The recently isolated alkaloid madangamine A (1) is a structurally unique member of a growing class of biogenetically related natural products obtained from marine sponges. Madangamine A has been shown to be active against several different types of cancer cell lines with ED50's in the microgram/milliliter range. The cis polyene functionally present in 1 would appear to inhibit a controlled and systematic modification of its structure through degradative methods. Moreover, the absolute configuration 1 has not yet been elucidated. Consequently, an enantiocontrolled total synthesis of 1 which is flexible enough to allow for the facile synthesis of analogs is proposed. The proposed route begins with a diastereoselective Diels-Alder reaction followed by an iodolactonization to generate the cyclohexane ring. The tricyclic core of 1 will then be assembled using an enamine cyclization with an N- acyliminium ion. Each of the larger rings will then be formed in a convergent manner using a tether/cyclization strategy which will be easily amenable to the incorporation of different tether lengths and functionality. Consequently, the production of analogs of 1 in order to study its structure/activity relationships and improve its medicinal value will be facilitated.
