Total syntheses of conformationally locked difluorinated pentopyranose analogues and a pentopyranosyl phosphate mimetic

Article abstract of DOI:10.1021/jo0620258

Trifluoroethanol has been elaborated, via a telescoped sequence involving a metalated difluoroenol, a difluoroallylic alcohol, [2,3]-Wittig rearrangement, and ultimately an RCM reaction and requiring minimal intermediate purification, to a number of cyclo

Full text of DOI:10.1021/jo0620258

Total Syntheses of Conformationally Locked Difluorinated
Pentopyranose Analogues and a Pentopyranosyl Phosphate Mimetic
Jonathan A. L. Miles,† Lisa Mitchell,†,‡ Jonathan M. Percy,*,‡ Kuldip Singh,†
and E. Uneyama†
Department of Chemistry, UniVersity of Leicester, UniVersity Road, Leicester LE1 7RH, U.K.,
and Department of Pure and Applied Chemistry, WestCHEM, UniVersity of Strathclyde,
Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
jonathan.percy@strath.ac.uk
ReceiVed September 30, 2006
Trifluoroethanol has been elaborated, via a telescoped sequence involving a metalated difluoroenol, a
difluoroallylic alcohol, [2,3]-Wittig rearrangement, and ultimately an RCM reaction and requiring minimal
intermediate purification, to a number of cyclooctenone intermediates. Epoxidation of these intermediates
followed by transannular ring opening or dihydroxylation, then transannular hemiacetalization delivers
novel bicyclic analogues of pentopyranoses, which were elaborated (in one case) to an analogue of a
glycosyl phosphate.
Introduction
networks of hydrogen bonds to them.1 The core six-membered
oxacycle in pyranose sugars also exerts a significant effect on
a range of conformational properties via the anomeric effect.2
The linkages between sugars in di- and higher saccharides are
acetals, and a wide range of glycosyltransferases and glycosi-
dases exist to synthesize and cleave those linkages, respectively.
Saccharide mimetics,3 which present hydroxyl groups in a useful
manner but cannot be cleaved from their sites of attachment by
glycosidases, could be useful probes of sugar-processing
enzymes. If the mimetics lack the pyranose oxygen and therefore
the anomeric effect, different conformers could become avail-
able.
Many groups have described the synthesis of five-, six-, and
seven-membered carbocyclic analogues of saccharides. More
recently, highly functionalized cyclooctane derivatives have
attracted attention as ring-expanded analogues (Chart 1). The
Sinay¨ group combined the ideas of the stability of carbasugars
with the potential for occupying uncharted conformational space,
synthesizing 1, which was shown by NOE to occupy a boat-
chair conformation related to that of the corresponding galac-
Saccharide recognition is a key event in a wide range of
biological processes. Sugars present arrays of hydroxyl groups
in a spatially defined manner, and proteins bind to and
distinguish between different saccharides by forming complex
† University of Leicester.
‡ University of Strathclyde.
(1) (a) Loganathan, D.; Aich, U. Glycobiology 2006, 16, 343. (b)
Laederach, A.; Reilly, P. J. Proteins: Struct., Funct., Bioinf. 2005, 60, 591.
(c) Carcabal, P.; Jockusch, R. A.; Hunig, I.; Snoek, L. C.; Kroemer, R. T.;
Davis, B. G.; Gamblin, D. P.; Compagnon, I.; Oomens, J.; Simons, J. P.
J. Am. Chem. Soc. 2005, 127, 11414. (d) Flint, J.; Bolam, D. N.; Nurizzo,
D.; Taylor, E. J.; Williamson, M. P.; Walters, C.; Davies, G. J.; Gilbert,
H. J. J. Biol. Chem. 2005, 280, 23718. (e) Fernandez, M. D.; Canada, F. J.;
Jimenez-Barbero, J.; Cuevas, G. J. Am. Chem. Soc. 2005, 127, 7379. (f)
Mitchell, E. P.; Sabin, C.; Snajdrova, L.; Pokorna, M.; Perret, S.; Gautier,
C.; Hofr, C.; Gilboa-Garber, N.; Koca, J.; Wimmerova, M.; Imberty, A.
Proteins: Struct., Funct., Bioinf. 2005, 58, 735. (g) Loris, R.; Imberty, A.;
Beeckmans, S.; Van, Driessche, E.; Read, J. S.; Bouckaertt, J.; De Greve,
H.; Buts, L.; Wyns, L. J. Biol. Chem. 2003, 278, 16297. (h) Vyas, N. K.;
Vyas, M. N.; Chervenak, M. C.; Bundle, D. R.; Pinto, B. M.; Quiocho,
F. A. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 15023. (i) Pathiaseril, A.;
Woods, R. J. J. Am. Chem. Soc. 2000, 122, 331. (j) Zacharias, M.; Straatsma,
T. P.; McCammon, J. A.; Quiocho, F. A. Biochemistry 1993, 32, 7428. (k)
Quiocho, F. A. Biochem. Soc. Trans. 1993, 21, 442. (l) Jimenez-Barbero,
J.; Canada, F. J.; Cuevas, G.; Asensio, J. L.; Aboitiz, N.; Canales, A.;
Chavez, M. I.; Fernandez-Alonso, M. C.; Garcia-Herrero, A.; Mari, S.; Vidal,
P. NMR Spectroscopy and Computer Modeling of Carbohydrates: Recent
AdVances; ACS Symposium Series 930; American Chemical Society:
Washington, DC, 2006; p 60. (m) Bryce, R. A.; Hillier, I. H.; Naismith,
J. H. Biophys. J. 2001, 81, 1373.
(2) (a) Kirby, A. The Anomeric Effect and Related Stereoelectronic Effects
at Oxygen; Springer-Verlag: Berlin, 1983. (b) For recent mechanistic
studies, see: Bennet, A. J.; Kitos, T. E. J. Chem. Soc., Perkin Trans. 2002,
2, 1207. (c) For a computational examination of the mechanism, see:
Dimelow, R. J.; Bryce, R. A.; Masters, A. J.; Hillier, I. H.; Burton, N. A.
J. Chem. Phys. 2006, 124. (d) Mohr, M.; Bryce, R. A.; Hillier, I. H.
J. Phys. Chem. A 2001, 105, 8216.
10.1021/jo0620258 CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/01/2007
J. Org. Chem. 2007, 72, 1575-1587
1575

Miles et al.
CHART 1
SCHEME 1. Outline of Sequence Showing the Development
of NDP Sugar Analogues
topyranose.4 The synthesis used carbohydrate starting materials
to provide most of the functionality in the products and ensure
stereocontrol, exploiting a Lewis acid mediated ring-expanding
Claisen rearrangement (described originally by Paquette) as the
key step. More recently, Paquette has shown that zirconocene-
promoted ring contraction can be used to convert vinylfurano-
sides to cyclooctane polyols via vinyl cyclobutanones, and a
[3,3]-sigmatropic rearrangement again secures the carbocycles.5
Using a quite different approach, Mehta and co-workers have
shown that unsaturated eight-membered ring compounds such
as cyclooctatetraene can be elaborated controllably to the
corresponding polyols.6
The ring-expanding Claisen rearrangement also allows the
synthesis of masked cyclooctanones 2. Van Boom and the
Leiden group exploited transannular strain-relieving nucleophilic
attack upon a ketone carbonyl group to close a number of
bicyclic systems, which provide conformationally locked ana-
logues of sugars 3 and azasugars 4.7 The bicyclic array is very
interesting because of the extremely low reactivity of the
pseudoglycosidic bond. Kirby and co-workers showed that 5
was 1013 times less reactive than 6 because of the way the
bicyclic architecture opposes stabilization of developing positive
charge at the pseudoanomeric carbon through oxacarbenium ion
formation as the pseudoglycosidic bond stretches toward cleav-
age.8 The idea of using conformational locking to allow mimicry
of conformations traversed at transition states has also been
explored extensively.9
We10 and others11 have developed a number of approaches
for the synthesis of fluorinated analogues of the molecules of
nature from commercial fluorinated starting materials, in which
RCM forms a key step. One of our projects aimed to develop
a de novo route via difluorinated cyclooctenones 7 to confor-
mationally locked difluorinated analogues 8 of pentoses and their
phosphates 9, which we would advance ultimately to analogues
of NDP sugars, with the global aim of the development of new
chemical tools for the study of glycosyltransferase enzymes.
The syntheses would start from sustainable fluorinated starting
materials, avoiding the use of materials banned under the
Montreal and Kyoto Protocols (Scheme 1). Although these
protocols deal with large-scale production, they affect the
availability and supply of materials for use on the laboratory
scale; the development of a new methodology based on banned
substances would therefore seem like nugatory effort.
The fluorine atoms would allow location of the compounds
in vitro or in vivo by 19F NMR, and they could report
conformational changes in the hydroxyl-bearing ring through
3JH-F coupling constants.12 In our preliminary publications, we
showed how we could use metalated difluoroalkene chemistry
to advance trifluoroethanol rapidly to precursors to eight-
membered rings and then close them via RCM13 to afford
difluorinated cyclooctenones, templates for stereoselective
oxidation (dihydroxylation14 or epoxidation15), and transannular
reactions. These preliminary findings delivered a number of
model polyol systems which contain the distinctly unnatural
gem-dimethyl and N,N-diethylcarbamoyloxy groups, which we
now wished to delete. We wished to explore a route, which
would avoid the use of strong base/low-temperature conditions
(3) (a) Haneda, T.; Goekjian, P. G.; Kim, S. H.; Kishi, Y. J. Org. Chem.
1992, 57, 490. (b) Goekjian, P. G.; Wu, T. C.; Kang, H. Y.; Kishi, Y.
J. Org. Chem. 1991, 56, 6422. (c) Kuntz, D. A.; Ghavami, A.; Johnston,
B. D.; Pinto, B. M.; Rose, D. R. Tetrahedron: Asymmetry 2005, 16, 25.
(d) Yang, G. L.; Schmieg, J.; Tsuji, M.; Franck, R. W. Angew. Chem., Int.
Ed. 2004, 43, 3818. (e) Mikkelsen, L. M.; Hernaiz, M. J.; Martin-Pastor,
M.; Skrydstrup, T.; Jimenez-Barbero, J. J. Am. Chem. Soc. 2002, 124, 14940.
For reviews, see: (f) Sears, P.; Wong, C. H. Angew. Chem., Int. Ed. 1999,
38, 2301. (g) Wong, C. H. Acc. Chem. Res. 1999, 32, 376.
(4) (a) Wang, W.; Zhang, Y. M.; Sollogoub, M.; Sinay¨, P. Angew. Chem.,
Int. Ed. 2000, 39, 2466. (b) Wang, W.; Zhang, Y. M.; Zhou, H. H.; Bleriot,
Y.; Sinay¨, P. Eur. J. Org. Chem. 2001, 1053.
(5) Paquette, L. A.; Zhang, Y. L. J. Org. Chem. 2006, 71, 4353.
(6) (a) Mehta, G.; Pallavi, K. Tetrahedron Lett. 2004, 45, 3865. (b) Mehta,
G.; Pallavi, K. Chem. Commun. 2002, 2828. (c) For a review of earlier
work, see: Mehta, G.; Singh, V. Chem. ReV. 1999, 99, 881.
(7) van Hooft, P. A. V.; Litjens, R.; van der Marel, G. A.; van Boeckel,
C. A. A.; van Boom, J. H. Org. Lett. 2001, 3, 731.
(8) Briggs, A. J.; Evans, C. M.; Glenn, R.; Kirby, A. J. J. Chem. Soc.,
Perkin Trans. 2 1983, 1637.
(9) For recent examples, see: (a) Bleriot, Y.; Vadivel, S. K.; Herrera,
A. J.; Greig, I. R.; Kirby, A. J.; Sinay¨, P. Tetrahedron 2004, 60, 6813. (b)
Lorthiois, E.; Meyyappan, M.; Vasella, A. Chem. Commun. 2000, 1829.
(10) (a) Audouard, C.; Fawcett, J.; Griffiths, G. A.; Percy, J. M.; Pintat,
S.; Smith, C. A. Org. Biomol. Chem. 2004, 2, 528. (b) Audouard, C.;
Fawcett, J.; Griffith, G. A.; Kerouredan, E.; Miah, A.; Percy, J. M.; Yang,
H. L. Org. Lett. 2004, 6, 4269. (c) Kariuki, B. M.; Owton, W. M.; Percy,
J. M.; Pintat, S.; Smith, C. A.; Spencer, N. S.; Thomas, A. C.; Watson, M.
Chem. Commun. 2002, 228. (d) Butt, A. H.; Percy, J. M.; Spencer, N. S.
Chem. Commun. 2000, 1691.
(11) (a) Fustero, S.; Catalan, S.; Piera, J.; Sanz-Cervera, J. F.; Fernandez,
B.; Acena, J. L. J. Org. Chem. 2006, 71, 4010. (b) Fustero, S.; Sanchez-
Rosello, M.; Jimenez, D.; Sanz-Cervera, J. F.; del Pozo, C.; Acena, J. L.
J. Org. Chem. 2006, 71, 2706. (c) Fustero, S.; Bartolome, A.; Sanz-Cervera,
J. F.; Sanchez-Rosello, M.; Soler, J. G.; de Arellano, C. R.; Fuentes, A. S.
Org. Lett. 2003, 5, 2523. (d) Yang, Y. Y.; Meng, W. D.; Qing, F. L. Org.
Lett. 2004, 6, 4257. (e) You, Z. W.; Wu, Y. Y.; Qing, F. L. Tetrahedron
Lett. 2004, 45, 9479. (f) De Matteis, V.; van Delft, F. L.; de Gelder, R.;
Tiebes, J.; Rutjes, F. Tetrahedron Lett. 2004, 45, 959. (g) Marhold, M.;
Buer, A.; Hiemstra, H.; van Maarseveen, J. H.; Haufe, G. Tetrahedron Lett.
2004, 45, 57.
(12) Thibaudeau, C.; Plavec, J.; Chattopadhyaya, J. J. Org. Chem. 1998,
63, 4967.
(13) Griffith, G. A.; Percy, J. M.; Pintat, S.; Smith, C. A.; Spencer, N.;
Uneyama, E. Org. Biomol. Chem. 2005, 3, 2701.
(14) Fawcett, J.; Griffiths, G. A.; Percy, J. M.; Pintat, S.; Smith, C. A.;
Spencer, N.; Uneyama, E. Chem. Commun. 2004, 302.
(15) Fawcett, J.; Griffith, G. A.; Percy, J. M.; Uneyama, E. Org. Lett.
2004, 6, 1277.
1576 J. Org. Chem., Vol. 72, No. 5, 2007

Syntheses of Difluorinated Pentopyranose Analogues
SCHEME 2. Retrosynthetic Analysis of Key Cyclooctenone
14
SCHEME 4. Cyclooctenone Syntheses Based on Metalated
Difluoroenol Acetal Chemistry
SCHEME 3. Attempted Halodifluoromethyl Ketone
Syntheses
if possible and minimize the number of purifications in the
sequences, to complete syntheses of a number of analogues of
sugar-like and an illustrative phosphate monoester through
stereoselective oxidation reactions and the development of an
effective phosphorylation strategy. We report the results of these
studies in this manuscript.
that aliphatic trifluoromethyl ketones undergo slow reductive
defluorination under the latter conditions; for 11a, the reaction
was prohibitively slow. We also attempted to use the conditions
described by Ishihara18 for direct aldol reaction between 11b
and acrolein or cinnamaldehyde. The best result (ca. 10%
conversion) was obtained with the latter electrophile despite
considerable efforts to optimize the reactions, which stopped
at very low conversion, and we were not able to isolate any of
13. We therefore decided to use our metalated difluoroenol
chemistry to develop a working strategy to the target aldol.
Successful Dehydrofluorination/Metalation Route. Known20
difluoroallylic alcohol 15 was synthesized in good yield (82%,
20 g scale) using our published procedure from the MEM-ether
of trifluoroethanol and 4-pentenal (Scheme 4).21 The Kugelrohr-
distilled alcohol was allylated under phase-transfer conditions22
to ether 16 (91%) and progressed without further purification
(Scheme 4).
The rearrangement of 16 took place over 4 h on warming
from -100 to -30 °C, and chromatography of the product
returned a disappointing yield of pure 17 (ca. 30%) initially.
We were able to purify hydroxyketone 13 (following enol ether
cleavage23) by Kugelrohr distillation improving the yield to 50%
over the two steps and removing two chromatographic purifica-
tions from the sequence if the enol ether was cleaved directly
from crude [2,3]-Wittig product. In the RCM reaction (5 mol
% of 21, 30 mol % of Ti(O-iPr)4, 5 mM in DCM), starting
material appeared to be consumed completely within 2 h but
the volatile cyclooctenone product 14 was difficult to isolate.
Careful removal of the dichloromethane solvent by distillation
at atmospheric pressure and then eluting the residue through a
polymer-bound thiol SPE tube with methanol afforded the
product in modest (estimated 60%) yield. This first-generation
synthesis provides proof of concept but delivered a rather
Results and Discussion
Attempted Development of a Scaleable Route Based on
Reductive Dehalogenation. Scheme 2 shows the retrosynthetic
analysis carried out for 14 from key intermediate R,R-difluoro-
â-hydroxy ketone 13. The literature describes a number of
methods for the generation of difluorinated silyl enol ether 12,
which could make 13 available through aldol chemistry under
potentially scaleable conditions (Scheme 2).
Ishihara16 and Uneyama17 have described methods for the
synthesis of difluoroenol silyl ethers such as 12 from chlorodi-
fluoromethyl and trifluoromethyl ketones, respectively, so we
prepared 11a and 11b from commercial 1-bromopent-4-ene via
reaction of the Grignard reagent with electrophiles 10 derived
from chlorodifluoroacetic or trifluoroacetic acids (Scheme 3).18
These starting materials are available at low cost and appear to
be sustainable.
Typical reaction conditions for this type of perhalomethylke-
tone synthesis use ester electrophiles or, alternatively, an excess
of Grignard reagent and the free acid.18 The latter procedure
would waste a moderately expensive bromide, so we preformed
the sodium or magnesium salts using NaH or i-PrMgCl.
A large number of unsuccessful experiments are summarized
in the Scheme. The ketones were isolated by distillation after
careful extraction of the product into pentane/diethyl ether, and
hydration of the ketones was a distinct problem during these
procedures. The poor yield of the trifluoromethyl ketone was
comparable to that obtained by Laurent and co-workers.19 We
were unable to synthesize 12 in more than trace amounts from
either 11a or 11b under published (Zn, Me3SiCl, MeCN, ∆ or
excess Mg/Me3SiCl, DMF) conditions. Uneyama17 has reported
(16) Yamana, M.; Ishihara, T.; Ando, T. Tetrahedron Lett. 1983, 24,
507.
(17) (a) Amii, H.; Kobayashi, T.; Hatamoto, Y.; Uneyama, K. Chem.
Commun. 1999, 1323. (b) For a review, see: Uneyama, K.; Amii, H.
J. Fluorine Chem. 2002, 114, 127.
(20) Griffith, G. A.; Hillier, I. H.; Percy, J. M.; Roig, R.; Vincent,
M. A. J. Org. Chem. 2006, 71, 8250.
(21) Patel, S. T.; Percy, J. M.; Wilkes, R. D. Tetrahedron 1995, 51, 9201.
(22) Patel, S. T.; Percy, J. M.; Wilkes, R. D. J. Org. Chem. 1996, 61,
166.
(18) Kuroboshi, M.; Ishihara, T. Bull. Chem. Soc. Jpn. 1990, 63, 428.
(19) Felix, C.; Laurent, A.; Mison, P. J. Fluorine Chem. 1995, 70, 71.
(23) Broadhurst, M. J.; Brown, S. J.; Percy, J. M.; Prime, M. E. J. Chem.
Soc., Perkin Trans. 1 2000, 3217.
J. Org. Chem, Vol. 72, No. 5, 2007 1577

Miles et al.
SCHEME 5. Attempted RCM with the Neolyst Catalyst
CHART 2
volatile product, which was not easy to characterize fully, in
ca. 20% overall yield from trifluoroethanol.
We therefore sought to optimize the sequence. The [2,3]-
Wittig step afforded good estimated yields (ca. 90%) of up to
24 mmol of homoallylic alcohol 17 which was sufficiently pure
1
by H and 19F NMR spectra and GC-MS to take on directly.
Material of the same quality could also be obtained by taking
crude undistilled difluoroallylic alcohol through the allylation/
rearrangement sequence (after checking the purity from the 1H
and 19F NMR spectra). We esterified 17 by shaking with benzoic
anhydride and polymer-supported base poly(4-vinylpyridine) in
dichloromethane to afford 18a and then cleaved the MEM group
directly from the crude material. Benzoate 19a was purified
before RCM in the first round of reactions and underwent RCM
(second-generation Grubbs’ catalyst 21, Ti(Oi-Pr)4 cocatalyst)
to afford 20a in acceptable (46%) yield after chromatography.
We subsequently found that the unpurified precursor also
underwent RCM in good yield. Trace contaminants of Ru could
be removed by eluting the columned material through thiol SPE
tubes with MeOH. The entire sequence from the starting
trifluoroethyl acetal therefore finally involves only a single
purification, which is a column after RCM, and the overall yield
of 20a is ca. 30% from trifluoroethanol. Rearrangement product
17 was also benzylated (92%, using an excess of sodium hydride
to ensure complete alkoxide formation), subjected to enol ether
methanolysis (94%), and taken through the RCM without
purification to afford 20b in good (75%) yield.
The reaction with Neolyst catalyst 2527 (10 mol %) returned
significant quantities of homodimeric cross-metathesis products
from 19a as a mixture of C2-symmetric racemic syn and achiral
and meso anti diastereoisomers 26a and 27a, respectively, in
moderate (34% isolated from a possible 50%) yield, along with
recovered starting material (42%) and traces of RCM product
20a (Scheme 5).
A similar result was observed from benzyl ether 19b with
the isolation of 26b and 27b (38% combined) along with
recovered starting material (36%) and a small amount of 20b
(4%). The reaction was started with a lower loading (5%) of
catalyst, followed by the addition of a further portion (5%) when
the reaction did not appear to proceed. The homodimerization
was observed with and without the Ti(IV) cocatalyst.
The isolation of terminal alkene open-chain homodimers from
an RCM reaction run at high dilution is relatively unusual.28
1
The H NMR spectra obtained for the mixtures of 26 and 27
are relatively simple and highly symmetrical, consistent only
with the formation of these dimers. The COSYs show the
relationship between the vinylic proton of the symmetrical
internal alkene and the allylic methylene protons clearly. The
connectivity between the terminal alkene and the allylic methine
Though superficially less attractive than the Ishihara and
Uneyama aldol syntheses because it contains two low-temper-
ature steps, our route delivers gram-scale quantities of the RCM
product reproducibly with 30 mmol of material coming through
the [2,3]-Wittig rearrangement (the most demanding step) and
with minimal purification.
1
is also established unambiguously. The 1D H and 13C NMR
spectra fail to show the presence of the different stereoisomers
clearly, though some of the methylene carbon signals are
doubled. The 1D {1H}19F NMR spectrum appears to show the
only difference between the diastereoisomers; formally, there
are four 19F environments arising from two pairs of enantiotopic
fluorines (two environments) in the achiral and meso stereo-
isomers and two pairs of homotopic fluorines (two environ-
ments) in the C2-symmetric species (similar considerations apply
to various protons, but the higher chemical shift range of fluorine
nucleii reveals more subtle differences in environment). Though
we observed four environments for 26b/27b, there were seven
for 26a/27a; given the rather flexible nature of these extended
Developing Conditions for the RCM Reaction. Many of
the RCM reactions24 which form medium rings25 use relatively
high loadings of ruthenium catalysts, suggesting that either
catalytic efficiency is low or cyclizations are very slow,26 or
both. We screened commercial precatalysts 21-25 (Chart 2)
for the cyclization of 19a and 19b at an initial loading of 5
mol %.
(24) For general reviews of RCM issues, see: (a) Conrad, J. C.; Fogg,
D. E. Curr. Org. Chem. 2006, 10, 185. (b) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490. (e) Furstner, A. Angew.
Chem., Int. Ed. 2000, 39, 3013.
(25) For reviews of medium ring forming RCM, see: (a) Deiters, A.;
Martin, S. F. Chem. ReV. 2004, 104, 2199. (b) Maier, M. E. Angew. Chem.,
Int. Ed. 2000, 39, 2073. (c) Yet, L. Chem. ReV. 2000, 100, 2963. (d) Michaut,
A.; Rodriguez, J. Angew. Chem., Int. Ed. 2006, 45, 5740. For recent
examples, see: (e) Bleriot, Y.; Giroult, A.; Mallet, J. M.; Rodriguez, E.;
Vogel, P.; Sinay¨, P. Tetrahedron: Asymmetry 2002, 13, 2553. (f) Bourgeois,
D.; Mahuteau, J.; Pancrazi, A.; Nolan, S. P.; Prunet, J. Synthesis 2000, 869.
(g) Boyer, F. D.; Hanna, I.; Nolan, S. P. J. Org. Chem. 2001, 66, 4094. (h)
Buono, F.; Tenaglia, A. J. Org. Chem. 2000, 65, 3869. (i) Furstner, A.;
Langemann, K. J. Org. Chem. 1996, 61, 8746. (j) Buszek, K. R.; Sato, N.;
Jeong, Y. Tetrahedron Lett. 2002, 43, 181.
(27) Furstner, A.; Guth, O.; Duffels, A.; Seidel, G.; Liebl, M.; Gabor,
B.; Mynott, R. Chem.-Eur. J. 2001, 7, 4811.
(28) (a) Creighton and co-workers identified an open-chain dimer by
LC-MS from a mixture of products generated during a cyclooctannulation
reaction: Creighton, C. J.; Du, Y. M.; Reitz, A. B. Bioorg. Med. Chem.
2004, 12, 4375. For recent applications, see: (b) Creighton, C. J.; Du,
Y. M.; Santulli, R. J.; Tounge, B. A.; Reitz, A. B. Bioorg. Med. Chem.
Lett. 2006, 16, 3971. (c) Abell, A. D.; Brown, K. M.; Coxon, J. M.; Jones,
M. A.; Miyamoto, S.; Neffe, A. T.; Nikkel, J. M.; Stuart, B. G. Peptides
2005, 26, 251.
(26) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
1578 J. Org. Chem., Vol. 72, No. 5, 2007

Syntheses of Difluorinated Pentopyranose Analogues
SCHEME 6. Dioxirane Oxidations
molecules, conformational erosion of symmetry is perhaps
unsurprising.
We were surprised by the homodimerization given the reports
that this ruthenium indenylidene complex is particularly suitable
for the formation of medium-sized rings by RCM. Indeed this
(pre)catalyst is more effective at closing the eight-membered
E-ring of Nakadomarin A 28 than either Grubbs’ catalyst 21 or
22.27
become prohibitive for normal laboratory equipment. We
therefore sought to explore the effects of concentration upon
the metathesis outcomes qualitatively. The RCM of benzoate
19a could be carried out successfully up to 20 mM, with
dimerization and other side reactions starting at higher concen-
trations. This is a relatively high concentration compared to most
of those used in the literature, and its use has allowed the
preparation of gram quantities of material. Higher dilution was
required for benzyl ether 19b (2.5 mM) and alcohol 13 (1 mM);
significant quantities of side products were formed at 20 mM
in these cases. Quantitative aspects of these investigations will
be presented elsewhere.
Elaboration of RCM Products to Protected Pentopyranose
Analogues via Oxidation Transformations. Epoxides 29a and
29b were made using the dioxirane method of Yang32 which
was diastereofacially selective (Scheme 6). In the case of benzyl
ether 20b, a trace of benzoate 29a was observed in the product
consistent with oxidation at the benzylic methylene by the
reactive dioxirane.33 The sharp 19F NMR spectra of the crude
products showed the formation of a single diastereoisomer in
each case with yield loss occurring on purification and removal
of the hydrate of the trifluoroacetone. Neither product formed
crystals of sufficient quality for the sense of stereoselection to
be confirmed directly, but the size of J between H-1 and H-2
provides a strong indication; at ca. 9 Hz, it is more likely to
arise from a trans pseudodiaxial relationship between these
protons in electron-deficient environments, consistent with a
trans relationship between the benzoyloxy (or benzyloxy) and
epoxide C-O bonds rather than a cis arrangement. This
conclusion is supported strongly by precedent from previous
systems which crystallized well14 and the outcome of epoxide-
opening reactions (vide infra).
The effectiveness of Neolyst 25 for slow RCM reactions is
attributed to higher stability in solution, though it is not clear if
this refers to slow initial dissociation of phosphane, slow
recapture of the catalytically active 14e complex, or slow
second-order decomposition of the latter reactive species.29 It
appears that the RCM is slow for 19a and 19b with this
precatalyst and that 26 and 27, once formed, either are too
unreactive to form η2-complexes with the methylidene 14e
complex which must now carry the chain or cannot progress to
metallocyclobutanes from the η2-complexes. The presence of
phosphane, rather than the NHC ligand, is known to make
metallocyclobutane formation less favorable. Relatively rapid
consumption and recycling of 26 and 27 would be expected
under these conditions. The internal alkene derives from cross
metathesis between type I alkenes,30 which is normally fast, so
we have observed an interruption of the normally rapid retro-
cross metathesis. Exposure of a purified 26b/27b mixture to 5
mol % of 21 in the presence of the Ti(IV) cocatalyst resulted
in 50% conversion to 20b after 18 h as the sole product by 19
F
NMR (the remainder was unreacted starting material). Mixing
the crude product with a sample of authentic 20b and running
the GC of the mixture resulted in a single peak being observed.
Clearly, the retro-cross metathesis is not rapid under these
conditions, even with the more reactive precatalyst 21.
Catalyst 22 alone will not catalyze RCM of any of our
substrates; the presence of the Ti(IV) cocatalyst is required to
achieve slow cyclization. Second-generation catalyst 21 is the
most effective catalyst explored for the cyclooctannulation
reaction, and despite the generally lower Lewis acidity of the
alkylidene when the NHC ligand replaces phosphane, the Ti-
(IV) cocatalyst still exerted a small positive qualitative effect
on the reaction outcome. Second-generation Grubbs-Hoveyda
catalyst31 24 showed comparable reactivity to 21 (in terms of
apparent rate of consumption of 19a) but afforded a lower yield
of eight-membered cyclic products under any given conditions
due to oligomer formation, whereas the corresponding first-
generation catalyst 23 was ineffective.
The results also appear to be consistent with the sense of
diastereofacial selection reported by Curci and co-workers34
during the acetone/potassium caroate epoxidation of cy-
clooctenol and in our preliminary studies; dioxirane attack occurs
on the more sterically open face of the alkene (assuming the
solution conformer type or population is not modified signifi-
cantly by the presence of the protecting group).13 Hydrogen bond
formation to a hydroxyl group clearly cannot play a part in
controlling this reaction because the outcome is the same when
the hydroxyl group is protected.
Epoxide hydrolysis was carried out under microwave condi-
tions in most cases. We used N-methylimidazole as a base
Scale-up requires reactions that can be run at concentrations
approaching 0.01 M or better, or the volumes of solvent required
(32) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887.
(33) For examples of related oxidations, see: (a) Csuk, R.; Dorr, P.
Tetrahedron 1994, 50, 9983. (b) Angibeaud, P.; Defaye, J.; Gadelle, A.;
Utille, J. P. Synthesis 1985, 1123. (c) Hayes, C. J.; Sherlock, A. E.; Selby,
M. D. Org. Biomol. Chem. 2006, 4, 193. (d) Ochiai, M.; Ito, T.; Takahashi,
H.; Nakanishi, A.; Toyonari, M.; Sueda, T.; Goto, S.; Shiro, M. J. Am.
Chem. Soc. 1996, 118, 7716. (e) Arnone, A.; Bernardi, R.; Cavicchioli,
M.; Resnati, G. J. Org. Chem. 1995, 60, 2314.
(29) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 6543.
(30) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
(31) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791. (b) For a review, see: Hoveyda,
A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.; Kataoka, O.; Garber,
S. B.; Kingsbury, J. S.; Harrity, J. P. A. Org. Biomol. Chem. 2004, 2, 8.
(34) Cicala, G.; Curci, R.; Fiorentino, M.; Laricchiuta, O. J. Org. Chem.
1982, 47, 2670.
J. Org. Chem, Vol. 72, No. 5, 2007 1579

Miles et al.
subsequent strain-relieving reaction,38 if we assume that hy-
droxide addition is at least as favorable as cyanohydrin
formation. The mechanism is supported strongly by the metha-
nolysis of 29b carried out with catalytic sodium methoxide in
methanol under microwave conditions. An inseparable mixture
containing two products and starting material (ratio 39:10:1 by
19F NMR) was obtained, but acetylation allowed separation, to
afford 32 and 33 (obtained as a mixture with 32). The presence
of the methoxy group at the pseudoanomeric position in 32 is
easily detectable in the HMBC spectrum by the presence of a
strong 3JC-H cross-peak between the methoxy protons and C-1.
The structure of this major product was also confirmed by the
elucidation of the molecular structure in the crystal. The only
credible route to major product 32 from 29b involves methoxide
attack at the ketone carbonyl of 29b followed by transannular
ring opening which confirms the sense of diastereofacial
selection assigned in Scheme 6.
SCHEME 7. Epoxide-Opening Reactions
The formation of 33 was unexpected. We detected a similar
3JC-H cross-peak between the methoxy protons and C-1 in the
HMBC spectrum, which proves that direct epoxide opening by
methoxide does not account for the formation of this second
product. The 1D NMR spectra showed smaller 3JH-F coupling
constants than usual (the biggest one visible was 9.9 Hz,
compared to 17.5 Hz for 32) suggesting a nonchairlike
conformation. One of the 19F NMR signals was very highly
split, indicating extended or through-space couplings involving
the methoxy group which appears as a doublet in the coupled
spectrum and simplifies to a singlet in the {19F}1H spectrum.
The structure 33 is assigned on the basis of this evidence; it
must be formed by transannular nucleophilic ring opening of
the epoxide from C-8 rather than from C-7. We were unable to
grow suitable crystals of this material. Unfortunately, hydro-
genolysis of the benzyl ether to afford 34 failed to deliver
crystalline material, but the HMBC spectrum showed a much
stronger CH3O/C-1 cross-peak. The full scope of this reaction
and its mechanism will be discussed elsewhere.
Dihydroxylation of benzyl ether 20b under UpJohn condi-
tions39 afforded a mixture of separable diols; both afforded
crystals of suitable quality for X-ray crystallographic analysis
allowing the identification of the major and minor products as
37 and 38 (3:1), arising from diols 35 and 36 which undergo
transannular collapse with relief of strain (Scheme 8).
We were surprised to note that the major product 37 arose
from oxidant attack cis to the benzyloxy group. In our
communication of related work, we advanced an explanation
which involved delivery of the osmium reagent to the less
accessible concave face of a boat-chair conformer by coordina-
tion to the Lewis basic carbonyl group oxygen. In the
preliminary case,13 we were confident of the identity of the
major conformer in solution; however, the 19F NMR spectra of
20a and 20b merely broaden at temperatures as low as 213 K
preventing conformational insight.
catalyst in our preliminary study14 but found subsequently that
sodium hydroxide works just as well. In the case of 29a,
microwave irradiation in water alone consumed starting material
to afford a mixture of products, which was saponified to afford
a single crude triol. The crude product was then treated with an
excess (5 equiv) of acetic anhydride in DCM containing poly-
(vinylpyridine) to afford bisacetate 30 (49% over three steps),
for which a crystal structure was obtained, confirming the
stereochemistry of the ring-opened product. The pseudoanomeric
hydroxyl group is expected to be the least nucleophilic in the
triol and was unaffected under these neutral acetylation condi-
tions (Scheme 7).
The hydrolysis of epoxy benzyl ether 29b was more
straightforward. Treatment with a dilute (5%) aqueous solution
of NaOH in the microwave resulted in the formation of 31 in
good (74%) yield. The structure and stereochemistry of this
educt also was confirmed by X-ray crystallography. We note
3
that although the two JH-F couplings visible in the 19F NMR
spectrum are consistent with the presence of a pseudoaxial
proton next to the CF2 center (and therefore a chair-type
conformation for this ring) one of the couplings is smaller than
the values reported for H-C-C-F dihedrals approaching the
antiperiplanar angle. These species are now highly oxygenated,
3
which will lower JH-F values generally.
The hydrolytic ring opening of the epoxide is believed to
take place via initial reversible attack on the carbonyl followed
by irreversible transannular epoxide opening35 with strain relief.
Though the addition of nucleophiles to the carbonyl group of
cyclooctanone is opposed by the development of additional
transannular strain (an I-strain effect), the equilibrium constant
for cyanohydrin formation from cyclooctanone is still as high
as 1.2.36 Fluorination next to a ketonic carbonyl group favors
the addition of nucleophiles,37 so there seems to be no difficulty
in postulating enough of the hydroxide adduct to trigger a
This product is still formed under the conditions developed
by Donohoe40 which involve the stoichiometric OsO4‚TMEDA
(38) (a) For a computational study of the prototypical transannular
reaction, see: Parveen; Singh, H.; Singh, T. V.; Bharatam, P. V.;
Venugopalan, P. Theochem: J. Mol. Struct. 2004, 685, 139. For a recent
elegant synthetic application of a transannular reaction, see: (b) Nicolaou,
K. C.; Carenzi, G. E. A.; Jeso, V. Angew. Chem., Int. Ed. 2005, 44, 3895.
(c) Park, C. M. J. Org. Chem. 2006, 71, 413.
(39) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973.
(40) Donohoe, T. J. Synlett 2002, 1223.
(35) White, J. D.; Hrnciar, P. J. Org. Chem. 2000, 65, 9129.
(36) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; Wiley-Interscience: New York, 1994; p 769.
(37) Gelb, M. H.; Svaren, J. P.; Abeles, R. H. Biochemistry 1985, 24,
1813.
1580 J. Org. Chem., Vol. 72, No. 5, 2007

Syntheses of Difluorinated Pentopyranose Analogues
SCHEME 8. Dihydroxylation and Transannular Collapse
FIGURE 1. Calculated lowest-energy conformations for 39-41. The
conformational descriptors refer to the carbon skeleton.
TABLE 1. Energies for RHF 6-31G* Optimized Structures and
Calculated Energies (RHF 6-31+G**) for the Lowest-Energy
Conformers of 39-41
SCHEME 9. Benzyl Ether Hydrogenolyses
E
rel/kcal mol-1
(6-31G*)
E
rel /kcal mol-1
(6-311+G**)
triol
conformer
39
39
40
40
41
41
boat-boat
boat-chair
boat-boat
boat-chair
boat-boat
boat-chair
0.594
3.028
0.000
2.118
2.742
4.774
0.000
2.310
0.276
2.397
3.150
4.126
We also examined the ruthenium-based dihydroxylation
described recently by Tiwari and Misra42 and found it most
effective with rapid conversion of 29b to the bicyclic products
after a short reaction time, though with lower stereoselectivity
(37/38 1.7:1) than under the UpJohn conditions. The elucidation
of the controlling factors in these oxidations will require
electronic structure calculations which lie outside the scope of
this manuscript.
SCHEME 10. Attempted Selective Phosphorylation
Unprotected Pentopyranose Analogues and Conforma-
tional Analysis. Diols 31, 37, and 38 were debenzylated
smoothly under conventional conditions to afford triols 39-41
completing the syntheses of the first three examples of this new
class of difluorinated and conformationally locked sugar ana-
logues (Scheme 9). As drawn, 39 represents a locked 2-deoxy-
2,2-difluoro analogue of the â-L-lyxo- or â-L-xylopyranoside
in the 1C4 conformation whereas 41 is the R-anomer in the 4C1
conformation. As drawn, triol 40 is the locked 2-deoxy-2,2-
difluoro analogue of â-D-arabino- or ribopyranoside.
The line formula representations of 39-41 conceal a number
of close contacts between atoms which will result in Van der
Waals strain, notably between 40 and 41 where there are pseudo-
1,3-diaxial heavy atoms.
The consequences were explored by carrying out a Monte
Carlo conformational search (MMFF94 force field) in Spartan
04.43 The geometries of all the conformers generated in this
way were optimized by ab initio calculations (RHF 6-31G*),
and energies were calculated using the 6-311+G** basis set.
Table 1 shows the relative energies of the lowest-energy
complex. In an NMR experiment, we observed an ca. 1:1
mixture of osmate esters41 before acidic methanolysis and a 1:1
mixture of 37 and 38 after workup. The presence of the chelating
TMEDA ligand appears to have made the unexpected pathway
less favorable but has not prevented its operation. Donohoe and
co-workers have suggested that the diamine and the metal oxide
appear to stay bound together under the dihydroxylation
conditions, so control via coordination to the carbonyl group
seems extremely unlikely under these conditions.
(41) Donohoe, T. J.; Johnson, P. D.; Pye, R. J.; Keenan, M. Org. Lett.
2005, 7, 1275. This paper describes a well-characterized cyclic osmate ester
complexed to TMEDA.
(42) Tiwari, P.; Misra, A. K. J. Org. Chem. 2006, 71, 2911.
(43) Spartan 04, version 1.0.3, Wavefunction Inc.: 18401 Von Karman
Avenue, Suite 370, Irvine, CA 92612, 2005.
J. Org. Chem, Vol. 72, No. 5, 2007 1581

Miles et al.
SCHEME 11. Phosphorylation Following Secondary Hydroxyl Protection
conformers; for all three sugar analogues, these have the
functionalized pyran ring in a chair conformation (Figure 1).
Formally, the eight-membered carbon skeleta of the bicycles
occupy oxygen-bridged boat-boat conformations in the lowest-
energy conformers, and the oxygen-bridged boat-chair confor-
mations are both ca. 2 kcal mol-1 higher in energy for 39 and
40 and ca. 1 kcal mol-1 higher in energy for 41. The boat-boat
conformer brings two groups (substituents on C-3 and C-7) very
close together. In 39, for example, H-3 and an H-7 proton are
within 2.1 Å, but it also allows each bridging C-O bond to be
close to antiperiplanar to a C-H and the exocyclic C-O bond
to be antiperiplanar to a C-C bond. In the boat-chair, H-2 and
an H-7 proton are within 2.25 Å, and one of the fluorine atoms
is within 2.25 Å of H-2. The antiperiplanar relationships with
the bridging C-O bonds in the boat-chair are lost.
Na salt. However, the poor conversion of 37 and loss of material
in 45 directed us toward protection of the secondary hydroxyl
group. Acetylation to 46 occurred selectively (89%), and the
regiochemistry was confirmed by an HMBC experiment which
shows a cross-peak (3JC-H) between the acetate carbonyl carbon
and H-4. Exposure of 46 to NaHMDS followed by the addition
of tetrabenzyl pyrophosphate allowed the isolation of 47 in good
yield, though deacetylated 44 was an occasional contaminant
after chromatography. Hydrogenolysis of the benzyl groups was
followed by deacetylation, lyophilization, and column chroma-
tography allowing the isolation of deprotected material (Scheme
11). No intermediates were purified during this sequence, but
we did check for 19F and 31P NMR spectral changes, obtaining
accurate ion masses of the crude materials at each stage.
Particularly broad (and rather uninformative) 31P NMR spectra
were obtained for the free phosphomonoester diacid intermedi-
ates.
The final structure 48 is assigned as the ammonium sodium
salt on the basis of the presence of ammonia in the chromato-
graphic eluent; chromatography over silica can lead to the
formation of monosodium salts, consistent with the results of
combustion analysis.
The successful development of a phosphorylation and depro-
tection strategy sets the stage for the preparation of a wider
range of analogues and the chemical or enzymatic synthesis of
the NDP sugar analogues themselves.
There is some distortion of structure 40 to allow the pseudo-
1,3-diaxial oxygen and fluorine atoms to relieve some Van der
3
Waals strain. The largest JH-F’s observed were for 40 and the
intermediates leading to and derived from it; a similar value
was observed for 39. These values are consistent with the
calculated low-energy conformations. Though 41 has the
potential to flip the functionalized ring into a boat and exchange
the two axial hydroxyl groups into equatorial environments, the
3JH-F suggests that the methine is equatorial and bisects the
F-C-F angle, a conclusion supported by the ab initio calcula-
tions (the alternate conformer is 1 kcal mol-1 higher in energy).
Synthesisof a PentopyranosylPhosphateAnalogue. Initially,
phosphorylation was attempted without further protection steps.
Diol 37 contains two hydroxyl groups which should differ
significantly in acidity.44 Treating diol 31 with one equivalent
of a strong base and allowing the system to equilibrate should
favor the formation of 42 at the expense of 43. The pKa of the
pseudoanomeric hydroxyl group should be lower than the
secondary hydroxyl because of the combined inductive effects
of the bridging oxygen and the two fluorine atoms; phospho-
rylation of 42 was therefore anticipated as the kinetic pathway
(Scheme 10).45
Conclusions
Telescoped syntheses of locked difluorinated analogues of
pentopyranosides have been achieved using metalated difluo-
roenol acetal chemistry and RCM as key steps in high-yielding
multistep sequences which contain minimal purifications. Di-
hydroxylation allows triol synthesis though with modest ste-
reoselectivity in the case of the all-cis triol and subsequent
bicyclic hemiacetal. The toxic osmium(VIII) reagent can be
replaced by Ru when stereoselectivity is not an issue. Epoxi-
dation and hydrolysis provide a highly stereoselective route to
a stereocomplementary class of analogue. A viable phospho-
rylation strategy involving blocking of the secondary hydroxyl
group followed alkoxide formation from the pseudoanomeric
hydroxyl group, and subsequent phosphorylation has been
developed. Conversion of the sensitive triester to the more robust
monoester then allows base-catalyzed deacetylation-completing
syntheses of a representative example of a new class of analogue
of important biomolecules.
Deprotonation with n-BuLi at -78 °C, slow warming to room
temperature, and equilibration overnight, followed by the
addition of tetrabenzyl pyrophosphate, afforded a mixture of
44 (14%), 45 (3%), and recovered 37 (35%). A higher yield
(43%) of the monophosphate 44 could be achieved by changing
the base to NaHMDS and adding Na-selective 15-crown-5,
consistent with the formation of a more ionic and dissociated
(44) (a) For calculations of hemiacetal pKa (the values are only ca. 2-3
pKa units lower than those of the analogous alcohols), see: Guthrie, J. P.;
Pitchko, V. J. Am. Chem. Soc. 2000, 122, 5520. (b) An estimate used by
Jencks suggests a larger difference of 5 pKa units: Jencks, W. P. Catalysis
in Chemistry and Enzymology; McGraw-Hill: New York, 1969; p 522.
(45) The rates of nucleophilic oxyanion attack at phosphotriesters were
shown to depend linearly on nucleophile pKa with a Bro¨nsted coefficient
(âN) of 0.3-0.48 (the size depends on the leaving group). See: Khan,
S. A.; Kirby, A. J. J. Chem. Soc. (B) 1970, 1172. We therefore anticipated
a competition. Though 42 sould be the major species present, 43 could be
as much as 2.5 log units more nucleophilic than 42 (assuming a maximum
âN of 0.5). This may explain the relatively low selectivity.
Experimental Section
Representative procedures only are described in this section. Full
preparative and characterization details for all other compounds
are in the electronic Supporting Information (SI). 2-(2′-Methoxy-
ethoxymethoxy)-1,1,1-trifluoroethane21 and 1,1-difluoro-2-(2′-meth-
oxy-ethoxymethoxy)-4,4-dimethyl-hepta-1,6-dien-3-ol 1520 were
prepared according to published procedures.
1582 J. Org. Chem., Vol. 72, No. 5, 2007

Syntheses of Difluorinated Pentopyranose Analogues
3-Allyloxy-1,1-difluoro-2-(2′-methoxy-ethoxymethoxy)-hepta-
1,6-diene 16. A mixture of 15 (68.24 mmol, 17.40 g) and allyl
bromide (81.90 mmol, 6.87 mL) was added over 1 min to a
vigorously stirred solution of tetra-n-butylammonium hydrogen-
sulfate (3.45 mmol, 1.16 g) and sodium hydroxide (488 mmol, 24.3
mL of a 50% aqueous solution) at 0 °C. The mixture was stirred at
this temperature for 30 min, allowed to warm to room temperature,
and stirred for a further 16 h. The yellow white solution was diluted
with water (40 mL), and the layers were separated. The aqueous
phase was extracted with diethyl ether (4 × 100 mL). The combined
organic extracts were washed with brine (2 × 30 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure to afford
16 as a pale yellow oil (18.24 g, 91%, 100% by GC), which was
used without any further purification: Rf (10% diethyl ether in
hexane) 0.42; δH (300 MHz, CDCl3) 5.96-5.83 (m, 1H), 5.81 (ddt,
ether (3 × 50 mL), and the combined organic extracts were washed
with brine, dried, and concentrated in vacuo to yield 18a as a brown
oil (6.85 g, 80%). The crude product was taken on without
purification: Rf (30% diethyl ether in hexane) 0.27; δH (300 MHz,
4
CDCl3) 8.09-8.05 (m, 2H), 7.58 (apparent tt, J ) 7.4, J ) 1.4,
1H), 7.48-7.42 (m, 2H), 6.01-5.89 (m, 2H), 5.73 (ddt, J ) 17.0,
10.2, 6.4, 1H), 5.62 (t, J ) 7.5, 1H), 5.53 (dd, J ) 16.0, 2J ) 1.3,
2
1H), 5.43 (dd, J ) 10.3, J ) 1.3, 1H), 5.00 (s, 2H), 5.00-4.90
(m, 2H), 3.94-3.80 (m, 2H), 3.60-3.55 (m, 2H), 3.38 (s, 3H),
2.33-2.23 (m, 2H), 2.13-2.04 (m, 2H); δC (75 MHz, CDCl3)
2
164.8, 144.8 (t, JC-F ) 25.7), 137.3, 133.4, 129.9, 129.5, 128.9
(dd, JC-F ) 3.6, 1.8), 128.4, 121.4, 120.2 (t, JC-F ) 5.1), 117.3
1
2
(dd, JC-F ) 251.2, 247.4), 115.4, 98.3, 72.8 (dd, JC-F ) 31.7,
26.9), 71.6, 68.9, 59.0, 33.9, 24.5; δF (282 MHz, CDCl3) -110.8
(dd, 2JF-F ) 253.2, JH-F ) 10.9, 1F), -112.4 (dd, JF-F ) 253.2,
2
2
4
J ) 16.1, 10.1, 6.6, 1H), 5.28 (ddd, J ) 17.2, J ) 3.0, J ) 1.8,
1H), 5.19 (ddd, J ) 10.2, 2J ) 3.0, 4J ) 1.2, 1H), 5.09-4.94 (env.,
4H), 4.10 (ddt, J ) 12.7, 5.1, 1.5, 1H), 4.06-4.00 (m, 1H), 3.94-
3.74 (m, 3H), 3.61-3.57 (m, 2H), 3.41 (s, 3H), 2.13-2.06 (m,
JH-F ) 12.3, 1F); νmax(film)/cm-1 2887w, 1730s, 1602w, 1452w,
1264s, 1096s, 988s, 709s; m/z (EI) 396 (3%, M+) 355 (7), 220
(39), 205 (100), 145 (21), 106 (68); HRMS (EI, M+) calcd for
C21H26F2O5 396.17473, found 396.17473.
2H), 1.95-1.70 (m, 2H); δC (75 MHz, CDCl3) 156.0 (dd, 1JC-F
)
3-Benzoyloxy-4,4-difluoro-deca-1,9-dien-5-one 19a. Thionyl
chloride (15.6 mmol, 1.12 mL) was added to a stirred solution of
benzoate 18a (15.6 mmol, 6.16 g) in methanol (156 mL) at 0 °C.
The solution was allowed to warm to room temperature and stirred
for 18h, and then the solvent was removed in vacuo. The resulting
paste was taken up in water (120 mL), and the mixture was extracted
with diethyl ether (5 × 100 mL). The combined organic extracts
were washed with NaHCO3 (200 mL) and brine (200 mL), dried
(MgSO4), filtered, and concentrated in vacuo to give ketone 19a
(100 mg, 75%, 88% by GC) as a brown oil, which could be used
crude or purified on silica gel eluted with 10% ethyl acetate in
hexane to afford a clear oil (3.60 g, 75%, 97% by GC): Rf (10%
diethyl ether in hexane) 0.56; δH (300 MHz, CDCl3) 8.06-8.01
(m, 2H), 7.60 (tt, J ) 7.5, 4J ) 1.3, 1H), 7.49-7.42 (m, 2H), 6.05-
5.88 (m, 2H), 5.71 (ddt, J ) 17.0, J ) 10.2, J ) 6.7, 1H), 5.57
291.8, 282.8), 137.7, 134.3, 117.3, 115.1, 112.4 (dd, 2JC-F ) 36.8,
9.8), 97.1, 73.8, 71.6, 69.3, 68.3, 59.0, 31.0, 29.6; δF (282 MHz,
2
4
CDCl3) -97.7 (dd, JF-F ) 63.5, JF-H ) 1.9, 1F), -109.5 (dd,
2JF-F ) 63.5, JF-H ) 3.8, 1F); νmax(film)/cm-1 2880s, 1748m,
4
1642w; m/z (FAB) 293 (20%, [M + H]+) 215 (24), 165 (74), 137
(90), 89 (100), 59 (84); HRMS (FAB, [M + H]+) calcd for
C14H23F2O4 293.15634, found 293.15634.
4,4-Difluoro-5-(2-methoxy-ethoxymethoxy)-deca-1,5,9-trien-
3-ol 17. A solution of ether 16 (34.25 mmol, 10.00 g) in THF (60
mL) was added dropwise over 15 min to a stirred solution of LDA
(prepared from nBuLi (68.50 mmol, 28.30 mL of a 2.42 M solution
in hexane) and diisopropylamine (75.30 mmol, 10.58 mL) in THF
(342 mL)) at -100 °C under a nitrogen atmosphere. The pale pink
solution was stirred at this temperature for 30 min before being
allowed to warm to -30 °C over 4 h and stirred for a further 3 h
at this temperature. The solution changed color during warming,
from yellow through orange to brown and finally black. The reaction
was quenched with ammonium chloride (10 mL of a saturated
aqueous solution), whereupon the black color disappeared and an
orange/red solution was observed. The layers were separated, and
the aqueous phase was extracted with diethyl ether (3 × 150 mL).
The combined organic extracts were washed with brine (2 × 50
mL), dried (MgSO4), and concentrated under reduced pressure to
give the homoallylic alcohol 17 (8.71 g, 95% conversion by NMR
and GC) as a red-brown oil, which was used without further
purification; Rf (30% ether in hexane) 0.12; δH (300 MHz, CDCl3)
5.93 (ddd, J ) 17.2, 10.5, 5.6, 1H), 5.80 (ddt, J ) 17.1, 10.1, 6.4,
1H), 5.57 (td, J ) 7.3, 1.3, 1H), 5.47 (dt, J ) 17.2, 2J ) 1.5, 1H),
5.35 (dt, J ) 10.5, 2J ) 1.5, 1H), 5.07-4.95 (m, 4H), 4.50 (broad
s, 1H), 3.86 (t, J ) 4.6, 1H), 3.85 (t, J ) 4.6, 1H), 3.58 (t, J ) 4.6,
2H), 3.38 (s, 3H), 2.92 (1H, broad s), 2.35-2.25 (m, 2H), 2.20-
4
4
(dd, J ) 16.0, J ) 0.9, 1H), 5.50 (dd, J ) 9.4, J ) 0.9, 1H),
5.02-4.94 (m, 2H), 2.74 (t, J ) 7.3, 2H), 2.05 (q, J ) 7.3, 2H),
1.71 (pentet, J ) 7.3, 2H); δC (75 MHz, CDCl3) 199.7 (dd,
2JC-F ) 28.7, 28.7), 164.4, 137.3, 133.7, 129.9, 128.9, 128.6, 127.7,
1
2
122.8, 115.7, 114.1 (dd, JC-F ) 260.9 256.1), 72.4 (dd, JC-F
)
29.9, 25.1), 36.7, 32.6, 21.5; δF (282 MHz, CDCl3) -113.7 (dd,
2JF-F ) 293.9, JF-H ) 9.0, 1F), -118.9 (dd, JF-F ) 273.9,
2
JF-H ) 14.2, 1F); νmax(film)/cm-1 3076w, 2937w, 1733s, 1642w;
m/z (EI) 308 (37%, M+), 105 (85); HRMS (EI, M+) calcd for
C17H18F2O3 308.12242, found 308.12240.
3-Benzoyloxy-2,2-difluoro-cyclooct-4Z-en-1-one 20a. A solu-
tion of diene 19a (4.07 mmol, 1.26 g) and Ti(OiPr)4 (1.21 mmol,
0.365 mL) in freshly degassed DCM (407 mL) was refluxed under
nitrogen for 30 min, and then Grubbs’ catalyst 21 (0.203 mmol,
173 mg, 5 mol %) was added via syringe in DCM (5 mL). Reflux
was maintained until the 19F NMR spectrum of an aliquot showed
that starting material had been consumed completely (after 18 h).
The solvent was then removed in vacuo, and the residue was taken
up in diethyl ether (30 mL) then filtered and concentrated to give
crude cyclooctenone as a brown oil which was purified by flash
column chromatography (silica gel, 10% diethyl ether in hexane)
to give cyclooctenone 20a which crystallized (0.531 g, 46%, 96% by
GC): Rf (10% diethyl ether in hexane) 0.20; mp 91-90 °C; δH
(300 MHz, CDCl3) 8.14-8.10 (m, 2H), 7.64-7.58 (m, 1H), 7.52-
2
2.08 (m, 2H); δC (75 MHz, CDCl3) 145.4 (dd, JC-F ) 27.5,
2JC-F ) 25.2), 135.5, 131.5, 119.8 (t, JC-F ) 5.4), 118.8, 118.2
1
1
(dd, JC-F ) 250.1, JC-F ) 247.1), 115.4, 97.2, 72.4 (dd,
2JC-F ) 30.5, JC-F ) 27.5), 70.5, 67.9, 58.0, 32.0, 23.6; δF (282
2
MHz, CDCl3) -109.5 (dd, 2JF-F ) 253.2, JH-F ) 8.3, 1F), -115.9
2
(dd, JF-F ) 253.5, JH-F ) 14.7, 1F); νmax(film)/cm-1 3434br,
2928w, 1682w, 1641w, 1452w, 1252w, 1170s, 1112s, 1006s, 933s;
m/z (FAB) 293 (44%, [M + H]+), 137 (100), 89 (90), 59 (100);
HRMS (FAB, MH+) calcd for C14H23F2O4 293.15648, found
293.15648.
3-Benzoyloxy-4,4-difluoro-5-(2′-methoxy-ethoxymethoxy)-
deca-1,5Z,9-triene 18a. Alcohol 17 (6.3 g, 21.7 mmol), benzoic
anhydride (4.90 g, 21.7 mmol), and DMAP (0.53 g, 4.3 mmol)
were dissolved in DCM (217 mL). Poly(vinylpyridine) (10.6 g, 10.6
mmol, 0.5 equiv) was added, and the reaction mixture was swirled
gently at room temperature overnight. The resin was collected at
the pump and washed with water (50 mL) and saturated NaHCO3
solution (50 mL). The aqueous layer was extracted with diethyl
4
7.45 (m, 2H), 6.36 (dddd, JH-F ) 21.3, 1.5, J ) 7.8, J ) 3.8,
1H), 6.07-5.96 (m, 1H), 5.65 (ddd, J ) 11.0, 7.8, 2.5, 1H), 2.82
2
2
(dddd, J ) 12.6, J ) 10.4, 3.9, 2.0, 1H), 2.68 (ddt, J ) 12.6,
4
J ) 7.2, J ) 3.7, 1H), 2.44-2.27 (m, 2H), 2.13-2.02 (m, 1H),
1.89-1.74 (m, 1H); δC (75 MHz, CDCl3) 199.5 (t, 2JC-F ) 25.5),
165.2, 135.6, 133.7, 130.0, 129.0, 128.6, 125.3, 116.6 (dd,
1JC-F ) 262.6, 260.0), 68.2 (dd, JC-F ) 24.2, 18.9), 36.8, 27.5,
2
27.1; δF (282 MHz, CDCl3) -111.0 (d, 2JF-F ) 239.8, 1F), -130.9
(dd, JF-F ) 239.8, JF-H ) 21.3, 1F); νmax (solid)/cm-1 2968m,
2919m, 1725w, 1743w; m/z (ES+) 281 (M + H+, 42%) 121
(PhCOO, 100%). Anal. calcd for C15H14F2O3: C, 64.28; H, 5.03.
2
3
J. Org. Chem, Vol. 72, No. 5, 2007 1583

Miles et al.
Found: C, 64.31; H, 5.16. Colorless or almost colorless material
of improved quality for further use can be obtained by taking the
crude oil (ca. 0.5 g, 2 mmol) up in a minimum volume of methanol
and eluting through a preconditioned (3 mL of MeOH per tube)
thiol SPE tube with MeOH (3 mL).
3-Benzyloxy-2,2-difluoro-cyclooct-4Z-en-1-one 20b. A solution
of 19b (2.21 mmol, 0.650 g) and Ti(OiPr)4 (0.66 mmol, 0.198 mL)
in freshly degassed DCM (1000 mL) was refluxed for 30 min under
nitrogen, and then a solution of Grubbs’ catalyst 21 (0.11 mmol,
94 mg, 5 mol %) in DCM (5 mL) was added via syringe. Reflux
was maintained until the 19F NMR spectrum of an aliquot showed
that starting material had been consumed completely (after 18h).
The solvent was removed in vacuo, and the residue was taken up
in diethyl ether (50 mL), then filtered, and concentrated to give
crude cyclooctenone 20b as a brown oil which was purified by
flash column chromatography (silica gel, 10% diethyl ether in
hexane) to afford cyclooctenone 20b as a yellow solid (440 mg,
75%, 96% by GC): Rf (30% diethyl ether in hexane) 0.40; mp
32-35 °C; δH (300 MHz, CDCl3) 7.40-7.22 (m, 5H), 5.93 (app.
3-Benzyloxy-4,4-difluoro-5-(2′-methoxy-ethoxymethoxy)-deca-
1,5Z,9-triene 18b. A solution of 17 (20.2 mmol, 5.9 g) in THF
(50 mL) was added cautiously to a suspension of NaH (101 mmol,
4.04 g of a 60% suspension in mineral oil, prewashed with hexane
3 × 30 mL) in THF at 0 °C under nitrogen. The mixture was stirred
at this temperature for 45 min as hydrogen evolved. TBAI (2.86
mmol, 1.05 g) then benzyl bromide (19.19 mmol, 2.28 mL) were
added, and the mixture was allowed to warm to room temperature
over 1 h and then stirred for a further 12 h. The reaction was
quenched by the cautious addition of water (150 mL), and the layers
were separated. The aqueous layer was extracted with ethyl acetate
(3 × 150 mL), and the combined organic extracts were washed
with brine (100 mL), dried (MgSO4), and concentrated in vacuo to
give benzyl ether 18b as a brown oil (7.10 g, 92%, 97% by GC)
which was used without further purification: Rf (30% ether in
hexane) 0.38; δH (400 MHz, CDCl3) 7.25-7.17 (m, 5H), 5.77 (ddd,
J ) 17.5, 10.1, 7.4, 1H), 5.72 (ddt, J ) 17.1, 10.2, 6.5, 1H), 5.50
(td, J ) 7.4, 4JH-F ) 1.4, 1H), 5.38-5.36 (m, 1H), 5.35-5.32 (m,
1H), 4.98-4.92 (dq, J ) 17.1, 4J ) 1.7, 1H), 4.89-4.87 (dq, J )
10.2, 4J ) 1.9, 1H), 4.87 (d, 2J ) 5.9), 4.86 (d, 2J ) 5.9), 4.58 (d,
2
q, J ) 9.2, 1H), 5.60 (ddd, J ) 11.1, 9.2, 1.2, 1H), 4.76 (d, J )
2
3
12.0, 1H), 4.66 (d, J ) 12.0, 1H), 4.66 (ddd, JH-F ) 20.0, J )
8.0, 1.3, 1H), 2.60-2.48 (m, 2H), 2.28 (dddd, J ) 13.7, 11.1, 5.6,
3.1, 1H), 2.04-1.86 (m, 2H), 1.80-1.46 (m, 1H); δc (75 MHz,
CDCl3) 200.4 (dd, 2JC-F ) 26.6, 24.8), 137.0, 135.4, 128.6, 128.1,
3
1
128.0, 127.7 (d, JC-F ) 6.0), 117.8 (dd, JC-F ) 263.9, 258.5),
173.0 (dd, 2JC-F ) 23.3, 19.7), 72.1, 36.7, 27.4, 27.1; δF (376 MHz,
2
323 K, CDCl3) -110.9 (d, JF-F ) 240.4, 1F), -130.8 (dd,
2JF-F ) 240.4, JH-F ) 19.5, 1F); νmax(solid)/cm-1 2866s, 1743s,
3
1648w, 1497w, 1455s, 1185s, 1100s, 1070s, 992w, 845s, 812s,
737s, 698s; m/z (CI+) 284 (100%, [M + NH4]+) 270 (5), 220 (3),
158 (7), 140 (11), 123 (6), 90 (8); HRMS (ES+, [M + NH4]+)
calcd for C15H20F2O2N 284.1456, found 284.1457. Anal. calcd for
C15H16F2O2: C, 67.66; H, 6.06. Found: C, 67.59; H, 6.15.
Carrying out the RCM with 7.12 mmol of 19b at 0.005 M
afforded 20b in 50% yield after purification. The crude material
contained significant quantities of higher molecular weight material,
so use of the lower concentration is therefore recommended.
2R*-Benzoyloxy-3,3-difluoro-9-oxa-(1S*,8S*)-bicyclo[6.1.0]-
2
2J ) 11.9, 1H), 4.44 (d, J ) 11.9, 1H), 4.14 (dddt, JH-F ) 14.2,
8.5, J ) 7.4, 4J ) 0.9), 3.71 (t, J ) 4.8, 1H), 3.69 (t, J ) 4.4, 1H),
3.46 (dd, J ) 5.1, 4.3, 2H), 3.29 (s, 3H), 2.26-2.18 (m, 2H), 2.09-
2
2.03 (q, J ) 7.1, 2H); δc (100 MHz, CDCl3) 145.4 (dd, JC-F
)
27.2, 24.8), 137.6, 137.5, 131.1 (dd, JC-F ) 3.6, 1.8), 128.3, 127.8,
127.7, 121.5, 119.7 (t, JC-F ) 5.1), 118.1 (dd, 1JC-F ) 251.0, 246.0),
2
115.3, 98.2, 79.0 (dd, JC-F ) 31.7, 25.7), 71.6, 71.4, 68.8, 59.0,
2
33.1, 24.6; δF (282 MHz, CDCl3) -108.1 (dd, JF-F ) 254.8,
nonan-4-one 29a. Disodium EDTA (7.2 mL of a 4 × 10-4
M
2
JH-F ) 8.5, 1F), -114.7 (dd, JF-F ) 154.8, JH-F ) 14.2, 1F);
aqueous solution, 2.9 µmol) followed by trifluoroacetone (3.6 mL
of a 60% aqueous solution, 25 mmol from a precooled syringe)
was added to a solution of 20a (0.5 g, 1.8 mmol) in acetonitrile
(18 mL) at 0 °C. Sodium hydrogen carbonate (2.3 g, 31.9 mmol)
and oxone (5.5 g, 8.6 mmol) were added in one portion. The mixture
was stirred for 6 h and allowed to warm to room temperature. The
solids were removed by filtration and washed at the pump with
DCM (25 mL). The aqueous phase was extracted with DCM (3 ×
20 mL), and the combined organic extracts and filter washings were
washed with brine (20 mL), dried (MgSO4), and concentrated in
vacuo to yield 29a as a white solid (0.40 g, 75%) which was used
without purification: Rf (30% ethyl acetate in hexane) 0.22; mp
ν
max(film)/cm-1 2923s, 1743w, 1678w, 1637w, 1454s, 1113s, 938s,
850w, 732w, 699s. A satisfactory mass spectrum could not be
obtained for this compound (ES-MS, EI, CI, FAB).
3-Benzyloxy-4,4-difluoro-deca-1,9-dien-5-one 19b. Thionyl
chloride (18.6 mmol, 1.34 mL) was added to a stirred solution of
enol ether 18b (18.6 mmol, 7.10 g) in methanol (180 mL) at 0 °C.
The solution was allowed to warm to room temperature over 1 h
and stirred for 15 h. The methanol was removed in vacuo, and the
resulting paste was taken up in water (40 mL) and extracted with
ethyl acetate (3 × 150 mL). The combined organic extracts were
washed with NaHCO3 (70 mL) and brine (2 × 100 mL), dried
(MgSO4), and concentrated in vacuo to give ketone 19b as a yellow
oil (5.13 g, 94%, 99% by GC) which was used in the next step
without purification. The following data were obtained from a
purified sample (flash chromatography, 10% diethyl ether in
hexane): Rf (30% ether in hexane) 0.68; δH (400 MHz, CDCl3)
7.37-7.21 (m, 5H), 5.85 (ddd, J ) 17.2, 10.5, 7.6, 1H), 5.72 (ddt,
75-78 °C; δH (300 MHz, CDCl3) 8.18-8.13 (m, 2H), 7.62 (dt,
4
J ) 7.3, J ) 1.5, 1H), 7.49 (t, J ) 7.3, 2H), 5.59 (ddd, JH-F
)
4
20.9, J ) 8.9, JH-F ) 4.4, 1H), 3.24 (ddt, J ) 8.9, 4.3, J ) 1.2,
1H), 3.05 (dt, J ) 10.6, 4.3, 1H), 2.86-2.65 (m, 2H), 2.49 (dddd,
2J ) 14.7, J ) 4.5, 4.3, 3.0, 1H), 2.20-2.10 (m, 1H), 2.05-1.90
(m, 1H), 1.37 (dddd, 2J ) 14.7, J ) 13.6, 10.6, 3.4, 1H); δC NMR
(75 MHz, CDCl3) 198.9, 164.0, 132.8, 129.2, 127.6, 127.6, 116.7
(t, 1JC-F ) 260.9), 68.9, 53.9, 52.0, 35.0, 27.5, 23.2; δF (282 MHz,
2
4
J ) 17.1, 10.2, 6.7, 1H), 5.53 (ddd, J ) 10.5, J ) 1.4, J ) 0.9,
2
2
1H), 5.48 (dt, J ) 17.2, J ) 1.4, 1H), 4.99 (ddd, J ) 17.1, J )
4
2
4
2
3.4, J ) 1.6, 1H), 4.96 (dddd, J ) 10.2, J ) 3.4, J ) 2.0, 1.2,
CDCl3) -113.2 (dd, JF-F ) 247.4, JH-F ) 4.4, 1F), -127.3 (dd,
2
2
2JF-F ) 247.4, JH-F ) 20.9, 1F); νmax(solid)/cm-1 2954w, 1736s,
1275, 1262, 1250 all m, 1081m, 1070m, 707s; m/z (EI+) 296 (30%,
M+) 224 (40), 174 (100, M - BzOH); HRMS (EI, M+) calcd for
C15H14F2O4 296.08602, found 296.08601. Anal. calcd for
C15H14F2O4: C, 60.8; H, 4.8. Found: C, 60.9; H, 4.8.
1H), 4.61 (d, J ) 11.5, 1H), 4.38 (d, J ) 11.5, 1H), 4.26 (dddt,
4
JH-F ) 16.6, 6.6, J ) 7.5, J ) 0.9, 1H), 2.68 (tt, J ) 7.3, 1.7,
4
2H), 2.03 (tdd, J ) 7.3, 6.7, J ) 1.2, 2H), 1.69 (pentet, J ) 7.3,
2
2H); δc (75 MHz, CDCl3) 201.7 (dd, JC-F ) 31.1, 25.1), 137.6,
136.8, 129.6 (dd, JC-F ) 3.6, 1.2), 128.4, 128.1, 128.0, 123.2, 115.4,
1
2
115.0 (dd, JC-F ) 261.5, 253.7), 79.4 (dd, JC-F ) 30.5, 23.9),
2R*-Benzyloxy-3,3-difluoro-9-oxa-(1S*,8S*)-bicyclo[6.1.0]-
nonan-4-one 29b. Prepared as for 29a, from 20b (0.620 g, 2.33
mmol), Na2EDTA (9.31 mL of a 4 × 10-4 M aqueous solution),
acetonitrile (23.30 mL), trifluoroacetone (4.66 mL of a 60% aqueous
solution, 25 mmol), NaHCO3 (2.94 g, 34.95 mmol), and oxone (7.16
g, 11.65 mmol) for 6 h at 0 °C. Purification (flash chromatography,
silica gel, 20% diethyl ether in hexane) gave epoxide 29b as a white
solid (495 mg, 50%, 98% by GC): Rf (30% diethyl ether in hexane)
0.20; mp 70-73 °C; δH (400 MHz, CDCl3) 7.44-7.29 (m, 5H),
71.4, 37.6, 32.7, 21.5; δF (282 MHz, CDCl3) -110.6 (dd, 2JF-F
)
1
263.0, JH-F ) 6.6, 1F), -124.1 (dd, JF-F ) 263.0, JH-F ) 16.6,
1F); νmax(film)/cm-1 1941w, 1740s (CdO), 1642w, 1455w, 1372w,
1217s, 1091s, 913s, 736s, 698s; m/z (CI+) 312 (100%, [M + NH4]+)
294 (4), 216 (33), 186 (20), 170 (9), 126 (8), 108 (11), 84 (8);
HRMS (CI+, [M + NH4]+) calcd for C17H24F2O2N 312.1770, found
312.1769. Anal. calcd for C17H20F2O2: C, 69.37; H, 6.85. Found:
C, 69.49; H, 6.98.
1584 J. Org. Chem., Vol. 72, No. 5, 2007

Syntheses of Difluorinated Pentopyranose Analogues
2
2
4.89 (d, J ) 11.9, 1H), 4.85 (d, J ) 11.9, 1H), 3.68 (ddd, JH-F
(20 mL), dried (MgSO4), filtered, and concentrated in vacuo to give
a gray paste which was purified (flash chromatography, silica, 20%
ethyl acetate in hexane) to give (in order of elution) 33 as a gray
paste (20 mg, ca. 18%, 83% of a mixture with 32 by 19F NMR)
followed by 32. 33: Rf (20% ethyl acetate in hexane) 0.30; δH (400
MHz, CDCl3) 7.38-7.30 (m, 5H), 5.15 (dd, J ) 5.7, 5.3, 1H),
4
) 20.3,J ) 8.6, 5.1, 1H), 3.07 (ddt, J ) 8.6, 4.3, J ) 1.6, 1H),
2
2.90 (dt,J ) 10.7, 4.3, 1H), 2.76-2.68 (m, 1H), 2.48 (dddd, J )
4
2
13.4, J ) 9.2, 4.1, J ) 2.2, 1H), 2.36 (dtd, J ) 14.7, 4.5, J )
3.1, 1H), 2.09-1.99 (m, 1H), 1.97-1.85 (m, 1H), 1.02 (dddd, J )
14.5, 13.7, 10.6, 3.3, 1H); δc (75 MHz, CDCl3) 201.1 (t, JC-F
)
25.7), 136.8, 128.5, 128.2, 128.1, 115.6 (dd, 1JC-F ) 161.5, 157.9),
4.84 (d, J ) 11.9, 1H), 4.57 (d, J ) 11.9, 1H), 4.42-4.38 (m,
5
2
2
2
4
75.3 (dd, JC-F ) 22.4, 18.7), 73.2 (d, JC-F ) 1.2), 54.6 (d, JC-F
) 10.8), 53.8, 35.8, 28.3, 24.0; δF (282 MHz, CDCl3) -113.6 (d,
2JF-F ) 245.9, 1F), -128.8 (dd, 2JF-F ) 245.9, JH-F ) 20.3, 1F);
1H), 4.33 (ddd, JH-F ) 9.9, 8.5, J ) 3.7, 1H), 3.49 (d, JH-F )
1.8, 3H), 2.11-1.96 (m, 2H), 1.92 (s, 3H), 1.70-1.28 (m, 4H); δC
(100 MHz, CDCl3) 169.6, 136.9, 128.5, 128.1, 128.1, 123.7 (dd,
2
ν
max(solid)/cm-1 3465w, 2923w, 1744s, 1499w, 1452s, 1340w,
1JC-F ) 267.2, 261.6), 105.8 (dd, JC-F ) 29.2, 18.0), 77.9 (d,
2
4
1236w, 1193s, 1105s, 1083s, 1019s, 1028s, 969s, 862s, 830s, 755s,
702s; m/z (CI+) 300 (100%, [M + NH4]+) 282 (6), 262 (2), 174
(3), 125 (3), 108 (3); HRMS (ES+, [M + NH4]+) calcd for
C15H20F2O3N 300.1406, found 300.1409. Anal. calcd for
C15H16F2O3: C, 63.82; H, 5.71. Found: C, 63.77; H, 5.78.
3R*-Benzyloxy-2,2-difluoro-9-oxa-1S*,5R*-bicyclo[3.3.1]nona-
1S*,4R*-diol 31. Epoxide 29b (0.44 mmol, 125 mg) and NaOH
(2.2 mL of a 0.5% aqueous solution, 0.28 mmol) were sealed in a
microwave vial containing a stirrer bead. The solution was irradiated
in the cavity of a CEM Discover instrument (30 W power to
maintain a temperature of 100 °C for 10 min, with a 10 min heating
ramp, no cooling). The vial was vented and opened, and the solution
was made just acidic (pH 6 to indicator paper) by the addition of
a few drops of HC1 (0.3 mL of a 3 M aqueous solution), which
caused a white solid to precipitate. The aqueous solution was
extracted with ethyl acetate (3 × 20 mL), and the combined organic
extracts were washed with NaHCO3 (20 mL) and brine (30 mL),
dried (MgSO4), and then filtered. The solvent was removed in vacuo
to give a white solid which was purified (flash silica, 50% ethyl
acetate in hexane) to give 31 as a white solid (98 mg, 74%): Rf
(50% ethyl acetate in hexane) 0.28; mp 127-130 °C; δH (300 MHz,
JC-F ) 9.6), 77.3 (dd, JC-F ) 16.0, 10.4), 72.4 (d, JC-F ) 2.4),
4
71.0, 51.8 (d, JC-F ) 5.6), 34.3, 30.1, 20.9, 18.0; δF (376 MHz,
CDCl3) -114.3 (dd, JF-F ) 235.0, JH-F ) 9.9, 1F), (-126.0)-
2
(-126.9) (m incl. apparent d, 2JF-F ) 235.0, 1F); νmax(film)/cm-1
2948s, 2359s, 1742s, 1454m, 1372m, 1238s, 1062s, 739w, 699w;
m/z (CI+) 374 (100%, [M + NH4]+) 284 (5), 208 (6), 106 (9), 77
(18), 52 (79); HRMS (ES+, [M + NH4]+) calcd for C18H26F2O5N
374.1774, found 374.1773. In the {19F}1H NMR spectrum, the
signal at 4.42-4.38 simplified to 4.40 (dd, J ) 6.5, 4.0, 1H) and
the signal at 3.49 simplified to 3.49 (s, 3H). 32 (45 mg, 39%): Rf
(20% ethyl acetate in hexane) 0.16; mp 92-93 °C; δH (400 MHz,
CDCl3) 7.41-7.32 (m, 5H), 5.21 (ddd, J ) 9.9, 6.5, 1.2, 1H), 4.96
2
2
(d, J ) 12.0, 1H), 4.70 (d, J ) 12.0, 1H), 4.46-4.42 (m, 1H),
5
4.16 (ddd, JH-F ) 17.4, 7.6, J ) 9.9, 1H), 3.51 (d, JH-F ) 1.5,
3H), 2.02 (s, 3H), 1.96-1.60 (m, 6H); δC (100 MHz, CDCl3) 169.5,
137.4, 128.4, 128.4, 128.0, 119.2 (dd, 1JC-F ) 259.2, 257.6), 95.8
2
2
(dd, JC-F ) 25.6, 17.6), 77.2 (dd, JC-F ) 21.6, 19.2), 74.1 (d,
4JC-F ) 2.4), 72.5 (d, JC-F ) 8.8), 69.6, 50.7 (d, JC-F ) 4.0),
4
25.9 (d, JC-F ) 2.4), 21.1, 20.7, 18.1; δF (376 MHz, CDCl3) -114.8
2
2
(dd, JF-F ) 248.3, JH-F ) 7.1), -128.0 (dddq, JF-F ) 248.3,
JH-F ) 17.5, J ) 3.8, JH-F ) 1.4, 1F); νmax(solid)/cm-1 2955w,
5
1737s, 1440w, 1363s, 1239s, 1029s, 892s, 758s; m/z (CI+) 374
(100%, [M + NH4]+) 284 (13), 208 (9), 108 (21), 77 (19); HRMS
(ES+, [M + NH4]+) calcd for C18H26F2O5N 374.1774, found
374.1777. Anal. calcd for C18H22F2O5: C, 60.67; H, 6.22. Found,
C, 60.76; H, 6.30. In the {19F}1H NMR spectrum, the signal at
3.51 simplified to 3.51 (s, 3H).
2
4
CDCl3) 7.45-7.32 (m, 5H), 5.01 (dd, J ) 11.3, J ) 1.1, 1H),
4.67 (d, 2J ) 11.3, 1H), 4.22 (t, J ) 5.1, 1H), 4.06-3.98 (m, 2H),
3.39 (d, J ) 5.4, 1H), 2.23 (br. s, 1H), 2.11-2.02 (m, 1H), 1.95-
1.52 (m, 5H); δC (75 MHz, CD3OD) 138.0, 127.9, 127.8, 127.4,
1
2
118.7 (dd, JC-F ) 257.6, 252.8), 93.6 (dd, JC-F ) 26.9, 20.3),
80.2 (dd, 2JC-F ) 19.1, 19.1), 74.4 (d, 4JC-F ) 2.4), 73.0, 71.4 (d,
3JC-F ) 8.4), 28.7 (d, 3JC-F ) 2.4), 20.0, 17.9; δF (282 MHz, CD3-
Crystal data: C18H22F2O5, crystal size 0.35 × 0.24 × 0.20 mm3,
M ) 356.36, triclinic, a ) 7.240(2) Å, b ) 9.607(3) Å, c ) 13.226-
(4) Å, R ) 98.732(5)°, â ) 102.590(5)°, γ ) 100.713(5)°, U )
864.2(4) Å3, T ) 150(2) K, space group P1, Z ) 2, µ(Mo KR) )
0.113 mm-1, 6306 reflections measured, 3024 [R(int) ) 0.0485]
which were used in all calculations. Final R indices [F2 > 2σ(F2)]
R1 ) 0.0455, wR2 ) 0.1179; R indices (all data) R1 ) 0.0554,
wR2 ) 0.1240.
2
OD) -115.8 (dd, JF-F ) 247.8, JH-F ) 7.6, 1F), (-128.7)-
(-129.8) (m, incl. app. d, JF-F ) 247.8, 1F); νmax(solid)/cm-1
2
3364br, 2949w, 1350w, 1213, 1080s, 1022s, 907s, 735s, 695s; m/z
(CI+) 318 (100%, [M + NH4]+) 228 (3), 210 (3), 108 (10), 91 (5),
52 (52); HRMS (ES+, [M + NH4]+) calcd for C15H22F2O4N
318.1511, found 318.1510. Anal. calcd for C15H18F2O4: C, 59.99;
H, 6.04. Found: C, 60.13; H, 6.10.
Crystal data: C15H18F2O4, crystal size 0.19 × 0.10 × 0.04 mm3,
M ) 300.29, triclinic, a ) 9.9359(15) Å, b ) 11.1641(17) Å, c )
13.130(2) Å, R ) 78.181(3)°, â ) 86.925(3)°, γ ) 88.750(3)°,
U ) 1423.4(4) Å,3 T ) 150(2) K, space group P1, Z ) 4, µ(Mo
KR) ) 0.117 mm-1, 10 395 reflections measured, 4966 [R(int) )
0.0818] which were used in all calculations. Final R indices [F2 >
2σ(F2)] R1 ) 0.0571, wR2 ) 0.0924; R indices (all data) R1 )
0.1002, wR2 ) 0.1055.
4R*-Acetoxy-3R*-benzyloxy-2,2-difluoro-1S*-methoxy-9-oxa-
1S*,5R*-bicyclo[3.3.1]nonane 32 and 5S*-Acetoxy-3R*-benzyl-
oxy-2,2-difluoro-1S*-methoxy-9-oxa-1S*,4R*-bicyclo[4.2.1]-
nonane 33. A solution of epoxide 29b (0.32 mmol, 90 mg) in
methanolic sodium methoxide (3.2 mL of a 0.1 M solution in
methanol) was irradiated in the microwave as for the hydrolysis of
29b (30 W, 100 °C for 20 min, 10 min heating ramp, no cooling).
The solvent was removed in vacuo, and the residue was taken up
in DCM (70 mL) and washed with cold HCl (10 mL of a 1 M
solution) and brine (20 mL), dried (MgSO4), then filtered. Poly-
(vinylpyridine) (340 mg) and acetic anhydride (1.17 mmol, 0.160
mL) were added to the filtrate, and the mixture was swirled at room
temperature for 64 h. The poly(vinylpyridine) was removed by
filtration and washed with DCM (70 mL). The combined organic
extracts and washings were washed with NaHCO3 (10 mL), brine
5S*-Acetoxy-2,2-difluoro-1S*-methoxy-9-oxa-1S*,4R*-bicyclo-
[4.2.1]nonan-3R*-ol 34. Acetate 33 (0.07 mmol, 25 mg) was
dissolved in ethanol (1 mL) containing 10% palladium on activated
carbon (10 mg). The atmosphere was removed and replaced with
hydrogen from a balloon. The solution was stirred at room
temperature for 72 h, and then the hydrogen atmosphere was
removed and replaced with air. The solution was filtered through
celite, then concentrated in vacuo, and purified by flash chroma-
tography (silica gel, 10-30% ethyl acetate/hexane) to give alcohol
34 as a gray paste (10 mg, 59%): Rf (30% ethyl acetate/hexane)
0.25; νmax(film)/cm-1 3447br, 2952w, 1736s, 1441w, 1374w, 1232s,
1036s, 973w, 787w; δH (400 MHz, CDCl3) 5.20-5.15 (m, 1H),
4.54 (ddd, 3JH-F ) 11.0, 8.1, J ) 3.5, 1H), 4.32 (ddd, J ) 6.4, 3.5,
4JH-F ) 1.7, 1H), 3.49 (d, 5JH-F ) 1.4, 3H), 2.12-1.94 (env., 6H),
1.74-1.60 (m, 3H); δC (100 MHz, CDCl3) 170.0, 122.8 (t,
2
3
1JC-F ) 262.8), 105.5 (dd, JC-F ) 28.8, 18.4), 80.0 (d, JC-F
)
2
4
9.6), 72.0 (dd, JC-F ) 28.0, 17.6), 71.2, 51.6 (d, JC-F ) 4.8),
33.7-33.6 (m), 29.75-29.70 (m), 21.0, 18.1; δF (376 MHz, CDCl3)
-119.6 (dd, 2JF-F ) 236.5, 3JH-F ) 11.1, 1F), (-126.6)-(-127.5)
(m, incl. app. d, JF-F ) 236.5, 1F); m/z (ES+) 289 (33%, [M +
2
Na]+) 155 (5), 136 (6), 73 (22), 51 (100); HRMS (ES+, [M +
NH4]+) calcd for C11H20F2O5N 374.1774, found 374.1778. In the
{19F}1H NMR spectrum, the signal at 4.32 collapses to 4.32 (dd,
J. Org. Chem, Vol. 72, No. 5, 2007 1585

Miles et al.
J ) 6.4, 3.5, 1H) and the signal at 3.49-3.49 (s, 3H). The signals
reported as multiplets in the 13C NMR spectrum are weak and
significantly broadened.
2,2-Difluoro-9-oxa-1S*,5R*-bicyclo[3.3.1]nona-1S*,3R*,4R*-
triol 39. Hemiacetal 31 (0.080 mmol, 24 mg) was dissolved in
ethanol (1 mL) containing 10% Pd-C (5 mg). The atmosphere was
removed and replaced several times by hydrogen from a double
balloon, and then the reaction was stirred at room temperature for
23 h. The hydrogen atmosphere was removed in vacuo and replaced
with air, and then the catalyst was removed by filtration through
celite. Concentration of the filtrate in vacuo afforded 39 (16 mg,
95%): Rf (100% ethyl acetate) 0.31; mp 156-158 °C; δH (300
3R*-Benzyloxy-2,2-difluoro-9-oxa-1S*,5R*-bicyclo[3.3.1]nona-
1S*,4S*-diol 37 and 3R*-Benzyloxy-2,2-difluoro-9-oxa-1R*,5S*-
bicyclo[3.3.1]nona-1R*,4R*-diol 38. NMO (295 mg, 2.52 mmol)
was added to a solution of cyclooctenone 20b (336 mg, 1.26 mmol)
in acetone (3.16 mL) and H2O (1.58 mL) at 0 °C. Osmium tetroxide
(0.790 mL of a 2.5% by wt. solution in t-BuOH, 0.063 mmol) was
added, and the black solution was stirred at 0 °C for 6 h. Solid
Na2SO3 (0.4 g) was added, and the suspension was stirred for 1 h,
then diluted with water (3 mL) and extracted with ethyl acetate
(3 × 30 mL). The combined organic extracts were washed with
brine (30 mL), dried (MgSO4), filtered, and concentrated in vacuo.
Flash chromatography (silica gel, 50-70% ethyl acetate in hexane)
gave (in order of elution) minor diastereoisomer 38 (44 mg, 12%)
followed by a mixture of 37 and 38 (106 mg, 28%) and then 37 as
a white solid. 38: Rf (50% ethyl acetate in hexane) 0.24; mp 128-
3
MHz, CD3OD) 4.06-3.92 (m, 2H), 3.76 (dd, J ) 9.5, 6.4, 1H),
1.92-1.48 (env., 6H); δC (100 MHz, CD3OD) 117.9 (dd, 1JC-F
)
2
156.4, 150.9), 93.5 (dd, JC-F ) 26.8, 20.4), 73.0, 72.9 (dd,
3
3
2JC-F ) 20.4, 20.4), 72.0 (d, JC-F ) 8.0), 28.7 (d, JC-F ) 2.4),
2
20.0, 18.9; δF (282 MHz, CD3OD) -118.2 (dd, JF-F ) 246.7,
2
JH-F ) 8.2, 1F), -129.4 (ddd, JF-F ) 246.7, JH-F ) 19.4,
4JH-F ) 4.3, 1F); νmax(solid)/cm-1 3296br, 2964w, 1440w, 1345w,
1207m, 1116m, 1034s, 996s, 929s, 823s; m/z (CI-) 209 (30%,
[M - H]-) 191 (11), 170 (18), 152 (15), 79 (22); HRMS (CI-,
[M - H]-) calcd for C8H11F2O4 209.0631, found 209.0630. Anal.
calcd for C8H12F2O4: C, 45.72; H, 5.75. Found: C, 45.68; H, 5.70.
2,2-Difluoro-9-oxa-1S*,5R*-bicyclo[3.3.1]nona-1S*,3R*,4S*-
triol 40. From 37 (0.077 mmol, 23 mg), 10% Pd-C (5 mg) in
ethanol (1 mL) over 72 h. Filtration through celite and concentration
afforded triol 40 (36 mg, 100%): Rf (100% ethyl acetate) 0.15;
mp 153-155 °C; δH (300 MHz, CD3OD) 4.17-4.04 (env. 2H,
containing 4.10 (ddd, JH-F ) 21.6, 3JH-F ) 8.6, J ) 4.8, 1H) and
4.11-4.09 (m, 1H)), 3.72 (broad s, 1H), 1.90 (broad d, J ) 9.6,
1H), 1.80-1.44 (m, 5H); δC (100 MHz, CD3OD) 117.9 (dd,
2
131 °C; δH (300 MHz, CDCl3) 7.40-7.29 (m, 5H), 4.89 (d, J )
11.5, 1H), 4.66 (d,2J ) 11.5, 1H), 4.21 (d, J ) 6.7, 1H), 3.97 (dddd,
3JH-F ) 13.2, J ) 6.4, 4.4, 0.9, 1H), 3.78-3.71 (m, 1H), 3.44 (d,
4JH-F ) 6.3, 1H), 2.46 (dd, 4J ) 7.9, 1.2, 1H), 2.24-2.06 (m, 2H),
1.92-1.81 (m, 1H), 1.78-1.68 (m, 3H); δC (75 MHz, CDCl3)
137.2, 128.6, 128.2, 127.9, 118.2 (dd, 1JC-F ) 268.1, 251.9), 94.7
(dd, 2JC-F ) 29.9, 20.3), 80.2 (dd, 2JC-F ) 30.4, 18.0), 77.0, 75.0
(d, 4JC-F ) 1.8), 71.5 (dd, 3J ) 3.0, 3.0), 29.6, 24.4, 15.9; δF (282
MHz, CDCl3) -109.5 (ddd, 2JF-F ) 259.6, JH-F ) 13.3, 5.5, 1F),
(-121.8)-(-122.8) (m incl. app. d, 2JF-F ) 259.6, 1F); νmax(solid)/
cm-1 3364br, 3166br, 2913s, 1470m, 1351s, 1210s, 1150s, 1072s,
1034s, 943s, 915s, 882m, 819w, 750s, 699s; m/z (CI+) 318 (100%,
[M + NH4]+), 288 (8), 258 (3), 241 (14), 228 (5), 212 (4), 192
(5), 163 (10), 108 (3); HRMS (ES+, [M + NH4]+) calcd for
C15H22F2O4N 318.1511, found 318.1512. Anal. calcd for
C15H18F2O4: C, 59.99; H, 6.04. Found: C, 59.86; H, 5.90.
Crystal data: C15H18F2O4, crystal size 0.16 × 0.13 × 0.08 mm3,
M ) 300.29, monoclinic, a ) 10.3624(14) Å, b ) 6.6363(9) Å,
c ) 11.0444(15) Å, R ) 90°, â ) 112.613(2)°, γ ) 90°, U )
701.11(16) Å3, T ) 150(2) K, space group P2(1), Z ) 2, µ(Mo
KR) ) 0.119 mm-1, 5059 reflections measured, 2397 [R(int) )
0.0672] which were used in all calculations. Final R indices [F2 >
2σ(F2)] R1 ) 0.0465, wR2 ) 0.0618; R indices (all data) R1 )
0.0684, wR2 ) 0.0683.
2
1JC-F ) 254.0, 254.0), 93.8 (dd, JC-F ) 26.8, 20.4), 75.9, 72.0
3
2
(dd, JC-F ) 8.0, 1.6), 68.8 (dd, JC-F ) 21.6, 19.2), 29.0 (d,
3JC-F ) 2.4), 23.0, 17.7; δF (282 MHz, CD3OD) -(-119.3)-
(-120.2) (m incl. app. d, 2JF-F )247.4, 1F), -127.3 (ddd, 2JF-F
)
247.4, JH-F ) 21.3, JH-F ) 3.8, 1F); νmax(solid)/cm-1 3346br,
2951w, 1647w, 1444w, 1353w, 1204s, 1076s, 1037s, 928s; m/z
(CI+) 228 (100%, [M + NH4]+) 123 (6); HRMS (ES+, [M +
NH4]+) calcd for C8H16F2O4N 228.1042, found 228.1038. Anal.
calcd for C8H12F2O4: C, 45.72; H, 5.75. Found: C, 45.79; H, 5.80.
2,2-Difluoro-9-oxa-1R*,5S*-bicyclo[3.3.1]nona-1R*,3R*,4R*-
triol 41. From 38 (0.067 mmol, 20 mg), 10% palladium-on-carbon
(5 mg) in ethanol (1 mL) over 23 h. Filtration through celite and
concentration in vacuo afforded triol 41 (25 mg, 91%): Rf (100%
ethyl acetate) 0.29; mp 57-60 °C; δH (300 MHz, CD3OD) 3.97
(broad s, 1H), 3.86 (ddd, JH-F ) 13.4, 12.5, J ) 6.9, 1H), 3.53 (dt,
J ) 6.9, 2.7, 1H), 2.00-1.90 (m, 1H), 1.72-1.38 (m, 5H); δC (400
3
4
37 (158 mg, 42%): Rf (50% ethyl acetate in hexane) 0.12; mp
109-112 °C; δH (300 MHz, CDCl3) 7.41-7.33 (m, 5H), 4.91 (d,
1
2
3
2J ) 11.7, 1H), 4.78 (d, J ) 11.7, 1H), 4.32 (d, J ) 6.6, 1H),
MHz, CD3OD) 118.1 (dd, JC-F ) 258.0, 258.0), 94.2 (dd,
2JC-F ) 31.2, 20.0), 77.0, 72.2 (dd, 2JC-F ) 28.8, 19.2), 70.6 (dd,
3JC-F ) 6.0, 2.0), 30.2, 24.8, 15.4; δF (282 MHz, CD3OD) -112.7
4.01 (ddd, JH-F ) 20.1, 7.8, J ) 4.8, 1H), 3.86-3.80 (m, 1H),
4
3.64 (d, J ) 5.5, 1H), 2.95 (s, 1H), 2.08-2.00 (m, 1H), 1.96-
2
4
(ddd, JF-F ) 253.5, J )H-F 12.5, JH-F ) 3.8, 1F), -125.1 (dd,
2JF-F ) 253.5, JH-F ) 13.4, 1F); νmax(solid)/cm-1 3289br, 2963w,
1351m,1205m, 1092s, 1000s, 958s, 894s; m/z (CI+) 228 (100%,
[M + NH4]+); HRMS (ES+, [M + NH4]+) calcd for C8H16F2O4N
228.1042, found 228.1038. Anal. calcd for C8H12F2O4: C, 45.72;
H, 5.75. Found: C, 45.84; H, 5.88.
1.70 (m, 3H), 1.50-1.37 (m, 2H); δC (75 MHz, CDCl3) 136.6,
1
128.6, 128.5, 128.2, 118.0 (dd, JC-F ) 258.8, 254.6), 94.1 (dd,
2JC-F ) 26.9, 20.3), 74.8, 74.6 (dd, JC-F ) 20.0, 17.6), 73.3 (d,
2
4JC-F ) 1.8), 71.0 (dd, JC-F ) 7.8, 1.2), 27.9 (d, JC-F ) 1.8),
23.0, 18.3; δF (282 MHz, CDCl3) (-114.0)-(-114.9) (m incl. app.
d, 2JF-F ) 287.8, 1F), -124.1 (dddd, 2JF-F ) 287.8, 3JH-F ) 20.1,
4JH-F ) 5.5, 2.4, 1F); νmax(solid)/cm-1 3364br, 3180br, 2902w,
1737s, 1453w, 1343w, 1155s, 1089s, 933s, 867w, 728s, 693s; m/z
(CI+) 318 (100%, [M + NH4]+) 302 (4), 228 (17), 212 (3), 121
(6), 52 (10); HRMS (ES+, [M + NH4]+) calcd for C15H22F2O4N
318.1511, found 318.1515. Anal. calcd for C15H18F2O4: C, 59.99;
H, 6.04. Found: C, 59.86; H, 5.95.
3
3
4S*-Acetoxy-3R*-benzyloxy-2,2-difluoro-9-oxa-1S*,5R*-bicyclo-
[3.3.1]nonan-1S*-ol 46. Acetic anhydride (0.214 mL, 2.26 mmol),
DMAP (16.5 mg, 0.14 mmol), and poly(vinylpyridine) (0.9 mmol,
450 mg at 2.0 mmol per gram of loading) were added to a solution
of diol 37 (136 mg, 0.45 mmol) in DCM (4.5 mL). The suspension
was shaken at room temperature for 75 h. TLC analysis showed
the reaction was incomplete, so additional acetic anhydride (200
µL, 2.11 mmol), DMAP (20 mg, 0.17 mmol), and poly(vinylpy-
ridine) (320 mg) were added. The reaction was shaken at room
temperature for a further 48 h until consumption of starting material
was observed by TLC. Workup as before afforded 46 (138 mg,
89%) as a white solid: Rf (50% ethyl acetate in hexane) 0.34; mp
28-30 °C; δH (300 MHz, CDCl3) 7.39-7.30 (m, 5H), 5.20 (ddd,
Crystal data: C15H18F2O4, crystal size 0.14 × 0.09 × 0.06 mm3,
M ) 300.29, monoclinic, a ) 15.5415(19) Å, b ) 6.6332(8) Å,
c ) 13.9404(17) Å, R ) 90°, â ) 106.126(2)°, γ ) 90°, U )
1380.6(3) Å3, T ) 150(2) K, space group P2(1)/c, Z ) 4, µ(Mo
KR) ) 0.121 mm-1, 9657 reflections measured, 2430 [R(int) )
0.0967] which were used in all calculations. Final R indices [F2 >
2σ(F2)] R1 ) 0.0514, wR2 ) 0.0661; R indices (all data) R1 )
0.1050, wR2 ) 0.0785. Crude cyclooctenone 20b could be used
in the dihydroxylation reaction to give diols 37 and 38 in 61%
combined yield over two steps from purified RCM precursor 19b.
4
2
J ) 4.9, JH-F ) 3.8, J ) 1.5, 1H), 4.76 (d, J ) 12.4, 1H), 4.73
(d, 2J ) 12.4, 1H), 4.22 (d, J ) 6.7, 1H), 4.04 (ddd, JH-F ) 21.8,
7.3, J ) 5.0, 1H), 3.61 (d, J ) 6.4, 1H), 2.15 (s, 3H), 2.06-1.38
1586 J. Org. Chem., Vol. 72, No. 5, 2007

Syntheses of Difluorinated Pentopyranose Analogues
(m, 6H); δC (100 MHz, CDCl3) 170.6, 136.7, 128.6, 128.3, 128,
for 90 h. The solution was filtered through celite, and the filtrate
was concentrated in vacuo (98 mg, 100%): {1H}δF (282 MHz,
CD3OD) -116.3 (d, 2JF-F ) 243.2, 1F), -121.2 (d, 2JF-F ) 243.2,
1F); δP (121 MHz, CD3OD) (+8)-(-12) (br. m); m/z (ES-) 331
(100%, [M - H]-) 289 (15), 167 (17), 89 (46), 75 (44); HRMS
(ES-, [M - H]-) calcd for C10H14F2O8 331.0400, found 331.0396.
Acetate Cleavage and Bis(triethylammonium) Salt Forma-
tion. The crude acid (0.28 mmol, 98 mg) was taken up in a mixture
of methanol, water, and triethylamine (5.9 mL, 5:2:1) and stirred
at room temperature for 22 h. The organic solvents were removed
in vacuo, then the residue was freeze-dried to afford the crude bis-
(triethylammonium) salt: δF (282 MHz, CD3OD) -119.7 (d,
2JF-F ) 245.0, 1F), -124.2 (dd, 2JF-F ) 245.0, JH-F ) 20.8, 1F);
δP (121 MHz, CD3OD) -3.9 (s); m/z (ES+) 493 (58%, [M + H]+)
392 (97), 242 (5), 102 (100), 74 (35); HRMS (ES+, [M + H]+)
calcd for C20H43F2N2O7P 493.2849, found 493.2851.
1
2
117.4 (dd, JC-F ) 256.4, 255.6), 94.3 (dd, JC-F ) 26.8, 20.4),
73.8-73.2 (m), 70.8 (dd, 3JC-F ) 9.2, 1.6), 27.8 (d, 3JC-F ) 1.6),
23.0, 21.0, 18.2; δF (282 MHz, CDCl3) (-116.8)-(-117.8) (m,
2
2
incl. app. d, JF-F ) 245.9, 1F), -127.0 (ddt, JF-F ) 245.8,
4
JH-F ) 21.8, JH-F ) 5.2, 1F); νmax(film)/cm-1 3434br, 2951s,
1730s, 1367s, 1074s, 908s, 733s; m/z (EI+) 342 (2%, [M + H]+)
176 (13), 116 (83), 91 (100), 43 (61); HRMS (ES+, [M + H]+)
calcd for C17H21F2O5 343.1352, found 343.1356. Anal. calcd for
C17H20F2O5: C, 59.64; H, 5.89. Found: C, 59.50; H, 5.73.
The 13C NMR spectrum contained a number of weak signals in
the 73.8-73.2 ppm region which could not be resolved well, hence
the recording of this signal as a multiplet.
4R*-Acetoxy-3R*-benzyloxy-1R*-(dibenzylphosphoryloxy)-
2,2-difluoro-9-oxa-1R*,5S*-bicyclo[3.3.1]nonane 47 and 3R*-
Benzyloxy-1R*- (dibenzylphosphoryloxy)-2,2-difluoro-9-oxa-
1R*,5S*-bicyclo[3.3.1]nonan-4R*-ol 44. NaHMDS (0.54 mmol,
317 µL of a 1.7 M solution in THF) was added dropwise to a
solution of 46 (0.49 mmol, 168 mg) in THF (10 mL) at 0 °C and
stirred at this temperature for 1 h. Tetrabenzyl pyrophosphate (0.54
mmol, 290 mg) was added, and the reaction was allowed to warm
to room temperature over 2 h, then stirred for 18 h after which a
white precipitate was observed. The reaction was quenched with
pH 7 buffer (10 mL) and extracted with ethyl acetate (2 × 50 mL).
The combined organic extracts were washed with brine (20 mL),
dried (MgSO4), filtered, and concentrated in vacuo to give a gray
paste which was purified (flash chromatography, silica, 50% ethyl
acetate in hexane) to afford 47 (188 mg, 64%): Rf (ethyl acetate)
0.60; δH (300 MHz, CDCl3) 7.38-7.28 (m, 15H), 5.22-5.18 (m,
1H), 5.17-5.05 (m, 4H), 4.75 (s, 2H), 4.35 (d, 3J ) 6.6, 1H), 4.05
Purification and Ammonium Sodium Salt Formation. Flash
chromatography (silica, ethanol/water/35% aqueous ammonia
(5:3:1)) afforded ammonium sodium salt 48 (60 mg, 66%): Rf
(ethanol/water/35% aqueous ammonia (5:3:1)) 0.13; mp 137-
139 °C; δH (400 MHz, D2O) 4.35 (ddd, JH-F ) 21.5, 8.1, J ) 4.8,
1H), 4.33-4.31 (m, 1H), 3.98-3.92 (m, 1H), 2.28 (ddd, 2J ) 14.2,
2
J ) 14.0, 7.3, 1H), 2.06 (dd, J ) 14.2, J ) 5.4, 1H), 1.95-1.75
(m, 2H), 1.71-1.60 (m, 1H), 1.57-1.50 (dd, J ) 14.0, 5.3, 1H);
1
δC (100 MHz, D2O) 117.4 (dd, JC-F ) 256.4, 250.1), 97.2 (ddd,
2JC-F ) 25.6, 18.4, 2JC-P ) 7.2), 76.8, 71.4 (dd, 3JC-F ) 8.0, 1.6),
68.4 (dd, 2JC-F ) 20.8, 18.4), 27.6, 22.3, 17.5; δF (282 MHz, D2O)
2
(-118.4)-(-119.4) (m. incl. app. d, JF-F ) 243.1, 1F), -123.7
(ddd, 2JF-F ) 243.1, JH-F ) 21.5, 4JH-F ) 5.9, 1F); δP (121 MHz,
D2O) -4.1 (s); νmax(film)/cm-1 2952br, 1444w, 1361w, 1167m,
1078s, 1040s, 910s, 808s, 751s, 685w; m/z (ES-) 289 (4%, [M -
H]-) 273 (5), 183 (3), 125 (56), 97 (100); HRMS (ES-, [M -
H]-) calcd for C8H12F2O7P 289.0294, found 289.0297. Anal. calcd
for C8H15F2NO7NaP: C, 29.18; H, 4.56; N, 4.26. Found: C, 29.48;
H, 4.32; N, 4.27.
3
(ddd, JH-F ) 20.5, J ) 7.0, 5.0, 1H), 2.56-2.40 (m, 1H), 2.16-
1.79 (envelope, 6H), 2.06 (s, 3H), 1.52-1.36 (m, 2H); δC (100
3
MHz, CDCl3) 170.5, 136.6, 136.0 (d, JC-P ) 8.8), 135.7 (d,
3JC-P ) 8.0), 128.6, 128.5, 128.5, 128.4, 128.4, 128.3, 128.1, 128.0,
2
3
127.9, 116.0 (ddd, JF-F ) 264.7, 256.9, JC-P ) 6.8), 99.8 (ddd,
2JC-F ) 27.2, 18.4, JC-P ) 7.2), 75.8, 73.3, 73.0 (ddd, JC-F
21.6, 17.6, JC-P ) 1.6), 70.4 (d, JC-F ) 9.6), 69.7 (dd, JC-P
)
)
2
2
4
3
2
Acknowledgment. We thank the EPSRC for studentships
(J.A.L.M., L.M.), the EPSRC Mass Spectrometry Service
(Swansea) for accurate mass measurements, Dr. Roland Wende
(Umicore) for a donation of the Neolyst catalyst, and Dr. A.
Caravano (Sanofi-Aventis) and Professor R. A. Field (University
of East Anglia) for helpful discussions.
6
2
6.4, JC-F ) 1.6), 69.4 (d, JC-P ) 6.4), 27.8, 22.6, 20.9, 18.4; δF
(282 MHz, CDCl3) (-117.7)-(-118.5) (m, 1F), -124.3 (ddd, 2JF-F
) 245.9, JH-F ) 20.5, J ) 5.2, 1F); δP (121 MHz, CDCl3) -8.8
(quintet, 3JH-P ) 7.3); νmax(film)/cm-1 3472w, 2955s, 1738s, 1496s,
1455s, 1371s, 1243s, 1017s, 873w, 738s; m/z (CI+) 603 (28%, [M
+ H]+) 513 (5), 360 (7), 125 (13), 108 (51), 106 (100); HRMS
(ES+, [M + H]+) calcd for C31H34F2O8P 603.1954, found 603.1955.
Traces of deprotected 44 (16 mg, 6%) were also produced, as
reported previously.
Supporting Information Available: Experimental procedures
for 11a, 11b, 13, 14, 26a-27b, 30, 44, and 45; NMR spectra (1H,
13C, 19F, 31P) for 11a, 11b, 13, 14, 16-19a, 26a-27b, 33, 34, 44,
45, and 47; Cartesian coordinates and energies for RHF 6-31G*
optimized structures for lowest-energy conformers of 39-41, and
calculated energies (RHF 6-31+G**) for 39-41. This material is
available free of charge via the Internet at http://pubs.acs.org.
2,2-Difluoro-3R*,4S*-dihydroxy-9-oxa-1S*,5R*-bicyclo[3.3.1]-
nonanyl-1S*-phosphate Ammonium Sodium Salt 48. Hydro-
genolysis. 10% Palladium-on-carbon (64 mg) was added to a
solution of 47 (0.28 mmol, 170 mg) in ethanol (5.6 mL). The
apparatus was pump-purged with hydrogen from a double balloon,
and the reaction was stirred under hydrogen at room temperature
JO0620258
J. Org. Chem, Vol. 72, No. 5, 2007 1587