Mikel Oiarbide

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.

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 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.

Fromβ-lactams toα- andβ-amino acid derived peptides

SummaryThe potential ofβ-lactams as intermediates for the access toα- andβ-amino acid-derived peptides is shortly reviewed, with major focus on the technologies developed in our group. The two general strategies lie, on one side, in the oxidative ring expansion of 3-hydroxyβ-lactams toN-carboxyα-amino acid anhydrides or Leuchs anhydrides and subsequent coupling withα-amino acid esters and, on the other side, in the nucleophilic ring opening ofN-Boc-β-lactams. Both approaches have been successfully applied to the synthesis ofα,β-diamino acid,α-amino-β-hydroxy acid, polyhydroxylatedα-amino acid,α,α-disubstitutedα-amino acid,β-amino acid,β-amino-α-hydroxy acid andβ,β-disubstitutedβ-amino acid derived peptides. Because of the mild reaction conditions needed for the above transformations and the highly stereoselective procedures employed for the construction of the startingβ-lactam ring, the whole process allows the production of optically pure final products.

Catalytic Conjugate Additions of Geminal Bis(sulfone)s: Expanding the Chemistry of Sulfones as Simple Alkyl Anion Equivalents

The value of cyclic gem-bis(sulfone) 4 as a simple alkyl nucleophile equivalent in catalytic C-C bond-forming reactions is demonstrated. The 1,4-type nucleophilic additions of bis(sulfone) 4 to alpha,beta-unsaturated ketones take place by assistance of catalytic guanidine base. On the other hand, pyrrolidines are able to catalyze the conjugate addition of 4 to both enones and enals, likely by means of iminium ion activation. Upon exploration of the best chiral pyrrolidine catalyst, it has been found that the addition of 4 to enals catalyzed by diphenylprolinol silyl ether 10 proceeds with very high enantioselectivity (beta-aryl-substituted enals >95% ee; beta-alkyl substituted enals up to 94% ee; ee = enantiomeric excess). Further reductive desulfonation of adducts gives rise to the corresponding beta-methyl aldehydes, as well as the derived alcohols, acetals, and methyl esters after simple (Mg, MeOH) well-established protocols. Application of the procedure to the synthesis of biologically relevant phenethyl building blocks is shown. Most interestingly, alpha-alkylation of initially obtained bis(sulfone) adducts can be done even with less reactive alkylating reagents, such as long linear-chain or branched-chain alkyl halides. Accordingly, upon the desulfonation process, a general, experimentally simple and highly enantioselective access to beta-branched aldehydes, alcohols, or esters is possible. Further exploration of the method includes the use of chiral alpha,beta-unsaturated aldehydes derived from citronellal as the Michael acceptor partners. In these instances, the sense of the conjugate addition of 4 is controlled by the chirality of the pyrrolidine catalyst, thus allowing for a stereochemically predictable access to 1,3-dimethyl arrays, such as those present in deoxygenated polyketide-type natural products. The intramolecular variation of this technology by using doubly unsaturated aldehyde-ester 22 illustrated the site selectivity of the procedure and its potential for tandem processes leading to highly substituted polycyclic systems, such as 24.

Catalytic asymmetric α-alkylation of aldehydesvia a SN2′-type addition-elimination pathway

A novel method for the direct, amine-catalyzed, highly enantioselective α-alkylation of aldehydes is described that is founded upon the use of electrondeficient allylic halides as alkylating agents and DABCO or DMAP as coadyuvant. Both experimental observations and DFT calculations, in support of a SN2′-type addition-elimination pathway involving ammonium salt intermediates, are provided.

Design and Evaluation of a Practical Camphor‐Based Methyl Ketone Enolate for Highly Stereoselective “Acetate” Aldol Reactions

A trajectory close to the chiral auxiliary must be followed by the electrophilic aldehyde on attacking the lithium enolate of II. Consequently, unprecedented diastereomeric excesses in the 95–98% range are obtained for the aldol reaction of II with a variety of aldehydes. This is the first methyl ketone-enolate strategy that allows recovery of the chiral controller of the process.