One-Pot Synthesis of Simple Alkaloids: 2,3-Polymethylene-4(3<i>H</i>)-quinazolinones, Luotonin A, Tryptanthrin, and Rutaecarpine

Abstract

2,3-Trimethylene-4(3H)-quinazolinone (deoxyvasicinone, 1aa) 1) and 2,3-tetramethylene-4(3H)-quinazolinone (mackinazolinone, 1ba) 2,3) are not only the alkaloids isolated from Peganum and Mackinlaya species, respectively, but are also prepared chemically before the isolation from natural sources. [4][5][6] The establishment of a simple and efficient synthetic method for these alkaloids has long been a challenging subject. [7][8][9][10][11][12][13][14][15][16][17][18][19][20] In addition, these substances are a part of the family of intriguing alkaloids that include the bronchodilator vasicinone (2a) from Adhatoda vasica, 21) antiendotoxic isaindigotone (2b) from Isatis indigotica, 22) topoisomerase Idependent cytotoxic luotonin A (3) from Peganum nigellastrum, 23) antibiotic tryptanthrin (4) from yeast (Candida lipolytica) 24,25) and later from cannon ball tree (Cououpita guianensis), 26) anti-inflammatory rutaecarpine (5) 27) from Evodia rutaecarpa, and related alkaloids (Fig. 1). 28)Since Niementowski's preparation of 4(3H)-quinazolinone by fusing anthranilic acid with formamide, 29) several methods attempting the synthesis of modified quinazolinones have been reported. 1,[30][31][32][33] Although most of these are applicable to acyclic amides, methods for cyclic amides, especially without an aryl group, are somewhat limited. [34][35][36][37] These limitations have led to the continuous development of new procedures for cyclic amides, such as cyclocondensation of isatoic anhydride with lactams, 12) metal catalyzed reductive N-heterocyclization of N-(2-nitrobenzoyl)lactams in the presence of CO,13,14) reaction of 2-aminobenzamide with succinic anhydride, 15) intramolecular aza-Wittig reaction of N-(2-azidobenzoyl)lactams, 9,16) condensation of anthranilic acid with O-alkyllactims 6,[18][19][20] or S-alkyllactims, 8) reaction of anthranilic acid with SOCl 2 followed by cyclization with lactams, 17) cyclization of iminochlorides generated from lactam and methyl anthranilate, 11) solid-phase synthesis, 7,9) and microwave assisted synthesis.10,12) Nevertheless, the biological importance of 4(3H)-quinazolinone and related compounds still spurred the development of a new and simple synthetic method for theses compounds. [38][39][40][41][42][43] As a part of our research on biologically important natural products, we herein described a simple one-pot procedure for the preparation of 1 as well as related alkaloids 3, 4 and 5 in multi-gram quantity.Although an earlier study revealed that iminoketene (8), generated from the reaction of anthranilic acid (6) and SOCl 2 , underwent cycloaddition to cyclic iminols, which are tautomers of the corresponding lactams (9), to yield 1 in 70-82% yield, 19) we sometimes have been unable to repeat the reactions.44) Whenever we failed to generate the desired products, imine compounds (10) were isolated as major products (Chart 1). Although we could convert these imines (10) to the desired 2,3-tri-and 2,3-tetramethylene-4(3H)-quinazolinones by employing polyphosphoric acid-catalyzed deh...

Synthesis and Biological Properties of Benzo-Annulated Rutaecarpines

“…Among a variety of synthetic methods for rutaecarpine, [16][17][18][19][20]24) the Fischer indole synthesis from the corresponding hydrazone of 6,7,8,9-tetrahydropyrido[2,1-b]quinazoline-6,11-dione (1) 24) and phenylhydrazine (2a) has been used as a simple and practical method and employed for preparing derivatives of rutaecarpines on ring E. 25) Benzo-annulation on ring E can, thus, be achieved by employing the ketone 1 and commercially available 1-and 2-hydrazinonaphthalenes.…”

“…Prerequisite starting compound 10 was, thus, prepared in 72% yield from 3-amino-2-naphthoic acid (9) and 2-piperidone in SOCl 2 by employing one-pot synthesis method for various 2,3-polymethylene-4(3H)-quinazolinones from anthranilic acid and lactams. 17) Reaction of 10 with benzaldehyde in the presence of acetic anhydride 24) or NaOAc in HOAc 36,37) afforded the corresponding benzylidene-derivative 11, which was subjected to ozonolysis and followed by reductive work up with (CH 3 ) 2 S to yield 12 in 83% yield.…”

“…15) Such a variety of intriguing biological properties have led not only to the development of synthetic methods [16][17][18][19][20] but also to the systematic examination of its metabolites. [21][22][23] Although the action mechanisms of antiinflammatory, 3) vasorelaxing, 6) antiplatelet, 8) and antiobesity 11) effect of rutaecarpine have been studied, those of cytotoxicity have not been pursued as yet.…”

“…[21][22][23] Although the action mechanisms of antiinflammatory, 3) vasorelaxing, 6) antiplatelet, 8) and antiobesity 11) effect of rutaecarpine have been studied, those of cytotoxicity have not been pursued as yet. Continuing interest in rutaecarpine 17,18,21,22,24,25) and in the effect of benzoannulation on chemical 26) and/or biological properties 27) spurred us to prepare a series of benzo-annulated rutaecarpines, especially on rings A and E, and to examine their biological properties focusing on the inhibitory activities in selected human cancer cell lines.…”

The chemistry of tryptanthrin and its derivatives

“…Recently, Jahng et al described a one-pot synthesis of tryptanthrin using anthranilic acid (15, Scheme 4) as starting material. 48 In this method 15 reacts with thionyl chloride to form a thio-analog of isatoic anhydride (16), which then condenses with isatin (13) to form tryptanthrin in excellent yield.…”