Orthoester protection

Protection of the 2,3-dihydroxy moiety of either (S,S)- or (i ,7 )-tartaric acid derivatives as an orthoester is attractive, because on the one hand the orthoester provides enough protective 

The coupling of 505 and 506 proceeds in 77% yield to furnish olefin 507 as a 2 1 Z mixture. In five steps this is transformed into epoxide 508. Further manipulation of 508 in six additional steps provides the tetrahydropyran 509 [162]. 

Vinylmagnesium bromide addition to 509 results in a tertiary alcohol that upon treatment with phosphorus tribromide undergoes rearrangement to furnish a 65% yield of the -allylic bromide 510 (along with 25% Z-bromide). This is coupled with the anion of 511 to afford 512, which is elaborated to the antibiotic 513 [162,163]. 

A convergent total synthesis of amphotericin B (517), with a jS-linked mycosamine at the C-19 hydroxyl position, a clinically useful antifungal agent isolated from Streptomyces nodosus, and its aglycon, amphoteronolide B (518), relies upon the stereocontrolled construction of enantiomerically pure (homochiral) structural units. Retrosynthetic analysis of 517 uncovers certain stereochemical features that allow construction of two of the essential chiral building blocks from 514, the chiral antipode of 503 and readily available from lb, by utilizing similar reaction conditions to those available for the synthesis of 503. Thus, chiral 

Whitesell observed that alkylation at the a-carbon of an amide of a C2-symmetric amine, in which the amine acts as a chiral auxiliary, should result in effective symmetric induction [166]. The C2-symmetric aziridines 519 and 520 are readily accessible from 503 and 514, respectively. Ring opening of either epoxide with sodium azide, mesyl activation of the free hy oxy group, and lithium aluminum hydride reduction of the azide with concomitant ring 

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Carboxylic acids can also be protected as orthoesters. Orthoesters derived from simple alcohols are very easily hydrolyzed, and the 4-methyl-2,6,7-trioxabicyclo[2.2.2]octane structure is a more useful orthoester protecting group. These... 

Although Z-alkene isosteres have been obtained from Wittig alkenation reactions of a-amino aldehydes using triphenyl[3-(trimethylsilyl)prop-2-ynylidene]phosphorane (Section 10.5.2.1.2.1), this stereoisomer was always obtained in minor amounts. Z-Selective alkena-tions were obtained using ylides containing dioxolane-protected aldehydes 42 or orthoester-protected carboxylic acid functions. 58 No experimental data were published, however. 

Scaringe SA, Wincott FE, Caruthers MH. Novel RNA synthesis method using 5 -0-silyl-2 -0-orthoester protecting groups. J Am Chem Soc 120 11820-11821, 1998. 

One attractive feature of the 2,3-dihydroxy groups present in tartaric acid derivatives is the fact that they can be incorporated into cyclic derivatives in which the protecting group also maintains a reactive center, as already discussed in the case of the orthoester protected tartrates. Cylic carbonates and cyclic sulfur compounds of tartaric acids offer additional opportunities for exploitation of the chirality of the tartaric acids in the preparation of very useful chiral intermediates. 

The first orthoester was derived from cyclohexanetriol (Scheme 3). The conversion of nitrile 26 to the cyclohexyl orthoester (28) first traversed trimethyl orthoester 27After multiple attempts to form and utilize cyclohexyl orthoester 28, it was determined that hydrolysis to the ester (29) was sufficiently problematic. Hydrolysis could be dealt with if needed, but instead we decided to use an alternative orthoester protecting group. 

Synthesis of the useful 2 -protected nucleoside has been undertaken by way of a 2, 3 -cyclic orthoester intermediate. The orthoester protects the 2, and 3 -hydroxyls so that the primary hydroxyl can then selectively be protected, if desired. Hydrolysis of the fully protected nucleoside with acid... 

The most commonly used protected derivatives of aldehydes and ketones are 1,3-dioxolanes and 1,3-oxathiolanes. They are obtained from the carbonyl compounds and 1,2-ethanediol or 2-mercaptoethanol, respectively, in aprotic solvents and in the presence of catalysts, e.g. BF, (L.F. Fieser, 1954 G.E. Wilson, Jr., 1968), and water scavengers, e.g. orthoesters (P. Doyle. 1965). Acid-catalyzed exchange dioxolanation with dioxolanes of low boiling ketones, e.g. acetone, which are distilled during the reaction, can also be applied (H. J. Dauben, Jr., 1954). Selective monoketalization of diketones is often used with good success (C. Mercier, 1973). Even from diketones with two keto groups of very similar reactivity monoketals may be obtained by repeated acid-catalyzed equilibration (W.S. Johnson, 1962 A.G. Hortmann, 1969). Most aldehydes are easily converted into acetals. The ketalization of ketones is more difficult for sterical reasons and often requires long reaction times at elevated temperatures. a, -Unsaturated ketones react more slowly than saturated ketones. 2-Mercaptoethanol is more reactive than 1,2-ethanediol (J. Romo, 1951 C. Djerassi, 1952 G.E. Wilson, Jr., 1968). 

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). 

Selective removal of the hydroxyl protecting groups included in this review is generally difficult to achieve and of little practical importance. Selective hydrolysis of cyclic orthoesters to give monoesters merits attention for its practical interest. 

Selective protection of 1,2- or 1,3-diols.1 Diols react with orthoesters in the presence of an acid catalyst (such as 10-camphorsulfonic acid, CSA) to form an orthoester that can be reduced, without isolation, by DIBAH to a monoacetal... 

Acyl protection should lead, as a consequence of neighboring-group participation and the anomeric effect, exclusively to a products. This has been proved in many experiments (Table XV) with Me3SiOTf as catalyst excellent yields could be obtained in cases where all other methods essentially failed (129). It could be shown that at least some of the reactions proceed via rapid orthoester formation (129), and this intermediate then rearranges under Me3SiOTf catalysis to the desired reaction product. 

Further, a large number of examples with simple alkyl substituents [168, 171, 176-184], cyclic alkanes [185], aryl substituents [177, 186-192], olefmic substituents [78, 177, 193-196], deuterated compounds [172], thioether groups [171], ester groups [197], orthoesters [198, 199], acetals [168, 182, 200-204], silyl-protected alcohols [198, 205-211], aldehydes [212], different heterocycles [213-217], alkyl halides [218, 219] and aryl halides [192, 220-223] have been reported. A representative example is the reaction of 92, possessing a free hydroxyl group, an acetal and a propargylic ether, to 93 [224] (Scheme 1.40). 

Mukhopadhyay, B. Field, R. A., A simple one-pot method for the synthesis of partially protected mono- and disaccharide bnilding blocks nsing an orthoesterification-benzylation-orthoester rearrangement approach. Carbohydr. Res. 2003,338,2149-2152. 

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