High‐Yielding Synthesis of the Anti‐Influenza Neuraminidase Inhibitor (−)‐Oseltamivir by Two “One‐Pot” Sequences

The efficient asymmetric total synthesis of (?)‐oseltamivir, an antiviral reagent, has been accomplished by using two “one‐pot” reaction sequences, with excellent overall yield (60 %) and only one required purification by column chromatography. The first one‐pot reaction sequence consists of a diphenylprolinol silyl ether mediated asymmetric Michael reaction, a domino Michael reaction/Horner–Wadsworth–Emmons reaction combined with retro‐aldol/Horner–Wadsworth–Emmons reaction and retro Michael reactions, a thiol Michael reaction, and a base‐catalyzed isomerization. Six reactions can be successfully conducted in the second one‐pot reaction sequence; these are deprotection of a tert‐butyl ester and its conversion into an acyl chloride then an acyl azide, Curtius rearrangement, amide formation, reduction of a nitro group into an amine, and a retro Michael reaction of a thiol moiety. A column‐free synthesis of (?)‐oseltamivir has also been established.     

Asymmetric Synthesis of Fully Substituted Cyclopentane‐Oxindoles through an Organocatalytic Triple Michael Domino Reaction

An efficient, highly stereoselective asymmetric synthesis of fully functionalized cyclopentanes bearing an oxindole moiety and several other functional groups in one pot has been developed. Key step is an organocatalytic triple Michael domino reaction forming three C?C bonds and six stereocenters, including a quaternary one. Starting from equimolar amounts of simple substrates, a high molecular complexity can be reached after a Wittig olefination in one pot. The new protocol can easily be scaled up to gram amounts.     

Organocatalytic Domino Michael–Knoevenagel Condensation Reaction for the Synthesis of Optically Active 3‐Diethoxyphosphoryl‐2‐oxocyclohex‐3‐enecarboxylates

Versatile dominoes : A novel, organocatalytic, Michael–Knoevenagel condensation domino reaction of ethyl 4‐diethoxyphosphoryl‐3‐oxobutanoate with various aryl‐ and aliphatic‐substituted α,β‐unsaturated aldehydes catalyzed by a chiral diarylprolinol ether has been successfully performed. The reaction proceeds in a highly enantio‐ and diastereoselective manner giving access to optically active 6‐substituted‐3‐diethoxyphosphoryl‐2‐oxocyclohex‐3‐enecarboxylates (see scheme).

     

On the Mechanism of the Organocatalytic Asymmetric Epoxidation of α,β‐Unsaturated Aldehydes

Mechanistic studies on the organocatalytic epoxidation of α,β‐unsaturated aldehydes explore the autoinductive behavior of the reaction and establish that the hydrate/peroxyhydrate of the product is acting as a phase‐transfer catalyst. Based on these studies, an improved methodology that provides high selectivities and decreased catalyst loading, through the addition of chloral hydrate, is developed.     

One‐Pot Sequential Organocatalysis: Highly Stereoselective Synthesis of Trisubstituted Cyclohexanols

A highly diastereoselective (d.r. >99:1) and enantioselective (ee value up to 96 %) synthesis of trisubstituted cyclohexanols was achieved by using a one‐pot sequential organocatalysis that involved a quinidine thiourea‐catalyzed tandem Henry–Michael reaction between nitromethane and 7‐oxo‐hept‐5‐en‐1‐als followed by a tetramethyl guanidine (TMG)‐catalyzed tandem retro‐Henry–Henry reaction on the reaction products of the tandem Henry–Michael reaction. Through a mechanistic study, it has also been demonstrated that similar results may also be achieved with this one‐pot sequential organocatalysis by using the racemic Henry product as the substrate.     

Catalytic Asymmetric Construction of 3,3′‐Spirooxindoles Fused with Seven‐Membered Rings by Enantioselective Tandem Reactions

The first catalytic asymmetric construction of a spirooxindole scaffold incorporated with a seven‐membered benzodiazepine moiety has been established by a three‐component (isatin, 1,2‐phenylenediamine, cyclohexane‐1,3‐dione) tandem reaction catalyzed by a chiral phosphoric acid. Structurally complex spirobenzodiazepine oxindoles with one quaternary stereogenic center are obtained in high yield with excellent enantioselectivity (up to 99 % yield, enantiomeric ratio>99.5:0.5). This approach takes advantage of organocatalytic asymmetric tandem reactions to efficiently construct the structurally rigid spirobenzodiazepine oxindole architecture with high enantiopurity in a single transformation, which involves a cascade enamine–imine formation/intramolecular Mannich reaction sequence.     

Cover Picture: Organocatalytic Domino Michael–Knoevenagel Condensation Reaction for the Synthesis of Optically Active 3‐Diethoxyphosphoryl‐2‐oxocyclohex‐3‐enecarboxylates (Chem. Eur. J. 13/2009)

In Buddhist imagery the gestures of the hand are very significant, which reflects the themes of asymmetry and chirality (derived from the word “hand”) found in the Full Paper by K. A. Jørgensen et al. on page 3093 ff. The professor is shown as a Buddha‐like image and is gesturing down with one hand and making the Buddhist gesture for “method and wisdom” with the other. Dice tumbling from his hand represent the organocatalytic Michael–Knoevenagel condensation domino reaction discussed in the paper, with the front die representing the cyclohexenone center of the molecule being formed. The two students standing by are making Buddhist gestures for “accomplishment” and “meditation”. Artwork by cartoonist Jorge Cham, http://www.phdcomics.com.

     

Organocatalytic Asymmetric Cascade Reactions of 7‐Vinylindoles: Diastereo‐ and Enantioselective Synthesis of C7‐Functionalized Indoles

The first catalytic asymmetric cascade reaction of 7‐vinylindoles has been established by the rational design of such substrates. Cascade reactions with isatin‐derived 3‐indolylmethanols in the presence of a chiral phosphoric acid derivative allow the diastereo‐ and enantioselective synthesis of C7‐functionalized indoles as well as the construction of cyclopenta[b]indole and spirooxindole frameworks (all >95:5 d.r., 94–>99 % ee). This approach not only addresses the great challenge of the catalytic asymmetric synthesis of C7‐functionalized indoles, but also provides an efficient method for constructing biologically important cyclopenta[b]indole and spirooxindole scaffolds with excellent optical purity. Investigation of the reaction pathway and activation mode has suggested that this cascade reaction proceeds through a vinylogous Michael addition/Friedel–Crafts process, in which dual H‐bonding activation of the two reactants plays a crucial role.     

An Organocatalytic Mannich/Denitration Reaction for the Asymmetric Synthesis of 3‐Ethylacetate‐Substitued 3‐Amino‐2‐Oxindoles: Formal Synthesis of AG‐041R

The highly enantioselective organocatalytic addition of ethyl nitroacetate to isatin‐derived N‐Boc ketimines (Boc=tert‐butoxycarbonyl), followed by the removal of the nitro group, is described. The scalable reaction sequence leads to the title compounds as important intermediates of pyrroloindoline alkaloids and related drugs in excellent yields and enantioselectivities. The synthesis of the hexahydrofurano[2,3‐b]indole skeleton, the spirocarbamate oxindole unit, and the formal synthesis of AG‐041R have been carried out to demonstrate the synthetic utility of this protocol.     

One‐Pot Organocatalytic Enantioselective Michael/Povarov Domino Strategy for the Construction of Spirooctahydroacridine‐3,3′‐oxindole Scaffolds

An asymmetric organocatalytic one‐pot strategy for the construction of spirooctahydroacridine‐3,3′‐oxindole scaffolds has been successfully developed by means of a domino Michael/Povarov reaction sequence. The one‐pot protocol affords the chiral spirocyclohexaneoxindoles bearing an octahydroacridine motif with five stereocenters in good to high yields (up to 89 % yield) with excellent to perfect diastereoselectivities (up to >20:1 d.r.) and enantioselectivities (up to >99 % ee). This highly efficient one‐pot domino procedure will allow diversity‐oriented syntheses of this intriguing class of compounds with potential biological activities.