A facile synthesis of 3'-deoxy-3'-fluorothymidine via a highly stereoselective glycosylation with 2,3-dideoxy-3-fluoro-D-erythro- pentofuranosyl diethyl phosphite

Article abstract of DOI:10.1055/s-1999-3166

Coupling of 2,3-dideoxy-3-fluoro-D-erythro-pentofuranosyl diethyl phosphite with 2,4-bis(trimethylsilyl)thymine under the influence of trimethylsilyl trifluoromethanesulfonate (TM-SOTf) provides a facile and highly stereoselective entry to 3'-deoxy-3'-fluorothymidine (FLT), wherein the use of propionitrile as a solvent as well as the α-configuration of the fluorine atom at C3 has been proven to be responsible for the high β- selectivity of up to 91:9.

Full text of DOI:10.1055/s-1999-3166

1274
LETTER
A Facile Synthesis of 3’-Deoxy-3’-fluorothymidine via a Highly Stereoselective
Glycosylation with 2,3-Dideoxy-3-fluoro-D-erythro-pentofuranosyl Diethyl
Phosphite
Jun Inagaki, Hiroki Sakamoto, Makoto Nakajima, Seiichi Nakamura, Shunichi Hashimoto*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Fax +81 (11) 7064981; E-mail: hsmt@pharm.hokudai.ac.jp
Received 20 May 1999
2,3-dideoxy-3-fluoro-D-erythro-pentofuranosyl diethyl
Abstract: Coupling of 2,3-dideoxy-3-fluoro-D-erythro-pentofura-
phosphite 2 as a glycosyl donor in the presence of
TMSOTf.
The furanosyl diethyl phosphite 27 was obtained from the
nosyl diethyl phosphite with 2,4-bis(trimethylsilyl)thymine under
the influence of trimethylsilyl trifluoromethanesulfonate (TM-
SOTf) provides a facile and highly stereoselective entry to 3’-
deoxy-3’-fluorothymidine (FLT), wherein the use of propionitrile as
corresponding furanose via coupling with diethyl phos-
a solvent as well as the a-configuration of the fluorine atom at C3
phorochloridite, which was prepared by demethylation of
has been proven to be responsible for the high b-selectivity of up to
methyl 2,3-dideoxy-3-fluoro-5-O-benzoyl-b-D-erythro-
91:9.
pentofuranoside (3)8a with BCl3·S(CH3)2.9 All the report-
Key words: FLT, glycosylation, pentofuranosyl phosphite, nitrili-
um ion, electrostatic interaction
ed coupling procedures to give 5'-O-protected FLT take
advantage of the Vorbrüggen glycosylation method,10
wherein the b:a ratios ranging from 2.2:1 to 5:1 are ob-
served.8a,11,12 Particularly noteworthy is that acetonitrile is
Since the discovery of 3’-azido-3’-deoxythymidine (AZT)
as an antiretroviral agent, a number of 3’-substituted-2’,3’-
dideoxynucleoside analogues have been synthesized and
used as a solvent in all cases, while no explanation for this
solvent is presented. Armed with the instructive prece-
dents, we were gratified to find that condensation of 2 (1.0
equiv) with 2,4-bis(trimethylsilyl)thymine (4) (1.5 equiv)
in the presence of TMSOTf (1.0 equiv) in propionitrile at
-50 °C proceeded smoothly to give the 5'-O-benzoyl-pro-
evaluated for their antiviral activity against human immu-
nodeficiency virus (HIV).1 Among them, 3’-deoxy-3’-flu-
orothymidine (FLT, 1) has been demonstrated to be a
more potent inhibitor of HIV replication than AZT.2
tected FLT 5 in 89% yield and with the b:a ratio of 91:9
While its toxicity precludes further investigation, an enor-
mous
(Table 1, entry 1), which, upon deprotection and subse-
quent ready separation,11c furnished FLT (1) in 86% yield.
R
R
O
N
TBDPSO
HO
BzO
X
Y
X
Y
X
Y
O
a or b
O
c
O
Me
HN
OP(OEt)2
R'
R'
O
O
HO
6 X=R=H, Y=OH
R'=OAllyl
8 X=F, Y=R=H
R'=OAllyl
10 X=F, Y=H
7 X=OH, Y=R'=H
R=OAllyl
9 X=R'=H, Y=I
R=OAllyl
11 X=H, Y=I
F
FLT (1)
amount of effort has been devoted to the design and syn-
thesis of its analogues to show a selectivity against HIV.3
In this regard, one of the major drawbacks in a convergent
strategy has been the poor to modest b-selectivity ob-
served with direct coupling between 2,3-dideoxy-3-fluo-
ro-D-erythro-pentofuranosyl derivative and nucleoside
bases, which is a general trend with the synthesis of other
2’-deoxyribonucleosides.4 As part of a program to extend
the recently developed glycosylation method capitalizing
on diethyl phosphite as a leaving group,5 our interest has
been centered on the feasibility of the stereocontrol by
means of the glycosyl phosphite method.6 We herein wish
to report a highly stereoselective construction of 2’-deoxy-
b-N-glycosidic linkage in FLT synthesis by employing
Synlett 1999, No. 8, 1274–1276 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Facile Synthesis of 3’-Deoxy-3’-fluorothymidine via a Highly Stereoselective Glycosylation
1275
The b-selectivity appeared to increase by lowering the the
reaction temperature, however, -50 °C was the limit tem-
perature to allow for the smooth coupling (entries 1 and
2). Switching the solvent from propionitrile to dichlo-
romethane or toluene was found to result in poor b-selec-
tivities (entries 3 and 4), while the use of ether exhibited
almost no stereoselectivity (entry 5). Thus, these results,
together with the precedents described above, manifested
the beneficial effects of nitriles as solvents on b-selectivi-
ties, although a remarkably high order of b-selectivity re-
quired excellent leaving groups such as a phosphite group
at very low temperatures. The dramatic effects of nitriles
as solvents on 1,2-trans-b-selective glycosidations of D-
gluco- and D-galactopyranosyl donors without neigh-
bouring group participation have been well-document-
ed,13 the role of which is assumed to be due to the
predominant formation of a-nitrilium ions (or a-nitrilium-
nitrile-conjugate ions).5a,14 However, there have been re-
ported no similar effects with 2-deoxypentofuranosyl do-
nors.
O
N
Me
HN
O
O
BzO
X
Y
X
4 (1.5 equiv.)
O
OP(OEt)2
TMSOTf (1.0 equiv.)
-50 °C, 30 min
Y
10 X=F, Y=H
11 X=H, Y=I
12 X=F, Y=H
13 X=H, Y=I
In order to gain a deep insight into the role of propionitrile
as the solvent, we then explored glycosylation with 2,3-
dideoxy-3-fluoro-5-O-benzoyl-D-threo-pentofuranosyl
diethyl phosphite (10)7, C3-epimer of 2, which was pre-
pared from allyl 2-deoxy-5-O-(tert-butyldiphenylsilyl)-a-
D-erythro-pentofuranoside (6)8b as shown in Scheme 1.
To our surprise, coupling of 10 with 4 under the foregoing
conditions provided the 2'-deoxynucleoside 12 in 74%
yield and with the b:a ratio of 37:63 (Table 2, entry 1).
From the finding that little
pentofuranoside (7)8c as depicted in Scheme 1, displayed
modest a-selectivities irrespective of the nature of sol-
vents (entries 3 and 4).
Based on the above results, we may now present the ste-
reochemical reaction course shown in Fig.1, while the
precise mechanism remains unclear. The present glycosy-
lation with 2 is assumed to proceed through the interme-
diacy of the a-nitrilium ion stabilized by the electrostatic
interaction15 with the suitably disposed fluorine atom fol-
lowed by the backside attack of 4 on this intermediate. A
similar stabilizing interaction is not expected with 10 be-
cause of the steric repulsion between the C4-substituent
and the b-nitrilium ion; thus, the reaction may proceed
without participation of propionitrile to give nearly the
same selectivity as that observed in dichloromethane.
R
R
TBDPSO
HO
BzO
X
Y
X
Y
X
Y
O
a or b
O
c
O
OP(OEt)2
R'
R'
6 X=R=H, Y=OH
R'=OAllyl
7 X=OH, Y=R'=H
R=OAllyl
8 X=F, Y=R=H
R'=OAllyl
9 X=R'=H, Y=I
R=OAllyl
10 X=F, Y=H
11 X=H, Y=I
Scheme 1 Reagents and conditions: a) (i) Tf2O (1.2 equiv), pyridine,
CH2Cl2, 0 °C, 30 min; (ii) Et3N•3HF (3.0 equiv), EtOAc, 50 °C, 8 h,
56% (2 steps from 6). b) (i) Ph3P (3.0 equiv), I2 (2.0 equiv), imidazole
(3.0 equiv), PhCH3-MeCN (2:1), 90 °C, 3 h; (ii) TBAF (1.1 equiv),
THF, 68% (2 steps from 7). c) (i) BzCl, pyridine, CH2Cl2; (ii)
BCl3•SMe2 (1.5 equiv), Et2O, 30 min; (iii) ClP(OEt)2 (1.2 equiv.),
Et3N (2.5 equiv.), CH2Cl2, -78 °C, 30 min, 26% (3 steps from 8), 33%
(3 steps from 9).
Et
Thymine
C
variation in stereoselectivities was observed using dichlo-
romethane as the solvent (entry 2), it was suggested that
an exceptionally high order of b-selectivity attained by
coupling of 2 with 4 at -50 °C might be attributable not
only to the use of propionitrile as the solvent but more im-
portantly to the a-configuration of the fluorine atom at C3
in the donor. Furthermore, the significance of the C3-a-
fluorine atom with large electronegativity as a stereodi-
recting element was disclosed by replacing it with the io-
dine atom, wherein glycosylation with 117, prepared from
allyl 2-deoxy-5-O-(tert-butyldiphenylsilyl)-b-D-threo-
δ-
F
N+
BzO
BzO
O
O
N+
C
δ-F
Thymine
Et
Figure 1 Stereochemical course of glycosylations with 2 and 10
In conclusion, we have developed a short-step synthesis
of FLT by exploiting the glycosyl phosphite method,
wherein the key to the success of the present method lies
Synlett 1999, No. 8, 1274–1276 ISSN 0936-5214 © Thieme Stuttgart · New York

1276
J. Inagaki et al.
LETTER
in a high-yield coupling in propionitrile at -50 °C. It has
also been demonstrated that the a-configuration of the flu-
orine atom at C3 in the donor is critical to a high order of
b-selectivity. We are currently investigating the applica-
bility of our protocol to the synthesis of purine deriva-
tives.
References and Notes
(1) For a review see: De Clercq, E. AIDS Res. Hum. Retrovir.
1992, 8, 119.
(2) Herdewijn, P.; Balzarini, J.; De Clercq, E.; Pauwels, R.; Baba,
M.; Broder, S.; Vanderhaeghe, H. J. Med. Chem. 1987, 30,
1270.
(3) (a) Kumar, R.; Wang, L.; Wiebe, L. I.; Knaus, E. E. J. Med.
Chem. 1994, 37, 3554. (b) Parang, K.; Knaus, E. E.; Wiebe, L.
I. Nucleosides, Nucleotides 1998, 17, 987 and references cited
therein.
(4) For recent reviews see: (a) Dueholm, K. L.; Pedersen, E. B.
Synthesis 1992, 1. (b) Huryn, D. M.; Okabe, M. Chem. Rev.
1992, 92, 1745. (c) Wilson, L. J.; Hager, M. W.; El-Kattan, Y.
A.; Liotta, D. C. Synthesis 1995, 1465.
(5) (a) Hashimoto, S.; Umeo, K.; Sano, A.; Watanabe, N.;
Nakajima, M.; Ikegami, S. Tetrahedron Lett. 1995, 36, 2251.
(b) Hashimoto, S.; Inagaki, J.; Sakamoto, H.; Sano, A.;
Nakajima, M. Heterocycles 1997, 46, 215.
(6) (a) Martin, T. J.; Schmidt, R. R. Tetrahedron Lett. 1992, 33,
6123. (b) Kondo, H.; Ichikawa, Y.; Wong, C.-H. J. Am. Chem.
Soc. 1992, 114, 8748. (c) Watanabe, Y.; Nakamoto, C.;
Yamamoto, T.; Ozaki, S. Tetrahedron 1994, 50, 6523.
(7) The donors could be stored in the freezer (at -30 °C) for
several months without decomposition.
(8) The furanosides 3, 6 and 7 were prepared in analogy with the
reported procedures: (a) Motawia, M. S.; Pedersen, E. B.
Liebigs Ann. Chem. 1990, 1137. (b) Hansen, P.; Pedersen, E.
B. Acta Chem. Scand., Ser. B 1990, 44, 522. (c) Walczak, K.;
Pupek, K.; Pedersen, E. B. Liebigs Ann. Chem. 1991, 1041.
(9) Congreve, M. S.; Holmes, A. B.; Hughes, A. B.; Looney, M.
G. J. Am. Chem. Soc. 1993, 115, 5815.
(10) Vorbrüggen, H. Acc. Chem. Res. 1995, 28, 509.
(11) (a) Fleet, G. W. J.; Son, J. C.; Derome, A. E. Tetrahedron
1988, 44, 625. (b) Hager, M. W.; Liotta, D. C. Tetrahedron
Lett. 1992, 33, 7083. (c) Mikhailopulo, I. A.; Pricota, T. I.;
Poopeiko, N. E.; Klenitskaya, T. V.; Khripach, N. B. Synthesis
1993, 700.
(12) Very recently, Poopeiko and co-workers reported the
synthesis of FLT from phenyl 5-O-benzyl-3-deoxy-3-fluoro-
1-seleno-a-D-arabino-furanoside through consecutive 2-OH
activation, 1,2-migration of the phenylselenenyl group and
glycosylation under the Mitsunobu conditions followed by
deselenization; however, the b:a ratio was 2:3: Poopeiko, N.;
Fernández, R.; Barrena, M. I.; Castillón, S.; Forniés-Cámer,
J.; Cardin, C. J. J. Org. Chem. 1999, 64, 1375.
(13) (a) Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett.
1984, 25, 1379. (b) Hashimoto, S.; Honda, T.; Ikegami, S. J.
Chem. Soc., Chem. Commun. 1989, 685.
(14) Schmidt, R. R.; Behrendt, M.; Toepfer, A. Synlett 1990, 694.
(15) For a review on Coulombic attractions between carbon-bound
fluorine and electrophilic metal cations, see: Plenio, H. Chem.
Rev. 1997, 97, 3363.
Typical procedure for the preparation of pentofurano-
syl diethyl phosphite:
Diethyl phosphorochloridite (0.065 mL, 0.45 mmol) was
added to a solution of 5-O-benzoyl-2,3-dideoxy-3-fluoro-
D-erythro-pentofuranose (90 mg, 0.38 mmol) and Et3N
(0.13 mL, 0.94 mmol) in dry CH2Cl2 (5 mL) at -78 °C. Af-
ter stirring at -78 °C for 30 min, the reaction was quenched
with ice, followed by stirring at 0 °C for 10 min. The mix-
ture was poured into a two-layer mixture of Et2O (5 mL)
and saturated aqueous NaHCO3 (5 mL), and the whole
was extracted with EtOAc (30 mL). The organic layer was
washed with brine, and dried over anhydrous Na2SO4. Fil-
tration and evaporation in vacuo followed by silica gel
column chromatography (8:1:0.5 hexane/EtOAc/Et3N)
furnished the phosphite 2 (95 mg, 70%, a:b=64:36) as a
1
colorless oil. Selected spectroscopic data: H NMR (500
MHz, CDCl3) d 5.96 (1 H, dd, J = 6.6, 5.4 Hz, H-1a), 5.99
(1 H, m, H-1b); 13C NMR (125 MHz, CDCl3) d 98.2 (d, J
= 14.0 Hz, C-1a), 98.4 (dd, J = 15.3, 2.3 Hz, C-1b); 31P
NMR (109 MHz, CDCl3) d 138.42 (a), 139.34 (b). HRMS
(FAB) calcd for C16H23FO6P (M++H) 361.1216, found
361.1191.
Typical procedure for the glycosidation of pentofura-
nosyl diethyl phosphite:
To a solution of 4 (70 mg, 0.26 mmol) in EtCN (2.5 mL)
at -50 °C was added a 1 M solution of TMSOTf in EtCN
(0.17 mL, 0.17 mmol), followed by addition of phosphite
2 (62 mg, 0.17 mmol) in EtCN (1 mL). After stirring at
-50 °C for 30 min, the reaction was quenched with Et3N
(0.5 mL), and the mixture was poured into a two-layer
mixture of Et2O (10 mL) and sat. aq NaHCO3 (10 mL).
The whole was extracted with EtOAc (30 mL), and the or-
ganic layer was washed with brine and dried over anhy-
drous Na2SO4. Filtration and evaporation in vacuo
followed by short-path column chromatography on silica
gel (1:2 hexane/EtOAc) afforded 5'-O-benzoyl-protected
FLT 511c (53 mg, 89%, b:a = 91:9) as a white solid. The
ratio was determined by integration of methyl protons at
C-5 in 500 MHz 1H NMR; 1H NMR (500 MHz, CDCl3) d
1.65 (3 H, s, 5-Me) (for b-anomer), 1.95 (3 H, s, 5-Me)
(for a-anomer).
Article Identifier:
1437-2096,E;1999,0,08,1274,1276,ftx,en;Y11099ST.pdf
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Acknowledgement
This research was supported in part by
a Grant-in-Aid
(No.08557119) from the Ministry of Education, Science, Sports and
Culture of Japan.
Synlett 1999, No. 8, 1274–1276 ISSN 0936-5214 © Thieme Stuttgart · New York