Chiral pool carbohydrates

General Three Carbon Chiral Synthons from Carbohydrates Chiral Pool and Chiral Auxiliary Approaches... 

Despite the greater awareness of carbohydrate synthons in recent years, the full potential of the carbohydrate chiral pool is still not... 

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. 

Two syntheses and one formal synthesis of (+)-preussin have been reported using sugars as chiral pool building blocks. In these syntheses parts of the sugar backbone have been implemented into the preussin skeleton. All four pyrrolidine carbon atoms stem from the carbohydrate. As a consequence, the two carbon-nitrogen bonds (N/C-2 and N/C-5) of the pyrrolidine ring... 

Carbohydrates are configurationally stable, easily available in enantiopure forms from the chiral pool, and they show a high density of chiral information per molecular unit. Their polyfunctionality and structural diversity fadhtate their tailor-made modification, derivatization, and structural optimization for a broad spectrum of synthetic applications. While derivatives of various saccharides have already been utilized as versatile starting materials and building blocks for chiral auxiliaries, ligands, and reagents [330] their obvious role as precursors for the... 

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. 

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. 

Many of the five- and six-carbon sugars, although well known, are rare, and too expensive to be used as chiral pool starting materials. David MacMillan of Caltech in an elegant series of papers (Angew. Chem. Int. Ed. 2004,43. 2152 Science 2004,305, 1752 Angew. Chem. Int. Ed. 2004,47,6722) has demonstrated a two-step route not just to protected six-carbon carbohydrates, but also to alkyl, thio and amino derivatives of those carbohydrates. 

G. Casiraghi, F. Zanardi, G. Rassu, and P. Spanu, Stereoselective approaches to bioactive carbohydrates and alkaloids—With a focus on recent syntheses drawing from the chiral pool, Chem. Rev. 95 1677 (1995). 

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. 

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

Although carbohydrates are cheap and readily available chiral compounds, their application in stereoselective synthesis was for a long time limited to ex-chiral-pool syntheses [3]. They have been considered too complex compared to other chiral auxiliaries, for example a-pinene in borane-chemistry [4] or BINAP-derivatives in reduction chemistry [5]. However, it has been shown during the past few years that carbohydrates can be successfully applied as stereodifferentiating tools in many different reaction types such as aldol- [6], hydrogenation- [7], carbonyl addition- [8], Michael- [9], Diels-Alder- [10], hetero-Diels-Alder [11], and rearrangement reactions [12]. 

These are (1) The chiral substrate approach. This approach involves using chiral precursors that transfer their chirality to the final cyclopentenone. This implies the synthesis of chiral substrates, which has generally been made from classic chiral pools. Examples include carbohydrate derivatives like 40 that give 41 with variable yields depending on the substitution pattern. 41 is transformed into cyclopenta[c]pyrane 42, which is the skeleton of iri-doids [93]. In another example epichlorhydrin (43) is used to construct chiral enyne 44 which gives cyclopentenone 45 [94] (Scheme 14). 

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. 

Isoxazolidines are useful and versatile intermediates in the synthesis of highly functionalized compoimds. Frequently, they are prepared by 1,3-DC of enantiomerically pure nitrones derived from compounds belonging to the chiral pool such as carbohydrates, amino acids, and hydroxy acids. 

In the meantime, the primary amines from the chiral pool (Sect. 4.3.1.3) and other amines have been tested for their induction ability, and found to give similar results as l-ferrocenyl-2-methyl-propylamine [40, 75, 76]. Although there has been some optimism towards a broader range of applications [164], it seems that carbohydrate-derived primary amines have a superior induction power in stereoselective 4CC and will therefore become the reagents for the future. 

For synthesis of phytosphingosine [40] and dihydrosphingosine [7], many methods have been reported. These utihzed a chiral pool strategy with amino acid or carbohydrate similar to that of sphingosine. 

In this chapter we introduce compounds which have been successfully applied in the construction of supramolecular assemblies. Only the amphiphiles which have been prepared in sufficient quantities have been admitted milligram quantities being considered unacceptable as starting materials for the preparation, analysis and application of assemblies. Experience proves that complicated dyes, pore builders, receptors etc. never reappear in the literature after their syntheses and spectroscopic properties have been reported. On the other hand, such easily attainable synkinons and surfactants around the ten gram scale need not, of course, be too simple. On the contrary, they may contain all the components of the chiral pool, i.e. amino acids, carbohydrates, steroids etc., as well as all commercial dyes of interest such as protoporphyrin, phthalo-cyanines, carotenes, viologen and quinones. 

Mechanistic considerations (e.g., the extensive work published on brush-type phases) or the practitioner s experience might help to select a chiral stationary phase (CSP) for initial work. Scouting for the best CSP/mobile phase combination can be automated by using automated solvent and column switching. More than 100 different CSPs have been reported in the literature to date. Stationary phases for chiral pSFC have been prepared from the chiral pool by modifying small molecules, like amino acids or alkaloids, by the deriva-tization of polymers such as carbohydrates, or by bonding of macrocycles. Also, synthetic selectors such as the brush-type ( Pirkle ) phases, helical poly(meth) acrylates, polysiloxanes and polysiloxane copolymers, and chiral selectors physically coated onto graphite surfaces have been used as stationary phases. 

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