Iridium‐Catalyzed Enantioselective Allylic Substitution of Unstabilized Enolates Derived from α,β‐Unsaturated Ketones

We report Ir‐catalyzed, enantioselective allylic substitution reactions of unstabilized silyl enolates derived from α,β‐unsaturated ketones. Asymmetric allylic substitution of a variety of allylic carbonates with silyl enolates gave allylated products in 62–94 % yield with 90–98 % ee and >20:1 branched‐to‐linear selectivity. The synthetic utility of this method was illustrated by the short synthesis of an anticancer agent, TEI‐9826.     

A Chiral N,N′‐Dioxide–ZnII Complex Catalyzes the Enantioselective [2+2] Cycloaddition of Alkynones with Cyclic Enol Silyl Ethers

A highly efficient enantioselective [2+2] cycloaddition between alkynones and cyclic enol silyl ethers was developed by using a chiral N,N′‐dioxide‐zinc(II) complex as a catalyst. This method functions well for a variety of terminal alkynes as well as cyclic enol silyl ethers, with good to excellent enantioselectivity (up to 97 % ee). This is also the first successful example for the catalytic enantioselective [2+2] cycloaddition of internal alkynes with cyclic enol silyl ethers to give fully substituted cyclobutenes. Meanwhile, the desired cyclobutene product can easily be transformed into fused cyclobutane derivatives.     

Metal‐Free Enantioselective Oxidative Arylation of Alkenes: Hypervalent‐Iodine‐Promoted Oxidative C−C Bond Formation

The enantioselective oxyarylation of (E)‐6‐aryl‐1‐silyloxylhex‐3‐ene was achieved using a lactate‐based chiral hypervalent iodine(III) reagent in the presence of boron trifluoride diethyl etherate. The silyl ether promotes the oxidative cyclization, and enhances the enantioselectivity. In addition, the corresponding aminoarylation was achieved.     

Deracemizing α‐Branched Carboxylic Acids by Catalytic Asymmetric Protonation of Bis‐Silyl Ketene Acetals with Water or Methanol

We report a highly enantioselective catalytic protonation of bis‐silyl ketene acetals. Our method delivers α‐branched carboxylic acids, including nonsteroidal anti‐inflammatory arylpropionic acids such as Ibuprofen, in high enantiomeric purity and high yields. The process can be incorporated in an overall deracemization of α‐branched carboxylic acids, involving a double deprotonation and silylation followed by the catalytic asymmetric protonation.     

Iridium‐Catalyzed Regio‐ and Enantioselective Allylic Substitution of Silyl Dienolates Derived from Dioxinones

Reported herein is the iridium‐catalyzed regio‐ and enantioselective allylic substitution reactions of unstabilized silyl dienolates derived from dioxinones. Asymmetric allylic substitution of a variety of allylic trichloroethyl carbonates with these silyl dienolates gave γ‐allylated products selectively in 60–84 % yield and 90–98 % ee.     

Amine‐Catalyzed Enantioselective 1,3‐Dipolar Cycloadditions of Aldehydes to C,N‐Cyclic Azomethine Imines

Amine‐catalyzed enantioselective 1,3‐dipolar cycloadditions of aldehydes to C,N‐cyclic azomethine imines were developed. The reactions between diversely substituted C,N‐cyclic azomethine imines and aldehydes proceeded smoothly in the presence of chiral prolinol silyl ether catalyst and gave the C‐1‐substituted tetrahydroisoquinolines in a highly stereoselective manner. These tetrahydroisoquinolines could be efficiently transformed to several other useful polycyclic frameworks.     

Nickel‐Catalyzed Conjugate Addition of Silyl Ketene Imines to In Situ Generated Indol‐2‐ones: Highly Enantioselective Construction of Vicinal All‐Carbon Quaternary Stereocenters

The first enantioselective conjugate addition of silyl ketene imines to in situ generated indol‐2‐ones was performed in the presence of a chiral N ,N ′‐dioxide/Ni^II catalyst. This method provides efficient access to chiral β‐alkyl nitriles bearing congested vicinal all‐carbon quaternary stereocenters in up to 90 % yield with 23:1 d.r. and 98 % ee . The products enable facile transformations to chiral pyrroloindoline frameworks and spirocyclohexane oxindole derivatives. A possible transition state was also proposed to explain the origin of the asymmetric induction.     

A Catalyst Designed for the Enantioselective Construction of Methyl‐ and Alkyl‐Substituted Tertiary Stereocenters

Tertiary methyl‐substituted stereocenters are present in numerous biologically active natural products. Reported herein is a catalytic enantioselective method for accessing these chiral building blocks using the Mukaiyama–Michael reaction between silyl ketene thioacetals and acrolein. To enable remote enantioface control on the nucleophile, a new iminium catalyst, optimized by three‐parameter tuning and by identifying substituent effects on enantioselectivity, was designed. The catalytic process allows rapid access to chiral thioesters, amides, aldehydes, and ketones bearing an α‐methyl stereocenter with excellent enantioselectivities, and allowed rapid access to the C4–C13 segment of (?)‐bistramide A. DFT calculations rationalized the observed sense and level of enantioselectivity.     

Dynamic Kinetic Resolution of Alcohols by Enantioselective Silylation Enabled by Two Orthogonal Transition‐Metal Catalysts

A nonenzymatic dynamic kinetic resolution of acyclic and cyclic benzylic alcohols is reported. The approach merges rapid transition‐metal‐catalyzed alcohol racemization and enantioselective Cu‐H‐catalyzed dehydrogenative Si‐O coupling of alcohols and hydrosilanes. The catalytic processes are orthogonal, and the racemization catalyst does not promote any background reactions such as the racemization of the silyl ether and its unselective formation. Often‐used ruthenium half‐sandwich complexes are not suitable but a bifunctional ruthenium pincer complex perfectly fulfills this purpose. By this, enantioselective silylation of racemic alcohol mixtures is achieved in high yields and with good levels of enantioselection.     

Catalytic Silylations of Alcohols: Turning Simple Protecting‐Group Strategies into Powerful Enantioselective Synthetic Methods

In recent years, remarkable progress has been made in the enantioselective silylation of alcohols. Owing to the successful site‐ and stereoselective functionalization of hydroxy groups, silyl ether formations have evolved from being a simple reaction for functional‐group protection into a powerful enantioselective process. In this Minireview, we highlight important recent findings in this emerging field.     

Copper‐Catalyzed Enantioselective Allylic Alkylation with a γ‐Butyrolactone‐Derived Silyl Ketene Acetal

Herein, we report a Cu‐catalyzed enantioselective allylic alkylation using a γ‐butyrolactone‐derived silyl ketene acetal. Critical to the development of this work was the identification of a novel mono‐picolinamide ligand with the appropriate steric and electronic properties to afford the desired products in high yield (up to 96 %) and high ee (up to 95 %). Aryl, aliphatic, and unsubstituted allylic chlorides bearing a broad range of functionality are well‐tolerated. Spectroscopic studies reveal that a Cu^I species is likely the active catalyst, and DFT calculations suggest ligand sterics play an important role in determining Cu coordination and thus catalyst geometry.     

Versatile Homoallylic Boronates by Chemo‐, SN2′‐, Diastereo‐ and Enantioselective Catalytic Sequence of Cu−H Addition to Vinyl‐B(pin)/Allylic Substitution

A highly chemo‐, diastereo‐ and enantioselective catalytic method that efficiently combines a silyl hydride, vinyl‐B(pin) (pin=pinacolato) and (E)‐1,2‐disubstituted allylic phosphates is introduced. Reactions, best promoted by a Cu‐based complex with a chiral sulfonate‐containing N‐heterocyclic carbene, are broadly applicable. Aryl‐, heteroaryl‐, alkenyl‐, alkynyl‐ and alkyl‐substituted allylic phosphates may thus be converted to the corresponding homoallylic boronates and then alcohols (after C−B bond oxidation) in 46–91 % yield and in up to >98 % S_N2′:S_N2 ratio, 96:4 diastereomeric ratio and 98:2 enantiomeric ratio. The reasons why an NHC−Cu catalyst is uniquely effective (vs. the corresponding phosphine systems) and the basis for different trends in stereoselectivity are provided with the aid of DFT calculations.     

Lewis‐Base‐Mediated Diastereoselective Silylations of Alcohols: Synthesis of Silicon‐Stereogenic Dialkoxysilanes Controlled by Chiral Aryl BINMOLs

In the past years, stereoselective functionalizations of hydroxyl groups of alcohol substrates with chlorosilanes leading to silyl ether formation have evolved from a functional‐group protection to an enantioselective synthetic strategy. This work comprises a controlled desymmetrization of dichlorosilanes by using a family of structurally specific chiral diols, chiral 1,1′‐binaphthalene‐2‐α‐arylmethanol‐2′‐ol (Ar‐BINMOL). This process led to the facile construction of silicon‐stereogenic organosilicon compounds with high yields and good diastereoselectivities. In addition, the diasteroselective silylation of chiral diols might not only be of interest for the development of highly stereoselective nucleophilic silylation, but also shed light on the construction of novel chiral phosphine ligands bearing a silicon‐stereogenic center.     

Rhodium(I)‐Catalyzed Intermolecular Aza‐[4+3] Cycloaddition of Vinyl Aziridines and Dienes: Atom‐Economical Synthesis of Enantiomerically Enriched Functionalized Azepines

A new synthetic application of vinyl aziridines as N‐containing three‐atom components in a rhodium‐catalyzed [4+3] cycloaddition reaction is described. The reaction proceeds well with various silyl dienol ethers and vinyl aziridines, and enables the efficient synthesis of highly functionalized azepines in an enantioselective manner with net inversion of absolute configuration. The salient features of the transformation include the use of readily available substrates, high selectivity, and mild reaction conditions, as well as the versatile functionalization of the products.     

A Photochemical Organocatalytic Strategy for the α‐Alkylation of Ketones by using Radicals

Reported herein is a visible‐light‐mediated radical approach to the α‐alkylation of ketones. This method exploits the ability of a nucleophilic organocatalyst to generate radicals upon S_N2‐based activation of alkyl halides and blue light irradiation. The resulting open‐shell intermediates are then intercepted by weakly nucleophilic silyl enol ethers, which would be unable to directly attack the alkyl halides through a traditional two‐electron path. The mild reaction conditions allowed functionalization of the α position of ketones with functional groups that are not compatible with classical anionic strategies. In addition, the redox‐neutral nature of this process makes it compatible with a cinchona‐based primary amine catalyst, which was used to develop a rare example of enantioselective organocatalytic radical α‐alkylation of ketones.     

Asymmetric Conjugate Addition of Grignard Reagents to 3‐Silyl Unsaturated Esters for the Facile Preparation of Enantioenriched β‐Silylcarbonyl Compounds and Allylic Silanes

A highly enantioselective conjugate addition of Grignard reagents to 3‐silyl unsaturated esters to deliver synthetically useful chiral β‐silylcarbonyl compounds was developed. The synthetic value of this methodology was further illustrated by the synthesis of enantioenriched β‐hydroxyl esters and the facile access granted to various α‐chiral allylic silanes. A plethora of diastereoselective transformations of β‐silylenolates were also investigated and afforded manifold organosilanes that contained contiguous stereogenic centers with excellent enantioselectivity.     

The Brønsted Acid Catalyzed,Enantioselective Vinylogous Mannich Reaction

The first catalytic, enantioselective vinylogous Mannich reaction of acyclic silyl dienolates is reported. A second‐generation 2,2′‐dihydroxy‐1,1′‐binaphthyl (BINOL)‐based phosphoric acid has been developed and further optimized as an enantioselective organocatalyst. Upon protonation of the imines, chiral contact ion pairs are generated in situ and attacked highly diastereoselectively by the nucleophile. γ‐Substituted silyl dienolates that lead to more highly substituted Mannich products with a second stereogenic center in good diastereoselectivity have been employed in these reactions. The reaction path has been elucidated with NMR spectroscopy and mass spectrometry, which suggest that the protic reaction medium found to be optimal in these reactions serves to trap the cationic silicon species as silanol. A crystal structure of a phosphoric acid bound imine was obtained that provides insight into the binding mode and a rationale for the stereochemical course of the reaction.     

Secondary Amine‐Catalyzed Asymmetric γ‐Alkylation of α‐Branched Enals via Dienamine Activation

The direct and enantioselective γ‐alkylation of α‐substituted α,β‐unsaturated aldehydes proceeding under dienamine catalysis is described. We have found that the Seebach modification of the diphenyl‐prolinol silyl ether catalyst in combination with saccharin as an acidic additive promotes an S_N1 alkylation pathway, while ensuring complete γ‐site selectivity and a high stereocontrol. Theoretical and spectroscopic investigations have provided insights into the conformational behavior of the covalent dienamine intermediate derived from the condensation of 2‐methylpent‐2‐enal and the chiral amine. Implications for the mechanism of stereoinduction are discussed.     

A highly efficient synthesis of (Z)‐1‐aryl‐2‐silyl‐1‐ stannylethenes and their conversion to (E)‐2‐ arylethenyl‐, (Z)‐2‐(2‐pyridyl)ethenyl‐ and allenyl‐silanes

A Pd(dba)₂–P(OEt)₃ combination allowed the silastannation of arylacetylenes, 1‐hexyne or propargyl alcohols with tributyl(trimethylsilyl)stannane to take place at room temperature, producing (Z)‐2‐silyl‐1‐stannyl‐1‐substituted ethenes in high yields. Novel silyl(stannyl)ethenes were fully characterized by ¹H‐, ¹³C‐, ²⁹Si‐ and ¹¹⁹Sn‐NMR as well as infrared and mass analyses. Treatment of a series of (Z)‐1‐aryl‐2‐silyl‐1‐stannylethenes and (Z)‐1‐(3‐pyridyl)‐2‐silyl‐1‐stannylethene with hydrochloric acid or hydroiodic acid in the presence of tetraethylammonium chloride (TEACl) or tetrabutylammonium iodide (TBAI) led to the exclusive formation of (E)‐trimethyl(2‐arylethenyl)silanes with high stereoselectivity. A similar reaction of (Z)‐1‐(2‐anisyl)‐2‐silyl‐1‐stannylethene also produced E‐type trimethyl[2‐(2‐anisyl)ethenyl]silane, while (Z)‐trimethyl [2‐(2‐pyridyl)ethenyl]silane was produced exclusively from (Z)‐1‐(2‐pyridyl)‐2‐silyl‐1‐stannylethene. Protodestannylation of (Z)‐1‐[hydroxy(phenyl)methyl]‐2‐silyl‐1‐stannylethene with trifluoroacetic acid took place via the β‐elimination of hydroxystannane, providing trimethyl(3‐phenylpropa‐1,2‐dienyl)silane quite easily. The destannylation products were also fully characterized. Copyright © 2007 John Wiley & Sons, Ltd.     

Silicon‐Free SuFEx Reactions of Sulfonimidoyl Fluorides: Scope,Enantioselectivity, and Mechanism

SuFEx reactions, in which an S?F moiety reacts with a silyl‐protected phenol, have been developed as powerful click reactions. In the current paper we open up the potential of SuFEx reactions as enantioselective reactions, analyze the role of Si and outline the mechanism of this reaction. As a result, fast, high‐yielding, “Si‐free” and enantiospecific SuFEx reactions of sulfonimidoyl fluorides have been developed, and their mechanism shown, by both experimental and theoretical methods, to yield chiral products.