4
192
J . Org. Chem. 1996, 61, 4192-4193
An Efficien t Asym m etr ic Ap p r oa ch to
Ca r bocyclic Nu cleosid es: Asym m etr ic
Syn th esis of 1592U89, a P oten t In h ibitor of
HIV Rever se Tr a n scr ip ta se
Sch em e 1
Michael T. Crimmins* and Bryan W. King
Venable and Kenan Laboratories of Chemistry,
The University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
Received April 19, 1996
Carbocyclic nucleosides have been the focus of much
recent attention in the development of new antitumor
and antiviral therapeutic agents.1 The search for anti-
viral agents, particularly for the treatment of human
immunodeficiency virus (HIV) and hepatitis B virus
4
-(hydroxymethyl)-2-cyclopenten-1-ol (4), each of which
gives access to the same π-allyl palladium intermediate
for coupling to the nucleoside base. Our approach to the
synthesis of 3 relies on the realization that combination
of an asymmetric aldol condensation with a ring closure
metathesis reaction can provide rapid entry into func-
tionalized, enantiomerically pure carbocycles. Condensa-
tion of the lithiated (S)-4-benzyl-2-oxazolidinone with the
pentenoic pivalic mixed anhydride 5 provided the pen-
tenoyloxazolidinone 610 in near-quantitative yield (Scheme
(HBV), resulted in the discovery of carbovir (1), which
has been shown to possess significant in vitro activity as
8
an inhibitor of HIV reverse transcriptase (Scheme 1).2
,3
9
More recently, a new reverse transcriptase inhibitor
592U89 (2), which is currently in phase II clinical trials,
1
has been discovered and reported to hold remarkable
promise for the treatment of HIV.4 Reduction of viral
load of greater than 99% as well as significant improve-
8
a
2
). Use of the Evans’ dialkylboron triflate protocol for
ments in CD4 counts for HIV-infected patients have been
observed after dosing for 12 weeks with 1592U89 (2).5
diastereoselective syn aldol condensation with acrolein
1
0
produced the aldol product 7 in 82% yield [(>99% de
Continuous improvement in the enantioselective synthe-
ses of carbocyclic nucleosides is required due to their
therapeutic significance. An efficient and general ap-
proach to the asymmetric synthesis of carbocyclic nucleo-
sides such as carbovir (1) and 1592U89 (2) is described
here.
2
4
[R]
D
3
+50.6° (c ) 0.89, CHCl )]. The critical ring closure
metathesis was accomplished in 97% yield by exposure
of a dichloromethane solution of diene 7 to 1% of the
Grubbs catalyst for 30 min to form the cyclopentenol
9
a
1
0
24
8
[[R]
iary was reductively removed with lithium borohydride
to provide the required diol 3 in 78% yield [[R]24 -125.1°
D
-92.5° (c ) 0.795, CHCl
3
)]. The chiral auxil-
1
1
An attractive convergent approach for the enantiose-
lective synthesis of carbocyclic nucleosides involves Trost’s6
palladium-catalyzed coupling of purine or pyrimidine
D
(
c ) 0.47, CHCl
p-toluate].
Diol 3 was converted to cyclic carbonate 9 (52%),
3
), >99.6% ee by chiral HPLC of the di-
7
bases with carbocyclic allylic carbonates or acetates. This
3
b
strategy requires ready access to enantiomerically pure
dicarbonate 10 (90%),3
a,f,k
and diacetate 11 (90%) for
10
5
-(hydroxymethyl)-2-cyclopenten-1-ol (3) or the isomeric
evaluation of the palladium-catalyzed coupling with
2-amino-6-chloropurine (12) and 2-amino-6-(cyclopropyl-
amino)purine (13). Reaction of diacetate 11 with 2-amino-
*
To whom correspondence should be addressed. Phone: (919) 966-
177. FAX: (919) 962-2388. E-mail: mtc@net.chem.unc.edu.
1) For recent reviews on the synthesis of carbocyclic nucleosides,
5
(
6
-chloropurine (12) in the presence of tetrakis(triphen-
see: (a) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand,
S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611-10670. (b)
Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571-623.
Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745-1768.
ylphosphine)palladium(0) and sodium hydride gave an
86:14 mixture of the carbocyclic nucleoside 14a 1 and the
corresponding N7 coupling product 15a (65% yield of 14a
after chromatography) (Scheme 3).12 The problem of N9-
N7 regioselectivity is a common problem in classic
0
(
2) Vince, R.; Hua, M. J . Med. Chem. 1990, 33, 17.
(3) For some recent carbovir syntheses, see: (a) Berranger, T.;
Langlois, Y. Tetrahedron Lett. 1995, 36, 5523-5526. (b) Hildebrand,
S.; Troxler, T.; Scheffold, R. Helv. Chim. Acta 1994, 77, 1236-1240.
13
Vorbruggen coupling of purines with sugars, but has
(
c) Legraverend, M.; Aubertin, A. M.; Obert, G.; Huel, C.; Bisagni, E.
Nucleosides Nucleotides 1994, 13, 915-923. (d) Diaz, M.; Ibarzo, J .;
J imenez, J . M.; Ortuno, R. M. Tetrahedron: Asymmetry 1994, 5, 129-
(8) (a) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc. 1981,
103, 2127-2129. (b) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi,
F. J . Am. Chem. Soc. 1991, 113, 1047-1049. (c) Yan, T.-Y.; Tan, C.-
W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y. J . Am. Chem. Soc. 1993, 115,
2613-2621. (d) Ahn, K. H.; Lee, S.; Lim, A. J . Org. Chem. 1992, 57,
5065-5066. (e) Bonner, M. P.; Thornton, E. R. J . Am. Chem. Soc. 1991,
113, 1299-1308. (f) Oppolzer, W.; Lienard, P. Tetrahedron Lett. 1993,
34, 4321-4324.
1
40. (e) J ung, M. E.; Rhee, H. J . Org. Chem. 1994, 59, 4719-4720. (f)
Nokami, J .; Matsuura, H.; Nakasima, K.; Shibata, S. Chem. Lett. 1994,
1
071-1074. (g) Asami, M.; Takahashi, J .; Inoue, S. Tetrahedron:
Asymmetry 1994, 5, 1649-1652. (h) MacKeith, R. A.; McCague, R.;
Olivo, H. F.; Palmer, C. F.; Roberts, S. M. J . Chem. Soc., Perkin Trans.
1
3
1993, 313-314. (i) J ung, M. E.; Rhee, H. Tetrahedron Lett. 1993,
4, 4449-4452. (j) Evans, C. T.; Robert, S. M.; Shoberu, K. A.;
Sutherland, A. G., J . Chem. Soc., Perkin Trans. 1 1992, 589-592. (k)
(9) Schwab, P.; Grubbs, R. H.; Ziller, J . J . Am. Chem. Soc. 1996,
118, 100-110. Grubbs, R. H.; Miller, S. J .; Fu, G. C. Acc. Chem. Res.
1995, 28, 446-452.
Trost, B. M.; Li, L.; Guile, S. D. J . Am. Chem. Soc. 1992, 114, 8745-
8
1
747. (l) Peel, M. R.; Sternbach, D. D.; J ohnson, M. R. J . Org. Chem.
991, 56, 4990-4993. (m) Hodgson, D. M.; Witherington, J .; Moloney,
(10) All new compounds gave satisfactory combustion analyses and
1
13
B. A. J . Chem. Soc., Perkin Trans. 1 1994, 3373-3378.
consistent H, C, and IR spectra. Yields are for isolated, chromato-
graphically purified material. Yields are not fully optimized.
(11) Evans, D. A.; Ng, H. P.; Rieger, D. L. J . Am. Chem. Soc. 1993,
115, 11446-11459.
(4) Daluge, S. M. U.S. Patent 5,034,394, 1991.
(5) (a) Saag, M. Abstracts from The Third Conference on Retroviruses
and Opportunistic Infections, 1996, abstract 195. (b) Torres, G. GMHC
Treatment Issues Feb 1996, 10, 8.
(12) (a) Gundersen, L.-L.; Benneche, T.; Rise, F.; Gogoll, A.; Und-
heim, K. Acta Chem. Scand. 1992, 46, 761-771. (b) Gosh, A.; Ritter,
A. R.; Miller, M. J . J . Org. Chem. 1995, 60, 5808-5813.
(13) (a) Vorbruggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber.
1981, 114, 1234-1255. (b) Vorbruggen, H.; Hofle, G.. Chem. Ber. 1981,
114, 1256-1268.
(
6) Trost, B. M.; Kuo, G.-H.; Benneche, T. J . Am. Chem. Soc. 1988,
10, 621-622.
7) Trost, B. M.; Verhoeven, T. R. Comprehensive Organometallic
1
(
Chemistry; Wilkinson, G., Ed.; Pergamon Press: Oxford, 1982; Vol. 8,
p 799.
S0022-3263(96)00708-6 CCC: $12.00 © 1996 American Chemical Society