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Fluorous Mixture Synthesis of Sch725674 and its Fifteen Stereoisomers

Moretti, Jared Daniel (2011) Fluorous Mixture Synthesis of Sch725674 and its Fifteen Stereoisomers. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Sch725674 is a 14-membered macrolactone isolated from the culture of an Aspergillus sp. by a group at Schering-Plough in 2005. A two-dimensional structure with four stereocenters was proposed for Sch725674, leaving sixteen candidate stereostructures for the natural product. Herein, we report the fluorous mixture synthesis (FMS) of all sixteen candidate stereoisomers of Sch725674 to determine its relative and absolute configuration. Initially, the synthesis of a single stereoisomer of Sch725674 was executed to secure a route to the natural product and to confirm the 2D connectivity of Sch725674. The synthesis established in the single isomer pilot study was then applied to the FMS of the 4,5-trans-dihydroxy isomer family of Sch725674, in which all eight members bear a trans relationship between the C4 and C5 stereocenters. An eight-member library of ring-open Sch725674 analogs was also prepared by demixing and detagging two intermediate mixtures from the FMS of the 4,5-trans-dihydroxy isomer family. We then executed a second, parallel FMS of the 4,5-cis-dihydroxy family of Sch725674, in which each member has a cis relationship between the C4 and C5 stereocenters. All three of these libraries employed a new minimalist tagging strategy which used two sorting tags in an FMS, only one of which was fluorous. By comparing spectra of the macrocycle library members with each other and the natural product, we confidently assigned the absolute configuration of natural Sch725674 as (4R,5S,7R,13R).


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Moretti, Jared
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairCurran, Dennis Pcurran@pitt.eduCURRAN
Committee MemberDoemling, Alexanderasd30@pitt.eduASD30
Committee MemberWilcox, Craigdaylite@pitt.eduDAYLITE
Committee MemberFloreancig, Paulflorean@pitt.eduFLOREAN
Date: 30 January 2011
Date Type: Completion
Defense Date: 3 December 2010
Approval Date: 30 January 2011
Submission Date: 22 November 2010
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: allylboration; fluorous mixture synthesis; fluorous tag; macrolide; natural products; ring-closing metathesis; stereoisomer library; HPLC; macrolactone
Other ID:, etd-11222010-191153
Date Deposited: 10 Nov 2011 20:05
Last Modified: 15 Nov 2016 13:51


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