Acetonide formation

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. ... 

The classical method for acetonide formation is by reaction of a diol with acetone and an acid catalyst. ... 

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). 

MeC(OEt)=CH2, cat. HCl, DMF, 25°, 12 h, 90-100% yield. This method is subject to solvent effects. In the formation of a /ran. -acetonide, the use of CH2CI2 did not give the acetonide, but when the solvent was changed to THF, acetonide formation proceeded in 90% yield.These conditions are used to obtain the kinetic acetonide. 

Lactone methanolysis followed by acetonide formation has also been observed. 

Tetramethoxybutane, TMOF, MeOH, CSA, 54-91% yield, trans-Diols are protected in preference to c/5-diols, in contrast to acetonide formation, which prefers protection of cis-diols." ... 

During attempted acetonide formation of an amino alcohol derivative, smooth tosyl cleavage was observed. The reaction is general for those cases having a carboxyl group, as in the following example, but fails for simple amino alcohol derivatives that lack this functionality. ... 

In the application of the above discovery, ( )-3-benzyloxy-2-methyl pro-pionaldehyde 52 is used as the starting material in the synthesis of rifamycin A. As outlined in Scheme 7-12, compound 52 is converted to allyic alcohol 55 via a series of chemical reactions. Epoxidation of 55 proceeded stereoselectively, giving a single epoxide that affords 57 after subsequent treatment. Compound 57 may be converted to 58 upon acetonide formation. 

Reductive y-lactone ring opening, with concomitant desilylation at the tertiary position by LiAlH4, gave triol 17 in 80% yield. Finally, acetonide formation followed by oxidation with tetra-n-propylammonium perruthenate/A-methylmorpholine / /-oxide oxidation, led to the target aldehyde 19 in 80% overall yield. 

A recently developed method for acyclic 1,3-diols rests on acetonide formation and 13C-NMR spectroscopic investigation of the acetonides. The conformational difference between the syn (chair) and anti (twist) diol acetonides results in significantly different 13C chemical shifts of the acetone derived carbons25°. This is a highly useful method in the context of the synthesis of polypropanoate-derived natural products260. 

These can be prepared by a) asymmetric dihydroxylation of allylic chlorides followed by acetonide formation and elimination with BuLi b) catalytic asymmetric transfer hydrogenation and c) reduction of alkynones with chiral metal hydrides, (a) Marshall, J. A. Jiang, H. Tetrahedron Lett. 1998, 39, 1493 Yadav, J. S. Chander, M. C. Rao, C. S. Tetrahedron Lett. 1989, 30, 5455 (b) Matsumura, K. Hashiguchi,... 

As shown in Scheme 9, when anti-syn-30 was subjected to the usual acetonide formation condition, the corresponding 5- and 6-membered acetonides, anti-syn-31 and anti-syn-32, respectively, were obtained in a ratio of 91 3 in spite of the steric congestion in the major product by the syn relationship of the two substituents, which would be a clear reflection of the above hypothesis. Anti-syn-31,... 

Step 1 Acetonide formation occurs selectively to give the five-membered ring dioxolane. 

In the total synthesis of (+)-trienomycins A and F, Smith et al. used an Evans aldol reaction technology to construct a 1,3-diol functional group8 (Scheme 2.1i). Asymmetric aldol reaction of the boron enolate of 14 with methacrolein afforded exclusively the desired xyn-diastereomer (17) in high yield. Silylation, hydrolysis using the lithium hydroperoxide protocol, preparation of Weinreb amide mediated by carbonyldiimidazole (CDI), and DIBAL-H reduction cleanly gave the aldehyde 18. Allylboration via the Brown protocol9 (see Chapter 3) then yielded a 12.5 1 mixture of diastereomers, which was purified to provide the alcohol desired (19) in 88% yield. Desilylation and acetonide formation furnished the diene 20, which contained a C9-C14 subunit of the TBS ether of (+)-trienomycinol. 

Acid-catalysed rearrangement/hydrolysis of the 3a,20a-disulphate (168) gave the 17/3-methyl-18-nor-compound (169). Rearrangement of the 17a-hydroxy-3-oxo-A -triene (170) to the c-ring aromatic compound (171) occurred in formic acid as did the rearrangement of 17a-ethynyloestradiol to the chrysene derivative (172). The 9,ll-epoxy-17-hydroxy-steroids (173) and (174) were converted with BF3-Et20 into the C-ring aromatic compounds (175) and (176) respectively. " Normal acetonide formation in the reaction of... 

Scheme 6. Reaction conditions a, 3-chloroperoxybenzoic acid (MCPBA)/dichloromethane/aq. bicarbonate, then lithium diisopropylamide (LDA) b, diimide c, POCl3/pyridine d, LiAlH4, BuLi/PhCOCI e, MCPBA f, (PhSe)2/NaBH4/EtOH, then MCPBA/Pr2NH g, 0s04/pyridine h, acetonide formation, then Barton deoxygenation i, Ba(OH)2, then H +. ...

Osmium tetroxide-catalyzed dihydroxylation of the chiral a-acetoxysulfones and acetonide formation affords versatile chemical intermediates. Reduction with DIBAL-H provides primary alcohols, and addition of Grignard reagents provides secondary alcohols with excellent stereochemical control of the newly formed chiral center. ... 

A recent application of the furan-carbonyl photocycloaddition involved the synthesis of the mycotoxin asteltoxin (147)." Scheme 16 shows the synthetic procedure that began with the photoaddition of 3,4-dimethylfuran and p-benzyloxypropanal to furnish photoaldol (148), which was epoxidized with MCPBA to afford the functionalized product (149) in 50% overall yield. Hydrolysis (THF, 3N HCl) provided the monocyclic hemiacetal which was protected as its hydrazone (150). Chelation-controlled addition of ethylmagnesium bromide to the latent a-hydroxy aldehyde (150) and acetonide formation produced compound (151), which was transformed through routine operations to aldehyde (152). Chelation-controlled addition of the lithium salt of pentadienyl sulfoxide (153) followed by double 2,3-sigma-tropic rearrangement provided (154) as a 3 1 mixture of isomers (Scheme 17). Acid-catalyzed cyclization of (154) (CSA/CH2CI2) gave the bicyclic acetal (155), which was transformed in several steps to ( )-asteltoxin (147). ... 

Although Vitamin C is not a commodity chemical and is manufactured by a sequential process that involves hydrogenation, oxidation, acetonide formation, oxidation, hydrolysis, and formation of the vitamin, this example illustrates that complex multistep processes are not excluded from commercial use and can yield products competitive with the natural product. Natural vitamin C for the commercial market is also extracted from certain plants. 

Use of the Wittig reaction on a reducing sugar is a handy method to generate a double bond, which can then be used as aradical acceptor. As shown in Scheme 8.18, D-galactose was classically transformed into a selectively protected hemiacetal 60 by benzyl alcohol glycosylation, protection of the primary hydroxyl, 3,4-acetonide formation and debenzylation. The Wittig reaction followed by desilylation afforded the triol 61, which was then selectively tosylated on the primary hydroxyl... 

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