Enolates zwitterionic

Lewis-Base Catalysis via Intermediate Formation of a Chiral Zwitterionic Enolate... 

In an alternative mode of catalyst action, a disubstituted ketene 66 initially suffers a nucleophilic attack of 64, leading to zwitterionic enolate 71 (Fig. 38). 

The Staudinger reaction [92], a [2 + 2]-cycloaddition of a ketene and a nucleophilic imine, usually proceeds by an initial imine attack on the ketene thus forming a zwitterionic enolate which subsequently cyclizes. This reaction is an expedient route to p-lactams, the core of numerous antibiotics (e.g., penicillins) and other biologically active molecules [93]. In contrast, for Lewis-base catalyzed asymmetric reactions, nonnucleophilic imines are required (to suppress a noncatalyzed background reaction), bearing, for example, an N-Ts [94] or -Boc-substituent [95]. 

In the first step, catalyst 64c attacks ketene 66 to form a zwitterionic enolate 71, followed by Mannich-type reaction with imine 76 (Fig. 40). A subsequent intramolecular acylation expels the catalyst under formation of the four-membered ring. Utilizing 10 mol% of 64c, N-Ts substituted (3-lactams 77 were prepared from symmetrically as well as unsymmetrically substituted ketenes 66, mainly, but not exclusively, with nonenolizable imines 76 as reaction partners [96]. Diastereos-electivities ranged from 8 1 to 15 1, yields from 76 to 97%, and enantioselectivities from 81 to 94% ee in the case of aliphatic ketenes 66 or 89 to 98% ee for ketenes bearing an aromatic substituent. Applying complexes 65 or the more bulky and less electron-rich 64b, ee values below 5% were obtained. 

A methodology for the catalytic asymmetric synthesis of [3-lactams has also been reported, resulting from the development of a catalyzed reaction of ketenes (or their derived zwitterionic enolates) and imines [76]. Despite the fact that simple tertiary... 

Molecular mechanics calculations also led to an explanation of the diastereose-lective course of the reaction. Several assemblies of the imino ester, 44, and the zwitterionic enolate were investigated [52]. In accordance with the experimental results it was found that the assembly leading to the cis diastereomer was of lowest energy. Because the lowest-energy trans assembly is several kilocalories higher, or-ganocatalytic / -lactam formation proceeds with an excellent cis diastereoselectivity. 

Enantioselective synthesis of /3-lactams from enolate and imine components uses a bifunctional Lewis acid/nucleophile strategy.76 A chiral nucleophile is used to form a zwitterionic enolate, and a metal ion coordinates the imine. The postulated mechanism is supported by kinetic, spectroscopic, and molecular modelling evidence. 

Methylimidazole 3-A-oxide (49) catalyses the Morita-Baylis-Hillman reaction at room temperature under solvent-free conditions addition to the enone reactant to give a zwitterionic enolate (50) is proposed, followed by reaction with aldehyde.177... 

Historically, the most effective N-based organic catalysts were nucleophilic unhindered tertiary amines such as DABCO (diazabicyclo[2.2.2]octane, 1) [23], qui-nuclidine (2), 3-hydroxy quinuclidine (3-HDQ, 3), 3-quinuclidone (4) and indoli-zine (5) (Fig. 5.1) [24]. A direct correlation has been found between pKa and the activity of the quinuclidine-based catalysts the higher the pKa, the faster the rate [25]. More recently, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 6), considered as a hindered and non-nucleophilic base, was shown to be a better catalyst than DABCO, or 3-HDQ [26]. The reason for the increased reactivity for this catalyst was attributed to stabilization of the zwitterionic enolate by delocalization of the positive charge. Other N-based catalysts such as N,N-(dimethylamino)pyridine... 

Whilst the elementary steps of the reaction were postulated in the earliest publications [3], and remain (globally) even today as the core of the mechanistic discussion, the fine details of the reaction - and in particular those controlling the asymmetric induction - have been highlighted only recently. The first critical mechanism [15a, 45, 46], which is based on pressure-dependence data, established a reversible Michael addition of the nucleophilic base to the activated al-kene (Scheme 5.3). In the following step, the formed zwitterionic enolate 11 adds to the electrophile and forms a second zwitterionic adduct 13. This step was considered to be the rate-determining step (RDS) of the reaction. Subsequent proton transfer and release of the catalyst provides finally the desired product 14. 

The currently accepted mechanism of the Baylis-Hillman reaction involves a Michael addition of the catalyst (tertiary amine) at the (3-position of the activated alkene to form a zwitterionic enolate. This enolate reacts with the aldehyde to give another zwitterion that is deprotonated, and the catalyst is released. Proton transfer affords the final product. 

As a logical extension of the discrete bifunctional catalytic systems described above, Lectka et al. developed the homogeneous salicylate indium complex 22, containing the chiral nucleophile (alkaloid) and the Lewis acid (In(OTf)3) in a single unit, which exhibited excellent catalytic activity and stereoselectivity (90% yield, 99% ee, and 10 1 diastereomeric ratio (dr)) (Scheme 4.20) [47, 48]. Mechanistic studies revealed that the chiral nucleophiles form zwitterionic enolates that react with the metal-coordinated imines to form a ternary complex 23 in which C—C bond formation occurs. 

In contrast to a-fluorination, direct a-chlorination and a-bromination were developed on the basis of ketene intermediate mechanism in the presence of O-benzoylquinine (122) by Lectka and coworkers in 2001 (Scheme 6.36) [64, 65], Ketenes derived from acid chlorides 120 with either BEMP resin or proton sponge are added to 122 to form zwitterionic enolates, which are a-halogenated by perha-loquinones 123, 124. Finally, O-benzoylquinine moiety is substituted by haloaro-matic phenolate anions, generated from 123 or 124, to afford chiral a-halocarbonyl products 121 up to 99% ee. 

As illustrated in Scheme 10.1, a tertiary amine base would react with the in situ generated ketenes to afford zwitterionic enolates. Then these intermediates would react with electrophilic o-quinones to deliver lactone adducts after the release of the tertiary amine catalyst [8]. 

The same class of [2 - - 2] cycloaddition reactions between ketenes and aldehydes has been the subject of subsequent studies, which have enlarged its scope to different substrates. Thus, key contributions by Lectka and coworkers have demonstrated the applicability of zwitterionic enolates from... 

Use of different bases allowed for in situ formation of the zwitterionic enolate species via a shuttle-deprotonation and circumvented the need for the ketene... 

The emergence of catalytic asymmetric methods to effect the Staudinger reaction appears to have largely displaced further efforts to identify new methodology based on the use of chiral auxiliaries. These methods rely on the nucleophilic activation of the ketene to form a zwitterionic enolate, which then undergoes nucleophilic addition to the imine, followed by cyclization. While the assembly of enantiodifferentiated transition states using Lewis acid catalysis has been well developed, the use of Lewis base catalysts to accomplish the same purpose is a relatively recent development and well suited to the Staudinger reaction. 

The mechanistic rationale put forth for product formation involved ketene attack on the amine moiety followed by an amino Claisen rearrangement of the zwitterionic enolate. An analogous reaction is observed with methyl propiolate and fused azabicyclic systems [14]. 

It is well known that a zwitterionic enolate intermediate can be generated via the addition of a Lewis base to ketenes, which can be oxidized by an appropriate oxaziridine to form the corresponding imine and zwitterionic epoxide. The obtained zwitterionic epoxide intermediate is expected to add to the in situ generated imine to furnish the final products. Based on this finding. Ye reported a novel enantioselective formal [3 + 2] cycloaddition of ketene 40 to racemic oxaziridine 41 for the synthesis of oxazolin-4-one. By using NHC 43 or 44 as the Lewis base catalyst [23], the product 42 could be obtained in good yield with high diastereo and enantioselectivity (Scheme 2.12). 

To address the limitation of the -lactam synthesis with regard to the often moderate chemical yield (typically 40-60%), Lectka and coworkers developed a pioneering tandem Lewis base/Lewis acid approach [11]. In this improved methodology the In(III) Lewis acid activates the imine providing (3-lactams in typically >90% yield. An exhaustive mechanistic investigation was undertaken and allowed the authors to propose the following cycle (Figure 3.2). In(III) complexed Lewis base BQ 11 adds to the ketene 7 to form a non-metal-coordinated zwitterionic enolate 12. Coordination of the imine 2 to the complexed In(III) forms ternary... 

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