Enantioselective synthesis of an all-syn four vicinal fluorine motif

Article abstract of DOI:10.1021/ja066188p

Alkanes bearing multiple vicinal fluorine atoms at adjacent stereocenters may be considered intermediate between alkanes and perfluoroalkanes, and as a class, their chemistry and behavior remain to be explored. We report here a stereoselective synthesis o

Full text of DOI:10.1021/ja066188p

Published on Web 11/24/2006
Enantioselective Synthesis of an All-syn Four Vicinal Fluorine Motif
Luke Hunter, David O’Hagan,* and Alexandra M. Z. Slawin
Centre for Biomolecular Sciences and School of Chemistry, UniVersity of St. Andrews, North Haugh, St. Andrews,
Fife, KY16 9ST, United Kingdom
Received August 25, 2006; E-mail: do1@st-andrews.ac.uk
Chart 1. R,â,γ-Trifluoroalkanes7
The incorporation of fluorine atoms into organic molecules is
well-known to have profound effects on their physical properties.1
In general terms, highly fluorinated compounds have contributed
significantly to materials science,2 whereas selectively fluorinated
compounds have been used effectively in pharmaceutical and
agrochemical products3 and in mechanistic enzymology research.4
We have been interested in developing novel partially fluorinated
motifs to expand the repertoire of fluorinated building blocks in
organic chemistry.5 Organic compounds with two vicinal fluorines
have conformations which are influenced by the fluorine gauche
Chart 2. All-syn Four Vicinal Fluorine Motif
effect,6 and it is attractive to consider the level of conformational
predictability if longer vicinal fluorine systems are developed which
bear multiple fluorine atoms at adjacent stereocenters; such
compounds may be considered intermediate between alkanes and
perfluoroalkanes, and as a class, their chemistry and behavior remain
to be explored.
Scheme 1a
As an initial contribution to the synthesis of such compounds,
we have reported the stereoselective preparation of R,â,γ-trifluo-
roalkanes in two diastereoisomeric series (Chart 1).7 This trifluoro
motif has the potential to be incorporated into a variety of
performance molecules which rely on conformation to optimize
their physical properties.
In this communication, we report a stereoselective synthesis of
an all-syn four vicinal fluorine motif (Chart 2) as a single enantiomer
and in a format which will allow its direct incorporation into larger
molecular architectures. Such a motif has prospects for a variety
of applications in the design of novel materials such as liquid
crystals and self-assembling monolayers or in the preparation of
elaborate deoxyfluoro sugar analogues and, in a general sense,
broadens the available range of functionalized alkanes.
a Reagents and conditions: (a) Et3N‚3HF, Na2SO4, 70 °C; (b) BnBr,
NaH, DMF, 40 °C; (c) Grubbs second generation catalyst, DCM, ∆; (d)
KMnO4, MgSO4, EtOH, H2O, -10 °C; (e) SOCl2, pyridine, DCM, 0 °C;
(f) NaIO4, RuCl3, MeCN, H2O, 0 °C; (g) TBAF, MeCN, rt; (h) H2SO4,
H2O, THF, rt.
The synthetic sequence commenced with (R)-butadiene monoxide
1 (Scheme 1), which is readily available in enantiomerically pure
form (>99% ee) by hydrolytic kinetic resolution of the com-
mercially available racemate according to a Jacobsen protocol.8 Our
synthetic approach required regioselective opening of epoxide 1
with HF at the 2-position, a transformation which has previously
been achieved with the racemate.9 However, the corresponding
transformation with a single enantiomer is complicated by the partial
SN1 character of the epoxide ring-opening reaction. Treatment of
1 with HF-triethylamine furnished fluorohydrin 2 with somewhat
reduced enantiopurity (80% ee), as determined by Mosher ester
analysis.10 This stereoselectivity could not be improved; however,
the loss of enantiopurity was circumvented as described below.
Protection of fluorohydrin 2 gave benzyl ether 3, a compound
which underwent cross metathesis upon treatment with Grubbs’
second generation catalyst11 to furnish the symmetrical alkene 4.
This reaction proceeded in good yield and gave a product with
exclusively the E double bond geometry. Notably, we were able to
exploit an additional stereochemical feature of the metathesis
reaction: since the starting material 3 (80% ee) consisted of a 9:1
mixture of (S)- and (R)-enantiomers, the product 4 was formed as
a statistical 81:18:1 mixture of (S,S)-, (R,S)-, and (R,R)-isomers,
and straightforward chromatographic removal of the (R,S)-isomer
then allowed the major diastereoisomer to be recovered directly in
98% ee, thereby overcoming the loss of enantiopurity suffered
during the epoxide opening step. Furthermore, alkene 4 was
amenable to recrystallization, which allowed an enantiomerically
pure sample to be recovered. Single-crystal X-ray analysis of 4
confirmed the E double bond geometry and the syn relationship
between the two fluorine substituents.12
The next stage of the synthesis required selective dihydroxylation
of the double bond of 4 (Scheme 1). Initial attempts at epoxidation
or dihydroxylation were hampered by low conversions, presumably
due to the rather electron-deficient nature of the double bond.
However, treatment of 4 with potassium permanganate gave the
required diol 5 in good yield, with the diastereoselectivity of cis-
dihydroxylation controlled by the two fluorine substituents. The
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10.1021/ja066188p CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2a
Figure 1. X-ray structure of 12 showing crystal packing arrangement.
an unexplored class of functionalized alkanes and which now has
prospects to be directly incorporated into a variety of performance
molecules.
a Reagents and conditions: (a) Tf2O, pyridine, DCM, -40 °C; (b) TBAF,
MeCN, 0 °C; (c) Deoxo-Fluor, 70 °C; (d) H2, Pd/C, MeOH, rt; (e) TsCl,
2,4,6-collidine, 50 °C.
Acknowledgment. We gratefully acknowledge the EPSRC for
funding this research, and Dr. Tomas Lebl for NMR assistance.
This paper is dedicated to Professor Neil Bartlett on the occasion
of his 75th birthday.
assignment of the relative stereochemistry of 5 is supported by
single-crystal X-ray data.13
Diol 5 was next converted to the corresponding cyclic sulfate 6
under standard conditions14 (Scheme 1), and subsequent ring
opening with TBAF gave the trifluoro derivative 7 in good yield,
along with a smaller amount of a byproduct arising through a
competing elimination pathway.
Supporting Information Available: Full experimental procedures
and characterization data for all compounds, 19F NMR spectrum of
12, and crystallographic data for 4, 5, and 12. This material is available
free of charge via the Internet at http://pubs.acs.org.
With the trifluoro alcohol 7 in hand, attention was turned toward
the introduction of the fourth fluorine atom. Alcohol 7 was first
converted to the corresponding triflate 8 (Scheme 2), but subsequent
treatment of 8 with TBAF led predominantly to elimination rather
than the desired SN2 displacement by fluoride. An alternate approach
was investigated, in which the free alcohol 7 was treated with excess
Deoxo-Fluor reagent15 or DAST16 (Scheme 2); unfortunately,
however, cyclization occurred to give the tetrahydrofuran derivative
9 as the only reaction product in both cases.17 In an attempt to
suppress this adventitious cyclization on steric grounds, the benzyl
ether was replaced by the 2,6-dichlorobenzyl ether protecting group.
However, it emerged that formation of the corresponding tetrahy-
drofuran derivative remained the dominant reaction pathway.
Accordingly, we decided to investigate the tosyl ester as a
protecting group (Scheme 2). Hydrogenolysis of 7 gave triol 10,
which was selectively reprotected to give the ditosylate 11. In this
case, 11 was cleanly converted to the desired tetrafluoro compound
12 upon treatment with Deoxo-Fluor at 50 °C. This reaction was
not accompanied by the previously observed cyclization, elimina-
tion, or loss of the tosyl groups. At 70 °C, conversion to 12 was
improved to a satisfactory level, although some elimination products
also became apparent at these more forcing conditions.
References
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(12) X-ray crystal structure of 4 (see Supporting Information for details):
The all-syn tetrafluoro compound 12 was crystalline and proved
amenable to single-crystal X-ray analysis (Figure 1), which
unambiguously confirmed the absolute configuration of each
stereocenter. The crystal structure, which has C2 symmetry, displays
gauche relationships between all four fluorines with dihedral angles
of 66.7° (F9-C-C-F10) and 59.7° (F10-C-C-F10′) between
vicinal fluorines, consistent with the fluorine gauche effect. In the
crystal packing structure, the aryl and fluoroalkyl groups pack in
separate domains, and intermolecular interactions include a hydro-
gen bond (2.52 Å) from the fluorine atom of C10 (and C10′) to
the hydrogen atom at C9 (and C9′) of an adjacent molecule.
In summary, we have described the preparation of an enantio-
merically pure all-syn four vicinal fluorine motif, which represents
(13) X-ray crystal structure of 5 (phenyl rings optimized due to disorder in
the electron density map; see Supporting Information for details):
(14) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538.
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(16) Lal, G. S.; Labach, E.; Evans, A. J. Org. Chem. 2000, 65, 4830.
(17) Cyclization of δ-hydroxy benzyl ethers has been observed previously;
for example, see: Persky, R.; Albeck, A. J. Org. Chem. 2000, 65, 3775.
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