Asymmetric synthesis from chiral pool compounds

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. 

Most asymmetric syntheses require rather more than one or two steps from chiral pool constituents. Male bark beetles of the genus Ips produce a pheromone that is a mixture of several enantiomerically pure compounds. One is a simple diene alcohol (S)-(-)-ipsenol. Japanese chemists in the 1970s noted the similarity of part of the structure of ipsenol (in black) to the widely available amino acid (S)-leucine and decided to exploit this in a chiral pool synthesis, using the stereogenic centre (green ring) of leucine to provide the stereogenic centre of ipsenol. 

As resolution procedures are often tedious, and asymmetric synthesis provides chiral products with only limited enantiomeric excess, it seems an obvious strategy to use an enantiomerically pure material from the chiral pool to construct chiral ferrocenes by incorporating these compounds in the final product. As such chiral materials, cheap terpenes (menthone, a- and -pinene, and camphor) were chosen. The reaction of ferrocene with carbonyl compounds under acidic conditions is a very convenient way to obtain directly a-ferrocenylalkyl carbocations. The starting materials were therefore converted to aldehydes or their enol ethers (menthone and camphor are too sterically hindered and do not react with ferrocene). Joint dissolution of the aldehydes and ferrocene in trifluoroacetic acid or in the trichloroacetic acid/ fluorosulfonic acid system gives a-ferrocenylalkyl carbocations, which can either... 

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... 

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. 

The stereogenic centers of chiral dendrimers synthesized so far are either generated by asymmetric synthesis, or they are derived from molecules of the pool of chiral building blocks. The only investigation on chiral dendrimers, consisting of achiral building blocks exclusively, was published by Meijer et al., who synthesized dendrimers such as 31 [61] (Fig. 14). This compound ows its chiral-... 

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. 

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. 

Sometimes the natural products that are needed are immediately obvious from the structure of the target molecule. An apparently trivial example is the artificial sweetener aspartame (marketed as Nutrasweet), which is a dipeptide. Clearly, an asymmetric synthesis of this compound will start with the two members of the chiral pool, the constituent (natural) (S)-amino acids, aspartic acid and phenylalanine. In fact, because phenylalanine is relatively expensive for an amino acid, significant quantities of aspartame derive from synthetic (S)-phenylalanine made by one of the methods discussed later in the chapter. 

The obvious approach for chiral synthesis would be to find a chiral starting material, such as a natural amino acid, carbohydrates, carboxylic acids or terpene. The major source of these chiral starting materials sometimes called chirons is nature itself. The synthesis of a complex enantiopure chemical compound from a readily available enantiopure substance such as natural amino acids is known as chiral pool synthesis. For example, chiral lithium amides 1.39 that are used for several types of enantioselective asymmetric syntheses can be prepared in both enantiomeric forms starting from the corresponding optically active amino acids, and these are often available commercially. 

The practicing organic chemist now has available a variety of synthetic tools for preparing enantiomerically pure compounds (2). These methods all derive, ultimately, from a naturally occurring chiral molecule. The means by which this natural chirality is applied to preparing other chiral molecules varies widely in concept and execution. These concepts fall, however, into three general areas resolution, asymmetric synthesis, and the use of the chiral carbon pool. Comprehensive reviews of these methods exist (3-5), and thus only a brief outline of each will be presented here. 

It is much more useful to make enantiomerically pure as well as diastereoisomerically pure compounds, particularly in the synthesis of a drug. The strategy used here is to make the starting material from an enantiomerically pure compound available from nature in this case an amino acid. These available enantiomerically pure compounds are known collectively as the chiral pool. You can read more about this in Chapter 41 on asymmetric synthesis. 

Likewise, starting a synthesis with an enantiomerically pure compound which has been selected from the large stock of enantiopure natural compounds [77] such as carbohydrates, amino acids, terpenes or steroids - the so-called chiral pool -has its limitations. According to a survey from 1984 [78] only about 10-20% of compounds are available from the chiral pool at an affordable price in the range of US 100-250 per kg. Considering the above-mentioned problems with the alternative ways of obtaining enantiomerically pure compounds, it is obvious that enzymatic methods represent a valuable addition to the existing toolbox available for the asymmetric synthesis of fine chemicals [79]. 

Outside the amino acid and carbohydrate pools, derivatives of natural and unnatural tartaric acid (l- and d- respectively) merit attention as chiral syn-thons, in addition to their more familiar applications in classical resolution and asymmetric synthesis. Biologically active compounds prepared from tartrates (Scheme 5.34) include the symmetry-based HIV protease inhibitor (78) [96] and the endotoxin inhibitors (79) [97]. 

Fluorine substitutions at chiral C atoms can have some advantages, because fluorine causes only a small steric hindrance but induces large dipole moments. Chiral fluorine compounds cannot be obtained from the natural pool, thus asymmetric synthesis is required. Figure 4.11 shows two examples [22], [23]. 

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