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The Rhodium-Catalyzed Dynamic Kinetic Asymmetric Pauson−Khand Reaction of Allenyl Carboxy Esters

Burrows, Lauren (2018) The Rhodium-Catalyzed Dynamic Kinetic Asymmetric Pauson−Khand Reaction of Allenyl Carboxy Esters. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The Rh(I)-catalyzed allenic Pauson−Khand reaction (APKR) is an efficient, redox-neutral method of synthesizing α-acyloxy cyclopentenones. An enantioselective APKR would provide access to chiral, nonracemic α-acyloxy and α-hydroxy cyclopentenones and their corresponding redox derivatives. Rapid scrambling of axial chirality of allenyl acetates in the presence of Rh(I) catalysts enables the conversion of racemic allene to enantiopure cyclopentenone product in a Type I dynamic kinetic asymmetric transformation (DyKAT). A combined experimental and computational approach was taken to develop an effective catalytic system to achieve the asymmetric transformation. The optimization of the denticity, and steric and electronic properties of the ancillary ligand (initially (S)-MonoPhos, 16% ee), afforded a hemilabile bidentate (S)- MonoPhos-alkene-Rh(I) catalyst that provided α-acyloxy cyclopentenone product in up to 72% ee. Upon discovery of the reactive and enantioselective (S)-MonoPhos-alkene catalyst, the remaining reaction conditions were optimized using a statistical design of experiments (DOE) strategy. Reaction temperature, CO atmosphere, catalyst counteranion, concentration, solvent identity, additive equivalents, and ligand/Rh stoichiometry were evaluated simultaneously in two iterations of DOE experimentation. Discovery of optimal conditions enabled an increase in enantioselectivities and an expansion of the APKR scope to include methyl-substituted alkynes and a three-carbon-tethered allene-yne. The good yields and enantioselectivities effected by the phosphoramidite class of ligands in the APKR inspired an exploration of electron-deficient phosphoramidite ligands in the enantioselective Pauson−Khand reaction (PKR) of 1,6-enynes. Lowest-energy reaction profiles of the cationic Rh(I)-(R)-BINAP, Rh(I)-(S)-MonoPhos, and Rh(I)-“CO-only” catalysts were calculated, and agreement between experimental reaction rates and the activation energies of the oxidative cyclization step was found. We observed that the PKR of cationic Rh(I)- catalyst is accelerated 3000-fold in the presence of (R)-BINAP, and 180-fold in the presence of either one or two (S)-MonoPhos ligands (ligand to Rh ratio of 1.1 or 2.2). The absolute configuration of the PKR product was confirmed by VCD spectroscopy and matches that predicted by calculations. We anticipate that these mechanistic studies will enable the application of phosphoramidite ligands in the PKR of new enyne substrates.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Burrows, LaurenLCP18@pitt.eduLCP18
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBrummond,
Committee MemberLiu,
Committee MemberNelson,
Committee MemberNoonan,
Date: 26 September 2018
Date Type: Publication
Defense Date: 18 May 2018
Approval Date: 26 September 2018
Submission Date: 9 August 2018
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 405
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: allene, carbonylation, rhodium catalysis, DyKAT, design of experiments, Pauson-Khand reaction
Date Deposited: 26 Sep 2018 21:48
Last Modified: 26 Sep 2023 05:15


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