Benzyl deprotection

Tr ping of these soH Ued dipole-stabilized anions with eitho oxygen or the complex of oxodiper-oxymolybdenum with HMPA and pyridine gives honiaminals which provide secondary amides. The procedure can therefore be used as a method of benzyl deprotection of amides (equation 31). 

Compound 636 was converted to 638 under Mitsunohu conditions. Reduction upon heating led to the cyclization product 639. Coupling with a (R)-phenylalanine derivative yielded tetrapeptide 640, which was deprotected to give free diol 641. Diacid 642 was obtained after two consecutive oxidation steps with Dess-Martin periodinane and NaC102. Fmoc-deprotection, DCC-mediated cyclization (—> 643) and benzyl deprotection furnished diketopiperazine enf-WIN 64821 (644). 

The total synthesis of ditryptophenaline (651) used stereoisomer 637, which was oxidized (—> 645) and reduced to give diol 646 (Scheme 10.5). Analogous to the previously described synthesis, 646 was subjected to a Mitsunobu reaction and reduction to furnish cyclization product 647. Benzyl deprotection and coupling with a Fmoc-protected W-methyl-(5)-phenylalanine derivative yielded tetrapeptide 648. TMSE-deprotection, two oxidations (—> 650), Fmoc-deprotection, and DCC-mediated cyclization finally led to the natural product ditryptophenaline (651). 

The synthesis commences with alkylation of oxindole 120 with spiroaziri-dinium triflate 109, providing the 3,3-disubstituted 121 in 53% yield (cf. Scheme 2.17). Treatment of 121 with boron trifluoride etherate at 100°C in toluene initiates the tandem retro Diels-Alder/intramolecular aza Diels-Alder process, leading to spiro-tetracyclic oxindoles 122 and 123 (1.5/1) in 61% yield. Addition of 2-lithio-l,l-diethoxy-2-propene to oxindole 122 provides carbinolamine 124 (95%). Exposure of 124 to p-toluenesulfonic acid in acetone-water followed by treatment with excess triethylamine in acetonitrile at 80°C effects the biomimetic transformation to adduct 126, which possesses the pentacyclic carbon framework of pseudotabersonine. This unique two-step one-pot transformation generates the inherently unstable dihydropyridine portion of dehydrosecodine 125, which participates in an intramolecular reverse electron-demand Diels-Alder reaction, providing 126 in 50% yield. The total synthesis is completed by transformation of the formyl group into the requisite carbomethoxy unit followed by N-benzyl deprotection (Scheme 2.19). 

Deprotection by this method rests on the ease with which benzyl esters are cleaved by nucleophilic attack at the benzylic carbon m the presence of strong acids Bromide ion IS the nucleophile... 

Carboxyl groups of ammo acids and peptides are normally protected as esters Methyl and ethyl esters are prepared by Fischer esterification Deprotection of methyl and ethyl esters is accomplished by hydrolysis m base Benzyl esters are a popular choice because they can also be removed by hydrogenolysis Thus a synthetic peptide protected at both... 

Its N terminus with a Z group and at its C terminus as a benzyl ester can be completely deprotected m a single operation... 

Section 27 16 Carboxyl groups are normally protected as benzyl methyl or ethyl esters Hydrolysis m dilute base is normally used to deprotect methyl and ethyl esters Benzyl protecting groups are removed by hydrogenolysis... 

CF3CO2H, PhSCH3, 25°, 3 h. ° The use of dimethyl sulfide or anisole as a cation scavenger was not as effective because of side reactions. Benzyl ethers of serine and threonine were slowly cleaved (30% in 3 h complete cleavage in 30 h). The use of pentamethylbenzene had been shown to increase the rate of deprotection of 0-Bn-tyrosine. ... 

Benzyl carbamates are readily cleaved under strongly acidic conditions HBr, AcOH 50% CF3COOH (25°, 14 days, partially cleaved) - 70% HF, pyridine CF3S03H FSOaH, or CHjSO.H.- In cleaving benzyl carbamates from peptides, 0.5 M 4-(methylmercapto)phenol in CF3CO2H has been recommended to suppress Bn additions to aromatic amino acids. To achieve deprotection via an Sn2 mechanism that also reduces the problem of Bn addition, HF-Me2S-p-cresol (25 65 10, v/v) has been recommended for peptide deprotection. 

Pd/C, H2, EtOAc, >52% yield. The p-phenylbenzyl ether is more easily cleaved by hydrogenolysis than are normal benzyl ethers. This property was used to great advantage in the deprotection of the following vineo-mycinone intermediate ... 

Benzyltriethylammonium tetrathiomolybdate in CH3CN in 61-97% yield. Deprotection is compatible with esters such as benzyl, allyl, acetate, and -butyl esters. ... 

Sml2, THE or DMPU, it, 76-94% yield. Deprotection of the pyridinesul-fonamide in the presence of a cinnamoyl group was possible when done without a proton source. BOC, A-benzyl, A-allyl, and trifluoroacetamido groups were all stable to these conditions. ... 

Na, ammonia. These conditions also remove cyanoethyl- and benzyl-protective groups. Phosphorothioates are similarly deprotected. 

The completion of the synthesis of 1 only requires two deprotection steps. Hydrogenolysis of the four benzyl ethers, followed by cleavage of the triisopropylsilyl ether with hydrofluoric acid in acetonitrile, provides paeoniflorin (1) in an overall yield of 92 %. 

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