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(4, Scheme 2C, 8.00 equiv).6d While we have reasoned that the
C11-stereochemistry of alcohol (–)-15 is a consequence of the
■ RESULTS AND DISCUSSION
1
2
3
4
5
6
7
8
9
The sensitivity of the epipolythiodiketopiperazines’ polysul-
fane bridge to various reducing or oxidizing reaction conditions,
and their propensity toward elimination and degradation re-
quires precise timing for their introduction into complex molec-
ular frameworks. These considerations are compounded in the
context of dimeric epipolythiodiketopiperazines that require the
introduction of challenging quaternary stereogenic centers.2
Informed by prior biosynthetic studies of sirodesmin by How-
lett,12a and the cysteine feeding experiments by Kirby,12b and
given the presence of various polysulfane congeners in distinct
families of natural ETPs, we posited2a,6a that the introduction of
the carbon–sulfur bonds in the biosynthesis of these alkaloids
may involve a C–H hydroxylation followed by nucleophilic
glutathione thiolation of N-acyl iminium ion intermediates
(Scheme 1).2,6a-b
C12 substituent, the double oxidation at C15 was surprising
given the monohydroxylation of the structurally related diketop-
iperazine of (+)-12. Interestingly, bis(pyridine)silver (I) per-
manganate promoted hydroxylation of diketopiperazine (+)-16,
a substrate with the same diketopiperazine stereochemistry as
substrates (+)-10a–10b, led to alcohol (+)-17 (Scheme 2D, 3.00
equiv), along with recovery of 41% of the substrate (+)-16,
without oxidation at C15-position, illustrating the strong impact
of the N-formyl group. Furthermore, hydroxylation of diketop-
iperazine (+)-18 gave the triketopiperazine (+)-19 (Scheme 2E,
3.00 equiv) with double oxidation at the methylene, consistent
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12
13
14
15
16
17
18
19
20
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60
with our observations in the oxidation of diketopiperazine (–)-
14, without C–H oxidation adjacent to the acetylated diketop-
iperazine nitrogen, consistent with the lack of oxidation at C15
with diketopiperazine (+)-16. Given the nuanced reaction out-
comes in the representative cases illustrated in Scheme 2, we
envisioned a substrate based parameterization of our permanga-
nate promoted diketopiperazine hydroxylation reaction could
provide a detailed analysis of these reactivity trends and form
the basis for more informed future applications of the chemistry.
O
O
O
O
YS
H
HO
RN
R'
RN
R'
R'
R'
NMe
R''
NMe
R''
OH
NMe
R''
NMe
R''
OH
S
S
RN
RN
H
O
6
O
7
O
9
O
8
nucleophilic
thiolation
ETP
synthesis
DKP
hydroxylation
A) Tetrahydroxylation of a Dimeric Diketopiperazine:
Scheme 1. Key steps in the conversion of diketopiperazines
(DKPs) to the corresponding epidithiodiketopiperazines (ETPs).
SO2Ph
N
H
SO2Ph
N
H
O
O
HO
H
R
R
Py2AgMnO4
N
N
O
O
O
O
H
MeN
Importantly, this biogenetically inspired approach to the
chemical synthesis of epipolythiodiketopiperazines led to the
development of our permanganate promoted hydroxylation of
diketopiperazines and laid the foundation for the synthesis of a
number of natural and designed complex epipolythiodiketop-
iperazines.2a Additionally, consistent with this hypothesis, C–H
hydroxylation of a phenylalanine-serine diketopiperazine fol-
lowed by nucleophilic addition of glutathione has recently been
experimentally observed in the biosynthesis of (–)-gliotoxin (5,
Figure 1).13 While our late-stage permanganate promoted C–H
hydroxylation of complex diketopiperazines has enabled strate-
gic access to the corresponding N-acyl iminium ions as a prel-
ude to our epipolythiodiketopiperazine syntheses,2a we have
sought to better understand the critical substrate characteristics
that govern the reaction outcome.
Application of this permanganate oxidation to complex
diketopiperazines has proven successful in a variety of total
synthetic efforts.6 As illustrated in Scheme 2A, the
bis(pyridine)silver (I) permanganate promoted oxidation of
dimeric diketopiperazine (+)-10a (4.80 equiv) led to the for-
mation of the corresponding tetrahydroxylated dimer (+)-11a,
with hydroxylation at C11 and C15, en route to the synthesis of
(+)-12,12'-dideoxyverticillin A (1).6a Similarly, hydroxylation of
dimeric diketopiperazine (+)-10b afforded the corresponding
tetrahydroxylated dimer (+)-11b (Scheme 2A. 8.00 equiv). No-
tably, the desired hydroxylation proceeds even at the more elec-
tron-deficient C15-center next to the acetoxy group to give
tetraol (+)-11b.14 However, oxidation of the C11-epimer of
dimeric diketopiperazine (+)-10a (not shown) under identical
conditions only afforded a diol product where C–H oxidation is
limited to the C15-positions without oxidation at the C11-
positions,6a highlighting the impact of the diketopiperazine ste-
reochemistry on the reaction outcome.6a The hydroxylation of
diketopiperazine (+)-12 using the tetra-n-butyl ammonium per-
MeN
HO
CH2Cl2
NMe 23 °C
11
OH
H
NMe
R
O
O
15
N
R
N
H
N
H
(+)-11a
(+)-11b
OH
N
H
SO2Ph
SO2Ph
63%, R=Me
(+)-10a, R=Me
(+)-10b,R=CH2OAc
key intermediates for total
synthesis of ETPs (+)-1–3
55%, R=CH2OAc
B) Dihydroxylation of a Diketopiperazine:
H
N
H
N
O
O
n-Bu4NMnO4
H
HO
NMe
NMe
11
CH2Cl2
23 °C
15
N
H
N
H
H
OH
N
H
N H
O
O
SO2Ph
SO2Ph
41%
(+)-12
(−)-13
key intermediates for total
synthesis of (+)-gliocladin B and C
C) Triple Oxidation of a Diketopiperazine:
Boc
N
Boc
N
Boc
Boc
O
O
O
Py2AgMnO4
O
O
H
HO
NMe
NMe
12
11
CH2Cl2
23 °C
15
3
N
H
N
O
H
N
H
N H
O
SO2Ph
45%
SO2Ph
(−)-14
(−)-15
key intermediate for total
synthesis of ETP (+)-4
D) Mono Oxidation of a Diketopiperazine:
O
O
H
HO
Py2AgMnO4
Br
Br
NCHO
NCHO
11
11
15
15
3
N
N
Me
Me
CH2Cl2
23 °C
H
H
N
H
N H
O
O
SO2Ph
SO2Ph
11%
(+)-16
(+)-17
E) Double Oxidation of a Diketopiperazine:
AcO
O
AcO
O
H
H
Py2AgMnO4
Me
NMe
H
Me
NMe
manganate reagent provided diol (–)-13, which served as a key
CH2Cl2
23 °C
AcN
AcN
O
intermediate en route to (+)-gliocladins B and C (Scheme 2B,
H
3.79 equiv).6c Notably, bis(pyridine)silver (I) permanganate
O
O
44%
(+)-18
(+)-19
promoted hydroxylation of diketopiperazine (–)-14 resulted in
the triketopiperazine alcohol (–)-15 en route to (+)-bionectin A
Scheme 2. Representative application of our permanganate–
mediated diketopiperazine oxidation chemistry.
2
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