This document describes a synthetic approach towards the tricyclic unit contained within the natural product halichlorine based upon a semipinacol rearrangement reaction as a key transformation.
A number of synthetic approaches involving the synthesis of halichlorine and the structurally related compounds pinnaic acid and tauropinnaic acid have been published; this work is described in chapter 1.
In chapter 2, a detailed account of our first approach towards the tricyclic core of halichlorine is described. This approach involves formation of one of the rings of halichlorine by a ring closing metathesis reaction. To achieve this goal, a new, modified version of Grubbs’ “second generation” ring closing metathesis catalyst was synthesized. This catalyst exhibits high reactivity and successfully closed a 6-membered ring in a compound that contains structural features similar to those found in halichlorine.
Our approach towards the synthesis of the tricyclic core of halichlorine led to the development of a new method to form 6-azaspirocyclopentanones. When piperidine-based allylic cyclobutanols are treated with N-bromosuccinimide, a ring expansion reaction takes place that results in the formation of highly functionalized 6-azaspirocyclopentanones. These high yielding, diastereoselective reactions were successful with several ring expansion substrates. The synthesis of the ring expansion substrates led to the development of a new method to construct alkenyl stannanes from isolated enol triflates using lithium trimethylstannyl copper (I) cyanide reagent.
The semipinacol rearrangement reactions outlined in chapter 2 gave products with the incorrect relative configuration required for halichlorine. These results led to the development and implementation of a new asymmetric synthetic sequence towards the tricyclic core of halichlorine that is discussed in chapter 3. This synthetic sequence involves the N-bromosuccinimide promoted ring expansion reaction of a piperidine-based allylic cyclobutanol that contains a substituent on the cyclobutane ring. This ring expansion reaction resulted in the formation of a densely functionalized azaspirocyclopentanone that contains four of the five stereocenters and two of the four rings required to make halichlorine. Ultimately a late stage intermediate was achieved in 22 steps (longest linear sequence) from 1,3-propanediol.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:BVAU.2429/79 |
| Date | 11 1900 |
| Creators | Hurley, Paul |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Format | 17293029 bytes, application/pdf |
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