Nonconventional Stereochemical Issues in the Design of the Synthesis of the Vancomycin Antibiotics: Challenges Imposed by Axial and Nonplanar Chiral Elements in the Heptapeptide Aglycons

Abstract

Controlling the elements of planar and axial chirality are the principal challenges in the synthesis of the aglycon of vancomycin. Vancomycin is the prototypical member of the glycopeptide family of antibiotics which are effective for the treatment of infections by methicillin-resistant Staphylococcus aureus. The first total syntheses of the vancomycin and eremomycin aglycons provide insight into the influence of structure on kinetic and thermodynamic control of atropselective macrocyclizations.

The cyclization of peptides and depsipeptides

“…However, their key macrocyclization steps illustrate important themes. In the Evans et al [198,199] approach to vancomycin aglycone synthesis, the A-B diphenyl link was accomplished using vanadyl trifluoride oxidative cyclization, while the diphenyl [200][201][202][203] saw the A-B system effected by the Suzuki conditions [Pd(Ph 3 P) 4 ]/Na 2 CO 3 for coupling an iodoaryl compound to a boronic acid aryl group, while diphenyl ethers were produced via their in-house triazene-based technology (Scheme 21).…”

Methods for the Chemical Synthesis of Noncoded α‐Amino Acids found in Natural Product Peptides

“…The total synthesis of both vancomycin and vancomycin aglycon were completed by the research groups of Evans and Nicolaou [268][269][270][271][272], and later by Boger [273][274][275]. During these synthetic efforts two distinct tactics were used to form the biarylcontaining amino acids of vancomycin.…”

“…During these synthetic efforts two distinct tactics were used to form the biarylcontaining amino acids of vancomycin. Evans et al employed his well-known diastereoselective aldol reaction [268] to set the a-stereocenter of the amino acid, whereas Nicolaou et al and Boger et al chose a Sharpless amino hydroxylation approach [270,274]. To couple the two aryl groups 239 and 240, various transition metal catalyzed reactions have been used including Suzuki coupling, as employed in Nicolaou et als synthesis (Scheme 5.57) [270,274].…”

“…Another approach was employed in Evans et als synthesis of vancomycin [268]. They chose an oxidative cyclization strategy to connect the AB-fragments 243.…”

Synthesis and Characterization of 4-Phenacyloxy Benzaldehyde Derivatives

“…Phenolic ether is also applied in chemical engineering 2 , as a food coloring agent, perfume, and polymer additives 4 . In the pharmaceutical industry ether derivatives act as antibiotics for example Teicoplanin [5][6][7] and vancomycin [8][9][10][11] ; bouvardin as antitumor [12][13] , and peptide K-13 as an example antiviral [14][15][16] . Polybrominated diphenyl ether (PBDE) is applied as the polymer for plastic products and electronic [17][18][19] .…”