Formation
of All-Carbon
Quaternary
Centers
via Enantioselective
Pd-Catalyzed
α
‑
Vinylation
of
γ
‑
Lactams
Farbod
A. Moghadam,
‡
Jay P. Barbor,
‡
Melinda
Chan,
‡
Carina
Jette,
Shunya
Sakurai,
and Brian
M. Stoltz
*
Cite This:
Org.
Lett.
2024,
26, 7551−7554
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*
sı
Supporting
Information
ABSTRACT:
Herein,
we report
an enantioselective
vinylation
of
α
-substituted
γ
-lactams
that forges
quaternary
centers
in up to 59%
yield
with
94%
ee. The use of canonically
inactive
vinyl
chloride
electrophiles
afforded
the highest
yields
and levels
of stereo-
selectivity,
and a range
of trisubstituted
vinyl
chlorides
were
found
to be proficient
in promoting
this transformation.
These
stereogenic
products
could
be further
elaborated
to functionally
rich scaffolds,
thereby
highlighting
the synthetic
utility
of this process.
γ
-Lactams
are ubiquitous
heterocyclic
motifs
found
in
pharmaceuticals
and
natural
products
alike
(Figure
1).
1
Despite
this, the direct
vinylation
of these
and other
2
scaffolds
largely
remains
an unsolved
problem
in organic
synthesis,
which
limits
the feasibility
of convenient
disconnections
in the
synthesis
of complex
scaffolds
with
potential
biological
applications.
Our
group
previously
disclosed
a novel,
Pd-
catalyzed
strategy
toward
the
α
-arylation
of PMP
(
para
-
methoxy
phenyl)-protected
γ
-lactams
containing
substitution
at the
α
-position.
3
As such,
we successfully
achieved
the first
asymmetric
α
-arylation
of
γ
-lactams
to form
enantioenriched
all-carbon
quaternary
centers.
We were
next
interested
in
translating
this reaction
to the unprecedented
vinylation
of
these
nucleophiles.
Our investigation
commenced
by utilizing
the same
catalytic
conditions
disclosed
in our prior
report.
Initial
efforts
illustrated
the superiority
of vinyl
chloride
electrophiles
and
lithium
bases
(Table
1). We observed
a dramatic
counterion
effect,
as the use of NaHMDS
or KHMDS
afforded
no desired
product,
whereas
LiHMDS
afforded
a 46% yield
of
3a
with an
excellent
90%
ee. Exploration
of similar
lithium
bases,
like
LiTMP,
garnered
diminished
yields.
Similarly,
vinyl
chlorides
were
found
to be essential
for both yield
and enantioselectivity,
as the use of the corresponding
vinyl
bromide
2b
afforded
3a
in a low 27%
yield
and 77%
ee. Use of the more
sterically
encumbered
ligand
L2
did not improve
the reaction
further.
Although
we initially
found
that CPME
(cyclopentyl
methyl
ether)
resulted
in a slight
improvement
of the ee to 92%,
we
found
that 1,4-dioxane
was ultimately
the optimal
solvent
for
this transformation.
Additionally,
the dilution
of the reaction
to
0.05 M allowed
for an improved
58% yield
and 94% ee (entry
10).
With
optimized
conditions
in hand,
we sought
to investigate
the range
of compatible
substitution
patterns
on the vinyl
halide
coupling
partner
(Scheme
1). Vinyl
electrophiles
featuring
cyclopentyl,
cyclohexyl,
and cycloheptyl
substitution
at the 2,2-position
of the vinyl
chloride
afforded
products
3b
−
Received:
July 11, 2024
Revised:
August
20, 2024
Accepted:
August
27, 2024
Published:
September
3,
2024
Figure
1.
(A) Pd-catalyzed
α
-arylation
of
γ
-lactams.
(B) Selected
examples
of
γ
-lactams
in pharmaceuticals
and natural
products.
Letter
pubs.acs.org/OrgLett
© 2024
The Authors.
Published
by
American
Chemical
Society
7551
https://doi.org/10.1021/acs.orglett.4c02551
Org.
Lett.
2024,
26, 7551
−
7554
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3d
with high enantioselectivity,
although
formation
of product
3d
was observed
in diminished
yields
likely
due to increased
steric
hindrance.
Additionally,
saturated
heterocyclic
moieties,
such as a pyran
and thiopyran,
were
well tolerated
(
3e
and
3f
).
Although
acyclic
substrate
3h
could
also
be obtained
in
comparable
yield
and ee,
3i
was isolated
in decreased
yield.
Substitution
at the
α
-position
was limited
to methyl,
but we
were
pleased
to find that pre-existing
substitution
at the
γ
-
position
of the lactam
resulted
in a predictable
match/
mismatch
situation.
Enhancement
of dr and higher
reaction
efficiency
was observed
for product
4
, whereas
lower
yield
and
diastereoselectivity
was observed
for its epimer
5
.
4
We were
also able to implement
our method
at a 3 mmol
scale,
thereby
obtaining
over
450
mg of
3a
in a similar
yield
and
enantioselectivity
(59%
yield,
94% ee).
While
exploring
the scope
of this transformation,
we found
that use of 1,1-disubstituted
or
trans
-1,2-disubstituted
electro-
philes
resulted
in either
a diminished
yield
or enantioselectiv-
ity, respectively
(Figure
2). Hypothesizing
that
reductive
elimination
is both inner-sphere
and enantiodetermining,
5,6
we
posit
that
the diminished
yield
of the 1,1-disubstituted
electrophiles
originates
from
steric
congestion
at the metal
center,
which
may deter
transmetalation
of the lithium
enolate
to palladium.
Conversely,
we propose
that
the greatly
minimized
interactions
between
the ligand
and
trans
-1,2-
disubstituted
electrophiles
result
in high
conversion
but with
poor
enantiocontrol.
These
enantioenriched
heterocycles,
adorned
with
highly
substituted
quaternary
centers,
exhibit
significant
potential
for
pharmaceutical
and total
synthetic
applications.
7
As a result,
we embarked
on a series
of derivatizations
of product
3a
to
generate
differentially
substituted
pyrrolidinone
derivatives
(Scheme
2). Our initial
strategy
involved
the hydrogenation
of
product
3a
to yield
α
-quaternary
lactam
6
. Given
the inherent
challenges
associated
with
enantioselective
α
-alkylation
of
lactams
using
conventional
methods,
we postulate
that this
alternative
approach
offers
great
synthetic
value.
Reduction
of the lactam
with
lithium
aluminum
hydride
yielded
β
-quaternary
pyrrolidine
7
. This
derivative
contains
a
heterocycle
of significant
pharmaceutical
importance,
8
as
pyrrolidines
are ubiquitous
in various
existing
drug
molecules
and natural
products.
9
Hydration
of the newly
introduced
vinyl
group
with
p
-TsOH
produces
the tertiary
alcohol
8
.
10
Allylic
oxidation
with
SeO
2
results
in the formation
of aldehyde
9
.
Additionally,
the deprotection
of the PMP
group
with
ceric
ammonium
nitrate
(CAN)
reveals
unprotected
lactam
10
.
Finally,
3a
can undergo
oxidative
cleavage
to yield
the
corresponding
aldehyde
11
through
ozonolysis.
From
11
, a
Wittig
reaction
can be conducted
to generate
vinylated
lactam
12
with no substitution
at the terminal
position.
11
In conclusion,
our study
showcases
an enantioselective
vinylation
method
for
γ
-lactams
yielding
α
-quaternary
centers
in up to 58% yield
and 94% ee. Notably,
the reaction
exhibits
Table
1. Reaction
Optimization
a
entry
ligand
X
base
solvent
yield
(%)
ee (%)
1
L1
CI
NaHMDS
dioxane
0
2
L1
CI
KHMDS
dioxane
0
3
L1
CI
LiHMDS
dioxane
46
90
4
L1
CI
LiTMP
dioxane
29
ND
5
L1
Br
LiHMDS
dioxane
27
77
6
L2
CI
LiHMDS
dioxane
43
88
7
b
L1
CI
LiHMDS
THF
19
ND
8
b
L1
CI
LiHMDS
CPME
43
92
9
c
L1
CI
LiHMDS
CPME
38
ND
10
c
L1
CI
LiHMDS
dioxane
58
93
a
Reactions
performed
at 0.1 mmol
scale
and
0.1 M. Yields
determined
by
1
H NMR
with
CH
2
Br
2
internal
standard.
b
Reaction
performed
at 70
°
C for 48 h.
c
Reaction
performed
at 0.05
M
concentration.
Scheme
1. Substrate
Scope
a
a
Reactions
performed
at 0.1 mmol
scale.
b
Reaction
performed
at 3
mmol
scale.
c
Yields
determined
by
1
H NMR
with
CH
2
Br
2
internal
standard.
Figure
2.
Reaction
with 1,1- and 1,2-disubstituted
electrophiles.
Organic
Letters
pubs.acs.org/OrgLett
Letter
https://doi.org/10.1021/acs.orglett.4c02551
Org.
Lett.
2024,
26, 7551
−
7554
7552
distinct
preferences
among
different
classes
of electrophiles.
Particularly,
we observed
that trisubstituted
vinyl
chlorides
outperformed
other
vinyl
halides
under
these
conditions
in
terms
of both
yield
and ee. Moreover,
these
highly
substituted
γ
-lactams
hold
significant
synthetic
potential,
offering
diverse
functional
handles
for the synthesis
of complex
drug molecules
or natural
products.
■
ASSOCIATED
CONTENT
Data Availability
Statement
The data underlying
this study
are available
in the published
article
and its Supporting
Information.
*
sı
Supporting
Information
The
Supporting
Information
is available
free of charge
at
https://pubs.acs.org/doi/10.1021/acs.orglett.4c02551.
Experimental
procedures,
spectroscopic
data (
1
H NMR,
13
C NMR,
IR, HRMS),
and SFC and HPLC
data (PDF)
Accession
Codes
CCDC
2375577
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 Katherine
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
Farbod
A. Moghadam
−
The Warren
and Katherine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States
Jay P. Barbor
−
The Warren
and Katherine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States;
orcid.org/0000-0003-2787-4923
Melinda
Chan
−
The Warren
and Katherine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States;
orcid.org/0000-0002-2495-0110
Carina
Jette
−
The Warren
and Katherine
Schlinger
Laboratory
for Chemistry
and Chemical
Engineering,
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States
Shunya
Sakurai
−
The Warren
and Katherine
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/acs.orglett.4c02551
Author
Contributions
‡
F.A.M.,
J.P.B.,
and M.C.
contributed
equally
to this research.
Funding
The
NIH-NIGMS
(R01GM080269
and
R35GM145239),
Heritage
Medical
Research
Investigators
Program,
and Caltech
are thanked
for their
support
of our research
program.
Notes
The authors
declare
no competing
financial
interest.
■
ACKNOWLEDGMENTS
The authors
would
like to thank
Dr. Mona
Shagholi
(Caltech)
for mass
spectrometry
assistance
and Dr. Scott
Virgil
(Caltech)
for assistance
with instrumentation.
■
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Scheme
2. Product
Derivatization
a
a
Conditions:
(a) H
2
, Pd/C
(10 mol %), MeOH,
12 h, 74% yield.
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°
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Organic
Letters
pubs.acs.org/OrgLett
Letter
https://doi.org/10.1021/acs.orglett.4c02551
Org.
Lett.
2024,
26, 7551
−
7554
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