Acetonides, from diols

Starting from commercially available ethyl sorbate (64) dihydroxylation with standard AD-mixes afforded diol 65 with 80% ee in 61% chemical yield [94). Protection as the acetonide followed by ozonolysis led to the formation of key intermediate 66 in a four step sequence from diol 65 in 33% overall yield. Further transformations gave fluoroglycoside 67, which was then used in a stereoselective glycosylation. 

Reductive decyanation. This reaction is a key step in a route to syn-l,3-diol acetonides from P-trimethylsilyloxy aldehydes (1). Reaction of 1 with trimethylsilyl cyanide followed by acetonation gives a 1 1 mixture of a protected cyanohydrin (2). This mixture is converted into a single isomer (3) on alkylation of the anion of the cyanohydrin acetonide. Reductive decyanation with Na-NH3 at -78° produces a syn-diol acetonide (4). The apparent retention of configuration in the reduction results from preferential formation of an intermediate axial anion. 

Cyclic sulfates can even be prepared from diols containing acid-sensitive groups acetonide, silyloxy) by reaction with thionyl chloride and N(C2H5)3 followed by oxidation of the isolated sulfites with Ru04 (catalytic). After reactions with a nucleophile, the resulting sulfate esters can be hydrolyzed by water (0.5-1.0 equiv.) in THF catalyzed by H2S04. The use of a minimal amount of water is crucial for chemoselectivity.2... 

Dimethyldiacetoxysilane reacts in a similar manner to dimethyldichlorosilane. Pyridine, trimethylamine, etc., can serve as solvents [112,113]. In a similar way acetonid s [114] are prepared from diols prior to GC. 

Attempted preparation of acetonides from a 4a-methyl-4/(,6a-diol, or the analogous 6a-methyl-4oc,6j -diol, also gave cyclic ethers resulting from intramolecular electrophilic addition to an olefinic bond (see p. 247). Comparable cyclizations occurred on solvolysis of the 5,10-secosteroid (101)— (102) (see also Part II, Chap. 2, p. 404), and in the synthetically useful formation of... 

Protection and deprotection. Tetrahydropyranyl ether cleavage is catalyzed by CAN at pH 8. Acetonides are formed from diols under the influence of CAN. ... 

Propanone (acetone) carbon acidity, 10 protection of diols as "acetonides , 158, 266-267, 276-277, 321, 322 reaction with pyrrole, 250-251 Propanoyl chloride, 2- acetyloxy)-2-methyI-(Moffatt s reagent) O-protection, 160 chlorohydrtns from diols, 160, 327-328 2-Propenal (acrolein, acrylaldehyde) pr., 174... 

A library of dihydroxytetrahydrofurans was readily prepared from isosorbide." Epoxide 73 was produced in two steps from isosorbide (72)."" Subsequently, 73 was heated with secondary amines 68 to afford the corresponding amino alcohols 74 (Scheme 7.15). PS-lsocyanate resin was used to remove excess secondary amine 68. Treatment of alcohols 74 with isocyanates 75 gave the desired carbamates " PS-Trisamine resin removed excess isocyanate. Aqueous, acid-promoted hydrolysis of acetonides gave diols 76. 

FIGURE 8.27 NMR chemical shift correlations for 1,3-diol acetonides. (From Rychnovsky, S. D., B. N. Rogers, and T. I. Richardson, Accounts of Chemical Research 31 (1998) 9-17.)... 

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... 

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. ... 

Acetonides are the most suitable base-stable protecting group for 16,17-cis-diols. They can be readily prepared from 16,17-disecondary alcohols with either the a- or j5-configurations. ... 

Acetonides and other ketonides can also be smoothly prepared from pregnane-16oc,17a-diols with or without a 21-hydroxyl substituent. 

The completion of the synthesis of key intermediate 2 requires only a straightforward sequence of functional group manipulations. In the presence of acetone, cupric sulfate, and camphorsulfonic acid (CSA), the lactol and secondary hydroxyl groups in 10 are simultaneously protected as an acetonide (see intermediate 9). The overall yield of 9 is 55 % from 13. Cleavage of the benzyl ether in 9 with lithium metal in liquid ammonia furnishes a diol (98% yield) which is subsequently converted to selenide 20 according to Grie-co s procedure22 (see Scheme 6a). Oxidation of the selenium atom... 

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-... 

The next key step, the second dihydroxylation, was deferred until the lactone 82 had been formed from compound 80 (Scheme 20). This tactic would alleviate some of the steric hindrance around the C3-C4 double bond, and would create a cyclic molecule which was predicted to have a greater diastereofacial bias. The lactone can be made by first protecting the diol 80 as the acetonide 81 (88 % yield), followed by oxidative cleavage of the two PMB groups with DDQ (86% yield).43 Dihydroxylation of 82 with the standard Upjohn conditions17 furnishes, not unexpectedly, a quantitative yield of the triol 84 as a single diastereoisomer. The triol 84 is presumably fashioned from the initially formed triol 83 by a spontaneous translactonization (see Scheme 20), an event which proved to be a substantial piece of luck, as it simultaneously freed the C-8 hydroxyl from the lactone and protected the C-3 hydroxyl in the alcohol oxidation state. 

Scheme 9). Although cyanohydrin acetonide 64 could conceivably have been used, the silyl ether 75 was chosen. This compound is readily available from (l)-malic acid, and can undergo electrophilic activation under far more mild conditions than compound 64. Alkylation of the 1,3-diol synthon 75 with bromide 76 created the C11-C26 framework of roflamycoin, in 85% yield. A two-step conversion of the terminal siloxy group to the primary iodide (78) proceeded in 80% overall yield. 

Axial addition to oxocarbenium ions derived from 1,3-dioxanes provides protected a f/-l,3-diols. Our group has developed 4-acetoxy-1,3-dioxanes as oxocarbenium ion precursors. This general strategy for the convergent preparation of anfz-l,3-diols complements cyanohydrin acetonide methodology, which gives access to sy -l,3-diol synthons (Sect. 2). 

New synthetic methods are the lifeblood of organic chemistry. Synthetic efforts toward natural products often provide the impetus for the development of novel methodology. Reactive synthons derived from 1,3-dioxanes have proven to be valuable intermediates for both syn- and anfz-1,3-diols found in many complex natural products. Coupling reactions at the 4-position of 1,3-dioxanes exploit anomeric effects to generate syu-1,3-diols (cyanohydrin acetonides), autz-1,3-diols (4-acetoxy-1,3-dioxanes), and either syn- or azztz-1,3-diols (4-lithio-1,3-dioxanes). In the future, as biologically active polyol-containing natural products continue to be discovered, the methods described above should see much use. 

Our retrosynthesis of (—)-kinamycin F (6) is shown in Scheme 3.20 [45]. It was envisioned that (—)-kinamycin F (6) could be prepared from the protected diazofluorene 114 by conversion of the ketone function of 114 to a trans-], 2-diol, followed by deprotection of the acetonide and methoxymethyl ether protecting groups. The diazofluorene 114 was envisioned to arise from diazo transfer to the hydroxyfulvene 115. The cyclopentadiene substructure of 115 was deconstructed by a two-step annulation sequence, to provide the bromoquinone 116 and the p-trimethylsilylmethyl unsaturated ketone 117. The latter two intermediates were prepared from juglone (118) and the silyl ether 119, respectively. 

The reaction appears to be general and the additions are regiospecific and stereoselective. The product from the reaction with 2-propanol has been used for the synthesis of cis-chrysanthemic acid,8 and the product with methanol has been used for the construction of novel 2, 3 -dideoxy-3 -hydroxymethylnucleosides.9 In addition, ethane-1,2-diol provides the expected photoadduct as a 1 1 mixture of the two possible diastereoisomers, and these can be easily separated as their acetonides, to provide compounds with three contiguous chiral centers emanating from furan-ones with only one chiral center.9 More recently, we have shown that photoinduced-... 

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