Substrate and reagent control

In addition to the terms defined in the previous section, the above terms are frequently used in this volume as guidelines for organization of the material. Here the subject is treated, grosso motio. according to Masamune26 who introduced the terms substrate and reagent control which are used in conjunction with syntheses of complex targets. 

Our earlier statements on substrate and reagent control of stereoselectivity during hydro-borations are incorporated in Figure 3.31. Because of the obvious analogies between the old and the new reactions, the following can be predicted about the product distribution shown ... 

If, as in the reaction example in Figure 3.32, during the addition to enantiomerically pure chiral alkenes, substrate and reagent control of diastereoselectivity act in opposite directions, we have a so-called mismatched pair. For obvious reasons it reacts with relatively little diastereoselectivity and also relatively slowly. Side reactions and, as a consequence, reduced yields are not unusual in this type of reaction. However, there are cases in which mismatched paris still give rise to highly diastereoselective reactions, just not as high as the matched pair. 

Keywords Stereogenic reactions. Mechanism control. Substrate and reagent control. Stereoselectivity, Simple diastereoselectivity, exo-endo-Diastereoselectivity, Double stereodifferentiation, Chiral catalysts, Chiraphor and catalaphor. Hybrid catalysts. Chiral auxiliary... 

A quite remarkable and useful mix of substrate and reagent control is at work in the epoxidation of olefins 15 and 16 [6],... 

Scheme 2. Substrate-controlled epoxidation of 12 and reagent-controlled epoxidation of 15.

The aldol reaction between a chiral a-amino aldehyde 16 and an acetate derived enolate 17 creates a new stereogenic center and two possible diastereomers. Several different methods for the synthesis of statine derivatives following an aldol reaction have been reported most of them lead to a mixture of the (35,45)- and (3/ ,45)-diastereomers 18 (Scheme 3), which have to be separated by laborious chromatographic methods.[17 211 Two distinct approaches for stereochemical control have been used substrate control and reagent control. 

The /3-lactone was formed by the cyclization of a 3-hydroxycarboxylic acid with sulfonyl chloride. An alternative synthesis attempted to control all stereochemical relationships in the molecule using the properties of silyl moieties attached to substrates and reagents <20040BC1051>. Stereoselective reactions of this type included the use of silyl groups in enolate alkylations, hydroboration of allylsilanes, and an anti Se2 reaction of an allenyl silane with an aldehyde and ry -silylcupration of an acetylene. The /3-lactone was again formed by the standard sulfonyl chloride cyclization method. 

Conversely, the addition of enantiomerically pure chiral dialkylboranes to enantiomerically pure chiral alkenes can also take place in such a way that substrate control and reagent control of diastereoselectivity act in the same direction. Then we have a matched pair. It reacts faster than the corresponding mismatched pair and with especially high diastereoselectivity. This approach to stereoselective synthesis is also referred to as double stereodifferentiation. 

The addition of vinyl and aryl Grignard reagents to propargyl alcohols followed by reaction with a nitrile provides access to furans and butenolides in a one-pot procedure. These reactions are believed to involve a magnesium-chelate intermediate. Highly substituted furans can be prepared with control over the substitution pattern by the judicious choice of substrates and reagents (Scheme 26) <2000TL17>. 

Asymmetric synthesis (1) Use a chiral auxiliary (chiral acetal—the synthetic equivalent of an aldehyde chiral hydrazone—the synthetic equivalent of a ketone) covalently attached to an achiral substrate to control subsequent bond formations. The auxiliary is later disconnected and recovered, if possible. (2) Use a chiral reagent to distinguish between enantiotopic faces or groups (asymmetric induction) to mediate formation of a chiral product. The substrate and reagent combine to form diastereomeric transition states. (3) Use a chiral catalyst to discriminate enantiotopic groups or faces in diastereomeric transition states but only using catalytic amounts of a chiral species. 

Achiral allylic stannaries and chiral aldehydes. Thomas has pioneered the use of allylic trichlorostannanes in various combinations of chiral substrates and reagents [92]. The simplest illustration is the reaction of in-situ generated 119 with a- and y -alkoxy aldehydes (Scheme 10-54). Not surprisingly the reactions of (S)-26 and (S)-52 ord products primarily of chelation control [93]. 

These aldols have all had just one chiral centre in the starting material. Should there be more than one, double diastereomeric induction produces matched and mismatched pairs of substrates and reagents, perfectly illustrated by the Evans aldol method applied to the syn and anti aldol products 205 themselves derived from asymmetric aldol reactions. The extra chiral centre, though carrying just a methyl group, has a big effect on the result. The absolute stereochemistry of the OPMB group is the same in both anti-205 and yvn-205 but the stereoselectivity achieved is very different. The matched case favours Felkin selectivity as well as transition state 201 but, with the mismatched pair, the two are at cross purposes. It is interesting than 1,2-control does not dominate in this case.33... 

In Sj reactions, substrate and reagent combine to form a diastereomeric transition state. In the case of auxiliary-controlled reactions, the asymmetric induction is promoted by a chiral element temporarily linked to the arene or the nucleophile. The ideal chiral auxiliary has to fulfill several requirements (i) it must be easily available in both enantiomeric forms to permit selective synthesis of both enantiomers, (ii) it must induce good stereoselectivity, (iii) the diastereomeric products must be easily separated, and (iv) cleavage of the chiral auxiliary must provide the requisite enantiomer in high yield without racanization. Additionally, an efficient work-up to allow easy recovay of expensive chiral auxiliaries is highly desirable. Most chiral auxiliaries are either natural products (alcohols, amino acids, carbohydrates, etc.) or derived from natural products. 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

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