aranotin family (4),4 as well as epicorazine B (2).5 They bear
the same absolute configuration in their monomer structure.
All of these substances are mycotoxins, exhibiting important
biological characteristics such as activities against viruses,3,4
fungi,3 and bacteria.3,5 Their complex structures and impor-
tant biological activities clearly mark them as important
synthetic targets. However, to the best of our knowledge,
within the large class of thiodiketopiperazine natural prod-
ucts, only gliotoxin (3)6 and (+)-11,11′-dideoxyverticillin
A7 have been reached by total synthesis so far.
Scheme 2. Synthesis of the Precursor 12
We report here the synthesis of the epicoccin scaffold, in
which we use a new stereoselective approach to azabicyclic
cyclohexenones. Our route to the cyclohexenone structure
involves a ring-closing metathesis reaction of an intermediate
lactol 6, generated by isomerization of a terminal double
bond in lactone 7 and subsequent vinylation (Scheme 1).
Scheme 1. Retrosynthetic Analysis of the Bicyclic System 5
aminal,10b,11 the dehydration proceeds smoothly at room
temperature and gave the enecarbamate 10 reliably in good
yield.12
To build up the azabicyclic cyclobutanone scaffold 11,
we used a method previously reported by Valle et al.13,10b
The enecarbamate 10 was submitted to a [2 + 2]
cycloaddition with an allylketene, in situ generated from the
corresponding pent-4-enoyl chloride and triethylamine. The
endo-cycloadduct 11 was isolated as single diastereoisomer
in 75% yield. The relative configuration could be proven by
NOESY experiments and was consistent with observations
reported by Valle et al. for similar substrates. The obtained
stereoselectivity can be explained by a preferred endo-
approach of the ketene from the less hindered side of the
enecarbamate 10 and pointing its substituent in the opposite
direction of the ring (A, Scheme 2).13
The intermediate cyclobutanone 11 was subsequently
converted into lactone 12 by a completely regioselective
Baeyer-Villiger oxidation.10b,13 It is noteworthy that the
terminal double bond is not oxidized under these conditions.
The allylic side chain of lactone 12 was then successfully
isomerized (Scheme 3) under ruthenium hydride catalysis,
the active species being generated from Grubbs II catalyst14
The final diketopiperazine unit was built through a one-
step phosphite-promoted coupling of two identical proline-
type amino acids. This methodology, previously elaborated
in our group,8 has proved to be ideal for the synthesis of
C2-symmetrical and unsymmetrical diketopiperazines, thus
enabling us to apply our results reported herein to the
syntheses of gliotoxin (3) and epicorazine B (2) in the future.
As starting material for the synthesis of epicoccin, we used
the inexpensive L-pyroglutamic acid (8), which was con-
verted by conventional methods into the protected amino acid
derivative 9 (Scheme 2).9 The required enecarbamate 1010
was generated by reduction of the lactam carbamate 9 with
Super-Hydride, followed by dehydration with TFAA (trif-
luoroacetic anhydride), Hu¨nig base, and DMAP as catalyst.
It is noteworthy that by performing this sequence as a one-
step procedure, instead of isolating the intermediate
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