This thesis describes the development of chemical pathways for the preparation of more than 80 novel fully synthetic tetracyclines with structural variability at positions C5 and C5a. Progress toward the synthesis of 5-hetero-tetracyclines, another new class of tetracycline antibiotics, is also described. The results detailed herein – including successful C-ring-forming Michael–Claisen cyclizations of numerous modified AB precursors with just a few of the extraordinarily diverse D-ring precursors known to be effective nucleophiles in this key coupling reaction – represent the first steps toward a multiplicative expansion of the pool of fully synthetic tetracyclines. Novel and versatile \(\beta\)-functionalization reaction sequences employing tris(methylthio)methyllithium and 2-lithio-1,3-dithiane have been developed to transform the AB enone 10 (the key precursor to fully synthetic tetracyclines) into a diverse range of \(\beta\)-substituted AB enone products, including a highly efficient, single-operation method for the synthesis of a \(\beta\)-methyl ester-substituted AB enone (20). It is demonstrated that the six-membered C ring of tetracyclines comprising a C5a quaternary carbon center (e.g. 29) can be assembled by stereocontrolled coupling reactions of \(\beta\)-substituted AB enones and o-toluate ester anion D-ring precursors. A C5a–C11a-bridged cyclopropane tetracycline precursor (37) was found to undergo efficient and regioselective ring-opening reactions with a range of nucleophiles in the presence of magnesium bromide, thus providing another avenue for the preparation of fully synthetic tetracyclines containing an all-carbon quaternary center at position C5a. The AB enone 10 has also been transformed into structurally diverse \(\gamma\)-substituted AB precursors, which in turn have been converted into fully synthetic tetracyclines with unprecedented modifications at position C5, including 5-fluorotetracyclines such as 94. Numerous fully synthetic tetracyclines and tetracycline precursors have been shown to serve as diversifiable branch-points, allowing maximally expedient synthesis of C5- and C5a-substituted tetracyclines by late-stage diversification. The substrate scope of the Michael–Claisen cyclization reaction has been expanded to include new heterocyclic enone electrophiles such as dihydro-4-pyridones, affording cycloadducts such as 142. In this way, the viability of an iterative Michael–Claisen strategy for constructing 5-hetero-tetracyclines has been established. Numerous examples in this thesis serve to further demonstrate the broad applicability of the Michael–Claisen cyclization reaction as a powerful method for the assembly of stereochemically complex six-membered rings. / Chemistry and Chemical Biology
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/10364587 |
| Date | 05 March 2013 |
| Creators | Wright, Peter Maughan |
| Contributors | Myers, Andrew G. |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis or Dissertation |
| Rights | open |
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