Document Type

Dissertation

Date of Degree

Summer 2017

Access Restrictions

Access restricted until 08/31/2018

Degree Name

PhD (Doctor of Philosophy)

Degree In

Chemistry

First Advisor

Gregory K. Friestad

Abstract

There are many diverse classes of biologically active natural products containing chiral 1,5- or 1,5,7-polyol moieties, including the novel fibrinogen receptor antagonist tetrafibricin, a potential antiplatelet therapeutic drug to treat various arterial thrombotic diseases. There have been some elegant synthetic strategies developed to synthesize these challenging 1,5-diol motifs; however, many of them suffer from a variety of inherent limitations.

To overcome many of these challenges, our group has developed an iterative configuration-encoded strategy to access 1,5-polyols with unambiguous stereocontrol by exploiting Julia–Kocienski couplings of enantiopure α-siloxy-γ-sulfononitrile building blocks with alcohol stereocenters previously established via asymmetric catalysis.

Our method is a strategy level innovation that allows for the efficient and rapid access to all stereoisomers of a 1,5-polyol family from cheap and easily accessible reagents, without the need to determine the configuration of each alcohol stereocenter in the growing polyol chain.

We were able to modify our configuration-encoded 1,5-polyol methodology to access the anti,syn-1,5,7-triol within the C15–C25 fragment of tetrafibricin with excellent selectivity by incorporating differentiable protection and merging this approach with the tactic of diastereoselective intramolecular conjugate addition via benzylidene acetal construction to access the syn-1,3-diol functionality.

We also applied our iterative configuration-encoded strategy to the synthesis of the 1,5-polyol-containing C26–C40 fragment of tetrafibricin with excellent stereoselectivity by modifying our previous route to the C27–C40 segment. By overcoming the challenges associated with the reduction of α-siloxynitriles and extending the carbon chain to alter the subsequent Mukaiyama aldol coupling location, we were able to furnish the C26–C40 fragment with the correct protection and functionality for further coupling to the C15–C25 segment.

With the C15–C25 and C26–C40 fragments in hand, we joined these segments via asymmetric BF3⋅OEt2-mediated Mukaiyama aldol construction with high 1,3-anti stereoinduction. We determined the preceding stereoselectivity by first using the simplified model C26–C40 fragment and found that replacing the TBDPS with TBS protection of the β-siloxy aldehyde increased the level of 1,3-anti induction. To complete the C15–C40 fragment of tetrafibricin, we performed an intramolecular hydroxyl-directed anti-reduction to furnish the desired anti,anti,anti-1,3,5,7-tetraol moiety. We were able to establish the configurations of these chiral alcohols using a battery of 2D NMR experiments.

Finally, to complete the total synthesis of tetrafibricin, we have proposed a route to couple our C15–C40 fragment with the C8–C14 segment via a precedented asymmetric aldol reaction, followed by coupling to the known C1–C7 polyene fragment. With minor functional group transformations and a global deprotection, access to the natural product tetrafibricin should be achievable.

Keywords

Asymmetric Synthesis, Configuration-Encoded, Methodology, Natural Product, Polyol, Tetrafibricin

Pages

xxi, 329 pages

Bibliography

Includes bibliographical references (pages 191-199).

Copyright

Copyright © 2017 Ryan Maxwell Friedrich

Available for download on Friday, August 31, 2018

Included in

Chemistry Commons

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