Benzyloxy carbamates

Benzyloxycarbonyloxy)phenyl]dimethylsulfonium methyl sulfate, NaOH, H20,51-95% yield. " This is a water-soluble reagent for benzyloxy carbamate formation. Analogous reagents for the introduction of BOC and Fmoc were also prepared and give the respective derivatives in similar high yields. 

The deprotection of the Cbz protected amino acid proceeds via a two step mechanism (Figure 1). The first step comprises the catalytic hydrogenolysis of the benzyloxy group of the Cbz-protected amino acid (1). Toluene (3) is formed from the O-benzyl group as well as an unstable carbamic acid intermediate (2). This intermediate decomposes to form the unprotected amino acid (4) and carbon dioxide (5). 

The syntheses of these three compounds share a common route as described by Brickner et al. [53] and Barbachyn et al. [54]. Namely, the coupling reaction of 3,4-difluoronitrobenzene (82) with piperazine, morpholine, or thiomorpholine to yield the corresponding 4-substituted 3-fluoro-nitrobenzene (83), which upon reduction gives rise to the aniline derivative (84). Carbobenzoxy protection of the active nitrogen of 84 using benzyloxy-carbonyl chloride (CbzCl) results in the formation of carbamates 85a and 85b. Treatment of 85a,b with n-BuLi and (i -glycidyl butyrate yields a 5-(R)-... 

Thus, reaction of tetrahydrofuroic acid (40-1) with triphenylphosphoryl azide leads to isocyanate (40-2). Treatment of this intermediate with benzyl alcohol then affords the corresponding carbamate (40-3). Catalytic hydrogenation removes the benzyloxy group, leading to the free primary amine. That product is then resolved by way of its camphorsulfonyl salt to afford (40-5). Reaction of this intermediate with desamino chloroadenosine (40-6) affords tecadenoson (40-7) [42]. 

The amino group of the A-benzyloxycarbonyl derivative is protected as the amide half of a carbamate ester (a urethane, Section 21-16), which is more easily hydrolyzed than most other amides. In addition, the ester half of this urethane is a benzyl ester that undergoes hydrogenolysis. Catalytic hydrogenolysis of the A-benzyloxy carbonyl amino acid gives an unstable carbamic acid that quickly decarboxylates to give the deprotected amino acid. 

Cleavage of carbamates. N-Benzyloxy- and N-r-butoxycarbonyl protected peptide derivatives can be selectively cleaved by reaction with ISilCHsls at 25-50° in the presence of side-chain blocking groups such as methyl esters or benzyl ethers. 

Despite the high synthetic value of 1,2-amino alcohols, which are precursors of several therapeutically important sugar fragments, such as daunosamine, vancosamine and ristosamine, the osmylation of allylic amines or their derivatives often occurs with disappointing stereochemical results40 41. (Z)-Substituted allylic carbamates, however, show moderate syn selectivity105. A successful example is illustrated in the synthesis of l-benzyl-3,4-bis(benzyloxy)-5-(l,2-dihy-droxyethyl)pyrrolidine42. 

An alternative procedure is available for the preparation of iodocarbonates which utilizes homoallylic carbamates as the starting material. For example, (/f )-( )-5-(aminocarbonyloxy)-l-benzyloxy-2,8-nonadiene [12, R1 = ( )-CH2OBn R2 = (CH2)2CH = CH2 R3 = H]9 with two equivalents of iodine in a two-phase medium consisting of diethyl ether and sodium hydrogen carbonate solution at 20 CC affords the corresponding cyclic iodocarbonate 13, a precursor of 1,3,5-triols1 °, in 76% yield and 93 7 (cis1,traits ) selectivity. 

As discussed, conjugate addition reactions involving chiral y-alkyl-substituted unsaturated carbonyl derivatives usually occur with low levels of diastereoselectivity. In accord with this general trend, the benzyloxy and silyloxy derivatives 103 and 104 (Scheme 6.23) both reacted with a silyl cuprate in non-selective fashion, to give the conjugate adducts 108 and 109, respectively (entries 1 and 2, Tab. 6.3) [39]. Conversely, hi levels of diastereoselectivity were found for the corresponding carbamates, and even better results were obtained for carbonates, giving the anti esters 110-112 as the major diastereomers (entries 3-5) [39]. 

Amino-l-hydroxyethyl)phosphonic acid occurs in the plasma membrane of Acanthamoeba castellani and the 2R isomer is formed, in that organism, by the hydroxy-lation of (2-aminoethvl)phosphonic acid This biosynthesis step in vitro has been studied by Hammerschmidt" who synthesized various chiral deuterium-labelled derivatives of both compounds using the isotopically labelled 2-benzyloxyethanal in Abramov reactions to obtain, initially, the dimethyl (2-benzyloxy-l-hydroxyethyl)phosphonate (362). This ester was resolved through the diastereoisomeric carbamates 363 the separated carbamates were sequentially de-l-O-protected, silylated at the a-HO group, debenzylat-ed and, by means of the Mitsunobu reaction, converted into dimethyl [2-eizido- -(tert-butyldimethylsilyloxy)ethyl]phosphonates. Subsequently, standard reactions were used to transform the latter into the diastereoisomeric, isotopically labelled (2-amino-1-hydroxy-ethyl)phosphonic acid. 

Meldrum s acid (0.413 g, 2.87 mmol) was refluxed under nitrogen in 35 mL trimethyl orthoformate for 2 h. 0-Benzyl lV-2-(5-amino-4-benzyloxy-3-methoxyphenyl)-2-(fert-butyldimethylsilyloxy)ethyl carbamate (1.14 g, 2.39 mmol) dissolved in 15 mL trimethyl orthoformate, was added to the solution of Meldrum s acid, and the mixture was refluxed for 4 h. The solvent was removed in vacuo and the residue was subjected to flash chromatography (2 1 hexane/EtOAc) to give l.OOg 5-[5-[2-(benzyloxycarbonylamino)-l-(ferf-butyldimethylsilyloxy)ethyl]-2-benzyloxy-3-methoxyphenylaminomethylene]-2,2-dimethyl-l,3-dioxane-4,6-dione as a white solid, in a yield of 87%, m.p. 110-111°C after recrystallization from EtOAc/hexanes. 

To a solution of 100 mL diphenyl ether was added 1.09 g l,3-dioxane-4,6-dione (1.57 mmol). A stream of nitrogen was passed through the solution for 20 min and the flask was then lowered into a large silicone oil bath preheated to 240°C. The temperature of the bath dropped to 225°C and rose again to 240°C in 5-7 min. The solution was stirred in the bath for a total of 18 min, then removed and allowed to cool. The solvent was removed under vacuum (0.1 mmHg, 110°C). Hash chromatography (1 2 to 6 1 hexanes/EtOAc) gave 0.326 g O-benzyl A-2-(rert-butyldimethylsilyloxy)-2-[8-benzyloxy-7-methoxy-4(l//)-quinolinon-5-yl]ethyl carbamate as a tan solid, in a yield of 35%. An analytical sample, m.p. 63-65°C, was obtained by recrystallization from EtOAc/ hexanes. 

Proton shift then gives the benzyloxy carbamate product. 

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