Aspidosperma skeleton

For a Lewis-acid-mediated cyclization reaction of a tryptamine-derived vinylogous amide that affords the Aspidosperma skeleton, see Huizenga RH, Pandit UK (1991) Tetrahedron 47 4155 1164... 

The versatility of strictosidine as a central intermediate for the biosynthesis of a variety of alkaloids is based on the highly reactive dialdehyde produced by the action of strictosidine p-D-glucosidase. This reactive intermediate is converted by uncharacterized enzymes into the major corynanthe, iboga, and aspidosperma skeletons that are elaborated into die several hundred alkaloids found in Catharanthns roseus. Since the biosynthesis of strictosidine appears to occur within plant vacuoles, there has been much speculation, but little is known, about the factors that regulate the accumulation of strictosidine within the vacuole, or which trigger its mobilization for further elaboration. It is well known that glycosides of different natural product classes are located within plant vacuoles. 

A similar route to these alkaloids has been employed by Gramain and coworkers22. Irradiation of compound 39 produced the tricyclic dihydroindole 40, which was converted in five steps to the tetracyclic aspidosperma skeleton 41 in 57% overall yield as outlined in Scheme 10. 

A regioselective peroxidation by ra-chloroperbenzoic acid was accomplished during the multistep synthesis of alkaloids of pentacyclic Aspidosperma skeleton. By operating at low temperature, oxidation of the enamine double bond was effected more rapidly than that of the sulphoxide group and the epoxide intermediate was isolated49 (Scheme 33). 

A number of-synthetic approaches to the Aspidosperma skeleton have been developed in recent years. This section attempts to highlight some of the features of these routes. 

One of the crucial points which arose during the syntheses of the Aspidosperma skeleton by the groups of Ban and Stork was a controversy over the stereochemistry of the tricyclic amino ketone intermediate. Thus Stork assigned structure 373 to this compound and Ban assigned structure 374 to his intermediate prepared by a different route. 

In carrying out the further steps to the Aspidosperma skeleton, only the compound in the major series—the tricyclic keto lactam 400—was used... 

As the next step in the synthetic program, Ban envisaged a synthesis of the Aspidosperma skeleton via a double Michael cyclization in which attack occurs successively at the a- and /8-positions of an , -unsaturated ketone. The success of this novel cyclization reaction was first achieved on compound 428 to give a compound having the aspidofractinine-type skeleton (207). 

Yet another variation of the Aspidosperma skeleton is that of fendleri dine (aspidoalbidine) (210), in which the C-18 carbon is attached to C-21 via an ether bridge. By a route quite analogous to that used for N-acetylaspidospermidine (252), Ban has completed a synthesis of N-acetyl-aspidoalbidine (445) using deoxylimapodine (446) as the key intermediate (211). 

Stevens and co-workers have also attempted to develop a fundamentally different approach to the tricyclic amino ketone 463 which is used in the Fischer cyclization approach to the Aspidosperma skeleton (240). Condensation of the aldehyde-ester 553 with protected keto amine 554 gave an imine (555) which, upon heating with ammonium chloride at 160°, afforded the 2-pyrroline ester 556 in 70% yield. Treatment with dry hydrochloric acid gas in ether was followed by acid hydrolysis of the ketal, and base-catalyzed cyclization produced a mixture of two enol ethers (557 and 558) the latter predominating. The major isomer was reduced with lithium aluminum hydride and the hydroxy enol ether dehydrated in hot... 

The Harley-Mason approach to the Aspidosperma skeleton was discussed in Volume XI (p. 225), and very brief mention was made of the successful synthesis of aspidospermidine (249) using this route (241). In view of the complication involving cis/trans C/D ring stereochemistry involved in a number of other approaches, it is amazing that the Harley-Mason approach should be stereoselective. The process in question is typically reaction of the hydroxyester 560 with tryptamine to give a compound (561) having a sero-ebumane skeleton. When this compound is treated with 40% sulfuric acid or boron trifluoride etherate at 100°, the indolenine lactam 562 is produced. Lithium aluminum hydride reduction then gives racemic aspidospermidine (249 Scheme 33). 

A further example of synthetic approaches to the Aspidosperma skeleton is provided by Potier s synthesis of 5-oxo-20-deethyl vincadifformamide (579) (245). This approach differs fundamentally from the available syntheses in that it begins with a 2-substituted indole followed by cyclization in a single step to the A,B,C,D system lacking the tryptamine bridge carbons. 

A number of miscellaneous attempts at the synthesis of the Aspidosperma skeleton have been reported in preliminary forms (246-248). 

Vilsmeier-Haack-type reaction provided the C ring of the Aspidosperma skeleton, and elaboration of the E ring was achieved by the addition of a radical generated from the xanthate derivative of the primary alcohol to give nonacyclic compound 111. The final steps for the completion of the total synthesis consisted of the formation of a lactone ring, which was achieved by oxidation of the tertiary amine with potassium ferricyanide,... 

The C-atoms marked by in strychnine and brucine are derived from acetate. Vinblastine (vincaleucoblastine) and vincristine are dimeric alkaloids containing both the iboga and the aspidosperma skeletons... 

In 2011, the Fukuyama group reported the first total synthesis of (-)-conophylline, whose structure consists of two pentacyclic aspidosperma skeletons (Scheme 13.5) [6]. The two aspidosperma skeletons were both constructed through a similar intramolecular Michael addition/Mannich reaction cascade stfategy, which could produce three new rings and three new stereogenic centers with complete stereoselectivity in just one step. 

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