An olefin metathesis-iodoetherification based synthesis of tetrahydrofuran containing acetogenins.
Item
-
Title
-
An olefin metathesis-iodoetherification based synthesis of tetrahydrofuran containing acetogenins.
-
Identifier
-
AAI3144159
-
identifier
-
3144159
-
Creator
-
Zhu, Lei.
-
Contributor
-
Adviser: David R. Mootoo
-
Date
-
2004
-
Language
-
English
-
Publisher
-
City University of New York.
-
Subject
-
Chemistry, Organic
-
Abstract
-
The tetrahydrofuran containing acetogenins are a group of naturally occurring compounds that have attracted attention because of their novel structures and potent biological activities. Bullatanocin, also known as squamostatin C, and mucocin belong to a subgroup of structures that non-adjacently linked cyclic ether subunits. The IC50 against human lung carcinoma A-549 was less than 10-8 mug/mL for both compounds. Bullatanocin was also active against human colon adenocarcinoma HT-29, and mucocin showed remarkable inhibitory activity against pancreatic cancer PACA-2. Like other tetrahydrofuran (THF) containing acetogenins, the cytotoxic activity is believed to involve disruption of electron transfer in the mitochondria, which leads to a decrease in ATP production, and cell death. Several synthetic studies have been motivated by the need for analogues for structure activity investigations.;The work reported in this thesis involves the development of a potentially general strategy for the synthesis of non-adjacently linked, ether containing, acetogenins. The methodology is based on a three component modular synthesis. The key precursors are a butenolide segment and two cyclic ether-alkene subunits (tetrahydrofuran or tetrahydropyran). The butenolide was synthesized via known literature procedures. The synthesis of the cyclic ether-alkene components involved novel methodology. The THF subunits were accessed through the iodoetherification of the 1,2-O-isopropylidene 5-alkene precursors. The tetrahydropyran (THP) subunit was prepared through elaboration of a dithiane precursor. The key coupling reaction for the cyclic ether subunits was an olefin cross metathesis. The bis-cyclic ether intermediates that were derived from the metathesis reactions in the bullatanocin and mucocin syntheses were later coupled to a butenolide component via Wittig and Julia olefination procedures respectively. Final functional group processing provided materials that displayed essentially identical physical data as the natural products. Total synthesis of bullatanocin was achieved in 45 total steps, and 4.8% overall yield with a longest linear sequence of 22 steps. Total synthesis of mucocin was accomplished in 40 total steps, and 3.6% overall yield with the longest linear sequence of 19 steps.
-
Type
-
dissertation
-
Source
-
PQT Legacy CUNY.xlsx
-
degree
-
Ph.D.
