Efficient Conversion of Tomatidine into Neuritogenic Pregnane Derivative

Abstract

The steroidal hormones are mainly derivatized from Dioscoreacea plants to produce birth controllable medicine, the pill. The raw material bearing steroidal hormones are strongly disired. The aerial parts of tomatoes are discarded after picking the fruits of tomatoes. Taking into the consideration of an effective utilization for tomato rejectings, we tried an efficient conversion of tomatidine (1) into a pregnane derivative, possessing the NGF-like neurite extension capability being available for dementia.Tomatidine (1) is the sapogenol of tomatine which is contained in ca. 0.1% in the aerial parts of tomato. Effective application of the aerial parts after picking the fruits is strongly desired. Previously, Sato et al. reported that refluxing of tomatidine with anhydrous acetic acid produced a hydrogenable triaetate, d20(22) -pseudo compound, which was subsequently oxidized with chromic acid to give 5a-pregn-16-en3b-ol-20-one in an overall ca. 27.3% yield. 1) We have now developed a new conventional method into a pregnane derivative from tomatidine. In addition, we have revealed that the product of the pregnane derivative possesses neuritogenic and NGF-enhancing activities.Tomatidine (1) was acetylated with anhydrous acetic acid and pyridine for 20 h at r.t. After the reaction mixture was poured into ice-water and left to stand overnight, the deposited white precipitate was collected by filtration. The product was purified by using silica gel column chromatography to provide a homogeneous acetate (2) in a 62.1% yield, whose EI-MS exhibited a molecular ion at m/z 499 corresponding to C 31 H 49 NO 4 . The Next, to a solution of 2 in MeOH, ozone gas was introduced for 10 min at Ϫ40°C. The solution was evaporated to give a residue, which was then refluxed with 3% KOH dioxane-water (1 : 1) and neutralized. The product was purified by silica gel column chromatography to give the pregnane derivative (3), which was obtained in a 87.0% yield as colorless needles, mp 203-205°C, [a] D ϩ48.2°(EtOH). Compound 3 showed a peak due to a molecular ion at m/z 316, corresponding C 21 H 32 O 2 in the EI-MS. The 1 H-NMR spectrum showed signals due to three tertiary methyls at d 0.82 (3H, s, H 3 -19), 0.94 (3H, s, H 3 -18), 2.26 (3H, s, H 3 -21), along with one oxygen bearing a methine proton at d 3.85 (1H, m, H-3) and one olefinic proton at d 6.62 (1H, dd, Jϭ1.8, 3.1 Hz,, of which assignments were made by the 2D-NMR measurements. The 13 C-NMR signals were also assigned as follows: C-1-21, 32.5, 32.2, 70.6, 37.3, 45.5 Chikusa-ku, Nagoya 464-8601, Japan. Received February 1, 2007; accepted March 26, 2007; published online April 19, 2007 Moderate acetylation of tomatidine with anhydrous acetic acid and pyridine for 20 h at r.t., followed by pseudomerization in ice-water, gave a d d 20(22) -pseudo compound, which was then subjected to ozonolysis to provide a pregnane derivative in a total 54% yield showing neuritogenic and NGF-enhancing activities.

Access to 27-Nortomatidine and 27-Norsoladulcidine Derivatives

“…Analogous changes were also observed for other pairs of the spectra of compounds 19b/20b and 19c/20c . For comparison, the literature 16α-H chemical shifts for soladulcidine ( 2 ) (22 R ) and tomatidine ( 3 ) (22 S ) are 4.29 and 4.12 ppm, respectively.…”

Concise Large-Scale Synthesis of Tomatidine, A Potent Antibiotic Natural Product

“…206–208 °C][ 47 ]. The spectroscopic data were in agreement with previously reported data [ 15 , 48 ].…”

Tomatidine inhibits iNOS and COX‐2 through suppression of NF‐κB and JNK pathways in LPS‐stimulated mouse macrophages

“…Tomatidine may benefit cancer chemotherapy by inhibiting multidrug resistance in human cancer cells [19] and by inhibiting the growth of colon and liver cancer cells [20]. Tomatidine was developed into a pregnane derivative possessing neuritogenic and NGF‐enhancing activities [21]. In addition, tomatidine suppresses the oxidative burst and is able to suppress induced plant defense responses [22,23].…”