Cbz-protected a-amino

Boc- and Cbz-protective groups turned out to be not tolerable in this protocol as indicated by epimerization of Boc- or Cbz-protected a-amino aldehydes substrates (e.g., N-Boc-protected 2-amino-3-phenyl-propionaldehyde 70% yield/24h, antijsyn ratio 50 50, 20% ee with 186). 

Very recently, the reaction of the dianion-enolate of a Cbz-protected a-amino ester with a cyanomethylamine as an imine precursor toward several /3-lactam derivatives has been described <2007BML358>. 

A useful modification of the Knorr pyrrole synthesis was developed in the laboratory of J.M. Hamby for the construction of tetrasubstituted pyrroles. The necessary a-amino ketones were prepared from A/-methoxy-A/-methylamides of amino acids (Weinreb amides). These Weinreb amides were prepared by the mixed anhydride method and treated with excess methylmagnesium bromide in ether to afford the corresponding Cbz-protected a-amino ketones in excellent yield. The Cbz group is removed by catalytic hydrogenation in the presence of the active methylene compound (e.g., acetoacetic ester), the catalyst is then filtered and the resulting solution is heated to reflux to bring about the condensation. 

Thionation of Cbz-protected a-amino acid dimethylamides of type 6 proceeds smoothly under the standard conditions to give selectively Cbz-protected o -amino acid thioamides 7 (eq 3), i.e., thionation of carboxamides is preferred to that of carbamates. 

The described approach also allows a simple access to indole alkaloids of the vallesiachotamine type. In this process, the Cbz-protected secondary amino function in the formed cycloadducts such as ent-2-805 is deprotected by hydrogenolysis. There follows an attack at the lactone moiety to form a lactam. In this way, the indole alkaloid (-)-dihydroantirhin (2-797) was prepared [400, 401]. 

Chiral a-amino ketones.3 N-Methoxycarbonyl-protected a-amino acid chlorides undergo Friedel-Crafts reactions with high retention of chirality. Cbz-protected amino acids under the same conditions give intractable tars. 

Thus, reaction of N-Cbz-protected a-, fl- or y-amino aldehydes 190 with 1,3-dicarbonyl compound 191 in the presence of benzyl enol ether 192 followed by hydrogenation led to substituted pyrrolidines, piperidines and azepanes as a mixture of diastereomers in >95% chemical purity in most cases. 

In a different context, chiral reagents have been implemented in this chemistry. For instance, Liebscher and Itho developed the use of chiral acylating agents such as amino acid-fluorides 158 and -chlorides 156, respectively, (Scheme 21). The outcome of the reaction of isoquinoline (6), TMS-CN (14) and A -protected a-amino acid fluorides is dictated by the nature of the protecting group whereas Cbz- and... 

If selenophenol is used in place of thiophenol, ethyl (7 )-2-(phenylseleno)propionate (177) is formed also in high yield. Partial reduction of the ester to aldehyde affords (/ )-2-(phe-nylseleno)propanal (178) with 90-98% ee. This intermediate has been used for the synthesis of a variety of Cbz-protected D-amino acids [66] (Scheme 25). 

S,3R)-Aziridine-2-carboxylic amide 258 (Scheme 3.95) has been used in the synthesis of the cyclic guanidino amino acid, L-epicapreomycidine (260) [145]. Treatment of 258 with saturated ammonia in methanol at 30 °C for 4 days in a pressure bottle resulted in the aziridine ring-opening product, which afforded 259 in 52 % yield after removal of the Cbz protecting group. 

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). 

Figure 1 Reaction scheme for the hydrogenolysis of a Cbz-protected amino acid.

The removal of a carbobenzyloxy group can be separated into two steps (Figure 1). The first step comprises the hydrogenolysis of the benzyl oxygen bond of the Cbz-protected amino acid 1 to form a carbamic acid intermediate 2 and toluene 3. The carbamic acid intermediate decaiboxylates to give the deprotected amino acid 4 and one equivalent of carbon dioxide 5. 

In addition to the already known inhibiting effect of N-containing bases on debenzylation reactions we have shown that similar modifiers can increase the rate of hydrogenolysis of a CBz protected amino acid. As these reactions are carried out on industrial scale the addition of certain modifiers can increase the reaction rate, thus leading to shorter reaction times and higher productivity. 

Photo-induced conversions are also important synthetically. The photocycloaddition of 5-substituted uracils 69 with ethylene has been used for the synthesis of 2-aminocyclobutanecarboxylic acids. The addition reaction worked well with carbon and fluorine substituents and also with a Cbz-protected amino. However, uracils with other 5-nitrogen substituents (NH2, NHBn and NO2) failed, only starting material being recovered. The sequence also worked for the 6-isomers but somewhat less consistently <06SL1394>. 

To increase the load of liposomes and micelles with reporter metals, we designed a new family of amphiphilic single-terminus modified polymers containing multiple chelating groups that could be incorporated into the hydrophobic domains of liposomes and micelles. The approach is based on the use of CBZ-protected polylysine (PL) with a free terminal amino group, which is derivatized into a reactive form with subsequent deprotection and incorporation of DTPA residues. This was initially suggested by us for heavy metal load on proteins and antibodies [17]. 

Although several routes have been published for the preparation of hydroxamic acids on solid phase, these generally involve the preparation of a special linker to which hydrox-ylamine is attached. Dankwardt s approach obviates the need for special linkers or protecting groups, by displacing the desired hydroxamic acid from the resin directly using hydroxylamine, as illustrated in Scheme 86. CarboxyUc-acid-ester-linked, polymer-supported, Cbz-protected amino acids 195 (formed from 194) were displaced from the resin with aqueous hydroxylamine to provide the corresponding hydroxamic acids 196. 

Schistosoma japonicum. The carbobenzoxy (CBz) protected template 160 was initially converted to the a, p-dehydrolactone 161 via the phosphate ester, before undergoing cycloaddition to ylide 162, generated in situ by acidic treatment of A(-benzyl-A(-(methoxymethyl)trimethylsilyl amine. The resultant cycloadduct (163) was isolated in 94% yield as a single diastereoisomer. Destructive template removal, by catalytic hydrogenation, released (5)-( )-cucurbitine, after ion-exchange chromatography, as the free amino acid in 90% yield (Scheme 3.46). 

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