Claudio Palomo

Current progress in the asymmetric aldol addition reaction

Control of stereochemistry during aldol addition reactions has attracted considerable interest over the years as the aldol reaction is one of the most fundamental tools for the construction of new carbon-carbon bonds. Several strategies have been implemented whereby eventually any single possible stereoisomeric aldol product can be accessed by choosing the appropriate procedure. With earlier methods, stoichiometric quantities of chiral reagents were required for efficient asymmetric induction, with the auxiliary most often attached covalently to the substrate carbonyl. Lewis acid catalyzed addition reactions of silyl enolates to aldehydes (Mukaiyama reaction) later opened the way for catalytic asymmetric induction. In the last few years, both chiral metal complexes and small chiral organic molecules have been found to catalyse the direct aldol addition of unmodified ketones to aldehydes with relatively high chemical and stereochemical efficiency. These techniques along with the more recent developments in the area are discussed in this tutorial review.

α,α-Diarylprolinol Ethers: New Tools for Functionalization of Carbonyl Compounds

Alpha,alpha-diaryl(dialkyl)prolinol ethers constitute a potent organocatalyst family which has been shown to be very general for a broad range of reactions involving enamine and iminium ion activation or a combination of both. The reactions are characterized by an efficient steric control approach and can lead to a variety of alpha-, beta-, gamma-, and alpha,beta-functionalized carbonyl compounds with excellent stereocontrol. As a full expression of their catalytic activity, these compounds are also excellent promoters of elegant cascade processes and valuable catalysts in water-compatible systems.

Asymmetric Synthesis of β-Lactams by Staudinger Ketene-Imine Cycloaddition Reaction

[2 + 2] Cycloaddition reactions between ketenes, bearing amino-, oxy-, or halo- groups, and imines are recognized as being amongst the most important and direct routes to β-lactams. Alkyl-substituted ketenes also furnished the corresponding β-lactams upon reaction with activated imines (iminoesters). In general, ketenes are generated from the appropriate acid chloride and a tertiary amine. The major or sole product of the cycloaddition is usually the cis-β-lactam, although a few exceptions showing trans selectivity are known. In this way β-lactams with a widely varying substitution pattern at the C-3 and C-4 positions of the ring are constructed stereoselectively. The diastereoselection of the cycloaddition process can be controlled with variable success from chiral groups attached to either the ketene or the imine component, or alternatively to both. This method, in turn, has proved to be valuable for the synthesis of precursors of important β-lactam antibiotics, and new successful applications can be expected in the near future.

The aldol addition reaction: An old transformation at constant rebirth

The main recent conceptual advances in asymmetric aldol reactions are presented. Methods ranging from stoichiometric chiral auxiliary-mediated to direct, catalytic reactions are covered, including the Mukaiyama aldol reactions which use stoichiometric base and silylating reagents, but catalytic (substoichiometric) amounts of the chiral inductor. The salient features of each new development are noted, paying special attention to practical concerns and to the potential implementation for large scale production. After examination of pros and cons of each strategy, gaps and limitations that deserve further investigation are highlighted.

Phosphazene bases for the preparation of biaryl thioethers from aryl iodides and arenethiols

In the presence of phosphazene P2-Et base as well as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) the coupling of aryl iodides with arenethiols only requires catalytic amounts of CuBr. Under these conditions the reaction can be performed in refluxing toluene to give biaryl thioethers in excellent yields.

Asymmetric aza-Henry reaction under phase transfer catalysis: an experimental and theoretical study.

An efficient catalytic asymmetric aza-Henry reaction under phase transfer conditions is presented. The method is based on the reaction of the respective nitroalkane with alpha-amido sulfones effected by CsOH x H2O base in toluene as solvent and in the presence of cinchone-derived ammonium catalysts. This direct aza-Henry reaction presents as interesting features its validity for both nonenolizable and enolizable aldehyde-derived azomethines and the tolerance of nitroalkanes, other than nitromethane, for the production of beta-nitroamines. The synthetic value of the methodology described is demonstrated by providing (a) a direct route for the asymmetric synthesis of differently substituted 1,2-diamines and (b) a new asymmetric synthesis of gamma-amino alpha,beta-unsaturated esters through a catalytic, highly enantioselective formal addition of functionalized alkenyl groups to azomethines. Finally, a preferred TS that nicely fits the observed enantioselectivity has been identified. Most remarkable, an unusual hydrogen bond pattern for the catalyst-nitrocompound-imine complex is predicted, where the catalyst OH group interacts with the NO2 group of the nitrocompound.

Highly stereoselective synthesis of α-hydroxy β-amino acids through β-lactams: application to the synthesis of the taxol and bestatin side chains and related systems.

Abstract Formation of α-hydroxy β-lactams, followed chemical elaboration at C 4 and further βlactam cleavage afforded functionalised α-hydroxy β-amino acids or their derivatives in a highly stereoselective manner.

1,8-diazabicyclo[5.4.0]undec-7-ene (dbu): An effective base for the introduction of tbutyldimethylsilyl group in organic compounds.☆

Abstract Reaction of alcohols, thiols, amines, carboxylic acids, phenols, hydroquinones, ketoesters and amides with equimolecular amounts of t-butyldimethylchlorosilane and DBU, even in solvents other than dimethylformamide affords the corresponding t-butyldimethylsilyl derivatives in high yield.

N,N-Dimethylchlorosulfitemethaniminium chloride (SOCl2-DMF) a versatile dehydrating reagent.☆

Abstract N,N-dimethylchlorosulfitemethaniminium chloride formed from thionyl chloride and dimethylformamide was found and efficient reagent for the synthesis of acyl azides from carboxylic acids and nitriles from oximes. It is also highly efficient for the direct synthesis of beta-lactams from carboxylic acids and imines avoiding the use of acid chlorides.

Highly Enantioselective Conjugate Additions of Aldehydes to Vinyl Sulfones

Joined together, organocatalysts aldehydes and sulfones: A diaryl prolinol silyl ether was found to catalyse efficiently and enantioselectively the conjugate addition of aldehydes to vinyl sulfones (see scheme). The ample synthetic utility of the resulting adducts is illustrated.