Chiral pool method

To a first approximation, the chiral discrimination should be independent of the nucleophile. The palladium-catalyzed desymmetrization protocol utilizing a heterocyclic nucleophile provides enantio- and diastereoselective entries to diverse carbo-nucleosides. As shown in Scheme 8E.9, introduction of purine bases rather than the hydroxymethyl synthon also affords high enantioselectivities [61]. A variety of natural and unnatural nucleosides can be flexibly prepared because the simple change of ligand chirality or, alternatively, switching the alkylation sequence leads to opposite enantiomers. The palladium-catalyzed approach sharply contrasts with the chiral-pool method, whose enantiodivergency is limited by the availability of the starting material. 

Therefore, a practical retrosynthetic analysis was made for the intermediate [B], which was divided into three main segments, A (Q-C23), B (C1-C7, C24, C25, C26), and C (C27-C30 or C3]). We chose an acetylenic compound as segment A, because its acetylide would act as a good nucleophile for an aldehyde (segment B), and the acetylenic bond would be selectively reduced to a (Z)-olefin at an appropriate step after coupling. The chiral pool method was applied during the synthesis of each segment. 

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... 

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... 

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. 

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. 

In the case of diastereomeric mixtures of chiral hydroperoxides, standard chromatography on achiral phase can be employed to separate the diastereomers. As one example for the preparation of optically pure hydroperoxides via this method, the ex-chiral pool synthesis of the pinane hydroperoxides 11 is presented by Hamann and coworkers . From (15 )-cw-pinane [(15 )-cw-10], two optically active pinane-2-hydroperoxides cA-lla and trans-llb were obtained by autoxidation according to Scheme 17. Autoxidation of (IR)-c -pinane [(17 )-cw-10] led to the formation of the two enantiomers ent-lla and ent-llh. The ratio of cis to trans products was 4/1. The diastereomers could be separated by flash chromatography to give optically pure compounds. 

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 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. 

Reviews on Ex-Chiral-Pool Synthesis A Vasel-la. Mod. Synth. Methods 1980. 1. 

Larry Overman also used (J. Am. Chem. Soc. 2004,126, 14043) a chiral pool starting material, but in a different way. The prochiral enolate 12 showed substantial diastereoselectivity in its reaction with the bis-triflate 13, almost 10 1. Through the power of algebra, it followed that the three diastereomers of 14 were formed in a ratio of 90 9 1. The crystalline 14 was easily isolated in diastereomerically-pure form, and carried on to phenserine 15. This is a new method for the stereocontrolled construction of chiral quaternary centers. 

Around 70% of the pharmaceuticals on the market are chiral, and approximately one third of these are chiral amines [1], This represents a substantial number of achve drug substances that are typically manufactured at a scale of 1-100 l y . The three main manufacturing processes used to introduce these homochiral centers are from optically active starting materials (the so-called Chiral Pool approach), by asymmetric synthesis and by resolution. The last technique is widely practiced but results in waste of the undesired enantiomer. This chapter deals with developments in asymmetric transformations, that is to say methods for augmenting the yield of amine resolution processes to theory 100%, resulting in an alternative to asymmetric synthesis and a practical Green Chemistry solution to the synthesis of optically active amines. Figure 13.1 shows different approaches to the asymmetric transformation that will be discussed in the chapter. 

The epoxy-Ramberg-Backlund reaction (ERBR) has been used for the conversion of a,/3-epoxy sulfones into a range of mono-, di-, and tri-substituted allylic alcohols.34 Modification of this method has permitted the preparation of enantio-enriched allylic alcohols following the diastereoselective epoxidation of enantio-enriched vinyl sulfones that were accessed efficiently from the chiral pool. 

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