Acetonide ketal

Figure 28 Triamcinolone acetonide ketal hydrolysis under acidic conditions.

Additional mono- and difluorinated analogues for topical application include fluorometholone (6a-methyl-9a-fluoro ophthalmic use), flurandrenolide (6a-fluoro-16a,17a-acetonide), fluocinolone acetonide (a 6a, 9a-difluoro-16a,17a-acetonide), and fluocinonide (21-acetate ester of fluocinolone acetonide) (Fig. 33.13). These compounds are classified as high to medium potency anti-inflammatory agents depending on the concentration and vehicle used (Table 33.4). The acetonide (ketal) derivatives at the 16,17-position enhance lipophilicity to provide potent topical anti-inflammatory agents (Table 33.4). 

Compounds having the 16,17 ketal, eg, budesonide, amcinonide, fluocinonide, halcinonide, triamcinolone acetonide, and flurandrenohde, also undergo metabohsm by routes that parahel that of cortisol metabohsm. Unsymmetrical acetals such as budesonide are also metabolized by routes not available to the more metabohcahy stable symmetrical 16a,17a-isopropyhdiene-dioxysubstituted compounds (desonide, flunisohde, and triamcinolone acetonide). Isozymes within the cytochrome P450 3A subfamily are thought to catalyze the metabohsm of budesonide, resulting in formation of 16a-hydroxyprednisolone and 6P-hydroxybudesonide (19,20) (Fig. 3) in addition to the more common metabohc steps (oxidation via reduction of A, etc). 

I60C-Hydroxy Derivatives of Gorticoids and their Acetonides. The preparation of 16a-hydroxy-9a-fluoroprednisolone (48) from the 3,20-bisethylene ketal of hydrocortisone acetate (49) has been reported (73). The latter was dehydrated with thionyl chloride in pyridine to yield the 4,9(11),16-triene (50). The 16,17-unsaturated linkage was selectively hydroxylated with OsO /pyridine to yield the 16a,17a-diol (51), which was converted... 

CYCLIC ACETALS AND KETALS 123 7. Acetonide (Isopropylidene Ketal) (Chart 3)... 

Acetonide formation is the most commonly used protection for 1,2- and 1,3-diols. The acetonide has been used extensively in carbohydrate chemistiy to mask selectively the hydroxyls of the many different sugars. In preparing acetonides of triols, the 1,2-derivative is generally favored over the 1,3-derivative, but the extent to which the 1,2-acetonide is favored is dependent on stmcture. Note that the 1,2-selectivity for the ketal from 3-pentanone is better than that from acetone. ... 

In the following example the acetonide protective group is selectively converted to one of two t-butyl groups. The reaction appears to be general, but the alcohol bearing the t-butyl group varies with structure.Benzyli-dene ketals are also cleaved. 

Catechols can be protected as diethers or diesters by methods that have been described to protect phenols. However, formation of cyclic acetals and ketals (e.g., methylenedioxy, acetonide, cyclohexylidenedioxy, diphenylmethylenedioxy derivatives) or cyclic esters (e.g., borates or carbonates) selectively protects the two adjacent hydroxyl groups in the presence of isolated phenol groups. 

Aldosterone reacts in the lactol form (101) by exchange with acetone ketals to yield the acetonide (102). ... 

Compounds i, ii, and iii can be prepared by an acid-catalyzed reaction of a diol and the cycloalkanone in the presence of ethyl orthoformate and mesitylene-sulfonic acid. The relative ease of acid-catalyzed hydrolysis [0.53 M H2SO4, H2O, PrOH (65 35), 20°] for compounds i, iii, acetonide, and ii is C5 C7 > acetonide C (e.g., t.//s for 1,2-O-alkylidene-a-D-glucopyranoses of C5, C7, acetonide, and C derivatives are 8, 10, 20, and 124 h, respectively). The efficiency of cleavage seems to be dependent upon the electronic environment about the ketal. ... 

The C2-symmetric epoxide 23 (Scheme 7) reacts smoothly with carbon nucleophiles. For example, treatment of 23 with lithium dimethylcuprate proceeds with inversion of configuration, resulting in the formation of alcohol 28. An important consequence of the C2 symmetry of 23 is that the attack of the organometallic reagent upon either one of the two epoxide carbons produces the same product. After simultaneous hydrogenolysis of the two benzyl ethers in 28, protection of the 1,2-diol as an acetonide ring can be easily achieved by the use of 2,2-dimethoxypropane and camphor-sulfonic acid (CSA). It is necessary to briefly expose the crude product from the latter reaction to methanol and CSA so that the mixed acyclic ketal can be cleaved (see 29—>30). Oxidation of alcohol 30 with pyridinium chlorochromate (PCC) provides alde-... 

In principle, a number of different types of acetal or ketal might be produced. In this section, we want to exemplify a small number of useful reactions in which two of the hydroxyl groups on the sugar are bound up by forming a cyclic acetal or ketal with a snitable aldehyde or ketone reagent. Aldehydes or ketones react with 1,2- or 1,3-diols under acidic conditions to form cyclic acetals or ketals. If the diol is itself cyclic, then the two hydroxyl groups need to be cA-oriented to allow the thermodynamically favourable fused-ring system to form (see Section 3.5.2). Thus, dx-cyclohexan-1,2-diol reacts with acetone to form a cyclic ketal, a 1,2-O-isopropylidene derivative usually termed, for convenience, an acetonide. 

Compatibility of asymmetric epoxidation with acetals, ketals, ethers, and esters has led to extensive use of allylic alcohols containing these groups in the synthesis of polyoxygenated natural products. One such synthetic approach is illustrated by the asymmetric epoxidation of 15, an allylic alcohol derived from (S)-glyceraldehyde acetonide [59,62]. In the epoxy alcohol (16) obtained from 15, each carbon of the five-carbon chain is oxygenated, and all stereochemistry has been controlled. The structural relationship of 16 to the pentoses is evident, and methods leading to these carbohydrates have been described [59,62a]. 

Triamcinolone acetonide contains a cyclic ketal group that can be readily cleaved by a variety of organic acids (Fig. 28) (44). 

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... 

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