Tristan H. Lambert

Multicatalysis: Advancing Synthetic Efficiency and Inspiring Discovery

Heavy reliance on iterative synthetic strategies represents one of the most serious drawbacks of modern organic synthesis. There has been increasing interest of late in the development of processes that attempt to alleviate this dependence by achieving multiple transformations in a single vessel, thereby circumventing the need for intermittent isolation and purification. One such strategy is encompassed by the term multicatalysis, an approach wherein multiple catalytic reactions are executed in a single flask, either in tandem or sequentially. In this Minireview, some recent efforts in the field of multicatalysis, including our own work, are discussed. In addition, a case regarding the need for consistent terminology in this rapidly developing field is advanced.

Multicatalytic Synthesis of α-Pyrrolidinyl Ketones via a Tandem Palladium(II)/Indium(III)-Catalyzed Aminochlorocarbonylation/Friedel−Crafts Acylation Reaction

An oxidative carbonylation reaction that generates acid chloride functionality has been developed. Furthermore, this aminochlorocarbonylation reaction has been merged with a catalytic Friedel-Crafts acylation to produce a highly efficient tandem multicatalytic synthesis of pyrrolidinyl ketones. Significant variation of the aromatic nucleophile and substrate are shown. Two examples of incorporation of this method in triple-catalytic sequences are also demonstrated.

Tropylium Ion Mediated α-Cyanation of Amines

Tropylium ion mediated α-cyanation of amines is described. Even in the presence of KCN, tropylium ion is capable of oxidizing various amine substrates, and the resulting iminium ions undergo salt metathesis with cyanide ion to produce aminonitriles. The byproducts of this transformation are simply cycloheptatriene, a volatile hydrocarbon, and water-soluble potassium tetrafluoroborate. Thirteen total substrates are shown for the α-cyanation procedure, including a gram scale synthesis of 17β-cyanosparteine. In addition, a tropylium ion mediated oxidative aza-Cope rearrangement is demonstrated.

Enantioselective Brønsted Base Catalysis with Chiral Cyclopropenimines

Cyclopropenimines are shown to be a highly effective new class of enantioselective Brønsted base catalysts. A chiral 2,3-bis(dialkylamino)cyclopropenimine catalyzes the rapid Michael reaction of a glycine imine substrate with high levels of enantioselectivity. A preparative scale reaction to deliver 25 g of product is demonstrated, and a trivial large scale synthesis of the optimal catalyst is shown. In addition, the basicity of a 2,3-bis(dialkylamino)cyclopropenimine is measured for the first time and shown to be approximately equivalent to the P(1)-tBu phosphazene base. An X-ray crystal structure of the protonated catalyst is shown along with a proposed mechanistic and stereochemical rationale.

Cyclopropenimine-Catalyzed Enantioselective Mannich Reactions of tert-Butyl Glycinates with N-Boc-Imines

Cyclopropenimine 1 is shown to catalyze Mannich reactions between glycine imines and N-Boc-aldimines with high levels of enantio- and diastereocontrol. The reactivity of 1 is shown to be substantially greater than that of a widely used thiourea cinchona alkaloid-derived catalyst. A variety of aryl and aliphatic N-Boc-aldimines are effective substrates for this transformation. A preparative-scale reaction to deliver >90 mmol of product is shown using 1 mol % catalyst. The products of this transformation can be converted into several useful derivatives.

Development of a Formal [4 + 1] Cycloaddition: Pd(OAc)2-Catalyzed Intramolecular Cyclopropanation of 1,3-Dienyl β-Keto Esters and MgI2-Promoted Vinylcyclopropane-Cyclopentene Rearrangement

A formal [4 + 1] cycloaddition of 1,3-dienyl beta-keto esters has been developed. This two step process involves Pd(II)-catalyzed intramolecular cyclopropanation to produce vinylcyclopropanes and a subsequent mild vinylcyclopropane-cyclopentene rearrangement promoted by MgI(2). The cyclopropanation method notably requires the use of Mg(ClO(4))(2), presumably to facilitate keto-enol tautomerization, and is greatly improved by the use of copper(II) isobutyrate as co-oxidant. A range of substrates with various substitution patterns is demonstrated.

Multicatalytic Synthesis of Complex Tetrahydrofurans Involving Bismuth(III) Triflate Catalyzed Intramolecular Hydroalkoxylation of Unactivated Olefins

A multicatalytic synthesis of complex tetrahydrofurans has been developed involving a Bi(OTf)(3)-catalyzed nucleophilic addition/hydroalkoxylation sequence. Complex tetrahydrofuranyl products may be formed rapidly in high yield and with good diastereoselectivity. The demonstrated scope of hydroalkoxylation has also been expanded to include substrates bearing useful functional handles including carboxylate ester, olefin, nitrile, and nitro groups.

Nucleophilic acyl substitution via aromatic cation activation of carboxylic acids: rapid generation of acid chlorides under mild conditions.

The first example of aromatic cation-activated nucleophilic acyl substitution has been achieved. The conversion of carboxylic acids to their corresponding acid chlorides occurs rapidly in the presence of 3,3-dichlorocyclopropenes via the intermediacy of cyclopropenium carboxylate complexes. The effect of cyclopropene substituents on the rate of conversion is examined. The addition of tertiary amine base is found to dramatically accelerate reaction, and conditions were developed for the preparation of acid sensitive acid chlorides. Preparative scale peptide couplings of two N-Boc amino acids were achieved with this method.

Aromatic cation activation of alcohols: conversion to alkyl chlorides using dichlorodiphenylcyclopropene.

A novel paradigm for the activation of alcohols toward nucleophilic displacement via formation of cyclopropenium ethers is described. The conversion of a range of alcohol substrates to the corresponding alkyl chlorides occurs rapidly upon treatment with 3,3-dichloro-1,2-diphenylcyclopropene. (1)H NMR data support the intermediacy of a cyclopropenium intermediate, and the reaction is demonstrated to proceed primarily via the S(N)2 mechanism for 1-phenylethanol. A total of 12 examples of substrate scope are provided.

Cyclopropenium-activated cyclodehydration of diols.

The dehydrative cyclization of diols to cyclic ethers via cyclopropenium activation is described. Using 2,3-diphenylcyclopropene and methanesulfonic anhydride, a series of 1,4- and 1,5-diols are rapidly cyclized to furnish tetrahydrofurans and tetrahydropyrans in high yield. Eleven total substrates are shown, including a gram scale cyclization of a diterpene derivative.