Published on Web 12/23/2004
r,â,γ-Trifluoroalkanes: A Stereoselective Synthesis Placing Three Vicinal
Fluorines along a Hydrocarbon Chain
Marcello Nicoletti, David O’Hagan,* and Alexandra M. Z. Slawin
School of Chemistry, UniVersity of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST, UK
Received August 4, 2004; E-mail: do1@st-andrews.ac.uk
Organofluorine compounds have had a huge impact in the design
of performance materials with outstanding examples found in
pharmaceuticals,1 agrochemicals2 and organic materials3,4 products.
In the pharmaceuticals and agrochemicals arena selective fluorina-
tion of aromatics or the incorporation of a CF3 group represents
the typical strategy for incorporation of organic fluorine.5
a′ or b and b′; however it proved more efficient to separate these
diastereoisomers after treatment with HF‚pyridine. This resulted
in a stereo- and, importantly, a completely, regiospecific ring
opening and generated the fluorohydrins 5a and 5a′ or 5b and 5b′,
retaining the 2:1 mixture. These diastereoisomers were readily
separated by silica gel chromatography (Scheme 1).
Within the materials arena highly fluorinated or perfluorinated
compounds have been used as lubricants and polymers for a
diversity of products and applications;6 however the properties of
organic materials with an intermediate level of fluorination, and
particularly with multiple fluorines at stereogenic centers, have been
hardly explored. There is clear evidence that the C-F bond can be
exploited as a tool for influencing the conformation of organic
molecules, particularly when it is used as a replacement for
hydrogen.7 This is most easily illustrated by the well-known gauche
effect which recognizes that 1,2-difluoroethane prefers a gauche
over an anti conformation.8 This gauche preference of vicinal
fluorines can also influence the conformation of longer hydrocarbon
chains such as meso- and (()-2,3-difluorobutanes and (()-erythro-
and (()-threo-9,10-difluorostearic acids.9 For example in the latter
case the erythro isomer has a similar conformational stability to
the hydrocarbon (stearic acid), whereas the threo isomer shows
significant conformational disorder. This was attributed to the
preference of the vicinal C-F bonds preferring to align gauche to
each other in both systems, the former stabilizing and the latter
destabilizing the classical anti-zigzag conformation of the hydro-
carbon chain. Recognizing that the relative stereochemistry of
vicinal C-F bonds can have a significant influence on the
conformation of hydrocarbons, we have now decided to explore
R,â,γ-trifluorohydrocarbons where three fluorines are arranged
along a hydrocarbon chain. Such systems have up to four diaste-
reoisomers and eight enantiomers, and clearly any meaningful
synthesis to this class of compounds requires stereocontrol, such
that the properties of different diastereoisomers can be evaluated.
As an initial contribution to the preparation of these compounds, a
method for the synthesis of two of the diastereoisomers of the
vicinal trifluoro alkyl motif, is described for the two different
molecular systems, 1a and 2a as well as 1b and 2b. In the first
instance the racemic diastereoisomers of 2,3,4-trifluorononanes 1a
and 2a were prepared to develop the synthetic protocol, and the
method was then applied to the synthesis of the racemic 6,7,8-
trifluoro-1-phenylheptadecanes 1b and 2b. The latter route started
from allylic alcohol 3b which derived from a condensation of
6-phenylaldehyde and non-1-yne followed by LAH reduction of
the resultant propargylic alcohol 10 (Scheme 2).
The vicinal diols of both diastereoisomeric series were then
converted to their cyclic sulfates 6a and 6a′ or 6b and 6b′ using
the method developed by Sharpless, and the sulfates were ring
opened, again in both a regio- and stereospecific manner to generate
8a (or 8b) and 8a′ (or 8b′) after in situ hydrolysis of the ring opened
difluorosulfates 7a (or 7a′) and 7b (or 7b′).10,11 The third fluorine
atom was introduced by activation of the remaining alcohol
functionality in 8a (or 8a′) and 8b (or 8b′) to the corresponding
triflates 9 followed by a nucleophilic substitution reaction with
fluoride ion using TBAF. This reaction led to the desired R,â,γ-
trifluoroproducts. The products were always accompanied by
elimination products, and despite considerable experimentation the
current yield for this final step remains modest. Nonetheless the 1
and 2 diastereoisomers of the products a and b could be secured
after chromatography.
Enantiomerically pure products can be accessed by initiating the
synthetic protocol with a Sharpless asymmetric epoxidation/kinetic
resolution. This was explored only in the a series to confirm the
stereochemical course of the first two fluorination reactions in
Scheme 1. A Sharpless asymmetric epoxidation on allylic alcohol
3a and using (+)-DIPT and a limiting (0.5 equiv) amount of
tBuOOH generated the (2S,3R,4S) enantiomer of allylic epoxide
4a′. The (2S,3R,4S) configuration of this product has been
established previously.12,13 Epoxide 4a′ was then converted to 8a′
as described above, and this crystalline difluoro alcohol proved
amenable to X-ray structure analysis14 (Figure 1).
The resultant structure revealed a stereochemistry consistent with
two configurational inversions during formation of each of the R-
and γ-C-F bonds. The trifluoroalkane products 1 and 2 are liquids
and were not readily amenable to crystallization; however the final
fluorination which results from fluoride ion displacement of a triflate
is assumed to proceed with an inversion of configuration. Com-
pounds 1a and 2a proved to be particularly volatile, but 1b and 2b
gave materials which were more amenable to longer term storage.
The vicinal trifluoroalkanes were analyzed by 19F NMR spec-
troscopy, and the resultant data are shown in Table 1. It is most
informative to compare the chemical shift of 1b and 2b. The
configurational arrangement of the fluorines in diastereoisomer 1b
posesses a pseudo symmetry, and consequently the R and γ
fluorines have identical chemical shifts, whereas this pseudo
symmetry does not exist in diastereoisomer 2b and each fluorine
signal is now well resolved. These spectra reinforce the stereo-
chemical assignments of the two diastereoisomers. For the 1 series
The sequential introduction of the fluorine atoms in a stereospe-
cific manner relied heavily on Sharpless cyclic sulfate methodology.
Epoxidation of the appropriate allylic alcohols 3 afforded the
diastereoisomeric epoxides 4a and 4a′ or 4b and 4b′ as a 2:1
mixture for both series. These isomers could be separated in each
case to progress toward each of the diastereoisomeric series a and
the vicinal coupling constants (Table 1) J2
(1a 12.9 Hz and
FR-Fâ
1b 12.3 Hz) and J2
(1a 11.2 Hz and 1b 12.3 Hz) are similar
Fâ-Fγ
9
482
J. AM. CHEM. SOC. 2005, 127, 482-483
10.1021/ja045299q CCC: $30.25 © 2005 American Chemical Society
Nicoletti, Marcello
