Mendeleev Communications Electronic Version, Issue 5, 1998 (pp. 169–205) Direct synthesis of 17a-ethoxyimino-8-aza-D-homogonanes by annelation of 3,4-dihydroisoquinolines with 2-acetyl-5,5-dimethyl-3-ethoxyiminocyclohexanone Olga V. Gulyakevich, Irene L. Rubinova, Dmitry B. Rubinov* and Alexander L. Mikhal’chuk Institute of Bioorganic Chemistry, Belarus National Academy of Sciences, 220141 Minsk, Belarus.Fax: + 7 017 263 7274; e-mail: iboch@ns.igs.ac.by The annelation reaction of Schiff bases by b,b'-tricarbonyl compounds has been extended to 3-ethoxyimino derivatives of 2-acylcyclohexane- 1,3-diones. The first direct synthesis of 8-aza-D-homogonanes with a modified carbonyl group at the pharmacologically significant C(17a) position has been carried out. The 8-aza-steroids (benzo[a]cycloalkano[f]quinolizines) 1, being structurally similar to the important bioregulators of both the animal and plant kingdoms, represent a wide class of condensed nitrogen-containing heterocycles, which have both steroid and alkaloid isosteric fragments.1 These compounds possess valuable biological properties.For example, 8-aza-Dhomogona- 12,17a-diones 2 act as immunomodulators; moreover, both the degree and the direction of their effect may be modulated by transformations in the CD fragment of the ABCD tetracyclic 8-azasteroidal skeleton.2 This, unambigously, makes 8-azasteroids very interesting objects as a basis for the development of safe remedies for the correction of human and animal immunity.However, the possibilities for regioselective transformation of the C(12,17a)-b-dicarbonyl group of 2 are very limited,3 and there are no methods for selective conversion of the C(17a) carbonyl group, for example, into the imino or oxyimino functions.The annelation of Schiff bases by 2-acetylcycloalkanones,4 2-acylcycloalkane-1,3-diones5 and 2-(1-aminoethylidene)cyclohexane- 1,3-diones6 is well documented. Thus, among several approaches to the (17a)-modified derivatives of 2 the most attractive is the cyclocondensation of 3,4-dihydroisoquinolines 3 with accessible oxyimines 4 (Scheme 1),7 which contain the b-dicarbonyl fragment necessary for the condensation.Advantageously, and contrary to the unsubstituted oximes of b-di- and b,b'-tricarbonyl compounds, they fail to convert into isoxazoles by means of intramolecular cyclodehydration.8 Cyclocondensation of 3,4-dihydroisoquinolines 3a,b with an equimolar quantity of b,b'-oxyiminodiketone 4 has been carried out in boiling methanol or ethanol (inert atmosphere, 11–20 h, TLC control) as described for the general method of annelation for b-di- and b,b'-triketones.4,5 In contrast to the latter reaction, which yields derivatives of type 2, annelation of 3a,b with oximine 4 leads to dienones 6a,b (yields 69–71%) or to a mixture of the derivatives 5a,b and 6a,b,† the latter being predominant.If contact with atmospheric and acidic catalysis are avoided, both in the course of the reaction, and during the product isolation, only enones 5a,b are obtained in 83–89% yields. Studies of the properties of enones 5a,b reveal their sensitivity to an acidic environment and to atmospheric oxygen, as well as their thermal lability.Keeping the sample of 5a in a solution containing catalytic quantities of p-toluenesulfonic acid in air, and filtration of the solution of 5b through acidic silica gel, as well as raising the temperature of the reaction (boiling in isopropanol or butanol), afforded the corresponding dienones 6.Thus, the derivatives 6 are the products of dehydration of the initially formed enones 5. It is noteworthy that there are no molecular peaks in the mass spectra of 5, so they are identical with those of 6. This indicates the lability of † Satisfactory elemental analyses, as well as IR, UV, 1H and 13C NMR spectra, were obtained for all new compounds.For 5a: mp 167–171 °C (decomp.); 1H NMR (200 MHz, CDCl3) d: 1.04 [s, 3H, C(16)–Me], 1.10 [s, 3H, C(16)–Me], 1.30 (t, 3H, NOCH2Me, J 7.0 Hz), 2.31 [d, 1H, C(17)HB, J 16.5 Hz], 2.40 [d, 1H, C(15)HB, J 16.0 Hz], 2.43 [d, 1H, C(17)HA, J 16.5 Hz], 2.60 [t, 1H, C(11)HB, J 15.5 Hz], 2.64 [d, 1H, C(15)HB, J 16.0 Hz], 2.78 [tt, 1H, C(6)He, J 15.0, 4.0, 4.0 Hz], 2.87 [dd, 1H, C(11)HA, J 15.5, 4.0 Hz], 3.02 [m, 1H, C(6)Ha, J 15.0, 12.0, 4.0 Hz], 3.22 [ddd, 1H, C(7)He, J 12.0, 12.0, 4.0 Hz], 3.86 (s, 3H, OMe), 3.88 (s, 3H, OMe), 4.14 [tt, 1H, C(7)Ha, J 12.0, 4.0, 4.0 Hz], 4.23 (q, 2H, NOCH2Me, J 7.0 Hz), 4.70 [dd, 1H, C(9)HX, J 15.5, 4.0 Hz], 6.60 [s, 1H, C(4)H], 6.66 [s, 1H, C(1)H]; 13C NMR (90 MHz, CDCl3) d: 14.79 (q, NOCH2Me), 28.04 [q, C(18)], 29.36 [s, C(16)], 29.60 [q, C(19)], 29.76 (t), 36.14 (t), 41.53 (t), 43.96 (t), 47.09 (t), 55.97 (q, OMe), 56.03 (q, OMe), 56.91 [d, C(9)], 69.10 (t, NOCH2Me), 104.66 [s, C(13)], 108.39 (d), 110.96 (d), 125.61 (s), 126.13 (s), 148.08 (s), 148.35 (s), 151.99 (s), 163.06 (s), 187.47 (s).IR (KBr, n/cm–1): 3000–2830, 1645, 1522, 1466–1447, 1357, 1330, 1275, 1222, 1205, 1130, 1062, 866; UV (MeOH) lmax/nm (e): 201 (41.770), 234 (10.485), 275 (13.685), 339 (9.190), lmin/(e): 219 (8.005), 248 (7.035), 302 (3.940).For 6a: mp 87–92 °C (decomp.); 1H NMR (200 MHz, CDCl3) d: 1.07 [s, 6H, MeC(16)Me], 1.31 (t, 3H, NOCH2Me, J 7.0 Hz), 2.62 [s, 2H, C(17)H2], 2.64 [s, 2H, C(15)H2], 3.02 [t, 2H, C(6)H2, J 6.0 Hz], 3.94 [s, 6H, C(2)OMe, C(3)OMe], 4.08 [t, 2H, C(7)H2, J 6.0 Hz], 4.32 (q, 2H, NOCH2Me, J 7.0 Hz), 6.74 [s, 1H, C(11)H], 6.95 [s, 1H, C(4)H], 7.18 [s, 1H, C(1)H]; 13C NMR (90 MHz, CDCl3) d: 14.73 (q, NOCH2Me), 27.84 (t), 28.87 [q, C(18), C(19)], 29.99 [s, C(16)], 35.94 (t), 41.49 (t), 44.82 (t), 58.09 (q, OMe), 58.22 (q, OMe), 69.65 (t, NOCH2Me), 108.38 (d), 109.87 (d), 113.626 (d), 118.27 (s), 121.00 (s), 127.48 (s), 144.15 (s), 148.80 (s), 149.75 (s), 151.23 (s), 151.76 (s) , 175.08 [s, C(12)].IR (KBr, n/cm–1): 3000–2830, 1639, 1618, 1525 (sh), 1515, 1475, 1362, 1275, 1218, 1159, 1066, 876; UV (MeOH), lmax/nm (e): 232 (21.240), 275 (21.040), 324 (13.700), lmin/nm (e): 218 (19.125), 260 (15.745), 302 (11.255). For 5b: mp 110–113 °C (decomp.). For 6b: mp 95–100 °C (decomp.). N (CH2)n N Z O O R2 R2 R2 R1 R1 A B C D 1 2 n= 1, 2 R1 = H, OH, OMe R2 = H, alkyl ...Z = bond, CH2, CHMe, CMe2 ... 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 17a N R1 R2 O NOEt O N R1 R2 O NOEt 3 N R1 R2 O NOEt or + 4 5 6 a R1 = R2 = OMe b R1 = H, R2 = OMe Scheme 1 17a 18 19Mendeleev Communications Electronic Version, Issue 5, 1998 (pp. 169-206) these compounds under the conditions of mass spectral analysis. In order to obtain the derivatives 5 it was necessary to use an inert reaction atmosphere and to avoid acidic catalysis in all stages during the synthesis and isolation.Thus, the present work has demonstrated the possibility of annelation of the 2-acylcyclohexane-1,3-diones with a modified ring carbonyl group with Schiff bases. This provides a simple, one-step synthesis of 8-azasteroid derivatives with a modified carbonyl group at the pharmacologically significant C(17a) position.The authors express their thanks to Academician Aphanasy A. Akhrem for his kind attention to this work and useful discussions. References 1 A. A. Akhrem and Yu. A. Titov, Total Steroid Synthesis, Plenum Press, New York, 1970, p. 362. 2 (a) A. A. Akhrem, B. B. Kuz’mitsky, F. A. Lakhvich, V. A. Khripach and Yu.L. Zhuravkov, Khimiya i biologiya bioregulyatorov (Chemistry and Biology of Immunoregulators), Zinatne, Riga, 1985, p. 265 (in Russian); (b) B. B. Kuz’mitsky, I. G. Dad’kov, Yu. L. Zhuravkov, N. A. Konoplya, G. A. Shafranskaya, O. V. Gulyakevich, V. N. Pshenichny and V. A. Khripach, Vesti Akad. Nauk BSSR, Ser. Biol. Nauk, 1987, 79 (in Russian); (c) B. B. Kuz’mitsky, I.G. Dad’kov, Yu. L. Zhuravkov, N. A. Konoplya, G. S. Lyubin, A. E. Mashkovich, V. M. Nasek, O. V. Gulyakevich, V. N. Pshenichny and V. A. Khripach, Vesti Akad. Nauk BSSR, Ser. Khim. Nauk, 1989, 64 (in Russian); (d) N. A. Konoplya, O. V. Gulyakevich, A. L. Mikhal’chuk and B. B. Kuz’mitsky, Vesti Akad. Nauk BSSR, Ser. Khim. Nauk, 1994, 91 (in Russian). 3 (a) A. L. Mikhal’chuk, O. V.Gulyakevich and A. A. Akhrem, Zh. Obshch. Khim., 1993, 63, 1917 (Russ. J. Gen. Chem., 1993, 63, 1338); (b) O. V. Gulyakevich, A. L. Mikhal’chuk and A. A. Akhrem, Khim. Geterotsikl. Soedin., 1995, 187 [Chem. Heterocycl. Compd. (Engl. Transl.), 1995, 160]; (c) O. V. Gulyakevich, A. S. Lyakhov and A. L. Mikhal’chuk, Dokl. Ross. Akad. Nauk, 1996, 349 (2), 202 [Dokl. Chem. (Engl. Transl.), 1996, 172]. 4 M. von Strandtmann, M. P. Cohen and John Shavel, Jr., J. Org. Chem., 1966, 31, 797. 5 (a) A. L. Mikhal’chuk, O. V. Gulyakevich, A. A. Zenyuk, A. V. Korchik, L. G. Lis, V. A. Khripach and L. I. Ukhova, Dokl. Akad. Nauk SSSR, 1991, 317, 1397 [Dokl. Chem. (Engl. Transl.), 1991, 106]; (b) A. L. Mikhal’chuk, O. V. Gulyakevich, A. A. Zenyuk, Yu. V. Shklyaev, V. S. Shklyaev and A.A. Akhrem, Zh. Obshch. Khim., 1993, 63, 1891 (Russ. J. Gen. Chem., 1993, 63, 1319); (c) A. L. Mikhal’chuk, O. V. Gulyakevich, D. B. Rubinov and A. A. Akhrem, Khim. Geterotsikl. Soedin., 1993, 374 [Chem. Heterocycl. Compd. (Engl. Transl.), 1993, 313]; (d) O. V. Gulyakevich, A. L. Mikhal’chuk and A. A. Akhrem, Zh. Obshch. Khim., 1994, 64, 1544 (Russ. J. Gen. Chem., 1994, 64, 1382). 6 O. V. Gulyakevich, A. L. Mikhal’chuk and V. A. Khripach, Zh. Org. Khim., 1991, 27, 213 [J. Org. Chem. USSR (Engl. Transl.), 1991, 27, 187]. 7 F. A. Lakhvich, L. G. Lis, D. B. Rubinov, I. L. Rubinova, V. Z. Kurbako and A. I. Bykhovets, Vesti Akad. Nauk BSSR, Ser. Khim. Nauk, 1989, 51 (in Russian). 8 (a) H. Smith, J. Chem. Soc., 1953, 803; (b) M. V. Ablovatskaya, E. Yu. Gudriniece and A. Ya. Strakov, Izv. Akad. Nauk Latv. SSR, Ser. Khim., 1989, 601 (in Russian). Received: Moscow, 26th March 1998 Cambridge, 19th June 1998; Com. 8/02401D