Chiral catalytic technologies

EXAMPLES OF INDUSTRIALLY READY CHIRAL CATALYTIC TECHNOLOGIES AND THEIR APPLICATION... 

Methodology for the enantioselective synthesis of a broad range of chiral starting materials, by both chiral catalytic and controller-directed processes, is rapidly becoming an important factor in synthesis. The varied collection of molecules which are accessible by this technology provides another type of chiral S-goal for retrosynthetic analysis. 

The renaissance of biocatalysis, supported by the advent of recombinant DNA, is only about 20 years old. Recently several publications have appeared which deal specifically with the attitudes listed above (Rozzell, 1999 Bommarius, 2001 Rasor, 2001). Most of the points above can either be refuted or they can be levied against any novel catalytic technology the situation with some competing technologies such as chiral homogeneous catalysts is similar to that with enzymes (Chapters 18 and 20). 

The desire to produce enantiomerically pure pharmaceuticals and other fine chemicals has advanced the field of asymmetric catalytic technologies. Since the independent discoveries of Knowles and Homer [1,2] the number of innovative asymmetric catalysis for hydrogenation and other reactions has mushroomed. Initially, nature was the sole provider of enantiomeric and diastereoisomeric compounds these form what is known as the chiral pool. This pool is comprised of relatively inexpensive, readily available, optically active natural products, such as carbohydrates, hydroxy acids, and amino acids, that can be used as starting materials for asymmetric synthesis [3,4]. Before 1968, early attempts to mimic nature s biocatalysis through noble metal asymmetric catalysis primarily focused on a heterogeneous catalyst that used chiral supports [5] such as quartz, natural fibers, and polypeptides. An alternative strategy was hydrogenation of substrates modified by a chiral auxiliary [6]. 

The ability to efficiently synthesize enantiomerically enriched materials is of key importance to the pharmaceutical, flavor and fragrance, animal health, agrochemicals, and functional materials industries [1]. An enantiomeric catalytic approach potentially offers a cost-effective and environmentally responsible solution, and the assessment of chiral technologies applied to date shows enantioselective hydrogenation to be one of the most industrially applicable [2]. This is not least due to the ability to systematically modify chiral ligands, within an appropriate catalyst system, to obtain the desired reactivity and selectivity. With respect to this, phosphorus(III)-based ligands have proven to be the most effective. 

Most chiral chemicals are relatively small-scale products (1 to 1000 tonnes per year for pharmaceuticals, 500 to 10000 tonnes per year for agrochemicals) that are usually produced in multipurpose batch equipment This is probably the case for most catalytic reactions described in this chapter however, as a rule very little information on process technology is provided by the manufacturers. Here, we will discuss only briefly the reactor choices for hydrogenation reaction typically carried out in the liquid phase. For a successful implementation the following demands must be met ... 

In addition to its utility in the enantioselective formation of C-0 bonds (cf. Scheme 15), Trost s chiral ligand 102 has been used in the catalytic asymmetric synthesis of C-N bonds. An impressive application of this protocol is in the enantioselective total synthesis of pancrastatin by Trost (Scheme 17) H9i Thus, Pd-catalyzed desymmetrization of 112 leads to the formation of 113 efficiently and in > 95 % ee. The follow-up use of the N3 group to fabricate the requisite cyclic amide via isocyanate 117 demonstrates the impressive versatility of this asymmetric technology. 

This section will only discuss examples of catalytic kinetic resolution, DKR, desymmetrization and asymmetrization. Deracemization will not be considered because, although an important developing technology, examples of its application to the production of chiral late-stage intermediates in API production have yet to appear. 

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