From Natural to Rationally Designed Artificial Enediynes: Towards New Anticancer Antibiotics Activable at Will - Polyynes: Synthesis, Properties, and Applications - page 469

illustrated above on compound 17 ( Scheme 19.5 ) . Azabicyclo[7.3.1]enediyne
102, obtained after adamantyl carbamate removal under acidic conditions,
exhibits an interesting antitumor activity both in vitro (HCT116 human
colon carcinoma cells) and in vivo (P388 leukemia assays using CDF1
mices). 103 Differently from the other cases, the cycloaromatization is
supposed to follow here a polar, nonradical pathway.
A more recent approach to simplified enediynes has been proposed by
Semmelhack et al. (Scheme 19.28). 59 In this case a very simple bicyclic[7.3.1]
enediyne was designed: in the prodrug, however, it was planned to introduce
a third ring (a g -lactone) in such a position that the 6-membered ring
connected with the enediyne is forced to assume a boat conformation, thus
creating a situation unsuitable for cycloaromatization. The triggering event
is then the opening of the lactone, which will permit the boat-to-chair
conversion of the 6-membered ring, thus allowing the enediyne to assume a
conformation favourable to the cycloaromatization.
SCHEME 19.28
The simpler enediyne 103 could not be synthesized, since any attempt to
exploit the usual cyclization of an acetylide onto a carbonyl moiety failed,
giving a dimeric derivative arising from an intramolecular double coupling
as the only product. This problem was solved using a different chromium(II)-
mediated cyclization, followed by the base-induced elimination of mesylate
104 to introduce the conjugated double bond during the last step. Derivative
105 showed, as expected, an appreciable stability with a t 1/2 >100 h when
heated to 74 C, while, when the same compound was treated with MeONa/
MeOH in the presence of 1,4-cyclohexadiene as hydrogen donor, the only
isolated product was cycloaromatized ester 106 (with an estimated half life
time of the hydroxy ester equipped with the enediyne moiety of less than
about 2 h at 23 C), thus supporting the working hypothesis of the authors.
The same behaviour was observed upon reduction of the lactone with