Amino alcohol benzyl-protected

Catalytic hydrogenolysis of an O-benzyl protective group is a mild, selective method introduced by Bergmann and Zervas to cleave a benzyl carbamate (>NC0-0CH2C6H5 —> >NH) prepared to protect an amino group during peptide syntheses. The method has also been used to cleave alkyl benzyl ethers, stable compounds prepared to protect alkyl alcohols benzyl esters are cleaved by catalytic hydrogenolysis under neutral conditions. 

Dimethylaminoethane-2-ol (20) is a compound that, by virtue of its nucleophilic center (Me2NH+C2H40), is employed to convert protected segments bound to supports as benzyl esters into acids by transesterification into dimethylaminoethyl esters [C(=0)0C2H4NMe2] that are hydrolyzable by a dimethylformamide-water (1 1) mixture. Compound 20 readily forms esters from acid chlorides. The hydrolysis and esterification are facilitated by anchimeric assistance by the adjacent nitrogen atom (see Section 2.10). The amino alcohol also reacts with dichloromethane. 

The enzymatically catalyzed kinetic resolution of amino alcohols has been established on the multi-ton scale by BASF [7] (Scheme 7.14). Initial studies gave poor selectivity for the unprotected alcohols, as the resolution of trows-2-aminocyclopen-tanol (racemic 28) gave the amine (S,S) 29 and the amide (R,R) 30 in 25% . When the hydroxy functionality was protected as an ether, then resolution of racemic benzyl ether 31 proceeds with high to the give the amine (S,S) 32 and the RR amide 33 with >99.5 and 93 % respectively [33, 34]. 

The first step in the overall synthetic scheme (Scheme 6) is the condensation of an appropriate carboxylic acid with trifluoroacetaldehyde. The carboxylic acid is chosen to impart specificity for the target enzyme. In one example,[28 the dianion of cyclohexanepropanoic acid (29) was formed by the addition of LDA and then quickly condensed with trifluoroacetaldehyde to form the p-hydroxy acid 30 as a racemic mixture of erythro- and threo-isomers. The p-hydroxy acid 30 is then protected with TBDMSOTf forming 31. Diphenyl phosphorazidate, TEA, and benzyl alcohol were then utilized in a Curtius rearrangement of the protected alcohol 31, which proceeds through an isocyanate intermediate that yields the protected amino alcohol 32 upon reaction with benzyl alcohol. In order for this step to occur at an appreciable rate, a second equivalent of triethylamine had to be added. The amino alcohol 32 was then deprotected and coupled with Boc-Phe-Leu-OH to give the trifluoromethyl alcohol 33, which was oxidized to the corresponding trifluoromethyl ketone 34 as a 1 1.2 mixture of diastereomers using the Dess-Martin periodinane procedure. Thus far, the compound shown in Scheme 6 is the only compound that has been synthesized by this method, but it is reasonable to assume that many other similar fluoro ketones can be produced by this scheme. 

Ser, Thr, and Trp were left unprotected for short sequences (i.e., 5 to 6 amino acids in length). Initially we used benzyl-protecting groups for the alcohols, but resulting from incomplete deprotection for some libraries, we left the side-chain unprotected. For Trp, alkylations during activation/ deprotection step was sometimes observed. As such we sometimes include the formyl protecting group on the indole for difficult sequences. 

Suitably protected spiro isoxazoline 129 afforded the amino alcohol 130 with concomitant hydrogenolysis of benzyl ethers and reductive cleavage of the N-O bond by hydrogenation over Pd(OH)2/C (Equation 14) <2006TL6143>. 

The base-catalyzed addition of alcohols to nitriles to give imidates proceeds well, if there are electron-attracting groups in the a-position. In such cases the Pinner synthesis is less effective, because nitrile basicity is less. TTiis shows that both methods are complementary. Recently attention has been paid to the long-known addition of alcohols to trichloroacetonitrile, since it was found that imidates prepared from protected saccharides, amino alcohols etc. and trichloroacetonitrile are useful reagents for the synthesis of nucleosides, disaccharides and other natural products. The trichloroacetimidic acid esters (240 equation 131) of fluorinated, unsaturated aliphatic alcohols °° and benzyl alcohol have been prepared for synthetic purposes. 

Also, oxidation of alcohols and Al-protected amino alcohols with IBX in [bmim] [Cl] without HjO was reported by Perumal et al. [15]. In comparison with the previous method, these reactions, for example, oxidation of benzyl alcohol, require longer time for completion. 

In the case of amino sugars with the hydroxyl group at position 2, the use of the benzyl group as the hydroxyl protective group leads to stereoselective formation of 1,2-cw-glycoside. Thus, the 2-O-benzyl-protected glycosyl bromide 40 was coupled with the alcohol derivative 41 to produce conveniently the a-glycosidic product 42 in 44% yield [45] (compoimds 40-42 ). 

Cyclohexylpropionic acid was deprotonated with 2.2 equivalent of lithium diisopropylamide and the resulting dianion was condensed with trifluoroacetaldehyde which was generated in situ from its ethyl hemiacetal. The P-hydroxy acid 1 was isolated as a racemic mixture of two diastereomers. Silylation with tert-butyldimethylsilyl triflate was followed by ester hydrolysis to give the acid 2. A Curtius rearrangement with diphenylphosphoryl azide in the presence of benzyl alcohol afforded the protected P-amino alcohol 3 which was used in the preparation of the trifluoromethyl alcohol I. Oxidation using the Dess-Martin periodinane reagent (9) yielded the trifluoromethyl ketone II as a mixture of diastereomers. The signal for the carbonyl carbon in the 13C-NMR spectrum of this ketone appeared at 94.5 ppm and this is consistent with the hydrated form of the trifluoromethyl ketone. 

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