Total
Synthesis
of Aleutianamine
Hao Yu,
‡
Zachary
P. Sercel,
‡
Samir
P. Rezgui,
Jonathan
Farhi,
Scott
C. Virgil,
and Brian
M. Stoltz
*
Cite This:
J. Am. Chem.
Soc.
2023,
145,
25533−25537
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*
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Supporting
Information
ABSTRACT:
Aleutianamine
is a recently
isolated
pyrroloiminoquinone
natural
product
that
displays
potent
and
selective
biological
activity
toward
human
pancreatic
cancer
cells
with
an
IC
50
of 25
nM
against
PANC-1,
making
it a potential
candidate
for
therapeutic
development.
We
report
a synthetic
approach
to aleutianamine
wherein
the
unique
[3.3.1]
ring
system
and
tertiary
sulfide
of this
alkaloid
were
constructed
via
a novel
palladium-catalyzed
dearomative
thiophene
functionalization.
Other
highlights
of the
synthesis
include
a palladium-catalyzed
decarboxylative
pinacol-type
rearrangement
of an
allylic
carbonate
to install
a ketone
and
a late-stage
oxidative
amination.
This
concise
and
convergent
strategy
will
enable
access
to analogues
of aleutianamine
and
further
investigation
of the
biological
activity
of this
unique
natural
product.
C
ancer-related
illnesses
are
the
second
leading
cause
of
death
in
the
United
States
behind
only
heart
disease.
1
Pancreatic
cancer
is the
third
leading
cause
of cancer
death
and
is
projected
to
be
the
second
deadliest
cancer
by
2040,
exemplified
by
a dismal
12%
five
year
survival
rate
for
patients
with
the
disease.
2,3
These
alarming
statistics
can
be
attributed
to
difficulties
in early
disease
detection,
the
lack
of common
genetic
mutations
associated
with
the
disease,
and
overall
ineffective
treatment
options.
4
Despite
advances
in
new
therapeutics
for
pancreatic
cancer,
5,6
patient
survival
has
only
marginally
increased
in the
past
several
decades.
Historically,
natural
products
have
contributed
significantly
toward
drug
discovery
and
novel
therapeutics,
particularly
in
the
areas
of cancer
and
infectious
disease.
7
Indeed,
several
of
the
state-of-the-art
therapies
for
pancreatic
cancer
are
natural
products
or
natural
product
derivatives.
3
Aleutianamine
(
1
),
isolated
in
2019
by
Hamann
and
co-workers,
is a marine-
derived
alkaloid
that
possesses
potent
and
selective
cytotoxicity
toward
solid
tumor
cell
lines.
8
Most
notably,
it displays
25
nM
IC
50
against
the
human
pancreatic
adenocarcinoma
cell
line
PANC-1.
This
potency
is over
160
times
greater
than
that
of
the
FDA-approved
chemotherapeutic
agent
gemcitabine,
demonstrating
the
therapeutic
potential
of
the
natural
product.
9
Aleutianamine
(
1
)
belongs
to
the
pyrroloiminoquinone
alkaloid
family
of natural
products
defined
by
their
conserved
central
planar,
tricyclic
ring
system.
These
natural
products
have
received
significant
attention
from
the
synthetic
community
due
to
their
complex
molecular
frameworks
and
broad
biological
activites.
10
Structurally,
aleutianamine
(
1
)
possesses
a unique
heptacyclic
ring
system
which
consists
of a
pyrroloiminoquinone
unit,
a bridged
azabicyclo[3.3.1]nonane
ring
system
substituted
with
a congested
tertiary
alkyl
sulfide
and
an
alkenyl
bromide,
and
another
bridging
thioaminal
linkage
(Figure
1A).
The
multibridged
ring
system
of
the
natural
product
bears
three
stereocenters
and
is highly
strained
due
to
extensive
unsaturation.
The
congested
sulfide,
the
potentially
labile
thioaminal
moiety,
and
the
remote
alkenyl
bromide
represent
considerable
synthetic
challenges.
Aleutianamine
(
1
)
is proposed
to arise
biosynthetically
from
either
makaluvamine
F (
2
)
or
discorhabdin
B (
3
)
(Figure
Received:
September
16,
2023
Revised:
October
27,
2023
Accepted:
October
31,
2023
Published:
November
15,
2023
Figure
1.
(A)
Aleutianamine
and
the
proposed
biosynthesis
from
related
alkaloids.
(B)
Retrosynthetic
logic.
(C)
Key
transformation
for
the
proposed
strategy.
Communication
pubs.acs.org/JACS
© 2023
The Authors.
Published
by
American
Chemical
Society
25533
https://doi.org/10.1021/jacs.3c10212
J. Am. Chem.
Soc.
2023,
145,
25533
−
25537
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1A).
8
Recently,
Tokuyama
accomplished
the
first
total
synthesis
of
aleutianamine
(
1
)
by
a biomimetic
approach
wherein
a discorhabdin
B
analog
underwent
a cationic
rearrangement
to
produce
the
ring
system
of
aleutianamine
(
1
),
supporting
the
proposed
biosynthetic
pathway
(see
Supporting
Information
(SI)).
11
We
devised
an
alternative
nonbiomimetic
approach
centered
around
formation
of the
bridging
[3.3.1]
ring
system
followed
by
late-stage
arene
oxidation,
a strategy
that
is unique
in
comparison
to
previous
pyrroloiminoquinone
syntheses
(Figure
1B).
The
dearomative
arylation
of
a thiophene
was
envisioned
as a key
transformation
to
enable
this
strategy,
as
this
reaction
would
construct
the
bridging
[3.3.1]
ring
system
and
congested
tertiary
bridgehead
sulfide
in a single
synthetic
step
(Figure
1C).
We
were
inspired
by
previous
reports
of
dearomative
phenol
cross-couplings,
but
the
analogous
trans-
formation
of thiophenes
has
yet
to be
reported.
12
Retrosynthetically,
oxidation
state
adjustment
and
cleavage
of the
aryl
C
−
N
bond
of aleutianamine
(
1
)
would
lead
back
to
thiolactone
8
(Scheme
1).
This
intermediate
would
arise
from
partially
saturated
thiolactone
9
by
installation
of
vinyl
bromide.
Retrosynthetic
cleavage
of
the
Csp
2
−
Csp
3
bond
of
the
[3.3.1]
ring
system
by
the
proposed
dearomative
arylation
simplifies
the
target
to aryl
bromide
10
,
which
could
be
rapidly
prepared
in
a convergent
fashion
from
tryptamine
11
and
aminothiophene
12
.
Our
studies
commenced
with
the
Fischer
indole
synthesis
of
tryptophol
14
from
known
arylhydrazine
13
13
and
dihydrofur-
an
(Scheme
2A).
14
A
three-step
sequence
involving
a
Mitsunobu
reaction
with
DPPA,
subsequent
N
-tosylation,
and
Staudinger
reduction
yielded
protected
tryptamine
11
.
Finally,
intramolecular
Buchwald
−
Hartwig
amination
provided
tricyclic
aniline
15
.
15
The
synthesis
of
thiophene
coupling
fragment
12
(Scheme
2B)
began
with
aminothiophene
16
,
which
was
prepared
in
one
step
from
1,4-cyclohexanedione
monoethylene
ketal
via
Gewald
aminothiophene
synthesis.
16
Saponification
and
decarboxylation
served
to remove
the
ester
group,
and
the
resulting
amine
was
readily
protected
as
the
trifluoroacetamide.
Subsequent
ketal
cleavage
afforded
the
ketothiophene
coupling
partner
12
.
Coupling
of tricyclic
aniline
15
with
ketothiophene
12
was
achieved
by
employing
indium
hydride
mediated
reductive
amination
conditions
developed
by
Yang
17
(Scheme
3).
Subsequent
bromination
yielded
the
cyclization
precursor
10
.
To
our
delight,
treatment
of bromoaniline
10
with
Pd(dba)
2
and
XPhos
in
the
presence
of
base
led
to
the
desired
Scheme
1. Retrosynthetic
Analysis
Scheme
2. (A) Synthesis
of Tricyclic
Aniline
15; (B)
Synthesis
of Aminothiophene
12
Scheme
3. Synthesis
of Thioimidate
18 via Novel
Thiophene
Dearomatization
Scheme
4. Synthesis
of
N
-Tosyl
des
-Bromoaleutianamine
(23)
and Failed
Late-Stage
Bromination
Attempts
Journal
of the American
Chemical
Society
pubs.acs.org/JACS
Communication
https://doi.org/10.1021/jacs.3c10212
J. Am. Chem.
Soc.
2023,
145,
25533
−
25537
25534
dearomative
cyclization
with
concomitant
cleavage
of
the
trifluoroacetamide
to yield
free
thioimidate
17
.
18
In addition
to
completing
the
carbon
skeleton
of
aleutianamine
(
1
)
and
assembling
the
tertiary
alkyl
sulfide,
this
reaction
constitutes
the
first
dearomative
arylation
of
a thiophene
derivative
to
date.
The
product
of this
coupling
(
17
)
was
then
N
-tosylated
to
provide
thioimidate
18
�
the
N
-tosyl
group
proved
critical
for
further
functionalization,
as
free
thioimidate
17
was
recalcitrant
to
hydrolysis
and
other
electron-withdrawing
groups
were
excessively
labile.
To
circumvent
the
challenging
purification
of free
thioimidate
17
,
the
dearomative
arylation
and
tosylation
steps
were
telescoped
to
provide
an
improved
yield
of tosyl
thioimidate
18
on
multigram
scale.
Subjection
of intermediate
18
to aqueous
alkaline
conditions
led
to
the
hydrolysis
of
the
tosyl
thioimidate,
yielding
thiobutenolide
9
(Scheme
4).
While
a variety
of
standard
conditions
failed
to
promote
vinylogous
desaturation
of
this
intermediate
(
9
),
soft
enolization
with
TBSOTf
afforded
an
intermediate
silyl
ketene
thioacetal
that
was
treated
with
DDQ
to provide
diene
19
,
the
structure
of which
was
confirmed
by
X-ray
crystallography.
Reasoning
that
the
electronics
of diene
19
would
promote
bromination
at the
undesired
C1
position,
we
opted
to delay
the
installation
of the
alkenyl
bromide
until
the
final
stage
of the
synthesis.
Thus,
DIBAL
reduction
of the
thiolactone
smoothly
provided
thiolactol
20
.
Treatment
with
CAN
oxidized
the
arene
to
the
desired
pyrroloiminoquinone
21
,
and
addition
of aqueous
ammonia
effected
amination
and
aerobic
oxidation
to deliver
pyrroloiminoquinone
22
.
19
Finally,
the
addition
of
TFA
led
to
dehydrative
cyclization
to
yield
thioaminal
23
,
which
bears
the
full
ring
system
of
aleutian-
amine
(
1
).
Unfortunately,
direct
bromination
of
N
-tosyl
des
-
bromoaleutianamine
(
23
)
was
unsuccessful
in our
hands;
all
surveyed
bromination
conditions
led
to
decomposition
or
undesired
regioselectivity.
To
circumvent
the
unsuccessful
late-stage
bromination,
we
attempted
to
increase
the
oxidation
state
at C2
on
diene
19
,
which
would
provide
a functional
handle
for
bromination.
However,
the
incorporation
of
a suitable
functional
handle
proved
to be
a significant
challenge.
Installation
of a ketone
or
an
equivalent
thereof
at
the
C2
position
was
attempted
by
allylic
oxidation,
thia-Michael
addition
and
Pummerer
Rearrangement,
and
organosilane
or
organoborane
1,6-
addition
(see
SI).
Additionally,
incorporation
of an
oxidation
handle
into
aminothiophene
coupling
fragment
12
proved
unsuccessful.
Ultimately,
ketone
installation
was
achieved
via
an
unconventional
sequence.
Beginning
with
diene
19
,
γ
,
δ
-
dihydroxylation
with
OsO
4
provided
diol
25
,
which
was
readily
advanced
to carbonate
26
(Scheme
5).
Treatment
with
Pd(0)
and
dppe
led
to a decarboxylative
pinacol-type
rearrangement,
presumably
via
putative
π
-allyl
Pd(II)
intermediate
27
,
which
could
undergo
decarboxylation
to afford
28
,
and
subsequent
β
-
hydride
elimination
and
tautomerization
to afford
the
desired
ketone
29
.
To
the
best
of our
knowledge,
this
represents
the
first
palladium-catalyzed
decarboxylative
pinacol-type
rear-
rangement
of allylic
carbonates.
20
Conversion
to
enol
triflate
30
was
followed
by
Shirakawa
and
Hayashi’s
Ru-catalyzed
triflate
−
halogen
exchange
to provide
desired
alkenyl
bromide
8
.
21
Finally,
in
an
analogous
fashion
to
the
synthesis
of
des
-
bromo
compound
23
,
1,2-reduction
with
DIBAL
followed
by
oxidative
amination
and
cyclization
yielded
penultimate
intermediate
24
,
and
tosyl
group
cleavage
with
NaOMe
afforded
aleutianamine
(
1
)
in a longest
linear
sequence
of 20
steps.
22
This
total
synthesis
represents
a nonbiomimetic
synthetic
approach
to aleutianamine
(
1
).
Key
to the
synthetic
approach
were
the
Pd-catalyzed
intramolecular
dearomative
arylation
of
an
aminothiophene,
ketone
installation
by
the
Pd-catalyzed
pinacol-type
rearrangement
of
a cyclic
carbonate,
and
late-
stage
arene
oxidative
amination.
Efforts
to prepare
analogues
of
aleutianamine
with
related
sequences
and
to
establish
a
structure
−
activity
relationship
against
biologically
relevant
cancer
cell
lines
are
ongoing.
■
ASSOCIATED
CONTENT
*
sı
Supporting
Information
The
Supporting
Information
is available
free
of
charge
at
https://pubs.acs.org/doi/10.1021/jacs.3c10212.
Experimental
procedures,
spectroscopic
data
(
1
H NMR,
13
C NMR,
IR,
HRMS),
and
crystallographic
data
(PDF)
Accession
Codes
CCDC
2293946
contains
the
supplementary
crystallographic
data
for
this
paper.
These
data
can
be
obtained
free
of charge
via
www.ccdc.cam.ac.uk/data_request/cif,
or
by
emailing
data_request@ccdc.cam.ac.uk,
or
by
contacting
The
Cam-
bridge
Crystallographic
Data
Centre,
12
Union
Road,
Cambridge
CB2
1EZ,
UK;
fax:
+44
1223
336033.
■
AUTHOR
INFORMATION
Corresponding
Author
Brian
M. Stoltz
−
The Warren
and Katharine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
Scheme
5. Completion
of the Total
Synthesis
of Aleutianamine
(1)
Journal
of the American
Chemical
Society
pubs.acs.org/JACS
Communication
https://doi.org/10.1021/jacs.3c10212
J. Am. Chem.
Soc.
2023,
145,
25533
−
25537
25535
States;
orcid.org/0000-0001-9837-1528;
Email:
stoltz@
caltech.edu
Authors
Hao Yu
−
The Warren
and Katharine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of
Chemistry
and Chemical
Engineering,
California
Institute
of
Technology,
Pasadena,
California
91125,
United
States
Zachary
P. Sercel
−
The Warren
and Katharine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States
Samir
P. Rezgui
−
The Warren
and Katharine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States
Jonathan
Farhi
−
The Warren
and Katharine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States
Scott
C. Virgil
−
The Warren
and Katharine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States
Complete
contact
information
is available
at:
https://pubs.acs.org/10.1021/jacs.3c10212
Author
Contributions
‡
H.Y.
and
Z.P.S.
contributed
equally
Notes
The
authors
declare
no
competing
financial
interest.
■
ACKNOWLEDGMENTS
The
authors
gratefully
acknowledge
Caltech,
the
NSF
(CHE-
2247315),
and
the
Heritage
Medical
Research
Investigators
Program
for
financial
support.
Z.P.S.
and
S.P.R.
thank
the
NSF
GRFP
for
predoctoral
fellowships.
Dr.
Mike
Takase
(Caltech)
and
Dr.
Mona
Shahgholi
(Caltech)
are
thanked
for
assistance
with
X-ray
crystallography
and
mass
spectrometry,
respectively.
Dr.
David
VanderVelde
(Caltech)
is acknowledged
for
NMR
instrumentation.
■
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