Synthesis of (±)-4′-ethynyl-5′,5′-difluoro-2′,3′-dehydro-3′-deoxy- carbocyclic thymidine: a difluoromethylidene analogue of promising anti-HIV agent Ed4T

Article abstract of DOI:10.1016/j.tet.2009.06.095

Synthesis of (±)-4′-ethynyl-5′,5′-difluoro-2′,3′-dehydro-3′-deoxy-carbocyclic-thymidine (8) was carried out. The difluoromethylylidene group of 8 was constructed by the electrophilic fluorination to the cyclopentenone 11 by using Selectfluor. I

Full text of DOI:10.1016/j.tet.2009.06.095

Tetrahedron 65 (2009) 7630–7636
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Synthesis of (ꢀ)-40-ethynyl-50,50-difluoro-20,30-dehydro-30-deoxy- carbocyclic
thymidine: a difluoromethylidene analogue of promising anti-HIV agent Ed4T
,
a
a
a
a
Hiroki Kumamoto a , Kazuhiro Haraguchi , Mayumi Ida , Kazuo T. Nakamura , Yasuyuki Kitagawa ,
*
Takayuki Hamasaki b, Masanori Baba b, Satoko Shimbara Matsubayashi a, Hiromichi Tanaka a
a School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
b Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences,
Kagoshima University, Kagoshima 890-8544, Japan
a r t i c l e i n f o
a b s t r a c t
Synthesis of (ꢀ)-40-ethynyl-50,50-difluoro-20,30-dehydro-30-deoxy-carbocyclic-thymidine (8) was carried
out. The difluoromethylylidene group of 8 was constructed by the electrophilic fluorination to the
cyclopentenone 11 by using SelectfluorÒ. Introduction of thymine base was investigated based on the
Mitsunobu reaction by employing cyclopentenyl allyl alcohols variously substituted at the 4-position. It
was found the 4-methoxycarbonyl derivative 14 gave the highest selectivity both in terms of regio- and
stereochemistry.
Article history:
Received 7 April 2009
Received in revised form 25 June 2009
Accepted 25 June 2009
Available online 30 June 2009
Keywords:
Carbocyclic nucleoside
d4T
Ó 2009 Elsevier Ltd. All rights reserved.
gem-Difluoromethylidene
Mitsunobu reaction
O
1. Introduction
Me
O
Me
NH
O
The finding that thymidine derivatives having 40-azido (1),1 40-
cyano (2),2 and 40-ethynyl (3)3 substituents show significant in-
hibitory activity against HIV proliferation stimulated the synthesis
of 40-substituted thymidine analogues (Fig. 1). As a result of our
studies carried out along this line, the 40-ethynyl derivative (Ed4T,
5)4 of stavudine (d4T, 4) was found to be a promising anti-HIV agent:
more anti-HIV active than d4T; has a lower cellular and mitochon-
drial toxicity than d4T;4a,b active against many drug-resistant HIV-1
strains, in which the reverse transcriptase (RT) bears amino acid
substitutions such as M184V (3TC-resistant) and A62V/V75I/F77L/
F116Y/Q151M (multidrug-resistant);4c its 50-triphosphate showed
much less inhibitory effects toward major host DNA polymerases.4d
This compound (5) has recently entered into Phase I clinical trial.
As a part of the structure–activity relationship studies of 5,
synthesis of the carbocyclic (6)5 and the 40-thio (7)6 analogues has
also been carried out. In the present study, we designed and syn-
thesized 8, in which the furanose ring oxygen of 5 is replaced with
a geminal-difluoromethylidene (CF2) group, because the CF2 group
has been suggested to work as an isopolar and isosteric substituent
for oxygen.7
NH
O
HO
N
1'
HO
N
O
O
4'
3' 2'
R
R
HO
1: R = N3
4: R = H (d4T)
5: R = ethynyl (Ed4T)
2: R = CN
3: R = ethynyl
O
Me
X
Me
O
NH
O
NH
F
F
HO
6'
N
HO
N
5'
4'
O
1'
3' 2'
6: X = CH2
7: X = S
8
Figure 1. Compounds 1–8.
2. Results and discussion
2.1. Preparation of allylalcohol (9)
For the preparation of the gem-difluoro carbocyclic unit 9, the
cyclopentenol 10 reported from our laboratory,5 was selected
(Scheme 1). Oxidation of 10 by using PDC gave the cyclopentenone
* Corresponding author. Tel.: þ81 3 3784 8187; fax: þ81 3 3784 8252.
E-mail address: kumamoto@pharm.showa-u.ac.jp (H. Kumamoto).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.095

H. Kumamoto et al. / Tetrahedron 65 (2009) 7630–7636
7631
11. To introduce the fluorine atom, the ketone 10 was first con-
verted to the corresponding silyl enol ether, and then reacted with
SelectfluorÒ.8 This procedure gave the monofluorinated ketone 12
in 82% yield. Simply by repeating this procedure for 12, the
difluorocyclopentenone 13 was obtained in moderate yield. It was
fortunate that the Luche reduction9 of 13 proceeded stereo-
selectively to give the alcohol 14 as the sole product. The stereo-
chemistry of 14 was confirmed by NOE experiments.10
the substituent at the 4-position of 9 could have a significant in-
fluence on the regiochemical bias.
To inspect our assumption, two 4-substituted cyclopentenyl
alcohols 18 and 19 (Fig. 2) were prepared from the 4-methoxy-
carbonyl derivative 14. The 4,4-bis-(tert-butyldiphenylsilyloxy)-
methyl derivative 18 was prepared by the following sequence of
reactions: protection of the allyl alcohol, reduction of the ester
group followed by protection of the resulting primary alcohol as
TBDPS ether, and finally deprotection of the allyl alcohol.
Compound 14 was also converted to the cyano derivative 19: partial
reduction of the ester to give the aldehyde, oxime formation,
O-acetylation, and elimination.
PgO
PgO
b
a
OH
O
MeO2C
MeO2C
10
11
F
F
Pg = tert-butyldiphenylsilyl (TBDPS)
F F
TBDPSO
NC
TBDPSO
TBDPSO
F
F
F
OH
OH
PgO
PgO
c
d
O
O
MeO2C
18
Figure 2. Compounds 18 and 19.
19
MeO2C
12
13
F
F
As shown in Scheme 3, upon being reacted with N3-ben-
zoylthymine under similar conditions to the case of 9, 18 gave
a mixture of 20 and the SN20 product (21) with a slightly improved
SN2-selectivity. In contrast, the cyano derivative (19) gave exclu-
sively the SN20 product (22).17 The highest SN2-selectivity was ob-
served in the reaction of the 4-methoxycarbonyl derivative 14,
forming 23 as the sole product in 58% yield.
F
F
PgO
PgO
e
OH
OH
MeO2C
14
9
Scheme 1. Reagents and conditions: (a) PDC, CH2Cl2 (78%); (b) (i) TMSCl, Li/HMDS,
THF, ꢁ78 ꢂC, (ii) SelectfluorÒ, MeCN; (c) (i) TMSCl, Li/HMDS, THF, ꢁ78 ꢂC, (ii) Select-
fluorÒ, MeCN (76% from 11); (d) NaBH4, CeCl3$7H2O, MeOH, THF, ꢁ78 ꢂC (quant); (e) (i)
DIBAL-H, CH2Cl2, ꢁ78 ꢂC, (ii) P(O)(OMe)2C(N2)COMe (15), K2CO3, MeOH (81% from 14).
F
F
TBDPSO
18: R = CH2OTBDPS
19: R = CN
14: R = CO2Me
OH
Conversion of the ester function of 14 to an ethynyl group was
carried out by partial reduction with DIBAL-H, which was followed
by treatment with the Ohira–Bestman reagent (15)11 in the pres-
ence of K2CO3. This procedure gave the desired cyclopentenol 9 in
81% yield in two steps.
R
3
1) N -benzoylthymine
DIAD, Ph3P, THF
2) K2CO3, MeOH
or
NH3/MeOH
2.2. Introduction of thymine base through the Mitsunobu
reaction
F
F
TBDPSO
Me
N
O
R
F
F
TBDPSO
NH
Introduction of thymine base was next examined (Scheme 2).
Compound 9 was reacted with N3-benzoylthymine under the
conventional Mitsunobu conditions12 (DIAD and Ph3P in THF, at rt).
After removal of the N3-benzoyl group, there were formed three
+
N
Me
O
O
R
NH
O
N1-alkylated products: one was the desired 16 and others were 17
a
21: R = CH2OTBDPS (16%)
22: R = CN (55%)
20: R = CH2OTBDPS (41%)
23: R = CO2Me (58%)
and 17b 13
confirmed by NOE experiments.14 The fact that 16 was formed
through SN2 process, while 17 and 17
resulted from SN20 process
came from their HMBC spectra: in the case of 16, the correlation
was observed between H-60 protons ( 3.90 and 3.94) and sp2-hy-
bridized carbon (C-30,
136.6); in the cases of 17 and 17 , the
correlation between H-60 protons and sp3-hybridized carbon (C-30,
.
The depicted stereochemistry of these products was
Scheme 3. Mitsunobu reaction of compounds 18, 19 and 14.
a
b
Since methoxycarbonyl group is not seemingly bulky enough,
one may consider that the above observed exclusive formation of
23 from 14 is not a consequence of its bulkiness, but of its partici-
pation to an allyl cation intermediate as depicted in Figure 3, which
could prevent the reaction taking place at the 3-position as well as
from concave face. Although such participation is unlikely due to
anticipated severe strain, we nevertheless carried out an additional
reaction with a hope that some supportive evidence might be
obtained for SN2 mechanism for the formation of 23.
d
d
a
b
d
62.1 and 65.1, respectively) was apparent.
Konno,15 Okano,16 and Kim7h have independently reported that
fluoroalkyl-substituted allylic alcohols undergo nucleophilic sub-
stitution exclusively at remote carbon atom from the electron-
withdrawing fluoroalkyl group, presumably as a result of electronic
effect of the fluorine atom. We assumed, however, that bulkiness of
Me
N
F
F
O
TBDPSO
3
1) N -benzoylthymine
F
F
DIAD, Ph3P, THF
TBDPSO
NH
+
9
R2
2) NH3/MeOH
O
R1
17α: R1 = thymin-1-yl, R2 = H (21%)
17β: R1 = H, R2 = thymin-1-yl (20%)
16 (26%)
Scheme 2. Mitsunobu reaction of compound 9.

7632
H. Kumamoto et al. / Tetrahedron 65 (2009) 7630–7636
F
not to be inhibitory against HIV proliferation (data not shown)
(Fig. 4).
F
TBDPSO
MeO
3. Conclusion
O
Figure 3.
The synthesis of racemic 50,50-difluoromethylidene analogue of
a promising anti-HIV agent Ed4T has been carried out. Preparation
of the difluoro carbocyclic unit 9 was initiated with repeating
electrophilic fluorination with SelectfluorÒ to the enolate derived
from 11. The resulting difluoroenone 13 was stereoselectively re-
duced to the allyl alcohol 14 by employing the Luche reduction.
Manipulation of the methoxycarbonyl group of 14 allowed to pre-
pare 9.
Thus, the epimeric ally alcohol 2418 was prepared from 14 by
reacting with p-nitrobenzoic acid under the Mitsunobu conditions
followed by treating the product with NaOMe (Scheme 4). When 24
was reacted with N3-benzoylthymine as described for the case of 9,
again only the SN2 product 25 was isolated in 56% yield after
debenzoylation.19
F
F
3
TBDPSO
MeO2C
1) p-NO2-C6H4CO2H
DIAD, Ph3P, THF
1) N -benzoylthymine
F
F
TBDPSO
MeO2C
OH
Me
O
DIAD, Ph3P, THF
N
14
2) NaOMe, MeOH
2) NaOMe, MeOH
O
N
H
25 (57%)
24 (75%)
Scheme 4. Preparation and Mitsunobu reaction of compound 24.
2.3. Synthesis of compound 8 and its brief conformational
analysis based on X-ray structure
Introduction of thymine base to 9 under the Mitsunobu condi-
tions resulted in the formation of the SN2 product 16 and the two
SN20 products 17
a and 17b. It was found that the methoxycarbonyl
The 40-methoxycarbonyl carbocyclic nucleoside 23 was reacted
with DIBAL-H and then with P(O)(OMe)2C(N2)COMe (15), by
a similar manner described for the transformation of 14 to 9, to give
16 in 80% yield. The title compound 8 was obtained in a good yield
after desilylation with Bu4NF/THF in the presence of AcOH. The
depicted stereochemistry of 8 shown in Figure 4 came from its
X-ray crystallographic analysis.
derivative 14 gave exclusively the SN2 product 23 in good yield. The
title compound 8 was finally prepared from 23 through a series of
reactions. A brief conformational analysis of 8 was also carried out
based on its X-ray crystallographic data.
4. Experimental
4.1. General
The glycosyl tortional angle (
c
¼ꢁ94.9ꢂ) of 8 showed its anti
(ꢁanticlinal) orientation, which is similar to that of the parent
compound stavudine (4,
c
¼ꢁ100.8ꢂ).20 However, the orientation
Melting points were determined on a Yanaco micro melting
point apparatus, and are uncorrected. 1H and 13C NMR spectra were
recorded either at JEOL JNM-GX 400 (400 MHz). Chemical sifts are
reported relative to Me4Si. 19F NMR spectra were measured at
500 MHz with CFCl3 as an internal standard. Mass spectra (MS)
were taken in FAB mode with m-nitrobenzyl alcohol as a matrix on
a JEOL JMS-700. Infrared spectra (IR) were recorded on a JASCO FT/
IR-410 spectrophotometer. Column chromatography was carried
out on silica gel (Micro Bead Silica Gel PSQ 100B, Fuji Silysia
Chemical Ltd). Thin-layer chromatography (TLC) was performed on
precoated silica gel plate F254 (Merck). When necessary, analytical
samples were purified by high performance liquid chromatography
(HPLC). HPLC was carried out on a Shimadzu LC-6AD with a Shim-
pack PREP-SIL (H)ꢃ KIT column (2ꢄ25 cm). THF was distilled from
benzophenone ketyl.
of the hydroxylmethyl group at the C-40 position adopted
trans,gauche (ꢁsynclinal,
g
¼ꢁ144.8ꢂ) conformation, which was
completely different from that of
4
(þsynclinal,
g
¼52.8ꢂ).
Moreover, the cyclopentene ring of 8 has an envelope type
puckering, due to sticking out of the CF2 group from the cyclo-
pentene plane toward the thymine base: the C-50 of 8 deviates ca.
0.44 Å from the plane consisting of C10, C20, C30 and C40. It has
been proposed that planarity of the furanose ring of 4 plays one
important role for the recognition by cellular kinase.21 Pre-
sumably due to these conformational differences, 8 was found
4.2. ( )-1-(tert-Butyldiphenylsiloxymethyl)-4-oxo-cyclopent-
2-enecarboxylic acid methyl ester (11)
To a CH2Cl2 (60 mL) solution of 10 (8.5 g, 20.7 mmol) were
added MS 4 Å (8 g) and PDC (15.6 g, 41.4 mmol). The resulting
mixture was stirred at rt for 40 h. The reaction mixture was then
diluted by slow addition of EtOAc (100 mL) and stirred for further
0.5 h. After filtration by a Celite pad, the resulting filtrate was
evaporated and the residue was purified by column chromatogra-
phy (hexane/EtOAc¼7/1). This gave 11 (6.6 g, 78%) as an oil. 1H NMR
(CDCl3)
d
1.03 (9H, s, t-Bu), 2.44 (1H, d, Jgem¼18.8, CH2), 2.84 (1H, d,
Jgem¼18.8, CH2), 3.73 (3H, s, OMe), 3.86 (1H, d, Jgem¼9.6, SiOCH2),
3.92 (1H, d, Jgem¼9.6, SiOCH2), 6.23 (1H, d, J¼5.6, CH]CH), 7.37–
7.47 (7H, m, Ph and CH]CH), 7.58–7.62 (4H, m, Ph); 13C NMR
Figure 4. ORTEP drawing of compound 8.
(CDCl3) d 19.2, 26.6, 41.1, 52.6, 58.3, 67.9, 127.8, 130.0, 132.5, 132.6,

H. Kumamoto et al. / Tetrahedron 65 (2009) 7630–7636
7633
134.9, 135.5, 135.6, 162.4, 172.2,206.9: HRFAB-MS m/z 409.1862
(C^C); 1H NMR (CDCl3)
d
1.03 (9H, s, t-Bu), 2.15 (1H, dd, J¼10.9
(MþþH), calcd for C24H29O4Si (MþþH) 409.1835.
and 4.0, OH), 2.35 (1H, s, C^CH), 3.65 (1H, dd, J¼10.4 and 2.9,
SiOCH2), 3.98 (1H, d, J¼10.4, SiOCH2), 4.92–4.97 (1H, m, CHOH),
5.82–5.83 (1H, m, CH]CH), 6.01–8.02 (1H, m, CH]CH), 7.38–7.46
4.3. ( )-1-(tert-Butyldiphenylsiloxymethyl)-5,5-difluori-4-
oxo-cyclopent-2-enecarboxylic acid methyl ester (13)
(6H, m, Ph), 7.62–7.66 (4H, m, Ph); 13C NMR (CDCl3)
d 19.2, 26.7,
53.9 (dd, JC,F¼24.0 and 20.4), 64.9 (d, JC,F¼4.8), 74.7, 77.6 (dd,
JC,F¼30.0 and 21.6), 78.3 (d, JC,F¼7.2), 125.3 (dd, JC,F¼269.9 and
256.7), 127.8, 129.8, 129.9, 132.3, 132.5, 133.2, 133.3, 135.5, 135.7;
A
mixture of 11 (6.05 g, 14.8 mmol) and TMSCl (3.76 mL,
29.6 mmol) in THF (100 mL) was treated with dropwise addition of
LHMDS (1.1 M solution of THF, 27.0 mL, 29.6 mmol) at ꢁ78 ꢂC under
positive pressure of dry Ar. After being stirred for 0.5 h at same
temperature, the mixture was partitioned between EtOAc and satu-
rated aqueous NaHCO3. The organic layer was dried (Na2SO4), filtered,
and evaporated. The resulting crude silyl enol ether was dissolved in
MeCN (120 mL) and reacted with SelectfluorÒ (10.49.g, 29.6 mmol).
After stirring for 24 h at rt, the reaction mixture was partitioned
between EtOAc and 1 M HCl. Column chromatography (hexane/
EtOAc¼1/1) of the organic layer gave the crude monofluoride 12 (ca.
6.6 g) as an oil. The above procedure was repeated to 12 by using
TMSCl (3.76 mL, 29.6 mmol), LHMDS (1.1 M solution of THF, 27.0 mL,
29.6 mmol) and SelectfluorÒ (10.49.g, 29.6 mmol). Column chroma-
tography (hexane/EtOAc¼9/1) of the organic layer gave the crude
19F NMR (CDCl3)
d
ꢁ113.1 (d, JF,F¼228.9), ꢁ123.1 (d, JF,F¼228.9);
HRFAB-MS m/z 413.1751 (MþþH), calcd for C24H27F2O2Si (MþþH)
413.1748.
4.6. The Mitsunobu reaction of 9
To a THF (3 mL) solution of Ph3P (291 mg, 1.11 mmol) was added
DIAD (219 m
L, 1.11 mmol) at 0 ꢂC. After stirring for 10 min, a THF
(5 mL) solution of 9 (150 mg, 0.37 mmol) and N3-benzoylthymine
(256 mg, 1.11 mmol) were added at ꢁ40 ꢂC. The reaction mixture
was allowed to warm to rt, and stirred for further 50 h at ambient
temperature. The mixture was partitioned between Et2O and H2O.
After evaporation of the organic layer, the residue was treated with
NH3/MeOH (30 mL) at ꢁ4 ꢂC for 12 h. After evaporation, the residue
was carefully purified by column chromatography (hexane/Et2O¼2/
difluoride 13 (5.03 g, 76% from 11) as an oil. 1H NMR (CDCl3)
(9H, s, t-Bu), 3.79 (3H, s, OMe), 3.95(1H, d, Jgem¼9.6, SiOCH2), 4.13 (1H,
d, Jgem¼9.6, SiOCH2), 6.52–6.54 (1H, m, CH]CH), 7.38–7.46 (6H, m,
Ph), 7.56–7.59 (4H, m, Ph), 7.88–7.91 (1H, m, CHwCH); 13C NMR
d 1.00
1 to 1/4). This gave 16 (50 mg, 26% as a solid), 17a (40 mg, 21%, as
a foam) and 17 (39 mg, 20% as a foam).
b
(CDCl3)
d
19.2, 26.5, 53.1, 61.6 (t, JC,F¼19.2), 64.1 (d, JC,F¼9.6),113.0 (dd,
JC,F¼271.1 and 255.5), 127.9, 128.0, 130.2, 132.0, 135.5,161.2 (d,
4.7. Physical data for 16
JC,F¼4.8), 166.8 (d, JC,F¼4.8), 191.6 (t, JC,F¼25.2); 19F NMR (CDCl3)
d
ꢁ112.8 (d, JF,F¼283.4), ꢁ129.5 (d, JF,F¼283.4); HRFAB-MS m/z
IR (neat) 2080 cmꢁ1 (C^C); 1H NMR (CDCl3)
d 1.08 (9H, s, t-Bu),
445.1647 (MþþH), calcd for C24H27F2O4Si (MþþH) 445.1640.
1.83 (3H, s, Me), 2.44 (1H, s, C^CH), 3.90 (1H, d, J¼10.4, SiOCH2),
3.94 (1H, d, J¼10.4, SiOCH2), 5.81–5.83 (1H, m, CH]CH), 6.08–6.13
(1H, m, NCH), 6.16–6.19 (1H, m, CH]CH), 6.81 (1H, m, H-6), 7.36–
7.47 (6H, m, Ph), 7.67–7.70 (4H, m, Ph), 8.39 (1H, br, NH); 13C NMR
4.4. ( )-r-1-(tert-Butyldiphenylsiloxymethyl)-5,5-difluori-t-4-
hydroxy-cyclopent-2-enecarboxylic acid methyl ester (14)
(CDCl3)
d
12.3, 19.4, 26.6, 54.0 (dd, JC,F¼26.4 and 21.6), 62.7 (dd,
To a mixture of 13 (380 mg, 0.85 mmol), CeCl3$7H2O (317 mg,
0.85 mmol) and THF (3 mL) in MeOH (20 mL) was added NaBH4
(76 mg, 1.7 mmol) at ꢁ78 ꢂC. The mixture was stirred at same
temperature for 16 h. After treatment with acetone (ca. 3 mL), the
mixture was concentrated, partitioned between CH2Cl2 and 1 M
HCl. Column chromatography (hexane/EtOAc¼1/1) of the organic
JC,F¼30.0 and 19.2), 64.1 (d, JC,F¼9.6), 74.9, 78.1 (d, JC,F¼4.8), 110.9,
125.4 (dd, JC,F¼272.3 and 264.0), 126.9 (d, JC,F¼7.2), 127.8, 129.9,
132.7, 132.8, 135.6, 136.6, 137.0, 150.6, 163.2; 19F NMR (CDCl3)
d
ꢁ106.3 (d, JF,F¼228.9), ꢁ119.2 (d, JF,F¼228.9); HRFAB-MS m/z
521.2022 (MþþH), calcd for C29H31F2N2O3Si (MþþH) 521.2072.
layer gave 14 (379 mg, quant.) as an oil.1H NMR (CDCl3)
d
1.03 (9H, s,
4.8. Physical data for 17
a
t-Bu), 2.27 (1H, dd, J¼11.2 and 2.8, OH), 3.75 (3H, s, OMe), 3.94 (1H, d,
Jgem¼9.6, SiOCH2), 3.99 (1H, d, Jgem¼9.6, SiOCH2), 4.76.4.83 (1H, m,
CHOH), 6.02–6.06 (1H, m, CH]CH), 6.16–6.19 (1H, m, CH]CH),
IR (neat) 2090 cmꢁ1 (C^C); 1H NMR (CDCl3)
d
1.03 (9H, s, t-Bu),
1.91 (3H, d, J¼1.6, Me), 2.32 (1H, s, C^CH), 4.03 (2H, s, SiOCH2),
6.11–6.13 (1H, m, NCH), 6.30–6.31 (1H, m, CH]CH), 6.39–6.41 (1H,
m, CH]CH), 6.89 (1H, q, J¼1.6, H-6), 7.37–7.48 (6H, m, Ph), 7.65–
7.37–7.46 (6H, m, Ph), 7.60–7.63 (4H, m, Ph); 13C NMR (CDCl3)
d 19.2,
26.7, 52.7, 64.0 (d, JC,F¼6.0), 64.6 (t, JC,F¼21.6), 78.0 (dd, JC,F¼30.0 and
20.4), 125.5 (dd, JC,F¼268.7 and 255.5), 127.8, 129.9, 130.0, 132.4,
132.6 (d, JC,F¼8.4), 133.1 (d, JC,F¼8.4), 135.5, 135.6, 169.1; 19F NMR
7.72 (4H, m, Ph), 9.21 (1H, br, NH); 13C NMR (CDCl3)
d 12.5, 19.3,
26.6, 53.5 (dd, JC,F¼22.8 and 19.2), 62.1 (d, JC,F¼4.8), 65.6 (d,
JC,F¼7.2), 75.5 (d, JC,F¼6.0), 78.5, 110.4, 127.4 (dd, JC,F¼255.5 and
249.5), 127.7, 127.8, 129.8, 129.9, 132.3, 132.4, 133.7 (t, JC,F¼27.6),
(CDCl3)
d
ꢁ116.9 (d, JF,F¼239.8), ꢁ120.0 (d, JF,F¼239.8); HRFAB-MS
m/z 447.1788 (MþþH), calcd for C24H29F2O4Si (MþþH) 447.1803.
135.6, 137.1, 137.2 (t, JC,F¼8.4), 151.1, 163.9; 19F NMR (CDCl3)
ꢁ78.2
d
4.5. ( )-t-4-(tert-Butyldiphenylsiloxymethyl)-c-4-ethynyl-5,5-
difluoro-cyclopent-2-en-r-1-ol (9)
(d, JF,F¼261.6), ꢁ110.2 (d, JF,F¼261.6); HRFAB-MS m/z 521.2048
(MþþH), calcd for C29H31F2N2O3Si (MþþH) 521.2072.
To a CH2Cl2 (100 mL) solution of 14 (3.5 g, 7.83 mmol) was
added DIBAL-H (1.0 M solution in toluene, 23.5 mL, 23.5 mmol)
dropwise over 1 h at ꢁ78 ꢂC. The mixture was stirred for further
0.5 h at same temperature. The reaction mixture was partitioned
between CH2Cl2 and 1 M HCl. The crude aldehyde was obtained
after evaporation of the organic layer. A solution of this aldehyde
in MeOH (90 mL) was treated with K2CO3 (3.25 g, 23.5 mmol)
followed by MeC(O)C(N2)P(O)(OMe)2 (3.76 g, 19.6 mmol). The
resulting mixture was stirred for 20 h at rt. Partition of the reaction
mixture between CH2Cl2 and saturated aqueous NH4Cl was fol-
lowed by column chromatography (hexane/EtOAc¼2/1) of the or-
ganic layer. This gave 9 (2.59 g, 81%) as an oil. IR (neat) 2090 cmꢁ1
4.9. Physical data for 17
b
IR (neat) 2070 cmꢁ1 (C^C); 1H NMR (CDCl3)
d
1.04 (9H, s, t-Bu),
1.68 (3H, d, J¼1.2, Me), 2.45 (1H, s, C^CH), 3.75 (2H, s, SiOCH2),
6.00–6.07 (1H, m, NCH), 6.28–6.30 (1H, m, CH]CH), 6.33–6.35
(1H, m, CH]CH), 6.79 (1H, q, J¼1.2, H-6), 7.33–7.36 (4H, m, Ph),
7.39–7.43 (2H, m, Ph), 7.54–7.57 (2H, m, Ph), 7.61–7.63 (2H, m, Ph),
8.82 (1H, br, NH); 13C NMR (CDCl3)
d 12.3, 19.2, 26.7, 52.4 (t,
JC,F¼22.8), 61.7 (d, JC,F¼7.2), 65.1, 74.3, 79.9, 110.8, 127.6, 127.7 (dd,
JC,F¼279.5 and 223.1), 127.8, 129.8, 129.9, 132.3, 132.4, 132.6 (t,
JC,F¼26.4), 135.5, 135.7, 136.5, 137.4 (t, JC,F¼9.6), 150.7, 163.1; 19F
NMR (CDCl3)
d
ꢁ106.3 (d, JF,F¼228.9), ꢁ119.3 (d, JF,F¼228.9);

7634
H. Kumamoto et al. / Tetrahedron 65 (2009) 7630–7636
HRFAB-MS m/z 521.2081 (MþþH), calcd for C29H31F2N2O3Si
(MþþH) 521.2072.
4.12. The Mitsunobu reaction of 18: formation to 20 and 21
Compound 18 (360 mg, 0.55 mmol) was reacted as described
above for 9. After purification by a preparative TLC (CHCl3 three
times elution), compound 20 (172 mg, 41%, foam) and 21 (66 mg,
16%, foam) were obtained.
4.10. ( )-4,4-Bis-(tert-Butyldiphenylsiloxymethyl)-5,5-
difluoro-cyclopent-2-en-1-ol (18)
To a mixture of 14 (350 mg, 0.78 mmol) and PPTS (20 mg, 0.08
ooml) in CH2Cl2 (3 mL) was added 2,3-dihydrofuran (77 mL,
4.12.1. Physical data for 20
1H NMR (CDCl3)
d 0.96 (9H, s, t-Bu), 1.06 (9H, s, t-Bu), 1.86 (3H, d,
1.02 mmol). The resulting mixture was stirred for 0.5 h at rt. The
mixture was partitioned between CH2Cl2 and saturated aqueous
NaHCO3. The organic layer was evaporated and the residue was
dissolved in THF (5 mL). The resulting THF solution was treated
with LiAlH4 (30 mg, 0.78 mmol) at 0 ꢂC for 0.5 h with stirring. The
reaction mixture was quenched by adding EtOAc and H2O, and
then filtered through a Celite pad. The filtrate was evaporated and
dissolved in MeCN (5 mL). A mixture of this solution, imidazole
J¼0.4, 5-Me), 3.77 (2H, s, SiOCH2), 3.83 (1H, d, Jgem¼10.0, SiOCH2),
3.99 (1H, d, Jgem¼10.0, SiOCH2), 5.79–5.80 (1H, m, CH]CH), 6.04–
6.07 (1H, m, CH]CH), 6.07–6.13 (1H, m, CH-N), 6.83 (1H, q, J¼0.4,
H-6), 7.26–7.45 (12H, m, Ph), 7.54–7.57 (4H, m, Ph), 7.61–7.67 (4H,
m, Ph), 8.45 (1H, br, NH); 13C NMR (CDCl3)
d 12.4, 19.1, 19.2, 26.6,
59.5 (t, JC,F¼20.2), 61.5 (d, JC,F¼10.8), 63.4 (d, JC,F¼9.6), 63.9 (dd,
JC,F¼30.0 and 20.4), 110.3, 127.3 (d, JC,F¼8.4), 127.6 (dd, JC,F¼267.5
and 261.5), 127.7, 127.8, 129.7, 129.8, 129.9, 132.5, 132. 6, 132.7, 132.8,
135.5, 135.6, 135.7, 137.4, 137.6, 150.8, 163.6; 19F NMR (CDCl3)
(106 mg, 1.56 mmol) and TBDPSCl (244 mL, 0.94 mmol) was stirred
for 1 h. The reaction mixture was partitioned between CH2Cl2 and
saturated aqueous NaHCO3. The organic layer separated was
evaporated, and the residue was treated with PPTS (20 mg,
0.08 mmol) in MeOH (8 mL) at rt for 3 h. After quenching with
Et3N (2 mL), the mixture was evaporated and purified by column
chromatography (hexane/EtOAc¼2/1). This gave 18 (206 mg, 40%
d
ꢁ114.9 (d, JF,F¼239.8), ꢁ116.1 (d, JF,F¼239.8); HRFAB-MS m/z
765.3368 (MþþH), calcd for C44H51F2N2O4Si2 (MþþH) 765.3355.
4.12.2. Physical data for 21
1H NMR (CDCl3)
d 0.91 (9H, s, t-Bu), 1.05 (9H, s, t-Bu), 1.72 (3H, d,
J¼0.8, 5-Me), 3.41 (1H, d, Jgem¼10.8, SiOCH2), 3.67 (1H, d, Jgem¼10.8,
SiOCH2), 3.75 (1H, d, Jgem¼10.4, SiOCH2), 4.23 (1H, d, Jgem¼10.4,
SiOCH2), 6.07–6.09 (1H, m, CH–N), 6.18–6.19 (1H, m, CH]CH),
6.29–6.31 (1H, m, CH]CH), 6.74 (1H, q, J¼0.8, H-6), 7.21–7.33 (4H,
m, Ph), 7.35–7.52 (12H, m, Ph), 7.65–7.74 (4H, m, Ph), 8.03 (1H, br,
from 14) as an oil. 1H NMR (CDCl3)
d 0.93 (9H, s, t-Bu), 1.03 (9H, s, t-
Bu), 3.17 (1H, d, J¼10.4, OH), 3.68–3.76 (3H, m, SiOCH2ꢄ3), 3.93
(1H, d, J¼10.4, SiOCH2), 4.50–4.57 (1H, m, H-4), 5.84–5.86 (1H, m,
CH]CH), 6.05–6.15 (1H, m, CH]CH), 7.28–7.32 (4H, m, Ph), 7.36–
7.46 (8H, m, Ph), 7.50–7.53 (4H, m, Ph), 7.62–7.66 (4H, m, Ph); 13C
NH); 13C NMR (CDCl3)
d
12.4, 19.0, 19.3, 26.6, 26.7, 54.2 (t, JC,F¼19.2),
NMR (CDCl3)
d
19.1, 19.2, 26.6, 26.8, 58.5 (t, JC,F¼21.6), 62.5 (d,
59.6 (d, JC,F¼9.6), 61.2, 63.9 (d, JC,F¼9.6), 110.3, 127.5, 127.7, 127.8,
129.7, 129.8, 130.3 (dd, JC,F¼249.9 and 240.5), 132.1, 132.5, 132.7,
134.2 (t, JC,F¼28.8), 135.4, 135.5, 135.6,135.7, 136.9, 137.7 (t, JC,F¼9.6),
JC,F¼12.0), 63.4 (d, JC,F¼6.0), 77.5 (dd, JC,F¼35.2 and 21.2), 127.7,
126.4 (dd, JC,F¼265.1 and 259.1), 127.9, 129.6, 129.7, 129.9, 130.0,
132.1, 132.3, 132.9, 134.9 (d, JC,F¼5.8), 135.4, 135.5, 135.6, 135.7; 19F
150.5, 162.9; 19F NMR (CDCl3)
d
ꢁ90.1 (d, JF,F¼272.5), ꢁ110.2 (d,
NMR (CDCl3)
d
ꢁ117.0 (d, JF,F¼239.8), ꢁ124.4 (d, JF,F¼239.8);
JF,F¼272.5); HRFAB-MS m/z 765.3368 (MþþH), calcd for
HRFAB-MS m/z 657.3032 (MþþH), calcd for C39H47F2O3Si2 (MþþH)
C44H51F2N2O4Si2 (MþþH) 765.3355.
657.3032.
4.13. The Mitsunobu reaction of 19: formation to 22
4.11. ( )-t-4-(tert-Butyldiphenylsiloxymethyl)-c-4-cyano-5,5-
difluoro-cyclopent-2-en-r-1-ol (19)
Compound 19 (194 mg, 0.48 mmol) was reacted as described
above for 9. After purification by a preparative TLC (CH2Cl2/
AcOEt¼3/1), compound 22 (138 mg, 55%) was obtained as a foam.
A CH2Cl2 (16 mL) solution of 14 (500 g, 1.12 mmol) was treated
with DIBAL-H (1.0 M solution in toluene, 3.36 mL, 3.36 mmol)
dropwise over 1 h at ꢁ78 ꢂC and then stirred for 0.5 h at same
temperature. The resulting aldehyde obtained by partition (CH2Cl2/
1 M HCl) of the reaction mixture was dissolved in pyridine (15 mL)
and reacted with NH2OH$HCl (1.56 g, 22.4 mmol) at rt for 12 h. The
oxime obtained by partition (CH2Cl2/0.5 M HCl) of the reaction
4.13.1. Physical data for 22
IR (neat) 2250 cmꢁ1 (C^N); 1H NMR (CDCl3)
d 1.06 (9H, s, t-Bu),
1.94 (3H, d, J¼1.2, 5-Me), 4.06 (1H, d, Jgem¼10.0, SiOCH2), 4.13 (1H, d,
Jgem¼10.0, SiOCH2), 6.00–6.02 (1H, m, CH–N), 6.32–6.33 (1H, m,
CH]CH), 6.39–6.40 (1H, m, CH]CH), 6.90 (1H, q, J¼1.2, H-6), 7.41–
7.46 (6H, m, Ph), 7.65–7.70 (4H, m, Ph), 8.73 (1H, br, NH); 13C NMR
mixture was acetylated with Ac2O (317
(20 mL) in the presence of DMAP (343 mg, 2.8 mmol) and i-Pr2NEt
(585 L, 3.36 mmol) for 1 h. The diacetate obtained by partition
mL, 3.36 mmol) in MeCN
(CDCl3)
d
12.6, 19.2, 26.5, 55.6 (dd, JC,F¼26.4 and 18.0), 61.1, 63.2 (d,
m
JC,F¼8.4), 112.2, 113.7 (d, JC,F¼4.8), 126.2 (t, JC,F¼256.7), 127.9, 130.1,
131.7, 131.8, 132.7 (t, JC,F¼26.4), 135.6, 137.2 (t, JC,F¼9.6), 150.6, 163.0.
(CH2Cl2/1 M HCl) was subjected to elimination by reacting with
NaOAc (82 mg, 1.0 mmol) in AcOH (18 mL) at 100 ꢂC for 3 h. The
resulting product obtained by partition (CH2Cl2/saturated aqueous
NaHCO3) was treated with NH3/MeOH (10 mL) below 0 ꢂC over-
night. The requisite cyano derivative (19) was isolated from the
reaction mixture by column chromatography (hexane/EtOAc¼3/1).
This gave 19 (244 mg, 53% from 14) as an oil. IR (neat) 2080 cmꢁ1
19F NMR (CDCl3)
d
ꢁ78.7 (d, JF,F¼261.6), ꢁ105.5 (d, JF,F¼261.6);
HRFAB-MS m/z 522.2049 (MþþH), calcd for C28H30F2N3O3Si
(MþþH) 522.2025.
4.14. The Mitsunobu reaction of 14: formation to 23
(C^N); 1H NMR (CDCl3)
d
1.08 (9H, s, t-Bu), 3.84 (1H, d, Jgem¼10.4,
To a THF (7 mL) solution of Ph3P (583 mg, 2.22 mmol) was
added DIAD (440 m
L, 2.22 mmol) at 0 ꢂC. After stirring for 10 min,
SiOCH2), 3.94 (1H, dd, J¼10.4 and 0.8, SiOCH2), 4.83–4.87 (1H, m, H-
4), 5.91–5.94 (1H, m, CH]CH), 6.13–6.17 (1H, m, CH]CH), 7.39–
a THF (15 mL) solution of 14 (330 mg, 0.74 mmol) and N3-ben-
zoylthymine (511 mg, 2.22 mmol) was added dropwise at ꢁ40 ꢂC to
the above mixture. The whole mixture was allowed to warm to rt,
and stirred for 50 h at rt. The reaction mixture was partitioned
between Et2O and H2O. After evaporation of the organic layer, the
residue was treated with NaOMe (1.0 M solution of MeOH, 7.4 mL)
at rt for 2 h. The resulting mixture was partitioned between CH2Cl2
7.49 (6H, m, Ph), 7.60–7.65 (4H, m, Ph); 13C NMR (CDCl3)
d 19.2, 26.6,
54.6 (dd, JC,F¼25.2 and 20.4), 63.3 (d, JC,F¼6.0), 77.0 (dd, JC,F¼31.2
and 20.4), 115.2 (d, JC,F¼4.8), 123.9 (dd, JC,F¼269.9 and 260.3), 128.1,
129.5, 130.2, 130.3, 131.6, 131.8, 135.5, 135.6, 135.7; 19F NMR (CDCl3)
d
ꢁ111.9 (d, JF,F¼239.8), ꢁ120.2 (d, JF,F¼239.8); HRFAB-MS m/z
414.1679 (MþþH), calcd for C23H26F2NO2Si (MþþH) 414.1701.

H. Kumamoto et al. / Tetrahedron 65 (2009) 7630–7636
7635
and 1 M HCl. Column chromatography (hexane/EtOAc¼1/1) of the
organic layer gave 23 (239 mg, 58% from 14) as a solid.
(hexane/EtOAc¼2/3), 16 (415 mg, 80% from 23) was obtained as
a solid.
4.14.1. Physical data for 23
4.18. ( )-1-(t-4-Ethynyl-5,5-difluoro-c-4-hydroxymethyl-
cyclopent-2-en-r-1-yl)-thymine (8)
Mp 207–211 ꢂC; 1H NMR (CDCl3)
d 1.05 (9H, s, t-Bu), 1.75 (3H, d,
J¼0.8, 5-Me), 3.79 (1H, d, Jgem¼10.0, SiOCH2), 3.80 (3H, s, OMe),
4.30 (1H, d, Jgem¼10.0, SiOCH2), 5.94–5.99 (2H, m, CH]CH and CH–
N), 6.45–6.47 (1 h, m, CH]CH), 6.72 (1H, q, J¼0.8, H-6), 7.39–7.48
(6H, m, Ph), 7.63–7.67 (4H, m, Ph), 8.05 (1H, br, NH); 13C NMR
To a stirred solution of 23 (415 mg, 0.8 mmol) in THF (8 mL)
containing AcOH (57
mL, 0.8 mmol) was added Bu4NF (1.0 M solu-
tion in THF, 800
m
L, 0.8 mmol) at 0 ꢂC. The resulting mixture was
(CDCl3)
d
12.4,19.3, 26.6, 53.0, 63.5 (d, JC,F¼12.0), 64.1 (dd, JC,F¼34.8
stirred for 17 h at rt, and then evaporated. Column chromatography
(CH2Cl2/EtOH¼20/1) of the residue gave 8 (192 mg, 85%) as a solid,
which was recrystallized from acetone/1,2-dichloroethane: mp
and 19.2), 65 8 (dd, JC,F¼34.8 and 21.5), 111.0, 124.8 (t, JC,F¼267.5),
127.6 (d, JC,F¼7.2),127.9,130.1,132.3,132.7,135.5,136.2,137.2,150.5,
162.9, 168.0; 19F NMR (CDCl3)
d
ꢁ102.0 (d, JF,F¼239.8), ꢁ115.7 (d,
>224 ꢂC (dec); IR (KBr) 2120 cmꢁ1 (C^C); 1H NMR (CD3OD)
d 1.83
JF,F¼239.8); HRFAB-MS m/z 555.2137 (MþþH), calcd for
C29H33F2N2O5Si (MþþH) 555.2127.
(3H, d, J¼1.2, 5-Me), 2.89 (1H, d, JC,F¼1.2, C^CH), 3.78 (1H, dd,
Jgem¼11.5, JC,F¼1.2, CH2OH), 3.84 (1H, dd, Jgem¼11.5, JC,F¼1.7, CH2OH)
5.80–5.83 (1H, m, H-10), 5.98–6.01 (1H, m, CH]CH), 6.17–6.20 (1H,
m, CH]CH), 7.29 (1H, q, J¼1.2, H-6); 13C NMR (CD3OD)
d 12.3, 56.2
4.15. ( )-r-1-(tert-Butyldiphenylsiloxymethyl)-5,5-difluori-c-
4-hydroxy-cyclopent-2-enecarboxylic acid methyl ester (24)
(dd, JC,F¼26.4 and 21.2), 64.4 (d, JC,F¼8.4), 65.2 (dd, JC,F¼40.0 and
20.4), 76.6, 78.7 (d, JC,F¼6.0), 110.6, 126.0 (t, JC,F¼265.1), 128.2 (d,
JC,F¼7.2), 138.7, 139.9, 153.0, 166.4; 19F NMR (DMSO-d6)
d
ꢁ117.4 (d,
To
2.66 mmol) and 4-nitrobenzoic acid (444 mg, 2.66 mmol) in THF
(15 mL) was dropwise added DIAD (524
L, 2.66 mmol) at 0 ꢂC.
a mixture of 14 (780 mg, 1.77 nnol), Ph3P (698 mg,
JF,F¼239.8), ꢁ96.6 (d, JF,F¼239.8); HRFAB-MS m/z 283.0879 (MþþH),
calcd for C13H13F2N2O3 (MþþH) 283.0894. Anal. Calcd for
C13H12F2N2O3: C, 55.32; H, 4.29; N, 9.93. Found: C, 55.18; H, 4.12; N,
9.80.
m
After 24 h stirring at ambient temperature of the mixture, this was
partitioned between aq NaHCO3 and CH2Cl2. Short column chro-
matography (hexane/AcOEt¼7/1) of the organic layer gave the
crude benzoate (ca. 978 mg). The benzoate was dissolved in MeOH
(40 mL) and treated with NaOMe (478 mg, 8.85 mmol). After 6 h
stirring of the resulting mixture, this was partitioned between 0.5 N
HCl and CH2Cl2. Column chromatography (hexane/AcOEt¼1/1) of
the organic layer gave 24 (587 mg, 75%) as an oil. 1H NMR (CDCl3)
Acknowledgements
Financial support from the Japan Society for the Promotion of
Science (KAKENHI, Grant No. 19590106 to K.H.) is gratefully ac-
knowledged. The authors are also grateful to Ms. K. Shiohara and
Ms. Y. Odanaka (Center for Instrumental Analysis, Showa Uni-
versity) for technical assistance with NMR, MS and elemental
analysis.
d
1.02 (9H, s, t-Bu), 2.97 (1H, d, J¼10.0, OH), 3.69 (3H, s, OMe), 3.78
(1H, d, Jgem¼10.0, SiOCH2), 4.09 (1H, d, Jgem¼10.0, SiOCH2), 4.50–
4.54 (1H, m, CHOH), 6.15–6.23 (2H, m, CH]CH), 7.38–7.45 (6H, m,
Ph), 7.61–7.64 (4H, m, Ph); 13C NMR (CDCl3)
d 19.1, 26.7, 52.7, 63.9,
64.7 (t, JC,F¼24.0), 76.6 (dd, JC,F¼37.2 and 20.4), 124.2 (dd, JC,F¼271.1
and 254.3), 128.0, 130.1, 130.2, 131.7, 131.9, 132.9, 134.4 (d, JC,F¼4.8),
References and notes
135.5, 135.7, 168.4; 19F NMR (CDCl3)
d
ꢁ107.2 (d, JF,F¼239.8), ꢁ124.7
(d, JF,F¼239.8); HRFAB-MS m/z 447.1778 (MþþH), calcd for
C24H29F2O4Si (MþþH) 447.1803.
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B. Chem. Scr. 1986, 26, 21; (f) Blackburn, G. M.; Brown, D.; Martin, S. J.; Parratt, M.
J. J. Chem. Soc., Perkin Trans. 1 1987, 181; (g) Yang, Y.-Y.; Meng, W.-D.; Qing, F. L.
Org. Lett. 2004, 6, 4257; (h) Yang, Y.-Y.; Xu, J.; You, Z.-W.; Xu, X.; Qiu, X.-L.; Qing, F.
L. Org. Lett. 2007, 9, 5437; (i) Recently, we reported the synthesis of 8 as a com-
munication Nucleic Acids Symp. Ser. 2008, 52, 809.
4.16.1. Physical data for 25
1H NMR (CDCl3)
d
1.05 (9H, s, t-Bu), 1.91 (4H, d, J¼1.2, Me), 3.76
(3H, s, OMe), 3.99 (1H, d, Jgem¼10.0, SiOCH2), 4.07 (1H, d,
Jgem¼10.0, SiOCH2), 5.85–5.95 (1H, m, CH]CH), 6.00–6.05 (1H, m,
CH–N), 6.45–6.47 (1H, m, CH]CH), 6.91 (1H, q, J¼1.2, H-6), 7.39–
7.49 (6H, m, Ph), 7.60–7.63 (4H, m, Ph), 8.48 (1H, br, NH); 13C NMR
(CDCl3)
d
12.4, 19.2, 26.6, 52.8, 62.9 (dd, JC,F¼28.8 and 18.0), 64.5
(dd, JC,F¼9.6 and 3.6), 65.2 (t, JC,F¼21.6), 110.9, 125.5 (dd, JC,F¼273.5
and 259.1), 127.5 (d, JC,F¼8.4),127.8, 127.9, 130.0, 132.2, 135.5, 135.6,
136.2, 137.2 (d, JC,F¼3.6), 150.8, 163.6, 168.0 (d, JC,F¼6.0); 19F NMR
(CDCl3)
d
ꢁ108.7 (d, JF,F¼239.8), ꢁ115.4 (d, JF,F¼239.8); HRFAB-MS
m/z 555.2120 (MþþH), calcd for C29H33F2N2O5Si (MþþH)
555.2127.
4.17. Conversion of 23 to 16
8. Lai, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96, 1737.
9. Luche, J. L.; Genal, A. L. J. Am. Chem. Soc. 1979, 101, 5848.
10. NOE data for 14: H-4/CH2OTBDPS (2.0%).
11. Ohira, S. Synth. Commun. 1989, 19, 561.
12. Mitusunobu, O. Synthesis 1981, 1.
Compound 23 (555 mg, 1.0 mmol) was converted to 16 by the
similar procedure described for the conversion of 14 to 9. After
purification of the reaction mixture by column chromatography

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H. Kumamoto et al. / Tetrahedron 65 (2009) 7630–7636
13. In this reaction, no O2-alkylated product was formed, which is usually the case
under the present reaction conditions: (a) Ludek, O. K.; Meier, C. Synlett 2005,
3145; (b) Ludek, O. K.; Meier, C. Synlett 2006, 324.
16. Okano, T.; Matsubara, H.; Kusukawa, T.; Fujita, M. J. Organomet. Chem. 2003,
676, 43.
17. NOE data for 22 measured in CDCl3: H-60/H-30 (5.6%).
18. NOE for 24 measured in CDCl3: OH/CH2OTBDPS (0.4%); HMBC for 24:
CH2OTBDPS/C-3.
14. The stereochemistry of 16, 17a and 17b were determined by NOE experiments;
NOE data for 16 measured in CDCl3: H-6/H-60 (1.5%). NOE data for 17
H-30 (5.1%); H-6/C^CH (0.5%). NOE data for 17b: H-30/C^CH (0.5%).
a
: H-60/
19. NOE for 25 measured in CDCl3: H-60/OMe (0.2%); HMBC for 25: CH2OTBDPS/C-30.
20. Viterbo, D.; Milanesio, M.; Pomes-Hernandez, R.; Rodriguez-Tanty, C.; Cola-
Gonzalez, I.; Sablon-Carrazana, M.; Duque-Rodriguez, J. Acta Crystallogr., Sect. C
2000, 56, 580.
21. Choi, Y.; George, C.; Comin, M. J.; Barchi, J. J., Jr.; Kim, H. S.; Jacobson, K. A.;
Balzarini, J.; Mitsuya, H.; Boyer, P. L.; Hughes, S. H.; Marquez, V. E. J. Med. Chem.
2003, 46, 3292.
15. (a) Konno, T.; Ishihara, T.; Yamanaka, H. Tetrahedron Lett. 2000, 41, 8467; (b)
Konno, T.; Daitoh, T.; Ishihara, T.; Yamanaka, H. Tetrahedron: Asymmetry 2001,
12, 2743; (c) Konno, T.; Nagata, K.; Ishihara, T.; Yamanaka, H. J. Org. Chem. 2002,
67, 1768; (d) Konno, T.; Takehana, T.; Ishihara, T.; Yamanaka, H. Org. Biomol.
Chem. 2004, 2, 93; (e) Konno, T.; Takehana, T.; Mishima, M.; Ishihara, T. J. Org.
Chem. 2006, 71, 3545.