Thesis_Liu_Ligong_Redacted.pdf (16.66 MB)

New syntheses of protoberberines: Cycloaddition and carbanionic methodology leading to the production of highly enantioselective products

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Version 2 2021-11-15, 20:38
Version 1 2017-12-06, 00:00
posted on 2021-11-15, 20:38 authored by L Liu
New synthetic methods are explored for the synthesis of protoberberines using carbanionimine (CAI) cycloaddition, aza Diels-Alder (DA) cycloaddition.. Protoberberine alkaloids are widely distributed in numerous plant families, and commonly found as active components in many folklore medicines in Asia, Europe and North America. Due to their broad diversity of biological activities, there are great efforts about chemical, biogenetic and enzymatic synthesis, transformation, pharmacology, and culture development studies of these alkaloids. In this thesis, new synthetic methods are explored for the synthesis of protoberberines using the following approaches a) carbanionimine (CAI) cycloaddition, b) aza Diels-Alder (DA) cycloaddition. The structure elucidation of products using various analytical techniques, such as IR, UV-vis., MS, NMR and X-ray, are broadly discussed. Detailed stereostructure and conformation analysis have been studied using various one and two dimensional NMR techniques, which show great advantage for structure analysis in the liquid state, and give the consistent conclusion as the solid state structure as determined by the single crystal X-ray diffraction method. The carbanion-cyclic imine approach has been most successful in the synthesis of protoberberines, which contain a four-ring system (ABCD). Cycloaddition of 3,4-dihydroisoquinoline (DHIQ, eg A-I) with phthalide anion (eg A-2) gives stereo and regia selective 13-hydroxy protoberberines (eg A-3) with single diastereomers observed and isolated, which are transformed to various functionalised derivatives. The novel reaction of 3-methoxyphthalide anion (A-4) with DHIQ, where a 2+1 adduct (A-6) is formed, is broadly studied. The mechanisms are studied in details and highly suggestive via tandem nucleophilic condensation of the anion, in which the 8,13-dioxo intermediate (eg A-5) plays an important role. The geometry change due to the replace of angular 13a-H with methyl group accounts for the different facial selectivity of 13-keto to nucleophiles in A-5a A-5b. These are supported by theoretical AMl calculation and Surface Probe Analysis on model compounds (A-8). The phthalide anion-acyclic imine approach has been used to provide open chain products (eg A-10 and A-11). NMR and AMl calculation prove trans stereochemistry of major isomers (eg A-10). The conclusion is in contrast to previous assignments by MacLean, Cushman, and Prager on similar compounds. The direct asymmetric synthesis is also explored by using a chiral o-toluamide anion (eg A-12) instead of a phthalide counterpart. A series of chiral amine auxiliary agents have been studied and the tertiary o-toluamide with a bulky cyclohexyl group in addition to the chiral substituent on the amide nitrogen atom (A-12) gives the highest enantioselectivity (>96% ee). This approach established a new, fast entry to both enantiomers of protoberberines and exhibits predictable regiochemistry. This is an obvious advantage in all anion-imine cycloaddition reactions in our study and others. DA methodology is also studied, however only the reaction between DHIQ (AB synthon) and phthalazine (A-14, CD synthon) works. This reaction is the first example of aza DA reaction with phthalazine as an aza diene with an aza dienophile. The other AB+CD approaches with DHIQ (AB) as dienophile allowed to react with different dienes (CD), such as isobenzofuran and cyclopentadienone, do not give any adducts under thermal, Lewis acid catalyst or high pressure conditions. While the first step of an AB+C+D approach which involves sequential DA reaction of DHIQ with s-tetrazine (A-16) was successful, the second step involving benzyne or cyclic enamine cycloaddition failed.



Central Queensland University

Open Access

  • No

External Author Affiliations

Department of Chemistry;

Era Eligible

  • No


Professor Ronald N Warrener

Thesis Type

  • Doctoral Thesis

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