A two-directional approach to enantiopure 1,4-difluoro-cyclohexenes: Synthesis of difluorinated cyclitol analogues

Article abstract of DOI:10.1021/ol8017402

(Chemical Equation Presented) Enantiopure 1,4-difluoro-cyclohexenes were prepared from readily available acetonide-protected (3S,4S)-hexa-1,5-diene-3,4- diol. In a two-directional mode, a double cross-metathesis reaction using allyltrimethylsilane as the olefinic partner, followed by electrophilic fluorination, afforded diastereomeric acetonide-protected 3,6-difluoro-octa-1,7- diene-4,5-diols. These dienes were found to be suitable substrates for ring-closing metathesis, delivering cyclohexenes featuring fluorine atoms on the two allylic positions flanking the double bond. Upon dihydroxylation, novel difluorinated cyclitol analogues were formed.

Full text of DOI:10.1021/ol8017402

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4263-4266
A Two-Directional Approach to
Enantiopure 1,4-Difluoro-cyclohexenes:
Synthesis of Difluorinated Cyclitol
Analogues
Sophie Purser,† Timothy D. W. Claridge,† Barbara Odell,† Peter R. Moore,‡ and
Ve´ronique Gouverneur*,†
UniVersity of Oxford, Chemistry Research Laboratory, Mansfield Road,
Oxford, OX1 3TA, U.K., and AstraZeneca DiscoVery Chemistry, Alderley Park,
Macclesfield, Cheshire, SK10 4TG, U.K.
Veronique.gouVerneur@chem.ox.ac.uk
Received July 29, 2008
ABSTRACT
Enantiopure 1,4-difluoro-cyclohexenes were prepared from readily available acetonide-protected (3S,4S)-hexa-1,5-diene-3,4-diol. In a two-directional
mode, a double cross-metathesis reaction using allyltrimethylsilane as the olefinic partner, followed by electrophilic fluorination, afforded
diastereomeric acetonide-protected 3,6-difluoro-octa-1,7-diene-4,5-diols. These dienes were found to be suitable substrates for ring-closing
metathesis, delivering cyclohexenes featuring fluorine atoms on the two allylic positions flanking the double bond. Upon dihydroxylation,
novel difluorinated cyclitol analogues were formed.
The inclusion of fluorine into organic molecules can induce
dramatic changes in their conformation, reactivity, and
physical properties. As a result, fluorinated compounds have
been used frequently in the pharmaceutical and agrochemical
industry as well as in material science.1 Fluorinated building
blocks are consequently in great demand, inclusive of
functionalized molecules that feature the fluorine on a
stereogenic center. Alkenes and alkynes flanked by fluorine
substituents emerged as highly versatile molecules that can
be manipulated in various ways.2 The reactivity of difluori-
nated alkenes of general structure A with the fluorine
installed on the two allylic positions has been scarcely
explored, a notable exception being the work of O’ Hagan
and co-workers.3 In the context of a detailed conformational
study, these compounds were used as intermediates for the
enantioselective synthesis of all-syn, anti-syn-anti, and syn-
syn-anti four vicinal fluorine motifs. Rapid progress in this
area is hampered by the difficulties associated with the
preparation of these difluorinated alkenes, especially when
stereocontrol at the two fluorinated allylic positions is
required. O’ Hagan et al. successfully prepared enantioen-
riched acyclic syn-1,4-difluoro-alk-2-enes from allylic fluo-
rides relying on a cross homometathesis process.3 This
chemistry is intrinsically limited to the preparation of
† University of Oxford.
‡ AstraZeneca Discovery Chemistry.
(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH Verlag
GmbH & Co. KgaA: Weinheim, 2004. (b) O’Hagan, D. Chem. Soc. ReV.
2008, 37, 308–319. (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur,
V. Chem. Soc. ReV. 2008, 37, 320–330. (d) Ismail, F. M. D. J. Fluorine
Chem. 2002, 118, 27–33. (e) Jeschke, P. ChemBioChem 2004, 5, 570–589.
(f) Hougham, G. G.; Cassidy, P. E.; Johns, K.; Davidson, T. Fluoropolymers:
Synthesis and Properties; Kluwer Academic: New York, 1999.
(2) Pacheco, M.; Purser, S.; Gouverneur, V. Chem. ReV. 2008, 108,
1943–1981.
(3) (a) Hunter, L.; O′Hagan, D.; Slawin, A. M. Z J. Am. Chem. Soc.
2006, 128, 16422–16423. (b) Hunter, L.; Slawin, A. M. Z.; Kirsh, P.;
O’Hagan, D. Angew. Chem., Int. Ed. 2007, 46, 7887–7890.
10.1021/ol8017402 CCC: $40.75
Published on Web 09/03/2008
2008 American Chemical Society

symmetrical syn derivatives.4 In recognition of the impor-
tance of these compounds, we have reported that syn-1,4-
difluoro-alk-2-enes were accessible upon electrophilic flu-
orodesilylation of monofluorinated (E)-allylsilanes in the
presence of Selectfluor.5 This approach allowed for the
preparation of unsymmetrical derivatives. To date, no
syntheses of the corresponding cyclic anti- and syn-1,4-
difluorocycloalkenes B are known, and therefore, no infor-
mation is available on their reactivity or physical properties.
These compounds have however been identified as minor
products of three isolated and distinct transformations, the
fluorination of cyclopentadiene, of epoxycyclopentene, and
of benzene (Figure 1).6
known two-step synthesis of (3S,4S)-hexa-1,5-diene-3,4-diol
1 from D-mannitol (Scheme 2).7 With diol 1 in hand, the
Scheme 2. Two-Directional Synthesis of 3,6-Difluoro-1,7-dienes
Figure 1. Alkenes flanked by two fluorine substituents.
In this communication, we report the first synthesis of
enantiopure 1,4-difluorocyclohexenes, and we demonstrate
that these novel molecules are precursors of difluorinated
cyclitols. In our retrosynthetic analysis, 1,4-difluorinated
cyclohexenes might be formed upon ring closing metathesis
of an acyclic 3,6-difluoro-octa-1,7-diene, a compound featur-
ing two allylic fluoride groups. Given the accessibility of
allylic fluorides from allylsilanes, an unprecedented two-
directional electrophilic fluorination of a bis-silylated diene
was chosen to prepare the acyclic difluorinated precursor
necessary for the ring closure. A double cross-metathesis was
planned to access the bis-silylated diene (Scheme 1).
first reaction to be validated was the two-directional cross-
metathesis process. Double cross-metathesis reactions are not
common in the literature. Cossy et al. reported that unpro-
tected 1,5-dien-3-ol underwent double cross-metathesis in
the presence of 3 equiv of acrolein, but under identical
reaction conditions, the corresponding acetyl- and TBS-
protected diene led to chemoselective single cross-metathesis
despite the presence of an excess of olefinic partner.8 With
this in mind, the unprotected diol 1 was reacted with 3 equiv
of allyltrimethylsilane in the presence of 5 mol % of Grubbs
second-generation catalyst. Pleasingly, double cross-metath-
esis took place and afforded after 12 h the desired bis-
silylated dienol 2 in 82% yield.
Scheme 1. Retrosynthetic Analysis
The two-directional fluorination of 2 was attempted next.
When the fluorodesilylation was carried out in the presence
of 2.2 equiv of Selectfluor and 2.4 equiv of NaHCO3 in
acetonitrile, the desired product was formed in only 11%
yield. This experiment suggested that the presence of the
unprotected hydroxy groups is likely to be detrimental for
the fluorination to proceed efficiently. The acetonide-
protected bisallylsilane 3 was therefore prepared and isolated
in 79% yield as a mixture of the two geometrical isomers
EE and EZ present in a 3:1 ratio. Compound 3 was subjected
As the chemistry was designed with the view to access
difluorinated cyclitols, the sequence commenced with the
(4) For an early example of homometathesis of racemic allylic fluoride,
see: Thibaudeau, S.; Fuller, R.; Gouverneur, V. Org. Biomol. Chem. 2004,
2, 1110–1112.
(5) Sawicki, M.; Kwok, A.; Tredwell, M.; Gouverneur, V. Beil. J. Org.
Chem. 2007, 3, 34–38.
(6) (a) Shellhamer, D. F.; Chiaco, M. C.; Gallego, K. M.; Low, W. S. C.;
Carter, B.; Heasley, V. L.; Chapman, R. D. J. Fluorine Chem. 1995, 72,
83–87. (b) Zweig, A.; Fischer, R. G.; Lancaster, J. E. J. Org. Chem. 1980,
45, 3597–3603.
(7) Burke, S. D.; Sametz, G. M. Org. Lett. 1999, 1, 71–74.
(8) (a) Bouzbouz, S.; Cossy, J. Org. Lett. 2001, 3, 1451–1454. (b)
Bouzbouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, 6, 3465–3467.
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Org. Lett., Vol. 10, No. 19, 2008

to the crucial fluorodesilylation applying the reaction condi-
tions used for the fluorination of 2. Pleasingly, the reaction
did proceed successfully delivering the three diastereomeric
3,6-difluorinated-1,7-dienes 4a, 4b, and 4c in 54% overall
yield. The low level of selectivity was not unexpected since
the bis-silylated diene does not feature stereogenic silylated
centers.5 Partial separation by silica gel chromatography
delivered two fractions (each containing two diastereomers)
that were not further purified prior to the subsequent ring-
closing event.
Scheme 3. RCM of Dienes 4a-c
1
Figure 2.
Selected H and 19F NMR data for 5a-c. Tables show
coupling constants in hertz. When no values are given, J ∼ 0 Hz.
Our next goal was to validate the RCM (Scheme 3). Upon
treatment with 5 mol % of Grubbs second-generation catalyst,
we found that a 3:1 mixture of 4a and 4c underwent smooth
metathesis to afford the separable ring-closed products 5a
and 5c in 75% overall yield. Compound 5c was crystalline,
and its structure was confirmed by single-crystal X-ray
analysis.9 Under similar conditions, an 8:1 mixture of 4b
and 4c delivered the difluorinated tetrahydrobenzodioxole
5b in 70% isolated yield. For this transformation, the ring-
closed product derived from minor 4c was not recovered after
purification.
Initial assessments of JHH coupling constants were made
from the fully 19F-decoupled 1H data, prior to consideration
1
of the 19F-coupled spectra. While the H{19F} spectrum of
asymmetric 5a was amenable to direct analysis, the C2-
symmetric molecules 5b and 5c required spin system
simulation, as did all 19F-coupled proton spectra. For all three
systems 5a-c, the resulting NMR data were consistent with
the anticipated half-chair conformations (Figure 2). The
proton relationships were clearly delineated from their vicinal
3JHH coupling constants and NOE interactions, with the
corresponding 3JHF couplings providing complimentary evi-
dence. Thus, the proton-fluorine axial-pseudoaxial geom-
etries observed for 5a and 5c correlated with correspondingly
With stereoisomers 5a-c in hand, a detailed study was
carried out to probe their characteristic spectroscopic data.
Fluorine configurations and ring conformations for 5a-c
1
1
were determined from analysis of H-1H, H-19F, and
19F-19F coupling constants combined with 1H-1H NOESY
data (Figure 2).
3
high JHF values of ∼ 24 Hz, whereas the alternative
axial-pseudoequatorial relationships in 5a and 5b displayed
3JHF closer to 14 Hz. Also noteworthy as being sensitive to
(9) See details in Supporting Information.
Org. Lett., Vol. 10, No. 19, 2008
4265

the substituent’s configurations are the long-range five-bond
fluorine-fluorine couplings across the alkene. When both
fluorines occupy the pseudoaxial positions (5c), the JFF
Scheme 4. Dihydroxylation of Difluorocyclohexenes 5a-c
5
coupling increases to ∼19 Hz, while this decreases to ∼4
Hz when both are pseudoequatorial (5b). An intermediate
value of 8.5 Hz was observed for 5a. This favored
axial-pseudoaxial coupling pathway is also reflected, but
5
to a lesser degree, in the corresponding long-range JHH
proton-proton couplings. The data are in line with the ones
previously reported on structurally related monofluorinated
cyclohexenes.10
The next stage of the synthesis of difluorinated cyclitol
analogues required selective dihydroxylation of 5a-c (Scheme
4). Treatment with 5 mol % of OsO4 and 3 equiv of the
co-oxidant NMO (Upjohn conditions)11 gave the required
diols 6a-c in moderate yields. The substitution pattern of
5b and 5c naturally led to a single diastereomeric product,
and we were pleased to find that the hydroxylation of the
non C2-symmetric cyclohexene 5a led to the formation of a
single diastereomer resulting from an anti approach with
respect to the fluorine substituents.
In summary, this work has validated the first enantiose-
lective synthesis of cyclohexenes flanked on the two allylic
positions by fluorine substituents, an unexplored class of
compounds. Successful dihydroxylation of these building
blocks delivered novel deoxyfluoro-myo-inositols that may
be regarded as highly valuable compounds to intervene with
the phosphatidylinositol cycle.12 Alternative functional ma-
nipulation of these difluorinated cyclohexenes may allow
access to additional high value targets, such as for example
cyclohexanes featuring four stereodefined vicinal fluorine
motifs.
Acknowledgment. We thank the EPSRC and AstraZeneca
for generous financial support.
(10) Purser, S.; Odell, B.; Claridge, T. D. W.; Moore, P. R.; Gouverneur,
V. Chem.-Eur. J. 2006, 12, 9176–9185.
Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Van Rheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
17, 1973–1976.
(12) (a) Schedler, D. J. A.; Baker, D. C. Carbohydr. Res. 2004, 339,
1585–1595. (b) Potter, B. V. L.; Lampe, D. Angew. Chem., Int. Ed. 1995,
34, 1933-1972. For a specific example of a difluorinated cyclitol, see: Faug,
A. H. US Pat Appl. Publ. US19900626, 1990.
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