Chiral pool compounds from

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. 

On an industrial scale, resolution of racemates is still in many cases the preferred way of producing enantiomerically pure compounds. If chiral-pool compounds are not available as optically active starting materials, a cost comparison of asymmetric and resolution processes often attributes advantages to the latter. Among the top 15 optically active pharmaceutical drugs and their intermediates, a chemical asymmetric process could be established only in the case of naproxen. For all others, diastereomeric and biocatalytic resolution are the methods, apart from fermentation, of creating optically pure compounds. 

This subject has recently been reviewed6 and we shall concentrate on the different approaches to grandisol outlined in that review. Many of these approaches can clearly be used for the other compounds. An early approach was a chiral pool strategy from the simpler and commercially available terpene (R)-( (-linalool 38. Though this did not lead to a useful synthesis, it pointed the way to effective methods, particularly the Cu(I)-catalysed photochemical closure of the four-membered ring. 

Table 9.4 Representative substances from the chiral pool Compound...

As described above, a novel preparation of homochiral mono-, di-, as well as trifluoromethylated aldol structures starting from the readily available chiral pool compound, D-glucose, has been demonstrated. Further synthetic utilization of optically active cyclic materials as well as investigation of the similar route with different sugars is under way in our laboratory. 

Clearly, there is a need for techniques which provide access to enantiomerically pure compounds. There are a number of methods by which this goal can be achieved . One can start from naturally occurring enantiomerically pure compounds (the chiral pool). Alternatively, racemic mixtures can be separated via kinetic resolutions or via conversion into diastereomers which can be separated by crystallisation. Finally, enantiomerically pure compounds can be obtained through asymmetric synthesis. One possibility is the use of chiral auxiliaries derived from the chiral pool. The most elegant metliod, however, is enantioselective catalysis. In this method only a catalytic quantity of enantiomerically pure material suffices to convert achiral starting materials into, ideally, enantiomerically pure products. This approach has found application in a large number of organic... 

We now tum our attention to the C21-C28 fragment 158. Our retrosynthetic analysis of 158 (see Scheme 42) identifies an expedient synthetic pathway that features the union of two chiral pool derived building blocks (161+162) through an Evans asymmetric aldol reaction. Aldehyde 162, the projected electrophile for the aldol reaction, can be crafted in enantiomerically pure form from commercially available 1,3,4,6-di-O-benzylidene-D-mannitol (183) (see Scheme 45). As anticipated, the two free hydroxyls in the latter substance are methylated smoothly upon exposure to several equivalents each of sodium hydride and methyl iodide. Tetraol 184 can then be revealed after hydrogenolysis of both benzylidene acetals. With four free hydroxyl groups, compound 184 could conceivably present differentiation problems nevertheless, it is possible to selectively protect the two primary hydroxyl groups in 184 in... 

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... 

Enantioenriched alcohols and amines are valuable building blocks for the synthesis of bioactive compounds. While some of them are available from nature s chiral pool , the large majority is accessible only by asymmetric synthesis or resolution of a racemic mixture. Similarly to DMAP, 64b is readily acylated by acetic anhydride to form a positively charged planar chiral acylpyridinium species [64b-Ac] (Fig. 43). The latter preferentially reacts with one enantiomer of a racemic alcohol by acyl-transfer thereby regenerating the free catalyst. For this type of reaction, the CsPhs-derivatives 64b/d have been found superior. 

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

This includes future potential applications in radiopharmaceuticals. Furthermore, new chiral enantiopure NJ, 0 tripod ligands have been developed starting from cheap compounds of the chiral pool. 

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. 

Stereocontrol in the synthesis of such compounds is quite challenging and the use of synthons from the chiral pool in stereocontrolled transformations might be an attractive alternative to be considered, as shown recently [94]. 

In planning the synthesis of biologically active compounds, strategies using aldonolactones or other compounds from the chiral pool should therefore continue to be considered, since they can provide attractive routes in comparison with alternative methods by asymmetric synthesis. 

The third approach is the main topic of this volume. According to the definition given above it involves enantiomerically pure starting materials which at some point must be provided by resolution or ex-chiral-pool synthesis. It is more or less equivalent to the term asymmetric synthesis defined by Marckwald in 19047 as follows Asymmetric syntheses are those reactions which produce optically active substances from symmetrically constituted compounds with the intermediate use of optically active materials but with the exclusion of all analytical processes . In today s language, this would mean that asymmetric syntheses are those reactions, or sequences of reactions, which produce chiral nonracemic substances from achiral compounds with the intermediate use of chiral nonracemic materials, but excluding a separation operation. 

Relations of this type, if carefully applied, are unambiguous and do not depend on mechanistic and/or stereochemical assumptions. From a practical point of view one may distinguish between cases where (i) the correlation is achieved by simple manipulations or by preparing the compound of unknown configuration or its enantiomer by a different route, using, for example, the chiral-pool approach (ii) complex correlation schemes (iii) synthetic correlations, where a compound obtained in an asymmetric reaction is related with a sometimes much more complex natural product of known configuration. 

Neonepetalactone, 61 (Fig. 1.2.3), a bioactive compound found to be quite attractive to cats [41], was isolated in 1965 from the leaves and galls of Actinidia polygama by T. Sakan et al. and its absolute configuration was determined in 1980 [41b]. As some syntheses of the racemic mixture or ex-chiral-pool syntheses had already been reported, we realized that our SAMP/RAMP hydrazone methodology would make it possible to develop a very short asymmetric synthesis of this bioactive 8-lactone. 

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