Synthesis of 2′,3′-dideoxy-2′-fluoro-4′- thionucleosides from a fluoroxanthate

Article abstract of DOI:10.1055/s-2008-1042904

The synthesis of a thiobutyrolactone as precursor of modified nucleosides is reported from a fluoroxanthate and a protected allylic alcohol. This approach opens a new and straightforward route for the synthesis of 2′,3′- dideoxy-2′-fluoro-4′-thiothymidine derivatives in few steps, including the formation of a fluorothiolactone and a Vorbrüggen thymine base alkylation reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042904

LETTER
817
Synthesis of 2¢,3¢-Dideoxy-2¢-Fluoro-4¢-Thionucleosides from a Fluoroxanthate
Synthesis of
2
¢
,3
a
¢
-Dideoxy
ë
-2
¢
-Fluoro-
4
t
¢
-Thio
i
nucleos
t
ides
f
r
i
om
a
F
l
a
uoroxanthate Jean-Baptiste, Pierre Lefebvre, Emmanuel Pfund, Thierry Lequeux*
Laboratoire de Chimie Moléculaire et Thio-organique, ENSICAEN, Université de Caen Basse-Normandie, CNRS,
6 Boulevard du Maréchal Juin, 14050 Caen, France
Fax +33(2)31452865; E-mail: thierry.lequeux@ensicaen.fr
Received 8 January 2008
useful to prepare sulfur-containing analogues of the anti-
Abstract: The synthesis of a thiobutyrolactone as precursor of
modified nucleosides is reported from a fluoroxanthate and a pro-
tected allylic alcohol. This approach opens a new and straightfor-
ward route for the synthesis of 2¢,3¢-dideoxy-2¢-fluoro-4¢-
viral drugs FddA and FMAU, such as 4¢S-FddA and 4¢S-
dFMAU (Figure 1).8 In this paper is described a free-rad-
ical approach for the preparation of a fluorothiolactone
thiothymidine derivatives in few steps, including the formation of a and its derivation into nucleoside analogues.
fluorothiolactone and a Vorbrüggen thymine base alkylation reac-
tion.
RO
HO
S
S
Key words: fluorine, free radical, nucleosides, lactones
O
B
F
F
X
X
Modified nucleosides have been introduced several years
ago to develop new anticancer and antiviral agents.1 One
of the limitations in the use of such drugs lies in their pos-
sible degradation by nucleoside phosphorylases. To en-
hance the length of their half-life, a variety of
modifications have been introduced in order to stabilize
the nucleosidic bond. Among them, the replacement of the
4¢-oxygen atom by a sulfur atom,2 or the introduction of
fluorine atoms at the 2¢-C carbon atom,3 have conferred
resistance to nucleoside cleavage, as in the case of the 4¢-
thiothymidine and the gemcitabine.4 It has been estab-
lished that these modifications contributed to the destabi-
lization of the carbocation involved in the nucleoside
degradation, and consequently produced metabolically
stable nucleoside analogues.5
X = H, F
R = Bn, TBDPS
4'S-FddA; X = H, B = A
4'S-dFMAU; X = F, B = T
Figure 1
Fluorothionucleosides synthesis is often difficult and sev-
eral steps are usually required to obtain the target com-
pound. Among the reported methods, some involved the
use of carbohydrates as starting materials to afford, after
chemical-group transformations, the intermediate thiolac-
tones as precursors of thionucleosides. Fluorine atoms are
commonly introduced by using electrophilic or nucleo-
philic fluorinating reagents to produce the corresponding
mono- or difluorothionucleosides.9 Other approaches in-
cluded the fluorination of oxo- or hydroxy-tetrahy-
drothiophene intermediates, followed by nucleic-base
introduction via the Vorbrüggen reaction,10 or a Pummer-
er-like reaction.11 A recent straightforward synthesis of
thiolactone intermediates has been reported by using a
free-radical chemistry approach.12 In this latter, car-
boxymethyl xanthate added onto allylic phosphonate af-
forded after intramolecular cyclization a thiolactone as
thionucleoside precursors. Inspired by this unique exam-
ple, this approach was selected to explore the preparation
of 2-fluoro- and 2,3-difluoro-thiolactones from the xan-
thate 1 and a protected allylic alcohol 2 (Scheme 1).
The synthesis of fluoro- or thionucleosides is not trivial
and some difficulties appeared during the coupling reac-
tion between the sugar moiety and the purine or the pyri-
midine heterocycle under the Vorbrüggen conditions.
From 2¢-difluoronucleosides the displacement of the in-
termediate acetate derivative is difficult due to the strong
electron-withdrawing character of the difluoromethylene
group. In this case the use of a more reactive alkylsul-
fonate derivative is required for the success of the reac-
tion.4 In contrast the presence of only one fluorine atom at
the 2¢-position affects moderately the acetate-group reac-
tivity and the introduction of the nucleic base is easier.6 In
order to prepare novel drug candidates resistant to nucle-
oside cleavage, the introduction of both sulfur and fluo-
rine atoms appeared attractive. In connection with our
current interest in the preparation of fluorinated nucleo-
sides,7 the present work was focused on the development
of a straightforward route to synthesize 2¢-fluoro- and
2¢,3¢-difluoro-4¢-thionucleosides. This approach would be
F
EtO(S)CS
RO
CO2Et
RO
1
EtO(S)CS
RO
CO2Et
F
S
O
+
F
X
X
X = H, F
R = TBDPS, Bn
2
X
Scheme 1
SYNLETT 2008, No. 6, pp 0817–0820
x
x.
x
x.
2
0
0
8
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042904; Art ID: G00508ST
© Georg Thieme Verlag Stuttgart · New York

818
L. Jean-Baptiste et al.
LETTER
The xanthate 1 was prepared from the commercially avail- crude product afforded the g-thiobutyrolactone 6b in 72%
able ethyl bromofluoroacetate, and we have reported pre- yield. Both diastereomers were separated by flash column
viously its reaction with a large variety of alkenes by chromatography. The consistency of their NMR data with
using dilauroyl peroxide or triethylborane as initiators.7b those reported in the literature,18 permitted the identifica-
Triethylborane (1 M in n-hexane) was first tested as radi- tion of the cis and trans isomers.19 In contrast, moderate
cal initiator. The reaction of the protected alcohol 2a with yield (30–40%) was obtained from 5a due to a partial
1 in dichloromethane afforded the desired fluoroester 3a cleavage of the silylether protecting group in 6a.
(Scheme 2). The reaction was slower than those reported
piperidine,
CH2Cl2,
20 °C, 2 h
from simple alkenes and needed at least overnight at room
EtO(S)CS
RO
F
temperature to reach completion. However, in this case
the reaction was not reproducible and the formation of the
product 3a is strongly depending on the quality of the tri-
ethylborane solution. In some case the presence of the
dimeric product 4 was observed up to 30%.13 Attempts to
limit its formation by changing the nature of the solvent,
the concentration of the alkene or the rate of the addition
were unsuccessful. In contrast, the use of dilauroyl perox-
ide as initiator in refluxing 1,2-dichloroethane afforded
exclusively the expected ester 3a. A slow addition of a so-
lution of dilauroyl peroxide (0.3 equiv) to a mixture of
alkene 2a and xanthate 1 over two hours followed by 30
minutes of stirring gave reproducible results. The ester 3a
was isolated by flash column chromatography in 65–70%
yield as a 1:1 mixture of diastereomers. From the O-ben-
zyl alcohol 2b similar results were obtained, and the ad-
duct 3b was exclusively formed and isolated in 62%
yield.14 No traces of the dimer 4 were detected.
SH
F
RO
CO2Et
CO2Et
3
5
a: 67%
b: 74%
a: R = TBDPS
b: R = Bn
RO
TFA, CH2Cl2,
20 °C, 18 h
S
O
F
6
cis/trans = 1:1
a: 35%
b: 72%
Scheme 3
Reduction of the thiolactone 6b with DIBAL-H (1 M in n-
hexane) at –40 °C or 0 °C afforded a mixture of fluorinat-
ed products, while NaBH4 gave better results at –17 °C. In
these conditions, the thiolactol 7b was obtained in 55–
60% yield (Scheme 4). In this case, one major isomer was
formed in a 85:15 ratio, when the reduction was conduct-
ed separately from both cis- and trans-thiolactones 6b.
This selective reduction was probably due to the steric de-
mand of the O-benzylether group, leading preferentially
to the b-isomer as major isomer. It is worthy of note that
scrupulous control of the reaction temperature is needed
during the reduction of 6b to avoid any ring-opening reac-
tion by the solvent. Acetylation of 7b afforded 8b in 90%
yield, which was ready to be involved in the Vorbrüggen
reaction with the bistrimethylsilylthymine. A stoichio-
metric amount of SnCl4 was used to introduce the thymine
base from the acetate 8b (Scheme 4). By working either
under refluxing acetonitrile or at 20 °C, a total degrada-
tion of the starting acetate 8b was observed. No reaction
occurred at lower temperatures. In contrast, in the pres-
ence of freshly distilled TMSOTf the reaction reached
completion after 18 hours at 20 °C under stirring.9a The
crude mixture was purified by flash column chromatogra-
phy, and afforded the thionucleoside analogue 9b in 75%
yield.20 The NMR analysis of the mixture presented the
four isomers: the 2¢,4¢-cis and -trans isomers in 3:2 a/b ra-
tio.
Et3B, CH2Cl2,
20 °C, 18 h
F
RO
+
EtO(S)CS
CO2Et
2
or dilauroyl
peroxide, DCE,
reflux, 4 h
1
a: R = TBDPS
b: R = Bn
F
EtO(S)CS
RO
F
EtO2C
+
CO2Et
CO2Et
F
4
3
Scheme 2
The formation of the corresponding thiol by sulfur–car-
bon bond cleavage of the dithiocarbonate function is usu-
ally realized by using primary amine. However, the
presence of the fluorine atom enhances the electrophilic
character of the ester function, and competitive addition
of the amine onto the ester could occur.15 Indeed, treat-
ment of the dithiocarbonate 3a with a primary amine, such
as the ethylene diamine, afforded a mixture of the desired
thiol and other products (presumably the corresponding
amides),16 even at –20 °C. At lower temperature (–78 °C)
no reaction occurred. The use of a secondary amine, such
as piperidine, allowed us to avoid this competitive reac- The a/b ratio was deduced from the {19F}-1H HOESY
tion,17 and thiol 5 was exclusively formed. Flash column NMR experiment. The assignment of the spatial proximi-
chromatography of the crude yielded a diastereomeric ty between the fluorine atom and the hydrogen atoms H1¢,
mixture of 5a and 5b in 67% and 74%, respectively H4¢, or H6 for each diastereomer is depicted in Figure 2.
(Scheme 3). Due to its rapid degradation at room temper-
ature, 5 was directly involved in the next step. The ring-
This approach was transposed to the synthesis of 2¢,3¢-di-
fluorothionucleoside by trapping the free radical with a
closure reaction was performed in the presence of an ex-
terminal monofluoroalkene.21 However, no expected free-
cess of TFA over 18 hours at 20 °C. Purification of the
Synlett 2008, No. 6, 817–820 © Thieme Stuttgart · New York

LETTER
Synthesis of 2¢,3¢-Dideoxy-2¢-Fluoro-4¢-Thionucleosides from a Fluoroxanthate
819
BnO
Acknowledgment
BnO
NaBH4, EtOH, 2 h,
–17 °C
S
S
O
OH
This work has been performed within the Institut Normand de Chi-
mie Moléculaire Macromoléculaire et Médicinale (INC3M), and
the PUNCHOrga network (Pôle Universitaire de Chimie Orga-
nique). Le Ministère de la Recherche et des Nouvelles Technolo-
gies, the CNRS (Centre National de la Recherche Scientifique), the
Région Basse-Normandie and the European Union (FEDER fun-
ding) are gratefully thanks for their financial supports.
55–60%
F
F
6b
7b
cis/trans = 1:1
Ac2O, Et3N,
DMAP, CH2Cl2,
3 h, 20 °C
BnO
S
OAc
References and Notes
90%
(1) (a) Simons, C. Nucleoside Mimetics, In Advanced Chemistry
Texts, Vol. 3; Gordon and Breach Science Publishers:
Amsterdam, 2001. (b) Isanbor, C.; O’Hagan, D. J. Fluorine
Chem. 2006, 127, 303. (c) Clark, J. L.; Mason, J. C.;
Hollecker, L.; Stuyver, L. J.; Tharnish, P. M.; McBrayer, T.
R.; Otto, M. J.; Furman, P. A.; Schinazi, R. F.; Watanabe, K.
A. Bioorg. Med. Chem. Lett. 2006, 16, 1712. (d) Jeannot,
F.; Gosselin, G.; Mathé, C. Org. Biomol. Chem. 2003, 1,
2096.
F
8b
OTMS
N
H
O
TMSO
N
N
BnO
O
TMSOTf, CH2Cl2, 18 h,
20 °C
S
N
75%
(2) Yokoyama, M. Synthesis 2000, 1637.
F
9b
(3) Len, C.; Mackenzie, G. Tetrahedron 2006, 62, 9085.
(4) (a) Rahim, S. G.; Trivedi, N.; Bogunovic-Batchelor, M. V.;
Hardy, G. W.; Mills, G.; Selway, J. W. T.; Snowden, W.;
Littler, E.; Coe, P. L.; Basnak, I.; Whale, R. F.; Walker, R.
T. J. Med. Chem. 1996, 39, 789. (b) Hertel, L. W.; Kroin, J.
S.; Misner, J. W.; Tustin, J. M. J. Org. Chem. 1988, 53,
2406.
(5) (a) Otter, G. P.; Elzagheid, M. I.; Jones, G. D.; MacCulloch,
A. C.; Walker, R. T.; Oivanen, M.; Klika, K. D. J. Chem.
Soc., Perkin Trans. 2 1998, 2343. (b) Tuttle, J. V.; Tisdale,
M.; Krenitsky, T. A. J. Med. Chem. 1993, 36, 119.
(6) McAtee, J. J.; Schinazi, R. F.; Liotta, D. C. J. Org. Chem.
1998, 63, 2161.
α/β = 3:2
Scheme 4
α/β = 3:2
H
N
O
H
N
O
BnO
O
BnO
O
H1'
N
S
S
N
H6
F
F
cis-α-9b
62:38
cis-β-9b
(7) (a) Gouault, S.; Pommelet, J. C.; Lequeux, T. Synlett 2002,
996. (b) Jean-Baptiste, L.; Yemets, S.; Legay, R.; Lequeux,
T. J. Org. Chem. 2006, 71, 2352.
H
H
N
O
O
N
BnO
O
BnO
O
(8) (a) Jin, F.; Wang, D.; Confalone, P. N.; Pierce, M. E.; Wang,
Z.; Xu, G.; Choudhury, A.; Nguyen, D. Tetrahedron Lett.
2001, 42, 4787. (b) Caille, J. C.; Miel, H.; Armstrong, P.;
McKervey, M. A. Tetrahedron Lett. 2004, 45, 863.
(c) Huang, J. T.; Chen, L. C.; Wang, L.; Kim, M. H.;
Warshaw, J. A.; Armstrong, D.; Zhu, Q. Y.; Chou, T. C.;
Watanabe, K. A.; Matulic-Adamic, J.; Su, T. L.; Fox, J. J.;
Polsky, B.; Baron, P. A.; Gold, J. W. M.; Hardy, W. D.;
Zuckerman, E. J. Med. Chem. 1991, 34, 1640. (d) Jeong, L.
S.; Marquez, V. E. J. Org. Chem. 1995, 60, 4276.
(e) Watanabe, K. A.; Reichman, U.; Hirota, K.; Lopez, C.;
Fox, J. J. J. Med. Chem. 1979, 22, 21. (f) Boydell, A. J.;
Vinader, V.; Linclau, B. Angew. Chem. Int. Ed. 2004, 43,
5677.
S
S
N
H1'
N
H4'
H4'
H6
F
F
trans-α-9b
58:42
trans-β-9b
Figure 2
radical addition occurred, the dimer 4 was exclusively
formed. Current investigations to solve this problem are
under way.
(9) (a) Seaong, L. S.; Marquez, V. E. Chem. Lett. 1995, 301.
(b) Watts, J. K.; Sadalapure, K.; Choubdar, N.; Pinto, B. M.;
Damha, M. J. J. Org. Chem. 2006, 71, 921. (c) Katayama,
S.; Takamatsu, S.; Naito, M.; Tanji, S.; Ineyama, T.; Izawa,
K. J. Fluorine Chem. 2006, 127, 524. (d) Takamatsu, S.;
Maruyama, T.; Katayama, S.; Hirose, N.; Naito, M.; Izawa,
K. J. Org. Chem. 2001, 66, 7469.
(10) (a) Jeong, L. S.; Moon, H. R.; Yoo, S. J.; Lee, S. N.; Chun,
M. W.; Lim, Y. H. Tetrahedron Lett. 1998, 39, 5201.
(b) Yoshimura, Y.; Endo, M.; Sakata, S. Tetrahedron Lett.
1999, 40, 1937.
In conclusion, the synthesis of 2¢,3¢-dideoxy-2¢-fluoro-4¢-
thionucleosides is reported in six steps from the fluorox-
anthate 1 and a protected allylic alcohol. We have shown
that this approach is flexible and can be applied to the
preparation of fluorothionucleosides. This additional ex-
ample illustrates the continuous growing of the xanthate
chemistry in synthesis.22 However, some limitations of
this method appeared as described by our failure when at-
tempting to trap the free radical with the terminal fluoro-
alkene analogue of 2. The debenzylation and the HPLC
separation of the four isomers of 9b are in progress in or-
der to evaluate their biological activity.
(11) (a) Yoshimura, Y.; Kitano, K.; Yamada, K.; Satoh, H.;
Watanabe, M.; Miura, S.; Sakata, S.; Sasaki, T.; Matsuda, A.
J. Org. Chem. 1997, 62, 3140. (b) Zheng, F.; Zhang, X. H.;
Qiu, X. L.; Zhang, X.; Qing, F. L. Org. Lett. 2006, 8, 6083.
Synlett 2008, No. 6, 817–820 © Thieme Stuttgart · New York

820
L. Jean-Baptiste et al.
LETTER
Trifluoroacetic acid (1 mL, 13.46 mmol) was added to a
(12) Boivin, J.; Ramos, L.; Zard, S. Z. Tetrahedron Lett. 1998,
39, 6877.
(13) Syvret, R. G.; Vassilaros, D. L.; Parees, D. M.; Pez, G. P.
J. Fluorine Chem. 1994, 67, 277.
solution of thiol 5b (0.20 g, 0.7 mmol) in CH2Cl2 (5 mL).
The mixture was stirred for 18 h at 20 °C, then poured into a
sat. aq NaCl soln (10 mL). The aqueous layer was extracted
twice with CH2Cl2 (10 mL), and the organic layer was dried
(MgSO4) then the solvent was evaporated. The crude
product was purified by flash column chromatography on
silica (pentane–EtOAc, 95:5) to afford the less polar isomer
2,4-trans-6b (68 mg, 0.28 mmol, 40%) and the more polar
isomer 2,4-cis-6b (52 mg, 0.22 mmol, 31%).
(14) Experimental for 3b
A solution of O-benzyl allylic alcohol 2b (1.08 g, 7.28
mmol, 1.1 equiv), and xanthate 1 (1.50 g, 6.62 mmol, 1
equiv) in deoxygenated DCE (80 mL) was heated at 85 °C
(oil bath). A solution of lauroyl peroxide (0.79 g, 1.99 mmol,
0.3 equiv) in deoxygenated DCE (20 mL) was added
dropwise (over 2 h by using a syringe pump), then the
mixture was stirred 30 min. The solution was cooled to r.t.,
and the solvent was removed under reduced pressure. The
crude product was purified by silica gel column
chromatography (pentane–EtOAc, 95:5) to afford 3b as a
mixture of diastereomers (1.54 g, 62%, 1:1) as a light yellow
liquid.1H NMR (250 MHz, CDCl3): d = 1.32 [t, 6 H,
3JHH = 7.1 Hz, CH3 (2 dia)], 1.40 [t, 3JHH = 7.1 Hz, 6 H, CH3
(2 dia)], 2.12–2.75 [m, 4 H, CH2CHF (2 dia)], 3.80–3.99 [m,
4 H, CH2O (2 dia)], 4.03–4.16 [m, 2 H, CHS (2 dia)], 4.27
[q, 3JHH = 7.1 Hz, 4 H, CH2 (2 dia)], 4.56 [s, 4 H, PhCH2O (2
dia)], 4.59 [q, 3JHH = 7.1 Hz, 2 H, CH2 (dia 1)], 4.60 [q,
3JHH = 7.1 Hz, 2 H, CH2 (dia 2)], 5.00 [ddd, 2JHF = 49.0 Hz,
3JHH = 8.4 Hz, 3JHH = 4.1 Hz, 1 H, CHF (dia 1)], 5.08 [ddd,
2JHF = 49.0 Hz, 3JHH = 10.2 Hz, 3JHH = 2.9 Hz, 1 H, CHF (dia
2)], 7.25–7.35 [m, 10 H, Ph (2 dia)]. 19F NMR (235 MHz,
CFCl3, CDCl3): d = –191.46 [ddd, 2JHF = 49.0 Hz,
3JHF = 28.0 Hz, 3JHF = 20.0 Hz, 1 F, (dia 1)], –191.42 [ddd,
2JHF = 49.0 Hz, 3JHF = 36.0 Hz, 3JHF = 16.0 Hz, 1 F, (dia 2)].
13C NMR (62.5 MHz, CDCl3): d = 12.7, 13.1 (s, CH3), 32.85
[d, 2JCF = 20.6 Hz, CH2 (dia 1)], 32.2 [d, 2JCF = 20.9 Hz, CH2
(dia 2)], 44.9, 45.4 (s, CHS), 60.7, 69.1, 69.2, 69.6, 70.7,
71.9 (s, OCH2), 85.8 [d, 1JCF = 184.5 Hz, CF (dia 1)], 85.9 [d,
1JCF = 184.8 Hz, CF (dia 2)], 126.6, 126.7, 127.1, 136.7 (s,
Ph), 168.3 [d, 2JCF = 23.9 Hz, C=O (dia 1)], 168.5 [d,
2JCF = 23.3 Hz, C=O (dia 2)], 211.7 [C=S (dia 1)], 211.8
[C=S (dia 2)]. MS (ESI, 9 eV): m/z 375 (73) [M + H]+, 329
(18), 269 (26), 267 (61), 251 (49), 223 (100), 207 (25), 163
(35), 91 (20). ESI-HRMS: m/z [M + H]+ calcd for
C17H24FO4S2: 375.1100; found: 375.1099.
g-Thiobutyrolactone 2,4-trans-6b: 1H NMR (250 MHz,
CDCl3): d = 2.30–2.40 (m, 2 H, H3), 3.50–3.75 (m, 2 H, H5),
4.20 (m, 1 H, H4), 4.50 (s, 2 H, OCH2Ph), 5.15 (ddd,
2JHF = 51.2 Hz, 3JHH = 3JHH = 6.8 Hz, 1 H, H2) 7.15–7.35 (m,
5 H, Ph). 19F NMR (235 MHz, CFCl3, CDCl3): d = –184.65
(ddd, 2JHF = 51.2 Hz, 3JHF = 3JHF = 18.8 Hz). 13C NMR (62.5
MHz, CDCl3): d = 32.6 (d, 2JCF = 20.8 Hz, C3), 42.0 (d,
3JCF = 5.9 Hz, C4), 71.2, 75.0, 93.0 (d, 1JCF = 190.2 Hz, C2),
127.5, 128.0, 128.9, 137.5 (s, Ph), 200.7 (d, 2JCF = 17.4 Hz,
C1).
g-Thiobutyrolactone 2,4-cis-6b: 1H NMR (250 MHz,
CDCl3): d = 2.18 (m, 1 H, H3), 2.71 (m, 1 H, H3’), 3.62 (m, 1
H, H5), 3.80 (m, 1 H, H5¢), 3.95 (m, 1 H, H4), 4.57 (s, 2 H,
OCH2Ph), 5.10 (ddd, 2JHF = 50.4 Hz, 3JHH = 9.8 Hz,
3JHH = 6.8 Hz, 1 H, H2), 7.15–7.35 (m, 5 H, Ph). 19F NMR
(235 MHz, CFCl3, CDCl3): d = –183.7 (ddd, 2JHF = 50.4 Hz,
3JHF = 18.8 Hz, 3JHF = 9.4 Hz). 13C NMR (62.5 MHz,
CDCl3): d = 33.6 (d, 2JCF = 19.6 Hz, C3), 42.6 (d, 3JCF = 7.2
Hz, C4), 71.7, 74.8, 93.3 (d, 1JCF = 196.2 Hz, C2), 127.5,
127.9, 128.9, 137.6 (s, Ph), 201.7 (d, 2JCF = 17.6 Hz, C1). IR
(NaCl): n = 1714 (C=O) cm–1. ESI-HRMS: m/z [M + Na]+
calcd for C12H13FNaO2S: 263.0518; found: 263.0525.
(20) Selected Analytical Data for the Four Isomers of 9b
1H NMR (250 MHz, CDCl3): d = 1.79 [s, 3 H, CH3 (dia 1)],
1.86 ]s, 3 H, CH3 (dia 2)], 1.93 [s, 3 H, CH3 (dia 3)], 1.97 [s,
3 H, CH3 (dia 4)], 1.75–2.62 [m, 8 H, CH2CHF (4 dia)],
3.58–4.10 (m, 12 H, CHCH2OBn and CH2OBn (4 dia)],
4.48–4.56 [m, 8 H, CH2Ph (4 dia)], 5.18 (br d, 2JHF = 49.4
Hz, 2 H, H2¢ (2 dia)], 5.20 (br d, 2JHF = 54.1 Hz, 2 H, H2¢ (2
dia)], 6.17 (dd, 3JHF = 12.5 Hz, 3JHH = 4.0 Hz, 1 H, H1¢ (dia
1)], 6.19 (dd, 3JHF = 10.6 Hz, 3JHH = 1.4 Hz, 1 H, H1¢ (dia 2)],
6.40 (dd, 3JHF = 19.9 Hz, 3JHH = 4.2 Hz, 1 H, H1¢ (dia 3)],
6.44 (dd, 3JHF = 12.5 Hz, 3JHH = 3.7 Hz, 1 H, H1¢ (dia 4)],
7.19–7.34 [m, 20 H, Ph (4 dia)], 7.59 [s, 2 H, CHCH3 (2
dia)], 7.93 [s, 2 H, CHCH3 (2 dia)] 9.40–9.70 (br s, 4 H, NH).
19F NMR (235 MHz, CFCl3, CDCl3): d = –171.54 [m (dia
1)], –175.88 [dddd, 2JHF = 49.4 Hz, 3JHF = 40.0 Hz,
3JHF = 14.1 Hz, 3JHF = 10.6 Hz (dia 2)], –187.00 [m (dia 3)],
–190.75 [ddddd, 2JHF = 54.1 Hz, 3JHF = 42.4 Hz, 3JHF = 23.5
Hz, 3JHF = 12.5 Hz, 4JHF = 2.4 Hz (dia 4)]. ESI-HRMS: m/z
[M + H]+ calcd for C17H20FN2O3S: 351.1179 [M + H]+;
found: 351.1180 [M + H]+.
(15) (a) Annedi, S. C.; Li, W.; Samson, S.; Kotra, L. P. J. Org.
Chem. 2003, 68, 1043. (b) Gouault, S.; Guérin, C.;
Lemoucheux, L.; Lequeux, T.; Pommelet, J. C. Tetrahedron
Lett. 2003, 44, 5061.
(16) The 19F NMR spectra of the crude mixture revealed two
multiplets: –188.2 (dddd, 2JFH = 49.4 Hz, 3JFH = 25.9 Hz,
3JFH = 21.2 Hz, 4JF–NH = 4.7 Hz) and –191.0 (dddd,
2JFH = 49.4 Hz, 3JFH = 40.0 Hz, 3JFH = 16.5 Hz, 4JF–NH = 4.7
Hz).
(17) Brown, M. D.; Gillon, D. W.; Meakins, G. D.; Whitham, G.
H. J. Chem. Soc., Perkin Trans. 1 1985, 1623.
(18) (a) Choo, H.; Chong, Y.; Choi, Y.; Mathew, J.; Schinazi, R.
F.; Chu, C. K. J. Med. Chem. 2003, 46, 389. (b) Young, R.
J.; Miller, J. A. EP 514036, 1992; Chem. Abstr. 1993, 118,
169532.
(21) Van Steenis, J. H.; van der Gen, A. J. Chem. Soc., Perkin
Trans. 1 2002, 2117.
(22) (a) Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672.
(b) Quiclet-Sire, B.; Zard, S. Z. Chem. Eur. J. 2006, 12,
6002.
(19) Typical Procedure: Preparation of the g-Thiobutyro-
lactone 6b
Synlett 2008, No. 6, 817–820 © Thieme Stuttgart · New York