Prochirality, defined

The general subject of asymmetric synthesis has been reviewed extensively (1-5). The term asymmetric synthesis has been defined in more than one way (1,4) however, a useful definition is the one given by Morrison and Mosher (1) a process which converts a prochiral unit [refs. 6 and 7] into a chiral unit so that unequal amounts of stereoisomeric products result. The stereoisomeric products may be enantiomeric or they may be diastereomeric. The substrate molecule must contain either enantiotopic or diastereotopic groups or faces (8,9), since the attack of a reagent at equivalent groups or faces cannot lead to isomeric products. 

The process of obtaining homochiral product from a prochiral starting material is known as asymmetrization. This encompasses reactions where a faster rate of attack of a reactive species occurs on one enantiotopic face of a prochiral trigonal biplanar system, or at one enantiotopic substituent of a C2 symmetrical system, resulting in the preferential formation of one product enantiomer. The latter is also frequently referred to as the meso-trick or desymmetrization . These transformations can be more easily defined in pictorial form (Figure 1.8). 

Isotactic polymer that contains two chiral or prochiral atoms with defined stereochemistry in the main chain of the configurational base unit. 

Define chiral, enantomer, diastereomer, epimer, anomer (see Chapter 4), prochiral (see Chapter 9). What is meant by the statement that biochemical reactions are stereochemically specific Why is such stereospecificity to be expected in organisms (which are constructed from asymmetric units) See Chapter 9 for further discussion. 

At this point mechanistic studies have reached an impasse. All of the observable intermediates have been characterized in solution, and enamide complexes derived from diphos and chiraphos have been defined by X-ray structure analysis. Based on limited NMR and X-ray evidence it appears that the preferred configuration of an enamide complex has the olefin face bonded to rhodium that is opposite to the one to which hydrogen is transferred. There are now four crystal structures of chiral biphosphine rhodium diolefin complexes, and consideration of these leads to a prediction of the direction of hydrogenation. The crux of the argument is that nonbonded interactions between pairs of prochiral phenyl rings and the substrate determine the optical yield and that X-ray structures reveal a systematic relationship between P-phenyl orientation and product configuration. 

Often (e.g. in asymmetric synthesis) one is interested in the fact that in certain molecules, such as propionic acid (2, Fig. 1), an achiral center (here C ) can be transformed into a chiral center by replacement of one or other of two apparently identical1 ligands2 by a different one. Thus the replacement of HA at C in propionic add (Fig. 1) by OH generates the chiral center of (lactic acid. C in propionic acid is therefore called a prochiral center 4) HA and HB are called heterotopic ligands 5 7) (from Greek heteros = different and topos" = place — see also below). Prochiral axes and planes may similarly be defined in relation to chiral axes and planes (see below)... 

High resolution NMR studies, in combination with molecular mechanics, were performed to unequivocally assign the prochiral P-protons for the phenylalanine sidechain and to define the shape of the sweet receptor [49], The previous assignment [48] of the NMR signals for the P-protons of phenylalanine was shown to be in error. 

In all the examples of exodendrally functionalized enantioselective den-drimer catalysts, the active sites in the periphery of the support were well-defined immobilized molecular catalysts. An alternative is provided by the possibility of attaching chiral multi-functional molecules to the end groups of dendrimers which, due to their high local concentrations, may interact more or less strongly with an achiral reagent and thus induce enantioselectivity in a transformation of a prochiral substrate. Asymmetric induction thus occurs by way of a chiral functionalized microenvironment for a given reaction. 

Enantioselective reactions are defined as transformations in which a prochiral substrate is converted into a chiral product such that one of the two enantiomers is formed in significant excess. The degree of enantioselectivity is measured by the enantiomeric excess (ee), as defined in Scheme 1. In this schematic example the prochiral substrate S represented by a triangle, is converted into the two enantiomeric, chiral tetrahedral products P1 and ent-P1 (enantioface-differentiat-ing reaction). Alternatively, but less commonly used, enantioselectivity can be induced by the differentiation of enantiotopic substituents, as depicted for S2 and Y 2lent-P2. 

In summary, chiral solvents have only induced limited enantioselectivity into different types of photochemical reactions as pinacolization, cyclization, and isomerization reactions. These studies are nevertheless very important, because they are among the early examples of chiral induction by an asymmetric environ ment. Based on our classification of chiral solvents as chiral inductors that only act as passive reaction matrices, effective asymmetric induction by this means seems to be intrinsically difficult. From the observed enantioselectivities it can be postulated that defined interactions with the prochiral substrate during the conversion to the product are a prerequisite for effective template induced enantioselectivity. 

Because the energies of the enantiomeric (prochiral) 1-phenylethyI/l-naphthoxy radical parrs from (R)-3h and their rate constants leading to (/f)-3b and (5)-3b are the same,S = 2Bj v/(l inv Fret). wheref i vand/ retaretheprobabilitiesthataradical pair will form the (S)- and (F)-enantiomers of 3b, respectively. The expressions for Finv, Fret, and S based on Scheme 13.5 are very complex, and even it does not describe all of the processes involved in the tumbling of the 1-phenylethyl radicals because F, really should not be described by one rate constant. To do so requires the introduction of Ft 3, and Ft 4B, defined as the specific tumbling rate constants inside a cage for... 

SUylenes with two different substituents, R R Si, are prochiral, and insertion into an alcoholic RO-H bond should create chirality on the silicon. In particular, if one of the two substituents is chiral, a diastereotopic face can be defined and diastereoselective addition can be expected. Quite recently, the first example of diastreoselective addition of alcohol to diastereotopic silylene has been reported. ... 

Song / t/. have designed a series of structurally and electronically well-defined (72-symmetric chiral ketones 84-86 for use in the epoxidation of unfunctionalized olefins (max. 59% ee for /ra r-stilbene oxide) <1997TA2921>. Adam reported the synthesis and application of chiral (72-symmetric ketones 87 and 88, derived from mannitol and TADDOL, respectively, in the epoxidation of prochiral olefins (ee s up to 80.5%) (TADDOL = (-)-/ra r-4,5-bis(diphenyl-hydroxymethyl)-2,2-dimethyl-l,3-dioxolane) <1997TA3995>. 

The factors which direct the diene to the top (Ca re) or bottom face (Ca si) of dienophile (XXXI) may be of steric and/or stereoelectronic origin. Moreover, the overall stereofacial bias is intrinsically dependent on the conformation of (XXXI). Thus the rotational freedom around the single bonds which link the chiral and prochiral centers in (XXXI) needs to be restricted in a well-defined manner. 

Note that new terminology has been proposed. The concept of sphericity is used, and the terms homospheric, enantiospheric, and hemispheric have been coined to specify the nature of an orbit (an equivalent class) assigned to a coset representation. Using these terms, prochirality can be defined if a molecule has at least one enantiospheric orbit, the molecule is defined as being prochiral. ... 

This chapter is concerned in part with prochirality. In order to define terms we consider sp3 and sp2 hybridized carbons separately. 

Optimization of the enantioselective catalytic key steps calls for careful experimental investigation of many reaction parameters. Besides temperature, concentration of substrate, solvent effects, pressure, and conversion rate, a defined robustness of the process towards impurities, for example contained in reagents, as well as its sensitivity towards air (oxygen) or moisture at various temperatures are important aspects. In particular, the purity of prochiral substrates is of utmost importance for the success of asymmetric hydrogenation experiments. As a consequence, considerable attention had to be paid to even the smallest differences in the impurity profile of substrates, which may be due to different preparation and/or purification procedures at lab, pilot, or production scale. 

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