Synthesis of γ-monofluorinated goniothalamin analogues via regio- and stereoselective ring-opening hydrofluorination of epoxide

Article abstract of DOI:10.1021/jo200611w

A stereoselective synthesis of the biologically interesting γ-monofluorinated goniothalamin analogue 2a was described. The features of the synthesis included regioselective reduction of the unprotected hydroxypropynyl moiety of compound 10 by Red-Al, asymmetric Sharpless epoxidation of allyl alcohol 11, and regio- and stereoselective ring-opening hydrofluorination of the hydroxypropynyl epoxide 14 with Et₃N? 3HF in high ee and dr. The chiral hydroxypropynyl fluorohydrin 15 was used as a valuable building block for preparation of a range of γ-monofluorinated α,β-unsaturated δ-lactones.

Full text of DOI:10.1021/jo200611w

ARTICLE
pubs.acs.org/joc
Synthesis of γ-Monofluorinated Goniothalamin Analogues via Regio-
and Stereoselective Ring-Opening Hydrofluorination of Epoxide
Jun-Ling Chen,† Feng Zheng,‡ Yangen Huang,† and Feng-Ling Qing*,†,‡
†College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620,
China
‡Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Lu,
Shanghai 200032, China
S Supporting Information
b
ABSTRACT: A stereoselective synthesis of the biologically
interesting γ-monofluorinated goniothalamin analogue 2a was
described. The features of the synthesis included regioselective
reduction of the unprotected hydroxypropynyl moiety of
compound 10 by Red-Al, asymmetric Sharpless epoxidation
of allyl alcohol 11, and regio- and stereoselective ring-opening
hydrofluorination of the hydroxypropynyl epoxide 14 with Et3N 3HF in high ee and dr. The chiral hydroxypropynyl fluorohydrin
3
15 was used as a valuable building block for preparation of a range of γ-monofluorinated R,β-unsaturated δ-lactones.
’ INTRODUCTION
Natural products possessing an R,β-unsaturated δ-lactone
moiety usually display interesting biological activities, such as
insect growth inhibition, antitumor, antibacterial, antifungal, and
immunosuppressive properties.1 The R,β-unsaturated δ-lactone
unit is presumed to serve as the pharmacophore and be respon-
sible for biological activities as a result of its ability to act as a
Michael acceptor.1d,f,h,2 In pharmaceutical research, fluorine has
been considered as a suitable bioisostere for hydrogen on steric
grounds.3 Quite often, fluorine is introduced to improve meta-
bolic stability4 and modulate physicochemical properties, such as
lipophilicity or basicity,3,5 because of its electronegative proper-
ties and the chemical inertness of the CÀF bond. With a long-
term interest in development of efficient methodologies for
Figure 1. Rationale for the design of the target molecule 2a.
introduction of the fluorine atom into organic molecules and
synthesis of fluorinated biologically interesting compounds, we
chiral γ-monofluorinated R,β-unsaturated δ-lactone are rather
intended to introduce the fluorine atom(s) into the γ-position of
scarce, although the synthesis of propargylic fluorides from the
R,β-unsaturated δ-lactone. Such modification could make the
dehydroxyfluorination reactions of propargylic alcohols with
double bond more electron deficient and lead to a better Michael
diethylaminosulfur trifluoride (DAST) has been thoroughly
acceptor with minimum steric change. Recently, an efficient and
investigated by Renꢀe Grꢀee and co-workers.7,8 Furthermore, the
general strategy to construct γ-difluoromethylenated R,β-unsa-
hydroxypropenyl fluorohydrin and its precursor, hydroxypropy-
turated δ-lactones from various aldehydes has been developed in
nyl fluorohydrin, are valuable building blocks, by which a wide
our group, which was successfully applied to the synthesis of two
library of chiral fluorinated compounds could be accessed via
enantiomers of gem-difluoromethylenated goniothalamin.6 To
simple functional group manipulations.9
study the effect of fluorine substituents on bioactivities of R,β-
unsaturated δ-lactone containing compounds, besides γ-difluori-
’ RESULTS AND DISCUSSION
nated derivatives, the γ-monofluorinated counterparts are an-
other important class to be evaluated (Figure 1). Herein, we
report a novel route for the enantio- and diastereoselective
synthesis of hydroxypropynyl fluorohydrin, from which a range
of chiral γ-monofluorinated R,β-unsaturated δ-lactones was
prepared. It should be noteworthy that synthetic approaches to
Our synthetic strategy for the synthesis of γ-monofluorinated
goniothalamin 2a was outlined in Scheme 1. We envisioned that the
Received: March 22, 2011
Published: July 08, 2011
r
2011 American Chemical Society
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|

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ARTICLE
Scheme 1
Scheme 2
styryl moiety would be installed via a HornerÀWadsworthÀ
Emmons (HWE) reaction, and the key lactone could be
constructed by oxidative ring closure of monofluorodiol 3
which in turn would be obtained from propargyl alcohol 4
through partial hydrogenation. The two stereocenters of com-
pound 4 could be established via regio- and stereoselective ring-
opening hydrofluorination of enantiopure epoxide 5. The
enantiopure expoxide 5 could be prepared by Sharpless asym-
metric epoxidation of allyl alcohol 6.
Silyl ether 8 and 3-iodoprop-2-yn-1-ol 9 were straightfor-
wardly prepared from commercially available propargyl alcohol 7
via TBS protection and iodination,10 respectively (Scheme 2).
The Sonogashira cross-coupling of compounds 8 and 9 afforded
intermediate 10 in 69% yield. Regioselective reduction of the
unprotected hydroxypropynyl moiety of 10 by Red-Al provided
allyl alcohol 11 in 88% yield, which was then subjected to the
Sharpless asymmetric epoxidation to afford the corresponding
epoxide 12 in 84% yield. The primary hydroxyl group of 12 was
then protected with the benzyl group to afford silyl ether 13 in
90% yield. Treatment of compound 13 with tetrabutylammo-
nium fluoride (TBAF) gave the precursor of ring-opening
hydrofluorination 14 in 96% yield with 92% ee.
With epoxide 14 in hand, we then turned our attention to the
key step for the construction of fluorohydrin 15 via ring-opening
hydrofluorination of 14 with different nucleophilic fluorinating
reagents.11,12 The optimization of the reaction of epoxide 14 with
fluoride sources was summarized in Table 1. Reaction 14 with
bifluoride (KHF2) in the presence of 18-crown-6 in DMF failed
to generate any of the desired fluoride adduct (Table 1, entry 1).
Table 1. Preparation of the Hydroxypropynyl Fluorohydrin
15 via Ring-Opening Hydrofluorination of 14
entry
reaction conditions
solvent
yield (%)
a
1
2
3
4
5
KHF2, 18-Crown-6, 100 °C
DMF
CH2Cl2
CH2Cl2
---
À
HF Py, 0 °C
tracea
3
a
BF3 Et2O, À35 °C
À
3
n-Bu4NF 2HF, 95 °C
30%b
54%b
3
Et3N 3HF, 70 °C
---
3
a Determined by 19F NMR. b Isolated yield.
Unfortunately, cleavage of the benzyl ether protecting group in
lactone 17 using DDQ, BCl3, or TiCl4 failed to give alcohol 18,
probably due to the decomposition of the unsaturated lactone
structure under these reaction conditions.
With Olah’s reagent Py HF as the fluorine source, only trace of
3
product 15 was detected by 19F NMR (entry 2). Treatment of 14
with BF3 Et2O resulted in complex reaction (entry 3). The
It was decided to introduce the styryl moiety prior to the
construction of the lactone ring. Protection of diol 15 with
TBSOTf afforded silyl diether 19 which was subjected to partial
hydrogenation, giving (Z)-silyl diether 20 in 95% yield
(Scheme 4). However, as shown in Table 2, the debenzylation
reactions of 20 with different deprotecting reagents resulted in
complex reaction or low yield of alcohol 21 due to the desilyla-
tion of the primary silyl ether and the subsequent side reactions
under these reaction conditions.
3
fluorohydrin 15 was obtained in 30% yield when n-Bu4NF 2HF
3
was used as the fluorine source (entry 4). To our delight, the ring-
opening hydrofluorination of 14 with more nucleophlic Et3N 3
3
HF gave fluorohydrin 15 in 54% yield as a single product (entry
5). This complete regio- and stereocontrol reaction was consis-
tent with a mechanism involving a stereoselective SN2-type
epoxide ring-opening process. The fluoride attacked the epoxide
14 at the C4 carbon with the inversion of the stereochemistry to
give 4-fluoro-2-ol regioselectively owing to the higher density of
positive charge at C4 carbon caused by the electron-withdrawing
property of the adjacent hydroxypropynyl group.
As the TBDPS-ether was much more stable than the TBS-
ether, protection of the primary hydroxyl of compound 15 as
TBDPS-ether and followed by silylation of the secondary hydro-
xyl group with TBSOTf afforded compound 22 in 89% yield
(Scheme 5). Fortunately, removal of the benzyl group in 22 with
DDQ delivered the desired alcohol 23 in 83% yield. Oxidation of
Partial hydrogenation of the fluorohydrin 15 with Pd/
BaSO4 proceeded smoothly to afford (Z)-1,5-diol 16 in 80%
yield (Scheme 3). Oxidative cyclization of 16 with 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) and bisacetoxyiodo-
benzene (BAIB)13 gave the desired lactone 17 in 97% yield.
alcohol 23 with SO3 Py14 gave aldehyde 24 in 90% yield. The
3
HWE reaction of 24 with diethylbenzylphosphonate gave the
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ARTICLE
Scheme 3
Scheme 4
Table 2. Attempts at Removal of the Benzyl Group of 21
entry
reagent
temp. (°C) solvent
results
1
2
3
4
5
6
TiCl4
BCl3
0
À78
40
DCM
DCM
DCM/H2O 40%a
complex
complex
Figure 2. ORTEP drawing of the X-ray crystallographic structure of 2a.
DDQ
unambiguously confirmed the relative anti-configuration of the
fluorine atom and the hydroxyl group of compound 15. The
absolute configuration was established by the known enantios-
electivity of the Sharpless epoxidation.
The utility of the fluorinated building block 24 was demon-
strated by the further synthesis of a range of γ-monofluorinated
R,β-unsaturated δ-lactones. Carbon extension of the molecular
skeleton of aldehyde 24 via HWE olefination with diethyl (4-
methoxyphenyl)- and (4-fluorophenyl)-methylphosphonate
gave (2Z,6E)-diene 25b and 25c in high stereoselectivity,
respectively. Removal of the silyl groups followed by oxidative
ring closure afforded the corresponding p-substituted phenyl
Li, naphthaline
À78
65
THF
complex
HCOONH4, Pd/C
MeOH
EtOH
complex
complex
1-methyl-1,4-cyclohexadiene, Pd/C
a Isolated yield of alcohol 21.
55
(2Z,6E)-diene 25a as the major product (C6, E:Z = 98:2).
Treatment of diene 25a with TBAF gave diol 26a. Finally,
oxidation of 26a with TEMPO and BAIB afforded the γ-mono-
fluorinated goniothalamin analogue 2a.
The relative configuration of product 2a was determined by
single-crystal X-ray diffraction analysis (Figure 2), which
Scheme 5
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ARTICLE
Table 3. Syntheses of γ-Monofluorinated r,β-Unsaturated δ-Lactones 2bÀd
γ-monofluorinated goniothalamin analogues 2b and 2c (Table 3),
respectively. Moreover, γ-monofluorinated (6Z,2Z)-lactone 2d,
an analogue of natural product (À)-argentilactone that exhibited
both antiprotozoal15 and cytotoxic activity,16 was also prepared
through a similar process as described above. The Z geometry of
the double bond in the heptenyl moiety of 2d was readily
constructed via the Wittig olefination (Z:E = 92:8).
g, 69%) as a red liquid: 1H NMR (400 MHz, CDCl3) δ 4.38 (s, 2H), 4.34
(s, 2H), 1.75 (br, 1H), 0.90 (s, 9H), 0.12 (s, 6H).
(E)-6-(tert-Butyldimethylsilyloxy)hex-2-en-4-yn-1-ol (11).17
To 6-(tert-butyldimethylsilyl)oxy-2,4-hexadiyn-1-ol 10 (19.80 g, 88.39
mmol) in THF (250 mL) was slowly added Red-Al (3.4 M in toluene,
39 mL, 132.60 mmol) at À78 °C over 30 min. The temperature was slowly
warmed to 0 °C, and the mixture was stirred for another 1.5 h. The reaction
was quenched at 0 °C with H2O (133 mL). Then 10% (m/V) NaOH in
water (133 mL) was added, and the mixture was stirred vigorously and then
filtered. The layers were separated, and the aqueous phase was extracted
twice with ethyl acetate. The combined organic layers were dried over
Na2SO4. The residue was purified by column chromatography on silica gel
(petroleumether:ethyl acetate = 10:1) to givealcohol11 (17.60 g, 88%) as
a colorless oil: 1H NMR (400 MHz, CDCl3) δ 6.24 (dt, J = 16.0, 5.2 Hz,
1H), 5.77 (d, J = 15.9 Hz, 1H), 4.43 (s, 2H), 4.22 (d, J = 5.1 Hz, 2H), 1.59
(br, 1H), 0.91 (s, 9H), 0.13 (s, 6H).
’ CONCLUSION
In conclusion, we have designed and synthesized a new range
of γ-monofluorinated R,β-unsaturated δ-lactones, including the
analogues of naturally occurring goniothalamin and argentilac-
tone. Our synthesis is highlighted by the construction of the
chiral hydroxypropynyl fluorohydrin in high efficiency via asym-
metric Sharpless epoxidation and regio- and stereoselective ring-
opening hydrofluorination of the derived epoxy.
((2S,3S)-3-(3-(tert-Butyldimethylsilyloxy)prop-1-ynyl)oxiran-
2-yl)methanol (12). To anhydrous CH2Cl2 (200 mL) were added
sequentially powdered 4 Å molecular sieves (8 g), L-(+)-diethyl tartrate
(3.90 g, 18.53 mmol), and Ti(OiPr)4 (4.66 mL, 15.44 mmol) at À20 °C.
The resultant mixture was stirred for 20 min at À20 °C, and a solution of 11
(17.45 g, 77.21 mmol) in CH2Cl2 (60 mL) was added over a period of
15 min. The reaction mixture was allowed to stir at À20 °C for another
30 min before addition of tert-butylhydroperoxide (35 mL, 4.5 M). The
resultant reaction mixture was stirred at À20 °C for an additional 18 h, and
’ EXPERIMENTAL SECTION
6-(tert-Butyldimethylsilyloxy)hexa-2,4-diyn-1-ol (10).17
CuCl (2.47 g, 25.0 mmol) was dissolved in a mixture of 233 mL of
H2O and 100 mL of n-butylamine. Then, tert-butyldimethyl(prop-2-
ynyloxy)silane 8 (21.25 g, 125.0 mmol) was added at 0 °C, followed by
the dropwise addition of 3-iodoprop-2-yn-1-ol 9 (15.17 g, 83.4 mmol).
then a solution of L-tartaric acid (8.8 g, 60.0 mmol) and FeSO4 7H2O (23.0
3
Whenever the reaction mixture turned to green, a few crystals of NH2OH
g, 82.7 mmol) in H2O (400 mL) was added. The resultant mixture was
stirred vigorously at room temperature for 1 h. The layers were separated,
and the aqueous layer was further extracted with CH2Cl2 (3Â 100 mL). The
combined organic layers were dried over anhydrous Na2SO4 and concen-
trated. Purification of the residue by flash column chromatography (silica gel,
3
HCl were added. After stirring for 20 min at 0 °C and for another 30 min at
room temperature, the reaction mixture was filtered through a pad of silica
gel. After aqueous workup, the crude product was purified by column
chromatography (petroleum ether:ethyl acetate = 15:1) to give 10 (12.88
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ARTICLE
petroleum ether:ethyl acetate = 7:1) afforded the epoxy 12 (15.70 g, 84%) as
(d, J= 25.9 Hz), 73.4, 71.4 (d, J= 23.8 Hz), 69.4, 50.3; 19F NMR (400 MHz,
CDCl3) δ À183.4 to À183.5 (m, 1F); IR (thin film) vmax 3399, 3060,
3031, 2922, 2868, 2230, 1636, 1450, 1362, 1216, 1106 cmÀ1; MS (ESI)
m/z 256.0 [M + NH4]+, 261.0 [M + Na]+; HRMS (ESI) m/z [M + Na]+
calcd for C13H15FNaO3, 261.0903; found, 261.0908.
26.7
1
a pale yellow oil: [R]D +25.3 (c 1.00, CHCl3); H NMR (400 MHz,
CDCl3) δ 4.32 (d, J = 1.4 Hz, 2H), 3.94 (dd, J = 13.0, 1.7 Hz, 1H), 3.70 (d,
J = 12.8 Hz, 1H), 3.47 (d, J = 1.6 Hz, 1H), 3.31À3.28 (m, 1H), 1.88 (s, 1H),
0.89 (s, 9H), 0.10 (s, 6H); 13C NMR (100.6 MHz, CDCl3) δ 83.1, 80.6,
60.2, 59.8, 51.7, 42.6, 25.8, 18.3, À5.2; IR (thin film) vmax 3446, 2940, 2860,
2239, 1640, 1256, 1086, 840 cmÀ1; MS (ESI) m/z 260.1 [M + NH4]+. Anal.
Calcd for C12H22O3Si: C, 59.46; H, 9.15. Found: C, 59.31, H, 9.35.
(3-((2S,3S)-3-((Benzyloxy)methyl)oxiran-2-yl)prop-2-ynyl-
oxy)(tert-butyl)dimethyl-silane (13). To a suspension of sodium
hydride (80% in oil, 2.55 g, 85.00 mmol) in anhydrous THF (150 mL)
was added a solution of 12 (13.69 g, 56.57 mmol) in THF (150 mL) for
20 min at À40 °C. Benzyl bromide (10.0 mL, 84.21 mmol) and
tetrabutylammonium iodide (1.08 g, 2.87 mmol) were then added
sequentially, and the resulting mixture was stirred at 25 °C under
nitrogen for another 2 h. Water (100 mL) was added, and the mixture
was extracted with ethyl acetate (3 Â 100 mL). The combined organic
layers were dried over anhydrous Na2SO4 and concentrated. The residue
was purified by flash chromatography on silica gel (petroleum ether:ethyl
(Z,4R,5S)-6-(Benzyloxy)-4-fluorohex-2-ene-1,5-diol (16).
To a solution of diol 15 (940 mg, 3.95 mmol) in n-hexane (24 mL)
and acetone (16 mL) were added quinoline (332 mg) and Pd/BaSO4
(166 mg) and stirred under a hydrogen atmosphere at room tempera-
ture for 1 h. The reaction mixture was filtered, evaporated, and purified
by column chromatography (petroleum ether:ethyl acetate = 16:9) to
25.2
afford 16 (758 mg) in 80% yield as a pale yellow syrup: [R]D À57.5 (c
1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.38À7.28 (m, 5H), 5.99
(dtdd, J = 7.9, 6.6, 2.2, 1.1 Hz, 1H), 5.72À5.63 (m, 1H), 5.30 (dt, J =
46.6, 7.2 Hz, 1H), 4.57 (s, 2H), 4.17 (dd, J = 11.9, 8.1 Hz, 2H),
3.91À3.84 (m, 1H), 3.67 (ABdd, J = 9.8, 3.9, 2.1 Hz, 1H), 3.59 (ABdd, J
= 9.8, 6.3, 1.9 Hz, 1H), 2.74 (s, 1H), 2.16 (s, 1H); 13C NMR (100.6
MHz, CDCl3) δ 137.6, 135.0 (d, J = 10.3 Hz), 128.5, 127.9, 127.8, 126.8
(d, J = 21.6 Hz), 88.1 (d, J = 166 Hz), 73.6, 71.1 (d, J = 26.4 Hz), 70.3 (d,
J = 4.5 Hz), 58.4; 19F NMR (400 MHz, CDCl3) δ À184.5 to À184.7 (m,
1F); IR (thin film) vmax 3401, 3041, 3027, 2919, 2869, 1629, 1453, 1415,
1365, 1210, 1026 cmÀ1; MS (ESI) m/z 258.1 [M + NH4]+, 263.2 [M +
Na]+; HRMS (ESI) m/z [M + Na]+ calcd for C13H17FNaO3, 263.1060;
found, 263.1053.
26.7
acetate = 60:1) to afford 13 (16.94 g, 90%) as a colorless liquid: [R]D
À30.2 (c 3.53, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.38À7.26 (m,
5H), 4.56 (s, 2H), 4.33 (d, J = 1.5 Hz, 2H), 3.73 (ABd, J = 11.7, 3.0 Hz,
1H), 3.54 (ABd, J = 11.8, 4.7 Hz, 1H), 3.37 (dd, J = 3.4, 1.4 Hz, 1H), 3.33
(ddd, J = 5.1, 3.0, 2.2 Hz, 1H), 0.91 (s, 9H), 0.12 (s, 6H); 13C NMR
(100.6 MHz, CDCl3) δ 137.6, 128.4, 127.8, 127.7, 82.8, 80.8, 73.4, 68.7,
58.6, 51.6, 42.8, 25.8, 18.2, À5.2; IR (thin film) vmax 3450, 3068, 3023,
2939, 2859, 1640, 1461, 1368, 1255, 1091 cmÀ1; MS (ESI) m/z 350.1
[M + NH4]+. HRMS (ESI) m/z [M + Na]+ calcd for C19H28NaO3Si,
355.1706; found, 355.1710.
(5R,6S)-6-((Benzyloxy)methyl)-5-fluoro-5,6-dihydropyran-
2-one (17). To a solutionof 16 (160mg, 0.67 mmol) inCH2Cl2 (6 mL)
was added bisacetoxyiodobenzene (657 mg, 2.0 mmol) and 2,2,6,6-
tetramethyl-1-piperidinyloxy (21 mg, 20 mol %) at room temperature.
After stirring for 2 h, the reaction mixture was quenched with a saturated
solution of Na2S2O3 (30 mL) and extracted with CH2Cl2 (30 mL). The
combined organic extracts were washed with saturated solutions of
NaHCO3 (30 mL), NH4Cl (30 mL), and brine (30 mL) in turn, dried
over anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by flash chromatography on silica gel (petroleum ether:ethyl
3-((2S,3S)-3-((Benzyloxy)methyl)oxiran-2-yl)prop-2-yn-1-
ol (14). A solution of TBAF in THF (1 M, 55.0 mL) was added to a
solution of 13 (16.90 g, 50.90 mmol) in THF (250 mL) at À5 °C. After
stirring for 20 min, the reaction mixture was quenched with saturated
NH4Cl solution and extracted with ethyl acetate (3 Â 100 mL). The
combined organic extracts were concentrated and purified by flash
chromatography on silica gel (petroleum ether:ethyl acetate = 5:2) to
afford 4 (10.65 g, 96%, 92% ee) as a colorless oil: Chiral HPLC
(Phenomenex Lux 5 μ CelluloseÀ2,2-propanol:hexane = 1:9, 250 Â
4.6 mm, 214 nm, 0.7 mL/min), tR = 39.78 min (minor), tR = 42.83 min
21.9
acetate= 10:1) toafford 17(152mg, 97%) as a yellowoil:[R]D À37.7
(c 1.0, CHCl3); 1H NMR(400 MHz, CDCl3) δ 7.38À7.27 (m, 5H), 6.89
(td, J = 9.9, 2.9 Hz, 1H), 6.10 (dt, J = 10.0, 1.7 Hz, 1H), 5.41 (dddd, J =
47.7, 7.4, 2.9, 1.4 Hz, 1H), 4.66À4.59 (m, 1H), 4.62 and 4.57 (AB, JAB
=
12 Hz, 2H), 3.79 (ABdd, J = 11.1, 3.6, 1.4 Hz, 1H), 3.75 (ABdd, J = 11.1,
3.5, 1.1 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ 163.7 (d, J = 3.2 Hz),
144.4 (d, J = 20.8 Hz), 139.6, 130.9, 130.3, 130.0, 125.1 (d, J = 8.3 Hz),
83.4 (d, J = 172 Hz), 81.3 (d, J = 25.6 Hz), 76.1, 70.2 (d, J = 3.1 Hz); 19F
NMR (376 MHz, CDCl3) δ À188.63 (dt, J = 47.8, 10.8 Hz, 1F); vmax
(major); [R]D À64.6 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
28
7.36À7.24 (m, 5H), 4.53 (s, 2H), 4.22 (s, 2H), 3.71 (ABd, J = 11.7, 2.9
Hz, 1H), 3.50 (ABd, J = 11.8, 4.7 Hz, 1H), 3.37 (dd, J = 3.5, 1.5 Hz, 1H),
3.36À3.32 (m, 1H), 2.93 (s, 1H); 13C NMR (100.6 MHz, CDCl3) δ
139.8, 130.9, 130.3, 130.2, 85.1, 83.7, 75.8, 70.9, 61.1, 53.1, 53.0, 45.3; IR
(thin film) vmax 3432, 3060, 3029, 2940, 2863, 1637, 1448, 1363, 1233,
1094 cmÀ1; MS (ESI) m/z 236.1 [M + NH4]+; HRMS (ESI) m/z [M +
Na]+ calcd for C13H14NaO3, 241.0841; found, 241.0846.
3070, 3032, 2923, 2867, 1740, 1637, 1596, 1456, 1380, 1234, 1118 cmÀ1
;
MS (ESI) m/z 259.1 [M + Na]+; HRMS (ESI) m/z [M + Na]+ calcd for
C13H13FNaO3, 259.0747; found, 259.0740.
(8R,9S)-9-(Benzyloxymethyl)-8-fluoro-2,2,3,3,11,11,12,12-
octamethyl-4,10-dioxa-3,11-disilatridec-6-yne (19). To a solu-
tion of 15 (1.13 g, 4.75 mmol) in CH2Cl2 (80 mL) was added 2,6-
lutidine (1.66 mL, 14.25 mmol), and the mixture was cooled to À40 °C.
Then TBSOTf (4.36 mL, 19.0 mmol) was added slowly, and the mixture
was stirred for another 4 h at room temperature. The mixture was
quenched with brine (100 mL) and was extracted with ethyl acetate (3 Â
100 mL). The combined organic extracts were concentrated and purified
by flash chromatography on silica gel (petroleum ether:ethyl acetate =
(4R,5S)-6-(Benzyloxy)-4-fluorohex-2-yne-1,5-diol (15). A
mixture of 14 (9.83 g, 45.1 mmol) and Et3N 3HF (50 mL, 304 mmol)
3
was stirred at 70 °C overnight under a nitrogen atmosphere. Water
(200 mL) was added, and the mixture was extracted with ethyl acetate (3
 150 mL). The combined organic layers were washed with a saturated
solution of NaHCO3 (3 Â 150 mL) and then water (150 mL), dried over
anhydrous MgSO4, and concentrated. The residue was purified by flash
chromatography on silica gel (petroleum ether:ethyl acetate = 16:9) to
afford 15 (16.94 g, 54%, 93% ee) as a yellowish syrup: Chiral HPLC
(Phenomenex Lux 5 μ CelluloseÀ2,2-propanol:hexane = 3:7, 250 Â 4.6
mm, 214 nm, 0.5 mL/min), tR = 12.48 min (minor), tR = 13.48 min
(major); [R]D28.3 +116 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.38À7.27 (m, 5H), 5.20 (ddt, J = 47.6, 5.0, 1.5 Hz, 1H), 4.54 (d, J = 1.2
Hz, 2H), 4.26 (dd, J = 6.9, 1.4 Hz, 2H), 4.05 (td, J = 10.6, 5.0 Hz, 1H),
3.64 (ABdd, J = 9.9, 4.8, 0.8 Hz, 1H), 3.60 (ABdd, J = 11.7, 5.7, 1.8 Hz,
1H), 3.35 (s, 2H); 13C NMR (100.6 MHz, CDCl3) δ 137.4, 128.4,
127.8, 127.7, 88.7 (d, J = 10.2 Hz), 82.8 (d, J = 171.6 Hz), 79.1
20.0
100: 1) to afford 19 (2.19 g, 99%) as a colorless oil: [R]D À50.9 (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.39À7.29 (m, 5H),
5.35À5.13 (dt, J = 47.4, 1.6 Hz, 1H), 4.55 (s, 2H), 4.39 (dd, J = 6.7,
1.4 Hz, 2H), 4.12 (ddd, J = 8.6, 4.8, 2.9 Hz, 1H), 3.65À3.60 (m, 1H),
3.56À3.52(m, 1H), 0.94 (s, 9H), 0.93 (s, 9H), 0.15(s, 6H), 0.09 (s, 6H);
13C NMR (101 MHz, CDCl3) δ 137.0, 127.3, 126.6, 126.6, 87.3, 82.9 (d,
J = 173 Hz), 77.9 (d, J = 7.0 Hz), 72.5, 71.8 (d, J = 23.1 Hz), 70.0 (d, J =
6.0 Hz), 50.6 (d, J = 3.2 Hz), 24.8, 24.7, 17.2, 17.1, À5.8, À5.8, À6.2,
À6.2; 19F NMR (376 MHz, CDCl3) δ À183.15 to À183.32 (m, 1F); IR
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ARTICLE
(thin film) vmax 3060, 3041, 2941, 2863, 1590, 1464, 1265, 1106 cmÀ1
;
0.86 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100.6 MHz, CDCl3)
δ 136.9, 134.8 (d, J = 10.2 Hz), 134.5, 134.5, 132.5, 132.4, 128.7, 128.6,
127.3, 126.7, 126.7, 126.5, 126.5, 123.0 (d, J = 21.1 Hz), 87.5 (s, J = 156
Hz), 86.70, 72.3, 71.7 (d, J = 23.2 Hz), 70.1 (d, J = 7.2 Hz), 59.4 (d, J = 1.4
Hz), 25.7, 24.7, 18.1, 17.1, À5.8, À5.8; 19F NMR (376 MHz, CDCl3) δ
À179.59 (dt, J = 47.1, 11.9 Hz, 1F); IR (thin film) vmax 3061, 3039, 2941,
2860, 1591, 1464, 1421, 1255, 1106 cmÀ1; MS (ESI) m/z 615.3 [M +
Na]+; HRMS (ESI) m/z [M + Na]+ calcd for C35H49FNaO3Si2,
615.3102; found, 615.3097.
MS (ESI) m/z 489.3 [M + Na]+; HRMS (ESI) m/z [M + Na]+ calcd for
C25H43FNaO3Si2, 489.2633; found, 489.2632.
(8R,9S,Z)-9-(Benzyloxymethyl)-8-fluoro-2,2,3,3,11,11,12,12-
octamethyl-4,10-dioxa-3,11-disilatridec-6-ene (20). To a solu-
tion of 19 (2.00 g, 4.29 mmol) in n-hexane (80 mL) was added Pd/BaSO4
(180 mg) and stirred under hydrogen atmosphere at room temperature for
2 h. The reaction mixture was filtered, evaporated, and purified by column
chromatography on silica gel (petroleum ether:ethyl acetate = 100:1) to
afford 20 (1.91 g, 95%): [R]D À219 (c 1.0, CHCl3); 1H NMR (400
23.0
(2S,3R,Z)-2-(tert-Butyldimethylsilyloxy)-6-(tert-butyldiphenyl-
silyloxy)-3-fluorohex-4-en-1-ol (23). To a solution of compound 22
(1.41 g, 2.38 mmol) in 1,2-dichloroethane (40 mL) and water (1.6 mL) were
added DDQ (2.20 g, 6.2 mmol) and Celite (1.10 g). The reaction mixture was
stirred vigorously for 8 h at 50 °C and then filtered. The filtrate was washed
with saturated solutions of NaHCO3 (100 mL). The layers were separated,
and the aqueous phase was extracted twice with CH2Cl2 (80 mL). The
combined organic layers were dried over anhydrous Na2SO4 and concen-
trated to dryness under vacuum. The residue was purified by column
chromatography on silica gel (petroleum ether:ethyl acetate = 50:1) to give
MHz, CDCl3) δ 7.38À7.29 (m, 5H), 5.92À5.87 (m, 1H), 5.72À5.63 (m,
1H), 5.37À5.22 (m, 1H), 4.52 (s, 2H), 4.39À4.33 (m, 1H), 4.26À4.20
(m, 1H), 4.14 (ddd, J = 8.8, 5.9, 3.6 Hz, 1H), 3.47À3.41 (m, 1H),
3.41À3.35 (m, 1H), 0.94 (s, 9H), 0.88 (s, 9H), 0.11 (s, 6H), 0.08 (s, 6H);
13C NMR (101 MHz, CDCl3) δ140.3, 138.9 (d, J= 10.1 Hz), 130.7, 130.0,
129.9, 126.0 (d, J = 20.7 Hz), 90.9 (d, J = 166 Hz), 75.8, 75.1 (d, J = 23.4
Hz), 73.6 (d, J = 7.3 Hz), 62.0, 28.3, 28.1, 20.6, 20.5, 3.4, À2.4, À2.5, À2.8,
À2.9; 19F NMR (376 MHz, CDCl3) δ À179.54 to À179.70 (m, 1F); IR
(thin film) vmax 3462, 30720 2954, 2930, 2859, 1582, 1467, 1255,
1110 cmÀ1; MS (ESI) m/z 491.3 [M + Na]+; HRMS (ESI) m/z [M +
Na]+ calcd for C25H45FNaO3Si2, 491.2789; found, 491.2784.
20.0
alcohol 23 (988 mg, 83%) as a colorless liquid: [R]D À116 (c 1.0,
CHCl3);1H NMR (400 MHz, CDCl3) δ7.70 (d, J= 6.5 Hz, 4H), 7.47À7.39
(m, 6H), 5.95 (dtd, J = 9.0, 6.2, 2.8 Hz, 1H), 5.65 (q, J = 11.0 Hz, 1H), 5.12
(ddd,J= 47.2, 8.9, 4.8 Hz, 1H), 4.36À4.26 (m, 2H), 3.88 (dq, J= 10.2, 5.0 Hz,
1H), 3.57 (ABd, J = 10.8, 4.2 Hz, 1H), 3.51 (ABd, J = 11.3, 5.2 Hz, 1H), 1.97
(s, 1H), 1.08 (s, 9H), 0.89 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR
(100.6 MHz, CDCl3) δ 135.6, 135.5, 135.4, 133.3 (d, J = 10.3 Hz), 129.8,
129.8, 127.8, 125.2 (d, J= 20.8 Hz), 87.8 (d, J= 167 Hz), 73.8 (d, J= 24.7 Hz),
63.0 (d, J = 6.0 Hz), 60.4, 26.8, 25.8, 19.1, 18.1, À4.6, À4.8; 19F NMR (376
MHz, CDCl3) δÀ180.51 (dt, J= 47.1, 11.1 Hz, 1F); IR (thin film) vmax 3463,
3072, 2955, 2932, 2858, 1582, 1468, 1426, 1255, 1111 cmÀ1; MS (ESI) m/z
525.3 [M + Na]+;HRMS(ESI):m/z[M+Na]+ calcd for C28H43FNaO3Si2,
525.2633; found, 525.2621.
(2S,3R,Z)-2,6-Bis(tert-butyldimethylsilyloxy)-3-fluorohex-
4-en-1-ol (21). To a solution of compound 20 (920 mg, 1.96 mmol) in
CH2Cl2 (24.8 mL) and water (1.2 mL) was added DDQ (1.84 g, 7.86
mmol). The reaction mixture was stirred vigorously for 20 h at 40 °C and
then filtered. The filtrate was washed with saturated solution of
NaHCO3 (30 mL). The layers were separated, and the aqueous phase
was extracted twice with CH2Cl2 (50 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated to dryness under
vacuum. The residue was purified by column chromatography on silica
gel (petroleum ether:ethyl acetate = 50:1) to give alcohol 21 (297 mg,
23.7
40%) as a pale yellow oil: [R]D À209 (c 0.79, CHCl3); 1H NMR (400
MHz, CDCl3) δ 5.83À5.76 (m, 1H), 5.59 (q, J = 11.0 Hz, 1H), 5.33
(ddd, J = 47.0, 9.0, 4.5 Hz, 1H), 4.26 (ddd, J = 6.1, 3.7, 1.3 Hz, 2H), 3.97
(td, J = 10.8, 4.9 Hz, 1H), 3.59 (ABdd, J = 11.5, 4.9, 1.6 Hz, 1H), 3.51
(ABd, J = 11.5, 6.1 Hz, 1H), 2.40 (s, 1H), 0.90 (s, 9H), 0.88 (s, 9H), 0.09
(s, 6H), 0.08 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 135.2 (d, J = 10.2
Hz), 125.7 (d, J = 20.9 Hz), 87.8 (d, J = 165.7 Hz), 73.7 (d, J = 23.9 Hz),
62.9 (d, J = 6.2 Hz), 59.5 (d, J = 1.3 Hz), 25.9, 25.8, 18.3, 18.1, À4.6,
À4.8, À5.1, À5.3; 19F NMR (376 MHz, CDCl3) δ À181.42 to À181.58
(m, 1F); IR (thin film) vmax 3465, 3070, 2933, 2855, 1562, 1470, 1257,
1109 cmÀ1; MS (ESI): m/z 401.2 [M + Na]+; HRMS (ESI): m/z [M +
Na]+ calcd for C18H39FNaO3Si2, 401.2320; found, 401.2314.
(2S,3R,Z)-2-(tert-Butyldimethylsilyloxy)-6-(tert-butyldiphenyl-
silyloxy)-3-fluorohex-4-enal (24). To a solution of alcohol 23 (1.49 g,
3.53 mmol) in CH2Cl2 (30.0 mL) at À30 °C was added (i-Pr)2NEt
(1.80 mL, 1.04 mmol). After stirring for 5 min, a solution of SO3 Pyridine
3
(1.44 g, 8.89 mmol) in DMSO (3.8 mL) was added. The reaction mixture was
stirred for 30 min at À30 °C, then quenched by the slow addition of a
saturated solution of NaHCO3 (10 mL). The layers were separated, and the
aqueous phase was extracted twice with CH2Cl2 (40 mL). The combined
organic layers were dried over anhydrous Na2SO4 and concentrated. The
residue was purified by column chromatography on silica gel (petroleum
22.8
ether:ethyl acetate = 80:1) to give aldehyde 24 (1.33 g, 90%): [R]D À136
(c 0.70, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.52 (dd, J = 4.8, 1.2 Hz,
1H), 7.71À7.69 (m, 4H), 7.48À7.40(m,6H),6.00À5.93 (m, 1H), 5.67 (tdt,
J = 10.7, 8.8, 1.7 Hz, 1H), 5.26 (dddd, J = 46.9, 8.8, 4.1, 1.0 Hz, 1H), 4.34
(dddd, J = 14.1, 6.5, 4.0, 1.7 Hz, 1H), 4.24 (ABdd, J = 9.9, 5.0, 1.7 Hz, 1H),
4.19 (ABdd, J= 13.1, 4.1, 1.2 Hz, 1H), 1.08 (s, 9H), 0.93 (s, 9H), 0.10 (s, 3H),
0.09 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 201.1 (d, J = 7.4 Hz), 136.4
(d, J = 10.1 Hz), 135.5, 133.3, 133.2, 129.8, 127.8, 122.9 (d, J = 21.2 Hz), 87.6
(d, J = 172 Hz), 79.2 (d, J = 24.7 Hz), 60.5 (d, J = 1.6 Hz), 26.7, 25.6, 19.1,
18.2, À4.9, À5.0; 19F NMR (376 MHz, CDCl3) δ À180.8 to À181.2 (m,
1F); IR (thin film) vmax 3071, 3049, 2972, 2959, 2893, 2859, 2247, 1740,
1576, 1468, 1428, 1257, 1110 cmÀ1; MS (MALDI) m/z 523.2 [M + Na]+;
HRMS (MALDI) m/z [M + Na]+ calcd for C28H41FNaO3Si2, 523.2476;
found, 523.2483.
(8R,9S,Z)-9-(Benzyloxymethyl)-8-fluoro-2,2,11,11,12,12-
hexamethyl-3,3-diphenyl-4,10-dioxa-3,11-disilatridec-6-ene
(22). To a solution of compound 16 (1.40 g, 5.83 mmol) in CH2Cl2
(60 mL) were added imidazole (595 mg, 8.75 mmol) and TBDPSCl
(1.92 g, 7.00 mmol), and the mixture was stirred for 0.5 h at room
temperature before the mixture was quenched with brine (50 mL). The
aqueous phase was extracted with ethyl acetate (3 Â 50 mL). The
combined organic extracts were dried over anhydrous Na2SO4 and
concentrated to dryness. The residue was redissolved in CH2Cl2
(60 mL) and cooled to À40 °C, and then 2,6-lutidine (1.35 mL, 11.60
mmol) was added. Then TBSOTf (1.85 g, 7.00 mmol) was added slowly.
After stirring for 12 h at room temperature, the mixture was quenched
with brine (50 mL) and extracted with ethyl acetate (3 Â 50 mL). The
combined organic extracts were concentrated and purified by flash
chromatography on silica gel (petroleum ether:ethyl acetate = 100:1)
(8R,9S,2Z,6E)-8-Fluoro-2,2,11,11,12,12-hexamethyl-3,3-
diphenyl-9-styryl-4,10-dioxa-3,11-disilatridec-6-ene (25a).
To a solution of diethyl benzylphosphonate (359 mg, 1.56 mmol) in
THF (5 mL) at À78 °C under nitrogen atmosphere was added n-BuLi
(0.62 mL, 2.5 M in hexanes, 1.56 mmol). After stirring for 20 min, the
mixture was warmed to À30 °C, left to stand for 30 min, and recooled to
À78 °C, and a solution of 24 (520 mg, 1.04 mmol) in THF (5 mL) was
then added dropwise. The mixture was stirred for 3 h at room
20.0
to afford 22 (3.06 g, 89% for two steps) as a colorless liquid. [R]D
À205 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.69À7.66 (m,
4H), 7.45À7.35 (m, 6H), 7.29À7.19 (m, 5H), 5.98À5.91 (m, 1H),
5.70À5.61 (m, 1H), 5.08(dddd, J = 47.0, 8.9, 3.5, 0.9Hz, 1H), 4.40À4.33
(m, 1H), 4.37 (s, 2H), 4.27À4.21 (m, 1H), 4.07À4.00 (m, 1H), 3.34
(ddd, J = 9.5, 5.6, 2.6 Hz, 1H), 3.27 (dd, J = 9.7, 6.6 Hz, 1H), 1.06 (s, 9H),
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ARTICLE
temperature and then diluted with brine (10 mL) and extracted with
ethyl ether (3 Â 15 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated. Flash chromatography
(m, 2H), 6.53 (d, J = 15.8 Hz, 1H), 5.99À5.93 (m, 1H), 5.90 (dd, J = 15.9,
6.6 Hz, 1H), 4.93 (ddd, J = 47.7, 8.4, 4.1 Hz, 1H), 4.44À4.36 (m, 1H),
4.36À4.32 (m, 1H), 4.29À4.22 (m, 1H), 3.85 (s, 3H), 1.10 (s, 9H), 0.93 (s,
9H), 0.10 (s, 3H), 0.07 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 161.7,
137.9, 137.9, 137.7, 135.8 (d, J = 10.2 Hz), 133.8, 132.0, 131.9, 130.0, 127.8,
127.7, 127.3 (d, J = 21.2 Hz), 116.3, 92.7 (d, J = 171 Hz), 77.6 (d, J = 24.8
Hz), 63.0, 57.7, 29.1, 28.2, 21.4, 20.6, À2.12, À2.42; 19F NMR (376 MHz,
CDCl3) δ À176.12 to À176.62 (m, 1F); IR (thin film) vmax 3040, 2939,
2895, 2859, 1605, 1511, 1465, 1424, 1253, 1104 cmÀ1; MS (ESI) m/z 627.3
[M + Na]+; HRMS (ESI) m/z [M + Na]+ calcd for C36H49FNaO3Si2,
627.3102; found, 627.3091.
on silica gel (petroleum ether:ethyl acetate = 100:1) of the residue
22.6
yielded 25a (325 mg, 54%) as colorless oil: [R]D
À194 (c 1.0,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.8 Hz, 4H),
7.47À7.37 (m, 6H), 7.37À7.23 (m, 5H), 6.60 (d, J = 15.9 Hz, 1H), 6.06
(dd, J = 15.9, 6.4 Hz, 1H), 6.00À5.93 (m, 1H), 5.74À5.63 (m, 1H), 4.96
(ddd, J = 47.6, 8.4, 4.1 Hz, 1H), 4.47À4.41 (m, 1H), 4.39À4.33 (m, 1H),
4.27 (dt, J = 9.8, 4.2 Hz, 1H), 1.08 (s, 9H), 0.94 (s, 9H), 0.10 (s, 3H),
0.08 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 136.6, 135.6, 135.5,
135.4 (d, J = 9.7 Hz), 133.5, 133.4, 132.0, 129.7, 129.7, 128.6, 127.7,
127.6, 126.5, 124.6 (d, J = 21.5 Hz), 90.3 (d, J = 171 Hz), 75.1 (d, J = 24.9
Hz), 60.7, 26.8, 25.8, 19.1, 18.3, À4.5, À4.7; 19F NMR (376 MHz,
CDCl3) δ À176.3 to À176.5 (m, 1F); IR (thin film) vmax 3068, 3023,
2956, 2933, 2891, 2858, 1581, 1576, 1468, 1424, 1362, 1256,
1108 cmÀ1; MS (ESI) m/z 597.3 [M + Na]+; HRMS (ESI) m/z [M
+ Na]+ calcd for C35H47FNaO2Si2, 597.2997; found, 597.3001.
(2Z,4R,5S,6E)-4-Fluoro-7-(4-methoxyphenyl)hepta-2,6-
diene-1,5-diol (26b). Compound 26b (50 mg, 99%) was prepared
from compound 25b (120 mg, 4.53 mmol) using the same process as
21.3
described for compound 26a. Colorless oil: [R]D
À131 (c 0.40,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.35À7.31 (m, 2H),
6.88À6.84 (m, 2H), 6.65 (d, J = 15.9 Hz, 1H), 6.07 (dd, J = 15.9, 6.9
Hz, 1H), 6.00 (dddd, J = 12.9, 7.5, 6.5, 1.2 Hz, 1H), 5.79À5.65 (m, 1H),
5.28 (ddd, J = 47.6, 8.1, 5.0 Hz, 1H), 4.43À4.37 (m, 1H), 4.29À4.18 (m,
2H), 3.81 (s, 3H), 2.04 (s, 2H); 13C NMR (100.6 MHz, CDCl3) δ 159.7,
134.9 (d, J = 10.0 Hz), 133.2, 128.9, 127.9, 126.5 (d, J = 22.0 Hz), 123.6,
123.5, 114.0, 114.0, 90.6 (d, J = 168.8 Hz), 74.0 (d, J = 25.0 Hz), 58.9,
55.3; 19F NMR (376 MHz, CDCl3) δ À181.70 to À182.10 (m, 1F); IR
(thin film) vmax 3318, 3032, 2925, 2895, 2852, 1605, 1511, 1468, 1250,
1029 cmÀ1; MS (EI) m/z 252.1 M+; HRMS (EI) m/z M+ calcd for
C14H17FO3, 252.1162; found, 252.1161.
(2Z,4R,5S,6E)-4-Fluoro-7-phenylhepta-2,6-diene-1,5-diol
(26a). A solution of TBAF in THF (1 M, 1.3 mL) was added to a
solution of 25a (300 mg, 0.52 mmol) in THF (8 mL) at room
temperature. After stirring for 2 h, the reaction mixture was quenched
with saturated NH4Cl solution and extracted with ethyl acetate (3 Â
20mL). Thecombinedorganic extractswereconcentratedandpurifiedby
flash chromatography on silica gel (petroleum ether:ethyl acetate = 16:9)
24.0
to afford 26a (108 mg, 93%) as a colorless oil: [R]D À183 (c 0.72,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.40À7.23 (m, 5H), 6.69 (d, J =
15.9 Hz, 1H), 6.21 (dd, J = 16.0, 6.6 Hz, 1H), 6.00À5.93 (m, 1H),
5.74À5.65 (m, 1H), 5.25 (dddd, J = 47.7, 8.1, 5.2, 1.1 Hz, 1H), 4.42À4.35
(m, 1H), 4.26À4.15 (m, 2H), 3.18(s, 1H), 2.71 (s, 1H);13C NMR(100.6
MHz, CDCl3) δ 136.2, 134.8 (d, J = 10.0 Hz), 133.4, 128.7, 128.1, 126.7,
126.6 (d, J = 17.5 Hz), 126.1 (d, J = 4.6 Hz), 90.1 (d, J = 169 Hz), 73.7 (d,
J = 25.5 Hz), 58.7; 19F NMR (376 MHz, CDCl3) δ À181.27 to À182.02
(m, 1F); IR (thin film) vmax 3555, 3411, 3027, 2925, 2855, 1652, 1599,
1494, 1415, 1424, 1301, 1011 cmÀ1; MS (ESI) m/z 245.1 [M + Na]+;
HRMS (ESI) m/z [M + Na]+ calcd for C13H15FNaO2, 245.0954; found,
245.0952.
(5R,6S)-6-(4-Methoxystyryl)-5-fluoro-5,6-dihydropyran-2-
one (2b). Compound 2b (47 mg, 96%) was prepared from compound
26b (50 mg, 0.20 mmol) using the same process as described for
22.6
compound 2a. White solid: mp 108À110 °C; [R]D
+135 (c 0.21,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.36À7.32 (m, 2H), 6.94 (td,
J = 9.2, 3.0 Hz, 1H), 6.89À6.86 (m, 2H), 6.76 (d, J = 15.9 Hz, 1H), 6.18
(ddd, J = 10.0, 1.8, 1.3 Hz, 1H), 6.05 (dd, J = 15.9, 6.4 Hz, 1H), 5.16
(dddd, J = 48.3, 7.0, 3.0, 1.2 Hz, 1H), 5.14(dddd, J = 13.5, 9.8, 6.8, 1.2 Hz,
1H), 3.82 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 160.1, 141.7 (d, J =
20.9 Hz), 135.2, 128.2, 128.0, 123.5 (d, J = 8.1 Hz), 119.4, 119.4, 114.1,
84.0 (d, J = 176 Hz), 80.5 (d, J = 25.5 Hz), 55.3; 19F NMR (376 MHz,
CDCl3) δ À186.15 to À186.40 (m, 1F); IR (thin film) vmax 2923, 2849,
1730, 1642, 1597, 1508, 1238, 1009 cmÀ1; MS (EI) m/z 248.1 M+;
HRMS (EI) m/z M+ calcd for C14H13FO3, 248.0849; found, 248.0853.
(8R,9S,Z)-8-Fluoro-9-(4-fluorostyryl)-2,2,11,11,12,12-hex-
amethyl-3,3-diphenyl-4,10-dioxa-3,11-disilatridec-6-ene
(25c). Compound 25c (186 mg, 52%) was prepared from compound 24
(300 mg, 0.60 mmol) using the same process as described for compound
(5R,6S)-5-Fluoro-5,6-dihydro-6-styrylpyran-2-one (2a). To
a solution of 26a (100 mg, 0.45 mmol) in CH2Cl2 (6 mL) was added
bisacetoxyiodobenzene (444 mg, 1.35 mmol) and 2,2,6,6-tetramethyl-1-
piperidinyloxy (15 mg, 20 mol %) at room temperature. After stirring for
2 h, the reaction mixture was quenched with a saturated solution of
Na2S2O3 (30 mL) and extracted with CH2Cl2 (30 mL). The combined
organic extracts were washed in turn with saturated solutions of
NaHCO3 (30 mL), NH4Cl (30 mL), and brine (30 mL), dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was purified
by flash chromatography on silica gel (petroleum ether:ethyl acetate =
21.9
25a. Colorless oil: [R]D À153 (c 0.95, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.66 (dt, J = 8.1, 1.5 Hz, 4H), 7.45À7.34 (m, 6H), 7.29À7.24
(m, 2H), 7.00À6.95 (m, 2H), 6.53 (d, J = 15.9 Hz, 1H), 5.94 (dd, J =
16.0, 4.0 Hz, 1H), 5.94À5.90 (m, 1H), 5.64 (ddd, J = 11.7, 10.2, 8.5 Hz,
1H), 4.93 (ddd, J = 47.5, 8.4, 4.1 Hz, 1H), 4.43À4.37 (m, 1H),
4.36À4.28 (m, 1H), 4.25À4.18 (m, 1H), 1.05 (s, 9H), 0.90 (s, 9H),
0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 162.4 (d,
J = 247 Hz), 135.5, 135.4, 135.3 (d, J = 10.0 Hz), 133.4 (d, J = 8.2 Hz),
132.7, 130.7, 129.7 (d, J = 3.5 Hz), 128.0, 128.0, 127.7, 127.7, 127.4,
124.5 (d, J = 21.3 Hz), 115.5 (d, J = 21.2 Hz), 90.3 (d, J = 171 Hz), 74.9
(d, J = 24.9 Hz), 60.7, 26.7, 25.8, 19.1, 18.2, À4.5, À4.8; 19F NMR (376
MHz, CDCl3) δ À114.06 to À114.29 (m, 1F), À176.30 to À176.61 (m,
1F); IR (thin film) vmax 3043, 2943, 2860, 1592, 1509, 1418, 1242,
1005 cmÀ1; MS (MALDI) m/z 615.3 [M + Na]+; HRMS (MALDI)
m/z [M + Na]+ calcd for C35H46F2NaO2Si2, 615.2902; found, 615.2906.
(2Z,4R,5S,6E)-4-Fluoro-7-(4-fluorophenyl)hepta-2,6-diene-
1,5-diol (26c). Compound 26c (60 mg, 93%) was prepared from
compound 25c (160 mg, 0.27 mmol) using the same process as described
23.5
10:1) to afford 2a (95 mg, 97%) as a white solid: mp 43À45 °C; [R]D
+145 (c 0.30, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.42À7.28 (m,
5H), 6.93 (tdd, J = 8.7, 5.7, 3.0 Hz, 1H), 6.82 (dd, J = 15.9, 5.6 Hz, 1H),
6.20 (dd, J = 15.8, 6.3 Hz, 1H), 6.20À6.16 (m, 1H), 5.23À5.16 (m, 1H),
5.09 (dddd, J = 46.8, 7.1, 3.0, 1.3 Hz, 1H); 13C NMR (100.6 MHz,
CDCl3) δ 161.3 (d, J = 2.9 Hz), 141.7 (d, J = 21.0 Hz), 135.4 (d, J = 8.9
Hz), 128.8, 126.9, 123.5, 123.4, 121.8, 121.8, 84.0 (d, J = 176 Hz), 80.2
(d, J = 24.9 Hz); 19F NMR (376 MHz, CDCl3) δ À186.4 to À186.7 (m,
1F); IR (thin film) vmax 3060, 3027, 2924, 2856, 1739, 1626, 1576, 1438,
1382, 1232, 1012 cmÀ1; MS (ESI) m/z 241.1 [M + Na]+; HRMS (ESI)
m/z [M + Na]+ calcd for C13H11FNaO2, 241.0641; found, 241.0641.
(8R,9S,Z)-8-Fluoro-9-(4-methoxystyryl)-2,2,11,11,12,12-hexa-
methyl-3,3-diphenyl-4,10-dioxa-3,11-disilatridec-6-ene (25b).
Compound 25b (130 mg, 20%) was prepared from compound 24 (540
mg, 1.08 mmol) using the same process as described for compound 25a.
Colorless oil: [R]D À206 (c 0.86, CHCl3); 1H NMR (400 MHz, CDCl3)
for compound 26a. White solid: mp = 92À93 °C; [R]D À144 (c 0.50,
21.4
21.7
δ 7.70À7.67 (m, 4H), 7.49À7.37 (m, 6H), 7.30À7.27 (m, 2H), 6.88À6.85
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.43À7.38 (m, 2H), 7.09À7.03
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The Journal of Organic Chemistry
ARTICLE
(m, 2H), 6.72 (d, J = 16.0 Hz, 1H), 6.18 (dd, J = 16.0, 6.6 Hz, 1H),
6.08À6.01 (m, 1H), 5.81À5.72 (m, 1H), 5.33 (dddd, J = 47.6, 8.1, 5.1, 1.2
Hz, 1H), 4.49À4.42 (m, 1H), 4.35À4.24 (m, 2H), 2.19 (s, 2H); 13C
NMR (100.6 MHz, CDCl3) δ 162.6 (d, J = 248 Hz), 134.9 (d, J = 10.0
Hz), 132.2, 128.3, 128.2, 126.5 (d, J = 22.1 Hz), 125.7, 115.6 (d, J = 21.5
Hz), 90.5 (d, J = 169 Hz), 73.6 (d, J = 25.4 Hz), 58.9; 19F NMR (376
MHz, CDCl3) δ À113.10 to À113.55 (m, 1F), À181.79 to À182.06 (m,
1F); IR (thin film) vmax 3405, 3043, 2926, 2870, 1584, 1508, 1415, 1229,
1013 cmÀ1; MS (EI) m/z 240.1 M+; HRMS (EI) m/z M+ calcd for
C13H14F2O2, 240.0962; found, 240.0966.
(5R,6S)-6-(4-Fluorostyryl)-5-fluoro-5,6-dihydropyran-2-
one (2c). Compound 2c (34 mg, 96%) was prepared from com-
pound 26c (36 mg, 0.15 mmol) using the same process as described
for compound 2a. White solid: mp 93À94 °C. [R]D21.0 +226 (c 0.12,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.41À7.36 (m, 2H),
7.07À7.01 (m, 2H), 6.94 (td, J = 9.7, 2.8 Hz, 1H), 6.79 (d, J = 15.9
Hz, 1H), 6.18 (dt, J = 10.0, 1.4 Hz, 1H), 6.13 (dd, J = 16.0, 6.1 Hz,
1H), 5.16 (dddd, J = 47.6, 7.3, 2.8, 1.3 Hz, 1H), 5.19À5.12 (m, 1H);
13C NMR (100.6 MHz, CDCl3) δ 163.0 (d, J = 248 Hz), 161.3, 141.9
(d, J = 20.9 Hz), 134.3, 131.5 (d, J = 3.6 Hz), 128.5 (d, J = 8.2 Hz),
123.3 (d, J = 8.1 Hz), 121.6, 115.8 (d, J = 21.8 Hz), 84.1 (d, J = 176
Hz), 80.0 (d, J = 25.2 Hz); 19F NMR (376 MHz, CDCl3) δ À112.35
to À112.44 (m, 1F), À187.34 (dt, J = 49.4, 9.1 Hz, 1F); IR (thin film)
vmax 3065, 2921, 2851, 1731, 1633, 1594, 1510, 1415, 1378, 1232,
1014 cmÀ1; MS (EI) m/z 236.1 M+; HRMS (EI) m/z M+ calcd for
C13H10F2O2, 236.0649; found, 236.0648.
3391, 3020, 2927, 2862, 1575, 1418, 1020 cmÀ1; MS (EI) m/z 198.1
[M+ À H2O]; HRMS (EI) m/z [M+ À H2O] calcd for C12H19FO,
198.1420; found, 198.1422.
(5R,6S)-5-Fluoro-6-((Z)-hept-1-enyl)-5,6-dihydropyran-2-
one (2d). Compound 2d (55 mg, 81%) was prepared from compound
26d (70 mg, 0.32 mmol) using the same process as described for
compound 2a. Colorless oil: [R]D À392 (c 0.61, CHCl3); 1H NMR
22.1
(400 MHz, CDCl3) δ 6.94 (td, J = 9.8, 2.8 Hz, 1H), 6.18 (d, J = 9.6 Hz,
1H), 5.87 (dt, J = 10.5, 7.6 Hz, 1H), 5.42 (t, J = 9.8 Hz, 1H), 5.35À5.28
(m, 1H), 5.03 (ddd, J = 47.6, 6.3, 2.5 Hz, 1H), 2.23À2.08 (m, 2H),
1.51À1.38 (q, J = 6.8 Hz, 2H), 1.38À1.26 (m, 4H), 0.92 (t, J = 6.8 Hz,
3H); 13C NMR (100.6 MHz, CDCl3) δ 161.6 (d, J = 3.1 Hz), 141.6 (d, J
= 20.3 Hz), 139.2, 123.7 (d, J = 8.2 Hz), 122.7 (d, J = 3.1 Hz), 83.9 (d, J =
176 Hz), 76.1 (d, J = 25.6 Hz), 31.4, 28.9, 28.0, 22.4, 14.0; 19F NMR (376
MHz, CDCl3) δ À185.24 (dt, J = 47.5, 9.6 Hz, 1F); IR (thin film) vmax
3021, 2930, 2860, 1741, 1635, 1462, 1379, 1229, 1019 cmÀ1; MS (EI)
m/z 212.0 M+; HRMS (EI) m/z M+ calcd for C12H17FO2, 212.1213;
found, 212.1212.
’ ASSOCIATED CONTENT
S
Supporting Information. Chiral HPLC analytical spec-
b
tra of compounds 14 and 15, copies of 1H NMR and 13C NMR
spectra of all the new compounds, and crystallographic data for
compound 2a (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
(8R,9S,Z)-8-Fluoro-9-((Z)-hept-1-enyl)-2,2,11,11,12,12-hexa-
methyl-3,3-diphenyl-4,10-dioxa-3,11-disilatridec-6-ene (25d).
To a solution of CH3(CH2)5P+Ph3BrÀ (380 mg, 0.89 mmol) in THF
(5 mL) was added NaHMDS (0.44 mL, 0.89 mmol) at À78 °C under
nitrogen atmosphere. After stirring for 20 min, the mixture was warmed to
À30 °C, left to stand for 30 min, and recooled to À78 °C, and a solution of
24 (200 mg, 0.40 mmol) in THF (5 mL) was then added dropwise. The
mixture was stirred for 3 h at room temperature and then diluted with brine
(10 mL) and extracted with ethyl ether (3 Â 15 mL). The combined
organic layers were dried over anhydrous Na2SO4 and concentrated. The
residue was purified by flash chromatography on silica gel (petroleum ether:
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: flq@mail.sioc.ac.cn.
’ ACKNOWLEDGMENT
The National Natural Science Foundation of China
(21072018, 20632008) is greatly acknowledged for funding
this work.
21.3
ethyl acetate = 100:1) to give 25d (209 mg, 92%) as a colorless oil: [R]D
À105 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.67À7.69 (m, 4H),
7.46À7.37 (m, 6H), 5.95À5.89 (m, 1H), 5.67À5.59 (m, 1H), 5.43À5.37
(m, 1H), 5.15 (t, J = 9.7 Hz, 1H), 4.74 (ddd, J = 48.4, 8.4, 4.0 Hz, 1H),
4.57À4.51 (m, 1H), 4.34À4.25 (m, 1H), 4.25À4.19 (m, 1H), 2.05À1.88
(m, 2H), 1.32 (q, J = 6.8 Hz, 2H), 1.31À1.19 (m, 4H), 1.06 (s, 9H), 0.88 (t,
J = 6.7 Hz, 3H), 0.85 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (100.6
MHz, CDCl3) δ 135.5, 135.1, 135.0, 133.5 (d, J = 11.0 Hz), 132.7, 129.7,
129.7, 128.5, 128.4, 127.7, 124.8 (d, J = 21.6 Hz), 90.1 (d, J = 171 Hz), 70.3
(d, J = 24.9 Hz), 60.6, 31.5, 29.1, 28.0, 26.8, 25.7, 22.5, 19.1, 18.1, 14.0, À4.6,
À4.8; 19F NMR (376 MHz, CDCl3) δ À176.10 (dt, J = 47.5, 11.5 Hz, 1F);
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1
compound 26a. Colorless oil: [R]D
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25.7 Hz), 58.6, 31.5, 29.2, 28.0, 22.5, 14.0; 19F NMR (376 MHz,
CDCl3) δ À181.93 (dt, J = 47.8, 13.3 Hz, 1F); IR (thin film) vmax
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