Intermolecular nucleophilic acyl substitution

Intermolecular nucleophilic acyl substitution is a fundamental carbon—carbon bondforming reaction. In spite of its high synthetic potential, however, its intramolecular version, that is, intramolecular nucleophilic acyl substitution (INAS) is rather rare because of the intrinsic difficulties involved in carrying it out. One difficulty associated with the INAS reaction is that a reactive nucleophilic species must be generated in the presence of carbonyl functionality, and at the same time this nucleophile is expected to react only with... 

Carbonates of y-vinyl alcohols such as 87 undergo the intermolecular nucleophilic acyl substitution reaction to afford the corresponding alkyltitanium complex 88 having a lactone moiety (Scheme 12.59). The titanium-carbon bond in the... 

An interesting intermolecular version of this reaction has likewise been put forward for the preparation of seven-, eight-, and nine-mem-bered carbocycle, as illustrated with a sole example in Scheme 3 [7]. In contrast to the above, these reactions begin with a carbonyl addition reaction of chloroiodoalkanes to cyclic or acyclic keto esters leading to the formation of an intermediate lactone. An intramolecular nucleophilic acyl substitution then terminates the sequence. The example in Scheme 3 represents a simple method for the construction of the 5 8 5 tricyclic ring system. 

Intermolecular ketyl alkene coupling reactions have been incorporated into a cascade that ultimately affords medium sized rings [58]. Specifically, chloroalkyl ketones react with acrylates, whereupon chloroalkyl lactones are formed in situ. Photolysis of these intermediates in the presence of excess Sml2 initiates an intramolecular nucleophilic acyl substitution reaction between the halide and the lactone, creating the medium-sized ring (Eq. 50). 

The mechanism of the intramolecular Claisen cyclization, sho-wn in Figure 17.13, is the same as that of the intermolecular Claisen condensation. One of the two ester groups is converted into an enolate ion, which then carries out a nucleophilic acyl substitution on the second ester group at the other end of the molecule. A cyclic 8-keto ester product results. 

Fig. 2.19 Effective methods to generate all-carbon substituted quaternary stereocenters (a) Diels-Alder assembly of a complicated building block for the synthesis of (-tj-aspidospermidine (b) intermolecular C-acylation using a planar nucleophilic ferrocene type catalyst.

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