Enantiopure cyclopentane building blocks from iridoid glucosides: Conversion into carbocyclic homo-N-nucleosides.

Jon Holbech Rasmussen

    Research output: Book/ReportBook


    The main objective of this work has been to investigate the use of the plant metabolites iridoid glucosides as starting materials in the synthesis of versatile cyclopentanoid building blocks. With the aim of isolating the iridoid glucoside catalpol (5) several species of the genus Scutellaria, i.e. S. albida, S. woronowic, S. subvelutina, S. lateriflora, S. altissima, were investigated. It was found that in the water-soluble part of an ethanolic extract, a cinnamic ester of catalpol, scutellarioside I (348), was extractable into EtOAc. A method was developed in which the preparation of a water-soluble extract of the plant material, extraction of 348 into EtOAc and acetylation of the crude EtOAc-extract, gave an acetylated crude product, from which scutellarioside I pentaacetate (351) was crystallised. Thus, 351 was obtained without the use of chromatography. Conversely, the purification of 5 was only achieved by chromatography. It was found that S. woronowic and S. subvelutina were the best sources of 348, while S. albida was a good source of 5. Catalpol (5) and scutellarioside I (348) were used as starting materials in the syntheses of cyclopentanoid building blocks. Through a short sequence, pentaacetate 351 was transformed into an iridoid glucoside diacetonide 371. Ozonolysis of 371 followed by a reductive work-up procedure (NaBH4) led to the partially protected cyclopentane derivative 352. The ozonolysis/reduction sequence constitutes a new method in iridoid chemistry to obtain cyclopentanoid building blocks in a short and efficient way. Two enantiopure carbocyclic homo-N-nucleosides, 382 and 391, were synthesised from 352. In another approach, catalpol (5) was transformed into cyclopentane derivative 59. Selective protection of 59, a subsequent coupling sequence with 6-iodopurine tetrabutylammonium salt 339 and a final deprotection/substitution step, afforded homo-N-nucleoside 359. Iridolactone 369 was prepared through a third sequence, and treatment of 369 with ammonia in methanol gave the a,b-unsaturated cyclopentene amide 370. A fourth sequence starting with 236 led to iridoid alcohol 396, which in an attempt to couple a nucleoside, eliminated water and gave an 8,9-unsaturated iridoid 401. Additionally, the ozonolysis procedure was carried out with antirrhinoside (270). This gave rise to two products, an expected product 405 and an unexpected product 406. The unexpected product 406 was formed from 405 through an intramolecular cyclisation to form a 2-oxabicylco[2.2.1]heptane frame-work. It was found that by changing the work-up conditions, exclusively 405 or 406 could be formed. An extension of a coupling method in carbocyclic nucleoside chemistry was carried out. Three new tetrabutylammonium salts of 6-substituted purines were prepared and tested in a reaction with a primary carbohydrate triflate (332). 6-Iodopurine tetrabutylammonium salt (339) gave superior results both considering the N-9/N-7 regioselectivity and yield. The coupling reaction followed by a deprotection/substitution step gave nucleoside 346. Nucleosides 359 and 346 together with scutellarioside I (348) were tested against HIV virus and HSV-1. They were, however, found to be inactive.
    Original languageEnglish
    Place of PublicationLyngby
    PublisherTechnical University of Denmark
    Publication statusPublished - 1998

    Cite this