2702 J. Org. Chem. 2010, 75, 2702–2705 Published on Web 03/22/2010 DOI: 10.1021/jo100400z r 2010 American Chemical Society pubs.acs.org/joc Total Synthesis of Proposed Auranthine Umesh A. Kshirsagar, † Vedavati G. Puranik, ‡ and Narshinha P. Argade* ,† † Division of Organic Chemistry and ‡ Centre for Material Characterization, National Chemical Laboratory (CSIR), Pune 411 008, India np.argade@ncl.res.in Received December 18, 2009 Starting from CBz-protected glutamic anhydride and Boc-protected o-aminobenzyl amine, the first total synthe- sis of proposed structure of auranthine has been reported. An intramolecular aza-Wittig reaction involving a lactam carbonyl group that delivered the diazepine core unit was the key step in the synthesis. Quinazolinone is a building block for a large number of structurally diverse alkaloids boasting a wide range of biological activities, several of which are now in clinical use. 1 In the course of isolating nephrotoxins, a new fungal metabolite, (-)-auranthine, was isolated from Penicillium aurantiogriseum but the configuration at the asymmetric center was not determined. 2 Structurally, auranthine bears a close resemblance to the novel microbial metabolite (-)- asperlicin, a potent neuropeptide antagonist 3 (Figure 1). A look at the structure of auranthine reveals that (-)-glutamic acid and anthranilamide could be potential building blocks for constructing this structurally intriguing alkaloid. How- ever, studies on the total synthesis of 1 by Bergman and co- workers indicate that the instability of the potential inter- mediate 2 and the presence of an active methylene group in the product were the major impediments in accessing it. 4 Auranthine is a structurally unique quinazoline alkaloid that contains an unusually positioned diazepine moiety, a feature that has largely rendered its total synthesis a challenge to date. 5 On the basis of our continuing interest in the chemistry of cyclic anhydrides and their applications in natural product synthesis, 6 we herein report a facile synthesis of the target compound (Scheme 1). Starting the synthesis of auranthine (1) from CBz-pro- tected (S)-glutamic anhydride 4, we could foresee that our major challenges would lie in the following: (i) regioselective nucleophilic ring-opening of the unsymmetrical anhydride 4 with an aromatic amine, (ii) intramolecular cyclization reac- tion involving the lactam carbonyl using an aromatic amine/ azide that would deliver the diazepine ring system, and (iii) the smooth pool of enantiomeric purity throughout the synthesis. As per the literature reports, 7 the nucleophilic regioselective ring-opening of an anhydride 4 in DMSO with the amine 3 exclusively furnished the expected anilic acid 5 in 92% yield. Carrying out the reaction in a polar solvent such as DMSO brings about intermolecular hydrogen bonding of the hydrogen atom on an amide nitrogen with the solvent, rather than the five-membered intramolecular hydrogen bonding with an adjacent carbonyl group of anhydride 4. The incoming nucleophile, the primary aromatic amine, thus exclusively attacks on an unhindered carbonyl group of anhydride 4 to form the product 5. Diazomethane esterifica- tion of anilic acid 5 provided the methyl ester 6 in 97% yield. Cleaving the Boc-protection in 6 resulted in instantaneous intramolcular dehydrative cyclization to 7, which upon an FIGURE 1. Auranthine, (-)-asperlicin, and unstable imide inter- mediate. (1) (a) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009, 48, 348 and references cited therein. (b) Roy, A. D.; Subramanian, A.; Roy, R. J. Org. Chem. 2006, 71, 382 and references cited therein. (c) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787 and references cited therein. (2) Yeulet, S. E.; Mantle, P. G.; Bilton, J. N.; Rzepa, H. S.; Sheppard, R. N. J. Chem. Soc., Perkin Trans. 1 1986, 1891. (3) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc. 1998, 120, 6417. (4) Witt, A.; Gustavsson, A.; Bergman, J. J. Heterocycl. 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