Synthesis of the Vancomycin CD and DE Ring Systems

Abstract

Full details of the synthesis of the fully substituted vancomycin CD and DE ring systems are described and a potential solution to the control of the atropisomer stereochemistry is defined.

Chemistry, Biology, and Medicine of the Glycopeptide Antibiotics

“…Synthesis of AA-4 derivative (R)-33 of vancomycin through enzymatic resolution according to Zhu et al [114] The catalytic asymmetric epoxidation (AE) of allylic alcohols, [115] the asymmetric dihydroxylation (AD) of olefins [116] and the asymmetric aminohydroxylation (AA) of olefins, [117] all developed by the Sharpless group, have been applied productively to the synthesis of aryl glycines as shown in Schemes 6, [118] 7, [119] and 8, [120] respectively. [119,120] The electrophilic amination of oxazolidinone derived enolates was developed by the Evans group in the late 1980s. Since the starting oxazolidinones are easily accessible from amino acids, this method offers access to a variety of substituted phenyl glycines and tyrosines with excellent stereoselectivities.…”

“…Studies by the Boger group with model D-O-E (125, Scheme 32) [120] and C-O-D-O-E (127, Scheme 33) [194,195] ring [120] systems, as well as a degradatively derived vancomycin aglycon (128,Scheme 34), [196] demonstrated a higher flexibility for the D-O-E framework relative to the C-O-D system. Thus, in bi-or tri-macrocyclic systems, such as 127 and 128, no thermal isomerization could be observed in the C-O-D ring system.…”

“…Thus, the fully functionalized C-O-D and D-O-E ring systems as well as the complete C-O-D-O-E scaffold of vancomycin were constructed using the o-nitrofluoride ± phenol methodology. [120,194,238] [120] Roussi et al accomplished the synthesis of a 15-membered macrocyclic model system 175 of kistamicin (Scheme 47) [239] as well as a synthesis of a chloropeptin model. Scheme 47.…”

Total Syntheses of Vancomycin and Eremomycin Aglycons

“…The mixture of nitro atropisomers was reduced (Zn, AcOH, EtOH, 40 8C) to provide two diastereomeric anilines which were separated by silica gel chromatography, affording a single atropisomer in 80 % yield. Sandmeyer transformation [26] to the protected vancomycin aglycon 25 proceeded in 81 % yield.…”

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

“…It is evident from this and related investigations that there is a negligible stereochemical bias imparted by the amide backbone from amino acids 1 ± 3 to the cyclization process. [15,16] At the next level of architectural complexity, M(2 ± 4) cyclizations on hexapeptide substrates containing the M(4 ± 6) subunit were investigated. Cyclization (CsF, DMSO, 25 8C, 6 h) of 20 was weakly diastereoselective (dr 2:1), favoring the desired R atropisomer (Scheme 4 b).…”