COMMUNICATIONS
S. Leonce, P. Renard, A. Pierre, G. Atassi, J. Nat. Prod. 1998, 61, 982 ±
986.
Selenium-Based Solid-Phase Synthesis of
Benzopyrans II: Applications to Combinatorial
Synthesis of Medicinally Relevant Small
Organic Molecules**
[10] a) G. K. Hughes, F. N. Lakey, J. R. Price, L. J. Webb, Nature 1948, 162,
223 ± 224; b) R. T. Dorr, J. D. Liddil, D. D. Von Hoff, M. Soble, C. K.
Osborne, Cancer Res. 1989, 49, 340 ± 344, and references therein.
[11] a) L. A. Sorbera, P. Leeson, J. Castaner, Drugs Future 1999, 24, 235 ±
245; b) Y. Kashman, K. R. Gustafson, R. W. Fuller, J. H. Cardellina II,
J. B. McMahon, M. J. Currens, R. W. Buckheit, Jr., S. H. Hughes,
G. M. Cragg, M. R. Boyd, J. Med. Chem. 1992, 35, 2735 ± 2743; c) Z.-
Q. Xu, M. G. Hollingshead, S. Borgel, C. Elder, A. Khilevich, M. T.
Flavin, Bioorg. Med. Chem. Lett. 1999, 9, 133 ± 138, and references
therein.
K. C. Nicolaou,* Guo-Qiang Cao, and
Jeffrey A. Pfefferkorn
In the preceding communication we described a novel
selenium-based simultaneous cyclization and loading (cyclo-
loading) strategy for the solid-phase combinatorial synthesis
of natural products containing the 2,2-dimethylbenzopyran
moiety.[1] Given the vast number and diverse biological
activities of these benzopyran natural products, it is reason-
able to consider whether this structural motif might be of
value in the construction of designed pharmaceutical agents,
particularly since natural-product-based mechanistic investi-
gations have revealed that such structures interact with a
variety of protein and nucleic acid cellular targets.[2] Not
surprisingly, a search of the patent literature revealed a host of
pharmaceutical ligands that contain the 2,2-dimethylbenzo-
pyran skeleton (Scheme 1). Among these are the potassium-
channel activators 1 and 2,[3] aldosterone biosynthesis inhib-
itors 3 and 4,[4] 5-hydroxytryptamine-3 receptor antagonist 5,[5]
phosphodiesterase IV inhibitor 6,[6] and the ampicillin-derived
antibacterial agent 7.[7] However, in spite of the potential
utility of this substituted benzopyran motif in ligand design,
only a limited number of solid-phase methods for its
construction has been reported.[8] Hence we investigated
whether our current cyclo-loading approach might be a useful
tool in medicinal chemistry for future combinatorial inves-
tigations of this class of compounds. Since structures 1 ± 7,
unlike the natural products previously described, are struc-
turally quite diverse and possess a variety of heteroatom
functionalities, we sought to effect the solid-phase function-
alization of several of the previously described resin-bound
benzopyrans[1] with various heteroatom-based functional
groups in order to produce scaffolds embodying their
structural features. Herein we describe the synthesis of
several representative scaffolds as well as a solid-phase
synthesis of androsterone biosynthesis inhibitor 4 (Scheme 1)
and a small library of analogues using radiofrequency
[12] a) N. Fang, J. E. Casida, Proc. Natl. Acad. Sci. USA 1998, 95, 3380 ±
3384; b) N. Fang, J. E. Casida, J. Natl. Prod. 1999, 62, 205 ± 210; c) M.
Kaouadji, A. Agban, A. M. Mariotte, M. Tissut, J. Nat. Prod. 1986, 49,
281 ± 285.
[13] A. C. Whyte, J. B. Gloer, D. T. Wicklow, P. F. Dowd, J. Nat. Prod. 1996,
59, 1093 ± 1095.
[14] a) M. Takasugi, S. Nagao, S. Ueno, T. Masamune, A. Shirata, K.
Takahashi, Chem. Lett. 1978, 1239 ± 1240; b) A. Shirata, K. Takahashi,
M. Takasugi, S. Nagao, S. Ishikawa, S. Ueno, L. Munoz, T. Masamune,
Sanshi Shikenjo Hokoku 1983, 28, 793 ± 806.
[15] For a solution precedent of selenium-mediated 6-exo-trig cyclizations
of ortho-prenylated phenols and related systems, see a) D. L. J. Clive,
G. Chittattu, N. J. Curtis, W. A. Kiel, C. K. Wong, J. Chem. Soc. Chem.
Commun. 1977, 725 ± 727; b) P. B. Anzeveno, J. Org. Chem. 1979, 44,
2578 ± 2580; c) K. C. Nicolaou, Z. Lysenko, J. Am. Chem. Soc. 1977, 99,
3185 ± 3187.
[16] All ortho-prenylated phenols employed were prepared in one of three
ways: a) Friedel ± Crafts-type alkylation, see F. Bohlmann, U. Buh-
mann, Chem. Ber. 1972, 105, 863 ± 873; see also L. Jurd, K. Stevens, G.
Manners, Tetrahedron Lett. 1971, 25, 2275 ± 2278; b) anionic alkyla-
tion, see R. W. Bates, C. J. Gabel, Tetrahedron Lett. 1993, 34, 3547 ±
3550; c) aromatic Claisen rearrangement, see F. Bohlmann, E.
Vorwerk, Chem. Ber. 1980, 113, 261 ± 266; also see D. Bell, M. R.
Davies, G. R. Geen, I. S. Mann, Synthesis 1995, 707 ± 712.
[17] S. P. Hollinshead, Tetrahedron Lett. 1996, 37, 9157 ± 9160.
[18] a) K. C. Nicolaou, X.-Y. Xiao, Z. Parandoosh, A. Senyei, M. P. Nova,
Angew. Chem. 1995, 107, 2476 ± 2479; Angew. Chem. Int. Ed. Engl.
1995, 34, 2289 ± 2291; b) E. J. Moran, S. Sarshar, J. F. Cargill, M. J. M.
Shahbaz, A. Lio, A. M. M. Mjalli, R. W. Armstrong, J. Am. Chem. Soc.
1995, 117, 10787 ± 10788.
[19] We thank Mr. Rick Brown of Discovery Partners International (DPI)
for a generous gift of IRORI MicroKans (K.C.N. is an advisor of DPI).
[20] IRORI microreactors were not applicable for the synthesis of
compounds 1, 2, 55, and 62 because of the high reaction temperature
(1658C) required. All other compounds (56 ± 61 and 63 ± 68) were
synthesized using IRORI microreactor split-and-pool technology.[18, 19]
[21] a) Wittig reaction: H. Ishii, K. Kenmotsu, W. Dopke, T. Harayama,
Chem. Pharm. Bull. 1992, 40, 1770 ± 1772; b) b-ketoester reaction: J.-
R. Yang, M. E. Langmuir, J. Heterocycl. Chem. 1991, 28, 1177 ± 1180;
see also T. Besson, G. Coudert, G. Guillaumet, J. Heterocycl. Chem.
1991, 28, 1517 ± 1523.
[22] R. X. Tan, J.-L. Wolfender, L. X. Zhang, W. G. Ma, N. Fuzzati, A.
Marston, K. Hostettmann, Phytochemistry 1996, 42, 1305 ± 1313.
[23] K. Takai, K. Nitta, K. Utimoto, J. Am. Chem. Soc. 1986, 108, 7408 ±
7410.
[*] Prof. Dr. K. C. Nicolaou, Dr. G.-Q. Cao, J. A. Pfefferkorn
Department of Chemistry
and The Skaggs Institute for Chemical Biology
The Scripps Research Institute
[24] Yields of reactions performed on the resin were estimated by
oxidatively cleaving a portion of the resin after each step and
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (1)858-784-2469
1
determining the conversion by H NMR analysis.
and
[25] Recent review: C. L. Kingsbury, S. J. Mehrman, J. M. Takacs, Curr.
Org. Chem. 1999, 3, 497 ± 555.
[26] T. G. Mayer, B. Kratzer, R. R. Schmidt, Angew. Chem. 1994, 106,
2289 ± 2293; Angew. Chem. Int. Ed. Engl. 1994, 33, 2177 ± 2181.
[27] R. R. Schmidt, J. Michel, Angew. Chem. 1980, 92, 763 ± 764; Angew.
Chem. Int. Ed. Engl. 1980, 9, 731 ± 732.
Department of Chemistry and Biochemistry
University of California San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] We are indebted to Nicolas Winssinger for advice and preparation of
the selenium bromide resin employed in these studies. Financial
support for this work was provided by The Skaggs Institute for
Chemical Biology, the National Institutes of Health (USA), the
Department of Defense (fellowship to J.A.P.), and grants from
Abbott, Amgen, Boehringer-Ingelheim, GlaxoWellcome, Hoffmann-
LaRoche, DuPont, Merck, Novartis, Pfizer, and Schering Plough.
Angew. Chem. Int. Ed. 2000, 39, No. 4
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0570-0833/00/3904-0739 $ 17.50+.50/0
739