Year

2015

Degree Name

Doctor of Philosophy

Department

School of Chemistry

Abstract

The main aim of this project was to develop a new synthetic methodology towards the total synthesis of the pentacyclic Stemona alkaloid stemocurtisine by first preparation of a tricyclic A-B-C ring precursor and then its tetracyclic ether derivative by an oxidative photolysis reaction.

In Chapter 2, we report our efforts to construct the A-ring of stemocurtisine using three different synthetic strategies. Synthetic strategy 1 failed due to unexpected ring opening of the hemiaminal product formed from the reactions between alkynyl Grignard reagents and a glutarimide derivative. Synthetic strategy 2 was not efficient due to the unsucessful conversion of a terminal alkynyltrimethylsilane to its corresponding propiolate methyl ester following the method of Kondo. Using synthetic strategy 3 we obtained the racemic desired ene-yne lactam A-ring derivative in 11 synthetic steps and in 12.1% overall yield from 4-pentyne-1-ol. In Chapter 3, we describe our successful method to construct the bicyclic A-B ring system of stemocurtisine following Mori’s ene-yne ring-closing metathesis procedure. The successful synthesis of the tricyclic A-B-C ring system of stemocurtisine is also discussed in this chapter. The synthesis of this tricyclic compound was achieved via a bromolactonization process using NBS/PhSeSePh followed by a base-catalysed elimination of the resulting bromolactone. Our attempts to reduce the resulting α,β-unsaturated lactone to its saturated derivative were not initially successful using the standard reducing reagents NaBH4/NiCl2 or NaBH4/CuCl. However, reduction of this α,β-unsaturated lactone using Mg/MeOH provided the saturated lactone derivative as a single diastereomer having the desired relative configuration at C-1, C-3a, C-11, C-11a and C-11b as stemocurtisine. Making the ether bridge of stemocurtisine was examined on two different substrates, a tricyclic hydroxyl piperidinone and a tricyclic hydroxy piperidine. Treatment of the piperidinone substrate under oxidative photochemical conditions gave an unexpected aldehyde byproduct having an O-acetyl hemiaminal structure. Detailed NMR analysis of this compound indicated that the piperidinone had undergone oxidative cleavage to give a bicyclic compound. The structure of this compound is only tenuous since the NMR spectroscopic and the MS spectromertic data were not consistent.

Chapter 4 reports on an alternative pathway to construct the A-B ring system and our attempts to make the A-B-C ring system of stemocurtisine. The key step of this approach involves the use of the borono-Mannich reaction to prepare a piperidinediene. A RCM reaction of this compound led to the corresponding pyrrido[1,2- a]azepine. Esterification of the hydroxyl group followed by epoxidation of this bicyclic compound resulted in the corresponding epoxide. Base-catalysed cylization was then attempted to convert this epoxide ester to a tricyclic compound. Under several reaction conditions this attempted cyclization was not successful and only the unreacted starting material was recovered.

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