Control reagent approach

The key issue for synthesis of pure stereoisomers, in either racemic or enantiomerically pure form, is that the configuration at newly created chiral centers must be controlled in some way. This may be accomplished in several ways. An existing functional group may control the approach of a reagent by coordination. An existing stereocenter may control reactant conformation, and thereby the direction of approach of a reagent. Whatever the detailed mechanism, the synthetic plan must include the means by which the required stereochemical control is to be achieved. When this cannot be done, the price to be paid is a separation of stereoisomers and the resulting reduction in overall yield. 

The experiments with optically active 1-propylene oxide have established clearly the need to control the polymer symmetry if crystalline products are to be obtained from monomers which contain or can yield an asymmetric centre. It follows that the main object of research in this field is to discover the manner in which certain catalysts exercise this control. One approach has been to examine a wide variety of reagents for catalytic activity in the hope that structural relationships between... 

Fully as expected from the inspection of molecular models, the generation of the oxetane ring has the effect of heightening the structural curvature in compounds such as 85 and 86. Reagent approach from the exterior should materialize under kinetically controlled conditions. These features are reflected in the catalytic hydrogenation of 86, which results in saturation of the double bond from the (3 surface along with reductive debromination to furnish 87. The lesson learned here is that the oxetane ring should be released or not formed at all if an opportunity to approach C9 from the a direction has any chance to take place. 

In the presence of oxidizing agents (e.g. sodium metaperiodate, hydrogen peroxide, m-chloroperbenzoic acid, t-butyl-hypochlorite, iodobenzene dichloride, etc.) both penicillins and cephalosporins undergo facile oxidation to either sulphoxides or sulphones. The esters of penicillin sulphox-ides (4) were described in 1949 [1]. It was found later [5] that the free acids could be oxidized by periodate. When a 6(7)-/3-acylamino side-chain is present in the molecule the resulting reagent-approach control due to the N-H proton promotes the formation of the (S)-sulphoxide (4a) [6,7]. 

In 1978, Larcheveque and coworkers reported modest yields and diastereoselectivities in alkylations of enolates of (-)-ephedrine amides. However, two years later, Evans and Takacs and Sonnet and Heath reported simultaneously that amides derived from (S)-prolinol were much more suitable substrates for such reactions. Deprotonations of these amides with LDA in the THF gave (Z)-enolates (due to allylic strain that would be associated with ( )-enolate formation) and the stereochemical outcome of the alkylation step was rationalized by assuming that the reagent approached preferentially from the less-hindered Jt-face of a chelated species such as (133 Scheme 62). When the hydroxy group of the starting prolinol amide was protected by conversion into various ether derivatives, alkylations of the corresponding lithium enolates were re-face selective. Apparently, in these cases steric factors rather than chelation effects controlled the stereoselectivity of the alkylation. It is of interest to note that enolates such as (133) are attached primarily from the 5/-face by terminal epoxides. ... 

Haubenstock and Davidson found that reduction of 3,3,5-trimethylcyclohexanone (dihydroisophorone) with the reagent is highly stereospecific but dependent upon the reaction conditions. When a solution of the ketone in benzene is added to excess reagent the product consists of 96% of the axial /rans-aicohol in this kinetic-ally controlled reduction the reagent approaches on the less hindered a-face to give... 

The factors controlling the direction of reagent approach have also been studied in norbornan-2-ones. The stereochemistry of a number of reactions of the parent system and the 7,7-dimethyl derivative have been examined. Some of the results are included in Table 2.4. These compounds reveal a reversal of the preferred direction of attack with the introduction of the 7,7-dimethyl substituents. In the parent system the exo direction of attack is preferred because the single CH2 group at C(7) offers less steric resistance than the -CH2CH2- unit on the endo side of the molecule. The endo... 

A.L Alkylation. If the aldol condensation reaction that produces 330 could be controlled, one diast-ereomer might be formed in preference to the other, making the reaction diastereoselective. There are two essential factors that control diastereoselectivity in this reaction the face from which the two reagents approach and the relative orientation of the two molecules. 

Another system in which the factors controlling the direction of reagent approach has been studied systematically is the bicyclo[2.2.1]heptene ring system. 

At reacting the syndiotactic 1,2-PB and the catalyst complex [r-BuOOH - Mo(CO)g] a steric control at approaching the reagents to the double polymer bond is carried out [21,22,25], This results in participation of less active but more available vinyl groups of macromolecules in the reaction (Table 3.1, Scheme 1). 

A satisfying explanation of this remarkable reagent control is not easy. Suffice it to state that the space-demanding tert-butylperoxide reagent approaches the molecule from the less hindered a-side. 

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