N-Tritylamino Acids and Peptides. A New Method of Peptide Synthesis<sup>1</sup>

Zervas, Leonidas; Theodoropoulos, Dimitrios

doi:10.1021/ja01588a027

Cited by 157 publications

(58 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Further experiments were directed towards on-resin oxidative deblocking of tBu protection using Tl(tfa) 3 . 20 The fully protected Boc-DPhe 1 -Ncy(tBu) 2 -Phe 3 -DTrp(Boc) 4 -Lys(Boc) 5 -Thr(tBu) 6 -Ncy(tBu) 7 -Thr (tBu) 8 All of the crude peptides (7-9) were purified 21 by RP-HPLC in at least two different solvent systems (TEAP pH 2.25 and 0.1% TFA on C 18 silica). The analytical techniques used for the characterization of the analogs in Table 1 octreotide-amide synthesized in parallel using resolved Boc-Ncy(Mob)-OH 1 and Bocstrategy.…”

Section: Nih Public Accessmentioning

confidence: 99%

Synthesis of protected norcysteines for SPPS compatible with Fmoc strategy

Samant

Rivier

2007

Tetrahedron Letters

View full text Add to dashboard Cite

We report the synthesis of racemic Alloc-Ncy(Tmob)-OH, the resolution of its methyl ester, and demonstrate its application to form a norcystine bridge in octreotide-amide using the Fmoc-strategy on solid phase. N-Alloc and S-Tmob protections of norcysteine (Ncy) were found to be a preferred choice for Fmoc-strategy over three other protected norcysteines synthesized i.e. Fmoc-Ncy(tBu)-OH, Alloc-Ncy(tBu)-OH and Alloc-Ncy(Trt)-OH. Keywordsnorcysteine; norcystine; SPPS; somatostatin; octreotide Norcysteine (Ncy) or α-thiolglycine (H 2 N-CH(SH)-COOH) is an unnatural amino acid possessing an electronegative sulfur atom attached directly to the α-carbon atom. Recently, we described the synthesis of Boc-D, L-Ncy(Mob)-OH, the resolution of its methyl ester, and the introduction of both D-and L-Ncy in cyclic gonadotropin-releasing hormone (GnRH) analogues. 1 Boc-Ncy(Mob)-OH is compatible with SPPS using Boc-strategy and can be introduced in peptides as a bridge head to constrain peptide conformation via norcysteine-containing disulfide bridges that are shorter in ring size than the cystine bridges by one or two methylene groups. Herein we describe the synthesis of N-and S-protected norcysteines for Fmoc strategy.In studies directed towards the protected norcysteines for Fmoc-strategy, the α-amino group of norcysteine was protected with Fmoc 2 and Alloc, 3 as both can be easily removed during SPPS under basic and neutral conditions, respectively. The sulfhydryl function was protected either with tBu 4 /Trt 5 /Tmob 6 for their stability during deprotection of Fmoc/Alloc groups and for their lability 7 after the cleavage of the desired peptide from the resin or during the cleavage step. The synthesis of racemic N-and S-protected norcysteines (4a-d) is illustrated in Scheme 1. In short, refluxing Fmoc-or Alloc-carbamate (1) and glyoxylic acid monohydrate (2) in acetone for 5 h or stirring in diethylether at room temperature (RT) overnight yielded the α-hydroxy intermediate (3). The reaction of tert-butylthiol/tritylthiol/2,4,6-trimethoxybenzylthiol 8 in toluene with 3 in the presence of PTSA afforded the racemic N-and S-protected norcysteines (4a-d). We attempted to separate the enantiomers of 4a-d by *Jean E. Rivier, The Salk Institute for Biological Studies, The Clayton Foundation Laboratories for Peptide Biology, 10010 North Torrey Pines Road, La Jolla, CA 92037, Tel.: (858) 453-4100, Fax: (858) 552-1546, e-mail: E-mail: jrivier@salk.edu. Supplementary Data: Experimental procedures for the synthesis of amino acids in Scheme 1 and for the synthesis of peptide analog 9 in Table 1.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all ...

show abstract

Section: Nih Public Accessmentioning

confidence: 99%

Synthesis of protected norcysteines for SPPS compatible with Fmoc strategy

Samant

Rivier

2007

Tetrahedron Letters

View full text Add to dashboard Cite

show abstract

“…The method used was a modified version of the method described by Zervas and Theodoropoulos (40). To a stirred solution of ethyl 8-aminooctanoate (190.9 mg, 1.02 mmol) dissolved in 5 mL of chloroform were added triethylamine (103.7 mg, 1.02 mmol) and trityl chloride (1.05 equiv.).…”

Section: N-trityl Erhyl 8-arninoocranoarementioning

confidence: 99%

Synthesis, C-13 NMR, and X-ray crystal structure of N6,N9-octamethylenepurinecyclophane

Bell¹,

Faggiani²,

Hunter³

et al. 1992

Can. J. Chem.

View full text Add to dashboard Cite

). The synthesis and structure determination of N6,N9-octamethylenepurine cyclophane by single crystal X-ray diffraction is reported. The cyclophane was prepared from 6-chloropurine a i d 8-aminooctanoic acid as starting materials. The aminooctyl fragment was first attached to N9 of 6-chloropurine by means of the Mitsunobu reaction and cyclization to the cyclophane effected by nucleophilic attack of the amino group at the C6 position and displacement of chloride ion. Reversing the reaction strategy did not result in formation o[ the cyclophane. Crystals of the cyclophane were monoclinic, P2,/n, a = 9.620(3), b = 12.266(3), c = 1 1.994(2), A, P = 1 1 1.25(2)", Z = 4. Intensities were measured with a Nicolet P3 diffractometer and MoKa radiation at room temperature. The structure was solved by direct methods and refined to R = 0.0683, R,,. = 0.0493 based on 1730 reflections. The molecule shows some strain, but bond lengths and angles are normal. Attempts to relieve the strain are made by a small distortion of tbe purine rings and bending of the N6 and C8' atoms out of the planes to which they are attached (0.314(4), 0.459(5) A). Further, the N6,H6,Clf group is twisted by 30" from the pyrimidine plane and the torsion angles in the aliphatic chain are distorted from the idealized 60, 120, 180" (average, 13.6"; range 5.1-24.9"). These distortions result in some weakening of the T-bonding in the adenine moiety.Key words: purinophane synthesis, nucleophilic aromatic substitution, conformational analysis, crystal structure. On a rkalise la synthkse du cyclophane N6,N9-octamCthylene purine et on dttern~inC sa structure par diffraction des rayons-X par un cristal unique. On a prepare ce cyclophane en utilisant la 6-chloropurine et I'acide 8-amino-octanoi'que comme produits de depart. On a d'abord relie la fragment amino-octyle a I'azote N9 de la 6-chloropurine 2 l'aide de la rCaction de Mitsunobu et on a ensuite effectuk la cyclisation en cyclophane en faisant appel a une attaque nuclCophile du groupe amin6 sur la position C6 qui provoque un dCplacement de I'ion chlorure. Lorsque la strategie des reactions est inversCe, il n'y a pas de formation de cy~lophane. Les cristaux du cyclophane sont monocliniques, P 2 , / n , avec LZ = 9,620(3), b = 12,266(3) et c = 11.994(2) A, P = 1 1 1,25(2)" et Z = 4. On a mesurC les intensit6 a l'aide d'un diffractomktre P3 de Nicolet et en utilisant la radiation MoKa, la temperature ambiante. On a rksolu la structure par des mCthodes directes et on l'a affinCe jusqu'i des valeurs de R = 0,683 et R,,. = 0,0493 pour 1730 reflexions. La molCcule presente des tensions, toutefois les longeurs des liaisons et les angles sont normaux. Une partie de la tension est CliminCe par une faible distorsion des n9yaux purines et un dCplacement des atomes N6 et C8' hbrs des plans auxquels ils sont attaches (0,314(4) et 0,459(5) A respectivement). De plus, le groupe N6,H6,C11 fait un angle de 30" avec le plan de la pyrimidine et les angles de torsions dans la chaine aliphatique sont dCformes par rapport aux va...

show abstract

“…It was therefore decided to attach N-tritylamino acids to the side chain amino group of the nucleotide ( Figure 5). In previous work in our laboratory, [19,20] N-trityl derivatives of different substituted phenylalanines, glycine and histidine were prepared by the method of Zervas and Theodoropoulos [21] and attached to puromycin amino nucleoside (PANS) for studies on protein synthesis. Couplings of N-trityl amino acids to PANS were facilitated by NHS activation of carboxyl groups.…”

Section: Resultsmentioning

confidence: 99%

“…N-Tritylglycine (9) and the N-trityl derivatives of o-(10), m-(11) and p-(12) fluorophenylalanine were prepared by Nel and Ariatti [19] using the method of Zervas and Theodoropoulos. [21] The N-hydroxysuccinimide derivative of N-trityl-m-fluorophenylalanine (6) was prepared from 11 by the procedure of Nel and Ariatti. [19] Assay for RNA-Dependent DNA Polymerase Activity of M-MuLV Reverse Transcriptase The nucleotide-palmitate compound (2, Figure 1) was also solubilized in an aqueous solution as follows: An EtOH solution of nucleotide-palmitate (400 µg/40 µl) was taken to dryness and the residue suspended in 500 µl H 2 O.…”

Section: Methodsmentioning

confidence: 99%

Studies on the Inhibition of Moloney Murine Leukemia Virus Reverse Transcriptase by N-Tritylamino Acids and N-Tritylamino Acid-Nucleotide Compounds

Hawtrey

Pieterse

Zyl

et al. 2008

Nucleosides, Nucleotides and Nucleic Acids

View full text Add to dashboard Cite

N-Acylated derivatives of 8-(6-aminohexyl) amino-adenosine-5 '-phosphate were prepared and studied with regard to their effect on DNA synthesis by the Moloney leukemia virus reverse transcriptase. N-palmitoyl and N-nicotinyl derivatives and bis-8-(6-aminohexyl) amino-5'-AMP inhibited the enzyme partially using poly (rA).oligo d(pT)(16-18) as template-primer with [(3)H]dTTP. In order to increase hydrophobicity in the acyl component tethered to the 8-(6-aminohexyl) amino group on the adenine nucleotide, N-trityl-L-phenylalanine and the N-trityl derivatives of the o, m, and p-fluoro-DL-phenylalanine were initially examined for inhibition of the enzyme using the above template-primer system. The compounds all inhibited the reverse transcriptase with IC(50) values of approximately 60-80 microM. However, when N-trityl-m-fluoro-DL-phenylalanine was coupled to the nucleotide 8-(6-aminohexyl) amino-adenosine-5'-phosphate, the inhibitory activity of this compound increased significantly (IC(50) = 5 microM).

show abstract

N-Tritylamino Acids and Peptides. A New Method of Peptide Synthesis¹

Cited by 157 publications

References 0 publications

Synthesis of protected norcysteines for SPPS compatible with Fmoc strategy

Synthesis of protected norcysteines for SPPS compatible with Fmoc strategy

Synthesis, C-13 NMR, and X-ray crystal structure of N6,N9-octamethylenepurinecyclophane

Studies on the Inhibition of Moloney Murine Leukemia Virus Reverse Transcriptase by N-Tritylamino Acids and N-Tritylamino Acid-Nucleotide Compounds

Contact Info

Product

Resources

About

N-Tritylamino Acids and Peptides. A New Method of Peptide Synthesis1

Cited by 157 publications

References 0 publications

Synthesis of protected norcysteines for SPPS compatible with Fmoc strategy

Synthesis of protected norcysteines for SPPS compatible with Fmoc strategy

Synthesis, C-13 NMR, and X-ray crystal structure of N6,N9-octamethylenepurinecyclophane

Studies on the Inhibition of Moloney Murine Leukemia Virus Reverse Transcriptase by N-Tritylamino Acids and N-Tritylamino Acid-Nucleotide Compounds

Contact Info

Product

Resources

About

N-Tritylamino Acids and Peptides. A New Method of Peptide Synthesis¹