Synthesis of 1′-C-fluoromethyl-ddC by selectfluor-induced glycosylation of exo-glycals

Article abstract of DOI:10.1055/s-2003-36792

1′-C-fluoromethyl-ddC has been synthesized from 4-pentene-1,2-diol which is easily obtained from glycidol. The key steps are the synthesis of an exo-glycal by a 5-exo iodo-cyclization of a 4-pentene-1,2-diol and elimination, and a fluoro-glycosylation using an exo-glycal as glycosyl donor.

Full text of DOI:10.1055/s-2003-36792

LETTER
207
Synthesis of 1′-C-Fluoromethyl-ddC by Selectfluor-Induced Glycosylation
of exo-Glycals
Synthesis of
1
i
′
-
C
-Flu
n
oromethyl-d
e
dC da Molas, Yolanda Díaz, M. Isabel Matheu,* Sergio Castillón*
Departament de Química Analítica i Química Orgànica, Facultat de Química, Universitat Rovira i Virgili, Pl. Imperial Tarraco 1,
43005 Tarragona, Spain
Fax +34(9775)59563; E-mail: matheu@quimica.urv.es; E-mail: castillon@quimica.urv.es
Received 14 October 2002
through a substitution9 or a radical5,10 reaction (Scheme 1,
via a), or by glycosylation of a ketose (Scheme 1, via b).11
In this case, fructose in its furanose form has been the
most widely used starting material.
Abstract: 1′-C-fluoromethyl-ddC has been synthesized from 4-
pentene-1,2-diol which is easily obtained from glycidol. The key
steps are the synthesis of an exo-glycal by a 5-exo iodo-cyclization
of a 4-pentene-1,2-diol and elimination, and a fluoro-glycosylation
using an exo-glycal as glycosyl donor.
Recently, we described an efficient procedure for syn-
thesizing biologically active isonucleosides based on the
iodo-cyclization of pentenetriols.12 In this paper, we re-
port the synthesis of 1′-C-halomethyl derivatives of ddC
from exo-glycals, which in turn can be obtained from
hexenediols through an iodo-cyclization (Scheme 2).
Key words: nucleosides, fluorine, glycosylation, electrophilic ad-
dition, cyclization
2′,3′-Dideoxynucleosides are among the most powerful
agents against HIV.1 AZT, d4T and ddC are pyrimidinyl
nucleosides currently used in HIV treatment. Some 1′-C-
branched nucleosides such as angustmycin2 and
hydantocidin3 are of natural origin. In this sense, the syn-
thesis of hydanticidin homologues has been described,4
and side chain introduction has been investigated in order
to modify properties of natural nucleosides.5 However,
only a few examples of 1′-C-branched-2′,3′-dideoxy de-
rivatives are known. Thus, a derivative of 1′-C-methyl-
AZT6 (1, X = CH3), 1′-C-cyano-d4T7 (2, X = CN) and
one example of 1′-C-cyano-2′-deoxycytidine have been
reported. No examples of 1′-C-branched-2′,3′-dideoxy-
cytidine (3) have been described (Figure 1).8
Y Base
OR
OR
RO
RO
O
O
Z
OR
OR
via a
via b
RO
.
RO
)
Y
(+ or
Base
+
O
O
Z
OR
OR
base introd.
chain introd.
1′-Branched nucleosides are usually synthesized by intro-
ducing a chain at position 1′ into natural nucleosides
Base
RO
O
Z
OR
O
N
NH2
N
O
N
H3C
O
H3C
NH
O
NH
O
Scheme 1
O
N
HO
HO
HO
O
O
In contrast to endocyclic glycals which have been exten-
sively used as important glycosyl donors,13 exo-glycals
have a shorter history in this field. However, they are be-
coming important as useful intermediates in the synthesis
of C-glycosides,14 and C-disaccharides.14c,d
N3
d4T
AZT
ddC
O
N
O
NH2
H3C
O
H3C
NH
O
NH
O
N
O
N
X
N
X
HO
HO
HO
Cyt
RO
RO
O
O
O
O
X
N3
X
1
2
3
OH
Figure 1
RO
(R)-(+)-glycidolm
Synlett 2003, No. 2, Print: 31 01 2003.
Scheme 2
Art Id.1437-2096,E;2003,0,02,0207,0210,ftx,en;G29402ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

208
P. Molas et al.
LETTER
We thought that exo-glycals could be appropriate starting Particularly, when we attempted purification by flash
materials for preparing 1′-branched nucleosides. Initially, chromatography it isomerized towards the endocyclic
we obtained alcohol 515 from (R)-glycidol by protecting derivative. So, we decided to use it directly in the glyco-
the hydroxyl group as trityl ether and subsequent reaction sylation step without further purification.
with allylmagnesium bromide (Scheme 3). The iodine-in-
2′-Deoxy- and 2′,3′-dideoxy-nucleosides have been ob-
duced cyclization of alcohol 5 was performed under kinet-
tained with high levels of stereoselectivity from endocy-
ic control.16 Under these conditions, the reaction is
clic glycals by PhSeCl,19 NIS20 and PhSCl21 induced
irreversible and the exo cyclization product is preferred.
glycosylation. exo-Glycals, however, have not previously
been used in this kind of glycosylations. Initially, we
In this way, furanose 6 was obtained as a 1:1 diastereo-
meric mixture in 73% yield as a result of a 5-exo cycliza-
treated 9 with silylated N4-acetylcytosine using NIS as
tion.17
electrophilic agent.22 Nucleoside 1123 was isolated from
From the tetrahydrofuran derivative 6 a base promoted the reaction mixture in very low yield. NMR spectra con-
elimination can provide the desired exo-glycal.18 The firmed that glycosylation took place at the anomeric posi-
elimination was attempted using AgF and DBU, but the tion. NOESY experiments established a β stereochemistry
results were best when t-BuOK was used. In this case the of the glycosidic linkage: protons H-6′ were correlated
starting material reacted quantitatively to give the exocy- with H-6 which suggests that the trityloxymethylene
clic glycal 9. Compound 9 proved to be stable enough to group and the base are on the same face of the molecule.
be characterized by NMR techniques but it slowly decom- Compound 11 proved to be quite unstable on standing.
poses on standing.
In an attempt to provide greater stability to the 1′-
branched nucleoside, we decided to use electropositive
fluorine as activator. Selectfluor24 has been used recently
TrO
OH
a
O
to synthesize 2-deoxy-2-fluoroglycosides,25 2-deoxy-2-
fluoro-glycosyl-aminoacids,26 and nucleosides27 from
endoglycals. With this aim exo-glycal 9 was treated
with Selectfluor in the presence of the same nucleobase.
The desired product 12 was obtained as a 1:1 inseparable
α/β mixture in 58% yield. As in the case of furanoid gly-
cals isolation of the primary addition product was not
possible.28 The most significant spectroscopic data sup-
porting structure 12 were the presence in the 19F NMR
spectrum of two triplet signals (CH2F) at δ = –94.50 ppm
and –95.21 ppm, respectively.
TrO
70%
4
5
RO
RO
O
O
e
b
I
9
R = Tr
6 R = Tr
7 R = H
73%
82%
64%
c
10 R = DMTr
d
8 R = DMTr
Attempts to hydrolyze the trityl group with TFA gave a
mixture of the degradation products, probably because of
the hydrolysis of the glycosidic bond under these condi-
tions. Then, we therefore attempted to exchange the trityl
group for the more labile dimethoxytrityl. Thus, treatment
of iodine derivative 6 with TFA led to the unprotected
compound 7, which was then treated with DMTrCl to give
the dimethoxytrityl ether derivative 8. The subsequent one
pot elimination-addition led to nucleoside 1329 in 61%
yield as an α/β inseparable mixture. In this case, the
deprotection of the hydroxyl group was performed with
HOAc 80% in 15 minutes to give 14. Finally, deprotection
of the acetyl group at the base moiety in NH3/MeOH led
to 1′-C-fluoromethyl-ddC (15).30 Attempts of separation
of 15, as well as 13 and 14, by column chromatography,
medium pressure liquid chromatography and by radial
chromatography were unsuccessful.
NHAc
N
N
O
f or g
RO
O
X
11 R = Tr, X=I
14% (β)
12 R = Tr, X=F
13 R = DMTr, X= F
58% (α/β= 1:1)
61% (α/β= 1:1)
NHAc
N
NH2
N
N
O
N
O
HO
HO
h
i
O
O
13
69%
50%
F
F
In conclusion, 1′-C-branched-ddC derivatives have been
obtained for the first time using two electrophilically
induced reactions, an iodo-cyclization of a suitable pro-
tected 5-hexen-1,2-diol as an entry to exo-glycals, and a
fluoro-glycosylation of the obtained exo-glycal.
14
15
Scheme 3 a) CH2=CH-CH2MgBr, Et2O, –20 °C to 0 °C, 1.5 h; b) I2,
Na2CO3, CH3CN, 45 min, 0 °C; c) TFA, CHCl3, r.t. 3 h; d) DMTrCl,
pyridine, DMAP, r.t., 3 h; e) t-BuOK, CH2Cl2, r.t., 2.5 h; (9), 40 min
(10). f) N4-AcCyt(SiMe3)2, NIS, CH2Cl2, r.t., 2 h; g) N4-Ac-
Cyt(SiMe3)2, Selectfluor, CH3NO2, r.t., 3 h (12), 25 min (13); h)
HOAc 80%, r.t. 15 min; i) NH3, MeOH, r.t., 1 h.
Synlett 2003, No. 2, 207–210 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of 1′-C-Fluoromethyl-ddC
209
1997, 53, 16355. (f) Bandzouzi, A.; Chapleur, Y.
Carbohydr. Res. 1987, 171, 13. (g) Chapleur, Y. J. Chem.
Soc., Chem. Commun. 1984, 449.
Acknowledgment
Financial support by DGESIC PB98-1050 (Ministerio de Educa-
ción y Cultura, Spain) and CIRIT (Generalitat de Catalunya) is
acknowledged. PM thanks DGESIC for a grant. Authors thank
Serveis de Recursos Científics (URV) for support.
(15) For the preparation of (S)-enantiomer see: Evans, D. A.;
Ripin, D. H. B.; Halstead, D. P.; Campos, K. R. J. Am. Chem.
Soc. 1999, 121, 6816.
(16) Bartlett, P. A.; Myerson, J. J. Am. Chem. Soc. 1978, 100,
3950.
(17) Nicotra, F.; Panza, L.; Ronchetti, F.; Russo, G.; Toma, L.
Carbohydr. Res. 1987, 171, 49.
(18) (a) Tatibouët, A.; Rollin, P.; Martin, O. R. J. Carbohydr.
Chem. 2000, 19, 641. (b) Hirota, K.; Takasu, H.; Tsuji, Y.;
Sajiki, H. Chem. Commun. 1999, 1827. (c) Link, J. T.;
Raghavan, S.; Gallant, M.; Danishefsky, S. J.; Chou, T. C.;
Ballas, L. M. J. Am. Chem. Soc. 1996, 118, 2825.
(19) (a) Díaz, Y.; El-Laghdach, A.; Matheu, M. I.; Castillón, S. J.
Org. Chem. 1997, 62, 1501. (b) Díaz, Y.; El-Laghdach, A.;
Castillón, S. Tetrahedron 1997, 53, 10921.
(20) (a) McDonald, F. E.; Gleason, M. M. Angew. Chem., Int. Ed.
Engl. 1995, 34, 350. (b) Kim, C. U.; Misco, P. F.
Tetrahedron Lett. 1992, 33, 5733.
(21) Wang, J.; Wurster, J. A.; Wilson, L. J.; Liotta, D.
Tetrahedron Lett. 1993, 34, 4881.
(22) (a) Robles, R.; Izquierdo, I.; Rodríguez, C.; Plaza, M. T.;
Mota, A. J.; Alvarez de Cienfuegos, L. Tetrahedron:
Asymmetry 2002, 13, 399. (b) Noort, D.; Veeneman, G. H.;
Boons, G. P. H.; van der Marel, G. A.; Mulder, G. J.; van
Boom, J. H. Synlett 1990, 205.
References
(1) (a) De Clercq, E. Int. J. Antimicrob. Agents 2001, 18, 309.
(b) Herdewijn, P.; Balzarini, J.; De Clercq, E. Adv. Antiviral
Drug 1993, 1, 233. (c) Huryn, D. M.; Okabe, M. Chem. Rev.
1992, 92, 1745. (d) Périgaud, C.; Gosselin, G.; Imbach, J. L.
Nucleosides Nucleotides 1992, 11, 903.
(2) Yüntsen, H.; Yonehara, H.; Ui, H. J. Antibiot. Ser A 1956, 9,
195.
(3) (a) Nakajima, M.; Itoi, K.; Takamatsu, Y.; Kinoshita, T.;
Okazaki, T.; Kawakubo, K.; Shindo, M.; Honma, T.;
Tohjigamori, M.; Haneishi, T. J. Antibiot. 1991, 44, 293.
(b) Haruyama, H.; Takayama, T.; Kinoshita, T.; Kondo, M.;
Nakajima, M.; Haneishi, T. J. Chem. Soc., Perkin Trans. 1
1991, 1637.
(4) Paquette, L. A.; Brand, S.; Behrens, C. J. Org. Chem. 1999,
64, 2010.
(5) (a) Cappelaci, L.; Barboni, G.; Palmieri, M.; Pasqualini, M.;
Grifantini, M.; Costa, B.; Martini, C.; Franchetti, P. J. Med.
Chem. 2002, 45, 1196. (b) Kodama, T.; Shuto, S.; Nomura,
M.; Matsuda, A. Chem.–Eur. J. 2001, 7, 2332.
(23) Compound 11: t-BuOK (165 mg, 1.35 mmol) was added to
a solution of 6 (220 mg, 0.52 mmol) in dry CH2Cl2 (10 mL).
The mixture was kept at r.t. for 2.5 h, poured into 10%
Na2S2O3 and extracted with CH2Cl2. The organic phase was
dried with MgSO4 and concentrated to obtain 9. To a
solution of the previously obtained exo-glycal 9 in CH2Cl2
(2.5 mL) N4-Acetyl-bis(trimethylsilyl)cytosine (0.68 mmol)
and NIS (155 mg, 0.68 mmol) were added, and the reaction
was kept at r.t. for 2 h, diluted with NaHCO3 and extracted
with CH2Cl2. The combined organic layers were dried with
MgSO4 and concentrated. Purification by column
chromatography (Merck silica gel 60, 0.040-0.063 mm,
eluent: EtOAc–hexane, 5:3) and radial chromatography
(Merck silica gel 60 F254) gave 11 (40 mg, 14% yield).
1H NMR (300 MHz, CDCl3): δ (ppm) = 9.79 (s, 1 H, NH),
8.13 (d, 1 H, J6,5 = 7.5 Hz, H-6), 7.50–7.46, 7.36–7.24 (2 m,
16 H, H-Ar, H-5), 4.50 (d, 1 H, Jgem = 10.8 Hz, H-1′a), 4.30–
4.25 (m, 1 H, H-5′), 3.71 (d, 1 H, H-1′b), 3.30–3.22 (m, 2 H,
H-6′), 2.97–2.89, 2.75–2.65 (2 m, 2 H, H-3′), 2.27 (s, 3 H,
CH3), 2.00–1.88 (m, 2 H, H-4′).
(6) Faivre-Buet, V.; Grouiller, A.; Descotes, G. Nucleosides
Nucleotides 1992, 11, 1411.
(7) Uteza, V.; Chen, G.-R.; Le Quan Tuoi, J.; Descotes, G.;
Fenet, B.; Grouiller, A. Tetrahedron 1993, 49, 8579.
(8) Yoshimura, Y.; Kano, F.; Miyazaki, S.; Ashida, N.; Sakata,
S.; Haragushi, K.; Itoh, Y.; Tanaka, H.; Miyasaka, T.
Nucleosides Nucleotides 1996, 15, 305.
(9) (a) Itoh, Y.; Haraguchi, K.; Tanaka, H.; Gen, E.; Miyasaka,
T. J. Org. Chem. 1995, 60, 656. (b) Haraguchi, K.; Itoh, Y.;
Tanaka, H.; Yamaguchi, K.; Miyasaka, T. Tetrahedron Lett.
1993, 34, 6913.
(10) Gimisis, T.; Chatgilialoglu, C. J. Org. Chem. 1996, 61, 1908.
(11) From D-fructose: (a) Prisbe, E. J.; Smejkal, J.; Verheyden, J.
P. H.; Moffatt, J. G. J. Org. Chem. 1976, 41, 1836.
(b) Grouiller, A.; Chattopadhyaya, J. Acta Chem. Scand.
1984, B38, 367. (c) Bouali, A.; Ewing, D. F.; Mackenzie, G.
Nucleosides Nucleotides 1994, 13, 491. (d)FromD-fructose
via aminooxazolidine intermediate: Yoshimura, Y.; Ueda,
T.; Matsuda, A. Tetrahedron Lett. 1991, 32, 4549. (e) See
also: Yoshimura, Y.; Otter, B. A.; Ueda, T.; Matsuda, A.
Chem. Pharm. Bull. 1992, 40, 1761. (f) From nitrosugar:
Mahmood, K.; Vasella, A.; Bernet, B. Helv. Chim. Acta
1991, 74, 1555. (g) From D-ribonolactone: Hayakawa, H.;
Miyazawa, M.; Tanaka, H.; Miyasaka, T. Nucleosides
Nucleotides 1994, 13, 297.
(12) (a) Bravo, F.; Castillón, S. Eur. J. Org. Chem. 2001, 507.
(b) Bravo, F.; Díaz, Y.; Castillón, S. Tetrahedron:
Asymmetry 2001, 12, 1635.
(13) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1380.
(14) (a) Yang, W. B.; Yang, Y. Y.; Gu, Y. F.; Wang, S. H.;
Chang, C. C.; Lin, C. H. J. Org. Chem. 2002, 67, 3773.
(b) Lakhrissi, Y.; Taillefumier, C.; Lakhrissi, M.; Chapleur,
Y. Tetrahedron: Asymmetry 2000, 9, 417. (c) Rubinstenn,
G.; Mallet, J.-M.; Sinaÿ, P. Tetrahedron Lett. 1998, 39,
3697. (d) Johnson, C. R.; Johns, B. A. Synlett 1997, 1406.
(e) Gervay, J.; Flaherty, T. M.; Holmes, D. Tetrahedron
13C NMR (75.4 MHz, CDCl3): δ(ppm) = 179.0 (CO), 163.0
(C-2), 145.0 (C-6), 143.5 (C-Arq), 128.5, 127.8, 127.0 (CH-
Ar), 98.2 (C-2′), 95.6 (C-5), 86.7 (C-Ph3), 80.5 (C-5′), 65.3
(C-6′), 35.3 (C-3′), 27.8 (C-4′), 24.9 (CH3), 12.1 (C-1′).
(24) (a) Stavber, S.; Sotler-Pecan, T.; Zupan, M. Tetrahedron
Lett. 1994, 35, 1105. (b) Stavber, S.; Sotler-Pecan, T.;
Zupan, M. Bull. Chem. Soc. Jpn. 1996, 69, 169.
(25) (a) Vincent, S. P.; Burkart, M. D.; Tsai, C. Y.; Zhang, Z.;
Wong, C. H. J. Org. Chem. 1999, 64, 5264. (b) Taylor, S.
D.; Kotoris, C. C.; Hum, G. Tetrahedron 1999, 55, 12431.
(c) Albert, M.; Dax, K.; Ortner, J. Tetrahedron 1998, 54,
4839. (d) Burkart, M. D.; Zhang, Z.; Hung, S. C.; Wong, C.
H. J. Am. Chem. Soc. 1997, 119, 11743.
(26) Albert, M.; Paul, B.; Dax, K. Synlett 1999, 1483.
(27) Dax, K.; Albert, M.; Ortner, J.; Paul, B. J. Curr. Org. Chem.
1999, 3, 287.
(28) Dax, K.; Albert, M.; Ortner, J.; Paul, B. J. Carbohydr. Res.
2000, 327, 47.
Synlett 2003, No. 2, 207–210 ISSN 0936-5214 © Thieme Stuttgart · New York

210
P. Molas et al.
LETTER
(29) Compound 13: Following a similar procedure for the
synthesis of 9, exo-glycal 10 was prepared starting from 8
(290 mg, 0.52 mmol) in dry CH2Cl2 (10 mL) using t-BuOK
(176 mg, 1.56 mmol). To a solution of exo-glycal 10 in
CH3NO2 (4 mL) N4-Acetyl-bis(trimethylsilyl)cytosine (1.04
mmol) was added. Selectfluor {1-(chloromethyl)-4-fluoro-
1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)}
(272 mg, 0.77 mmols) was added and the reaction was kept
at r.t. for 25 min. Then, the mixture was diluted with EtOAc,
filtered and concentrated to dryness. Purification by radial
chromatography (Merck silica gel 60 F254, eluent: CH2Cl2–
CH3OH, 50:1) gave 191 mg (61% yield) of 13 as an
(C-5), 86.3, 86.1 (C-Ph3), 83.1 (JC,F = 181.3), 83.3 (JC,F
nbsp;= 179.3) (C-1′), 80.9 (C-5′), 65.2, 64.1 (C-6′), 55.1
(OCH3), 32.8, 32.2 (C-3′), 27.1, 26.4 (C-4′), 24.8 (CH3).
19F NMR (400 MHz, CDCl3): δ (ppm) = –228.03 (t, J = 48.9
Hz), –228.73 (t, J = 50.0 Hz).
&
(30) Compound 15: A solution of 13 (64 mg, 0.10 mmol) in 0.1
M 80% HOAc was stirred at r.t. for 15 min, then was
neutralized with 1 M NaHCO3 and extracted with EtOAc.
Purification by radial chromatography (Merck silica gel 60
F254, eluent: CH2Cl2–CH3OH, 25:1) gave 14 (19 mg, 63%
yield). Then, a solution of 10% NH4OH (1 mL) was added to
14 (10 mg, 0.03 mmol) in MeOH. The mixture was kept at
r.t. for 1 h. Purification by preparative chromatography
(Merck silica gel 60 F254, eluent: CH2Cl2–CH3OH, 10:1)
gave 15 as an inseparable α/β mixture (5 mg, 69% yield).
1H NMR (400 MHz, CDCl3): δ (ppm) = 8.09 (d, 1 H, J = 7.2
Hz, H-6a), 7.60 (d, 1 H, J = 8.0 Hz, H-6b), 5.78 (d, 1 H, H-
5a), 5.74 (d, 1 H, H-5b), 4.81–4.60 (m, 4 H, H-1′a, H-1′b),
4.39–4.33, 4.21–4.18 (2 m, 2 H, H-5′a, H-5′b), 3.76–3.55
(m, 4 H, H-6′a, H-6′b), 2.65–2.63, 2.51–2.48 (2 m, 4 H, H-
3′a, H-3′b), 2.01–1.98, 1.86–1.83 (2 m, 4 H, H-4′a, H-4′b).
19F NMR (400 MHz, CDCl3): δ (ppm) = –225.40 (t, J = 50.0
Hz), –226.12 (t, J = 50.4 Hz).
inseparable diastereomeric mixture.
1H NMR (400 MHz, CDCl3) diastereomeric mixture: δ
(ppm) = 9.90 (br s, 2 H, NH), 8.27 (d, 1 H, J = 7.6 Hz, H-6a),
8.19 (d, 1 H, J = 8.0 Hz, H-6b), 7.46–7.45 (m, 2 H, H-5a, H-
5b), 7.38–7.19, 6.84–6.82 (m, 26 H, H-Ar), 5.03–4.59 (m, 4
H, H1′a, H1′b), 4.48–4.47, 4.31–4.27 (2 m, 2 H, H5′a, H5′b),
3.89 [s, 6 H, CH3(DMTr)], 3.35–3.17 (m, 4 H, H6′a, H6′b),
2.96–2.36 (m, 4 H, H3′a, H3′b), 2.27 [s, 3 H, CH3(OAc)],
2.24 [s, 3 H, CH3(OAc)], 1.93–1.75 (m, 4 H, H-4′a, H-4′b).
13C NMR (100.6 MHz, CDCl3): δ (ppm) = 158.5 (C=O),
146.4, 145.0 (C-6), 135.8, 135.6, 135.5, 130.0, 129.9, 128.0,
127.9, 127.7, 126.8 (C-Ar), 113.2, 113.1 (C-2′), 99.2, 96.4
Synlett 2003, No. 2, 207–210 ISSN 0936-5214 © Thieme Stuttgart · New York