Alkene difunctionalization, the addition of two functional groups across a double bond, exemplifies a class of reactions with significant synthetic potential. This emerging area examines recent developments of palladium-catalyzed difunctionalization reactions, with a focus on mechanistic strategies that allow for functionalization of a common palladium alkyl intermediate.

The mechanism of an enantioselective palladium-catalyzed alkene difunctionalization reaction has been investigated. Kinetic analysis provides evidence of turnover limiting attack of a proposed quinone methide intermediate with MeOH and suggests that Cu is involved in productive product formation, not just catalyst turnover. Through examination of substrate electronic effects, a Jaffé relationship was observed correlating rate to electronic perturbation at two positions of the substrate. Ligand effects were evaluated to provide evidence of rapid ligand exchange between palladium and copper as well as a correlation between ligand electronic nature and enantioselectivity.

Hydrogen bonding is ubiquitous in nature and is a prevalent mode of substrate activation in enzymes. Recently, chemists have begun to exploit this mode of activation in asymmetric catalysis by designing synthetic catalysts that use hydrogen bonds. [1][2][3] These catalysts feature a variety of structural motifs and hydrogen-bond-donating functional groups. In light of the rapid development of new hydrogen-bond-catalyzed reactions, we felt that a greater understanding of the connection between catalyst activity and structure would aid the advancement of the field. While detailed mechanistic studies have been performed to clarify the role of hydrogen bonding in many enzymatic systems and on general acid catalysis, [4,5] few have been performed on synthetic asymmetric catalysts. [6] Herein, we present a systematic study on the effect of catalyst acidity in a hydrogen-bond-catalyzed reaction, wherein linear free energy relationships are observed between the catalyst acidity and both the reaction rate and enantioselectivity.We have developed a hydrogen-bond catalyst which has a unique design featuring an oxazoline core with a pendant amine and alcohol group. This design provides two sites with hydrogen-bond donating groups which can be independently tuned (Scheme 1).[7] Catalysts of this type have been shown to be effective in the asymmetric hetero-Diels-Alder reaction between Rawals diene (D) and benzaldehyde (A). [7][8][9][10][11] The modular nature of the catalyst makes it well suited for a mechanistic study, as catalyst derivatives can be rapidly synthesized and evaluated to probe the relationship between the catalyst structure and activity.We hypothesized that a more acidic catalyst would be a better hydrogen-bond donor and thus would lead to enhanced substrate activation, as has been previously demonstrated. [12][13][14] To investigate this connection, systematic changes to the acidity of the N-H proton were made by synthesizing halogenated acetamide derivatives of the catalyst (Scheme 1). These variations were selected because of the substantial pK a range that may be studied while avoiding significant structural changes [15,16] and because the catalyst derivatives can be synthesized from a common precursor.[17]Compounds 1-5 were then evaluated as catalysts in the hetero-Diels-Alder reaction. [8][9][10][11] The yields of the isolated products after a 48 h reaction time suggest a relationship between acidity and catalyst activity (Scheme 1).[18] To our surprise, a trend in enantioselectivity was also observed, with the highest enantiomeric excess measured for the most acidic catalyst.To better understand the observed trends corresponding to the electronic nature of the catalyst, kinetic measurements were performed to probe the general mechanistic features of the reaction. Using the optimal catalyst 1, the following rate dependencies were observed: first-order dependence on [1], saturation in [aldehyde] (Figure 1), and first-order dependence on [diene] at high [aldehyde].[17] Based on these findings, a mechanism ...

A sequential intramolecular-intermolecular enantioselective alkene difunctionalization reaction has been developed which is thought to proceed through Pd-catalyzed quinone methide formation. The synthesis of new chiral heterocyclic compounds with adjacent chiral centers is achieved in enantiomeric ratios up to 99:1 and diastereomeric ratios up to 10:1.The formation of two carbon-heteroatom bonds across an alkene is a process which rapidly increases molecular complexity. The osmium-catalyzed Sharpless dihydroxylation 1 is the epitome of enantioselective alkene difunctionalization, though recent research has included other metal catalysts and expanded to the formation of functional groups other than 1,2-diols. 2 Currently, significant focus has been on palladium catalysis, likely due to the efficiency with which palladium activates olefins for nucleophilic attack. 3 However, in order to achieve the second bond construction, β-hydride elimination from a Pd-alkyl intermediate A, which leads to a Wacker-type monofunctionalized alkene product 1 ,4 must be prevented (Scheme 1). The alkene dialkoxylation reaction developed in our laboratory is believed to accomplish this through the formation of a quinone methide intermediate, which allows for attack by a second equivalent of alcohol. 5 Based on this mechanistic proposal, we envisioned an alkene difunctionalization reaction where a sequential intra-intermolecular process would allow for the selective formation of two distinct carbon-heteroatom bonds by employing substrates which contain a nucleophile tethered to the alkene (Scheme 1). We hypothesized initial intramolecular nucleopalladation to form heterocyclic intermediate B. Subsequent formation of a quinone methide intermediate C allows for attack by an exogenous nucleophile to form the product and release Pd 0 , which is reoxidized using molecular oxygen. Herein we report a highly enantioselective addition of two distinct nucleophiles across alkenes capable of quinone methide formation to access oxygen-based heterocycles with contiguous chiral centers.In exploring the possibility of sequential intra-intermolecular alkene functionalization reactions, we examined 2 as a substrate 6 with methanol as the exogenous nucleophile. Under the standard conditions for enantioselective intermolecular alkene dialkoxylation, 5b using (S)-i PrQuinox as the chiral ligand, a low yield of the desired product was observed with promising enantioselectivity, but low diastereoselectivity (Table 1, entry 1). 7 Addition of a catalytic amount of base and removal of molecular sieves led to modest improvements in product yield (entry 2). Reflecting on our intermolecular asymmetric dialkoxylation reaction, where copper improved yield and chemoselectivity but was removed in order to achieve high sigman@chem.utah.edu. Supporting Information Available: Experimental procedures and full spectroscopic data for new compounds are available free of charge via the internet at http://pubs.acs.org. enantioselectivity, we revisited the use of copper...