Nickel-catalyzed regiodivergent approach to macrolide motifs

Shareef, Abdur Rafay; Sherman, David H.; Montgomery, John

doi:10.1039/c2sc00866a

Cited by 48 publications

(20 citation statements)

References 44 publications

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“…42 Utilizing the inherent substrate biases of the terminal alkyne of 24 , the use of IMes ligand proved satisfactory in an endocyclization process to access product 25 in 58% yield as a 4:1 mixture of diastereomers with only endocyclization products being observed (Scheme 10). Alternatively, the unique properties of DP-IPr with terminal alkynes are illustrated by the highly selective exocyclization of the same substrate to afford 26 in 59% yield as a single regio- and stereoisomer.…”

Section: Mechanistic Insights Inform Regiodivergent Strategies In Nicmentioning

confidence: 99%

Mechanistic Basis for Regioselection and Regiodivergence in Nickel-Catalyzed Reductive Couplings

et al. 2015

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CONSPECTUS The control of regiochemistry is a considerable challenge in the development of a wide array of catalytic processes. Simple π-components such as alkenes, alkynes, 1,3-dienes, and allenes are among the many classes of substrates that present complexities in regioselective catalysis. Considering an internal alkyne as a representative example, when steric and electronic differences between the two substituents are minimal, differentiating among the two termini of the alkyne presents a great challenge. In cases where the differences between the alkyne substituents are substantial, overcoming those biases to access the regioisomer opposite that favored by substrate biases often presents an even greater challenge. Nickel-catalyzed reductive couplings of unsymmetrical π-components make up a group of reactions where control of regiochemistry presents a challenging but important objective. In the course of our studies of aldehyde-alkyne reductive couplings, complementary solutions to challenges in regiocontrol have been developed. Through careful selection of the ligand and reductant, as well as the more subtle reaction variables such as temperature and concentration, effective protocols have been established that allow highly selective access to either regiosiomer of the the allylic alcohol products using a wide range of unsymmetrical alkynes. Computational studies and an evaluation of reaction kinetics have provided an understanding of the origin of the regioselectivity control. Throughout the various procedures described, the development of ligand-substrate interactions play a key role, and the overall kinetic descriptions were found to differ between protocols. Rational alteration of the rate-determining step plays a key role in the regiochemistry reversal strategy, and in one instance, the two possible regioisomeric outcomes in a single reaction were found to operate by different kinetic descriptions. With this mechanistic information in hand, the empirical factors that influence regiochemistry can be readily understood, and more importantly, the insights suggest simple and predictable experimental variables to achieving a desired reaction outcome. These studies thus present a detailed picture of the influences that control regioselectivity in a specific catalytic reaction, but they also delineate strategies for regiocontrol that may extend to numerous classes of reactions. The work provides an illustration of how insights into the kinetics and mechanism of a catalytic process can rationalize subtle empirical findings and suggest simple and rational modifications in procedure to access a desirable reaction outcome. Furthermore, these studies present an illustration of how important challenges in organic synthesis can be met by novel reactivity afforded by base metal catalysis. The use of nickel catalysis in this instance not only provides an inexpensive and sustainable method for catalysis, but also enables unique reactivity patterns not accessible to other metals.

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Section: Mechanistic Insights Inform Regiodivergent Strategies In Nicmentioning

confidence: 99%

Mechanistic Basis for Regioselection and Regiodivergence in Nickel-Catalyzed Reductive Couplings

et al. 2015

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“…[6,7] While both [1,3-bis(2,6-di-iso-propylphenyl)]-imidazolidin-2-ylidene (SIPr) and imidazol-2-ylidene (IPr) were effective ligands in the racemic tail-to-tail cross-hydroalkenylation, [7] the use of the corresponding NHC ligand rac-A1 led to a significant drop in reactivity (Table 1, entry 1). [8] We suspected the vicinal Ph groups to have an unfavorable steric effect, by pushing the N-aryl groups with their bulky isopropyl substituents in ortho position too close to the reaction center, thereby increasing the activation energy for the coordination of the substrate and lowering the reactivity. Further studies showed that both the size and the number of N-aryl ortho substituents played very important roles in determining the reactivity and selectivity of the hydroalkenylation (Table 1, entries 2-4).…”

mentioning

confidence: 99%

Catalytic Asymmetric Hydroalkenylation of Vinylarenes: Electronic Effects of Substrates and Chiral N‐Heterocyclic Carbene Ligands

Chan

2015

Angew Chem Int Ed

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An asymmetric tail-to-tail cross-hydroalkenylation of vinylarenes with terminal olefins was achieved by catalysis with NiH complexes bearing chiral N-heterocyclic carbenes (NHCs). The reaction provides branched gem-disubstituted olefins with high enantioselectivity (up to 94 % ee) and chemoselectivity (cross/homo product ratio: up to 99:1). Electronic effects of the substituents on the vinylarenes and on the N-aryl groups of the NHC ligands, but not a π,π-stacking mechanism, assist the steric effect and influence the outcome of the cross-hydroalkenylation.

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“…The optimized process has been subsequently applied to the preparation of modified macrolide structures. 243 In another example involving nickel, in this case as a co-catalyst, the use of mixtures of PEG 400 /MeOH as solvent enabled an intramolecular Glaser-Hay coupling 244 of simple terminal alkynes (140) to form 14-to 27-membered macrocyclic diynes (141,Scheme 11.18) to be conducted at comparatively high concentrations (up to 0.1 M). This was attributed to the aggregation properties of the PEG preferentially solubilizing the organic substrates, thus creating a phase separation from the copper-nickel catalyst system.…”

Section: Nickel-mediated Reactionsmentioning

confidence: 99%

The Synthesis of Macrocycles for Drug Discovery

Peterson¹

2014

Macrocycles in Drug Discovery

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Despite the attractive nature of macrocyclic compounds for use in new pharmaceutical discovery, applications have been hindered due to the lack of appropriate synthetic methods, in particular for the construction of libraries of such molecules. However, over the last decade, a number of effective and versatile methodologies suitable for macrocyclic scaffolds have been developed and applied successfully. These include classical coupling and substitution reactions, ring-closing metathesis (RCM), cycloaddition (“click”) chemistry, multicomponent reactions (MCR), numerous organometallic-mediated processes and others. This chapter presents a comprehensive compilation of these strategies and provides examples of their use in drug discovery, along with a description of those approaches that have proven effective for the assembly of macrocyclic libraries suitable for screening.

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Nickel-catalyzed regiodivergent approach to macrolide motifs

Cited by 48 publications

References 44 publications

Mechanistic Basis for Regioselection and Regiodivergence in Nickel-Catalyzed Reductive Couplings

Mechanistic Basis for Regioselection and Regiodivergence in Nickel-Catalyzed Reductive Couplings

Catalytic Asymmetric Hydroalkenylation of Vinylarenes: Electronic Effects of Substrates and Chiral N‐Heterocyclic Carbene Ligands

The Synthesis of Macrocycles for Drug Discovery

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