Tandem reactions functionalized chains

In principle, bifunctional aldehydes should be able to engage in twofold enzymatic aldol additions to both of their acceptor carbonyls in a fashion to be classified as a tandem reaction, that is, without the need for isolation of intermediates. Depending on the specificity of the enzyme used and on the functionalization in the starting material, the isomeric constitution as well as the absolute and relative stereochemistry should be deliberately addressable. Therefore, we engaged in a program to evaluate the scope and the Hmitations of such two-directional chain elongation processes for the construction of extended poly functional molecules [36]. 

In this reaction chain, ZAP kinase performs an essential function. Tlie phosphorylated ARAM motives recruit ZAP70 kinase to the T cell receptor complex and mediate high affinity binding to the kinase. The two SH2 domains of ZAP70 kinase bind in tandem fashion to the twice-phosphorylated ARAM motif ZAP70 kinase shows a complex pattern of Tyr phosphorylation, including phosphorylations with an inhibitory effect. 

The three-component method is applicable to the synthesis of various C(6)- or C(7)-functionalized PGs. Scheme 11 illustrates the tandem conjugate addition-aldol reaction that affords 7-hydroxy-PGE derivatives (18). Both saturated and unsaturated C7 aldehydes can be used as a side-chain units. The aldol adducts can be transformed to naturally occurring PGs (5a, 19) and, more importantly, to a variety of analogues such as tumor-suppressing A7-PGA, (20) or 7-fluoro-PGI2, a stabilized prostacyclin (21). The unique cellular behavior displayed by A7-PGA methyl ester is well correlated to its chemical reaction with thiols (20). 

A synthesis of the Inhoffen-Lythgoe diol (46.7, Scheme 2.46), a useful intermediate in the synthesis of Vitamin D derivatives, demonstrates the use of a chiral acetal in an asymmetric tandem cyclisation reaction.102 Once again, Lewis acid co-ordination to the less hindered oxygen of the acetal 46.1 initiated a Prins-like cyclisation that terminated by attack of the propargylsilane on an incipient tertiary carbocation. After removal of the chiral auxiliary, the allene function in the alcohol 46.4 was transformed into the side chain of 46.7 with the creation of two new stereogenic centres. 

A modification called tandem [2,3] sigmatropic rearrangement of sulfonium ylide—bromine allylic rearrangement has been reported (88JOC5149). Thus, reaction of the C5 brominated 2-pyrone 224 with ethyl diazoacetate under rhodium catalysis results not only in transfer of the ester moiety to C5, as described earlier, but also in the transfer of the bromine atom from C5 to the side chain at C6 in such a way that the functional group remaining at that side chain, as in 225, can be further elaborated (89JHC1205). 

One of the most important cascade sequences by rhodium catalysis is the tandem RCM/cross-metathesis (CM) sequence, which includes two metathesis processes. The first process builds up the cyclic framework via an RCM process and then functionalizes the lateral chain of the intermediate vinyl intermediate 5, thanks to a subsequent CCM reaction with a conveniently chosen alkene. 

The easy detection of the end of the a-aminoxylation reaction catalyzed by (S)-prolrne (21) has allowed the in situ transformation of compounds 97 into interesting chiral functionalized compounds through the use of tandem one-potprocesses [118]. This synthetic strategy has been applied to the formal synthesis of HRV 3C-protease inhibitor (lR,2S)-thysanone [119], the synthesis of the atorvastatin side chain (a building block present in the statin family that acted as cholesterol regulator) [120], and the synthesis of the lactone moiety of compactin and mevinoUn [121]. 

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