Fluorinated analogues of amicetose and rhodinose - Novel racemic and asymmetric routes

Article abstract of DOI:10.1002/ejoc.200801130

Trifluoroethanol was converted into difluorinated (racemic) analogues of amicetose and rhodinose by metallated difluoroenol acetal chemistry, protection, release of the latent difluoromethyl ketone, stereoselective reduction and ozonolysis in acidic metha

Full text of DOI:10.1002/ejoc.200801130

FULL PAPER
DOI: 10.1002/ejoc.200801130
Fluorinated Analogues of Amicetose and Rhodinose – Novel Racemic and
Asymmetric Routes
Jonathan M. Percy,*[a] Ricard Roig,[b][‡] and Kuldip Singh[b]
Keywords: Synthetic methods / Carbohydrates / Fluorination / Diastereoselectivity / Epoxidation
Trifluoroethanol was converted into difluorinated (racemic)
analogues of amicetose and rhodinose by metallated di-
fluoroenol acetal chemistry, protection, release of the latent
difluoromethyl ketone, stereoselective reduction and ozon-
olysis in acidic methanol. A fortuitous separation of dia-
stereoisomers allowed the diastereoisomeric pyranoses to be
obtained cleanly. Though reductive defluorination allowed a
facile entry to the route, the corresponding monofluoro sugar
analogues could not be separated. Instead, Sharpless asym-
metric epoxidation followed by epoxide ring-opening with
an unusual nucleophilic fluoride source allowed enantiomer-
ically highly enriched and selectively protected fluorodiols to
be obtained. Ozonolysis then afforded the methyl pyranos-
ides, which could be transformed in a number of ways.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
hexoses fluorinated at C-6 have been synthesised by using
DAST to transform isolated hydroxy groups, and fluoride
ion to open cyclic sulfates derived from carbohydrates.
Lundt and co-workers[13] prepared an amicetoside from
-gluconic acid by an epoxide-opening reaction, but we
found few other examples of syntheses of fluorinated ana-
logues of the highly deoxygenated sugars.
Introduction
Amicetose (1) and rhodinose (2) (Figure 1) are highly
deoxygenated (2,3,6-trideoxy) sugars which occur in a range
of important antibiotic natural products; kigamicins,[1] po-
lyketomycins[2,3] and tetracenomycins[4] contain 1, whereas
lactonamycins,[5] landomycins[6–9] and urdamycins[10] fea-
ture 2 in their saccharide motifs.
Syntheses from carbohydrates are valuable, and allow the
preparation of enantiomerically enriched materials from
chiral-pool sources. However, it is often the case that an
entirely new synthesis is required for each target. One of
the goals of our work is the development of divergent meth-
odologies by which families of related sugars can be synthe-
sised in enantiomerically enriched form using asymmetric
transformations of achiral precursors,[14–16] or by resolu-
tion.[17] Very direct synthetic access, even if it leads to the
preparation of racemic modifications in the first instance, is
also useful in certain contexts. Our metallated difluoroenol
chemistry[18,19] appeared to offer an extremely direct ap-
proach to a range of difluorinated amicetose and rhodinose
analogues 3, through the reaction with pentenal, un-
masking of the ketone latent in 4 and reduction, followed
by alkene ozonolysis (Scheme 1).
Figure 1. -Amicetose (1) and -rhodinose (2).
There are many chemical syntheses of the free
sugars,[11,12] but the 6-fluoro analogues are less well known
and may have a role to play in elucidating aspects of the
mechanisms of sugar transfer. Our own interest lies in
quantifying fluorine atom effects on glycoside hydrolytic re-
activity.
Nucleophilic fluorinating agents have played a valuable
role in the synthesis of fluorinated carbohydrates. Deoxy-
The separate evolution of the two diol hydroxy groups
affords an opportunity for selective protection, and the abil-
[a] WestCHEM Department of Pure and Applied Chemistry, Uni- ity to form furanoses or pyranoses at will. Also, the rela-
versity of Strathclyde, Thomas Graham Building,
tively high reactivity of difluoroalkenes like 4 towards re-
295 Cathedral Street, Glasgow G1 1XL, UK
ductive defluorination potentially extends the strategy to
monofluorinated analogues. We decided to explore this very
direct route, because even the racemic materials were useful
for an ongoing programme which studied structure-reactiv-
ity relationships. Furthermore, we could use these racemic
routes to develop the key oxidative and other transforma-
tions needed to deliver the free sugars.
Fax: +44-141-548-4822
E-mail: jonathan.percy@strath.ac.uk
[b] Department of Chemistry, University of Leicester, University
Road,
Leicester LE1 7RH, UK
[‡] Current address: International Flavours and Fragrances,
Avda. Felipe Klein 2, 12580 Benicarlo (Castellon), Spain
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Fluorinated Analogues of Amicetose and Rhodinose
The signals of three anomeric protons were clearly visible
in the {19F}1H NMR spectrum; J values between 3.6 and
4.2 Hz, and cross peaks in the HMBC spectrum (which es-
tablished the C-1/4-H and C-4/1-H connections clearly, and
was used to deconvolute the complex 1D spectrum) showed
that the three major products, assigned tentatively as 12a,
12b and 13 (ratio 12a/12b/13 = 2.9:2.5:1) were furanosides.
Upon standing in the NMR solvent (CDCl3), 14 crystal-
lised, and we were able to obtain the molecular structure in
the crystal (Scheme 3).[24,25] We were also able to prepare
this material by leaving the ozonolysis solution overnight
(after dimethyl sulfide treatment) before product isolation.
Though the isolated yield of this product was low, the 19F
NMR spectrum of the crude ozonolysis product identifies
14 as the major product under these conditions. The confor-
mation of 14 in the solid state resembles the “up-down-up-
down” solution conformation described for a related
macrocycle by Winkler et al. by NMR elucidation. We
therefore believe that macrocycle 14 tells us about the vici-
nal coupling constants in a furanose with a pseudoaxial C–
O bond at C-1 (J1,2a value of 4.2 Hz), as well as confirming
the anti configuration of major diol 9. As the initial diol
diastereoisomer ratio from 8 is 6:1, it seems most likely that
12b arises from the major diol, and contains a pseudoaxial
C–O bond with 13, the same anomer of the furanoside from
the minor syn-diol. We searched the conformers available
to 12b using the molecular mechanics (MMFF94) Monte–
Carlo method implemented in Spartan’06,[26] and found no
conformers with a pseudoaxial C–O bond at C-1. Single-
point energy calculations (B3LYP/6-31G*) were carried out
for each of the (30+) conformers generated, the geometries
of the six lowest-energy conformers were optimised (with-
out constraints), and frequencies were calculated by using
the MP2 method. Conformational searching was carried
out again, restricting the geometry around C-1 and C-2 to
resemble the arrangement in 14, and then optimising (with-
out constraints). The global minima for 12a and 13 were
now found; these had a pseudoaxial C–O bond at C-1 and
a hydrogen bond from the C-5 hydroxy group across to the
exocyclic acetal oxygen atom (the calculated O–H···O dis-
tance is 1.9 Å) and were up to 4 kJmol–1 lower in (free)
energy than the lowest-energy species from the uncon-
strained search.
Scheme 1.
Results and Discussion
The initial steps were well established and could be
scaled easily. Metallated difluoroenol acetal 6, generated in
situ from 5, reacted smoothly with pentenal to afford 7 in
good yield.[20] The protecting group was removed in acidic
methanol; we obtained crystalline dioxolane 8, which
underwent relatively rapid reduction with sodium borohy-
dride in diethyl ether delivering anti-diol 9 as the major
product in good yield, with syn-10 present as a side prod-
uct. The (Felkin–Anh) sense of stereoselection is normal for
the reduction of ketones with α-C–O bonds.[21] The relative
configuration was also confirmed by formation of aceto-
nide 11 and NOESY; both ring methine protons show cross
peaks to the same methyl group (Me*) of the acetonide
(Scheme 2).
Scheme 2.
Ozonolysis is the mildest and most direct way to com-
plete the synthesis, and a mixture of amicetose and rhodi-
nose was prepared by using this approach;[22] Weinreb and
co-workers described an extremely effective ozonolysis reac-
tion of alkene polyols absorbed on silica gel;[23] so we ex-
plored this methodology. We obtained a complex product
mixture, which appeared to contain oligomers and was dif-
ficult to deconvolute. However, the ozonolysis in methanol
containing chlorotrimethylsilane delivered a much simpler
mixture of products following reductive (dimethyl sulfide)
workup.
Scheme 3.
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J. M. Percy, R. Roig, K. Singh
FULL PAPER
Hydroxy groups next to fluorinated centres are very 1.8 Hz for the rhodinoside). Some oxidation of the benzyl
good hydrogen-bond donors because of the strong ad- ether methylene group to a benzoyl carbonyl group during
ditional polarisation arising from the electronegative fluor- ozonolysis was noted; we removed the benzoate by the ad-
ine atoms; so the role of this hydroxy group is unsurprising. dition of solid sodium hydroxide to the ozonolysis solution
Figure 2a overlays macrocycle 14 and monomeric furano- after the reduction was complete. Glycoside hydrolysis was
side 12b and shows quite good agreement between them. carried out efficiently in THF in with microwaves to afford
Figure 2b shows the overlay of 12b and 13. Whereas we the hemiacetals 21a and 21b, and 22a and 22b, as a 2.5:1
realise that packing forces are likely to influence the confor- mixture in each case (Scheme 5).
mation in the crystal and may produce an arrangement dif-
ferent to that adopted in solution, the similarities between
the coupling constants measured for 12b, 13 and 14 sug-
gests that our calculated low-energy conformers are repre-
sentative of the species present in chloroform solution.
Figure 2. Overlays of (a) X-ray structure of 14 and calculated
(MP2/6-31G*) structure of furanoside 12b; (b) calculated (MP2/6-
31G*) structures of furanosides 12b and 13, which differ only in
the configuration at C-5.
Scheme 5.
We really wanted to synthesise the pyranosides, so modi-
fication of the route was essential. Benzylation of alcohol 7
under phase-transfer-catalysed conditions[27] afforded a
moderate yield of 15, but unfortunately, reduction following
enol-acetal methanolysis, was unselective and afforded a 1:1
mixture of syn/anti diastereoisomers 16 and 17. Ozonolysis
afforded stable ozonide 18 as a complex mixture of dia-
stereoisomers in the first instance (Scheme 4).
Once again, the assignment of the anomeric configura-
tion based on the differences in J1,2a values appears unam-
biguous (vide supra). The α-anomer of the 4-O-benzylam-
icetose 21a crystallised sufficiently well for the molecular
structure in the crystal to be determined by X-ray methods
supporting all the stereochemical assignments strongly. We
also removed the benzyl ether from a mixture of 19 and 20
by hydrogenolysis in ethanol to afford (an inseparable mix-
ture of) 23 and 24 in good yield. Monofluoro analogues of
both pyranosides could be approached by reductive defluo-
rination[28,29] of 7, which afforded a mixture of alkene dia-
stereoisomers 24 and 25. Hydrolysis and reduction afforded
a mixture of anti- and syn-diol monobenzyl ethers 26 and
27 (Scheme 6).
Scheme 4.
However, extended exposure to dimethyl sulfide secured
the separable methyl pyranosides 19 and 20; our illustra-
tions represent the  sugars though of course these are race-
mic. Both 19 and 20 appear to have axial C–O bonds at the
anomeric carbon atom; 1-H appears as a doublet in each
case (J1,2a = 3.2 or 3.0 Hz), inconsistent with the presence
of diaxial couplings; both pyranosides show NOESY cross
peaks between the methoxy group and 5-H, consistent with
this assignment. Amicetoside 19 and rhodinoside 20 can be
distinguished by J4,5 (J4,5 = 9.8 Hz for the amicetoside or Scheme 6.
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Fluorinated Analogues of Amicetose and Rhodinose
Ozonolysis then secured a 1:1 mixture of amicetosides ing,[38] but various TBAF·HF salts have proved very effec-
1
28 and rhodinosides 29; the H NMR spectra were heavily tive. We failed to ring-open 34 upon exposure to
[39]
overlapped, but we could see what appeared to be one Bu4NH2F3
or cat. KHF2/Bu4NH2F3,[40,41] recovering
major anomer in each case, with small J values (J1,2a = 3.2 starting material under a range of conditions. With KHF2
or 3.0 Hz) to 1-H in each case, but a full assignment was in ethylene glycol,[42] we recovered mostly the product of
impossible. A full discussion of the anomer population and ring opening by the conjugate base of the solvent, whereas
the analogy with 19 and 20 lies outside the scope of this TBAF alone achieved ring opening in low conversion to 36
paper and will be published elsewhere. Another route was (Scheme 8).
clearly required, and the key goal was the control of the diol
configuration; fortunately, methodology is available which
addresses both relative and absolute diol configuration, and
ensures pyranose formation. Scheme 7 shows the synthesis
of enantiomerically enriched epoxy alcohol starting materi-
als.
Scheme 8.
The serendipitous combination of KHF2 and TBAF at
100 °C (effectively a molten salt mixture) achieved a com-
pletely regioselective and high-yielding reaction to deliver
36. Ozonolysis was carried out as described previously to
Scheme 7.
afford the -amicetoside anomers 37a and 37b. NOESY (5-
H/OMe for 37a and 1-H/5-H for 37b) cross peaks were used
Sharpless asymmetric epoxidation[30–33] is rarely per-
to support the assignment of anomeric configuration in
formed on terminal secondary allylic alcohols, with the ex-
each case. We also progressed 33 through the fluorination
ception of divinyl alcohol.[34] Racemic heptadienol 30a was
reaction to 39 via benzyl ether 38 (Scheme 9).
prepared from vinyl bromide and pentenal by the Grignard
reagent, and Sharpless asymmetric epoxidation to 31 was
carried out at –30 °C, requiring 15 d to reach completion
(full conversion of one enantiomer).[35] Payne rearrange-
ment could be suppressed if the exposure time of crude
product to aqueous hydroxide in the workup is limited to
30 min; significant quantities of Payne product 32 was ob-
Scheme 9.
tained if the workup was carried out over a longer
period.[36] Traces of 30 were present in 31, even after the
The ee values of 36 (92% ee) and 39 (95% ee) were deter-
mined by chiral HPLC (Chiralcel OD-H column, 0.1%
most rigorous purification we could achieve.
Enantiomer 33 (of 31) was prepared by using the comple-
iPrOH in petroleum ether as eluant); these represent the
mentary tartrate ligand, and the alcohol 30b resolved dur-
levels of enantiomeric enrichment after the Sharpless
ing the preparation of 31. The absolute configuration was
epoxidation, benzylation and fluorination, so it is extremely
assigned on the basis that the expected epoxy alcohol prod-
unlikely that fluorination leads to a significant loss in enan-
ucts have optical rotations of the same sign as those re-
ported for the corresponding divinyl alcohol products.
Benzylation of 31 was carried out in dichloromethane by
using sodium hydride as the base affording 34 in good (64%
tiomeric purity. The ee values are only slightly lower than
the 96% ee reported for the synthesis of 40 by asymmetric
epoxidation of the internal secondary allylic alcohol, a reac-
tion which takes only 3 d (Figure 3).[35]
yield) with Payne co-product 35 (11%) setting the stage for
the crucial fluorination step.
Amine·HF salts are the most widely used reagents for
the nucleophilic ring opening of epoxides with fluoride ion,
though they can deliver low regioselectivities with terminal
epoxides.[37] We therefore examined methods based on
TBAF; the salt itself has been used for epoxide ring-open- Figure 3. Epoxy alcohol 40 prepared by Page et al.[35]
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J. M. Percy, R. Roig, K. Singh
FULL PAPER
Subsequent reactions were carried out for 36 only, on the formation of a mixture of diastereoiosmers, the location of
assumption that the same results would be obtained from the protecting group and thus the formation of pyranosides
the reactions of enantiomer 39.
is unambiguous. The ozonolysis procedure in acidic meth-
Debenzylation of 37a and 37b by hydrogenolysis oc- anol suppressed oligosaccharide formation and assisted
curred cleanly to afford 41a and 41b, and 37a and 37b were with the isolation of monosaccharides.
hydrolysed cleanly under microwave conditions in acidic
The asymmetric route to the monofluoro species was
THF to afford the free 4O-benzylamicetoses 42a and 42b.
successful, delivering the products in high degrees of enan-
Ozonolysis at 0 °C delivered good yields of benzoates 43a tiomeric enrichment. Clearly the epoxide-based route can-
and 43b by in situ oxidation of the benzyl ether.[43] This not be used to deliver the difluoro sugars, but the evolution
sequence is potentially useful because it preserves the or- of the asymmetric route to address initially a problem of
thogonality of C-4 and C-1 (hemiacetal) hydroxy group relative configuration has yielded very satisfying results and
protection but switches the manifold of conditions available allowed the identification of an interesting reagent combi-
for release of the former hydroxy group. Acetal exchange nation for effective and highly regioselective nucleophilic
with CD3OD proved facile and was a useful tactic allowing epoxide ring opening with fluoride ion. The investigation
4-H and 5-H signals to be seen clearly in 44a and 44b with- of the scope and limitations of this reagent are ongoing; a
out overlap from the methoxy group signal (Scheme 10).
fuller study of furanose/pyranose equilibria for these and
related sugars will be published elsewhere.
Experimental Section
General: General experimental procedures and details of instru-
mentation are given in the Supporting Information. The prepara-
tions of 7 and 8 have been reported fully.[20] Magnesium turnings
(127 mmol, 3.1 g) were washed with HCl (15 mL of a 5  solution),
then water (2ϫ10 mL), then acetone (2ϫ10 mL), then dried in
vacuo and cooled under Ar. Powdered molecular sieves (4 Å)
(6.3 g) in a 250 mL single-necked round-bottomed flask equipped
with a magnetic stirrer bead, were heated under vacuum (below
50 Torr) with a Bunsen burner, and cooled to room temperature
under argon. The cooled sieves were then covered with solvent
through cannula. PE = petroleum ether.
CCDC-709168 (for 14), -709169 (for 21a) and -709170 (for 45a)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request.cif.
Scheme 10.
The separation was difficult and attenuated the isolated
purified yield of two individual anomers (a mixed fraction
was also recovered). The -rhodinoside series could be en-
tered in 45a and 45b by Mitsunobu inversion of 41a and
41b.[44,45] Crystals of adequate quality for crystallographic
analysis were obtained for 45a showing that the relationship
between the stereogenic centres at C-1, C-4 and C-5 was
assigned correctly (Scheme 11).
(2R*,3R*)-1,1-Difluorohept-6-enediol (9) and (2S*,3R*)-1,1-Di-
fluorohept-6-enediol (10): Sodium borohydride (1.2 mmol, 46 mg)
was added in portions to a solution of dioxolane 8 (0.58 mmol,
0.19 g) in diethyl ether (10 mL). After stirring at room temperature
overnight, the mixture was diluted with water (5 mL), neutralised
with concentrated HCl, and extracted with EtOAc (3ϫ15 mL).
The combined organic extracts were dried (MgSO4), filtered, and
concentrated in vacuo to leave a colourless oil, which was purified
by Biotage column chromatography (gradient 20% Ǟ 50% EtOAc/
PE) to afford an inseparable mixture of diols 9 and 10) (0.16 g,
84%, 99% by GC-MS, 6:1 by NMR) as a clear colourless oil. Rf
(20% EtOAc/PE) = 0.20. IR (neat): ν
= 3366 [br. (OH)], 2923
˜
max
[w (CH2)], 1642 [w (C=C)], 1417 (w), 1151 [s (C–O)], 1048 [s (C–
O)] cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.90 (ddd, 2JH,F = 56.0,
2JH,F = 55.0, J = 4.0 Hz, 1 H, 1-H), 5.84 (ddt, J = 17.1, J = 10.2,
Scheme 11.
2
4
J = 6.8 Hz, 1 H, 6-H), 5.09 (ddd, J = 17.1, J = 3.3, J = 1.7 Hz,
2
4
1 H, 7a-H), 5.02 (ddd, J = 10.2, J = 3.3, J = 1.2 Hz, 1 H, 7b-H),
3.95–3.66 (m, 2 H, 2-H, 3-H), 3.04 (br. s, 1 H, OH), 2.46 (br. s, 1
H, OH), 2.36–2.06 (m, 2 H, 5-H), 1.79–1.58 (m, 2 H, 4-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 137.8 (C-6), 137.6, 115.5 (C-7),
115.0 (dd, 1JC,F = 241.9 Hz, 1JC,F = 242.5 Hz, C-1), 77.4 (dd, 2JC,F
Conclusions
The racemic route to the difluoro sugars was direct and
effective; though mixtures of amicetosides and rhodinosides
were produced, they were separable. While the additional
2
3
3
= 23.3 Hz, JC,F = 20.4 Hz, C-2), 70.7 (dd, JC,F = 4.4 Hz, JC,F
=
4
1
3.0 Hz, C-3), 31.3 (d, JC,F = 2.0 Hz, C-4), 29.8 ppm; the H and
steps related to the protecting-group chemistry result in the 13C NMR spectra are effectively those of major diastereoisomer 9.
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Fluorinated Analogues of Amicetose and Rhodinose
19F NMR (282 MHz, CDCl3): major diastereoisomer 9: δ = –128.3
(ddd, JF,F = 292.1, JF,H = 55.0, JF,H = 7.1 Hz, 1 F, CHFaFb),
H), 5.05 (dd, J = 3.6 Hz, J = 1.4 Hz, 1 H, 1-H), 4.18 (ddd, J =
2
2
3
3
13.1 Hz, J = 5.5 Hz, 1.8, 1 H, 4-H), 3.84 (dddd, JH,F = 16.2 Hz,
2
2
3
–132.0 (ddd, JF,F = 292.1, JF,H = 56.2, JF,H = 15.2 Hz, 1 F,
3JH,F = 7.7 Hz, J = 5.5 Hz, J = 3.6 Hz, 1 H, 5-H), 3.33 (s, 3 H,
CHFaFb) ppm; minor diastereoisomer 10: 19F NMR (282 MHz,
OCH3), 2.96 (s, 1 H, OH) ppm; for 12b: δ = 5.83 (td, JH,F
=
2
2
2
3
CDCl3): δ = –129.2 (dddd, JF,F = 292.0, JF,H = 55.7, JF,H = 9.9,
55.1 Hz, J = 3.3 Hz, 1 H, 6-H), 4.99 (dd, J = 4.2 Hz, J = 0.9 Hz,
4JF,H = 1.1 Hz, 1 F, CHFaFb), –130.4 (ddd, JF,F = 292.0, JF,H
=
1 H, 1-H), 4.38 (td, J = 7.0 Hz, J = 3.8 Hz, 1 H, 4-H), 3.93 (ddt,
2
2
56.6, JF,H = 10.6 Hz, 1 F, CHFaFb) ppm. HRMS (EI): calcd. for 3JH,F = 12.7 Hz, JH,F = 11.7 Hz, J = 3.8 Hz, 1 H, 5-H), 3.38 (s, 3
3
3
C7H12F2O2 [M+] 166.08054; found 166.08044. MS (EI): m/z (%) =
148 (2) [M+ + NH4], 130 (4), 111 (5), 97 (19), 85 (30), 67 (100), 57
(42). tR (GC) = 8.95 min (major diastereoisomer).
H, OCH3), 2.88 (s, 1 H, OH); for 13: δ = 5.77 (td, 2JH,F = 56.0 Hz,
J = 4.8 Hz, 1 H, 6-H), 5.10 (dd, J = 4.2 Hz, J = 1.4 Hz, 1 H, 1-
3
H), 4.29 (td, J = 7.0 Hz, J = 2.8 Hz, 1 H, 4-H), 3.66 (tdd, JH,F
=
9.8 Hz, J = 5.4 Hz, J = 2.8 Hz, 1 H, 5-H), 3.48 (s, 1 H, OH), 3.34
(s, 3 H, OCH3) ppm; common to all three furanosides 12a, 12b and
13: δ = 2.19–1.81 (m, 12 H, 2-H, 3-H) ppm. 13C NMR (100 MHz,
CDCl3): the following signals are distinct for 12a and 12b: δ = 115.3
(2R*,3S*)-1,1-Difluoro-O-isopropylidenehept-6-ene (11): p-Tolyl-
uenesulfonic acid monohydrate (0.15 mmol, 28 mg) was added to
a stirred solution of anhydrous copper sulfate (2.6 mmol, 0.403 g)
and diols 9 and 10 (0.76 mmol, 127 mg, 6:1 by NMR) in dry ace-
tone (25 mL). After 5 h at reflux, the mixture was cooled, filtered,
and concentrated in vacuo to leave a colourless oil. Kugelrohr dis-
tillation afforded acetonide 11 (100 mg, 63%, 99% by GC-MS) as
a mixture of isomers (6:1 by NMR) as a clear colourless oil. Rf
1
1
1
(t, JC,F = 242.4 Hz, C-6), 115.0 (dd, JC,F = 243.2 Hz, JC,F
=
=
3
241.6 Hz, C-6), 105.4 [C-1 (12b)], 105.2 [C-1 (12a)], 78.8 (t, JC,F
2
4.0 Hz, C-4), 76.1 (t, 3JC,F = 4.1 Hz, C-4), 72.6 (t, JC,F = 22.4 Hz,
C-5), 72.1 (t, 2JC,F = 22.0 Hz, C-5), 32.8 [OCH3 (12b)], 31.9 [OCH3
(12a)], 32.8 (C-2), 31.9 (C-2), 24.3 (C-3), 23.0 (C-3) ppm; for 13: δ
(20% EtOAc/PE) = 0.67. B.p. 20 °C/0.07 Torr. IR (neat): ν
=
˜
max
1
3
= 115.1 (t, JC,F = 256.9 Hz, C-6), 105.7 (C-1), 74.8 (t, JC,F
=
2988 [w (CH2)], 2939 [w (CH2)], 1642 [w (C=C)], 1373 (w), 1220
2
3.8 Hz, C-4), 72.3 (t, JC,F = 21.4 Hz, C-5), 32.1 (OCH3), 32.1 (C-
1
(s), 1070 (s) cm–1. H NMR (400 MHz, CDCl3): δ = 5.75 (ddd, J
2), 25.5 (C-3) ppm. 19F NMR (282 MHz, CDCl3): for 12a: δ =
2
= 17.1, J = 10.2, J = 6.9 Hz, 1 H, 6-H), 5.61 (ddd, JH,F = 55.7,
2
2
3
–129.7 (d, JF,F = 290.3 Hz, JF,H = 55.2 Hz, JF,H = 7.7 Hz, 1 F),
2
2JH,F = 54.6, J = 5.6 Hz, 1 H, 1-H), 5.00 (dddd, J = 17.1, J = 1.9,
–133.0 (d, JF,F = 290.3 Hz, 2JF,H = 55.2 Hz, 3JF,H = 16.2 Hz, 1 F);
2
4
2
4
4J = 1.6, J = 1.2 Hz, 1 H, 7a-H), 4.94 (ddt, J = 10.2, J = 1.9, J
2
2
3
for 12b: δ = –130.0 (d, JF,F = 291.3 Hz, JF,H = 55.1 Hz, JF,H
=
3
= 1.2 Hz, 1 H, 7b-H), 4.18 (dddd, J = 8.0, J = 6.4, J = 5.8, JH,F
2
2
3
11.7 Hz, 1 F), –130.4 (d, JF,F = 291.3 Hz, JF,H = 55.1 Hz, JF,H
= 2.3 Hz, 1 H, 3-H), 4.00 (ddt, 3JH,F = 10.5, 3JH,F = 9.0, J = 5.8 Hz,
1 H, 2-H), 2.30–2.17 (m, 1 H, 5a-H), 2.15–2.03 (m, 1 H, 5b-H),
= 12.7 Hz, 1 F) ppm; for 13: δ = –128.60 (d, 2JF,H = 56.0 Hz, 1 F),
2
–128.63 (d, JF,H = 56.0 Hz, 1 F). HRMS (EI): calcd. for
1.72–1.62 (m, 1 H, 4-H), 1.41 (CH3), 1.30 (CH3) ppm. 13C NMR
C7H11O3F2 [M+ – H] 181.06763; found 181.06765. MS (EI): m/z
(%) = 182 (1) [M+], 150 (14), 133 (1), 104 (10), 101 (68), 85 (6),
69 (100). tR (GC) = 8.96 min (12a), 9.06 min (12b), 9.31 min (13)
(assigned by integrating the GC curve).
1
(75 MHz, CDCl3): δ = 137.3 (C-6), 115.5 (C-7), 113.9 (dd, JC,F
244.7, JC,F = 242.2 Hz, C-1), 110.6, 76.0 (dd, JC,F = 28.2, JC,F
= 21.5 Hz, C-2), 75.7 (dd, JC,F = 4.5, JC,F = 0.6 Hz, C-3), 30.7
(d, JC,F = 1.3 Hz, C-5), 27.8 (d, JC,F = 3.0 Hz, C-4), 27.6, 25.3
ppm. 19F NMR (282 MHz, CDCl3): δ = –125.1 (ddd, 2JF,F = 297.2,
2JF,H = 54.6, 3JF,H = 9.0 Hz, 1 F), –127.3 (dddd, 2JF,F = 297.2, 2JF,H
= 55.7, JF,H = 10.5, JF,H = 2.3 Hz, 1 F) ppm; distinct signals can
also be observed for the acetonide of the minor diastereoisomer
10. 13C NMR (75 MHz, CDCl3): δ = 137.5 (C-6), 115.2 (C-7), 114.8
(dd, 1JC,F = 244.0 Hz, 1JC,F = 243.2 Hz, C-1), 110.6, 79.3 (dd, 2JC,F
=
1
2
2
3
3
5
4
(1S*,3S*,4S*,7S*,9S*,10S*)-3,9-Bis(difluoromethyl)-2,8,13,14-
tetraoxatricyclo[8.2.1.14,7]tetradecane (14): Chlorotrimethylsilane
(0.08 mmol, 10 µL) was added to a stirred solution of diols 9 and
10 (0.30 mmol, 0.05 g) in methanol (5 mL). The solution was co-
oled to –78 °C, and a stream of O3 (0.2 L/min) was carefully
bubbled through the solution until it became blue (30 min). The
solution was purged with a stream of O2 until the blue colour was
discharged, then dimethyl sulfide (5.4 mmol, 0.4 mL) was added.
The mixture was stirred at room temperature overnight (18 h), then
concentrated in vacuo to leave a colourless oil, which was taken up
in CDCl3 (0.35 mL). After 1 h, the solution was concentrated in
vacuo to leave a colourless oil, which was purified by Biotage col-
umn chromatography (gradient 20% Ǟ 50% EtOAc/PE) to afford
tricycle 14 (10 mg, 22%, 99% by GC-MS) as clear colourless need-
les. M.p. 105–109 °C. Rf (20 % EtOAc/PE) = 0.46. C12H16O4F4
3
4
2
= 27.0 Hz, JC,F = 24.9 Hz, C-2), 77.2 (C-3), 32.8, 29.8, 27.3, 26.4
ppm. 19F NMR (282 MHz, CDCl3): δ = –124.0 (ddd, JF,F
=
2
2
3
2
296.0 Hz, JF,H = 55.4 Hz, JF,H = 9.1 Hz, 1 F), –128.8 (ddd, JF,F
2
3
= 296.0 Hz, JF,H = 55.5 Hz, JF,H = 9.9 Hz, 1 F) ppm. HRMS
(EI): calcd. for C10H16O2F2 [M+] 206.11184; found 206.11187. MS
(EI): m/z (%) = 206 (1) [M+], 191 (100), 164 (11), 151 (16), 131
(25), 111 (66), 91 (29), 85 (26), 67 (25), 59 (40). tR (GC) = 9.17 min
(major).
Racemic Methyl 6,6-Difluoroamicetosides (12a and 12b), and Race-
mic Methyl 6,6-Difluororhodinoside (13): Trimethylchlorosilane
(0.08 mmol, 10 µL) was added to a stirred solution of diol 9 and
10 (0.44 mmol, 73 mg) in methanol (5 mL). The solution was co-
oled to –78 °C, and a stream of O3 (0.2 L/min) was carefully
bubbled through the solution until it became blue (30 min). The
solution was purged with a stream of O2 until the blue colour was
discharged, then dimethyl sulfide (5.4 mmol, 0.4 mL) was added.
The mixture was stirred at room temperature overnight (18 h), then
concentrated in vacuo to leave a colourless oil, which was purified
by Biotage column chromatography (gradient 35% Ǟ 50% EtOAc/
PE) to afford an inseparable mixture of methyl furanosides 12a,
12b and 13 (50 mg, 63%, 99% by GC-MS, 2.9:2.5:1 by NMR) as
(300.10): calcd. C 48.0, H 5.4; found C 47.9, H 5.2. IR (neat): ν
˜
max
= 2967 [w (CH2)], 2925 [w (CH2)], 1317 (w), 1196 (w), 1092 [s (C–
O)], 1046 [s (C–O)] cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.52
(td, 2JH,F = 55.2, J = 4.8 Hz, 2 H, 15-H, 16-H), 5.09 (d, J = 4.2 Hz,
2 H, 1-H, 7-H), 4.26 (t, J = 7.9 Hz, 2 H, 4-H, 10-H), 4.07–3.96 (m,
2 H, 3-H, 9-H), 2.34–2.16 (m, 2 H, 5a-H, 11a-H), 2.11–1.97 (m, 2
H, 6a-H, 12a-H), 1.87–1.66 (m, 4 H, 6b-H, 12b-H, 5b-H, 11b-H)
1
ppm. 13C NMR (75 MHz, CDCl3): δ = 115.1 (t, JC,F = 245.3 Hz,
3
C-15, C-16), 103.5 (C-1, C-7), 78.0 (t, JC,F = 4.0 Hz, C-4, C-10),
2
75.1 (d, JC,F = 21.3 Hz, C-3, C-9), 33.6 (C-6, C-12), 21.7 (C-5, C-
2
11) ppm. 19F NMR (282 MHz, CDCl3): δ = –126.3 (dd, JF,H
=
=
3
2
3
55.2 Hz, JF,H = 6.6 Hz, 2 F), –126.3 (dd, JF,H = 55.2 Hz, JF,H
a clear oil. R (50% EtOAc/PE) = 0.66. IR (neat): νmax = 3409 [br.
7.4 Hz, 2 F). HRMS (EI): calcd. for C12H16O4F4 [M+] 300.09847;
found 300.09841. MS (EI): m/z (%) = 300 (1) [M+], 239 (11), 219
(16), 192 (28), 176 (56), 150 (29), 138 (32), 133 (33), 104 (18), 99
(16), 85 (55), 69 (100). tR (GC) = 15.87 min. The relative stereo-
˜
f
(OH)], 2959 [w (CH2)], 1444 (w), 1207 (w), 1150 (w), 1031 [s (C–
O)] cm–1. 1H NMR (400 MHz, CDCl3): the following signals are
2
distinct for 12a: δ = 5.78 (td, JH,F = 55.2 Hz, J = 3.6 Hz, 1 H, 6-
Eur. J. Org. Chem. 2009, 1058–1071
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1063

J. M. Percy, R. Roig, K. Singh
FULL PAPER
chemistry and identity of this product were confirmed by XRD
analysis; crystal data: empirical formula C12H16O4F4, M = 300.25,
crystal size 0.25 ϫ 0.17 ϫ 0.15 mm, monoclinic, space group
C2/c, unit cell dimensions a = 17.5445(16), b = 9.0382(8), c =
(ddd, 2JH,F = 56.5, 2JH,F = 55.8, J = 5.2 Hz, 1 H, 1-H major), 5.11–
2
4.98 (m, 2 H, 7-H), 4.66 (d, J = 11.2 Hz, 1 H, CHaHbPh major),
2
4.52 (d, J = 11.2 Hz, 1 H, CHaHbPh major), 3.74–3.61 (m, 2 H,
2-H, 3-H), 2.76 (d, J = 8.5 Hz, 1 H, OH major), 2.33–1.67 (m, 4
2
2
8.2241(8) Å, β = 102.802(2)°, V = 1271.7(2) Å3, Z = 4, Dcalcd.
=
H, 4-H, 5-H), 5.90 (ddd, JH,F = 56.2, JH,F = 55.0, J = 3.7 Hz, 1
H, 1-H minor), 5.90–5.77 (m, 1 H, 6-H), 5.11–4.98 (m, 2 H, 7-H),
1.568 Mg m–3, F(000) = 624, µ(Mo-Kα) = 0.152 mm–1, T =
150(2) K, 4503 total reflections measured, 1126 independent (Rint
= 0.0368), which were used in all calculations. Final R indices [for
reflections with IϾ2σ(I)] were R1 = 0.0505, ωR2 = 0.1428; R in-
dices (all data) were R1 = 0.0536, ωR2 = 0.1454.
2
2
4.61 (d, J = 11.3 Hz, 1 H, CHaHbPh), 4.55 (d, J = 11.3 Hz, 1 H,
3
3
CHaHbPh), 3.86 (dddd, JH,F = 17.0, JH,F = 6.2, J = 6.0, J =
3.7 Hz, 1 H, 2-H), 3.74–3.61 (m, 1 H, 3-H), 2.56 (d, J = 5.2 Hz, 1
H, OH), 2.33–1.67 (m, 4 H, 4-H, 5-H) ppm. 13C NMR (75 MHz,
CDCl3): two distinct series of signals observed, but not assigned: δ
= 138.1 (C-6), 137.7, 137.6 (C-6), 128.6, 128.1, 128.1, 128.0, 127.9,
115.5 (t, 1JC,F = 244.1 Hz, C-1), 115.5 (C-7), 115.2 (C-7), 115.1 (dd,
3-Benzyloxy-1,1-difluoro-2-[(2Ј-methoxyethoxy)methoxy]hepta-1,6-
diene (15): A mixture of alcohol 7 (5.0 mmol, 1.26 g), benzyl bro-
mide (7.3 mmol, 0.88 mL), sodium hydroxide (37 mmol, 2.96 mL
of a 50% aqueous solution), and tetrabutylammonium hydrogen
sulfate (0.26 mmol, 90 mg) was stirred at 0 °C for 30 min. The mix-
ture was warmed to room temperature and stirred overnight. Satu-
rated aqueous ammonium chloride solution (10 mL) was added,
and the mixture was extracted with diethyl ether (3ϫ20 mL). The
combined organic extracts were washed with water (10 mL), dried
(MgSO4) and concentrated in vacuo to give a clear oil, which was
purified by Biotage column chromatography (gradient 0% Ǟ 20%
EtOAc/PE) to afford benzyl ether 15 (1.19 g, 69%, 99% by GC-
MS) as a clear colourless oil. Rf (20% EtOAc/PE) = 0.59. IR (neat):
1JC,F = 242.9, JC,F = 241.1 Hz, C-1), 77.4 (dd, JC,F = 3.9, JC,F
1
3
3
3
3
= 3.6 Hz, C-3), 75.7 (dd, JC,F = 4.8, JC,F = 2.7 Hz, C-3), 72.5
(CH2Ph), 72.4 (CH2Ph), 72.0 (dd, 2JC,F = 24.9, 2JC,F = 23.2 Hz, C-
2
2
2), 71.7 (dd, JC,F = 23.0, JC,F = 20.6 Hz, C-2), 29.6, 29.4, 29.0,
28.9 ppm. 19F NMR (282 MHz, CDCl3): major diastereoisomer: δ
2
2
3
= –128.5 (dddd, JF,F = 290.0 Hz, JF,H = 55.8 Hz, JF,H = 9.4 Hz,
4JF,H = 1.5 Hz, 1 F, CHFaFb), –129.4 (ddd, JF,F = 290.0 Hz, JF,H
2
2
= 56.5 Hz, 3JF,H = 10.9 Hz, 1 F, CHFaFb) ppm; minor diastereoiso-
2
2
3
mer: δ = –129.1 (ddd, JF,F = 289.8 Hz, JF,H = 55.0 Hz, JF,H
=
=
2
2
6.2 Hz, 1 F, CHFaFb), –132.7 (ddd, JF,F = 289.8 Hz, JF,H
3
56.2 Hz, JF,H = 17.0 Hz, 1 F, CHFaFb) ppm. HRMS (EI): calcd.
for C14H18F2O2 [M+] 256.12749; found 256.12753. MS (EI): m/z
(%) = 256 (1) [M+], 175 (12), 157 (8), 107 (8), 91 (100). tR (GC) =
16.51 min (major), 16.61 min (minor).
ν
= 2881 [w (CH2)], 1748 (s), 1641 [w (C=C)], 1454 (w), 1228
˜
max
(s), 1091 [s (C–O)], 1069 [s (C–O)] cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 7.35–7.24 (m, 5 H, Ph), 5.76 (ddt, J = 16.9, J = 10.2,
J = 6.6 Hz, 1 H, 6-H), 5.08 (2J = 6.1 Hz, 1 H, OCHaHbO), 4.96
(2J = 6.1 Hz, 1 H, OCHaHbO), 5.02–4.92 (m, 2 H, 7-H), 4.64 (2J
= 11.7 Hz, 1 H, CHaHbPh), 4.33 (2J = 11.7 Hz, 1 H, CHaHbPh),
3-Benzyloxy-1,1-difluoro-5-(1,2,4-trioxolan-3-yl)pentan-2-ol (18):
Dry silica gel (1.41 g) was added to a solution of alcohols 16 and
17 (0.60 mmol, 155 mg) in dry dichloromethane (5 mL). The sol-
vent was evaporated in vacuo, and the silica gel mixture was dried
under vacuum at room temperature for 1 h. The mixture was co-
oled to –78 °C, and a stream of dry O3 was carefully passed up-
wards through the silica gel supported by a frit in a U-shaped tube.
After 1 h, the mixture was purged with O2 and N2, eluted from
the silica with methanol (50 mL), quenched with dimethyl sulfide
(0.5 mL) and stirred for 6 h. After concentration, purification by
silica gel column chromatography (gradient 0 Ǟ 20% EtOAc/PE)
afforded ozonide 18 (56 mg, 30%, 80% by GC-MS) as a complex
mixture of diastereoisomers as a colourless oil. Rf (20% EtOAc/
4
4
4.06 (dddd, J = 10.0, JH,F = 3.7, J = 3.1, JH,F = 2.1 Hz, 1 H, 3-
2
H), 3.90 (ddd, J = 10.9, J = 5.3, J = 3.7 Hz, 1 H, CHaHbOMe),
3.78 (ddd, 2J = 10.9, J = 5.3, J = 3.7 Hz, 1 H, CHaHbOMe), 3.56–
3.52 (m, 2 H, OCH2CH2OMe), 3.37 (s, 3 H, OCH3), 2.19–2.01 (m,
2 H, 5-H), 1.97–1.67 (m, 2 H, 4-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 156.1 (dd, 1JC,F = 294.2, 1JC,F = 284.8 Hz, C-1), 137.9,
2
137.7 (C-6), 128.4, 127.9, 127.7, 115.1 (C-7), 112.4 (dd, JC,F
=
2
3
36.5, JC,F = 9.9 Hz, C-2), 97.1 (OCH2O), 73.9 (t, JC,F = 3.2 Hz,
C-3), 71.6 (OCH2CH2OMe), 70.4 (CH2Ph), 68.3 (OCH2CH2OMe),
59.0 (OCH3), 31.2 (t, JC,F = 2.0 Hz, C-4), 29.6 (C-5) ppm. 19F
4
2
4
NMR (282 MHz, CDCl3): δ = –97.5 (d, JF,F = 63.1, JF,H
=
2.1 Hz, 1 F), –109.2 (d, 2JF,F = 63.1, 4JF,H = 3.7 Hz, 1 F) ppm. MS
(EI): m/z (%) = 112 (2), 105 (3), 91 (85), 59 (100). tR (GC) =
19.83 min. A satisfactory ion peak for HRMS (CI, EI, ES) could
not be obtained for this compound despite repeated attempts with
a number of ionisation techniques.
1
PE) = 0.36. H NMR (400 MHz, CDCl3): δ = 7.39–7.28 (m, 10 H,
2
2
Ph), 5.90 (ddd, JH,F = 56.0, JH,F = 54.9, J = 3.4 Hz, 1 H, 1-H),
2
2
5.76 (ddd, JH,F = 56.1, JH,F = 56.0, J = 4.9 Hz, 1 H, 1-H), 5.20
(s, 1 H, 6-H), 5.19 (s 1 H, 6-H), 5.18 (s, 1 H, OCH2O), 5.17 (s, 1
H, OCH2O), 5.07 (s, 1 H, OCH2O), 5.05 (s, 1 H, OCH2O), 4.68–
4.42 (m, 4 H, CH2Ph), 3.91–3.58 (m, 4 H, 2-H, 3-H), 2.55 (br. s, 1
H,OH), 2.22 (br. s, 1 H, OH), 1.98–1.55 (m, 8 H, 4-H, 5-H) ppm.
(2S*,3S*)-Benzyloxy-1,1-difluorohept-6-en-2-ol (16) and (2S*,3R*)-
Benzyloxy-1,1-difluorohept-6-en-2-ol (17): Chlorotrimethylsilane
(4.73 mmol, 0.6 mL) was added to a solution of 15 (4.7 mmol,
1.60 g) in MeOH (5 mL). The mixture was stirred overnight (18 h),
then concentrated in vacuo and the residue taken up in Et2O
13C NMR (100 MHz, CDCl3): δ = 137.4, 137.3, 128.61, 128.59,
128.21, 128.11, 128.08, 127.97, 127.95, 127.80, 115.3 (t, JC,F
244.2 Hz, C-1), 114.9 (dd, JC,F = 243.7, JC,F = 240.5 Hz, C-1),
1
=
1
1
(5 mL); sodium borohydride (9.2 mmol, 0.35 g) was added in por- 103.4, 103.2, 94.14, 94.11, 77.24, 76.96 (t, 3JC,F = 3.8 Hz, C-3), 75.4
2
tions, and the mixture was stirred overnight. The mixture was di-
luted with water (5 mL), neutralised with concentrated HCl, and
extracted with EtOAc (3ϫ15 mL). The combined organic extracts
were dried (MgSO4), filtered, and concentrated in vacuo to leave a
colourless oil, which was purified by Biotage column chromatog-
raphy (gradient 20% Ǟ 50% EtOAc/PE) to afford an inseparable
mixture of alcohols 16 and 17 (0.732 g, 61%, 99% by GC-MS, 1.2:1
(t, 3JC,F = 3.4 Hz, C-3), 72.7 (CH2Ph), 72.3 (CH2Ph), 72.2 (t, JC,F
2
= 24.5 Hz, C-2), 71.5 (t, JC,F = 22.5 Hz, C-2), 27.0, 26.3, 24.8,
23.5 ppm. Signals of four distinct diastereoisomers are visible in
the 19F NMR spectrum: 19F NMR (376 MHz, CDCl3): first dia-
2
3
stereoisomer: δ = –128.86 (dd, 2JF,F = 290.52, JF,H = 55.8, JF,H
=
2
2
10.1 Hz, 1 F, CHFaFb), –129.35 (dd, JF,F = 290.52, JF,H = 56.2,
3JF,H = 14.8 Hz, 1 F, CHFaFb) ppm; second diastereoisomer: δ =
2
2
3
by GC-MS) as a mixture of diastereoisomers as a clear colourless –128.88 (dd, JF,F = 290.50 Hz, JF,H = 55.6 Hz, JF,H = 10.8 Hz,
2
2
oil. R (10% EtOAc/PE) = 0.25. IR (neat): ν
= 3434 [br. (OH)],
1 F, CHFaFb), –129.32 (dd, JF,F = 290.50 Hz, JF,H = 56.1 Hz,
˜
f
max
2934 [w (CH2)], 1641 [w (C=C)], 1455 (w), 1056 [s (C–O)]. 1H
NMR (300 MHz, CDCl3): signals for both diastereoisomers, unless
specified: δ = 7.42–7.29 (m, 5 H, Ph), 5.90–5.77 (m, 1 H, 6-H), 5.76
3JF,H = 17.3 Hz, 1 F, CHFaFb) ppm; third diastereoisomer: δ =
–129.86 (dd, JF,F = 289.46 Hz, JF,H = 54.9 Hz, JF,H = 4.8 Hz, 1
F, CHFaFb), –133.12 (dd, JF,F = 289.46 Hz, JF,H = 56.0 Hz, JF,H
2
2
3
2
2
3
1064
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1058–1071

Fluorinated Analogues of Amicetose and Rhodinose
= 17.5 Hz, 1 F, CHFaFb) ppm; fourth diastereoisomer: δ = –129.72 17.34 min. (iii) Mixed fraction containing a mixture of diastereo-
2
2
3
(dd, JF,F = 289.45 Hz, JF,H = 55.0 Hz, JF,H = 5.8 Hz, 1 F,
isomers (132 mg, 12%).
CHFaFb), –133.27 (dd, 2JF,F = 289.45 Hz, JF,H = 56.1 Hz, JF,H
=
2
3
Racemic α-5-O-Benzyl-6,6-difluoroamicetose (21a) and Racemic β-
5-O-Benzyl-6,6-difluoroamicetose (21b): Concentrated hydrochloric
acid (20 µL) was added to a solution of amicetoside 19 (0.11 mmol,
30 mg) in THF (4 mL) containing water (250 µL). The solution was
stirred and heated (microwaves, 50 W) to 100 °C for 2 h. The tube
was cooled, opened, and the contents were diluted with Et2O
(10 mL), dried (MgSO4), filtered, and concentrated in vacuo to
leave a colourless oil containing a mixture of anomers, which was
purified by Biotage column chromatography (gradient 20% Ǟ 50%
EtOAc/PE) to afford α- and β-amicetoses 21a and 21b (20 mg,
70%, 95% by GC-MS) as an inseparable 2.6:1 mixture (by NMR),
from which anomer 21a crystallized as white needles. M.p. 62–
65 °C. Rf (35% EtOAc/PE) = 0.57. C13H16O3F2 (258.11): calcd. C
17.3 Hz, 1 F, CHFaFb). HRMS (EI): calcd. for C14H18F2O5 [M+]
304.11223; found 304.11226. MS (EI): m/z (%) = 304 (2) [M+], 240
(35), 191 (3), 151 (39), 105 (55), 85 (99), 51 (100).
Racemic α-Methyl 5-O-Benzyl-6,6-difluoroamicetoside (19) and Ra-
cemic α-Methyl 5-O-Benzyl-6,6-difluororhodinoside (20): Chlorotri-
methylsilane (0.79 mmol, 100 µL) was added to a stirred solution
of alcohols 16 and 17 (3.99 mmol, 1.02 g) in methanol (50 mL).
The solution was cooled to –78 °C, and a stream of dry O3 (0.2 L/
min) was carefully bubbled through the solution until it became
blue (30 min). The solution was purged with a stream of O2 until
it became colourless (5 min), then dimethyl sulfide (68 mmol,
5.0 mL) was added. The mixture was stirred at room temperature
(12 h) overnight (18 h), then solid NaOH (0.2 g, 5 mmol) was
added. After 1 h, the solution was neutralised with concentrated
HCl (0.7 mL), diluted with Et2O (50 mL), dried (MgSO4), filtered,
and concentrated in vacuo to leave a colourless oil containing a
mixture of diastereoisomers (1:1), which was purified by Biotage
column chromatography (gradient 5% Ǟ 10% EtOAc/PE) to af-
ford (in order of elution): (i) α-Methyl rhodinoside 20 (396 mg,
37%, 99% by GC-MS) as a clear colourless oil. Rf (20% EtOAc/
60.5, H 6.2; found C 60.3, H 6.3. IR (neat): νmax = 3410 [br. (OH)],
˜
2954 [w (CH2)], 2873 [w (CH2)], 1400 (w), 1353 (w), 1221 (w), 1150
[s (C–O)], 1079 [s (C–O)], 1045 [s (C–O)] cm–1 1H NMR
.
(400 MHz, CDCl3): α-anomer 21a: δ = 7.38–7.28 (m, 5 H, Ph), 6.06
2
2
(ddd, JH,F = 54.5, JH,F = 54.0, J = 1.1 Hz, 1 H, 6-H), 5.35 (d, J
2
= 2.8 Hz, 1 H, 1-H), 4.66 (d, J = 11.4 Hz, 1 H, CHaHbPh), 4.48
2
3
3
(d, J = 11.4 Hz, 1 H, CHaHbPh), 4.11 (dddd, JF,H = 20.5, JH,F
= 7.4, J = 9.9, J = 1.8 Hz, 1 H, 5a-H), 3.75–3.47 (m, 1 H, 4-H),
2.71 (br. s, 1 H, OH), 2.30–1.44 (m, 4 H, 2-H, 3-H) ppm; β-anomer
21b: 1H NMR (400 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H, Ph), 6.04
PE) = 0.59. IR (neat): νmax = 2939 [w (CH2)], 2902 [w (CH2)], 1454
˜
[w (CH3)], 1337 (w), 1219 [w (C–O–C)], 1131 [s (C–O)], 1076 [s (C–
2
2
(ddd, JH,F = 54.5, JH,F = 54.4, J = 2.0 Hz, 1 H, 6-H), 4.92 (d, J
O)] cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H,
2
= 7.3 Hz, 1 H, 1-H), 4.62 (d, J = 11.4 Hz, 1 H, CHaHbPh), 4.50
2
2
Ph), 5.93 (ddd, JH,F = 58.1, JH,F = 55.0, J = 6.8 Hz, 1 H, 6-H),
4.80 (d, J = 3.2 Hz, 1 H, 1-H), 4.63 (d, 2J = 11.7 Hz, 1 H,
CHaHbPh), 4.44 (d, 2J = 11.7 Hz, 1 H, CHaHbPh), 3.85 (dddd,
2
(d, J = 11.4 Hz, 1 H, CHaHbPh), 3.75–3.47 (m, 2 H, 4-H, 5-H),
3.08 (br. s, 1 H, OH), 2.30–1.44 (env, 4 H, 2-H, 3-H) ppm. 13C
NMR (100 MHz, CDCl3): signals for both anomers, unless stated
otherwise: δ = 137.8, 137.6, 128.5, 128.5, 128.0, 127.9, 127.8, 127.7,
3JH,F = 11.4, J = 6.8, JH,F = 4.1, J = 1.8 Hz, 1 H, 5-H), 3.71 (br.
3
2
s, 1 H, 4-H), 3.39 (s, 3 H, OCH3), 2.01 (ddt, J = 14.0, J = 14.0, J
1
1
114.1 (dd, JC,F = 243.8, JC,F = 242.5 Hz, C-6), 95.8 [C-1 (21b)],
= 4.6 Hz, 1 H, 2a-H), 1.98–1.91 (m, 1 H, 3a-H), 1.84 (ddd, 2J =
14.0, J = 14.0, J = 4.2, J = 2.5 Hz, 1 H, 3b-H), 1.60–1.53 (m, 1 H,
2b-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.9, 128.4, 127.8,
3
3
91.0 [C-1 (21a)], 72.2 (dd, JC,F = 6.1, JC,F = 1.93 Hz, C-4), 71.2
[CH2Ph (21b)], 70.7 [CH2Ph (21a)], 70.3 (t, JC,F = 18.8 Hz, C-5),
2
30.0 [C-2 (21b)], 28.3 [C-2 (21a)], 26.1 [C-3 (21b)], 22.9 [C-3 (21a)]
1
1
128.8, 114.9 (dd, JC,F = 243.3, JC,F = 237.9 Hz, C-6), 97.9 (C-1),
ppm. 19F NMR (376 MHz, CDCl3): δ = –131.5 [dddd, JF,F
=
2
2
2
71.0 (CH2Ph), 70.2 (dd, JC,F = 30.5, JC,F = 22.9 Hz, C-5), 69.8
286.3, 2JF,H = 54.5, 3JF,H = 7.7, 4JF,H = 1.5 Hz, 1 F, CHFaFb (21b)],
(dd, 3JC,F = 6.9, 3JC,F = 2.0 Hz, C-4), 54.8 (OCH3), 23.7 (C-2), 20.0
2
2
3
4
–133.3 [dddd, JF,F = 283.1, JF,H = 54.0, JF,H = 7.4, JF,H
=
=
=
(C-3) ppm. 19F NMR (376 MHz, CDCl3): δ = –130.5 (ddd, 2JF,F
=
2
2
1.8 Hz, 1 F, CHFaFb (21a)], –133.7 [ddd, JF,F = 286.3, JF,H
2
3
295.4, JF,H = 58.1, JF,H = 11.4 Hz, 1 F, CHFaFb), –131.4 (dddd,
3
2
54.4, JF,H = 17.4 Hz, 1 F, CHFaFb (21b)], –135.8 [ddd, JF,F
2JF,F = 295.4, JF,H = 55.0, JF,H = 4.1, JF,H = 1.8 Hz, 1 F,
CHFaFb) ppm. HRMS (EI): calcd. for C14H18F2O3 [M+]
272.12240; found 272.12241. MS (EI): m/z (%) = 272 (1) [M+], 240
(4), 191 (3), 160 (3), 134 (4), 125 (4), 107 (17), 101 (24), 91 (100).
tR (GC) = 17.81 min. (ii) α-Methyl amicetoside 19 (352 mg, 32%,
99% by GC-MS) as a clear colourless oil. Rf (20% EtOAc/PE) =
2
3
4
2
3
283.1, JF,H = 54.5, JF,H = 20.5 Hz, 1 F, CHFaFb (21a)] ppm.
HRMS (EI): calcd. for C13H16F2O3 [M+] 258.10675; found
258.10671. MS (EI): m/z (%) = 258 (1) [M+], 240 (1), 177 (3), 154
(1), 134 (4), 107 (27), 91 (100). tR (GC) = 18.54 min. The stereo-
chemistry and identity of the crystalline anomer 21a were con-
firmed by XRD analysis. Crystal data: empirical formula
C13H16O3F2, M = 258.26, crystal size 0.36ϫ0.11ϫ0.04 mm, mo-
noclinic, space group P21/n, unit cell dimensions a = 20.750(3), b
= 4.6956(8), c = 26.025(4) Å, β = 98.453(3)°, V = 2508.1(7) Å3, Z
= 8, Dcalcd. = 1.368 Mg m–3 , F(000) = 1088, µ(Mo-Kα ) =
0.115 mm–1, T = 150(2) K, 17038 total reflections measured, 4424
independent (Rint = 0.0885), which were used in all calculations.
Final R indices [for reflections with IϾ2σ(I)] were R1 = 0.0471,
ωR2 = 0.0880; R indices (all data) were R1 = 0.0850, ωR2 = 0.0999.
0.53. IR (neat): ν
= 2939 [w (CH2)], 1455 [s (CH3)], 1372 (w),
˜
max
1224 [s (C–O–C)], 1127 [s (C–O)], 1050 [s (C–O)] cm–1. H NMR
1
2
(400 MHz, CDCl3): δ = 7.37–7.26 (m, 5 H, Ph), 6.06 (dd, JH,F
=
2
54.6, JH,F = 53.8 Hz, 1 H, 6-H), 4.76 (d, J = 3.0 Hz, 1 H, 1-H),
2
2
4.64 (d, J = 11.5 Hz, 1 H, CHaHbPh), 4.46 (d, J = 11.5 Hz, 1 H,
3
3
CHaHbPh), 3.84 (ddd, JH,F = 20.7, J = 9.8, JH,F = 7.3 Hz, 1 H,
5-H), 3.53 (ddd, J = 10.1, J = 9.8, J = 4.5 Hz, 1 H, 4-H), 3.37 (s,
3 H, OCH3), 2.10–2.03 (m, 1 H, 3a-H), 1.88–1.64 (m, 3 H, 2-H, 3b-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.8, 128.5, 127.9,
1
1
127.7, 114.0 (dd, JC,F = 243.5, JC,F = 242.5 Hz, C-6), 102.1 (C-
Racemic α-5-O-Benzyl-6,6-difluororhodinose (22a) and Racemic β-
5-O-Benzyl-6,6-difluororhodinose (22b): Concentrated hydrochloric
3
3
1), 72.0 (dd, JC,F = 6.3, JC,F = 1.8 Hz, C-4), 70.6 (CH2Ph), 70.0
(t, 2JC,F = 18.9 Hz, C-5), 54.7 (OCH3), 28.3 (C-2), 23.7 (C-3) ppm. acid (20 µL) was added to a solution of rhodinoside 20 (0.46 mmol,
19F NMR (376 MHz, CDCl3): δ = –133.5 (dddd, JF,F = 283.2,
126 mg) in THF (4 mL) containing water (250 µL). The solution
was stirred and heated (microwaves, 50 W) to 100 °C for 2 h. The
tube was cooled, opened, and the contents were diluted with Et2O
(10 mL), dried (MgSO4), filtered, and concentrated in vacuo to
2
2JF,H = 53.8, JF,H = 7.3, JF,H = 1.7 Hz, 1 F, CHFaFb), –136.1
3
4
2
2
3
(ddd, JF,F = 283.2, JF,H = 54.6, JF,H = 20.7 Hz, 1 F, CHFaFb)
ppm. HRMS (EI): calcd. for C14H18F2O3 [M+] 272.12240; found
272.12236. MS (EI): m/z (%) = 272 (1) [M+], 240 (4), 191 (3), 160 leave a colourless oil containing a mixture of anomers, which was
(5), 134 (4), 125 (3), 107 (16), 101 (17), 91 (100). tR (GC) =
purified by Biotage column chromatography (gradient 20% Ǟ 50%
Eur. J. Org. Chem. 2009, 1058–1071
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1065

J. M. Percy, R. Roig, K. Singh
FULL PAPER
EtOAc/PE) to afford the rhodinose (78 mg, 65%, 99% by GC-MS)
as a 2.5:1 (by NMR) mixture of inseparable α- and β-anomers 22a
and 22b as a clear colourless oil. Rf (35% EtOAc/PE) = 0.51. IR
chloric acid. The mixture was extracted with EtOAc (3ϫ20 mL),
then the combined organic extracts were dried (MgSO4), filtered,
and concentrated in vacuo to leave a colourless oil as a mixture
of diastereoisomers (8:1 by NMR), which was purified by Biotage
(neat): νmax = 3411 [s (OH)], 2954 [w (CH2)], 2913 [w (CH2)], 1150
˜
(s), 1077 (s), 1046 (s), 1018 (s) cm–1. α-anomer: 1H NMR column chromatography (gradient 20% Ǟ 50% EtOAc/PE) to af-
(400 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H, Ph), 5.94 (ddd, 2JH,F
=
ford (E)-fluoroallylic alcohol 24 (1.38 g, 73%, 99% by GC-MS) as
a clear colourless oil. R (35% EtOAc/PE) = 0.78. IR (neat): ν
2
58.2, JH,F = 54.8, J = 6.8 Hz, 1 H, 6-H), 5.37 (s, 1 H, 1-H), 4.63
˜
f
max
(d, 2J = 11.6 Hz, 1 H, CHaHbPh), 4.44 (d, 2J = 11.6 Hz, 1 H,
= 2931 [w (CH2)], 2879 (CH2), 1641 [w (C=C)], 1454 (w), 1097 [s
3
3
CHaHbPh), 4.12 (dddd, JH,F = 11.2, J = 6.4, JH,F = 4.2, J =
1.7 Hz, 1 H, 5-H), 3.81–3.09 (m, 2 H, 4-H, OH), 2.22–1.46 (m, 4
(C–O)], 1069 [s (C–O)] cm–1. 1H NMR (400 MHz, CDCl3): δ =
2
7.36–7.24 (m, 5 H, Ph), 7.10 (d, JH,F = 80.8 Hz, 1 H, 1-H), 5.79
H, 2-H, 3-H) ppm. β-anomer: 1H NMR (400 MHz, CDCl3): δ = (ddt, J = 16.9, J = 10.2, J = 6.6 Hz, 1 H, 6-H), 4.99 (ddd, J = 16.9,
7.38–7.28 (m, 5 H, Ph), 5.98 (ddd, JH,F = 57.5, JH,F = 55.0, J =
6.6 Hz, 1 H, 6-H), 4.80 (dd, J = 9.3, J = 2.4 Hz, 1 H, 1-H), 4.61
(d, 2J = 11.6 Hz, 1 H, CHaHbPh), 4.44 (d, 2J = 11.6 Hz, 1 H,
2
2
J = 3.4, J = 1.6 Hz, 1 H, 7a-H), 4.97–4.92 (m, 3 H, OCH2O, 7b-
2
4
H), 4.58 (d, J = 11.8 Hz, 1 H, CHaHbPh), 4.41 (td, J = 7.4, JH,F
2
= 3.5 Hz, 1 H, 3-H), 4.38 (d, J = 11.8 Hz, 1 H, CHaHbPh), 3.76
2
2
CHaHbPh), 3.81–3.09 (m, 3 H, 4-H, 5-H, OH), 2.22–1.46 (m, 4 H, (dt, J = 11.0, J = 4.7 Hz, 1 H, OCHaHbCH2OMe), 3.72 (dt, J =
2-H, 3-H) ppm. 13C NMR (100 MHz, CDCl3): both anomers: δ =
11.0, J = 4.7 Hz, 1 H, OCHaHbCH2OMe), 3.55 (t, J = 4.7 Hz, 2
H, CH2OMe), 3.39 (s, 3 H, OMe), 2.21–2.01 (m, 2 H, 5-H), 1.95–
1
1
137.8, 137.7, 128.4, 127.9, 127.8, 114.9 (dd, JC,F = 243.1, JC,F
=
=
1
1
238.2 Hz, C-6, α-anomer), 114.2 (dd, JC,F = 243.0, JC,F
1.86 (m, 1 H, 4a-H), 1.71 (ddt, 2J = 13.3, J = 9.1, J = 6.5 Hz, 1 H,
2
239.1 Hz, C-6, β-anomer), 96.3 (C-1, β-anomer), 91.4 (C-1, α-an-
4b-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.7 (d, JC,F
=
omer), 77.3 (dd, 2JC,F = 28.8, 2JC,F = 24.2 Hz, C-5, β-anomer), 71.0
25.1 Hz, C-2), 139.6 (d, JC,F = 20.6 Hz, C-1), 138.3, 137.9 (C-6),
1
2
3
(CH2Ph, β-anomer), 70.9 (CH2Ph, α-anomer), 70.2 (dd, JC,F
=
128.3, 128.0, 127.6, 115.0 (C-7), 94.8 (OCH2O), 71.8 (d, JC,F =
2
3
30.7, JC,F = 22.6 Hz, C-5, α-anomer), 69.7 (dd, JC,F = 6.9 Hz,
1.3 Hz, C-3), 71.5 (OCH2CH2OMe), 70.6 (CH2Ph), 67.5 (OCH2-
3
3
4
1.9, C-4, α-anomer), 68.8 (dd, JC,F = 6.1, JC,F = 2.5 Hz, C-4, β-
anomer), 27.0 (C-2, β-anomer), 24.3 (C-3, β-anomer), 23.9 (C-3, α-
anomer), 19.2 (C-2, α-anomer) ppm. 19F NMR (376 MHz, CDCl3):
CH2OMe), 59.0 (OCH3), 31.1 (d, JC,F = 2.4 Hz, C-4), 29.7 (C-5)
2
ppm. 19F NMR (282 MHz, CDCl3): δ = –171.2 (dd, JF,H = 80.8,
4JF,H = 3.5 Hz) ppm. MS (EI): m/z (%) = 175 (1), 166 (1), 157 (2),
129 (1), 122 (3), 112 (11), 91 (100), 59 (98). tR (GC) = 20.8 min.
Satisfactory HRMS (CI, EI, ES) could not be obtained for this
compound. (Z)-fluoroallylic alcohol 25 could not be separated fully
2
2
3
δ = –130.2 (ddd, JF,F = 296.3, JF,H = 57.5, JF,H = 9.8 Hz, 1 F,
CHFaFb, α-anomer), –130.5 (ddd, 2JF,F = 296.2, 2JF,H = 58.2, 3JF,H
2
= 11.2 Hz, 1 F, CHFaFb, β-anomer), –130.8 (dddd, JF,F = 296.3,
2JF,H = 55.0, JF,H = 4.9, JF,H = 1.8 Hz, 1 F, CHFaFb, α-anomer), from 24. Rf (35 % EtOAc/PE) = 0.81. 19F NMR (282 MHz,
3
4
2
2
3
4
2
–131.5 (dddd, JF,F = 296.2, JF,H = 54.8, JF,H = 4.2, JF,H
=
CDCl3): δ = –155.8 (d, JF,H = 77.5 Hz, 1 F) ppm. MS (EI): m/z
2.0 Hz, CHFaFb, β-anomer) ppm. HRMS (EI): calcd. for
C13H16F2O3 [M+] 258.10675; found 258.10676. MS (EI): m/z (%)
= 258 (1) [M+], 240 (1), 177 (3), 160 (3), 134 (3), 107 (23), 91 (100).
tR (GC) = 18.3 min.
(%) = 175 (1), 166 (1), 157 (2), 129 (1), 122 (3), 112 (11), 91 (100),
59 (98); tR (GC) 20.9 min. The (E)/(Z) configuration was assigned
on the basis of a NOESY cross peak between signals at δ = 7.10
(=CHF) and 4.97–4.92 (OCH2O) ppm for 24. A mixture of 24 and
25 can be used satsifactorily in the next step; the sample of 24 was
purified for characterisation purposes.
α-Methyl 6,6-Difluororhodinoside (23): A solution of 20 (0.38
mmol, 104 mg) in ethanol containing 10% palladium on carbon
(40 mg) was stirred under hydrogen for 48 h. The mixture was fil-
tered through Celite, and the filter bed was washed with EtOH
(3ϫ2 mL); the combined filtrate and washings were concentrated
in vacuo to afford methyl rhodinoside 23 (35 mg, 50%) as a clear
(2S*,3S*)-3-Benzyloxy-1-fluorohept-6-en-2-ol (26) and (2S*,3R*)-
Benzyloxy-1-fluorohept-6-en-2-ol (27): Hydrochloric acid (0.5 mL
of a 3  aqueous solution) was added to a solution of 24
(3.78 mmol, 1.23 g) in THF (10 mL). The mixture was stirred for
12 h, then diluted with Et2O (10 mL), then sodium borohydride
(5.93 mmol, 0.229 g) was added in several portions. The mixture
was stirred overnight, then diluted with water (5 mL), neutralised
(to pH paper) with concentrated HCl, and extracted with EtOAc
(3ϫ15 mL). The combined organic extracts were dried (MgSO4),
filtered, and concentrated in vacuo to leave a colourless oil, which
was purified by Biotage column chromatography (gradient 20% Ǟ
50% EtOAc/PE) to afford alcohols 26 and 27 (0.625 g, 69%, 99%
by GC-MS) as an inseparable (1:1 by NMR) mixture as a clear
colourless oil. R (20% EtOAc/PE) = 0.31. IR (neat): ν
= 3366
˜
f
max
(OH), 2953 (CH2), 1460 (w), 1317 (w), 1117 (w), 1050 (s), 978 (s)
2
cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.86 (ddd, JH,F = 56.6,
2JH,F = 55.4, J = 6.3 Hz, 1 H, 6-H), 4.81 (s, 1 H, 1-H), 4.00 (s, 1
H, 4-H), 3.91–3.82 (m, 1 H, 5-H), 3.39 (s, 3 H, OCH3), 2.11–1.53
(m, 5 H, 2-H, 3-H, OH) ppm. 13C NMR (75 MHz, CDCl3): δ =
1
1
114.9 (dd, JC,F = 241.7, JC,F = 240.1 Hz, C-6), 98.0 (C-1), 69.9
(dd, 2JC,F = 27.6, 2JC,F = 24.6 Hz, C-5), 63.1 (dd, 3JC,F = 5.0, 3JC,F
= 3.6 Hz, C-4), 54.9 (OCH3), 25.0 (C-3), 23.3 (C-2) ppm. 19F NMR
colourless oil. R (20% EtOAc/PE) = 0.46. IR (neat): ν
= 3431
˜
f
max
2
2
(282 MHz, CDCl3): δ = –130.5 (ddd, JF,F = 296.6, JF,H = 56.6,
[br. (OH)], 2921 [w (CH2)], 1641 [w (C=C)], 1454 (w), 1073 [s (C–
O] cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.41–7.27 (m, 5 H, Ph),
5.91–5.75 (m, 1 H, 6-H), 5.11–4.94 (m, 2 H, 7-H), 4.83–4.36 (m, 4
H, 6-H, CH2Ph), 4.02–3.72 (m, 1 H, 2-H), 3.62–3.52 (m, 1 H, 3-
H), 2.37–1.62 (m, 5 H, 4-H, 5-H, OH) ppm. 13C NMR (75 MHz,
3JF,H = 9.9 Hz, 1 F), –131.0 (ddd, 2JF,F = 296.6, 2JF,H = 55.4, JF,H
3
= 7.4 Hz, 1 F) ppm. HRMS (EI): calcd. for C7H12F2O3 [M+]
182.07545; found 182.07542. MS (EI): m/z (%) = 182 (2) [M+], 151
(30), 133 (16), 125 (43), 101 (51), 88 (100).
(1E)-3-Benzyloxy-1-fluoro-2-[(2Ј-methoxyethoxy)methoxy]hepta- CDCl3): δ = 138.2 (C-6), 138.1, 137.9 (C-6), 128.6, 128.5, 128.0,
1,6-diene (24) and (1Z)-3-Benzyloxy-1-fluoro-2-[(2Ј-methoxyethoxy)- 127.9, 127.9, 115.2 (C-7), 115.1 (C-7), 84.5 (d, 1JC,F = 166.8 Hz, C-
1
3
methoxy]hepta-1,6-diene (25): A solution of difluorobenzyl ether 7
(5.85 mmol, 2.0 g) and sodium bis(2-methoxyethoxy)aluminium
hydride (Red-Al, 22.7 mmol, 6.5 mL of a 3.5  solution in toluene)
in dry pentane (20 mL) was heated to reflux over 3 h. The reaction
mixture was cooled and poured carefully onto ice (5 g). The white
suspension was neutralised (to pH paper) with concentrated hydro-
1), 83.9 (d, JC,F = 170.0 Hz, C-1), 78.3 (d, JC,F = 6.5 Hz, C-3),
77.6 (d, 3JC,F = 5.3 Hz, C-3), 72.7 (CH2Ph), 72.5 (CH2Ph), 71.7 (d,
2JC,F = 18.8 Hz, C-2), 71.2 (d, JC,F = 19.8 Hz, C-2), 29.7, 29.5,
2
29.4, 29.2 ppm. 19F NMR (282 MHz, CDCl3): δ = –230.0 (td, 2JF,H
3
2
3
= 47.3, JF,H = 16.9 Hz, CH2F), –232.9 (td, JF,H = 47.5, JF,H
= 19.7 Hz, CH2F) ppm. HRMS (EI): calcd. for C14H19FO2 [M+]
1066
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1058–1071

Fluorinated Analogues of Amicetose and Rhodinose
238.13691; found 238.13690. MS (EI): m/z (%) = 238 (1) [M+], 175
(9), 157 (8), 131 (2), 107 (7), 91 (100). tR (GC) = 16.47 min (both
diastereoisomers).
(m, 2 H, 5-H), 1.68–1.50 (m, 2 H, 4-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 141.0 (C-2), 138.3 (C-6), 114.8, 114.7 (C-1, C-7), 72.5
(C-3), 36.0 (C-4), 29.6 (C-5) ppm. HRMS (EI): calcd. for C7H12O
[M+] 112.08882; found 112.08879. MS (EI): m/z (%) = 112 (1) [M+],
111 (2) [M+ – 1], 97 (11), 83 (23), 79 (100), 70 (45), 57 (79). The
spectroscopic data are in agreement with those reported by Salo-
mon et al.[46]
Racemic Methyl 5-O-Benzyl-6-fluoroamicetoside (28) and Racemic
Methyl 5-O-Benzyl-6-fluororhodinoside (29): Chlorotrimethylsilane
(0.16 mmol, 20 µL) was added to a stirred solution of alcohols 26
and 27 (0.39 mmol, 93 mg) in methanol (5 mL). The solution was
cooled to –78 °C, and a stream of dry ozone (0.2 L/min) was care-
fully bubbled through the solution until a blue colour persisted (ca.
30 min). The solution was purged with a stream of dry oxygen until
colourless (5 min), then dimethyl sulfide (5.4 mmol, 0.4 mL) was
added. The mixture was stirred at room temperature overnight
(18 h), then solid sodium hydroxide (0.1 g, 2.5 mmol) was added.
After 1 h, the solution was neutralised with concentrated HCl
(0.7 mL), diluted with Et2O (50 mL), dried (MgSO4), filtered, and
concentrated in vacuo to leave a colourless oil, which was purified
by Biotage column chromatography (gradient 1% Ǟ 2% EtOAc/
PE) to afford an inseparable mixture of methyl pyranosides 28 and
29 (85 mg, 86%, 99% by GC-MS) as a clear colourless oil. Rf (20%
(–)-(2S,3R)-1,2-Epoxyhept-6-en-3-ol (31) and (+)-(2R,3R)-2,3-Ep-
oxyhept-6-en-1-ol (32): Titanium tetraisopropoxide (4.79 mmol,
1.50 mL), (–)-diisopropyl -tartrate (5.36 mmol, 1.15 mL), dienol
30a (50 mmol, 5.6 g) and tert-butyl hydroperoxide (49.5 mmol,
15 mL of a 3.3  solution in toluene) were added successively to a
stirred suspension of powdered molecular sieves (4 Å) in cold (be-
low –20 °C) dry CH2Cl2 (100 mL). The mixture was stirred in the
freezer below –20 °C for 15 d, then the mixture was filtered through
filter paper into a cold (0 °C) solution of ferrous sulfate (72 mmol,
20 g) and tartaric acid (40 mmol, 6 g) in water (60 mL). The two-
phase mixture was stirred for 15 min, then the phases were sepa-
rated, and the aqueous phase was extracted with Et2O (3ϫ30 mL).
The combined organic phase and extracts were treated with cold
EtOAc/PE) = 0.68. IR (neat): ν
= 2938 [w (CH2)], 2896 [w
˜
max
(CH2)], 1454 [s (CH3)], 1217 [s (C–O–C)], 1128 (s), 1071 [s (C–O)]. (0 °C) NaOH (10 mL of a 30% w/v solution in brine) at 0 °C, and
Amicetoside 28 (one major anomer): 1H NMR (300 MHz, CDCl3): the phases were stirred vigorously at 0 °C for 30 min. The phases
δ = 7.36–7.25 (m, 5 H, Ph), 4.88–4.34 (m, 5 H, 1-H, 6-H, CH2Ph), were separated, and the organic phase was dried (MgSO4), filtered,
4.09–3.99 (m, 1 H, 5-H), 3.83–3.44 (m, 1 H, 4-H), 3.35 (s, 3 H,
and concentrated in vacuo to leave a colourless oil, from which the
OCH3), 2.22–1.21 (m, 4 H, 2-H, 3-H) ppm. 13C NMR (75 MHz, resolved (3S)-hepta-1,6-dien-3-ol (30b) distilled at reduced pressure
1
CDCl3): δ = 138.3, 128.4, 127.8, 127.7, 97.6 (C-1), 82.7 (d, JC,F
=
=
(Kugelrohr, 25 °C/0.01 Torr) to afford a mixture: (i) Epoxy alcohol
31 (2.5 g, 39 %, 80 % by GC-MS) as a colourless oil. Rf (35 %
3
2
171.1 Hz, C-6), 71.8 (d, JC,F = 6.8 Hz, C-4), 70.9 (d, JC,F
18.0 Hz, C-5), 70.7 (CH2Ph), 54.5 (OCH3), 28.8 (C-2), 23.9 (C-3)
EtOAc/PE) = 0.42. IR (neat): ν
= 3401 (OH), 2925 [w (CH2)],
˜
max
2
ppm. 19F NMR (282 MHz, CDCl3): δ = 234.8 (td, JF,H = 47.7,
1641 [s (C=C)], 1453 (w), 1258 (w), 1018 (s), 911 (s). [α]1D9 = –16.1
3JF,H = 28.4 Hz) ppm. Rhodinoside 29 (one major anomer): 1H
NMR (300 MHz, CDCl3): δ = 7.36–7.25 (m, 5 H, Ph), 4.88–4.34
(m, 5 H, 1-H, 6-H, CH2Ph), 4.09–3.99 (m, 1 H, 5-H), 3.83–3.44
(c = 1.00, CHCl3). H NMR (300 MHz, CDCl3): δ = 5.84 (ddd, J
1
2
= 17.3, J = 10.5, J = 6.7 Hz, 1 H, 6-H), 5.06 (ddd, J = 17.3, J =
3.2, 4J = 1.5 Hz, 1 H, 7a-H), 4.99 (ddd, J = 10.5, 2J = 3.2, 4J =
(m, 1 H, 4-H), 3.38 (s, 3 H, OCH3), 2.22–1.21 (env., 4 H, 2-H, 3- 1.2 Hz, 1 H, 7b-H), 3.88–3.81 (m, 1 H, 3-H), 3.01 (ddd, J = 4.0, J
2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.2, 128.4, 127.8,
= 3.0, J = 2.8 Hz, 1 H, 2-H), 2.81 (dd, J = 5.0, J = 2.8 Hz, 1 H,
1
3
2
127.7, 97.9 (C-1), 83.7 (d, JC,F = 166.8 Hz, C-6), 70.4 (d, JC,F
=
1a-H), 2.73 (dd, J = 5.0, J = 4.0 Hz, 1 H, 1b-H), 2.35–2.10 (m, 2
2
7.0 Hz, C-4), 69.2 (d, JC,F = 21.9 Hz, C-5), 70.8 (CH2Ph), 54.7
(OCH3), 24.1 (C-2), 20.5 (C-3) ppm. 19F NMR (282 MHz, CDCl3):
δ = –230.3 to –230.7 (m) ppm. HRMS (EI): calcd. for C14H19FO3
[M+] 254.13182; found 254.13189. MS (EI): m/z (%) = 254 (1) [M+],
222 (1), 191 (3), 147 (1), 107 (17), 101 (14), 91 (100). tR (GC) =
17.94 and 18.15 min (not assignable).
H, 5-H), 1.96 (br. s, 1 H, OH), 1.78–1.52 (m, 2 H, 4-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 138.0 (C-6), 115.1 (C-7), 67.9 (C-3),
54.5 (C-2), 43.5 (C-1), 32.5 (C-4), 29.5 (C-5) ppm. HRMS (EI):
calcd. for C7H12O2 [M+] 128.08373; found 128.08372. MS (EI): m/z
(%) = 128 (1) [M+], 108 (18), 97 (18), 95 (19), 79 (96), 67 (100). tR
(GC) = 8.05 min. (ii) Epoxy alcohol 32 (Payne product) (0.32 g,
5%, 95% by GC-MS) as a colourless oil. Rf (35% EtOAc/PE) =
(؎)-Hepta-1,6-dien-3-ol (30a): Vinylmagnesium bromide was pre-
pared by slow addition of cold (0 °C) vinyl bromide (125 mmol,
9 mL) to freshly activated magnesium turnings (127 mmol, 3.1 g) in
dry THF (50 mL) at 0 °C beneath a dry ice condenser (containing
acetone/solid CO2). The mixture was warmed gently to initiate the
reaction. After the reaction was complete (most of the magnesium
was consumed), the Grignard reagent solution was diluted with dry
THF (50 mL). 5-Pentenal (90 mmol, 8 g) was added dropwise to
the mixture at 0 °C, which was stirred for 30 min, then quenched
at 0 °C with NH4Cl (25 mL of a saturated aqueous solution), di-
luted with water (50 mL) and extracted with Et2O (3ϫ100 mL).
The combined organic extracts were dried (MgSO4) and concen-
trated carefully in vacuo to leave a colourless oil, which was dis-
tilled (Kugelrohr, b.p. 20–25 °C/0.2 Torr) to afford alcohol 30a
(8.2 g, 81%, 95% by GC-MS) as a colourless oil. Rf (20% EtOAc/
0.27. IR (neat): ν
= 3395 [br. (OH)], 2927 [w (CH2)], 1641 [s
˜
max
(C=C)], 1448 (w), 1084 (w), 912 (s). [α]2D3 = +30.5 (c = 1.00, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 5.83 (ddt, J = 17.0, J = 10.2, J
= 6.7 Hz, 1 H, 6-H), 5.06 (ddd, J = 17.0, J = 3.2, J = 1.4 Hz, 1
2
4
2
4
H, 7a-H), 5.00 (ddd, J = 10.2, J = 3.2, J = 1.7 Hz, 1 H, 7b-H),
2
2
3.89 (ddd, J = 12.6, J = 6.1, J = 2.6 Hz, 1 H, 1a-H), 3.58 (ddd, J
= 12.6, J = 6.7, J = 4.7 Hz, 1 H, 1b-H), 3.00–2.92 (m, 2 H, 2-H, 3-
H), 2.74 (dd, J = 6.7, J = 6.1 Hz, 1 H, OH), 2.31–2.11 (m, 2 H, 5-
H), 1.69 (t, J = 7.6 Hz, 1 H, 4a-H), 1.69 (t, J = 7.3 Hz, 1 H, 4b-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 137.4 (C-6), 115.3 (C-7),
61.8 (C-1), 58.8 (C-2), 55.5 (C-3), 30.8 (C-4), 30.0 (C-5) ppm.
HRMS (EI): calcd. for C7H12O2 [M+] 128.08373; found 128.08372.
MS (EI): m/z (%) = 128 (1) [M+], 110 (5), 97 (37), 91 (13), 83 (27),
79 (48), 67 (100). tR (GC) = 8.68 min.
PE) = 0.76. IR (neat): νmax = 3350 [br. (OH)], 2934 [w (CH2)], 1641 (+)-(2R,3S)-1,2-Epoxyhept-6-en-3-ol (33): As for 31, from pow-
˜
[w (C=C)], 1425 (w), 991 (s). 1H NMR (300 MHz, CDCl3): δ =
dered molecular sieves (4 Å) (3.2 g), titanium tetraiisopropyloxide
5.88–5.73 (m, 2 H, 1-H, 6-H), 5.19 (ddd, J = 17.2, J = 1.6, J = (2.39 mmol, 0.75 mL), diisopropyl -tartrate (2.83 mmol, 0.6 mL),
2
4
2
4
1.4 Hz, 1 H, 1a-H), 5.07 (ddd, J = 10.4, J = 1.6, J = 1.4 Hz, 1 H,
resolved alcohol 30b (from the previous procedure) (22.3 mmol,
2
4
1b-H), 5.01 (ddd, J = 17.1, J = 3.5, J = 1.6 Hz, 1 H, 7a-H), 4.94 2.5 g) and tert-butyl hydroperoxide (22.2 mmol, 6 mL of a 3.7 
(ddd, J = 10.2, J = 3.5, J = 1.6 Hz, 1 H, 7b-H), 4.08 (ddd, J =
2
4
solution in toluene) in dry CH2Cl2 (25 mL) at –20 °C over 15 d.
6.4, J = 6.3, J = 1.2 Hz, 1 H, 3-H), 2.31 (s, 1 H, OH), 2.16–2.06 The workup was performed with ferrous sulfate (36 mmol, 10 g)
Eur. J. Org. Chem. 2009, 1058–1071
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1067

J. M. Percy, R. Roig, K. Singh
FULL PAPER
and tartaric acid (20 mmol, 3 g) in water (30 mL). The rest of the
workup and isolation were performed as for 31 to afford alcohol
33 (2.1 g, 74%, 99% by GC-MS) as a colourless oil. [α]1D9 = +27.6
(c = 1.00, CHCl3). The rest of the data are identical to those re-
ported for 32. The product of Payne rearrangement has spectral
properties identical to those of 32 and was not characterised fur-
ther.
organic phase and extracts were dried (MgSO4), filtered, and con-
centrated in vacuo to leave a dark red oil, which was purified by
Biotage column chromatography (gradient 10% Ǟ 20% EtOAc/
PE) to afford alcohol 36 (162 mg, 68%, 99% by GC-MS, 92% ee
by HPLC) as a colourless oil. Rf (20 % EtOAc/PE) = 0.51. IR
(neat): ν
= 3424 [br. (OH)], 2920 [w (CH2)], 1641 [w (C=C)],
˜
max
1
1455 (w), 1090 [s (C–O)] cm–1. [α]2D3 = –4.6 (c = 1.00, CHCl3). H
NMR (300 MHz, CDCl3): δ = 7.36–7.23 (m, 5 H, Ph), 5.80 (ddt,
J = 17.0, J = 10.2, J = 6.6 Hz, 1 H, 6-H), 5.01 (ddd, J = 17.0, J
(+)-(2S,3R)-3-Benzyloxy-1,2-epoxyhept-6-ene (34) and (–)-(2R,3R)-
1-Benzyloxy-2,3-epoxyhept-6-ene (35): Sodium hydride (1.28 mmol,
51 mg of a 60% dispersion in mineral oil, from which the oil had
been washed with dry PE), was added in portions to a stirred solu-
tion of epoxy alcohol 31 (1.00 mmol, 0.130 g), benzyl bromide
(1.07 mmol, 0.130 mL) and tetrabutylammonium iodide
(1.00 mmol, 0.379 g) in dry dichloromethane (2 mL) at room tem-
perature. After 2 h, the white suspension was filtered through filter
paper (CAUTION: The filter residue contains unreacted sodium
hydride!), concentrated in vacuo, and the filtrate was diluted with
diethyl ether (10 mL), filtered through cotton wool and concen-
trated in vacuo to leave a colourless oil, which was purified by
Biotage column chromatography (gradient 3% Ǟ 10% EtOAc/PE)
to afford: (i) Ether 34 (140 mg, 64%, 99% by GC-MS) as a colour-
2
2
2
4
= 3.4, J = 1.6 Hz, 1 H, 7a-H), 4.99 (ddd, J = 10.2, J = 3.4, J =
2
1.1 Hz, 1 H, 7b-H), 4.54 (s, 2 H, CH2Ph), 4.50 (ddd, JH,F = 47.5,
2J = 9.6, J = 3.8 Hz, 1 H, CHaHbF), 4.49 (ddd, JH,F = 47.5, J =
2
2
3
9.6, J = 5.6 Hz, 1 H, CHaHbF), 3.87 (dtd, JH,F = 20.1, J = 5.6, J
= 3.8 Hz, 1 H, 2-H), 3.49 (ddd, J = 7.3, J = 5.6, J = 4.4 Hz, 1 H,
3-H), 2.72 (s, 1 H, OH), 2.29–2.04 (m, 2 H, 5-H), 1.79–1.58 (m, 2
H, 4-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.4 (C-6), 138.2,
1
128.5, 128.0, 127.9, 115.1 (C-7), 84.6 (d, JC,F = 166.9 Hz, C-1),
3
2
78.4 (d, JC,F = 6.5 Hz, C-3), 72.5 (CH2Ph), 71.7 (d, JC,F
=
18.7 Hz, C-2), 29.5 (C-4), 29.3 (C-5) ppm. 19F NMR (282 MHz,
CDCl3): δ = –232.3 (td, 2JF,H = 47.5, 3JF,H = 20.1 Hz) ppm. HRMS
(EI): calcd. for C14H19FO2 [M+] 238.13691; found 238.13692. MS
(EI): m/z (%) = 254 (1) [M+], 200 (1), 157 (8), 91 (100). tR (GC) =
16.71 min. HPLC: Chiralcel OD-H, PE/iPrOH (99:1), 1 mL/min,
254 nm, tR = 17.5 min (36, major), tR = 15.9 min (39, minor).
less oil. R (20% EtOAc/PE) = 0.80. IR (neat): ν
= 2921 [w
˜
f
max
(CH2)], 1640 [s (C=C)], 1454 (s), 1070 [s (C–O)] cm–1. [α]2D3 = +14.5
(c = 1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.38–7.24 (m,
5 H, Ph), 5.80 (ddt, J = 17.0, J = 10.2, J = 6.6 Hz, 1 H, 6-H), 5.02
(–)-L-α-Methyl 4-O-Benzyl-6-fluoroamicetoside (37a) and (–)-L-β-
2
4
(ddd, J = 17.0, J = 3.4, J = 1.7 Hz, 1 H, 7a-H), 4.96 (ddd, J =
Methyl 4-O-Benzyl-6-fluoroamicetoside (37b): Prepared as for 28
and 29 from alcohol 36 (0.78 mmol, 0.187 g) and chlorotrimethyl-
silane (0.39 mmol, 50 µL), in methanol (5 mL) at –78 °C. The reac-
tion, workup and isolation were carried out as for 28 and 29 to
afford a colourless oil containing a 4:1 mixture of α/β anomers (by
GC-MS), which was purified by Biotage column chromatography
(gradient 1% Ǟ 2% EtOAc/PE) to afford: (i) α-Methyl amicetoside
37a (98 mg, 49%, 99% by GC-MS) as a clear colourless oil. Rf
2
4
2
10.2, J = 3.4, J = 1.7 Hz, 1 H, 7b-H), 4.66 (d, J = 11.6 Hz, 1 H,
CHaHbPh), 4.49 (d, 2J = 11.6 Hz, 1 H, CHaHbPh), 3.28 (dt, J =
6.7, J = 5.4 Hz, 1 H, 3-H), 2.93 (ddd, J = 5.4, J = 3.9, J = 2.6 Hz,
2
2
1 H, 2-H), 2.77 (dd, J = 5.3, J = 3.9 Hz, 1 H, 1a-H), 2.71 (dd, J
= 5.3, J = 2.6 Hz, 1 H, 1b-H), 2.36–2.09 (m, 2 H, 5-H), 1.77–1.62
(m, 2 H, 3-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.5, 138.2
(C-6), 128.4, 127.8, 127.7, 115.0 (C-7), 77.5 (C-3), 72.4 (CH2Ph),
53.5 (C-2), 45.7 (C-1), 32.1 (C-5), 29.4 (C-4) ppm. HRMS (EI):
calcd. for C14H19FO3 [M+] 218.13068; found 218.13064. MS (EI):
m/z (%) = 218 (1) [M+], 175 (1), 157 (1), 107 (38), 91 (100). tR (GC)
= 16.30 min. (ii) Payne product 35 (24 mg, 11%, 98% by GC-MS)
(20% EtOAc/PE) = 0.63. IR (neat): ν
= 2950 [w (CH2)], 2897
˜
max
[w (CH2)], 1455 [s (CH3)], 1223 [s (C–O–C)], 1053 [s (C–O)] cm–1.
[α]2D3 = –144.0 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ
1
= 7.40–7.29 (m, 5 H, Ph), 4.70 (d, J = 3.1 Hz, 1 H, 1-H), 4.67 (ddd,
as a colourless oil. R (20% EtOAc/PE) = 0.74. IR (neat): ν
=
˜
2JH,F = 47.7, J = 10.0, J = 3.7 Hz, 1 H, CHaHbF), 4.63 (d, 2J =
f
max
3330 [br. (OH)], 2926 [w (CH2)], 1721 (w), 1641 (w), 1452 (w), 1272
(s), 1096 [s (C–O)], 1070 (s) cm–1. [α]2D2 = –7.3 (c = 0.80, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.38–7.25 (m, 5 H, Ph), 5.83
(ddt, J = 16.9, J = 10.2, J = 6.6 Hz, 1 H, 6-H), 5.06 (ddd, J = 16.9,
2
11.6 Hz, 1 H, CHaHbPh), 4.57 (ddd, JH,F = 47.7, J = 10.0, J =
1.6 Hz, 1 H, CHaHbF), 4.48 (d, 2J = 11.6 Hz, 1 H, CHaHbPh), 3.75
3
(dddd, JH,F = 28.4, J = 9.7, J = 3.7, J = 1.6 Hz, 1 H, 5-H), 3.48
(ddd, J = 10.1, J = 9.7, J = 4.7 Hz, 1 H, 4-H), 3.34 (s, 3 H, OCH3),
2.13–2.06 (m, 1 H, 3a-H), 1.91–1.68 (m, 3 H, 2-H, 3b-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 138.3, 128.4, 127.8, 127.7, 97.6 (C-
4
2
4
2J = 3.3, J = 1.6 Hz, 1 H, 7a-H), 5.00 (ddd, J = 10.2, J = 3.0, J
2
= 1.2 Hz, 1 H, 7b-H), 4.59 (d, J = 11.9 Hz, 1 H, CHaHbPh), 4.55
(d, J = 11.9 Hz, 1 H, CHaHbPh), 3.71 (dd, J = 11.4, J = 3.3 Hz,
1 H, 1a-H), 3.47 (dd, J = 11.4, J = 5.6 Hz, 1 H, 1b-H), 2.96 (ddd,
2
2
1
3
1), 82.7 (d, JC,F = 171.1 Hz, C-6), 71.8 (d, JC,F = 6.7 Hz, C-4),
2
2
70.9 (d, JC,F = 18.0 Hz, C-5), 70.8 (CH2Ph), 54.5 (OCH3), 28.8
J = 5.6, J = 3.3 Hz, 2.3, 1 H, 2-H), 2.85 (ddd, J = 5.8, J = 5.6, J
= 2.3 Hz, 1 H, 3-H), 2.31–2.11 (m, 2 H, 5-H), 1.78–1.55 (m, 2 H,
4-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.0, 137.5 (C-6),
128.4, 127.7, 127.7, 115.3 (C-7), 73.3 (CH2Ph), 70.4 (C-1), 57.1 (C-
2), 55.6 (C-3), 31.0 (C-4), 30.1 (C-5) ppm. HRMS (EI): calcd. for
C14H19FO3 [M+] 218.13068; found 218.13075. MS (EI): m/z (%) =
218 (1) [M+], 201 (1), 175 (15), 107 (47), 91 (100). tR (GC) =
17.0 min. (iii) Mixed fraction containing both regioisomers (41 mg,
19%).
(C-2), 23.9 (C-3) ppm. 19F NMR (282 MHz, CDCl3): δ = –234.51
2
3
(td, JF,H = 47.7, JF,H = 28.4 Hz) ppm. HRMS (EI): calcd. for
C14H19FO3 [M+] 254.13182; found 254.13184. MS (EI): m/z (%) =
254 (1) [M+], 222 (2), 191 (5), 107 (16), 101 (37), 91 (100). tR (GC)
= 17.71 min. (ii) Minor β-methyl amicetoside 37b (35 mg, 18%,
82% by GC-MS). R (20% EtOAc/PE) = 0.54. IR (neat): ν
=
˜
f
max
2954 [w (CH2)], 2869 [w (CH2)], 1455 [s (CH3)], 1221 [s (C–O–C)],
1063 [s (C–O)] cm–1. [α]1D8 = –7.4 (c = 1.00, CHCl3). 1H NMR
2
(400 MHz, CDCl3): δ = 7.37–7.26 (m, 5 H, Ph), 4.63 (dd, JH,F
=
(–)-(2R,3R)-3-Benzyloxy-1-fluorohept-6-en-2-ol (36): Epoxy ether
34 (1.00 mmol, 0.218 g) was added to a stirred mixture of tetrabu-
tylammonium fluoride trihydrate (1.10 mmol, 0.356 g) and potas-
sium hydrogen difluoride (3.88 mmol, 0.302 g) at 110 °C. After 2 h,
the mixture was cooled to room temperature, diluted with EtOAc
(10 mL) and water (10 mL), then carefully neutralised with
NaHCO3 (0.25 g). The organic phase was separated, and the aque-
ous phase was extracted with EtOAc (3ϫ10 mL). The combined
47.6, J = 3.3 Hz, 2 H, 6-H), 4.61 (d, 2J = 11.4 Hz, 1 H, CHaHbPh),
4.47 (d, 2J = 11.4 Hz, 1 H, CHaHbPh), 4.41 (dd, J = 8.7, J = 2.2 Hz,
1 H, 1-H), 3.54 (ddt, JH,F = 24.7, J = 9.2, J = 3.2 Hz, 1 H, 5-H),
3
3.49 (s, 3 H, OCH3), 3.48 (ddd, J = 9.4, J = 9.2, J = 4.8 Hz, 1 H,
4-H), 2.26 (ddd, J = 4.6, J = 3.9, J = 3.0 Hz, 1 H, 3a-H), 1.91 (ddd,
J = 7.8, J = 3.0, J = 2.2 Hz, 1 H, 2a-H), 1.60–1.46 (m, 2 H, 2b-H,
3b-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.0, 128.5, 127.9,
1
2
127.8, 102.7 (C-1), 82.6 (d, JC,F = 171.8 Hz, C-6), 77.3 (d, JC,F
=
1068
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1058–1071

Fluorinated Analogues of Amicetose and Rhodinose
3
18.0 Hz, C-5), 71.8 (d, JC,F = 6.8 Hz, C-4), 71.3 (CH2Ph), 56.4
= 6.8 Hz, C-4), 56.5 (OCH3), 30.7 (C-3), 29.9 (C-2) ppm. 19F NMR
(282 MHz, CDCl3): δ = –233.1 (td, JF,H = 45.1, JF,H = 22.6 Hz)
ppm. The minor product could not be purified rigorously and was
characterised more fully after the next step.
(OCH3), 29.7 (C-2), 27.1 (C-3) ppm. 19F NMR (282 MHz, CDCl3):
2
3
2
3
δ = –232.72 (td, JF,H = 47.6, JF,H = 24.7 Hz) ppm. HRMS (EI):
calcd. for C14H19FO3 [M+] 254.13182; found 254.13175. MS (EI):
m/z (%) = 254 (1) [M+], 222 (1) [M+ – MeOH], 191 (3), 107 (16),
101 (22), 91 (100). tR (GC) = 17.84 min. (iii) Mixed fraction con-
taining both anomers (28 mg, 14%).
L-α-5-O-Benzyl-6-fluoroamicetose (42a) and L-β-5-O-Benzyl-6-fluo-
roamicetose (42b): Concentrated hydrochloric acid (20 µL) was
added to a solution of 37a and 37b (0.40 mmol, 101 mg) in THF
(4 mL) and H2O (150 mg). The solution was stirred and heated
(microwaves, 50 W) at 120 °C for 1 h. The mixture was diluted with
Et2O (5 mL), dried (MgSO4), filtered, and concentrated in vacuo
to leave a colourless oil, which was purified by Biotage column
chromatography (gradient 20% Ǟ 50% EtOAc/PE) to afford an
inseparable (1.7:1 by NMR) mixture of 42a and 42b (76 mg, 80%,
99% by GC-MS) as a clear colourless oil. Rf (35% EtOAc/PE) =
(–)-(2R,3S)-3-Benzyloxy-1,2-epoxyhept-6-ene (38): Prepared as for
34 from sodium hydride (2.45 mmol, 98 mg of a 60% dispersion in
mineral oil), epoxy alcohol 33 (2.00 mmol, 0.254 g), benzyl bromide
(2.06 mmol, 0.250 mL) and tetrabutylammonium iodide
(1.13 mmol, 0.425 g) in dichloromethane (4 mL). The same workup
and isolation afforded a colourless oil, which was purified by Bi-
otage column chromatography (gradient 3% Ǟ 10% EtOAc/PE)
to afford ether 38 (307 mg, 71%, 99% by GC-MS) as a colourless
oil. Rf (20% EtOAc/PE) = 0.80. [α]1D8 = –18.8 (c = 1.00, CHCl3).
The rest of the spectroscopic data are identical to those reported
for 34. The Payne product was neither isolated nor characterised.
0.43. IR (neat): ν
= 3414 [br. (OH)], 2951 [w (CH2)], 2874 [w
˜
max
(CH2)], 1455 (w), 1220 (w), 1068 [s (C–O)], 978 (s) cm–1. α-Anomer
1
(42a, major): H NMR (300 MHz, CDCl3): δ = 7.38–7.25 (m, 5 H,
Ph), 5.29 (d, J = 3.1 Hz, 1 H, 1-H), 4.77–4.44 (m, 4 H, 6-H,
3
CH2Ph), 4.03 (dddd, JH,F = 27.5, J = 9.6, J = 3.8, J = 1.4 Hz, 1
(+)-(2S,3S)-3-Benzyloxy-1-fluorohept-6-en-2-ol (39): Prepared as
for 36 from 34 (1.17 mmol, 0.256 g), tetrabutylammonium fluoride
trihydrate (1.23 mmol, 0.399 g) and potassium hydrogen difluoride
(5.11 mmol, 0.395 g) at 100 °C. After 1 h, the mixture was cooled
to room temperature. The same workup and isolation as for 36
afforded a colourless oil, which was purified by Biotage column
chromatography (gradient 10 % Ǟ 20 % EtOAc/PE) to afford
alcohol 39 (175 mg, 63%, 99% by GC-MS, 95% ee by HPLC) as
a colourless oil. Rf (20% EtOAc/PE) = 0.51. [α]1D8 = +5.3 (c = 1.00,
CHCl3). HRMS (EI): calcd. for C14H19FO2 [M+] 238.13691; found
238.13698. HPLC: Chiralcel OD-H, PE/iPrOH (99:1), 1 mL/min,
254 nm, tR = 15.5 min (39, major), tR = 17.5 min (36, minor).
The rest of the spectroscopic data are identical to those reported
for 36.
H, 5-H), 3.73–3.35 (m, 1 H, 4-H), 2.32–1.42 (m, 5 H, 2-H, 3-H,
OH) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.2, 128.5, 127.9,
1
3
127.7, 91.0 (C-1), 82.9 (d, JC,F = 170.9 Hz, C-6), 72.1 (d, JC,F
=
6.9 Hz, C-4), 71.0 (d, 2JC,F = 17.4 Hz, C-5), 70.8 (CH2Ph), 28.9 (C-
3), 23.1 (C-2) ppm. 19F NMR (282 MHz, CDCl3): δ = –234.5 (td,
2JF,H = 47.7, JF,H = 27.6 Hz) ppm. β-Anomer (42b, minor): 1H
3
NMR (300 MHz, CDCl3): δ = 4.84 (dd, J = 8.6, J = 1.8 Hz, 1 H,
1-H), 4.77–4.44 (m, 4 H, 6-H, CH2Ph), 3.73–3.35 (m, 2 H, 4-H, 5-
H), 2.32–1.42 (m, 5 H, 2-H, 3-H, OH) ppm. 13C NMR (75 MHz,
1
CDCl3): δ = 137.9, 128.5, 127.9, 127.8, 96.1 (C-1), 82.6 (d, JC,F
=
=
2
3
171.5 Hz, C-6), 77.4 (d, JC,F = 17.7 Hz, C-5), 71.5 (d, JC,F
6.8 Hz, C-4), 71.3 (CH2Ph), 31.3 (C-2), 27.3 (C-3) ppm. 19F NMR
2
3
(282 MHz, CDCl3): δ = –233.2 (td, JF,H = 47.6, JF,H = 24.9 Hz)
ppm. HRMS (EI): calcd. for C13H17FO3 [M+] 240.11617; found
240.11611. MS (EI): m/z (%) = 240 (1) [M+], 176 (1), 147 (3), 136
(23), 107 (2), 91 (100). tR (GC) = 19.37 min (42b), 19.43 min (42a).
The anomers were assigned on the basis of the 1-H coupling con-
stant and a deconvolution of the connectivity from the dqfCOSY
spectrum.
L-α-Methyl 6-Fluoroamicetoside (41a) and L-β-Methyl 6-Fluoroam-
icetoside (41b): A solution of 37a and 37b (0.39 mmol, 98 mg, 4:1
mixture of anomers) in ethanol (6 mL) containing 10% palladium
on carbon (30 mg) was stirred under hydrogen at room temperature
and atmospheric pressure for 48 h. The mixture was filtered
through Celite; the filter bed was washed with EtOH (3ϫ2 mL),
and the combined filtrates were concentrated in vacuo to leave a
dark oil, which was purified by Biotage column chromatography
(gradient 30% Ǟ 50% EtOAc/PE) to afford: (i) 41a (49 mg, 77%,
99% by GC-MS) as a clear colourless oil. Rf (35% EtOAc/PE) =
(–)-L-α-Methyl 5-O-Benzoyl-6-fluoroamicetoside (43a) and (–)-L-β-
Methyl 5-O-Benzoyl-6-fluoroamicetoside (43b): Prepared as for 28
and 29 from alcohol 36 (2.15 mmol, 0.513 g) and chlorotrimethyl-
silane (0.39 mmol, 50 µL) in methanol (10 mL), though at the
higher temperature of 0 °C over 5 h. The workup and isolation were
0.28. IR (neat): ν
= 3408 [br. (OH)], 2943 [w (CH2)], 1370 (w), carried out as for 28 and 29 to afford a yellow oil, which was puri-
˜
max
1129 [s (C–O)], 1048 [s (C–O)] cm–1. [α]2D0 = –135.6 (c = 0.70,
fied by Biotage column chromatography (gradient 1 % Ǟ 2 %
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 4.71 (d, J = 2.6 Hz, 1 EtOAc/PE) to afford amicetosides 43a and 43b as clear colourless
2
2
H, 1-H), 4.68 (ddd, JH,F = 47.6, J = 10.0, J = 3.6 Hz, 1 H, 6a- oils. (i) Major α-amicetoside 43a (247 mg, 46%, 99% by GC-MS).
2
H), 4.60 (ddd, JH,F = 47.6, 2J = 10.0, J = 1.8 Hz, 1 H, 6b-H),
R (35% EtOAc/PE) = 0.70. IR (neat): νmax = 2954 [w (CH2)], 1718
˜
f
3.71–3.58 (m, 2 H, 4-H, 5-H), 3.47 (s, 3 H, OCH3), 2.20 (br. s, 1 [s (C=O)], 1451 [w (CH3)], 1276 (s), 1051 [s (C–O)] cm–1. [α]2D3
=
H, OH), 1.93–1.73 (m, 4 H, 2-H, 3-H) ppm. 13C NMR (75 MHz,
–155.5 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ = 8.02
1
1
4
4
CDCl3): δ = 97.5 (C-1), 82.8 (d, JC,F = 170.4 Hz, C-6), 72.2 (d, (dd, J = 7.5, J = 1.3 Hz, 2 H, Ph), 7.56 (tt, J = 7.5, J = 1.3 Hz,
2JC,F = 17.5 Hz, C-5), 65.2 (d, JC,F = 7.1 Hz, C-4), 54.6 (OCH3),
1 H, Ph), 7.43 (t, J = 7.5 Hz, 2 H, Ph), 5.03 (ddd, J = 10.3, J =
10.2, J = 5.0 Hz, 1 H, 4-H), 4.77 (t, J = 2.2 Hz, 1 H, 1-H), 4.54
(dd, 2JH,F = 47.5, J = 3.9 Hz, 1 H, CHaHbF), 4.54 (d, 2JH,F = 47.5,
3
29.0 (C-3), 27.4 (C-2) ppm. 19F NMR (282 MHz, CDCl3): δ =
–234.7 (td, 2JF,H = 47.6, JF,H = 26.8 Hz) ppm. HRMS (EI): calcd.
3
for C7H12FO3 [M+ – 1] 163.07705; found 163.07703. MS (EI): m/z
J = 2.5 Hz, 1 H, CHaHbF), 4.07 (dddd, JH,F = 24.6, J = 10.2, J
3
(%) = 164 (1) [M+], 133 (15), 115 (6), 102 (17), 76 (15), 69 (37), 58
= 3.9, J = 2.5 Hz, 1 H, 5-H), 3.41 (s, 3 H, OCH3), 2.18–2.12 (m, 1
(100). tR (GC) = 9.90 min. (ii) 41b (12 mg, 19 %). 1H NMR H, 3a-H), 2.06–1.82 (m, 3 H, 2-H, 3b-H) ppm. 13C NMR (75 MHz,
(400 MHz, CDCl3): δ = 4.68–4.64 (m, 1 H, 6a-H), 4.54–4.51 (m, 1
CDCl3): δ = 165.3 (C=O), 133.2, 129.9, 129.6, 128.4, 97.5 (C-1),
H, 6b-H), 4.38–4.34 (m, 1 H, 1-H), 3.68–3.23 {m [incl. 3.43 (s, 3 H, 82.4 (d, 1JC,F = 172.8 Hz, C-6), 69.5 (d, 2JC,F = 18.3 Hz, C-5), 67.6
3
OCH3)], 6 H, OH, 4-H, 5-H, OCH3}, 2.10–1.42 (m, 4 H, 2-H, 3-
(d, JC,F = 7.3 Hz, C-4), 54.7 (OCH3), 28.6 (C-3), 24.0 (C-2) ppm.
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 102.7 (C-1), 83.0 (d,
19F NMR (282 MHz, CDCl3): δ = –232.9 (td, JF,H = 47.5, JF,H
2
3
2
3
1JC,F = 168.8 Hz, C-6), 78.1 (d, JC,F = 18 Hz, C-5), 65.4 (d, JC,F
= 24.6 Hz) ppm. HRMS (EI): calcd. for C14H16FO4 [M+ – 1]
Eur. J. Org. Chem. 2009, 1058–1071
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1069

J. M. Percy, R. Roig, K. Singh
FULL PAPER
267.10326; found 267.10323. MS (EI): m/z (%) = 268 (1) [M+], 237
(5), 206 (1), 145 (15), 114 (11), 105 (100). tR (GC) = 18.61 min. (ii) 128.5, 127.9, 127.8, 102.6 (C-1), 82.6 (d, JC,F = 171.8 Hz, C-6),
(m, 2 H, 2b-H, 3b-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.0,
1
2
3
Minor β-methyl amicetoside 43b (59 mg, 11%, 94% by GC-MS) as
a clear colourless oil. R (35% EtOAc/PE) = 0.56. IR (neat): ν
77.3 (d, JC,F = 18.1 Hz, C-5), 71.8 (d, JC,F = 6.8 Hz, C-4), 71.3
(CH2Ph), 29.7 (C-2), 27.1 (C-3) ppm. 19F NMR (282 MHz,
˜
f
max
2
3
= 2959 [w (CH2)], 1718 [s (C=O)], 1451 [w (CH3)], 1267 (s), 1059
CDCl3): δ = –232.72 (td, JF,H = 47.7, JF,H = 24.8 Hz) ppm.
HRMS (EI): calcd. for C14H19D3FO3 [M+] 257.15035; found
257.15071. MS (EI): m/z (%) = 257 (1) [M+], 222 (1), 194 (2), 107
(5), 104 (9), 91 (100). tR (GC) = 17.83 min. (iii) Mixed fraction
containing both anomers (238 mg, 35%).
[s (C–O)] cm–1. [α]2D1 = –18.0 (c = 1.00, CHCl3). 1H NMR
4
(400 MHz, CDCl3): δ = 8.02 (dd, J = 7.5, J = 1.3 Hz, 2 H, Ph),
4
7.58 (tt, J = 7.5, J = 1.3 Hz, 1 H, Ph), 7.45 (t, J = 7.5 Hz, 2 H,
Ph), 4.97 (ddd, J = 9.2, J = 9.0, J = 4.9 Hz, 1 H, 4-H), 4.58 (d,
2
2JH,F = 47.5, J = 3.5 Hz, 1 H, CHaHbF), 4.57 (d, JH,F = 47.2, J
(+)-L-α-Methyl 4-O-Benzoyl-6-fluororhodinoside (45a) and (–)-L-β-
= 4.7 Hz, 1 H, CHaHbF), 4.54 (d, J = 2.5 Hz, 1 H, 1-H), 3.89
3
Methyl 4-O-Benzoyl-6-fluororhodinoside (45b): Diethyl azodicar-
boxylate (4.76 mmol, 0.75 mL) was added to a stirred solution of
a mixture of methyl pyranosides 41a and 41b (0.81 mmol, 0.133 g,
2.5:1) and triphenylphosphane (4.95 mmol, 1.312 g) in dry toluene
(10 mL) at room temperature, followed immediately by benzoic
acid (4.95 mmol, 0.610 g). After 3 h, the mixture was concentrated
in vacuo to leave a yellow liquid, which was purified by Biotage
column chromatography (gradient 10% Ǟ 20% EtOAc/PE) to af-
ford: (i) 45a (95 mg, 44%, 98% by GC-MS), as a clear colourless
oil, which crystallized very slowly as white needles. M.p. 51–54 °C.
(dddd, JH,F = 21.0, J = 9.0, J = 4.7, J = 3.5 Hz, 1 H, 5-H), 3.52
(s, 3 H, OCH3), 2.42–2.32 (m, 1 H, 3a-H), 2.04–1.66 (m, 3 H, 2-H,
3b-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.5 (C=O), 133.3,
1
129.8, 129.6, 128.5, 102.3 (C-1), 82.4 (d, JC,F = 173.1 Hz, C-6),
2
3
75.8 (d, JC,F = 19.2 Hz, C-5), 67.5 (d, JC,F = 6.9 Hz, C-4), 56.4
(OCH3), 29.2 (C-2), 26.6 (C-3) ppm. 19F NMR (282 MHz, CDCl3):
2
3
δ = –230.7 (td, JF,H = 47.2, JF,H = 21.0 Hz) ppm. HRMS (EI):
calcd. for C14H16FO4 [M+ – 1] 267.10326; found 267.10320. MS
(EI): m/z (%) = 268 (1) [M+], 237 (3), 146 (10), 126 (4), 114 (6),
105 (100). tR (GC) = 18.90 min. (iii) Mixed fraction containing
both anomers (30 mg, 6%).
R (35% EtOAc/PE) = 0.71. IR (neat): νmax = 2941 [w (CH2)], 2900
˜
f
[w (CH2)], 1716 [s (C=O)], 1451 (w), 1268 (s) , 1111(s), 1022 [s (C–
L-α-([D3]Methyl) 5-O-Benzyl-6-fluoroamicetoside (44a) and L-β-
O)]. [α]2D0 = +59.6 (c = 1.00, CHCl3). 1H NMR (300 MHz, CDCl3):
([D3]Methyl) 5-O-Benzyl-6-fluoroamicetoside (44b): Prepared as for δ = 8.13–8.06 (m, 2 H, Ph), 7.63–7.54 (m, 1 H, Ph), 7.50–7.41 (m,
28 and 29 from alcohol 36 (2.65 mmol, 0.633 g) and chlorotrimeth-
ylsilane (0.39 mmol, 50 µL) in methanol (10 mL) at –78 °C over
30 min. The solution was purged with a stream of O2 until it be-
came colourless (5 min), then dimethyl sulfide (13.6 mmol, 1.0 mL)
was added. The mixture was stirred overnight (18 h) at room tem-
perature, concentrated in vacuo, taken up in a mixture of [D4]meth-
anol (1 mL) and chlorotrimethylsilane (10 µL) and stirred for 1 h.
Solid NaOH (0.2 g, 5 mmol) was added, and after 1 h the solution
was neutralised with concentrated HCl (0.7 mL), concentrated in
vacuo to leave a colourless oil containing a mixture of anomers,
which was purified by Biotage column chromatography (gradient
1% Ǟ 2% EtOAc/PE) to afford: (i) 44a (134 mg, 20%, 99% by
GC-MS) as a clear colourless oil. Rf (20% EtOAc/PE) = 0.63. IR
2 H, Ph), 5.21 (s, 1 H, 4-H), 4.88 (d, J = 2.4 Hz, 1 H, 1-H), 4.51
2
2
(dd, JH,F = 46.9, J = 5.8 Hz, 1 H, 6a-H), 4.49 (dd, JH,F = 46.9, J
3
= 5.8 Hz, 1 H, 6b-H), 4.27 (dtd, JH,F = 15.2, J = 5.8, J = 1.0 Hz,
1 H, 5-H), 3.44 (s, 3 H, OCH3), 2.25–1.74 (m, 2a-H, 3-H), 1.70–
1.61 (m, 1 H, 2b-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.8
1
(C=O), 133.6, 130.0, 129.7, 128.5, 97.9 (C-1), 83.0 (d, JC,F
=
=
2
3
169.7 Hz, C-6), 68.1 (d, JC,F = 21.6 Hz, C-5), 67.1 (d, JC,F
7.2 Hz, C-4), 54.9 (OCH3), 24.3 (C-2), 22.6 (C-3) ppm. 19F NMR
2
3
(282 MHz, CDCl3): δ = –230.8 (td, JF,H = 46.9, JF,H = 15.2 Hz)
ppm. HRMS (EI): calcd. for C14H17FO4 [M+] 268.11109; found
268.11107. MS (EI): m/z (%) = 268 (1) [M+], 237 (6), 206 (4), 146
(5), 126 (3), 114 (6), 105 (100). tR (GC) = 18.43 min. The stereo-
chemistry and identity of the crystalline anomer were confirmed
by XRD analysis; crystal data: empirical formula C14H17O4F, M
= 268.28, crystal size 0.13ϫ0.10ϫ0.08 mm, orthorhombic, space
(neat): νmax = 2952 [w (CH2)], 2895 [w (CH2)], 1456 [s (CH3)], 1371
˜
(w), 1224 [s (C–O–C)], 1046 [s (C–O)] cm–1. [α]2D0 = –141.1 (c =
1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.36–7.22 (m, 5 group P2(1)2(1)2, unit cell dimensions
a
=
13.508(3),
b
=
=
2
2
H, Ph), 4.68 (d, J = 3.0 Hz, 1 H, 1-H), 4.66 (ddd, JH,F = 47.7, J
7.6277(15), c = 13.127(3) Å, V = 1352.6(4) Å3, Z = 4, Dcalcd.
= 9.9, J = 3.8 Hz, 1 H, CHaHbF), 4.63 (d, 2J = 11.6 Hz, 1 H,
1.317 Mgm–3, F(000) = 568, µ(Mo-Kα) = 0.104 mm–1, T =
150(2) K, 1401 total reflections measured, 1401 independent, (Rint
= 0.0000), which were used in all calculations. Final R indices [for
CHaHbPh), 4.56 (ddd, JH,F = 47.7, 2J = 9.9, J = 1.7 Hz, 1 H,
2
CHaHbF), 4.46 (d, 2J = 11.6 Hz, 1 H, CHaHbPh), 3.74 (dddd, 3JH,F
= 28.3, J = 9.7, J = 3.8, J = 1.7 Hz, 1 H, 5-H), 3.47 (ddd, J = 9.9, reflections with IϾ2σ(I)] were R1 = 0.0512, ωR2 = 0.0701; R in-
J = 9.7, J = 4.7 Hz, 1 H, 4-H), 2.09–1.99 (m, 1 H, 3a-H), 1.86–1.61 dices (all data) were R1 = 0.0763, ωR2 = 0.0757. (ii) 45b (51 mg,
(m, 3 H, 2-H, 3b-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.3,
128.4, 128.2, 127.7, 97.5 (C-1), 82.7 (d, 1JC,F = 171.2 Hz, C-6), 71.9
23%, 99% by GC-MS) as a clear colourless oil. Rf (35% EtOAc/
PE) = 0.51. IR (neat): νmax = 2961 [w (CH2)], 2842 [w (CH2)], 1716
˜
3
2
(d, JC,F = 6.8 Hz, C-4), 70.9 (d, JC,F = 17.6 Hz, C-5), 70.8 [s (C=O)], 1452 (w), 1268 (s) , 1110 (s), 1078 [s (C–O]. [α]1D9 = –32.7
(CH2Ph), 28.8 (C-2), 23.9 (C-3) ppm. 19F NMR (282 MHz, (c = 1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 8.13–8.05 (m,
2
3
CDCl3): δ = –234.40 (td, JF,H = 47.7, JF,H = 28.3 Hz) ppm.
2 H, Ph), 7.62–7.55 (m, 1 H, Ph), 7.50–7.41 (m, 2 H, Ph), 5.19–
HRMS (EI): calcd. for C14H19D3FO3 [M+] 257.15035; found
5.16 (m, 1 H, 4-H), 4.57 (dd, JH,F = 46.8, J = 6.4 Hz, 1 H, 6a-H),
2
257.15072. MS (EI): m/z (%) = 257 (1) [M+], 222 (2), 194 (4), 107 4.56 (dd, JH,F = 46.8, J = 5.2 Hz, 1 H, 6b-H), 4.52 (dd, J = 8.5, J
2
3
(10), 104 (25), 91 (100). tR (GC) = 17.73 min. (ii) 44b (60 mg, 9%, = 2.7 Hz, 1 H, 1-H), 4.03 (dddd, JH,F = 13.2, J = 6.3, J = 5.6, J
99% by GC-MS) as a clear colourless oil. Rf (20% EtOAc/PE) =
= 1.6 Hz, 1 H, 5-H), 3.58 (s, 3 H, OCH3), 2.29–2.15 (m, 1 H, 2a-
0.54. IR (neat): ν
= 2953 [w (CH2)], 2865 [w (CH2)], 1455 [s H), 1.96–1.71 (env., 3 H, 2b-H, 3-H) ppm. 13C NMR (75 MHz,
˜
max
(CH3)], 1397 (w), 1169 [s (C–O–C)], 1074 [s (C–O)] cm–1. [α]2D0
=
CDCl3): δ = 165.8 (C=O), 133.3, 130.2, 129.8, 128.5, 103.0 (C-1),
–3.8 (c = 1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.38– 82.2 (d, 1JC,F = 169.7 Hz, C-6), 75.2 (d, 2JC,F = 22.3 Hz, C-5), 66.0
2
3
7.24 (m, 5 H, Ph), 4.63 (dd, JH,F = 47.7, J = 3.2 Hz, 2 H, 6-H),
(d, JC,F = 6.4 Hz, C-4), 56.5 (OCH3), 26.8 (C-2), 26.2 (C-3) ppm.
2
2
2
3
4.62 (d, J = 11.5 Hz, 1 H, CHaHbPh), 4.47 (d, J = 11.5 Hz, 1 H,
CHaHbPh), 4.41 (dd, J = 8.8, J = 2.2 Hz, 1 H, 1-H), 3.54 (ddt,
19F NMR (282 MHz, CDCl3): δ = –230.6 (td, JF,H = 46.8, JF,H
=
13.2 Hz) ppm. HRMS (EI): calcd. for C14H17FO4 [M+] 268.11109;
3JH,F = 24.8, J = 9.1, J = 3.2 Hz, 1 H, 5-H), 3.50–3.39 (m, 1 H, 4- found 268.11120. MS (EI): m/z (%) = 268 (1) [M+], 237 (2), 206
H), 2.28–2.20 (m, 1 H, 3a-H), 1.95–1.85 (m, 1 H, 2a-H), 1.67–1.44
(3), 146 (4), 126 (4), 105 (100). tR (GC) = 18.60 min.
1070
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Eur. J. Org. Chem. 2009, 1058–1071

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Received: November 14, 2008
Published Online: January 13, 2009
Eur. J. Org. Chem. 2009, 1058–1071
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1071