N protecting group

In each step of the usual C-to-N peptide synthesis the N-protecting group of the newly coupled amino acid must be selectively removed under conditions that leave all side-chain pro-teaing groups of the peptide intact. The most common protecting groups of side-chains (p. 229) are all stable towards 50% trifluoroacetic acid in dichloromethane, and this reagent is most commonly used for N -deprotection. Only /ert-butyl esters and carbamates ( = Boc) are solvolyzed in this mixture. 

APA may be either obtained directly from special Penicillium strains or by hydrolysis of penicillin Q with the aid of amidase enzymes. A major problem in the synthesis of different amides from 6-APA is the acid- and base-sensitivity of its -lactam ring which is usually very unstable outside of the pH range from 3 to 6. One synthesis of ampidllin applies the condensation of 6-APA with a mixed anhydride of N-protected phenylglydne. Catalytic hydrogenation removes the N-protecting group. Yields are low (2 30%) (without scheme). 

Tandem cyclization/3-substitution can be achieved starting with o-(trifluoro-acetamido)phenylacetylenes. Cyclization and coupling with cycloalkenyl trif-lates can be done with Pd(PPh3)4 as the catalyst[9]. The Pd presumably cycles between the (0) and (II) oxidation levels by oxidative addition with the triflate and the reductive elimination which completes the 3-alkenylation. The N-protecting group is removed by solvolysis under the reaction conditions, 3-Aryl groups can also be introduced using aryl iodides[9]. 

An important reaction parameter is the choice of the base and NajCO or NaOAc have been shown to be preferable to EtjN in some systems[2]. The inclusion of NH4CI has also been found to speed reaction[2]. An optimization of the cyclization of A -allyl-2-benzyloxy-6-bromo-4-nitroaniline which achieved a 96% yield found EtjN to be the preferred base[3]. The use of acetyl or inethanesulfonyl as N-protecting groups is sometimes advantageous (see Entries 4 and 5, Table 4.1). 

The details of the solid-phase technique have been improved substantially over the years, but the fundamental idea remains the same. The most commonly used resins at present are either the Wang resin or the PAM (phenyl-acetamidomethyl) resin, and the most commonly used N-protecting group is the fluorenylmethyloxycarbonyl, or Fmoc group, rather than Boc. 

A tert-butyl ester serves as an efficient organyl-stabilizing group for a lithiated aziridine when the N-protecting group is a chelating moiety. Deprotonation/elec-... 

A general step ahead in polycondensation was achieved by the application of the active ester method by DeTar et al.19) and Kovacs et al.291 Very soon, the nitrophenyl ester, the pentachlorophenyl ester, or the hydroxysucdnimido ester were used exclusively. The esters of the protected tripeptides could be purified by crystallization, then the N-protecting group was split off and the free peptide esters were purified again. Addition of base starts the polycondensation, resulting quickly in the formation of a viscous solution at low temperature. 

HydTOX5 proline-derived polyesters are usually readily soluble in a variety of organic solvents (benzene, toluene, chloroform, dichloro-methane, carbon tetrachloride, tetrahydrofuran, dimethylformamide, etc.) As expected, the solubility in hydrophobic solvents increased with increasing chain length of the N protecting group, while the solubility in polar solvents decreased. For example, poly(N-hexanoyl-hydroxyproline ester) is slightly soluble in ether but easily soluble in acetonitrile, while poly(N-palmitoylhydroxyproline ester) is readily soluble in ether but virtually insoluble in acetonitrile. 

Installation of an N-protecting group was optimized to suppress formation of O-benzylation. 

The catalytic preparation of substituted tetrahydrofurans and pyrrolidines with a number of N-protecting groups has been reported. The use of 1,2-... 

The reaction tolerates different N-protecting groups as well as a variety of substituted 3-keto-phosphonates. In all cases, the tetracyclic structures were obtained as single diastereomers, however with respect to the natural product with the undesired trans-junction between the rings A and B. 

Scheme 21.12 Effect of N-protecting groups on the dynamic kinetic resolution.

The reaction depends on various factors including solvent, initial pressure, catalyst precursor and the N-protecting group. Due to the high stability of (S,S)-3-Pt-FerroPHOS towards air, it may be used in an industrial process. 

L Zervas, D Borovas, E Gazis. New methods in peptide synthesis. I. Tritylsulfenyl and o-nitrophenylsulfenyl groups as N-protecting groups. J Am Chem Soc 85, 3660, 1963. 

Y Okada, J Wang, T Yamamoto, Y Mu, T Yokoi. Amino acids and peptides. Part 45. Development of a new N-protecting group of histidine, NK-( -adamantyloxymethyl)-histidine, and its evaluation for peptide synthesis. J Chem Soc Perkin Trans 1 2139. 1996. 

The methylenemalonate moiety was used as an N-protecting group at the esterification of amino acids. After the esterification of the carboxyl group with the appropriate alkyl bromide in acetone in the presence of... 

Furthermore, attempted cyclization of N-carboxymethyl meroquinene ethyl ester failed to afford any of the enone, suggesting that the carboxylic acid was an intermediate. The N-protecting groups, in addition to benzoyl, that are tolerated include CC Me, pivaloyl, acetyl, toluenesulfonyl, CBz, and alkyl. 

N-deprotection Removal of N-protecting groups, nonpeptidomimetics Nonpeptide analogues, usually small molecules, nonpolar Hydrophobic molecules that are poorly soluble in water, oligopeptide A few amino acids joined by peptide bonds. 

Azido aldehydes and a-protected amino aldehydes have been used to incorporate the nitrogen in the aldolase-catalyzed reaction (for an extensive review on aldolase-mediated synthesis of iminocyclitols, see [28] and references therein). The steri-cally unhindered azido and N-formylamino aldehydes display a marked kinetic advantage over analogs having larger and/or poor water-soluble N-protecting groups [29]. 

A -Benzyl groups on pyrimidinones and quinazolinones are removable by hydrogenolysis, although it is now more common to use a PMB substituent that can be removed with either TFA or CAN. Other N-protecting groups to be commonly used include benzyloxymethyl (BOM), removable by hydrogenation, ferZ-butoxycarbonyl (BOC), removable by anhydrous acid, and pivaloyloxymethyl (POM), which is removable by methanolic ammonia at room temperature. Alkenyl pyrimidinones have been employed in 1,3-dipolar cycloaddition reactions to prepare heterocyclic nucleotides. 

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