Chiral tertiary amine-based nucleophilic catalysts

SCHEME 6.32 General overview about the possible applications of chiral tertiary amine-based nucleophilic catalysts. 

In many examples of Brpnsted base catalysis, the combination of a chiral tertiary amine and a hydrogen-bonding donor, such as a urea or thiourea moiety, significantly enhances the selectivity of the formation of carbon-carbon bonds. Catalysts possessing this combination of functional groups have proven useful due to their ability to simultaneously stabilize and activate both electrophilic and nucleophilic components. 

Chiral base catalysis is one of the most versatile and broadly applicable types of catalysis. In particular, the potential of tertiary amines to act both as a base and as a nucleophilic catalyst makes chiral tertiary amines like Cinchona alkaloids a privileged catalyst structure in modem synthesis chemistry. In addition, the field of achiral phosphine and carbene catalysis has proven its potential in numerous applications in the past and it is probably only a matter of time until chiral phosphines and carbenes will also be used routinely for other presently demanding natural product total synthesis (Table 7). 

The first catalytic asymmetric Staudinger reaction to be described used chiral tertiary amines 14 and 15 derived from the Cinchona alkaloids as the nucleophile to activate the ketene via zwitterion formation. The ketene was conveniently generated in situ from the acid chloride. Because the HCl generated in the elimination would consume the chiral tertiary amine catalyst, a nonnucleophilic strong base (e.g.. Proton Sponge) was included to remove the HCl formed. Yields of -lactams were on the order of 60% in 99% ee. 

Besides their use as Brpnsted bases, chiral tertiary amines have very successfully been used as asymmetric nucleophilic catalysts. Their catalytic potential has been known for decades, and systematic investigations have led to the development of a variety of powerful (a)chiral methodologies [88, 92]. Some of the most prominent applications involve the in situ generation of chiral ammonium enolates, which can then be employed for an impressively diverse variety of reactions as illustrated in Scheme 6.32 (for a detailed overview of this rather broad application field of chiral tertiary amines, please see more focused reviews and the literature cited therein [92]). Besides the good... 

Asymmetric organocatalytic Morita-Baylis-Hillman reactions offer synthetically viable alternatives to metal-complex-mediated reactions. The reaction is best mediated with a combination of nucleophilic tertiary amine/phosphine catalysts, and mild Bronsted acid co-catalysts usually, bifunctional chiral catalysts having both nucleophilic Lewis base and Bronsted acid site were seen to be the most efficient. Although many important factors governing the reactions were identified, our present understanding of the basic factors, and the control of reactivity and selectivity remains incomplete. Whilst substrate dependency is still considered to be an important issue, an increasing number of transformations are reaching the standards of current asymmetric reactions. 

In general, most chiral Br0nsted base catalysts are equipped with an additional hydrogen bond donor (Brpnsted acid), which activates the electrophile. Moreover, coordination of both the nucleophile and electrophile to the rigid chiral backbone of the bifunctional catalyst via hydrogen bonding and a basic tertiary amine anchors the electrophile and nucleophile in an optimal transition state, which seems essential for the highly stereoselective and predictable formation of a... 

In the preceding examples, the asymmetric catalyst is a Lewis acid and hence the catalytic processes reported so far involve electrophilic activation by a metal-centred chiral Lewis acid. There is another strategy, although less explored, which consists of designing chiral Lewis bases for nucleophilic catalysis. It is well known that Lewis bases such as nitrogen heterocycles and tertiary phosphines and amines catalyse a variety of important chemical processes. For instance 4-(dimethylamino)pyridine (DMAP) catalyses the acylation of alcohols by anhydrides the mechanism by which DMAP accelerates this process provides an instmctive illustration of how nucleophiles can... 

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