Christine M. Le

Rhodium-Phosphoramidite Catalyzed Alkene Hydroacylation: Mechanism and Octaketide Natural Product Synthesis

We describe a method that allows salicylaldehyde derivatives to be coupled with a wide range of unactivated alkenes at catalyst loadings as low as 2 mol %. A chiral phosphoramidite ligand and the precise stoichiometry of heterogeneous base are key for high catalytic activity and linear regioselectivity. This protocol was applied in the atom- and step-economical synthesis of eight biologically active octaketide natural products, including anticancer drug candidate cytosporone B. Mechanistic studies provide insight on parameters affecting decarbonylation, a side reaction that limits the turnover number for catalytic hydroacylation. Deuterium labeling studies show that branched hydride insertion is fully reversible, whereas linear hydride insertion is largely irreversible and turnover-limiting. We propose that ligand (R(a),R,R)-SIPHOS-PE effectively suppresses decarbonylation, and helps favor a turnover-limiting insertion, by lowering the barrier for reductive elimination in the linear-selective pathway. Together, these factors enable high reactivity and regioselectivity.

Synergistic Steric Effects in the Development of a Palladium‐Catalyzed Alkyne Carbohalogenation: Stereodivergent Synthesis of Vinyl Halides

We report our finding that by exploiting the synergistic steric effects between substrate and catalyst, an intramolecular Pd-catalyzed alkyne carbohalogenation can be achieved. This operationally simple method uses the bulky Pd/Q-Phos combination and allows access to tetrasubstituted vinyl halides from the corresponding aryl chlorides, bromides, and iodides. Steric effects in the substrate play a key role by promoting C sp 2-halogen reductive elimination and enabling catalytic turnover. Through a reversible oxidative addition mechanism, a thermodynamically driven isomerization reaction is observed at elevated temperatures. Thus by changing the reaction temperature, both stereoisomers of the reaction become readily accessible.

Remarkably Stable Chalcogen(II) Dications

Air-stable, chalcogen-centered dications have been synthesized and comprehensively characterized. These represent the first diiminopyridine (DIMPY) complexes of the chalcogens as well as the single nonmetallic (sulfur) complex of this ubiquitous ligand. Their stability under ambient conditions is a distinct contrast to other highly charged main-group cations.

The Use of Silyl Ketene Acetals and Enol Ethers in the Catalytic Enantioselective Alkylative Ring Opening of Oxa/Aza Bicyclic Alkenes

Silyl ketene acetals and enol ethers are employed as reactive and functional group tolerant nucleophiles in the enantioselective rhodium-catalyzed alkylative ring opening of a diverse class of oxa/azabicyclic alkenes. This method provides access to enantioenriched dihydronaphthalene and cyclohexene scaffolds, which have the potential to be derivatized toward core motifs of naphthoquinone and sesquiterpene natural products.

An Exclusively trans-Selective Chlorocarbamoylation of Alkynes Enabled by a Palladium/Phosphaadamantane Catalyst

Pharmaceutically relevant methylene oxindoles are synthesized by a palladium(0)-catalyzed intramolecular chlorocarbamoylation reaction of alkynes. A relatively underexplored class of caged phosphine ligands is uniquely suited for this transformation, enabling high levels of reactivity and exquisite trans selectivity. This report entails the first transition-metal-catalyzed atom-economic addition of a carbamoyl chloride across an alkyne.

CHAPTER 7:Pd(0)-Catalyzed Carboiodination: Early Developments and Recent Advances

The field of palladium-catalyzed cross-coupling has seen tremendous growth since the 2010 Nobel Prize in Chemistry was awarded. Significant efforts have been made to develop highly active and selective catalysts, which have been used to realize particularly challenging cross-couplings. Beyond extending the reaction scope and tolerance of well-established Pd-catalyzed cross-coupling, novel transformations have been developed by rationally combining elementary catalytic steps with the newly invented catalyst systems. This chapter focuses largely on the discovery and recent developments of a palladium-catalyzed carboiodination reaction, which incorporates a rare Csp3–I reductive elimination as an elementary step in the catalytic cycle. As a prelude to the discussion of carboiodination, the seminal reports of carbon–halogen reductive elimination from transition metal complexes [i.e., Pd(II), Pd(IV), Pt(V) and Rh(III)], which laid the necessary groundwork for the discovery of this novel reaction, are discussed.

CuH-Catalyzed Enantioselective Anti-Markovnikov Hydroamination

Significance: β-Chiral amines are ubiquitous motifs in a range of biologically active molecules, including pharmaceuticals and natural products. The catalytic enantioselective hydroamination of alkenes provides an efficient route to such molecules using simple, and often commercially available, starting materials. Herein, Buchwald and coworkers present an enantioselective CuH-catalyzed anti-Markovnikov hydroamination of 1,1disubstituted alkenes. Comment: The report expands upon the authors’ previous work on the Cu-catalyzed enantioselective hydroamination of styrene derivatives (J. Am. Chem. Soc. 2013, 135, 15746). The proposed mechanism involves hydrocupration of the 1,1disubstitued olefin in an anti-Markovnikov manner, which is intercepted by the hydroxylamine ester to give the final product and a Cu(I) alkoxide complex. The active CuH catalyst is regenerated by the addition of stoichiometric amounts of hydrosilane. 32 examples up to 96% yield up to 99% ee R2 R1 N R4

Enantioselective C–H Insertion Reactions of Donor–Donor Carbenoids

Significance: Transition-metal carbenoids, which can be generated in situ from a variety of different precursors, demonstrate a diverse range of reactivity, such as the ability to perform allylic and benzylic C–H functionalizations (see Review below). While the use of acceptor–acceptor and donor– acceptor metal carbenoids is commonplace, the application of donor–donor metal carbenoids in a diastereoand enantioselective C–H functionalization has not been previously demonstrated. Herein, Shaw and co-workers report the first Rh-catalyzed asymmetric insertion reactions of donor– donor carbenoids, which provide access to substituted dihydrobenzofurans. Comment: The donor–donor rhodium carbenoid is generated in situ from the corresponding hydrazine in the presence of MnO2. The methodology demonstrates a broad substrate scope, with a variety of functional groups tolerated on the benzylic or allylic ether as well as on the hydrazine motif. Allylic ethers containing a 1,2-disubstituted olefin do not undergo E/Z-isomerization under the reaction conditions. To demonstrate the utility of the method, an enantioselective total synthesis of E-δviniferin was achieved.

Synthesis of trans-Cycloalkenes via Cyclopropanation and Rearrangement

Significance: There are few ways to access chiral medium-sized rings possessing a trans double bond (for selected examples, see: A. Deiters et al. Chem. Eur. J. 2002, 8, 1833; X.-N. Wang et al. J. Am. Chem. Soc. 2014, 136, 9802). Such motifs often exhibit planar chirality and may find application in the synthesis of complex polycyclic frameworks. The authors report an efficient procedure for the asymmetric synthesis of piperidine-fused trans-cycloalkenes 3 from triazoles 1 and methylenecyclopropenes 2. Comment: The reaction is initiated by the in situ formation of an α-imino rhodium carbenoid from triazole 1. Cyclopropanation of the exocyclic methylene group of 2 leads to the formation of spiropentane A, which can then undergo a thermal rearrangement under microwave irradiation to give trans-cycloalkene 3. The authors propose a concerted mechanism, which draws similarity to the retro-Claisen [3,3]-sigmatropic rearrangement. Substrate scope: Method A 3 7 examples up to 93% yield up to 98% ee O

Diastereo- and Enantioselective Iridium-Catalyzed Allylation of Ketone Enolates

Significance: The transition-metal-catalyzed asymmetric allylic alkylation (AAA) reaction is a versatile and powerful method for the construction of C–C bonds. Although palladium catalysts are routinely used in this reaction, iridium catalysts have been shown to have complementary and comparable reactivity to palladium (see Review below). Within this area of research, the diastereoand enantioselective allylic alkylation of unstabilized ketone enolates remains a significant challenge. Herein, Hartwig and co-workers report a diastereoand enantioselective iridium-catalyzed allylation of barium enolates derived from cyclic ketones. Comment: The branched-selective allylic alkylation method developed by the authors provides access to products containing a vicinal quaternary and a tertiary stereogenic center – a difficult class of molecules to access using traditional Pd-catalyzed methods. The method is highly efficient and demonstrates a broad substrate scope. The authors show that good levels of diastereoselectivity can be achieved in this reaction simply through the facial selectivity of the prochiral barium enolate without necessitating coordination of the enolate directly to the metal center.