The greening of peptide synthesis

 

The greening of peptide synthesis

Abstract

The synthesis of peptides by amide bond formation between suitably protected amino acids is a fundamental part of the drug discovery process. However, the required coupling and deprotection reactions are routinely carried out in dichloromethane and DMF, both of which have serious toxicity concerns and generate waste solvent which constitutes the vast majority of the waste generated during peptide synthesis. In this work, propylene carbonate has been shown to be a green polar aprotic solvent which can be used to replace dichloromethane and DMF in both solution- and solid-phase peptide synthesis. Solution-phase chemistry was carried out with Boc/benzyl protecting groups to the tetrapeptide stage, no epimerisation occurred during these syntheses and chemical yields for both coupling and deprotection reactions in propylene carbonate were at least comparable to those obtained in conventional solvents. Solid-phase peptide synthesis was carried out using Fmoc protected amino acids on a ChemMatrix resin and was used to prepare the biologically relevant nonapeptide bradykinin with comparable purity to a sample prepared in DMF.

Graphical abstract: The greening of peptide synthesis
Boc-Ala-Phe-OBn 5a    ref S1
Boc-Ala-OH (324 mg, 1.71 mmol) and HCl.H-Phe-OBn (500 mg, 1.71 mmol) were coupled according to the general coupling procedure. The residue was purified using flash column chromatography (35:65, EtOAc:PE) to give Boc-Ala-Phe-OBn 5a as a white crystalline solid (682 mg, 93%). RF = 0.34 (40:60, EtOAc:PE);
mp 95.6-96.3 °C;
[α]D 23 -27.7 (c 1.0 in MeOH);
IR (Neat) νmax 3347 (m), 3063 (w), 3029 (w), 2928 (m), 2852 (w), 1735 (w), 1684 (w) 1666 (w) and 1521 (s) cm-1;
1H NMR (400 MHz, CDCl3): δ = 7.36-7.31 (m, 3H, ArH), 7.29-7.24 (m, 2H, ArH), 7.26-7.21 (m, 3H, ArH), 7.04-6.97 (m, 2H, ArH), 6.72 (d J 7.7 Hz, 1H, Phe-NH), 5.16-5.10 (m, 1H, Ala-NH), 5.13 (d J 12.1 Hz, 1H, OCH2Ph), 5.07 (d J 12.1 Hz, 1H, OCH2Ph), 4.88 (dt, J 7.7, 5.9 1H, PheNCH), 4.11 (br, 1H, Ala-NCH), 3.13 (dd J 13.9, 6.1 Hz, 1H, CH2Ph), 3.08 (dd J 13.9, 6.1 Hz, 1H, CH2Ph), 1.41 (s, 9H, C(CH3)3), 1.29 (d J 6.6 Hz, 3H, CH3);
13C NMR (100 MHz, CDCl3): δ = 172.3 (C=O), 171.2 (C=O), 155.6 (NC=O), 135.7 (ArC), 135.1 (ArC), 129.5 (ArCH), 128.7 (ArCH), 128.6 (ArCH), 127.2 (ArCH), 80.2 (CMe3), 67.4 (OCH2Ph), 53.3 (Phe-NCH), 50.3 (Ala-NCH), 38.0 (CH2Ph), 28.4 (C(CH3)3), 18.5 (CH3);
MS (ESI) m/z 449 [(M+Na)+ , 100]; HRMS (ESI) m/z calculated for C24H30N2O5Na 449.2048 (M+Na)+ , found 449.2047 (0.6 ppm error).
S1 J. Nam, D. Shin, Y. Rew and D. L. Boger, J. Am. Chem. Soc., 2007, 129, 8747–8755; Q. Wang, Y. Wang and M. Kurosu, Org. Lett., 2012, 14, 3372–3375.
General procedure for peptide coupling reactions in PC To a suspension of an N-Boc-amino acid (1.0 eq.) and an amino acid or peptide benzyl ester (1.0 eq.) in PC (5 mL mmol-1), at 0 °C, was added a solution of HOBt (1.1 eq.) and i Pr2EtN (3.0 eq.) in a minimal quantity of PC. EDC (1.1 eq.) was added dropwise and the reaction mixture was allowed to stir at room temperature for 16h. The reaction mixture was then diluted using EtOAc (50 mL) and washed with 1M HClaq (3 × 25 mL), saturated Na2CO3 (3 × 25 mL) and H2O (3 × 25 mL). The organic layer was dried (MgSO4 ), filtered and concentrated in vacuo. Any residual PC was removed via short path distillation. Purification details for each peptide and characterising data are given in the supplementary information. General procedure for Boc deprotections in PC An N-Boc-peptide benzyl ester (1.0 eq.) was dissolved in a minimum amount of PC and trifluoroacetic acid (60 eq.) was added. The reaction mixture was allowed to stir for 3h. at room temperature before being concentrated in vacuo. Any residual PC was removed via short path distillation. Characterising data for each deprotected peptide are given in the supplementary information.
Procedure for Boc deprotection of dipeptide 5a using HCl in PC Boc-Ala-Phe-OBn 5a (50 mg, 0.117 mmol) was dissolved in PC (2.34 mL). MeOH (0.40 mL, 9.8 mmol) was added and the solution cooled to 0 o C. Acetyl chloride (0.67 mL, 9.36 mmol) was added dropwise and the solution allowed to stir at room temperature for 2h. Then, PC was removed by short path distillation. The residue was suspended in Et2O and stirred for 5 minutes before being filtered to give HCl.Ala-Ph-OBn as a white solid (32.4 mg, 76%).
Propylene carbonate 1 has been shown to be a green replacement for reprotoxic amide based solvents which are widely used in peptide synthesis. Both solution- and solidphase peptide synthesis can be carried out in propylene carbonate using acid and base labile amine protecting groups respectively. No significant racemisation of the activated amino acids occurs in propylene carbonate and the viability of solid-phase peptide synthesis in propylene carbonate was demonstrated by the synthesis of the nonapeptide bradykinin.
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Microwave-Assisted Three-Component “Catalyst and Solvent-Free” Green Protocol: A Highly Efficient and Clean One-Pot Synthesis of Tetrahydrobenzo[b]pyrans,

851924.sch.001
Scheme 1: Synthesis of 4H-benzo[b]pyran derivatives under MW irradiation.

 

Microwave-Assisted Three-Component “Catalyst and Solvent-Free” Green Protocol: A Highly Efficient and Clean One-Pot Synthesis of Tetrahydrobenzo[b]pyrans,

Organic Chemistry International
Volume 2014 (2014), Article ID 851924, 8 pages
http://dx.doi.org/10.1155/2014/851924

 

Sougata Santra, Matiur Rahman, Anupam Roy, Adinath Majee, and Alakananda Hajra
Volume 2014 (2014), Article ID 851924, 8 pages

http://www.hindawi.com/journals/oci/2014/851924/

A green and highly efficient method has been developed for the one-pot synthesis of tetrahydrobenzo[b]pyrans via a three-component condensation of aldehydes, 1,3-cyclic diketones, and malononitrile under MW irradiation without using any catalyst and solvent. This transformation presumably occurs by a sequential Knoevenagel condensation, Michael addition, and intramolecular cyclization. Operational simplicity, solvent and catalyst-free conditions, the compatibility with various functional groups, nonchromatographic purification technique, and high yields are the notable advantages of this procedure.

851924.sch.002
Scheme 2: Plausible reaction mechanism.
851924.sch.003

 

A truly green synthesis of α-aminonitriles via Strecker reaction

A truly green synthesis of α-aminonitriles via Strecker reaction

Debasish Bandyopadhyay, Juliana M Velazquez, Bimal K BanikOrganic and Medicinal Chemistry Letters 2011, 1:11 (4 October 2011)

Background
The classical Strecker reaction is one of the simplest and most economical methods for the synthesis of racemic α-aminonitriles (precursor of α-amino acids) and pharmacologically useful compounds.Results
Indium powder in water is shown to act as a very efficient catalyst for one-pot, three-component synthesis of α-aminonitriles from diverse amines, aldehydes and TMSCN. This general rapid method is applicable to a wide range of amines and aldehydes and produces products in excellent yield.

Conclusions
The present one-pot, three-component environmentally benign procedure for the synthesis of α-aminonitriles will find application in the synthesis of complex biologically active molecules.