The greening of peptide synthesis

 

The greening of peptide synthesis

Stefan B. Lawrenson,^a  Roy Arav^a  and  Michael North*^a 

*Corresponding authors

^aGreen Chemistry Centre of Excellence, Department of Chemistry, University of York, York, UK
E-mail: Michael.north@york.ac.uk

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.

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 1666 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.

///////////

A two-step efficient preparation of a renewable dicarboxylic acid monomer 5,5[prime or minute]-[oxybis(methylene)]bis[2-furancarboxylic acid] from D-fructose and its application in polyester synthesis

A two-step efficient preparation of a renewable dicarboxylic acid monomer 5,5[prime or minute]-[oxybis(methylene)]bis[2-furancarboxylic acid] from D-fructose and its application in polyester synthesis

Green Chem., 2017, 19,1570-1575
DOI: 10.1039/C6GC03314H, Paper

Ananda S. Amarasekara, Loc H. Nguyen, Nnaemeka C. Okorie, Saad M. Jamal
A renewable monomer 5,5[prime or minute]-[oxybis(methylene)]bis[2-furancarboxylic acid] from D-fructose.

A two-step efficient preparation of a renewable dicarboxylic acid monomer 5,5′-[oxybis(methylene)]bis[2-furancarboxylic acid] from D-fructose and its application in polyester synthesis

Ananda S. Amarasekara,*^a   Loc H. Nguyen,^a  Nnaemeka C. Okorie^a and   Saad M. Jamal^a  

*Corresponding authors

^aDepartment of Chemistry, Prairie View A&M University, Prairie View, USA
E-mail: asamarasekara@pvamu.edu
Fax: +1 936 261 3117
Tel: +1 936 261 3107

Green Chem., 2017,19, 1570-1575

DOI: 10.1039/C6GC03314H

D-Fructose was converted to the dialdehyde 5,5′-[oxybis(methylene)]bis[2-furaldehyde] by heating at 110 °C in DMSO with the Dowex 50 W X8 solid acid catalyst in 76% yield without the isolation of the intermediate 5-hydroxymethylfurfural. This dialdehyde was then converted to the dicarboxylic acid monomer, 5,5′-[oxybis(methylene)]bis[2-furancarboxylic acid], using oxygen (1 atm.) and 5% Pt/C catalyst in 1.5 M aqueous NaOH at room temperature in 98% yield. The new dicarboxylic acid monomer can be considered as a renewable resource based alternative to terephthalic acid as demonstrated by the preparation of polyesters with 1,2-ethanediol and 1,4-butanediol in 87–92% yield.

Synthesis of 5,5′-[oxybis(methylene)]bis[2-furancarboxylic acid]

pale yellow crystals. 260 mg, 98 % yield. M.pt. 207-209 °C, Lit. M. pt. 209-210 °C 37 .

IR (ATR) 761, 891, 951, 1029, 1059, 1159, 1208, 1283, 1342, 1424, 1525, 1674, 3128 cm-1

1 H NMR (DMSO-d6 ) δ 3.38 (2H, bs, 2XCOOH), 4.51 (4H, s, 2X-CH2O ), 6.61 (2H, d, J = 3.6 Hz, C-4,4′), 7.15 (2H, d, J = 3.6 Hz, C-3,3′).

13C NMR (DMSO-d6 ) δ 63.8, 112.2, 118.8, 145.3, 155.5, 159.6

37. T. Iseki and T. Sugiura, J. Biochem., 1939, 30, 113-118.

NMR PREDICT

1H NMR PREDICT

13C NMR PREDICT

//////////////O=C(O)c2ccc(COCc1ccc(o1)C(=O)O)o2

Synthesis of cyclic organic carbonates via catalytic oxidative carboxylation of olefins in flow reactors

 

Synthesis of cyclic organic carbonates via catalytic oxidative carboxylation of olefins in flow reactors

Catal. Sci. Technol., 2017, Advance Article
DOI: 10.1039/C6CY01974A, Paper

Ajay A. Sathe, Anirudh M. K. Nambiar, Robert M. Rioux
The direct catalytic conversion of olefins into cyclic carbonates using peroxide and carbon dioxide is demonstrated using continuous flow reactors.

Ajay A. Sathe,^a   Anirudh M. K. Nambiar^b and  Robert M. Rioux*^ab  

*Corresponding authors

^aDepartment of Chemistry, The Pennsylvania State University, University Park, USA
E-mail: rioux@engr.psu.edu
Fax: 814 865 7846
Tel: 814 867 2503

^bDepartment of Chemical Engineering, The Pennsylvania State University, University Park, USA

Catal. Sci. Technol., 2017, Advance Article

DOI: 10.1039/C6CY01974A

http://pubs.rsc.org/en/Content/ArticleLanding/2017/CY/C6CY01974A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2Fcy+%28RSC+-+Catalysis+Science+%26+Technology+latest+articles%29#!divAbstract

Methodology for direct catalytic conversion of olefins into cyclic carbonates using peroxide and carbon dioxide under relatively mild conditions is demonstrated. The protocol utilizes packed bed flow reactors in series to couple rhenium catalyzed olefin epoxidation and aluminum catalyzed epoxide carboxylation in a single sequence.

 

 

 

////////Synthesis,  cyclic organic carbonates, catalytic oxidative carboxylation, olefins, flow reactors

Microbial cyclosophoraose as a catalyst for the synthesis of diversified indolyl 4H-chromenes via one-pot three component reactions in water

Green Chem., 2016, 18,3620-3627
DOI: 10.1039/C6GC00137H, Paper

Someshwar D. Dindulkar, Daham Jeong, Eunae Cho, Dongjin Kim, Seunho Jung
A novel biosourced saccharide catalyst, microbial cyclosophoraose, a cyclic [small beta]-(1,2) glucan, was used for the synthesis of indolyl 4H-chromenes via a one pot three-component Knoevenagel-Michael addition-cyclization reaction in water under neutral conditions.

Someshwar D. Dindulkar,^a   Daham Jeong,^a   Eunae Cho,^a  Dongjin Kim^b and   Seunho Jung*^ac  

 *corresponding authors

^a

Institute for Ubiquitous Information Technology and Applications (UBITA) & Center for Biotechnology Research in UBITA (CBRU), Konkuk University, Seoul 143-701, South Korea
E-mail: shjung@konkuk.ac.kr

^b

Nelson Mandela African Institution of Science and Technology, PO box 447, Arusha, Tanzania

^c

Department of Bioscience and Biotechnology, Microbial Carbohydrate Resource Bank (MCRB), Konkuk University, Seoul 143-701, South Korea

Green Chem., 2016,18, 3620-3627

DOI: 10.1039/C6GC00137H

As a novel biosourced saccharide catalyst, microbial cyclosophoraose, a cyclic β-(1,2) glucan, was used for the synthesis of therapeutically important versatile indolyl 4H-chromenes via a one pot three-component Knoevenagel–Michael addition–cyclization reaction of salicylaldehyde, 1,3-cyclohexanedione/dimedone, and indoles in water under neutral conditions. A possible reaction mechanism through molecular complexation is suggested based on 2D ROESY NMR spectroscopic analysis. Moreover, green chemistry metric calculations were carried out for a model reaction, indicating the satisfactory greener approach of this method, with a low E-factor (0.18) and high atom economy (AE = 91.20%). The key features of this protocol are based on two critical factors where the first is to use a novel eco-friendly supramolecular carbohydrate catalyst and the second is its fine green properties such as compatibility with various substituted reactants, recyclability of the catalyst, chromatography-free purification, high product selectivity, and clean conversion with moderate to excellent yields in an aqueous medium.

 

 

//////Microbial cyclosophoraose, catalyst,  synthesis , diversified indolyl 4H-chromenes , one-pot three component reactions, water

Microbial cyclosophoraose as a catalyst for the synthesis of diversified indolyl 4H-chromenes via one-pot three component reactions in water

.

 

Microbial cyclosophoraose as a catalyst for the synthesis of diversified indolyl 4H-chromenes via one-pot three component reactions in water

Green Chem., 2016, Advance Article DOI: 10.1039/C6GC00137H, Paper Someshwar D. Dindulkar, Daham Jeong, Eunae Cho, Dongjin Kim, Seunho Jung A novel biosourced saccharide catalyst, microbial cyclosophoraose, a cyclic [small beta]-(1,2) glucan, was used for the synthesis of indolyl 4H-chromenes via a one pot three-component Knoevenagel-Michael addition-cyclization reaction in water under neutral conditions.

Someshwar D. Dindulkar,^a   Daham Jeong,^a   Eunae Cho,^a  Dongjin Kim^b and   Seunho Jung*^ac  

*Corresponding authors

^aInstitute for Ubiquitous Information Technology and Applications (UBITA) & Center for Biotechnology Research in UBITA (CBRU), Konkuk University, Seoul 143-701, South Korea
E-mail: shjung@konkuk.ac.kr

^bNelson Mandela African Institution of Science and Technology, PO box 447, Arusha, Tanzania

^cDepartment of Bioscience and Biotechnology, Microbial Carbohydrate Resource Bank (MCRB), Konkuk University, Seoul 143-701, South Korea

Green Chem., 2016, Advance Article

DOI: 10.1039/C6GC00137H

http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC00137H?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

As a novel biosourced saccharide catalyst, microbial cyclosophoraose, a cyclic β-(1,2) glucan, was used for the synthesis of therapeutically important versatile indolyl 4H-chromenes via a one pot three-component Knoevenagel–Michael addition–cyclization reaction of salicylaldehyde, 1,3-cyclohexanedione/dimedone, and indoles in water under neutral conditions. A possible reaction mechanism through molecular complexation is suggested based on 2D ROESY NMR spectroscopic analysis. Moreover, green chemistry metric calculations were carried out for a model reaction, indicating the satisfactory greener approach of this method, with a low E-factor (0.18) and high atom economy (AE = 91.20%). The key features of this protocol are based on two critical factors where the first is to use a novel eco-friendly supramolecular carbohydrate catalyst and the second is its fine green properties such as compatibility with various substituted reactants, recyclability of the catalyst, chromatography-free purification, high product selectivity, and clean conversion with moderate to excellent yields in an aqueous medium.

 

 

 

////////Microbial cyclosophoraose,  catalyst,  synthesis,  diversified indolyl 4H-chromenes, one-pot three component reactions, water

Cooperative catalyst system for the synthesis of oleochemical cyclic carbonates from CO2 and renewables

Green Chem., 2016, Advance Article
DOI: 10.1039/C6GC00671J, Paper

Nils Tenhumberg, Hendrik Buttner, Benjamin Schaffner, Daniela Kruse, Michael Blumenstein, Thomas Werner
Taking Control! The binary catalyst system composed of MoO₃ and an organic phoshponium salt [Bu₄P]X proved very efficient to produce oleochemical cyclic carbonates from renewables.

Cooperative catalyst system for the synthesis of oleochemical cyclic carbonates from CO2 and renewables

Nils Tenhumberg,^a   Hendrik Büttner,^a   Benjamin Schäffner,^b  Daniela Kruse,^b   Michael Blumenstein^c and   Thomas Werner*^a  

*Corresponding authors

^aLeibniz-Institut für Katalyse e. V. (LIKAT Rostock), Albert-Einstein-Str. 29 a, 18059 Rostock, Germany
E-mail: thomas.werner@catalysis.de

^bEvonik Industries AG, Paul-Baumann-Str. 1, 45772 Marl, Germany

^cHobum Oleochemicals, Seehafenstraße 20, 21079 Hamburg, Germany

Green Chem., 2016, Advance Article

DOI: 10.1039/C6GC00671J. http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC00671J?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Phosphonium salts and various (transition-) metals were studied as catalysts in the synthesis of carbonated oleochemicals from the corresponding epoxides and carbon dioxide. In combination with tetra-n-butylphosphonium bromide molybdenum compounds were identified as highly active co-catalysts for the formation of cyclic carbonates. The co-catalyst accelerates the conversion of the epoxidized fatty acid ester considerably.

The chemo- as well as the stereoselectivity of the carbonated oleochemicals can be controlled by the choice of the catalyst and the reaction conditions. Under optimized reaction conditions this new catalyst system allows the conversion of both mono- and polyepoxidized oleo compounds into the corresponding carbonates in good to excellent yields up to >99% under comparatively mild reaction conditions. This procedure has been applied to the synthesis of a potential renewable plasticizer and works well even at larger scale (200 g).

/////////Cooperative catalyst system, synthesis, oleochemical cyclic carbonates,  CO2, renewables

Solvent-free Mizoroki–Heck reactions and its application in the synthesis of Axitinib

A green method for the synthesis of a D-glucosamine-derived triazole@palladium catalyst is described. The synthesized catalyst containing a 2-pyridyl-1,2,3-triazole ligand was prepared via a click route in high yields and was explored in Heck cross-coupling reactions between different aryl halides and olefins under solvent-free conditions. The catalyst can be separated from the reaction mixture and reused at least six times with superior activity. In addition, using this protocol, the marketed drug Axitinib (antitumor) could be synthesized easily.

 

A novel D-glucosamine-derived pyridyl-triazole@palladium catalyst for solvent-free Mizoroki–Heck reactions and its application in the synthesis of Axitinib

Chao Shen,^ab   Hongyun Shen,^b   Ming Yang,^b   Chengcai Xia^b and   Pengfei Zhang*^b  

*Corresponding authors

^aCollege of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou 310015, China

^bCollege of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, China
E-mail: zpf100@163.com
Fax: +86-571-28862867
Tel: +86-571-28862867

Green Chem., 2015,17, 225-230

DOI: 10.1039/C4GC01606H

http://pubs.rsc.org/en/content/articlelanding/2015/gc/c4gc01606h/unauth#!divAbstract

Atheroprotective Activity of Spirulina

Atheroprotective activity of Spirulina may be due to it having a protein with a similar structure to bilirubin

Spirulina platensis, a water blue-green alga and food supplement due to its high amount of proteins, polysaccharides, and vitamins, has been associated with potent biological effects.

Read more

Atheroprotective Activity of Spirulina

http://www.chemistryviews.org/details/news/5279011/Atheroprotective_Activity_of_Spirulina.html

In order for our body to ensure all organ functions it needs natural nutrients in the best and highest concentration. Spirulina’s “natural treasure chest” contains a unique and balanced combination of the highest levels of natural substances that are essential for good health. Spirulina has a very thin cell wall, which enables vital nutrients to be easily absorbed by the body.

Spirulina in comparison

Spirulina contains more than 4.000 vital substances and nutrients and it is also nutritionally superior compared to usual foods.

Spirulina contains:

• 300 % more calcium than unskimmed milk
• 2.300 % more iron than spinach
• 3.900 % more beta-carotene than carrots
• 375 % more protein than tofu

Further information: www.algae-facts.com

Crystal Structure of C-Phycocyanin from Spirulina Platensis.

Crystal structure of Spirulina platensis for Phycocyanin with PDB ID 1GH0 was revealed to contain 24 chains named from 1GH0A to 1GH0X. It was observed that the alternate chains consisted of same sequence however, the odd chains (1GH0A, 1GH0C, 1GH0E… 1GH0W) and even chains (1GH0B, 1GH0D, 1GH0F… 1GH0X) contained 162 and 172 amino acid residues respectively in a similar pattern. Sequence comparison revealed 100 BLAST hits and phylogenetic tree was traced for alternate chains. Similarity percentages of hits were calculated for 1GH0A chain was revealed to have 84 % hits of cyanobacterial sequences, 12 % hits of rhodophyta sequences, and 4% hits of eugliphida, cyanophora and artificial vector sequences respectively. Similarity percentages of hits were calculated for 1GH0B chain was revealed to have 73 % hits of cyanobacterial sequences, 20% hits of rhodophyta sequences, and 5% hits of cryptophyta

sequences, and 1% hits of eugliphida and 1% hits of cyanophora sequences respectively. Structure comparisons of these sequences examined by VAST showed residues of alternate entire chains from 1 to 162 and from 1 to 172 residues to contain 1323 structure neighbors. 1628 structure neighbors were found for the phycobilisome domain family which is the major accessory lightharvesting complexes of cyanobacteria and red algae.

Sequence and Structure Comparison Studies of Phycocyanin in Spirulina Platensis

Lakshmi P.T.V.1 *, Uma Maheswari S.1, Karthikeyan P.P.1, Annamalai A.2

1Phytomatics Laboratory, Department of Bioinformatics, Bharathiar University, Coimbatore- 46, Tamil Nadu, India, Fax. 0422-2424387; E-mail: lakshmiptv@yahoo.co.in,   ppkarthikeyan@gmail.com

1Department of Bioinformatics, Aloysius Institute of Computer Sciences, St. Aloysius   College, Light House Hill, Mangalore -3, Karnataka, India. E. mail: ugdreams@gmail.com

2Plant Cell and Molecular Biology Laboratory, School of Biotechnology, Karunya University,  Coimbatore – 114.  Tamil   Nadu, India,  E. mail: aannamalai2001@yahoo.com

*Corresponding author: Dr. Lakshmi, P.T.V., Email  : lakshmiptv@yahoo.co.in   http://www.omicsonline.org/ArchiveJCSB/2008/December/03/JCSB1.063.php

Porous Organic Polymer Captures CO2

 

 

 

 

 

A moisture-stable porous organic polymer containing carboxy and triazole groups reversibly and selectively captures carbon dioxide

Read more

A flexible Pinner preparation of orthoesters: the model case of trimethylorthobenzoate

 

 

Marco Noè,  Alvise Perosa and   Maurizio Selva    

Dipartimento di Scienze Molecolari e Nanosistemi dell’Universita Ca’ Foscari Venezia, Centre for Sustainable Technologies, calle Larga S. Marta, 2137-30123 Venezia, Italy 
E-mail: marco.noe@unive.it

Green Chem., 2013,15, 2252-2260

DOI: 10.1039/C3GC40774H
Received 24 Apr 2013, Accepted 10 Jun 2013

 

A flexible Pinner preparation of orthoesters: the model case of trimethylorthobenzoate

The Pinner preparation of orthoesters was revisited achieving remarkable improvements. Outstandingly an unprecedented synthesis of trimethylorthobenzoate starting from benzonitrile has been described.

In the absence of additional solvents,

a novel procedure was implemented for the synthesis oftrimethylorthoesters through the Pinner reaction. At 5 °C, the reaction of both aliphatic and aromatic nitriles (RCN; R = Et, Bu, Ph) with a moderate excess of MeOH and gaseous HCl gave the corresponding imidate hydrochlorides [RC(NH)OR′·HCl]

 

in excellent yields (>90%). At 25–65 °C, the methanolysis of alkyl imidate salts provided trimethylortho-propionate and valerate, while only traces of trimethylorthobenzoate (TMOB) were observed. However, the aromatic hydrochloride could be readily converted into the hydrogenphosphate salt [PhC(NH)OR′·H₃PO₄] which, in turn, underwent a selective (>80%) reaction with MeOH to produce TMOB in a 62% isolated yield. This allowed for an unprecedented Pinner-type synthesis of TMOB starting from benzonitrile, rather than from the highly toxic trichloromethylbenzene. Overall, remarkable improvements in safety and process intensification were achieved.