Sinteza cefalandola C in razvoj avtomatizirane metode za določevanje struktur organskih molekul na podlagi eksperimentalnih spektroskopskih podatkov

Jakoš, Jure (author), Gazvoda, Martin (mentor)

V delu smo se ukvarjali s sintezo naravnega produkta cefalandola C, za katerega, kot tudi za njegov kislinski derivat, se predvidevajo različne biološke aktivnosti. Cefalandol C je bil odkrit leta 2006 na Tajvanu kot komponenta metanolnega ekstrakta rastline Cephalanceropsis gracilis. Leta 2016 so kitajski raziskovalci ločeno odkrili njegov kislinski derivat med raziskovanjem naravnih substanc v tradicionalnem zdravilu za respiratorne bolezni (ban lan gen). Razviti smo uspeli 8-stopenjsko sintezno pot do cefalandola C iz metil antranilata in pri tem uporabljali cenovno ugodne kemikalije, s čimer smo želeli neodvisno potrditi predlagano strukturo izolirane spojine. Strukturo cefalandola C smo razdelili na 3 ključne fragmente in sicer centralni indolni skelet, glukozni del in metil antranilatni fragment. Sintezo smo pričeli s pripravo centralnega indolnega skeleta iz metil antranilata in metil bromoacetata. Nato smo na indolni skelet z amidno vezjo pripojili metil antranilat in z O-glikozidacijo z uporabo acetobromo--D-glukoze, dodali še sladkorno komponento. S pomočjo 2D NMR spektroskopskih metod smo sintetiziranemu glikozidu določili stereokemijo. Glikozidu smo s pomočjo trietil amina odstranili acetilne zaščitne skupine in tako pripravili cefalandol C. 1H NMR spekter sintetiziranega cefalandola C se je skladal s poročanim 1H NMR spektrom te spojine, ki je bila izolirana iz naravnega materiala. V sodelovanju z raziskovalci s Fakultete za računalništvo in informatiko Univerze v Ljubljani smo nadaljevali z razvojem algoritma za avtomatsko določevanje struktur organskih molekul na podlagi eksperimentalnih spektroskopskih podatkov (IR, 1H, 13C NMR in HRMS), poimenovanega Schmarnica. Prva različica je uporabljala tabelirane spektroskopske podatke, ki jih je bilo potrebno v tabele izpisati iz spektrov, kar je zamudno in lahko vodi do napak. Zato je uporaba surovih spektroskopskih podatkov ključnega pomena pri poenostavitvi in pospešitvi procesa. Poleg tega smo v algoritem pričeli vključevati 2D NMR eksperimente (COSY, 1H–13C HSQC, 1H–13C HMBC), kar poveča zmožnosti algoritma za razreševanje strukture bolj zapletenih molekul.

• Language: Slovenian
• Keywords: organska sinteza, cefalandol C, NMR spektroskopija, IR spektroskopija, kemoinformatika
• Work type: Master's thesis/paper
• Typology: 2.09 - Master's Thesis
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Year: 2022
• PID: 20.500.12556/RUL-142000
• COBISS.SI-ID: 134236931
• Publication date in RUL: 14.10.2022

Secondary language

• Language: English
• Title: Synthesis of Cephalandole C and development of automated elucidation of organic molecules based on their spectroscopic data

Abstract

This thesis describes the synthesis of the natural product cephalandole C and together with its acid analog they are thought to have different biological activities. Cephalandole C was discovered in 2006 in Taiwan as a component of the methanol extract from the plant Cephalanceropsis gracilis. In 2016 a team of Chinese researchers independently discovered the acid derivative while investigating natural products in traditional medicine for respiratory diseases (ban lan gen). We developed an 8-step synthesis of cephalandole C from methyl anthranilate while using relatively cheap reagents, with which we wished to independently confirm the purposed structure of the isolated compound. We divided the structure of cephalandole C into 3 key fragments, i.e., the central indole structure, the glucose part, and the methyl anthranilate fragment. We started by synthesizing the indole central structure of the molecule from methyl anthranilate and methyl bromoacetate. We then added the methyl anthranilate molecule to the indole via an amide bond and with the O-glycosylation with acetobromo--D-glucose attached the sugar part of the molecule. With the aid of 2D NMR spectroscopic methods, we were able to determine the stereochemistry of the prepared glycoside. We removed the protective acetyl groups from the synthesized glycoside and obtained cephalandole C using triethylamine. The 1H NMR spectrum of the synthesized cephalandole C was in agreement with the reported 1H NMR spectrum of the compound that was isolated from the natural material Cephalanceropsis gracilis. In collaboration with researchers from the Faculty of Computer and Information Science at the University of Ljubljana, we continued the development of an algorithm for the automatic structure elucidation of organic molecules from experimental spectroscopic data (IR, 1H, 13C NMR in HRMS) named Schmarnica. The first version used tabular spectroscopic data that we had to tabulate from spectra, which is quite time-consuming and it can lead to errors. Therefore, using raw spectroscopic data is key to making the elucidator easier and faster to use. We also started to add 2D NMR experiments (COSY, 1H–13C HSQC, 1H–13C HMBC) that expand the elucidation capabilities of the algorithm to more complex structures.

• Keywords: organic synthesis, cephalandole C, NMR spectroscopy, IR spectroscopy, chemoinformatics