119153-87-6

Upstream product

• 13734-34-4 N-tert-butoxycarbonyl-L-phenylalanine 
• 541-41-3 chloroformic acid ethyl ester 
• 24424-99-5 di-tert-butyl dicarbonate 
• 63-91-2 L-phenylalanine 
• 80994-44-1 {[(tert-butoxycarbonyl)oxy]amino}(phenyl)acetonitrile 

Downstream Products

• 102123-74-0 (S)-tert-butyl (4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate 
• 51987-73-6 (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid methyl ester 
• 60398-41-6 (3S)-tert-butyl 1-benzyl-3-diazo-2-oxopropylcarbamate 
• 169566-77-2 N-tert-butyloxycarbonyl-(L)-phenylalanine cyclohexylamide 
• 871679-99-1 tert-butyl (S)-1-((S)-3-methyl-1-(phenylselanyl)butan-2-ylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 
• 871680-07-8 tert-butyl (S)-1-((S)-3-methyl-1-(phenylthio)butan-2-ylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 
• 81110-27-2 N-(tert-butyloxycarbonyl)-L-phenylalanine azide 
• 99281-90-0 (S)-2-(tert-butoxycarbonylamino)-3-phenylpropanenitrile 
• 51871-62-6 (S)-3-tert-butoxycarbonylamino-4-phenylbutanoic acid 
• 312311-58-3 (S)-3-tert-butoxycarbonylamino-4-phenylbutanamide 
• 17186-53-7 L-phenylalanine cyclohexylamide 
• 81000-39-7 (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanethioic S-acid 
• 1040485-11-7 (2S)-2-amino-3-phenylmethyl-1-[bis(phenylmethyl)amino]propane 

Relevant academic research and scientific papers

The development and application of a novel safety-catch linker for BOC-based assembly of libraries of cyclic peptides

Cyclic peptides are appealing targets in the drug-discovery process. Unfortunately, there currently exist no robust solid-phase strategies that allow the synthesis of large arrays of discrete cyclic peptides. Existing strategies are complicated, when synthesizing large libraries, by the extensive workup that is required to extract the cyclic product from the deprotection/cleavage mixture. To overcome this, we have developed a new safety-catch linker. The safety-catch concept described here involves the use of a protected catechol derivative in which one of the hydroxyls is masked with a benzyl group during peptide synthesis, thus making the linker deactivated to aminolysis. This masked derivative of the linker allows BOC solid-phase peptide assembly of the linear precursor. Prior to cyclization, the linker is activated and the linear peptide deprotected using conditions commonly employed (TFMSA), resulting in deprotected peptide attached to the activated form of the linker. Scavengers and deprotection adducts are removed by simple washing and filtration. Upon neutralization of the N-terminal amine, cyclization with concomitant cleavage from the resin yields the cyclic peptide in DMF solution. Workup is simple solvent removal. To exemplify this strategy, several cyclic peptides were synthesized targeted toward the somatostatin and integrin receptors. From this initial study and to show the strength of this method, we were able to synthesize a cyclic-peptide library containing over 400 members. This linker technology provides a new solid-phase avenue to access large arrays of cyclic peptides.

Synthesis of C-protected 2,2-dideutero β3-amino acids

A simple three-step procedure for the preparation of C-protected 2,2- 2H-β3-amino acids has been developed starting from the natural α-amino acids. Our synthetic path is based on the homologation reaction of α-amino acids through the

Traceless selenocarboxylates for the one-pot synthesis of amides and derivatives

We have recently reported a one-pot procedure for glycosyl amides synthesis using selenocarboxylate as traceless reagent. Herein, we present a further application of selenocarboxylate-azide reaction for amide bond formation on a broader range of substrates, including heterocyclic systems and fatty acid. This method proved to be highly efficient for the synthesis of primary and secondary amides, sulfonamides, imides, phosphoramide and also carbamate.

Design and Optimization of a Continuous Stirred Tank Reactor Cascade for Membrane-Based Diazomethane Production: Synthesis of α-Chloroketones

The development of a continuous diazomethane generator comprising a continuous stirred tank reactor (CSTR) cascade and membrane separation technology is reported. This reactor concept was applied for the telescoped three-step synthesis of a chiral α-chloroketone, a key building block for many HIV protease inhibitors, via a modified Arndt-Eistert reaction starting from N-protected l-phenylalanine. The initial mixed anhydride was generated in a coil reactor and directly introduced into the CSTR diazomethane cascade. The use of a semipermeable Teflon membrane (AF-2400) allowed the generation of anhydrous diazomethane, which diffuses through the membrane into the CSTR where it is immediately consumed by the anhydride to furnish the corresponding diazoketone. The subsequent halogenation with concentrated HCl was performed downstream in batch and allowed production of the α-chloroketone on a multigram scale, with a productivity of 1.54 g/h (5.2 mmol/h).

Synthesis of Acetaminophen Analogues Containing α-Amino Acids and Fatty Acids for Inhibiting Hepatotoxicity

Acetaminophen is a popular antipyretic analgesic medicine that has weaker anti-inflammatory properties and lower incidence of side effects than nonsteroidal anti-inflammatory drugs (NSAIDs). However, acetaminophen causes hepatotoxicity due to the reactive metabolite N -acetyl- p -benzoquinone imine (NAPQI). We have obtained acetaminophen analogues in 57-99percent yields by using aniline derivatives with protected α-amino acids and fatty acids via the corresponding mixed carbonic carboxylic anhydrides in aqueous MeCN. We have also succeeded in synthesizing AM404 analogues in 76-97percent yields, which are expected to be promising candidates for reducing hepatotoxicity.

METHOD FOR THE PREPARATION OF DIAZOALKANES

The present invention relates to a method of forming diazoalkanes. One aspect of the present invention provides a method for the production of a N-alkyl-N-nitroso compound from a starting material, comprising the use of a tribasic acid to acidify an amine. A second aspect of the present invention provides a method for the production of a diazoalkane, comprising reacting a N-alkyl-N-nitroso compound with a base and a phase transfer catalyst, wherein no organic solvent is used.

Highly Diastereo- and Enantioselective Michael Addition of Nitroalkanes to 2-Enoyl-Pyridine N-Oxides Catalyzed by Scandium(III)/Copper(II) Complexes

A C2-symmetric Schiff-base ligand, derived from tridentate-Schiff-base, was developed and successfully applied to the asymmetric Michael addition of nitroalkanes to 2-enoyl-pyridine N-oxides. With this newly catalytic system, an unprecedented diastereoselectivity was obtained in the asymmetric Michael addition of nitroalkanes to 2-enoyl-pyridine N-oxides. In addition, a switch in enantioselectivity was achieved by using this newly catalytic system and our previous catalyst. After a facile reduction, the optically active adduct was converted to a biologically active dihydro-2H-pyrrol 4a. Furthermore, a connection of two tridentate-Schiff-base subunits proved to be an effective strategy in ligand design. Complex chemistry! A C2-symmetric Schiff-base ligand, derived from tridentate-Schiff-base, was developed and successfully applied to the asymmetric Michael addition of nitroalkanes to 2-enoyl-pyridine N-oxides with unprecedented diastereoselectivity (see scheme).

Continuous flow synthesis of α-halo ketones: Essential building blocks of antiretroviral agents

The development of a continuous flow process for the multistep synthesis of α-halo ketones starting from N-protected amino acids is described. The obtained α-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor. The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber. The α-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide. This method eliminates the need to store, transport, or handle diazomethane and produces α-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of α-chloro ketone from the respective N-protected amino acid within ～4.5 h (87% yield).

Continuous flow synthesis of β-amino acids from α-amino acids via Arndt-Eistert homologation

A fully continuous four step process for the preparation of β-amino acids from their corresponding α-amino acids utilizing the Arndt-Eistert homologation approach is described. the Partner Organisations 2014.

One-pot synthesis of orthogonally protected dipeptide selenazoles employing Nα-amino selenocarboxamides and α-bromomethyl ketones

A simple and efficient protocol for the synthesis of selenazole containing dipeptidomimetics using Nα-amino selenocarboxamides and α-bromomethyl ketones is described. All the compounds made were isolated in good yields and fully characterized.