Enantioselective Pd(0)-Catalyzed Activation of Secondary C(sp3)−H Bonds and Mechanistic Studies

Zuccarello, Marco. Enantioselective Pd(0)-Catalyzed Activation of Secondary C(sp3)−H Bonds and Mechanistic Studies. 2022, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: https://edoc.unibas.ch/90573/

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Direct transition metal catalyzed C−H bond functionalization has emerged as a powerful strategy to form new C−C or C−X bonds over the past decades. Advantages such as no requirement for pre-functionalization of the reagents and therefore the reduced metal waste makes it an attractive alternative to the well-established cross-coupling reactions. In this regard, Pd(0)-catalyzed C(sp3)−H activation has been applied in the past for the construction of complex molecules and in numerous total syntheses of natural products. In addition, elegant enantioselective methodologies have granted access to important scalemic products for the pharmaceutical and agrochemical industry. However, most of these methods rely on the desymmetrization of prochiral alkyl groups leading to the formation of the stereogenic center distal to the activation site. The activation of enantiotopic secondary C−H bonds remains underdeveloped, mainly attributed to their low intrinsic reactivity, with only one report on the synthesis of β-lactams.
To address this long-standing challenge, a highly reactive Pd/NHC catalytic system was design and optimized for the synthesis of chiral indanes. A variety of products were obtained in good to high yields and high enantioselectivities using IBioxR NHC ligands developed by the Glorius group. Furthermore, the first synthesis of chiral 3ary amides by Pd(0)-catalyzed C(sp3)−H activation was described in consistent high enantioselectivites. Moreover, a stereochemical analysis provided valuable insights on the relationship between ligand structure and enantioinduction.
Mechanistic studies were performed on the newly developed Pd/NHC catalyzed activation of methylene C−H bonds to examine the selectivity trends observed in the course of the development of the Pd(0)-catalyzed C(sp3)−H activation reaction. For instance, primary C−H bonds are preferentially activated over secondary C−H bonds or the selectivity between C−H bonds is altered by changing the substituent in α-position. In contrast to C(sp2)−H bond activation, where the use of Hammet plots has helped to quantify the influence of substituents with different electronic properties on the C−H activation process, the design and development of new C(sp3)−H activation methods has been mainly guided by chemical intuition. In this context, a reactivity scale was constructed putting C(sp3)−H bonds differing in α-substitution on a series of most to least reactive by performing initial rate experiments. Prior kinetic isotope studies and kinetic analysis of the reaction to obtain the orders in reaction components confirmed the C−H activation step to be rate-limiting, thus suggesting that the comparison of the different C−H bonds is significant.
The activation of remote C(sp3)−H bonds enabled by 1,4-Pd shift has experienced significant growth in the past 5 years. With this strategy new type of complex molecules, lacking structural motifs promoting the ring closure otherwise required for direct C−H activation, could be synthesized. Nevertheless, no enantioselective methods are reported to this date. To this end, new substrates were designed and synthesized and preliminary screening of chiral ligand families previously applied in direct enantioselective Pd(0)-catalyzed C−H activation was undertaken to contribute to the progress of asymmetric remote C(sp3)−H activation.
Advisors:Baudoin, Olivier and Sparr, Christof and Mazet, Clément
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Synthetische Chemie (Baudoin)
UniBasel Contributors:Baudoin, Olivier and Sparr, Christof
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14864
Thesis status:Complete
Number of Pages:VIII, 368
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss148642
edoc DOI:
Last Modified:06 Dec 2022 05:30
Deposited On:05 Dec 2022 15:05

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