The asymmetric total synthesis of (+)- and (-)-trypargine via Noyori asymmetric transfer hydrogenation

Abstract

Uma síntese total e eficiente da (+) e (-)-tripargina, alcalóide b-carbolínico isolado da pele da rã africana K. Senegalensis, foi realizada em 6 etapas e 38% de rendimento global, a partir da triptamina, tendo como base a construção do sistema b-carbolínico via reação de BischlerNapieralski e a redução enantiosseletiva do intermediário diidro-b-carbolínico via reação de transferência de hidrogênio assimétrica usando o protocolo de Noyori.A concise and efficient total synhesis of (+)-and (-)-trypargine (6 steps and 38% overall yield), a 1-substituted b-carboline guanidine alkaloid isolated from the skin of the African frog K. senegalensis, was developed based on the construction of the b-carboline moiety via BischlerNapieralski reaction and the enantioselective reduction of the dihydro-b-carboline intermediate via an asymmetric transfer hydrogenation reaction using Noyori´s protocol.Keywords: trypargine, tetrahydro b-carboline alkaloid, Bischler-Napieralski reaction, Noyori asymmetric transfer hydrogenation IntroductionThe b-carboline skeleton is widely distributed among natural products including yohimbine (yohimbine and alloyohimbine), corynantheidine (corynantheidine), Rauwolfia (reserpine) and Vinca (vincamine) alkaloids. 1 (-)-Trypargine (1) is a b-carboline alkaloid which has been isolated from the skin of the African racophorid frog, Kassina senegalensis, by Akizawa et al. 2 in 1982 and more recently has also been isolated in nearly racemic form from the methanol extract of the ground ascidian Eudistoma sp. 3 The absolute configuration of natural (-)-trypargine (1) was initially assigned via resolution of its racemate, prepared via the Pictet-Spengler reaction between tryptamine and 4-guanidino butyraldehyde ethyleneacetal, followed by optical rotatory dispersion and circular dichroism studies. 4 Ishikawa and co-workers 4,5 established its absolute configuration by total synthesis via the Pictet-Spengler reaction between (R)-N-benzyl tryptophan methyl ester and 2-ketoglutaric acid, followed by X-ray diffraction analysis of the corresponding methyl ester of the major diastereoisomer. Synthetic (-)-(S)-1-(3´-guanidinopropyl)-1,2,3,4-tetrahydro-bcarboline was shown to be identical to natural (-)-trypargine (1) thus establishing its absolute configuration.The presence of a b-carboline and a guanidine moieties in the structure of (-)-trypargine (1) has led to preliminary evaluation of its biological profile. Neither a full account of the biological properties nor its biosynthetic origin have been reported although one may envision trypargine (1) to be formed from tryptophan and the 2-keto carboxylic acid derived from arginine. It has been reported to be toxic to mice (LD 50 = 16.9 mg kg -1 , intravenous administration) although complete details of this study are lacking. 5,6 Ireland and co-workers 3 have failed to observe significant cytotoxicity in fractions containing trypargine alkaloids against human colon tumor cells. Additionally, (-)-trypargine (1) has been reported to block voltage gated sodium channe...

Catalytic Asymmetric Transfer Hydrogenation of Imines: Recent Advances

“…The stereocenter of both enantiomers of trypargine 47 (an alkaloid isolated from the skin of the African racophorid frog) was created by an ATH of the corresponding imine with formic acid and triethylamine catalyzed by both enantiomers of complex 2b …”

“…The stereocenter of both enantiomers of trypargine 47 (an alkaloid isolated from the skin of the African racophorid frog) was created by an ATH of the corresponding imine with formic acid and triethylamine catalyzed by both enantiomers of complex 2b. [31] The same reaction conditions, in terms of catalyst and hydrogen source, were used for the stereoselective synthesis of norephedrine (48) and norpseudoephedrine (49) (two members of the amphetamine family of Ephedra alkaloids with sympathomimetic psychoactivity), the key step being the ATH of the racemic sulfamidate imine 50. [32] Furthermore, the same combination of reagents and conditions were applied to generate the stereocenter at C-1 in the β-carboline alkaloid eudistomidin G (51) (isolated from marine tunicates of the genus Eudistoma) by an ATH of the corresponding imine.…”

The chemistry and biology of organic guanidine derivatives

“…The natural product (+)-267 was obtained after deprotection of 275 using McMurry's conditions, followed by introduction of the guanidine moiety with 1H-pyrazol-1-carboxyamidine hydrochloride in 69% yield for the two steps. 293…”