The chirality pool

The chirality pool refers to the rich diversity of chiral molecules such as amino acids, hydroxy acids, carbohydrates, terpenes and alcohols which are commercially available in the range 10 -10 tonnes per annum. These compounds either occur in nature or can be obtained readily by fermentation processes, the latter being synonymous with microbial synthesis. The chirality pool also includes the so called new pool such as 6-aminopeni- 

Chirality pool substances can be transformed into synthetic products either by using them as chiral synthons or as auxiliaries in chirality transfer processes. 

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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... 

Stork and Takahashi took -glyceraldehyde synthon from the chiral pool and condensed it with methyl oleate, using lithium diisopropyl amide as catalyst for the mixed aldol reaction, leading to The olefinic linkage is a latent form... 

Several elegant synthetic strategies have been devised for biotin (1) this chapter describes one of the total syntheses developed at Hoffmann-La Roche. This insightful synthesis employs a derivative of L-cysteine, a readily available member of the chiral pool,2 as the starting material, and showcases the powerful intramolecular nitrone-olefin [3+2] cycloaddition reaction. 

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... 

Highly uMtr-diastereofacial selective cycloaddition of isoprene (2) with 4-isopropyl-2-cyclohexenone allowed a short regiocontrolled and stereocon-trolled synthesis [13] of jS-cadinene and (y2-cadinene, Scheme 3.3). High anti-diastereofacial selectivity also occurs in the Diels-Alder reaction of optically active cyclohexenones 6-9 (Figure 3.2), readily available from the chiral pool, with open chain dienes [14-16]. Their cycloadducts are valuable intermediates in the synthesis of optically active sesquiterpenes in view of the easy conversion of the gem-dimethylcyclopropane and gem-dimethylcyclobutane in a variety of substituents. 

In conclusion, many chiral pyridine-based ligands have been prepared from the chiral pool and have been successfully tested as ligands for the copper- or rhodium-catalyzed cyclopropanation of olefins. Alfhough efficient systems have been described, sometimes leading interestingly to the major cis isomer, the enantioselectivities usually remained lower than those obtained with the copper-bis(oxazoline) system. 

A review was published covering recent progress in the stereoselective synthesis of piperidines <00S1781>. Routes described in detail include those derived from the chiral-pool, chiral auxiliaries, and catalytic asymmetric methodology. 

One of the fundamental operations in organic synthesis remains the stereoselective reduction of carbonyl groups1241. In a process related to that reported by Hosomi et u/.[25], using hydrosilanes as the stoichiometric oxidant and amino acid anions as the catalytic source of chirality, a variety of ketones were reduced in good to excellent yield and with good stereoselectivity1261. This process reduces the amount of chiral catalyst needed and utilizes catalysts from the chiral pool that can be used directly in their commercially available form. 

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. 

In addition to elimination reactions, the methoxylated amide products from electrolysis reactions have been treated with a variety of nucleophiles [47]. In recent studies, these efforts have been utilized to expand the chiral pool of starting materials available to synthetic chemists. For example, consider the reactions illustrated in Scheme 23 [52, 53]. In these efforts, Steckhan and coworkers have used the oxidation reaction to make a stable -a-methoxy amide that... 

Scheme 23 Building blocks for the chiral pool by anodic or-methoxylation of amides.

One purpose of our work is to mimic the chiral environment of the enzymes. Therefore, we thought it a reasonable goal to supply chiral models for the active sites of metalloenzymes. This was achieved before by Alsfasser et al. 113) or Vahrenkamp et al. 114) via amino acids that have been incorporated into the ligand systems. Modification of Tp ligands by chiral pyrazoles derived from the chiral pool is another way to chiral W,W,iV tripod ligands and has been achieved before by W. B. Tolman and coworkers (115). Thus, first we focused on the synthesis of a racemic mixture of a chiral NJtl,0 scorpionate... 

Modification of Tp ligands by chiral pyrazoles derived from the chiral pool is another way to chiral N,N,N tripod ligands and has been achieved before by Tolman and coworkers (115). 

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. 

TABLE 11.1. Representative substances from the chiral pool ... 

In connection with the synthetic work directed towards the total synthesis of polyene macrolide antibiotics -such as amphotericin B (i)- Sharpless and Masamune [1] on one hand, and Nicolaou and Uenishi on the other [2], have developed alternative methods for the enantioselective synthesis of 1,3-diols and, in general, 1, 3, 5...(2n + 1) polyols. One of these methods is based on the Sharpless asymmetric epoxidation of allylic alcohols [3] and regioselective reductive ring opening of epoxides by metal hydrides, such as Red-Al and DIBAL. The second method uses available monosaccharides from the "chiral pool" [4], such as D-glucose. 

Most of the useful auxiliaries are chiral amine or alcohol derivatives readily available from the chiral pool, and most of them possess rigid cyclic or bicyclic structures to allow efEcient differentiation of the two competing diastereomorphic transition states. In some cases, additional rigidity was achieved with the aid of an external chelating Lewis acid (entries 6, 10, 12). In certain cases, however, acyclic auxiliaries may also be useful (see entry 15). 

Chiral benzamides I and the pyrrolobenzodiazepine-5,11-dio-nes n have proven to be effective substrates for asymmetric organic synthesis. Although the scale of reaction in our studies has rarely exceeded the 50 to 60 g range, there is no reason to believe that considerably larger-scale synthesis will be impractical. Applications of the method to more complex aromatic substrates and to the potentially important domain of polymer supported synthesis are currently under study. We also are developing complementary processes that do not depend on a removable chiral auxiliary but rather utilize stereogenic centers from the chiral pool as integral stereodirectors within the substrate for Birch reduction-alkylation. 

Consequently, a number of stereoselective syntheses have been developed leading to a variety of paraconic acids either in racemic or in enantiopure form, using starting materials from the chiral pool, chiral auxiliaries or applying catalytic asymmetric methodology. Moreover, a number of strategies leading to paraconic acids in a non-stereoselective way have been reported, which will not be described in detail in this review [4, 5]. 

Recently, chiral economic techniques have been developed which allow the complete transformation of a starting material into the desired enantiomer. According to a study by the market research firm of Frost and Sullivan, worldwide revenues due to chiral technology, which amounted to US 4.8 billion in 1999, will have reached more than triple the sum by 2009 — US 14.9 billion. One valuable approach is using the chiral pool as a large reservoir of optically pure building blocks, mainly derived from natural sources. 

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