169825-21-2

Upstream product

• 42564-51-2 4-fluoro-3-nitrobenzaldehyde 
• 15017-52-4 4-(bromomethyl)-1-fluoro-2-nitrobenzene 
• 391213-68-6 (Z)-methyl 2-(acetylamino)-3-(4-fluoro-3-nitrophenyl)propenoate 
• 391213-69-7 methyl (R)-2-(acetylamino)-3-(4-fluoro-3-nitrophenyl)propanoate 
• 331731-26-1 (R)-N-(tert-butoxycarbonyl)-4-fluoro-3-nitrophenylalanine methyl ester 
• 169825-20-1 (3R,6S)-2,5-dimethoxy-6-isopropyl-3-(4-fluoro-3-nitrophenyl)-3,6-dihydro-1,4-pyrazine 

Downstream Products

• 169825-22-3 (R)-2-[(R)-2-(tert-Butoxycarbonyl-methyl-amino)-4-methyl-pentanoylamino]-3-(4-fluoro-3-nitro-phenyl)-propionic acid methyl ester 
• 331731-25-0 (R)-N-trimethylsilylethoxycarbonyl-4-fluoro-3-nitrophenylalanine methyl ester 
• 331731-29-4 (R)-N-(2,2,2-trichloro-1,1-dimethylethoxycarbonyl)-4-fluoro-3-nitrophenyl-alanine methyl ester 
• 185112-24-7 {(R)-1-[(R)-1-{(S)-1-[(R)-2-(tert-Butyl-dimethyl-silanyloxy)-1-(3-hydroxy-phenyl)-ethylcarbamoyl]-ethylcarbamoyl}-2-(4-fluoro-3-nitro-phenyl)-ethylcarbamoyl]-3-methyl-butyl}-methyl-carbamic acid tert-butyl ester 
• 169825-29-0 (R)-2-[(R)-2-(tert-Butoxycarbonyl-methyl-amino)-4-methyl-pentanoylamino]-3-(4-fluoro-3-nitro-phenyl)-propionic acid 
• 331731-43-2 C₅₄H₆₆FN₅O₁₆Si 
• 331731-45-4 [1-({{3-[5-(2-benzyloxy-1-tert-butoxycarbonylamino-ethyl)-2-methoxy-phenoxy]-5-methoxy-phenyl}-[1-(3,5-dihydroxy-4-methoxy-phenyl)-2-hydroxy-ethylcarbamoyl]-methyl}-carbamoyl)-2-(4-fluoro-3-nitro-phenyl)-ethyl]-carbamic acid tert-butyl ester 
• 331731-39-6 (R)-tert-Butoxycarbonylamino-(3-{3-[(S)-1-[(R)-3-(4-fluoro-3-nitro-phenyl)-2-(2-trimethylsilanyl-ethoxycarbonylamino)-propionylamino]-2-(2-methoxy-ethoxymethoxy)-ethyl]-5-methoxy-phenoxy}-4-methoxy-phenyl)-acetic acid 
• 331731-38-5 [(R)-1-[(S)-1-{3-[5-((R)-1-tert-Butoxycarbonylamino-2-hydroxy-ethyl)-2-methoxy-phenoxy]-5-methoxy-phenyl}-2-(2-methoxy-ethoxymethoxy)-ethylcarbamoyl]-2-(4-fluoro-3-nitro-phenyl)-ethyl]-carbamic acid 2-trimethylsilanyl-ethyl ester 

Relevant academic research and scientific papers

First and second generation-total synthesis of the teicoplanin aglycon

Full details of studies leading to the total synthesis of the teicoplanin aglycon are provided. Key elements of the first generation approach (26 steps from constituent amino acids, 1% overall) include the coupling of an EFG tripeptide precursor to the common vancomycin/teicoplanin ABCD ring system and sequential DE macrocyclization of the 16-membered ring with formation of the diaryl ether via a phenoxide nucleophilic aromatic substitution of an o-fluoronitroaromatic (80%, 3:1 atropisomer diastereoselection) followed by 14-membered FG ring closure by macrolactamization (66%). Subsequent studies have provided a second generation total synthesis which is shorter, more convergent, and highly diastereoselective (22 steps, 2% overall). This was accomplished by altering the order of ring closures such that FG macrolactamization (95%) preceded coupling of the EFG tripeptide to the ABCD ring system and subsequent DE ring closure. Notably, DE macrocyclization via diaryl ether formation on substrate 57, the key intermediate in the latter approach incorporating the intact FG ring system, occurred with exceptional diastereoselection for formation of the natural atropisomer (> 10:1, 76%) without problematic C23 epimerization provided the basicity of the reaction is minimized.

Synthesis of modified carboxyl binding pockets of vancomycin and teicoplanin

Sixteen-membered macrocycle 3 and 16+14 bicyclic compound 4, incorporating a terminal primary hydroxyl group in the peptide sequence, have been designed and synthesized. The syntheses feature the use of an efficient cycloetherification based on an intramolecular S(N)Ar reaction for the formation of biaryl ether bonds. Cyclization of linear tetrapeptide 30, prepared via a convergent [2+2] segment coupling between 26 and 29, gave macrocycle 31 (P configuration) as a single isolable atropisomer. Removal of the Boc protecting group afforded the modified carboxyl binding pocket of vancomycin 3. A sequential 2-fold intramolecular S(N)Ar reaction has been used to construct the model bicyclic system (i.e. 4) of the D-O-E-F-O-G ring of teicoplanin. Cyclization conditions (CsF, DMF, room temperature) are sufficiently mild that the configuration of the racemization-prone arylglycine residue was not affected. Chiral building blocks such as D-(1R)-[2-[(tert-butyldimethylsilyl)oxy]1-[3-(allyloxy)phenyl]ethyl]am ine 16, and L-(S)-N-Boc-[3-(isopropyloxy)phenyl]glycine (32) were synthesized employing Evans' asymmetric azidation method, while L-(S)-4-fluoro-3-nitrophenylalanine methyl ester 23 was prepared using Schollkopf's bislactim ether as chiral glycine template. Compound 3 showed interesting conformational properties compared to vancomycin and its binding with Ac-D-Ala was studied by NMR titration experiments. A dissociation constant (Kd) = 5 x 10-4) was calculated by a curve fitting method. Compound 4 is currently the most advanced synthetic intermediate toward the total synthesis of teicoplanin.

Synthesis of A Modified Carboxylate-binding Pocket of Vancomycin

A 16-membered tetrapeptidic macrocycle (4), analog of vancomycin binding pocket, has been designated and synthesized using the efficient macrocyclisation of the corresponding linear tetrapeptide (14) via biaryl ether formation.In aceton, compound 4 adopte