Ester, amide Protection

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. 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

The dimethoxytrityl ester protecting group is now removed by treatment with mild acid (CCI3CO2H), which is insufficiently reactive to hydrolyse the amide protection of bases, or the cyanoethyl protection of the phosphate. The coupling cycle can now be repeated using a phosphoramidite derivative of the next appropriate nucleoside. The sequences will be continued as necessary until the desired oligonucleotide is obtained. 

It then remains to remove protecting groups and release the product from the support. All of these tasks, except for the removal of the dimethoxytrityl group, are achieved by use of a single deprotection reagent, aqueous base (ammonia). The cyanoethyl groups are lost from the phosphates by base-catalysed elimination, and amide protection of the bases is removed by base-catalysed hydrolysis. The latter process also achieves hydrolysis of the succinate ester link to the support. 

Very recently, Mordini and coworkers" have overcome the problems associated with the long reaction times that are normally required for the synthesis of hydroxamic acids from esters by performing these transformations under MW irradiation. The protective groups are also well tolerated under these reaction conditions, though a partial deprotection of the feri-butoxycarbonyl (Boc) group was observed in the reaction with Boc-proline ester. Amidic bonds and ketals also survive without any detectable decomposition. All the reactions go to completion in about six minutes, except in the case of the conversion of Boc-protected phenylalanine methyl ester, which required longer reaction times (12 min). 

Chiral homoallylamines are valuable synthons for the preparation of biologically active components including P-amino carboxylic acids or esters, obtained by oxidation of the ally lie functionality.1-29 Because removal of the chiral auxiliary by hydrogenation leads to the loss of the allylic functionality, we developed alternative routes for the conversion of the adduct into the unprotected homoallylamines. As a typical example, (f ,f )-PGA-homoallylamine derived from isobutyraldehyde Hi was used to develop the so-called mroStrecker and the decarbonylation method for the conversion of (R)-phenylglycine amide protected homoallylamines into /V-benzylidene protected homoallylamines 15 (Scheme 25.7). 

For subsequent transformations, it was necessary to protect the amino and C-2 carboxyl groups of fra/w-4-hydroxy-L-proline 34. Throughout all of the synthetic work to be described, A-benzoyl amide protection was chosen as it was felt likely that such a functional group would be resistant to most reaction conditions. Initially, a C-2 terf-butyl ester was chosen in an attempt to maximize the stereoselectivity in the planned enamine alkylation reaction however, later experiments revealed that the more straightforward to introduce C-2 methyl ester was equally effective. The preparations for all of the derivatives used are described here. 

Various functional groups can be protected and released in high yields, such as alcohols (as ethers), carboxylic acids (as esters), amides (as amides), and amines (as carbamates). In the latter case, however, two drawbacks must be noted ... 

In contrast to esters amide hydrolysis usually requires rather forcing conditions hence, amide protection of amines is not as common as gentler alternatives. Notable exceptions include trifluoroacetamides10 and phthalimides. Trifluoroacet-amides are so labile that they can be removed with potassium carbonate in methanol under conditions that preserve some methyl esters. 

The reaction is effective with electron-rich carbonyls such as trimethylsilyl esters and thioesters, as Table 20 indicates. Lactones ate substrates for alkylidenation however, hydroxy ketones are formed as side products, and yields are lower than with alkyl esters. Amides are also effective, but form the ( )-isomer predominantly. This method has been applied to the synthesis of precursors to spiroacetals (499) by Kocienski (equation 115). ° The reaction was found to be compatible with THP-protected hy- oxy groups, aromatic and branched substituents, and alkene functionality, although complex substitution leads to varying rates of reaction for alkylidenation. Kocienski and coworkers found the intramolecular reaction to be problematic. As with the CrCb chemistry, this reaction cannot be used with a disubstituted dibromoalkane to form the tetrasubstituted enol ether. Attempts were made to apply this reaction to alkene formation by reaction with aldehydes and ketones, but unfortunately the (Z) ( )-ratio of the alkenes formed is virtu ly 1 1. ... 

The same methodology has been extensively developed for the synthesis of optically active p-ketophosphonates from (3/ ,l 7 )-methyl T-phcnylethyl 3-hydroxypentanedioate. Low-temperature condensation of this unprotected hydroxy diester with dimethyl 1-lithiomethylphosphonate in excess in THF gives the desired optically active functionalized P-ketophosphonate in fair yield (43%). It has been observed that the methyl ester reacts faster than the I -phenethyl ester, and it is necessary to operate without the silyl protecting group to avoid a P-elimination reac-tion. - 2< By an analogous route, the reaction of dimethyl 1-lithiomethylphosphonate (1.3 eq) with the corresponding protected hydroxy ester-amide (Nahm-Weinreb amide) provides the... 

Mg, MeOH, 8-75% yield. These conditions were used to cleave a tosyl group from an aziridine, a special case over normal amines. The reaction should work better with a benzenesulfonamide. This method is very good for carbamate and amide protected sulfonamides, but does not work with normal aliphatic amines. Since sulfonamides are readily acylated, this constitutes a relatively mild method for the cleavage of sulfonamides. Lactones and esters are compatible with this methodology. 

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