Synthesis of enantiomerically pure fire ant venom alkaloids: Solenopsins and isosolenopsins A, B and C

Abstract

Concise and efficient methods for the synthesis of enantiomers of fire ant venom alkaloids solenopsin and isosolenopsin A, B, and C are described. These syntheses are based on diastereoselective electrophilic substitution of enatiomerically‐pure α‐lithiated 2‐alkylpiperidine.

Stereoselective Synthesis of δ- and ε-Amino Ketone Derivatives from N-tert-Butanesulfinyl Aldimines and Functionalized Organolithium Compounds

“…It was not possible to determine by HPLC, or GC using chromatographic columns with a chiral packing, the enantiomeric purities of compounds 11e and ent-11e, but we consider that these values should be similar to the diastereomeric ratios of their precursors aminoketone derivatives 7e (>95:5 dr after column chromatography purification). Piperidines 11e and ent-11e [33] are, respectively, the alkaloids (−)-isosolenopsin A and (+)-isosolenopsin A, that have been isolated from the venom of the fire ants of the genus Solenopsis and display cytotoxic, antibacterial, insecticidal and antifungal activity (Scheme 4) [34,35]. It is worth noting that, by comparison of the optical rotation values of these natural products with those reported in the literature, we were able to confirm that the attack of the organolithium compound 4b occurred through the Re-face of chiral sulfinyl imine 5e, to give N-tert-butanesulfinyl δ-amino ketone derivative 7e as the major diastereoisomer, with S configuration at the stereocenter that is formed after this addition, as in piperidine 11e.…”

“…(3R,R S )-3-Amino-N-(tert-butanesulfinyl)-2-methyloctan-7-one (7c). Following the general procedure, compound 7c was obtained from sulfinyl imine 5c and 5-chloro-2-methoxypent-1-ene (2b) as a yellow oil (19 mg, 0.073 mmol, 36%): C 13 H 27 NO 2 S; R f 0.32 (hexane/EtOAc 1:2); [α] 20 D −28.5 (c 0.44, CH 2 Cl 2 ); IR (film) ν 2954, 2877, 1708, 1365, 1052, 732 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 0.92 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 1.23 (s, 9H), 1.35-1.48 (m, 2H), 1.50-1.79 (m, 2H), 1.91-2.06 (m, 1H), 2.14 (s, 3H), 2.41-2.47 (m, 2H), 3.03-3.07 (m, 1H), 3.16 (d, J = 7.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 18.0 (CH 3 ), 18.5 (CH 3 ), 20.4 (CH 2 ), 22.9 (CH 3 ), 30.1 (CH 3 ), 31.5 (CH 2 ), 32.4 (CH 3 ), 43.5 (CH 2 ), 56.2 (C), 61.9 (CH), 208.7 (C); LRMS (EI) m/z 261 (M + , 0.58%), 205 (25), 144 (11), 141 (11), 123 (62), 120 (14), 111 (11), 104 (13), 97 (17), 95 (12), 85 (15), 83 (46), 81 (19), 72 (17), 71 (33), 70 (14), 69 (16), 59 (28), 57 (76), 56 (21), 55 (33), 43 (100), 41 (37); HRMS (EI-TOF) Calcd for C 9 H 19 NO 2 S [M + -C 4 H 8 ] 205.1136, found 205.1137.…”

“…Following the general procedure, compound 9d was obtained as the major diastereoisomer from sulfinyl imine 5d and 6-chloro-2-methoxyhex-1-ene (2c) as a yellow oil (23 mg, 0.064 mmol, 32%): C 20 H 42 NO 2 S; R f 0.54 (hexane/EtOAc 1:2); [α] 20 D −31.9 (c 0.58, CH 2 Cl 2 ); IR (film) ν 2923, 2854, 1712, 1461, 1361, 1164, 1052, 721 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 0.86 (t, J = 6.8 Hz, 3H), 1.20 (s, 9H), 1.23-1.31 (br s, 18H), 1.41-1.62 (m, 4H), 2.13 (s, 3H), 2.43 (t, J = 7.23 Hz, 2H), 2.99 (d, J = 6.4 Hz, 1H), 3.14-3.24 (m, 1H); 13 (20), 156 (14), 123 (21), 111 (14), 109 (40), 97 (30), 95 (45), 83 (56), 81 (25), 71 (28), 69 (41), 57 (88), 55 (27), 43 (100), 41 (36); HRMS (EI-TOF) Calcd for C 16 (7R,R S )-7-Amino-N-(tert-butanesulfinyl)hexadecan-2-one (9d ). Following the general procedure, compound 9d was obtained as the minor diastereoisomer from sulfinyl imine 5d and 6-chloro-2-methoxyhex-1-ene (2c) as a yellow oil (14 mg, 0.039 mmol, 19%): (36), 239 (32), 196 (16), 156 (13), 123 (18), 112 (20), 111 (19), 109 (33), 97 (35), 95 (39), 85 (15), 83 (55), 81 (23), 71 (30), 70 (14), 69 (44), 57 (91), 56 (15), 55 (32), 43 (100), 41 (38); HRMS (EI-TOF) Calcd for C 16 H 33 NO 2 S [M + -C 4 H 9 ] 303.2232, found 303.2238. lective acidic hydrolysis of enol ether functionality. These amino ketone derivatives can be in turn used as direct precursors of 2-substituted 6-methylpiperidines, including natural alkaloids (−)-, and (+)-isosolenopsin A, and 2-substituted 7-methylazepanes, in a stereoselective manner.…”

Venom Isosolenopsin A Delivers Rapid Knockdown of Fire Ant Competitors

“…Synthetic racemic solenopsins (Table S1) were purchased from WuXi AppTec (ShangHai, China) after synthesis according with Pianaro et al (2012) for cis isomers and Herath & Nanayakkara (2008) for trans isomers. Synthetic racemic nicotine was purchased from Sigma.…”