Asymmetric synthesis of thymine nucleoside analogues based on the isochroman core

Article abstract of DOI:10.1016/j.tetlet.2005.05.091

Diastereoisomeric analogues of d4T having an isochroman core as the glycone moiety have been prepared in seven steps. Starting from phthalaldehyde, two chiral centres analogous to the α/β anomers of D/L sugars were created. The first was obtained enantiom

Full text of DOI:10.1016/j.tetlet.2005.05.091

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4835–4838
Asymmetric synthesis of thymine nucleoside analogues based on the
isochroman core
Christophe Len* and Bruno Violeau
` ´ ´
Synthese et Reactivite des Substances Naturelles, CNRS UMR 6514, FR 2703, Universite de Poitiers,
40 Avenue du Recteur Pineau, 86022 Poitiers Cedex, France
´
Received 11 April 2005; revised 18 May 2005; accepted 20 May 2005
Available online 4 June 2005
Abstract—Diastereoisomeric analogues of d4T having an isochroman core as the glycone moiety have been prepared in seven steps.
Starting from phthalaldehyde, two chiral centres analogous to the a/b anomers of D/L sugars were created. The first was obtained
enantiomerically pure via asymmetric dihydroxylation and the second via cyclisation of an aldehyde group with a primary hydroxyl
group. Retention of chiral integrity at the C4 site enabled enantiomerically pure nucleoside analogues to be obtained.
Ó 2005 Elsevier Ltd. All rights reserved.
Over the past two decades, nucleoside chemistry has
evolved to facilitate efficient routes to effective agents
for the treatment of AIDS,1 herpes2 and viral hepatitis.3
Consequently, a large number of modifications have
been made to both the base and sugar moieties of natu-
ral nucleosides, accordingly, with the objective of
increasing the therapeutic index of established antiviral
agents. One of the most important discoveries in this
area was the insertion of insaturation in the 20,30-posi-
tion of the glycone moiety to give the 20,30-didehydro-
20,30-dideoxy series of nucleosides (d4Ns). Various
derivatives of the approved drug, Stavudine (20,30-dide-
hydro-20,30-dideoxythymidine, d4T, 1)4 have been syn-
thesised in which the 20- and/or 30-positions have been
modified. Recent examples include the introduction of
a fluoro atom,5 cyano group,6 alkyl chain7 and a fused
benzene ring system.8 Replacement of the five-mem-
bered furanose ring with (i) an acyclic group such as acy-
clovir (2),9 (ii) a cyclopentene core such as Abacavir
(3)10 and (iii) a six-membered ring such as D- and L-
cyclohexenyl guanine (4)11 have also been reported
(Fig. 1).
mitted a more intrusive investigation into the conforma-
tional aspects of enzyme–substrate interactions.12
Recently, we synthesised the series of pyrimidine nucleo-
side analogues, 5–7, which have a benzo[c]furan core
and are analogues of d4Ns (Fig. 1). As a part of our
continuing studies on the chemistry of d4Ns, we have
synthesised the isochroman derivatives 8 and 9.
Retrosynthetic analysis of the target compounds 8 and 9
suggested that o-phthalaldehyde 10 was the most prom-
ising starting point. Thus, phthalaldehyde 10 afforded
the acetal derivative 11, in 78% yield, by reaction with
propan-1,3-diol in the presence of PTSA. The remaining
aldehyde group of 11 was easily converted into the styr-
ene analogue 12 via a classical Wittig homologation.
Asymmetric dihydroxylation of the ethene derivative
12 with commercial AD-mix a gave the corresponding
enantiomerically pure diol 13 (ee 98%). The absolute
configuration S of this novel chiral centre was assigned
by both the asymmetric dihydroxylation mnemonic
rules and X-ray study.13 The diol 13 was converted,
using HCl in methanol, into a mixture of the corre-
sponding 1-methoxy derivatives 14 and 15 having iso-
chroman and isobenzofuran structures, respectively,
in 75% yield. The mixture was difficult to separate by sil-
ica gel chromatography. Also, subsequent acetylation of
the secondary hydroxyl group afforded the correspond-
ing acetates 16 (51% yield, ratio 1:1) and 17 (34% yield,
ratio 1:1), which were cleanly separated by column chro-
matography. Under such conditions the competitive
cyclisation between the primary and secondary hydroxyl
In the search for new agents with a higher therapeutic
index, conformationally restricted nucleosides have per-
Keywords: d4T; Nucleoside analogues; Isochroman; Asymmetric
dihydroxylation.
*
Corresponding author. Tel.: +33 5 49 45 38 62; fax: +33 5 49 45 35
01; e-mail: christophe.len@univ-poitiers.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.091

4836
C. Len, B. Violeau / Tetrahedron Letters 46 (2005) 4835–4838
O
N
O
HN
NH
N
N
N
N
NH
NH2
N
O
1
O
O
N
HO
NH
HO
HO
N
HO
2
3
O
N
O
N
O
O
O
NH
N
B
HO
N
NH
O
8
HO
O
N
NH2
O
HO
HO
4
5 B = T
6 B = U
7 B = C
9
Figure 1. Nucleoside analogues 1–9.
groups gave the more stable isochroman derivative 14.
Glycosylation of the methoxy derivatives 16 with
bis(trimethylsilyl)thymine using the Vorbruggen meth-
odology14,15 afforded the two epimeric nucleoside ana-
logues 1816 and 1917 in 35% and 33% yields,
respectively. Classical deprotection of the secondary hy-
droxyl group on each of 18 and 19 afforded the target
nucleosides 818 and 919 in quantitative yield (Scheme 1).
O
H
H3C
NH
O
H
O
H
O
H
H
H
N
O
N
NH
O
O
H
O
O
H
H
O
H
CH3
19
18
0
Assignment of the (S)-configuration at the C4 atom was
Figure 2. NOE experiments of nucleosides 18 and 19.
made on the basis that the AD step occurred without
any loss of chiral integrity during the successive cyclisa-
tion, glycosylation and deacetylation reactions. Ano-
meric configurations were established by NMR
spectroscopy. The b-configuration of the thymine deriv-
0
irradiation of the proton at C1 gave an enhanced signal
0
for H3 b and irradiation of the proton H3 b gave en-
0
0
0
hanced signals for H4 and H1 b and vice versa. It is
notable that no NOE was detected for the protons
0
ative 18 (i.e., C1 atom having R configuration) was
0
H3 a and H6.
established by NOE (Fig. 2): irradiation of the proton
0
at C1 gave an enhanced signal for H3 a and irradiation
0
0
0
0
of the proton H3 b gave enhanced signals for H4 and
H6 and vice versa. These results showed that the thy-
mine base was in the anti conformation in the nucleoside
Comparison of the coupling constants between the H3
0
0
0
protons (H3 a and H3 b) and H4 proton for the two dia-
stereoisomers 18 and 19 was also interesting (Fig. 3). In
the case of the nucleoside 18, correlation between the
0
18. The a-configuration of 19 (i.e., C1 atom having S
configuration) was also established by NOE (Fig. 2):
0
coupling constants (JH3 a,H4 = 5.9 Hz; JH3 b,H4 =
0
0
0
O
O
OMe
O
HO
OH O
13
O
O
OMe
O
O
HO
R
HO
iv
i
iii
+
15
10
11 R = O
12 R = CH2
14
ii
v
O
O
O
O
O
NH
OMe
OMe
vi
AcO
N
NH
O
RO
AcO
N
O
+
+
O
RO
19 R = Ac
9 R = H
18 R = Ac
8 R = H
16
17
vii
vii
Scheme 1. Reagents and conditions: (i) propan-1,3-diol, PTSA, toluene, reflux, 78%; (ii) CH3(C6H5)3PBr, BuLi, THF, 77%; (ii) AD-mix a, t-BuOH,
H2O, 85%; (iv) MeOH, HCl 1%, 75%; (v) Ac2O, pyridine, 85%; (vi) silylated thymine, SnCl4, C2H4Cl2, 68%; (vii) NH3, MeOH (quant.).

C. Len, B. Violeau / Tetrahedron Letters 46 (2005) 4835–4838
4837
(c) Martin, J. A.; Busshnell, D. J.; Duncan, I. B.;
Dunsdon, S. J.; Hall, M. J.; Machin, P. J.; Merrett, J.
H.; Parkes, K. E. B.; Roberts, N. A.; Thomas, G. J.;
Galpin, S. A. J. Med. Chem. 1990, 33, 2137–2145; (d)
Tann, C. H.; Brodfueher, P. R.; Brundidge, S. P.; Sapino,
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Van Aerschot, A.; Herdewijn, P.; Balzarini, J.; Pauwels,
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Chong, Y.; Gumina, G.; Mathew, J. S.; Schinazi, R. F.;
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W.; Gumina, G.; Chong, Y.; Wang, J.; Schinazi, R. F.;
Chu, C. K. J. Med. Chem. 2004, 47, 3399–3408; (h) Chen,
S. H.; Wang, Q.; Mao, J.; King, L.; Dutschman, G. E.;
Gullen, E. A.; Cheng, Y. C.; Doyle, T. W. Bioorg. Med.
Chem. Letters 1998, 8, 1589–1594.
CH
3
CH
N
3
O
H
O
6
O
H '
6
H '
4
H '
HN
N
3
HN
H '
4
O
OAc
H '
3
H '
1
O
H '
3
O
OAc
H '
H '
1
3
18
18
O
H '
3
H '
1
HN
H '
3
N
H '
1
O
H '
4
H '
3
O
O
H '
4
O
N
H
OAc
6
HN
O
H C
3
H
AcO
H '
3
6
CH
6. (a) Matsuda, A.; Satoh, M.; Nakashima, H.; Yamamoto,
N.; Ueda, T. Heterocycles 1988, 27, 2545–2548; (b) Faul,
M. M.; Huff, B. E.; Dunlap, S. E.; Frank, S. A.; Fritz, J.
E.; Kaldor, S. W.; Le Tourneau, M. E.; Stazak, M. A.;
Ward, J. A.; Werner, J. A.; Winneroski, L. L. Tetrahedron
1997, 53, 8085–8104; (c) Zhu, W.; Gumina, G.; Schinazi,
R. F.; Chu, C. K. Tetrahedron 2003, 59, 6423–6431; (d)
Wu, J. C.; Chattopadhyaya, J. Tetrahedron 1989, 45, 855–
862; (e) Matsuda, A.; Nakajima, Y.; Azuma, A.; Tanaka,
M.; Sasaki, T. J. Med. Chem. 1991, 34, 2917–2919; (f)
Azuma, A.; Nakajima, Y.; Nishizono, N.; Minakawa, N.;
Suzuki, M.; Hanaoka, K.; Kobayashi, T.; Tanaka, M.;
Sasaki, T.; Matsuda, A. J. Med. Chem. 1993, 36, 4183–
4189; (g) Lee, K.; Choi, Y.; Gullen, E.; Schlueter-Wirtz,
S.; Schinazi, R. F.; Cheng, Y. C.; Chu, C. K. J. Med.
Chem. 1999, 42, 1320–1328; (h) Lee, K.; Choi, Y.;
Gumina, G.; Zhou, W.; Schinazi, R. F.; Chu, C. K.
J. Med. Chem. 2002, 45, 1313–1320.
7. (a) Fedorov, I. I.; Kazmina, E. M.; Novicov, N. A.;
Gurskaya, G. V.; Bochkarev, A. V.; Kasko, M. V.;
Victorova, L. S.; Kukhanova, M. K.; Balzarini, J.; De
Clercq, E.; Krayevski, A. A. J. Med. Chem. 1992, 35,
4567–4575; (b) Matsuda, A.; Okajima, H.; Ueda, T.
Heterocycles 1989, 29, 25–28; (c) Czernecki, S.; Ezzitouni,
A.; Krausz, P. Synthesis 1990, 651–653; (d) Chiacchio, U.;
Rescifina, A.; Iannazzo, D.; Romeo, G. J. Org. Chem.
1999, 64, 28–36.
3
19
19
Figure 3. Nucleoside analogues 18 and 19.
4.3 Hz) and the Karplus equation permitted prediction
0
0
0
0
of the dihedral angles H3 aC3 C4 H4 (ꢀꢁ140°) and
0
0
0
0
H
the conformation of the target nucleoside 18 since both
3 bC3 C4 H4 (ꢀꢁ22°), respectively, and consequently,
0
0
0
the dihedral angles C1 C9 C10 C4 are planar and an
0
NOE was obtained between the H1 and H3 a protons
indicating syn axial positions. Using a similar procedure
0
for compound 19, the weak J coupling of H4 proton be-
0
tween both H3 a and H3 b protons (JH3 a,H4 = 2.4 Hz;
0
0
0
0
0
0
JH3 b,H4 = 1.7 Hz) enabled the dihedral angles
0
0
0
0
0
0
0
0
0
H
be predicted, and as a consequence, the conformation
3 aC3 C4 H4 (ꢀꢁ70°) and H3 bC3 C4 H4 (ꢀ+50°) to
of the target nucleoside 19.
In conclusion, a convenient route has been achieved to
the highly enantiomerical pure bicyclic nucleosides
involving AD using AD-mix a. The synthesis and bio-
logical evaluation of the corresponding cytosine, ade-
nine and guanine derivatives, and their corresponding
enantiomers are currently under investigation. Also,
the secondary hydroxyl groups will be converted to
phosphonates as prodrug analogues.
8. (a) Ewing, D. F.; Fahmi, N.; Len, C.; Mackenzie, G.;
Ronco, G.; Villa, P.; Shaw, G. Nucleos. Nucleot. 1999, 18,
2613–2630; (b) Ewing, D. F.; Fahmi, N.; Len, C.;
Mackenzie, G.; Pranzo, A. J. Chem. Soc., Perkin Trans.
1 2000, 21, 3561–3565.
9. De Clercq, E. Nucleos. Nucleot. Nucleic Acids 2000, 19,
1531–1541.
Acknowledgements
10. Weller, S.; Radomaki, K. M.; Lou, Y.; Stein, D. S.
Antimicrob. Agents Chemother. 2000, 44, 2052–2060.
11. Wang, J.; Froeyen, M.; Hendrix, C.; Andrei, G.; Snoeck,
R.; De Clercq, E.; Herdewijn, P. J. Med. Chem. 2000, 43,
736–745.
C.L. thank CNRS for financial support.
References and notes
12. (a) Russ, P.; Schelling, P.; Scapozza, L.; Folkers, G.; De
Clercq, E.; Marquez, V. E. J. Med. Chem. 2003, 46, 5045–
5054; (b) Marquez, V. E.; Russ, P.; Alanso, R.; Siddiqui,
M. A.; Shin, K. J.; George, C.; Nicklaus, M. C.; Dai, F.;
Ford, H. Nucleos. Nucleot. 1999, 18, 521–530; (c) Kva-
erno, L.; Nielsen, C.; Wightman, R. H. J. Chem. Soc.,
Perkin Trans. 1 2000, 2903–2906.
13. Selouane, A.; Vaccher, C.; Villa, P.; Postel, D.; Len, C.
Tetrahedron: Asymmetry 2002, 13, 407–413.
14. Vorbruggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber.
1981, 114, 1234–1255.
1. De Clercq, E. Biochim. Biophys. Acta 2002, 1587, 258–275.
2. Brady, R. C.; Bernstein, D. I. Antiviral Res. 2004, 61, 73–
81.
3. Papatheodoridis, G. V.; Dimou, E.; Papadimitropoulos,
V. Am. J. Gastroenterol. 2002, 97, 1618–1628.
4. (a) Cheer, S. M.; Goa, K. L. Drugs 2002, 62, 2667–2674;
(b) Hurst, M.; Noble, S. Drugs 1999, 58, 919–949.
5. (a) Huang, J. T.; Chen, L. C.; Wang, L.; Kim, M. H.;
Warshaw, J. A.; Armastrong, D.; Zhu, Q. Y.; Chou, T. C.;
Watanabe, K. A.; Matulic-Adamic, J.; Su, T. S.; Fox, J. J.;
Polsky, B.; Baron, P. A.; Gold, J. W. M.; Hardy, W. D.;
Zuckerman, E. J. Med. Chem. 1991, 34, 1640–1646; (b)
Sterzycki, R. Z.; Ghazzouli, I.; Brankovan, V.; Martin, J.
C.; Mansuri, M. M. J. Med. Chem. 1990, 33, 2150–2157;
15. A suspension of thymine (567 mg, 4.50 mmol) and a
crystal of ammonium sulfate in 1,1,1,3,3,3-hexamethyl-
disilazane (10 mL) was refluxed with exclusion of moisture
until a clear solution was obtained (3 h). Volatiles were

4838
C. Len, B. Violeau / Tetrahedron Letters 46 (2005) 4835–4838
NH). 13C NMR (75 MHz, CDCl3, ppm) d: 13.0 (CH3–C5),
removed by repeated co-evaporation with toluene to leave
0
0
0
the syrup. This syrup and the isochroman derivative 16
(500 mg, 2.25 mmol) were taken up in dry C2H4Cl2
(12 mL) and SnCl4 (528 lL, 4.50 mmol) added at
ꢁ15 °C. After stirring overnight at room temperature,
satd NaHCO3 solution (20 mL) was added, the mixture
stirred for 30 min and then extracted with CH2Cl2. This
extract was worked up and the crude product chromato-
graphed (hexane–EtOAc, 7:3, v/v) to give the diastereo-
isomer 18 (249 mg) in 35% yield as the first eluting
compound and the diastereoisomer 19 (235 mg) in 33%
yield as the second eluting compound.
21.7 (CH3 acetyl), 66.3 (C4 ), 68.2 (C3 ), 80.5 (C1 ), 112.4
(C5), 126.1, 129.1, 130.6, 130.9 (4C, C arom), 133.2, 133.6
0
0
(2C, C9 , C10 ), 136.9 (C6), 151.7 (C2), 164.1 (C4), 170.1
(COCH3). MS (ES) 339.10 [M+Na]+. Anal. Calcd for
C16H16N2O5 (316.11 g/mol): C, 60.75; H, 5.10; N, 8.86.
Found: C, 60.79; H, 5.07; N, 8.88.
18. Selected spectral data for compound 8: 1H NMR
(300 MHz, (CD3)2SO, ppm) d: 1.66 (s, 3H, CH3–C5),
0
3.70 (dd, J = 11.2 Hz, J = 8.1 Hz, 1H, H3 a), 4.12 (dd,
0
J = 5.0 Hz, 1H, H3 b), 4.81 (dd, 1H, H4 ), 6.91 (s, 1H, H6),
0
0
7.00 (m, 2H, H1 , H arom), 7.30–7.61 (m, 3H, H arom),
16. Selected spectral data for compound 18: 1H NMR
(300 MHz, CDCl3, ppm) d: 1.81 (d, J = 1.0 Hz, 3H,
CH3–C5), 2.17 (s, 3H, CH3 acetyl), 3.98 (dd, J = 12.3 Hz,
11.5 (br s, 1H, NH). 13C NMR (75 MHz, (CD3)2SO, ppm)
0
0
0
d: 12.8 (CH3–C5), 63.4 (C4 ), 69.2 (C4 ), 80.6 (C1 ), 110.9
(C5), 125.9, 128.1, 128.6, 129.4 (4C, C arom), 130.3, 132.5
0
J = 5.9 Hz, 1H, H3 a), 4.27 (dd, J = 4.3 Hz, 1H, H3 b), 6.06
0
(dd, 1H, H4 ), 6.64 (br s, 1H, H5), 7.07 (d, J = 7.0 Hz, 1H,
0
0
0
(2C, C9 , C10 ), 137.9 (C6), 152.0 (C2), 164.7 (C4). MS (ES)
297.08 [M+Na]+. Anal. Calcd for C14H14N2O4 (274.10 g/
mol): C, 61.31; H, 5.14; N, 10.21. Found: C, 61.35; H,
5.12; N, 10.25.
0
H arom), 7.19 (s, 1H, H1 ), 7.43–7.47 (m, 3H, H arom),
8.73 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3, ppm) d:
19. Selected spectral data for compound 9: 1H NMR
(300 MHz, (CD3)2SO, ppm) d: 1.67 (s, 3H, CH3–C5),
0
12.9 (CH3–C5), 21.5 (CH3 acetyl), 65.4 (C3 ), 65.6 (C4 ),
0
0
80.3 (C1 ), 111.8 (C5), 126.4, 128.6, 129.9, 130.0 (4C, C
0
0
0
3.96 (dd, J = 12.0 Hz, J = 2.8 Hz, 1H, H3 a), 4.05 (dd,
0
J = 2.5 Hz, 1H, H3 b), 4.49 (br s, 1H, H4 ), 6.83 (s, 1H, H6),
arom), 132.0, 134.5 (2C, C9 , C10 ), 136.9 (C6), 152.0 (C2),
164.5 (C4), 171.2 (COCH3). MS (ES) 339.10 [M+Na]+.
Anal. Calcd for C16H16N2O5 (316.11 g/mol): C, 60.75; H,
5.10; N, 8.86. Found: C, 60.77; H, 5.06; N, 8.91.
0
0
7.00 (d, J = 7.5 Hz, 1H, H arom), 7.23 (s, 1H, H1 ), 7.30–
7.50 (m, 3H, H arom), 11.5 (br s, 1H, NH). 13C NMR
17. Selected spectral data for compound 19: 1H NMR
(300 MHz, CDCl3, ppm) d: 1.85 (d, J = 1.0 Hz, 3H,
CH3–C5), 2.18 (s, 3H, CH3 acetyl), 4.16 (dd, J = 13.3 Hz,
(75 MHz, (CD3)2SO, ppm) d: 12.9 (CH3–C5), 63.9 (C4 ),
0
70.0 (C4 ), 80.3 (C1 ), 110.7 (C5), 125.9, 129.3, 129.6, 130.3
(4C, C arom), 133.2, 139.0 (2C, C9 , C10 ), 138.1 (C6),
152.1 (C2), 164.7 (C4). MS (ES) 297.08 [M+Na]+. Anal.
Calcd for C14H14N2O4 (274.10 g/mol): C, 61.31; H, 5.14;
N, 10.21. Found: C, 61.35; H, 5.12; N, 10.25.
0
0
0
0
0
J = 2.4 Hz, 1H, H3 a), 4.32 (dd, J = 1.7 Hz, 1H, H3 b), 5.84
0
0
0
(dd, 1H, H4 ), 6.93 (q, 1H, H5), 7.04 (s, 1H, H1 ), 7.08 (m,
1H, H arom), 7.42–7.50 (m, 3H, H arom), 8.73 (br s, 1H,