Chiral pool terpenes

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. 

The most widely applicable method of optical resolution utilizes a chiral auxiliary, which is taken from either the chiral pool 14 (carbohydrates, terpenes, amino acids etc.) or obtained by previous optical resolution. The auxiliary A, in an optically pure form, combines with the racemic substrate S to form two diastereomers p and n, respectively. 

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. 

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). 

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. 

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. 

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... 

Planar chiral compounds should also be accessible from the chiral pool. An example (with limited stereoselectivity) of such an approach is the formation of a ferrocene derivative from a -pinene-derived cyclopentadiene (see Sect. 4.3.1.3 [81]). A Cj-symmetric binuclear compound (although not strictly from the chiral pool, but obtained by resolution) has also been mentioned [86]. Another possibility should be to use the central chiral tertiary amines derived from menthone or pinene (see Sect. 4.3.1.3 [75, 76]) as starting materials for the lithiation reaction. In these compounds, the methyl group at the chiral carbon of iV,iV-dimethyl-l-ferrocenyl-ethylamine is replaced by bulky terpene moieties, e.g., the menthane system (Fig. 4-2 le). It was expected that the increase in steric bulk would also increase the enantioselectivity over the 96 4 ratio, as indicated by the results with the isopropyl substituent [118]. However, the opposite was observed almost all selectivity was lost, and lithiation also occurred in the position 3 and in the other ring [134]. Obviously, there exists a limit in bulkiness, where blocking of the 2-position prevents the chelate stabilization of the lithium by the lone pair of the nitrogen. 

As an alternative to resolution, one can start with an enantiomerical-ly pure compound that occurs naturally, and the most common examples of these are amino acids, sugars and terpenes. This group of compounds is known collectively as the chiral pool . The procedure then is to transform the compound of choice from the above group into the desired product by chemical synthesis, with care taken to avoid racem-ization at stereogenic centres. 

The variety of terpenes is great but they may not be available in high ee. Here is a selection these are all monoterpenes (C10) and may be linear, cyclic or bicyclic. We have included the new chiral pool members 8-phenyl-menthol 83 and camphorsulfonic acid 94. 

In chapter 27 we recommended 8-phenylmenthol 21 as a chiral auxiliary. The three chiral centres in 8-phenylmenthol are made by from the terpene pulegone 22 (chiral pool) having only one chiral centre. The new chiral centres have 1,3- and 1,4-relationships to the centre already present in pulegone and the key to their successful control is conformational analysis. 8-Phenylmenthol has all three substituents equatorial. 

A simple heterocyclic acid needed for an anti-HIV drug A chiral pool synthesis from aspartic acid Choosing a new reaction to solve the stereochemistry problem Making the new reaction asymmetric Part III - Grandisol and Some Bicyclo[3.2.0]Heptan-2-Ols A bicyclic insect attractant used in agriculture Chiral Pool Syntheses from Other Terpenes An attempt from linalool... 

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