Chemistry Reference
In-Depth Information
N
3
NH
2
OR
h
ν
N
98-100%
ROH
N
NEt
2
NEt
2
SCHEME 3.22.
Michael facilitator does not appear to be an essential element in an effective
nitrenium PAL agent. In fact, if the nitro group is replaced by a ring nitrogen
atom to produce a pyridinium aryl azide, cross-linking become significantly more
effective as indicated in Scheme 3.22 (V. Voskresenska and R.M. Wilson,
unpublished work). PAL agents of this type have not been investigated in biological
environments. However, for many applications, the ring nitrogen might be much less
intrusive than is the much larger nitro group.
The popular fluorinated aryl azides have received a great deal of attention, since
they do not undergo ring expansion and produce persistent singlet nitrenes, which
might insert into even unreactive biomolecules. However, there are few cases in
which fluorinated aryl azides with activating
para
-amino groups have been studied,
and what little mechanistic work that has been done has been in an aprotic
environment.
115
Therefore, it was not possible to evaluate whether this type of
aryl azide might serve as a precursor for fluorinated nitrenium ions. In one case, the
farnesyl analog
was prepared and used to study the process by which a Ras protein
incorporates a farnesyl unit (Scheme 3.23). The attachment of the hydrophobic
farnesyl unit is necessary for the Ras protein to become bound to the inner plasma
membrane where it is activated by guanosine triphosphate and regulates certain
critical metabolic processes. The enzyme that attaches the farnesyl unit to the Ras
protein, farnesyltransferase, accepts
39
39
as a farnesyl analogue and is inactivated to
the extent of 70% by irradiation.
116
Again no studies of the mechanism of enzyme
inactivation were done. Fluorinated nitrenium ions of the type that might be
generated from
are particularly interesting PAL species, since they would be
expected to undergo Michael addition followed by fluoride ion elimination to
regenerate an active cross-linking agent.
117
Thus, fluorinated nitrenium ion might
be expected to form two or more cross-links from a single activation event.
One final aspect of concern in the implementation of nitrenium PAL strategies is
the acidity of the nitrenium ion. In most biological applications of the aryl azide PAL
agents, the
para
-amino group is a secondary amine. This gives rise to a nitrenium ion
39
O
O
F
F
N
P
P
O
O
O
O
N
3
F
39
F
SCHEME 3.23.
