Zhao, Jianxiong; (2020) Synthesis of Tetrahydroisoquinoline Alkaloids using Norcoclaurine Synthase and Phosphate Buffer mediated Pictet-Spengler Reactions. Doctoral thesis (Ph.D), UCL (University College London).

Text J Zhao PhD thesis final.pdf - Accepted Version Access restricted to UCL open access staff until 1 December 2024. Download (20MB)

Abstract

Tetrahydroisoquinoline (THIQ) alkaloids are a family of structurally diverse natural products with medicinal properties, such as anti-bacterial and anti-tumour effects. Recently, the use of biocatalysts in organic synthesis offers a new possibility to access these molecules, which is more cost-effective than traditional isolation methods and chemical synthesis. Norcoclaurine synthase (NCS) is a key enzyme that catalyses the Pictet-Spengler reaction (PSR) of dopamine and 4-hydroxyphenylacealdehyde in the biosynthetic pathway of morphine. In this thesis, NCS and phosphate mediated PSRs towards bioactive THIQ alkaloids have been explored. In Chapter 2, non-natural phenethylamine analogues and functionalized aldehydes have been used in the developed one-pot, two-step chemoenzymatic routes to antibacterial (S)-trolline and analogues. No general PSR side product ortho-THIQs were observed with NCS, and product purification could be typically achieved by an acid-base extraction method using the green solvent dimethyl carbonate. Compared to the previous asymmetric synthesis of trolline, this chemo-enzymatic route using NCS is more productive, sustainable and atom-efficient. In Chapter 3, phosphate was unprecedentedly found to catalyse the PSRs between metahydroxyl phenylethylamines and unreactive ketones in basic buffer condition with methanol as co-solvent, efficiently giving 1,1'-disubstituted and spiro-THIQ alkaloids in excellent yields. A range of ketones such as monocyclic, bicyclic and acyclic ketones have been demonstrated to be accepted, showing broad synthetic applicability to access diverse THIQs. In Chapter 4, NCS was firstly confirmed to be capable of tolerating ketones in the PSR, leading to asymmetric formation of 1,1'-disubstituted and spiro-THIQ alkaloids. Apart from HPLC, Marfey‘s reagent has been used to derivatize the THIQ products, which assists the stereoselectivity determination. A variety of ketones were accepted by NCS and mutants, particularly tetralones, phenyl acetones and monocyclic ketones. In Chapter 5, NCS has been coupled with transaminase to generate THIQ alkaloids in cascade reactions using primary amines. Transamination of amines can produce aldehyde intermediates, which are directly consumed in the subsequent NCS mediated PSRs without isolation of the aldehydes. Different sources of transaminases combined with the wild-type NCS were investigated on a number of functionalized amines.

Download activity - last month

Export as XMLJSONCSV

Download activity - last 12 months

Export as JSONXMLCSV

Downloads by country - last 12 months

Export as CSVXMLJSON

Archive Staff Only

View Item