A Pyridine
Dearomatization
Approach
for the Gram
Scale
Synthesis
of (
±
)-Sparteine
Pik Hoi Lam,
Jeff K. Kerkovius,
and Sarah
E. Reisman
*
Cite This:
Org.
Lett.
2023, 25, 8230−8233
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ABSTRACT:
Both
enantiomers
of sparteine
have
suffered
from
pricing
and
supply
chain
variability,
which
has
inspired
efforts
toward
efficient
chemical
synthesis.
Here,
we build
upon
our
reported
synthesis
of the matrine-type
lupin
alkaloids
in order
to synthesize
(
±
)-sparteine.
Specifically,
selective
quenching
of
the cyclization
between
glutaryl
chloride
and
pyridine
with
methanol
provides
a
functionalized
quinolizidine
core
that
was
elaborated
to (
±
)-sparteine
in six
additional
steps
on gram
scale.
This
synthesis
provides
a scalable
route
to
sparteine
from
inexpensive
commodity
chemicals
utilizing
a dearomative
cyclization.
In addition,
this
route
provides
concise
access
to (
±
)-lupinine.
S
parteine
(
1
, Scheme
1) is a unique
quinolizidine
alkaloid
first
isolated
from
Lupinus
Barbiger
S. (Watson)
in 1932.
1
Biological
studies
have
determined
that
1
exhibits
antiar-
rhythmic
activities;
2
however,
it is better
known
as a chiral
ligand
for
organic
synthesis,
especially
for
enantioselective
lithiation.
3
The
cage-like
conformation
of
1
spatially
positions
both
nitrogen
lone
pairs
inward
allowing
η
2
-coordination
to a
variety
of metals.
4
The
ability
of sparteine
to coordinate
alkyl
lithium
reagents
and
generate
configurationally
stable
anions
was
first
developed
in the
1990s
and
is still
commonly
leveraged
in modern
total
syntheses.
5,6
Despite
its broad
use
and
ready
extraction
from
Lupinus
plants,
periodic
supply
chain
issues
have
motivated
the development
of synthetic
approaches
to access
sparteine
or sparteine
surrogates.
7
Here
we report
a
concise
gram-scale
synthesis
of (
±
)-sparteine
from
the
commodity
chemicals
pyridine
and
glutaryl
chloride.
To
date,
over
20 total
syntheses
of sparteine
have
been
reported.
8
More
than
half
of these
strategies
involve
forming
the B and
C rings
through
an
N
-alkylation
via lactamization,
Mannich,
or Appel
reaction.
The
shortest
synthesis
was
accomplished
in 1950
by Leonard
and
co-workers
(Scheme
1a),
9
and
featured
an innovative
exhaustive
hydrogenation
of
pyridine-quinolizone
3
. Although
the
hydrogenation
pro-
ceeded
in a low
yield,
this
approach
provided
access
to
(
±
)-
1
in only
two
steps
from
ethyl
2-(pyridin-2-yl)acetate
(
2
).
The
first
asymmetric
gram-scale
synthesis
of sparteine
was
accomplished
in 2018
by O’Brien
(Scheme
1b).
7a
Enzymatic
resolution
of the
racemic
ester
(
±
)-
6
provided,
after
re-
esterification,
(+)-
6
in >99%
ee. Condensation
of ester
(+)-
6
with
1 equiv
of formaldehyde
gave
unsaturated
ester
(+)-
5
,
which
underwent
1,4-addition
with
the enolate
of ester
(
−
)-
6
to give
diester
7
. Benzyl
deprotection
and
one-pot
lactamiza-
tion,
followed
by global
reduction,
gave
access
to (
−
)-
1
in a
total
of ten steps.
Received:
October
2, 2023
Revised:
November
5, 2023
Accepted:
November
7, 2023
Published:
November
10,
2023
Scheme
1. (a) First Synthesis
of (
±
)-Sparteine;
(b) First
Enantioselective
Synthesis
of (
−
)-Sparteine
Letter
pubs.acs.org/OrgLett
© 2023 The Authors.
Published
by
American
Chemical
Society
8230
https://doi.org/10.1021/acs.orglett.3c03242
Org.
Lett.
2023, 25, 8230
−
8233
This article is licensed under CC-BY 4.0
We
recently
reported
the synthesis
of isomatrine,
matrine,
and
additional
matrine
alkaloids
using
a dearomative
annulation
reaction
of pyridine
(
10
).
Mechanistic
studies
revealed
that
the cascade
cyclization
between
10
and
glutaryl
chloride
(
8
)
occurs
via a stepwise
pathway
that
could
be
interrupted
by addition
of methanol
(Scheme
2a).
10,11
We
hypothesized
that
if instead
of methanol,
intermediate
11
could
be trapped
with
4-pyridone
(
12
),
subsequent
enolization
and
conjugate
addition
could
form
the
sparteine
tetracycle
(Scheme
2b).
Unfortunately,
initial
attempts
to trap
acid
chloride
11
(formed
in situ
by the reaction
of
8
with
10
)
with
2- or 4-pyridone
led predominately
to
O
-acylation.
When
4-
trimethylsiloxy
pyridine
(
14
)
was
used
as a protected
pyridone
equivalent,
a product
assigned
by
1
H NMR
as
N
-acylated
pyridone
15
could
be formed
in 40%
yield
(Scheme
2c);
however,
attempts
to purify
15
resulted
in significant
hydrolysis
to the corresponding
carboxylic
acid.
The
reaction
of acyl
chloride
11
with
piperidine
was
also
investigated,
anticipating
that
a late-stage
oxidation/enolate
addition
could
allow
elaboration
to
1
. However,
the
acylation
of piperidine
with
acid
chloride
11
proceeded
in low
yields
with
challenging
purification.
Due
to the
challenges
encountered
directly
leveraging
acid
chloride
11
,
we decided
to capitalize
on the
high
yielding
methanol
quench/partial
reduction
to form
9
(Scheme
3), which
we envisioned
could
be engaged
with
an
appropriate
pyridine
surrogate
at a later
stage.
Although
our
initial
plan
called
for forming
the sparteine
C
ring
through
the cyclization
of
13
, based
on related
synthetic
work
from
Gray
and
Gallagher,
11
our revised
approach
pursued
a route
involving
epimerization
at C7 and
cyclization
to form
the B ring
(Scheme
3). The
use
of
t
-BuOK
in
t-
BuOH
was
found
to be
optimal
for
this
task,
giving
the
more
thermodynamically
stable
trans
isomer
16
with
a 10:1
dr.
The
crude
material
was
hydrogenated
using
catalytic
Pd/C
(1
mol
%) to yield
17
in 55%
yield
over
two
steps.
Removal
of the
minor
epimer
was
difficult
at this
stage,
so the
material
was
advanced
as a mixture
of diastereomers.
Chemoselective
reduction
of the
ester
of
17
with
L
-selectride
and
direct
quenching
of the reaction
mixture
with
tosyl
chloride
provided
primary
tosylate
18
in 73%
yield.
S
N
2 reaction
between
tosylate
18
and
glutarimide
provided
the
N
-alkylation
product
19
in 93%
yield.
Initial
attempts
to convert
19
to
20
by formation
of the C9
enolate
and
intramolecular
addition
to glutarimide
were
unsuccessful.
For
example,
treatment
with
LDA
followed
by
warming
to room
temperature
and
stirring
overnight
resulted
in complex
reaction
mixtures
with
only
trace
product
formation.
It was
discovered
that
by decreasing
the
reaction
temperature
to
−
78
°
C
side
product
formation
was
sup-
pressed;
however,
low
yields
of the desired
product
were
still
obtained
when
standard
aqueous
workup
conditions
were
Scheme
2. (a) Key Precedent
for the Interrupted
Cascade;
(b) Initial
Retrosynthetic
Analysis;
(c) Investigation
of
Pyridine
Trapping
Scheme
3. Gram
Scale
Total
Synthesis
of (
±
)-Sparteine
Organic
Letters
pubs.acs.org/OrgLett
Letter
https://doi.org/10.1021/acs.orglett.3c03242
Org.
Lett.
2023, 25, 8230
−
8233
8231
used.
Upon
further
investigation
it was
discovered
that
the
cyclization
was
very
fast and
decreasing
the reaction
time
to 2
min
provided
significantly
enhanced
yields
with
cleaner
reaction
profiles.
Allowing
the
reaction
to warm
up at all,
even
during
the
quenching
process,
led again
to significant
byproduct
formation.
Ultimately,
it was
determined
that
quenching
at
−
78
°
C with
a solution
of acetic
acid
in THF
was
crucial
to minimize
byproduct
formation
and
product
degradation.
The
optimized
procedure
was
found
to be
scalable
and
could
deliver
gram
quantities
of
20
in 56%
yield.
Reduction
of
20
with
LiAlH
4
provided
(
±
)-
1
on a gram
scale,
which
could
be purified
by distillation
(56%
yield
(
±
)-
1
by qNMR)
and
then
recrystallized
as the bis-hydrogen
sulfate
salt from
ethanol
(30%
yield
of (
±
)-
1
·
2H
2
SO
4
).
In addition
to sparteine,
ester
9
also
provides
access
to the
lupin
alkaloid
lupinine
(
21
)
(Scheme
4). In this
case,
direct
hydrogenation
of
9
provided
the
diastereomeric
ester
of
17
.
Further
reduction
with
LiAlH
4
then
provided
(
±
)-
21
in three
steps
from
pyridine.
In summary,
the
total
syntheses
of sparteine
and
lupinine
have
been
completed
in seven
and
three
steps,
respectively,
from
pyridine.
Key
to both
syntheses
is the
interrupted
dearomative
cascade
cyclization
between
pyridine
and
glutaryl
chloride
to yield
quinolizidine
9
. A two-step
reduction
sequence
provides
a concise
route
to lupinine,
while
a key
intramolecular
enolate
addition
provides
the
carbocyclic
scaffold
of sparteine.
This
synthesis
highlights
the power
of a
dearomative
approach
toward
complex
alkaloids
and
can
provide
(
±
)-
1
on gram
scale.
■
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.3c03242.
Experimental
procedures,
characterization
data
(
1
H and
13
C NMR)
for all new
compounds
(PDF)
■
AUTHOR
INFORMATION
Corresponding
Author
Sarah
E. Reisman
−
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States;
orcid.org/0000-0001-
8244-9300;
Email:
reisman@caltech.edu
Authors
Pik Hoi Lam
−
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States;
orcid.org/0009-0005-
2013-6030
Jeff K. Kerkovius
−
Division
of Chemistry
and Chemical
Engineering,
California
Institute
of Technology,
Pasadena,
California
91125,
United
States;
orcid.org/0000-0001-
5692-0285
Complete
contact
information
is available
at:
https://pubs.acs.org/10.1021/acs.orglett.3c03242
Notes
The
authors
declare
no competing
financial
interest.
■
ACKNOWLEDGMENTS
The
California
Institute
of Technology
Center
for Catalysis
and
Chemical
Synthesis
is gratefully
acknowledged
for access
to analytical
equipment.
Fellowship
support
was
provided
by
the
Natural
Sciences
and
Engineering
Research
Council
(NSERC)
of Canada
(PGS-D
fellowship
to J.K.K.
(under
Grant
No.
PGSD3-532535-2019)).
P. K. L. was
supported
as a
John
Stauffer
SURF
Fellow
at Caltech.
S.E.R.
acknowledges
financial
support
from
the NIH
(No.
R35GM118191).
■
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