Kombinatorische Synthese

Industrial drug research is undergoing radical changes. Advances in molecular biology and gene technology have resulted in the development of test systems with which a very large number of substances can be screened for their biological activity. In order to keep pace with this high-throughput screening procedure, preparative chemists need to reconsider conventional synthetic strategies.     

Synthese von Cotarnin-Iodid

Summary Starting from 4-methoxy-1,3-benzodioxol-5-carbaldehyde (croweacin aldehyde,3) a six-step synthesis of cotarnin iodide (9, 67% total yield) is described.

     

Synthese neuer N-Vinylpyrrole

Syntheses of New N-Vinylpyrroles The reactions of pyrrolyl potassium ( 1 ) with (ethoxymethylene)malonic acid derivatives 2a–e yielded the carbanions 3a–e , which could be hydrolyzed to 4a–e , but with the exception of 4b they were not isolated, because a transformation to the N-vinylpyrroles 5a , c–e by elimination of ethanol took place; 1 reacted with 2b at 80°C to give 4b and 6 . Hydrolysis of 4b with KOH yielded 4g , which eliminated 1 mol of ethanol to form 5f , decarboxylation of which led to N-vinylpyrrole 7 . By cyclization of 5e under various conditions the pyrrolizines 8a , b are obtained, the hydrolysis of which did not give ketone 9 but only amino alcohol 10 . Some other cyclizations of 11a–c and 13 yielded the 3H-pyrrolizine derivatives 12a–c and 14 , respectively.     

Synthese des Dysidins

Synthesis of Dysidin The synthesis of dysidin ((?)- 1 ), the enantiomer of a metabolite of the marine sponge Dysidea herbacea, is described. To effect the synthesis, (±)-5-isopropyl-4-methoxy-3-pyrrolin-2-one ( 7 ) is converted to its lithium salt and reacted with (?)-(5R,2E)-3-methoxy-5-trichloromethyl-2-hexenoyl chloride ((-)- 11 ) to give (?)- 1 and its diastereoisomer (+)-5-epidysidin ((+)- 12 ) epimeric at C(5) of the pyrrolinone ring. The (?)-acyl chloride (?)- 11 has been synthesized from (+)-(R)-3-(trichloromethyl)butanoic acid ((+)- 8 ) via the intermediates (+)- 9 and (?)- 10 , the pyrrolinone 7 from N-benzyl-oxycarbonyl-L-valine via the intermediate 5 . The enantiomers of acid 8 have been resolved by fractional crystallization of their diastereoisomeric N-(1-phenylethyl)amides. The (R)-chirality of (+)- 8 was determined by comparing the ¹H-NMR spectra of the diastereoisomeric N-(1-phenylethyl)amides 16 and 17 , made from (+)- 8 by substituting deuterium for chlorine, with the spectra of the N-(1-phenylethyl)amides 14 and 15 of known absolute configuration. This correlation shows that literature value (R) for (?)- 8 is in error. Therefore, the structural formulae of (?)-dysidenin and (+)-isodysidenin, two other metabolites of D.herbacea, have to be changed to their mirror images as shown in formulae (?)- 3 and (+)- 4 , respectively.     

Synthese von Hydroxybenzylbenzimidazolen

Zusammenfassung Eine Reihe von Hydroxybenzylbenzimidazolen wurde durch Kondensation verschiedener aromatischer o-Diamine mit Brommandelsäuren unter Verwendung von 6n-HCl als Kondensationsmittel hergestellt. Für die Substituenten in der Benzolhälfte wurden die Stellungen 4(7)-, 5(6)-, 5,6- oder 4,6(5,7)- ge-wählt; der Phenylrest der Hydroxybenzylhälfte trägt ein Bromatom in der o- oder p-Stellung. Die Darstellung der o-Brom-mandelsäure wird beschrieben.

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A series of hydroxybenzylbenzimidazoles has been synthesized by condensing various aromatic o-diamines with bromomandelic acids using 6 N hydrochloric acid as condensing agent. o-Phenylene diamines to yield benzimidazoles substituted at positions 4(7)-, 5(6)- or 4,6(5,7)- were selected; the phenyl group of the hydroxybenzyl moiety carries a bromo substituent in the o- or p-position. The preparation of o-bromomandelic acid is described in some detail.

     

Synthese des Gentisins

Ohne Zusammenfassung     

Synthese von Orellin

Synthesis of Orelline Orelline (1) , a metabolite of the toadstool Cortinarius Overllauns Fries with 2,2′-bipyridine structure, has been synthesized by the following method. The easily accessible 2-bromo-3-hydroxypyridine (3) was converted into the corresponding [2-(trimethylsilyl)ethoxy]methyl (SEM) ether 4 and coupled with Zn and NiCl₂/Ph₃P to form the bipyridine derivative 5 in 79% yield. Due to the chelating effect of the two SEM-ether groups in 5 , it was possible to from selectively the dilithium compound 6 by an exchange reaction with BuLi at ?50° in Et₂O. Reaction of 6 with electrophiles at ?20° afforded the 4- and 4,4′-substituted bipyridines 7–14 in excellent-to-reasonable yield. Oxidation of 6 with 2-(phenylsulfonyl)-3-phenyloxaziridin and with bis(trimethylsilyl)peroxide gave the 4,4′-diol 9 in 22 and 10% yield, respectively. Methanolysis of 9 directly afforded crystalline 1 in high yield, with properties identical with those of natural orelline. Formylation of 6 with N-formylmorpholine gave 45% of the dicarbaldehyde 13. Removal of the SEM groups in 13 by hydrolysis afforded the dihydroxydicarbaldehyde 15 that could be oxidized to 1 with alkaline H₂O₂. Attempts to oxidize 1 to orellanine (2) with 35% H₂O₂ according to a known procedure were unsuccessful (cf. Exper. Part). Compound 7 with two Me₃Si groups in 4,4′-position gave after methanolysis the fluorescence dye 16 with an appreciable Stokes shift in cyclohexane.     

Synthese des Rubremetiniumbromides

Zusammenfassung Es wird die Synthese des d,I-Rubremetiniumbromides beschrieben und die UV-Absorption mit dem aus natürlichem Emetin durch Dehydrierung hergestellten d-Rubremetiniumbromid identisch gefunden. Damit wurde ein weiterer Beweis für die von uns seinerzeit auf dem Abbauweg ermittelte Konstitutionsformel des Emetins erbracht und ein gangbarer Weg für die präparative Herstellung des Naturstoffes gewiesen.Herrn Prof. Dr.F. Wessely zum 60. Geburtstag in Verehrung gewidmet.