YNuT 9 Nik O

.. f O-SsBr v ( V1 Fl inntir\nali7fl r-i9 I 1 «-«_ □slaaca / I \

191: polycyclic scaffold 192 193

W Me

197: benzopyran

191: polycyclic scaffold 192 193

W Me

197: benzopyran

201: polycycllc indoline

203: bicyclo[3.3.1]nonane

Scheme 21.21. General strategy for solid-phase cycloloading reactions using an electrophilic selenyl bromide resin (a) and representative hetero- and carbocyclic resin-bound scaffolds useful in the construction of natural product-like libraries (b) [44-46].

205: Functionalized bicyclo[3.3.1]nonane

203: bicyclo[3.3.1]nonane

Scheme 21.21. General strategy for solid-phase cycloloading reactions using an electrophilic selenyl bromide resin (a) and representative hetero- and carbocyclic resin-bound scaffolds useful in the construction of natural product-like libraries (b) [44-46].

201: polycycllc indoline

205: Functionalized bicyclo[3.3.1]nonane thereby making it an optimal template for construction of a natural product-like library (see below). The cycloloading of o-allylanilines (198) affords resin-bound indolines 199 which can be further functionalized and then cleaved under radical hydride conditions [45]. Interestingly, if a conjugated radical acceptor is placed in a suitably proximal position to the generated carbon-centered radical, complex poly-cyclic indolines reminiscent of alkaloid-type natural products can be obtained. Lastly, cycloloading of alkenyl-substituted b-ketoesters 202 provided access to a series of resin-bound bicyclic scaffolds which could be derivatized and cleaved to afford highly functionalized carbocycles of type 205. The last compounds resemble a family of natural products from the Guttiferae classification with promising biological activities [46].

As an illustration of the utility of such cycloloading strategies in the construction of large natural product-like libraries, the benzopyran strategy was recently employed in the construction a 10,000-member natural product-like library, as outlined in Scheme 21.22 [40-42]. This library was constructed by directed split-and-pool techniques employing the NanoKan™ optical encoding platform recently developed by Irori, a Discovery Partners International Company [47]. Synthesis of this diverse library commenced with a series of resin-bound benzaldehydes (207) which were subjected to various reactions, including organometallic additions, reductive aminations, condensations, acylations, Mitsunobu inversions, and glyco-

Scheme 21.22. Optically encoded split-and-pool solid-phase synthesis of 10,000-member natural product-like library based on 2,2-dimethylbenzopyran template [40-42], sidations. An automated cleavage protocol employing H2O2 furnished 2- to 3-mg quantities of each library member in high purity (often > 90%) with the entire library formatted in 96-well microtiter plates for use in various chemical biology studies [48].

21.5

Conclusion

Merrifield's pioneering work on solid-phase chemistry revolutionalized the field of peptide synthesis. It subsequently influenced profoundly the field of oligonucleo-tide synthesis where similar concepts were utilized to construct much-needed DNA sequences for the genetic engineering revolution. The same philosophy of solid-phase chemistry is now being implemented in the latest revolution in organic synthesis to deliver small organic molecules urgently needed to confront the human genome via biological screening. Indeed, in the 1990s, we have seen a strong push in research directed at the discovery and invention of new methods for solid-phase synthesis and the application of the latter for the construction of compound libraries for, among others, biological screening purposes. Many of these efforts focused on developing new resins and linkers for convenient loading and cleavage, others focused on suitable synthetic strategies to construct specific libraries, and yet others focused on designing and synthesizing novel molecular diversities. Given their molecular complexities, natural products are playing a crucial role in this process by serving as challenging targets for solid-phase synthesis, frequently demanding the development of new linking and synthesis strategies. When successful, such endeavors can deliver, in addition to the natural substances, highly valuable analog libraries of these compounds for biological investigations.

In contrast to the repetitive nature of peptide and oligonucleotide synthesis, the construction of small nonoligomeric natural products demands a mastery of a much wider range of synthetic chemistry. For this reason, chemists will remain busy for some time inventing, discovering, and developing enabling technologies that will enhance the power of solid-phase synthesis, and, in turn, sharpen the tools of combinatorial chemistry. The benefits of such efforts to biology and medicine are already becoming apparent and are bound to increase in the future.

21.6

Addendum

Since the submission of this chapter for publication, an important contribution to the field of natural product-based combinatorial chemistry has been reported. Specifically, the laboratory of Shair and coworkers described the biosynthetically inspired construction of a 2527-membered library using the natural product gal-anthamine as a scaffold. The galanthamine skeleton was functionalized at four sites using solid phase split-and-pool chemistry. While the natural product itself is a potent acetylcholinesterase inhibitor, the authors were interested in creating a non-focused, diversity oriented library. The resulting library was screened and a molecule capable of interfering with protein trafficking was identified for use as a chemical probe. The interested reader is referred to a full account of this work: H. E. Pelish, N. J. Westwood, Y. Feng, T. Kirchhausen, M. D. Shair, J. Am. Chem. Soc. 2001, 123, 6740-6741.

References

1 a) G. M. Cragg, D. J. Newman, K. M. Snader, J. Nat. Prod. 1997, 60, 52-60; b) Y.-Z. Shu, J. Nat. Prod. 1998, 61, 1053-1071.

2 a) K. Hinterding, D. Alonso-Diaz, H. Waldmann, Angew. Chem. Int. Ed.

1998, 37, 688-749; b) D. T. Hung, T. F. Jamison, S. L. Schreiber, Chem. Biol. 1996, 3, 623-639.

1999, 38, 1903-1908.

4 S. Bertels, S. Frormann, G. Jas, K. U. Bindseil, Drug Discovery Nat. 1999, 72-105.

5 A. Atuegbu, D. Maclean, C. Nguyen, E. M. Gordon, J. W. Jacobs, Bioorg. Med. Chem. 1996, 4, 10971106.

6 T. C. Norman, N. S. Gray, J. T. Koh, P. G. Schultz, J. Am. Chem. Soc. 1996, 118, 7430-7431.

7 N. S. GRAY, L. WODICKA, A.-M. W. H. Thunnissen, T. C. Norman, S. Kwon, F. H. Espinoza, D. O. Morgan, G. Barnes, S. LeClerc, L. Meijer, S.-H. Kim, D. J. Lockhart, P. G. Schultz, Science 1998, 281, 533-538.

8 H. M. Geysen, S. J. Rodda, T. J. Mason, G. Tribbick, P. G. Schoofs, J. Immunol. Methods 1987, 102, 259274.

9 G. R. Rosania, J. Merlie, Jr, N. Gray, Y.-T. Chang, P. G. Schultz, R. Heald, Proc. Natl. Acad. Sci. USA 1999, 96, 4797-4802.

10 X.-Y. Xiao, Z. Parandoosh, M. P. Nova, J. Org. Chem. 1997, 62, 60296033.

11 For a review, see: K. C. Nicoiaou, W.-M. Dai, R. K. Guy, Angew. Chem. Int. Ed. Engl. 1994, 33, 15-44.

12 a) K. C. Nicoiaou, X.-Y. Xiao, Z. Parandoosh, A. Senyei, M. P. Nova, Angew. Chem. Int. Ed. Engl. 1995, 107, 2476-2479; b) E. J. Moran, S. Sarshar, J. F. Cargiii, M. J. M. Shahbaz, A. Lio, A. M. M. Mjaiii, R. W. Armstrong, J. Am. Chem. Soc. 1995, 117, 10787-10788.

13 K. C. Nicoiaou, N. Winssinger, D. Vourioumis, T. Ohshima, S. Kim, J. Pfefferkorn, J. Y. Xu, T. Li, J. Am. Chem. Soc. 1998, 120, 10814-10826.

14 For a review, see: K. C. Nicoiaou, J. Pfefferkorn, J. Xu, N. Winssinger, T. Ohshima, S. Kim, S. Hosokawa, D. Vourioumis, F. van Delft, T. Li, Chem. Pharm. Bull. 1999, 47, 11991213.

15 K. C. Nicoiaou, J. Xu, S. Kim, J. Pfefferkorn, T. Ohshima, D. Vourioumis, S. Hosokawa, J. Am. Chem. Soc. 1998, 120, 8661-8673.

16 X.-T. CHEN, B. ZHOU, S. K. Bhattacharya, C. E. Gutteridge, T. R. Pettus, S. J. Danishefsky, Angew. Chem. Int. Ed. 1998, 37, 789-792.

17 K. C. Nicoiaou, N. Winssinger, R. Hughes, C. Smethurst, S. Y. Cho, Angew. Chem. Int. Ed. 2000, 39, 19841989.

18 For reviews, see: a) K. C. Nicoiaou, C. N. C. Boddy, S. BrAse, N. Winssinger, Angew. Chem. Int. Ed. 1999, 111, 2230-2287; b) D. H. Williams, B. Bardsley, Angew. Chem. Int. Ed. 1999, 38, 1172-1193.

19 R. Nagarajan, J. Antibiot. 1993, 46, 1181-1195.

20 a) K. C. Nicoiaou, J. Pastor, S. Barluenga, N. Winssinger, Chem. Commun. 1998, 1947-1948; for preparation of related selenium-based resins, see: b) T. Ruhiand, K. Andersen, H. Pedersen, J. Org. Chem. 1998, 63, 9204-9211; c) K. Fujita, K. Watanabe, A. Oishi, Y. Ikeda, Y. Taguchi, Synlett 1999, 11, 1760-1761.

21 S. Chen, K. D. Janda, J. Am. Chem. Soc. 1997, 119, 8724-8725.

22 For an early use of soluble polymers in peptide synthesis, see: a) M. Narita, M. Hirat, K. Kusano, S.-I. Itsuno, M. Ue, M. Okawara in: Peptide Chemistry. Yonehara, J. (ed.), Protein Research Foundation, Osaka 1979, vol. 99, pp. 107-112; b) M. Narita, Bull. Chem. Soc. Jpn. 1978, 51, 1477; c) E. Bayer, M. Mutter, Nature 1972, 237, 512-513; for a review, see: d) C. W. Harwig, D. J. Gravert, K. D. Janda, Chemtracts 1999, 12, 1-26.

23 K. J. Lee, A. Anguio, P. Ghazai, K. D. Janda, Org. Lett. 1999, 1, 18591862.

24 a) L. A. Thompson, F. L. Moore, Y.-C. Moon, J. A. Eiiman, J. Org. Chem. 1998, 63, 2066-2067; b) D. R. Dragoii, L. A. Thompson, J. O'Brien, J. A. Eiiman, J. Comb. Chem. 1999, 1, 534-539.

25 a) K. C. Nicoiaou, N. Winssinger, J. Pastor, S. Ninkovic, F. Sarabia Y. He, D. Vourioumis, Z. Yang, T. Li, P. Giannakakou, E. Hamei, Nature 1997, 387, 268-272; b) K. C. Nicoiaou, D. Vourioumis, T. Li, J. Pastor, N. Winssinger, Y. He, S. Ninkovic, F. Sarabia, H. Vallberg, F. Roschangar, N. P. King, M. R. V. Finiay, P. Giannakakou, P. Verdier-Pinard, E. Hamei, Angew. Chem. Int. Ed. Engl. 1997, 36, 2097-2103.

26 For a review, see: a) K. C. Nicoiaou, F. Roschangar, D. Vourioumis, Angew. Chem. Int. Ed. 1998, 37, 20142045.

27 For a review, see: J. H. van Maarseveen, Comb. Chem. High Throughput Screening 1998, 1, 185-214.

28 K. C. Nicoiaou, N. Winssinger, J. Pastor, F. Murphy, Angew. Chem. Int. Ed. 1998, 37, 2534-2537.

29 K. Kalivretenos, J. K. Stille, L. S. Hegedus, J. Org. Chem. 1991, 56, 2883-2894.

30 K. C. Nicoiaou, J. Pastor, N. Winssinger, F. Murphy, J. Am. Chem. Soc. 1998, 120, 5132-5133.

31 T. Doi, I. Hijikuro, T. Takahashi, J. Am. Chem. Soc. 1999, 121, 67496750.

32 C. W. Lindsley, L. K. Chan, B. C. Goess, R. Joseph, M. D. Shair, J. Am. Chem. Soc. 2000, 122, 422-423.

33 O. L. Chapman, M. R. Engel, J. P. Springer, J. C. Ciardy, J. Am. Chem. Soc. 1971, 93, 6696.

34 S. L. Schreiber, Bioorg. Med. Chem. 1998, 6, 1127-1152.

35 a) G. R. Lenz, H. M. Nash, S. Jindal, Drug Discovery Today 2000, 5, 145156; b) E. S. Razvi, L. J. Leytes, Mod. Drug Discovery 2000, 41-42; c) J. Rosamond, A. Allsop, Science 2000, 287, 1973-1976; d) M. D. Garrett, P. Workman, Eur. J. Cancer 1999, 35, 2010-2030; e) C. E. Barry, R. A. Siayden, A. E. Sampson, R. E. Lee, Biochem. Pharmacol. 1999, 59, 221231.

36 D. S. TAN, M. A. FOLEY, B. R. Stockwell, M. D. Shair, S. L. Schreiber, J. Am. Chem. Soc. 1999,

121, 9073-9087.

37 D. Lee, J. K. Sello, S. L. Schreiber, J. Am. Chem. Soc. 1999, 121, 1064810649.

38 D. Lee, J. K. Sello, S. L. Schreiber, Org. Lett. 2000, 2, 709-712.

39 D. R. Spring, S. Krishnan, S. L. Schreiber, J. Am. Chem. Soc. 2000,

122, 5656-5657.

G.-Q. Cao, A. J. Roecker, S. Barluenga, H. J. Mitchell, J. Am. Chem. Soc. in press.

H. J. Mitchell, A. J. Roecker, S. Barluenga, G.-Q. Cao, R. L. Affleck, J. E. Lillig, J. Am. Chem. Soc. in press.

42 K. C. Nicoiaou, J. A. Pfefferkorn, S. Barluenga, H. J. Mitchell, A. J. Roecker, G.-Q. Cao, J. Am. Chem. Soc. in press.

43 B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPardo, R. M. Freidinger, W. L. Whitter, G. F. Lundell, D. F. Veber, P. S. Anderson, R. S. L.

Chang, V. J. LotTi, D. J. Cerino, T. B. Chen, P. J. Kling, K. A. Kunkel, J. P. Springer, J. HirshFieid, J. Med. Chem. 1988, 31, 2235-2246.

44 a) K. C. NicoiAou, J. A. Pfefferkorn, G.-Q. Cao, Angew. Chem. Int. Ed. 2000, 39, 734-739; b) K. C. NicoiAou, G.-Q. Cao, J. A. Pfefferkorn, Angew. Chem. Int. Ed. 2000, 39, 739-743.

45 K. C. NicoiAou, A. J. Roecker, J. A. Pfefferkorn, G.-Q. CAo, J. Am. Chem. Soc. 2000, 122, 2966-2967.

46 a) K. C. NicoiAou, J. A. Pfefferkorn, G.-Q. Cao, S. Kim, J. Kessabi, Org. Lett. 1999, 5, 807-810; b) K. C. NicoiAou, J. A. Pfefferkorn,

S. Kim, H. X. Wei, J. Am. Chem. Soc. 1999, 121, 4724-4725.

47 X.-Y. Xiao, C. Zhoa, H. Potash, M. P. Nova, Angew. Chem. Int. Ed. Engl. 1997, 36, 780-782.

48 K. C. NicoiAou, J. A. Pfefferkorn, F. Schuler, A. J. Roecker, G.-Q. Cao, J. E. Casida, J. Chem. Biol. in press.

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