Nonchiral synthesis

Typical production batches of nerve agents formerly intended for military use are mixtures of enantiomers obtained from nonchiral synthesis (Figure 50.1). Sarin, cyclosarin, tabun, and VX consist of mixtures of two enantiomers each of which differs in the chirality at the central phosphorus atom thus enabling rotation of linearly polarized light clockwise [P(+)-enantiomers] or anticlockwise [P(—)-enantiomers] (Figure 50.1). In contrast, chirality of soman appears more complex based on two chiral centers, which reside at the phosphorus atom, P(-f) and P(—), and additionally in the pinacolyl moiety, C(-f) and C( ). Hence, soman occurs in four stereoisomeric conformations as two pairs of diastereomers P(-E)C(+),... 

Enantiomer separation is of special importance in the pharamaceutical and clinical helds as many drugs are made of asymmetric molecules. Both forms as obtained by common (nonchiral) synthesis often produce different effects in the body and the pharmacokinetics may also differ. 

Scheme 5.14. Nonchiral synthesis of 7,8-dehydro analogs of LTA4 and LTD4.

Flash chromatography is widely employed for the purification of crude products obtained by synthesis at a research laboratory scale (several grams) or isolated as extracts from natural products or fermentations. The solid support is based on silica gel, and the mobile phase is usually a mixture of a hydrocarbon, such as hexane or heptane, with an organic modifier, e.g. ethyl acetate, driven by low pressure air. (Recently the comparison of flash chromatography with countercurrent chromatography (CCC), a technique particularly adapted to preparative purposes, has been studied for the separation of nonchiral compounds [90].)... 

The second section of the book, entitled Total Synthesis of Carbohydrates , focuses on strategies for the generation of monomeric carbohydrates, with major emphasis on the use of nonchiral, acyclic precursors. The contributors do not reinvent the wheel by providing tedious synthetic access to abundant natural sugars. Rather, they show... 

Following route A (Fig. 1), Yan Xiao et al. reported the chemoenzymatic synthesis of poly(8-caprolactone) (PCL) and chiral poly(4-methyl-8-caprolactone) (PMCL) microparticles [5]. The telechelic polymer diol precursors were obtained by enzymatic polymerization of the corresponding monomers in the presence of hexanediol. Enzymatic kinetic resolution polymerization directly yielded the (R)-and (S )-enriched chiral polymers. After acrylation using acryloylchloride, the chiral and nonchiral particles were obtained by crosslinking in an oil-in-water emulsion photopolymerization. Preliminary degradation experiments showed that the stereoselectivity of CALB is retained in the degradation of the chiral microparticles (Fig. 2). 

Asymmetric synthesis using nonchiral crystals was also performed. See [lb] and (a) Chenchaiah, P. C., Holland, H. L., and Richardson, M. F. (1982) A new approach to the synthesis of chiral molecules from nonchiral reactants. Asymmetric induction by reaction at one surface of a single (nonchiral) crystal, J. Chem. Soc. Chem. Commun., 436-437. (b) Chenchaiah, P. C., Holland, H. L., Munoz, B., and Richardson, M. F. (1986) Synthesis of chiral molecules from non-chiral crystals by controlled reaction at a single surface, J. Chem. Soc. Perkin Trans. 2, 1775-1777. 

Another use of compound (1) involves synthesis of NADH models incorporating chiral and nonchiral l/f-pyrrolo[2,3-6]pyridine derivatives. In this latter application, the products derived from compound (1) have been useful for the study of systems that were unreactive with similar reagents. By the appropriate manipulation of reaction conditions, products derived from compound (1) selectively form either (but only one) enantiomer in reduction of a prochiral ketone. Finally, the products derived from compound (1) are useful reagents in the preparation of chiral precursors of target molecules <91T429>. 

The solid-state photoreaction using chiral crystals is an absolute asymmetrical synthesis crystallization of a nonchiral compound in a chiral crystal followed by a topochemical photoreaction. A similar interesting case of absolute asymmetrical synthesis has been reported by others including Addadi et al. [54]. 

Asymmetric synthesis using nonchiral crystals was also performed. 

Currently there is a trend toward the synthesis and large-scale production of a single active enantiomer in the pharmaceutical industry [61-63]. In addition, in some cases a racemic drug formulation may contain an enantiomer that will be more potent (pharmacologically active) than the other enantiomer(s). For example, carvedilol, a drug that interacts with adrenoceptors, has one chiral center yielding two enantiomers. The (-)-enantiomer is a potent beta-receptor blocker while the (-i-)-enantiomer is about 100-fold weaker at the beta-receptor. Ketamine is an intravenous anesthetic where the (+)-enantiomer is more potent and less toxic than the (-)-enantiomer. Furthermore, the possibility of in vivo chiral inversion—that is, prochiral chiral, chiral nonchiral, chiral diastereoisomer, and chiral chiral transformations—could create critical issues in the interpretation of the metabolism and pharmacokinetics of the drug. Therefore, selective analytical methods for separations of enantionmers and diastereomers, where applicable, are inherently important. 

McCarthy and coworkers126 229 reported a template-guided synthesis of water-soluble chiral PAn nanocomposites. The nanoparticles were prepared by the physical adsorption of aniline monomer onto a templating poly(acrylic acid) in the presence of (+)- or (-)-CSA, followed by chemical oxidation. Using this approach, optically active nanocomposites of approximately 100 nm diameter were formed. Earlier work by Sun and Yang230 using polyelectrolytes produced similar nonchiral dispersions in which the PAn chain is interwound with a water-soluble polymer by electrostatic forces.231 Similar work by Samuelson and coworkers utilized DNA as a chiral template for PAn.232... 

First encouraging results for a stereoselective synthesis in general were reported by Seebach in 1982, who investigated the syn/anti-diastereoselectivity starting from achiral aldehydes and nitroalkanes [4,5]. Barrett et al. examined the influence of nonchiral Lewis acids on the syn/anti diastereoselectivity [6]. Stoichiometric amounts of an enantiomerically pure aldehyde were used in a di-astereoselective reaction with 3-nitropropionate by Hanessian et al. [7]. However, an approach to enantioselective synthesis of nitroalcohols via the route of the asymmetric Henry reaction could not be carried out until almost one hundred years after the discovery of the nitroaldol reaction. 

In 1968 Knowles at Monsanto Company, St. Louis showed that a chiral transition metal based catalyst could transfer chirality to a nonchiral substrate resulting in a chiral product with one of the enantiomers in excess. Knowles s aim was to develop an industrial synthesis process for the rare amino acid LDOPA which had proved useful in the treatment of Parkinson s... 

Thus, traMi-3-alkyl-6-(phthalimido)cyclopentenes were prepared in excellent to modest yields from the corresponding tran -chloroalkene by the palladium coupling reaction [84d]. Inexpensive and efficient Pd-TMG systems, Pd(OAc)2-TMG or PdC -TMG, have been developed for the Heck reaction of an olefin with an aryl halide, in which TMG (1) acts as a ligand [84e]. In the reaction of iodobenzene with butyl acrylate the turnover numbers were up to 1000000. TMG (1) was used as a base for the palladium catalysed asymmetric Wagner-Meerwein shift of nonchiral vinylcyclopropane and cyclobutane derivatives leading to asymmetric synthesis of cyclobutanones, cyclopentenones, y-butyrolactones and 5-valerolactones [85] (Scheme 4.34). Replacement of TMG (1) with an inorganic bases such as lithium or cesium carbonate resulted in little effect. 

Synthesis starting with a nonchiral substrate and a chiral auxiliary that is attached to the substrate and is removed after serving its purpose... 

Synthesis starting with a nonchiral substrate that is directly converted to the chiral product by using a chiral reagent... 

Synthesis using a chiral catalyst to direct the conversion of a nonchiral substrate to the desired chiral product. 

Although the SMB technique can be used for solving both chiral and nonchiral separation problems, the focus of actual research topics is in the area of chiral separations. This is because for chiral separations alternative processes such as asymmetric crystallization or enantioselective synthesis are either difficult or in addition also expensive and time consuming. Furthermore, these separation problems can often be brought down to binary separations. 

Total Synthesis Using Chiral Nonchiral Pool Sources 405... 

Total Synthesis of Hyacinthacines from Nonchiral Pool Sources... 

While most of the syntheses of hyacinthacines are based on the modification and elaboration of precursors from the chiral pool, less effort has been directed toward the construction of the pyrrolizidine skeleton using non-natural precursors. This chapter summarizes racemic as well as enantioselective total synthesis of hyacinthacines reported to date, which start from nonchiral pool sources. In this context, biocatalysis constitutes the most widely used alternative to the chiral pool approach. Enzymatic kinetic resolution using lipases but also aldolase-mediated reactions have been successfully employed to provide precursors that were later elaborated toward hyacinthacines. Synthetic chiral auxiliaries have also been used successfully in this context. 

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