Synthesis by the Merrifield method of a protected nonapeptide amide with the amino acid sequence of oxytocin (original) (raw)
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Journal of Organic Chemistry, 1993
The repetitive deprotection of the Nu-tert-butyloxycarbonyl group during solid phase peptide synthesis was found to be efficient and quantitative by the use of a mild new reagent containing 1 M chlorotrimethylsilane and 1 M phenol in dichloromethane. Kinetic studies showed that the half-life for the reaction at 22 "C with Boc-Val-resin was 17.5 min, a 40-fold increase over the rate in the absence of phe'nol. The reaction is not due to the presence of HC1 in the reagent. The selectivity between the removal of the W-tert-butyloxycarbonyl group and benzylic esters, ethers, and carbonate side chain protecting groups was >lo6 and relative to the anchoring benzyl ester bond to the resin support it was 6 X 103. This is a marked improvement over the selectivity of the conventional 50% trifluoroacetic acid in CHzClz deprotecting agent and significantly reduces the accumulated byproducts resulting from losses of benzylic groups. The cleavage of the tert-butyl urethane was first order in Me3SiCl and second order in CsH60H. The preferred reagent is 1 M MesSiCl-3 M CsH6OH-CH2C12 and the deprotection time is 20 min (ti/2 = 1.8 min for Boc-Val-OCH2-resin). Evidence for the mechanism of the reaction was deduced. Several peptides, including Leu-enkephalin, [valine-5]angiotensin 11, and glucagon were successfully synthesized in high yields and excellent purity by the stepwise solid phase method using this new reagent.
The Journal of Organic Chemistry, 1993
A study of the utilization of tert-butyloxycarbonyl-protected amino acid N-carboxyanhydrides (Boc-NCAs) in solid-phase peptide synthesis revealed that coupling rates were favored in solvents with a high dielectric constant such as DMF. Tertiary amines such as DIEA are not required for efficient coupling in DMF. However, the use of 1 equiv of DIEA in DMF in the synthesis of a pentapeptide resulted in a cleaner crude product as compared with that obtained in the absence of DIEA. The rate of BwNCA coupling was comparable to that found for (benzotriazol-l-yloxy)tris(dimethy~o)phosphonium hexafluorophosphate (BOP) coupling or 2 4 1H-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU) coupling as judged by kinetic analysig of coupling of BocIleNCA or BocValNCA to an Ala-PAM-resin or an ne-Ala-PAM-resin. Coupling df Boc-L-ValNCA to a Phe-PAM resin or of Boc-L-PheNCA to an Ala-PAM resin resulted in 0.2%4.25% formation of D-Val-Phe and D-Phe-Ala, respectively, indicating that racemization during UNCA coupling is comparable to that found using BOP or HBTU.
Cyclohexyloxycarbonyl based orthogonal solid phase peptide synthesis in Boc chemistry
Tetrahedron, 1998
Application of N-cyclohex'yloxTcafoonyl (Choc) protection in Boc chemistry on solid phase provides a new possibility for the preparation of protected peptide fragments. A Choc/OcHex protection scheme allows also the assembly of cyclic lactam peptides linked to the resin through the C-terminus. Choc protection is stable under the 1M TMSOTf-thioanisole/TFA cleavage condition at 0°C, but it is removable by anhydrous HF. We have utilized cyclohexTloxycarbonyl as an orthogonal protecting group for the synthesis of a i) bicyclic epitope peptide of glycoprotein D of HSV 1 on BHA resin and ii) fully protected hexapeptide involved in protein transport on Merrifield resin.
Synthesis of a new protected lactam-bridged dipeptide
Tetrahedron Letters, 1990
A method has been developed for the synthesis of a new protected y-lactam-bridged dipeptide. This R,S lactam has been prepared in good yield and lncorpomted into a peptide which is analogous to hGH (7-13) using standard solid phase peptide synthesis methodolgy. The peptide showed insulin-potentiating activity ofthesame~~asthosecontaininganimideinplaceofthelactam.
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