Acetal acetonides

In this section, the formation and cleavage of eight protecting groups for alcohols and phenols are presented acetate acetonides for diols benzyl ether para-methoxybenzyl (PMB) ether methyl ether methoxymethylene (MOM) ether ferf-butyldiphenylsilyl (TBDPS) silyl ether and tetrahydropyran (THP). 

The Sharpless procedure for effecting osmium-catalyzed ligand-accelerated asymmetric dihydroxylation was utilized successfully the reaction could also be scaled up. Bis(3-methylthien-2-yl) ketone (59) was also a product in these reactions and was accompanied by an impurity whose structure has not been elucidated. Optimum yields of the dihydroxy material were obtained in dioxane-water/t-butanol-water mixtures. Use of osmium tetroxide instead of potassium osmate led to a slower reaction and increased the formation of undesired products. The material derived from synthesis revealed complete identity with the tablet degradates Any diastereomers that formed were not resolved under our chromatographic conditions. Attempted functionalization of the vicinal dihydroxy groups (acetate, acetonide, trflate) was unsuccessful and led to complex mixtures of products. 

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... 

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)... 

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. 

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. 

I2, MeOH, reflux, 2 h, 79% HCIO4, H2O, 25°, 16 h, 87% yield. These conditions also cleave acetonides and benzylidene acetals. ... 

Isotope labeling by derivative formation with deuterated reagents is useful for the preparation of analogs such as dg-acetonides, da-acetates, da-methyl ethers, dg-methyl esters, etc. The required reagents are either commercially available or can be easily prepared. (The preparation of da-methyl iodide is described in section IX-F. Various procedures are reported in the literature for the preparation of dg-acetone, da-diazometh-ane57.i63.i73 and da-acetyl chloride. ) These reactions can be carried out under the usual conditions and they need no further discussion. A convenient procedure has been reported for the da-methylation of sterically hindered or hydrogen bonded phenolic hydroxyl functions by using da-methyl iodide and sodium hydroxide in dimethyl sulfoxide solution. This procedure should be equally applicable to the preparation of estradiol da-methyl ether derivatives. 

Selective protection of 1,2- and m-l,3-diols can be achieved by formation of acetonides, acetals or orthoesters. Further selectivity is possible in special cases (e.g., acetonide formation). With 17a,20,21-triols, the 20,21-acetonide is obtained exclusively. 16a,17a,21-Trihydroxy-20-lcetopregnanes (20) react selectively with acetone to give 16,17-acetonides (21). 

Acetonides are quite stable to base, and to oxidation, dehydration and acylation reactions carried out in pyridine. They are cleaved by acid hydrolysis. The 17,21-acetonides of 17a,21-dihydroxy-20-keto steroids and related acetals are split by very mild acid conditions. ... 

Acetonides of 21-hydroxy- and 21-desoxy-20-ketones and related acetals are often stable to dilute boiling mineral acid " but in certain instances, acetonides are cleaved in modest yield by 0,5 A hydrochloric acid in... 

Diols yield acetonides, even in the presence of a 17oc-hydroxylgroup. Reaction with acetone in the presence of zinc chloride as catalyst leads to the formation of diacetone alcohol acetal as a by-product. ... 

However, 17a,21-acetonides (103), as well as acetals of other ketones or aldehydes, can be easily prepared by acid-catalyzed exchange reaction with dimethoxypropane or other alkyl acetals in dimethylformamide or benzene. Enol etherification of the A -S-ketone also occurs with the former procedure. 

In the following example the ethylidene acetal was used, because attempts to make the acetonide led to the formation of a 1 1 mixture of the 1,3- and 1,4-acetonides. ... 

A benzylidene acetal is a commonly used protective group for 1,2- and 1,3-diols. In the case of a 1,2,3-triol, the 1,3-acetal is the preferred product, in contrast to the acetonide, which gives the 1,2-derivative. The benzylidene acetal has the advantage that it can be removed under neutral conditions by hydrogenolysis or by acid hydrolysis. Benzyl groups and isolated olefins have been hydrogenated in the presence of 1,3-benzylidene acetals. Benzylidene acetals of 1,2-diols are more susceptible to hydrogenolysis than are those of 1,3-diols. In fact, the former can be removed in the presence of the latter. A polymer-bound benzylidene acetal has also been prepared. ... 

Me2BBr, TEA, BH3-THF, —78° warm to —20° over 1 h, 70-97% yield. These conditions cleave the benzylidene acetal, to leave the least hindered alcohol as a free hydroxyl. If diborane is omitted from the reaction mixture and the reaction is quenched with PhSH and TEA, the benzylidene group is cleaved to give an (9,5 -acetal [ROCH(SPh)Ph]. Acetonides are cleaved similarly." ... 

BH3 SMe2, CH2CI2, 0°, 1 h, then BF3, 5 min. Simple benzylidene acetals are cleaved efficiently without hydroboration of alkenes that may be present, and acetonides are converted to the hydroxy isopropyl ethers. 

Methylene, 287 Pivaldehyde Acetal, 289 Acetonide, 289 Cyclohexylidene. 289 Diphenylmethylene, 289 Ethyl Orthoformate, 290 Diisopropylsilylene Derivative, 290... 

Acetonide Derivative 11. Benzylidene Acetal 13. p-Methoxybenzylidene Acetal 18. Methoxymethylene Acetal 20. Dimethoxymethylenedioxy Derivative... 

Fluprednisolone Acetate Hydrocortisone Acetate Methylprednisolone Methylprednisone 163-MethyIpredni sone Prednylidene Triamcinolone Triamcinolone Acetonide... 

A solution of 50 mg of 6a-fluoro-triamcinolone acetonide in 1 ml of pyridine and 1 ml of acetic anhydride is allowed to stand at room temperature for 18 hours. Removal of the reagents in vacuo gives a crystalline residue which after crystallization from acetone-hexane gives the pure 16a,17a-isopropylidene 6o -fluoro-triamcinolone 21 acetate (fluocinonide), as described in U.S. Patent 3,197,469. 

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