Current Organic Chemistry - Volume 9, Issue 15, 2005

All the major reactions taking part in the biosynthesis of ajmaline in cell suspension cultures of the Indian medicinal plant Rauvolfia have now been established at the enzyme level. Of the well investigated 10 steps six of the involved enzymes have been functionally cloned. These are strictosidine synthase (STR), strictosidine glucosidase (SG), polyneuridine aldehyde esterase (PNAE), vinorine synthase (VS), cytochrome P450 reductase (CPR) and acetylajmalan acetylesterase (AAE). Because the cDNAs of these enzymes are now known their detailed molecular analysis became attainable for the first time. Some of these enzymes such as STR, SG or VS could be produced in E. coli at a preparative scale resulting in mg amounts of pure enzymes. They also have been crystallized and their preliminary X-ray analyses were published recently. It is only a matter of time that their molecular structure and the mechanisms of the catalyzed reactions will be elucidated. Of the soluble enzymes vomilenine reductase and 1.2-dihydrovomilenine reductase remain to be heterologously expressed. Appropriate cDNA clones have recently been isolated. What membrane bound enzymes of this pathway is concerned cloning could not be achieved up to now. Our future strategy is to purify these enzymes first and to use the "reverse genetic" approach as we did for the soluble enzymes. The sarpagine bridge enzyme (SBE), vinorine hydroxylase (VH) and norajmaline N-methyltransferase (NAMT) are the only enzymes which remain as the major candidates for expression studies in order to express heterologously the complete ajmaline biosynthetic pathway.

A number of monoterpenoid indole and oxindole alkaloids have been isolated from botanical sources, and many of them have been found to possess significant pharmacological activities and are utilized as key lead compounds in new drug development. In this review, the recent results of our phytochemical and synthetic studies of indole alkaloids having the Corynanthe-type related skeleton from genera Uncaria, Nauclea, and Mitragyna, which are classified under tribe Cinchoneae, family Rubiaceae, are described.

The synthetic efforts of the author's research team in several areas within the monoterpene indole alkaloid family are summarized. Most of the work was accomplished in the field of the Aristotelia alkaloids, where some 25 natural products were synthesized for the first time. Systematic investigations on the oxidative rearrangement of indoles to oxindoles and pseudoindoxyl derivatives led to control over the chemoselectivity and stereoselectivity of this process, which served for enantioselective preparations of the simple alkaloids horsfiline and elacomine. In addition, recent developments in a novel approach to Iboga alkaloids containing a hydroxyl group at C(19) are presented. The key steps involved a self-immolating 1,4-chirality transfer in an Ireland-Claisen rearrangement and an intramolecular nitrone-olefin [2+3]-cycloaddition to give the aliphatic isoquinuclidine core of the target molecules. The first synthesis of (19R)- hydroxyibogamine was completed by grafting a 3-ethylindole unit onto the aliphatic nitrogen, followed by closing the 7- membered ring.

Indoles that are substituted at the 2- or 3-position with electron-withdrawing groups (nitro, phenylsulfonyl) undergo nucleophilic addition, 1,3-dipolar cycloaddition, and Diels-Alder reactions to give a variety of indoles, pyrroloindoles, and carbazoles. New methods for the synthesis of furo[3,4-b]indoles and the novel ring system furo[3,4- b]pyrrole are described for the first time. Diels-Alder reactions of furo[3,4-b]pyrroles afford indoles after dehydration of the primary cycloadducts. Efficient syntheses of both 2- and 3-nitroindoles from indole are reported, and the first generation and successful electrophilic trapping of a 2,3-dilithioindole has been achieved.

Supported reagents and scavengers have become key tools for the synthesis of biologically important molecular entities. The complexity of the target molecules attainable and the synthetic flexibility afforded by these systems now rivals any solution phase approach whilst offering the added advantage of rapid purification and work-up. This short review highlights the application of these immobilized reagents to the preparation of alkaloid natural products.

Molybdenum and ruthenium alkylidene-catalyzed ring-closing metathesis (RCM) reactions have emerged as key constructs for the facile assembly of the polycyclic frameworks of a variety of natural products. Advances in catalyst development, particularly of highly reactive ruthenium species, have enabled facile ene-ene and ene-yne bond metatheses to create both carbocyclic and heterocyclic systems, sometimes possessing remarkable functional and structural complexity in a single operation. The operational simplicity, ease of handling, and generally high turnover numbers of the ruthenium-catalysts have brought RCM reactions to the forefront of practical carbon-carbon bond forming transformations. Some recent applications of RCM to the synthesis of alkaloid natural products are reviewed.

The marine natural product (-)-palau'amine from the sponge Stylotella aurantium represents one of the toughest challenges to total synthesis. It possesses a strained hexacyclic skeleton which leads current methods of organic synthesis to their limit. Recently, several research groups have undertaken independent approaches, focussing on possibly biomimetic approaches involving the underlying biogenetic key metabolite oroidin. Oroidin is the parent compound of the pyrrole-imidazole alkaloids. In this review, recent developments in the field since 2003 are discussed, outlining progress on the dimerization of 4(5)-alkenylimidazoles, total syntheses of non-cyclized pyrrole-imidazole alkaloids, of dibromophakellstatin, agelastatin, and an update on hymenialdisine. Although palau'amine has not yet been synthesized, there are original approaches to the system which have afforded biologically active, smaller pyrrole-imidazole alkaloids such as dibromophakellstatin and agelastatin A.

The pyrroloiminoquinone alkaloid family consisting of discorhabdins and makaluvamines exhibits antitumor activities derived from their unique highly-fused structures. The total synthesis of them and the key reactions used in the total synthesis of these compounds are described.

Pyrroles and gem-dihalocyclopropanes are both readily accessible classes of compound. They have considerable potential as building blocks in the construction of alkaloid frameworks. This review details work, carried out within the authors' laboratories, directed towards such ends and with a particular emphasis on the engagement of the title moieties in intramolecular processes. An emerging area involving efforts to exploit the complementary electronic characteristics of pyrroles and gem-dihalogenocyclopropanes in the synthesis of alkaloids is also discussed.

Using organometallic chemistry several novel methods for the efficient construction of pyrroles, indoles, and carbazoles have been developed. The key reactions are transition metal-mediated or -catalyzed oxidative cyclizations and cycloadditions. In the present article we summarize some recent applications of these methods to short and convergent total syntheses of naturally occurring biologically active alkaloids including fused indolizidines, yohimbanes, Amaryllidaceae alkaloids, and carbazoles.