Domino diels-alder approaches to aromatic steroids
Date
2014
Authors
Mackay, Emily Grace
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The Diels-Alder reaction is widely acknowledged to be one of the most synthetically useful reactions available to the organic chemist. Introducing carbocyclic and heterocyclic rings in one operation, its utility in the construction of the tetracyclic steroid nucleus in particular is pronounced. This thesis explores the application of the Diels-Alder reaction in the synthesis of steroids, and is divided into four chapters. The first chapter reviews the myriad ways the Diels-Alder reaction has been applied to the preparation of the steroidal skeleton comprehensively and systematically for the first time. In the second chapter, the domino intramolecular Diels-Alder aromatisation cascade is developed, in which an acyclic precursor, containing two dienes and two dienophiles, undergoes a double Diels-Alder sequence, generating all four rings of the aromatic D-homosteroid skeleton. The polyunsaturated precursor is accessed in a convergent manner in only five steps in 49% overall yield. The application of this methodology in total synthesis is subsequently explored, leading to the preparation of a domino Diels-Alder substrate containing a 2,2'-bifuran unit. The parent 2,2'-bifuran is found to be a useful building block for the synthesis of complex polycyclic products via double Diels-Alder sequences. In Chapter Three the dendralene family of cross-conjugated polyenes is introduced. The dendralenes have recently been the subject of a comprehensive review, and this chapter serves as an overview of the inherent synthetic utility of this family of highly unsaturated hydrocarbons. In particular, their diene-transmissive Diels-Alder sequences, and the applications of these sequences in target-oriented synthesis are examined. Finally, in Chapter Four, the diene-transmissive Diels-Alder sequence of a substituted [3]dendralene is developed, generating the aromatic steroid framework in only two steps. The possibility for the application of this methodology in total synthesis is subsequently explored. In particular, the diastereoselectivity of the first, intramolecular Diels-Alder reaction is probed, and methods of control for the second, intermolecular Diels-Alder are explored. The development of the first regioselective Diels-Alder reaction of an acyclic diene with a substituted aryne is reported.
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