Synthesis of heterocycles from oxetanes and total synthesis of daphgraciline

Abstract

Developing new synthetic methods and total synthesis of natural products are two important parts in organic chemistry. Heterocycles occur in a range of natural products, drug molecules, and organic materials. Oxetane is a useful building block that has been utilized to construct heterocycles. Daphniphyllum alkaloids are a structurally and bio-actively diverse family of natural products. Daphniphyllum alkaloids contain a complex aza-polycyclic skeleton with multiple stereogenic carbon centers and exhibit various biological activities such as anticancer, antitumor, and anti-HIV activities. This thesis describes several Lewis acid catalyzed syntheses of heterocycles from oxetanes and synthetic studies toward daphgraciline, a yuzurine-type Daphniphyllum alkaloid.

Chapter 1 is an introduction to oxetane ring, mainly describing its structural features, representative applications in synthesis of heterocycles.

In Chapter 2, a Lewis acid catalyzed synthesis of various β-branched tetrahydroindolizines by intramolecular ring opening of oxetane with pyrrole has been achieved. This process proceeded to construct tetrahydroindolizines with a tertiary or quaternary carbon center on the β position of pyrrole in good yields.

In Chapter 3, a Lewis acid catalyzed oxetane ring expansion has been developed to form a series of tetrahydrofurans. The oxetanes tethered with indoles, carbazoles or esters could be converted to the desired tetrahydrofurans. For the indoles and carbazoles substrates, the aza-spirocyclic rings might be the key intermediates.

In Chapter 4, an introduction to Daphniphyllum alkaloids including the isolation and classification, biological activities, biosynthesis, total synthesis about six types of Daphniphyllum alkaloids is presented.

In Chapter 5, a synthetic study toward total synthesis of daphgraciline is summarized. Type II [5+2] cycloaddition, IMDA reaction, benzilic acid rearrangement, and Ti(III)-promoted reductive epoxide coupling reaction were applied as key reactions to construct the skeleton of daphgraciline. This total synthesis was finished in 26 steps and provided a novel synthetic strategy for the synthesis of the yuzurine-type Daphniphyllum alkaloids.

Date of Award	2022
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Jianwei SUN (Supervisor) & Chuangchuang Li (Supervisor)