DOI 10.1007/s10600-016-1612-9 Chemistry of Natural Compounds, Vol. 52, No. 2, March, 2016
SYNTHESIS OF N-ACYLAMINO-ACID DERIVATIVES OF CYTISINE
A. V. Yazlovitskii,1 M. M. Garazd,1* and V. G. Kartsev2
N-acylamino-acid derivatives of cytisine were prepared by reacting cytisine with methyl esters of aminoacid isocyanates. Keywords: cytisine, N-derivatives of cytisine, isocyanates, amino-acid derivatives. Cytisine is a quinolizidine alkaloid that is widely distributed in plants of the family Fabaceae and in most instances the genera Laburnum, Thermopsis, Cytisus, Genista, and Sophora [1, 2]. Cytisine derivatives possess broad spectra of biological activity [1]. In particular, N-carboxamide cytisine derivatives exhibit nootropic [3, 4] and antiviral [5] activity, act as NF-NB and STAT1 inhibitors [6], NFAT transcription factor activity modulators [7], and nicotinic acetylcholine receptor ligands [8, 9]. Therefore, the development of modern methods for modifying cytisine is interesting for targeted synthesis of new biologically active compounds. Herein, the synthesis of cytisine N-derivatives via modification by amino-acid motifs is reported. Amino-acid ester isocyanates were prepared by reacting the corresponding amino-acid methyl esters with phosgene in toluene in the presence of Et3N [10]. The reaction of cytisine with amino-acid ester isocyanates (glycine, L-alanine, L-valine, L-methionine, L-leucine, L-isoleucine, L-phenylalanine, E-alanine, and 6-aminohexanoic acid) with heating in anhydrous toluene [11] gave high (72–92%) yields of the corresponding N-(aminoacylcarbonyl)cytisine esters 2–10. PMR spectra of the products showed resonances characteristic of cytisine and the amino-acid residue. The NH resonance of the resulting carbamoyl group appeared at 6.33–6.87 ppm. Alkaline hydrolysis of 2–10 followed by acidolysis of the reaction mixture formed the corresponding N-(aminoacylcarbonyl)cytisine derivatives 11–19 with a free carboxylic acid. PMR spectra of these compounds contained resonances of the cytisine and amino-acid residue, the carbamoyl NH at 6.10–6.71 ppm, and the carboxylic acid at 12.01–12.35 ppm. R O
COOH NH
R O
N
COOMe NH
H N
N 13
a
b N
N O
11 - 17
7
N
O
(CH2)nCOOMe b
10
N
N
1
(CH2)nCOOH
N
c
O
3
2-8
H N
O
N
11 9
5
H N
O
O
O 9, 10
18, 19
2, 11: R = H; 3, 12: R = CH3; 4, 13: R = CH(CH3)2; 5, 14: R = CH2CH2SCH3; 6, 15: R = CH2CH(CH3)2 7, 16: R = CH(CH3)CH2CH3; 8, 17: R = CH2C6H5; 9, 18: n = 2; 10, 19: n = 5 a. O=C=N-CHR-COOMe; b. 1. NaOH, 2. HCl; c. O=C=N-(CH2)n-COOMe
1) Eximed, 50 Kharckovskoe Shosse, Kiev, Ukraine 02160; e-mail:
[email protected]; 2) InterBioScreen, P. O. Box 218, Moscow, 119019 Russia. Translated from Khimiya Prirodnykh Soedinenii, No. 2, March–April, 2016, pp. 239–242. Original article submitted April 8, 2015. 272
0009-3130/16/5202-0272
©2016
Springer Science+Business Media New York
The synthesis produced optically active cytisine N-derivatives containing glycine (2, 11), L-alanine (3, 12), L-valine (4, 13), L-methionine (5, 14), L-leucine (6, 15), L-isoleucine (7, 16), L-phenylalanine (8, 17), E-alanine (9, 18), and 6-aminohexanoic acid (10, 19). Obtained cytisine N-derivatives 2–19 were interesting as multi-facetted synthons for organic synthesis because they contained active ester or carboxylic acid, which opened new pathways for further modification of the cytisine derivatives.
EXPERIMENTAL The course of reactions and purity of products were monitored by TLC on Merck 60 F254 plates using CHCl3–MeOH (9:1 and 19:1). Melting points were measured on a Kofler apparatus. PMR spectra were recorded relative to TMS internal standard on a Varian VXR-300 spectrometer at 300 MHz. Optical rotations were measured on a PerkinElmer 341 polarimeter. Elemental analyses of all compounds agreed with those calculated. Amino-acid methyl ester isocyanates were prepared as before [10]. Pharmacopoeial cytisine isolated from Thermopsis lanceolata was used. Methyl Esters of N-(Cytisinocarbonyl)amino-acids 2–10. A solution of cytisine (1.14 g, 6 mmol) in anhydrous toluene (50 mL) was treated with the appropriate amino-acid methyl ester isocyanate (6 mmol), heated at 90–100°C for 1–2 h (end of reaction determined using TLC), and cooled. The resulting precipitate was filtered off and crystallized from MeOH. 20 –206.2q Methyl Ester of N-(Cytisinocarbonyl)glycine (2). Yield 91%, mp 165–166qÑ, Ñ15Í19N3Î4, [D]D 1 (c 1.4%, CHCl3). H NMR spectrum (300 MHz, DMSO-d6, G, ppm, J/Hz): 7.32 (1Í, dd, J = 6.9, 9.0, H-4), 6.87 (1Í, t, J = 5.1, NH), 6.20 (1Í, dd, J = 1.2, 9.0, H-3), 6.12 (1Í, dd, J = 1.2, 6.9, H-5), 4.03 (1Í, d, J = 12.6, H-11e), 3.95 (1Í, d, J = 12.6, H-13e), 3.87 (1Í, d, J = 15.9, H-10e), 3.69 (1Í, dd, J = 6.3, 6.9, H-10a), 3.59 (2Í, d, J = 6.0, H2-2c), 3.54 (3Í, s, OCH3), 3.08 (1H, br.s, Í-7), 2.97 (2Í, d, J = 13.2, H-11a, 13a), 2.43 (1H, br.s, Í-9), 1.87 (2Í, br.s, CH2-8). 20 –162.3q Methyl Ester of N-(Cytisinocarbonyl)-L-alanine (3). Yield 84%, mp 159–160qÑ, Ñ16Í21N3Î4, [D]D (c 2.2%, DMSO). 1H NMR spectrum (300 MHz, DMSO-d6 G, ppm, J/Hz): 7.32 (1Í, dd, J = 6.9, 9.0, H-4), 6.67 (1Í, d, J = 6.9, NH), 6.20 (1Í, dd, J = 1.2, 9.0, H-3), 6.12 (1Í, dd, J = 1.2, 6.9, H-5), 3.88–4.09 (4Í, m, H-10e, 11e, 13e, 2c), 3.67 (1Í, dd, J = 6.0, 6.9, H-10a), 3.53 (3Í, s, OCH3), 3.07 (1H, br.s, Í-7), 2.97 (2Í, t, J = 11.4, H-11a, 13a), 2.41 (1H, br.s, Í-9), 1.87 (2Í, br.s, H2-8), 1.18 (3Í, d, J = 7.2, CH3-2c). 20 –172.0q Methyl Ester of N-(Cytisinocarbonyl)-L-valine (4). Yield 81%, mp 138–139qÑ, Ñ18Í25N3Î4, [D]D (c 3.0%, DMSO). 1H NMR spectrum (300 MHz, DMSO-d6 G, ppm, J/Hz): 7.30 (1Í, dd, J = 6.9, 9.0, H-4), 6.34 (1Í, d, J = 7.8, NH), 6.18 (1Í, dd, J = 1.2, 9.0, H-3), 6.10 (1Í, dd, J = 1.2, 6.9, H-5), 4.14 (1Í, d, J = 12.6, H-11e), 4.07 (1Í, d, J = 12.6, H-13e), 3.90 (1Í, d, J = 15.6, H-10e), 3.78 (1Í, t, J = 7.8, H-2c), 3.66 (1Í, dd, J = 6.6, 6.6, H-10a), 3.55 (3Í, s, OCH3), 3.05 (1H, br.s, Í-7), 2.96 (2Í, t, J = 11.4, H-11a, 13a), 2.41 (1H, br.s, Í-9), 1.89–1.99 (1Í, m, H-3c), 1.87 (2Í, br.s, H2-8), 0.80 and 0.76 (3H each, d, J = 6.9, CH3-3c). Methyl Ester of N-(Cytisinocarbonyl)-L-methionine (5). Yield 72%, mp 125–126qÑ, Ñ18Í25N3Î4S. 1H NMR spectrum (300 MHz, DMSO-d6 G, ppm, J/Hz): 7.30 (1Í, dd, J = 6.9, 9.0, H-4), 6.66 (1Í, d, J = 7.8, NH), 6.18 (1Í, dd, J = 1.2, 9.0, H-3), 6.11 (1Í, dd, J = 1.2, 6.9, H-5), 4.02–4.11 (3Í, m, H-11e, 13e, 2c), 3.88 (1Í, d, J = 15.6, H-10e), 3.66 (1Í, dd, J = 6.6, 6.6, H-10a), 3.53 (3Í, s, OCH3), 3.06 (1H, br.s, Í-7), 2.97 (2Í, t, J = 12.6, H-11a, 13a), 2.24–2.47 (3H, m, Í-9, H2-3c), 1.99 (3Í, s, SCH3), 1.79–1.87 (4Í, m, H2-8, 4c). 20 –209.7q Methyl Ester of N-(Cytisinocarbonyl)-L-leucine (6). Yield 81%, mp 139–140qÑ, Ñ19Í27N3Î4, [D]D (c 1.6%, CHCl3). 1H NMR spectrum (300 MHz, DMSO-d6 G, ppm, J/Hz): 7.30 (1Í, dd, J = 6.9, 9.0, H-4), 6.56 (1Í, d, J = 7.8, NH), 6.19 (1Í, dd, J = 1.2, 9.0, H-3), 6.10 (1Í, dd, J = 1.2, 6.9, H-5), 3.96–4.12 (3Í, m, H-11e, 13e, 2c), 3.86 (1Í, d, J = 15.6, H-10e), 3.66 (1Í, dd, J = 6.3, 6.6, H-10a), 3.52 (3Í, s, OCH3), 3.05 (1H, br.s, Í-7), 2.98 and 2.92 (2Í, d, J = 13.2, H-11a, 13a), 2.40 (1H, br.s, Í-9), 1.87 (2Í, br.s, H2-8), 1.28–1.60 (3H, m, H2-3c, H-4c), 0.83 and 0.72 (3Í each, d, J = 6.0, CH3-4c). 20 –207.8q Methyl Ester of N-(Cytisinocarbonyl)-L-isoleucine (7). Yield 78%, mp 134–135qÑ, Ñ19Í27N3Î4, [D]D (c 1.5%, CHCl3). 1H NMR spectrum (300 MHz, DMSO-d6 G, ppm, J/Hz): 7.30 (1Í, dd, J = 6.9, 9.0, H-4), 6.34 (1Í, d, J = 7.2, NH), 6.18 (1Í, dd, J = 1.2, 9.0, H-3), 6.10 (1Í, dd, J = 1.2, 6.9, H-5), 4.12 (1Í, d, J = 12.6, H-11e), 4.07 (1Í, d, J = 12.6, H-13e), 3.89 (1Í, d, J = 15.6, H-10e), 3.85 (1Í, t, J = 7.5, H-2c), 3.67 (1Í, dd, J = 6.6, 6.6, H-10a), 3.54 (3Í, s, OCH3), 3.05 (1H, br.s, Í-7), 2.95 (2Í, t, J = 14.4, H-11a, 13a), 2.40 (1H, br.s, Í-9), 1.87 (2Í, br.s, H2-8), 1.65–1.79 (1Í, m, Í-3c), 1.26–1.39 (1Í, m, Í-4cD), 1.00–1.15 (1Í, m, Í-4cE), 0.76 (3Í, t, J = 7.2, ÑÍ3-5c), 0.73 (3Í, d, J = 6.9, ÑÍ3-3c).
273
Methyl Ester of N-(Cytisinocarbonyl)-L-phenylalanine (8). Yield 92%, mp 169–170qÑ, Ñ22Í25N3Î4, [D]20 D –129.0q (c 1.0%, CHCl3). 1H NMR spectrum (300 MHz, DMSO-d6 G, ppm, J/Hz): 7.30 (1Í, dd, J = 6.9, 9.0, H-4), 7.10–7.24 (5Í, m, Ph), 6.69 (1Í, d, J = 6.9, NH), 6.22 (1Í, dd, J = 1.2, 9.0, H-3), 6.10 (1Í, dd, J = 1.2, 6.9, H-5), 4.13 (1Í, q, J = 7.2, H-2c), 4.00 (1Í, d, J = 12.6, H-11e), 3.96 (1Í, d, J = 12.6, H-13e), 3.83 (1Í, d, J = 15.6, H-10e), 3.67 (1Í, dd, J = 6.6, 6.6, H-10a), 3.49 (3Í, s, OCH3), 3.06 (1H, br.s, Í-7), 2.88–2.94 (4Í, m, H-11a, 13a, H2-3c), 2.41 (1H, br.s, Í-9), 1.85 (2Í, br.s, H2-8). Methyl Ester of N-(Cytisinocarbonyl)-E-alanine (9). Yield 85%, mp 161–162qÑ, Ñ16Í21N3Î4. 1H NMR spectrum (300 MHz, DMSO-d6 G, ppm, J/Hz): 7.32 (1Í, dd, J = 6.9, 9.0, H-4), 6.48 (1Í, t, J = 5.7, NH), 6.20 (1Í, dd, J = 1.2, 9.0, H-3), 6.12 (1Í, dd, J = 1.2, 6.9, H-5), 4.02 (1Í, d, J = 12.6, H-11e), 3.94 (1Í, d, J = 12.6, H-13e), 3.89 (1Í, d, J = 15.9, H-10e), 3.64 (1Í, dd, J = 6.3, 6.9, H-10a), 3.55 (3Í, s, OCH3), 3.04–3.15 (3H, m, Í-7, H2-3c), 2.95 (2Í, t, J = 13.2, H-11a, 13a), 2.39 (1H, br.s, Í-9), 2.25–2.31 (2Í, m, H2-2c), 1.87 (2Í, br.s, H2-8). Methyl Ester of N-(Cytisinocarbonyl)-6-aminohexanoic Acid (10). Yield 79%, mp 152–153qÑ, Ñ19Í27N3Î4. 1H NMR spectrum (300 MHz, DMSO-d G, ppm, J/Hz): 7.32 (1Í, dd, J = 6.9, 9.0, H-4), 6.33 (1Í, t, J = 5.4, NH), 6.18 (1Í, 6 dd, J = 1.2, 9.0, H-3), 6.10 (1Í, dd, J = 1.2, 6.9, H-5), 4.05 (1Í, d, J = 12.6, H-11e), 3.96 (1Í, d, J = 12.6, H-13e), 3.88 (1Í, d, J = 15.9, H-10e), 3.64 (1Í, dd, J = 6.3, 6.9, H-10a), 3.58 (3Í, s, OCH3), 3.05 (1H, br.s, Í-7), 2.78–2.94 (4Í, m, H-11a, 13a, H2-6c), 2.38 (1H, br.s, Í-9), 2.26 (2Í, t, J = 7.5, H2-2c), 1.87 (2Í, br.s, H2-8), 1.39–1.49 (2Í, m, H2-5c), 1.10–1.26 (4Í, m, H2-3c, 4c). N-(Cytisinocarbonyl)amino Acids 11–19. A solution or suspension of ester 2–10 (3 mmol) in MeOH (10 mL) was treated with a solution of NaOH (10 mL, 10 mmol, 1 M), stirred, heated for 0.5–1 h (end of reaction determined by TLC), cooled, transferred into ice water (50 mL), and acidified to pH 6–7. The resulting precipitate was filtered off and crystallized from MeOH. 20 –178.1q (c 1.4%, DMSO). N-(Cytisinocarbonyl)glycine (11). Yield 85%, mp 178–179qÑ, Ñ14Í17N3Î4, [D]D 1H NMR spectrum (300 MHz, DMSO-d G, ppm, J/Hz): 12.20 (1Í, br.s, COOH), 7.30 (1Í, dd, J = 6.9, 9.0, H-4), 6.71 (1Í, 6 t, J = 5.1, NH), 6.19 (1Í, dd, J = 1.2, 9.0, H-3), 6.10 (1Í, dd, J = 1.2, 6.9, H-5), 4.04 (1Í, d, J = 12.6, H-11e), 3.95 (1Í, d, J = 12.6, H-13e), 3.87 (1Í, d, J = 15.9, H-10e), 3.69 (1Í, dd, J = 6.3, 6.9, H-10a), 3.59 (2Í, d, J = 6.0, CH2-2c), 3.08 (1H, br.s, Í-7), 2.97 (2Í, d, J = 13.2, H-11a, 13a), 2.44 (1H, br.s, Í-9), 1.87 (2Í, br.s, H2-8). 20 –142.9q (c 1.7%, DMSO). N-(Cytisinocarbonyl)-L-alanine (12). Yield 82%, mp 171–172qÑ, Ñ15Í19N3Î4, [D]D 1H NMR spectrum (300 MHz, DMSO-d G, ppm, J/Hz): 12.01 (1Í, br.s, COOH), 7.32 (1Í, dd, J = 6.9, 9.0, H-4), 6.52 (1Í, d, J = 6.9, 6 NH), 6.20 (1Í, dd, J = 1.2, 9.0, H-3), 6.12 (1Í, dd, J = 1.2, 6.9, H-5), 3.88–4.08 (4Í, m, H-10e, 11e, 13e, 2c), 3.68 (1Í, dd, J = 6.0, 6.9, H-10a), 3.07 (1H, br.s, Í-7), 2.94 (2Í, t, J = 11.4, H-11a, 13a), 2.41 (1H, br.s, Í-9), 1.87 (2Í, br.s, H2-8), 1.17 (3Í, d, J = 7.2, CH3-2c). 20 –168.0q (c 1.0%, DMSO). N-(Cytisinocarbonyl)-L-valine (13). Yield 84%, mp 147–148qÑ, Ñ17Í23N3Î4, [D]D 1H NMR spectrum (300 MHz, DMSO-d G, ppm, J/Hz): 12.15 (1Í, br.s, COOH), 7.30 (1Í, dd, J = 6.9, 9.0, H-4), 6.10–6.19 6 (3H, m, H-3, 5, NH), 4.13 (1Í, d, J = 12.6, H-11e), 4.08 (1Í, d, J = 12.6, H-13e), 3.90 (1Í, d, J = 15.6, H-10e), 3.79 (1Í, t, J = 7.8, H-2c), 3.67 (1Í, dd, J = 6.6, 6.6, H-10a), 3.06 (1H, br.s, Í-7), 2.98 and 2.93 (2Í, d, J = 13.2, H-11a, 13a), 2.40 (1H, br.s, Í-9), 1.91–2.00 (1Í, m, H-3c), 1.87 (2Í, br.s, H2-8), 0.79 and 0.77 (3Í each, d, J = 6.9, CH3-3c). 20 –153.8q (c 0.7%, N-(Cytisinocarbonyl)-L-methionine (14). Yield 81%, mp 139–140qÑ, Ñ17Í23N3 Î4S, [D]D 1 DMSO). H NMR spectrum (300 MHz, DMSO-d6 G, ppm, J/Hz): 12.35 (1Í, br.s, COOH), 7.30 (1Í, dd, J = 6.9, 9.0, H-4), 6.50 (1Í, d, J = 6.9, NH), 6.18 (1Í, dd, J = 1.2, 9.0, H-3), 6.11 (1Í, dd, J = 1.2, 6.9, H-5), 4.00–4.11 (3Í, m, H-11e, 13e, 2c), 3.89 (1Í, d, J = 15.6, H-10e), 3.66 (1Í, dd, J = 6.6, 6.6, H-10a), 3.06 (1H, br.s, Í-7), 2.95 (2Í, t, J = 12.6, H-11a, 13a), 2.25–2.44 (3H, m, Í-9, H2-3c), 1.99 (3Í, s, SCH3), 1.78–1.87 (4Í, m, H2-8, 4c). 20 –158.9q (c 2.7%, DMSO), N-(Cytisinocarbonyl)-L-leucine (15). Yield 86%, mp 144–145qÑ, Ñ18Í25N3Î4, [D]D –217.2q (c 1%, EtOH). 1H NMR spectrum (300 MHz, DMSO-d6 G, ppm, J/Hz): 12.19 (1Í, br.s, COOH), 7.30 (1Í, dd, J = 6.9, 9.0, H-4), 6.42 (1Í, d, J = 7.8, NH), 6.18 (1Í, dd, J = 1.2, 9.0, H-3), 6.10 (1Í, dd, J = 1.2, 6.9, H-5), 4.07 (2Í, d, J = 12.6, H-11e, 13e), 3.91–3.99 (1Í, m, H-2c), 3.85 (1Í, d, J = 15.6, H-10e), 3.67 (1Í, dd, J = 6.3, 6.6, H-10a), 3.05 (1H, br.s, Í-7), 2.98 and 2.90 (2Í, d, J = 13.2, H-11a, 13a), 2.40 (1H, br.s, Í-9), 1.87 (2Í, br.s, H2-8), 1.30–1.58 (3H, m, H2-3c, H-4c),0.83 and 0.71 (3Í each, d, J = 6.0, CH3-4c). 20 –166.4q (c 2.2%, DMSO), N-(Cytisinocarbonyl)-L-isoleucine (16). Yield 88%, mp 147–148qÑ, Ñ18Í25N3Î4, [D]D 1 –206.2q (c 1%, EtOH). H NMR spectrum (300 MHz, DMSO-d6 G, ppm, J/Hz): 12.30 (1Í, br.s, COOH), 7.30 (1Í, dd, J = 6.9, 9.0, H-4), 6.10–6.19 (3H, m, H-3, 5, NH), 4.12 (1Í, d, J = 12.6, H-11e), 4.07 (1Í, d, J = 12.6, H-13e), 3.90 (1Í, d, J = 15.6, H-10e), 3.84 (1Í, t, J = 7.5, H-2c), 3.67 (1Í, dd, J = 6.6, 6.6, H-10a), 3.06 (1H, br.s, Í-7), 2.95 (2Í, t, J = 14.4, H-11a, 13a), 2.39 (1H, br.s, Í-9), 1.87 (2Í, br.s, H2-8), 1.66–1.75 (1Í, m, Í-3c), 1.25–1.39 (1Í, m, Í-4cD), 1.00–1.15 (1Í, m, Í-4cE), 0.76 (3Í, t, J = 7.2, ÑÍ3-5c), 0.73 (3Í, d, J = 6.9, ÑÍ3-3c). 274
20 –140.0q (c 0.3%, N-(Cytisinocarbonyl)-L-phenylalanine (17). Yield 92%, mp 182–183qÑ, Ñ21Í23N3Î4, [D]D 1 DMSO). H NMR spectrum (300 MHz, DMSO-d6 G, ppm, J/Hz): 12.19 (1Í, br.s, COOH), 7.30 (1Í, dd, J = 6.9, 9.0, H-4), 7.10–7.28 (5Í, m, Ph), 6.54 (1Í, d, J = 8.1, NH), 6.21 (1Í, dd, J = 1.2, 9.0, H-3), 6.11 (1Í, dd, J = 1.2, 6.9, H-5), 4.05–4.13 (1Í, m, H-2c), 3.98 (1Í, d, J = 12.6, H-11e), 3.96 (1Í, d, J = 12.6, H-13e), 3.81 (1Í, d, J = 15.6, H-10e), 3.69 (1Í, dd, J = 6.6, 6.6, H-10a), 3.06 (1H, br.s, Í-7), 2.81–2.96 (4Í, m, H-11a, 13a, H2-3c), 2.42 (1H, br.s, Í-9), 1.84 (2Í, br.s, H2-8). N-(Cytisinocarbonyl)-E-alanine (18). Yield 88%, mp 178–179qÑ, Ñ15Í19N3Î4. 1H NMR spectrum (300 MHz, DMSO-d6 G, ppm, J/Hz): 12.15 (1Í, br.s, COOH), 7.47 (1Í, dd, J = 6.9, 9.0, H-4), 6.44 (1Í, t, J = 5.7, NH), 6.41 (1Í, dd, J = 1.2, 9.0, H-3), 6.32 (1Í, dd, J = 1.2, 6.9, H-5), 4.06 (1Í, d, J = 12.6, H-11e), 3.95 (1Í, d, J = 12.6, H-13e), 3.89 (1Í, d, J = 15.9, H-10e), 3.74 (1Í, dd, J = 6.3, 6.9, H-10a), 3.06–3.14 (3H, m, Í-7, H2-3c), 2.95 (2Í, t, J = 13.2, H-11a, 13a), 2.42 (1H, br.s, Í-9), 2.17–2.23 (2Í, m, H2-2c), 1.88 (2Í, br.s, H2-8). N-(Cytisinocarbonyl)-6-aminohexanoic Acid (19). Yield 82%, mp 167–168qÑ, Ñ18Í25N3Î4. 1H NMR spectrum (300 MHz, DMSO-d6 G, ppm, J/Hz): 12.10 (1Í, br.s, COOH), 7.32 (1Í, dd, J = 6.9, 9.0, H-4), 6.31 (1Í, t, J = 5.7, NH), 6.19 (1Í, dd, J = 1.2, 9.0, H-3), 6.11 (1Í, dd, J = 1.2, 6.9, H-5), 4.06 (1Í, d, J = 12.6, H-11e), 3.96 (1Í, d, J = 12.6, H-13e), 3.90 (1Í, d, J = 15.9, H-10e), 3.67 (1Í, dd, J = 6.3, 6.9, H-10a), 3.05 (1H, br.s, Í-7), 2.75–2.95 (4Í, m, H-11a, 13a, H2-6c), 2.38 (1H, br.s, Í-9), 2.16 (2Í, t, J = 7.2, H2-2c), 1.85 (2Í, br.s, H2-8), 1.37–1.47 (2Í, m, H2-5c), 1.06–1.27 (4Í, m, H2-3c, 4c).
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