Asymmetric α Alkylation of Aldehydes: Efficiency with Elegance

Abstract

alkylation · enamines · nucleophile substitution · organocatalysis · stereoselective catalysis Alkylations using the substitution reaction can be found in the first chapters of introductory level organic chemistry textbooks. Despite its apparent simplicity, the asymmetric a alkylation of aldehydes, even today, presents many unsolved practical problems.[1] Unlike aldol, Mannich, and 1,4-addition reactions, direct a alkylations of aldehydes are often characterized by narrow substrate scope or low stereoselectivity, or often both. As the majority of diastereoselective a alkylations of carbonyl compounds developed use preformed metal or metalloid enolates, [2] the replacement of these enolates by catalytically generated chiral enamines appears straightforward. Regardless of the daunting epimirization problem of the created asymmetric center, the challenge in developing an enantiocatalytic protocol for alkylation is to find reaction conditions for the synthesis of so-called unstabilized enolates in an environment where the nucleophilic catalyst may efficiently compete for the same substrate.The a alkylation of aldehydes using simple alkyl halides as the electrophilic partner is problematic. Reaction conditions have been established for the intramolecular direct S N 2-type a alkylation of haloaldehydes using a-methyl proline as the catalyst.[3] Although this reaction offered a practical solution for the formation of cyclopropanes and five-membered cycles, and is still used in domino transformations, [4] the method performed poorly under intermolecular conditions owing to a number of competing side reactions, and in particular to the deactivation of the nucleophilic catalyst by alkylation. An elegant solution has been presented for the intermolecular asymmetric allylic alkylation (AAA) of a-branched aldehydes; in seminal work by List and Mukherjee the enantiodifferentiation was achieved by a chiral counteranion/anionic ligand rather than a more commonly used neutral ligand. [5] The reaction allows the creation of all-carbon quaternary stereogenic centers, but it is not suitable for the preparation of chiral tertiary centers. Reaction conditions are emerging for intermolecular alkylation by electron-transfer (ET) reactions.[6] The MacMillan group developed an impressive and complex array of highly enantioselective ET-mediated transformations including a allylation, enolation, vinylation, styrenation, polyene cyclization, benzylation, and alkylation of aldehydes.[6c] The inherent limitation of this elegant chemistry is in the substrate scope, as it cannot be used, for example, for the simple a methylation of enolisable aldehydes.In parallel with the ET-mediated a alkylation reactions S N 1-type reactions between stabilized carbocations and enamines are gaining synthetic importance. Somewhat surprisingly S N 1-type transformations have been seldom considered in asymmetric organocatalysis until very recently. Pioneered by Petrini, Melchiorre, and co-workers, [7] and considerably extended by Cozzi et al.[8] the reaction of...

Intra- and Intermolecular Alkylation ofN,O-Acetals and π-Activated Alcohols Catalyzed by in Situ Generated Acid

“…As many organic reactions are promoted by Brønsted acid catalysis, this method is expected to have utility in many more situations beyond the iminium ion chemistry reported here. As a preliminary effort into this direction, we questioned whether our methodology could also encompass π-activated alcohols. − , We were delighted to observe that the alcohols VI A – VI D reacted successfully with β-diketones in our thermal alkylative method, giving the desired alkylated products in excellent yields (Table ).…”

“…One common method for the generation of carbocations is by loss of a leaving group attached to carbon, and this can be assisted by protonation or metalation as in the case of alcohols and their derivatives. Over the past decade, many different catalytic systems based on the use of Lewis and Brønsted acids for this activation mode have been reported, therefore considerably improving the value of cationic chemistry. , While highly stabilized carbenium ions can be generated under extremely mild conditions, for example simply using hot water or fluorinated alcohols as both solvents and promoters, , highly reactive carbocations need to be generated from alcohol derivatives with markedly reduced polarizability, and therefore much stronger acidic promoters (and/or greater amounts of them) are required. This trend generally follows Mayr’s scale: i.e., the strength and/or load of the catalyst grow as the E parameter of the cations increases.…”

“…We reasoned that release should still occur at significantly lower temperatures and provide very low levels of anhydrous HCl in the reaction solution. As opposed to the commercially available solutions of HCl which are supplied in hydrogen-bond acceptor solvents, this in situ generated “free” HCl is expected to be significantly more active, while avoiding the need for dealing with gaseous HCl and also preserving compatibility with the range of neutral carbon nucleophiles commonly used in alkylative chemistry. − If these assumptions were confirmed, efficient catalytic alkylation methods could be developed through successful use of one of the simplest acid catalysts, HCl. To the best of our knowledge, HCl has not been demonstrated as an efficient catalyst in S N 1-type alkylation involving N -acyliminium ions, while other common Brønsted acids such as PTSA and TFA are typically used in superstoichiometric amounts for such reactions.…”

Enantioselective Synthesis of Acyclic Orthogonally Functionalized Compounds Bearing a Quaternary Stereocenter Using Chiral Ammonium Salt Catalysis

“…The enantioselective construction of quaternary stereogenic centers, or so called all-carbon stereocenters, has for decades been a topic of uttermost importance [1] and the development of novel, especially asymmetric catalysis-based, strategies is a worthwhile task. [1][2][3] Enantioselective catalytic α-alkylation reactions of suited prochiral C-pronucleophiles, [4] i. e. enolate analogues, are amongst the most versatile approaches to install stereogenic centers and the use of appropriately α-trisubstituted carbonyl-or carboxylic acid-analogues allows for the direct formation of quaternary stereogenic centers. [3,4] Asymmetric ion-pairing organocatalysis, i. e. chiral ammonium salt catalysis, has emerged as one of the outstanding non-covalent catalysis principles over the last four decades.…”

“…[1][2][3] Enantioselective catalytic α-alkylation reactions of suited prochiral C-pronucleophiles, [4] i. e. enolate analogues, are amongst the most versatile approaches to install stereogenic centers and the use of appropriately α-trisubstituted carbonyl-or carboxylic acid-analogues allows for the direct formation of quaternary stereogenic centers. [3,4] Asymmetric ion-pairing organocatalysis, i. e. chiral ammonium salt catalysis, has emerged as one of the outstanding non-covalent catalysis principles over the last four decades. [5] Very remarkably, this concept has proven its potential for stereoselective enolate α-functionalizations ever since the pioneering contributions by Merck scientists, who first reported the chiral ammonium salt catalyzed α-alkylation of phenylindanone derivatives in 1984 already, [6] and O'Donnell's group who introduced glycine Schiff base α-alkylations in 1989.…”