Catalytic,asymmetric Mannich-type reactions of N-acylimino esters: reactivity,diastereo- and enantioselectivity,and application to synthesis of N-acylated amino acid derivatives

In the presence of a catalytic amount of Cu(OTf)(2)-chiral diamine 3e complex, N-acylimino esters reacted with silyl enol ethers to afford the corresponding Mannich-type adducts in high yields with high enantioselectivities. A wide variety of silyl enol ethers derived from ketones, as well as esters and thioesters, reacted smoothly. In the reactions of alpha-substituted silyl enol ethers (alpha-methyl or benzyloxy), the desired syn-adducts were obtained in high yields with high diastereo- and enantioselectivities. Several intermediates for the synthesis of biologically important compounds were prepared using this novel catalytic asymmetric Mannich-type reaction, and at the same time, absolute and relative stereochemical assignments were made. In addition, it has been revealed that alkyl vinyl ethers reacted with N-acylimino esters in the presence of a catalytic amount of the Cu(II) catalyst to give the corresponding Mannich-type adducts in high yields with high enantioselectivities. This is the first example of catalytic asymmetric Mannich-type reactions with alkyl vinyl ethers. The reaction mechanism, structure of chiral catalyst-electrophile complexes, and transition states of these catalytic asymmetric reactions were assumed based on X-ray crystallographic analysis of the Cu(II)-chiral amine complex, PM3 calculations, and FT-IR analyses, etc. Finally, (1R,3R)-N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12, 1), a new inhibitor of ceramide trafficking from endoplasmic reticulum to the site of sphingomyerin (SM) synthesis, has been synthesized efficiently using the present Mannich-type reaction as a key step. The synthesis involved three steps (two-pot), and total yield was 82.9%.     

Intramolecular construction of trifluoromethyl group by the palladium-catalyzed reaction of 2,3,3-trifluoroallylic carbonates with O-nucleophiles

The synthesis of the trifluoromethyl group containing enol ethers by the palladium-catalyzed intermolecular reaction of 2,3,3-trifluoroallylic carbonates with oxygen nucleophiles was accomplished. The reaction proceeds through the intermolecular attack of oxygen nucleophiles on the C-2 carbon atom of the allylic unit, and the intramolecular fluorine atom shift from the C-2 position to the C-3 position. The reactions with several types of alcohols and phenols proceeded smoothly, and afforded the corresponding trifluoromethyl group containing enol ethers in good to high yields.     

One-pot synthesis of tropinone by tandem (domino) ene-type reactions of acetone silyl enol ethers

A synthetic approach for tropane alkaloids on the basis of tandem (domino) ene-type reactions of acetone silyl enol ethers with iminium ions is shown to be triggered by intermolecular ene-type reactions followed by 6-(2,5) silatropic ene-type cyclizations.     

Facile ring transformation from gluconolactone to cyclitol derivative via spiro sugar ortho ester

[reaction: see text] A short step preparation of cyclitol derivative 8 which is a versatile synthon for the synthesis of valiolamine and its related compounds is described. Key steps in this preparation are a novel enol ether formation from spiro sugar ortho esters with AlMe3 and an intramolecular Aldol condensation of alkyl enol ethers catalyzed by ZnCl2 in THF-H2O. With these reactions, gluconolactone derivative 1 was efficiently converted into 8 in short steps.     

1,4-silatropy of S-alpha-silylbenzyl thioesters: a convenient route to silyl enol and dienol ethers accompanied by C-C bond formation via thiocarbonyl ylides

A novel convenient method for the generation of thiocarbonyl ylides from readily accessible starting materials and the first synthetic application of in situ generated ylides in the synthesis of silyl enol and dienol ethers, accompanied by C-C bond formation, is described. Under completely neutral conditions without any catalyst or additive, thermal reactions of S-alpha-silylbenzyl thioesters in sealed tubes at 180 degrees C provided silyl enol and dienol ethers in good to excellent yields with high stereoselectivities. This procedure consists of a multistep reaction in a one-pot process, i.e., 1,4-silatropy of S-alpha-silylbenzyl thioesters to give thiocarbonyl ylides, 1,3-electrocyclization of the ylides to give thiiranes, and the extrusion of sulfur from thiiranes to give silyl enol and dienol ethers.     

Ag-catalyzed asymmetric mannich reactions of enol ethers with aryl, alkyl, alkenyl, and alkynyl imines

An efficient catalytic and enantioselective method (up to >98% ee) for Mannich reactions between trimethylsilyl enol ethers derived from acetone and acetophenone and aryl, alkenyl, alkynyl, and alkyl imines is disclosed. A large variety of beta-amino ketones can be synthesized in the presence of 1-5 mol % AgOAc and an inexpensive and readily available amino acid-derived phosphine. All Ag-catalyzed asymmetric Mannich reactions can be run in undistilled THF and air. The o-anisyl activating groups of product amines can be removed in >70% isolated yield through a single vessel operation. The synthetic utility of the catalytic asymmetric method is illustrated by a four-pot synthesis of optically pure alkaloid (-)-sedamine.     

Catalytic Reactions with Hydrosilane and Carbon Monoxide [New synthetic methods (30)]

The reagent hydrosilane/carbon monoxide opens up new possibilities for organic synthesis. Four cases will be discussed: 1. The reaction of olefins with hydrosilane (trialkylsilane) and carbon monoxide in the presence of Co, Ru, and Rh complexes leads to enol silyl ethers having one more carbon atom that the olefins. 2. Cyclic ethers underto carbonylative ring opening to ω-siloxyaldehydes when reacted with hydrosilane and carbon monoxide in the presence of Co₂(CO)₈ as catalysts 3. Aldehydes are catalytically converted into the next higher α-siloxyaldehydes or 1,2-bis(siloxy)alkenes depending on the reaction conditions used. 4. The reaction of alkyl acetates proceeds in various ways depending on the nature of the alkyl group; enol silyl ethers or alkenes are optained.–Mechanisms of these Co₂(CO)₈ catalyzed reactions using hydrosilane and carbon monoxide are discussed in which HCo(CO)_n or R₃SiCo(CO)_nL function as catalytically active agents. With these species there are four types of catalytic cycles.–The synthetic possibilities of these catalytic reactions have still not been fully explored.     

Alkoxy radical cyclizations onto silyl enol ethers relative to alkene cyclization, hydrogen atom transfer, and fragmentation reactions

This study examines the chemoselectivity of alkoxy radical cyclizations onto silyl enol ethers compared to competing cyclizations, 1,5-hydrogen atom transfers (1,5-HATs), and β-fragmentations. Cyclization onto silyl enol ethers in a 5-exo mode is greatly preferred over cyclization onto a terminal alkene. The selectivity decreases when any alkyl substitution is present on the competing alkene radical acceptor. Alkoxy radical 5-exo cyclizations displayed excellent chemoselectivity over competing β-fragmentations. Alkoxy radical 5-exo cyclizations onto silyl enol ether also outcompeted 1,5-HATs, even for activated benzylic hydrogen atoms. In tetrahydropyran synthesis, where 1,5-HAT has plagued alkoxy radical cyclization methodologies, 6-exo cyclizations were the dominant mode of reactivity. β-Fragmentation still remains a challenge for tetrahydropyran synthesis when an aryl group is present in the β position.     

Recent applications of N-sulfonyloxaziridines (Davis oxaziridines) in organic synthesis

N-Sulfonyloxaziridines are the most commonly used oxaziridines in organic synthesis. Most applications of these stable, commercially available reagents involve the stereo- and regioselective oxidation of nucleophiles which have found many applications in the synthesis of architecturally complex molecules. In addition, these oxaziridines have been used in cycloaddition reactions (oxyamination), epoxidation of alkenes, silyl enol ethers and enamines, as well as C-H oxidation and amination reactions. The object of this review is to highlight recent applications of N-sulfonyloxaziridines in organic synthesis.     

Structure-nucleophilicity relationships for enamines

The kinetics of the reactions of benzhydryl cations with 22 enamines, three pyrroles, and three indoles were investigated photometrically in dichloromethane. The nucleophilicity parameters N and slope parameters s of these electron-rich pi-systems were derived from equation log k (20 degrees C)=s(E+N) and compared with the nucleophilicities of other pi-systems (silyl enol ethers, silyl ketene acetals) and carbanions. It is shown that the nucleophilic reactivities of enamines cover more than ten orders of magnitude, comparable to enol ethers on the low reactivity end and to carbanions on the high reactivity end. Since the products of N-attack are thermodynamically less stable than the reactants, the observed rate constants refer to the formation of the carbon bond;carbon bonds. In some cases, equilibrium constants for the formation of iminium ions were measured, which allow one to determine the intrinsic rate constants of these reactions.     

The chemical effects of molecular sol-gel entrapment

Chemical conversions within the cages of doped sol-gel porous oxides take place with unique advantages over reactions in solution as the glassy matrix has tremendous effects on the reactivity of the entrapped molecules. The chemical properties of sol-gel materials can be tailored in an immense range of values and chemists are increasingly achieving control on reactions taking place within these matrices, including crucially important photovoltaics. Highlighting recent major advancements, we show in this tutorial review how this is actually taking place.     

Polarity‐Reversed Allylations of Aldehydes,Ketones, and Imines Enabled by Hantzsch Ester in Photoredox Catalysis

The polarity reversal (umpolung) reaction is an invaluable tool for reversing the chemical reactivity of carbonyl and iminyl groups, which subsequent cross‐coupling reactions to form C?C bonds offers a unique perspective in synthetic planning and implementation. Reported herein is the first visible‐light‐induced polarity‐reversed allylation and intermolecular Michael addition reaction of aldehydes, ketones, and imines. This chemoselective reaction has broad substrate scope and the engagement of alkyl imines is reported for the first time. The mechanistic investigations indicate the formation of ketyl (or α‐aminoalkyl) radicals from single‐electron reduction, where the Hantzsch ester is crucial as the electron/proton donor and the activator.     

Organoselenium Chemistry in Stereoselective Reactions

Selenium-based methods have developed rapidly over the past few years asnd organoselenium chemistry has become a very useful tool in the hands of synthetic chemists. The different reactivity of selenium-containing compounds in contrast to the sulfur analogues has led to versatile and new synthetic methods in organic chemistry. Various functionalities can be selectively introduced into complex molecules under very mild reaction conditions. In this review, the principles of organoselenium chemistry are traced back to their origins and are highlighted with respect to stereoselective synthesis. The unique properties of selenium allow the development of new and highly selective transformations, which can be employed subsequently in new routes for the synthesis of versatile chiral building blocks and for natural product synthesis.     

Highly Stereoselective Gold‐Catalyzed Coupling of Diazo Reagents and Fluorinated Enol Silyl Ethers to Tetrasubstituted Alkenes

We report a highly stereoselective synthesis of all‐carbon or fluorinated tetrasubstituted alkenes from diazo reagents and fluorinated enol silyl ethers, using C−F bond as a synthetic handle. Cationic Au^I catalysis plays a key role in this reaction. Remarkable fluorine effects on the reactivity and selectivity was also observed.     

Polarity‐Reversed Allylations of Aldehydes,Ketones, and Imines Enabled by Hantzsch Ester in Photoredox Catalysis

The polarity reversal (umpolung) reaction is an invaluable tool for reversing the chemical reactivity of carbonyl and iminyl groups, which subsequent cross‐coupling reactions to form C−C bonds offers a unique perspective in synthetic planning and implementation. Reported herein is the first visible‐light‐induced polarity‐reversed allylation and intermolecular Michael addition reaction of aldehydes, ketones, and imines. This chemoselective reaction has broad substrate scope and the engagement of alkyl imines is reported for the first time. The mechanistic investigations indicate the formation of ketyl (or α‐aminoalkyl) radicals from single‐electron reduction, where the Hantzsch ester is crucial as the electron/proton donor and the activator.     

Reaction of enol ethers with zinc carbenoid reagents. Cyclopropanation and subsequent isomerization to allylic ethers

The reactions of enol ethers (ROCC, R = alkyl, silyl) with zinc carbenoid reagents were found to give allylic ethers in several cases along with the expected cyclopropyl ethers. The ratio of these two products was highly dependent on the concentration of the reaction mixture. Thus, the selective formation of each product was conveniently attained by merely changing the amounts of the solvent used. Zinc iodide, a by-product of the reaction, plays a key role in the present cyclopropyl to allylic rearrangement. Ring-opened ionic intermediates are proposed.     

Arylsulfonate-based nucleophile assisting leaving groups

[Chemical reaction: See text] The synthesis and unique reactivity of a series of arylsulfonate-based nucleophile assisting leaving groups (NALG) containing oligomeric ether units (including crown ethers) attached to the arylsulfonyl ring in the ortho orientation are described. The reactions of a variety of these ether-containing alkyl sulfonates with metal halides proceeded at substantially greater rates than electronically similar sulfonates. These ether-containing leaving groups also displayed marked selectivity for lithium halides relative to the corresponding sodium and potassium salts in nucleophilic displacement reactions.     

Total Syntheses of Hyperforin and Papuaforins A–C,and Formal Synthesis of Nemorosone through a Gold(I)‐Catalyzed Carbocyclization

The remarkable biological activities of polyprenylated polycyclic acylphloroglucinols (PPAPs) combined with their highly decorated bicyclo[3.3.1]nonane‐2,4,9‐trione frameworks have inspired synthetic organic chemists over the last decade. The concise total syntheses of four natural products PPAPs; hyperforin and papuaforins A–C, and the formal synthesis of nemorosone are reported. Key to the realization of this strategy is the short and scalable synthesis of densely substituted PPAP scaffolds through a gold(I)‐catalyzed 6‐endo‐dig carbocyclization of cyclic enol ethers for late‐stage functionalization.     

Total Syntheses of Hyperforin and Papuaforins A–C,and Formal Synthesis of Nemorosone through a Gold(I)‐Catalyzed Carbocyclization

The remarkable biological activities of polyprenylated polycyclic acylphloroglucinols (PPAPs) combined with their highly decorated bicyclo[3.3.1]nonane‐2,4,9‐trione frameworks have inspired synthetic organic chemists over the last decade. The concise total syntheses of four natural products PPAPs; hyperforin and papuaforins A–C, and the formal synthesis of nemorosone are reported. Key to the realization of this strategy is the short and scalable synthesis of densely substituted PPAP scaffolds through a gold(I)‐catalyzed 6‐endo‐dig carbocyclization of cyclic enol ethers for late‐stage functionalization.     

Halogen-Induced Controllable Cyclizations as Diverse Heterocycle Synthetic Strategy

In organic synthesis, due to their high electrophilicity and leaving group properties, halogens play pivotal roles in the activation and structural derivations of organic compounds. Recently, cyclizations induced by halogen groups that allow the production of diverse targets and the structural reorganization of organic molecules have attracted significant attention from synthetic chemists. Electrophilic halogen atoms activate unsaturated and saturated hydrocarbon moieties by generating halonium intermediates, followed by the attack of carbon-containing, nitrogen-containing, oxygen-containing, and sulfur-containing nucleophiles to give highly functionalized carbocycles and heterocycles. New transformations of halogenated organic molecules that can control the formation and stereoselectivity of the products, according to the difference in the size and number of halogen atoms, have recently been discovered. These unique cyclizations may possibly be used as efficient synthetic strategies with future advances. In this review, innovative reactions controlled by halogen groups are discussed as a new concept in the field of organic synthesis.