of 10
Divergent
Catalysis:
Catalytic
Asymmetric
[4+2] Cycloaddition
of
Palladium
Enolates
Kaylin
N. Flesch,
Alexander
Q. Cusumano,
Peng-Jui
Chen,
Christian
Santiago
Strong,
Stephen
R. Sardini,
Yun E. Du, Michael
D. Bartberger,
William
A. Goddard,
III,
*
and Brian
M. Stoltz
*
Cite This:
J. Am. Chem.
Soc.
2023,
145,
11301−11310
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*
Supporting
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ABSTRACT:
An asymmetric
decarboxylative
[4+2]
cycloaddition
from a catalytically
generated
chiral Pd enolate
was developed,
forging
four contiguous
stereocenters
in a single transformation.
This was achieved
through
a strategy
termed
divergent
catalysis,
wherein
departure
from a known
catalytic
cycle enables
novel reactivity
of a targeted
intermediate
prior to re-entry
into the original
cycle. Mechanistic
studies
including
quantum
mechanics
calculations,
Eyring
analysis,
and KIE studies
offer insight
into the reaction
mechanism.
1. INTRODUCTION
Enantioselective
construction
of all-carbon
quaternary
stereo-
genic centers
represents
a central
and ongoing
challenge
in
synthetic
organic
chemistry.
1
The asymmetric
allylic alkylation
of enolate
nucleophiles
serves
as a powerful
strategy
for
accessing
such motifs.
2
A unique
aspect
of the Pd-catalyzed
allylic
alkylation
methods
developed
by our group is the inner-sphere
reductive
elimination
from a chiral O-bound
Pd enolate
intermediate
(
2
), yielding
enantioenriched
ketones
(
3
) (Figure
1A).
3,4
This
intermediate
is generated
catalytically
from achiral
or racemic
enolate
precursors,
such as allyl enol carbonates
5
and
β
-
ketoesters
6
(
1
). The Pd enolate
is accessed
in the absence
of a
base, under
neutral
conditions,
and in a regiospecific
fashion.
Conversely,
canonical
conditions
for enolate
formation
are
plagued
by regioselectivity
challenges
and typically
require
the
use of a strong
base or Lewis
acid. Given
the inherent
advantages
of Pd enolates,
we sought
to exploit
their reactivity
beyond
simple
allylic alkylations
in more general
asymmetric
transformations.
Highlighting
the utility
of this concept,
our lab has
demonstrated
the enantioselective
protonation
of Pd enolates
as a valuable
strategy
to access
ketones
with tertiary
stereocenters
(
4
).
7
Building
upon
this success,
we subse-
quently
developed
methods
to construct
quaternary
centers
via
enantioselective
conjugate
additions
8
(
5
) and intramolecular
aldol reactions
(
6
).
9
Taken
together,
these advances
under-
score the feasibility
of employing
Pd enolates
as stereogenic
nucleophiles.
In a unique
example
of enolate
reactivity,
Fukumoto
and co-
workers
reported
a formal
[4+2]
reaction
from in situ-
generated
conjugated
lithium
enolate
8
, forging
tricyclic
adduct
9
in a racemic
fashion
(Figure
1B).
10
We envisioned
that an
analogous
asymmetric
transformation
would
be tractable
from
a chiral,
conjugated
Pd enolate
derived
from the decarbox-
ylation
of unsaturated
β
-ketoester
10a
using an asymmetric
ligand
on Pd (Figure
1C).
To realize
this transformation,
we sought
to develop
a
conceptual
framework
based on our mechanistic
understanding
to expand
the general
utility
of the Pd enolate.
As such, we
employed
a strategy
of divergent
catalysis
(Figure
1D), where
deviation
occurs
at the common
Pd enolate
(i.e.,
C
, Figure
1D,
cf. Scheme
1, vide infra),
allowing
for desired
alternative
reactivity
in the diverged
cycle. Subsequent
re-entry
into the
original
catalytic
cycle
turns
over the catalyst,
allowing
regeneration
of the Pd enolate.
Applying
this strategy
of divergent
catalysis,
we developed
a
catalytic
decarboxylative
asymmetric
intramolecular
[4+2]
Received:
February
26, 2023
Published:
May 15,
2023
Article
pubs.acs.org/JACS
© 2023
American
Chemical
Society
11301
https://doi.org/10.1021/jacs.3c02104
J. Am. Chem.
Soc.
2023,
145,
11301
11310
cycloaddition
from conjugated
Pd enolates.
Mechanistic
studies
including
quantum
mechanics
calculations,
Eyring
analysis,
and KIE studies
offer insights
into the reaction
mechanism.
This transformation
enables
access
to tricyclic
scaffolds
bearing
at least four contiguous
stereocenters,
at least
one of which
is quaternary.
2. RESULTS
AND DISCUSSION
2.1. Reaction
Design
and Optimization.
Employing
unsaturated
β
-ketoester
12
as a precursor
for conjugated
Pd
enolate
13
, we hypothesized
that the precedented
allylic
alkylation
forming
14
could
be interrupted
by a [4+2]
cycloaddition
to generate
15
(Figure
2A). Alkylation
of the
transposed
enolate
(
15
) would
then turn over the catalyst
and
forge tricyclic
product
16
.
Unfortunately,
direct
allylic
alkylation
of enolate
13
kinetically
outcompetes
the desired
divergent
reactivity.
Treatment
of
β
-ketoester
12
under
our standard
conditions
produces
ketone
14
in 98% yield and 84% ee (Figure
2B). This
prompted
us to redesign
our exit strategy
(Figure
1D).
Increasing
the rate of the cycloaddition
through
modification
of the diene or dienophile
could circumvent
the formation
of
premature
allylic
alkylation
product
14
but would
limit the
generality
of this transformation.
Therefore,
we sought
to
impede
alkylation
through
modification
of the allyl moiety.
Computational
investigation
of a model
system
(
TS1
)
suggested
that introducing
terminal
substitution
on the allyl
group raises the barrier
to reductive
elimination,
decreasing
the
rate of allylic alkylation
(Figure
2B, see SI for computational
details).
11
For example,
phenyl
substitution
(entry
2, Figure
2B) slows the rate of inner-sphere
reductive
elimination
by
roughly
three
orders
of magnitude.
Inspired
by these
computational
results,
we explored
the efficacy
of the cinnamyl
ester substrate
17
in the transformation.
In line with our
hypothesis,
the desired
tricyclic
core was observed
(
18
), albeit
as a complex
mixture
of isomers
hampering
the synthetic
utility.
To this end, we sought
to develop
an alternative
strategy
for catalyst
turnover
that could potentially
simplify
the
product
outcomes.
Building
upon previous
findings
from our group,
we sought
to employ
stoichiometric
acidic additives
for catalyst
turnover.
The exogenous
acid serves the dual purpose
of protonating
the
final enolate
(analogous
to
15
) and turning
over the catalyst
by
trapping
the cinnamyl
group.
Addition
of 3,5-dimethylphenol
9
exclusively
yielded
undesired
protonation
product
19a
along
with aryl ether
20
(Figure
3A). To our delight,
replacing
the
phenol
additive
with 4-methylaniline
afforded
the desired
endo
[4+2] cycloadduct
(
11a
) as a single diastereomer
in 83% yield
and 88% ee.
Seeking
to improve
the reaction
yield, the competency
of
β
-
ketoester
10a
, derived
from the commodity
chemical
prenyl
alcohol,
was explored.
According
to our computations,
a
substrate
containing
a di-substituted
allyl fragment
would
be
similarly
effective
in hindering
premature
allylic alkylation
by
Figure
1.
(A) Examples
of chiral Pd enolate
reactivity.
(B) Lithium
base-promoted
intramolecular
formal
[4+2]
cycloaddition.
(C)
Proposed
asymmetric
intramolecular
[4+2]
reaction.
(D) Divergent
catalytic
cycle.
Figure
2.
(A) General
reactivity
paradigm
from Pd enolate
13
. (B)
Computed
substituent
effects
on the rate of C
C bond formation
and
successful
application.
See SI for computational
details
and discussion
of other isomeric
transition
states.
Yield determined
by
1
H NMR with
respect
to 1,3,5-trimethoxybenzene
as internal
standard.
Enantiomeric
excess
determined
by chiral SFC.
Journal
of the American
Chemical
Society
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Article
https://doi.org/10.1021/jacs.3c02104
J. Am. Chem.
Soc.
2023,
145,
11301
11310
11302
increasing
the barrier
to reductive
elimination
(Figure
2B,
entry 3). Perplexingly,
while the desired
tricyclic
product
was
generated
in 73% isolated
yield and 88% ee, no alkylated
4-
methylaniline
(analogous
to
21
) was observed
as a byproduct
(entry
8, Table 1).
A control
reaction
excluding
4-methylaniline
was carried
out,
and surprisingly,
desired
product
11a
was formed
in 83% yield
and 87% ee (Figure
3B). This suggests
that an alternative
catalyst
turnover
mechanism
is operative.
Further
NMR
experiments
revealed
the stoichiometric
evolution
of isoprene
(
22
) accompanying
the formation
of product
11a
. Intrigued
by
this unexpected
finding
and clean reaction
profile,
we pursued
the optimization
of additive-free
reaction
conditions.
The reaction
proceeds
in THF and benzene
albeit in slightly
diminished
yield and enantioselectivity
(entries
2
3, Table 1).
Employing
1,4-dioxane
as the solvent,
protonation
product
19a
was obtained
as the major product
in 63% yield and 49% ee,
while cycloadduct
11a
was observed
in only 12% yield (entry
4, Table
1). Lowering
the temperature
to 40
°
C slightly
improved
the ee to 89% at the cost of decreased
conversion
(entry
5, Table 1). Modification
of the electronic
properties
of
the PHOX
ligand
deleteriously
impacted
the product
distribution
(entries
6
7, Table
1). Phenol
and aniline
additives
do not improve
the reaction
(entries
8
10,
Table
1). Ultimately,
optimized
reaction
conditions
were determined
to be additive-free
with
(S)
-
t
-BuPHOX
in toluene
at 60
°
C.
The reaction
affords
11a
, a bridged
bicycle
with a pendant
fused
ring, in 83% isolated
yield
and 87% ee. The
transformation
allows
for the simultaneous
construction
of
four contiguous
stereocenters,
including
one all-carbon
quaternary
center.
Gratifyingly,
the reaction
can be performed
with reduced
catalyst
loading
(0.625
mol %) on a 1.0 mmol
scale to afford
11a
in 59% yield and 89% ee. The ability
to
efficiently
construct
these complex
building
blocks
on scale
highlights
the synthetic
utility of this transformation.
2.2. Proposed
Mechanism.
We sought
to capitalize
on
these initial
exciting
results
by constructing
a mechanistic
framework
to inform
rational
design.
Based
on our lab’s prior
investigations
of Pd-catalyzed
decarboxylative
asymmetric
allylic alkylation
reactions,
we propose
that oxidative
addition
of Pd
0
to
β
-ketoester
10a
proceeds
through
complex
23
to
afford
the
η
1
-allyl carboxylate
resting
state
24
(Scheme
1).
12
Rate-limiting
decarboxylation
ensues,
affording
O-bound
Pd
enolate
25
.
3,12
This chiral conjugated
enolate
then serves as the
diene in a [4+2] cycloaddition
with the pendant
dienophile
to
form tricyclic
enolate
26
. Subsequent
proton
transfer
would
generate
product
11a
. Concomitant
isoprene
generation,
followed
by ligand
exchange,
allows
for re-entry
into the
original
catalytic
cycle at
23
. We posit that the formation
of
undesired
ketone
19a
arises from an off-cycle
pathway,
where
catalyst
turnover
occurs
prior to cycloaddition
via premature
proton
transfer
to
25
.
2.3. Substrate
Scope.
With
a working
mechanistic
hypothesis
in hand,
we sought
to draw further
mechanistic
insights
from substrate
design
while simultaneously
exploring
the limits of the reaction.
Considering
the inverse
relationship
between
diene ring size
and Diels
Alder
reaction
rate,
13
we explored
whether
this
trend impacts
the generality
of our transformation.
However,
with cyclopentyl
diene derived
from enone
10c
, a decrease
in
yield and ee, relative
to a six-membered
parent
substrate
10a
,
was noted
(Table
2). In comparison
to smaller
ring sizes,
seven-membered
cyclic
dienes
require
increased
distortion
energy
to reach the desired
transition
state.
13
Despite
this, a
seven-membered
ring substrate
10d
leads to a high yield and
improved
ee. Thus, this transformation
represents
a powerful
method
to synthesize
various
challenging
bicyclic
cores.
The dienophile
tether length
was subsequently
modulated
to
test its influence
on product
distribution.
The ethylene
tethered
substrate
10e
yields solely the premature
protonation
product
19e
, likely due to insurmountable
developing
ring
strain in the cycloaddition
transition
state. In contrast
to the
propylene
tethered
substrate
10a
, the butylene-tethered
Figure
3.
(A) Sacrificial
additives
to enable
catalyst
turnover.
a
Equivalents
include
a mixture
of branched
and linear constitutional
isomers,
as well as double
alkylation
of aniline.
(B) Additive-free
reaction
with prenyl
ester
10a
.
b
Isoprene
observed
in 0.94:1
ratio with
11a
by
1
H NMR (J Young
tube, toluene-
d
8
).
Table
1. Optimization
of [4+2]
Reaction
Conditions
a
,
b
a
Conditions:
0.02 mmol
10a
, 2.5 mol % Pd
2
(dba)
3
, 6.5 mol % ligand,
in 1.0 mL of solvent
(0.02 M).
b
Yields
determined
by
1
H NMR with
respect
to 1,3,5-trimethoxybenzene
as internal
standard.
Isolated
yields on a 0.2 mmol scale in parentheses.
Journal
of the American
Chemical
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Article
https://doi.org/10.1021/jacs.3c02104
J. Am. Chem.
Soc.
2023,
145,
11301
11310
11303
substrate
10f
leads to a near equal distribution
of cycloadduct
11f
(42%
yield)
and prematurely
protonation
product
19f
(45%
yield).
Following
this trend,
the pentylene-tethered
substrate
10g
leads
only to protonation
product
19g
.
Rationalizing
this phenomenon,
we propose
that lengthening
the tether
increases
conformational
flexibility
and imposes
a
greater
entropic
penalty
to the highly
organized
[4+2]
transition
state.
In contrast,
increased
tether
length
is
inconsequential
to the protonation
process,
which
does not
involve
the dienophile.
Eyring
analysis
of product
distributions
from reactions
of
10a
and
10f
further
supports
the hypothesis
of an entropic
preference
for the formation
of
19a/f
over
11a/f
(Figure
4).
With
10a
, cycloaddition
(
11a
) is enthalpically
favored
(
ΔΔ
H
= 7 kcal/mol)
but entropically
disfavored
(
ΔΔ
S
= 14 eu) over
protonation
(
19a
).
As anticipated,
increasing
the tether length
to four methylene
units (
10f
) further
increases
the relative
entropic
penalty
for cycloaddition
(
ΔΔ
S
= 20 eu), while the
differential
enthalpy
of activation
remains
similar
(
ΔΔ
H
= 7
kcal/mol).
Hence,
entropy
differences
associated
with tether
length
lead to the formation
of differential
amounts
of
undesired
ketones
19a
and
19f
.
We then surveyed
the scope of functional
groups
that are
tolerated
in this reaction
(Table
2). The cycloaddition
does
not proceed
in the absence
of a
π
-acceptor
(
10h
),
and
carboxylic
acid
10i
exclusively
affords
undesired
ketone
19i
. To
our delight,
a variety
of functional
groups
are compatible,
including
ethyl ester
10b
, phenyl
ketone
10j
, phenyl
ester
10k
,
mesityl
ester
10l
, N-hydroxyphthalimido
(NHP)
ester
10m
,
enecarbamate
10n
, and
N
-acyl
oxazolidinone
10o
. Addition-
ally, further
conjugated
cinnamic
ester dienophile
10p
affords
tetracycle
11p
. These
results
demonstrate
the ability
to tolerate
varying
dienophile
electronics,
incorporate
additional
func-
tional handles,
and access
alternate
ring systems.
The majority
of the substrate
scope
is reflective
of a
stereospecific
process,
yielding
only
endo
and
exo
diaster-
eomers.
We sought
to exploit
this property
of the reaction
to
access
other diastereomers
of
11a
by employing
(Z)
-olefin
dienophile
10q
. Gratifyingly,
desired
cycloadducts
11q
(
endo
)
and
11q
(
exo
) are furnished
in a 1.6:1 ratio with a 92%
combined
yield, in 84 and 29% ee, respectively.
Further
substitution
patterns
on the substrate
were explored
with the aim of increasing
the stereochemical
complexity
of the
products.
Trisubstituted
benzyl
ester dienophile
10r
furnished
cycloadduct
11r
, featuring
two all-carbon
quaternary
centers,
in 47% yield and 90% ee.
β
-Methyl
(
10s
) and
β
-ethoxy
(
10t
)
α
,
β
-unsaturated
enones
are also competent
substrates,
forging
additional
tetrasubstituted
bridgehead
stereocenters.
Finally,
we explored
α
-methyl
substituted
enone
10u
. The correspond-
ing product
11u
was produced,
bearing
five contiguous
stereocenters
in >20:1
dr.
In summary,
the transformation
described
herein
represents
a versatile
method
for the preparation
of a variety
of
enantioenriched
polycyclic
scaffolds.
Inspired
by these results,
we sought
to explore
the origins
of enantioinduction
and the
mechanism
by which
catalyst
turnover
is achieved.
2.4. C
C Bond Formation.
In order to probe the origins
of enantioinduction
in the transformation,
we first aimed
to
elucidate
the enantiodetermining
step in the catalytic
cycle. We
hypothesized
that either
the cycloaddition
is irreversible
and
dictates
the stereochemical
outcome,
or a reversible
[4+2]
is
coupled
to a subsequent
enantiodetermining
step. First, we
computationally
evaluated
the energetics
of the [4+2] process.
Cycloaddition
directly
from conjugated
enolate
25
to trans-
posed
enolate
26
via
TS2
is achieved
with a
Δ
G
of 9.8 and
Δ
G
of
22.3
kcal/mol
(Figure
5A). The 32.1 kcal/mol
barrier
to the reverse
process
renders
the cycloaddition
step
irreversible
under
the reaction
conditions.
Hence,
our
Scheme
1. Proposed
Divergent
Catalytic
Cycle
a
a
Undesired
reaction
pathways
in gray.
Journal
of the American
Chemical
Society
pubs.acs.org/JACS
Article
https://doi.org/10.1021/jacs.3c02104
J. Am. Chem.
Soc.
2023,
145,
11301
11310
11304