DMAP-based nucleophilic catalysts

Oxygen-based nucleophiles can also be employed for the catalysis of acyl transfer. For example, pyridine-A-oxide derivatives such as 4-DMAP-A-oxide have long been known as such catalysts although, interestingly, these catalophores are reportedly particularly efficient at mediating sulfonyl and phosphoryl transfer [229-230]. 

The key intermediate chloromethyloxadiazole 18 was prepared in two steps from inexpensive, commercially available materials as shown in Scheme 5.10. Bishydrazide 19 was prepared in a one-pot procedure by reaction of 35% aqueous hydrazine with ethyl trifluoroacetate in acetonitrile and subsequent addition of chloroacetyl chloride and base. This procedure affords the unsymmetrical bis(hydrazide) 19 in higher than 95% assay yield. While a number of dehydrating agents were found to be effective in the dehydration to prepare 18, phosphorus oxychloride was chosen because of its low cost and relatively benign waste stream. Sub-stoichiometric (0.3 equiv.) amounts were found to be as effective as full equivalents in the reachon when used in conjunction with catalyhc amounts of DMAP as a nucleophilic catalyst. The entire sequence was transformed into a one-pot through process in order to improve efficiency. Following the cyclization, an aqueous work-up was performed and the organic extracts carried directly into the next step. 

This process relies on rapid base-induced racemization of the azlactone and rate-limiting ring opening by the alcohol nucleophile. In this process the DMAP derivative 79a acts as both Bronsted-basic and as nucleophilic catalyst. With 2-propanol as reagent enantiomeric excesses up to 78% were achieved for the product amino acid esters [87]. 

This is how the N-Boc pyrrole was made for use in the synthesis of epibatidine. The base used was the pyridine derivative DMAP, which you met earlier in the chapter. It has a p Tan of 9.7 and so produces small, equilibrating amounts of the anion as well as acting as a nucleophilic catalyst. Boc anhydride is used as the acylating agent. 

On this topic, several outstanding contributions were reported by Fu and coworkers,in which new asymmetric nucleophilic catalysts based on chiral ferrocene-type heterocycles were designed. To this end the planar-chiral PPY ferrocene complex (PPY = 4-(pyrrolidino)-pyridine (3.61) was prepared and resolved. Complex 3.61 catalysed the enantioselective rearrangement of A-acylated Azlactones to give C-acylated isomers with high yields and ee of 82-90%. The powerful effect of the chiral ferrocene scaffold was clearly evident if compared to the same reaction with the organic catalyst DMAP reported in 1970 by Steglich and Hofle where only racemic compounds were formed (Scheme 3.26). 

In designing an organic catalyst for the ROP of cyclic esters, we turned towards the likely active nucleophilic species of biocatalysis. Lewis bases including tertiary amines and phosphines, pyridines and imidazoles have been shown to be effective nucleophilic catalysts accelerating a wide variety of processes. For example, 4-(dimethylamino)pyridine (DMAP) and related... 

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... 

Acylation catalysts, typically nucleophilic amines and imines that activate caiboxylates by forming highly nucleophile-susceptible acyliminium intermediates, promote a wide variety of synthetically useful caiboxylate transformations. Many are sufiSciently water-soluble to evaluate as anhydride hydrolysis catalysts. Scheme 1 depicts a representative example of this class of reaction, the hydrolysis of a P(NB/MA) polymer matrix in aqueous base (TMAH) catalyzed by 4-(dimethylamino)pyridine (DMAP). 

Recently, a dual organocatalysis approach, namely, the combination of the achiral nucleophilic Lewis base catalyst DMAP (23) and the chiral anion-binding thiourea catalyst 27, was applied to the Steglich rearrangement to provide a,a-disubstituted amino acid derivatives 24 in a highly enantioselective fashion (Scheme 43.5) [14]. Notably, replacement of the nucleophilic codiamino acid derivatives with excellent enantiomeric excesses (88-93% ee). 

Seitzberg, J.G., Dissing, C., Sotofte, L, Norrby, P.-O., and Johannsen, M. (2005) Design and synthesis of a new type of ferrocene-based planar chiral DMAP analogues. A new catalyst system for asymmetric nucleophilic catalysis. J. Org. Chem., 70, 8332-8337. 

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