Efficient fluorination with tetrabutylammonium dihydrogen trifluoride in a novel approach toward 1-α-fluoro-25-hydroxy-vitamin D3 analogues

Article abstract of DOI:10.1021/jo980764l

The known, but hardly accessible, A-ring phosphine oxide 20, a building block for 1-α-fluoro-25-hydroxy-vitamin D₃, was prepared by a new route in gram amounts from (S)-(+)-carvone in 20 steps and 0.6% overall yield. Fluorine was introduced at an early stage by the completely regio-and stereoselective trans-diaxial opening of key-epoxide 5 with neat tetrabutylammonium dihydrogen trifluoride at 95 °C. The required 2-carbon chain extension of cyclohexanol 13 was accomplished in moderate yield via S(N)' substitution with cesium phenylselanyl acetate followed by Ireland- Claisen rearrangement of the resulting ester 15. Spontaneous elimination of the derived phenyl selenoxide led stereorandomly to a 1:1 mixture of dienoates E/Z-17, which was transformed into 20 as previously described.

Full text of DOI:10.1021/jo980764l

6984
J . Org. Chem. 1998, 63, 6984-6989
Efficien t F lu or in a tion w ith Tetr a bu tyla m m on iu m Dih yd r ogen
Tr iflu or id e in a Novel Ap p r oa ch tow a r d
1-r-F lu or o-25-h yd r oxy-vita m in D3 An a logu es
Pierre Barbier, Peter Mohr, Marc Muller, and Raffaello Masciadri*
F. Hoffmann-La Roche Ltd., Pharma Research Preclinical, Infectious Diseases,
CH-4070 Basel, Switzerland
Received April 23, 1998
The known, but hardly accessible, A-ring phosphine oxide 20, a building block for 1-R-fluoro-25-
hydroxy-vitamin D3, was prepared by a new route in gram amounts from (S)-(+)-carvone in 20
steps and 0.6% overall yield. Fluorine was introduced at an early stage by the completely regio-
and stereoselective trans-diaxial opening of key-epoxide 5 with neat tetrabutylammonium dihy-
drogen trifluoride at 95 °C. The required 2-carbon chain extension of cyclohexanol 13 was
accomplished in moderate yield via SN′ substitution with cesium phenylselanyl acetate followed by
Ireland-Claisen rearrangement of the resulting ester 15. Spontaneous elimination of the derived
phenyl selenoxide led stereorandomly to a 1:1 mixture of dienoates E/ Z-17, which was transformed
into 20 as previously described.
In tr od u ction a n d P la n s
drogen trifluoride (NBu4H2F3),9 a powerful and safe
source of fluoride, compatible with standard glassware.
Our second key transformation was adapted from Ta-
kano’s highly efficient synthesis of the A-ring phosphine
oxide precursor of 1R,25-dihydroxy-vitamin D3, where an
epoxide similar to 12 is rearranged to the corresponding
allylic alcohol.10 We speculated that this process should
be applicable to the 1R-fluoro analogue. Third, the
missing 2-carbon fragment would be installed via Ireland-
Caisen rearrangement of ester 15, in analogy with a
strategy devised by Posner.11
De novo construction of so-called A-ring phosphine
oxides, crucial intermediates in the countless vitamin D
syntheses, is a long-standing topic in this area, and many
ingenious solutions have been provided by leading labo-
ratories over the last two decades.1 We required building
block 20 (Scheme 1) for our current medicinal chemistry
program aimed at novel vitamin D derivatives as antip-
soriatics. We intended to design an approach that would
allow us to make optimal use of previous work in the area
and, at the same time, to overcome some limitations. In
planning so, we realized that easy mode of operation and
potential for scale-up would play a decisive role, since
the number of synthetic steps would be in the range of
15-20, thus reducing the overall yield to ca. 1%, assum-
ing a mean efficiency of 80% for each step. The 17-step
synthesis of 20 by Uscocov´ıc2 harbors the advantage of
starting from readily available and cheap (S)-(+)-carvone,
but suffers from the use of rather exotic reagents such
as Martin’s sulfurane and (diethylamino)sulfur trifluoride
(DAST). We planned to introduce fluorine via trans-
diaxial opening of epoxide 5 (Scheme 1), in analogy to
the pioneering synthesis of 1-R-fluoro-25-hydroxy-vitamin
D3 by DeLuca,3,4 which in turn would be accessible from
(S)-(+)-carvone (1), thus combining advantageous fea-
tures of the DeLuca and the Uskokov´ıc approach, respec-
tively. Regio- and stereoselective opening of epoxides
with fluoride is an extremely valuable process,5-8 facili-
tated by the introduction of tetrabutylammonium dihy-
Resu lts a n d Discu ssion
Our synthesis of key phosphine oxide 20 started from
(S)-(+)-carvone (1) (Scheme 1): Diastereoselective reduc-
tion with sodium dihydridobis(2-methoxyethoxy)alumi-
nate (REDAL) in THF at -70 °C afforded an inseparable
8:1 mixture of (+)-cis-carveol (2a )12 and (+)-trans-carveol
(2b) in 95% combined yield. Regioselective syn-epoxi-
dation of the allylic double bond of mixture 2a ,b was
achieved with m-CPBA in CH2Cl2 at -40 °C producing
quantitatively a crude mixture of epoxides containing
85% of the desired compound 3.13 Mitsunobu reaction
of this crude epoxide mixture with 4-nitrobenzoic acid
and DEAD/TPP in toluene occurred with inversion of
configuration at C-1 of 3 affording crude nitrobenzoate
4, which was conveniently purified by filtration over silica
gel followed by crystallization, thus removing all stereo-
and regioisomeric impurities generated in the two pre-
ceding steps. Nitrobenzoate 4 was cleaved with LiOH
in THF/H2O at 0 °C (strict temperature control manda-
tory) yielding the crystalline epoxide 5 in 80% yield over
(1) Zhu, G.-D.; Okamura, W. Chem. Rev. 1995, 95, 1877.
(2) Baggiolini, E. G.; Kulesha, I.; Shiuey, S. J .; Uskokovic, M. R. J .
Org. Chem. 1990, 55, 243.
(3) DeLuca, H. F.; Ikekawa, N.; Takazuto, S.; Oschima, E. Chem.
Pharm. Bull. 1984, 32, 3518.
(4) DeLuca, H. F.; Ikekawa, N.; Takazuto, S.; Oschima, E.; Hiroshi,
S.; Kobayashi, Y.; Tanaka, J . Chem. Pharm. Bull. 1984, 32, 3525.
(5) Alvernhe, G.; Laurent, A. J . Fluorine Chem. 1986, 34, 147.
(6) Armi, H.; El Gaied, M. M. J . Fluorine Chem. 1990, 46, 75.
(7) Landini, D.; Albanese, D.; Penso, M. Tetrahedron 1992, 48, 4163.
(8) Giannini, G. Gazz. Chim. Ital. 1996, 126, 771.
(9) Landini, D.; Molinari, H.; Penso, M.; Rampoldi, A. Synthesis
1988, 953.
(10) Hatakeyama, S.; Numata, H.; Osanai, K.; Takano, S. J . Org.
Chem. 1989, 54, 3515.
(11) Posner, G. H.; Crouch, D. R.; Kinter, C. M.; Carry, J .-C. J . Org.
Chem. 1991, 56, 6981.
(12) Nozaki, H.; Yamamoto, H.; Yasuda, A. Bull. Chem. Soc. J pn.
1979, 52, 1757.
(13) Kover, B. W.; J ones, J . J . Synth. Commun. 1995, 25, 3907.
S0022-3263(98)00764-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/11/1998

1-R-Fluoro-25-hydroxy-vitamin D3 Analogues
J . Org. Chem., Vol. 63, No. 20, 1998 6985
Sch em e 1a
a
Legend for reaction conditions: (a) NaAlH2(OCH2CH2OMe)2, THF, -70 °C (80%); (b) m-CPBA, CH2Cl2, -40 °C (99%); (c) TPP/DEAD,
PNBA, toluene, (82%); (d) LiOH, 1:1 THF/H2O, 0 °C (99%); (e) neat Bu4NH2F3, 95 °C (99%); (f) MsCl, pyridine, CH2Cl2 (99%); (g) K2CO3,
MeOH (85%); (h) OsCl3, NaIO4, 1:1 THF/ H2O (83%); (i) m-CPBA, CH2Cl2 (94%); (k) K2CO3, MeOH (79%); (l) (TBDMS)Cl, imidazole, DMF
(91%); (m) EtMgTMP, THF (72%); (n) DIEA, MsCl, CH2Cl2 (99%); (o) PhSeCH2CO2Cs, cat. NBu4I, DMF, 50 °C (32%); (p) (1) DIEA, TBSOTf,
CH2Cl2, (2) NaOH, THF, (3) MeOH, DCC/DMAP, CH2Cl2 (44%); (q) NaIO4, THF/H2O/MeOH (87%); (r) DIBALH, THF, -70 °C (72%); (s)
NCS, Me2S, CH2Cl2 (65%); (t) (1) LiPPh2, THF, -70 °C, (2) H2O2 (51%).
Sch em e 2
these two steps. Small-scale fluorination of epoxide 5
with 2 equiv of NBu4H2F3 in 1,2-dichloroethane at reflux
gave rise to the desired fluoro diol 6a in 80% yield. A
minor byproduct was isolated and identified as 6b, which
resulted from incorporation of chlorine instead of fluorine
into the molecule. The diols 6a ,b were fully character-
ized as the corresponding crystalline mesylates 7a ,b.
Since the solvent 1,2-dichloroethane was the only possible
source of chlorine, and byproduct formation became even
more substantial (15-20%) on scale-up, we performed the
fluorination of epoxide 5 in neat NBu4H2F3 (prepared by
a slight modification of Landini’s procedure)9 at 95 °C,
affording exclusively the fluoro diol 6a in quantitative
yield. Our safety laboratory recommended a maximal
process temperature of 100 °C on the basis of thermal
decomposition studies, which indicated no exothermic
decomposition of NBu4H2F3 up to 360 °C but a slight rise
in pressure (180 mbar/h) in a closed vessel. Transforma-
tion of the crude fluoro diol 6a to the epoxide 8 was
achieved by regioselective mesylation of the secondary
hydroxyl group in the presence of pyridine as weak base,
followed by ring closure with K2CO3/MeOH in 83% yield.
Oxidative degradation of the isopropenyl group of 8 was
attempted by two well-established literature procedures,
first by ozonolysis in MeOH to an R-methoxy hydroper-
oxide which upon treatment with acetic anhydride and
triethylamine underwent in situ Criegee rearrangement
affording epoxy alcohol 11 in only 40% yield.14 We
therefore switched to the higher yielding two-step pro-
cedure encompassing Lemieux-J ohnson oxidation of 8
with 0.5 mol % of OsO4 (prepared in situ from nonvolatile
OsCl3) and 2 equiv of NaIO4 (83% yield) followed by
Baeyer-Villiger oxidation of 9 with m-CPBA (94% yield).
At this stage the protective group on the secondary
hydroxyl had to be exchanged for TBDMS. The acetate
10 was cleaved with K2CO3/MeOH affording in 79% yield
the somewhat water-soluble, crystalline alcohol 11, which
was silylated in 91% yield. Silyl ether 12 was then
exposed to the complex prepared in situ from Me2AlCl
and LiTMP. Unexpectedly, we obtained a symmetrical
dichloride (Scheme 2).
This result confirms the exceedingly high affinity of
aluminum for fluorine, which in this case could not be
exploited in a constructive manner.15 No reaction of 12
was observed under Noyori’s conditions with TMS-OTf/
DBU.16 Next, we explored a series of magnesium amides17
which were prepared form the corresponding lithium
amides (LDA, LiN(c-hex)(i-Pr), LiTMP) and ethylmag-
nesium chloride, and obtained the desired allylic alcohol
13 in 20%, 53%, and 72%, respectively. This rearrange-
ment proceeded slowly and incompletely at room tem-
(15) Ooi, T.; Kagoshima, N.; Maruoka, K. J . Am. Chem. Soc. 1997,
119, 5754.
(16) Noyori, R.; Murata, S.; Suzuki, M. Tetrahedron 1981, 37, 3899.
(17) Mosset, P.; Manna, S.; Viala, J .; Falk, J . R. Tetrahedron Lett.
1986, 27, 299.
(14) Brabander, J . D. M.; Vandewalle, M.; Kulkarni, A.; Garcia-
Lopez, R. Tetrahedron: Asymmetry 1997, 8, 1721.

6986 J . Org. Chem., Vol. 63, No. 20, 1998
Barbier et al.
perature, but longer reaction times led to extensive
decomposition, revealing the instability of 13. 1,3-
Transposition of the secondary allylic alcohol 13 was
attempted in several ways: Pd-catalyzed isomerization
of the corresponding acetate failed.18 Mitsunobu reaction
with phenylselanyl acetic acid produced the unrear-
ranged ester.19 Attempted (trimethylsilyl)trioxorhenium-
catalyzed isomerization led to clean removal of the
TBDMS group but left the allylic moiety untouched.20
Treatment with SOCl2/pyridine in tert-butyl methyl ether
afforded a mixture which contained only 30% of the
desired chloride.21 Exposure to chlorodiphenylphosphine/
imidazole/iodine22 or MsCl/DMAP/NaI10 produced again
mixtures of iodides and elimination products. Finally,
we managed to transform mesylate 14 directly in one pot
to the rearranged ester 15 in 33% overall yield using a
catalytic amount of tetrabutylammonium iodide and an
excess of crystalline cesium phenylselanyl acetate in
DMF at 50 °C.23,24 Again, elimination products and
unrearranged ester were concomitantly formed at the
expense of 15. Thermally induced Ireland-Claisen rear-
rangement of ester 15 with an excess of Hu¨nig’s base and
fresh TBDMSOTf in CH2Cl2, cleavage of the intermediary
silyl ester with NaOH, and reesterification with DCC/
DMAP/MeOH lead to a crude, inseparable mixture of
diastereomeric R-phenylselanyl esters 16a -d . Ensuing
oxidation with NaIO4 in THF/H2O/MeOH afforded di-
rectly a 1:1 mixture of Z/ E-17 in 38% overall yield from
15. This finding stood in contrast to our unpublished
results in the classical series (1R,25-dihydroxy-vitamin
D3), where we had obtained a Z/ E ) 9:1 ratio. Although
the mixture of Z/ E-17 is normally photochemically
isomerized25 to Z-17, we performed a silica gel separation,
characterized both compounds, and found that Z-17 was
stable and amenable to further manipulation whereas
pure E-17 rapidly polymerized in our hands thus pre-
cluding its photoisomerization. Since the ethyl ester
analogue of E-17 has been previously successfully isomer-
ized to the Z-isomer,2 one may conclude that the slightly
increased steric bulk of the ethyl ester group contributes
to the stability of the corresponding E-isomer. Reduction
of Z-17 with DIBALH in THF at -70 °C afforded in 72%
yield the known allylic alcohol 18,2 which was converted
uneventfully into the desired phosphine oxide 20 as
previously reported.2
mations proceeded with moderate yield due to inherent
compound instability. We suspect from our work that
the allylic fluoride substructure common to compounds
13-20 is particularly sensitive to SN′ nucleophilic dis-
placement, limiting thereby the overall efficiency of our
process.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. All reagents and solvents were
commercially available and used as received, unless otherwise
stated. Small-scale fluorinations were performed with 50-
55% weight solution of NBu4H2F3 in 1,2-dichloroethane avail-
able from ACROS. All reactions, including the fluorination
step, were run in normal glassware, except for the preparation
of NBu4H2F39 (see below). All organic extracts were dried over
Na2SO4, filtered, and evaporated under vacuum. All chro-
matographic separations were performed on Flash 40 or 150M
cartridges (40 g, 90 g, 2.5 kg), KP-Sil silica, 32-63 µm, 6 nm,
unless otherwise stated. Chemical yields are corrected for the
purity (GC or HPLC) of starting material and product. 13C
NMR spectra (100 MHz) were measured in CDCl3.
(1S,5S)- a n d (1R,5S)-5-Isop r op en yl-2-m eth ylcycloh ex-
2-en ol (2a ,b). A 3.5 M solution of sodium dihydridobis(2-
methoxyethoxy)aluminate in toluene (880 mL, 3.1 mol) was
added under argon to THF (3 L) at -70 °C. Then (S)-(+)-
carvone (1) (810 mL, 5.2 mol) was added dropwise over 4 h at
-70 °C. Stirring was continued for 1 h at -70 °C. Excess
reagent was destroyed by slow addition of AcOEt (500 mL, 5
mol) over 1 h at -70 °C and allowing the solution to warm to
0 °C. Finally, the yellow solution was poured into cold 3 N
HCl, stirred for 15 min (check pH 2-3), and extracted with
AcOEt. The organic layer was washed with saturated NaCl.
The crude oil (821 g) was distilled at 75 °C/0.4 mbar (bath-T:
100 °C) affording a colorless oil (751 g, yield 80%, GC-purity
84% + 10% (1R)-epimer).
(1S,2S,3R,5R)-2,3-Ep oxy-5-isop r op en yl-2-m eth ylcyclo-
h ex-2-en ol (3).13 Alcohols 2a ,b (367 g, 2.4 mol) were dissolved
in CH2Cl2 (4 L) and cooled under argon at -40 °C (bath-T:
-50 °C). Then m-CPBA (594 g, 2.4 mol) was added in 3
portions (30 min of stirring after each addition) and stirring
continued for 5 h at -40 to -30 °C. The reaction was
monitored by GC of a sample having been extracted with
saturated Na2CO3. The cold reaction mixture (-30 °C) was
poured into the extraction vessel on ice and then slowly mixed
while stirring with an aqueous solution of Na2CO3‚10H2O (3
mol). The layers did separate, but
a voluminous white
precipitate remained in the upper aqueous layer, which was
back-extracted with CH2Cl2. The organic layers were again
extracted with an aqueous solution of Na2CO3‚10H2O (3 mol)
and finally with a saturated solution of NaCl. One obtained
a yellowish oil (397 g, yield 99%, GC purity 85%). 13C NMR:
δ 19.2, 20.2, 29.1, 34.0, 40.5, 60.4, 62.3, 72.3, 109.7, 147.6.
Con clu sion s
The first 11 steps of this approach to phosphine oxide
20 represent a very robust and high yielding route.
Except for one silica gel filtration, chromatographic
separations could be avoided, and most reactions worked
well with crude intermediates. However, as soon as the
allylic fluoride moiety was generated, several transfor-
4-Nit r oben zoic Acid (1R,2R,4S,6R)-4-Isop r op en yl-1-
m eth yl-7-oxa bicyclo[4.1.0]h ep t-2-yl Ester (4). Alcohol 3
(379 g, 2.25 mol), 4-nitrobenzoic acid (376.5 g, 2.25 mol), and
triphenylphosphine (590 g, 2.25 mol) were dissolved under
argon in toluene (5 L) and cooled in ice. Then DEAD (368 mL,
2.25 mol) was added dropwise over 1 h (slightly exothermic)
while keeping the temperature below 10 °C. Stirring without
cooling was continued for 2 h. The reaction mixture was
filtered through a pad of toluene-wetted silica gel (2 kg) in a
porcelain funnel (35 × 10 cm), and the filter cake was washed
with more toluene (10 L). The yellow filtrate was evaporated,
and the resulting solid was crystallized from hot ethanol (4
L). After stirring of the mixture for 1 h in ice, the crystals
were filtered off and dried at 50 °C/0.1mbar for 24 h. One
obtained white crystals (518 g, yield 77%, HPLC purity 90%).
The mother liquor was concentrated to ca. 1 L and allowed to
crystallize once more at 4 °C over the weekend. One obtained
white crystals (40 g, yield 5%, HPLC purity 86%), mp 130 °C:
1H NMR (250 MHz, CDCl3) δ 1.38 (s, 3H), 1.68 (s, 3H), 1.70-
1.93 (m, 3H), 2.13-2.43 (m, 2H), 3.22 (d, J ) 5 Hz, 1H), 4.69
(18) Sulikowski, M. M.; Ellis Davies, G. E. R.; Smith, A. B., III. J .
Chem. Soc., Perkin Trans. 1 1992, 979.
(19) Burke, S. D.; Pacofsky, G. J .; Piscopio, A. D. Tetrahedron Lett.
1986, 27, 3345.
(20) Osborn, J . A.; Bellemin-Laponnaz, S.; Gisie, H.; Le Ny, J .-P.
Angew. Chem. 1997, 109, 1011.
(21) Wong, G.; Fraser-Reid, B. Can. J . Chem. 1994, 72, 69.
(22) Ioannidis, P.; Soederman, P.; Samuelsson, B.; Classon, B.
Tetrahedron Lett. 1993, 34, 2993.
(23) Reich, H. J .; Chow, F.; Shah, S. K. J . Am. Chem. Soc. 1979,
101, 6638.
(24) Kruizinga, H.; Strijtveen, B.; Kellogg, R. M. J . Org. Chem. 1981,
46, 4321.
(25) Baggiolini, E. G.; Iacobelli, J . A.; Hennessy, B. M.; Uscokov´ıc,
M. R. J . Am. Chem. Soc. 1982, 104, 2945.

1-R-Fluoro-25-hydroxy-vitamin D3 Analogues
J . Org. Chem., Vol. 63, No. 20, 1998 6987
(m, 2H), 5.59 (m, 1H), 8.28 (m, 4H); 13C NMR δ 19.3, 20.3,
28.8, 29.7, 34.2, 56.8, 59.8, 73.4, 110.0, 123.7, 130.8, 135.5,
147.6, 150.7, 163.9; TSP/MS m/z (%) 318 (M+, 1), 299 (1), 259
(10), 150 (100). Anal. Calcd for C17H19NO5 (317.345): C,
64.34; H, 6.04; N, 4.41. Found: C, 64.15; H, 6.03; N, 4.31.
dissolved in 1,2-dichloroethane (150 mL) and heated at 90 °C
bath-T for 24 h. Extraction: AcOEt, H2O. Chromatography:
2:1 CH2Cl2/AcOEt. One obtained an inseparable fluoro:chloro
) 74:20 mixture as a colorless oil (43 g, 81%). Separation of
the corresponding mesylates was feasible.
[R]20 ) +121.2 (c 0.5, CHCl3).
D
Met h a n esu lfon ic Acid (1R,2S,3S,5R)-3-Ch lor o-2-h y-
dr oxy-5-isopr open yl-2-m eth ylcycloh exyl Ester (7b). Mix-
ture 6a ,b (43 g, 228 mmol) and pyridine (55 mL, 685 mmol)
were dissolved in CH2Cl2 (500 mL) and cooled in ice. Then
MsCl (53 mL, 685 mmol) was added and stirring continued
for 24 h at 20 °C. Extraction: 1 N HCl, H2O. Chromatogra-
phy: 2:1 CH2Cl2/TBME. 7b was eluted first yielding white
crystals (12 g, 18%), mp 73 °C: 1H NMR (250 MHz, CDCl3) δ
1.59 (d, 3H), 1.79 (s, 3H), 1.82-1.96 (m, 4H), 2.30 (s, 1H), 2.32-
2.46 (m, 2H), 2.58 (br, 1H), 3.11 (s, 3H), 4.02 (dd, 1H, J 1 ) 8
Hz, J 2 ) 4 Hz), 4.61 (dd, 1H, J 1 ) 8 Hz, J 2 ) 4 Hz), 4.99 (s,
1H), 5.01 (s, 1H); 13C NMR δ 16.6, 22.1, 31.2, 34.8, 37.0, 38.3,
64.3, 75.5, 82.4, 112.2, 144.0; EI/MS m/z (%) 282 (2), 246 (8),
186 (50), 151 (85), 133 (100). Anal. Calcd for C11H19ClO4S
(282.789): C, 46.72; H, 6.77; S, 11.34; Cl, 12.54. Found: C,
46.80; H, 6.79; S, 11.36; Cl, 12.37.
(1R,2S,3R,5R)-2,3-Ep oxy-5-isop r op en yl-2-m eth ylcyclo-
h ex-2-en ol (5). Ester 4 (580 g, 1.83 mol) was dissolved in
THF (2 L) under argon and cooled to 0 °C. Then a solution of
LiOH‚H2O (306 g, 7.3 mol) in H2O (2 L) was added over ca. 1
h while the temperature was kept below 5 °C. Stirring was
continued for 3 h at 5 °C. Extraction: Et2O, 10% Na2CO3,
saturated NaCl. One obtained a crude solid (300 g, yield 99%,
GC purity 91%), mp 46 °C: 1H NMR (400 MHz, CDCl3) δ 1.42
(s, 3H), 1.52 (ddd, J 1 ) 13.8 Hz, J 2 ) 5.0 Hz, J 3 ) 2.6 Hz, 1H),
1.66 (d, J ) 5 Hz, 1H), 1.69 (s, 3H), 1.71 (dd, J 1 ) 13.8, J 2
)
3.4 Hz, 1H), 1.76 (ddd, J 1 ) 13.8 Hz, J 2 ) 13.6 Hz, J 3 ) 3.0
Hz, 1H), 2.07 (dddd, J 1 ) 15.3 Hz, J 2 ) 6.8 Hz, J 3 ) 5.0 Hz, J 4
) 2.0 Hz, 1H), 2.39 (dddd, 1H), 3.11 (d, J ) 5.2 Hz, 1H), 4.18
(br, 1H), 4.70 (m, 2H); 13C NMR δ 19.5, 20.3, 29.0, 32.9, 33.0,
58.6, 60.0, 69.6, 109.6, 148.5; TSP/MS m/z (%) 153 (5), 135 (23),
125 (28), 109 (100). Anal. Calcd for C10H16O2 (168.238): C,
(1S ,2S ,4R ,6S )-2-F lu o r o -4-is o p r o p e n y l-1-m e t h y l-7-
oxa bicyclo[4.1.0]h ep ta n e (8). Crude mesylate 7a (290 g,
0.96 mol) was dissolved in MeOH (1.7 L), treated with K2CO3
(200 g, 1.45 mol), and stirred at 20 °C for 17 h. Extraction:
hexane, ice/water, 10% NaCl. Careful evaporation gave a
crude oil (136 g, 85% yield, GC purity 90%), which was used
without further purification in the next step: 1H NMR (250
MHz, CDCl3) δ 1.43 (d, 3H, J ) 2 Hz), 1.55-1.82 (m, 3H), 1.69
(s, 3H), 2.05-2.16 (m, 1H), 2.27-2.38 (m, 1H), 3.17 (d, 1H, J
) 5.2 Hz), 4.71 (m, 2H), 4.86 (d, 1H, J HF ) 48 Hz); 13C NMR
δ 18.8, 20.3, 28.8, 30.5, 30.7, 33.4, 56.3, 56.6, 60.2, 90.1, 91.8,
109.9, 147.8; EI/MS m/z (%) 155 (12), 137 (18), 112 (100). Anal.
Calcd for C10H15FO (170.229): C, 70.56; H, 8.88; F, 11.16.
71.39; H, 9.59. Found: C, 71.29, H, 9.62. [R]20 ) +84.2 ( c
D
0.5, CHCl3).
Tetr a bu tyla m m on iu m Dih yd r ogen Tr iflu or id e.9 In a
polymethylpentene (TPX) 5 L beaker with mechanical stirrer,
tetrabutylammonium hydrogen sulfate (339.5 g, 1 mol) in
chloroform (3 L) was treated with a solution of KHCO3 (100.1
g, 1 mol) in water (300 mL) and stirred for 10 min at 20 °C.
Then solid KHF2 (390.5 g, 5 mol) was added and stirring
continued for 1 h at 20 °C. The suspension was filtered
through a glass microfiber filter (Whatman) in a Buchner
funnel with suction, the salts were washed with chloroform
(200 mL), the filtrate was poured into a separatory funnel,
the lower clear organic layer was separated, and the filtrate
was concentrated to ca. 500 mL. The resulting solution,
containing still some solid, was filtered through normal paper
in a funnel, evaporated, and dried while stirred magnetically
for 1 day at 20 °C/0.1 mbar. The resulting solvent-free colorless
oil (296 g, 98%) was used directly in the next step.
Found: C, 70.43; H, 8.81; F, 11.28. [R]20 ) -74.9 (c 0.71,
D
CHCl3).
(1S,3R,5S,6S)-1-(5-F lu or o-6-m eth yl-7-oxa bicyclo[4.1.0]-
h ep t-3-yl)eth a n on e (9). Epoxide 8 (136 g, 0.8 mol), NaIO4
(409 g, 1.9 mol), and OsCl3 (1.2 g, 4 mmol) were stirred under
argon in 1:1 THF/H2O (1.8 L). The reaction temperature was
increased to 35 °C in order to initiate the process, which then
proceeded exothermally reaching a maximum of 44 °C after 1
h. The reaction was completed after 4 h in total. Extraction:
AcOEt, H2O, 10% Na2S2O5, NaHCO3, saturated NaCl. One
obtained a brownish oil (114 g, 83% yield, GC purity 90%):
1H NMR (250 MHz, CDCl3) δ 1.44 (d, 3H, J ) 2 Hz), 1.62-
2.25 (m, 4H), 2.15 (s, 3H), 2.70 (m, 1H), 2.27-2.38 (m, 1H),
3.18 (d, J ) 4.6 Hz, 1H), 4.91 (dt, 1H, J HF ) 48 Hz, J 2 ) 2 Hz);
13C NMR δ 18.6, 24.9, 27.7, 27.9, 28.1, 40.0, 56.3, 56.6, 59.0,
89.1, 90.8, 209.2; EI/MS m/z (%) 139 (4), 131 (15), 112 (32), 97
(28), 43 (100). Anal. Calcd for C9H13FO2 (172.201): C, 62.78;
(1S,2R,4R,6S)-6-F lu or o-4-isop r op en yl-1-m et h ylcyclo-
h exa n e-1,2-d iol (6a ). Epoxide 5 (173.5 g, 1.03 mol) and
NBu4H2F3 (602 g, 2 mol) were heated at 95 °C for 24 h.
Extraction: AcOEt, ice/H2O. One obtained a crude brown oil
(194 g, yield 99%, GC purity 90%), which was used without
further purification in the next step: 1H NMR (250 MHz,
CDCl3) δ 1.44 (d, J ) 2 Hz, 3H), 1.59 (d, J ) 4.3, 1H), 1.76 (s,
3H), 1.75-2.18 (m, 5H), 2.51 (m, 1H), 3.66 (m, 1H), 4.55 (dt,
J HF ) 48 Hz, J 2 ) 6 Hz, 1H), 4.81 (m, 2H); 13C NMR δ 19.7,
21.3, 31.2, 31.3, 32.3, 33.0, 73.7, 94.8, 96.5, 110.0, 147.4; TSP/
MS m/z (%) 170 (10), 168(8), 155 (18), 152 (36), 107 (100), 71
(100).
Met h a n esu lfon ic Acid (1R,2S,3S,5R)-3-F lu or o-2-h y-
d r oxy-5-isop r op en yl-2-m eth ylcycloh exyl Ester (7a ). Diol
6a (194 g, 1.02 mol) was dissolved in CH2Cl2 (900 mL) and
cooled to 15 °C. Then pyridine (123 mL, 1.53 mol) and MsCl
(119 mL, 1.53 mol) were added while holding the temperature
between 15° and 25 °C and stirring continued for 40 h at 20
°C. Extraction: CH2Cl2, cold 1 N HCl, 10% NaCl. The crude
brown oil (280 g, yield 99%, GC purity 88%), which crystallized
spontaneously upon refrigeration, was used without further
purification in the next step, mp 82 °C: 1H NMR (250 MHz,
CDCl3) δ 1.43 (d, 3H, J ) 2 Hz), 1.77 (s, 3H), 1.80 (s, 1H),
1.83-2.25 (m, 4H), 2.59 (br, 1H), 3.08 (s, 3H), 4.46 (ddd, 1H,
J HF ) 48 Hz, J 2 ) 6 Hz, J 3 ) 4 Hz), 4.67 (dd, 1H), 4.86 (m,
2H); 13C NMR δ 20.3, 21.3, 31.0, 31.2, 31.8, 32.9, 38.6, 71.5,
71.8, 81.7, 92.4, 94.2, 110.8, 146.2; EI/MS m/z (%) 248 (2), 246
H, 7.61; F, 11.03. Found: C, 62.73; H, 7.54; F, 11.17. [R]20
) -101.4 (c 1.0, CHCl3).
D
Acetic Acid (1S,3R,5S,6S)-5-Fluoro-6-methyl-7-oxabicyclo-
[4.1.0]h ep t-3-yl Ester (10). Methyl ketone 9 (114 g, 0.66 mol)
was dissolved in CH2Cl2 (1.1 L) and stirred with m-CPBA (328
g, 1.33 mol, purity 70%) for 4 days at 20 °C yielding eventually
a suspension. GC analysis: 74% product, 14% starting mate-
rial. More m-CPBA (74 g, 0.3 mol) was added and stirring
continued for 2 days at 20 °C. GC analysis: 82% product, 4%
starting material. Extraction: CH2Cl2, cold 10% Na2S2O5, Na2-
CO3, 50% saturated NaCl. One obtained a yellow oil (106 g,
yield 94%, GC purity 95%): 1H NMR (250 MHz, CDCl3) δ 1.43
(d, J ) 2 Hz, 3H), 1.72-2.14 (m, 3H), 2.03 (s, 3H), 2.46-2.59
(m, 1H), 3.10 (d, J ) 15 Hz,1H), 4.93 (dt, 1H, J HF ) 48 Hz, J 2
) 2 Hz), 4.90-5.10 (m, 1H); 13C NMR δ 18.4, 21.1, 29.4, 31.0,
31.2, 56.3, 56.6, 58.4, 64.1, 89.8, 91.5, 170.3; EI/MS m/z (%)
145 (5), 128 (20), 82 (64), 43 (100). Anal. Calcd for C9H13FO3
(188.201): C, 57.44; H, 6.96; F, 10.10. Found: C, 57.44; H,
(2), 170 (100), 155 (60). Anal. Calcd for
C11H19FO4S
(266.334): C, 49.61; H, 7.19; S, 12.04; F, 7.13. Found: C,
49.53; H, 7.04; S, 11.95; F, 7.21. [R]20D ) -12.2 (c 0.5, CHCl3).
0.90; F, 9.85. [R]20 ) -85.4 (c 1.0, CHCl3).
D
Mixtu r e of (1S,2R,4R,6S)-6-F lu or o-4-isop r op en yl-1-m e-
th ylcycloh exan e-1,2-diol (6a) an d (1S,2R,4R,6S)-6-Ch lor o-
4-isop r op en yl-1-m et h ylcycloh exa n e-1,2-d iol (6b ). Ep-
oxide 5 (47.4 g, 0.28 mol) and NBu4H2F3 (180 g, 0.6 mol) were
(1S,3R,5S,6S)-5-F lu or o-6-m et h yl-7-oxa b icyclo[4.1.0]-
h ep ta n -3-ol (11). Acetate 10 (204 g, 1.08 mol) and K2CO3
(182 g, 1.32 mol) were stirred in MeOH (1.1 L) at 20 °C for
2.5 h. Extraction: AcOEt, 1:1 saturated NaCl/ice, attention:

6988 J . Org. Chem., Vol. 63, No. 20, 1998
Barbier et al.
product is water-soluble). Chromatography of the crude
product (151 g) in 2:1 hexane/AcOEt afforded a purified oil
(129 g) which was suspended in hexane (500 mL), cooled, and
seeded. One obtained white crystals (109 g, yield 79%, GC
purity 99%), mp 53 °C: 1H NMR (250 MHz, CDCl3) δ 1.43 (d,
3H, J ) 2 Hz), 1.77 (d, J ) 6.8 Hz, 1H), 1.86-2.10 (m, 3H),
2.26-2.40 (m, 1H), 2.27-2.38 (m, 1H), 3.14 (d, J ) 5.2 Hz,
1H), 4.00 (sx, 1H), 4.91 (dt, 1H, J HF ) 48 Hz, J 2 ) 4 Hz); 13C
NMR δ 18.4, 32.6, 34.9, 35.1, 57.1, 57.4, 59.4, 62.0, 89.5, 91.2;
EI/MS m/z (%) 146 (5), 129 (5), 102 (30), 76 (56), 43 (100). Anal.
Calcd for C7H11FO2 (146.163): C, 57.52; H, 7.59; F, 13.00.
a solution of phenylselanyl acetic acid (86 g, 0.4 mol) in MeOH
(200 mL) by addition over 30 min. Stirring at 20 °C was
continued for 1 h. The reaction mixture was evaporated and
the residue redissolved in MeOH (200 mL) and i-PrOH (1.6
L) at 60 °C. The hot solution was filtered and concentrated
to ca. 500 mL. Crystallization was allowed to proceed first at
20 °C and then in ice. One obtained white, nonhygroscopic
crystals in two fractions (111 g + 10 g, 87%), mp > 240 °C.
[(4R,6S)-P h en ylsela n yl]a cet ic Acid [4-((ter t-Bu t yld i-
m eth ylsila n yl)oxy)-6-flu or ocycloh ex-1-en yl]m eth yl Es-
ter (15). Allylic alcohol 13 (47 g, 0.18 mol) was dissolved
under argon in CH2Cl2 (470 mL) and cooled to -70 °C. Then
N-ethyldiisopropylamine (39.4 mL, 0.23 mol) was added, and
finally a solution of MsCl (17 mL, 0.22 mol) in CH2Cl2 (10 mL)
was added slowly over 20 min at -70 °C. The mixture was
allowed to warm, stirring at 20 °C was continued for 3 h, and
then the mixture was poured on ice/water and extracted: Et2O,
1 M citric acid, saturated NaCl. The resulting labile mesylate
14 was dissolved under argon in DMF (600 mL) and treated
with cesium phenylselanyl acetate (76 g, 0.22 mol) and a
catalytic amount of Bu4NI (11 g, 30 mmol) at 50 °C for 15 h.
The reaction mixture was poured on ice/water and extracted:
Et2O, H2O, saturated NaCl. Chromatography of the crude oil
(74 g) in 95:5 to 9:1 hexane/AcOEt gave a yellow oil (25.8 g,
yield 32%, GC purity 95%): 1H NMR (250 MHz, CDCl3) δ 0.07
(s, 3H), 0.08 (s, 3H), 0.89 (s, 9H), 1.45-2.45 (m, 4H), 3.53 (s,
2H), 4.02 (br, 1H), 4.60 (br, 2H), 4.93 (dt, 1H, J HF ) 48 Hz, J 2
) 4 Hz), 5.88 (br, 1H), 7.27 (m, 3H), 7.5 (m, 2H); 13C NMR δ
-4.74, -4.72, 18.1, 25.8, 27.4, 35.1, 38.3, 38.5, 63.8, 65.5, 85.7,
87.3, 127.9, 129.1, 129.2, 130.3, 130.5, 131.4, 131.5, 133.4,
133.5, 170.6; EI/MS m/z (%) 438.5 (3), 401 (20), 273 (100), 271
(50), 111 (95).
Found: C, 57.40; H, 7.45; F, 12.82. [R]20 ) -52.7 (c 1.0,
D
CHCl3).
(1S,3R,5S,6S)-ter t-Bu tyl((5-flu or o-6-m eth yl-7-oxabicyclo-
[4.1.0]h ep t-3-yl)oxy)d im eth ylsila n e (12). Alcohol 11 (42 g,
0.287 mol) and imidazole (45 g, 0.66 mol) were dissolved under
argon in DMF (60 mL) and treated in portions with (TBDMS)-
Cl (46 g, 0.31 mol). The reaction mixture was stirred for 16 h
at 20 °C. Extraction: Et2O, cold 3 N HCl, 50% saturated NaCl.
The crude oil (72 g, 91% yield, GC purity 94%) was used
without further purification: 1H NMR (250 MHz, CDCl3) δ
-0.01 (s, 6H), 0.82 (s, 9H), 1.34 (d, 3H, J ) 2 Hz), 1.5-1.9 (m,
3H), 2.14-2.29 (m, 1H), 3.00 (d, J ) 5.2, 1H), 3.90 (m, 1H),
4.83 (dt, 1H, J HF ) 48 Hz, J 2 ) 4 Hz);13C NMR δ -4.8, -4.7,
18.0, 18.5, 25.8, 33.6, 35.1, 35.3, 56.1, 56.4, 59.0, 61.8, 91.0,
92.6; EI/MS m/z (%) 203 (40), 183 (6), 161 (50), 129 (100). Anal.
Calcd for C13H25FO2Si (260.427): C, 59.96; H, 9.68; F, 7.30.
Found: C, 59.68; H, 9.67; F, 7.48. [R]20 ) -49.2 (c 0.5,
D
CHCl3).
(1S,3S,5R)-5-((ter t-Bu tyld im eth ylsila n yl)oxy)-3-flu or o-
2-m eth ylen ecycloh exa n ol (13). Meth od A. N-Cyclohexy-
lisopropylamine (134.5 mL, 0.8 mol) was dissolved in THF (1
L) under argon and cooled to -70 °C. Then a 1.6 M solution
of n-BuLi in hexane (500 mL, 0.8 mol) was added dropwise
and stirring continued for 15 min at -70 °C. Then a 2.8 M
solution of ethylmagnesium chloride in THF (286 mL, 0.8 mol)
was added dropwise and stirring continued for 15 min at -70
°C. Finally a solution of epoxide 12 (52 g, 0.2 mol) in THF
(100 mL) was added at -70 °C, the temperature was allowed
to rise to 20 °C, and stirring was continued for 5 h at 20 °C.
The reaction mixture was poured on ice/3 N HCl and extracted
twice with AcOEt. Chromatography of the crude oil (55 g) in
5:1 hexane/AcOEt gave a yellow oil (27.5 g, 53%).
(1′RS,2RS,3′S,5′R)-[5′-((ter t-Bu tyld im eth ylsila n yl)oxy)-
3′-flu o r o -2′-m e t h y le n e c y c lo h e x y l](p h e n y ls e la n y l)-
a cetic Acid Meth yl Ester (16a-d ). Ester 15 (28 g, 61 mmol)
was dissolved under argon in CH2Cl2 (280 mL), molecular
sieves (0.4 nm) were added, and the mixture was cooled in
ice. Finally, N-ethyldiisopropylamine (51 mL, 0.3 mol) and a
solution of fresh TBDMSOTf (28 mL, 0.12 mol) in CH2Cl2 (20
mL) was added slowly over 20 min at 5 °C. The reaction
mixture was stirred at 20 °C for 15 h. The resulting solution
was poured on 1 M citric acid/ice and extracted: CH2Cl2, ice
water. The resulting residue was dissolved in THF (600 mL),
cooled to 10 °C, and treated with 1 N NaOH (160 mL) for 3 h
at 20 °C. The resulting solution was poured on 1 M citric acid/
ice and extracted: AcOEt, ice/water, saturated NaCl. The
resulting residue was dissolved under argon in CH2Cl2 (300
mL), 4-DMAP (36.6 g, 0.3 mol), DCC (25.1 g, 0.12 mol), and
MeOH (15 mL) were added, and stirring was continued for 15
h at 20 °C. The resulting solution was poured on 1 M citric
acid/ice and extracted: CH2Cl2, ice water, saturated NaCl.
Chromatography in 20:1 to 9:1 hexane/AcOEt gave a partially
purified yellow oil (17.2 g, yield 44%, GC purity 70%): 1H NMR
(250 MHz, CDCl3) δ 0.09 (s, 3H), 0.11(s, 3H), 0.90 (s, 9H), 1.00-
2.30 (m, 6H), 2.80-3.00 (m, 1H), 3.54 (s, 3H), 3.88 and 3.96
(d, J ) 12, 1H), 4.21 (br, 1H), 4.7-5.3 (m, 3H), 5.88 (br, 1H),
7.28 (m, 3H), 7.58 (m, 2H); EI/MS m/z (%) 472 (3), 415 (95),
73 (100).
Meth od B. This was analogous to method A, using 2,2,6,6-
tetramethylpiperidine instead of N-cyclohexylisopropylamine,
yield 72% and GC purity 95%. Compound 13 should be stored
in the freezer because of limited stability: 1H NMR (250 MHz,
CDCl3) δ 0.115 (s, 3H), 0.120 (s, 3H), 0.90 (s, 9H), 1.78-2.22
(m, 4H), 3.27 (d, J ) 8, 1H), 4.34 (br, 1H), 4.43 (br, 1H), 5.13
(s, 2H), 5.45 (dq, 1H, J HF ) 48 Hz, J 2 ) 4 Hz); 13C NMR δ
-5.0, -4.7, 17.9, 25.7, 41.5, 41.6, 68.4, 71.7, 88.6, 90.3, 109.0,
147.9; EI/MS m/z (%) 243 (3), 203 (40), 185 (45) 183 (75), 165
(34), 111 (100). Anal. Calcd for C13H25FO2Si (260.427): C,
59.96; H, 9.68; F, 7.3. Found: C, 59.90; H, 9.69; F, 7.1. [R]20
) +48.6 (c 0.8, CHCl3).
D
P h en ylsela n yl Acetic Acid .23 Diphenyl diselenide (90 g,
0.288 mol) was dissolved in EtOH (900 mL) by heating at 50
°C and then cooled again to 25 °C. Sodium hydroxymethyl
sulfoxylate (46.7 g, 0.3 mol) was added, and the resulting
suspension was treated with a solution of NaOH (31 g, 0.78
mol) in H2O (300 mL) over 20 min. The mixture was heated
at 50 °C for 15 min, and then a solution of bromoacetic acid
(80.5 g, 0.58 mol) in EtOH (300 mL) was added dropwise over
20 min and stirring at 50 °C was continued for 20 h. After
cooling, a saturated solution of NaHCO3 was added dropwise.
The resulting mixture was poured on ice and extracted with
toluene. The aqueous layer was washed with toluene, acidified
to pH 2 with 25% HCl, and extracted twice with toluene. The
toluene layers were washed with water and brine. One
obtained a yellow oil (86 g, 69%), which crystallized upon
refrigeration. Anal. Calcd for C8H8O2Se (215.112): C, 27.69;
H, 2.03. Found: C, 27.42; H, 2.19.
(E,3S,5R)-[5-((ter t-Bu tyld im eth ylsila n yl)oxy)-3-flu or o-
2-m eth ylen ecycloh exylid en e]a cetic Acid Meth yl Ester
(E-17) a n d (Z,3S,5R)-[5-((ter t-Bu tyld im eth ylsila n yl)oxy)-
3-flu or o-2-m eth ylen ecycloh exylid en e]a cetic Acid Meth -
yl Ester (Z-17). Diastereomeric mixture 16a -d (10 g, 21.2
mmol) was dissolved in THF (150 mL) and cooled in ice. Then
a solution of NaIO4 (13.5 g, 63.6 mmol) in 1:1 MeOH/H2O (120
mL) was added dropwise keeping the temperature below 15
°C. Stirring at 20 °C was continued overnight. The reaction
mixture was filtered and the filtrate diluted with water and
then extracted: Et2O, saturated NaCl. Chromatography of the
crude product (6 g) in 8:1 hexane/ethyl acetate eluted first E-17
(2.1 g, 44%) and then Z-17 (2 g, 43%), both as colorless oils.
The former was apparently less stable on the shelf. E-17: 1H
NMR (250 MHz, CDCl3) δ 0.08 (s, 3H), 0.81 (s, 3H), 0.88 (s,
9H), 1.60-2.30 (m, 3H), 2.98 (dd, J 1 ) 8 Hz, J 2 ) 14 Hz, 1H),
Cesiu m P h en ylsela n yl Aceta te.24 Cesium carbonate (65
g, 0.2 mol) was suspended in MeOH (200 mL) and mixed with

1-R-Fluoro-25-hydroxy-vitamin D3 Analogues
J . Org. Chem., Vol. 63, No. 20, 1998 6989
3.14 (dd, J 1 ) 4 Hz, J 2 ) 14 Hz, 1H), 3.71 (s, 3H), 4.24 (sept,
1H), 5.19 (s, 1H), 5.24 (dt, J HF ) 48 Hz, J 2 ) 6 Hz, 1H), 5.99
(m, 1H); 13C NMR δ -4.66, -4.55, 18.4, 26.2, 37.8, 40.8, 41.0,
51.5, 66.8, 90.4, 92.1, 114.0, 117.5, 147.0, 147.2, 155.0, 167.0;
EI/MS m/z (%) 299 (2), 283 (3), 257 (100), 151 (30), 89 (45);
(314.47): C, 61.11; H, 8.65; F, 6.04. Found: C, 61.00; H, 8.78;
F, 6.03. [R]20 ) +15.4 (c 0.4, CHCl3).
D
Ack n ow led gm en t. We are indebted to our safety
laboratory (Dr. Panter) and to our analytical services
(NMR, MS, elemental analysis), especially to Dr. W.
Arnold for elucidating NMR data of the fluorinated
intermediates. We are especially thankful to Willy
Glettig for his collaboration in setting up advanced
chromatographic systems. Skillful technical assistance
byNadine Nock and GuyWassner is greatlyacknowledged.
[R]20 ) +15.3 (c 0.4, CHCl3). Z-17: 1H NMR (250 MHz,
D
CDCl3) δ 0.08 (s, 3H), 0.81 (s, 3H), 0.88 (s, 9H), 1.84-2.24 (m,
3H), 2.30 (dd, J 1 ) 8 Hz, J 2 ) 12 Hz, 1H), 2.51 (dd, J 1 ) 4 Hz,
J 2 ) 12 Hz, 1H), 3.68 (s, 3H), 4.22 (sept, 1H), 5.22 (dm, J 1
)
48 Hz, 1H), 5.27 (s, 1H), 5.37 (m, 1H); 13C NMR δ -4.84, -4.80,
18.0, 25.7, 41.4, 41.6, 46.1, 51.2, 67.0, 90.8, 92.5, 115.5, 118.6,
142.0, 142.2, 150.9, 166.1; EI/MS m/z (%) 314 (M+, 3), 299 (2),
257 (100), 151 (65), 89(88). Anal. Calcd for C16H27FO3Si
J O980764L