Ivan Franzoni

Palladium-Catalyzed Hydrohalogenation of 1,6-Enynes: Hydrogen Halide Salts and Alkyl Halides as Convenient HX Surrogates

Difficulties associated with handling H2 and CO in metal-catalyzed processes have led to the development of chemical surrogates to these species. Despite many successful examples using this strategy, the application of convenient hydrogen halide (HX) surrogates in catalysis has lagged behind considerably. We now report the use of ammonium halides as HX surrogates to accomplish a Pd-catalyzed hydrohalogenation of enynes. These safe and practical salts avoid many drawbacks associated with traditional HX sources including toxicity and corrosiveness. Experimental and computational studies support a reaction mechanism involving a crucial E-to-Z vinyl-Pd isomerization and a carbon-halogen bond-forming reductive elimination. Furthermore, rare examples of C(sp3)-Br and -Cl reductive elimination from Pd(II) as well as transfer hydroiodination using 1-iodobutane as an alternate HI surrogate are also presented.

Access to congested quaternary centers by Pd-catalyzed intermolecular γ-arylation of unactivated α,β-unsaturated aldehydes

A palladium-catalyzed intermolecular γ-arylation of γ-branched α,β-unsaturated aldehydes has been developed. The reaction allows congested quaternary centers to be forged on a remote position from the carbonyl group, affording a variety of products in high yield and with consistently high stereoselectivity using very low catalyst loadings. The synthetic utility of the products has been highlighted by a series of derivatizations and the potential of the method to be extended to remote e-functionalization has been demonstrated.

Small Molecule Antagonists of the Interaction between the Histone Deacetylase 6 Zinc-Finger Domain and Ubiquitin

Inhibitors of HDAC6 have attractive potential in numerous cancers. HDAC6 inhibitors to date target the catalytic domains, but targeting the unique zinc-finger ubiquitin-binding domain (Zf-UBD) of HDAC6 may be an attractive alternative strategy. We developed X-ray crystallography and biophysical assays to identify and characterize small molecules capable of binding to the Zf-UBD and competing with ubiquitin binding. Our results revealed two adjacent ligand-able pockets of HDAC6 Zf-UBD and the first functional ligands for this domain.

Convenient Reagent for the Copper-Catalyzed Asymmetric Methyl 1,4-Addition Reaction

Significance: Tertiary and quaternary stereocenters bearing a methyl group are common structural units in a wide array of natural products and pharmaceuticals. The synthesis of such compounds is usually performed by the asymmetric conjugate methyl addition to α,β-unsaturated carbonyl compounds. Unfortunately, this approach usually relies on the use of impractical reagents (e.g. pyrophoric reagents, low functional group compatibility). In this work, the authors disclosed the use of Cp2ZrMeCl as an efficient and operationally friendly reagent in copper-catalyzed methyl 1,4-addition reactions. Comment: The use of Cp2ZrMeCl as a methyl source in combination with a chiral copper catalyst allowed the formation of βand δ-tertiary and quaternary centers in generally good yields and excellent enantioselectivities. The reaction was applied to a variety of cyclic and acyclic carbonyl compounds, allyl chlorides and in the synthesis of (R)-(–)-muscone. The zirconium reagent was prepared on a 10 g scale reaction from Cp2ZrCl2 and was demonstrated to be stable for up to six months when stored under inert gas at room temperature. Asymmetric conjugate addition for the formation of tertiary centers: 12 examples 21–84% yield 87–94% ee Zr Cl

Copper-Catalyzed Asymmetric Nucleophilic Addition to Ketones

Significance: Enantioenriched alcohols represent a recurring structural motif in biologically active molecules and pharmaceuticals. The synthesis of this class of compounds usually relies on the addition of nucleophiles to carbonyl compounds. The limitations of this approach in terms of functionalgroup tolerance and versatility prompted the authors to develop a novel copper-catalyzed asymmetric addition of nucleophiles, generated in situ from olefins, to ketones. Comment: A chiral copper catalyst promoted the reaction between a number of enyne substrates with ketones. (MeO)2MeSiH and t-BuOH are required to generate the nucleophile in situ and to terminate the catalytic cycle, respectively. The reaction delivers the corresponding chiral alcohols in good yields and excellent enantioselectivities. A 13 gram scale reaction, derivatizations of the final products and applications in the synthesis of pharmaceutical agents were provided. Furthermore, computational studies were carried out to explain the observed enantioand diastereoselectivity. 35 examples 45−95% yield 90−99.5% ee up to dr > 10:1

Asymmetric Michael Addition Reaction via Rhodium Catalyst Fragmentation

Significance: Dual catalysis has emerged as a powerful approach for the synthesis of enantioenriched compounds. The use of a single catalyst containing two or more functionalities, or the cooperation of two different catalysts, represents the common approach. The authors present an unusual dual catalytic system based on the disintegration of a single chiral rhodium complex in situ. This process was applied in the asymmetric Michael addition of aldehydes to give α,β-unsaturated 2-acyl imidazoles. Comment: Reaction between α,α-disubstituted aldehydes and α,β-unsaturated 2-acyl imidazoles was catalyzed by a single chiral rhodium catalyst. The corresponding products were obtained in excellent yields, moderate diastereoand excellent enantioselectivities. The authors propose a mechanism in which the rhodium catalyst decomposes into a chiral Lewis acid, which activates the 2-acyl imidazole substrate 1, and L-β-phenylalanine, which activates the aldehyde 2. 21 examples 66−99% yield dr = 1.8:1 to 5.8:1 89–99% ee

Intermolecular Carboamination Catalyzed by Palladium

Significance: As part of the family of indole alkaloids, furoindoline structures represent a recurrent motif in many biologically active compounds and pharmaceuticals. The authors capitalized on their previous palladium-catalyzed stereoselective intermolecular carboetherification of dihydrofuranes for the development of a novel palladium-catalyzed syn-carboamination. In addition to the high levels of diastereoselectivity obtained, the authors present preliminary results toward the development of an enantioselective version of the reaction. Comment: After careful optimization of the reaction conditions, mesyl-protected 2-bromo anilines were reacted with an excess of dihydrofuran and dihydrofuran derivatives in the presence of [Pd2(dba)3] and CPhos to afford the corresponding furoindoline products in moderate to good yields and good to excellent diastereoselectivities. Preliminary studies toward the development of an enantioselective version of the reaction are exemplified by the six examples reported (20–70% yield, 63–73% ee). O HN Br R2 R1 Ms (5.0 equiv) [Pd2(dba)3] (2.5 mol%) CPhos (5.0 mol%) t-BuOLi (1.5 equiv)