Реакция аминоацильного включения в синтезе модельных циклопептидов тема автореферата и диссертации по химии, 02.00.10 ВАК РФ

Список сокращений.

I. ВВЕДЕНИЕ.

И. ЛИТЕРАТУРНЫЙ ОБЗОР. Реакция аминоацильного включения.

V. выводы

1. Разработан эффективный способ синтеза Glp-OBu1 — ключевого интермедиата реакции ацилирования лактамов.

2. Исследованы различные подходы к синтезу ключевых интермедиатов РААВ -N-аминоацилпироглутаматов. Для синтеза этих соединений использовалось три подхода: ацилирование металлированных лактамов активированными эфирами аминокислот, окисление пролинового остатка в дипептиде и циклизация внутреннего остатка глутаминовой кислоты. На основе этих методов было синтезировано более новых 20 N-аминоацилпироглутаматов.

3. Исследованы различные условия проведения РААВ и показано, что оптимальными условиями для РААВ является водно-органический буферный раствор.

4. Синтезирован ряд дилактамов, содержащих глутаминовую кислоту и моно- и диаминокарбоновые кислоты, а также 3 циклодепсипептида на основе произодных серина, треонина. Было установлено, что N-аминоациллактамы, содержащие остатки диаминокислот с геминальным расположением аминогрупп не изомеризуются в лактамы в условиях, используемых для РААВ.

5. Проведённые нами исследования позволяют заключить, что РААВ не является простым и однозначным подходом к синтезу циклодипептидов - в каждом случае необходимо подбирать условия, в которых выход необходимых циклопептидов оптимален, а образование побочных продуктов реакции — лактамов - минимально.

Б. Заключение

РААВ является удобным с практической точки зрения способом синтеза циклопептидов. Благодаря этой реакции нам удалось синтезировать ряд труднодоступных циклодипептидов - потенциальных структурных блоков, представляющих интерес для конструирования новых пептидных молекул. Соединения, полученные с помощью РААВ, приведены в таблице 3. Однако, эта реакция имеет ряд существенных ограничений. К сожалению, РААВ не является универсальным способом синтеза циклопептидов. В каждом конкретном случае необходимо подбирать условия, которые позволяют синтезировать необходимую циклическую структуру с оптимальным выходом. Необходимо отметить также, что все синтезированные соединения принадлежат к одному структурному классу (IV группа, рис. 1) или являются их аналогами. Распространить этот подход на синтез соединений других классов нам не удалось. Соединения II группы на основе пироглутаминовой кислоты, по-видимому, не существуют, как и их более простые аналоги. Кроме того, по нашим данным, циклопептиды, содержащие диаминокислоты с геминальным положением аминогрупп, не могут быть получены с помощью РААВ.

Тем не менее, РААВ является весьма эффективным подходом к синтезу большой группы органических соединений - циклопептидов, и, несомненно, является перспективным инструментом современной химии пептидов.

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