Optically active products

It IS a general principle that optically active products cannot be formed when opti cally inactive substrates react with optically inactive reagents This principle holds irre spective of whether the addition is syn or anti concerted or stepwise No matter how many steps are involved m a reaction if the reactants are achiral formation of one enan tiomer is just as likely as the other and a racemic mixture results... 

Optically inactive starting materials can give optically active products only if they are treated with an optically active reagent or if the reaction is catalyzed by an optically active substance The best examples are found m biochemical processes Most bio chemical reactions are catalyzed by enzymes Enzymes are chiral and enantiomerically homogeneous they provide an asymmetric environment m which chemical reaction can take place Ordinarily enzyme catalyzed reactions occur with such a high level of stereo selectivity that one enantiomer of a substance is formed exclusively even when the sub strate is achiral The enzyme fumarase for example catalyzes hydration of the double bond of fumaric acid to malic acid m apples and other fruits Only the S enantiomer of malic acid is formed m this reaction... 

Section 7 9 A chemical reaction can convert an achiral substance to a chiral one If the product contains a single chirality center it is formed as a racemic mixture Optically active products can be formed from optically inactive... 

Trimethyl(l-phenyl-2-propenyl)silane of high enantiomeric excess has also been prepared by asymmetric cross coupling, and reacts with aldehydes to give optically active products in the presence of titanium(IV) chloride. The stereoselectivity of these reactions is consistent with the antiperiplanar process previously outlined75. 

A solution of the sulfoxide in THF is added to a slight molar excess of LDA in Till- while maintaining the temperature below —75 C. then the a-haloester is added dropwisc to the yellowish solution of the anion at the same temperature. The usual workup gives optically active product in high yield. 

Subsequently, a number of reactions at poly-L-valine coated carbon electrodes 237-243) gj.g reported to yield optically active products. Reductions, e.g. of citraconic acid or l,l-dibromo-2,2-diphenylcyclopropane as well as the oxidation of aryl-alkyl sulfides proceeded with chiral induction at such electrodes... 

In the special case of the prochiral carboxylic acids (36), dehydrohalogenation with an optically active lithium amide gave an optically active product with enantiomeric excesses as high as 82%. 

Some solid-solid reactions were shown to proceed efficiently in a water suspension medium in Sect. 2.1. When this reaction, which gives a racemic product, is combined with an enantioselective inclusion complexation with a chiral host in a water suspension medium, a unique one-pot preparative method of optically active product in a water medium can be constructed. Some such successful examples are described. 

Asymmetric Allylation. One of the recent new developments on this subject is the asymmetric allylation reaction. It was found that native and trimethylated cyclodextrins (CDs) promote enantiose-lective allylation of 2-cyclohexenone and aldehydes using Zn dust and alkyl halides in 5 1 H2O-THF. Moderately optically active products with ee up to 50% were obtained.188 The results can be rationalized in terms of the formation of inclusion complexes between the substrates and the CDs and of their interaction with the surface of the metal. 

Bromination of an optically active form of the corresponding chloro compound (l-chloro-2-methylbutane) also results in an optically active product, and retention of configuration. It may be that an actual bridged radical is formed, but a somewhat less concrete interaction seems more likely, as halogenation with the more reactive chlorine is found to lead wholly to racemisation. 

Optically active product(s) requires chiral reactants, reagents, and/or solvents ... 

It will be noted that the non-planar propeller form lacks a plane of symmetry and that the production of optically active products by way of an intermediate radical might therefore be possible. Attempts to make precursory optically active phenylxenyl-a-naphthylmethyl halides failed, but the corresponding active thioglycolic acid has been prepared. It is racemized by the reaction with triphenylmethyl free radicals.19 Various other reactions believed to involve radical intermediates also give inactive products ... 

In the kinetic resolution, the yield of desired optically active product cannot exceed 50% based on the racemic substrate, even if the chiral-discriminating ability of the chiral catalyst is extremely high. In order to obtain one diastereomer selectively, the conversion must be suppressed to less than 50%, while in order to obtain one enantiomer of the starting material selectively, a higher than 50% conversion is required. If the stereogenic center is labile in the racemic substrate, one can convert the substrate completely to gain almost 100% yield of the diastereomer formation by utilizing dynamic stereomutation. 

If the catalyst is chiral, it can transfer hydride selectively to one prochiral face of an acceptor to provide an optically active product (Fig. 35.1). 

Homogeneous enantioselective hydrogenation constitutes one of the most versatile and effective methods to convert prochiral substrates to valuable optically active products. Recent progress makes it possible to synthesize a variety of chiral compounds with outstanding levels of efficiency and enantioselectivity through the reduction of the C=C, C=N, and C=0 bonds. The asymmetric hydrogenation of functionalized C=C bonds, such as enamide substrates, provides access to various valuable products such as amino acids, pharmaceuticals, and... 

Miyafuji and Katsuki95 reported the desymmetrization of meso-tetrahydrofuran derivatives via highly enantioselective C-H oxidation using Mn-salen catalysts. The optically active product lactols (up to 90% ee) are useful chiral building blocks for organic synthesis (Scheme 8-48). 

Another achievement in recent asymmetric reaction study is the so-called chiral autocatalysis—where the product itself catalyzes its own asymmetric synthesis. In this process, the chiral catalyst and the products are the same in an asymmetric autocatalytic reaction. The separation of chiral catalyst from the product is not required, because the product itself is the catalyst. Starting from an optically active product with very low ee, this process allows the formation of a product with high ee values.106,114... 

The addition of trimethylsilyl (TMS) cyanide to aldehydes produces TMS-protected cyanohydrins. In a recent investigation a titanium salen-type catalyst has been employed to catalyse trimethylsilylcyanide addition to benzaldehyde at ambient temperature1118]. Several other protocols have been published which also lead to optically active products. One of the more successful has been described by Abiko et al. employing a yttrium complex derived from the chiral 1,3-diketone (41)[119] as the catalyst, while Shibasaki has used BINOL, modified so as to incorporate Lewis base units adjacent to the phenol moieties, as the chiral complexing agent11201. 

In this volume we indicate some of the different natural and non-natural catalysts for hydrolysis, oxidation, reduction and carbon-carbon bond forming reactions leading to optically active products. Literature references are given to assist the reader to pertinent reviews. The list of references is not in the least comprehensive and is meant to be an indicator rather than an exhaustive compilation. It includes references up to mid-1999 together with a handful of more recent reports. 

When applied to an optically active substrate (4) derived from nerol or geraniol, optically active products (5) are obtained in about 50% yield with a diastereose-lectivity of 5-9 1. 

Related phosphine-substituted derivatives were also obtained, and the chirality of the clusters demonstrated by the NMR spectra of the compounds (246). Molecules of this type have obvious utility in establishing the potential intermediacy of the polynuclear adduct in a catalytic reaction by the formation of optically active products. 

There are two possible approaches for the preparation of optically active products by chemical transformation of optically inactive starting materials kinetic resolution and asymmetric synthesis [44,87], For both types of reactions there is one principle in order to make an optically active compound we need another optically active compound. A kinetic resolution depends on the fact that two enantiomers of a racemate react at different rates with a chiral reagent or catalyst. Accordingly, an asymmetric synthesis involves the creation of an asymmetric center that occurs by chiral discrimination of equivalent groups in an achiral starting material. This can be done either by enan-tioselective (which involves the reaction of a prochiral molecule with a chiral substance) or diastereoselective (which involves the preferential formation of a single diastereomer by the creation of a new asymmetric center in a chiral molecule) synthesis. 

One of the oldest mechanisms of interaction between adsorbed reactant and adsorbed TA has been proposed by Klabunovskii and Petrov [212], They suggested that the reactant adsorbs stere-oselectively onto the modified catalyst surface. The subsequent surface reaction is itself nonstere-ospecific. Therefore, the optically active product is a result of the initial stereoselective adsorption of the reactant, which in turn, is a consequence of the interactions between reactant, modifier, and catalyst. The entities form an intermediate chelate complex where reactant and modifier are bound to the same surface atom (Scheme 14.4). The orientation of the reactant in such a complex is determined by the most stable configuration of the overall complex intermediate. The mechanism predicts that OY only depends on the relative concentrations of keto and enol forms of the reactant,... 

Which are the possible approaches for the preparation of optically active products by chemical transformation of optically inactive starting materials ... 

Rychnovsky et al. considered the formation of achiral conformers from chiral molecules and trapping the prochiral radical with a hydrogen atom donor based on memory of chirality (Scheme 12) [41], The photo-decarboxylation of optically active tetrahydropyran 40 leads to an intermediate 43, which now does not contain a stereocenter. If the intermediate 43 can be trapped by some hydrogen atom source before ring inversion takes place, then an optically active product 41 will be formed. This is an example of conformational memory effect in a radical reaction. It was reported that the radical inversion barrier is low (< 0.5 kcal/mol) while the energy for chair flip 43 44 is higher (5 to... 

DPIBF, which does not apply at 53 °C. These findings are in line with a calculated barrier to enantiomerization of 15-18 kcalmol-1 (see Scheme 6.3). In their second investigation, Balci and Jones [46] eliminated hydrogen bromide from 32b at 53 °C with a pure enantiomer of potassium menthoxide in the presence of DPIBF, which gave rise to optically active products 50. Again, racemic products were formed on repetition of the experiment at 100 °C. Here, the base causes an enantioselective elimination from 32b with formation of non-racemic 6, which is trapped at 53 °C before complete racemization occurs. 

Chiral amino alcohols react with achiral nitroalkenes such as 1-nitrocyclohexene almost stereospecifically to give optically active products, e.g. equation 96305. 

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