Synthesis of trans-2-(indol-3-yl)cyclopropylamines: Rigid tryptamine analogues

Suwanna Vangveravong, Purdue University

Abstract

This thesis project involved the synthesis of a series of trans-2-(indol-3-yl)cyclopropylamines, the simplest conformationally rigid analogues of tryptamine. Derivatives bearing substituents of varying electronic nature on the C-4 and C-5 positions were prepared. The total synthesis is based on the work of Arvidsson et al. Indole-3-carboxaldehydes were first protected at the N-atom as the N-p-toluenesulfonyl derivatives to enhance the reactivity of the aldehydes towards nucleophilic attack by malonic acid to give trans-$\beta$-(indol-3-yl)acrylic acids. The methyl ester derivatives of the acids underwent palladium(II)-catalyzed cyclopropanation with diazomethane, followed by alkaline hydrolysis to give cyclopropane carboxylic acids. Conversion of the resulting carboxylic acids to amines was accomplished by a modified Curtius rearrangement. Deprotection of the p-toluenesulfonyl group at the final step by an application of Trost's buffered sodium amalgam method gave the target compounds in moderate yields. The pure optical isomers of the unsubstituted compound were also successfully obtained. The racemic compound quickly revealed itself to be a relatively unstable molecule, and it was considered unlikely that the enantiomers could be separated by multiple recrystallizations of diastereomeric salts. Therefore, the optically active trans-2-(indol-3-yl)cyclopropylamines were prepared based on the method of Vallgarda and Hacksell. Cyclopropanation of the indol-3-acryloyl derivative of Oppolzer's chiral sultam with diazomethane at 0$\sp\circ$C produced the stereoisomeric cyclopropanated sultams in ratios of about 82:18, determined by HPLC. The chromatographic properties of the two diastereomers are so similar that they could not be completely separated by chromatography, however, the major diastereomer was isolated in pure form (greater than 99% de, by HPLC analysis) by recrystallization. Hydrolysis of the sultam chiral auxiliary gave the chiral indolecyclopropane carboxylic acids. These were converted into the enantiomers of the final compound using the sequence employed to prepare the racemic material. Thus, through this series of reactions we have prepared optically active trans-2-(indol-3-yl)cyclopropylamines, rigid tryptamine analogues.

Degree

Ph.D.

Advisors

Nichols, Purdue University.

Subject Area

Pharmaceuticals

COinS