Drug synthesis stereoselective reactions

This chapter has introduced the aldol and related allylation reactions of carbonyl compounds, the allylation of imine compounds, and Mannich-type reactions. Double asymmetric synthesis creates two chiral centers in one step and is regarded as one of the most efficient synthetic strategies in organic synthesis. The aldol and related reactions discussed in this chapter are very important reactions in organic synthesis because the reaction products constitute the backbone of many important antibiotics, anticancer drugs, and other bioactive molecules. Indeed, study of the aldol reaction is still actively pursued in order to improve reaction conditions, enhance stereoselectivity, and widen the scope of applicability of this type of reaction. 

Nonorganic and organometallic catalysts are also used to channel the reactions toward the chiral synthesis pathway. The drug called levodopa, (5)-3,4-dihydroxyalanine, is an effective drug against Parkinson s disease. It is stereoselectively manufactured using catalysts such as rhodium or ruthenium complexes. 

Recently, another interesting application of nitrilases has been demonstrated for the synthesis of pregabalin-the API of the neurophatic pain drug Lyrica. In this approach, the key step is the resolution of racemic isobutylsuccinonitrile (Scheme 10.8) [18], the process takes place with total regio- and stereoselectivity, and the (S)-acid is obtained and the (R)-substrate can be recycled under basic conditions. To improve the biocatalytic step, directed evolution was applied using the electronic polymerase chain reaction and in the first round of evolution a single C236S mutation led to a mutant with 3-fold increase in activity [19]. 

The synthesis of an antifungal drug was completed by tl palladium-catalysed reaction. Give a mechanism and explain t regio- and stereoselectivity. 

In this case, the achiral reagents reacting via an achiral (or racemic) intermediate in an achiral solvent should produce racemic product. Over 40 years ago, this is all we could expect of such a reaction in terms of stereoselectivity. If the purpose of the transformation was to obtain one or the other enantiomer, then special and often tedious methods were required to resolve the racemic product. Today, the goal of synthesis chemists often is to produce molecules that are not only chiral, but also enantiomerically pure. Biologically active molecules typically exist in only one enantiomeric form. Efficacious drugs are also often most effective if they exist as only one enantiomer in order to interact properly with a chiral active site. A racemic drug is a mixture of enantiomers, only 50% of which is usually efficacious. The other 50% is at best worthless and at worst toxic, sometimes severely so.2... 

Hydroxylation of sodium and potassium enolates side reaction with lithium Substrate controlled stereoselectivity asymmetric hydroxylation Asymmetric hydroxylation with camphor sultam derivatives Asymmetric synthesis of tetracycline precursors Synthesis of a calcium channel opening drug Asymmetric synthesis ofbuproprion Summary... 

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