Date of Graduation

12-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry (PhD)

Degree Level

Graduate

Department

Chemistry & Biochemistry

Advisor/Mentor

McIntosh, Matthias C.

Committee Member

Allison, Neil T.

Second Committee Member

Thallapuranam, Suresh

Third Committee Member

Shi, Wei

Keywords

Pure sciences; Amide bond formation; Amino-claisen rearrangement; Antascomicin B; FKBP12; Ireland-Claisen rearrangement; Ring-closing olefin metathesis

Abstract

Antascomicin B is a macrolide isolated from a strain of Micromonospora. It possesses structural similarities to FK506 and rapamycin and exhibits potent binding ability to FKBP12. Recent reports suggest that small molecule ligands of FKBP12 possess potent neuroprotective and neurodegenerative properties in mouse models of Parkinson's disease. Our approach to the C1-21 fragment of antascomicin B involves an asymmetric amino-Claisen rearrangement originally developed by Tsunoda et al.35 report the scalability of the preparation and rearrangement of an allylic amide possessing a silyloxy group at the terminal position of the alkene. The Tsunoda-Claisen rearrangement uses inexpensive (S)-α-methylbenzylamine as the chiral auxiliary. The allylic amide underwent rearrangement to establish the C14 and C15 stereocenters in high yield and good diastereoselectivity. We found a surprisingly high yielding acid mediated lactonization that was employed to cleave the α-methylbenzyl amide. Details of these studies and further elaboration of the lactone are discussed. We also describe the progress toward the synthesis of the C1-21 fragment of the natural product.

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