Vancomycin is an important antibiotic. It is isolated from the bacterium
Streptomyces orientalis and functions by inhibiting bacterial mucopeptide
synthesis. It is a last line of defense against the resistant Staph organisms
that are now common in hospitals.
In 1999, Professor Dale Boger (The Scripps Research Institute) reported a
synthesis of vancomycin aglycon (aglycon = lacking a sugar) involving the
following steps, among others. Compound (I) was prepared from simple starting
materials by a series of steps involving forming amide bonds.
(a) Suggest reasonable precursors and show how the bonds could be formed (the
actual reagents used have not been introduced, but they work in a similar way
to those you know).
(b) Give reagents for this reaction and suggest the mechanism.
One of the interesting features of this synthesis is that ring \(C\) in compound
(II) (and subsequent compounds in this synthesis) has extremely hindered
rotation. As a result, compound (II) exists as two atropisomers (Section 3.2)
that are interconverted only at \(140^{\circ} \mathrm{C}\).
(c) Show these two isomers.
(II) was then converted to (III).
(d) Suggest reagents to accomplish this transformation.
Compound (III) was then converted to (IV).
(e) Suggest reagents and the ring A fragment that could be used for this
reaction.
Closure of an amide link between the amine on ring A (after removal of the
protecting group) and the carbomethoxy group above it led to a precursor of
vancomycin.
(f) Show the ring closure reaction of the deprotected free amino group and its
mechanism.
Another interesting feature of this synthesis is that rings \(A\) and \(B\) also
form atropisomers. These can be converted into a \(3: 1\) mixture of the desired
and undesired atropisomers on heating at \(120^{\circ} \mathrm{C}\).
(g) Draw these atropisomers and show that only one can be converted to
vancomycin. The synthesis of the aglycon was completed by functional
manipulation and addition of ring \(\mathrm{E}\) by chemistry similar to that
detailed earlier. Yet, another set of atropisomers (this time of ring E) was
formed! However, this one was more easily equilibrated than the others; model
studies had shown that the activation barrier for this set of atropisomers
should be lower than that of the others.
