Chemistry and Biology of Mycotoxins and Related Fungal Metabolites

The convergent stereocontrolled, asymmetric total synthesis of (+)-paraherquamide B is described. Key features of this synthesis include (1) an improved procedure to effect reduction of unprotected oxindoles to indoles; (2) a complex application of the Somei/Kametani coupling reaction; (3) a high-yielding and entirely stereocontrolled intramolecular SN2‘ cyclization reaction that constructs the core bicyclo[2.2.2] ring system; (4) a mild Pd(II)-mediated cyclization reaction that constructs a complex tetrahydrocarbazole; and (5) the chemoselective reduction of a highly hindered tertiary lactam in the presence of an unhindered secondary lactam, utilizing precoordination of the more reactive secondary lactam to triethylaluminum.

Stereocontrolled Total Synthesis of (+)-Paraherquamide B⊥

As a commercial antibiotic, bicyclomycin (BCM) is currently the only known natural product targeting the transcription termination factor rho. It belongs to a family of highly functionalized diketopiperazine (DKP) alkaloids and bears a unique O-bridged bicyclo[4.2.2]piperazinedione ring system, a C1 triol, and terminal exo-methylene groups. We have identified and characterized the BCM biosynthetic pathway by heterologous biotransformations, in vitro biochemical assays, and one-pot enzymatic synthesis. A tRNA-dependent cyclodipeptide synthase guides the heterodimerization of leucine and isoleucine to afford the DKP precursor; subsequently, six redox enzymes, including five α-ketoglutarate/Fe2+ -dependent dioxygenases and one cytochrome P450 monooxygenase, regio- and stereoselectively install four hydroxy groups (primary, secondary, and two tertiary), an exo-methylene moiety, and a medium-sized bridged ring through the functionalization of eight unactivated C-H bonds.

A Six-Oxidase Cascade for Tandem C-H Bond Activation Revealed by Reconstitution of Bicyclomycin Biosynthesis.

A new chiral auxiliary (3S)-N,N′-bis(p-methoxybenzyl)-3-isopropylpiperazine-2,5-dione 7 has been developed for the asymmetric synthesis of α-amino acids. The auxiliary 7 employs a novel chiral relay network based on non-stereogenic N-benzyl protecting groups which enhance the diastereoselectivity observed during alkylation of its C6 enolate 25.

A chiral relay auxiliary for the synthesis of homochiral α-amino acids

Chiral relay auxiliary for the synthesis of enantiomerically pure α-amino acids

Bridgehead carbanion generation of bicyclo[5.2.2] and bicyclo[7.2.2] allyl ether bridged piperazinediones result in novel ring contractions via unusual [2,3] Wittig type and [3,3] Claisen rearrangements. The application of the [2,3] Wittig rearrangements to the construction of 2-desoxy-2-methylenebicyclomycin (3) is described. Introduction Bicyclomycin (1) is a commercially significant antimicrobial natural product' that has been the subject of numerous synthetic: mechanistic,j and biological4 studies. Maag and associatesS (1) For a review, see: Williams, R. M.: Durham, C. A. Chem. Reo. 1988, 88, 511 . (2) (a) Dunkerton, K. V.; Ahmed, R. M. Tetrahedron Lett. 1980,21, 1803. (b) Nakatsuka, S.: Yoshida, K.; Goto, T. Tetrahedron Left. 1981,22, 2009. (c) Williams, R. M. Tetrahedron Left. 1981, 22, 2341. (d) Shin, C.: Sato, Y.: Yoshimura, J. Tetruhedron Lett. 1981, 22, 2401. (e) Nakatsuka, S.: Yoshida, K.: Goto, T. Tetrahedron Lett. 1981, 22,4973. (f) Fukuyama, T.; Robins, B. D.; Sachleben, R. A. Tefrahedron Lett. 1981,22,4155. (g) Hoare, J . H.: Yates, P. J . Chem. SOC., Chem. Commun. 1981, 126. (h) Yates, P.: Hoare, J . H. Can. J . Chem. 1983, 61, 519. (i) [bid. 1983, 61, 1397. 6 ) Dirlam, J. P.: James, R. B.; Shoop, E. V., 185th National Meeting of the American Chemical Society, Seattle, WA, March 1983. Division of Organic Chemistry Abstr. 009. (k) Williams, R. M.: Anderson, 0. P.; Armstrong, R. W.: Josey, J.: Meyers, H.: Ericksson, C. J. Am. Chem. Soc. 1982,104,6092. ( I ) Williams, R. M.; Dung, J-S.; Josey, J.: Armstrong, R. W.: Meyers, H. J . Am. Chem. Soc. 1983,105,3214. (m) Sera, A.: Itoh, K.: Yamada, H.; Aoki, R. Heferocycles 1984, 22,713. (n) Sato, Y.: Shin, C.: Sumiya, S.: Nakajima, Y.; Yoshimura. J . Bull. Chem. SOC. Jpn. 1984, 57, 1265. ( 0 ) Shin, C.: Nakajima, Y.; Sato, Y. Heferocycles 1985, 23, 2217. (p) Walker, F. J. Ph.D. Thesis, Yale University, New Haven, CT, 1981. (9) Uang, B-J. Ph.D. Thesis, Yale University, New Haven, CT, 1986. (r) Dung, J-S.: Armstrong, R. W.: Williams, R. M. J . Org. Chem. 1984,49, 3416. (s) Maruyama-Kirms, L. K.: Williams, R. M. J . Org. Chem. 1987,52,4044. See also: Maruyama-Kirms, L. K. Ph.D. Thesis, Colorado State University, Fort Collins, CO, 1987. (t) Williams, R. M.: Kwast, A. J . Org. Chem. 1988,53, 5785. (u) Nakatsuka. S.: Yamada. K.; Yoshida, K.: Asano, 0.: Murakami, Y.: Goto, T. Tefrahedron Left. 1983,24, 5627. (v) Nakatsuka, S.: Goto, T. Heterocycles 1984, 21,61. (w) Nakatsuka, S. Pharmacia 1985, 21, 324. (x) Williams, R. M.; Armstrong, R. W.; Dung, J-S. J . Am. Chem. Soc. 1984, 106,5748. (y) Williams, R. M.; Armstrong, R. W.: Dung, J-S. J . Am. Chem. SOC. 1985, 107, 3253. (z) Williams, R. M.; Armstrong, R. W.: Maruyama, L. K.; Dung, J-S.; Anderson, 0. P. J . Am. Chem. SOC. 1985, 107, 3246. Wacker, 0.; Kump, W.: Muller, B. W. Tefrahedron Left. 1983,24,5607. (aa) Armstrong, R. W. Ph.D. Thesis, Colorado State University, Fort Collins, CO, 1984. (bb) Yamaura, M.: Suzuki, T.; Hashimoto, H.: Yoshimura, J.; Shin, C. Chem. Lett. 1984, 1547. (cc) Yoshimura, J.; Yamaura, M.: Suzuki, T.; Hashimoto, H. Chem. LPtl. 1984, 2157. (dd) Yamaura, M.; Suzuki, T.; Hashimoto, H.: Yoshimura, J.: Shin, C. Bull. Chem. Soc. Jpn. 1985,58, 2812. (ee) Yamaura, M.: Nakayama, T.; Hashimoto, H.: Shin, C.: Yoshimura, J.: Kodama, H. J. Org. Chem. 1988,53,6035. (ff) Dung, J-S.: Armstrong, R. W.; Anderson, 0. P.; Williams, R. M. J . Org. Chem. 1983, 48, 3592. (gg) Yoshimura, J.; Hara, K.; Yamura, M.: Mikami, K.: Hashimoto, H. Bull. Chem. SOC. Jpn. 1982.55,933. (hh) Dawson, 1. M.; Gregory, J. A.: Herbert, R. B.: Sammes, P. G. J . Chem. Soc.. Chem. Commun. 1986, 620.(3) (a) Someya, A.: Iseki, M.: Tanaka, N. J . Anfibiof. 1979,32,402. (b) Williams, R. M.; Tomizawa, K.: Armstrong, R. W.; Dung, J-S. J . Am. Chem. SOC. 1985, 107, 6419. (c) Williams, R. M.: Tomizawa, K.: Armstrong, R. W.: Dung, J-S. J. Am. Chem. Soe. 1987, 109,4028. (d) Kohn, H.; Abuzar, S. J. Am. Chem. SOC. 1988, 110, 3661. (e) Abuzar, S.: Kohn, H. J. Am. Chem. SOC. 1988, 110,4089. (0 Abuzar, S.; Kohn, H. J. Org. Chem. 1989, 54, 4000. (8) Kohn, H.; Abuzar, S. J . Org. Chem. 1988, 53, 2769. (h) Abuzar, S.: Kohn. H. J. Am. Chem. Soc. 1990, 112, 3114. (4) (a) Tanaka, N.: Iseki, M.: Miyoshi, T.: Aoki. H.: Imanaka, H. J. Antibiot. 1976, 29, 155. (b) Tokuma, Y.; Koda, S.: Miyoshi, T.: Morimoto, Y. Bull. Chem. SOC. Jpn. 1974,47, 18. (c) Miyoshi, T.: Iseki, M.: Konomi, T.: Imanaka, H. J. Anfiblot. 1980, 33, 480. (d) Iseki, M.: Miyoshi, T.: Konomi, T.; Imanaka, H. J . Antibiof. 1980. 33,488. (e) &hi, K.: Tsurumi, Y.: Shigematsu, N.: Iwami, M.; Umehara, K.; Okuhara, M. J . Antibiot. 1988, 41, 1106. (0 Someya, A.; Tanaka, K.: Tonaka, N. Antimicrob. Agents Chemother. 1979, 16,87. (g) Someya, A,: Iseki, M.: Tanaka, N. J . Antibiot. 1978, 31, 712. (h) Muller, B. W.: Zak, 0.: Kump, W.; Tosch, W.; Wacker, 0. J . Anfibiof. 1979, 32, 689. 0002-7863/91/1513-6621%02.50/0 demonstrated over 10 years ago that bicyclomycin undergoes a thermodynamically driven bis-spiro ring-forming dehydration to the tricyclic substances 2. The significance of the putative (leucyland isoleucyl-derived) amino acid oxidation states a t the a-positions (both carrying oxygenation) has been the subject of several provocative studies3v6 and remains an unresolved issue requiring further experimental clarification.

Novel ring contractions via [2,3] Wittig type rearrangements: synthesis of 2-desoxy-2-methylenebicyclomycin

Synthese a partir d'acide N-Z pipecolique et de phenylalaminate de methyle via la reduction du cycle piperazinedione-2,5 en alcoxy piperazinone

Mark R. Sabol

Papers

Novel ring contractions via [2,3] Wittig type rearrangements: synthesis of 2-desoxy-2-methylenebicyclomycin

Synthesis of Verruculotoxin

Novel Ring Contractions via (2,3) Wittig Type Rearrangements: Synthesis of 2-Desoxy-2-methylenebicyclomycin.