Isopropylidene ketals protecting group

Difluorocyclopentadiene was prepared via a pyrolysis reaction the difluoro-methylene centre was installed (Eq. 119) using a DAST fluorination [318]. A fluorobutenolide building block was prepared by a Wadsworth-Emmons reaction of isopropylidene glyceraldehyde removal of the ketal protecting group led to the formation (Eq. 120) of the unsaturated lactone in acceptable overall yield... 

The phosphorylation of ascorbic acid under basic conditions has been studied extensively. The synthesis of ascorbic acid 2-phosphate, 22, has been reported by Seib et al. (9) via treatment of 5,6-O-isopropylidene ascorbic acid, with phosphorus oxychloride under highly basic conditions (pH 12). Hydrolysis of the ketal protecting group of the 2-phosphate intermediate 20 affords the 2-O-phosphate 22, whose structure has been... 

Acetals and ketals protect two hydroxyls at a time by forming either a 1,3-dioxane or a 1,3-dioxolane ring (Scheme 2.12). The most common ketal and acetal protecting groups are isopropylidene or acetonide and the benzylidene-type groups with... 

Another approach that led to differentiation is the combination of bulky group and isopropylidene ketal. With the ketal strongly favoring formation onto vicinal cis-diols, the 6-O-protected galactoside 47 [169,170] and mannoside 49 [171] provided the 2-alcohol 48 and 4-alcohol 50 in high yields, respectively (Scheme 2.18). 

The acid-catalysed formation of acetals and ketals of ascorbic acid is particularly useful for the. selective protection of the molecule whilst structural modification is being carried out. The 5,6-0-derivatives such as the isopropylidene ketal and benzylidene acetal are well known but, more recently, it has proved po.ssible to protect the C-2/C-3 positions selectively using particularly reactive aldehydes (Figure 4.14). This new development has paved the way for selective modification of the primary and secondary alcohol groupings on the ascorbic acid side chain. 

Diols represent a special case in terms of applicable protecting groups. 1,2-Diols and 1,3-diols form cyclic acetals and ketals with aldehydes and ketones unless cyclization is precluded by the geometry of the molecule. The isopropylidene derivatives (acetonides) formed by reaction with acetone are probably the most common example ... 

Being a ketal, this protective group shares with tetrahydropyranyl derivatives the property of being resistant to basic and nucleophilic reagents, but is readily removed by aqueous acid. The isopropylidene group can be introduced by acid-catalyzed condensation with acetone, or by acid-catalyzed exchange with 2,2-... 

When a carbohydrate reacts with a vinyl ether such as 2-methoxy-l-propene, the product is a ketal. The reaction of a-d-glucopyranose (71) with this vinyl ether in the presence of an acid catalyst leads to 85. This reaction essentially protects the C4- and C6-OH units as a 1,3-dioxane (see Chapter 18, Section 18.6.6). (Protecting groups were introduced in Chapter 25, Section 25.4.3.) The name of 102 reflects the presence of this ketal it is 4,6-0-isopropylidene-a-d-glucopyranose. The isopropylidene group is the CMe2 unit, and the 0-isopropylidene name refers to the presence of the acetone ketal unit. When 71 reacts with acetaldehyde in the presence of an acid catalyst, the product is 4,6-0-ethylidene-a-d-glucopyranose, 86. The ethylidene term refers to the CHEt unit and benzylidene refers to the CHPh unit. 

There are numerous examples of the use of cyclic acetal and ketal groups for the protection of 1,2- and 1,3-glycol systems in steroid [30], glyceride [128], sugar [126, 127] (including nucleoside) and cyclitol [69] chemistry. The most commonly used protecting groups of this type are isopropylidene ketals [30, 126-8] and benzylidene acetals [126-8]. Methylene and ethylidene acetals have also been used frequently [126, 127]. 

The isopropylidene protecting group owes its wide use to its ease of introduction, its stability [30] in most neutral and basic media, and its lability under comparatively mild conditions of acidic hydrolysis. However, the actual conditions of acidic hydrolysis required vary considerably. Thus while the 20, 21-ketal (83) readily undergoes hydrolysis in 60-80% AcOH at room temperature, the 17o ,20 kctal (84) needs to be heated with 80% AcOH, under reflux, to effect its hydrolysis [157]. 

This variation in stability of isopropylidene protecting groups is also illustrated by the behaviour of l,2 5,6-di-0-isopropylidene-a-D-glucofuranose (1) which may be converted into (85) under mild conditions of acidic hydrolysis [158]. In this case, it should be noted that (85) is not a simple ketal as the 1-hydroxyl group is not alcoholic but part of a hemiacetal system. 

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