Chiral-pool material

In a study which was conducted simultaneously to the work in the Mehta group and which also aimed to prove the absolute configuration of natural kelsoene (1), Schulz et al. used a stereoselective approach starting from the enantiomerically pure chiral pool material (i )-pulegone 17 [9, 10] (see above). The final steps of their synthesis of the unnatural enantiomer of kelsoene (ent-l) were similar to the above-described first total synthesis of natural kelsoene (1) (Scheme 8). Taking into account the steric limitations of the system as communicated by Srinivas and Mehta, diquinane enone ent-6... 

Nature has provided a wide variety of chiral materials, some in great abundance. The functionality ranges from amino acids to carbohydrates to terpenes (Chapters 2-5). All of these classes of compounds are discussed in this book. Despite the breadth of functionality available from natural sources, very few compounds are available in optically pure form on large scale. Thus, incorporation of a chiral pool material into a synthesis can result in a multistep sequence. However, with the advent of synthetic methods that can be used at scale, new compounds are being added to the chiral pool, although they are only available in bulk by synthesis. When a chiral pool material is available at large scale, it is usually inexpensive. An example is provided by L-aspartic acid, where the chiral material can be cheaper than the racemate. 

How some of these chiral pool materials have been incorporated into syntheses of biologically active compounds is illustrated throughout this book. In addition, chiral pool materials are often incorporated, albeit in derivatized form, into chiral reagents and ligands that allow for the transfer of chirality from a natural source into the desired target molecule. 

Biological catalysts for asymmetric transformations have been used in specific cases for a considerable period of time, excluding the chiral pool materials. However, until recently, the emphasis has been on resolutions with enzymes rather than asymmetric transformations (Chapter 19 see also Chapters 20 and 21). With our increasing ability to produce mutant enzymes that have different or broad-spectrum activities compared to the wild types, the development of biological catalysts is poised for major growth. In addition to high stereospecificities, an organism can be persuaded to perform more than one step in the overall reaction sequence and may even make the substrate (Chapter 3). 

When reactions that are robust are considered, only a relatively small number are available. Each of these reaction types are discussed within this book, although some do appear under the chiral pool materials that allowed for the development of this class of asymmetric reagent. Such an example is the use of terpenes that have allowed for the development of chiral boranes (Chapter 5). 

In addition to being useful reagents for the reductions of carbonyl compounds, boron-based reagents can also be used for the conversion of an alkene to a wide variety of functionalized alkanes. Because the majority of these reagents carry a terpene substituent, they are discussed under these chiral pool materials (Chapter 5). 

The 20 proteinogenic amino acids have become key building blocks as chiral pool materials. In addition to these 20 amino acids, there are many analogues with modified sidechains, backbones, or different stereochemistry. Some of these other amino acids, such as D-alanine, are found in nature, but in this chapter they will be collected under the descriptor of unnatural amino acids. 

Although nature has been the primary source of the proteinogenic amino acids through extraction processes, many of the unnatural analogues have to be synthesized. Modem asymmetric synthetic methodology is now in the position to provide cheap, pure, chiral materials at scale. Some of the unnatural amino acids are now made at scale and have been used to extend the chiral pool. To avoid duplicating sections of this book, this chapter discusses the problems associated with the synthesis of unnatural amino acids at various scales. This illustrates that a single, cheap method need not fulfill all of the criteria to provide a chiral pool material to a potential customer, and a number of approaches are required. 

A wide variety of simple transformations on chiral pool materials can lead to unnatural amino acid derivatives. This is illustrated by the Pictet-Spengler reaction of L-phenylalanine, followed by amide formation and reduction of the aromatic ring (Scheme 2.18).52 The resultant amide (11) is an intermediate in a number of commercial human immunodeficiency virus (HIV) protease inhibitors. 

This chapter will cover the uses of carbohydrates as chiral pool materials. Because hydroxy acids are closely related, they are also discussed here. 

All the optically active terpenes mentioned in this chapter are commercially available in bulk (>kg) quantities and are fairly inexpensive. Although many of them are isolated from natural sources, they can also be produced economically by synthetic methods. Actually, two thirds of these monoterpenes sold in the market today are manufactured by synthetic or semi-synthetic routes. These optically active molecules usually possess simple carbocyclic rings with one or two stereo-genic centers and have modest functionality for convenient structural manipulations. These unique features render them attractive as chiral pool materials for synthesis of optically active fine chemicals or pharmaceuticals. Industrial applications of these terpenes as chiral auxiliaries, chiral synthons, and chiral reagents have increased significantly in recent years. The expansion of the chiral pool into terpenes will continue with the increase in complexity and chirality of new drug candidates in the research and development pipeline of pharmaceutical companies. 

An interesting example of a chirality pool material used as a chiral auxiliary, is the industrial synthesis of -naproxen, reported by Zambon [15]. Naproxen is the generic name of the non-steroidal anti-inflammatory drug, S-2-(6-methoxy-2-naphthyl) propanoic acid, described originally by Syntex in 1967 [16]. It is interesting to compare the Syntex and Zambon strategies for the production of S-naproxen (Schemes 7.2 and 7.3, respectively). 

The Zambon process is an example of a chirality pool material used as a covalently bound auxiliary, i.e. a diastereoselective reaction. Chirality pool materials may also be used as catalysts, modifiers, ligands and metal-based reagents. These have been adequately reviewed by Blaser [18]. A good example of an industrial scale synthesis has been reported by workers at Roche [19] and related examples have been reviewed by Kagan [20] (equation 7.1). 

Direct separation of enantiomers by chromatography Use of covalent chiral auxiliaries Stereoselective synthesis of individual enantiomers Separation of diastereoisomers by physical techniques Synthesis from chirality pool materials... 

Palkowitz and coworkers [15] reported classical resolution of the imidazo-lyl carboxylic acid (1) with (-)-cinchonidine, as part of an integrated approach to triacid angiotensin II antagonists. The (/ )-enantiomer of (1) thus obtained was then subjected to peptidic coupling with amino ester (2), prepared from rran -4-hydroxy-L-proline, a widely available chirality-pool material. 

Of the three basic types of methodologies employed for the provision of chiral target molecules in optically enriched form, synthesis from chirality pool materials can often be the method of choice, providing that (i) suitable starting materials are readily available at reasonable cost, and (ii) it is not necessary to introduce extra steps which would otherwise be avoided, in, for example, the synthesis of an easily resolvable racemate. A distinct advantage of chirality pool synthesis over resolution techniques is the facility to correlate absolute configuration of the product with that of the starting material. 

One can broadly identify five main technology classes for introducing chirality use of chiral pool materials, crystallization methods, chromatographic separations, chemoca-talysis, and biocatalysis. When faced with a new chiral target to synthesize, careful evaluation of the possible routes must be undertaken to ensure that the final route is a competitive and economic one. Sometimes it is necessary to travel down two (or more) paths at the start until it becomes obvious as to which will be the chiral method of choice. Biocatalysis is very frequently one of the favored technologies, and it is the aim of this chapter to illustrate the use of biocatalytic mediods for the synthesis of chiral intermediates and, in particular, highlight some of the factors that have influenced the choice of biocatalyst used. 

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