Regioselective synthesis of 1,4-disubstituted 1,2,3-triazole derivatives

Abstract

Cilj ovog rada bila je sinteza novih 1,2,3-triazolnih derivata 4,5-didehidro-5,6-dideoksi-L-askorbinske kiseline (5–13) regioselektivnom 1,3-dipolarnom cikloadicijom odgovarajućih terminalnih alkina i C-6-azidnog derivata L-askorbinske kiseline (4). Pored konvencionalne sintetske metode, provedeno je optimiranje "klik" reakcija (14–27) u mikroreaktorskom sustavu uz pomoć ultrazvučnog zračenja pri protoku od 0,5 μl/min i temperaturi od 50 °C. Analiza reakcijskih smjesa primjenom visokoučinkovite tekućinske kromatografije (HPLC) pokazala je da je većina "klik" reakcija provedenih u mikroreaktoru bila uspješnija, uz veća iskorištenja i znatno kraće vrijeme reakcija u odnosu na konvencionalnu sintezu. Triazolnim derivatima 2,3-O,O-dibenzil-4,5-didehidro-5,6-dideoksi-L-askorbinske kiseline (7–9) potom je uklonjena benzilna zaštitna skupina pomoću boron-triklorida pri čemu su izolirani spojevi 11–13 sa slobodnim hidroksilnim skupinama. Strukture svih sintetiziranih spojeva potvrđene su spektroskopijom 1H- i 13C-NMR. Novosintetiziranim spojevima ispitat će se antitumorska aktivnost na više tumorskih staničnih linija porijeklom iz čovjeka, a spojevima sa slobodnim hidroksilnim skupinama (11–13) ispitat će se i antioksidativna aktivnost.The aim of this work was the synthesis of new 1,2,3-triazole 4,5-didehydro-5,6-dideoxy-L-ascorbic acid derivatives (5–13) using regioselective 1,3-dipolar cycloaddition of the corresponding terminal alkynes and C-6-azido L-ascorbic acid derivative (4). Besides the conventional synthetic approach, reactions of "click" chemistry were optimized in a microreactor at a flow rate of 0.5 μL/min and 50 °C under ultrasonic irradiation (14–27). The analysis of reaction mixtures by high performance liquid chromatography (HPLC) demonstrated that most of the click reactions in microreactors were more efficient and proceeded with higher yields and shorter reaction time than those for conventional syntheses. The benzyl groups from the triazole 2,3-O,O-dibenzyl-4,5-didehydro-5,6-dideoxy-L-ascorbic acid derivatives 7–9 were remowed using boron trichloride and compounds (11–13) with free hydroxyl groups were obtained. The structures of all synthesized compounds were determined by 1H- and 13C-NMR spectroscopy. The novel compounds will be evaluated for their antitumor activity in several human tumor cell lines and antioxidant capacity of compounds (11–13) with free hydroxyl groups will be also tested