Practical enantiodivergent syntheses of both enantiomers of carbovir, 1592U89 and six-membered ring analogues

Article abstract of DOI:10.1039/a708261d

The hydroxylactones 4a-b (both available in optically pure form from biocatalytic processes) have been used in the preparation of carbovir, 1592U89, and their six-membered ring analogues.

Full text of DOI:10.1039/a708261d

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Practical enantiodivergent syntheses of both enantiomers of carbovir,
1592U89 and six-membered ring analogues
Horacio F. Olivo* and Jiaxin Yu
Division of Medicinal and Natural Products Chemistry, College of Pharmacy,
The University of Iowa, Iowa City, IA 52242, USA
The hydroxylactones 4a–b (both available in optically pure
form from biocatalytic processes) have been used in the
preparation of carbovir, 1592U89, and their six-membered
ring analogues.
membered ring series. This new route to both enantiomers of
carbovir and 1592U89 avoids the protection–deprotection steps
used in our previous synthesis,10 and also allows access to enan-
tiomerically pure cyclohexenyl carbonucleosides represented by
1b and 2b.
Carbocyclic analogues of nucleosides display a wide range of
biological activity and have attracted considerable attention as
antitumor and antiviral agents.1 In particular, carbonucleosides
carbovir (1a)2 and 1592U89 (2a)3 have been shown to act as
potent antiviral agents. Carbovir emerged as a potent and
selective anti-HIV agent;4 however, it was removed from clinical
trials due to toxicity issues. More recently 1592U89, the cyclo-
propylamine derivative of carbovir, was reported to have excel-
lent oral bioavailability and to penetrate the central nervous
system as well as AZT.5 A unique activation pathway enables
1592U89 to overcome the pharmacokinetic and toxicological
deficiencies of carbovir while maintaining potent and selective
anti-HIV activity.6 Having demonstrated an excellent pre-
clinical profile, 1592U89 is now in clinical evaluation in HIV-
infected patients.
Considerable effort has been devoted to the practical syn-
thesis of both enantiomers of these compounds and also to
their six-membered ring analogues.7 Interest in the cyclohexenyl
analogues arose from the observation that pyranosyl-like
nucleosides have also shown antiviral activity.7 An efficient,
convergent approach to the synthesis of carbonucleosides has
proved to be Trost’s palladium-catalyzed coupling8 of carbon-
ates or allylic acetates with heterocyclic bases.9 Carbovir (1a)
and 1592U89 (2a) have been prepared by Crimmins from
bicyclic carbonate 3a.2e Carbovir was also prepared by Roberts
and Olivo from endo-hydroxylactone 4a.10 The cyclohexenyl
nucleosides 1b and 2b have been recently prepared by Vince in
racemic form.7a We report herein a practical synthesis of
bicyclic carbonates 3a–b from optically pure endo-hydroxy-
lactones 4a–b, and an extension of this methodology to the six-
endo-Hydroxylactones 4a–b were easily obtained by the
water-promoted reaction of glyoxylic acid with cyclopentadiene
and 1,3-cyclohexadiene, respectively.11 The versatile hydroxy-
lactone 4a has been used previously in the synthesis of ses-
banimide,12 brefeldin A,13 carbonucleosides,10,14 and anti-hyper-
cholesterolemic agents.15
Hydroxylactone ( )-4a has been kinetically resolved using
Pseudomonas fluorescens lipase in both the hydrolysis and the
esterification modes.16 Optically pure hydroxylactone (ϩ)-4a
and its acetyl ester (Ϫ)-5a were obtained by enzymatic esterifi-
cation of ( )-4a in vinyl acetate. Acetyl esters ( )-5a–b were
also enzymatically hydrolyzed in a buffer solution (0.1  phos-
phate, pH 7.0) to yield hydroxylactone (Ϫ)-4a–b {[α]D Ϫ104 (c
1.0, CHCl3)10 and [α]D Ϫ144 (c 1.0, CHCl3),17 respectively}† and
acetyl ester (ϩ)-5a–b {[α]D Ϫ6.6 (c 1.0, CHCl3)10 and [α]D
Ϫ22.3 (c 1.0, CHCl3),17 respectively}. The resolved alcohols and
esters were easily separated by flash column chromatography.
(Ϫ)-Hydroxylactones 4a–b were converted in three steps to
(Ϫ)-diols 6a–b in 70–75% overall yield, Scheme 1. Diol 6a has
R-O
H
(
)
n
(
)
n
O
HO
(
)
n
a,b,c
d
O
O
O
HO
O
H
4a R = H, n = 1
4b R = H, n = 2
5a R = Ac, n = 1
5b R = Ac, n = 2
6a n = 1 (75%)
6b n = 2 (70%)
3a n = 1 (76%)
3b n = 2 (72%)
e
Cl
N
R
H
N
N
(
)
n
O
HO
N
(
)
n
N
N
HO
N
(
)
n
NH2
O
O
N
H
NH2
7a n = 1 (53%)
7b n = 2 (69%)
3a n = 1
3b n = 2
1a R = OH, n = 1 carbovir
1b R = OH, n = 2
2a R = NHCH(CH2)2, n = 1 1592U89
2b R = NHCH(CH2)2, n = 2
Scheme 1 Reagents and conditions: a, LiAlH4, THF, reflux; b, NaIO4,
Et2O–H2O; c, NaBH4, EtOH; d, triphosgene, Et3N, CH2Cl2; e, 2-amino-
6-chloropurine, Pd(PPh3)4, DMSO–THF (1:1).
RO
H
H
(
)
n
also been elegantly synthesized by Crimmins, in a combination
of an asymmetric aldol condensation with a ring closure
metathesis.2e (Ϫ)-Bicyclic carbonates 3a–b were obtained by the
addition of triphosgene to diols 6a–b in 72 and 76% yield.18
O
O
4a R = H, n = 1
4b R = H, n = 2
5a R = Ac, n = 1
5b R = Ac, n = 2
† [α]D Values are given in 10Ϫ1 deg cm2 gϪ1
.
J. Chem. Soc., Perkin Trans. 1, 1998
391

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M. Nakayama, Synth. Commun., 1997, 27, 2371; (c) L. E. Martinez,
Palladium-catalyzed coupling of bicyclic allylic carbonate
(Ϫ)-3a with 2-amino-6-chloropurine [Pd(PPh3)4, DMSO–THF]
in the absence of base provided a separable mixture of N9–N7
coupling products in 53 and 24% yields respectively.19 Coup-
ling of carbonate (Ϫ)-3b under the same conditions furnished
coupling product (Ϫ)-7b in 69% yield. In this case, we were not
able to identify the N7 coupling product regioisomer.
Direct hydrolysis of the 2-chloro-4-aminopurine adduct
(Ϫ)-7a20 provided (Ϫ)-carbovir (1a) in 89% yield. Similarly,
hydrolysis of adduct (Ϫ)-7b provided homocarbovir 1b in 90%
yield.21 Treatment of the 2-chloro-4-aminopurine adduct
(Ϫ)-7a with cyclopropylamine in refluxing ethanol provided
(Ϫ)-1592U89 (2a) in 72% yield, and similarly the six-membered
ring analogue 2b was obtained in 69% yield.21 The dextro-
rotatory carbonucleosides 1a–b and 2a–b were obtained when
the acetyl esters (ϩ)-5a–b were used as starting material and the
same methodology was followed.
In summary, we have presented a simple preparation of
either racemic or enantiomerically pure cyclic carbonates 3a–b.
Short syntheses of both enantiomers of carbonucleosides car-
bovir and 1592U89 were achieved by palladium coupling of the
cyclic allylic carbonate prepared from enzymatically resolved
hydroxylactones. This enantiodivergent methodology was suc-
cessfully extended to the syntheses of optically pure six-
membered ring analogues 2a–b.
W. A. Nugent and E. N. Jacobsen, J. Org. Chem., 1996, 61, 7963;
(d) B. M. Trost, R. Madsen, S. G. Guile and A. E. H. Elia, Angew.
Chem., Int. Ed. Engl., 1996, 35, 1569; (e) M. T. Crimmins and B. W.
King, J. Org. Chem., 1996, 61, 4192; ( f ) M. Tanaka, Y. Norimine,
T. Fujita, H. Suemune and K. Sakai, J. Org. Chem., 1996, 61, 6952;
(g) T. Berranger and Y. Langlois, Tetrahedron Lett., 1995, 36, 5523;
(h) B. M. Trost, M. G. Organ and G. A. O’Doherty, J. Am. Chem.
Soc., 1995, 117, 9662.
3 For syntheses of 1592U89: see S. M. Daluge, U.S. Patent, 5 034 394,
1991; also ref. 2e.
4 (a) R. Vince, M. Hua, J. Brownell, S. Daluge, F. Lee, W. M. Shannon,
G. C. Lavelle, J. Qualls, O. S. Weislow, R. Kiser, P. G. Canonico,
R. H. Schultz, V. L. Narayanan, J. G. Mayo, R. H. Shomaker and
M. R. Boyd, Biochem. Biophys. Res. Commun., 1988, 156, 1046;
(b) R. Vince and M. Hua, J. Med. Chem., 1990, 33, 17.
5 (a) S. M. Daluge, S. S. Good, M. B. Faletto, W. H. Miller, M. H.
St. Clair, L. R. Boone, M. Tisdale, N. R. Parry, J. E. Reardon, R. E.
Dornsife, D. R. Averett and T. A. Krenitsky, Antimicrob. Agents
Chemother., 1997, 41, 1082; (b) S. S. Good, S. M. Daluge, S. V.
Ching, K. M. Ayers, W. B. Mahoney, M. B. Faletto, B. A. Domin,
B. S. Owens, R. E. Dornsife, J. A. McDowell, S. W. LaFon and
W. T. Symonds, Antiviral Res., 1995, 26, A229.
6 M. B. Faletto, W. H. Miller, E. P. Garvey, M. H. St. Clair and
S. M. Daluge, Antimicrob. Agents Chemother., 1997, 41, 1099.
7 (a) M. J. Konkel and R. Vince, Tetrahedron, 1996, 52, 799; (b) M. J.
Konkel and R. Vince, Nucleosides and Nucleotides, 1995, 14, 2061.
8 (a) B. M. Trost, G.-H. Kuo and T. Benneche, J. Am. Chem. Soc.,
1988, 110, 621; (b) L.-L. Gundersen, T. Benneche and K. Undheim,
Tetrahedron Lett., 1992, 33, 1085.
9 (a) B. M. Trost and T. R. Verhoeven, in Comprehensive Organo-
metallic Chemistry, ed., G. Wilkinson, Pergamon Press, Oxford,
1982; vol. 8, ch. 57; (b) B. M. Trost and D. L. Van Vranken, Chem.
Rev., 1996, 96, 395.
10 R. A. MacKeith, R. McCague, H. F. Olivo, C. F. Palmer and S. M.
Roberts, J. Chem. Soc., Perkin Trans. 1, 1993, 313.
[4-(2Ј-Amino-6Ј-chloropurin-9Ј-yl)cyclohex-2-en-1-yl]methanol
7b
To a solution of carbonate 3b (0.110 g, 0.714 mmol) in a 1:1
mixture of dimethylsulfoxide–tetrahydrofuran (4 cm3) was
added Pd(PPh3)4 (0.042 g, 0.036 mmol) and 2-amino-6-
chloropurine (0.121 g, 0.714 mmol). The solution was stirred at
60 ЊC for 8 h. The solution was cooled to room temperature,
poured into water (10 cm3) and extracted with ethyl acetate
(3 × 10 cm3). The combined organic layers were washed with
brine (15 cm3), dried over MgSO4, filtered and the solvent evap-
orated under reduced pressure. Purification of the residue by
silica gel column chromatography (dichloromethane–methanol,
19:1) furnished the title compound (137 mg, 69% yield) as a
white solid.
11 A. Lubineau, J. Augé and N. Lubin, Tetrahedron Lett., 1991, 32,
7529.
12 P. A. Grieco, K. J. Henry, J. J. Nunes and J. E. Matt Jr., J. Chem.
Soc., Chem. Commun., 1992, 368.
13 (a) A. J. Carnell, G. Casy, G. Gorins, A. Kompany-Saeid,
R. McCague, H. F. Olivo, S. M. Roberts and A. J. Willetts, J. Chem.
Soc., Perkin Trans. 1, 1994, 3431; (b) G. Casy, G. Gorins,
R. McCague, H. F. Olivo and S. M. Roberts, J. Chem. Soc., Chem.
Commun., 1994, 1085.
14 (a) V. K. Aggarwal and N. Monteiro, J. Chem. Soc., Perkin Trans. 1,
1997, 2531; (b) F. Burlina, A. Favre, J.-L. Fourrey and M. Thomas,
Bioorg. Med. Chem. Lett., 1997, 7, 247; (c) V. K. Aggarwal,
N. Monteiro, G. J. Tarver and S. D. Lindell, J. Org. Chem., 1996, 61,
1192.
15 (a) R. McCague, H. F. Olivo and S. M. Roberts, Tetrahedron Lett.,
1993, 34, 3785; (b) S. M. Roberts, H. F. Olivo and R. McCague,
Patent Appl. WO 94 07 888.
16 R. A. MacKeith, R. McCague, H. F. Olivo, S. M. Roberts, S. J. C.
Taylor and H. Xiong, Bioorg. Med. Chem., 1994, 2, 387.
17 D. E. Hibbs, M. B. Hursthouse, L. J. S. Knutsen, K. M. Abdul
Malik, H. F. Olivo, S. M. Roberts, D. R. Varley and H. Xiong, Acta
Chem. Scand., 1995, 49, 122.
18 S. Hildbrand, T. Troxler and R. Scheffold, Helv. Chim. Acta, 1994,
77, 1236.
Rf 0.35 (10% MeOH in CHCl3); mp 167–169 ЊC; [α]25 Ϫ53.1
2
(c 0.2, CH3OH); δH(360 MHz; [H6]DMSO) 7.99 (1H, s), 6.92
(2H, s), 6.12 (1H, d, J 10),‡ 5.85 (1H, d, J 10), 4.97 (1H, m), 4.70
(1H, t, J 5.4), 3.46 (2H, m), 2.26 (1H, m), 1.92 (2H, m), 1.65
(1H, m) and 1.42 (1H, m); δC(90 MHz; [2H6]DMSO) 159.7 (C),
153.5 (C), 149.4 (C), 141.7 (CH), 135.9 (CH), 124.5 (CH), 123.7
(C), 63.9 (CH2), 48.5 (CH), 37.7 (CH), 26.8 (CH2) and 20.4
(CH2); νmax/cmϪ1 3420, 3316, 3202, 1617, 1562, 1507, 1466, 1402
and 1363; m/z (FAB) 280 (M ϩ Hϩ, 46%), 170 (36), 91 (100),
73 (38) (Found: M ϩ Hϩ, 280.0969. C12H15N5OCl requires
M ϩ Hϩ, 280.0965).
19 Crimmins reported similar ratio of regioisomeric coupling products,
see ref. 2e.
‡ J Values are given in Hz.
20 R. Vince and M. Hua, U.S. Patent 4 931 559, 1990. Compound 7a
was also employed by Daluge, see ref. 3.
21 Carbovirref. 11 (1a): [α]D Ϫ62 (c 0.4, MeOH); 1592U89ref. 2e (2a): [α]D
Ϫ31.8 (c 0.51, MeOH); homocarbovir (1b): [α]D Ϫ26.8 (c 0.53,
MeOH); homo-1592U89 (2b): [α]D Ϫ37.3 (c 0.18, MeOH).
References
1 (a) L. Agrofoglio, E. Suhas, A. Farese, R. Condom, S. R. Challand,
R. A. Earl and R. Guedj, Tetrahedron, 1994, 50, 10 611; (b) A. D.
Borthwick and K. Biggadicke, Tetrahedron, 1992, 48, 571; (c) D. M.
Huryn and M. Okabe, Chem. Rev., 1992, 92, 1745.
2 For recent syntheses of carbovir: (a) N. Katagiri, M. Takebayashi,
H. Kokufuda, C. Kaneko, K. Kanehira and M. Torihara, J. Org.
Chem., 1997, 62, 1580; (b) S. Tanimori, M. Tsubota, M. He and
Paper 7/08261D
Received 17th November 1997
Accepted 12th December 1997
392
J. Chem. Soc., Perkin Trans. 1, 1998