic
acid derivative 7 could be hydrolytically cleaved with H2O2
and LiOH in a THF/H2O mixture. This transformation proved
remarkably efficient, allowing the syn-â-fluorinated R-ben-
zylated carboxylic acid 9 to be recovered in 90% yield. No
side-product resulting from an elimination process or from
partial epimerisation could be detected in the crude reaction
mixture or recovered after purification. Similarly, anti-7 was
easily converted to the desired carboxylic acid anti-9 in
excellent yield (Scheme 3).
Acknowledgment. This work was generously supported
by the EPSRC (GR/S43283/01 to M.T.), the Spanish Ministry
of Education (EX-31/10/03), and the European Community
(Marie-Curie Intra-European Fellowship 2003-EIF-515589)
for generous funding to M.P. We also thank the National
Research Foundation of South Africa for supporting K.T.
and Dr. A. Cowley (Oxford) for performing the X-ray
crystallographic studies.
Supporting Information Available: Experimental details
and spectroscopic data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
The fluorinated carboxylic acid syn-9 was subjected to
further functional group manipulation. The fluorinated alco-
hol syn-10 was obtained in 62% yield by reduction of the
carboxylic acid using LiAlH4 in THF at room temperature
OL0518535
Org. Lett., Vol. 7, No. 20, 2005
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