Amidines deprotection

When solid-phase peptide synthesis was initially being developed, the question of whether or not a separate neutralization step is necessary was considered. Since it was known from the work of others that the chloride ion promotes racemization during the coupling step in classical peptide synthesis, and since we were deprotecting the Boc group with HC1, it seemed advisable to neutralize the hydrochloride by treatment with TEA and to remove chloride by filtration and washing. This short, additional step was simple and convenient and became the standard protocol. Subsequently, we became aware of three other reasons why neutralization was desirable (1) to avoid weak acid catalysis of piperazine-2,5-dione formation, 49 (2) to avoid acid-catalyzed formation of pyroglutamic acid (5-oxopyr-rolidine-2-carboxylic acid), 50 and (3) to avoid amidine formation between DCC and pro-tonated peptide-resin. The latter does not occur with the free amine. 

An original application of such a C,-extrusion is the reported cycloreversion of diaminocyclopropanes 18 under flash-vacuum pyrolysis (FVP) to yield amidines 20 along with the corresponding cycloalkenes 19 this reaction can also be regarded as deprotection of a C-C double bond. 

On the other hand, more base-labile amino protecting groups were developed, thereby limiting the exposure of the 2 -0-TBDMS group to extended basic treatment. Aside from the amidine chemicals described in Section II.A.2, the main chemical used in RNA synthesis is phenoxyacetyl (PAC) [13,14,147], mainly used for the ribopurine phosphoramidites because the iV4-acetyl protection of cytidine is quite optimal. Phenoxyacetyl protecting groups and tert-hutyl or isopropyl-phenoxyacetyl derivatives [15] are considerably more labile under basic conditions. Typically, they can be quantitatively cleaved from the exocyclic amino functions after 15 min to 1 h incubation at 65°C using ammonium hydroxide-ethanol (3 1). Alternately, 2 to 4 h at room temperature also allows complete deprotection. 

McBride LJ, Kierzek R, Beaucage SL, Caruthers, MH. Amidine protecting groups in oligonucleotide synthesis. J Am Chem Soc 108 2040-2048, 1986. Vinayak R, Anderson P, McColum C, Hampel A. Chemical synthesis of RNA using fast oligonucleotide deprotection chemistry. Nucleic Acids Res 20 1265-1269, 1992. 

Reaction of the ketoacid 191 with amidines gave the respective pyrimidine acyclo-C-nucleoside analogues, which could be deprotected by acid to give 192 (84AQ45). 

One-step conversion of A-(o)-azidoalkyl)lactams to bicychc amidines, avoiding the protection-deprotection sequence on the amine part, is explored by applying the intramolecular Staudinger-type reaction [26]. Oxalyl chloride [(COCl)2] and bromide [(COBr)2] are found to be effective trigger reagents and the corresponding bicyclic amidines are produced in high yield (Table 3.1). 

Diazabicyclo[4.3.0]nonene-based peptidomimetics with a quaternary chiral centre are prepared via intramolecular condensation of A -aminopropyl-y-lactam [27]. Reductive amination of oxazolidinone aldehydes with A -monoprotected propylenediamine give A -phthalimidopropyl lactams however, trials of cyclization to bicyclic amidines after deprotection under dehydration conditions are unsuccessful. To solve this problem, the phthalimides are converted to thiolactams with Lawesson reagent. Deprotection followed by treatment with mercury (11) chloride (HgCl2) yields desired cyclic amidines (Scheme 3.14). 

It was shown on some examples that the deprotection of the 2,5-diarylated amidines to give 2,5-disubstituted pyrrolidines was easily performed by treatment with H2NNH2/CF3CO2H (Scheme 18) [11]. 

Amidine pseudodisaccharides, e.g. 69, were prepared as potential glycosidase inhibitors by condensadon, e.g. of an V,0-benzyl-protected lactam (acdvated by reacdon with MeOTf) with an O-benzyl protected amino-sugar, followed by deprotection (Hx, Pd/C). ... 

Fmoc deprotection and sequential coupling of anthranilic acid and Fmoc-Gly yielded linear tripeptide 8, which could be cyclized to give immobilized oxazine 9. Treatment of 9 with piperidine cleaved the Fmoc group and promoted rearrangement of the oxazine into amidine carboxamide 10. 

Other authors presented methods based on surrogates of ammonia such as amidine hydrochlorides [241], 2,2,2-trifluoroacetamides [156], benzophenone imine [242] and sodium azide (cf. Sect. 2.4.1) [243-248]. Although efficient, these systems require an additional deprotection step to get anilines and sometimes the use of stoichiometric amounts of a copper precursor. 

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