of 5
Enantioselective
Nickel-Catalyzed
α
Spirocyclization
of Lactones
Allison
M. Stanko,
Melissa
Ramirez,
Adrian
J. de Almenara,
Scott
C. Virgil,
and Brian
M. Stoltz
*
Cite This:
Org.
Lett.
2024,
26, 6793−6797
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Online
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*
Supporting
Information
ABSTRACT:
Herein
we report
a strategy
for the enantioselective
synthesis
of spirocycles
containing
all-carbon
quaternary
centers
via
nickel-catalyzed
intramolecular
addition
of lactone
enolates
to aryl
nitriles.
The
established
lactone
α
-spirocyclization
efficiently
and
enantioselectively
forges
5-, 6-, and 7-membered
rings,
performing
best
in the synthesis
of 7-membered
rings
(up to 90%
ee). This
discovery
represents
an expansion
of the synthetic
toolkit
for
enantioselective
spirocyclization,
providing
access
to chiral,
pharmaceutically
relevant
spirocyclic
products.
S
pirocyclic
scaffolds
frequently
appear
in molecules
of
interest
to the chemical
and
biological
communities
(Figure
1A).
Spironolactone
(
1
),
aptly
named
after
its
spirocyclic
lactone
core,
is an FDA-approved
drug
for the
treatment
of hypertension
and heart
failure.
1
Spirocycles
also
comprise
the backbones
of chiral
ligands,
including
(
R
)-SDP
(
2
),
which
has been
employed
for enantioselective
ketone
hydrogenation.
2,3
Additionally,
spirocyclic
cores
can be found
in bioactive
natural
products
such
as exiguaquinol
(
3
).
4,5
Despite
the medicinal
and synthetic
utility
of spirocycles,
the
enantioselective
construction
of these
motifs
remains
a
significant
synthetic
challenge,
necessitating
costly
chiral
separations
and limiting
their
potential
applications.
6
Methods
for the asymmetric
synthesis
of spirocycles
bearing
a stereogenic
quaternary
center
as the spiro
atom
are even
less
common,
due
to the added
challenge
of installing
the all-
carbon
quaternary
center
enantioselectively.
7
10
Furthermore,
there
are few existing
methods
for the catalytic
enantioselective
synthesis
of
α
-spirocyclic
lactones.
11
13
In 2016,
our
laboratory
disclosed
a unique
strategy
for the enantioselective
synthesis
of all-carbon
quaternary
centers
via a nickel-catalyzed
C
-acylation
of lactams,
furnishing
β
-keto
lactam
products
(
6
)
in up to 92%
yield
(Figure
1B).
14
Chiral
Mandyphos
ligand
SL-M004
1
was employed
in conjunction
with
Ni(COD)
2
,
imparting
enantioselectivities
as high
as 94%
ee. This
reaction
is thought
to proceed
through
the addition
of a metal
enolate
species
to an aryl nitrile,
giving
rise to
N
-aryl
imine
products
7
.
Subsequent
hydrolysis
of these
species
gives
rise
to the
corresponding
β
-keto
lactams
(
6
).
We
recognized
that
an intramolecular
version
of this
transformation
using
α
-alkylated
substrates,
such
as
8
, would
give rise to spirocycles
bearing
an all-carbon
quaternary
center
(Figure
1C).
Subjecting
8
to the optimal
conditions
for the
previously
established
intermolecular
reaction
gave
spirocycle
9
in 68%
yield,
but in only
5% ee. We suspected
that a base-
promoted
background
reaction
could
be competing
with
the
transition
metal-catalyzed
process
for substrate
8
, explaining
the poor
enantioselectivity.
Indeed,
when
8
was treated
with
a
stoichiometric
amount
of LHMDS
in the absence
of the nickel
catalyst,
spirocycle
9
was formed
in an 83%
yield.
The
facile
background
reaction
observed
for
8
can be rationalized
by the
favorable
kinetics
of 5-membered
ring formation.
15
We surmised
that altering
the sterics
and electronics
of the
enolate
nucleophile
could
perhaps
lower
the rate
of back-
ground
reactivity
and improve
enantioselectivity.
Specifically,
we became
interested
in employing
lactone
nucleophiles,
owing
to their
synthetic
utility
and prevalence
in pharmaceuti-
cally
relevant
small
molecules.
16
Moreover,
on the basis
of
p
K
a
,
17,18
and the weaker
resonance
donation
of O vs N,
19
we
predicted
that
a lactone
enolate
should
be less nucleophilic
than
a lactam
enolate,
thereby
slowing
the rate of background
reaction.
To our delight,
when
α
-substituted
lactone
10a
was
treated
with
LHMDS
and PhBr
in the presence
of Ni(COD)
2
and Mandyphos
ligand
SL-M004
1,
spirocyclic
lactone
11a
was obtained
in 85%
yield
and 62%
ee (Figure
1D).
As suspected,
when
Ni(COD)
2
was
omitted
from
the
reaction,
11a
was observed
in only
6% yield
(Table
1, entry
1),
indicating
that the rate of base-promoted
background
reaction
was
much
slower
for lactone
10a
compared
to more
nucleophilic
lactam
8
. Similarly,
in the absence
of PhBr,
11a
was formed
in only
5% yield
(entry
2), suggesting
that
the
lactone
α
-spirocyclization
was proceeding
through
a mecha-
nistic
framework
similar
to the
previously
described
intermolecular
lactam
acylation.
Indeed,
the corresponding
spirocyclic
N
-aryl
imine
product
may be isolated
prior
to acid-
Received:
May
9, 2024
Revised:
July 3, 2024
Accepted:
July 5, 2024
Published:
August
1,
2024
Letter
pubs.acs.org/OrgLett
© 2024
The Authors.
Published
by
American
Chemical
Society
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Org.
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2024,
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catalyzed
hydrolysis,
if desired
(see
Supporting
Information).
The optimal
reaction
conditions
for spirocyclization
employed
Ni(COD)
2
as the catalyst,
Mandyphos
ligand
SL-M001
1
as
the chiral
ligand,
LHMDS
as the base,
PhBr
as the aryl halide,
and TBME
as the reaction
solvent,
affording
11a
in 90%
yield
and 83%
ee (entry
3). When
ligand
SL-M009
1
was used
in
place
of SL-M001
1,
the reaction
yield
improved
to 97%,
but
11a
was formed
with
lower
enantioselectivity
(69%
ee, entry
4). Interestingly,
11a
was obtained
in 91%
yield
and 57%
ee
when
diphosphine
ligand
(S,S)
-BDPP
was employed
(entry
5).
Extensive
investigation
of additional
chiral
ligands
was
facilitated
via an automated
reaction
setup
(see
Supporting
Information
for
details),
but
failed
to improve
the
enantioselectivity
of the reaction
beyond
83%
ee. When
toluene
was
employed
as the reaction
solvent
in place
of
TBME,
11a
was formed
in 78%
yield
and 78%
ee (entry
6).
The addition
of LiBr
to the reaction
mixture
had no impact
on
reaction
yield
or enantioselectivity
(entry
7). This
contrasts
with
what
was observed
for the previously
described
lactam
acylation,
where
the addition
of LiBr
led to a significant
improvement
in reaction
yield
and ee (Figure
1B).
Finally,
LHMDS
was the optimal
base
in regard
to enantioselectivity,
with
LiO
t
Bu affording
11a
in 91% yield
but only
72% ee (entry
8). We also
probed
the effect
of varying
the sterics
and
electronics
of the aryl halide
component,
but none
of the other
aryl
halides
investigated
led to greater
reaction
yield
or
enantioselectivity
(see
Supporting
Information).
Reaction
temperatures
below
30
°
C were
evaluated
as well,
but these
conditions
furnished
products
in reduced
yields
and
enantioselectivities
(see
Supporting
Information).
Air-stable
nickel
precatalysts
such
as Ni(COD)DQ
were
also investigated
in this chemistry
but failed
to afford
11a
.
20
With
the optimal
conditions
in hand,
we began
investigating
the scope
of the lactone
α
-spirocyclization
with
respect
to 5
and 6-membered
ring formation
(Table
2). We evaluated
the
performance
of the two best
ligands,
SL-M001
1,
and SL-
Figure
1.
Spirocyclic
motifs
in molecules
of synthetic
interest,
disclosure
of a nickel-catalyzed
C
-acylation
of lactams,
and
initial
discovery
of enantioselective
lactone
spirocyclization.
Table
1. Reaction
Investigation
a
Yield
was
determined
by HPLC
relative
to (4,4
)-di-
tert
-
butylbiphenyl.
b
Enantiomeric
excess
was determined
via chiral
SFC,
and absolute
stereochemistry
was assigned
in analogy
to X-ray
crystal
structures
of
13b
and
13c
.
Table
2. Substrate
Scope
of Spirocyclization
for
5 and
6-
Membered
Ring
Formation
a
Yield
determined
via HPLC
relative
to (4,4
)-di-
tert
-butylbiphenyl.
The remainder
of yields
depicted
represent
isolated
yields,
with
those
shown
in blue
(top)
corresponding
to SL-M001
1
as the ligand
and
yields
in green
(bottom)
corresponding
to SL-M009
1.
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Org.
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2024,
26, 6793
6797
6794
M009
1,
for each
substrate.
(see
Supporting
Information
for
detailed
procedures
for substrate
synthesis).
Arene
substitution
para
to the nitrile
with
an electron-donating
methoxy
group
(
10b
)
resulted
in lower
yield
but improved
enantioselectivity
with
both
SL-M001
1
(52%
yield,
84%
ee) and SL-M009
1
(67%
yield,
83%
ee) compared
to electron-neutral
substrate
10a
. This
effect
of substitution
on reaction
yield
may be due to
the lower
electrophilicity
of the aryl nitrile
when
an electron-
donating
group
is introduced.
Conversely,
substitution
para
to
the
nitrile
with
a slightly
electron-withdrawing
fluorine
afforded
11c
with
reduced
levels
of enantioselectivity
for
both
ligands
employed.
Finally,
when
substrate
10d
was
employed,
6-membered
ring formation
occurred
in good
yield
but dramatically
reduced
enantiomeric
excess
for both
SL-
M001
1
(81%
yield,
50%
ee) and SL-M009
1
(90%
yield,
35%
ee), suggesting
that the mechanism
of enantioinduction
might
be different
for 6-membered
ring
formation
versus
5-
membered
ring formation.
We aim to better
understand
this
phenomenon
via computational
investigation
of the reaction
mechanism,
which
is currently
underway.
Next,
we investigated
the possibility
of 7-membered
ring
formation
within
this reaction
manifold
(Table
3). Medium-
sized
rings
are prevalent
in both
pharmaceutical
drugs
and
natural
products,
but their
preparation
is often
complicated
by
entropic
factors
and transannular
interactions.
21
Substrate
12a
was
prepared
from
known
α
-allyl-
γ
-butyrolactone
and
2-
vinylbenzonitrile
in a facile
two
step
sequence
of olefin
metathesis
followed
by hydrogenation
(see
Supporting
Information).
This
synthetic
sequence
provided
access
to
12b
12g
in good
yields.
When
12a
was
subjected
to the
optimized
conditions
for spirocyclization
at a slightly
elevated
temperature
of 40
°
C, we were
pleased
to observe
spirocycle
13a
in 54%
yield
and 78%
ee for SL-M001
1
and 84%
yield
and
86%
ee for SL-M009
1.
This
ligand
performance
is
complementary
to the trend
observed
for 5- and 6-membered
ring formation.
Notably,
this reaction
represents
a fundamen-
tally
new
approach
to the formation
of 7-membered
carbo-
cycles
containing
all-carbon
quaternary
centers.
22
Substitution
of the arene
with
an electron-donating
methoxy
group
para
to
the
aryl
nitrile
(
12b
)
resulted
in improved
reaction
enantioselectivity
but reduced
yield
for both
ligands
employed,
in analogy
to the trend
observed
for 5-membered
ring
formation.
Spirocycle
13c
,
containing
a methyl
group
para
to
the aryl ketone,
was obtained
in good
yield
and enantiose-
lectivity
with
both
SL-M001
1
(57%
yield,
90%
ee) and SL-
M009
1
(62%
yield,
90%
ee). When
substrates
13d
13f
were
surveyed,
a strong
electronic
effect
was noted.
As the
σ
p
value
of the substituent
para
to the nitrile
increased
from
F to
CO
2
Et to
CF
3
, the corresponding
spirocyclic
product
was
obtained
with
lower
enantioselectivity.
23
Curious
to see if
background
reactivity
was
responsible
for this
erosion
of
enantioselectivity,
we treated,
12f
with
a stoichiometric
amount
of LHMDS
in the absence
of the nickel
catalyst.
Spirocycle
13f
was
not
observed
under
these
conditions,
suggesting
that the lower
levels
of enantioselectivity
observed
for electron-poor
substrates
were
not a result
of competitive
background
reaction.
Further
mechanistic
and computational
studies
are required
to uncover
a detailed
explanation
for this
phenomenon.
One
might
hypothesize
that electronic
influence
somehow
lowers
the
ΔΔ
G
between
the two
enantiomeric
products
for the enantiodetermining
step.
Another
potential
explanation
is a change
in enantiodetermining
step altogether
for electron-deficient
substrates
compared
to electron-neutral
or electron-rich
substrates.
We were
pleased
to find that the
reaction
was tolerant
of an aryl chloride
functional
handle,
with
spirocycle
13g
obtained
in modest
yield
and enantioselectivity
for both
ligand
systems
employed.
While
other
unidentified
species
were
formed
in these
reactions,
protodechlorination
byproducts
were
not
observed.
Lastly,
substrate
12h
,
containing
a
Z
-olefin
embedded
in the tether
between
the
lactone
and
aryl
nitrile,
was
evaluated.
Unfortunately,
low
conversion
was observed
with
this substrate,
and spirocycle
13h
was isolated
in low yield
and enantioselectivity
for both
ligand
systems
tested.
We posited
that the rigidity
in the tether
imparted
by the
Z-
olefin
might
affect
the mechanism
of C
C
bond
formation
for this substrate,
leading
to lower
yield
and
enantioselectivity.
Nevertheless,
the olefin
functional
handle
remained
intact
under
the reaction
conditions.
Finally,
we investigated
the impact
of altering
the enolate
nucleophile
on the spirocyclization
(Scheme
1). When
δ
-
valerolactone
substrate
14
was
subjected
to the reaction
conditions,
employing
SL-M009
1
as the ligand
and toluene
as the solvent,
spirocycle
15
was obtained
in a low 27%
yield
with
moderate
enantioselectivity
of 78%
ee. Undesired
indanone
byproduct
16
was also
isolated
in 46%
yield.
We
hypothesized
that
16
was
formed
via ring
opening
and
decarboxylation
of spirocycle
15
. Previous
literature
reports
demonstrate
that
δ
-valerolactone
undergoes
acid-promoted
ring-opening
more
readily
than
γ
-butyrolactone,
explaining
why
15
was
unstable
to the conditions
for
N
-aryl
imine
hydrolysis.
24
This
undesired
reactivity
was not observed
for
γ
-
butyrolactone
substrates.
Lastly,
we were
pleased
to find that
Table
3. Substrate
Scope
for
7-Membered
Ring
Formation
a
a
Isolated
yields,
with
those
shown
in blue (top)
corresponding
to SL-
M001
1
as the ligand
and yields
in green
(bottom)
corresponding
to
SL-M009
1.
Organic
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2024,
26, 6793
6797
6795
α
-alkylated
tetralone
substrate
17
underwent
spirocyclization
in excellent
yield
and moderate
enantioselectivity
(91%
yield,
73%
ee) when
SL-M009
1
was employed
as the ligand.
A
solvent
mixture
of 1:1
toluene/TBME
provided
better
substrate
solubility
in this case.
Our working
mechanistic
hypothesis
is outlined
in Figure
2.
We propose
that
initial
oxidative
addition
of PhBr
to Ni
complex
A
yields
oxidative
addition
complex
B
. Subsequent
ligand
substitution
and C
N
addition
produces
intermediate
C
. Nickel
imine
complex
C
can
then
undergo
reductive
elimination,
affording
an
N
-aryl
imine
product.
Upon
addition
of aqueous
acid and ethyl
acetate
to the reaction
mixture,
the
N
-aryl
imine
was
hydrolyzed
to the corresponding
β
-keto
lactone.
In summary,
we have
discovered
a nickel-catalyzed
enantioselective
lactone
α
-spirocyclization,
affording
5-, 6-,
and 7-membered
spirocycles
in good
yield
and enantioselec-
tivity.
The
reaction
proceeds
through
an
N
-aryl
imine
intermediate,
which
is hydrolyzed
upon
workup
to provide
enantioenriched
β
-keto
lactone
products.
Interestingly,
the
reaction
enantioselectivity
was greatest
for 7-membered
ring
formation
(up
to 90%
ee),
good
for 5-membered
ring
formation
(up
to 84%
ee) and
moderate
for 6-membered
ring
formation
(up
to 50%
ee),
suggesting
mechanistic
differences
in the enantiodetermining
steps
across
different
ring
sizes.
During
our investigation
of substrate
scope,
we
uncovered
complementary
ligand
performance
for many
substrates
by investigating
both
SL-M001
1
and SL-M009
1 as ligands
on nickel.
The
spirocyclization
was tolerant
of
multiple
synthetically
modular
functional
groups,
including
esters,
aryl chlorides,
and alkenes.
Finally,
the spirocyclization
could
be extended
to tetralone
nucleophiles,
representing
a
potential
avenue
to expand
this
reaction
manifold
beyond
lactone
α
-spirocyclization.
Presently,
we are investigating
the
free energy
profile
of the reaction
to elucidate
the elementary
steps
of the catalytic
cycle
and
understand
the origins
of
enantioselectivity.
Ultimately,
we aim
to leverage
computa-
tional
insights
on the reaction
mechanism
to tailor
our catalyst
and achieve
higher
levels
of enantioselectivity
with
a broader
scope
of enolate
nucleophiles.
ASSOCIATED
CONTENT
Data
Availability
Statement
The
data
underlying
this study
are available
in the published
article
and its Supporting
Information.
*
Supporting
Information
The
Supporting
Information
is available
free
of charge
at
https://pubs.acs.org/doi/10.1021/acs.orglett.4c01661.
Experimental
Procedures
and Spectroscopic
Data
(PDF)
X-ray
Crystallography
Data
(PDF)
Accession
Codes
CCDC
2353008
2353010
contain
the supplementary
crys-
tallographic
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
Cambridge
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
States;
orcid.org/0000-0001-9837-1528;
Email:
stoltz@
caltech.edu
Authors
Allison
M. Stanko
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
Melissa
Ramirez
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
Adrian
J. de Almenara
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,
Scheme
1. Spirocyclization
with
Other
Nucleophiles
Figure
2.
Working
mechanistic
hypothesis.
Organic
Letters
pubs.acs.org/OrgLett
Letter
https://doi.org/10.1021/acs.orglett.4c01661
Org.
Lett.
2024,
26, 6793
6797
6796
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/acs.orglett.4c01661
Notes
The authors
declare
no competing
financial
interest.
ACKNOWLEDGMENTS
The
NIH-NIGMS
(R35GM145239),
Heritage
Medical
Research
Investigators
Program,
and Caltech
are thanked
for
the support
of our research
program.
The authors
are grateful
to the Caltech
Presidential
Postdoctoral
Fellowship,
National
Science
Foundation
MPS-Ascend
(2137996
for MR),
and NIH
MOSAIC
K99/R00
(GM152819-02
for MR)
programs
for
financial
support.
Additionally,
we thank
Lucas
Abounader
for
experimental
assistance
and Umicore
for graciously
providing
the olefin
metathesis
catalysts
used
in this investigation.
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pubs.acs.org/OrgLett
Letter
https://doi.org/10.1021/acs.orglett.4c01661
Org.
Lett.
2024,
26, 6793
6797
6797