Carbocyclic nucleosides, in which the furanose oxygen is
replaced with a methylene unit, have attracted much attention
in the development of novel antitumor and antiviral thera-
peutic agents. The absence of a glycosidic linkage within
the ring of the carbocyclic nucleoside confers stability toward
cleavage by nucleoside phosphorylases or hydrolases.12
However, the relative lack of conformational rigidity induced
by the methylene function may result in reduced activity
compared to that of the natural furanose ring.13 Thus, novel
structural modifications of carbocyclic nucleosides, including
conformationally restricted analogs, are of interest. Several
research groups have successfully prepared different types
of nucleoside analogs that address conformational and other
concerns.14
Syntheses of interesting biologically relevant molecules using
versatile chemical methodologies is of growing interest for our
research group.15 We have successfully used nitroso Diels-Alder
reactions to obtain cycloadducts as versatile building blocks for
a variety of synthetic applications,16 including preparation of
carbocylic nucleoside analogs.11f-h To further explore this
area, we designed the novel spirocyclic dienes 3a and 3b as
key components for the preparation of new spirocyclic
scaffolds and novel spirocarbocyclic nucleosides that incor-
porate an amine handle for further diversification.
The synthesis of spirocyclic dienes 3a and 3b is shown in
Scheme 1. Dialkylation of cyclopentadiene with N-protected
Scheme 1
(11) (a) Jana, C. K.; Studer, A. Chem.-Eur. J. 2008, 14, 6326. (b)
Zimmer, R.; Collas, M.; Czerwonka, R.; Hain, U.; Reissig, H.-U. Synthesis
2008, 2, 237. (c) Zhu, L.; Lauchli, R.; Loo, M.; Shea, K. J. Org. Lett. 2007,
9, 2269. (d) Korboukh, I.; Kumar, P.; Weinreb, S. M. J. Am. Chem. Soc.
2007, 129, 10342. (e) Jana, C. K.; Studer, A. Angew. Chem., Int. Ed. 2007,
46, 6542. (f) Mulvihill, M. J.; Cage, J. L.; Miller, M. J. J. Org. Chem.
1998, 63, 3357. (g) Mulvihill, M. J.; Miller, M. J. Tetrahedron 1998, 54,
6605. (h) Li, F.-Z.; Brogan, J. B.; Gage, J. L.; Zhang, D.-Y.; Miller, M. J.
J. Org. Chem. 2004, 69, 4538.
(12) (a) Crimmins, M. T. Tetrahedron 1998, 54, 9229. (b) Ferrero, M.;
Gotor, V. Chem. ReV. 2000, 100, 4319. (c) Jeong, L.-S.; Lee, J.-A. AntiViral
Chem. Chemother. 2004, 15, 235.
(13) (a) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1972, 94,
8205. (b) Choi, Y.; Moon, H.-R.; Yoshimura, Y.; Marquez, V. E.
Nucleosides, Nucleotides Nucleic Acids 2003, 22, 547. (c) Marquez, V. E.;
Hughes, S. H.; Sei, S.; Agbaria, R. AntiViral Res. 2006, 71, 268.
(14) (a) Roy, A.; Achari, B.; Mandal, S. B. Tetrahedron Lett. 2006, 47,
3875. (b) Fischer, R.; Hyrosova, E.; Fisera, L.; Hametner, C.; Cyranski,
M. K. J. Org. Chem. 2004, 69, 7442. (c) Hartung, R. E.; Paquette, L. A.
Synthesis 2005, 19, 3209. (d) Kittaka, A.; Asakura, T.; Kuze, T.; Tanaka,
H.; Yamada, N.; Nakamura, K. T.; Miyasaka, T. J. Org. Chem. 1999, 64,
7081. (e) Ravindra Babu, B.; Keinicke, L.; Petersen, M.; Nielsen, C.;
Wengel, J. Org. Biomol. Chem. 2003, 1, 3514. For interesting changes in
the nucleobase see for example: (f) Haraguchi, K.; Delaney, M. O.;
Wiederholt, C. J.; Sambandam, A.; Hantosi, Z.; Greenberg, M. M. J. Am.
Chem. Soc. 2002, 124, 3263. . (g) Moss, R. J.; Petrie, C. R.; Meyer, R. B.;
Nord, L. D.; Willis, R. C.; Smith, R. A.; Larson, S. B.; Kini, G. D.; Robins,
R. K. J. Med. Chem. 1988, 31, 786.
bis-2-chloroethylamine was the key step required for construc-
tion of the spirocycle. Commercially available bis(2-chloro-
ethyl)amine hydrochloride 1 was converted to the corresponding
N-Cbz- and N-Boc-protected derivatives 2a and 2b in quantita-
tive yields.17 Of numerous different conditions attempted to
form spirocyclic dienes 3a and 3b, the dimsyl anion initiated
substitution of compound 2 with cyclopentadiene was found
to be the most effective.18 Spirocyclic dienes 3a and 3b were
thus prepared in 79% and 68% yields, respectively, on a 20
mmol scale. Dienes 3a and 3b can be stored at room temper-
ature without problematic dimerization.
(15) (a) Ding, P-Y.; Helquist, P.; Miller, M. J. Bioorg. Med. Chem. 2008,
16, 1648. (b) Fennell, K. A.; Mo¨ellmann, U.; Miller, M. J. J. Org. Chem.
2008, 73, 1018. (c) Ding, Pingyu; Schous, Clara E.; Miller, M. J.
Tetrahedron Lett. 2008, 49, 2306. (d) Gebhardt, P.; Crumbliss, A. L.; Miller,
M. J.; Moellmann, U. BioMetals 2008, 21, 41. (e) Walz, A. J.; Miller, M. J.
Tetrahedron Lett. 2007, 48, 5103. (f) Walz, A. J.; Mollmann, U.; Miller,
M. J. Org. Biomol. Chem. 2007, 5, 1621. (g) Huang, W.-Q.; Miller, M. J.;
De Clercq, E.; Balzarini, J. Org. Biomol. Chem. 2007, 5, 1164.
(16) (a) Li, F-Z.; Yang, B-Y.; Miller, M. J.; Zajicek, J.; Noll, B. C.;
Mo¨ellmann, U.; Dahse, H-M.; Miller, P. A. Org. Lett. 2007, 7, 2923. (b)
Krchnak, V.; Waring, K. R.; Noll, Br. C.; Moellmann, U.; Dahse, H.-M.;
Miller, M. J. J. Org. Chem. 2008, 73, 4559. (c) Krchnak, V.; Moellmann,
U.; Dahse, H.-M.; Miller, M. J. J. Comb. Chem. 2008, 10, 94. (d) Krchnak,
V.; Moellmann, U.; Dahse, H.-M.; Miller, M. J. J. Comb. Chem. 2008, 10,
104. (e) Krchnak, V.; Moellmann, U.; Dahse, H.-M.; Miller, M. J. J. Comb.
Chem. 2008, 10, 112. (f) Bodnar, B. S.; Miller, M. J. J. Org. Chem. 2007,
72, 3929. (g) Li, F.-Z.; Miller, M. J. J. Org. Chem. 2006, 71, 5221. (h)
Jiang, M. X.-W.; Warshakoon, N. C.; Miller, M. J. J. Org. Chem. 2005,
70, 2824. (i) Lee, W. L.; Miller, M. J. J. Org. Chem. 2004, 69, 4516. (j)
Li, F.-Z.; Miller, M. J. J. Org. Chem. 2006, 71, 5221. (k) Jiang, M. X.-W.;
Warshakoon, N. C.; Miller, M. J. J. Org. Chem. 2005, 70, 2824.
(17) (a) Bergmann, M.; Zervas, L. Ber. 1932, 65, 1192. (b) Chambers,
M. S.; Baker, R.; Billington, D. C.; Knight, A. K.; Middlemiss, D. N.; Wong,
E. H. F. J. Med. Chem. 1992, 35, 2033.
A series of iminonitroso compounds 5 were prepared in
moderate yield from aminoheterocyclic derivatives 4 in a
two-step sequence (N,N-dimethylsulfilimine derivative for-
mation, followed by the oxidation using m-CPBA).19 Most
of the iminonitroso compounds could be stored for several
months at -20 °C, except for compounds 5l-o, which were
prepared and used immediately without purification. The
nitroso Diels-Alder reaction between spirocylic dienes 3 and
iminonitroso species 5 usually was complete within 2 h at
room temperature (Scheme 2). The corresponding racemic
Scheme 2
(18) (a) Jimonet, P.; Boireau, A.; Cheve, M.; Damour, D.; Genevois-
Borella, A.; Imperato, A.; Pratt, J.; Randle, J. C. R.; Ribeill, Y.; Stutzmann,
J.-M.; Mignani, S. Bioorg. Med. Chem. Lett. 1999, 9, 2921. (b) Chambers,
M. S.; Baker, R.; Billington, D. C.; Knight, A. K.; Middlemiss, D. N.; Wong,
E. H. F. J. Med. Chem. 1992, 35, 2033. (c) Efange, S. M. N.; Khare, A. B.;
Foulon, C.; Akella, S. K.; Parsons, S. M. J. Med. Chem. 1994, 37, 2574.
(19) (a) Taylor, E. C.; Tseng, C. P.; Rampal, J. B. J. Org. Chem. 1982,
47, 552. (b) Coburn, M. D.; Hayden, H. H. Synthesis 1985, 490.
(20) Gaggero, N.; D’Accolti, L.; Colonna, S.; Curci, R. Tetrahedron
Lett. 1997, 38, 5559.
spirocycloadducts 6a-j were obtained in good to excellent
yields after column chromatography. The instability of
450
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