Total
Synthesis
of Hypersampsone
M
Adrian
E. Samkian,
Scott
C. Virgil,
*
and Brian
M. Stoltz
*
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ABSTRACT:
We report
the first total synthesis
of hypersampsone
M, an archetypal
member
of the homoadamantane
polycyclic
polyprenylated
acylphloroglucinols
(PPAPs).
Commencing
from cyclohexenone,
a key cyclopentene
annulation
followed
by ring-
expansion
results
in an elusive
hydrazulene
that undergoes
a series of unexpected
late-stage
transformations,
ultimately
enabling
completion
of the synthesis.
The route detailed
herein
represents
a potentially
general
strategy
for the synthesis
of related
homoadamantane
PPAPs.
S
ince their
discovery,
the polycyclic
polyprenylated
acylphloroglucinols
(PPAPs)
have provided
scientists
a
continuous
reservoir
of diverse
natural
products
with a broad
spectrum
of bioactivities
and structural
architectures.
1
A large
part of why the PPAP
class of compounds
has attracted
continued
interest
from synthetic
chemists
is that a viable
structure
−
activity
relationship
(SAR)
has not yet been
established
for them,
and in many
cases,
small structural
changes
lead to unexpected
“turn on” or “turn off” effects
on
biological
activity.
2
With over 400 isolated
compounds
as of
2018, it becomes
useful to further
subdivide
the PPAP class of
compounds
into the bicylic
polyprenylated
acylphloroglucinols
(BPAPs),
the caged
adamantane
and homoadamantane
PPAPs,
and other spirocyclic
or otherwise
rearranged
PPAPs
(Figure
1, top).
1e
This interest
has led dozens
of researchers
to develop
synthetic
approaches
to PPAPs,
with many having
completed
sophisticated
total syntheses.
The bicyclo[3.3.1]nonane
subclass
(BPAPs)
in particular
has enjoyed
significant
attention
in the realm
of natural
product
synthesis,
reflecting
their
overall
prevalence
within
the PPAP
family,
well-established
structural
diversity,
and medicinal
potential.
3
Despite
these
extensive
efforts,
to date there exist only three syntheses
of
adamantane
PPAP
natural
products.
4
Moreover,
there are no
homoadamantane
PPAP
syntheses,
which
is surprising
in
relation
to the subclasses’
substantial
scope
of at least 70
members.
1e,5
We identified
hypersampsone
M (
1
), isolated
from
Hyper-
icum sampsonii
in 2014, to be a prototypical
representative
of
this subclass,
making
it an excellent
target
for our initial
investigations
into this family
of PPAPs.
6
Many
homoada-
mantane
PPAPs
have been known
for decades
7
and many
more have provided
glimpses
into the promising
bioactivity
of
this class, with several
being implicated
to have antitumor,
7c
anti-inflammatory/immunosuppressive,
5i,8
hepatoprotective,
5c
and antiadipogenesis
9
properties.
Like other homoadamantane
PPAPs,
the phloroglucinol
moiety
in hypersampsone
M (
1
) is
clearly
conserved
(Figure
1, highlighted
in blue),
yet the
unsymmetrical
homoadamantane
core and fused cyclopentane
make it difficult
to utilize an alkylative
dearomatization
strategy
such as was cleverly
applied
to an adamantane
PPAP by Porco
and co-workers.
4b
We instead
devised
a retrosynthetic
strategy
that centers
on
the C4-cycloheptanone
ring (Scheme
1A, highlighted
in blue),
Received:
May 22, 2024
Revised:
June 23, 2024
Accepted:
June 24,
2024
Figure 1.
Hypersampsone
M and representative
PPAP
classes
with
examples
of related
homoadamantane
PPAPs.
Communication
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© XXXX
The Authors.
Published
by
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A
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electing
to employ
a late stage Claisen
condensation
and
bridgehead
benzoylation
on C1 from tricycle
3
. Utilizing
the
C4 ketone
as a handle,
prenylation
and cyclization
would
allow
access
to tricycle
3
from simplified
hydrazulene
4
, which could
finally
be traced
back to cycloheptenone
5
through
a key
cyclopentene
annulation.
We began
by targeting
cycloheptenone
7
(Scheme
1B).
Acylation
of known
ketone
6
10
with NaH and dimethyl
carbonate
provides
access
to the required
β
-ketoester.
Cleavage
of the acetal,
followed
by a Knoevenagel
condensation,
delivers
cycloheptenone
7
. While
several
cyclopentene
annulation
reactions
were considered,
the demanding
gem
-dimethyl
moiety
excluded
most obvious
options.
11
After significant
optimization,
our observations
indicated
that 1,1-dimethylpro-
pargylzinc
bromide
8
undergoes
facile 1,4-addition
to enone
7
,
providing
zinc enolate
9
as a single
isomer.
12
Subsequent
heating
of zinc enolate
9
following
conjugate
addition
was
sufficient
to effect
cyclization,
affording
the hydrazulene
product
(
10
) in a single
step.
13
To our surprise,
14
NOESY
studies
indicated
that the undesired
syn
-isomer
(i.e., C20 and
C7) was exclusively
isolated
as a 4:1 mixture
of diastereomers
at C3 (i.e.,
cis
and
trans
ring junctures).
Attempts
to control
the addition
temperature
or alter solvents
did not invert
the
stereochemical
outcome,
and we propose
that the bulky nature
of the nucleophile
was likely responsible
for the undesired
initial
syn
conjugate
addition
stereochemistry,
perhaps
through
torsional
steering
effects.
In response,
we rationalized
that a cyclohexenone
substrate
would
provide
a more predictable
stereochemical
outcome
in
the cyclopentene
annulation
and a successive
ring expansion
would
intercept
the original
retrosynthesis
at hydrazulene
4
.
We began
by targeting
the annulation
substrate
(
13
, Scheme
2). We were able to access
ketone
12
from cyclohexenone
(
11
)
in a single step using a radical
HAT coupling.
15
Acylation
and
selenoxide
elimination
provided
activated
enone
13
in 73%
yield over 2 steps.
Proceeding
to the key cyclopentene
annulation,
we were surprised
to still observe
the presence
of
the
syn
addition
product
at C7. Fortunately,
further
lowering
the temperature
to
−
40
°
C during
the propargylzinc
(
8
)
addition
resulted
in the formation
of the desired
anti
-isomer
14
(6.3:1)
with exclusively
cis
ring fusion.
Following
hydro-
genation
of the cyclopentene,
we shifted
our focus to ring-
expansion
of the hydroindene
system
to access
the required
hydrazulene
(
4
). Significant
effort was made on this front, and
it was found
necessary
to use a designer
diazoacetate
(
15
).
16
Deprotonation
of
15
with LDA enabled
nucleophilic
addition
to the neopentylic
ketone
on hydroindene
14
, furnishing
alcohol
16
.
17
Catalytic
Rh
2
(TFA)
4
was found
to be uniquely
effective
in initiating
the ring-expansion
rearrangement,
resulting
in
β
-ketoester
17
as a mixture
of three inseparable
isomers,
which
were putatively
assigned
to the enol and two
ketone
diastereomers.
Commercially
available
ethyl diazoace-
tate and
tert
-butyl
diazoacetate
undergo
similar
rearrangements
but ultimately
proved
to be synthetic
impasses,
as selective
decarboxylation
of the newly
installed
esters
could
not be
accomplished
in the presence
of the neighboring,
preexistent
methyl
ester. The trimethylsilylethyl
ester thus proved
vital, as
following
prenylation
to form bicycle
18
, treatment
with TBAF
resulted
in the selective
decarboxylation
of the trimethylsily-
lethyl ester. Concomitant
TBS cleavage
produces
the desired
primary
alcohol
as a single
diastereomer,
which
upon DMP
oxidation
results
in aldehyde
19
in excellent
yield (79%,
2
steps).
17
With a scalable
route to aldehyde
19
established,
we were
optimistic
about the aldol reaction
proposed
to provide
tricycle
20
. Unfortunately,
classic
aldol conditions
lead to decom-
position
or, in most cases, return
the starting
aldehyde
without
any trace of desired
tricycle
20
. In fact, TsOH
·
H
2
O in CH
2
Cl
2
was the only set of conditions
evaluated
that resulted
in a
product
of interest,
forging
caged
lactone
21
slowly
in
moderate
yield. We hypothesized
that the aldol reaction
to
form tricycle
20
is likely
highly
reversible
under
most
conditions,
and perhaps
even favors
aldehyde
19
due to strain
induced
upon cyclization.
Further
lactonization
of the aldol
product
(
20
) provides
a powerful
thermodynamic
driving
force
for cyclization
and highlights
the opportune
placement
of the
methyl
ester.
Formation
of the lactone
(
21
) seemed
so favorable
that
attempts
to reopen
or saponify
it (Table
1,
21
→
24
) with any
number
of acidic or basic conditions
resulted
in no reaction
or
decomposition
(entries
1
−
4).
We concluded
that the lactone
would
need to be opened
in an irreversible
fashion
and
hypothesized
that an amide
would
be suitably
stable.
While
this approach
seemed
promising,
it introduced
the eventual
synthetic
challenge
of needing
to activate
an extremely
hindered
amide
in order
to progress
with our plans.
For
example,
opening
the lactone
with AlMe
3
/
N
,
O
-dimethylhy-
droxylamine
to afford the Weinreb
amide
proceeded
smoothly
Scheme
1. (A) Retrosynthetic
Strategy
and (B)
Cyclopentene
Annulation
of Enone 7
Journal
of the
American
Chemical
Society
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Communication
https://doi.org/10.1021/jacs.4c07007
J. Am. Chem.
Soc.
XXXX,
XXX,
XXX
−
XXX
B
(entry
5), but following
oxidation,
we were unable
to further
transform
amide
25
in a useful
fashion
(
25
→
2
). Some
amides,
such as the unsubstituted
ammonia-derived
amide,
were also formed
successfully
(entry
6), but subsequent
oxidation
resulted
in decomposition.
Many
disubstituted
amides
simply
failed
to form,
as was the case with
dimethylamide
(entry
7). Fortunately,
we were able to install
aniline
(entry
8) and oxidize
the revealed
alcohol,
providing
anilide
22
(Scheme
2) in good yield (70%,
2 steps).
We next aimed
to methanolyze
the anilide
(
22
) to the
methyl
ester, targeting
homoadamantane
2
via Dieckmann
cyclization.
The direct
installation
of a methyl
ester with
MeOH/H
+
was not successful;
however,
we believed
that
treatment
with Me
3
OBF
4
(methyl-Meerwein’s
salt) would
form the methyl
imidate,
which
could then be hydrolyzed
to
the methyl
ester.
18
Excitingly,
we observed
direct cyclization
to
the homoadamantane
cage instead,
isolating
imine
23
.
Mechanistically,
we propose
that methyl
imidate
formation
likely occurs
first. We then envision
that one of two scenarios
is
likely for bond construction.
In one case, enol addition
would
occur directly
to the imidate
to form a particularly
sterically
hindered
tetrahedral
intermediate.
Alternatively,
elimination
of
MeOH
or Me
2
O could form a nitrilium
that can cyclize
to the
observed
imine
(
23
).
Following
optimization,
2,6-di-
tert
-
butylpyridine
(DTBP)
was added
to suppress
decomposition
of the prenyl
group,
and an acidic
workup
was performed
to
hydrolyze
the imine product
and provide
access
to trione
2
in a
single step.
To install the final benzoyl
group,
we attempted
variations
of
the Danishefsky
protocol
involving
an intermediate
bridgehead
iodide,
3b
as well as Shair’s
direct
bridgehead
acylation
protocol.
3p
Deuterium
incorporation
experiments
with
LiTMP
showed
that no deprotonation
occurs
at
−
78
°
C,
whereas
complete
decomposition
is observed
at 0
°
C. A screen
of several
intermediary
temperatures
established
that 40%
deuterium
incorporation
could be achieved
at
−
35
°
C. It has
been shown
that deprotonation
of bridgehead
homoadaman-
tane protons
is challenging
compared
to those
on
bicyclo[3.3.1]nonane
systems.
19
Interestingly,
the challenge
associated
with bridgehead
acylations
in the sister
BPAP
systems
seems to stem from lack of anion reactivity,
rather than
generation
of the stabilized
anion itself.
3h
This was found to be
in stark contrast
with homoadamantane
2
, as despite
the
difficulty
in generating
the required
anion,
treatment
with BzCl
directly
affords
hypersampsone
M (
1
) in moderate
yield with
an equivalent
amount
of isolated
starting
trione
(
2
).
To conclude,
we have completed
the synthesis
of hyper-
sampsone
M (
1
) in 15 steps starting
from cyclohexenone,
thus
achieving
the first total synthesis
of a homoadamantane
PPAP
natural
product.
Additionally,
the enabling
cyclopentene
Scheme
2. Total Synthesis
of Hypersampsone
M
Journal
of the
American
Chemical
Society
pubs.acs.org/JACS
Communication
https://doi.org/10.1021/jacs.4c07007
J. Am. Chem.
Soc.
XXXX,
XXX,
XXX
−
XXX
C
annulation
provides
an orthogonal
method
for installing
highly
substituted
five-membered
rings using simple
reagents
and
techniques.
This strategy
is likely of sufficient
generality
to
allow
access
to other
homoadamantane
PPAPs.
Biological
studies
and further
development
of this route to synthesize
additional
PPAPs
are in progress.
■
ASSOCIATED
CONTENT
*
sı
Supporting
Information
The Supporting
Information
is available
free of charge
at
https://pubs.acs.org/doi/10.1021/jacs.4c07007.
Experimental
procedures,
spectroscopic
data (
1
H NMR,
13
C NMR,
IR, and HRMS)
(PDF)
■
AUTHOR
INFORMATION
Corresponding
Authors
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
States;
orcid.org/0000-0001-9837-1528;
Email:
stoltz@
caltech.edu
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
;
Email:
svirgil@caltech.edu
Author
Adrian
E. Samkian
−
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.4c07007
Notes
The authors
declare
no competing
financial
interest.
■
ACKNOWLEDGMENTS
The NIH-NIGMS
(R35GM145239),
Heritage
Medical
Research
Investigators
Program,
and Caltech,
are thanked
for
their support
of our research
program.
Preparative
HPLC
was
performed
with instrumentation
at the Caltech
Center
for
Catalysis
and Chemical
Synthesis,
a facility
of the Beckman
Institute
at Caltech.
We thank
Dr. David
VanderVelde
(Caltech)
for NMR
expertise
and Dr. Mona
Shagholi
(Caltech)
for mass spectrometry
assistance.
We graciously
thank
Kasam
Poonswat,
Hanh
T. Nguyen,
and Kevin
J.
Gonzalez
for many helpful
discussions.
A.E.S.
would
like to
thank Prof. Robert
H. Grubbs
for his support,
and the NSF
GRFP
for funding.
■
ABBREVIATIONS
PPAP,
polycyclic
polyprenylated
acylphloroglucinol;
BPAP,
bicylic
polyprenylated
acylphloroglucinol;
DMP,
Dess-Martin
periodinane.
■
REFERENCES
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±
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by Regioselective
Lithiation
of
Table 1. Functionalization
of Lactone
21: Selected
Experiments
entry
conditions
R
results
a
1
NaOMe/MeOH
−
OMe
decomp
2
Bu
3
SnOMe
−
OMe
0%
3
Al(O
i
-Pr)
3
/MeOH
−
OMe
0%
4
KOH/H
2
O
−
OH
decomp
5
NHMe(OMe)
·
HCl/AlMe
3
−
NMe(OMe)
85%
6
NH
4
Cl/AlMe
3
−
NH
2
73%
7
NHMe
2
·
HCl/AlMe
3
−
NMe
2
0%
8
PhNH
2
·
HCl/AlMe
3
−
NHPh
84%
b
a
Determined
by
1
H NMR analysis.
b
Isolated
yield.
Journal
of the
American
Chemical
Society
pubs.acs.org/JACS
Communication
https://doi.org/10.1021/jacs.4c07007
J. Am. Chem.
Soc.
XXXX,
XXX,
XXX
−
XXX
D