Chiral building block approach

No attempt has been made to cover all drug classes or enzyme classes instead, a flavour of the potential benefits that can be achieved by the adoption of biocatalytic methods as a compliment to chemical approaches is given. Biocatalytic methods of accessing chiral building blocks will only occasionally be discussed here and the reader is referred to a number of comprehensive reviews that have been published elsewhere. 

As seen in Section 1.3.4.1 (synthesis of lotrafiban), the recycling of an unwanted enantiomer resulting from a kinetic resolution allows theoretical yields of up to 100% to be achieved, but it can also create a bottleneck in a production process. DKR, where a starting material undergoes racemization in situ, either spontaneously or through the action of a second catalyst, offers a more efficient approach. This technique has been applied, particularly in academia, to the preparation of a broad range of chiral building blocks, and a number of recent reviews are available. 

In the last decades, cyanohydrins have become versatile chiral building blocks, not only for laboratory synthesis, but also for a range of pharmaceuticals and agrochemicals. Several methods for the enantioselective preparation of these compounds have been published [1, 2]. The most important synthetic approaches are catalysis by oxynitrilases, also termed hydroxynitrile lyases (HNLs), wording used in this chapter, [3] and by transition metal complexes [4], whereas the relevance of cyclic dipeptides as catalysts is decreasing [2]. 

M. T. Reetz, New approaches to the use of amino acids as chiral building blocks in organic synthesis, Angew. Chem. Ini. Ed. Engl. 30 1531 (1991). 

E Santaneillo, P Ferraboschi, P Grisenti, A Manzocchi. The biocatalytic approach to the preparation of enantiomerically pure chiral building blocks. Chem Rev 92 1071-1140, 1992. 

Additionally, the environmental issue of utilizing waste cellulosic material and waste biomass products should be considered as an alternative green chemistry application to the production of many value added products. The combinatorial utilization of carbohydrate scaffolds based on chiral building block functionalization will also constitute attractive and relatively cheap starting materials. This rich selection of potential approaches, combined with further developments of new procedures and modem reagents, creates an enormous opportunity for the field to be at the frontier for many years to come. 

M. T. Reetz, New Approaches to the Use of Amino Acids as Chiral Building Blocks in Organic Synthesis, Angew Chem. Int. Ed. Engl. 1991, 30, 1531-1546. 

In principle, three approaches may be adopted for obtaining an enantio-merically pure compound. These are resolution of a racemic mixture, stereoselective synthesis starting from a chiral building block, and conversion of a prochiral substrate into a chiral product by asymmetric catalysis. The last approach, since it is catalytic, means an amplification of chirality that is, one molecule of a chiral catalyst produces several hundred or a thousand molecules of the chiral product from a starting material that is optically inactive In the past two decades this strategy has proved to be extremely useful for the commercial manufacture of a number of intermediates for biologically active compounds. A few recent examples are given in Table 9.1. 

Since the publication in 1976 of a standard reference book by Jones, Sih and Perlman (2), an increasing number of organic chemists has become involved in studies on the application of biochemical systems in organic chemistry. Their approach is often different from that by biochemists, because organic chemists are much more aware of the general utility of a chiral building block obtainable by a particular biochemical reaction. 

For the enantiopure production of human rhinovirus protease inhibitors scientists from Pfizer developed a kinetic resolution and recycling sequence (Scheme 6.14 A). The undesired enantiomer of the ester is hydrolysed and can be racemised under mild conditions with DBU. This enzymatic kinetic resolution plus racemisation replaced a significantly more expensive chemical approach [52]. An enzymatic kinetic resolution, in combination with an efficient chemically catalysed racemisation, is the basis for a chiral building block for the synthesis of Talsaclidine and Revatropate, neuromodulators acting on cholinergic muscarinic receptors (Scheme 6.14B). In this case a protease was the key to success [53]. Recently a kinetic resolution based on a Burkholderia cepacia lipase-catalysed reaction leading to the fungicide Mefenoxam was described [54]. Immobilisation of the enzyme ensured >20 cycles of use without loss of activity (Scheme 6.14 C). 

The Biocatalytic Approach to the Preparation of Enantiomerically Pure Chiral Building Blocks. Santaniello, E. Ferraboschi, P. Grisenti, P Manzochi, A. Chem. Rev. 1992, 92, 1071. 

The BINAL-H reduction works well with alkenic - and alkynic ketones affording alcohols with satisfactory optical purities (Scheme It is noteworthy that (S)-BINAL-H [(S)-(28)] reduces 1-halo-l-octen-3-one and 2-cyclopentene-l,4-dione to give the corresponding carbinols, which are important chiral building blocks for the synthesis of prostaglandins by the conjugate addition approach. ... 

Two key chiral building blocks used in the total synthesis of a-tocopherol were prepared via microbial reduction of unsaturated carbonyl compounds with baker s yeast and with Geotrichum candidum Similarly, a key intermediate in the total synthesis of optically active natural carotenoids was prepared by microbial reduction of oxoisophorone with baker s yeast. An alternative approach to the synthesis of a-tocopherol employs a chiral building block that was obtained by baker s yeast reduction of 2-methyl-5-phenylpentadienal. ... 

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