Catalytic Enantioselective Transformations with Chiral Cyclopentadienyl Ruthenium(II) Complexes

The chemistry of cyclopentadienyl ruthenium(II) complexes plays an important role in ruthenium catalysis because of its high potential for various transformations. However, asymmetric catalysis with chiral cyclopentadienyl ruthenium(II) complexes is still at an infant stage, but rapidly developing because of its expected impact on multiple enantioselective applications.

This thesis discusses the synthesis of a novel class of chiral cyclopentadienyl ligands, which can be readily accessed by a two-step process from alpha, beta-unsaturated aldehydes and cyclopentadiene. The novel C2-symmetric chiral cyclopentadienyl ligands were complexed with ruthenium(II) and successfully applied in asymmetric catalysis.

The cyclopentane-fused CpxRu complex enables the enantioselective synthesis of benzonorcaradienes by coupling of oxa-benzonorbornadienes with internal alkynes in high enantioselectivity (up to 97.5:2.5 er). The reaction mechanism was investigated by computational studies and control experiments.

The chiral cyclopentadienyl ruthenium(II) complexes show promising results for other transformations. An alkylative cycloetherification of allenols and aryl vinyl ketones was investigated using binaphthyl-derived chiral cyclopentadienyl ruthenium(II) complex. After an initial optimization study, allenol and phenyl vinyl ketone gave the desired enantio-enriched cyclic ether with a promising enantioselective ratio of 90:10.

Furthermore, preliminary studies were undertaken for the [2+1] cycloaddition of enynes via ruthenium vinyl carbenes. Model substrate, 1,6-enyne, delivered the desired enantio-enriched bicyclo[3.1.0]hexane in a good yield of 72% (E:Z = 1.6:1), with enantiomeric ratios of 72.5:27.5 and 63.5:36.5 for the E- and Z-isomer, respectively.

New Vinylation and Alkynylation Strategies with Hypervalent Iodine Reagents and Diazo Compounds

Guillaume Dominique Pisella

The development of a sequential copper-catalyzed oxy-alkynylation/intramolecular [4+2] cycloaddition of allenes and arenes was investigated at first. This one-pot protocol allowed the construction of complex polycylic architectures with high efficiency from aryldiazo esters and ethynylbenziodoxolone reagents (EBX). The mild reaction conditions (23 to 90 Â°C) for the dearomatization step was unusual compared to previous literature reports and DFT computations showed that substituents on the aryl ring resulted in favorable dispersive interactions, decreasing the activation energy barrier of the cycloaddition. The bicyclo[2.2.2]octadiene products were successfully applied as ligands for rhodium. The prepared diene-rhodium complexes were extensively characterized by NMR spectroscopy and X-ray crystallography. Finally, an enantiopure ligand having a pseudo C2-symmetry was used in the conjugate addition of phenylboronic acid to cyclohexenone and furnished the Î²-functionalized ketone in good yield and with high enantioselectivity.The vinylation reactions of diazo compounds are scarce. A successful copper-catalyzed vinylation of diazo compounds with vinylbenziodoxolone reagents (VBX) as partners was reported. The transformation allowed an unprecedented gem-oxy-vinylation at the carbene center, providing functionalized Î±-vinyl-hydroxyacid derivatives in high atom and step economy. The products were obtained in excellent yields and contained synthetically versatile functional groups for post-modifications. The development of an enantioselective version of this reaction was limited and further investigations will be required to obtain high enantioselectivities. In addition, a practical synthesis of alkyl-substituted VBX reagents has been established; VBX reagents being limited to aryl substituents until then. Multicomponent reactions provide efficient means to rapidly access molecular diversity. A copper(I)-catalyzed threeâcomponent reaction utilizing diazo compounds, alcohols as nucleophiles and vinyl- or ethynylbenziodoxole reagents, was successfully developed. The transformation allowed the synthesis of highly functionalized allyl and propargyl ethers. The scope is broad, and extensive variations of the three partners of the reaction is possible, leading to maximal structural diversity. Extension of this work to N-nucleophiles was not as straightforward as anticipated, but good results could be obtained with anilines, trifluorodiazoethane and EBX reagents as components.Questions about the reaction mechanisms of the copper-catalyzed difunctionalizations of diazo compounds with VBX and EBX reagents have been frequent all-along this research work. Preliminary results of in-depth mechanistic investigations have been obtained. The initial assumption of an internal alkyne transfer step was first invalidated by DFT computations and was latter refuted experimentally. A complexation between the carboxylate of ethynylbenziodoxolone reagents and the copper catalyst was characterized by NMR spectroscopy and contrasted to a alkyne-copper interaction observed with ethynylbenziodoxole reagents. These two possible complexes were supported by DFT calculations. Finally, non-classical sigmoidal kinetic profiles of the oxy-alkynylation reaction were obtained by in situ 19F NMR monitoring and the Cu-EBX complex is presumably involved in the observed induction periods.

EPFL2021

Catalytic Asymmetric Functionalization of Inert Bonds and Synthesis of Bioactive Natural Products

Nicolai Cramer

The direct and enantioselective functionalization of inert bonds such as carbon-hydrogen and carbon-carbon is an emerging tool towards more sustainable and efficient synthetic methods. The individual activation pathways like concerted deprotonation metalations, directed activations, beta-carbon eliminations or retro-allylations proceed by completely different mechanisms and therefore have complementary requirements and different associated challenges. A careful fine-tuning of the transition-metal complex is critical for each mechanism, but a very broad structural space can be covered as well. These methods enhance the synthetic chemist's toolbox allowing more concise, efficient synthetic routes to be executed in target-oriented synthesis. This is illustrated by the examples of a synthesis of largazole and the core of stachyflin from our group.

2011

Nickel(0)-Catalyzed Enantioselective Annulations of Alkynes and Arylenoates Enabled by a Chiral NHC Ligand: Efficient Access to Cyclopentenones

Joachim Sven Ernst Ahlin, Nicolai Cramer, Pavel Alexandrovich Donets

Cyclopentenones are versatile structural motifs of natural products as well as reactive synthetic intermediates. The nickel-catalyzed reductive [3+2] cycloaddition of alpha,beta-unsaturated aromatic esters and alkynes constitutes an efficient method for their synthesis. Here, nickel(0) catalysts comprising a chiral bulky C-1-symmetric N-heterocyclic carbene ligand were shown to enable an efficient asymmetric synthesis of cyclopentenones from mesityl enoates and internal alkynes under mild conditions. The bulky NHC ligand provided the cyclopentenone products in very high enantioselectivity and led to a regioselective incorporation of unsymmetrically substituted alkynes.

Wiley-Blackwell2014

New Vinylation and Alkynylation Strategies with Hypervalent Iodine Reagents and Diazo Compounds

Guillaume Dominique Pisella

EPFL2021