We have recently demonstrated in a total synthesis of 17
that intramolecular cycloaddition strategies (following an A
f ABC scheme) allow for the efficient construction of ring
systems related to colchicine. We here disclose the applica-
tion of a related concept to the synthesis of 6-oxa-allocolchi-
cinoids of type 4, some of which were found to possess
pronounced apoptosis-inducing properties.
introduction of the first alkyne moiety through Sonogashira
cross-coupling using PdCl2(PPh3)2 and CuI as catalysts.11 It
is noteworthy that aldehyde 7a reacted smoothly at room
temperature in THF to give 9a in high yield, whereas heating
to 60 °C in DMSO was necessary to obtain full conversion
in the case of 7b. The carbonyl compounds 9a and 9b were
then treated with NaBH4 and KF in methanol (one-pot
procedure) to afford the alcohols 6a and rac-6b, respectively.
In addition, treatment of alcohol 6a with iodine in the
presence of PPh3 and imidazole12 cleanly afforded the iodide
10 as an alternative building block.
Scheme 1. Retrosynthetic Analysis
Scheme 2. Preparation of Phenylacetylene Building Blocks
Our synthetic concept is outlined in Scheme 1. Exploiting
a metal-catalyzed intramolecular [2 + 2 + 2]-cycloaddition
(Reppe-Vollhardt alkyne cyclotrimerization)8 as a key step,
the target molecules would be derived from triynes of type
5. These in turn could be assembled in a straightforward
fashion (via 6) starting from readily accessible precursors
of type 7. Besides requiring only a few linear steps, such a
scheme would open access to a rather broad diversity of new
allocolchicinoids (especially with respect to the ring C
substitution pattern). Moreover, by means of a substituent
R at ring B a conformational bias could be induced to also
predetermine the biaryl twist.9
The next task was the preparation of cyclization precursors
of type 5 (compare Scheme 1). First experiments in this
direction were performed employing building block rac-6b,
which was efficiently O-alkylated by the propargylic bro-
mides 11 and 13 to afford the products rac-12 (after THP
cleavage) and rac-14, respectively, in good yield (Scheme
3). The nitrogen-containing triynes rac-17 and rac-18 were
then prepared by reaction of rac-12 with the sulfonamides
15 and 16 under Mitsunobu-type conditions.13 Remarkably,
all attempts to directly O-alkylate rac-6b with the tosyl-
protected amine-analog of bromoether 13 only led to a
complex mixture of “polymeric” products, which is why the
synthesis of rac-17 and rac-18 had to be performed under
nonbasic conditions via the three-step sequence described
(Scheme 3).
The preparation of the required phenylacetylene building
blocks of type 6 started with the Ag(CF3CO2)-promoted
iodination10 of aldehyde 8a and ketone 8b (Scheme 2). The
resulting products (7a and 7b) were then used for the
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