HO OTs H 9 8 vi O H 11 vii HO OH H 10 5 iv v 3 R1 = NH2; R2 = CO2H 4 R1 = OH; R2 = CO2H 5 R1 = OH; R2 = CO2Me 6 R1 = OTHP; R2 = CO2Me 7 R1 = OTHP; R2 = CH2OH 8 R1 = OTHP; R2 = CH2OTs i ii iii iv v R1 R2 H O O O O OH HO 12 D-Mannitol O O CHO 13 i O O CH OR CH3 14 R = H 15 R = OTs O O H 16 15 iv 10 v ii iii N MeO OMe OMe 17 N MeO OMe OMe 18 OH H i,ii + C5H11 OH H 26 + NH MeO OMe O 27 18 NH MeO OMe O 19 OH H iii iv 1 v,vi 2 6 J. CHEM. RESEARCH (S), 1998 J. Chem. Research (S), 1998, 6–7 J.Chem. Research (M), 1998, 0126–0142 Enantioselective Synthesis and Absolute Configuration of (R)-(+)-Lunacridine and (S)-(+)-Lunacrine Ramesh C. Anand* and N. Selvapalam Department of Chemistry, Indian Institute of Technology, Hauz Khas, New Delhi-110016, India (R)-(+)-Lunacridine 1 has been synthesised in 97.3% e.e. using a chiron approach through L-valine and D-mannitol as the starting compounds in order to corroborate its absolute configuration. The prenylated quinolinone alkaloids lunacridine and lunacrine have been isolated from Lunasia sp.1 of different sources in optically active form and given structures 1 and 2 respectively on the basis of degradative studies, spectroscopic data2 and a synthesis of the racemates (in extremely poor yield.3 An attempt was also made by Grundon and coworkers4 to assign absolute configurations to the title compounds through asymmetric synthesis in less than 1% e.e.The configurational assignments to compounds 1 and 2 were based on the assumption that (S)-peroxycamphoric acid on reaction with an olefin yields an (S)-epoxide and by comparison of the direction of specific rotation of their compound 1 with that reported for the natural product.In view of very low optical induction and magnitude of the specific rotation, [a]D 25=µ0.19 for 1, any assignment of absolute configuration to 1 and 2 needs further support to be unequivocal. Recently Barr et al.5 have used a cumbersome resolution procedure to prepare the title compounds in poor overall yield.Therefore, the present studies were planned in order to accomplish an unambiguous and highly enantioselective synthesis of 1 and 2 so as to assign absolute configurations to these compounds on firm grounds. The strategy used for the present asymmetric synthesis is based on a chiron approach wherein optically pure (S)-(+)-valine and (D)-(+)-mannitol were used as the starting compounds. The synthetic investigations carried out are delineated below.Synthesis of (S)-Epoxide 11.—(i)(S)-Valine as starting compound (Scheme 1). (ii) D-Mannitol as starting compound (Scheme 2). Transformation of 11 into Compounds 1 and 2.·First approach (Scheme 3). *To receive any correspondence. Scheme 1 Reagents and conditions: i, HNO2, 0 °C; ii, Amberlyst-15–MeOH; iii, DHP-H+; iv, LiAlH4; v, TosCl-py; vi, MeOH–H+; vii, NaOMe Scheme 2 Reagents and conditions: i, NaIO4–aq. MeCN; ii, MeMgI; iii, TosCl–py; iv, LiCuMe2; v, MeOH–H+ Scheme 3 Reagents and conditions: i, BuLi at µ78 °C; ii, 11; iii, anhyd.HCl–OEt2; iv, CH2N2; v, TosCl–py; vi, aq. NaOHO MeO2C O H 11 i O O H ii HO H MeO2C 21 20 THPO H MeO2C 22 THPO H HO2C 23 iv v iii CO2Me NH O MeO H OTHP 24 NH O MeO H OTHP 25 vi HO vii N O MeO H OTHP 26 MeO viii Me N O MeO H OH 1 MeO Me ix N O MeO 2 O Me x,xi H J. CHEM. RESEARCH (S), 1998 7 Second approach (Scheme 4). The synthetic material had [a]D 30=+28.47° (c, 1.5 in EtOH).Its mp and IR, UV and 1H NMR data were identical with those reported for the natural product. Optical purity was also checked by derivatization of 1 with Mosher’s reagent followed by 1H NMR analysis of the resulting compounds. The transformation 1h2 has already been reported.1 Financial assistance from CSIR, New Delhi, through the project 1(1343)/95-EMR-II is gratefully acknowledged. Techniques used: IR, 1H NMR, UV spectroscopy, polarimetry References: 9 Schemes: 4 Received, 7th April 1997; Accepted, 16th September 1997 Paper E/7/02352I References cited in this synopsis 1 J.R. Price, Aust. J. Chem., 1959, 12, 458; S. Goodwin and E. C. Horning, J. Am. Chem. Soc., 1959, 81, 1908; H. C. Beyerman and R. W. Rooda, Proc. K. Ned. Akad. Wet., Ser. B, 1959, 62, 187; S. Goodwin, A. F. Smith, A. A. Velasquez and E. C. Horning, J. Am. Chem. Soc., 1959, 81, 6209. 2 S. Goodwin, J. N. Shoolery and L. F. Johnson, J. Am. Chem. Soc., 1959, 81, 3065. 3 E. A. Clarke and M. F. Grundon, J. Chem. Soc., 1964, 438; R. Oels, R. Storrer and D. W. Young, J. Chem. Soc., Perkin Trans. 1, 1977, 2546. 4 R. M. Bowman, G. A. Gray and M. F. Grundon, J. Chem. Soc., Perkin Trans. 1, 1973, 1051. 5 S. A. Barr, D. R. Boyd, N. D. Sharma, T. A. Evans, J. F. Malone and V. D. Mehta, Tetrahedron, 1994, 50, 11219. 6 R. C. Anand and N. Selvapalam, Synth. Commun., 1994, 24, 1994. 7 A. Chattopadhyay and V. R. Mamdapur, J. Org. Chem., 1995, 60, 585. Scheme 4 Reagents and conditions: i, CH2(CO2Me)2; ii, NaCl– DMSO; iii, Amberlyst-15–MeOH; iv, DHP–H+; v, aq. NaOH–H+; vi, DCC followed by methyl 2-amino-3-methoxybenzoate; vii, 2 equiv. NaH–PhMe; viii, KOH–DMF–Me2SO4; ix, MeOH–H+; x, TosCl–py; xi, aq. NaOH