C N O C A B N A B C O O D N A B O O D C PhCH CHCOCl N Ar CO2Et CO2Et Ph O N Ph O Ar CO2H N Ph O Ar COCHN2 N Ph O ArNHCH(CO2Et)2 Ar 2 3a,b CO2Me N Ph O 4a,b KOH (2 equiv.) i, SOCl2, benzene Ar Et3N, benzene reflux CO2H EtOH–H2O/reflux ii, CH2N2, ether–CH2Cl2 5a,b 6a,b N O O H H Ar reflux Ag2O, MeOH 7a,b KOH, EtOH–H2O reflux PPA, 100 °C a Ar = p-chlorophenyl b Ar = m-nitrophenyl 8 1a,b + COCl N CO2Et CO2Et Ar O N HO2C O Ar N O Ar N2HC N O Ar MeO2C ArNHCH(CO2Et)2 Et3N, benzene reflux i, SOCl2 N O Ar 11a,b 9 10a,b HO2C 12a,b ii, CH2N2 13a,b 14a,b N O Ar Ag2O, MeOH 2 KOH, acetone–H2O reflux H H KOH, EtOH O reflux reflux 15a,b PPA O 100 °C 1a,b + 80 J.CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 80–81 J. Chem. Research (M), 1997, 0568–0583 Studies on g-Lactams: Synthesis of some 3-Aryl- 1,3a,4,9b-tetrahydrobenzo[e]indole-2,5-dione Derivatives and its Implication in the Total Synthesis of Functionalized 17-Azasteroids Gandhi K. Kar, Dandala Ramesh, Basanta G.Chatterjee and Jayanta K. Ray* Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India The g-lactam esters 3 and 10, prepared from anilinomalonates and 3-arylacryloyl chloride, are hydrolysed and selectively decarboxylated to the trans-acids 4 and 11; further homologation and cyclization produce the tri- and tetra-cyclic g-lactam derivatives 8 and 15 that simulate the B-C-D/A-B-C-D ring system of many azasteroids. g-Lactam moieties, fused to carbocyclic rings, are common in bioactive natural products1,2 and consequently many synthetic strategies have been recorded.3–6 We report here a novel sequence of reactions that synthesise g-lactams with appropriate functionalities for further elaboration and thus construction of azasteroids (Schemes 1 and 2).Our strategy involved the construction of the g-lactam moiety first, the starting materials already having rings B/A+B, followed by the construction of the ring C in the final stage to achieve model and target 17-azasteroids (Fig. 1). Thus condensation of arylaminomalonates 1 with b-arylacryloyl chlorides 2 in the presence of triethylamine extensively produced the g-lactam diesters 3 in good yields (Scheme 1). Saponification with in situ decarboxylation of 3 with alcoholic KOH (2 equiv.) under reflux exclusively produced the trans-acid 4 in excellent yield. The structure was confirmed by spectral data (IR, NMR, MS) and elemental analysis. The trans-geometry was assigned by the coupling constants of 4-H and 5-H (J ca. 4–5 Hz). Annulation of the CO2H side chain was achieved by the Arndt–Eistert method. Thus the g-lactam monoacid 4 was converted into the acid chloride with SOCl2 and subsequent treatment of the acid chloride with diazomethane gave the diazoketone 5 in excellent yield. The *To receive any correspondence. Fig. 1 Scheme 1 Scheme 2J. CHEM. RESEARCH (S), 1997 81 diazoketone when refluxed with Ag2O in MeOH produced the g-lactam ester 6 in 50–70% yield.Trans-stereochemistry of the 4-H and 5-H was proved by X-ray crystallography15 of 6a. Alkaline hydrolysis of the ester 6 gave the acid 7 (78–82%) which when cyclised with PPA (at 100 °C) produced the B-C-D ring simulating an azasteroid, i.e. 3-aryl- 1,3a,4,9b-tetrahydrobenzo[e]indole-2,5-dione in moderate to good yield. Following a similar reaction sequence and starting from an anilinomalonate derivative and 2-(2-naphthyl)acryloyl chloride 9 the high yielding total synthesis of the functionalized 17-azasteroid was achieved (Scheme 2).Anilinomalonates 1 on reaction with 9 in the presence of Et3N produced the g-lactam ester 10 in excellent yields. Compound 10 on hydrolysis (aq. acetone/KOH, 2 equiv., reflux), with decarboxylation followed by homologation of the CO2H sidechain by the Arndt–Eistert method produced 13 in high overall yields. Saponification (KOH/EtOH–H2O, reflux) of 13 afforded the acid 14 which when subjected to cyclization with PPA at 100 °C afforded the 17-azasteroid derivatives 15 in 59–63% yield in the final step of the reaction.The spectroscopic data as well as elemental analysis of the compounds gave satisfactory results. We are grateful to Dr A. K. Patra (University of Calcutta, India), Dr M. Ghosh (Stevens Institute of Technology, USA) and Dr E. Ali (IICB, Calcutta, India) for 1H and 13C NMR and mass spectral data. Thanks are due to DST and CSIR, New Delhi, for financial support. Techniques used: IR, 1H and 13C NMR, MS, elemental analysis Figures: 7 References: 15 Received, 24th April 1996; Accepted, 2nd December 1996 Paper E/6/02882I References cited in this synopsis 1 J. E. Baldwin, G. P. Lynch and J. Pitlik, J. Antibiot., 1991, 44, 1. 2 L. N. Jungheim and R. J. Ternansky, in The Chemistry of b-Lactams, ed. M. I. Page, Blackie, London, 1992, pp. 306– 324. 3 J. E. Baldwin, R. M. Adlington, R. H. Jones, C. J. Schofield, C. Zarocostas and W. C. Greengrass, J. Chem. Soc., Chem. Commun., 1984, 194. 4 J. E. Baldwin, R. T. Freeman and C. J. Schofield, Tetrahedron Lett., 1989, 30, 4011. 5 J. E. Baldwin, C. Lowe and C. J. Schofield, Tetrahedron Lett., 1986, 27, 3461. 6 J. E. Baldwin, M. F. Chan, G. Gallacher, M. Otsuka, P. Monk and K. Prout, Tetrahedron, 1984, 21, 4513. 15 G. K. Kar, B. G. Chatterjee and J. K. Ray, Synth. Commun., 1993, 23, 1953.