UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

The formation of 6-azaspirocycles via semipinacol rearrangement reactions and their application in a synthetic route towards halichlorine Hurley, Paul


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.

Item Media

Item Citations and Data


For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.