Chiral non-racemic substrates

Perhaps the simplest way to control the absolute stereochemistry at a newly formed stereogenic element involves the use of an enantiomerically pure substrate.3 In this case, the stereochemical information is transferred from the already present stereogenic element(s) (most likely, one (or more) stereocenter(s)) to the new one(s), in a process often, but somehow misleadingly, referred to as asymmetric induction .4 

The (iS)-configurated aldehyde of reaction A possesses two diastereotopic carbonyl faces. Thus, the two possible attacks of the Grignard reagent (on the Re or on the Si face) are diastereotopically related. The reaction leads to the formation of an excess of the syn isomer over the anti one [9], as predicted by the Cram-Felkin-Anh rule [10]. 

3 The substrate is a reactant whose structural features are almost entirely maintained throughout a reaction sequence. A reagent contributes to the target molecule only a part of its atomic components. 

4 On the basis of simple symmetry considerations it is obvious that in this type of process the asymmetry of the substrate is maintained throughout the reaction to the product independently of the creation of a new stereocenter. 

This model, as are many other rationalizations of the steric course of a stereoselective reaction, is based on a combination of stereochemical factors (such as the preferential conformations around the bond(s) connecting the stereocenter and the reacting carbon, and the relative steric requirements of the substituents at the stereocenter) and stereoelectronic effects (such as the substrate/reagent orbital interactions and the direction of attack of the nucleophile on the carbonyl). 

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The diastereoselectivities that can be achieved in the transformations of chiral, non-racemic substrates can be improved in certain cases by use of a chiral catalyst [10]. Because of the effect of double diastereoselection the correct absolute configuration of the catalyst is important. Hoveyda et al. chose the chiral ansa-zirconocene derivative 31, which can be synthesized according to a method described by Brintzinger (Scheme 3) [11]. 

Figure 2. Examples of stereoselective formation of new stereocenters by reaction of chiral non-racemic substrates with achiral reagents.

The different stereoselective routes explored toward the synthesis of the tricyclic p-lactam sanfetrinem cilexetil (GV 118819) [45] perfectly illustrate advantages and drawbacks of the approach to enantiomerically pure drugs based on the use of commercially available chiral non-racemic substrates. 

This topically active carbonic anhydrase inhibitor is a powerful controller of the elevated intraocular pressure associated with glaucoma, and has been prepared by Merck in > 32% yield in a multistep synthesis starting from (R)-3-hydroxybutyrate [49]. Although the key ketone reduction step has been recently improved by researchers at Zeneca by replacing a chemical process with a biological one [50], the Merck synthesis well illustrates the potentialities of the approach to enantiomerically pure drugs based on the use of chiral non-racemic substrates. 

The deprotonation of a stereogenic carbon in chiral non-racemic substrates with KHMDS has been used as a first step of sequences relying on the memory of chirality for asymmetric synthesis of organic products. The treatment of Al-Boc-protected amino esters featuring a Michael acceptor group with KHMDS in DMF-THF (1 1) at —78°C for 30 min provided trisubstituted pyrrolidines, piperidines and tetrahydroisoquinolines, and in good yields (65-74%) and diastereoselectivities (4 1 for pyrrolidine, and 1 0 for piperidines and tetrahydroisoquinoline) and excellent enantiomeric excesses (91-98% ee) (eqs 66 and 67). ... 

Another approach to the synthesis of chiral non-racemic hydroxyalkyl sulfones used enzyme-catalysed kinetic resolution of racemic substrates. In the first attempt. Porcine pancreas lipase was applied to acylate racemic (3, y and 8-hydroxyalkyl sulfones using trichloroethyl butyrate. Although both enantiomers of the products could be obtained, their enantiomeric excesses were only low to moderate. Recently, we have found that a stereoselective acetylation of racemic p-hydroxyalkyl sulfones can be successfully carried out using several lipases, among which CAL-B and lipase PS (AMANO) proved most efficient. Moreover, application of a dynamic kinetic resolution procedure, in which lipase-promoted kinetic resolution was combined with a concomitant ruthenium-catalysed racem-ization of the substrates, gave the corresponding p-acetoxyalkyl sulfones 8 in yields... 

However, the most common and important method of synthesis of chiral non-racemic hydroxy phosphoryl compounds has been the resolution of racemic substrates via a hydrolytic enzyme-promoted acylation of the hydroxy group or hydrolysis of the 0-acyl derivatives, both carried out under kinetic resolution conditions. The first attempts date from the early 1990s and have since been followed by a number of papers describing the use of a variety of enzymes and various types of organophosphorus substrates, differing both by the substituents at phosphorus and by the kind of hydroxy (acetoxy)-containing side chain. 

The phosphonium salt 21 having a multiple hydrogen-bonding site which would interact with the substrate anion was applied to the phase transfer catalyzed asymmetric benzylation of the p-keto ester 20,[18 191 giving the benzylated P-keto ester 22 in 44% yield with 50% ee, shown in Scheme 7 Although the chemical yield and enantiomeric excess remain to be improved, the method will suggest a new approach to the design of chiral non-racemic phase transfer catalysts. 

This preparation was previously described by Brandsma. Substrate 1 can be prepared In enantiomericeilly pure form beginning with chiral, non-racemic styrene oxide, available as either antipode from Aldrich Chemical Company, Inc., or by kinetic resolution of racemic styrene oxide. ... 

At about the same time of the work on diastereoselective fluorination, chiral non-racemic N-fluoro compounds for direct enantioselective fluorination of C H acidic substrates were developed. 

In this approach the substrate is attached to a chiral, non-racemic unit that controls the formation of one or more new chiral groups. Reaction of the coupled unit with a reagent or prochiral substrate is designed to produce one diastereomeric product in excess. The auxil-... 

This article presents a review of recent advances in the catalytic addition of alkylmetal reagents to olefins, excluding reactions that involve unsaturated carbonyl compounds as substrates (conjugate addition) [2]. As described below, these reactions provide efficient and selective routes to the synthesis of a wide variety of chiral, non-racemic organic molecules that can be used in the fabrication of a number of highly functionalized molecules. 

This process, that resolves enantiomers on the basis of their different reaction rates, is called kinetic resolution [28], Conceptually it is similar to the reactions of Fig. 4, as the enantiomerically pure reagent (in this context, the kinetic resolving agent) differentiates between the two enantiomerically related molecules of the racemic substrate. Obviously, in the reactions of Fig. 4 it is one molecule that features the enantiomerically related entities (e.g., the two carbonyl faces of benzaldehyde) which are differentiated by the chiral non-racemic reagent. 

In section 2.2.1.3 the stereoselective reactions of an achiral substrate with a stoichiometric amount of a chiral non-racemic species were described. 

A variety of chiral, non-racemic zirconium complexes were explored in attempts to develop an enantioselective variant of this reaction (Scheme 3) [7-9]. Eor example, when allyUc amines lla,b were treated with EtMgCl and 10% of C2-symmetric BINOL-zirconium bis(tetrahydroindenyl)ethane (12, Brintzinger s catalyst [10], BINOL is l,l -binaphthalene 2,2 -dioate), chiral ethylated products 13a,b were obtained in 34-39% yield with enantiomeric excesses (ee) of ca. 26% [8]. Use of a (neomenthylindene)ZrCpCl2 catalyst 14, designed to improve the steric differentiation of the diastereomeric transition states, improved the chemical yields of amines at lower catalyst loadings (2-4%) and increased the ees of the reactions by a factor of three in the case of 11a [8,9]. Similar reactivity is observed in zirconocene dichloride-catalyzed cyclization of 1,6- and 1,7-enynes with 12.5% Cp2ZrCl2 using EtsAl as the stoichiometric reductant. For these substrates, the alkyne coordinates... 

A point of further significance is whether the chirality of a non-racemic substrate would be transferred to the cycloadduct. Based on the high diasteieoselectivity and unparalleled efficiency of the cy-cloaddition of allene-vinylcyclopropane 58, this substrate was selected to study chirality transfer. This substrate is prepared from ethylene glycol in 10 steps. In the presence of 1 mol% RhCl(PPh3)j... 

Kinetic resolutions (KR) are reactions that occur at different rates with the two enantiomers of a chiral substrate. A kinetic resolution generates two sets of chiral, non-racemic materials. It generates a non-racemic mixture of the substrate enantiomers enriched in the less reactive of the two enantiomers, and it generates a non-racemic mixture of the product resulting from the predominant reaction of the more reactive enantiomer of the substrate. Because the reactant and product have different physical properties, they can be separated more easily than two enantiomers. 

A few years after this first report, a chiral non-racemic phosphonium yhde 4 having a stereogenic phosphorus center was prepared and used for asymmetric olefination (Scheme 7.2). Here, it was reported that monocarbonyl substrates 1 were converted into the olefinic products in enantiomerically enriched form, al-... 

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