Claisen iterative

Nature gives us some illustrative examples of iterative methodologies in its biochemical mechanisms. The fatty acid-polyketide biosynthesis is one of them. The assembly of acyl units by sequential Claisen-type condensations to form a polyketide or fatty acid takes place at a multi-enzyme complex, at which the initial molecule is lengthened by one C2-unit per pass of a reaction cycle (Fig. 2). 

Reduction of aldehyde (72) to its alcohol (74 Scheme 6) followed by rearrangement with acetal (68) at 110 C affords a 1 1 mixture (30% yield) of the initial Claisen rearrangement product (76) and the tandem Cope-Claisen product (75) that is formed from (76). These conditions illustrate the ease with which the Cope rearrangement can occur when a carbonyl function is present as a substituent. Once again, elevated temperature is required for the unsubstituted Cope transformation, (75) to (77). These operations provide another example of the iterative introduction of ( )-isoprene units into a growing chain. 

Vitamin E (a-tocopherol, 168) bears two secondary methyl groups at the stereogenic centers in its side chain. An ingenious solution to the synthesis of this chain has been realized employing iterative Claisen... 

A similar rearrangement was used in a stereoselective synthesis of (if, )-3,7-dimethyT2,6-deca-diene-l,10-diol (pheromone of the queen butterfly) in six steps from gcraniol (Table 3, entry 16)310. Use of 2-methoxy-l,3-butadienes and related compounds (e.g., unsaturated acetals311) allows an iterative Claisen rearrangement by reduction of the resulting enone28,309. 

An iterative in situ transvinylation-Claisen rearrangement was employed for the synthesis of the Cl8 Cecropia juvenile hormone (Jll). In this case, the stereoselectivity of the first-step rearrangement is unexpectedly low [(EjZ) 87 13]. The isomers can be separated by fractional distillation using a spinning band column. The second rearrangement proceeds with 100% E selectivity. 

In addition to introducing remote, oxygen-bearing acyclic stereocenters, the iterative Claisen rearrangement provides the ability to differentiate individual hydroxy groups, as demonstrated by the synthesis of ( )-16, a pheromone of the pine sawfly494. 

Many other reaction sequences which are referred to as tandem rearrangements are already described in several sections before, c.g.. tandem Claisen rearrangement/aldol reactions, cyclopropanation/Cope rearrangements, etc. Iterative as well as sequential rearrangements have also been discussed. 

The diastereomeric alcohol mixture resulting from reduction of 25 on iterative Claisen-Cope rearrangement affords a 80 20 mixture of E unsaturated aldehyde 27, torreyal, and its (Z)-stereoisomer. Reduction of the aldehyde group of the mixture provides dendrosalin (28)1158. 

The repetitive Claisen Cope rearrangement can be used as a strategy for the iterative introduction of ( )-isoprene units into a growing chain. Thus, reduction of intermediate aldehyde 44 (see above) to the corresponding alcohol 46 and treatment with acetal 40 affords a 1 1 mixture of the Claisen product 47 and Claisen-Cope product 48 in 30% yield. The tandem Claisen-Cope-Cope product 49 is obtained by heating 48 in decalin to 190°C. 

Kallmerten et al. used iterative glycolate Claisen rearrangements to establish the three stereocenters in pine sawfly pheromone (Scheme 4.126) [120]. An initial Ire-land-Claisen reanangement of the Z-allylic alkene afforded the anti pentenoic... 

An iterative Claisen rearrangement starting from allylic ester 38 was used in the synthesis of the tocopherol side chain 42 and pine sawfly pheromones (Scheme 5.2.12) [24]. Ireland-Claisen rearrangement of (Z)-allylic ester 38 and in situ reduction of the silyl ester afforded alcohol 39 as a single product Completion... 

The EF-ring of ciguatoxin 3C has been stereoselectively synthesized by iterative use of a cyclic ether formation process based on chirality-transferring Ireland-Claisen rearrangement and ring-closing alkene metathesis (Scheme 21). ... 

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