Enantio- and diastereoselective synthesis of 4'-α-substituted carbocyclic nucleosides

Article abstract of DOI:10.1016/S0957-4166(98)00065-2

Enantio- and diastereoselective synthesis of 4-α-alkylcarbovir derivatives 5 were achieved based on Sakai's asymmetric alkylation of β- keto esters. The key carbocyclic intermediate 14 was synthesized from 8 via an eleven-step sequence. Coupling of 14 with 2-amino-6-chloropurine followed by desilylation and subsequent hydrolysis gave the target compounds 5 in moderate yields.

Full text of DOI:10.1016/S0957-4166(98)00065-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 911–914
Enantio- and diastereoselective synthesis of 40-α-substituted
carbocyclic nucleosides
Keisuke Kato«,a,∗ Hisaki Suzuki,b Hiromichi Tanaka b and Tadashi Miyasaka« b
aSchool of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274, Japan
bSchool of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142, Japan
Received 16 January 1998; accepted 2 February 1998
Abstract
Enantio- and diastereoselective synthesis of 4-α-alkylcarbovir derivatives 5 were achieved based on Sakai’s
asymmetric alkylation of β-keto esters. The key carbocyclic intermediate 14 was synthesized from 8 via an eleven-
step sequence. Coupling of 14 with 2-amino-6-chloropurine followed by desilylation and subsequent hydrolysis
gave the target compounds 5 in moderate yields. © 1998 Elsevier Science Ltd. All rights reserved.
In recent years, carbocyclic nucleoside analogues have emerged as a promising group of compounds
for antiviral and antitumor agents. Carbovir 1 and other 2-cyclopentenyl nucleoside analogues have been
extensively investigated for their potential as anti-HIV agents.1 The numerous syntheses of carbovir
and other carbocyclic nucleosides have been reported.2 The most common approach to carbocyclic
nucleosides is a convergent synthesis which couples a purine or pyrimidine base with a cyclopentene
moiety, thus the former is easy to modify3 but the latter is generally little functionalized. Recently, Magg4
and Meguro5 reported the anti-HIV activity of various 4-α-substituted nucleosides 2 and 3 (Fig. 1).
Fig. 1.
On the other hand, few examples have been reported for the synthesis and biological evaluation of
40-α-substituted carbocyclic nucleosides.6 For example, 40-α-hydroxyl and 40-α-fluoro derivatives 4
have been synthesised by aristeromycin, which show potent anti-herpetic activity.6b The most common
synthesis of the 40-α-substituted carbocyclic nucleosides is transformation from a natural product,6a–d
∗
Corresponding author.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00065-2

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K. Kato et al. / Tetrahedron: Asymmetry 9 (1998) 911–914
therefore the functionalization of the cyclopentene moiety is restricted. We wish to report here the
enantio- and diastereoselective synthesis of 40-α-alkyl carbocyclic nucleosides 5.
Our synthetic plan is as follows (Scheme 1): (1) The construction of the stereogenic quaternary carbon
should be achieved by the asymmetric alkylation of chiral acetal 7. (2) The double bond of 11 may be
introduced utilizing the enol ether moiety of 8. (3) The hydroxy ester 12 could be stereoselectively pre-
pared from 11 by the regio- and diastereoselective Luche reduction. (4) The key carbocyclic intermediate
14 may be prepared from 12 via the stereospecific Pd-catalyzed allylic rearrangement. (5) The target
compounds 5 would be obtained by the Mitsunobu reaction of 14.
Scheme 1.
Asymmetric alkylation [LDA (3 equiv.), THF/HMPA (5 equiv.), RX (3 equiv.), −78 to −40°C]
of chiral acetal 7 derived from readily available methyl 2-oxocyclopentanecarboxylate 6 and (R,R)-
cycloheptane-1,2-diol,7 with methyl iodide, nonyl bromide, and benzyl bromide afforded the correspond-
ing alkylated enol ethers 8 in a completely diastereoselective manner (d.e.>99%).8 Iodoacetalization of
the enol ethers 8 using iodine (2 equiv.) in the presence of triethylamine (1 equiv.) in THF at −40°C
for 12 h gave the iodoacetals 9 as a single diastereomer.9 Treatment of the iodoacetals 9 with DBU at
95–100°C for 1 h afforded the olefinic acetals 10. Acid hydrolysis of 10 gave the chiral enone esters 11,
accompanied by (R,R)-cycloheptane-1,2-diol (71–81%). Luche reduction10 of 11 using NaBH4/CeCl3
in MeOH gave the hydroxy esters 12 in highly regio- and diastereoselective manner. Acetylation of
12 followed by treatment with Pd-catalyst in the presence of benzoquinone in THF gave the desired
rearranged products.11 Subsequent methanolysis of these products gave 13 as a single diastereomer. The
hydroxy esters 13 were converted into the key intermediate 14 by a four-step sequence [(i) DHP, PPTS
in CH2Cl2, r.t.; (ii) LAH in THF, r.t.; (iii) TBDPS-Cl, imidazole in DMF, r.t.; (iv) PPTS in MeOH,
40°C]. The Mitsunobu reaction12 of 14 with 2-amino-6-chloropurine followed by desilylation afforded
15,13 which when hydrolyzed with 1 N NaOH gave the target compounds 5 in 34–39% yields.14 The
attachment of carbo-sugar to the base at N9 is confirmed by the HMBC spectrum of 15, which showed

K. Kato et al. / Tetrahedron: Asymmetry 9 (1998) 911–914
913
0
long range coupling between the C1 –H and the purine carbons C4 and C8. The biological activity studies
are in progress.
Scheme 2.
Acknowledgements
Useful comments and suggestions by Professor H. Suemune (Kyushu University) are gratefully
acknowledged.
References
1. (a) Vince, R., Hua, M., Brownell, J., Daluge, S., Lee, F., Shannon, W. M., Lavelle, G. C., Qualls, J., Weislow, O. S., Kiser,
R., Canonico, P. G., Schultz, R. H., Narayanan, V. L., Mayo, J. G., Shoemaker, R. H., Boyd, M. R., Biochem. Biophys. Res.
Com. 1988, 156, 1046. (b) Vince, R., Hua, M., J. Med. Chem., 1990, 33, 17. (c) Peel, M. R., Sternbach, D. D., Johnson, M.
R., J. Org. Chem., 1991, 56, 4990. (d) Jones, M. F., Myers, P. L., Robertson, C. A., Storer, R., Williamson, C., J. Chem.
Soc., Perkin Trans. 1, 1991, 2479.
2. (a) Agrofoglio, L., Suhas, E., Farese, A., Condom, R., Challard, S. R., Earl, R. A., Guedj, R., Tetrahedron, 1994, 50, 10611.
(b) Borthwick, A. D., Biggadike, K., Tetrahedron, 1992, 48, 571. (c) Huryn, D. M., Okabe, M., Chem., Rev., 1992, 92,
1745. (d) Tanaka, M., Norimine, Y., Fujita, T., Suemune, H., Sakai, K., J. Org. Chem., 1996, 61, 6952. (e) Borthwick, A.
D., Crame, A. J., Exall, A. M., Weingarten, G. G., Mahmoudian, M., Tetrahedron Lett., 1995, 36, 6929. (f) Taylor, S. J. C.,
McCague, R., Wisdom, R., Lee, C., Dickson, K., Ruecroft, G., O’Brien, F., Littlechild, J., Bevan, J., Roberts, S. M., Evans,
C. T., Tetrahedron: Asymmetry, 1993, 4, 1117.
3. Popescu, A., Hornfeldt, A.-B., Gronowitz, S., Nucleosides Nucleotides, 1995, 14, 1639.
4. Maag, H., Rydzewski, R. M., McRoberts, M. J., Crawford-Ruth, D., Verheyden, J. P. H., Prisbe, E. J., J. Med. Chem., 1992,
35, 4098.
5. Waga, T., Ohrui, H., Meguro, H., Nucleosides Nucleotides, 1996, 15, 287.
6. (a) Biggadike, K.; Borthwick, A. D., J. Chem. Soc., Chem. Commun., 1990, 1380. (b) Borthwick, A. D., Biggadike, K. Eur.
Pat. Appl. 0 345 076, 1989. (c) Caamano, O., Fernandez, F., Neito, M. I., Nuclesides Nucleotides, 1995, 14, 295. (d) Bianco,
A., Mazzei, R. A., Tetrahedron Lett., 1997, 38, 6433. (e) Chao, Q., Nair, V., Tetrahedron Lett., 1995, 36, 7375.
7. (R,R)-Cycloheptane-1,2-diol can be prepared by enzymatic procedure. See Xie, Z.-F., Nakamura, I., Suemune, H., Sakai,
K. J. Chem. Soc., Chem. Commun., 1988, 966.
8. Kato, K., Suemune, H., Sakai, K. Tetrahedron, 1994, 50, 3315.
9. The stereochemistry of 9 was determined by NOE experiments.
10. Luche, J. L., Genal, A. L. J. Am. Chem. Soc., 1979, 101, 5848.
11. Oehlschlager, A. C., Mishra, P., Dhami, S., Can. J. Chem, 1984, 62, 791.
12. Jenny, T. F., Previsani, N., Benner, S. A., Tetrahedron Lett., 1991, 36, 7029.

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K. Kato et al. / Tetrahedron: Asymmetry 9 (1998) 911–914
13. In a preliminary experiment, the SN10-type Mitsunobu reaction of 17 derived from 10c via six-step sequence [(i) LAH, (ii)
H+, (iii) NaBH4/CeCl3, (iv) pivaloyl chloride, (v) TBDPSCl, (vi) KOH, MeOH] with 2-amino-6-chloropurine, followed by
desilylation afforded the β-isomer 15c (18%) accompanied by the α-isomer 18 (18%). The relative stereochemistry of 15c
and 18 was determined by NOE experiments (Scheme 2). In the case of 15a and 15b, the similar results of NOE experiments
with 15c were observed.
22
14. Satisfactory analytical data were obtained for all new compounds. 5a: white crystalline solid, m.p. 280–290°C (dec.); [α]D
1
−4.7 (c 0.2, MeOH); λmax(MeOH)/nm 206.0 (ε=19310), 253.4 (ε=10211); H-NMR (500 MHz, DMSO-d6): δ 1.05 (3H,
0
0
0
s, Me), 1.87 (1H, dd, J=13.4, 5.8 Hz, C5 –H-β), 2.12 (1H, dd, J=13.4, 8.5 Hz, C5 –H-α), 3.26 (1H, d, J=10.4 Hz, C6 –H),
0
0
0
0
3.34 (1H, d, J=10.7 Hz, C6 –H), 4.72 (1H, s, C6 –OH), 5.43 (1H, m, C1 –H), 5.73 (1H, dd, J=5.5, 2.1 Hz, C2 –H), 5.93 (1H,
dd, J=5.5, 2.1 Hz, C3 –H), 6.39 (2H, br s, NH2), 7.59 (1H, s, C8–H), 10.54 (1H, s, NH); 13C-NMR (500 MHz, DMSO-d6):
0
0
0
0
0
0
δ 23.4 (q, Me), 41.5 (t, C5 ), 50.9 (s, C4 ), 58.3 (d, C1 ), 68.2 (t, C6 ), 116.4 (s, C5), 127.7 (d, C2 ), 134.7 (d, C8), 143.6 (d,
+
0
C3 ), 150.6 (s, C4), 153.4 (s, C2 or C6), 156.6 (s, C2 or C6); FAB-MS m/z: 262 (M +1). 5b: White crystalline solid, m.p.
280–290°C (dec.); [α]D +59.9 (c 0.2, MeOH); λmax(MeOH)/nm 206.2 (ε=18953), 254.8 (ε=9731); 1H-NMR (500 MHz,
23
DMSO-d6): δ 0.87 (3H, t, J=6.7 Hz, C8H16–CH3), 1.25 (14H, m, CH2–C7H14–CH3), 1.36 (2H, t, J=7.9 Hz, CH2–C8H17),
0
0
0
1.79 (1H, dd, J=14.0, 5.8 Hz, C5 –H-β), 2.19 (1H, dd, J=14.0, 8.9 Hz, C5 –H-α), 3.28 (1H, dd, J=10.4, 5.2 Hz, C6 –H),
0
0
0
3.38 (1H, dd, J=10.4, 5.1 Hz, C6 –H), 4.79 (1H, t, J=5.2 Hz, C6 –OH), 5.35 (1H, m, H1 ), 5.75 (1H, dd, J=5.8, 2.1 Hz,
C2 –H), 5.87 (1H, dd, J=5.8, 2.1 Hz, C3 –H), 6.77 (2H, s, NH2), 7.57 (1H, s, H8), 10.90 (1H, s, NH); 13C-NMR (500 MHz,
0
0
0
DMSO-d6): δ 13.9 (q, C8H16–CH3), 22.0, 23.9, 28.7, 29.0, 29.8, 31.2, 35.9 (each as t, C8H16–CH3), 39.3 (t, C5 ), 54.8 (s,
0
0
0
0
0
C4 ), 58.5 (d, C1 ), 67.2 (t, C6 ), 116.5 (s, C5), 128.6 (d, C2 ), 134.7 (d, C8), 142.2 (d, C3 ), 150.6 (s, C4), 153.7 (s, C6),
156.6 (s, C2); FAB-MS m/z: 374 (M++1). 5c: White crystalline solid, m.p. 290–295°C; [α]D23+112.0 (c 0.410, MeOH);
1
λ
max(MeOH)/nm 206.8 (ε=23555), 255.2 (ε=9222); H-NMR (500 MHz, DMSO-d6): δ 1.78 (1H, dd, J=14.0, 5.5 Hz,
0
0
C5 –H-β), 2.31 (1H, dd, J=14.0, 9.0 Hz, C5 –H-α), 2.66, 2.77 (2H, each as d, J=13.2 Hz, CH2–Ph), 3.34 (1H, dd, J=10.6,
0
0
0
0
5.5 Hz, C6 –H), 3.41 (1H, dd, J=10.6, 5.1 Hz, C6 –H), 4.93–4.98 (2H, m, C1 –H and C6 –OH), 5.71 (1H, dd, J=5.5, 2.2 Hz,
0
0
C2 –H), 5.94 (1H, dd, J=5.5, 2.1 Hz, C3 –H), 6.71 (2H, s, NH2), 7.15–7.30 (5H, m, Ph), 7.55 (1H, s, C8–H), 10.83 (1H, s,
NH); 13C-NMR (500 MHz, DMSO-d6): δ 38.3(t, C5 ), 41.4 (t, CH2–Ph), 55.9 (s, C4 ), 58.2 (d, C1 ), 67.0 (t, C6 ), 116.5 (s,
0
0
0
0
0
0
C5), 129.4 (d, C2 ), 125.9, 127.7, 130.3 (each as d, Ph), 134.8 (d, C8), 138.5 (s, Ph), 141.8 (d, C3 ), 150.6 (s, C4), 153.6 (s,
C2 or C6), 156.7 (s, C2 or C6), FAB-MS m/z: 376 (M++K)