THE CHEMISTRY AND BIOLOGY OF VANCOMYCIN AND OTHER GLYCOPEPTIDE ANTIBIOTIC DERIVATIVES - Medicinal Chemistry of Bioactive Natural Products - page 45

AB. 64,65 Similarly, with this approach, it could be shown that N-methylation and
glycosylation are biosynthetic steps that follow the oxidative ring closure reactions.
Currently, the knowledge of biosynthetic glycopeptide assembly is used for the
generation of novel glycopeptide antibiotics with modifications in the aglycon
and of the carbohydrate residues.

2.6 TOTAL SYNTHESIS

The total synthesis of the vancomycin aglycon was accomplished by Evans et al.
(Harvard University, Cambridge, MA) 66,67 and Nicolaou et al. (Scripps Research
Institute, La Jolla, CA) 68-74 nearly at the same time. A short time later, Boger
et al. (Scripps Research Institute) contributed their total synthesis of the agly-
con. 75-78 With the attachment of the carbohydrate residues, the total synthesis
was formally completed by Nicolaou et al. 79 The various strategies and the number
of synthetic steps, which were tested for the synthetic assembly show, that only a
few groups worldwide can conduct research efforts on such a synthetic problem.
The achievement of the total synthesis is certainly one milestone in the art of
peptide synthesis, if not in organic synthesis. The main challenge of the synthetic
strategy was the atropisomerism of the diphenylether and of the biaryl ring systems.
From eight possible atropoisomers, there is only found one in nature. Additional
problems included the synthetic access to the amino acid building blocks and the
attachment of the carbohydrate residues to the aglycon, both of which require a
well-planned protecting group strategy. Accordingly, preceding the achievement
of the total synthesis, there was a decade of synthetic studies at model systems
also by other research groups, which are documented in several review arti-
cles. 6,7,80-82 In Schemes 2-7 and 2-8, some characteristics of the total synthesis
strategies are representatively highlighted. For detailed descriptions and discussions
of the total synthesis, it is recommended to review the literature cited here.
The syntheses of nonproteinogenic amino acids have been performed by three
different enantioselective reactions. These were the use of the Evans auxiliaries
(Evans et al.), the Sharpless hydroxylation/aminohydroxylation (Nicolaou et al.),
and the Sch¨llkopf bislactimether synthesis (Boger et al.). The second characteristic
of the total synthesis was the underlying chemistry of the side-chain cyclizations and
the sequence of the ring closure reactions. Evans et al. group used a tripeptide
amide with VOF 3 -mediated AB-biaryl formation (Scheme 2-7). The C-terminal
amide protection at 7 Dpg had to be introduced to prevent racemization of
this amino acid. The next steps were condensation of a 3,4,5-trihydroxyphenylgly-
cine and ring closure of the C-O-D-ring via nucleophilic aromatic substitution
(S N Ar). The remaining aromatic nitro group in the C-O-D ring was then converted
into a H-substituent. The AB/C-O-D-tetrapeptide was N-terminally coupled with a
tripeptide to the heptapeptide, which was then again submitted to a nucleophilic
aromatic substitution to yield the AB/C-O-D/D-O-E ring system. The atro-
postereoselectivity of the D-O-E ring was 5:1 of the desired protected aglycon
derivative.