Allylmetal Species Research Articles

Dispersion Interactions in Asymmetric Induction for Constructing Vicinal Stereogenic Centers.

ConspectusVicinal stereogenic centers are prevalent structural motifs of primary functional relevance in natural products and bioactive molecules. The quest for the rapid and controllable construction of vicinal stereogenic centers stands as a frontier endeavor in asymmetric organic synthesis. Over the past decade, stereodivergent synthesis has been intensely researched within the realm of bimetallic catalysis, aiming at establishing novel transition-metal dual-catalytic reactions that efficiently generate all stereochemical combinations of multichiral molecules from identical starting materials, thus offering new opportunities toward rapid complexity building and diversity-oriented chiral compound library generation. In this Account, we summarize our recent advancements in computational investigations of stereodivergent asymmetric allylic alkylation, an important reaction class heavily studied for the purpose of constructing vicinal stereogenic centers. Our discussions focus on synergistic bimetallic catalysis for the syntheses of α,α-disubstituted α-amino acids and cascade allylation/cyclization toward enantiomerically enriched indole-containing heterocycles. We describe our series of studies that converge in establishing the molecular mechanism of asymmetric induction for chiral copper-azomethine ylide, a nucleophile that holds widespread utility and is characterized by a distinctive, sterically biased surrounding enveloping the prochiral center. Notably, our studies revealed that attacks at the prochiral site by allylmetal species are significantly favored by dispersion attraction from one face (-PPh2) but blocked by steric repulsion and associated structural distortions on the opposite face (oxazoline), therefore building up a multimodal and highly robust face-selective stereoinduction. We showcase how a suite of systematic computational analyses generates precise atomistic insights into a number of systems of relevance. We also discuss how the same methodologies can be applied to chiral intermediates with shared interaction patterns, including the rhodium-Josiphos catalyst in asymmetric hydrogenation to create two continuous stereocenters. In the selectivity-controlling migratory insertion step, our computational models unveiled that the reaction is favored by ligand-substrate dispersion attraction on the -PPh2 side and hindered by steric repulsion on the opposite -PtBu2 side. These noncovalent interactions along with the distal ligand-auxiliary structural distortions enable strictly oriented three-dimensional stereoinduction. Our analysis of ligand-substrate dispersion interactions and steric effects in competing pathways highlights certain interaction-level similarities between PHOX-type and Josiphos-type ligands in asymmetric induction. In summary, this Account underscores the foundational significance and broad applicability of nonbonded dispersion interactions in asymmetric inductions for the construction of vicinal stereogenic centers. We envisage that the computational methodologies employed in these studies will shift toward a paradigm of interaction-based rational molecular and reaction design.

Palladium/Brønsted Acid Catalysis for Hydrofunctionalizations of Alkynes: From Tsuji‐Trost Allylations to Stereoselective Methodologies

AbstractAlkynes are one of the most abundant feedstocks for chemical transformations. By merging palladium and Brønsted acid catalysts, they are converted into reactive allylmetal species, which become suitable for Tsuji‐Trost functionalizations with complete atom‐economy. This approach, which overcomes the limitations of traditional methods that suffer from the formation of over‐stoichiometric amounts of by‐products, has been disclosed for developing new C−C and C−Het bond forming methodologies. Within this review, we aim to survey the latest advancements in this area including applications in polymer chemistry, deuterium‐labeling and stereoselective catalysis.

(Invited) Catalytic Allylation of Aldehydes Using Feedstock Alkenes

The efficient production of fine chemicals from simple and readily available bulk materials such as simple alkenes is an important research area in synthetic organic chemistry. Lower alkenes are produced by one of the most common chemical processes (i.e. hydrocarbon cracking) on over 500 million metric tons scale. Development of catalytic methods which enable the direct use of these abundant organic molecules as carbon sources is highly demanded for practical and selective chemical reactions. However, despite several previous examples, the use of feedstock alkenes in synthetically useful transformations remains a challenging task.Catalytic aldehyde allylation plays an important role in synthetic organic chemistry. Traditionally, nucleophilic allylmetal species as stoichiometric starting materials have contributed to the development of this catalytic process. Despite usefulness of this approach, however, there is room for improvement in the overall efficiency, redox/atom/step economy, and environmental sustainability. The catalytic generation of nucleophilic allylmetal species in situ from simple and feedstock alkenes via allylic sp3 C-H bond activation would be a straightforward approach. We envisioned that radical sp3 C-H bond activation followed by oxidative interception of the resulting carbon-centered radical by a metal complex is a promising strategy for the catalytic generation of organometallic species from inert substrates. We supposed the ternary hybrid catalysis comprising a photoredox catalyst, a hydrogen-atom-transfer (HAT) catalyst, and a metal catalyst would realize catalytic allylation of aldehydes with simple alkenes.We planned to use a combination of an acridinium photoredox catalyst (Mes-Acr+) and a thiophosphoric imide (TPI) HAT catalyst to activate an allylic C-H bond of the alkenes through the HAT process. Under visible light irradiation, single-electron oxidation of TPI by a photo-excited acridinium catalyst (*Mes-Acr+) generates a sulfur-centered radical (RS•). The RS• radical abstracts the allylic C-H bond of alkenes, affording allyl radicals. Based on the mechanism of Nozaki-Hiyama allylation, we expected that a chromium(II) complex catalyst oxidatively intercepted allyl radicals, giving allylchromium(III) species. This species reacts with aldehydes via a Zimmerman-Traxler transition state to produce chromium alkoxides in an anti-selective fashion. Protonolysis by the proton generated in the HAT catalysis should afford the target homoallylic alcohols and chromium(III) species. Single-electron reduction by the photoredox catalyst (Mes-Acr•) would close the catalytic cycle with regenerating a chromium(II) complex catalyst and the oxidized form of the photoredox catalyst (Mes-Acr+).Based on this mechanism, we studied the substrate scope with a combination of 5 mol% CrCl2, 10 mol% TPI catalyst (HAT) and 5 mol% acridinium photoredox catalyst (PC). First, the scope of alkenes was investigated. In all cases, the branched constitutional isomer was produced exclusively (>20/1). The reactions of C4 feedstocks, 1-butene and 2-butenes which are annually produced on a 105 metric ton scale, with benzaldehyde afforded the product in 94% and 100% yield, respectively, with high diastereoselectivity (14-16/1). This crotylation reaction using butenes as a starting material will significantly streamline polyketide synthesis. 3-Methyl-1-butene selectively afforded the product containing a quaternary carbon. Branched C6 alkenes were also competent substrates. Other alkenes, including cyclic, halide-containing, and ether-containing, all afforded the product in high yield. The aldehyde scope was then investigated by fixing the alkene substrate to 2-butene. A series of aromatic aldehydes bearing halogens, electron-withdrawing groups, and a boronate ester afforded the corresponding products with high diastereoselectivity. A methyl substituent at the ortho-, meta-, and para positions of the aromatic ring did not affect the results. The reactions of aliphatic aldehydes, including those containing potentially sensitive functional groups (e.g. amine, alkyl halide, sulfide and benzyl oxy moiety), also proceeded efficiently. Next, we investigated the application to highly functionalized substrates. Propranolol derivative bearing free hydroxy group were competent substrate. A dipeptide and a nucleic acid derivative containing coordinating polar functional groups such as amides and an adenine heterocycle did not affect the reaction progress. Therefore, the allylation of aldehydes mediated by the ternary hybrid catalysis realized high functional group compatibility and chemoselectivity using easily available feedstock alkenes.In conclusion, we developed a ternary hybrid catalysis, enabling catalytic allylation of aldehydes using simple alkenes, under visible light irradiation at room temperature. This hybrid catalysis is applicable to various types of unactivated alkenes including feedstock lower alkenes. Due to the high chemoselectivity and mild conditions, the reaction was applicable to highly functionalized bioactive molecules. The asymmetric variant enabled facile access to enantiomerically and diastereomerically enriched homoallylic alcohols by introducing a chiral ligand to the chromium catalyst. Further studies to expand the scope are ongoing. Figure 1

Redox-Neutral Propargylic C–H Functionalization by Using Iron Catalysis

AbstractIn spite of their rich stoichiometric chemistry, cyclopentadienyliron(II) dicarbonyl complexes are rarely used as catalysts in organic synthesis. Inspired by precedents in the chemistry of cationic olefin complexes and neutral allylmetal species, our group has developed a coupling of alkynes or alkenes with aldehydes and other carbonyl electrophiles to give homopropargylic and homoallylic alcohols, respectively, by using a substituted cyclopentadienyliron(II) dicarbonyl complex as the catalyst. In this article, we first contextualize this development within the conceptual background of C–H functionalization chemistry and relative to key stoichiometric precedents. We then give an account of our group’s discovery and development of the catalytic α-functionalization of alkenes and alkynes with electrophilic reagents.IntroductionPreliminary Stoichiometric WorkHydroxyalkylation Development and ScopeConclusions and Future Directions

Alkynes as Electrophilic or Nucleophilic Allylmetal Precursors in Transition-Metal Catalysis.

Diverse late transition metal catalysts convert terminal or internal alkynes into transient allylmetal species that display electrophilic or nucleophilic properties. Whereas classical methods for the generation of allylmetal species often form stoichiometric by-products, the recent use of alkynes as allylmetal precursors enables completely atom-efficient catalytic processes to be carried out, including enantioselective transformations.

Convergent diastereoselective preparation of adjacent quaternary stereocenters in an acyclic system

The combined carbometalation-zinc homologation-allylation reaction of the resulting stereodefined 3,3-disubstituted allylmetal species with ketones allow the preparation of allylic vicinal diol derivatives in good yields with excellent diastereomeric ratios from commercially available alkynes. Two adjacent quaternary centers are formed with the concomitant formation of three new carbon-carbon bonds in a single-pot operation in an acyclic system. The bulky substituent of the ketone occupies a pseudo-axial position in the Zimmerman-Traxler transition state.

Asymmetric synthesis of proline-based conformationally constrained tryptophan mimetic

The synthesis of an optically pure proline-based tryptophan mimetic is described. The strategy involves the in situ generation of an unprecedented allylmetal species containing the indole moiety, and its coupling with a chiral imine. The construction of the 3-substituted proline skeleton is then achieved through a hydrozirconation/iodination sequence applied to the resulting homoallylic amine.

Recent Developments in Three-Component Grignard-Barbier-Type Reactions

Recent developments in the preparation of homoallyl-amines or (homo)propargylamines via three-component Grignard-Barbier-type reactions are reviewed. The multicomponent coupling strategy that allows quick access to these compounds is discussed. 1 Introduction 2 Homoallylamines 2.1 Preparation with Allylmetal Species Formed in situ 2.2 Preparation with Presynthesized Allylmetal Species 3 Homopropargylamine Synthesis from Prepared Imines Forming in situ Propargylmetal Species 4 Propargylamines 4.1 Preparation via Alkynylation of Imines 4.2 Preparation via Aldehyde-Alkyne-Amine (A 3 ) Coupling 5 Perspectives

Development of Carbon—Carbon Bond‐Forming Reactions Using γ,γ‐Dialkoxyallylic Zirconium Species

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Isopulegol as a Model Compound: Metalation and Substitution of an Allylic Position in the Presence of an Unprotected Hydroxy Function

When treated with butyllithium and potassium tert-butoxide for 2 h at 0 °C in hexanes, the unsaturated monoterpenic alcohol isopulegol is simultaneously deprotonated at the hydroxy function and the allylic methyl group. The metaloxy allylmetal species thus generated can be silylated, alkylated, carboxylated and oxidized to afford the expected products in good to excellent yields. Thus, a specific protection of hydroxy groups is not required, alcohols being instantaneously converted by superbases into alcoholates.

Generation of allylic manganates from trimethylmanganate and allylic stannanes and their reactions with epoxides

A new method for forming allyldimethylmanganate has been developed. The preparation eliminated the need for prior generation of an allylmetal species such as allyllithium or allylmagnesium compounds. The reagents reacted with epoxides to give allylated products exclusively in good yields.

Neue 13C-spektroskopische untersuchungen zur struktur von allylmetall-verbindungen

High-resolution 13C NMR spectra of terminally monodeuterated allyl(earth)-alkalimetal compounds confirm earlier structure assignments: allylmagnesium bromide exists in a σ-covalent structure, which rapidly and reversibly goes over into its “metallomeric” mirror-image; allyllithium forms a distorted π-complex; allylpotassium and allylcaesium have the shape of perfectly symmetrical or slightly asymmetrical π-complexes. No NMR spectroscopic evidence is found in tetrahydrofuran solution for the presence of aggregates and mixed aggregates resulting from dimerization or oligomerization of monomeric allylmetal species.