Prochiral substances

The enantioselective hydrogenation of prochiral substances bearing an activated group, such as an ester, an acid or an amide, is often an important step in the industrial synthesis of fine and pharmaceutical products. In addition to the hydrogenation of /5-ketoesters into optically pure products with Raney nickel modified by tartaric acid [117], the asymmetric reduction of a-ketoesters on heterogeneous platinum catalysts modified by cinchona alkaloids (cinchonidine and cinchonine) was reported for the first time by Orito and coworkers [118-121]. Asymmetric catalysis on solid surfaces remains a very important research area for a better mechanistic understanding of the interaction between the substrate, the modifier and the catalyst [122-125], although excellent results in terms of enantiomeric excesses (up to 97%) have been obtained in the reduction of ethyl pyruvate under optimum reaction conditions with these Pt/cinchona systems [126-128],... 

Desymmetrization reactions. Cinchona alkaloids are relative abundant, morevover, the fact that the two series of quinine/cinchonidine and quinidine/cinchonine often can catalyze reactions in the opposite chirahty sense makes the use of them and their derivatives very valuable in creating new stereogenic centers from prochiral substances, in one or both optical series. 

Another impressive example of a catalytic enantioselective synthesis is the conversion of the prochiral substance 4 into the cyclic products 5 and 6 in >90% optical yield.Use of the amino acid 5-proline as the catalyst for the cyclization... 

Chiral chemical reagents can react with prochiral centers in achiral substances to give partially or completely enantiomerically pure product. An example of such processes is the preparation of enantiomerically enriched sulfoxides from achiral sulfides with the use of chiral oxidant. The reagent must preferential react with one of the two prochiral faces of the sulfide, that is, the enantiotopic electron pairs. 

The synthetic problem has now been substantially simplified. Retrosynthetic cleavage of the indicated carbon-carbon bond in 24 provides aldehyde 25 as a potential precursor. A simple carbonyl addition reaction could bring about the conversion of the latter substance to the former. Compound 25 could, in turn, be fashioned in a few straightforward steps from prochiral diol 26. 

The synthesis of the right-wing sector, compound 4, commences with the prochiral diol 26 (see Scheme 4). The latter substance is known and can be conveniently prepared in two steps from diethyl malonate via C-allylation, followed by reduction of the two ethoxy-carbonyl functions. Exposure of 26 to benzaldehyde and a catalytic amount of camphorsulfonic acid (CSA) under dehydrating conditions accomplishes the simultaneous protection of both hydroxyl groups in the form of a benzylidene acetal (see intermediate 32, Scheme 4). Interestingly, when benzylidene acetal 32 is treated with lithium aluminum hydride and aluminum trichloride (1 4) in ether at 25 °C, a Lewis acid induced reduction takes place to give... 

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. 

Asymmetric synthesis is a term first used in 1894 by E. Fischer and defined4 in 1904 by W. Markwald as a reaction which produces optically active substances from symmetrically constituted compounds with the intermediate use of optically active materials but with the exclusion of all analytical processes . A modem definition was proposed 5) by Morrison and Mosher An asymmetric synthesis is a reaction in which an achiral unit in an ensemble of substrate molecules is converted by a reactant into a chiral unit in such a manner that the stereosiomeric products (enantiomeric or diastereomeric) are formed in unequal amounts. This is to say, an asymmetric synthesis is a process which converts a prochiral6) unit into a chiral unit so that unequal amounts of stereoisomeric products result . When a prochiral molecule... 

Problem 5.25 (a) What is the necessary and sufficient condition for the existence of enantiomers (6) What is the necessary and sufficient condition for measurement of optical activity (c) Are all substances with chiral atoms optically active and resolvable (d) Are enantiomers possible in molecules that do not have chiral carbon atoms (e) Can a prochiral carbon ever be primary or tertiary (/) Can conformational enantiomers ever be resolved ... 

This possibility of intimate association of rhodium with the aromatic ring suggests further experiments. A logical extension of asymmetric syntheses involving prochir-al reactants is a kinetic resolution with related chiral reactants under similar conditions. In the one case of hydroboration-amination where this has been applied, it has proved to be very effective. The reactant was prepared directly by a Heck reaction on 1,2-dihydronaphthalene, and under the standard conditions of catalytic hydrobora-tion gave >45% of both enantiomerically pure recovered alkene with (after oxidative work-up) the alcohol of opposite hand, mainly as the trans-isomer. This procedure forms a simple and potentially useful route to pharmacologically active substances, demonstrated by the racemic synthesis shown [105] (Scheme 34). 

There are two ways of obtaining chiral substances using a chiral crystal environment. One is to produce the chiral compounds from the prochiral ones, and the other is to obtain the chiral compounds from racemic ones. The former method is called absolute asymmetric synthesis, since the asymmetry is introduced from the physical conditions such as the chiral crystal environment. Several examples [ 1 -7] have been reported since the first example of the chiral polymer produced in the photopolymerization of the chiral monomer crystal [8]. We also observed that chiral 3-lactam compounds were produced from the prochiral oxoamide crystals [9,10]. 

The development of the catalytic hydrogenation system based on RhCl(PPh3)3 and methods for the resolution of optical isomers of tertiary phosphines occurred around the same time (1965), and this led to the possibility of asymmetric catalytic hydrogenation of prochiral unsaturated substances with C=C, C=0, and C=N bonds using transition metal complexes with chiral phosphine ligands. Such tertiary phosphines are of three types ... 

When the unsaturated moiety is prochiral, the reaction stereoselectivity may deeply affect the nature of the product. In the reduction of carbonyl Mannich bases containing a chiral center, the formation of a diasteieomeiic mixture of aminoalcohols (Fig. 113) is to be expected. The relative amounts of isomers arc determined by steric hindrance of the asymmetric center as well as by the nature of the reducing agent. On varying the reaction conditions, it is often possible to affect the diastercomeric ratio of the aminoalcohols produced, so as to obtain the predominance of either isomer. This can be particularly relevant in the synthesis of pharmacologically active substances. 

The modification of aluminum or boron hydrides with chiral protic substances, such as R OH or RR NH, generates useful reagents for the asymmetric reduction of prochiral ketones or imines leading to optically active secondary alcohols and amines, respectively. Some reviews have appearered in the literature. ... 

Addition of H2 to a prochiral carbonyl double bond using catalysts modified with optically active substances yields a chiral alcohol. Despite intensive study of various chiral catalysts or ligands, synthetic utility seems limited. Optical yields are highly dependent on many variables. 

Enantioselective additions of organolithiums to prochiral ketones yield tertiary chiral alcohols, which are a synthetically highly attractive class of substances [85]. The formation of enolates via deprotonation (of a-hydrogens in the sub-... 

The essential feature for a selective synthesis of one optical isomer of a chiral substance is an asymmetric site that will bind a prochiral olefin preferentially in one conformation. The recognition of the preferred conformation can be accomplished... 

Figure 2.24 Ethanol, a substance with no chiral centres, has a prochiral CH2 group. The hydrogens of this group are assigned as pro-S and pro-R by imagining them replaced in turn by deuterium and applying the rules...

Decarboxylation of malonic acid derivatives is a well studied process in the biosynthesis of biomolecules such as long-chain fatty acids and polyketides. A decarboxylase that exhibits enantioselectivity for substituted malonates would be useful for producing ophcally active carboxylic acids, hi fact, malonyl-CoA decarboxylase does catalyze an enantioselective decarboxylation (Figure 3.2) [5], but malonyl-CoA is an unsuitable precursor for optically active substances. Instead, we focused on the prochiral-activated compoimd arylmalonate, an intermediate of malonic ester synthesis, to develop a method for enantioselective decarboxylation. Malonates are stable at room temperature but readily decompose to arylacetate and CO2 at high temperatures. This suggests that the decarboxylation of arylmalonate may occur naturally if arylmalonate acts as a substrate for a decarboxylase. 

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