Synthetic studies towards the penicisulfuranols: Synthesis of an advanced spirocyclic diketopiperazine intermediate

Article abstract of DOI:10.1016/j.tet.2019.01.032

The 2,5-diketopiperazine (DKP) moiety is a core feature of many natural products and medicinally relevant scaffolds. As part of our efforts directed towards a total synthesis of penicisulfuranol B, we have developed and report herein: (1) the preparation of an N-hydroxy diketopiperazine intermediate accessible via a molybdenum-mediated oxidation of a parent diketopiperazine, and (2) further synthetic studies leading to a novel spirocyclic dihydrobenzofuran-containing diketopiperazine.

Full text of DOI:10.1016/j.tet.2019.01.032

Accepted Manuscript
Synthetic studies towards the penicisulfuranols: Synthesis of an advanced spirocyclic
diketopiperazine intermediate
Kevin M. Gayler, Kyle M. Lambert, John L. Wood
PII:
S0040-4020(19)30059-6
https://doi.org/10.1016/j.tet.2019.01.032
TET 30084
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 December 2018
Revised Date: 11 January 2019
Accepted Date: 15 January 2019
Please cite this article as: Gayler KM, Lambert KM, Wood JL, Synthetic studies towards the
penicisulfuranols: Synthesis of an advanced spirocyclic diketopiperazine intermediate, Tetrahedron
(2019), doi: https://doi.org/10.1016/j.tet.2019.01.032.
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Synthetic Studies Towards the Penicisulfuranols: Synthesis
of an Advanced Spirocyclic Diketopiperazine Intermediate

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Tetrahedron
journal homepage: www.elsevier.com
Synthetic Studies Towards the Penicisulfuranols: Synthesis of an Advanced
Spirocyclic Diketopiperazine Intermediate.
∗
Kevin M. Gayler, Kyle M. Lambert, and John L. Wood
Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The 2,5-diketopiperazine (DKP) moiety is a core feature of many natural products and
medicinally relevant scaffolds. As part of our efforts directed towards a total synthesis of
penicisulfuranol B, we have developed and report herein: (1) the preparation of an N-hydroxy
diketopiperazine intermediate accessible via a molybdenum-mediated oxidation of a parent
Available online
diketopiperazine, and (2) further synthetic studies leading to
dihydrobenzofuran-containing diketopiperazine.
a novel spirocyclic
Keywords:
Penicisulfuranols
Diketopiperazine
Spirocycle
Hydroxamic Acid
Oxidation
∗
Corresponding author. Tel.: +1-254-710-4427; e-mail: John_L_Wood@Baylor.edu
1

1
.
Introduction
including work reported by Brown, Ottenheijm, Baran, and Liu
3
ACCEPTED MANUSCRIPT
(
Figure 3). While several ETP natural products have been
The Penicisulfuranol family of natural products was isolated
synthesized, the number of successful synthetic efforts towards
4
in late 2016 by Zhu and co-workers from the fungus Penicillium
janthinellum HDN13-309; obtained from the root of Sonneratia
caseolaris. The disulfide-containing compounds of this family,
have been found to display favorable cytotoxic properties
towards HeLa and HL-60 cell lines exhibiting IC50 values in the
low µM range. Penicisulfuranol B (2) is one of the more active
members of the family displaying IC50 values of 3.9 µM and 1.6
µM, respectively.
ETPs containing the N–O moiety have been limited. The most
notable of these efforts is the total synthesis of the structurally-
related natural product aspirochlorine (7) by Williams and co-
workers, which to date, represents the only reported synthesis of
1
4
a
a spirocyclic DKP natural product containing the N–O moiety.
Brown3a
O
O
S
O
O
OMe
OMe
H
H
N
N
N
R
O
OH
OH
O
N
HN
OH
AcO
MeO
AcO
dioxane, 85 °C
α
α
N
N
S
S
O
O
O
O
β
S
S
β
10
11
S
N
N
O
O
Ottenheijm3f
O
O
O
O
OH
O
OH
O
H
N
MeO
HN
O
O
Me
Me
t
N
KO Bu
R = Cl, Penicisulfuranol A (1)
R = OH, Penicisulfuranol B (2)
Penicisulfuranol C (3)
N
Me
N
BnO
O
MeOH, r. t.
Me
O
O
R
O
OH
OH
O
12
13
OH
S
N
S
N
S
S
Baran3g
N
N
O
O
O
OH
OH
OMe
O
O
OMe
O
O
N
N
O
O
Br
OH
OH
O
OH
O
N
O
N
OMe
O
O
BBr3
O
N
MeO
O
HO
O
HN
R = Cl, Penicisulfuranol D (4)
Penicisulfuranol F (6)
R = OH, Penicisulfuranol E (5)
O
Br
Br
Figure 1. Penicisulfuranols A-F
14
15
16
Liu3h
OMe
OMe
OMe
Although the biological activities of 1-6 are interesting, we were
drawn to this family due to the formidable synthetic challenge
that their unique molecular architectures present. A number of
complex structural features define the penicisulfuranols: an
oxazadecalin system, an N-alkoxy diketopiperazine core, a
spirocyclic dihydrobenzofuran moiety, and unusual disulfide
bridge connectivity in 1-3.
MeO
OMe
MeO
OMe
Ph
MeO
OMe
O
O
O
N
O
Ph
H
O
OH
aq. HCl
1,5-shift
N
H
H
O
N
H
H
2
N
N
NH
OBn
H
O
O
O
17
18
19
Figure 3. Representative N-Alkoxy DKP Fragmentations
As one could anticipate from past precedents, in our
investigations towards the penicisulfuranols, we encountered
similar challenges while advancing intermediates containing the
labile N–O bond. Given these difficulties, we opted to introduce
the N–O bond via a molybdenum-mediated oxidation of a pre-
functionalized DKP. The results of which are presented herein.
Figure 2. Representative ETPs
2
.
Results and Discussion
The penicisulfuranols are part of a much larger class of
epipolythiodiketopiperazine (ETP) fungal toxins (e.g. 7-9, Figure
), which are defined by the central 2,5-diketopiperazine moiety
As illustrated retrosynthetically in Scheme 1, our plan for
2
preparing penicisulfuranol B (2) called for late-stage introduction
of the oxazadecalin system and disulfide via oxidation of the
pendant phenol and masked disulfide in advanced intermediate
2
and a bridging polysulfide. While the polysulfide bridge is
usually located on the α-positions of the two amino acid residues
that form the DKP (e.g. 8-9, Figure 2), ring expanded variants
where the polysulfide bridge is located on the α-position of one
residue and the β-position of the second residue (e.g. 1-3 and 7,
Figures 1-2) are less common. Our current synthetic progress
towards installing these polysulfide functionalities is presented
herein, and highlights a unique, concomitant cyclization to
furnish a spirocyclic dihydrobenzofuran moiety such as those
found in compounds 1-7.
2
0. The latter was seen as arising from 21 via selective oxidation
of the electron-rich aromatic ring and concomitant sulfur
migration/spirocyclization; a process akin to the dehydrative
sulfur migration employed by Danishefsky and coworkers in
5
their synthesis of the aspirochlorine core. Importantly, the plan
calls for the introduction of the labile N-O bond on a DKP
intermediate (22) pre-functionalized with all of the carbon atoms
required for the synthesis.
In addition to this unique disulfide connectivity, the
penicisulfuranols contain a central N-alkoxy DKP, a synthetically
challenging functional group due to (1) the rather limited
synthetic options for the preparation of N-alkoxy DKPs, and (2)
the inability to further functionalize derivatives due to the
instability of the nitrogen-oxygen (N–O) bond. Numerous
examples of this latter reactivity can be found in the literature
2

OH
OH
O
OH
O
with MoO (HMPA). In the initial screen, we explored oxidations
5
ACCEPTED MANUSCRIPT
N
sulfur migration
N
N
with either stoichiometric or two-fold excesses of NaWO /UHP,
S
S
S R
4
S
N
O
HO
NaWO /UHP/HMPA,
4
MoO (HMPA)(Py),
5
MoO (HMPA),
5
O
O
OMe
OMe
13,14
OH
OR
O
O
MoO (DMF), and MoO (DMF) ).
As illustrated in Scheme 3,
5
5
2
OMe
OMe
aryl oxidation
of these reagents, the most satisfactory results were obtained with
Penicisulfuranol B (2)
20
MoO (HMPA). However, we were never able to achieve
5
sulfur
installation
complete oxidation of the intermediate trimethylsilyl imidate of
O
OR
O
O
2
2, thus, upon work-up we obtained an inseparable mixture of 28
OMe
OMe
Me
OMe
OMe
N
N
and starting material (22). To remedy this, treatment of the
mixture with TBSOTf to afford the protected N-hydroxy DKP 29
was pursued, but also generated the TBS imidate of 22. Selective
deprotection of the unwanted TBS imidate of 22 in the presence
of the desired product 29 was accomplished by stirring the
mixture in a slurry of silica gel in DCM solvent. This ultimately
allowed for the separation and isolation of 29 along with
recovered starting material 22. Overall, this process furnished
protected N-hydroxy DKP 29 in 15% yield over the four steps
from 22, with a 13% recovery of 22.
S R
S
N
HN
HO
amide
oxidation
O
OR
OR
21
22
R = protecting group
Scheme 1. Retrosynthetic analysis of penicisulfuranol B.
In the forward sense we considered a number alternatives for
the preparation of 22 and eventually employed an approach
developed by Liu. As illustrated in Scheme 2, this strategy calls
for the use of bis-N-acyl DKP 24, which can be implemented via
6
OBn
O
OBn
O
Me
OMe 1) i. BSA
MeCN, 82 °C , 1 h
Me
OMe
OMe
a single-pot procedure involving an interrupted bis-aldol
N
N
7
,
8
HN
N
OMe
ii. MoO (HMPA)
5
HO
condensation.
Importantly, the use of 24 as the point of
DCM, 25 ºC, 36 h
O
OBn
O
OBn
departure results in aldol products that undergo N-to-O-acyl
migration/elimination reactions and deliver intermediate aldol-
condensation products that have undergone deacylation of the
proximal amide which, in turn, allows for regioselective
functionalization. Applying this approach in our efforts toward
the penicisulfuranols involved initial condensation of 23 and 24
to produce 25 which is poised for a selective methylation that
2
2
28
along with residual SM (22)
OBn
O
OBn
O
Me
OMe
OMe
Me
OMe
OMe
N
N
2
) TBSOTf, NEt
3
+
N
N
DCM, 25 °C , 1 h
TBSO
O
OBn
OTBS
OBn
29
TBS-imidate from
residual SM (22)
,
7 9
delivers the second aldol substrate (26). Introduction of
benzaldehyde 27 into the reaction mixture at this stage then
delivers aldol condensation product 22 as the only isolable
product in 36% overall yield for this multistep, one-pot
inseparable mixture
OBn
OBn
O
O
Me
OMe
Me
N
OMe
OMe
3) SiO2, DCM
N
+
HN
N
7,10 1
25 °C , 14 h
OMe
sequence.
the single stereoisomer that had been produced possesses the
Z,Z)-olefin geometry illustrated in 22. Notably, in addition to
H NOESY analysis of the product indicated that
TBSO
O
OBn
O
OBn
2
9
recovered SM (22)
(13% yield)
(
(15% yield)
containing the requisite carbon atoms, 22 possesses two exo-
benzylidene moieties that are poised for conversion to thiols.
Scheme 3. Amide oxidation of bis-benzylidene DKP 22.
O
Having determined the feasibility of amide oxidation, albeit
low yielding and unoptimized, we decided to shift our
investigations toward installing the sulfur moieties. We were
drawn to reports from Schmidt and Olsen describing the
introduction of thioacetates onto bis-exomethylene-bis-N-methyl-
NAc
O
AcN
OBn O
OMe
OMe
i.
24
NH
ii. MeI
MeO
MeO
O
H
AcN
Cs
2
CO
3
, 3 Å MS
DMF, 25 °C, 2 h
–15 °C, 3 h
O
OBn
containing DKP substrates using thioacetic acid as the sulfur
2
3
25
15,16
source.
As illustrated in Scheme 4, we discovered that
OBn O
exposure of 22 to similar conditions results in the reasonably
efficient and chemoselective incorporation of only a single
thioacetate moiety. Thus indicating that more heavily substituted
alkylidenes are tolerated, but the presence of a simple N-H bond
is not (i.e., sulfur is only incorporated adjacent to the alkylated
nitrogen). Further efforts to explore the chemistry needed to
advance 22 revealed that deprotection can be accomplished under
acidic conditions in the presence of an alkylation scavenger and
that the derived phenol (31) can also serve as a substrate for
thioacetate introduction, albeit with similar chemoselectivity.
O
O
OBn
O
H
Me
OMe
iii.
Me
OMe
OMe
N
N
2
7
AcN
HN
OMe
9
5 °C, 2 h
OBn
(36% yield one pot)
O
OBn
2
2
2
6
Scheme 2. One-pot synthesis of bis-benzylidene DKP 22.
Having accessed 22, we next attempted oxidation of the
secondary amide to the corresponding hydroxamic acid. There is
only sparse precedent within the literature for the direct
conversion of a secondary amide in a DKP to an N-hydroxyl
1
1,12
DKP.
Thus, we opted to adapt more well-described
conditions developed by Sammes for the oxidation of secondary
amides and lactams to hydroxamic acids via the intermediacy of
13
the corresponding trimethylsilyl imidate. As illustrated in
Scheme 3, during our investigations with various reagents we
were able to oxidize the parent DKP 22 to N-hydroxy DKP (28)
3

OBn
O
O
OBn
O
ACCEPTED MANUSCRIPT
Me
OMe
Me
OMe
N
AcSH, HCl
N
HN
HN
OMe dioxane, 25 °C, 43 h
(60% yield)
OMe
SAc
OBn
O
OBn
2
2
30
TFA
pentamethylbenzene
5 °C , 20.5 h
54% yield)
2
(
OH
O
O
OH
O
O
Me
OMe
OMe
Me
OMe
OMe
N
AcSH, HCl
N
HN
dioxane, 25 °C , 24 h
HN
SAc
(
57% yield)
OH
OH
31
32
Scheme 4. Sulfur addition into bis-benzylidene DKP 22 and 31.
Figure 4. X-ray crystal structure of 36.
To determine if indeed the lack of amide functionalization
was thwarting introduction of the second thioacetate, 22 was
permethylated by exposure to methyl iodide and Cs CO . The
3
.
Conclusions
2
3
derived DKP (33) was deprotected, again using acid in the
presence of a scavenger, to furnish bis-phenol 34 in 74% yield.
Interestingly, exposure of 34 to the same thioacetic acid
conditions that had been employed to advance either 22 or 31
resulted in the an unexpected chemoselective spirocyclization to
afford two separable dihydrobenzofuran diastereomers 35 and 36
In ongoing efforts toward a synthesis penicisulfuranol B we
have developed an efficient one-pot method for generating a
DKP intermediate containing the requisite carbon atoms and have
demonstrated the viability of late-stage N-hydroxylation.
Preliminary studies on the core structure have provided insight
regarding eventual sulfur incorporation and revealed an
17
in an approximate 1:2 ratio, respectively (Scheme 5). Of note,
only the unsubstituted phenol was observed to undergo the
cyclization process, whereas, the bis-methoxylated phenol did
not. The nucleophilicity of the bis-methoxylated phenol is likely
attenuated due to an intramolecular hydrogen bond with the
interesting spirocyclization reaction that delivers
a
dihydrobenzofuran- containing DKP. Based on these results,
future W6 efforts toward the penicisulfuranol family are being
aimed at advancing thioacetate DKPs 30 and 32. Results from
these investigations will be reported in due course.
18
adjacent methoxy group on the aryl ring, thus, thioacetate
incorporation proceeds preferentially over cyclization.
Additionally, if cyclization precedes thioacetate incorporation, or
a reversible process is at play, the stability of the formed
spirocycle would dictate cyclization versus thioacetate
incorporation. To probe potential mechanistic pathways and gain
further insight into this process we attempted to induce
cyclization in the absence of thioacetic acid employing only HCl
in dioxane, but this resulted in decomposition of the starting
material with no desired product being obtained. The relative
stereochemistry of the dihydrobenzofuran spirocycle and
thioacetate was determined by X-ray crystallography (Figure 4).
4
4
.
Experimental section
.1 General Procedures
Unless otherwise stated, all reactions were performed in
flame-dried glassware under a nitrogen atmosphere, and
reagents were used as received. The reactions were monitored
by normal phase thin-layer chromatography (TLC) on
Millipore glass-backed 60 Å plates (indicator F-254, 250 ꢀM)
using the indicated eluents. Reactions were also monitored by
a Waters Acquity UPLC-MS equipped with a UPLC BEH
C18 1.7µm (2.1 x 50 mm) column, using H O:MeCN plus
0
2
OBn
O
OBn
O
.5% formic acid with a 95/5 to 10/90 gradient over 9 min.
Me
OMe
OMe
Me
OMe
OMe
N
MeI, Cs
2
CO
3
N
Dichloromethane, dimethyl formamide, acetonitrile, and
benzene were dried using a solvent purification system
manufactured by SG Water U.S.A., LLC. Anhydrous HCl in
dioxane was purchased from Oakwood Chemicals. Manual
flash chromatography was performed using the indicated
HN
DMF, -15 °C , 2h
N
Me
(
80% yield)
O
OBn
O
OBn
2
2
33
OH
O
Me
OMe
TFA
pentamethylbenzene
5 °C , 22 h
N
AcSH, HCl
dioxane, 25 °C , 19 h
®
N
solvent systems with Silicycle SiliaFlash P60 (230–400
Me
OMe
2
mesh) silica gel as the stationary phase. Automated flash
chromatography was performed on a Teledyne RF+UV-Vis
Ms Comp MPLC using the indicated solvent systems, and
Teledyne RediSep® Rf normal phase disposable columns of
the indicated size at the indicated flow rate. Normal phase
preparative HPLC was performed with the indicated solvent
system and 10 mL/min flow rate using a Sunfire Silica Prep
O
OH
(74% yield)
34
O
O
O
O
N
Me
OMe
OMe
Me
OMe
OMe
N
N
+
N
Me
Me
SAc
SAc
O
OH
O
OH
3
5
36
(34% yield)
(61% yield)
1
0 µM (10x250 mm) column to provide analytical samples.
1
13
H and C NMR spectra were recorded on either a Bruker
Ascend
Ascend 600 autosampler. Chemical shifts (δ) are reported
in parts per million (ppm) relative to the residual solvent
resonance and coupling constants (J) are reported in hertz
Scheme 5. Formation of an unexpected spirocycle.
TM
400 spectrometer autosampler or a Bruker
TM
(
Hz). NMR peak pattern abbreviations are as follows: s =
singlet, d = doublet, dd = doublet of doublets, t = triplet, at =
apparent triplet, q = quartet, ABq = AB quartet, m = multiplet.
NMR spectra were calibrated relative to their respective
4

1
residual NMR solvent peaks, CDCl = 7.26 ppm ( H NMR)/
7
in foil in a dark fume hood. After this period of time, the
reaction was quenched by addition of 2 mL of an aqueous 1M
3
ACCEPTED MANUSCRIPT
1
3
1
7.16 ppm ( C NMR), DMSO = 2.50 ppm ( H NMR). IR
spectra were recorded on Bruker Platinum-ATR IR
spectrometer using a diamond window. High resolution mass
spectra (HRMS) were obtained in the Baylor University Mass
Spectrometry Center on a Thermo Scientific LTQ Orbitrap
Discovery spectrometer using +ESI or –ESI and reported for
-
Na EDTA solution. The mixture was further diluted with 6
4
mL of DCM and stirred for 4 h. The organic layer was then
separated and the remaining aqueous portion was extracted
three times with 1.5 mL of DCM. The combined organic
layers were dried with Na SO and the solvent was removed
2
4
+
+
the molecular ion ([M+H]
&
[M+Na] or [M-H]
in vacuo. Initial purification of the crude material by column
chromatography with 40:60 EtOAc:Hex with 2.5% added
AcOH provided a mixture of 28 and 22. The mixture of 22
and 28 (23.6 mg, 0.04 mmol, 1 equiv) was transferred to a dry
vial with 0.5 mL of dry DCM to which, TBSOTf (45.8 µL,
respectively). Single crystal X-ray diffraction data were
collected on a BrukerApex II-CCD detector using Mo-Kα
radiation (λ = 0.71073 Å). Crystals were selected under oil,
mounted on micromounts then immediately placed in a cold
stream of N . Structures were solved and refined using
0.2 mmol, 5 equiv) and NEt (32.8 µL, 0.24 mmol, 6 equiv)
2
3
SHELXTL.
were added. This mixture was stirred at 25 °C for 1 h then
quenched by addition of 1.5 mL of water. The resulting
mixture was extracted with 1.5 mL of DCM three times, the
combined organic layers were dried and solvent removed
under reduced pressure to afford a crude residue. This residue,
which contained a mixture of an unwanted TBS-imidate and
4
.2 Experimental procedures and data of synthetic
intermediates
4
.2.1 DKP 22
title compound, was subjected to a slurry of SiO (500 mg) in
2
To a septum-capped, flame-dried flask containing a stir bar
2
mL of DCM solvent for 14 h at 25 °C, then purified using a
7,8
was added DKP 24 (5.9 g, 29.7. mmol, 1.0 equiv), followed
pipette column: 20:80 (EtOAc:Hex) to provide 3.6 mg (15%
yield) of the title compound as a colorless film along with 3.2
mg (13% yield) of recovered starting material 22. An
analytical sample was obtained by prep HPLC using the
7,9
by DMF (28 mL), aldehyde 23 (8.1 g, 29.7 mmol, 1 equiv),
g of 3 Å molecule sieves, and Cs CO (29.0 g, 89.1 mmol, 3
6
2
3
equiv). The resultant mixture was stirred for 3 h at 25 °C. The
reaction was then cooled to –15°C with an ice/salt bath, and
MeI (1.85 mL, 29.7 mmol, 1 equiv) was added and the
reaction mixture was allowed to stir for 2 h. At this point, the
1
following eluent; 20:80 (EtOAc:Hex): H NMR (400 MHz,
chloroform-d) δ 7.41 (d, J = 7.7 Hz, 2H), 7.37 – 7.29 (m, 6H),
7
.24 – 7.18 (m, 4H), 7.16 (d, J = 5.2 Hz, 2H), 6.94 (d, J = 7.3
7
,10
reaction mixture was treated with the second aldehyde 27
6.3 g, 29.7 mmol, 1 equiv) and then heated to 95 °C with
Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H),
(
6
6
.67 (d, J = 8.6 Hz, 1H), 5.12 (s, 2H), 4.98 (s, 2H), 3.90 (s,
13
stirring for 3 h. The reaction mixture was then allowed to cool
to room temperature, quenched by the addition of 100 mL
brine, and extracted two times with 500 mL EtOAc. The
combined organic layers were washed three times with 1 L of
H), 2.75 (s, 3H), 0.66 (s, 9H), 0.00 (s, 6H); C NMR (151
MHz, chloroform-d) δ 161.2, 157.8, 157.2, 154.5, 142.6,
1
1
37.1, 137.0, 132.6, 130.0, 129.4, 129.0, 128.9, 128.6, 128.4,
28.3, 127.8, 127.3, 125.4, 123.2, 121.7, 119.9, 118.1, 115.5,
brine and then dried with MgSO , filtered and the solvent was
4
111.4, 107.4, 75.3, 70.4, 61.1, 56.2, 34.7, 25.5, 18.1, 1.2, –5.1;
FTIR (thin film): 2928, 1687, 1624, 1595, 1493, 1449, 1425,
removed to yield a crude product. The crude material was
then purified by automated column chromatography: 220 g
1
328, 1281, 1255, 1206, 1139, 1094, 1063, 1011, 827, 811,
-1
SiO ; 30:70 to 50:50 (EtOAc:Hex) to provide 6.1 g (36%
2
788, 750, 732, 696 cm ; +ESI-HRMS m/z: calc’d for
1
+
+
yield) of the title compound as a yellow foam: H NMR (400
[
M+Na]
C H N NaO Si
7
=
729.2966,
found
41
46
2
7
+
MHz, chloroform-d) δ 8.41 (s, 1H), 7.43 (d, J = 7.3 Hz, 2H),
C H N NaO Si = 729.2959.
41
46
2
7
1
1
.39 – 7.29 (m, 8H), 7.27 (d, J = 1.5 Hz, 1H), 7.23 (dd, J =
2.8, 7.3 Hz, 2H), 7.16 (s, 1H), 7.07 – 7.02 (m, 2H), 6.99 (s,
H), 6.84 (d, J = 8.6 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H), 5.19
4
.2.4 DKP 30
1
3
(
(
s, 2H), 5.02 (s, 2H), 3.91 (s, 6H), 2.84 (s, 3H); C NMR
101 MHz, chloroform-d) δ 159.5, 158.9, 155.7, 154.4, 150.9,
To a septum-capped, flame-dried flask containing a stir bar
was added DKP 22 (250 mg, 0.43 mmol, 1.0 equiv), followed
by 4M HCl in dioxane (3 mL), and AcSH (3 mL). The
reaction mixture was then stirred at 25°C for 43 h, at which
point, the volatiles were evaporated under reduced pressure.
The crude mixture was dissolved in 50 mL of DCM and
washed with 75 mL of sat. aqueous K CO . The organic layer
1
1
1
2
1
42.6, 137.1, 136.0, 131.1, 130.5, 130.3, 128.9, 128.7, 128.5,
28.4, 128.3, 127.9, 126.4, 125.3, 123.1, 121.9, 116.7, 114.0,
13.7, 107.3, 75.4, 71.5, 61.1, 56.2, 35.7; FTIR (thin film):
934, 1680, 1620, 1593, 1491, 1449, 1423, 1373, 1341, 1278,
-1
092,1046, 993, 750, 695, 472 cm ; +ESI-HRMS m/z: calc’d
2
3
+
for C H N NaO [M+Na] , 599.2158 found 599.2178.
was then dried with Na SO , filtered, and the solvent removed
35
32
2
6
2 4
in vacuo to afford the crude material. Purification was
achieved by automated flash chromatography: (12 g SiO2;
4
.2.3 DKP 29
2
0:80 to 50:50 (EtOAc:Hex); to provide 169.4 mg (60%
1
To a flame-dried vial containing a stir bar was added DKP 22
100.0 mg, 0.173 mmol, 1.0 equiv) followed by 0.5 mL of
MeCN and BSA (51 µL, 0.2 mmol, 1.2 equiv). The vial was
sealed and heated to reflux for 2 h. At this point, the solvent
was removed in vacuo. The crude residue was dissolved in 2
mL of dry DCM and divided into 0.5-mL aliquots for the
yield) of the title compound as a yellow foam: H NMR (400
MHz, chloroform-d) δ 8.48 (s, 1H), 7.40 (s, 1H), 7.37 (d, J =
7
1
J = 7.9 Hz, 2H), 6.87 (s, 1H), 6.73 (s, 1H), 6.42 (d, J = 8.7
Hz, 1H), 5.18 (d, J = 11.0 Hz, 1H), 5.10 (s, 2H), 4.82 (d, J =
11.1 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 3.22 (d, J = 13.8 Hz,
(
.2 Hz, 5H), 7.33 (d, J = 7.1 Hz, 3H), 7.29 (d, J = 7.1 Hz,
H), 7.22 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 7.3 Hz, 1H), 6.94 (t,
screening of oxidation conditions with MoO (L) (L)
5
1
2
13
complexes. In the absence of light, to one of the vials was
added MoO (HMPA) (15.3 mg, 0.043 mmol, 2 equiv). The
1
H), 3.11 (d, J = 13.8 Hz, 1H), 2.96 (s, 3H), 2.25 (s, 3H);
C
5
1
NMR (101 MHz, chloroform-d) δ 193.3, 163.4, 158.8, 155.6,
resultant mixture was stirred for 36 h at 25 °C while wrapped
5

1
1
1
53.6, 151.9, 142.0, 137.2, 136.1, 130.7, 129.8, 128.7, 128.7,
28.5, 128.3, 128.1, 127.6, 125.8, 125.3, 123.3, 121.7, 118.7,
14.2, 112.0, 107.4, 77.7, 75.8, 71.3, 61.0, 35.9, 32.1, 30.3;
DMF (15 mL), and Cs CO (1.86 g, 5.7 mmol, 1.1 equiv).
2 3
ACCEPTED MANUSCRIPT
The reaction mixture was cooled to -15 °C with use of an
ice/salt bath then MeI (355 µL, 5.7 mmol, 1.1 equiv) was
added and the mixture was allowed to stir for 2 h. At this
point, the reaction mixture was quenched by addition of 50
mL of brine and then extracted two times with 500 mL of
EtOAc. The combined organic layers were washed three times
with 500 mL of brine and then dried with Na SO , filtered,
FTIR (thin film): 3271, 3031, 2937, 1690, 1632, 1597, 1494,
1
8
HRMS m/z: calc’d for C H N NaO S [M+Na] = 675.2141,
found C H N NaO S [M+Na] = 675.2141.
451, 1368, 1282, 1259, 1166, 1099, 1038, 995, 950, 908,
-1
81, 859, 803, 732, 697, 625, 570, 522, 456, 423 cm ; +ESI-
+
3
7
36
2
7
+
3
7
36
2
7
2
4
and the solvent removed in vacuo to afford a crude material
that was purified by automated flash chromatography: 80 g
4
.2.5 DKP 31
SiO ; 30:70 to 50:50 (EtOAc:Hex); to provide 2.1 g (80%
yield) of the title compound as a yellow foam: H NMR (600
MHz, chloroform-d) δ 7.40 (d, J = 7.3 Hz, 2H), 7.37 (d, J =
7.6 Hz, 2H), 7.32 – 7.26 (m, 3H), 7.25 (s, 1H), 7.22 (d, J = 4.9
Hz, 1H), 7.20 – 7.16 (m, 2H), 7.10 (s, 1H), 7.00 – 6.95 (m,
2H), 6.85 (d, J = 8.6 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H), 5.09
2
1
To a septum-capped, flame-dried flask containing a stir bar
was added DKP 22 (1.0 g, 1.7 mmol, 1.0 equiv), TFA (18
mL), and pentamethylbenzene (565.6 mg, 3.8 mmol, 2.2
equiv). The reaction mixture was stirred at 25°C for 20.5 h, at
which point, the volatiles were removed under reduced
pressure. The crude mixture was purified by automated flash
(
s, 2H), 4.99 (s, 2H), 3.91 (s, 6H), 2.90 (s, 3H), 2.81 (s, 3H);
C NMR (151 MHz, chloroform-d) δ 162.1, 162.0, 156.6,
1
3
chromatography: 40 g SiO 30:70 to 80:20 (EtOAc:Hex); to
2
;
provide 373 mg (31% yield) of the title compound as a yellow
1
54.4, 151.0, 142.6, 137.1, 136.5, 132.2, 131.0, 130.1, 128.7,
1
1
foam: H NMR H NMR (600 MHz, chloroform-d) δ 7.34 (s,
H), 7.28 (d, J = 8.3 Hz, 1H), 7.25 – 7.21 (m, 1H), 7.11 (d, J
8.2 Hz, 1H), 7.03 (s, 1H), 6.95 – 6.91 (m, 1H), 6.88 (d, J =
.6 Hz, 1H), 6.52 (d, J = 8.8 Hz, 1H), 3.93 (d, J = 2.1 Hz,
128.7, 128.5, 128.2, 128.1, 127.5, 125.4, 123.6, 121.5, 120.7,
117.4, 117.3, 112.2, 107.3, 75.4, 70.5, 61.2, 56.2, 34.7, 34.6;
FTIR (thin film): 2941, 1681, 1621, 1593, 1492, 1448, 1423,
1
=
8
3
1
6
373, 1338, 1280, 1244, 1197, 1171, 1093, 993, 802, 750,
1
3
-1
H), 3.91 (s, 3H), 3.07 (s, 3H). C NMR (151 MHz,
96, 609, 464, 418 cm ; +ESI-HRMS m/z: calc’d for
+
chloroform-d) δ 153.3, 153.0, 148.1, 135.4, 134.1, 131.1,
C H N NaO [M+Na] = 613.2315, found C H N NaO
[M+Na] = 613.2315.
36 34 2 6 36 34 2 6
+
1
1
3
1
30.3, 128.9, 128.6, 125.5, 124.4, 121.0, 120.7, 118.0, 117.2,
16.6, 114.3, 103.9, 61.2, 56.1, 35.9; FTIR (thin film):
271,1673, 1601, 1503, 1454, 1427, 1342, 1296, 1165, 1094,
4.2.8 DKP 34
-1
035, 971, 900, 794, 753, 695, 635, 523, 419 cm ; +ESI-
-
HRMS m/z: calc’d for C H N O = 395.1249, found
C H N O = 395.1249.
To a septum-capped, flame-dried flask containing a stir bar
was added DKP 33 (1.0 g, 1.69 mmol, 1.0 equiv), TFA (18
mL), and pentamethylbenzene (552.2 mg, 3.72 mmol, 2.2
equiv). The reaction mixture was stirred at 25°C for 21 h, at
which point, the volatiles were removed under reduced
pressure. The crude residue was purified by automated flash
2
1
19
2
6
-
2
1
19
2
6
4
.2.6 DKP 32
To a septum-capped, flame-dried flask containing a stir bar
was added DKP 31 (52.4 mg, 0.13 mmol, 1.0 equiv), followed
by 4M HCl in dioxane (1.2 mL), and AcSH (1.0 mL). The
reaction mixture was stirred at 25°C for 24 h, at which point,
the volatiles were removed under reduced pressure. The
crude residue was dissolved in 50 mL of DCM and washed
with 75 mL of sat. K CO . The organic layer was dried with
chromatography: 24 g SiO ; 50:50 to 80:20 (EtOAc:Hex) to
2
provide 515.8 mg (74% yield) of the title compound as an
1
orange foam: H NMR (400 MHz, chloroform-d) δ 7.24 –
7
.20 (m, 1H), 7.17 (d, J = 7.5 Hz, 1H), 6.92 (dd, J = 12.0, 8.0
Hz, 3H), 6.50 (d, J = 8.8 Hz, 1H), 6.25 (s, 1H), 3.92 (s, 3H),
13
2
3
3.90 (s, 3H), 3.01 (s, 3H), 2.96 (s, 3H); C NMR (101 MHz,
Na SO , filtered, and the solvent was removed under reduced
chloroform-d) δ 162.4, 154.2, 153.0, 148.2, 135.4, 132.7,
2
4
pressure to afford a crude residue, which was purified by
automated flash chromatography: 4 g SiO ; 40:60 to 80:20
1
30.7, 130.6, 130.5, 125.5, 120.9, 120.5, 117.7, 116.5, 116.1,
2
113.9, 103.9, 61.2, 56.1, 34.7; FTIR (thin film): 3297, 2980,
1676, 1614, 1504, 1461, 1429, 1351, 1300, 1163, 1098, 971,
756, 698 cm ; -ESI-HRMS m/z: calc’d for C H N O [M-
(
EtOAc:Hex); to provide 36.3 mg (57% yield) of the title
1
-1
compound as a yellow foam: H NMR (400 MHz,
22
21
2
6
-
–
chloroform-d) δ 9.92 (s, 1H), 8.50 (s, 1H), 7.21 – 7.14 (m,
H] = 409.1405, found C H N O [M-H] = 409.1384.
22 21 2 6
1
(
H), 7.10 (d, J = 7.2 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.88
t, J = 7.4 Hz, 1H), 6.77 (d, J = 8.6 Hz, 2H), 6.30 (d, J = 8.7
Hz, 1H), 6.19 – 6.13 (m, 1H), 3.78 (s, 3H), 3.70 (s, 3H), 3.49
4.2.9 DKPs 35 and 36
(
d, J = 14.1 Hz, 1H), 3.35 (d, J = 14.1 Hz, 1H), 3.23 (s, 3H),
To a septum-capped, flame-dried flask containing a stir bar
was added DKP 34 (41 mg, 0.1 mmol, 1.0 equiv), followed by
4M HCl in dioxane (0.5 mL), and AcSH (0.5 mL). The
reaction mixture was then stirred for 19 h at 25 °C, at which
point, the volatiles were removed under reduced pressure. The
crude mixture was dissolved in 25 mL of DCM and washed
with 50 mL sat. aqueous K CO . The organic layer was then
13
2
1
1
5
1
6
.33 (s, 3H); C NMR (101 MHz, chloroform-d) δ 194.2,
64.3, 159.3, 152.9, 152.2, 148.8, 135.4, 133.0, 130.4, 126.4,
24.4, 121.0, 120.3, 116.9, 114.1, 111.2, 104.2, 77.8, 61.0,
5.8, 35.7, 32.2, 30.5; FTIR (thin film): 3232, 2934, 1765,
689, 1613, 1506, 1466, 1377, 1279, 1200, 1037, 889, 758,
-
1
28 cm ; +ESI-HRMS m/z: calc’d for C H N NaO S
2
3
24
2
7
2
3
+
+
[
M+Na] = 495.1202, found C H N NaO S [M+Na]
=
dried with Na SO , filtered, and the solvent was removed in
2
3
24
2
7
2 4
4
95.1221.
vacuo to afford a crude material which was purified by
automated flash chromatography: 12 g SiO ; 0:100 to 80:20
(EtOAc:Hex); to provide 16.3 mg (34% yield) of compound
2
4
.2.7 DKP 33
3
5. Major product and relative stereochemistry was
To a septum-capped, flame-dried flask containing a stir bar
was added DKP 22 (5.9 g, 5.2 mmol, 1.0 equiv), followed by
unequivocally determined by X-ray crystallography:
6

Analytically pure sample of compound 35 was obtained by
ACCEPTED MANUSCRIPT
1
prep HPLC using 50:50 EtOAc:Hex. H NMR (400 MHz,
Danishefsky's dehydrative sulfur migration
O
chloroform-d) δ 7.15 (d, J = 7.3 Hz, 1H), 7.08 (t, J = 7.7 Hz,
H), 6.86 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 6.54
d, J = 8.0 Hz, 1H), 6.41 (d, J = 8.7 Hz, 1H), 6.04 (s, 1H),
O
1
(
4
1
(
N
S
S R
N
N
OH
OTBS
S
S R
triflic acid
Cl
N
.10 (s, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.49 (d, J = 13.9 Hz,
H), 3.42 (d, J = 17.4 Hz, 1H), 3.29 (d, J = 13.9 Hz, 1H), 3.15
O
O
OH
O
1
3
s, 3H), 2.72 (s, 3H), 2.31 (s, 3H); C NMR (101 MHz,
chloroform-d) δ 194.7, 165.0, 164.1, 158.3, 152.2, 148.7,
Cl
OMOM
R = PMB
1
6
3
1
28.2, 126.5, 125.2, 124.3, 121.3, 111.5, 108.5, 103.8, 94.7,
1.1, 55.9, 39.1, 36.2, 32.0, 30.6, 29.0; FTIR (thin film):
368, 2960, 1673, 1613, 1505, 1466, 1429, 1387, 1280, 1239,
6
. S. Liao, L. Du, X. Qin, L. Xu, J. Wang, X. Zhou, Z. Tu, J. Li,
Y. Liu Tetrahedron 2016, 72, 1051.
7. Methods for preparing 23, 24, and 27 are included as
supporting information.
. C. Wang, O. Lee, G. Hsiao, J. Lian, Y. Cheng Anticancer Res.
014, 34, 4013.
-1
099, 959, 869, 751, 630 cm ; -ESI-HRMS m/z: calc’d for
-
-
-
C H N O S [M-H] = 485.1388, found C H N O S [M-
2
4
25
2
7
24 25
2
7
8
2
9
–
H] = 485.1348.
. D. Ermolat’ev, J. Bariwal, H. Steenackers, H.; S. De
Keersmaecker, E. Van der Eycken Angew. Chem. Int. Ed. 2010,
The reaction also produced 29.6 mg (61% yield) of
diastereomer (36) as a yellow foam. An analytically pure
sample of compound 36 was obtained using prep HPLC
4
1
9, 9465.
0. K. Nakamura, K. Ohmori, K. Suzuki Chem. Commun. 2015,
conditions using 50:50 EtOAc:Hex; conditions for single
51, 7012.
1
crystal growth: slow diffusion of Et O into DCM; H NMR
11. M. Cryle, S. Bell, I. Schlichting Biochemistry 2010, 49, 7282.
12. H. Moser, Q. Lu, P. Patten, D. Wang, R. Kasar, S. Kaldor, B.
Patterson, WO2008154642A2, 2008.
13. S. Matlin, P. Sammes, R. Upton J. Chem. Soc., Perkin Trans.
1979, 2481.
4. R. Noyori, M. Aoki, K. Sato Chem. Commun. 2003, 1977.
5. H. Poisel, U. Schmidt Angew. Chem. Int. Ed. 1971, 10, 130.
6. A. Srinivasan, A. Kolar, R. Olsen J. Heterocycl. Chem. 1981,
8, 1545.
7. Our attempts to react a bis-N-Me, bis-Bn protected phenol
substrate with thioacetic acid resulted in an inseparable mixture
of monothioacetate isomers.
2
(
=
1
(
3
4
400 MHz, chloroform-d) δ 7.12 (t, J = 7.9 Hz, 1H), 6.95 (d, J
7.3 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.83 (t, J = 7.4 Hz,
H), 6.75 (d, J = 8.6 Hz, 1H), 6.44 (d, J = 8.8 Hz, 1H), 6.04
s, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.48 (d, J = 13.6 Hz, 1H),
1
1
1
1
1
1
.19 (d, J = 6.7 Hz, 4H), 2.91 (d, J = 16.9 Hz, 1H), 2.75 (s,
1
3
H), 2.35 (s, 4H), 2.23 (d, J = 16.7 Hz, 1H); C NMR (101
MHz, chloroform-d) δ 193.9, 165.2, 163.8, 159.0, 152.4,
1
9
3
1
6
49.0, 128.7, 126.9, 124.1, 123.9, 121.3, 112.0, 109.7, 103.9,
4.0, 61.2, 56.3, 40.4, 35.9, 32.5, 30.5, 28.7; FTIR (thin film):
368, 2980, 1672, 1610, 1505, 1464, 1427, 1387, 1325, 1279,
240, 1098, 1070, 1039, 999, 969, 889, 869, 795, 734, 698,
1
1
8. (a) X. Chen, J. I. Brauman J. Am. Chem. Soc. 2008, 130,
5038. (b) D. Kanamori, A. Furukawa, T. Okamura, H.
-
1
28 cm ; +ESI-HRMS m/z: calc’d for C H N NaO S
2
4
26
2
7
+
[
M+Na] =
Yamamoto, N. Ueyama Org. Biomol. Chem. 2005, 3, 1453.
+
5
09.1358, found C H N NaO S [M+Na] = 509.1358.
24 26 2 7
Acknowledgments
References and notes
The authors thank Prof. Kevin Klausmeyer and Dr. Mina Nahkla
for their assistance in obtaining and analyzing X-ray
crystallographic data. Crystallographic data (excluding structure
factors) for the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication nos. 1882213 CCDC. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-
mail: deposit@ccdc.cam.ac.Uk). Deposited data may be accessed
by the journal and checked as part of the refereeing process. If
data are revised prior to publication, a replacement file should be
sent to CCDC. We gratefully acknowledge financial support
from Baylor University, the Welch Foundation (Chair, AA-006),
the NSF (CHE-1764240), and the Cancer Prevention and
Research Institute of Texas (CPRIT, R1309). K.M.L. is grateful
for an NIH NRSA postdoctoral fellowship (F32GM129969).
1
. M. Zhu, X. Zhang, H. Feng, J. Dai, J. Li, Q. Che, Q. Gu, T.
Zhu, D. Li J. Nat. Prod. 2017, 80, 71.
2
6
1
1
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(a) R. Brown, G. Meehan Aust. J. Chem 1968, 21, 1581. (b) H.
(
Chem. 1980, 45, 1885. (d) J. Herscheid, R. Nivard, M. Tijhuis, H.
Scholten, H. Ottenheijm J. Org. Chem. 1980, 45, 1880. (e) J.
Herscheid, J. Colstee, H. Ottenheijm J. Org. Chem. 1981, 46,
3
346. (f) H. Ottenheijm, J. Herscheid Chem. Rev. 1986, 86, 697.
(g) D. W. Lin, T. Masuda, M. B. Biskup, J. D. Nelson, P. S.
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X. Zhen, J. Han, S. Liu Bioorg. Med. Chem. 2016, 24, 5197.
4
1
. (a) G. F. Miknis, R. M. Williams J. Am. Chem. Soc. 1993,
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5
2
. Z. Wu, L. Williams, S. Danishefsky Angew. Chem., Int. Ed.
000, 39, 3866.
7