New methods in peptide synthesis, based on supernucleophiles (original) (raw)
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The Journal of Organic Chemistry, 1992
A variety of new amino acids which contain an w-aminoakylene group on the N' -amino nitrogen were synthesized by alkylation of alkylenediamines with a-halogeno acids. The reaction proceeds with inversion of configuration; thus, optically pure products were obtained when optically active a-halogeno acids were used. The N-(w-aminoalky1ene)amino acids were protected by orthogonal protecting groups to allow their incorporation into dipeptides by the "solutionn techniques and i n b peptides by the solid-phase peptide synthesis (SPPS) methodology. A series of dipeptide analogs of Phe-Gly, Leu-Gly, Trp-Gly, Phe-Leu, and Phe-Ala in which the nitrogen of the peptide bond is alkylated by w-aminoalkylene chains with various lengths were prepared. These new protected N-(o-aminoalky1ene)amino acids and their derived dipeptide units may be used as building blocks for conformationally constrained N-backbone cyclic peptides.
Liebigs Annalen der Chemie, 1988
Condensation of amides of N-(benzyloxycarbony1)-and N-(trifluoroacety1)amino acid with pyruvic and phenylpyruvic acid yields, in the presence of p-toluenesulfonic acid as a catalyst, N-(benzyl-oxycarbony1)-and N-(trifluoroacety1)dehydro dipeptides with C-terminal AAla and APhe, respectively (Table 2 and 3). Synthese von Peptiden mil a,P-Dehydroaminosauren, I.-Synthese von N-(Benzyloxycarbonylb und N-(Trifluoracety1)dipeptiden von Dehydroalanin und Dehydrophenylalanin Die Kondensation von Na-(Benzyloxycarbonyl)-und Na-(Trifluoracetyl)arninosaureamiden mit Brenztrauben-und Phenylbrenztraubensaure in Gegenwart von p-Toluolsulfonsaure als Katalysator fuhrt zu N-(Benzyloxycarbony1)-und N-(Trifluoroacety1)dehydrodipeptiden rnit C-standigem AAla2) bzw. APhe (Tab. 2 und 3). N-protected a,B-dehydroamino acid which, among others, can be synthesized by condensation of carboxamides with a-keto acids3-'), have only a limited value in peptide synthesis. The deprotection of the enamine function is somewhat difficult ') and accompanied by side reaction^'.'^). The nucleophilicity of the deprotected amino group, particulary in APhe'), is diminished as compared with amino groups in common amino a~i d s~*~, * * "~'~'. Basing on the condensation of Z-Gly-NH2 with pyruvic acid which leads to Z-Gly-AAla6' and taking into account the considerable improvement in condensation method of amides with a-keto acids4*", to circumvent the above difficulties we put to trial the condensation of a-keto acids with suitably No-protected amino acid amides". We describe here our experiments, observations, and the obtained dehydro dipeptides. Model compounds were selected in that way to represent a given spectrum of N-protections and side chain residues and in consequence reactivity. W e condensed amides of Z-and TFA-glycine,-L-phenylalanine, and-L-valine (the derivatives of amino acids without side chain and with an aromatic or branched aliphatic one) with pyruvic or phenylpyruvic acid which both possess different chemical reactivity toward amides. Viz., they react in the absence4-" or presence4' of catalysts. Condensations led to Zand TFA-dipeptides with C-terminal AAla or APhe, thus, to peptides having the amino group protecting moieties
The use ofN-urethane-protectedN-carboxyanhydrides (UNCAs) in amino acid and peptide synthesis
Journal of Peptide Science, 1995
N-Urethane-protected N-carboxyanhydrides (UNCAs) are very reactive amino acid derivatives. They have been successfully used in peptide synthesis, in both solution and solid phase. We have demonstrated that UNCAs are interesting starting materials for the synthesis of various amino acid derivatives. Chemoselective reduction of UNCAs with sodium borohydride led the corresponding N-protected P amino alcohols. Reaction of UNCAs with Meldrum's acid, followed by cyclisation. yielded enantiomerically pure tetramic acid derivatives. Diastereoselective reduction of tetramic acid derivatives produced (4S,5S)-N-alkoxycarbonyl-4-hydroxy-5alkylpyrrolidin-2-ones derived from amino acids, which after hydrolysis yielded statine and statine analogues. Tetramic acid derivatives could also be obtained by reaction of UNCAs with benzyl ethyl malonate in the presence of sodium hydride to yield y-Kbenzyloxycarbonylamino-P-oxodicarboxyl esters followed by hydrogenolytic deprotection and decarboxylation. UNCAs also reacted with phosphoranes to produce the ketophosphorane in excellent yields. Subsequent oxidation with oxone or with [bis(acetoxy)-iodol-benzene produced vicinal tricarbonyl derivatives. These reactions usually proceeded smoothly and with high yields.
Tetrahedron Letters, 1997
The use of Alloc group in SPPS for the N t~ protection of amino acids is an alternative to the Boc and Fmoc protecting groups. The smooth removal of Alloc group in neutral conditions with catalytic amounts of Pd(PPh3)4 in the presence of PhSiH3 as a scavenger for the allyl system permits orthogonality with the most common protecting groups. Furthermore, a tandem deprotection-coupling reaction allows the suppression of DKP formation in cases where this side reaction is troublesome.
Synthesis of Novel Peptides Using Unusual Amino Acids
Iranian Journal of Pharmaceutical Research : IJPR, 2020
Small peptides are valuable peptides due to their extended biological activities. Their activities could be categorized according to their low antigenicity, osmotic pressure, and also because of their astonishing bioactivities. For example, the aggression of Phe-Phe fibers via self-assembly and intermolecular hydrogen bonding is the main reason for the formation of Alzheimer’s β-amyloid fibrils. Hydrogen bonding is the main intramolecular interaction in peptides, while the presence of aromatic ring leads to the π-π stacking and affects the self-assembly and aggression. Thus, insertion of an unusual amino acid into peptide sequence facilitates the formation of intramolecular bonds, lipophilicity and its conformation. To design new small peptides with remarkable lipophilicity, it is an idea to employ γ-amino acid, such as gabapentin (H2N-Gpn-OMe) and baclofen (H2N-Baclofen-OMe), in the structure of small peptides to increase cell-penetrating properties and to prevent aggression of Phe...
Journal of Peptide Science, 2000
Backbone cyclization has become an important method for generating or stabilizing the bioactive conformation of peptides without affecting the amino acid side-chains. Up to now, backbone cyclic peptides were mostly synthesized with bridges between N-amino-and N-carboxy-functionalized peptide bonds. To study the influence of a more flexible backbone on the biological activity, we have developed a new type of backbone cyclization which is achieved via the N-functionalized moieties of acylated reduced peptide bonds. As described in our previous publications, the formation of N-functionalized dipeptide units facilitates the peptide assembly compared with the incorporation of N-alkyl amino acids. Besides the racemization-free synthesis of Fmoc-protected pseudodipeptide esters with reduced peptide bonds, the new type of backbone modification allows the use of a great variety of-aminoand h,-dicarboxylic acids differing in chain length and chemical properties. Best results for the coupling of the-aminoand h,-dicarboxylic acids to the reduced peptide bond were obtained by the formation of mixed anhydrides with alkyl chloroformates. Whereas the protecting group combination of Z/OBzl in the dipeptide unit and Boc/OtBu for the N-functionalized moiety leads to the formation of 2-ketopiperazine during hydrogenation, the combination of Fmoc/ OtBu and Alloc/OAll is very suitable for the synthesis of backbone cyclic peptides on solid support.