Synthesis of Several 3,5- and 3-Substituted Thermopsine Derivatives

Abstract

In continuation of research on functionalization of the 2-pyridone core of quinolizidine alkaloids [1, 2], we synthesized 3,5-dibromo-, 3-bromo-, 3-nitro-, 5-nitro-, and 3-amino-derivatives of the quinolizidine alkaloid thermopsine (1).Thermopsine (1) was obtained in S. Yu. Yunusov Institute of the Chemistry of Plant Substances (Tashkent). Its physicochemical constants agreed with those in the literature [3].Bromination of 1 according to the literature [1] produced 3,5-dibromo-derivative 2 in 73% yield. Compound 2 was converted by zinc dust in HCl into 3-bromo-derivative 3 in 90% yield. Nitration of 1 in conc. H 2 SO 4 as before [2] gave 3-nitrothermopsine 4 and 5-nitrothermopsine 5 in a 7:1 ratio in 60% overall yield. Then, compound 4 was reduced by H 2 over Pd catalyst into amine 5 in quantitative yield. The structures of 2-5 were elucidated using PMR and 13 C NMR spectroscopy.Thus, thermopsine (1) derivatives containing functional groups on the 2-pyridone core were synthesized and were promising starting materials for further chemical transformations.The course of reactions was monitored by TLC on ALUGRAM ® plates. Column chromatography (CC) was performed on standard silica gel 60 (0.05-0.1 mm) (Macherey-Nagel, Germany). Melting points of crystalline compounds were determined on a Boetius apparatus. Optical rotation angles were measured on a PerkinElmer 341 LC polarimeter. PMR and 13 C NMR spectra were recorded on equipment at the Khimiya CCU, UfIC, RAS (Bruker Avance III pulsed spectrometer at operating frequency 500.13 MHz for 1 H and 125.47 MHz for 13 C vs. TMS internal standard).3,5-Dibromothermopsine (2). A solution of 1 (0.2 g, 0.8 mmol) in H 2 SO 4 (50%, 5 mL) was treated with KBr (0.29 g, 2.4 mmol) and H 2 O 2 (36%, 0.5 mL, 4.8 mmol), stirred on a magnetic stirrer at room temperature until starting 1 disappeared (TLC monitoring), poured onto ice, neutralized with anhydrous Na 2 CO 3 , and extracted (5 u 10 mL) with EtOAc. The extracts were combined, dried over Na 2 SO 4 , and evaporated. The residue was chromatographed over SiO 2 (C 6 H 6 -MeOH eluent, 9:1) to afford 2 (0.24 g, 73%), dark-yellow amorphous compound, [D] D 20 -40.1q (ñ 1.6, CHCl 3 ).

Quinolizidine Alkaloids with Antitomato Spotted Wilt Virus and Insecticidal Activities from the Seeds of Thermopsis lanceolata R. Br

“…The NMR spectroscopic data of 11 showed signals for five methylenes, eight methines, and three quaternary carbons. The aforementioned data suggested that 11 was a homolog of thermopsine ( 25 ) . The downfield shifts of C-12 (δ C 54.9, Δδ C + 25.1) and C-13 (δ C 51.6, Δδ C + 27.2), combined with HRESIMS, revealed the existence of a 12,13-epoxide unit in 11 , which can be confirmed by key 1 H- 1 H COSY signals of H 2 -10/H-9/H-11/H-12/H 2 –13/H-14/H-15 (Figure ).…”

“…The aforementioned data suggested that 11 was a homolog of thermopsine (25). 20 The downfield shifts of C-12 (δ C 54.9, 4). Consequently, the absolute configuration of 7R, 9R, 11R, 12R, 13S for 11 was established by ECD calculations (Figure S7).…”

“…Further separation of the crude alkaloids yielded 17 new QAs ( 1 – 17 ), including three new naturally occurring compounds ( 15 – 17 ), along with 15 known compounds ( 18 – 32 ) (Figure ). In addition, known analogues were identified as N -(β- d -glucopyranosyl) cytisine ( 17 ), cytisine ( 18 ), N -methylcytisine ( 19 ), (−)-12-hydroxycytisine ( 20 ), N -formylcytisine ( 21 ), N -acylcytisine ( 22 ), methyl ester of N -cytisinylacetic acid ( 23 ), cytisine-12-carbamide ( 24 ), thermopsine ( 25 ), 13β - hydroxythermopsine ( 26 ), anagyrine ( 27 ), epibaptifoline ( 28 ), baptifoline ( 29 ), (+)-5,6-dehydrolupanine ( 30 ), (−)­lupanine ( 31 ), and sparteine N1-oxide ( 32 ) …”

“…The NMR data of 8 were highly similar to those of thermopsine ( 25 ) (Table ). The notable difference was the existence of an extra methyl acetate group (δ C 173.4, 51.95, and 28.5) in 8 (Table ). The 1 H – 1 H COSY correlation of H-17/H 2 -18 and the key HMBC correlations from H 2 -18 and H 3 -21 to C-19 (δ C 173.4) demonstrated that the methyl acetate group was connected at C-17 (δ C 64.1).…”