Asymmetric synthesis auxiliary controlled, examples

Control of absolute asymmetry is a relatively untouched area for [2 + 2] photochemical cycloaddition reactions despite the recent advances in the field of asymmetric synthesis. The first example of the use of a removable chiral auxiliary was reported by Tolbert, who obtained impressive enantioselectivity in the photocycloaddition of bomyl fumarate to stilbenes (equation 37). More recently, Lange has shown that menthyl cyclohexenonecarboxylates are useful in control of absolute stereochemistry (equation 38). Baldwin and Meyers have also obtained excellent facial selectivity in systems where the stereogenic center which controls the diastereoselectivity can be excised to afford products of high enantiomeric purity (equations 39,40). 

A chiral carbon present in the alcohol portion of acetals might control the stereochemistry of the allylation. A few examples conducted in the presence of a titanium Lewis acid are shown in Eqs (82) [225], (83) [226], and (84) [227]. In contrast, an allylsilane with a chiral auxiliary derived from arabinose on the silicon atom has been used for asymmetric synthesis, although diastereoselectivity was low [228],... 

Upon was the use of chiral auxiliaries as counter ions of the carboxylate examples in (38a) and (39a). The authors conclude that the ionic chiral auxiliary approach is a viable general method for asymmetric synthesis. The irradiation of the biphenyl ketoamide (40) at 340 nm affords the two products (41) and (42) via the conventional Norrish Type II hydrogen abstraction process. When the reaction is carried out in the presence of an antibody microenvironment the reaction follows a different route and yields the tetrahy-dropyrazine derivative (43). The authors reason that there is interplay between conformational control and chemical catalysis that results in this high specificity. 

The latter work is a rare example in which a high stereoselectivity was reported for a substrate-controlled Ugi synthesis. In asymmetric Ugi reactions carried out with removable chiral auxiliaries, however, high diastei eoselections were achieved (see Section 1.4.4.3.1.). 

The utility of thiazolidinethione chiral auxiliaries in asymmetric aldol reactions is amply demonstrated in a recent enantioselective synthesis of apoptolidinone. This synthesis features three thiazolidinethione propionate aldol reactions for controlling the configuration of 6 of 12 stereogenio centers <05JA13810>. For example, addition of aldehyde 146 to the enolate solution of A -propionyl thiazolidinethione 145 produces aldol product 147 with excellent selectivity (>98 2) for the Evans syn isomer. Compound 145 also undergoes diastereoselective aldol addition with bisaryl aldehyde 148 to give the Evans syn product 149, which is converted to eupomatilone-6 in 6 steps <05JOC9658>. 

There are many synthetic techniques for stereoselective synthesis and because of the importance much research is currently devoted to expanding these techniques. Omeprazole, marketed as Prilosec , was the first proton pump inhibitor and is used as a treatment for gastric ulcers. It is a racemic mixture. The S enantiomer has better pharmacokinetics and pharmacodynamics than the racemic mixture and therefore higher efficacy in controlling acid secretion [38]. The S enantiomer is called esomeprazole and is marketed as Nexium . Nexium has annual sales of 8.4 billion [39]. The chiral center is at the sulfur and the enantiomers can be separated by derivatizing with a R-(-) mandelic acid chiral auxiliary to form two diastereomers. Unlike enantiomers, diastereomers have different physical properties. The diastereomers can be separated by HPLC and then the chiral auxiliary removed to afford each of the omeprazole enantiomers. Alternatively, the sulfide precursor can be asymmetrically oxidized to form esomeprazole in 99.99% enantiomeric excess (ee) [40]. Enantiomeric excess means the excess amount of one enantiomer over the racemic mixture. If something is 80% ee that means that 20% is a racemic mixture and the other 80% is excess of that enantiomer. In this example, for 100 g, there are 90 g of the predominant enantiomer and 10 g of the lesser enantiomer in other words, 20 g is a racemic mix (lOg of each enantiomer) and 80g is excess enantiomer. 

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