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M. M. Martı´nez et al. / Tetrahedron Letters 48 (2007) 8536–8539
Completion of the total synthesis required the reduction
of a-azido ketone 11 and self-condensation of the a-ami-
no ketone produced. The direct conversion of a-azido
ketones into 1,4-pyrazines using aqueous triphenylphos-
phine (Staudinger reaction) has been reported in the
synthesis of steroidal pyrazines.13 In our case, we found
that treatment of a-azido ketone 11 with aqueous tri-
phenylphosphine in THF for 16 h, followed by the addi-
tion of a catalytic amount of p-toluenesulfonic acid in
ethanol and further oxidation in air, afforded N-Boc-
barrenazine B 12 in 59% yield, accompanied with a
significant amount of dihydropyridinone 9, possibly
formed by azide elimination (Scheme 5).
In summary, an enantioselective synthesis of (ꢀ)-barren-
azine A and (ꢀ)-barrenazine B was achieved in nine
steps (19% overall yield) and eight steps (21% overall
yield), respectively. The key features of the synthesis
are a highly diastereoselective nucleophilic addition of
a Grignard reagent to a chiral acylpyridinium salt, a
radical azidation of a silyl enol ether, and the assembly
of the pyrazine ring by reductive dimerization of a func-
tionalized 5-azidopiperidin-4-one. The versatility of this
synthetic strategy should provide convenient access to a
variety of structural derivatives of barrenazines A and B
modified at the side chain.
With N-Boc-protected barrenazine 12 in hand, we went
straightforward toward the synthesis of natural barren-
azines. The acidic hydrolysis of 12 with trifluoroacetic
acid (TFA) in CH2Cl2, followed by neutralization with
saturated aqueous NaHCO3, resulted in clean removal
of the t-butoxycarbonyl groups, providing the optically
active (ꢀ)-barrenazine B in 86% overall yield.14 Finally,
we found that (ꢀ)-barrenazine B can be transformed
into (ꢀ)-barrenazine A by hydrogenation under Pd/C
(90% yield).15 The spectral data (1H NMR, 13C NMR,
MS, IR) for synthetic (ꢀ)-barrenazine A and (ꢀ)-bar-
renazine B are in full concordance with reported data
for naturally occurring and synthetic barrenazines. The
absolute configuration was confirmed by measuring
optical rotations. The measured optical rotations for
Acknowledgments
This research was supported by the Xunta de Galicia
(Spain, PGIDIT05BTF10301PR). M.M.M. thanks the
Xunta de Galicia for a research contract sponsored by
the Isidro Parga Pondal Program.
References and notes
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the barrenazines were in accordance with the values
22
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22
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Scheme 5. Synthesis of (ꢀ)-barrenazines A and B.