Optically active products chiral pools

When planning the synthesis of an optically active product, the easiest approach is to use an optically active starting material from the chirality pool. For many decades this was in fact the only source of enantiomeri-cally pure catalysts or auxiliaries, a situation which has now changed due to recent successes by organic chemists in the design and synthesis of new... 

Catalytic kinetic resolution can be the method of choice for the preparation of enantioenriched materials, particularly when the racemate is inexpensive and readily available and direct asymmetric routes to the optically active compounds are lacking. However, several other criteria-induding catalyst selectivity, efficiency, and cost, stoichiometric reagent cost, waste generation, volumetric throughput, ease of product isolation, scalability, and the existence of viable alternatives from the chiral pool (or classical resolution)-must be taken into consideration as well... 

Optically active five- or six-membered cyclic A -acyliminium ions of this type are generated from the a-inethoxy derivatives, easily obtainable through anodic methoxylation of intermediates that are prepared via ex-chiral-pool syntheses from certain natural amino acids. Reaction of 5-substituted five-membered cyclic A -acyliminium ions with various nucleophiles leads to the predominant formation of cw-products with moderate selectivity. The trans-selective reaction with alkyl copper reagents appears to be an exception. 

In the case of diastereomeric mixtures of chiral hydroperoxides, standard chromatography on achiral phase can be employed to separate the diastereomers. As one example for the preparation of optically pure hydroperoxides via this method, the ex-chiral pool synthesis of the pinane hydroperoxides 11 is presented by Hamann and coworkers . From (15 )-cw-pinane [(15 )-cw-10], two optically active pinane-2-hydroperoxides cA-lla and trans-llb were obtained by autoxidation according to Scheme 17. Autoxidation of (IR)-c -pinane [(17 )-cw-10] led to the formation of the two enantiomers ent-lla and ent-llh. The ratio of cis to trans products was 4/1. The diastereomers could be separated by flash chromatography to give optically pure compounds. 

Another contentious issue is how far the term ex-chiral-pool synthesis should be extended. Some researchers use it for any synthesis starting from an optically active natural product. However, in the original meaning, ex-chiral-pool synthesis is defined in the sense that only stereo-unambiguous operations must be performed on the substrate. Thus, all diastereoselec-tive processes (as discussed in Section 2.3.2.) are excluded. 

Despite its efficiency in numerous cases optical resolution is by no means a trivial operation. In each case the optimum method has to be found by laborious trial and error procedures the optical purity of the material has to be secured and its absolute configuration has to be established before the compound can be used in a synthetic sequence. These drawbacks of optical resolution led chemists to start their syntheses from optically active natural products (the so-called chiral carbon pool ). A variety of suitable ex-chiral-pool compounds including carbohydrates, amino acids, hydroxy acids, and terpenoids are shown. 

Chiral drug intermediates can be prepared by different routes. One approach is to obtain them from naturally derived chiral synthons, produced mainly by fermentation processes. The chiral pool refers primarily to inexpensive, readily available, optically active natural products. A second approach is to carry out the... 

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 chirality of the monomer units of microbiologically generated polyesters is of great interest for the chemical and pharmaceutical industry. They are considered to be the pool of chiral building blocks, which receive optically active derivates for the construction of enantiomer-pure products. 

The synthetic synthesis of known chiral polymers mostly starts from optically pure monomers obtained form the chiral pool. The optically pure fermentation product L-lactic acid, for example, is the starting material for the synthesis of poly(L-lactide). However, converting a racemic or achiral monomer quantitatively into a homochiral polymer is less straightforward [3]. This is surprising considering the enormous potential of biocatalysis and tandem catalysis that has emerged in the past decades to prepare optically active intermediates [4]. 

Only about 20% of the optically active pharmaceuticals are sold as pure enantiomers (6). This has resulted in an increasing interest in stereoselective syntheses based on chiral intermediates. The production of these so-called auxiliaries ultimately requires enantiomerically pure natural substances, with optically active amino acids playing an important part as chiral pool. Consequently, efficient analytical procedures for control of optical purity are needed to supplement modem procedures for asymmetric syntheses. 

The chiral pool refers to readily available optically active natural products, some of which are commercially used in quantities of 10 -10 tonnes per year [5], Among them, the most inexpensive compounds are a-amino acids, like monosodium L-glutamate, or carbohydrates, like dextrose or sorbitol. The success of the second method depends on the availability of particular catalysts. One rather special example, how efficient stereoselective synthesis can work, is the syn-selective aldol reaction followed by a stereoselective alkene hydroboration and ketone reduction (Figure 1.8) which were used by Paterson et aJ. [26] to synthesize intermediates for the antibiotic oleandomycin. According to Paterson et al., four new stereocenters are formed in only two synthetic steps [9]. For the purpose of separating racemic mixtures... 

This technique uses starting materials that are themselves optically active and in the same orientation as the desired product. These are often naturally occurring compounds such as carbohydrates or L-amino acids. The biochemist will choose from this chiral pool . The synthetic route is designed to keep any intermediates and the final product formed in the same enantiomeric form. As a result, there is no need to carry out the costly separation process needed when a racemic mixture is produced. 

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