An efficient and general route to gem-difluoromethylenated α,β-unsaturated δ-lactones: High enantioselective synthesis of gem-difluoromethylenated goniothalamins

Article abstract of DOI:10.1021/jo061012r

An efficient and general strategy to gem-difluoromethylenated α,β-unsaturated δ-lactones in high yields from various aldehydes (including aliphatic, aromatic, α,β-unsaturated, and sterically hindered aldehydes) has been developed. This methodology was suc

Full text of DOI:10.1021/jo061012r

An Efficient and General Route to gem-Difluoromethylenated
r,â-Unsaturated δ-Lactones: High Enantioselective Synthesis of
gem-Difluoromethylenated Goniothalamins
Zheng-Wei You,† Zhong-Xing Jiang,† Bing-Lin Wang,† and Feng-Ling Qing*,†,‡
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Science, 354 Fenglin Lu, Shanghai 200032, China, and Institute of Biological Sciences and
Biotechnology, Donghua UniVersity, 2999 North Renmin Lu, Shanghai 201620, China
flq@mail.sioc.ac.cn
ReceiVed May 17, 2006
An efficient and general strategy to gem-difluoromethylenated R,â-unsaturated δ-lactones in high yields
from various aldehydes (including aliphatic, aromatic, R,â-unsaturated, and sterically hindered aldehydes)
has been developed. This methodology was successfully applied for the preparation of two enantiomers of
gem-difluoromethylenated goniothalamins (S)-1 and (R)-1. gem-Difluoropropargylation of cinnamaldehyde
followed by the resolution of resulting homopropargylic alcohols mediated by lipase from Pseudomonas
(AK) gave alcohols (R)-6 and (S)-6. Selective hydrogenation of the triple bond of (S)-6 and (R)-6 to
double bond with Lindlar catalyst in the presence of quinoline afforded the expected product (S)-8 and
(R)-8, respectively. Deprotection of (S)-8 and (R)-8 followed by oxidation of the resulting 1,5-diols with
catalytic 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and excess bis-acetoxyiodobenzene (BAIB)
provided the target molecules gem-difluoromethylenated goniothalamins (S)-1 and (R)-1 in high yields,
respectively.
Introduction
ship studies that the R,â-unsaturated δ-lactone structure plays
a key role in the bioactivities of many natural products, because
such a structure unit is an excellent potential Michael acceptor
for nucleophilic amino acid residues of the natural receptors
interacting with these compounds.2c,3b,4
R,â-Unsaturated δ-lactone A is a common structural unit of
natural products with medicinal interest,1 such as Gonio-
thalamin,2 Forstriecin,3 and (+)-Boronolide,4 and is also a
versatile building block for complex natural products synthesis
(Figure 1).5 It has been revealed by structure-activity relation-
(3) (a) Lewy, D. S.; Gauss, C. M.; Soenen, D. R.; Boger D. L. Curr.
Med. Chem. 2002, 9, 2050-2032. (b) Buck, S. B.; Hardouin, C.; Ichi-
kawa, S.; Soenen, D. R.; Gauss, C.-M.; Hwang, I.; Swingle, M. R.; Bonness,
K. M.; Honkanen, R. E.; Boger, D. L. J. Am. Chem. Soc. 2003, 125,
15694-15695. (c) Maki, K.; Motoki, R.; Fujii, K.; Kanai, M.; Kobayashi,
T.; Tamura, S.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 17111-
17117.
* To whom correspondence should be addressed. Fax: 86-21-64166128.
† Shanghai Institute of Organic Chemistry.
‡ Donghua University.
(1) For a review see: Davies-Coleman, M. T.; Rivett, D. E. A. Prog.
Chem. Org. Nat. Prod. 1989, 55, 1-33.
(2) (a) de Fatima, A.; Kohn, L. K.; Antonio, M. A.; de Carvalho, J. E.;
Pilli, R. A. Bioorg. Med. Chem. 2005, 13, 2927-2933. (b) Chen, W.-Y.;
Wu, C.-C.; Lan, Y.-H.; Chang, F.-R.; Teng, C.-M.; Wu, Y.-C. Eur. J.
Pharmacol. 2005, 522, 20-29. (c) de Fatima, A.; Kohn, L. K.; Antonio,
M. A.; de Carvalho, J. E.; Pilli, R. A. Bioorg. Med. Chem. 2006, 14, 622-
631. (d) Chan, K. M.; Rajab, N. F.; Ishak, M. H. A.; Ali, A. M.; Yusoff,
K.; Din, L. B.; Inayat-Hussain, S. H. Chem.-Biol. Interact. 2006, 159, 129-
140.
(4) Kumar, P.; Naidu, S. V. J. Org. Chem. 2006, 71, 3935-3941 and
references therein.
(5) For recent examples see: (a) Nicolaou, K. C.; Pihko, P. M.; Bernal,
F.; Frederick, M. O.; Qian, W.; Uesaka, N.; Diedrichs, N.; Hinrichs, J.;
Koftis, T. V.; Loizidou, E.; Petrovic, G.; Rodriquez, M.; Sarlah, D.; Zou,
N. J. Am. Chem. Soc. 2006, 128, 2244-2257. (b) Khalaf, J. K.; Datta, A.
J. Org. Chem. 2005, 70, 6937-6940. (c) Ramachandran, P. V.; Prabhudas,
B.; Chandra, J. S.; Reddy, M. V. R. J. Org. Chem. 2004, 69, 6294-6304.
10.1021/jo061012r CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/16/2006
J. Org. Chem. 2006, 71, 7261-7267
7261

You et al.
SCHEME 2
FIGURE 1. Design of gem-difluoromethylenated R,â-unsaturated
δ-lactone B.
SCHEME 1
SCHEME 3
The strong electronegativity and relatively small size of
fluorine atoms combined with the chemical inertness of C-F
bonds make fluorine substitution a powerful tool for medicinal
chemistry studies.6 Special attention has been paid to the gem-
difluoromethylene group (CF2) because many compounds with
this structure exhibit extraordinary biological activities and
potential pharmaceutical applications.7 With a long-term interest
in the development of site-specific fluorine substitution meth-
odologies and synthesis of fluorinated bioactive compounds, we
intended to introduce gem-difluoromethylene group (CF2), a
strong electron-withdrawing group, to R,â-unsaturated δ-lac-
tones A at the γ-position (Figure 1). Thus, the conjugated double
bond of resulting B would be much more electron deficient than
that of A, making it a better candidate to enhance the reactivity
of the conjugated double bond as a Michael acceptor with
minimum steric change.
Although there are a few reports concerning the difluoro-
methylenated lactones or closely related compounds in the
literature,8 it is still desirable to develop new facile synthetic
methodologies to prepare such difluoromethylenated lactone B.
Recently, we also developed an efficient procedure to synthesize
γ,γ-gem-difluoromethylenated R,â-unsaturated δ-lactone B us-
ing ring-closing metathesis (RCM) reaction as the key step
(Scheme 1).9 We attempted to apply this methodology to the
synthesis of gem-difluoromethylenated goniothalamin 1, a
representative natural R,â-unsaturated δ-lactone displaying
cytotoxic activity against various cancerous cell lines.2 Accord-
ingly, indium-mediated allylation of cinnamaldehyde with
3-bromo-3,3-difluoropropene10 followed by acryloylation of the
resulting alcohol 2 afforded acryloyl ester 3 in good yield
(Scheme 2). Although the RCM reaction has been employed to
construct goniothalamin successfully,11 the RCM reaction of
acryloyl ester 3 under the same reaction conditions shown in
SCHEME 4
SCHEME 5
SCHEME 6
Scheme 1 failed to give the expected compound 1. It may be
that the electron-rich double bond next to phenyl was more
reactive under RCM reaction conditions than the other electron-
deficient terminal doubles. In addition, because of the strictly
anhydrous and oxygen-free conditions of RCM reaction and the
high cost of Grubbs’ II catalyst, we were eager to explore new
approaches for the synthesis of γ,γ-gem-difluoromethylenated
R,â-unsaturated δ-lactones.
(6) (a) Ojima, I. ChemBioChem 2004, 5, 628-635. (b) Bo¨hm, H.-J.;
Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Mu¨ller, K.; Obst-Sander,
U.; Stahl, M. ChemBioChem 2004, 5, 637-643. (c) Strunecka´, A.; Patoe`ka,
J.; Connett, P. J. Appl. Biomed. 2004, 2, 141-150.
(7) (a) Percy, J. M. Chim. Oggi. 2004, 22, 18-20. (b) Tozer, M. J.;
Herpin, T. F. Tetrahedron 1996, 52, 8619-8683.
(8) For examples see: (a) Chupp, J. P.; Molyneaux, J. M. J. Heterocycl.
Chem. 1989, 26, 1771-1780. Hu, Q.-S.; Hu, C.-M. J. Fluorine Chem. 1997,
83, 87-88. (c) Peng, W.; Zhu, S. Tetrahedron 2003, 59, 4395-4404.
(9) You, Z.-W.; Wu, Y.-Y.; Qing, F.-L. Tetrahedron Lett. 2004, 45,
9479-9481.
(10) Kirihara, M.; Takuwa., T.; Takizawa, S.; Momose, T.; Nemoto, H.
Tetrahedron 2000, 56, 8275-8280.
(11) (a) Gruttadauria, M.; Meo, P. L.; Noto, R. Tetrahedron Lett. 2004,
45, 83-85. (b) Sundby, E.; Anthonsen, T.; Hansen, T. V. et al. Tetrahedron
2004, 60, 521-524.
Results and Discussion
A new strategy to γ,γ-gem-difluoromethylenated R,â-unsatur-
ated δ-lactone B was outlined in Scheme 3. Lactone B could
be obtained from the corresponding 1,5-diol C via an oxidation-
lactone formation. Compound C could be prepared from
homopropargyl alcohol D via selective hydrogenation. The
reaction of aldehyde with fluorine-containing building block 5
should provide the intermediate D.
7262 J. Org. Chem., Vol. 71, No. 19, 2006

Synthesis of gem-Difluoromethylenated Goniothalamins
SCHEME 7
SCHEME 8
Fried and co-workers had reported the preparation of com-
pound 5 in 40% yield from the reaction of lithium acetylide
with ClCF2Br (Scheme 4).12 We found that the yield could be
improved to 63% when CF2Br2 was used instead of ClCF2Br.
Compound 5 could be prepared in 40 g scale with this procedure.
We then explored the synthesis of gem-difluoromethylenated
goniothalamin 1 starting from the gem-difluoropropargylation
of cinnamaldehyde with compound 5. Several years ago,
Hammond and co-workers described that treatment of triiso-
propylsilyldifluorobromopropyne (TIPS-CtC-CF2Br) with
indium and carbonyl electrophile in THF/H2O (1:4) at room
temperature gave only propargyl-containing products.13 We were
pleased to find that the reaction of cinnamaldehyde with 5 in
the presence of indium under Hammond’s reaction conditions
provided the expected compound 6 in 85% yield (Scheme 5).
With racemic gem-difluoromethylenated propargyl alcohol
6 in hand, the resolution of racemic 6 into optically active
alcohols was investigated. The resolution of racemic alcohols
through lipase-catalyzed transesterification is a widely used
methodology and has been successfully applied to gem-
difluoromethylenated alcohols.14 As the resolution of homopro-
pargylic alcohols mediated by lipase from Pseudomonas (AK)
was highly enantioselective,15 we first examined Pseudomonas
(AK) for its ability to mediate the transesterification of racemic
6. Delightfully, the acylation of 6 with vinyl acetate in the
presence of 0.5 mass equiv of Pseudomonas (AK) and 4 Å
molecular sieves in hexane at 30 °C afforded (R)-6 in 99% ee
and 49% yield, and compound 7 was isolated in 46% yield
(Scheme 6). The absolute configurations of compounds (R)-6
and 7 were determined by X-ray crystal structure of compound
10b.
SCHEME 9
cyclization precursor (S)-9 in quantitative yield. Recently,
Forsyth and co-workers described the oxidation of 1,5-diols to
δ-lactones with catalytic 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) and excess bis-acetoxyiodobenzene (BAIB).16 Ac-
cordingly, treatment of (S)-9 with 0.2 equiv of TEMPO and 3
equiv of BAIB in CH2Cl2 at room temperature afforded the
target molecule (S)-1 in 88% yield.
In the same way, gem-difluoromethylenated (-)-gonio-
thalamin (R)-1 was also synthesized from (R)-6 in 68% yield
over three steps without isolation of the intermediates (R)-8 and
(R)-9 (Scheme 8).
To evaluate the potential ability of 1 for further synthetic
transformation and to determine the absolute configuration of
1, epoxidation of (S)-1 was carried out. Reaction of (S)-1 with
m-chloroperoxybenzoic acid (2.0 equiv) in CH2Cl2 under reflux
afforded gem-difluoromethylenated goniothalamin epoxides 10a
and 10b in the ratio of 2.2:1 (determinated by 19F NMR before
column chromatography) in 95% yield (Scheme 9).17 The optical
rotation and NMR spectra of 10b were the same as we reported
previously.18 The absolute configuration of 10b was determined
by the X-ray crystallographic analysis.18 Therefore, compound
10b was assigned the 6S, 7R, 8S configuration as shown in
Scheme 8 and the absolute configuration of 1 was further
confirmed.
Deacylation of 7 with LiOH or K2CO3 led to partial
defluorination, and only a small amount of expected (S)-6 was
isolated (Scheme 7). Fortunately, treatment of 7 with NH3/
MeOH gave (S)-6 in 90% yield and 99% ee. Initial attempts to
hydrogenate the triple bond of (S)-6 to cis double bond in the
presence of Lindlar catalyst were not successful, leading to a
complex inseparable mixture. Interestingly, the selective hy-
drogenation proceeded smoothly in the presence of both Lindlar
catalyst and quinoline to provide the expected product (S)-8 in
85% yield. Deprotection of (S)-8 with n-Bu4NF (TBAF) gave
To demonstrate the efficiency and viability of our developed
methodology, the synthesis of a series of gem-difluoromethyl-
enated R,â-unsaturated δ-lactones was then carried out. As
shown in Table 1, gem-difluoropropargylation reaction of
(12) (a) Kwok, P.-Y.; Muellner, F. W.; Chen, C.-K.; Fried, J. J. Am.
Chem. Soc. 1987, 109, 3684-3692. (b) Rim, I.; Cantacuzene, D.; Wak-
selman, C. J. Chem. Soc., Perkin Trans. 1 1982, 1063.
(13) Wang, Z. G.; Hammond, G. B. J. Org. Chem. 2000, 65, 6547-
6552.
(14) For related exmaples see: (a) Itoh, T.; Kudo, K.; Tanaka, N.; Sakabe,
K.; Takagi, Y.; Kihara, H. Tetrahedron Lett. 2000, 41, 4591-4595. (b)
Kirihara, M.; Kawasaki, M.; Katsumata, H.; Kakuda, H.; Shiro, M.;
Kawabata, S. Tetrahedron: Asymmetry 2002, 13, 2283-2289. (c) Itoh, T.;
Kudo, K.; Yokota, K.; Tanaka, N.; Hayase, S.; Renou, M. Eur. J. Org.
Chem. 2004, 406-412. (d) Kaneda, T.; Komura, S.; Kitazume, T. J.
Fluorine Chem. 2005, 126, 17-26.
(16) Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.; Abrams, J.
N.; Forsyth, C. J. Tetrahedron Lett. 2003, 44, 57-59.
(17) (a) Goh, S. H.; Ee, G. C. L.; Chuah, C. H.; Wei, C. Aust. J. Chem.
1995, 48, 199-205. (b) Peng, X.; Li, A.; Shen, H.; Wu, T.; Pan, X. J.
Chem. Res. Synop. 2002, 330-332. (c) Lan, Y.-H.; Chang, F.-R.; Yu, J.-
H.; Yang, Y.-L.; Chang, Y.-L.; Lee, S.-J.; Wu, Y.-C. J. Nat. Prod. 2003,
66, 487-490.
(15) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113, 6129-
6139.
(18) You, Z.-W.; Zhang, X.-G.; Qing, F.-L. Synthesis, 2006, 2533-2542.
J. Org. Chem, Vol. 71, No. 19, 2006 7263

You et al.
TABLE 1. Synthesis of gem-Difluoromethylenated
r,â-Unsaturated δ-Lactones 14a-d
(3.57 g, 31.1 mmol) in H2O (200 mL) was added 3-bromo-3,3-
difluoropropene (4.88 g, 31.1 mmol) at room temperature. After
stirring for 16 h, the reaction mixture was quenched with 1 M HCl
aqueous solution (20 mL) and was extracted with Et2O. The
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by flash chromatography on silica gel (petroleum ether:
ethyl acetate ) 5:1) to afford 2 (3.29 g, 76% yield) as a yellow
oil: 1H NMR (300 MHz, CDCl3) δ 7.25-7.42 (m, 5H), 6.76 (d, J
) 15.9 Hz, 1H), 6.19 (dd, J ) 16.1, 6.5 Hz, 1H), 6.00 (ddd, J )
23.1, 17.4, 11.1 Hz, 1H), 5.70-5.78 (m, 1H), 5.55 (d, J ) 11.1
Hz, 1H), 4.45-4.55 (m, 1H), 2.28 (d, J ) 4.2 Hz, 1H); 19F NMR
(282 MHz, CDCl3) δ -108.7 (dt, J ) 248.0, 10.1 Hz, 1F), -110.7
(dt, J ) 249.3, 10.3 Hz, 1F).
(E)-4,4-Difluoro-1-phenylhexa-1,5-dien-3-yl acrylate (3). A
solution of fresh-distilled acryloyl chloride (0.23 mL, 2.8 mmol)
in dry CH2Cl2 (2 mL) was added dropwise to a solution of 2 (199
mg, 0.95 mmol), triethylamine (0.40 mL, 2.8 mmol), and DMAP
(12 mg, 1 mol %) in dry CH2Cl2 (5 mL) at -15 °C under nitrogen
atmosphere. The reaction mixture was warmed to room temperature
and was stirred for 2 h. Then, the mixture was quenched with a
saturated solution of NaHCO3 and was extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by flash chromatography on silica gel (petroleum ether:
ethyl acetate ) 20:1) to afford 3 (188 mg, 75% yield) as a yellowish
oil: 1H NMR (300 MHz, CDCl3) δ 7.27-7.42 (m, 5H), 6.78 (d, J
) 15.9 Hz, 1H), 6.50 (dd, J ) 17.3, 1.4 Hz, 1H), 6.19 (dd, J )
17.4, 10.5 Hz, 1H), 6.14 (d, J ) 7.2 Hz, 1H), 5.93 (dd, J ) 10.5,
1.2 Hz, 1H), 5.89-6.06 (m, 1H), 5.77-5.80 (m, 1H), 5.71-5.74
(m, 1H), 5.56 (d, J ) 10.8 Hz, 1H); 19F NMR (282 MHz, CDCl3)
δ -106.5 (dt, J ) 249.4, 9.4 Hz, 1F), -110.1 (dt, J ) 250.8, 11.4
Hz, 1F); IR (thin film) υmax 3031, 2962, 1735, 1654, 1635, 1580,
1498, 1451, 1406, 1261, 1178 cm-1; MS (ESI): m/z ) 282.1 [M
+ NH4]+, 287.1 [M + Na]+; Anal. Calcd for C15H14F2O2: C, 68.17;
H, 5.34. Found: C, 68.25, H, 5.20.
aldehydes (including aliphatic, aromatic, R,â-unsaturated, and
sterically hindered aldehydes) afforded the corresponding al-
cohols 11 in good yields. It is noteworthy that quinoline was
not required in the selective hydrogenation of compounds 11
and the over-reduction could be avoided by carefully monitoring
the reaction mixture by 19F NMR.19 Removal of the TBDMS
protective group of 12 with TBAF followed by oxidative-lactone
formation in the presence of BAIB and TEMPO gave the desired
gem-difluoromethylenated R,â-unsaturated δ-lactones 14 in
excellent yields.
tert-Butyldimethyl(prop-2-ynyloxy)silane (4). To a solution of
fresh-distilled propargyl alcohol (56.2 g, 1.0 mol), imidazole (75.1
g, 1.1 mol) and DMAP (1.22 g, 1 mol %) in DMF (400 mL) was
added TBSCl (159 g, 1.1 mol) at room temperature. After stirring
for 17 h, the reaction mixture was quenched with water and was
filtered through Celite, and the filter cake was washed with Et2O.
The aqueous layer was extracted with Et2O, and the combined
organic extracts were washed with water, dried over anhydrous
MgSO4, filtered, and concentrated. Vacuum distillation (25 Torr)
provided 4 (160 g, 94% yield) as a colorless liquid (57-63 °C):
1H NMR (300 MHz, CDCl3) δ 4.31 (d, J ) 2.4 Hz, 2H), 2.39 (t,
J ) 2.4 Hz, 1H), 0.91 (s, 9H), 0.13 (s, 6H).
(4-Bromo-4,4-difluorobut-2-ynyloxy)(tert-butyl)dimethylsi-
lane (5). To a solution of 4 (23.1 g, 0.14 mol) in dry THF (380
mL) was added BuLi (93 mL, 1.6 M solution in hexane) dropwise
over 1 h at 0 °C under nitrogen atmosphere. The reaction mixture
was stirred at room temperature for 1.5 h before being cooled to
-78 °C. Then, CF2Br2 (85.4 g, 0.41 mol) was added. After stirring
for 2.5 h at -78 °C, the reaction mixture was quenched with a
saturated solution of NH4Cl and was extracted with petroleum ether.
The combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated. Vacuum distillation
(1 Torr) provided 5 (25.7 g, 63% yield) as a yellow liquid (55-59
°C): 1H NMR (300 MHz, CDCl3) δ 4.45 (t, J ) 4.1 Hz, 2H), 0.92
(s, 9H), 0.14 (s, 6H); 19F NMR (282 MHz, CDCl3) δ -32.6 (t, J
) 4.1 Hz, 2F).
Conclusion
An efficient and general strategy to gem-difluoromethylenated
R,â-unsaturated δ-lactones from various aldehydes under mild
conditions in high yield was developed. This new approach had
entirely overcome the shortcomings of the early one to construct
the fluorinated unsaturated lactone structure unit via RCM
reaction. All the reactions were carried out at room temperature
and were insensitive to moisture and atmosphere. Furthermore,
the last three steps could be performed in sequence without
isolation of the intermediates. Using this strategy combined with
lipase-catalyzed enantioselective acylation, gem-difluorometh-
ylenated goniothalamin (S)-1 and (R)-1 were readily stereose-
lectively prepared in high enantiomer purity (99% ee) and good
yield, where the RCM reaction sequences were troublesome.
The generality and effectiveness of the strategy to construct gem-
difluoromethylenated δ-lactones were well demonstrated by
successful synthesis of various δ-substitution δ-lactones 14a-d
from corresponding aldehydes in high yield (52-73% over four
steps).
Experimental Section
19F NMR spectra were reported in ppm relative to FCCl3 as
outside standard and low field as positive.
(E)-4,4-Difluoro-1-phenylhexa-1,5-dien-3-ol (2). To a suspen-
sion of cinnamaldehyde (2.74 g, 20.7 mmol) and indium powder
(E)-7-(tert-Butyldimethylsilyloxy)-4,4-difluoro-1-phenylhept-
1-en-5-yn-3-ol ((()-6). To a stirred suspension of cinnamaldehyde
(2.99 g, 22.6 mmol) and 5 (8.81 g, 29.4 mmol) in H2O/THF (70
mL, 4/1, v/v) was added indium power (3.12 g, 27.2 mmol) at room
temperature. After stirring for 22 h, the reaction mixture was
quenched with a saturated solution of NH4Cl and was filtered
through Celite, and the filter cake was washed with ethyl acetate.
(19) Manthati, V. L.; Gree, D.; Gree, R. Eur. J. Org. Chem. 2005, 3825-
3829.
7264 J. Org. Chem., Vol. 71, No. 19, 2006

Synthesis of gem-Difluoromethylenated Goniothalamins
The aqueous layer was extracted with ethyl acetate, and the
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by flash chromatography on silica gel (petroleum ether:
ethyl acetate ) 10:1) to afford (()-6 (6.80 g, 85%) as a yellow
oil: 1H NMR (300 MHz, CDCl3) δ 7.38-7.42 (m, 2H), 7.24-
7.35 (m, 3H), 6.82 (d, J ) 15.9 Hz, 1H), 6.24 (dd, J ) 16.1, 6.5
Hz, 1H), 4.48-4.58 (m, 1H), 4.38 (t, J ) 4.5 Hz, 2H); 2.84 (br s,
1H), 0.88 (s, 9H), 0.10 (s, 6H); 13C NMR (75.5 MHz, CDCl3) δ
135.9, 135.4, 128.6, 128.4, 126.9, 122.3 (t, J ) 3.1 Hz), 113.4 (t,
J ) 238.4 Hz), 88.4 (t, J ) 6.8 Hz), 75.6 (t, J ) 39.7 Hz), 75.1 (t,
J ) 29.3 Hz), 51.3 (t, J ) 2.0 Hz), 25.7, 18.2, -5.2; 19F NMR
(282 MHz, CDCl3) δ -94.9 to -95.0 (m, 2F); IR (thin film) υmax
3417, 3030, 2957, 2932, 2860, 2258, 1656, 1579, 1498, 1473, 1465,
1257, 1106 cm-1; MS (ESI): m/z ) 370.2 [M + NH4]+, 375.2 [M
+ Na]+; HRMS (MALDI): m/z [M + Na]+ calcd for C19H26F2-
NaO2Si: 375.1562; found: 375.1574.
1F); IR (thin film) υmax 3396, 3031, 2931, 2859, 1664, 1473, 1257,
1098 cm-1; MS (ESI): m/z ) 377.2 [M + Na]+; HRMS (MAL-
DI): m/z [M + Na]+ calcd for C19H28F2NaO2Si: 377.1719;
found: 377.1733.
(S,2Z,6E)-4,4-Difluoro-7-phenylhepta-2,6-diene-1,5-diol ((S)-
9). A solution of TBAF in THF (1 M, 1.8 mL) was added to a
solution of (S)-8 (570 mg, 1.6 mmol) in THF (10 mL). After stirring
for 12 h, the reaction mixture was concentrated and purified by
flash chromatography on silica gel (petroleum ether:ethyl acetate
) 1:1) to afford (S)-9 (386 mg, quantitive yield) as a colorless oil:
1
[R]25 ) +21.6 (c 2.42, CHCl3); H NMR (300 MHz, CDCl3) δ
D
7.23-7.39 (m, 5H), 6.75 (d, J ) 16.5 Hz, 1H), 6.18 (dd, J ) 15.9,
6.3 Hz, 1H), 6.00-6.09 (m, 1H), 5.51-5.65 (m, 1H), 4.48 (dd, J
) 15.6, 9.3 Hz, 1H), 4.29-4.39 (m, 2H), 3.01 (br s, 2H); 13C NMR
(75.5 MHz, CDCl3) δ 138.6 (t, J ) 4.9 Hz), 135.9, 134.7, 128.7,
128.4, 126.8, 123.1 (dd, J ) 4.9, 1.9 Hz), 122.4 (t, J ) 25.9 Hz),
120.6 (t, J ) 245.1 Hz), 74.4 (t, J ) 31.0 Hz), 58.9 (t, J ) 3.6
Hz); 19F NMR (282 MHz, CDCl3) δ -100.7 (ddd, J ) 254.6, 13.7,
10.3 Hz, 1F), -102.9 (ddd, J ) 253.5, 13.5, 11.3 Hz, 1F); IR (thin
(R,E)-7-(tert-Butyldimethylsilyloxy)-4,4-difluoro-1-phenylhept-
1-en-5-yn-3-ol ((R)-6) and (S,E)-7-(tert-Butyldimethylsilyloxy)-
4,4-difluoro-1-phenylhept-1-en-5-yn-3-yl acetate (7). To a solu-
tion of alcohol (()-6 (6.87 g, 19.5 mmol) and vinyl acetate (8.74
mL, 94.6 mmol) in hexane (240 mL) was added the lipase (3.44 g,
0.5 mass equiv), activated 4 Å molecular sieves (3.44 g, 0.5 mass
equiv) at room temperature. After stirring for 24 h at 30 °C, the
reaction mixture was filtered and concentrated. The residue was
purified by flash chromatography on silica gel (petroleum ether:
ethyl acetate ) 20:1) to afford (R)-6 (3.37 g, 49% yield, 99% ee)
and compound 7 (3.57 g, 46%) both as yellow oils. Compound
(R)-6: Chiral HPLC (Chiralcel AD-H, 10% 2-propanol in hexane,
250 × 4.6 mm, 254 nm, 0.7 mL/min), tR ) 9.24 min (minor), tR )
film) υmax 3356, 3030, 2885, 1660, 1600, 1496, 1450, 1029 cm-1
;
MS (ESI): m/z ) 258.2 [M + NH4]+, 263.1 [M + Na]+, 279.2 [M
+ K]+; HRMS (MALDI): m/z [M + Na]+ calcd for C13H14F2-
NaO2: 263.0854; found: 263.0861.
(S,Z)-5,5-Difluoro-6-styryl-5,6-dihydropyran-2-one ((S)-1). To
a solution of (S)-9 (321 mg, 1.3 mmol) in CH2Cl2 (14 mL) was
added bis-acetoxyiodobenzene (1.29 g, 4.0 mmol) and 2,2,6,6-
tetramethyl-1-piperidinyloxy (42 mg, 20 mol %) at room temper-
ature. After stirring for 3 h, the reaction mixture was quenched
with a saturated solution of Na2S2O3 and was extracted with CH2-
Cl2. The combined organic extracts were washed with saturated
solutions of NaHCO3, NH4Cl, and brine; dried over anhydrous Na2-
SO4; filtered; and concentrated. The residue was purified by flash
chromatography on silica gel (petroleum ether:ethyl acetate ) 10:
1) to afford (S)-1 (278 mg, 88%) as a white solid: Mp ) 90-92
°C; [R]24D ) +111.7 (c 0.980, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.43-7.46 (m, 2H), 7.29-7.39 (m, 3H), 6.90 (d, J ) 15.6 Hz,
1H), 6.82-6.89 (m, 1H), 6.35 (d, J ) 9.9 Hz, 1H), 6.26 (dd, J )
15.9, 6.9 Hz, 1H), 5.12-5.22 (m, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 160.2 (t, J ) 2.5 Hz), 137.9, 137.8 (t, J ) 29.4 Hz),
135.2, 129.0, 128.8, 127.1, 126.6 (t, J ) 9.1 Hz), 117.1 (t, J ) 2.5
Hz), 112.1 (t, J ) 241.9 Hz), 80.2 (t, J ) 30.2 Hz); 19F NMR (282
MHz, CDCl3) δ -106.6 to -108.8 (m, 2F); IR (KBr) υmax 3065,
2920, 2852, 1742, 1645, 1452, 1106 cm-1; MS (ESI): m/z ) 254.1
[M + NH4]+, 259.1 [M + Na]+; HRMS (EI): m/z M+ calcd for
C13H10F2O2: 236.0649; found: 236.0647.
10.95 min (major); [R]26D ) -13.6 (c 1.79, CHCl3). Compound 7:
1
[R]26 ) +71.1 (c 1.68, EtOH); H NMR (300 MHz, CDCl3) δ
D
7.43-7.45 (m, 2H), 7.27-7.39 (m, 3H), 6.85 (d, J ) 15.9 Hz,
1H), 6.20 (dd, J ) 15.9, 7.5 Hz, 1H), 5.78 (dd, J ) 17.3, 8.6 Hz,
1H), 4.42 (t, J ) 4.5 Hz, 2H), 2.18 (s, 3H), 0.93 (s, 9H), 0.14 (s,
6H); 13C NMR (75.5 MHz, CDCl3) δ 169.1, 137.9, 135.5, 128.8,
128.7, 127.0, 119.0, 111.6 (t, J ) 237.9 Hz), 88.4 (t, J ) 6.7 Hz),
75.5 (t, J ) 39.3 Hz), 74.7 (t, J ) 31.0 Hz), 51.2, 25.7, 20.8, 18.2,
-5.2; 19F NMR (282 MHz, CDCl3) δ -93.4 to -93.5 (m, 2F); IR
(thin film) υmax 3031, 2958, 2860, 2257, 1757, 1655, 1580, 1498,
1473, 1225, 1106 cm-1; MS (ESI): m/z ) 412.1 [M + NH4]+, 417.1
[M + Na]+; HRMS (MALDI): m/z [M + Na]+ calcd for C21H28F2-
NaO3Si: 417.1668; found: 417.1674.
(S,E)-7-(tert-Butyldimethylsilyloxy)-4,4-difluoro-1-phenylhept-
1-en-5-yn-3-ol ((S)-6). A saturated solution of NH3 in MeOH (35
mL) was added to 7 (2.79 g, 7.1 mmol) at room temperature. After
stirring for 4 h, the reaction mixture was concentrated carefully by
rotary evaporation under reduced pressure. The residue was purified
by flash chromatography on silica gel (petroleum ether:ethyl acetate
) 10:1) to afford (S)-6 (2.24 g, 90%, 99% ee (determined by
(R,Z)-5,5-Difluoro-6-styryl-5,6-dihydropyran-2-one ((R)-1). To
a solution of (R)-6 (278 mg, 0.79 mmol) in hexane (8 mL) was
added Lindlar catalyst (45 mg) and quinoline (43 mg) at room
temperature. The suspension was stirred for 2 h before hydrogena-
tion. After stirring for another 3 h under hydrogen atmosphere, 19
F
HPLC)) as a yellow oil: [R]21 ) +12.6 (c 1.11, CHCl3).
D
NMR indicated the absence of starting material (R)-6. The reaction
mixture was filtered; washed with 1 M HCl, saturated NaHCO3,
and brine; dried over anhydrous Na2SO4; and concentrated to afford
crude (R)-8 as a yellow oil. The crude (R)-8 was dissolved in THF
(4 mL) followed by treatment with a solution of TBAF in THF (1
M, 0.87 mL) at room temperature. After stirring for 12 h, the solvent
was removed under reduced pressure. The resulting oil was
dissolved in ethyl acetate, washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated to afford crude (R)-9 as a yellow
oil. The crude (R)-9 was dissolved in CH2Cl2 (8 mL), followed by
treatment with bis-acetoxyiodobenzene (760 mg, 2.4 mmol) and
2,2,6,6-tetramethyl-1-piperidinyloxy (25 mg, 20 mol %) at room
temperature. After stirring for 3 h, the reaction mixture was
quenched with a saturated solution of Na2S2O3 and was extracted
with CH2Cl2. The combined organic extracts were washed with
saturated NaHCO3, NH4Cl, and brine; dried over anhydrous Na2-
SO4; filtered; and concentrated. The residue was purified by flash
chromatography on silica gel (petroleum ether:ethyl acetate ) 10:
(S,1E,5Z)-7-(tert-Butyldimethylsilyloxy)-4,4-difluoro-1-phen-
ylhepta-1,5-dien-3-ol ((S)-8). To a solution of (S)-6 (1.24 g, 3.5
mmol) in hexane (35 mL) was added Lindlar catalyst (201 mg)
and quinoline (194 mg) at room temperature. The suspension was
stirred for 2 h before hydrogenation. After stirring for another 2.5
h under hydrogen atmosphere, 19F NMR indicated the absence of
starting material (S)-6. The reaction mixture was filtered and
concentrated. The residue was purified by flash chromatography
on silica gel (petroleum ether:ethyl acetate ) 20:1) to afford (S)-8
(1.06 g, 85%) as a yellow oil: [R]25 ) -8.75 (c 2.17, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 7.26-7.43 (m, 5H), 6.80 (d, J )
15.9 Hz, 1H), 6.21 (dd, J ) 15.9, 6.3 Hz, 1H), 5.97-6.07 (m, 1H),
5.48-5.64 (m, 1H), 4.44-4.55 (m, 3H), 2.47 (br s, 1H), 0.91 (s,
9H), 0.07 (s, 6H); 13C NMR (75.5 MHz, CDCl3) δ 140.8 (t, J )
4.4 Hz), 136.1, 134.7, 128.6, 128.3, 126.8, 123.2 (dd, J ) 4.4, 2.9
Hz), 120.6 (t, J ) 244.9 Hz), 120.2 (t, J ) 26.1 Hz), 74.7 (t, J )
30.0 Hz), 60.0 (t, J ) 3.7 Hz), 25.9, 18.3, -5.3; 19F NMR (282
MHz, CDCl3) δ -101.5 to -102.5 (m, 1F), -103.1 to -104.1 (m,
J. Org. Chem, Vol. 71, No. 19, 2006 7265

You et al.
1) to afford (R)-1 (126 mg, 68% for three steps) as a white solid:
-94.9 to -95.9 (m, 1F), -96.0 to -97.0 (m, 1F); IR (thin film)
Mp ) 89-91 °C; [R]22 ) -108.2 (c 2.00, CHCl3).
υ ;
max 3426, 3039, 2933, 2860, 2259, 1677, 1473, 1257, 1103 cm-1
D
MS (ESI): m/z ) 308.1 [M + NH4]+, 329.0 [M + K]+; HRMS
(MALDI): m/z [M + Na]+ calcd for C14H24F2NaO2Si: 313.1406;
found: 313.1404.
(S)-5,5-Difluoro-6-((2S,3R)-3-phenyloxiran-2-yl)-5,6-dihydro-
pyran-2-one (10a) and (S)-5,5-Difluoro-6-((2R,3S)-3-phenyloxi-
ran-2-yl)-5,6-dihydropyran-2-one (10b). To a solution of (S)-1
(214 mg, 0.91 mmol) in CH2Cl2 (4.5 mL) was added m-CPBA (313
mg, 1.8 mmol) at room temperature. After stirring at reflux for 20
h, the reaction mixture was quenched with 5% Na2S2O3 solution
and was extracted with CH2Cl2. The combined organic extracts were
washed with saturated NaHCO3 and brine, dried over anhydrous
Na2SO4, filtered, and concentrated. The residue was purified by
flash chromatography on silica gel (petroleum ether:ethyl acetate
) 10:1) to afford 10a (132 mg) and 10b (65 mg) in 95% total
1-(tert-Butyldimethylsilyloxy)-4,4-difluorodec-2-yn-5-ol (11d).
Colorless oil (670 mg, 77%). 1H NMR (300 MHz, CDCl3) δ 4.40
(t, J ) 4.4 Hz, 2H), 3.74-3.84 (m, 1H). 1.90 (s, 1H), 1.25-1.78
(m, 8H), 0.88-0.94 (m, 3H), 0.91 (s, 9H), 0.13 (s, 6H); 13C NMR
(75.5 MHz, CDCl3) δ 114.4 (t, J ) 236.7 Hz), 87.8 (t, J ) 6.4
Hz), 75.8 (t, J ) 39.6 Hz), 74.2 (t, J ) 28.0 Hz), 51.3 (t, J ) 2.0
Hz), 31.5, 30.2 (t, J ) 1.5 Hz), 25.7, 25.0, 22.5, 18.2, 14.0, -5.2;
19F NMR (282 MHz, CDCl3) δ -95.3 to -96.3 (m, 1F), -96.4 to
-97.4 (m, 1F); IR (thin film) υmax 3443, 2958, 2933, 2862, 2258,
1472, 1364, 1257, 1106 cm-1; MS (ESI): m/z ) 321.2 [M + H]+,
338.4 [M + NH4]+, 343.3 [M + Na]+; HRMS (ESI): m/z [M +
Na]+ calcd for C16H30F2NaO2Si: 343.1875; found: 343.1879.
General Procedure for the Preparation of Compounds 12a-
d. To a solution of 11a (145 mg, 0.44 mmol) in hexane (7 mL)
was added Lindlar catalyst (19 mg) at room temperature. After
stirring under hydrogen atmosphere for 21 h, the reaction mixture
was filtered and concentrated. The residue was purified by flash
chromatography on silica gel (petroleum ether:ethyl acetate ) 10:
1) to afford 12a (146 mg, 100% yield).
yield as both white solids. Compound 10a: [R]22 ) +122.6 (c
D
1.37, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.29-7.41 (m, 5H),
6.88 (ddd, J ) 10.3, 8.0, 2.3 Hz, 1H), 6.35 (dd, J ) 10.2 Hz, 1H),
4.58 (dt, J ) 18.9, 5.1 Hz, 1H), 4.07 (d, J ) 1.5 Hz, 1H), 3.47 (dd,
J ) 5.1, 1.8 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 159.2 (t, J
) 2.3 Hz), 137.6 (dd, J ) 32.1, 25.4 Hz), 135.2, 128.9 (t, J ) 20.1
Hz), 128.7 (t, J ) 19.9 Hz), 126.6 (dd, J ) 10.1, 8.2 Hz), 125.8 (t,
J ) 19.9 Hz), 112.2 (dd, J ) 245.8, 240.2 Hz), 78.0 (dd, J ) 31.9,
28.0 Hz), 56.5 (d, J ) 4.5 Hz), 55.5; 19F NMR (282 MHz, CDCl3)
δ -106.6 (dd, J ) 292.0, 18.5 Hz, 1F), -110.0 (dt, J ) 291.0, 6.7
1
Hz, 1F). Compound 10b: [R]26 ) -123.0 (c 0.895, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 7.34-7.42 (m, 3H), 7.26-7.30 (m,
2H), 6.79 (dddd, J ) 10.2, 6.4, 3.8, 1.3 Hz, 1H), 6.38 (d, J ) 10.2
Hz, 1H), 4.83-4.90 (m, 1H), 4.01 (d, J ) 2.1 Hz, 1H), 3.42 (dd,
J ) 4.6, 2.3 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 159.0 (t, J
) 2.2 Hz), 135.5 (dd, J ) 30.8, 26.8 Hz), 134.9, 129.0 (t, J ) 20.0
Hz), 128.7 (t, J ) 19.9 Hz), 127.5 (t, J ) 10.0 Hz), 125.8 (t, J )
20.5 Hz), 112.5 (dd, J ) 242.7, 241.4 Hz), 76.9 (dd, J ) 31.4,
28.0 Hz), 57.3 (t, J ) 5.2 Hz), 54.1; 19F NMR (282 MHz, CDCl3)
δ -92.6 (ddd, J ) 291.4, 9.7, 3.2 Hz, 1F), -110.6 (ddt, J ) 291.3,
6.2, 2.4 Hz, 1F).
(Z)-5-(tert-Butyldimethylsilyloxy)-2,2-difluoro-1-phenylpent-
3-en-1-ol (12a). Colorless oil (146 mg, quantitive yield). 1H NMR
(300 MHz, CDCl3) δ 7.40-7.44 (m, 2H). 7.33-7.38 (m, 3H),
5.85-5.95 (m, 1H), 5.32-5.48 (m, 1H), 4.89 (td, J ) 9.6, 3.6 Hz,
1H), 4.06-4.26 (m, 2H), 2.79 (br s, 1H), 0.87 (s, 9H), 0.02 (s,
6H); 13C NMR (75.5 MHz, CDCl3) δ 140.8 (t, J ) 4.8 Hz), 136.0
(t, J ) 2.3 Hz), 128.8, 128.2, 127.6, 120.8 (t, J ) 245.1 Hz), 119.8
(t, J ) 26.8 Hz), 76.1 (t, J ) 29.0 Hz), 59.7 (t, J ) 3.9 Hz), 25.9,
18.2, -5.3; 19F NMR (282 MHz, CDCl3) δ -101.7 to -102.7 (m,
1F). -102.9 to -103.9 (m, 1F); IR (thin film) υmax 3409, 3068,
3037, 2957, 2931, 2859, 1668, 1497, 1473, 1456, 1257, 1060 cm-1
;
Compounds 11a-d were prepared from corresponding aldehydes
using the same procedure of preparation of alcohol (()-6.
5-(tert-Butyldimethylsilyloxy)-2,2-difluoro-1-phenylpent-3-yn-
1-ol (11a). Colorless oil (205 mg, 83%). 1H NMR (300 MHz,
CDCl3) δ 7.48-7.51 (m, 2H), 7.35-7.45 (m, 3H), 4.93 (t, J ) 8.9
Hz, 1H), 4.34 (t, J ) 4.5 Hz, 2H), 2.43 (br s, 1H), 0.88 (s, 9H),
0.07 (s, 6H);13C NMR (75.5 MHz, CDCl3) δ 135.4, 129.0. 128.2,
127.9, 113.6 (t, J ) 238.1 Hz), 88.8 (t, J ) 13.4 Hz), 76.3 (t, J )
58.4), 75.7 (t, J ) 75.7 Hz), 51.2 (t, J ) 2.0 Hz), 25.7, 18.2, -5.3;
19F NMR (282 MHz, CDCl3) δ -94.2 to -94.3 (m, 2F); IR (thin
film) υmax 3396, 3038, 2932, 2860, 2258, 1496, 1473, 1456, 1199,
1062, 781, 701 cm-1; MS (ESI): m/z ) 344.1 [M + NH4]+; HRMS
MS (ESI): m/z ) 329.1 [M + H]+; HRMS (MALDI): m/z [M +
Na]+ calcd for C17H26F2NaO2Si: 351.1562; found: 351.1568.
(Z)-5-(tert-Butyldimethylsilyloxy)-1-(2,6-dichlorophenyl)-2,2-
difluoropent-3-en-1-ol (12b). Colorless oil (354 mg, quantitive
1
yield). H NMR (300 MHz, CDCl3) δ 7.30 (t, J ) 9.0 Hz, 2H),
7.15-7.21 (m, 1H), 5.86-5.95 (m, 1H), 5.46-5.68 (m, 2H), 4.17-
4.45 (m, 2H), 3.94 (br s, 1H), 0.84 (s, 9H), 0.00 (s, 6H); 13C NMR
(75.5 MHz, CDCl3) δ 140.8 (t, J ) 4.8 Hz), 136.9, 134.4, 130.9,
130.5, 130.1, 129.0, 120.9 (t, J ) 247.9 Hz), 120.6 (t, J ) 26.0
Hz), 74.2 (t, J ) 30.1 Hz), 59.9 (t, J ) 4.1 Hz), 25.9 (t, J ) 19.6
Hz), 18.3, -5.3; 19F NMR (282 MHz, CDCl3) δ -100.5 to -100.7
(m, 2F); IR (thin film) υmax 3450, 2957, 2931, 2859, 1564, 1438,
1256, 1097 cm-1; MS (ESI): m/z ) 397.1 [M + H]+, 419.1 [M +
Na]+; HRMS (ESI): m/z [M + Na]+ calcd for C17H24Cl2F2NaO2-
Si: 419.0783; found: 419.0782.
-
(EI): m/z [M+ HF] calcd for C17H23FO2Si: 306.1451; found:
306.1461.
5-(tert-Butyldimethylsilyloxy)-1-(2,6-dichlorophenyl)-2,2-di-
fluoropent-3-yn-1-ol (11b). Colorless oil (715 mg, 80%). 1H NMR
(300 MHz, CDCl3) δ 7.16-7.39 (m, 3H), 5.75-5.87 (m, 1H), 4.36
(t, J ) 4.5 Hz, 2H), 4.08 (d, J ) 12.9 Hz, 1H), 0.89 (s, 9H), 0.09
(s, 6H); 13C NMR (75.5 MHz, CDCl3) δ 137.2, 134.4, 130.4, 130.3,
129.0, 113.0 (t, J ) 241.3 Hz), 88.5 (t, J ) 6.3 Hz), 75.9 (t, J )
38.6 Hz), 74.8 (t, J ) 29.5 Hz), 51.3 (t, J ) 1.9 Hz). 25.7 (t, J )
20.2 Hz), 18.2, -5.3; 19F NMR (282 MHz, CDCl3) δ -90.3 to
-91.4 (m, 1F), -91.6 to -92.6 (m, 1F); IR (thin film) υmax 3568,
(2E,6Z)-8-(tert-Butyldimethylsilyloxy)-5,5-difluoroocta-2,6-
dien-4-ol (12c). Colorless oil (246 mg, 96%). 1H NMR (300 MHz,
CDCl3) δ 5.84-6.02 (m, 2H), 5.41-5.57 (m, 2H), 4.40-4.45 (m,
2H), 4.19-4.28 (m, 1H), 2.24 (br s, 1H), 1.74-1.77 (m, 3H), 0.90
(s, 9H), 0.07 (s, 6H); 13C NMR (75.5 MHz, CDCl3) δ 140.5 (t, J
) 4.7 Hz), 132.1, 125.3 (dd, J ) 4.0, 2.4 Hz), 120.5 (t, J ) 244.5
Hz), 120.2 (t, J ) 25.9 Hz), 74.7 (dd, J ) 30.7, 29.0 Hz), 60.1 (t,
J ) 3.9 Hz), 25.9, 18.3, 17.9, -5.3; 19F NMR (282 MHz, CDCl3)
δ -102.8 to -103.8 (m, 1F), -104.3 to -105.3 (m, 1F); IR (thin
film) υmax 3418, 3039, 2958, 2932, 2860, 1668, 1475, 1464, 1257,
1095 cm-1; MS (ESI): m/z ) 293.2 [M + H]+, 315.1 [M + Na]+;
HRMS (EI): m/z [M+-CH3CtCH] calcd for C11H22F2O2Si:
252.1357; found: 252.1361.
3455, 3081, 2957, 2931, 2257, 1582, 1564, 1473, 1438, 1101 cm-1
;
MS (ESI): m/z ) 395.2 [M + H]+, 412.1 [M + NH4]+, 417.1 [M
+ Na]+; HRMS (MALDI): m/z [M + Na]+ calcd for C17H22Cl2F2-
NaO2Si: 417.0626; found: 417.0628.
(E)-8-(tert-Butyldimethylsilyloxy)-5,5-difluorooct-2-en-6-yn-
1
4-ol (11c). Yellowish oil (630 mg, 74%). H NMR (300 MHz,
CDCl3) δ 5.87-5.99 (m, 1H), 5.50-5.58 (m, 1H), 4.38 (t, J ) 4.4
Hz, 2H), 4.24-4.30 (m, 1H), 2.73 (d, J ) 3.9 Hz, 1H), 1.74-1.76
(m, 3H), 0.89 (s, 9H), 0.11 (s, 6H); 13C NMR (75.5 MHz, CDCl3)
δ 132.8, 124.8 (t, J ) 2.9 Hz), 113.4 (t, J ) 237.3 Hz), 88.0 (t, J
) 6.6 Hz), 75.8 (t, J ) 39.3 Hz), 75.0 (t, J ) 29.7 Hz), 51.3 (t, J
) 2.1 Hz), 25.7, 18.2, 17.9, -5.3; 19F NMR (282 MHz, CDCl3) δ
(Z)-1-(tert-Butyldimethylsilyloxy)-4,4-difluorodec-2-en-5-ol
(12d). Colorless oil (185 mg, 92%). H NMR (300 MHz, CDCl3)
δ 5.94-6.03 (m, 1H), 5.42-5.59 (m, 1H), 4.41-4.46 (m, 2H),
3.69-3.79 (m, 1H), 1.78 (br s, 1H), 1.26-1.59 (m, 8H), 0.88-
0.92 (m, 3H), 0.90 (s, 9H), 0.08 (s, 6H); 13C NMR (75.5 MHz,
CDCl3) δ 140.4 (t, J ) 4.9 Hz), 121.5 (t, J ) 243.9 Hz), 120.3 (t,
1
7266 J. Org. Chem., Vol. 71, No. 19, 2006

Synthesis of gem-Difluoromethylenated Goniothalamins
-
J ) 26.7 Hz), 73.9 (t, J ) 29.2 Hz), 60.0 (t, J ) 3.9 Hz), 31.6,
29.9 (t, J ) 2.8 Hz), 25.9, 25.2, 22.5, 18.3, 14.0, -5.2; 19F NMR
(282 MHz, CDCl3) δ -102.5 to -103.5 (m, 1F), -104.9 to -105.8
(m, 1F); IR (thin film) υmax 3424, 2938, 2922, 2860, 1668, 1472,
1465, 1410, 1257, 1099 cm-1; MS (ESI): m/z ) 323.2 [M + H]+;
HRMS (EI): m/z [M - H]+ calcd for C16H31F2O2Si: 321.2061;
found: 321.2051.
(ESI): m/z ) 226.1 [M + NH4]+; HRMS (EI): m/z [M+ OH]
calcd for C10H17F2O: 191.1247; found: 191.1239.
Compounds 14a-d were prepared from 13a-d using the same
procedure of preparation of compound (S)-1.
5,5-Difluoro-6-phenyl-5,6-dihydropyran-2-one (14a). White
solid (28 mg, 92%). Mp ) 95-97 °C; 1H NMR (300 MHz, CDCl3)
δ 7.42-7.50 (m, 5H), 6.91 (ddd, J ) 10.0, 8.3, 1.6 Hz, 1H), 6.40
(dt, J ) 10.0, 1.2 Hz, 1H), 5.57 (dd, J ) 20.3, 5.0 Hz, 1H); 13C
NMR (75.5 MHz, CDCl3) δ 160.7, 138.3 (dd, J ) 34.6, 25.0 Hz),
130.0, 129.9, 128.5, 128.1, 126.4 (t, J ) 9.0 Hz), 111.8 (dd, J )
247.9, 236.5 Hz), 80.7 (dd, J ) 32.4, 27.1 Hz); 19F NMR (282
MHz, CDCl3) δ -105.2 (dd, J ) 289.0, 20.2 Hz, 1F), -110.2 (dt,
J ) 288.3, 6.5 Hz, 1F); IR (KBr) υmax 3077, 2955, 2925, 2854,
1742, 1638, 1501, 1459, 1276 cm-1; MS (ESI): m/z ) 228.1 [M +
NH4]+, 233.0 [M + Na]+; HRMS (EI): m/z M+ calcd for
C11H8F2O2: 210.0499; found: 210.0492.
6-(2,6-Dichlorophenyl)-5,5-difluoro-5,6-dihydropyran-2-one
(14b). Colorless oil (18 mg, 96%). 1H NMR (300 MHz, CDCl3) δ
7.39-7.44 (m, 2H), 7.26-7.34 (m, 1H), 6.92 (ddd, J ) 10.2, 8.4,
1.8 Hz, 1H), 6.56 (dd, J ) 22.5, 8.1 Hz, 1H), 6.45-6.49 (m, 1H);
13C NMR (75.5 MHz, CDCl3) δ 159.5, 137.4 (dd, J ) 32.1, 25.6
Hz), 137.3, 136.5, 131.4, 130.9, 128.5, 126.7 (dd, J ) 9.7, 8.0 Hz),
126.0, 112.2 (dd, J ) 251.8, 236.0 Hz), 77.9 (dd, J ) 36.6, 25.8
Hz); 19F NMR (282 MHz, CDCl3) δ -94.3 (dd, J ) 288.3, 22.1
Hz, 1F), -103.4 (dt, J ) 288.5, 8.2 Hz, 1F); IR (thin film) υmax
3082, 2926, 2854, 1748, 1649, 1582, 1565, 1439, 1114 cm-1; MS
(ESI): m/z ) 279.0 [M + H]+, 296.0 [M + NH4]+; HRMS (EI):
m/z M+ calcd for C11H6Cl2F2O2: 277.9713; found: 277.9718.
(E)-5,5-Difluoro-6-(prop-1-enyl)-5,6-dihydropyran-2-one (14c).
Colorless oil (16 mg, 82%). 1H NMR (300 MHz, CDCl3) δ 6.78-
6.86 (m, 1H), 6.31 (d, J ) 10.2 Hz, 1H), 6.02-6.13 (m, 1H), 5.63
(qd, J ) 7.7, 1.4 Hz, 1H), 4.93 (td, J ) 11.6, 7.8 Hz, 1H). 1.83
(dd, J ) 6.8, 1.1 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) δ 160.5
(t, J ) 2.0 Hz), 137.9 (dd, J ) 29.7, 28.8 Hz), 136.3, 126.6 (t, J
) 8.9 Hz), 119.8 (dd, J ) 3.6, 2.0 Hz), 112.1 (dd, J ) 242.1,
240.4 Hz), 80.3 (dd, J ) 31.1, 29.8 Hz), 18.1; 19F NMR (282 MHz,
CDCl3) δ -108.5 (dd, J ) 11.4, 4.4 Hz, 2F); IR (thin film) υmax
3076, 2925, 2861, 1751, 1677, 1643, 1383, 1285, 1069 cm-1; MS
(EI): m/z (%) ) 174 (1) M+, 104 (100), 76 (48); HRMS (EI): m/z
M+ calcd for C8H8F2O2: 174.0492; found: 174.0497.
Compounds 13a-d were prepared from 12a-d using the same
procedure of preparation of compound (S)-9.
(Z)-4,4-Difluoro-5-phenylpent-2-ene-1,5-diol (13a). Colorless
1
oil (88 mg, 94%). H NMR (300 MHz, CDCl3) δ 7.32-7.43 (m,
5H), 5.88-5.99 (m, 1H), 5.36-5.52 (m, 1H), 4.88 (t, J ) 9.3 Hz,
1H), 4.09-4.18 (m, 1H), 3.96-4.05 (m, 1H), 3.70 (br s, 1H), 2.18
(br s, 1H); 13C NMR (75.5 MHz, CDCl3) δ 138.4 (t, J ) 5.2 Hz),
136.1 (dd, J ) 4.5, 1.4 Hz), 128.8, 128.2, 127.7, 122.0 (t, J ) 26.7
Hz), 120.8 (t, J ) 245.8 Hz), 75.7 (t, J ) 30.0 Hz), 58.7 (t, J )
3.4 Hz); 19F NMR (282 MHz, CDCl3) δ -99.8 to -100.8 (m, 1F),
-101.2 to -102.2 (m, 1F); IR (thin film) υmax 3367, 3039, 2918,
2854, 1668, 1497, 1455, 1029 cm-1; MS (ESI): m/z ) 232.1 [M +
NH4]+, 237.0 [M + Na]+; HRMS (ESI): m/z [M + Na]+ calcd for
C11H12F2NaO2: 237.0698; found: 237.0698.
(Z)-5-(2,6-Dichlorophenyl)-4,4-difluoropent-2-ene-1,5-diol (13b).
White solid (40 mg, 95%); Mp ) 67-69 °C. 1H NMR (300 MHz,
CDCl3) δ 7.35 (t, J ) 7.4 Hz, 2H), 7.20-7.27 (m, 1H). 5.97-6.06
(m, 1H), 5.60-5.74 (m, 2H), 4.24-4.43 (m, 3H), 2.12 (br s, 1H);
13C NMR (75.5 MHz, CDCl3) δ 138.8 (t, J ) 5.1 Hz), 136.9, 134.5,
130.7, 130.5, 130.2, 129.0, 122.7 (dd, J ) 27.4, 25.8 Hz), 120.9
(dd, J ) 248.7, 247.3 Hz), 74.0 (dd, J ) 31.9, 28.8 Hz), 59.0 (t, J
) 4.1 Hz); 19F NMR (282 MHz, CDCl3) δ -99.4 (ddd, J ) 252.1,
13.6, 10.0 Hz, 1F), -101.1 (dt, J ) 253.3, 15.9 Hz, 1F); IR (KBr)
υmax 3365, 2929, 1581, 1564, 1438, 1035 cm-1; MS (ESI): m/z )
305.1 [M + Na]+; HRMS (ESI): m/z [M + Na]+ calcd for C11H10-
Cl2F2NaO2: 304.9918; found: 304.9920.
(2Z,6E)-4,4-Difluoroocta-2,6-diene-1,5-diol (13c). Yellow oil
(78 mg, 90%). 1H NMR (300 MHz, CDCl3) δ 6.00-6.10 (m, 1H),
5.85-5.96 (m, 1H), 5.46-5.64 (m, 2H), 4.32-4.43 (m, 2H), 4.25
(dd, J ) 16.4, 9.5 Hz, 1H), 2.76 (br s, 1H), 2.20 (br s, 1H), 1.76
(d, J ) 6.3 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) δ 138.5 (t, J )
5.3 Hz), 132.2, 125.3 (dd, J ) 4.1, 2.6 Hz), 122.4 (t, J ) 26.4 Hz),
120.5 (t, J ) 244.5 Hz), 74.5 (t, J ) 30.2 Hz), 59.0 (t, J ) 3.4
Hz), 17.9; 19F NMR (282 MHz, CDCl3) δ -101.0 to -102.0 (m,
1F), -103.3 to -104.3 (m, 1F); IR (thin film) υmax 3350, 2922,
1672, 1450, 1413, 1026 cm-1; MS (ESI): m/z ) 196.1 [M + NH4]+,
201.1 [M + Na]+; HRMS (EI): m/z M+ calcd for C8H12F2O2:
178.0805; found: 178.0807.
5,5-Difluoro-6-pentyl-5,6-dihydropyran-2-one (14d). Yellow-
ish oil (40 mg, 85%). 1H NMR (300 MHz, CDCl3) δ 6.80 (ddd, J
) 10.2, 7.4, 2.9 Hz, 1H), 6.30 (d, J ) 10.2 Hz, 1H), 4.47 (ddd, J
) 17.3, 13.3, 7.3 Hz, 1H), 1.86 (dd, J ) 14.6, 7.4 Hz, 2H), 1.26-
1.76 (m, 6H), 0.89-0.94 (m, 3H); 19F NMR (282 MHz, CDCl3) δ
-109.5 (dd, J ) 288.3, 16.8 Hz), -110.5 (dt, J ) 287.9, 7.2 Hz).
(Z)-4,4-Difluorodec-2-ene-1,5-diol (13d). Colorless oil (81 mg,
1
88%). H NMR (300 MHz, CDCl3) δ 6.00-6.06 (m, 1H), 5.47-
Acknowledgment. We thank the National Natural Science
Foundation of China, Ministry of Education of China, and
Shanghai Municipal Scientific Committee for funding this work.
5.61 (m, 1H), 4.22-4.41 (m, 2H). 3.65-3.76 (m, 1H), 3.54 (s,
1H), 3.47 (s, 1H), 1.20-1.65 (m, 8H), 0.86-0.90 (m, 3H); 13C
NMR (75.5 MHz, CDCl3) δ 138.2 (t, J ) 5.2 Hz), 122.5 (dd, J )
27.4, 26.0 Hz), 121.4 (t, J ) 244.4 Hz), 73.6 (dd, J ) 30.9, 28.8
Hz), 58.8 (t, J ) 3.5 Hz), 31.6, 29.9 (dd, J ) 7.3, 1.3 Hz), 25.3,
22.5, 14.0; 19F NMR (282 MHz, CDCl3) δ -101.0 (dt, J ) 254.4,
6.8 Hz, 1F), -104.7 (dt, J ) 254.4, 13.0 Hz, 1F); IR (thin film)
υmax 3344, 2958, 2932, 2863, 1668, 1464, 1413, 1033 cm-1; MS
1
Supporting Information Available: Copies of H NMR and
13C NMR spectra of all the compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO061012R
J. Org. Chem, Vol. 71, No. 19, 2006 7267