Functionalized cyclopentanes via Sc(III)-catalyzed intramolecular enolate alkylation

We report herein the intramolecular α-tert-alkylation of unsaturated β-ketoesters which gives rise to highly functionalized cyclopentanes. This transformation is characterized by its operational simplicity, mild reaction conditions and the use of scandium (III) triflate as a Lewis acid catalyst. Of interest, cyclopentanes bearing heterocycles, sites for post reaction functionalization and spirocyclic architectures are accessible with this strategy.     

Electrocyclic ring-opening reactions may cause failure of enolate alkylation of 1,4-oxazin-2-one based chiral glycine equivalents

Attempted monoalkylation of 6-methyl-5,6-diphenyl-1,4-oxazin-2-one that had been designed as a chiral glycine equivalent gave even under optimized conditions only minute amounts of the desired monoalkylation product whereas an acyclic ketone was obtained repeatedly as the major product. This result indicates that the enolate of the chiral glycine equivalent is prone to an electrocyclic ring-opening reaction. This hypothesis could be further supported by additional experiments. Based on these results, it is reasonable to assume that electrocyclic ring-opening reactions are also the cause for the failure of alkylation reactions of structurally related glycine equivalents reported in the literature.     

Asymmetric synthesis of aldehydes via alkylation of lithiated chiral α-phenethylimines

The lithiation and alkylation of three aldehydes in the form of their α-phenethylimines has been shown to yield chiral α-alkylaldehydes of 67–70% optical purity.     

Molecular recognition of biotin, barbital and tolbutamide with new synthetic receptors

We have measured, by means of NMR titrations, the binding constants for the complexes between hosts N,N′-bis(6-methylpyridin-2-yl)-1,3-benzenedicarboxamide (7) and 4-chloro-N,N′-bis(6-methylpyridin-2-yl)-2,6-pyridinedicarboxamide (8, hydrated) with biotin methyl ester (1), N,N′-dimethylurea (2), 2-imidazolidone (3), N,N′-trimethylenurea (4), barbital (5) and tolbutamide (6) as guests. Molecular Mechanics calculations (Monte Carlo Conformational Search, AMBER and OPLS force fields, MacroModel v.8.1) on the complexes formed between the foregoing guests and hosts 7 and 8, comparatively with 4-oxo-N,N′-bis(6-methylpyridin-2-yl)-1,4-dihydro-2,6-pyridinedicarboxamide (9a) have been carried out in order to determine the correlation between experimental and theoretical results and to understand the behaviour of the designed new hosts. Finally we have performed single point DFT [B3LYP/6-31G(d,p)] calculations on the optimised Molecular Mechanics geometries for the complexes between hosts 7-9 and water.     

Asymmetric synthesis of all-carbon quaternary spirocycles via a catalytic enantioselective allylic alkylation strategy

Rapid access to enantioenriched spirocycles possessing a 1,4-dicarbonyl moiety spanning an all-carbon quaternary stereogenic spirocenter was achieved using a masked bromomethyl vinyl ketone reagent. The developed protocol entails an enantioselective palladium-catalyzed allylic alkylation reaction followed by a one-pot unmasking/RCM sequence that provides access to the spirocyclic compounds in good yields and selectivities.     

Synthesis of dihydroindenofuran scaffold via a Pd-catalyzed 5-endo-trig cyclization/enolate O-alkylation cascade

An efficient synthesis of dihydroindenofurans was carried out starting from the Baylis-Hillman adducts via a Pd-catalyzed 5-endo-trig-carbopalladation and enolate O-alkylation cascade as a key step. This is the first example of enolate O-alkylation with a C(sp³)-bound palladium intermediate.     

使用手性相转移催化剂的不对称烷基化反应

本文报道了用七种手性相转移催化剂(其中三种未见文献报道)催化氯化苄或溴丁烷对α-异丙基对氯苯乙腈或α-异丙基苯乙腈的不对称烷基化反应。考察了反应时间、温度、催化剂浓度和溶剂的极性等因素对不对称反应的影响。不对称烷基化产物的最大e.e.值达41.5%, 由比旋光度和带手性柱的气相色谱法测得。     

Palladium-catalyzed asymmetric allylic alkylation using chiral hydrazone ligands with ferrocene skeleton

Palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate (4) with a dimethyl malonate-BSA-LiOAc system has been successfully carried out in the presence of chiral phosphine-hydrazone ligands such as 3a in good yields with good enantioselectivities (up to 84% ee).     

Use of zinc enolate, free from other metals, in enantioselective palladium-catalyzed allylic alkylation

Zinc enolate, free from other metal cations directly prepared from malonate and diethylzinc, was proven to be an excellent nucleophile for enantioselective palladium-catalyzed allylic alkylation, particularly for the allylic cation bearing aromatic rings at the 1- and 3-positions.     

Solid-phase synthetic method for (±)-α-amino acids via phase-transfer catalytic alkylation

A solid supported glycineimine t-butyl ester was designed and successfully applied to the synthesis of (±)-α-amino acids. The phase-transfer catalytic alkylation, followed by acidic hydrolysis and benzoylation gave N-benzoyl-α-amino acid tert-butyl esters in high yields (up to 92%).     

Highly diastereo- and enantioselective construction of phthalide-oxindole hybrids bearing vicinal quaternary chiral centers via an organocatalytic allylic alkylation

A diastereo- and enantioselective synthesis of phthalide-oxindole hybrids including congested adjacent quaternary chiral centers was demonstrated through a Lewis base catalyzed asymmetric allylic alkylation reaction of Morita–Baylis–Hillman carbonates of isatins and 3-cyanophthalides. The various hybrid molecules with two valuable pharmacophores-combined frameworks can be obtained in good to high diastereo- and enantioselectivities.     

Asymmetric alkylation of an α-keto ester with chiral lithium alkoxy-tributylaluminates

Lithium tetrabutylaluminate modified by either (-)-N-methylephedrine or Darvon alcohol[(*)-(2S, 3R)-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol] readily reacts with phenylglyoxylic acid methyl ester to give the expected α-butyl α-hydroxy ester with a good chemical yield and an optical yield of 43% when Darvon alcohol is used.     

Synthesis of benzyl- and benzhydrylferrocenes via Friedel-Crafts alkylation of ferrocene. Access to ferrocenyl bisphenols with high affinities for estrogen receptors

Ferrocene reacts with methoxy-substituted benzyl- and benzhydryl alcohols in the presence of trifluoroacetic acid to afford methoxybenzyl- or benzhydrylferrocenes in 47-56% yield. Demethylation of these compound leads to the ferrocenyl phenols and bisphenols. Some of the synthesized compounds display high affinity for estrogen receptors ERα and ERβ.     

Palladium-catalyzed allylic alkylation using chiral P,O-ligands synthesized via sulfonamide directed ortho-lithiation

An efficient approach for the synthesis of chiral P,O-ligands containing sulfonamide and phosphine moieties is designed. The introduction of the chirality is achieved through different stereogenic groups attached to the sulfonamide nitrogen. The highly effective sulfonamide directed ortho-lithiation and the subsequent reaction with ClPPh₂ is the key step in the synthesis of the ligands. The prepared P,O-compounds are applied in Pd-catalyzed asymmetric allylic alkylation (AAA) under optimized conditions, to obtain high degrees of enantioselectivity.     

Practical asymmetric synthesis of a potent PDE4 inhibitor via stereoselective enolate alkylation of a chiral aryl-heteroaryl secondary tosylate

A practical, chromatography-free catalytic asymmetric synthesis of a potent and selective PDE4 inhibitor (L-869,298, 1) is described. Catalytic asymmetric hydrogenation of thiazole ketone 5a afforded the corresponding alcohol 3b in excellent enantioselectivity (up to 99.4% ee). Activation of alcohol 3b via formation of the corresponding p-toluenesulfonate followed by an unprecedented displacement with the lithium enolate of ethyl 3-pyridylacetate N-oxide 4a generated the required chiral trisubstituted methane. The displacement reaction proceeded with inversion of configuration and without loss of optical purity. Conversion of esters 2b to 1 was accomplished via a one-pot deprotection, saponification, and decarboxylation sequence in excellent overall yield.     

Fluorous chiral bisoxazolines. Synthesis and applications to an asymmetric allylic alkylation

The easily accessible fluorous bisoxazolines 3a-b bearing two fluorous ponytails are efficient ligands in the palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenylprop-2-enyl acetate with carbonucleophiles in benzotrifluoride or CH₂Cl₂, enantioselectivities of up to 95% being obtained. The ligand is easily separated from the reaction mixture by simple extraction with a fluorous solvent.     

Asymmetric alkylation of glycine imine esters using solid supports preloaded with base

Investigations into the use of solid supports preloaded with base for the asymmetric alkylation of a benzophenone-derived glycine-imine was described. Residual traces of water on the support dramatically accelerated the reactions to complete within a few minutes. The conditions employed in the present synthesis are mild, efficient and general.     

Asymmetric phase-transfer catalysis of homo- and heterochiral quaternary ammonium salts: development and application of conformationally flexible chiral phase-transfer catalysts

Inspired by the considerable difference of catalytic activity and stereocontrolling ability between the conformationally rigid, homo- and heterochiral quaternary ammonium bromides 1, conformationally flexible, N-spiro chiral quaternary ammonium bromides of type 4 have been designed and synthesized. Reliable procedures for the preparation of the appropriately substituted biphenyl subunits have been established by the repeated use of ortho magnesiation-halogenation as a key synthetic tool. The relationship between the structure of achiral biphenyl moiety and the reactivity and selectivity of 4 has been evaluated in the asymmetric alkylation of glycinate Schiff base 2 under typical phase-transfer conditions, leading to the identification of 4l as an optimal catalyst structure to exhibit an excellent enantiocontrol in the reactions with various alkyl halides. The molecular structure of 4l was determined by X-ray crystallographic analysis and its unique behavior in solution was examined by a variable-temperature ¹H NMR study. These investigations uncovered that the observed high chiral efficiency originated from the efficient asymmetric phase-transfer catalysis of homochiral-4l, which rapidly equilibrated with heterochiral-4l of low catalytic activity and stereoselectivity.     

Palladium(0)-catalyzed rearrangement of allyl enol ethers to form chiral quaternary carbon centers via asymmetric allylic alkylation

Herein we report the first palladium(0)-catalyzed asymmetric allylic alkylation (AAA) of allyl enol ether via π-allylpalladium intermediate using Trost chiral diphosphine. This unprecedented reaction produced very rare α-aryl quaternary aldehydes with multi-functional groups. The main novelty in the chemistry demonstrates that enol ethers can be used as precursors for π-allylpalladium intermediates, an observation that is certainly rare and to the best of our knowledge, perhaps without prior precedent. Chiral ligand (R,R)-L3 was found to be optimal in this Pd-AAA reaction and provided good to excellent yield (80–95%) and enantioselectivity (70–90%) with a range of analogs.