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2. Those where cyclization is simultaneous to the generation of the
enediyne at the double bond site (there are no examples of gener-
ation of the enediyne upon cyclization at the triple bond site).
3. Those that form the double bond after cyclization.
19.2.1 C
YCLIZATION AFTER
E
NEDIYNE
C
ONSTRUCTION
As far as the first strategy is concerned, the method most widely applied
involves the intramolecular nucleophilic addition of an acetylide onto a
carbonyl compound (Scheme 19.5). This cyclization has been realized
starting from terminal alkynes 14 by treatment with a base such as lithium
or potassium hexamethyldisilazide.
15,22,37
The use of CeCl
3
as additive may
be beneficial.
38
This method, however, affords poor results when the
carbonyl compound is an enolizable aldehyde and is also not compatible
with several functional groups. The most general and widely used procedure
is a variation of the Nozaki reaction and starts from iodoalkynes 15.
31,39
Treatment with stoichiometric CrCl
2
and catalytic NiCl
2
furnishes the
desired enediynic alcohol, through the intermediacy of an alkynyl chromium
species. This reaction gives moderate to good yields also for enolizable
aldehydes. An alternative methodology involves the fluoride mediated
cyclization of silylated alkynes 16.
40,41
SCHEME 19.5
A second, less used, strategy encompasses the Lewis acid catalyzed
intramolecular reaction of a silyl enol ether with a propargyl cation. The
latter can be conveniently generated by a cobalt complexed propargyl
ether.
31,42
This complexation strongly helps the carbocation formation.
By using cobalt complexation,
intramolecular aldol type reactions (for
R
4
OR
3
) have been accomplished.
43
For the construction of the required acyclic enediyne, the method of
choice is the Sonogashira coupling of terminal alkynes with Z dichloro-
ethylene. The complete stereoselectivity for the Z double bond and the mild
ΒΌ
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