93949-90-7

Upstream product

• 69555-14-2 ethyl N-diphenylmethylene glycine 
• 100-39-0 benzyl bromide 
• 156122-25-7 ethyl 2-benzyl-3-phenyl-2-nitropropionate 
• 99330-18-4 2-Benzyl-3-phenyl-2-{[1-phenyl-meth-(E)-ylidene]-amino}-propionic acid ethyl ester 

Downstream Products

• 6278-96-2 2-amino-2-benzyl-3-phenylpropanoic acid 
• 339079-54-8 N^α-(9-fluorenylmethoxycarbonyl)-2,2-dibenzylglycine 

Relevant academic research and scientific papers

Constraining the Side Chain of C-Terminal Amino Acids in Apelin-13 Greatly Increases Affinity, Modulates Signaling, and Improves the Pharmacokinetic Profile

Side-chain-constrained amino acids are useful tools to modulate the biological properties of peptides. In this study, we applied side-chain constraints to apelin-13 (Ape13) by substituting the Pro12 and Phe13 positions, affecting the binding affinity and signaling profile on the apelin receptor (APJ). The residues 1Nal, Trp, and Aia were found to be beneficial substitutions for Pro12, and the resulting analogues displayed high affinity for APJ (Ki 0.08-0.18 nM vs Ape13 Ki 0.7 nM). Besides, constrained (d-Tic) or α,α-disubstituted residues (Dbzg; d-α-Me-Tyr(OBn)) were favorable for the Phe13 position. Compounds 47 (Pro12-Phe13 replaced by Aia-Phe, Ki 0.08 nM) and 53 (Pro12-Phe13 replaced by 1Nal-Dbzg, Ki 0.08 nM) are the most potent Ape13 analogues activating the Gα12 pathways (53, EC50 Gα12 2.8 nM vs Ape13, EC50 43 nM) known to date, displaying high affinity, resistance to ACE2 cleavage as well as improved pharmacokinetics in vitro (t1/2 5.8-7.3 h in rat plasma) and in vivo.

Ligand-Controlled Regiodivergence in Nickel-Catalyzed Hydroarylation and Hydroalkenylation of Alkenyl Carboxylic Acids**

A nickel-catalyzed regiodivergent hydroarylation and hydroalkenylation of unactivated alkenyl carboxylic acids is reported, whereby the ligand environment around the metal center dictates the regiochemical outcome. Markovnikov hydrofunctionalization products are obtained under mild ligand-free conditions, with up to 99 % yield and >20:1 selectivity. Alternatively, anti-Markovnikov products can be accessed with a novel 4,4-disubstituted Pyrox ligand in excellent yield and >20:1 selectivity. Both electronic and steric effects on the ligand contribute to the high yield and selectivity. Mechanistic studies suggest a change in the turnover-limiting and selectivity-determining step induced by the optimal ligand. DFT calculations reveal that in the anti-Markovnikov pathway, repulsion between the ligand and the alkyl group is minimized (by virtue of it being 1° versus 2°) in the rate- and regioselectivity-determining transmetalation transition state.

Synthesis and use of achiral oxazolidine-2-thiones in selective preparation of trans 2,5-disubstituted tetrahydrofurans

The use of achiral N-acetyloxazolidine-2-thiones in the C-glycosylation of lactol acetates has allowed us to prepare with high diastereoselectivity the expected trans 2,5-disubstituted tetrahydrofurans. A study based on the role of the steric hindrance of the N-acetyloxazolidine-2-thiones is reported. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.

Sterically hindered Cα,α-disubstituted α-amino acids: Synthesis from α-nitroacetate and incorporation into peptides

The preparation of sterically hindered and polyfunctional Cα,α-disubstituted α-amino acids (ααAAs) via alkylation of ethyl nitroacetate and transformation into derivatives ready for incorporation into peptides are described. Treatment of ethyl nitroacetate with N,N-diisopropylethylamine (DIEA) in the presence of a catalytic amount of tetraalkylammonium salt, followed by the addition of an activated alkyl halide or Michael acceptor, gives the doubly C-alkylated product in good to excellent yields. Selective nitro reduction with Zn in acetic acid or hydrogen over Raney Ni gives the corresponding amino ester that, upon saponification, can be protected with the fluorenylmethyloxycarbonyl (Fmoc) group. The first synthesis of an orthogonally protected, tetrafunctional Cα,α-disubstituted analogue of aspartic acid, 2,2-bis(tert-butylcarboxymethyl)glycine (Bcmg), is described. Also, the sterically demanding Cα,α-dibenzylglycine (Dbg) has been incorporated into a peptide using solid-phase synthesis. It was found that once sterically congested Dbg is at the peptide N-terminus, further chain extension becomes very difficult using uronium or phosphonium salts (PyAOP, PYAOP/HOAt, HATU). However, preformed amino acid symmetrical anhydride couples to N-terminal Dbg in almost quantitative yield in nonpolar solvent (dichloroethane-DMF, 9:1).

Ethyl N-(diphenylmethylene)glycinate as anionic glycine equivalent. Monoalkylation, dialkylation and michael additions under solid-liquid phase-transfer catalysis

Ethyl N-(diphenylmethylene)glycinate, 1, undergoes monoalkylations, dialkylations and Michael additions to ethylenic and acetylenic acceptors under appropriate solid-liquid phase transfer catalysis conditions. Further transformations of the α-disubstituted ketimines lead to α-alkylated aspartic and glutamic acid derivatives 10, 15, 19 and 26, to bicyclic amino acids or derivatives featuring pyrazolone and isoxazolone moieties 30 and 33, and to α-substituted (E)-3,4-dehydroglutamic acids. Copyright

Synthesis of α-substituted and α,α-disubstituted α-amino acids by controlled mono- and dialkylation of ethyl N-diphenylmethyleneglycinate

Ethyl N-diphenylmethyleneglycinate reacts with one equivalent of alkylating agents in the presence of powdered potassium carbonate to afford, after hydrolysis, monoalkylated glycine esters. A similar process using two equivalents of alkylating agents in t