Acetonides

Cyclop entylidene are slightly easier to cleave than acetonides... 

Nonanedione, another 1,3-difunctional target molecule, may be obtained from the reaction of hexanoyl chloride with acetonide anion (disconnection 1). The 2,4-dioxo substitution pattern, however, is already present in inexpensive, symmetrical acetylacetone (2,4-pentanedione). Disconnection 2 would therefore offer a tempting alternative. A problem arises because of the acidity of protons at C-3 of acetylacetone. This, however, would probably not be a serious obstacle if one produces the dianion with strong base, since the strongly basic terminal carbanion would be a much more reactive nucleophile than the central one (K.G. Hampton, 1973 see p. 9f.). 

In all cases examined the ( )-isomers of the allylic alcohols reacted satisfactorily in the asymmetric epoxidation step, whereas the epoxidations of the (Z)-isomers were intolerably slow or nonstereoselective. The eryfhro-isomers obtained from the ( )-allylic alcohols may, however, be epimerized in 95% yield to the more stable tlireo-isomers by treatment of the acetonides with potassium carbonate (6a). The competitive -elimination is suppressed by the acetonide protecting group because it maintains orthogonality between the enolate 7i-system and the 8-alkoxy group (cf the Baldwin rules, p. 316). 

Unique chemistry is associated with the cyclopentenone all five carbon atoms can be functionalized, and the endo-methyl groups of the acetonide assure clean stereoselective addition of the alkenylcopper reagent from the convex side. The use of the acetonide group to control enolate regioselectivity and to mask alcohols should be generally applicable. 

The 9 — 15 fragment was prepared by a similar route. Once again Sharpless kinetic resolution method was applied, but in the opposite sense, i.e., at 29% conversion a mixture of the racemic olefin educt with the virtually pure epoxide stereoisomer was obtained. On acid-catalysed epoxide opening and lactonization the stereocentre C-12 was inverted, and the pure dihydroxy lactone was isolated. This was methylated, protected as the acetonide, reduced to the lactol, protected by Wittig olefination and silylation, and finally ozonolysed to give the desired aldehyde. 

Thiazolyloxy)propanediol-1.2-acetonide (198) has been prepared from 4-Br-thiazole (197) (Scheme 101) (440). Thiazolopyridazines (199) or thiazolooxazines (200) can be obtained from the 4-alkoxyderivalives (201) by treatment with hydrazine or hydroxylamine, respectively (Scheme 102) (441). 

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... 

The C. 100-C. 101 diol group, protected as an acetonide, was stable to the Wit-tig reaction used to form the cis double bond at C.98-C.99, and to all the conditions used in the buildup of segment C.99-C. 115 to fully protected palytoxin carboxylic acid (Figure 1,1). 

CH2(OMe)2, CH2 = CHCH2SiMe3, MeaSiOTf, P2O5, 93-99% yield." This method was used to protect the 2 -OH of ribonucleosides and deoxyribo-nucleosides as well as the hydroxyl groups of several other carbohydrates bearing functionality such as esters, amides, and acetonides. 

Me3SiBr, CH2CI2, 0°, 8-9 h, 80-97% yield.This reagent also cleaves the acetonide, THP, trityl, and r-BuMe2Si groups. Esters, methyl and benzyl ethers, r-butyldiphenylsilyl ethers, and amides are reported to be stable. 

CH3SCH3, CH3CN, (PhC0>202, 0°, 2 h, 75-95% yield. Acetonides, THP ethers, alkenes, ketones, and epoxides all survive these conditions. 

NCSBu2Sn)20 1%, THF, H20. Acetonides and TMS ethers are also cleaved under these conditions, but TBDMS, MTM, and MOM groups are stable. This catalyst has also been used to effect transesterifications. ... 

Pyridinium tosylate, -PrOH, 80-85% yield. An acetonide was not affected by these conditions. 

Dichlorodicyanoquinone (DDQ), CH2CI2, H2O, 40 min, it, 84-93% yield.This method does not cleave simple benzyl ethers. This method was found effective in the presence of a boronate. The following groups are stable to these conditions ketones, epoxides, alkenes, acetonides, to-sylates, MOM ethers, THP ethers, acetates, benzyloxymethyl (BOM) ethers, and TBDMS ethers. 

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 cases where two 1,2-acetonides are possible, the thermodynamically favored one prevails. Secondaiy alcohols have a greater tendency to form cyclic acetals than do primaiy alcohols,but an acetonide from a primaiy alcohol is preferred over an acetonide from two trans, secondaiy alcohols. 

In the case below, isomerized to ii, producing a trans derivative, but acetonide iii fails to isomerize to the internal derivative because the less favorable cis product would be formed. ... 

TsOH, DMF, Mc2C(OMe)2, 24 h. This method has become one of the most popular methods for the preparation of acetonides. It generally gives high yields and is compatible with acid-sensitive protective groups such as the TBDMS group. 

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