Despite this, that 12 was generated in only 3 steps from
indoline heterodimer 9 in a synthetically useful 33% overall
yield has enabled us to proceed in our kapakahine E and F
studies.
Negishi coupling reaction between known Zn alanine deriva-
tive 18 and iodoindole 17 (Scheme 3). Although 18 had been
widely employed in coupling reactions with aromatic and
vinylic halides and triflates,13 to the best of our knowledge
it had not been used in the synthesis of tryptophan deriva-
tives.14 To examine tryptophan formation, we synthesized
iodoindole 17 from 12 and then exposed 17 to 18 and the
conditions illustrated. Pleasingly, 17 underwent the desired
coupling reaction to give desired tryptophan heterodimer 19
in 74% yield, effectively completing our synthesis of the
kapakahine dimeric tryptophan core.
Scheme 3
.
Completion of the Synthesis of the Kapakahine
Bis-Trp Core
With a method to the desired R-carboline and imidazolone
rings in hand with model substrate 12, we next explored the
AlMe3 reaction on bis-tryptophan heterodimers (eq 3).
Representative of the substrates examined in these studies
was heterodimer 14 where only uncharacterizable mixtures
of products were observed when 14 was subjected to the
conditions that had been successful for 9.
With 19 in hand we were positioned to examine our
hypothesis that it would serve as a general precursor to the
kapakahine natural products. To kapakahine E, the coupling
of 19 with the requisite L-Phe-L-Pro-L-Tyr-L-Ala tetrapeptide
20 involved first subjecting 19 to hydrogenolysis conditions
at low temperature to selectively remove the benzyl ester in
the presence of the Fmoc group (Scheme 4). EDCI, HOBt
Our lack of success in the rearrangement of 14 forced us
to revise our approach and to consider the introduction of
the tryptophan side chain subsequent to R-carboline forma-
tion. Methods of carrying out such a conversion include
aziridine ring openings,10 conjugate additions,11 and Heck
coupling reactions.12 Because it would enable us to incor-
porate the side chain directly, our initial focus was on the
use of the aziridine ring-opening reaction to convert 12 into
16 (eq 4). Unfortunately, all attempts at this reaction were
unsuccessful, resulting in either the recovery of 12 or its
decomposition into unidentifiable mixtures of products.
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With the failure of the aziridine chemistry and our
perception that the conjugate addition and Heck approaches
would lead to indirect solutions to the problem, we turned
our attention to the development of a new method of
introducing the side chain and settled upon the use of a
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