COMMUNICATION
pubs.acs.org/JACS
Total Synthesis of Epicoccin G
K. C. Nicolaou,* Sotirios Totokotsopoulos, Denis Giguꢀere, Ya-Ping Sun, and David Sarlah
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037,
United States, and Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093,
United States
S Supporting Information
b
the growing molecule through selective endoperoxide formation
ABSTRACT: An expedient enantioselective total synthesis
of epicoccin G and related dithiodiketopiperazines through
a strategy featuring direct two-directional sulfenylation,
photooxygenation, and KornblumꢀDeLaMare rearrange-
ment is described.
effected by a photooxygenation reaction, followed by the rarely
employed KornblumꢀDeLaMare rearrangement7 and reduc-
tion of the remaining olefinic bonds. The requisite bisdiene
system 7 was to be formed from N-Boc tyrosine (9) through
intermediate 8 via appropriate functional group manipulations
and dimerization.
The construction of the C2-symmetric bisdiene diketopiper-
azine 7 from 9 is summarized in Scheme 1. Thus, 9 was conver-
ted to bicyclic hydroxy enone 10 through a known two-step
procedure.8 Deoxygenation of the latter was achieved through a
three-step sequence involving acetylation, zinc reduction, and
base-induced isomerization of the resulting β,γ-unsaturated
ketone to afford the desired bicyclic enone 8 in 51% overall
yield. Luche reduction9 of this enone led to hydroxy N-Boc
methyl ester 11 (92% yield), which was advanced through acid
(TFA) and base (LiOH) treatment to intermediates hydroxy
amine 12 and hydroxy acid 13, respectively. The dimerization
step was realized through BOP-Cl facilitated coupling of 12 and
13 to afford N-Boc methyl ester amide 14 (86% yield). Depro-
tection of the amine and Et3N-induced ring closure gave
pentacyclic bisallylic system 15 in 77% overall yield for the two
steps. The desired bisdiene 7 was generated from 15 through
intermediate bistrifluoroacetate 16 by treatment with (CF3CO)2O
and Et3N (69% yield) followed by exposure to Pd(PPh3)4 catalyst
(90% yield).10
With diketopiperazine bisdiene 7 in hand, the installation of
the sulfur atoms became the next task. Initial attempts to
accomplish bis-sulfenylation of 7 by the classical method11 of
treatment of the diketopiperazine substrate with base followed by
addition of S8 failed; at best, only trace amounts of bis-sulfeny-
lated products were obtained. Upon extensive experimentation,
we discovered that pretreatment of S8 with 3 equiv of NaHMDS
at ambient temperature followed by sequential addition of 7 and
an additional 2 equiv of NaHMDS provided a mixture of
oligosulfenylated compounds (17; Scheme 2). Bismethylthio
derivative 18 [together with its chromatographically separable
2,20-epi-diastereoisomer (2,20-epi-18, not shown)]12 was ob-
tained as the major product upon reduction of oligosuflide 17
with NaBH4 and subsequent quenching of the resulting dianion
with MeI (58% yield, ∼1.4:1 dr). Oxidation of the dianion
resulting from NaBH4 reduction of 17 with KI3 led to the
corresponding epidithiodiketopiperazine 19 as the major pro-
duct, formed together with its chromatographically separable
iketopiperazines are an important class of natural products
D
whose molecular structures are as varied as their biological
properties.1 Those that contain sulfur atoms within their struc-
tures are particularly interesting because of the synthetic chal-
lenge they present and their potent activities against viruses,
bacteria, and cancer cells.2 Combined with the scarcity of these
compounds, these properties have inspired studies leading
toward their synthesis as a means to develop new chemistry
and render them readily available for further biological investi-
gations.3 Epicoccin G (1) [Figure 1; isolated from the endophy-
tic fungus Epicoccum nigrum; exhibits anti-HIV activity in C8166
cells (IC50 = 13.5 μM)],4 rostratin B (2) [Figure 1; isolated from
the marine-derived fungus Exserohilum rostratum; exhibits cyto-
toxicity against human colon carcinoma HTC-116 (IC50 = 1.9
μM)],5 and exserohilone (3) (Figure 1; isolated from the
endophytic fungus Exserohilum holmii; suspected of antibacterial
and antifungal activity)6 are three examples representing this
class of compounds, whose structural motifs are situated on a
6ꢀ5ꢀ6ꢀ5ꢀ6 diketopiperazine framework (I, Figure 1). In this
communication, we report a total synthesis of epicoccin G (1)
and 8,80-epi-ent-rostratin B (4) featuring a direct and improved
procedure for the introduction of the sulfur atoms in diketopi-
perazines and a novel singlet oxygen/DeLaMare rearrangement
cascade sequence for the attachment of the oxygen functional-
ities of the target molecules.
Figure 2 shows, in retrosynthetic format, the evolution of the
synthetic strategy leading to epicoccin G (1). The C2 symmetry
of 1 allowed for a general two-directional strategy for all three
dithiodiketopiperazine natural products shown in Figure 1
(1ꢀ3), their diastereoisomers (e.g., 4), and their analogues. In
view of the special reactivity of the sulfur moieties, the timing of
their introduction was crucial. Thus, while early introduction of
sulfur may have thwarted subsequent steps required for pending
functionalizations, their late installation was excluded by the
higher reactivity of the ketone groups (relative to the diketopiper-
azine moiety) under the basic conditions needed for the sulfenyla-
tion reaction. On balance, we decided to explore the possibility of
introducing the sulfur atoms on bisdiene 7 and attempt to navigate
Received: April 8, 2011
Published: May 06, 2011
r
2011 American Chemical Society
8150
dx.doi.org/10.1021/ja2032635 J. Am. Chem. Soc. 2011, 133, 8150–8153
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Nicolaou
