ORGANIC
LETTERS
2000
Vol. 2, No. 24
3793-3796
A Remarkably Simple Chemicoenzymatic
Approach to Structurally Complex
Bicyclo[3.1.0]hexane Carbocyclic
Nucleosides
,†
Hyung R. Moon, Harry Ford, Jr., and Victor E. Marquez*
Laboratory of Medicinal Chemistry, DiVision of Basic Sciences, National Cancer
Institute, FCRDC, Frederick, Maryland 21702-1201
marquezV@dc37a.nci.nih.goV
Received August 23, 2000
ABSTRACT
Intramolecular cyclopropanation of a carbene engendered from the corresponding diazo â-ketoester produced the desired bicyclo[3.1.0]-
hexane pseudosugar. Purine nucleosides obtained via Mitsunobu coupling were resolved with adenosine deaminase. The requisite â-ketoester
was assembled in one step from ethyl acetoacetate and acrolein.
Over the past several years, our laboratory, in collaboration
with other investigators, has undertaken a systematic study
of the role of the sugar ring in the process of recognition
and binding of nucleosides, nucleotides, and oligonucleotides
to their target enzymes.1,2 The emerging picture from these
studies shows that the majority of enzymes appear to have
strict conformational requirements for substrate binding with
the furanose ring in a well-defined shape. In particular,
methanocarba nucleosides built on a rigid bicyclo[3.1.0]-
hexane template have been instrumental in defining the role
of sugar puckering in nucleosides and nucleotides by
stabilizing the active receptor-bound conformation and
thereby identifying the biologically favored sugar conformer.1
The two principal conformational parameters controlled by
the bicyclo[3.1.0]hexane template are the ring pucker, defined
by the phase angle of pseudorotation P (0°-360°, Figure
1), and the deviation from planarity indicated by the
maximum out-of-plane pucker νmax (νmax ) ν2/cos P).3 The
value of P depends on the five endocyclic torsion angles
ν0-ν4 (the fused cyclopropane ring being excluded) accord-
ing to the following relationship: tan P ) (ν4 + ν1) - (ν3
+ ν0)/2ν2 (sin 36° + sin 72°).3 By convention, a phase angle
† Fax: 301-846-6033.
(1) (a) Jeong, L. S.; Marquez, V. E.; Yuan, C.-S.; Borchardt, R. T.
Heterocycles 1995, 41, 2651. (b) Marquez, V. E.; Siddiqui, M. A.; Ezzitouni,
A.; Russ, P.; Wang, J.; Wagner, R. W.; Matteucci, M. D. J. Med. Chem.
1996, 39, 3739. (c) Marquez, V. E.; Ezzitouni, A.; Russ, P.; Siddiqui, M.
A.; Ford, H., Jr.; Feldman, R. J.; Mitsuya, H.; George, C.; Barchi, J. J., Jr.
Nucleosides Nucleotides 1998, 17, 1881. (d) Marquez, V. E.; Ezzitouni,
A.; Russ, P.; Siddiqui, M. A.; Ford, H., Jr.; Feldman, R. J.; Mitsuya, H.;
George, C.; Barchi, J. J., Jr. J. Am. Chem. Soc. 1998, 120, 2780. (e) Jeong,
L. S.; Buenger, G.; McCormack, J. J.; Cooney, D. A.; Hao, Z.; Marquez,
V. E. J. Med. Chem. 1998, 41, 2572. (f) Marquez, V. E.; Russ, P.; Alonso,
R.; Siddiqui, M. A.; Shin, K. J.; George, C.; Nicklaus, M. C.; Dai, F.; Ford,
H., Jr. Nucleosides Nucleotides 1999, 18, 521. (g) Marquez, V. E.; Russ,
P.; Alonso, R.; Siddiqui, M. A.; Hernandez, S.; George, C.; Nicklaus, M.
C.; Dai, F.; Ford, H., Jr. HelV. Chim. Acta 1999, 82, 2119. (h) Nandanan,
E.; Jang, S.-Y.; Moro, S.; Kim, H. O.; Siddiqui, M. A.; Russ, P.; Marquez,
V. E.; Busson, R.; Herdewjin, P.; Harden, T. K.; Boyer, J. L.; Jacobson, K.
A. J. Med. Chem. 2000, 43, 829. (i) Jacobson, K. A.; Ji, X.; Li, A.; Melman,
N.; Siddiqui, M. A.; Shin, K. J.; Marquez, V. E.; Ravi, R. G. J. Med. Chem.
2000, 43, 2196. (j) Prota, A.; Vogt, J.; Perozzo, R.; Pilger, B.; Wurth, C.;
Marquez, V. E.; Russ, P.; Schultz, G. E.; Folkers, G.; Scapozza, L.
Biochemistry 2000, 39, 9597.
(2) (a) Altmann, K.-H.; Kesselring, R.; Francotte, E.; Rihs, G. Tetrahe-
dron Lett. 1994, 35, 2331. (b) Altmann, K.-H.; Imwinkelried, R.; Kesselring,
R.; Rihs, G. Tetrahedron Lett. 1994, 35, 7625. (c) Rajwanshi, V. K.;
Håkansson, A. E.; Sørensen, M. D.; Pitsch, S.; Singh, S. K.; Kumar, R.;
Nielsen, P.; Wengel, J. Angew. Chem., Int. Ed. 2000, 39, 1656. (d) Ikeda,
H.; Fernandez, R.; Wilk, A.; Barchi, J. J., Jr.; Marquez, V. E. Nucleic Acids
Res. 1998, 26, 2237. (e) Berger, I.; Tereshko, V.; Ikeda, H.; Marquez, V.
E.; Egli, M. Nucleic Acids Res. 1998, 26, 2473.
(3) (a) Altona, C.; Sundaranlingam, M. J. Am. Chem. Soc. 1972, 94,
8205. (b) For a comprehensive review of these concepts see: Saenger, W.
Principles of Nucleic Acid Structure; Springer-Verlag: New York, 1984.
10.1021/ol000238s This article not subject to U.S. Copyright. Published 2000 by the American Chemical Society
Published on Web 11/10/2000