N-Protecting

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). 

In one method treatment of a solution containing the N protected and the C protected ammo acids with N N dicyclohexylcarbodiimide (DCCI) leads directly to peptide bond formation... 

Step 3 The resin bound C terminal ammo acid IS coupled to an N protected ammo acid by using N N dicyclohexylcarbodiimide Excess reagent and N N dicyclohexylurea are washed away from the resin after coupling is complete... 

Methylthiophene is metallated in the 5-position whereas 3-methoxy-, 3-methylthio-, 3-carboxy- and 3-bromo-thiophenes are metallated in the 2-position (80TL5051). Lithiation of tricarbonyl(i7 -N-protected indole)chromium complexes occurs initially at C-2. If this position is trimethylsilylated, subsequent lithiation is at C-7 with minor amounts at C-4 (81CC1260). Tricarbonyl(Tj -l-triisopropylsilylindole)chromium(0) is selectively lithiated at C-4 by n-butyllithium-TMEDA. This offers an attractive intermediate for the preparation of 4-substituted indoles by reaction with electrophiles and deprotection by irradiation (82CC467). 

Paal-Knorr synthesis, 4, 118, 329 Pariser-Parr-Pople approach, 4, 157 PE spectroscopy, 4, 24, 188-189 photoaddition reactions with aliphatic aldehydes and ketones, 4, 232 photochemical reactions, 4, 67, 201-205 with aliphatic carbonyl compounds, 4, 268 with dimethyl acetylenedicarboxylate, 4, 268 Piloty synthesis, 4, 345 Piloty-Robinson synthesis, 4, 110-111 polymers, 273-274, 295, 301, 302 applications, 4, 376 polymethylation, 4, 224 N-protected, 4, 238 palladation, 4, 83 protonation, 4, 46, 47, 206 pyridazine synthesis from, 3, 52 pyridine complexes NMR, 4, 165... 

RCO2H = Ph, 2,4,6-Me3C6H2—, N-protected amino acids R = Me, Et, PhCH2, -Bu... 

The Dppe group was developed for carboxyl protection in peptide synthesis. It is formed from an N-protected amino acid and the alcohol (DCC, DMAP, 3-12 h, 0°, It). It is most efficiently cleaved by quatemization with Mel followed by treatment with fluoride ion or K2CO3. The ester is stable to HBr/AcOH, BF3 Et20, and CF3CO2H. ... 

The Tcrom ester is prepared from the cesium salt of an N-protected amino acid by reaction with 2-(trifluoromethyl)-6-chromylmethyl bromide (DMF, 25°, 4 h, 53-89% yield). Cleavage of the Tcrom group is effected by brief treatment with n-propylamine (2 min, 25°, 96% yield). It is stable to HCl/dioxane, used to cleave a BOC group. ... 

A variety of 1,3-oxazolidines have been used as chiral formyl anion equivalents for addition to aldehydes. Thus, for example, reaction of N-protected norephedrine with Bu3Sn-CH(OEt)2 gives 48, and transmetallation with BuLi followed by addition of benzaldehyde affords the expected adduct 49. The selectivity at the newly formed alcohol center is poor, but the situation can be salvaged by oxidation and re-reduction, which affords the product 50 with >95% d.e. It is then a simple matter to hydrolyze off the oxazolidine, although the resulting hydroxyaldehydes... 

Similarly, the cross-coupling of N-protected 4-ethynylpyrazole with 1-(1-ethoxyethyl)-4-iodo- l//-pyrazole leads only to disubstituted butadiyne (2001 UP 1) (Scheme 50). 

The pyridine-N-oxide 245 was converted into the cyanopyridine 246 and its isomer (Scheme 80). Grignard reaction, Fischer s indole synthesis, and N-protection gave a pyridinyl indole 247. Selenium dioxide selectively oxidized the methyl group to give the isonicotinic acid. The synthesis of Flavocarpine (244) was finally accomplished by a set of standard reactions as outlined in Scheme 80 (87TL5259). 

Abwehr-ferment, n. protective ferment enzyme), defensive ferment (or enzyme), -mittel, n. preventive, prophylactic. 

A number of studies have recently been devoted to membrane applications [8, 100-102], Yoshikawa and co-workers developed an imprinting technique by casting membranes from a mixture of a Merrifield resin containing a grafted tetrapeptide and of linear co-polymers of acrylonitrile and styrene in the presence of amino acid derivatives as templates [103], The membranes were cast from a tetrahydrofuran (THF) solution and the template, usually N-protected d- or 1-tryptophan, removed by washing in more polar nonsolvents for the polymer (Fig. 6-17). Membrane applications using free amino acids revealed that only the imprinted membranes showed detectable permeation. Enantioselective electrodialysis with a maximum selectivity factor of ca. 7 could be reached, although this factor depended inversely on the flux rate [7]. Also, the transport mechanism in imprinted membranes is still poorly understood. 

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. 

Peptide synthesis requires the use of selective protecting groups. An N-protected amino acid with a free carboxyl group is coupled to an O-protected amino acid with a free amino group in the presence of dicydohexvlcarbodi-imide (DCC). Amide formation occurs, the protecting groups are removed, and the sequence is repeated. Amines are usually protected as their teit-butoxy-carbonyl (Boc) derivatives, and acids are protected as esters. This synthetic sequence is often carried out by the Merrifield solid-phase method, in which the peptide is esterified to an insoluble polymeric support. 

As described in Section 2.3.2, vinylaziridines are versatile intermediates for the stereoselective synthesis of (E)-alkene dipeptide isosteres. One of the simplest methods for the synthesis of alkene isosteres such as 242 and 243 via aziridine derivatives of type 240 and 241 (Scheme 2.59) involves the use of chiral anti- and syn-amino alcohols 238 and 239, synthesizable in turn from various chiral amino aldehydes 237. However, when a chiral N-protected amino aldehyde derived from a natural ot-amino acid is treated with an organometallic reagent such as vinylmag-nesium bromide, a mixture of anti- and syn-amino alcohols 238 and 239 is always obtained. Highly stereoselective syntheses of either anti- or syn-amino alcohols 238 or 239, and hence 2,3-trans- or 2,3-as-3-alkyl-2-vinylaziridines 240 or 241, from readily available amino aldehydes 237 had thus hitherto been difficult. Ibuka and coworkers overcame this difficulty by developing an extremely useful epimerization of vinylaziridines. Palladium(0)-catalyzed reactions of 2,3-trons-2-vinylaziri-dines 240 afforded the thermodynamically more stable 2,3-cis isomers 241 predominantly over 240 (241 240 >94 6) through 7i-allylpalladium intermediates, in accordance with ab initio calculations [29]. This epimerization allowed a highly stereoselective synthesis of (E) -alkene dipeptide isosteres 243 with the desired L,L-... 

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. 

The peptide is removed from the polystyrene resin by means of hydrogen fluoride. The couplings were nearly complete by using a threefold excess of the N-protected tripeptide. A fractionation of the resulting oligotripeptide, however, has been performed. The folding behavior in water was much more pronounced than in the case of the polymers obtained by the old TEPP method13 . 

Lithium catalyzed hetero-Diels-Alder reactions. Cyclocondensation of N-protected ot-amino aldehydes with 1-methoxy-3-fert-butyldimethylsilyloxybutadiene in the presence of lithium perchlorate [104]... 

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