N O R1 OR2 R3 O H CMe2, R3 = H 1 H CMe2, R3 = Me R1 = H, R2 = Me, R3 = Me R1 = H, R2 = SiMe2But, R3 = H R1 = H, R2 = CH2Ph, R3 = Me R1 = H, R2 = CH2C R1 = H, R2 = THP, R3 = H R1 = H, R2 = THP, R3 = Me R1 = H, R2 = THP, R3 = CH2OAc R1 = OMe, R2 = Me, R3 = Me R1 = H, R2 = CH2C R1 = H, R2 = H, R3 = CH2OAc R1 = H, R2 = H, R3 = Me R1 = H, R2 = CH2Ph, R3 = H R1 = H, R2 = H, R3 = H R1 = OMe, R2 = Me, R3 = H R1 = H, R2 = Me, R3 = H a b c d e f g h i j k l m n o NH OH R3 O OR2 R1 N O OMe 2 O OH OH Me R1 = OMe, R2 = Me, R3 = H R1 = H, R2 = Me, R3 = H R1 = H, R2 = CH2Ph, R3 = H R1 = H, R2 = H, R3 = H R1 = H, R2 = Me, R3 = CH2Ph 3 a b c d e 184 J.CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 184–185 J. Chem. Research (M), 1997, 1201–1215 Synthesis of Pyrano[3,2-c]quinolin-5-one Alkaloids: Veprisine, 7-Dimethylallyloxy-N-methylflindersine and cis- 3,4-Dihydroxy-7-methoxy-2,2,6-trimethyl-3,4,5,6-tetrahydro- 2H-pyrano[3,2-c]quinolin-5-one William H. Watters and Venkataraman N.Ramachandran* School of Applied Biological and Chemical Sciences, University of Ulster at Coleraine, Cromore Road, Coleraine, Northern Ireland BT52 1SA, UK Condensation of the appropriate 4-hydroxyquinolin-2-ones with 3-methylbut-2-enal gave pyrano[3,2-c]quinolin-5-ones which were further elaborated to the three alkaloids named in the title. Veprisine (1a), 7-dimethylallyloxy-N-methylflindersine (1b), 7-hydroxy-N-acetyloxymethylflindersine (1c) and the cis-diol of 7-methoxyflindersine (3) are examples of pyrano[3,2- c]quinolin-5-ones which have been isolated in recent years from plant species of the Rutaceae family.1–4 Most of the viable syntheses of these alkaloids involve the cyclisation of the corresponding 3-prenyl-4-hydroxyquinolin-2-ones. We now report the successful synthesis of the pyrano[3,2- c]quinolin-5-one alkaloids named in the title from the 4-hydroxyquinolin-2-ones 2 and 3-methylbut-2-enal by utilisation of the method of De Groot and Jansen7 for the formation of 2H-pyrans by one-step condensation of an a,b-unsaturated aldehyde with 1,3-diketones.The two starting 8-methoxy- and 7,8-dimethoxy-4-hydroxyquinolin- 2-ones (2b and 2a respectively) were prepared by the condensation of the corresponding aromatic amines and malonic acid in the presence of phosphorus oxychloride.8 The 8-benzyloxy-4-hydroxyquinolin-2-one (2c) could not be prepared this way since the acidic reaction conditions would result in the removal of the benzyl group.The alternative method to prepare 8-benzyloxy-4-hydroxyquinolin-2-one by the condensation of 2-benzyloxyaniline with diethyl malonate was unsuccessful. The modified scheme involved the synthesis of 7-hydroxy- flindersine (1f) which could be prepared by the condensation of 3-methylbut-2-enal with 4,8-dihydroxyquinolin-2-one (2d). Demethylation of 8-methoxy-4-hydroxyquinolin-2-one (2b) to 2d was unsuccessful. Synthesis of 2d was finally achieved by the aluminium chloride demethylation and debenzylation of 8-methoxy-3-benzyl-4-hydroxyquinolin-2-one (2e).9 Condensation of quinolin-2-ones 2a, 2b and 2d with 3-methylbut-2-enal in refluxing pyridine in the presence of anhydrous magnesium sulfate gave the desired pyrano[3,2- c]quinolin-5-ones 1g, 1h and 1f in yields ranging from 44 to 69%.N-Methylation of 7,8-dimethoxyflindersine (1g) using NaH–MeI gave veprisine (1a) in 90% yield. This synthesis is the most efficient to date with an overall yield of 51% for the three-step synthesis.The spectral data obtained for 1a corresponded to literature values.1 The cis-diol 3 was synthesised by the osmium tetroxide oxidation of 7-methoxy-N-methylflindersine (1i), formed by the methylation of 7-methoxyflindersine (1h). The spectral data obtained corresponded to the structure 3 for the oxidation product. No literature data are available in order to make a comparison. Since the synthesis of 7-dimethylallyloxy-N-methylflindersine (1b) from 7-hydroxyflindersine (1f) would involve Oalkylation and N-methylation and methylation by most conditions would result in a dimethylated product, protection of the hydroxy group is necessary prior to N-methylation.The first-choice protecting group was the tert-butyldimethylsilyl group and under normal silylating conditions 1f gave 7-tertbutyldimethylsilyloxyflindersine (1j) in 42% yield. N-Methylation with LDA and MeI was unsuccessful and methylation under more basic conditions resulted in desilylation giving 1f as the major product.The benzyl group was the second-choice protecting group and 7-benzyloxyflindersine (1e) was prepared in a modest 20% yield with NaOEt–PhCH2Cl. N-Methylation of 1e with NaH–MeI yielded 7-benzyloxy-N-methyflindersine (1k) but *To receive any correspondence. Fig. 1 Fig. 2J. CHEM. RESEARCH (S), 1997 185 deprotection by triphenylmethyl fluoroborate could not be achieved.At this stage it was decided that direct dimethylallylation might yield a reasonable amount of the O-allylated derivative which could then be N-methylated to give 1b. Treatment of 1f with 1-bromo-3-methylbut-2-ene in the presence of sodium methoxide gave 7-dimethylallyloxyflindersine (1l) in very low yield which was N-methylated to 1b. Spectral data confirmed the formation of 1l and 1b. Since the overall yield for the synthesis of 1b by the above method was very poor, it was decided to look for another protecting group for the hydroxy function and the tetrahydropyranyl group was an obvious choice.Tetrahydropyranylation of 1f with dihydropyran and toluene-p-sulfonic acid was achieved in 59% yield. 7-Tetrahydropyranyloxyflindersine (1m) was N-methylated nearly quantitatively to 7-tetrahydropyranyloxy- N-methylflindersine (1n). Deprotection of 1n was achieved by stirring in a 5% solution of methanolic hydrochloric acid to yield 7-hydroxy-N-methylflindersine (1d). 1b was finally prepared by reaction of 1d with 1-bromo- 3-methylbut-2-ene and anhydrous K2CO3 in dry acetone. All the structures for the intermediates and the final product were established by mass spectroscopy and 1H NMR. The spectral data were in complete agreement with literature values reported for the natural product.2 Synthesis of 7-hydroxy-N-acetyloxymethylflindersine (1c) could not be achieved since N-alkylation of 1m with chloromethyl acetate under a number of different conditions was unsuccessful. Techniques used: 1H NMR, IR, MS References: 10 Figures: 2 Received, 2nd December 1996; Accepted, 19th February 1997 Paper E/6/08110J References cited in this synopsis 1 J. F. Ayafor, B. L. Sondengam and B. T. Ngadjui, Phytochemistry, 1982, 21, 2733. 2 S. A. Khalid and P. G. Waterman, J. Nat. Prod., 1977, 45, 343. 3 F. R. Stermitz and I. A. Sharifi, Phytochemistry, 1977, 16, 2003. 4 A. I. Gray and J. J. O’Sullivan, unpublished data cited by I. Mester in Chemistry and Chemical Taxonomy of the Rutales, ed. P. G. Waterman and M. F. Grundon, Academic Press, London, 1983, p. 31. 7 A. De Groot and B. J. M. Jansen, Tetrahedron Lett., 1975, 3407. 8 T. Kappe and E. Ziegler, Tetrahedron Lett., 1968, 1947. 9 T. H. Kappe, H. Schmidt and E. Ziegler, Z. Naturforsch., Teil B, 1970, 25, 328.