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Aza-Michael reaction of 12-Ncarboxamide of (–)-cytisine under high pressure conditions a
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a
Inna P. Tsypysheva , Alexander N. Lobov , Alena V. Kovalskaya , b
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Polina R. Petrova , Sergey P. Ivanov , Shamil A. Rameev , Sophia a
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S. Borisevich , Rustam L. Safiullin & Marat S. Yunusov
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Institute of Organic Chemistry, Ufa Scientific Center of the Russian Academy of Sciences, 71, pr. Oktyabrya, 450054 Ufa, Russian Federation b
Department of Chemistry, Bashkir State University, 32, Validy Str., 450076 Ufa, Russian Federation Published online: 21 Oct 2014.
To cite this article: Inna P. Tsypysheva, Alexander N. Lobov, Alena V. Kovalskaya, Polina R. Petrova, Sergey P. Ivanov, Shamil A. Rameev, Sophia S. Borisevich, Rustam L. Safiullin & Marat S. Yunusov (2015) Aza-Michael reaction of 12-N-carboxamide of (–)-cytisine under high pressure conditions, Natural Product Research: Formerly Natural Product Letters, 29:2, 141-148, DOI: 10.1080/14786419.2014.968150 To link to this article: http://dx.doi.org/10.1080/14786419.2014.968150
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Natural Product Research, 2015 Vol. 29, No. 2, 141–148, http://dx.doi.org/10.1080/14786419.2014.968150
Aza-Michael reaction of 12-N-carboxamide of ( –)-cytisine under high pressure conditions Inna P. Tsypyshevaa*, Alexander N. Lobova, Alena V. Kovalskayaa, Polina R. Petrovab, Sergey P. Ivanova, Shamil A. Rameeva, Sophia S. Borisevicha, Rustam L. Safiullina and Marat S. Yunusova
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a
Institute of Organic Chemistry, Ufa Scientific Center of the Russian Academy of Sciences, 71, pr. Oktyabrya, 450054 Ufa, Russian Federation; bDepartment of Chemistry, Bashkir State University, 32, Validy Str., 450076 Ufa, Russian Federation (Received 24 July 2013; final version received 12 September 2014) The first example of aza-Michael reaction of 12-N-carboxamide of quinolizidine alkaloid ( –)-cytisine with a,b-unsaturated ketones, dimethyl acetylenedicarboxylate and b-nitrostyrene under high pressure condition has been described. It has been shown that the [4 þ 2]-cycloaddition takes place in the case with N-phenylmaleimide. Keywords: aza-Michael reaction; high pressure; ( – )-cytisine
1. Introduction The synthesis of new derivatives of quinolizidine alkaloid (– )-cytisine (1) (Figure 1), the natural ligand of nicotinic acetylcholine receptor (nAcChR), is interesting from the point of view of neuropharmacological activity. More than thousands of ( –)-cytisine analogues are obtained by chemical transformations, based on the reactions of its secondary amino group. It was demonstrated that the nature of the substituent in N-12 position can influence the affinity towards nAcChR (Canu Boido & Sparatore 1999; Canu Boido et al. 2003). Recently, we have shown that some (–)-cytisine derivatives with various topology of thioand carboxamide fragments at the starting molecule showed neuropharmacological activity in vivo (Tsypysheva et al. 2012; Tsypysheva, Koval’skaya, et al. 2013; Tsypysheva, Lobov, et al. 2013). Thereupon we decided to make an attempt to synthesise new derivatives of (–)-cytisine with carboxamide moieties at the 12th position (Figure 1). In spite of the fact that the reactivity of the ureas (as nucleophiles) in the aza-Michael reaction is very low, the intensification of this process is possible by carrying out the reaction under the high-pressure (HP) conditions (Jenner 2002). The publications (Azad et al. 2009; Moura et al. 2011; Rulev et al. 2012) have inspired us to use this approach for the synthesis of 12-N-carboxamides of (– )-cytisine with nitro, keto and carboxyl groups in urea’s fragment by reaction of cytisin-12-carboxamide (2) with such Michael acceptors as 3-buten-2-one (3), 2-cyclohexen-1-one (4), b-nitrostyrene (5), dimethyl acetylenedicarboxylate (DMAD) (6) and N-phenylmaleimide (NPM) (7). 2. Results and discussion Starting carboxamide 2 was synthesised from (– )-cytisine (1) and urea in boiling toluene (Tsypysheva et al. 2012). A mixture of 2, a Michael acceptor and 10 mol% of p-TsOH in CH3CN
*Corresponding author. Email: [email protected] q 2014 Taylor & Francis
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I.P. Tsypysheva et al. 11 5 6
4
13 9
1
2
O
NH
8
N
3
12
7
10
1
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Figure 1. (– )-Cytisine.
(ca. 1.3 mL) was placed in a Teflon reactor vessel and the mixture was allowed to react at 808C, pressure 0.6 GPa for 72 h leading to products 8 – 12 (Scheme 1). After the reaction mixture was cooled and the pressure was released, the CH3CN was evaporated in vacuo, and products were isolated by column chromatography (CC). The yields of Michael adducts 8, 9a,b and 10a,b were 48%, 81% and 67%, and the compounds 9a,b and 10a,b were obtained as diastereomeric pairs in < 1:1 ratio as determined by the integration of uniquely characteristic signals in the 1H NMR spectra of the crude reaction mixture. The individual diastereomers 9a, 9b, 10a and 10b were isolated by preparative HPLC and characterised. It is necessary to mention that the yield of 11 was low – 20% only, and the way of reaction of 2 with NPM differs from that discussed earlier – the main product in this case is Diels– Alder adduct 12 (Tsypysheva, Koval’skaya, et al. 2013; Tsypysheva, Lobov, et al. 2013; Borisevich et al. 2014). All structural elucidation and NMR signal assignments were performed using COSY, NOESY, HSQC and HMBC experiments and QC calculations (see Figures S1 – S34, Tables S1 – S9). Though NMR 1H and 13C spectra of individual diastereomers 9a, 9b, 10a and 10b have been registered, it was impossible to establish the stereochemistry of chiral C-16 centre of these compounds, because their spectral parameters are similar (Figures S7 –S18, Tables S1 and S2). The E-configuration of substituents in the compound 11 was proved by a comparison of the value of vicinal constant 3JC21-H17 (3.6 Hz) with the literary data (Vogeli et al. 1975; Pretsch et al. 2009). In addition, the optimisation of geometrical parameters of compound 11 and the total energies of Z and E isomers were located by the density functional theory calculations with the O O N
O Ph 3
O
5
H
N
6
4
a
3
CO2Me
11
7
6
8
13
N 2
1
N 12 NH2
10
9
12b 12 3a 4
13 14 5
O
a
O 12a
N 6
11 15 8
N H
N
CO2Me 6
O 3
8: R =
O
10
N 9
NH2 12
7
O
N O Ph 7
R
O 8-10 O
MeO2C
N
a
O
O
2 1
3 or 4 or 5
2
7 N
O
11
21 CO Me 2 16 N 17
Ph
12aS, 4S, 12bR, 3aR
O 4 NO2 5
9a,b: R =
16
10a,b: R =
16
Reagents and conditions: a) CH3CN, 80°C, 0.6 GPa, p-TsOH (10 mol %), 72 h.
Scheme 1. The aza-Michael reaction of 2 under HP conditions.
Ph
NO2
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Gaussian 03 at the B3LYP/6-311 þ G(2d, p) level of theory. It was proved that the E-product is more thermodynamically beneficial (DH 298 rel ¼ 6:3 kcal=mol) (Figures S19 and S20, Tables S3 –S5). The procedure of structural elucidation of Diels– Alder adduct 12 was carried out as described in our previous work (Tsypysheva, Koval’skaya, et al. 2013; Tsypysheva, Lobov, et al. 2013). The interprotonic distances for the four possible Diels– Alder adducts (Table 1) obtained by geometry optimisation at the B3LYP/6-311 þ G(2d,p) approximation (Figures S21 – S34, Tables S6– S9) and the evidence of key NOESY cross-peaks H-12b/Hsyn-15 (dH 3.52/2.15 ppm) and H-13/Hendo-11 (dH 6.65/4.70 ppm) (S6) unequivocally specified the formation of the ‘b-face attack’ adduct: mainly b-endo or b-exo diastereomer. It is known that 3JHH coupling constants between bridgehead (H-4) and adjacent (H-3a) protons were useful in determining the endo/exo orientation of dienophile residual for 2azabicyclo[2.2.2]oct-5-en-3-one derivatives (Afarinkia et al. 1992; Hoshino et al. 2008). In our case, the value of 3J4-3a (3.2 Hz) for the compound 12 indicated the exo orientation of H-3a and, hence, the endo orientation of the N-phenylsuccinimide fragment. And at last, the identical character of NMR spectra of compound 12 and the adduct of NPM with 12-N-methylcytisine with 3aR,4S,12aS,12bR stereochemistry (Tsypysheva, Koval’skaya, et al. 2013; Tsypysheva, Lobov, et al. 2013) can be useful in the establishment of the stereochemistry of 12 ‘by analogy’. Thus, it is possible to assume that the product 12 – the result of [4 þ 2]-cycloaddition of NPM to carboxamide 2 – is the b-endo adduct with 3aR,4S,12aS,12bR stereochemistry. 3. Experimental 3.1. General (– )-Cytisine [CAS 485-35-8], urea [CAS 57-13-6], 2-cyclohexen-1-one [CAS 930-68-7], 3buten-2-one [CAS 78-94-4], b-nitrostyrene [CAS 102-96-5], DMAD [CAS 762-42-5], NPM [CAS 941-69-5], acetonitrile [CAS 75-05-8] are commercially available. General rules and procedure of carrying out the reactions under HP conditions are described in Benito-Lopez et al. (2008), Jenner (2002) and Matsumoto (2007). The home-built HP device with following technical parameters has been used: limit effort 30 tons, maximum stroke 30 mm, allowable pressure 1.0 GPa, maximum temperature 2208C. CC was carried out on the 0.05 –0.1 mm standard silica 60 (kit I for low pressure flash chromatography, MACHEREY-NAGEL, Du¨ren, Germany). Chromatographic isolation of 4a, 4b and 5a, 5b was carried out with the Waters Breeze liquid chromatography system (Waters, Milford, MA, USA) with UV detection at 275 nm and reversed-phase column (Phenomenexw Luna C18, 10.00 mm £ 250 mm i.d., 10 mm particle size; Phenomenex, Torrance, CA, USA). The isocratic mobile phase was a mixture of acetonitrile and water (30:70, v/v) at flow rate 3 mL/min. The column temperature was maintained at 258C for both cases. Optical rotation was measured on Perkin-Elmer 341 (Waltham, MA, USA) LC digital polarimeter with a sodium lamp (D-line wavelength ¼ 589 nm). High-resolution electron ionisation mass spectra were recorded using the Thermo Finnigan MAT95XP mass spectrometer (Bremen, Germany) (EI, 70 eV). NMR spectra were recorded in CDCl3 or DMSO-d6 on the Bruker AVANCE-III 500 spectrometer (Fa¨llanden, Switzerland) (5 mm z-gradient BBO probe) operating at 500.30 MHz (1H) and 125.75 MHz (13C). 1H and 13C chemical shifts are expressed in parts per million (ppm) from tetramethylsilane as internal standard, 15N chemical shifts are reported relative to external liquid ammonia at 258C. The 1H NMR spectra were acquired with a spectral width of 5.6 kHz and 32 k data points and 8 scans, providing a digital resolution of ca. 0.5 Hz (1H 908 pulse
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˚ ) in theoretical modelsa for the four possible adducts 12. Table 1. Significant interprotonic distances (A Entry
Configuration
b-endo b-exo a-endo a-exo
12aS,4S,12bR,3aR 12aS,4S,12bS,3aS 12aR,4R,12bS,3aS 12aR,4R,12bR,3aR
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a
H13Hsyn15 – – 2.70 2.33
H12bHsyn15 2.24 3.78 – –
H13H12
H12bH12
H13Hendo11
H12bHendo11
2.93 3.13 2.41 2.40
2.87 2.42 3.34 2.68
2.04 1.96 – –
– – 2.14 3.19
B3LYP/6-311 þ G (2d, p) basis set.
width ¼ 11.5 ms). For 13C NMR spectra, a spectral width of 29.7 kHz was used with 64 k data points and 512 scans (13C 908 pulse width ¼ 9.7 ms). Gradient selected HSQC spectra were recorded using the standard Bruker sequence (hsqcetgp). These data were collected with 4096 £ 256 data points with 2 scans for each increment. The delay d4 was set to 1.72 ms. Gradient selected HMBC spectra (hmbcgpndqf) were collected with 4096 £ 256 data points with 4 scans for each increment. The delay d6 was set to 71.4 ms. Spectral widths of 5.6 and 29.7 kHz were used in the F2 (1H) and F1 (13C) domains, respectively. HSQC and HMBC data were processed using a sine window in the F2 and F1 dimensions. Gs-COSY data were collected with 2K £ 2K data points with 2 scans for each increment. For the 2D NOESY NMR experiments, the solution was degassed to remove any dissolved oxygen. The following parameters and procedures were commonly employed: spectral width 5.6 kHz, 2K £ 2K data matrix and 256 time increments of 2 transients each mixing time d8 ¼ 0.5 s. Fourier transformations were carried out with zerofilling using the shifted sine-bell apodization function in both dimensions. Geometry optimisation and vibrational frequency analysis of compounds 11 and 12 have been performed by the B3LYP/6-311 þ G(2d,p) approximation Gaussian03 (Frisch et al. 2003). 3.1. Aza-Michael reaction of 2 under HP conditions A mixture of 250 mg (1.1 mmol) 2 and a Michael acceptor (1.2 mmol) and 10 mol% of p-TsOH in CH3CN (ca. 1.3 mL) was placed in the Teflon reactor vessel (1.5 mL volume) and the mixture was allowed to react at 808C, pressure 0.6 GPa for 72 h leading to products 8 – 12. After the reaction mixture was cooled and the pressure was released, the CH3CN was evaporated in vacuo. The crude products were purified by flash column chromatography. 3.1.1. N-(3-Oxobutyl)cytisine-12-carboxamide (8) Compound 8 (156 mg) was obtained with 48% yield. ½a20 D ¼ 2 1088 (CHCl3, c 1.2). 13 C (CDCl3, d, ppm) 25.86 (C-8); 27.33 (C-9); 30.27 (C-19); 34.57 (C-7); 35.37 (C-16); 43.38 (C-17); 49.10 (C-10); 50.22 (C-11); 51.12 (C-13); 105.70 (C-5); 116.94 (C-3); 139.14 (C4); 149.29 (C-6); 157.54 (C-14); 163.48 (C-2); 209.47 (C-18). 15 N (CDCl3, d, ppm): 75.05 (N-12);79.16 (N-15); 174.88 (N-1). 1 H (CDCl3, d, ppm, J, Hz): 1.90 (dtd, 1H, 2J ¼ 12.7, 3J8anti-7 ¼ 3.4, 3J8anti-9 ¼ 3.4, 4J8anti2 3 3 4 10endo ¼ 1.3, Hanti-8); 1.96 (ddt, 1H, J ¼ 12.7, J8syn-7 ¼ 3.4, J8syn-9 ¼ 3.4, J8syn-11endo ¼ 1.7, 4 J8syn-13endo ¼ 1.7, Hsyn-8); 2.07 (s, 3H, H-19); 2.45 (m, 1H, H-9); 7.52 (t, 2H, 3J17-16 ¼ 5.8, H17); 3.00 (ddd, 1H, 2J ¼ 11.3, 3Jexo-9 ¼ 2.5, 4Jexo-10exo ¼ 1.0, Hexo-11); 3.02 (dd, 1H, 2J ¼ 13.4, 3 J13exo-7 ¼ 2.4, Hexo-13); 3.02 (m, 1H, H-7); 3.24 (q, 2H, 3J16-15 ¼ 5.8, 3J16-17 ¼ 5.8,H-16); 3.79 (ddd, 1H, 2J ¼ 15.6, 3J10exo-9 ¼ 6.6, 4J10exo-11exo ¼ 1.0, Hexo-10); 3.98 (ddt, 1H, 2J ¼ 13.4, 3 J13endo-7 ¼ 3.1, 4J13endo-11endo ¼ 1.7, 4J13endo-8syn ¼ 1.7, Hendo-13); 4.00 (ddt, 1H, 2J ¼ 11.3, 3 Jendo-9 ¼ 3.3, 4Jendo-13endo ¼ 1.7, 4Jendo-8syn ¼ 1.7, Hendo-11); 4.08 (dt, 1H, 2J ¼ 15.6, 3 J10endo-9 ¼ 1.0, 4J10endo-8anti ¼ 1.0, Hendo-10); 5.42 (t, 1H,3J15-16 ¼ 5.8,H-15); 6.06 (d, 1H,
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J5-4 ¼ 6.9, 4J5-3 ¼ 1.5, H-5); 6.38 (dd, 1H, 3J3-4 ¼ 9.1, 4J3-5 ¼ 1.5, H-3); 7.25 (d, 1H, J4-3 ¼ 9.1, 3J4-5 ¼ 6.9, H-4). HR-MS (EI): m/z calculated for C16H21N3O3 [Mþ] 303.1577; found 303.1566.
3.1.2. N-[(1R)-3-Oxocyclohexyl]cytisine-12-carboxamide and (N-[(1S)-3-oxocyclohexyl] cytisine-12-carboxamide (9a,b):
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The mixture of diastereomers 9a,b (235 mg) was obtained with 81% yield. 3.1.2.1. (9a). ½a20 D ¼ 2 2108 (CH3OH, c 1.4) 13 C (CDCl3, d, ppm): 22.08 (C-20); 25.92 (C-8); 27.44 (C-9); 31.18 (C-21); 34.58 (C-7); 40.97 (C-19); 48.14 (C-17); 49.10 (C-10); 49.84 (C-16); 50.64 (C-11); 51.15 (C-13); 105.60 (C-5); 117.13 (C-3); 139.12 (C-4); 149.22 (C-6); 156.77 (C-14); 163.40 (C-2); 209.63 (C18). 1 H (CDCl3, d, ppm, J, Hz): 1.53 (dddd, 1H, 2J ¼ 12.7, 3J21ax-20ax ¼ 10.1, 3J21ax-16 ¼ 8.9, 3 J21ax-20eq ¼ 5.5, 3J21ax-21eq ¼ 3.7, Hax-21); 1.65 (dtdd, 1H, 2J ¼ 14.0, 3J20ax-21ax ¼ 10.1, 3 J20ax-19ax ¼ 10.1, 3J20ax-19eq ¼ 5.5, 3J20ax-21eq ¼ 3.7, Hax-20); 1.83 (dtdd, 1H, 2J ¼ 14.0, 3J20eq3 3 3 21ax ¼ 5.5, J20eq-19ax ¼ 5.5, J20eq-19eq ¼ 5.0, J20eq-21eq ¼ 3.7, Heq-20); 1.91 (m, 1H, Heq-21); 2 3 3 1.95 (dtd, 1H, J ¼ 12.9, J8anti-7 ¼ 3.0, J8anti-9 ¼ 3.2, 4J8anti-10endo ¼ 1.0, Hanti-8); 2.02 (dtt, 1H, 2J ¼ 12.9, 3J8syn-7 ¼ 3.2, 3J8syn-9 ¼ 3.2, 4J8syn-11endo ¼ 1.6, 4J8syn-13endo ¼ 1.6, Hsyn-8); 2.16 (dd, 1H, 2J ¼ 14.5, 3J17ax-16 ¼ 9.5, Hax-17); 2.20 (ddd, 1H, 2J ¼ 14.0, 3J19ax-20ax ¼ 10.1, 3 J19ax-20eq ¼ 5.5, Hax-19); 2.33 (dddt, 1H, 2J ¼ 14.0, 3J19eq-20ax ¼ 5.5, 3J19eq-20eq ¼ 5.0, 4 J19eq-17eq ¼ 1.6, 4J19eq-21eq ¼ 1.6, Heq-19); 2.50 (m, 1H, H-9); 2.56 (ddt, 1H, 2J ¼ 14.5, 3 J17eq-16 ¼ 4.8, 4J17eq-19eq ¼ 1.6, 4J17eq-21eq ¼ 1.6, Heq-17); 3.05 (dd, 1H, 2J ¼ 12.4, 3 J13exo-7 ¼ 2.2, Hexo-13); 3.07 (m, 1H, H-7); 3.11 (ddd, 1H, 2J ¼ 13.2, 3Jexo-9 ¼ 2.8, 4Jexo2 3 4 10exo ¼ 1.2, Hexo-11); 3.85 (ddd, 1H, J ¼ 15.6, J10exo-9 ¼ 6.6, J10exo11exo ¼ 1.2, Hexo-10); 3 3 3 3 3.96 (ddddd, 1H, J16-17ax ¼ 9.5, J16-21ax ¼ 8.9, J16-15 ¼ 6.9, J16-17eq ¼ 4.8, 3J16-21eq ¼ 3.3, H-16); 4.01 (ddt, 1H, 2J ¼ 13.2, 3Jendo-9 ¼ 3.2, 4Jendo-8syn ¼ 1.6, 4Jendo-13endo ¼ 1.6, Hendo-11); 4.11 (ddt, 1H, 2J ¼ 12.4, 3J13endo-7 ¼ 3.2, 4J13endo-11endo ¼ 1.6, 4J13endo-8syn ¼ 1.6, Hendo-13); 4.17 (dt, 1H, 2J ¼ 15.6, 3J10endo-9 ¼ 1.0, 4J10endo-8anti ¼ 1.0, Hendo-10); 4.85 (d, 1H, 3 J15-16 ¼ 6.9, H-15); 6.10 (dd, 1H, 3J5-4 ¼ 6.9, 4J5-3 ¼ 1.5, H-5); 6.43 (dd, 1H, 3J3-4 ¼ 9.0, 4 J3-5 ¼ 1.5, H-3); 7.31 (dd, 1H, 3J4-3 ¼ 9.0, 3J4-5 ¼ 6.9, H-4). HR-MS (EI): m/z calculated for C18H23N3O3 [Mþ] 329.1734; found 329.1747. 3.1.2.2. (9b). ½a20 D ¼ 2 1628 (CH3OH, c 2.0) 13 C (CDCl3, d, ppm): 22.00 (C-20); 25.92 (C-8); 27.41 (C-9); 31.13 (C-21); 34.61 (C-7); 40.97 (C-19); 48.07 (C-17); 49.07 (C-10); 49.84 (C-16); 50.35 (C-11); 51.59 (C-13); 105.28 (C-5); 117.33 (C-3); 138.87 (C-4); 149.21 (C-6); 156.71 (C-14); 163.36 (C-2); 209.62 (C-18). 1 H (CDCl3, d, ppm, J, Hz): 1.52 (dddd, 1H, 2J ¼ 12.7, 3J21ax-20ax ¼ 10.1, 3J21ax-16 ¼ 8.9, 3 J21ax-20eq ¼ 5.5, 3J21ax-21eq ¼ 3.7, Hax-21); 1.64 (dtdd, 1H, 2J ¼ 14.0, 3J20ax-21ax ¼ 10.1, 3 J20ax-19ax ¼ 10.1, 3J20ax-19eq ¼ 5.5, 3J20ax-21eq ¼ 3.7, Hax-20); 1.83 (dtdd, 1H, 2J ¼ 14.0, 3 J20eq-21ax ¼ 5.5,3J20eq-19ax ¼ 5.5, 3J20eq-19eq ¼ 5.0, 3J20eq-21eq ¼ 3.7, Heq-20); 1.91 (m, 1H, Heq-21); 1.95 (dtd, 1H, 2J ¼ 12.9, 3J8anti-7 ¼ 3.0, 3J8anti-9 ¼ 3.2, 4J8anti-10endo ¼ 1.0, Hanti-8); 2.02 (dtt, 1H, 2J ¼ 12.9, 3J8syn-7 ¼ 3.2, 3J8syn-9 ¼ 3.2, 4J8syn-11endo ¼ 1.6, 4J8syn-13endo ¼ 1.6, Hsyn-8); 2.18 (dd, 1H, 2J ¼ 14.5, 3J17ax-16 ¼ 9.5, Hax-17); 2.19 (ddd, 1H, 2J ¼ 14.0, 3 J19ax-20ax ¼ 10.1, 3J19ax-20eq ¼ 5.5, Hax-19); 2.32 (dddt, 1H, 2J ¼ 14.0, 3J19eq-20ax ¼ 5.5, 3 J19eq-20eq ¼ 5.0, 4J19eq-17eq ¼ 1.6, 4J19eq-21eq ¼ 1.6, Heq-19); 2.50 (m, 1H, H-9); 2.58 (ddt, 1H, 2 J ¼ 14.5, 3J17eq-16 ¼ 4.8, 4J17eq-19eq ¼ 1.6, 4J17eq-21eq ¼ 1.6, Heq-17); 3.06 (ddd, 1H, 2 J ¼ 11.2,3Jexo-9 ¼ 2.8, 4Jexo-10exo ¼ 1.2, Hexo-11); 3.07 (m, 1H, H-7); 3.11 (dd, 1H, 2 J ¼ 12.8, 3J 13exo-7 ¼ 2.2, Hexo-13); 3.84 (ddd, 1H, 2 J ¼ 15.6, 3J 10exo-9 ¼ 6.5,
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J10exo11exo ¼ 1.2, Hexo-10); 3.95 (ddt, 1H, 2J ¼ 12.8, 3J13endo-7 ¼ 3.2, 4J13endo-11endo ¼ 1.6, J13endo-8syn ¼ 1.6, Hendo-13); 3.96 (ddddd, 1H, 3J16-17ax ¼ 9.5,3J16-21ax ¼ 8.9,3J16-15 ¼ 6.9, 3 J16-17eq ¼ 4.8, 3J16-21eq ¼ 3.3, H-16); 4.11 (ddt, 1H, 2J ¼ 11.2, 3Jendo-9 ¼ 3.2, 4Jendo-8syn ¼ 1.6, 4 Jendo-13endo ¼ 1.6, Hendo-11); 4.14 (dt, 1H, 2J ¼ 15.6, 3J10endo-9 ¼ 1.0, 4J10endo-8anti ¼ 1.0, Hendo10); 4.69 (d, 1H, 3J15-16 ¼ 6.9, H-15); 6.08 (dd, 1H, 3J5-4 ¼ 6.9, 4J5-3 ¼ 1.5, H-5); 6.44 (dd, 1H, 3 J3-4 ¼ 9.0, 4J3-5 ¼ 1.5, H-3); 7.29 (dd, 1H, 3J4-3 ¼ 9.0, 3J4-5 ¼ 6.9, H-4). HR-MS (EI): m/z calculated for C18H23N3O3 [Mþ] 329.1734; found 329.1747. 4 4
3.1.3. N-[(1S)-2-Nitro-1-phenylethyl]cytisine-12-carboxamide and N-[(1R)-2-nitro-1phenylethyl]cytisine-12-carboxamide (10a,b)
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The mixture of diastereomers 10a,b (274 mg) was obtained with 67% yield. 3.1.3.1. (10a). ½a20 D ¼ 2 1028 (DMSO, c 1.4). 13 C (DMSO, d, ppm): 24.85 (C-8); 26.49 (C-9); 33.71 (C-7); 48.63 (C-10); 48.89 (C-11); 50.22 (C-13); 51.93 (C-16); 78.39 (C-17); 104.91 (C-5); 115.54 (C-3); 126.08 (C-20(24)); 127.37 (C-22); 128.39 (C-21(23)); 138.73 (C-19); 138.95 (C-4); 149.89 (C-6); 155.86 (C-14); 162.28 (C-2). 15 N (DMSO, d, ppm): 85.65 (N-15); 175.90 (N-1); 383.76 (N-18). 1 H (DMSO, d, ppm, J, Hz): 1.87 (m, 1H, Hanti-8);1.90 (m, 1H, Hsyn-8); 2.42 (m, 1H, H-9); 2.92 (ddd, 1H, 2J ¼ 12.7, 3Jexo-9 ¼ 2.5, 4Jexo-10exo ¼ 1.0, Hexo-11); 3.09 (dd, 1H, 2J ¼ 12.7, 3 J13exo-7 ¼ 2.5, Hexo-13); 3.13 (m, 1H, H-7); 3.66 (ddd, 1H, 2J ¼ 15.6, 3J10exo-9 ¼ 6.6, 4J10exo2 3 4 11exo ¼ 1.0, Hexo-10); 3.78 (dt, 1H, J ¼ 15.6, J10endo-9 ¼ 1.0, J10endo-8anti ¼ 1.0, Hendo-10); 2 3 4 4.00 (ddt, 1H, J ¼ 12.7, J13endo-7 ¼ 3.1, J13endo-11endo ¼ 1.7, 4J13endo-8syn ¼ 1.7, Hendo-13); 4.16 (ddt, 1H, 2J ¼ 12.7, 3Jendo-9 ¼ 3.3, 4Jendo-13endo ¼ 1.7, 4Jendo-8syn ¼ 1.7, Hendo-11); 4.73 (dd, 1H, 2J17a-17b ¼ 13.1,3J17a-16 ¼ 10.4, Ha-17); 4.86 (dd, 1H, 2J17b-17a ¼ 13.1,3J17b-16 ¼ 4.9, Hb-17); 5.38 (ddd, 1H, 3J16-17a ¼ 10.4, 3J16-15 ¼ 8.4, 3J16-17b ¼ 4.9, H-16); 6.22 (dd, 1H, 3 J 5-4 ¼ 7.0, 4 J 5-3 ¼ 1.5, H-5); 6.26 (dd, 1H, 3J 3-4 ¼ 9.1, 4 J 3-5 ¼ 1.5, H-3); 6.98 (d, 1H,2J15-16 ¼ 8.4, H-15); 7.05 (d, 2H,3J20(24)-21(23) ¼ 7.7, H-20(24)); 7.23 (m, 1H, H22),7.25 (m, 2H, H-21(23)); 7.40 (d, 1H, 3J4-3 ¼ 9.1, 3J4-5 ¼ 7.0, H-4). HR-MS (EI): m/z calculated for C20H22N4O4 [Mþ] 382.1636; found 382.1646. 3.1.3.2. (10b). ½a20 D ¼ 2 1138 (DMSO, c 0.6) 13 C (DMSO, d, ppm): 24.93 (C-8); 26.57 (C-9); 33.69 (C-7); 48.49 (C-10); 49.26 (C-11); 49.97 (C-13); 52.27 (C-16); 78.42 (C-17); 104.73 (C-5); 115.56 (C-3); 126.03 (C-20(24)); 127.31 (C-22); 128.34 (C-21(23)); 138.79 (C-19); 138.90 (C-4); 150.01 (C-6); 155.98 (C-14); 162.28 (C-2). 15 N (DMSO, d, ppm): 85.65 (N-15); 383.76 (N-18). 1 H (DMSO, d, ppm, J, Hz): 1.89 (m, 1H, Hanti-8); 1.89 (m, 1H, Hsyn-8); 2.45 (m, 1H, H-9); 2.96 (dd, 1H, 2J ¼ 12.8, 3J13exo-7 ¼ 2.5, Hexo-13); 3.02 (ddd, 1H, 2J ¼ 12.7, 3Jexo-9 ¼ 2.5, 4 Jexo-10exo ¼ 1.0, Hexo-11); 3.02 (m, 1H, H-7); 3.72 (ddd, 1H, 2J ¼ 15.6, 3J10exo-9 ¼ 6.6, 4 J10exo-11exo ¼ 1.0, Hexo-10); 4.01 (ddt, 1H, 2J ¼ 12.8, 3J13endo-7 ¼ 3.1, 4J13endo-11endo ¼ 1.7, 4 J13endo-8syn ¼ 1.7, Hendo-13); 4.08 (dt, 1H, 2J ¼ 15.6, 3J10endo-9 ¼ 1.0, 4J10endo-8anti ¼ 1.0, Hendo-10); 4.09 (ddt, 1H, 2J ¼ 12.7, 3Jendo-9 ¼ 3.3, 4Jendo-13endo ¼ 1.7, 4Jendo-8syn ¼ 1.7, H endo-11); 4.69 (dd, 1H, 2J 17a-17b ¼ 12.8,3J 17a-16 ¼ 10.4, H a-17); 4.88 (dd, 1H, 2 J17b-17a ¼ 12.8, 3J17b-16 ¼ 4.3, Hb-17); 5.31 (ddd, 1H, 3J16-17a ¼ 10.4, 3J16-15 ¼ 8.8, 3 J16-17b ¼ 4.3, H-16); 6.10 (dd, 1H, 3J5-4 ¼ 7.0, 4J5-3 ¼ 1.5, H-5); 6.23 (dd, 1H, 3J3-4 ¼ 9.1, 4 J3-5 ¼ 1.5, H-3); 7.09 (d, 1H,2J15-16 ¼ 8.9, H-15); 7.15 (d, 2H, 3J20(24)-21(23) ¼ 7.3, H-20(24));
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7.15 (t, 1H, 3J22-21(23) ¼ 7.3, H-22); 7.28 (dd, 1H, 3J4-3 ¼ 9.1, 3J4-5 ¼ 7.0, H-4); 7.29 (t, 1H, 3 J21(23)-20(24) ¼ 7.3, 3J21(23)-22 ¼ 7.3, H-21(23)). HR-MS (EI): m/z calculated for C20H22N4O4 [Mþ] 382.1636; found 382.1646. 3.1.4. Dimethyl (2E)-2-[(cytisine-12-ylcarbonyl)amino]but-2-enedioate (11) Compound 11 (80 mg) was obtained with 20% yield. ½a20 D ¼ 2 2248 (CHCl3, c 0.9) 13 C (CDCl3, d, ppm):25.73 (C-8); 27.34 (C-9); 34.42 (C-7); 48.93 (C-10); 50.51 (C-11); 51.27 (C-13); 51.80 (C-20); 52.92 (C-23); 98.12 (C-17); 105.95 (C-5); 117.61 (C-3); 139.06 (C-4); 146.47 (C-16); 148.11 (C-6); 152.68 (C-14); 163.44 (C-2); 164.44 (C-21); 169.45 (C-18). 1 H (CDCl3, d, ppm, J, Hz): 2.00 (dtd, 1H, 2J ¼ 13.3, 3J8anti-7 ¼ 3.4, 3J8anti-9 ¼ 3.4, 4J8anti2 3 3 4 10endo ¼ 1.3, Hanti-8); 2.06 (ddt, 1H, J ¼ 13.3, J8syn-7 ¼ 3.4, J8syn-9 ¼ 3.4, J8syn-11endo ¼ 1.7, 4 J8syn-13endo ¼ 1.7, Hsyn-8); 2.58 (m, 1H, H-9); 3.13 (m, 1H, H-7); 3.20 (m, 1H, Hexo-11); 3.25 (m, 1H, Hexo-13); 3.73 (s, 1H, H-20); 3.74 (s, 1H, H-23); 3.94 (d, 1H, 2J ¼ 15.8, Hexo-10); 4.10 (m, 1H, Hendo-13); 4.16 (d, 1H, 2J ¼ 15.8, Hendo-10); 4.20 (m, 1H, Hendo-11); 5.36 (s, 1H, H-17); 6.13 (d, 1H, 3J5-4 ¼ 6.9, 4J5-3 ¼ 1.5, H-5); 6.49 (dd, 1H, 3J3-4 ¼ 9.1, 4J3-5 ¼ 1.5, H-3); 7.30 (d, 1H, 3J4-3 ¼ 9.1, 3J4-5 ¼ 6.9, H-4). HR-MS (EI): m/z calculated for C18H21N3O3 [Mþ] 375.1425; found 375.1413. 3.1.5. (3aR,4S,8S,12R,12aS,12bR)-1,3,5-Trioxo-2-phenyldecahydro-1H-4,12a-etheno-8,12methanopyrrolo[3 0 ,4 0 :3,4]pyrido[1,2-a][1,5]diazocine-10(7H)-carboxamide (12) Compound 12 (300 mg) was obtained with 69% yield. ½a20 D ¼ þ 12.08 (CH3OH, c 1.2) 13 C (CDCl3, d, ppm): 173.16 (C-5); 45.07 (C-4); 129.63 (C-14); 134.71 (C-13); 62.79 (C12a); 29.28 (C-12); 25.75 (C-15); 25.90 (C-8); 46.91 (C-7); 50.37 (C-9); 45.91 (C-11); 42.68 (C3a); 47.56 (C-12b); 174.13 (C-1); 174.56 (C-3); 131.29 (C-10 ); 126.32 (C-20 (60 )); 129.20 (C-30 (50 )); 129.01 (C-40 ); 158.33 (C-100 ). 1 H (CDCl3, d, ppm, J, Hz): 1.98 (dtd, 1H, 2J ¼ 13.7, 3J15anti-12 ¼ 3.7, 3J15anti-8 ¼ 3.7, 4 J15anti-7endo ¼ 1.7, Hanti-15); 2.15 (dtt, 1H, 2J ¼ 13.7, 3J15syn-12 ¼ 3.2,3J15syn-8 ¼ 3.2, 4J15syn4 2 3 9endo ¼ 1.5, J15syn-11endo ¼ 1.5, Hsyn-15); 2.22 (m, 1H, H-8); 2.92 (dd, 1H, J ¼ 13.9, Jexo2 3 4 12 ¼ 2.5, Hexo-11); 3.19 (m, 1H, H-12); 3.20 (ddd, 1H, J ¼ 12.0, J9exo-8 ¼ 2.3 J9exo2 3 4 7exo ¼ 1.2, Hexo-9); 3.28 (ddd, 1H, J ¼ 13.7, J7exo-8 ¼ 6.3, J7exo-9exo ¼ 1.2, Hexo-7); 3.34 (dd, 3 3 3 1H, J3a-12b ¼ 7.9, J3a-4 ¼ 3.2, H-3a); 3.52 (d, 1H, J12b-3a ¼ 7.9, H-12b); 3.70 (dt, 1H, 2 J ¼ 13.7, 3J 7endo-8 ¼ 1.7, 4J 7endo-15anti ¼ 1.7, H endo-7); 3.70 (ddt, 1H, 2 J ¼ 12.0, 3 J9endo-8 ¼ 3.0, 4J9endo-11endo ¼ 1.5, 4J9endo-15syn ¼ 1.5, Hendo-9); 3.90 (ddd, 1H, 3J4-14 ¼ 6.2, 3 J4-3a ¼ 3.2, 4J4-13 ¼ 1.5, H-4); 4.70 (ddt, 1H, 2J ¼ 13.9, 3Jendo-12 ¼ 3.0, 4Jendo-9endo ¼ 1.5, 4 Jendo-15syn ¼ 1.5, Hendo-11); 6.43 (dd, 1H, 3J14-13 ¼ 8.0, 3J14-4 ¼ 6.2, H-14); 6.65 (dd, 1H, 3J13-14 ¼ 8.0, 4J13-4 ¼ 1.5, H-13); 7.13 (dt, 2H, 3J20 (60 )-30 (50 ) ¼ 6.8, 4J20 (60 )-40 ¼ 1.7, 4J20 (60 )-60 3 4 3 0 0 0 (20 ) ¼ 1.7, H-2 (6 )); 7.40 (tt, 1H, J40 -30 (50 ) ¼ 8.2, J40 -20 (60 ) ¼ 1.7, H-4 ); 7.45 (ddd, 2H, J30 3 4 0 0 (50 )-40 ¼ 8.2, J30 (50 )-20 (60 ) ¼ 6.8, J30 (50 )-50 (30 ) ¼ 1.7, H-3 (5 )). HR-MS (EI): m/z calculated for C22H22N4O4 [Mþ] 406.1641; found 406.1633. 4. Conclusions Thus, the first example of an aza-Michael reaction of 12-N-carboxamide of quinolizidine alkaloid (–)-cytisine under HP condition is presented. The new unsymmetrical ‘cytisinecontaining’ ureas are synthesised from 12-N-carboxamide of (– )-cytisine and a,b-unsaturated ketones, DMAD and b-nitrostyrene. The [4 þ 2]-cycloaddition took place in the case of NPM.
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Supplementary material Supplementary material relating to this article is available online, alongside Figures S1 –S34 and Tables S1 –S9. Funding This study was supported by the Russian Foundation for Basic Research [grant number 12-03-00724-a] and Foundation of Bashkortostan Republic for Young Scientists (2014).
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References Afarinkia K, Vinader V, Nelson TD, Posner GH. 1992. Diels –Alder cycloadditions of 2-pyrones and 2-pyridones. Tetrahedron. 48:9111–9171. Azad S, Kobayashi T, Nakano K, Ichikawa Y, Kotsuki H. 2009. Efficient Bronsted acid-catalyzed aza-Michael reaction of amides and ureas with a,b-unsaturated enones under high-pressure conditions. Tetrahedron Lett. 50:48–50. Benito-Lopez F, Egberink RJM, Reinhoudt DN, Verboom W. 2008. High pressure in organic chemistry on the way to miniaturization. Tetrahedron. 64:10023–10040. Borisevich SS, Koval’skaya AV, Tsypysheva IP, Khursan SL. 2014. Thermodynamically controlled Diels–Alder reaction of 12-N-methylcytisine: a DFT study. J Theor Comput Chem. doi:10.1142/S0219633614500485 Canu Boido C, Sparatore F. 1999. Synthesis and preliminary pharmacological evaluation of some cytisine derivatives. Il Farmaco. 54:438–451. Canu Boido C, Tasso B, Boido V, Sparatore F. 2003. Cytisine derivatives as ligands for neuronal nicotine receptors and with various pharmacological activities. Il Farmaco. 58:265–277. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA, Vreven JT, Kudin KN, Burant JC, et al. 2003. Gaussian 03, Revision B.02. Pittsburgh, PA: Gaussian, Inc. Hoshino M, Matsuzaki H, Fujita R. 2008. Diels–Alder reaction of 2(1H)-pyridones acting as dienes. Chem Pharm Bull. 56:480–484. Jenner G. 2002. Comparative activation modes in organic synthesis. The specific role of high pressure. Tetrahedron. 58:5185–5202. Matsumoto K. 2007. High-pressure synthesis of heterocycles related to bioactive molecules. Top Heterocycl Chem. 8:1– 42. Moura S, Thomassigny C, Ligeour C, Greck C, Joseph D, Drege E, Dumas F. 2011. Asymmetric aza-Michael addition under ultra-high pressure: short bias to polyhydroxylated piperidines. Green Chem. 13(1812):1818. Pretsch E, Buehlmann P, Badertscher M. 2009. Structure determination of organic compounds. 4th ed. Berlin Heidelberg: Springer-Verlag. Rulev AYu, Kotsuki H, Maddaluno J. 2012. High pressure promoted aza-Michael addition of primary and secondary amines to a-substituted acrylates. Green Chem. 14:503–508. Tsypysheva IP, Koval’skaya AV, Makara NS, Lobov AN, Petrenko IA, Galkin EG, Sapozhnikova TA, Zarudii FS, Yunusov MS. 2012. Synthesis and specific nootropic activity of ( –)-cytisine derivarives with carbamide and thiocarbamide moieties in their structure. Chem Nat Compd. 48:629–634. Tsypysheva IP, Koval’skaya AV, Lobov AN, Salimgareeva MKh, Fatkullina USh, Petrova PR, Gabdrakhmanova SF, Makara NS, Suponitskii KYu, Vakhitova YuV, et al. 2013. Synthesis and neuropharmacological activity of N-1adamantylcytisine-12-carbamide and its 12-thiocarbonyl analog. Chem Nat Compd. 49:707–711. Tsypysheva IP, Lobov AN, Kovalskaya AV, Vinogradova VI, Suponitskii KYu, Khursan SL, Yunusov MS. 2013. Synthesis of Diels –Alder adducts of the quinolizidine alkaloids N-methylcytisine, ( –)-leontidine, and (– )thermopsine with N-phenylmaleimide. Tetrahedron: Asymmetry. 24:1318–1323. Vogeli U, von Philipsborn W. 1975. Vicinal C, H spin coupling in substituted alkenes. Stereochemical significance and structural effects. Org Magn Reson. 7:617– 627.
Natural Product Research: Formerly Natural Product Letters Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/gnpl20
Aza-Michael reaction of 12-Ncarboxamide of (–)-cytisine under high pressure conditions a
a
a
Inna P. Tsypysheva , Alexander N. Lobov , Alena V. Kovalskaya , b
a
a
Polina R. Petrova , Sergey P. Ivanov , Shamil A. Rameev , Sophia a
a
S. Borisevich , Rustam L. Safiullin & Marat S. Yunusov
a
a
Institute of Organic Chemistry, Ufa Scientific Center of the Russian Academy of Sciences, 71, pr. Oktyabrya, 450054 Ufa, Russian Federation b
Department of Chemistry, Bashkir State University, 32, Validy Str., 450076 Ufa, Russian Federation Published online: 21 Oct 2014.
To cite this article: Inna P. Tsypysheva, Alexander N. Lobov, Alena V. Kovalskaya, Polina R. Petrova, Sergey P. Ivanov, Shamil A. Rameev, Sophia S. Borisevich, Rustam L. Safiullin & Marat S. Yunusov (2015) Aza-Michael reaction of 12-N-carboxamide of (–)-cytisine under high pressure conditions, Natural Product Research: Formerly Natural Product Letters, 29:2, 141-148, DOI: 10.1080/14786419.2014.968150 To link to this article: http://dx.doi.org/10.1080/14786419.2014.968150
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Natural Product Research, 2015 Vol. 29, No. 2, 141–148, http://dx.doi.org/10.1080/14786419.2014.968150
Aza-Michael reaction of 12-N-carboxamide of ( –)-cytisine under high pressure conditions Inna P. Tsypyshevaa*, Alexander N. Lobova, Alena V. Kovalskayaa, Polina R. Petrovab, Sergey P. Ivanova, Shamil A. Rameeva, Sophia S. Borisevicha, Rustam L. Safiullina and Marat S. Yunusova
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a
Institute of Organic Chemistry, Ufa Scientific Center of the Russian Academy of Sciences, 71, pr. Oktyabrya, 450054 Ufa, Russian Federation; bDepartment of Chemistry, Bashkir State University, 32, Validy Str., 450076 Ufa, Russian Federation (Received 24 July 2013; final version received 12 September 2014) The first example of aza-Michael reaction of 12-N-carboxamide of quinolizidine alkaloid ( –)-cytisine with a,b-unsaturated ketones, dimethyl acetylenedicarboxylate and b-nitrostyrene under high pressure condition has been described. It has been shown that the [4 þ 2]-cycloaddition takes place in the case with N-phenylmaleimide. Keywords: aza-Michael reaction; high pressure; ( – )-cytisine
1. Introduction The synthesis of new derivatives of quinolizidine alkaloid (– )-cytisine (1) (Figure 1), the natural ligand of nicotinic acetylcholine receptor (nAcChR), is interesting from the point of view of neuropharmacological activity. More than thousands of ( –)-cytisine analogues are obtained by chemical transformations, based on the reactions of its secondary amino group. It was demonstrated that the nature of the substituent in N-12 position can influence the affinity towards nAcChR (Canu Boido & Sparatore 1999; Canu Boido et al. 2003). Recently, we have shown that some (–)-cytisine derivatives with various topology of thioand carboxamide fragments at the starting molecule showed neuropharmacological activity in vivo (Tsypysheva et al. 2012; Tsypysheva, Koval’skaya, et al. 2013; Tsypysheva, Lobov, et al. 2013). Thereupon we decided to make an attempt to synthesise new derivatives of (–)-cytisine with carboxamide moieties at the 12th position (Figure 1). In spite of the fact that the reactivity of the ureas (as nucleophiles) in the aza-Michael reaction is very low, the intensification of this process is possible by carrying out the reaction under the high-pressure (HP) conditions (Jenner 2002). The publications (Azad et al. 2009; Moura et al. 2011; Rulev et al. 2012) have inspired us to use this approach for the synthesis of 12-N-carboxamides of (– )-cytisine with nitro, keto and carboxyl groups in urea’s fragment by reaction of cytisin-12-carboxamide (2) with such Michael acceptors as 3-buten-2-one (3), 2-cyclohexen-1-one (4), b-nitrostyrene (5), dimethyl acetylenedicarboxylate (DMAD) (6) and N-phenylmaleimide (NPM) (7). 2. Results and discussion Starting carboxamide 2 was synthesised from (– )-cytisine (1) and urea in boiling toluene (Tsypysheva et al. 2012). A mixture of 2, a Michael acceptor and 10 mol% of p-TsOH in CH3CN
*Corresponding author. Email: [email protected] q 2014 Taylor & Francis
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4
13 9
1
2
O
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N
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12
7
10
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Figure 1. (– )-Cytisine.
(ca. 1.3 mL) was placed in a Teflon reactor vessel and the mixture was allowed to react at 808C, pressure 0.6 GPa for 72 h leading to products 8 – 12 (Scheme 1). After the reaction mixture was cooled and the pressure was released, the CH3CN was evaporated in vacuo, and products were isolated by column chromatography (CC). The yields of Michael adducts 8, 9a,b and 10a,b were 48%, 81% and 67%, and the compounds 9a,b and 10a,b were obtained as diastereomeric pairs in < 1:1 ratio as determined by the integration of uniquely characteristic signals in the 1H NMR spectra of the crude reaction mixture. The individual diastereomers 9a, 9b, 10a and 10b were isolated by preparative HPLC and characterised. It is necessary to mention that the yield of 11 was low – 20% only, and the way of reaction of 2 with NPM differs from that discussed earlier – the main product in this case is Diels– Alder adduct 12 (Tsypysheva, Koval’skaya, et al. 2013; Tsypysheva, Lobov, et al. 2013; Borisevich et al. 2014). All structural elucidation and NMR signal assignments were performed using COSY, NOESY, HSQC and HMBC experiments and QC calculations (see Figures S1 – S34, Tables S1 – S9). Though NMR 1H and 13C spectra of individual diastereomers 9a, 9b, 10a and 10b have been registered, it was impossible to establish the stereochemistry of chiral C-16 centre of these compounds, because their spectral parameters are similar (Figures S7 –S18, Tables S1 and S2). The E-configuration of substituents in the compound 11 was proved by a comparison of the value of vicinal constant 3JC21-H17 (3.6 Hz) with the literary data (Vogeli et al. 1975; Pretsch et al. 2009). In addition, the optimisation of geometrical parameters of compound 11 and the total energies of Z and E isomers were located by the density functional theory calculations with the O O N
O Ph 3
O
5
H
N
6
4
a
3
CO2Me
11
7
6
8
13
N 2
1
N 12 NH2
10
9
12b 12 3a 4
13 14 5
O
a
O 12a
N 6
11 15 8
N H
N
CO2Me 6
O 3
8: R =
O
10
N 9
NH2 12
7
O
N O Ph 7
R
O 8-10 O
MeO2C
N
a
O
O
2 1
3 or 4 or 5
2
7 N
O
11
21 CO Me 2 16 N 17
Ph
12aS, 4S, 12bR, 3aR
O 4 NO2 5
9a,b: R =
16
10a,b: R =
16
Reagents and conditions: a) CH3CN, 80°C, 0.6 GPa, p-TsOH (10 mol %), 72 h.
Scheme 1. The aza-Michael reaction of 2 under HP conditions.
Ph
NO2
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Gaussian 03 at the B3LYP/6-311 þ G(2d, p) level of theory. It was proved that the E-product is more thermodynamically beneficial (DH 298 rel ¼ 6:3 kcal=mol) (Figures S19 and S20, Tables S3 –S5). The procedure of structural elucidation of Diels– Alder adduct 12 was carried out as described in our previous work (Tsypysheva, Koval’skaya, et al. 2013; Tsypysheva, Lobov, et al. 2013). The interprotonic distances for the four possible Diels– Alder adducts (Table 1) obtained by geometry optimisation at the B3LYP/6-311 þ G(2d,p) approximation (Figures S21 – S34, Tables S6– S9) and the evidence of key NOESY cross-peaks H-12b/Hsyn-15 (dH 3.52/2.15 ppm) and H-13/Hendo-11 (dH 6.65/4.70 ppm) (S6) unequivocally specified the formation of the ‘b-face attack’ adduct: mainly b-endo or b-exo diastereomer. It is known that 3JHH coupling constants between bridgehead (H-4) and adjacent (H-3a) protons were useful in determining the endo/exo orientation of dienophile residual for 2azabicyclo[2.2.2]oct-5-en-3-one derivatives (Afarinkia et al. 1992; Hoshino et al. 2008). In our case, the value of 3J4-3a (3.2 Hz) for the compound 12 indicated the exo orientation of H-3a and, hence, the endo orientation of the N-phenylsuccinimide fragment. And at last, the identical character of NMR spectra of compound 12 and the adduct of NPM with 12-N-methylcytisine with 3aR,4S,12aS,12bR stereochemistry (Tsypysheva, Koval’skaya, et al. 2013; Tsypysheva, Lobov, et al. 2013) can be useful in the establishment of the stereochemistry of 12 ‘by analogy’. Thus, it is possible to assume that the product 12 – the result of [4 þ 2]-cycloaddition of NPM to carboxamide 2 – is the b-endo adduct with 3aR,4S,12aS,12bR stereochemistry. 3. Experimental 3.1. General (– )-Cytisine [CAS 485-35-8], urea [CAS 57-13-6], 2-cyclohexen-1-one [CAS 930-68-7], 3buten-2-one [CAS 78-94-4], b-nitrostyrene [CAS 102-96-5], DMAD [CAS 762-42-5], NPM [CAS 941-69-5], acetonitrile [CAS 75-05-8] are commercially available. General rules and procedure of carrying out the reactions under HP conditions are described in Benito-Lopez et al. (2008), Jenner (2002) and Matsumoto (2007). The home-built HP device with following technical parameters has been used: limit effort 30 tons, maximum stroke 30 mm, allowable pressure 1.0 GPa, maximum temperature 2208C. CC was carried out on the 0.05 –0.1 mm standard silica 60 (kit I for low pressure flash chromatography, MACHEREY-NAGEL, Du¨ren, Germany). Chromatographic isolation of 4a, 4b and 5a, 5b was carried out with the Waters Breeze liquid chromatography system (Waters, Milford, MA, USA) with UV detection at 275 nm and reversed-phase column (Phenomenexw Luna C18, 10.00 mm £ 250 mm i.d., 10 mm particle size; Phenomenex, Torrance, CA, USA). The isocratic mobile phase was a mixture of acetonitrile and water (30:70, v/v) at flow rate 3 mL/min. The column temperature was maintained at 258C for both cases. Optical rotation was measured on Perkin-Elmer 341 (Waltham, MA, USA) LC digital polarimeter with a sodium lamp (D-line wavelength ¼ 589 nm). High-resolution electron ionisation mass spectra were recorded using the Thermo Finnigan MAT95XP mass spectrometer (Bremen, Germany) (EI, 70 eV). NMR spectra were recorded in CDCl3 or DMSO-d6 on the Bruker AVANCE-III 500 spectrometer (Fa¨llanden, Switzerland) (5 mm z-gradient BBO probe) operating at 500.30 MHz (1H) and 125.75 MHz (13C). 1H and 13C chemical shifts are expressed in parts per million (ppm) from tetramethylsilane as internal standard, 15N chemical shifts are reported relative to external liquid ammonia at 258C. The 1H NMR spectra were acquired with a spectral width of 5.6 kHz and 32 k data points and 8 scans, providing a digital resolution of ca. 0.5 Hz (1H 908 pulse
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˚ ) in theoretical modelsa for the four possible adducts 12. Table 1. Significant interprotonic distances (A Entry
Configuration
b-endo b-exo a-endo a-exo
12aS,4S,12bR,3aR 12aS,4S,12bS,3aS 12aR,4R,12bS,3aS 12aR,4R,12bR,3aR
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a
H13Hsyn15 – – 2.70 2.33
H12bHsyn15 2.24 3.78 – –
H13H12
H12bH12
H13Hendo11
H12bHendo11
2.93 3.13 2.41 2.40
2.87 2.42 3.34 2.68
2.04 1.96 – –
– – 2.14 3.19
B3LYP/6-311 þ G (2d, p) basis set.
width ¼ 11.5 ms). For 13C NMR spectra, a spectral width of 29.7 kHz was used with 64 k data points and 512 scans (13C 908 pulse width ¼ 9.7 ms). Gradient selected HSQC spectra were recorded using the standard Bruker sequence (hsqcetgp). These data were collected with 4096 £ 256 data points with 2 scans for each increment. The delay d4 was set to 1.72 ms. Gradient selected HMBC spectra (hmbcgpndqf) were collected with 4096 £ 256 data points with 4 scans for each increment. The delay d6 was set to 71.4 ms. Spectral widths of 5.6 and 29.7 kHz were used in the F2 (1H) and F1 (13C) domains, respectively. HSQC and HMBC data were processed using a sine window in the F2 and F1 dimensions. Gs-COSY data were collected with 2K £ 2K data points with 2 scans for each increment. For the 2D NOESY NMR experiments, the solution was degassed to remove any dissolved oxygen. The following parameters and procedures were commonly employed: spectral width 5.6 kHz, 2K £ 2K data matrix and 256 time increments of 2 transients each mixing time d8 ¼ 0.5 s. Fourier transformations were carried out with zerofilling using the shifted sine-bell apodization function in both dimensions. Geometry optimisation and vibrational frequency analysis of compounds 11 and 12 have been performed by the B3LYP/6-311 þ G(2d,p) approximation Gaussian03 (Frisch et al. 2003). 3.1. Aza-Michael reaction of 2 under HP conditions A mixture of 250 mg (1.1 mmol) 2 and a Michael acceptor (1.2 mmol) and 10 mol% of p-TsOH in CH3CN (ca. 1.3 mL) was placed in the Teflon reactor vessel (1.5 mL volume) and the mixture was allowed to react at 808C, pressure 0.6 GPa for 72 h leading to products 8 – 12. After the reaction mixture was cooled and the pressure was released, the CH3CN was evaporated in vacuo. The crude products were purified by flash column chromatography. 3.1.1. N-(3-Oxobutyl)cytisine-12-carboxamide (8) Compound 8 (156 mg) was obtained with 48% yield. ½a20 D ¼ 2 1088 (CHCl3, c 1.2). 13 C (CDCl3, d, ppm) 25.86 (C-8); 27.33 (C-9); 30.27 (C-19); 34.57 (C-7); 35.37 (C-16); 43.38 (C-17); 49.10 (C-10); 50.22 (C-11); 51.12 (C-13); 105.70 (C-5); 116.94 (C-3); 139.14 (C4); 149.29 (C-6); 157.54 (C-14); 163.48 (C-2); 209.47 (C-18). 15 N (CDCl3, d, ppm): 75.05 (N-12);79.16 (N-15); 174.88 (N-1). 1 H (CDCl3, d, ppm, J, Hz): 1.90 (dtd, 1H, 2J ¼ 12.7, 3J8anti-7 ¼ 3.4, 3J8anti-9 ¼ 3.4, 4J8anti2 3 3 4 10endo ¼ 1.3, Hanti-8); 1.96 (ddt, 1H, J ¼ 12.7, J8syn-7 ¼ 3.4, J8syn-9 ¼ 3.4, J8syn-11endo ¼ 1.7, 4 J8syn-13endo ¼ 1.7, Hsyn-8); 2.07 (s, 3H, H-19); 2.45 (m, 1H, H-9); 7.52 (t, 2H, 3J17-16 ¼ 5.8, H17); 3.00 (ddd, 1H, 2J ¼ 11.3, 3Jexo-9 ¼ 2.5, 4Jexo-10exo ¼ 1.0, Hexo-11); 3.02 (dd, 1H, 2J ¼ 13.4, 3 J13exo-7 ¼ 2.4, Hexo-13); 3.02 (m, 1H, H-7); 3.24 (q, 2H, 3J16-15 ¼ 5.8, 3J16-17 ¼ 5.8,H-16); 3.79 (ddd, 1H, 2J ¼ 15.6, 3J10exo-9 ¼ 6.6, 4J10exo-11exo ¼ 1.0, Hexo-10); 3.98 (ddt, 1H, 2J ¼ 13.4, 3 J13endo-7 ¼ 3.1, 4J13endo-11endo ¼ 1.7, 4J13endo-8syn ¼ 1.7, Hendo-13); 4.00 (ddt, 1H, 2J ¼ 11.3, 3 Jendo-9 ¼ 3.3, 4Jendo-13endo ¼ 1.7, 4Jendo-8syn ¼ 1.7, Hendo-11); 4.08 (dt, 1H, 2J ¼ 15.6, 3 J10endo-9 ¼ 1.0, 4J10endo-8anti ¼ 1.0, Hendo-10); 5.42 (t, 1H,3J15-16 ¼ 5.8,H-15); 6.06 (d, 1H,
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J5-4 ¼ 6.9, 4J5-3 ¼ 1.5, H-5); 6.38 (dd, 1H, 3J3-4 ¼ 9.1, 4J3-5 ¼ 1.5, H-3); 7.25 (d, 1H, J4-3 ¼ 9.1, 3J4-5 ¼ 6.9, H-4). HR-MS (EI): m/z calculated for C16H21N3O3 [Mþ] 303.1577; found 303.1566.
3.1.2. N-[(1R)-3-Oxocyclohexyl]cytisine-12-carboxamide and (N-[(1S)-3-oxocyclohexyl] cytisine-12-carboxamide (9a,b):
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The mixture of diastereomers 9a,b (235 mg) was obtained with 81% yield. 3.1.2.1. (9a). ½a20 D ¼ 2 2108 (CH3OH, c 1.4) 13 C (CDCl3, d, ppm): 22.08 (C-20); 25.92 (C-8); 27.44 (C-9); 31.18 (C-21); 34.58 (C-7); 40.97 (C-19); 48.14 (C-17); 49.10 (C-10); 49.84 (C-16); 50.64 (C-11); 51.15 (C-13); 105.60 (C-5); 117.13 (C-3); 139.12 (C-4); 149.22 (C-6); 156.77 (C-14); 163.40 (C-2); 209.63 (C18). 1 H (CDCl3, d, ppm, J, Hz): 1.53 (dddd, 1H, 2J ¼ 12.7, 3J21ax-20ax ¼ 10.1, 3J21ax-16 ¼ 8.9, 3 J21ax-20eq ¼ 5.5, 3J21ax-21eq ¼ 3.7, Hax-21); 1.65 (dtdd, 1H, 2J ¼ 14.0, 3J20ax-21ax ¼ 10.1, 3 J20ax-19ax ¼ 10.1, 3J20ax-19eq ¼ 5.5, 3J20ax-21eq ¼ 3.7, Hax-20); 1.83 (dtdd, 1H, 2J ¼ 14.0, 3J20eq3 3 3 21ax ¼ 5.5, J20eq-19ax ¼ 5.5, J20eq-19eq ¼ 5.0, J20eq-21eq ¼ 3.7, Heq-20); 1.91 (m, 1H, Heq-21); 2 3 3 1.95 (dtd, 1H, J ¼ 12.9, J8anti-7 ¼ 3.0, J8anti-9 ¼ 3.2, 4J8anti-10endo ¼ 1.0, Hanti-8); 2.02 (dtt, 1H, 2J ¼ 12.9, 3J8syn-7 ¼ 3.2, 3J8syn-9 ¼ 3.2, 4J8syn-11endo ¼ 1.6, 4J8syn-13endo ¼ 1.6, Hsyn-8); 2.16 (dd, 1H, 2J ¼ 14.5, 3J17ax-16 ¼ 9.5, Hax-17); 2.20 (ddd, 1H, 2J ¼ 14.0, 3J19ax-20ax ¼ 10.1, 3 J19ax-20eq ¼ 5.5, Hax-19); 2.33 (dddt, 1H, 2J ¼ 14.0, 3J19eq-20ax ¼ 5.5, 3J19eq-20eq ¼ 5.0, 4 J19eq-17eq ¼ 1.6, 4J19eq-21eq ¼ 1.6, Heq-19); 2.50 (m, 1H, H-9); 2.56 (ddt, 1H, 2J ¼ 14.5, 3 J17eq-16 ¼ 4.8, 4J17eq-19eq ¼ 1.6, 4J17eq-21eq ¼ 1.6, Heq-17); 3.05 (dd, 1H, 2J ¼ 12.4, 3 J13exo-7 ¼ 2.2, Hexo-13); 3.07 (m, 1H, H-7); 3.11 (ddd, 1H, 2J ¼ 13.2, 3Jexo-9 ¼ 2.8, 4Jexo2 3 4 10exo ¼ 1.2, Hexo-11); 3.85 (ddd, 1H, J ¼ 15.6, J10exo-9 ¼ 6.6, J10exo11exo ¼ 1.2, Hexo-10); 3 3 3 3 3.96 (ddddd, 1H, J16-17ax ¼ 9.5, J16-21ax ¼ 8.9, J16-15 ¼ 6.9, J16-17eq ¼ 4.8, 3J16-21eq ¼ 3.3, H-16); 4.01 (ddt, 1H, 2J ¼ 13.2, 3Jendo-9 ¼ 3.2, 4Jendo-8syn ¼ 1.6, 4Jendo-13endo ¼ 1.6, Hendo-11); 4.11 (ddt, 1H, 2J ¼ 12.4, 3J13endo-7 ¼ 3.2, 4J13endo-11endo ¼ 1.6, 4J13endo-8syn ¼ 1.6, Hendo-13); 4.17 (dt, 1H, 2J ¼ 15.6, 3J10endo-9 ¼ 1.0, 4J10endo-8anti ¼ 1.0, Hendo-10); 4.85 (d, 1H, 3 J15-16 ¼ 6.9, H-15); 6.10 (dd, 1H, 3J5-4 ¼ 6.9, 4J5-3 ¼ 1.5, H-5); 6.43 (dd, 1H, 3J3-4 ¼ 9.0, 4 J3-5 ¼ 1.5, H-3); 7.31 (dd, 1H, 3J4-3 ¼ 9.0, 3J4-5 ¼ 6.9, H-4). HR-MS (EI): m/z calculated for C18H23N3O3 [Mþ] 329.1734; found 329.1747. 3.1.2.2. (9b). ½a20 D ¼ 2 1628 (CH3OH, c 2.0) 13 C (CDCl3, d, ppm): 22.00 (C-20); 25.92 (C-8); 27.41 (C-9); 31.13 (C-21); 34.61 (C-7); 40.97 (C-19); 48.07 (C-17); 49.07 (C-10); 49.84 (C-16); 50.35 (C-11); 51.59 (C-13); 105.28 (C-5); 117.33 (C-3); 138.87 (C-4); 149.21 (C-6); 156.71 (C-14); 163.36 (C-2); 209.62 (C-18). 1 H (CDCl3, d, ppm, J, Hz): 1.52 (dddd, 1H, 2J ¼ 12.7, 3J21ax-20ax ¼ 10.1, 3J21ax-16 ¼ 8.9, 3 J21ax-20eq ¼ 5.5, 3J21ax-21eq ¼ 3.7, Hax-21); 1.64 (dtdd, 1H, 2J ¼ 14.0, 3J20ax-21ax ¼ 10.1, 3 J20ax-19ax ¼ 10.1, 3J20ax-19eq ¼ 5.5, 3J20ax-21eq ¼ 3.7, Hax-20); 1.83 (dtdd, 1H, 2J ¼ 14.0, 3 J20eq-21ax ¼ 5.5,3J20eq-19ax ¼ 5.5, 3J20eq-19eq ¼ 5.0, 3J20eq-21eq ¼ 3.7, Heq-20); 1.91 (m, 1H, Heq-21); 1.95 (dtd, 1H, 2J ¼ 12.9, 3J8anti-7 ¼ 3.0, 3J8anti-9 ¼ 3.2, 4J8anti-10endo ¼ 1.0, Hanti-8); 2.02 (dtt, 1H, 2J ¼ 12.9, 3J8syn-7 ¼ 3.2, 3J8syn-9 ¼ 3.2, 4J8syn-11endo ¼ 1.6, 4J8syn-13endo ¼ 1.6, Hsyn-8); 2.18 (dd, 1H, 2J ¼ 14.5, 3J17ax-16 ¼ 9.5, Hax-17); 2.19 (ddd, 1H, 2J ¼ 14.0, 3 J19ax-20ax ¼ 10.1, 3J19ax-20eq ¼ 5.5, Hax-19); 2.32 (dddt, 1H, 2J ¼ 14.0, 3J19eq-20ax ¼ 5.5, 3 J19eq-20eq ¼ 5.0, 4J19eq-17eq ¼ 1.6, 4J19eq-21eq ¼ 1.6, Heq-19); 2.50 (m, 1H, H-9); 2.58 (ddt, 1H, 2 J ¼ 14.5, 3J17eq-16 ¼ 4.8, 4J17eq-19eq ¼ 1.6, 4J17eq-21eq ¼ 1.6, Heq-17); 3.06 (ddd, 1H, 2 J ¼ 11.2,3Jexo-9 ¼ 2.8, 4Jexo-10exo ¼ 1.2, Hexo-11); 3.07 (m, 1H, H-7); 3.11 (dd, 1H, 2 J ¼ 12.8, 3J 13exo-7 ¼ 2.2, Hexo-13); 3.84 (ddd, 1H, 2 J ¼ 15.6, 3J 10exo-9 ¼ 6.5,
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J10exo11exo ¼ 1.2, Hexo-10); 3.95 (ddt, 1H, 2J ¼ 12.8, 3J13endo-7 ¼ 3.2, 4J13endo-11endo ¼ 1.6, J13endo-8syn ¼ 1.6, Hendo-13); 3.96 (ddddd, 1H, 3J16-17ax ¼ 9.5,3J16-21ax ¼ 8.9,3J16-15 ¼ 6.9, 3 J16-17eq ¼ 4.8, 3J16-21eq ¼ 3.3, H-16); 4.11 (ddt, 1H, 2J ¼ 11.2, 3Jendo-9 ¼ 3.2, 4Jendo-8syn ¼ 1.6, 4 Jendo-13endo ¼ 1.6, Hendo-11); 4.14 (dt, 1H, 2J ¼ 15.6, 3J10endo-9 ¼ 1.0, 4J10endo-8anti ¼ 1.0, Hendo10); 4.69 (d, 1H, 3J15-16 ¼ 6.9, H-15); 6.08 (dd, 1H, 3J5-4 ¼ 6.9, 4J5-3 ¼ 1.5, H-5); 6.44 (dd, 1H, 3 J3-4 ¼ 9.0, 4J3-5 ¼ 1.5, H-3); 7.29 (dd, 1H, 3J4-3 ¼ 9.0, 3J4-5 ¼ 6.9, H-4). HR-MS (EI): m/z calculated for C18H23N3O3 [Mþ] 329.1734; found 329.1747. 4 4
3.1.3. N-[(1S)-2-Nitro-1-phenylethyl]cytisine-12-carboxamide and N-[(1R)-2-nitro-1phenylethyl]cytisine-12-carboxamide (10a,b)
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The mixture of diastereomers 10a,b (274 mg) was obtained with 67% yield. 3.1.3.1. (10a). ½a20 D ¼ 2 1028 (DMSO, c 1.4). 13 C (DMSO, d, ppm): 24.85 (C-8); 26.49 (C-9); 33.71 (C-7); 48.63 (C-10); 48.89 (C-11); 50.22 (C-13); 51.93 (C-16); 78.39 (C-17); 104.91 (C-5); 115.54 (C-3); 126.08 (C-20(24)); 127.37 (C-22); 128.39 (C-21(23)); 138.73 (C-19); 138.95 (C-4); 149.89 (C-6); 155.86 (C-14); 162.28 (C-2). 15 N (DMSO, d, ppm): 85.65 (N-15); 175.90 (N-1); 383.76 (N-18). 1 H (DMSO, d, ppm, J, Hz): 1.87 (m, 1H, Hanti-8);1.90 (m, 1H, Hsyn-8); 2.42 (m, 1H, H-9); 2.92 (ddd, 1H, 2J ¼ 12.7, 3Jexo-9 ¼ 2.5, 4Jexo-10exo ¼ 1.0, Hexo-11); 3.09 (dd, 1H, 2J ¼ 12.7, 3 J13exo-7 ¼ 2.5, Hexo-13); 3.13 (m, 1H, H-7); 3.66 (ddd, 1H, 2J ¼ 15.6, 3J10exo-9 ¼ 6.6, 4J10exo2 3 4 11exo ¼ 1.0, Hexo-10); 3.78 (dt, 1H, J ¼ 15.6, J10endo-9 ¼ 1.0, J10endo-8anti ¼ 1.0, Hendo-10); 2 3 4 4.00 (ddt, 1H, J ¼ 12.7, J13endo-7 ¼ 3.1, J13endo-11endo ¼ 1.7, 4J13endo-8syn ¼ 1.7, Hendo-13); 4.16 (ddt, 1H, 2J ¼ 12.7, 3Jendo-9 ¼ 3.3, 4Jendo-13endo ¼ 1.7, 4Jendo-8syn ¼ 1.7, Hendo-11); 4.73 (dd, 1H, 2J17a-17b ¼ 13.1,3J17a-16 ¼ 10.4, Ha-17); 4.86 (dd, 1H, 2J17b-17a ¼ 13.1,3J17b-16 ¼ 4.9, Hb-17); 5.38 (ddd, 1H, 3J16-17a ¼ 10.4, 3J16-15 ¼ 8.4, 3J16-17b ¼ 4.9, H-16); 6.22 (dd, 1H, 3 J 5-4 ¼ 7.0, 4 J 5-3 ¼ 1.5, H-5); 6.26 (dd, 1H, 3J 3-4 ¼ 9.1, 4 J 3-5 ¼ 1.5, H-3); 6.98 (d, 1H,2J15-16 ¼ 8.4, H-15); 7.05 (d, 2H,3J20(24)-21(23) ¼ 7.7, H-20(24)); 7.23 (m, 1H, H22),7.25 (m, 2H, H-21(23)); 7.40 (d, 1H, 3J4-3 ¼ 9.1, 3J4-5 ¼ 7.0, H-4). HR-MS (EI): m/z calculated for C20H22N4O4 [Mþ] 382.1636; found 382.1646. 3.1.3.2. (10b). ½a20 D ¼ 2 1138 (DMSO, c 0.6) 13 C (DMSO, d, ppm): 24.93 (C-8); 26.57 (C-9); 33.69 (C-7); 48.49 (C-10); 49.26 (C-11); 49.97 (C-13); 52.27 (C-16); 78.42 (C-17); 104.73 (C-5); 115.56 (C-3); 126.03 (C-20(24)); 127.31 (C-22); 128.34 (C-21(23)); 138.79 (C-19); 138.90 (C-4); 150.01 (C-6); 155.98 (C-14); 162.28 (C-2). 15 N (DMSO, d, ppm): 85.65 (N-15); 383.76 (N-18). 1 H (DMSO, d, ppm, J, Hz): 1.89 (m, 1H, Hanti-8); 1.89 (m, 1H, Hsyn-8); 2.45 (m, 1H, H-9); 2.96 (dd, 1H, 2J ¼ 12.8, 3J13exo-7 ¼ 2.5, Hexo-13); 3.02 (ddd, 1H, 2J ¼ 12.7, 3Jexo-9 ¼ 2.5, 4 Jexo-10exo ¼ 1.0, Hexo-11); 3.02 (m, 1H, H-7); 3.72 (ddd, 1H, 2J ¼ 15.6, 3J10exo-9 ¼ 6.6, 4 J10exo-11exo ¼ 1.0, Hexo-10); 4.01 (ddt, 1H, 2J ¼ 12.8, 3J13endo-7 ¼ 3.1, 4J13endo-11endo ¼ 1.7, 4 J13endo-8syn ¼ 1.7, Hendo-13); 4.08 (dt, 1H, 2J ¼ 15.6, 3J10endo-9 ¼ 1.0, 4J10endo-8anti ¼ 1.0, Hendo-10); 4.09 (ddt, 1H, 2J ¼ 12.7, 3Jendo-9 ¼ 3.3, 4Jendo-13endo ¼ 1.7, 4Jendo-8syn ¼ 1.7, H endo-11); 4.69 (dd, 1H, 2J 17a-17b ¼ 12.8,3J 17a-16 ¼ 10.4, H a-17); 4.88 (dd, 1H, 2 J17b-17a ¼ 12.8, 3J17b-16 ¼ 4.3, Hb-17); 5.31 (ddd, 1H, 3J16-17a ¼ 10.4, 3J16-15 ¼ 8.8, 3 J16-17b ¼ 4.3, H-16); 6.10 (dd, 1H, 3J5-4 ¼ 7.0, 4J5-3 ¼ 1.5, H-5); 6.23 (dd, 1H, 3J3-4 ¼ 9.1, 4 J3-5 ¼ 1.5, H-3); 7.09 (d, 1H,2J15-16 ¼ 8.9, H-15); 7.15 (d, 2H, 3J20(24)-21(23) ¼ 7.3, H-20(24));
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7.15 (t, 1H, 3J22-21(23) ¼ 7.3, H-22); 7.28 (dd, 1H, 3J4-3 ¼ 9.1, 3J4-5 ¼ 7.0, H-4); 7.29 (t, 1H, 3 J21(23)-20(24) ¼ 7.3, 3J21(23)-22 ¼ 7.3, H-21(23)). HR-MS (EI): m/z calculated for C20H22N4O4 [Mþ] 382.1636; found 382.1646. 3.1.4. Dimethyl (2E)-2-[(cytisine-12-ylcarbonyl)amino]but-2-enedioate (11) Compound 11 (80 mg) was obtained with 20% yield. ½a20 D ¼ 2 2248 (CHCl3, c 0.9) 13 C (CDCl3, d, ppm):25.73 (C-8); 27.34 (C-9); 34.42 (C-7); 48.93 (C-10); 50.51 (C-11); 51.27 (C-13); 51.80 (C-20); 52.92 (C-23); 98.12 (C-17); 105.95 (C-5); 117.61 (C-3); 139.06 (C-4); 146.47 (C-16); 148.11 (C-6); 152.68 (C-14); 163.44 (C-2); 164.44 (C-21); 169.45 (C-18). 1 H (CDCl3, d, ppm, J, Hz): 2.00 (dtd, 1H, 2J ¼ 13.3, 3J8anti-7 ¼ 3.4, 3J8anti-9 ¼ 3.4, 4J8anti2 3 3 4 10endo ¼ 1.3, Hanti-8); 2.06 (ddt, 1H, J ¼ 13.3, J8syn-7 ¼ 3.4, J8syn-9 ¼ 3.4, J8syn-11endo ¼ 1.7, 4 J8syn-13endo ¼ 1.7, Hsyn-8); 2.58 (m, 1H, H-9); 3.13 (m, 1H, H-7); 3.20 (m, 1H, Hexo-11); 3.25 (m, 1H, Hexo-13); 3.73 (s, 1H, H-20); 3.74 (s, 1H, H-23); 3.94 (d, 1H, 2J ¼ 15.8, Hexo-10); 4.10 (m, 1H, Hendo-13); 4.16 (d, 1H, 2J ¼ 15.8, Hendo-10); 4.20 (m, 1H, Hendo-11); 5.36 (s, 1H, H-17); 6.13 (d, 1H, 3J5-4 ¼ 6.9, 4J5-3 ¼ 1.5, H-5); 6.49 (dd, 1H, 3J3-4 ¼ 9.1, 4J3-5 ¼ 1.5, H-3); 7.30 (d, 1H, 3J4-3 ¼ 9.1, 3J4-5 ¼ 6.9, H-4). HR-MS (EI): m/z calculated for C18H21N3O3 [Mþ] 375.1425; found 375.1413. 3.1.5. (3aR,4S,8S,12R,12aS,12bR)-1,3,5-Trioxo-2-phenyldecahydro-1H-4,12a-etheno-8,12methanopyrrolo[3 0 ,4 0 :3,4]pyrido[1,2-a][1,5]diazocine-10(7H)-carboxamide (12) Compound 12 (300 mg) was obtained with 69% yield. ½a20 D ¼ þ 12.08 (CH3OH, c 1.2) 13 C (CDCl3, d, ppm): 173.16 (C-5); 45.07 (C-4); 129.63 (C-14); 134.71 (C-13); 62.79 (C12a); 29.28 (C-12); 25.75 (C-15); 25.90 (C-8); 46.91 (C-7); 50.37 (C-9); 45.91 (C-11); 42.68 (C3a); 47.56 (C-12b); 174.13 (C-1); 174.56 (C-3); 131.29 (C-10 ); 126.32 (C-20 (60 )); 129.20 (C-30 (50 )); 129.01 (C-40 ); 158.33 (C-100 ). 1 H (CDCl3, d, ppm, J, Hz): 1.98 (dtd, 1H, 2J ¼ 13.7, 3J15anti-12 ¼ 3.7, 3J15anti-8 ¼ 3.7, 4 J15anti-7endo ¼ 1.7, Hanti-15); 2.15 (dtt, 1H, 2J ¼ 13.7, 3J15syn-12 ¼ 3.2,3J15syn-8 ¼ 3.2, 4J15syn4 2 3 9endo ¼ 1.5, J15syn-11endo ¼ 1.5, Hsyn-15); 2.22 (m, 1H, H-8); 2.92 (dd, 1H, J ¼ 13.9, Jexo2 3 4 12 ¼ 2.5, Hexo-11); 3.19 (m, 1H, H-12); 3.20 (ddd, 1H, J ¼ 12.0, J9exo-8 ¼ 2.3 J9exo2 3 4 7exo ¼ 1.2, Hexo-9); 3.28 (ddd, 1H, J ¼ 13.7, J7exo-8 ¼ 6.3, J7exo-9exo ¼ 1.2, Hexo-7); 3.34 (dd, 3 3 3 1H, J3a-12b ¼ 7.9, J3a-4 ¼ 3.2, H-3a); 3.52 (d, 1H, J12b-3a ¼ 7.9, H-12b); 3.70 (dt, 1H, 2 J ¼ 13.7, 3J 7endo-8 ¼ 1.7, 4J 7endo-15anti ¼ 1.7, H endo-7); 3.70 (ddt, 1H, 2 J ¼ 12.0, 3 J9endo-8 ¼ 3.0, 4J9endo-11endo ¼ 1.5, 4J9endo-15syn ¼ 1.5, Hendo-9); 3.90 (ddd, 1H, 3J4-14 ¼ 6.2, 3 J4-3a ¼ 3.2, 4J4-13 ¼ 1.5, H-4); 4.70 (ddt, 1H, 2J ¼ 13.9, 3Jendo-12 ¼ 3.0, 4Jendo-9endo ¼ 1.5, 4 Jendo-15syn ¼ 1.5, Hendo-11); 6.43 (dd, 1H, 3J14-13 ¼ 8.0, 3J14-4 ¼ 6.2, H-14); 6.65 (dd, 1H, 3J13-14 ¼ 8.0, 4J13-4 ¼ 1.5, H-13); 7.13 (dt, 2H, 3J20 (60 )-30 (50 ) ¼ 6.8, 4J20 (60 )-40 ¼ 1.7, 4J20 (60 )-60 3 4 3 0 0 0 (20 ) ¼ 1.7, H-2 (6 )); 7.40 (tt, 1H, J40 -30 (50 ) ¼ 8.2, J40 -20 (60 ) ¼ 1.7, H-4 ); 7.45 (ddd, 2H, J30 3 4 0 0 (50 )-40 ¼ 8.2, J30 (50 )-20 (60 ) ¼ 6.8, J30 (50 )-50 (30 ) ¼ 1.7, H-3 (5 )). HR-MS (EI): m/z calculated for C22H22N4O4 [Mþ] 406.1641; found 406.1633. 4. Conclusions Thus, the first example of an aza-Michael reaction of 12-N-carboxamide of quinolizidine alkaloid (–)-cytisine under HP condition is presented. The new unsymmetrical ‘cytisinecontaining’ ureas are synthesised from 12-N-carboxamide of (– )-cytisine and a,b-unsaturated ketones, DMAD and b-nitrostyrene. The [4 þ 2]-cycloaddition took place in the case of NPM.
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Supplementary material Supplementary material relating to this article is available online, alongside Figures S1 –S34 and Tables S1 –S9. Funding This study was supported by the Russian Foundation for Basic Research [grant number 12-03-00724-a] and Foundation of Bashkortostan Republic for Young Scientists (2014).
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