Acyl transfer reactions kinetic resolution

The preparation of stereochemically-enriched compounds by asymmetric acyl transfer using chiral nucleophihc catalysts has received significant attention in recent years [1-8]. One of the most synthetically useful and probably the most studied acyl transfer reaction to date is the kinetic resolution (KR) of ec-alcohols, a class of molecules which are important building blocks for the synthesis of a plethora of natural products, chiral ligands, auxiliaries, catalysts and biologically active compounds. This research area has been in the forefront of the contemporary organocatalysis renaissance [9, 10], and has resulted in a number of attractive and practical KR protocols. 

Kinetic optical resolution of racemic alcohols and carboxylic acids by enzymatic acyl transfer reactions has received enormous attention in recent years56. The enzymes generally employed are commercially available lipases and esterases, preferentially porcine liver esterase (PLE) or porcine pancreatic lipase (PPL). Lipases from microorganisms, such as Candida cylindracea, Rhizopus arrhizus or Chromobacterium viscosum, are also fairly common. A list of suitable enzymes is found in reference 57. Standard procedures are described in reference 58. Some examples of the resolution of racemic alcohols are given39. 

Acyl Transfer Reactions. (6)-A7-benzoyloxazolidinones have been used as acyl transfer reagents to effect the kinetic resolution of racemic alcohols. The bromomagnesium alkoxides formed from phenyl n-alkyl alcohols selectively attack the exocyclic benzoyl moiety to afford recovered auxiliary and the derived (R)-benzoates in >90% ee and >90% yield (eq 47). The scope of this reaction seems to be limited to this class of substrates as selectivity drops with increasing the steric bulk of the alkyl group. 

The reversibility of hydrogen transfer reactions has been exploited for the racemi-zation of alcohols and amines. By coupling the racemization process with an enantioselective enzyme-catalyzed acylation reaction, it has been possible to achieve dynamic kinetic resolution reactions. The combination of lipases or... 

Catalytic kinetic resolution of amines has been a typical domain of enzymatic transformations. Attempts to use low-molecular-weight catalysts have notoriously been frustrated by the rapid uncatalyzed background reaction of the amine substrate with the acyl donor [40]. The first solution to this problem was recently developed by Fu, who used the planar chiral catalyst 21d and O-acyl azlactone 40 as the acyl donor (Scheme 12.19) [41]. In this process, the acyl transfer from the azlactone 40 to the nucleophilic catalyst 21d is rapid relative to both direct transfer to the substrate and to the transfer from the acylated catalyst to the substrate amine. Under these conditions, which implies use of low reaction temperatures, selectivity factors as high as 27 were achieved (Scheme 12.19) [41]. 

The preparation of stereochemically enriched compounds by asymmetric acyl transfer in a stoichiometric sense can be divided into two broad classes [1] (1) those in which a racemic or achiral /weso nucleophile reacts diastereoselectively with an enantiomerically highly enriched acyl donor (Type I, see below) and (2) those in which an enantiomerically highly enriched nucleophile reacts diastereoselectively with a racemic or achiral/meso acyl donor (Type II, see below). When a racemic component is involved, the process constitutes a kinetic resolution (KR) and the maximum theoretical yield of diastereomerically pure product - given perfect diastereoeselectivity - is 50%. When an achiral/meso component is involved, the process can constitute a site-selective asymmetric desymmetrization (ASD) or, in the case of 7r-nucleophiles and reactions involving ketenes, a face-selective addition process and the maximum theoretical yield of diastereomerically pure product - given perfect diastereoselectivity - is 100% (Scheme 8.1). 

This is a kinetic resolution that works by enantioselective acylation of the unwanted enantiomer of the alcohol. The reaction is therefore an ester exchange and vinyl acetate is an efficient acetate transfer agent since the other product is vinyl alcohol better known as the enol of acetaldehyde so the reaction is irreversible. 

The kinetic resolution of primary alcohols (RCH2OH) by enzymatic acylation is often demanding because of the remote position of the asymmetric center firom the reaction site. Moreover, special attention is needed to keep the acyl transfer irreversible and to prevent hydrolysis of the acylated product. 

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