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Synthesis of Neopeltolide and Analogs, Sulfur-Containing Heterocycles and Enantioenriched Allylated Chromenes

Cui, Yubo (2015) Synthesis of Neopeltolide and Analogs, Sulfur-Containing Heterocycles and Enantioenriched Allylated Chromenes. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Described herein is the total synthesis of neopeltolide and eleven analogs with modifications to its macrolactone and side chain. Preliminary biological assays showed neopeltolide and its analogs are not general cytotoxins as demonstrated by notable cell line selectivity. The introduction of different polar groups to the macrolactone at C8 and C9 positions is tolerated to variable extent, while alternations to the side chain generally lead to significantly diminished potency with the exception of using a furan ring to replace the oxazole ring. Experimental data also indicated p53 to play an auxiliary role in the potent antiproliferative activity of these compounds.

DDQ mediated oxidative C-H bond cleavage has been established as an effective and stereoselective method to prepare sulfur containing six- or five- member rings. The moieties for generating thiocarbenium ions are unsaturated sulfides including allyl sulfides and preferably vinyl sulfides, while the appended nucleophiles include enol acetates, enol carbamates and allylsilanes. Most cyclization reactions rapidly afford sulfur containing heterocycles with high stereocontrols and in good to excellent yields under very mild conditions.

Also described herein is an enantioselective addition reaction that employs DDQ-mediated carbon-hydrogen bond cleavage. 2H-Chromene can undergo oxidative carbon-hydrogen bond cleavage and, in the presence of a chiral Brønsted acid, the resulting acetal intermediate is converted to a chiral ion pair that reacts with intermolecular nucleophiles to prepare enantiomerically enriched products. While the scope of this process is still very limited, we were able to conduct reactions with good enantiocontrol at reasonable catalyst loadings in non-polar aromatic solvents.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFloreancig, Paulflorean@pitt.eduFLOREAN
Committee MemberWilcox, Craigdaylite@pitt.eduDAYLITE
Committee MemberKoide, Kazunorikoide@pitt.eduKOIDE
Committee MemberXie, Xiangqunxix15@pitt.eduXIX15
Date: 12 January 2015
Date Type: Publication
Defense Date: 25 November 2014
Approval Date: 12 January 2015
Submission Date: 1 December 2014
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 201
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: Nelpeltolide, sulfur chemistry, heterocycle synthesis, thiocarbenium, asymmetric allylation, carbon-hydrogen bond cleavage
Date Deposited: 12 Jan 2015 21:59
Last Modified: 15 Nov 2016 14:25


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