Enantioselective synthesis of (+)-trypargine and (+)-crispine E

Czarnocki, Stefan J.; Wojtasiewicz, Krystyna; Jóźwiak, Adam; Maurin, Jan K.; Czarnocki, Zbigniew; Drabowicz, J.

doi:10.1016/j.tet.2008.01.088

Cited by 36 publications

(22 citation statements)

References 48 publications

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“…18 The reaction is catalyzed by chiral N-sulfonated diamine-Ru(II)-h 6 arene complexes and has become the method of choice for the enantioselective reduction of cyclic imines due to the high yield and enantiomeric excess usually attained and the simplicity of the experimental protocol. 19,20 Despite the advantages of this methodology, relatively few examples of asymmetric synthesis of natural products containing the tetrahydro-b-carboline core have appeared since our first disclosure of the application of Noyori asymmetric transfer hydrogenation in the total synthesis of arborescidines A, B and C. 8,9,[21][22][23] The 16 electron catalytic active species II was generated upon treatment of pre-catalyst RuCl(S,S)-H 2 NCHPhCHPhNTs)(h-p-cymene) (I) in DMF at 80 o C in the presence of Et 3 N. 24,25 Then, a solution of prochiral imine 9 in DMF was added, followed by a 5:2 formic acid-triethylamine azeotropic mixture and the reaction mixture was kept at room temperature for 8 h. Under these conditions tetrahydro-b-carboline 10 was isolated in 75% overall yield from allyl carbamate 4. However, when longer reaction time was employed the hydrogenation of the allyloxy group present in 10 was also observed.…”

Section: Resultsmentioning

confidence: 99%

“…Allyl [3-(4,9-dihydro-3H-carbolin-1-yl)propyl]carbamate (9) A solution of 4 (1.18 g, 3.56 mmol) in a mixture (7:3 v/v) of toluene/acetonitrile (30 mL) was added POCl 3 (1 mL, 10 mmol) dropwise and the reaction mixture was refluxed for 5 h. The reaction mixture was cooled to rt and concentrated under vacuum. …”

Section: Allyl (4-{2-[1h-indol-3-yl)ethyl]amino)-4-oxobutyl) Carbamatmentioning

confidence: 99%

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

Pilli¹,

Rodrigues²

2009

J. Braz. Chem. Soc.

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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...

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Section: Resultsmentioning

confidence: 99%

Section: Allyl (4-{2-[1h-indol-3-yl)ethyl]amino)-4-oxobutyl) Carbamatmentioning

confidence: 99%

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

Pilli¹,

Rodrigues²

2009

J. Braz. Chem. Soc.

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“…In a key step in the enantioselective synthesis of mianserin and epinastine we applied the asymmetric reduction of the prochiral imine by asymmetric hydrogen transfer reaction (ATH) [10–14]. The proposed strategy could be used for the preparation of the title compounds and their structural analogues.…”

Section: Introductionmentioning

confidence: 99%

The enantioselective synthesis of (S)-(+)-mianserin and (S)-(+)-epinastine

Roszkowski¹,

Maurin²,

Czarnocki³

2015

Beilstein J. Org. Chem.

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“…20 Both routes required the synthesis of 6-bromotyramine 8 . As shown in Scheme 1, nitro olefination of 6-bromo-1 H -indole 9 , as prescribed by Büchi, 11 proceeded smoothly affording 10 in 98% yield.…”

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“…Thus, focus shifted towards a Bischler-Napieralski/Noyori asymmetric transfer hydrogenation approach. 14,20 …”

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confidence: 99%

Total Synthesis of (+)-7-Bromotrypargine and Unnatural Analogues: Biological Evaluation Uncovers Activity at CNS Targets of Therapeutic Relevance

Brogan

Stoops

Crews

et al. 2011

ACS Chem. Neurosci.

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The first total synthesis of (+)-7-bromotrypargine, a β-carboline alkaloid from Ancornia sp. is reported. The synthesis proceeds in 9 steps, 8 steps longest linear sequence, in 36.9% overall yield. Biological characterization found that (+)-7-bromotrypargine is an H3 antagonist, and a selective inhibitor of DAT and NET, without inhibiting SERT. Moreover, unlike electron rich congeners, (+)-7-bromotrypargine is not cytotoxic, and thus represents an attractive starting point for chemical optimization; therefore, we piloted a number of chemistries for the synthesis of unnatural analogs.

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Enantioselective synthesis of (+)-trypargine and (+)-crispine E

Cited by 36 publications

References 48 publications

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

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

The enantioselective synthesis of (S)-(+)-mianserin and (S)-(+)-epinastine

Total Synthesis of (+)-7-Bromotrypargine and Unnatural Analogues: Biological Evaluation Uncovers Activity at CNS Targets of Therapeutic Relevance

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