Extension of the Tandem Conjugate Addition-Dieckmann Condensation: The Formal Synthesis of Tetracenomycin A2 Denis V. Kozhinov and Victor Behar* Department of Chemistry MS-60, Rice University, Houston, Texas 77251-1892
[email protected] Received September 11, 2003
Abstract: Tandem cuprate addition-Dieckmann condensation is featured in the construction of the polyketide metabolite tetracenomycin A2 (2). Thus, cyclization substrate 11 was treated with Gilman cuprate Me2CuLi to afford anthracene 12. The phenolic acetate protecting group of 12 ensured its chemoselective oxidation to reveal terminal quinone 13, which intercepts the previously reported synthesis of tetracenomycin A2 (2).
Previously we reported a tandem conjugate additionDieckmann condensation strategy as a viable entry to the ABCD-ring system of lactonamycin 1.1 (Figure 1) The cyanide initiator for the tandem reaction served as a handle to install the A-ring lactam later in the synthesis of this system. Recognizing the utility of such a sequence to address a wide array of structurally diverse type II polyketide frameworks, we sought to demonstrate some generality to this type of synthetic approach. With this in mind, we targeted the metabolite tetracenomycin A2 (2). Tetracenomycin A2 (2) was first isolated in 1979 from Streptomyces glaucescens along with related metabolites collectively referred to as the tetracenomycins.2,3 (Figure 2) It is now generally accepted that tetracenomycin A2 is the biosynthetic precursor (converted by dioxygenase enzyme pathways)4,6 to the potent antibiotic tetracenomycin C isolated by Zeeck and co-workers in the same strain. Structural similarity between tetracenomycin C (3) and elloramycin (4) suggest similar biosynthetic origins.3-5 Tetracenomycin C was shown to have significant antitumor activity and cytotoxicity.7 The goals of this synthetic endeavor included streamlining of the chemistry used in the assembly of the cyclization substrate and demonstration of access to the tetracenomycin class of compounds8,9 by use of a cuprate initiator in the tandem sequence. These results are reported herein. A universal substrate for the construction of both lactonamycin and the tetracenomycin family of com* Corresponding author. (1) Deville, J. P.; Behar, V. Org. Lett. 2002, 4, 1403-1405. (2) Shen, B.; Nakayama, H.; Hutchinson, C. R. J. Nat. Prod. 1993, 56, 1288-1293. Egert, E.; Noltemeyer, M.; Siebers, J.; Rohr, J.; Zeeck, A. J. Antibiot. 1992, 45, 1190-1192. (3) Drautz, H.; Reuschenbach, P.; Zahner, H.; Rohr, J.; Zeeck, A. J. Antibiot. 1985, 38, 1291-1301. (4) Anderson, M. G.; Khoo, C. L. Y.; Rickards, R. W. J. Antibiot. 1989, 42, 640-643. (5) Decker, H.; Rohr, J.; Motamedi, H.; Za¨hner, H.; Hutchinson, C. R. Gene 1995, 166, 121-126. (6) Shen, B.; Hutchinson, C. R. J. Biol. Chem. 1994, 269, 3072630733. Udvarnoki, G.; Wagner, C.; Machinek, R.; Rohr, J. Angew. Chem., Int. Ed. Engl. 1995, 34, 565-567. Rafanan, E. R., Jr.; Hutchinson, C. R.; Shen, B. Org. Lett. 2000, 2, 3225-3227. Hutchinson, C. R. Chem. Rev. 1997, 97, 2525-2535. (7) Rohr, J.; Zeeck, A. J. Antibiot. 1990, 43, 1169-1178.
pounds was constructed beginning with diol 5,10 readily available through standard Stobbe chemistry. (Scheme 1) Benzylic alcohol 5 was converted to its chloride 611 and then to the homologated ester 7 by Stille carbonylation.12 Direct introduction of iodine was achieved in good yield, affording iodide 8 by treatment with iodine and morpholine in methylene chloride.13 It should be emphasized that our previous synthesis required a bromine-iodine exchange and had therefore incorporated difficult to remove methyl ether groups. This new sequence lent itself to exploring more routine phenolic blocking groups. In the event, phenol 8 was protected as is acetate 9, and this was subsequently treated with ortho ester 10 under standard Sonogashira conditions14 to give us a fully elaborated cyclization substrate 11 after workup with tosic acid in methanol. This five-step sequence is both shorter and more flexible than the previously reported sequence for the lactonamycin system. The cyclization of alkynyl ester 11 with the simple Gilman cuprate15 worked quite well, and the intermediate phenolic product was immediately methylated16 to give anthracene 12 as shown in Scheme 2. The terminal quinone system 14 was readily unveiled by CAN oxidation and subsequent removal of the phenolic acetate with HCl in acetone.10 The success of the CAN oxidation required the presence of the electron-withdrawing acetate protecting group on the center ring phenol; otherwise, oxidation preferentially occurred at the central ring of the anthracene system.17 Quinone 14 intercepts the known synthesis of tetracenomycin A2 reported by Cameron and co-workers and could be carried on utilizing this procedure.8 Thus, Diels-Alder cycloaddition with diene 15 and subsequent treatment with HCl/MeOH in air provides the target tetracenomycin A2 in accord with this established protocol. This synthesis of tetracenomycin A2 has demonstrated a concise approach to highly oxygenated type II polyketide systems. Expansion of the array of nucleophilic initiators (8) Cameron, D. W.; De Bruyn, P. J. Tetrahedron Lett. 1992, 33, 5593-5596. (9) Cameron, D. W.; Griffiths, P. G.; Riches, A. G. Aust. J. Chem. 1999, 52, 1173-1177. (10) Bloomer, J. L.; Stagliano, K. W.; Gazzillo, J. A. J. Org. Chem. 1993, 58, 7906-7912. (11) Obata, T.; Shimo, T.; Yasutake, M.; Shinmyozu, T.; Kawaminami, M.; Yoshida, R.; Somekawa, K. Tetrahedron 2001, 57, 15311541. (12) Cowell, A.; Stille, J. K. J. Am. Chem. Soc. 1980, 102, 41934198. (13) Uno, H.; Sakamoto, K.; Honda, E.; Ono, N. Chem. Commun. 1999, 1005-1006. (14) Sakamoto, T.; Shiga, F.; Yasuhara, A.; Uchiyama, D.; Kondo, Y.; Yamanaka, H. Synthesis 1992, 746-748. (15) Paczkowski, R.; Maichle-Moessmer, C.; Maier, M. E. Org. Lett. 2000, 2, 3967-3969. (16) Keck, G. E.; Wager, T. T.; Rodriquez, J. F. D. J. Am. Chem. Soc. 1999, 121, 5176-5190. (17) The following example is typical of the chemoselectivity in attempts to reveal the terminal quinone:
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Published on Web 01/16/2004
FIGURE 1. Tandem conjugate addition-Dieckmann condensation approach.
FIGURE 2. Representative tetracenomycins. SCHEME 1.
Synthesis of the Cyclization Substratea
a Reagents and conditions: (a) Ph P, CCl , THF, 2 h (95%); (b) PdCl (Ph P) , 1 atm CO, MeOH, THF (87%); (c) I , morpholine, CH Cl , 3 4 2 3 2 2 2 2 15 min (76%); (d) Ac2O, pyr. DMAP (95%); (e) 10, PdCl2(PPh3)2, CuI, Net3, MeCN, 0 °C to rt; then TsOH, MeOH (61%).
SCHEME 2.
a
Synthesis of Tetracenomycin A2a
Reagents and conditions: (a) Me2CuLi, THF; (b) NaH, MeI, DMF (60%); (c) CAN, CH3CN (63%); (d) HCl, acetone (70%); (e) ref 5.
for the tandem conjugate addition-Dieckmann sequence should make available a wide array of potentially valuable analogues. These may be screened as substrates for the dioxygenase enzymes involved in both the tetracenomycin C and lactonamycin biosynthetic pathways, thus allowing access to biologically important natural and unnatural polyketide structures.
Acknowledgment. This work was supported in part by the Robert A. Welch Foundation (Grant C-14189) and William Marsh Rice University. Supporting Information Available: Genereal procedures and preparation of all compounds 6-14 as well as copies of 1H and 13C NMR. This material is available free of charge via the Internet at http://pubs.acs.org. JO035341K
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