N deprotection

Then N-Boc-O-benzylserine is coupled to the free amino group with DCC. This concludes one cycle (N° -deprotection, neutralization, coupling) in solid-phase synthesis. All three steps can be driven to very high total yields (< 99.5%) since excesses of Boc-amino acids and DCC (about fourfold) in CHjClj can be used and since side-reactions which lead to soluble products do not lower the yield of condensation product. One side-reaction in DCC-promoted condensations leads to N-acylated ureas. These products will remain in solution and not reaa with the polymer-bound amine. At the end of the reaction time, the polymer is filtered off and washed. The times consumed for 99% completion of condensation vary from 5 min for small amino acids to several hours for a bulky amino acid, e.g. Boc-Ile, with other bulky amino acids on a resin. A new cycle can begin without any workup problems (R.B. Merrifield, 1969 B.W. Erickson, 1976 M. Bodanszky, 1976). 

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. 

The p-thiolactams 50 are obtained by the action of Lawesson s or Davy s reagent on 3-substituted 1-methoxy- or 1-benzyloxy-azetidinones followed by reductive N-deprotection. The simple P-thiolactam can be modified to give the thiolactam analogues of monobactams <96LA141>. 

Pipecolic acids substituted at the 2-position were obtained from lactones by simultaneous 0- and N-deprotection on 10% Pd/C (0.08 mol Pd/mol) in EtOH-AcOH (2 1) for 1 hour (Scheme 4.75).318... 

The benzyl C-N bond was hydrogenolyzed during a double O- and N-deprotection on Pd/C in mild acidic medium.352 The reaction flask was charged with a solution of the substrate in a mixture of EtOH-AcOH (2 1). After the addition of 10% Pd/C (0.085 mol Pd/mol compound) the apparatus was charged with hydrogen. The reaction was complete within 30 min to 1 hour under stirring and enantiomerically pure (S)-pipecolic acid (29) was produced (Scheme 4.105).353... 

Clavepictines A and B (210 and 211, respectively) were obtained from the allenic ester 227. The reduction of its ester group to aldehyde, followed of addition to the latter of hexylmagnesium bromide, OH protection, and N-deprotection gave compound 228. A silver(i)-mediated cyclization of this compound afforded quinolizidine 229 and its C-6 epimer in a 7 1 ratio (Scheme 44). The former compound was readily converted into the target alkaloids <1997JOC4550>. 

A similar strategy served to carry out the last step of an asymmetric synthesis of the alkaloid (—)-cryptopleurine 12. Compound 331, prepared from the known chiral starting material (l )-( )-4-(tributylstannyl)but-3-en-2-ol, underwent cross-metathesis to 332 in the presence of Grubbs second-generation catalyst. Catalytic hydrogenation of the double bond in 332 with simultaneous N-deprotection, followed by acetate saponification and cyclization under Mitsunobu conditions, gave the piperidine derivative 333, which was transformed into (—)-cryptopleurine by reaction with formaldehyde in the presence of acid (Scheme 73) <2004JOC3144>. 

Another method that yields quinolizidine derivatives by creation of two ct-bonds from acyclic precursors is based on a domino process involving a sequence of a double N-deprotection and a double intramolecular Michael addition sequence of reactions, as summarized in Scheme 75 <2002TL6505>. 

Santagada and coworkers have disclosed a reductive amination method for the generation of a reduced peptide bond by reaction of a protected amino acid aldehyde with an N-deprotected amino ester using sodium cyanoborohydride as reducing agent [296]. 

V-(9-Fluorcnylmethoxycarbonyl)aminooxy-2-chlorotrityl polystyrene was then N-deprotected within minutes by treatment with 20% v/v piperidine in DMF to afford the key intermediate aminooxy-2-chlorotrityl polystyrene. With this in hand, N-acylation was then carried out and, where appropriate, followed by a series of chemical transformations to yield resin-bound... 

Intramolecular cyclization DKP formation through intramolecular cyclization of the Nj—C2 bond is an efficient route to ring closure and the construction of these head-to-tail dipeptides involves the coupling of an N-protected a-amino acid to an a-amino ester, followed by N-deprotection and cyclization. " ... 

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. 

Even an oligopeptide has been attached to (Table 4.3, compound 130) [111]. This was achieved by a coupling reaction of the carboxylic group in the side chain of the cyclopropane ring as well. First, the tert-butylcarboxylate 129 was synthesized by the reaction of the corresponding diazomethylbenzoate with Cgg. After hydrolysis with trifluoromethanesulfonic acid, the acyl chloride was generated by treatment with oxalyl chloride. Finally, in a one-step procedure the fullerene peptide 130 was obtained by the reaction with the N-deprotected pentapeptide H-(L-Ala-Aib)2-L-Ala-OMe. 

Dihydromuscimol (49) is a conformationally restricted analogue of the physiologically important neurotransmitter y-aminobutyric acid (GABA) and has been prepared using the cycloaddition of dibromoformaldoxime to A-Boc-allylamine followed by N-deprotection with sodium hydroxide (Scheme 6.52) (278). The individual enantiomers of dihydromuscimol were obtained by reaction of the bromonitrile oxide with (5)-( + )-l,2-0-isopropylidene-3-butene-l,2-diol, followed by separation of the diastereoisomeric mixture (erythro/threo 76 24), hydrolysis of respective isomers, and transformation of the glycol moiety into an amino group (279). 

To a soln of the appropriate compound (1.1 mmol) in dry CH2Q2 (20mL) was added DTT (30.5mg, 198 mmol) and DIPEA (20 pL) in dry CH2C12 (5mL). The soln was then stirred at rt for 30 min. The reaction was followed by TLC and after complete N-deprotection and reduction, the solvent was removed and the residue dissolved in a mixture of Ac O (5mL) and pyridine (10 mL). After 3h at rt, the mixture was concentrated, any residual pyridine coevaporated with toluene, and the residue purified by chromatography on silica gel. 

Piperazine-2,5-diones can be symmetric or asymmetric. Symmetric DKPs are readily obtained by heating amino acid esters,1179-181 whereas asymmetric DKPs are obtained directly from the related dipeptides under basic or, more properly, acid catalysis, or by cyclocondensation of dipeptide esters.1182-185 As an alternative procedure hexafluoroacetone can be used to protect/activate the amino acid for the synthesis of symmetric DKPs or of the second amino acid residue for synthesis of the dipeptide ester and subsequent direct cyclocondensation to DKPs.1186 The use of active esters for the cyclocondensation is less appropriate since it may lead to epimerization when a chiral amino acid is involved as the carboxy component in the cyclization reaction. Resin-bound DKPs as scaffolds for further on-resin transformations are readily prepared using the backbone amide linker (BAL) approach, where the amino acid ester is attached to the BAL resin by its a-amino group and then acylated with a Fmoc-protected amino acid by the HATU procedure, N -deprotection leads to on-resin DKP formation1172 (see Section 6.8.3.2.2.3). 

Among the electrophilic handles proposed for head-to-tail and side-chain-to-tail cyclization of peptides on solid support by intrachain aminolysis with concurrent detachment of the product from the resin in the protected form (see Section 6.8.3.1.3), generally the oxime resin (also called Kaiser resin)1364 365 and a thioester resin[363l are recommended (see Scheme 14). In addition to the classical head-to-tail cyclization,[3431 the oxime resin is used for side-chain cyclizations as well as for the synthesis of multicyclic peptides vide infra). Due to its dual functions, the oxime resin can be employed only with Boc/Bzl chemistry it is not compatible with Fmoc/tBu chemistry where the basic N -deprotection leads to free amino groups and thus to premature cyclization reactions. To avoid this premature cleavage of the... 

Imidazo[4,5-/ ]pyridines are exclusively hydroxylated in the imidazole ring however, no yield was reported (Equation 3) . N-Alkylation, N-deprotection, palladium-catalyzed cross-coupling, and thionation of imidazo[4,5-/ ]pyridines were reviewed in <1996CHEC-II(7)283>. 

The key step is the addition of a large excess of the organolithium compound to carboxylic acid 2 to form ketone 3. This in turn is reduced via the thioketal to form 4 which is oxidized at the former alcohol position to give, after N deprotection, the desired amino acid 5. 

Hydrogenolytic N-deprotection of (17) led to piperazinedione (18) by opening the azetidinone ring (84T1039)... 

Unfortunately, A-(9-fluorenylmethoxycarbonyl)aziridine-2-carboxylic acid cannot be used in peptide synthesis, since N-deprotection of the respective peptides with secondary amines leads to oxazoline or dehydroamino acid side products. Similarly, N-(tert-butoxy-carbonyl)aziridine-2-carboxylic acid is inappropriate due to the instability of the aziridine moiety to TFA treatment. Attempts to convert A-tritylaziridine-2-carboxylic acid into homogenous and stable active esters as useful intermediates in peptide synthesis leads to positive results only in the case of the pentafluorophenyl ester. 47 Consequently, this active ester seems to be the method of choice for acylating peptides. The related Abhydroxysuc-cinimide and A-3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine ester could not be isolated in pure form and have therefore been used as crude products. 47 Access to 2-carbonylazir-idine peptides is also possible by carbodiimide-mediated coupling. Additionally, alkylamides of A-tritylaziridine-2-carboxylic acid are prepared by the azide method,1 5 yet this method fails in peptide coupling steps. 85 ... 

The spontaneous formation of piperazine-2,5-diones occurs mainly during N-deprotection or the acylation step to dipeptide esters (usually unhindered esters such as Me, Et, Bzl, and Pac esters) that contain an TV-alkyl amino acid especially at the C-terminusJ152 In some cases the formation of piperazine-2,5-diones becomes the major reaction product and thus prevents peptide elongation by the [1+2] or [1+3] segment condensation strategy in solution synthesis or elongation of the peptide from the C-terminus in SPPS. Piperazine-2,5-dione formation... 

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