Supplementary Materials for
A Pyridine Dearomatization Approach for the Gram Scale Synthesis of
(±)
-
Sparteine
Pik Hoi Lam
,
1
Jeff K. Kerkovius
,
1
Sarah E. Reisman
1*
1
Division of Chemistry and Chemical Engineering, California Institute of
Technology, Pasadena, CA 91125, USA.
*Correspondence to:
reisman@caltech.edu
Table of Contents
1.
General Procedures.......................................................................................S
2
2
. Synthetic
Procedures........................................................................
..
............S
4
3
.
Notes and References
....................................................................................S
1
8
4
.
1
H and
13
C Spectral Data .................................................................................S
19
S
2
General Procedures
Unless otherwise stated, reactions were performed under an
inert atmosphere (dry N
2
)
using freshly dried solvents and standard Schlenk techniques. Glassware was oven
-
dried at 120 °C
for a minimum of four hours. Tetrahydrofuran (THF), methylene chloride (DCM), acetonitrile
(ACN), methanol (MeOH), benzene (PhH), and toluene (PhMe) were dri
ed by passing through
activated alumina columns. CH
2
Cl
2
(D150
-
4), benzene (PhH, OmniSolv, BX0212
-
1), acetonitrile
(A998
-
4), pentane (P399
-
4), acetone (A18
-
20), hexanes (H292
-
20), and
n
-
butanol (A399
-
4) were
purchased from Fisher and
used as received. Anhydrous
N
,
N
-
dimethylformamide (DMF) was
purchased from VWR (EM
-
DX1727
-
6) and used as received. All reactions were monitored by
thin
-
layer chromatography using EMD/Merck silica gel 60 F254 pre
-
coated plates (0.25 mm) and
were visualized by UV or by staining with
p
-
anisaldehyde or potassium permanganate (KMnO
4
).
Flash column chromatography was performed as described by Still et al.
1
using silica gel (particle
size 0.032
–
0.063) purchased from MilliporeSigma.
1
H and
13
C NMR spectra were recorded on a
Bruker Avance III HD with Prodigy cryoprobe (at 400 MHz and 101 MHz, respectively), a Varian
Inova 500 (at 500 MHz and 126 MHz, respectively), a
Bruker 400 MHz Spectrometer with
broadband iProbe
, or a Varian Inova 600 (at 600 MHz and 150 MHz, respectively), and are
reported relative to internal CDCl
3
(
1
H, δ = 7.26;
13
C, δ = 77.16) or CD
2
Cl
2
1
H, δ = 5.32;
13
C, δ =
53.84). CDCl
3
was stored over anhydrous potassium carbonate (K
2
CO
3
). Data for
1
H NMR spectra
are reported as foll
ows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration).
Multiplicity and qualifier abbreviations are as follows: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad. IR spectra were recorded on a Perkin El
mer Paragon 1000
spectrometer and are reported in frequency of absorption (cm
–
1
). HRMS data were acquired using
an Agilent 6230 Series time
-
of
-
flight (TOF) mass spectrometer with an Agilent G1978A ion trap
or by LC
-
MS using a
Waters LCT Premier XE Electros
pray TOF mass spectrometer interfaced
with Waters UPLC chromatography, or by GC
-
MS interfaced with a JEOL JMS
-
T2000 GC
AccuTOF GC
-
Alpha with Field Ionization.
Molecular formulas of the compounds [M] are given,
with the observed ion fragment in brackets, e.g. [M+H]
+
. Melting points were determined using a
Büchi B
-
545 capillary melting point apparatus, and the values reported are uncorrected. Unless
otherwise stated, chemicals and reagents were used as received. Reagents were purchased from
commercial vendors
as follows: Solid potassium
tert
-
butoxide was purchased from STREM
S
3
Chemicals Inc., stored in a glovebox, and used as received.
Glutaryl chloride was purchased from
Oakwood Chemicals Inc. and was used as received. Anhydrous pyridine,
and
palladium on carbon
(10%)
were purchased from MilliporeSigma and were used as received.
1
H qNMR standards
trimethylphenyl silane (99% purity) and pyrazine (≥99% purity) were purchased from
MilliporeSigma and were used as received.
S
4
Preparation of
methyl
ester
9
:
A
3
-
neck 3 L
oven dried N
2
flushed
round bottom
flask
was equipped with an overhead
stirrer, a thermocouple, and a rubber septum. The flask
was charged with glutaryl chloride
8
(
22.8
mL
,
178
mmol, 1
.0
equiv) and DCM (
1.8
L, 0.1 M). The solution was cooled to
–
50 °C
and
then
pyridine (
71.8
mL,
888
mmol, 5
.0
equiv) was added dropwise
at such a rate as to prevent the
temperature from increasing above
–
40 °C
. The thick slurry was stirred at
–
50 °C for 15 minutes
and then allowed to warm to ambient temperature.
As soon as the
reaction
became
homogenous
(
ca.
30
-
60 minutes) methanol (
36.0
mL,
888
mmol,
5.0
equiv) was added. The solution was cooled
to 0 °C
and
then triethylsilane (
425
mL,
2.66
mol, 15 equiv) added
,
followed by a dropwise
addition
of
trifluoroacetic acid (
204
mL,
2.66
mmol, 15 equiv)
at such a rate as to prevent the
temperatu
re from increasing above 20 °C (
ca.
15 minutes)
.
Upon completion of the addition, t
he
reaction was allowed to warm to
21 °C
and stir for 18 hours. Once complete, the reaction was
quenched with
sat. Na
2
CO
3
, and the
mixture
was extracted with DCM (3 x
2
50 mL). The combined
organic layers were dried over anhydrous Na
2
SO
4
, filtered, and concentrated under reduced
pressure. The crude product was purified via SiO
2
column chromatography [1
900
g SiO
2
,
120
mm
diameter column, eluted with
5
0% Acetone/
5
0% Hexanes] to yield the alkenyl methyl ester
9
as a
pale yellow crystalline solid (
21.6
g,
58
% yield).
(±)
-
Methyl
E
ster
9
:
1
H NMR (
5
00 MHz, CDCl
3
):
δ
6.04
–
5.89 (m, 1H), 5.50 (ddt,
J
= 10.1, 2.9, 1.4 Hz, 1H), 4.76
(ddt,
J
= 12.8, 5.8, 1.3 Hz, 1H), 4.37 (ddt,
J
= 6.9, 4.9, 2.4 Hz, 1H), 3.69 (s, 3H), 3.01 (dt,
J
= 6.6,
4.9 Hz, 1H), 2.73 (td,
J
= 12.2, 4.2 Hz, 1H), 2.61 (ddd,
J
= 17.7, 7.8, 6.7 Hz, 1H), 2.43 (dt,
J
=
17.6, 6.5 Hz, 1H), 2.33 (ddtd,
J
= 20.3, 11.9, 6.0, 2.5 Hz, 1H), 2.10
–
1.96 (m, 3H).
13
C
NMR (101 MHz, CDCl
3
):
δ
172.0, 169.1, 129.1, 125.9, 55.8, 52.0, 43.1, 39.8, 30.4, 24.7,
21.6.
S
5
FTIR (NaCl, thin film):
3031, 2951, 2841, 1736, 1642, 1459, 1436, 1417, 1280, 1263, 1233,
1193, 1163, 1014, 988, 917
cm
-
1
.
HRMS:
(FI
-
TOF)
m/z: [M+H
+
]
calc’d for C
11
H
15
NO
3
H
+
209.1046, found 209.1048.
TLC
(50% acetone/50% hexanes),
R
f
:
0.23 (KMnO
4
).
M.P.
38.4
–
40.6 °C.
Preparation of methyl ester
S1
:
A 25 mL flask was charged with alkenyl methyl ester
9
(100 mg, 0.478 mmol, 1
.0
equiv),
10% palladium on carbon (25.4 mg, 23.9
μ
mol, 5 mol %) and methanol (4.78 mL, 0.1 M). The
flask was purged with N
2
(balloon) then with H
2
(balloon). The reaction was stirred vigorously
(1500 rpm) until complete consumption of the starting material was observed by TLC (
ca.
3 hours).
Upon completion
,
the reaction was filtered over celite, concentrated under reduced pressure, and
purified via SiO
2
column chromatography [20 g SiO
2
, 20 mm column diameter, eluted with 25%
acetone/75% hexanes] to yield the ester
S1
as a white crystalline solid (72.2 mg, 71% yield).
(±)
-
Methyl E
ster
16
:
1
H NMR (
5
00 MHz, CDCl
3
):
δ
4.76 (ddt,
J
= 12.8, 4.3, 2.0 Hz, 1H), 3.73 (s, 3H), 3.74
–
3.67 (m,
1H), 2.98 (dt,
J
= 11.0, 5.8 Hz, 1H), 2.60
–
2.44 (m, 2H), 2.40
–
2.28 (m, 1H), 2.09
–
1.98 (m, 2H),
1.95 (d,
J
= 13.6 Hz, 1H), 1.64 (ddd,
J
= 10.7, 8.4, 5.5 Hz, 1H), 1.60
–
1.52 (m, 1H), 1.51
–
1.36
(m, 3H).
13
C NMR (101 MHz, CDCl
3
):
δ
172.2, 167.9, 58.1, 52.2, 44.7, 43.5, 31.5, 28.4, 25.5, 25.0, 19.6.
FTIR (NaCl, thin film):
2985, 2952, 1738, 1635, 1439, 1420, 1275, 1262, 1168
cm
-
1
.
HRMS:
(FI
-
TOF)
m/z: [M+H
+
]
calc’d for C
11
H
17
NO
3
H
+
211.120
3
,
found 211.120
7
.
TLC
(25% acetone/75% hexanes),
R
f
:
0.22 (KMnO
4
).
M.P.
74.6
–
75.9 °C.
S
6
Preparation of
methyl ester
16
:
A 1 L
N
2
-
flushed flask was
charged with
9
(
21.6
g,
103
mmol, 1
.0
equiv) and
t
-
BuOH
(
413
mL, 0.
25
M). Next, potassium
t
-
BuOK
(
4.63
g,
41.3
mmol, 0.
4
equiv) was added
in a single
portion
.
T
he solution was stirred
at 21 °C
until a 10:1 ratio of
16
:
9
was reached as judged by
1
H
NMR aliquots (
ca.
4 hours
, CDCl
3
).
Upon completion, the
reaction
was quenched with acetic acid
(
2.36
mL,
41.3
mmol, 0.
4
equiv). The
reaction was concentrated
under reduced pressure. The
residue was diluted with sat. aq.
NaHCO
3
and was
extracted
with DCM (3 x 100 mL). The
combined organic layers were dried over anhydrous Na
2
SO
4
, filtered, and concentrated under
reduced pressure.
The crude product was used directly in the next step without additional
purification. An analytically pure sample was obtained by SiO
2
column chromatography (20 g
SiO
2
, 20 mm column, 40% Acetone/60% Hexanes) to provide
16
as a white crystalline
solid
(19.1
g, 88% yield).
(±)
-
M
ethyl
E
ster
16
:
1
H NMR (400 MHz, CDCl
3
):
δ 5.94
-
5.90 (m, 1H), δ5.56
-
5.50 (m, 1H), 4.83 (ddt,
J
= 12.9, 5.8,
1.4 Hz, 1H), 4.31 (dq,
J
= 10.6, 2.1 Hz, 1H), 3.76 (s, 3H), 2.64 (td,
J
= 12.4, 4.1 Hz, 1H), 2.56
(ddd,
J
= 17.7, 5.5, 2.5 Hz, 1H), 2.47 (ddd,
J
= 12.3, 10.6, 3.2 Hz, 1H), 2.40 (ddd,
J
= 18.1, 12.6,
6.3 Hz, 1H), 2.25 (dddq,
J
= 17.7, 11.9, 5.9, 2.6 Hz, 1H), 2.11
–
2.00 (m, 2H), 1.94 (qd,
J
= 12.6,
5.4 Hz, 1H).
13
C NMR (101 MHz, CDCl
3
):
δ 173.6, 168.1, 127.9, 127.1, 56.6, 52.7, 46.4, 39.0, 31.8, 25.3,
24.2
FTIR (NaCl, thin film):
3052, 2953, 1728, 1639, 1434 cm
-
1
.
HRMS
:
(ESI
-
TOF)
m/z: [M+H
+
]
calc’d for C
11
H
15
O
3
NH
+
210.1124, found 210.1124.
TLC:
50% acetone in 50% hexane,
R
f
= 0.44 (KMnO
4
).
S
7
Preparation of methyl ester
17
:
A 1 L flask was charged with all the trans methyl ester
16
from the previous step (
ca.
21.6
g, 103 mmol, 1.0 equiv), 10% palladium on carbon (971 mg, 0.91 mmol, 1 mol %), and MeOH
(456 mL, 0.2 M).
The
flask was purged with N
2
followed by
H
2
then the reaction was stirred at
1500 RPM
at 21 °C until full consumption of the starting material was observed by TLC (
ca.
2
hours).
Upon completion, the solution was then filtered through celite with DCM, concentrated
under
reduced pressure, and purified via
SiO
2
column chromatography (
1900 g SiO
2
, 120 mm
column, 40
:6
0
acetone
/
hexane) to
provide
17
as
a
white
crystalline solid
(10.6 g, 55% yield)
.
(±)
-
M
ethyl
E
ster
17
:
1
H NMR (400 MHz, CDCl
3
):
δ 4.80 (ddt,
J
= 13.2, 4.2, 2.1 Hz, 1H), 3.73 (s, 3H), 3.58 (ddd,
J
= 11.0, 8.2, 2.5 Hz, 1H), 2.59
–
2.40 (m, 3H), 2.34 (ddd,
J
= 17.2, 11.1, 5.5 Hz, 1H), 2.05
–
1.98
(m, 1H), 1.92 (dtd,
J
= 13.2, 11.0, 4.8 Hz, 1H), 1.87
–
1.77 (m, 2H), 1.69 (ddq,
J
= 13.4, 4.0, 2.1
Hz, 1H), 1.48 (qt,
J
= 12.2, 3.4 Hz, 1H), 1.43
–
1.32 (m, 1H), 1.25 (tdd,
J
= 13.1, 11.3, 3.5 Hz,
1H).
13
C NMR (101 MHz, CDCl
3
):
δ
174.0, 168.4, 58.4, 52.7, 47.1, 43.1, 33.8, 31.8, 25.5, 24.7, 23.5
FTIR (NaCl, thin film):
3050, 2856, 1732, 1645, 1454 cm
-
1
.
HRMS
:
(ESI
-
TOF)
m/z: [M+H
+
]
calc’d for C
11
H
17
O
3
NH
+
212.1281, found 212.1281.
TLC
:
50% acetone in 50% hexane,
R
f
= 0.48 (Seebach’s “Magic” Stain)
S
8
Preparation of (±)
-
tosylate
18
:
A 1 L N
2
flushed flask was charged with
17
(10.6 g, 50.2 mmol, 1
.0
equiv)
and
THF (
201
mL, 0.25 M)
.
The
solution was cooled to 0
°
C
and
then
L
-
Selectride (
1 M in THF,
105
mL,
105
mmol, 2.1 equiv)
was added over the course of 5 minutes
. The reaction was allowed to stir for 10
mins at 0
°
C
after which
p
-
toluenesulfonyl chloride (
16.3 g, 85.3
mmol
, 1.7 equiv
)
was added
as
a solution
in THF (
25
mL, 1 M)
at such a rate as to prevent the temperature from increasing above
10 °C (
ca.
10 minutes).
The
clear
solution was stirred for 15 min
utes, after which it was quenched
by the dropwise addition of a mixture of
hydro
gen peroxide (
30% in water, 9.2
mL,
90.1
mmol,
1.8
equiv)
and
sodium hydroxide (
4.0
g,
100
mmol, 2
.0
equiv)
.
The reaction mixture was stirred
at 0 °C for 1 hour.
Upon the completion, the
reaction
mixture was concentrated under reduced
pressure, diluted with sat.
NH
4
Cl (50 mL)
and extracted
with DCM (
3 x 75 mL
)
. The combined
organic layers were dried over
anhydrous Na
2
SO
4
, filtered,
and concentrated under reduced
pressure. The crude
product
was purified via column chromatography (
1500 g SiO
2
, 120 mm
column,
40:60
A
cetone
/H
exane) to
yield
18
in a
white
crystalline solid
(
12.4
g,
73
% yield).
(±)
-
T
osylate
18
:
1
H NMR (400 MHz, CDCl
3
):
δ 7.78 (d,
J
= 8.2 Hz, 2H), 7.37 (d,
J
= 8.0 Hz, 2H), 4.75 (ddt,
J
=
13.1, 4.2, 2.2 Hz, 1H), 4.30
–
3.74 (m, 2H), 3.04 (ddd,
J
= 11.5, 7.3, 2.5 Hz, 1H), 2.46 (s, 3H) 2.24
(ddd,
J
= 17.4, 10.3, 5.4 Hz, 2H), 2.24 (ddd,
J
= 17.4, 10.3, 5.4 Hz, 1H), 1.88
–
1.74 (m, 4H), 1.61
(dddd,
J
= 20.4, 15.2, 10.2, 3.7 Hz, 2H), 1.46
–
1.30 (m, 2H), 1.27
–
1.16 (m, 1H).
13
C NMR (101 MHz, CDCl
3
):
δ
168.6
, 1
45.7
,
133.0
,
130.5, 128.4, 71.1, 58.3, 43.5, 40.0, 33.5,
31.1, 25.5, 24.9, 22.1.
FTIR (NaCl, thin film):
3053, 2942, 1633, 1362, 1265 cm
-
1
.
HRMS
:
(ESI
-
TOF)
m/z: [M+H
+
]
calc’d for C
17
H
23
SO
4
NH
+
338.1424, found 338.1421.
TLC:
50% acetone in 50% hexane,
R
f
= 0.36 (KMnO
4
)
S
9
Preparation of (±)
-
glutar
imide
19
:
An oven dried N
2
flushed 250 mL flask was charged with
glutarimide (
9.56
g,
84.5
mmol,
2.
3
equiv)
and
DMF (
184
mL, 0.2 M)
.
To the solution was added
t
-
BuOK
(
5.77
g,
51.4
mmol, 1.4
equiv)
after which the mixture was allowed to stir for 15 minutes
.
A separate oven dried N
2
flushed
500 mL flask was charged with tosylate
18
(12.4 g, 36.7 mmol, 1.0 equiv) and DMF (92 mL, 0.4
M). The glutarimide solution was cannulated into the tosylate solution over the course of 5
minutes. The reaction
mixture was then heated at 100 °C
in an oil bath
until complete consumption
of the starting material was observed by TLC (
ca.
3 hours). Upon completion, the reaction mixture
was cooled to 21 °C. The flask was equipped with a short
-
path distillation head, and the majority
of the DMF was removed by distillation
under reduced pressure
(35 °C, 0.3 torr). The residue was
diluted in sat. NaHCO
3
(100 mL) and was extracted with DCM (3 x 75 mL). The combined organic
layers were dried over anhydrous Na
2
SO
4
, filtered, and concentrated under reduced pressure. The
crude product was purified by SiO
2
column chromatography (500 g SiO
2
, 80 mm column, 50%
Acetone/50% Hexanes) to yield the product
19
as a white crystalline solid (9.50 g, 93% yield).
(±)
-
G
lutar
imide
19
:
1
H NMR (400 MHz, CDCl
3
):
δ 4.81 (ddt,
J
= 13.2, 4.3, 2.2 Hz, 1H), 4.15
–
3.55 (m, 2H), 3.00
(ddd,
J
= 10.5, 7.5, 2.4 Hz, 1H), 2.69 (t,
J
= 6.5 Hz, 4H), 2.48 (dt,
J
= 17.3, 5.0 Hz, 1H), 2.38 (td,
J
= 12.9, 2.8 Hz, 1H), 2.18 (ddd,
J
= 16.8, 10.7, 5.3 Hz, 1H), 2.03
–
1.92 (m, 3H), 1.90
–
1.80 (m,
2H), 1.65 (ddt,
J
= 13.7, 9.3, 4.6 Hz, 2H), 1.55
–
1.34 (m, 3H), 1.29 (qd,
J
= 12.7, 3.6 Hz, 1H).
13
C NMR (101 MHz, CDCl
3
):
δ
173.2, 169.1, 60.9, 43.5, 42.3, 39.4, 33.8, 33.6, 31.5, 25.7, 25.2,
23.2, 17.6.
FTIR (NaCl, thin film):
3053, 2943, 1679, 1631, 1264 cm
-
1
.
HRMS
:
(ESI
-
TOF)
m/z: [M+H
+
]
calc’d for C
15
H
22
O
3
N
2
H
+
279.1705, found 279.1703.
TLC
:
50% acetone in 50% hexane,
R
f
= 0.48 (Seebach’s “Magic” Stain)
S
10
Preparation of (±)
-
bis
-
amide
20
:
A 250 mL oven dried N
2
flushed flask was charged with
diisopropylamine (
8.61
mL,
61.4
mmol, 1.8 equiv)
and
THF (
68
mL, 1
.0
M)
.
The solution was cooled to
0
°
C
then
n
-
buthyllithium
(
2.5 M in hexanes, 24.6
mL,
61.4
mmol,
1.8 equiv)
was added dropwise
after which the reaction
was allowed to
sti
r for 15 min
utes at 0 °C
.
A separate 500 mL oven dried N
2
flushed flask was
charged with glutarimide
19
(9.50 g, 34.1 mmol, 1.0 equiv) and THF (341 mL, 0.1 M) and then
cooled to
–
78 °C. The LDA solution was cannulated into the glutarimide solution at
–
78 °C rapidly
over the course of 2 minutes. The reaction was stirred for an additional 2 minutes at
–
78 °C
and
then quenched with acetic acid (9.8 mL, 171 mmol, 5.0 equiv) at
–
78 °C. The
reaction mixture
was removed from the cooling bath and was concentrated under reduced pressure. The crude
reaction mixture was diluted in sat. NH
4
Cl (100 mL) and was extracted with DCM (3 x 75 mL).
The combined organic layers were dried over anhydrous Na
2
SO
4
, filtered, and concentrated under
reduced pressure. The crude product was purified via SiO
2
column chromatography (500 g SiO
2
,
80 mm column, 15% MeOH/85% EtOAc) to yield the product
20
as a white crystalline solid (5.30
g, 56% yield).
(±)
-
Bis
-
amide
20
:
1
H NMR (400 MHz, CDCl
3
):
δ 4.93 (dd,
J
= 14.2, 10.7 Hz, 1H), 4.74 (ddt,
J
= 13.1, 4.2, 1.9 Hz,
1H), 4.07 (s, 1H), 3.02
–
2.97 (m, 1H), 2.72 (dt,
J
= 4.1, 2.0 Hz, 1H), 2.57
–
2.46 (m, 3H), 2.33
(ddd,
J
= 17.6, 12.6, 6.7 Hz, 1H), 2.23 (pq,
J
= 9.2, 3.2 Hz, 2H), 1.99
–
1.90 (m, 2H), 1.88
–
1.79
(m, 2H), 1.76
–
1.66 (m, 2H), 1.66
–
1.51 (m, 3H), 1.48
–
1.36 (m, 2H).
13
C NMR (101 MHz, CDCl
3
):
δ
170.8, 168.9, 84.6, 62.9, 49.1, 44.4, 38.7, 38.5, 32.3, 31.8, 31.2,
26.1, 25.2, 20.4, 16.4.
FTIR (NaCl, thin film):
3053, 1641, 1615, 1269, 1407 cm
-
1
.
HRMS
:
(ESI
-
TOF)
m/z: [M+H
+
]
calc’d for C
15
H
2
2
O
3
N
2
H
+
2
79
.1705, found 2
79
.1703
.
TLC:
15% methanol in 85% ethyl acetate,
R
f
= 0.26 (Seebach’s “Magic” Stain)
S
11
Preparation of sparteine (
(±)
-
1
)
and recrystallization as bis
-
hydrogen sulfate salt
:
An N
2
flushed oven dried 1L round bottom flask was charged with bis
-
amide
20
(5.00 g,
18.0 mmol, 1.0 equiv) and THF (180 mL, 0.1 M). To the solution at 21 °C was added LiAlH
4
(1.0
M solution in THF, 341 mL, 341 mmol, 19 equiv). The solution was heated to reflux
in an oil bath
for 16 hours. Upon completion, the solution was cooled to 21 °C
and
then poured into a solution
of sat. aq. Rochelles salt (500 mL) and ice (500 g). After quenching, 3 M NaOH (100 mL) was
added, and the mixture was stirre
d
for 15 minutes to break apart the aluminum solids into a white
slurry. The mixture was c
oncentrated under reduced pressure to remove the THF. Subsequently
,
the mixture was extracted with Et
2
O (3 x 100 mL). The combined organic layers were washed with
brine (100 mL), dried over anhydrous Na
2
SO
4
, filtered, and concentrated under reduced pressure.
The crude residue was purified via distillation under reduced pressure (300 mTorr, 80.0 °C
–
82.1 °C, 120 °C oil bath temperature)
to yield
2.30 g
of sparteine (
1
) (
80% purity by qNMR in
CDCl
3
, pyrazine standard
, 56% corrected yield
). The obtained pale
-
yellow oil was treated with 2
M H
2
SO
4
(
8.0
mL, 16 mmol, 2.1 equiv) followed by freezing and water removal through
lyophilization.
The
obtained
solids were
suspended
in boiling EtOH
(15 mL)
, cooled to 0 °C, and
the crystals were isolated by vacuum
filtration to provide sparteine bis
-
hydrogen
sulfate
as a
pentahydrate
,
a white crystalline solid
(
2.50 g, 30% yield
from
20
)
.
Characterization data match
previously reported data.
3
(±)
-
S
parteine (
1
):
1
H NMR (
6
00 MHz, CDCl
3
):
δ 4.93 (dd,
J
= 14.2, 10.7 Hz, 1H), 4.74 (ddt,
J
= 13.1, 4.2, 1.9 Hz,
1H), 4.07 (s, 1H), 3.02
–
2.97 (m, 1H), 2.72 (dt,
J
= 4.1, 2.0 Hz, 1H), 2.57
–
2.46 (m, 3H), 2.33
(ddd,
J
= 17.6, 12.6, 6.7 Hz, 1H), 2.23 (pq,
J
= 9.2, 3.2 Hz, 2H), 1.99
–
1.90 (m, 2H), 1.88
–
1.79
(m, 2H), 1.76
–
1.66 (m, 2H), 1.66
–
1.51 (m, 3H), 1.48
–
1.36 (m, 2H).
13
C NMR (101 MHz, CDCl
3
):
δ
170.8, 168.9, 84.6, 62.9, 49.1, 44.4, 38.7, 38.5, 32.3, 31.8, 31.2,
26.1, 25.2, 20.4, 16.4.
N
N
O
O
H
OH
LiAlH
4
THF, reflux
distillation
and then H
2
SO
4
30% yield
20
(±)-sparteine
·
2 H
2
SO
4
(
1
·
2 H
2
SO
4
)
[2.3 g scale]
N
N
H
H
H
H
2 HSO
4
–
S
12
FTIR (NaCl, thin film):
2985, 2933, 1421, 1268
cm
-
1
.
FTIR (ATR, diamond):
3045, 2956, 1195, 1013, 829 cm
-
1
H
RM
S:
(ESI
-
TOF)
m/z: [M+H
+
]
calc’d for C
15
H
27
N
2
H
+
235.2169, found 235.2177.
TLC:
15% methanol in 85% ethyl acetate,
R
f
= 0.26 (Seebach’s “Magic” Stain)
(±)
-
Sparteine·bis
-
hydrogen sulfate salt (1·2 H
2
SO
4
):
1
H
(600 MHz, D
2
O):
δ
3.66 (dd, J = 14.5, 11.3 Hz, 1H), 3.52
–
3.45 (m, 3H),
3.41 (dt, J = 12.1,
3.3 Hz, 1H), 3.31 (dd, J = 11.9, 2.5 Hz, 1H), 3.20
–
3.14 (m, 2H), 3.11 (td, J = 12.7, 3.5 Hz, 2H),
2.62 (d, J = 11.3 Hz, 1H), 2.30 (s, 1H), 2.15 (dq, J =
15.3, 4.1 Hz, 1H), 2.04 (d, J = 14.7 Hz, 1H),
1.98
–
1.86 (m, 6H), 1.86
–
1.71 (m, 3H), 1.71
–
1.56 (m, 3H).
13
C NMR
(101 MHz, D
2
O):
δ
66.5, 63.2, 57.1, 56.5, 55.0, 48.9, 32.0, 31.3, 29.1, 26.8, 22.7, 22.5,
22.4, 21.9, 21.5
HRMS:
(ESI
-
TOF)
m/z: [M
2+
]
calc’d for C
15
H
28
N
2
2+
118.1121, found 118.1123.
S
13
Table S1
.
1
H NMR data for authentic vs synthetic (
±
)
-
sparteine bis
-
hydrogen sulfate salt
(D
2
O).
(±)
-
1
·2 H
2
SO
4
literature
δ ppm (400 MHz, D
2
O)
3
(±)
-
1
·2 H
2
SO
4
recorded
δ ppm (600 MHz, D
2
O)
3.59 (br t,
J
= 13.0 Hz, 1H)
3.66 (dd,
J
= 14.5, 11.3 Hz, 1H)
3.48
–
3.31 (m, 4H)
3.52
–
3.45 (m, 3H)
–
3.41 (dt,
J
= 12.1, 3.3 Hz, 1H)
3.24 (br d,
J
= 11.0 Hz, 1H)
3.31 (dd,
J
= 11.9, 2.5 Hz, 1H)
3.17
–
2.96 (m, 4H)
3.20
–
3.14 (m, 2H)
–
3.11 (td,
J
= 12.7, 3.5 Hz, 2H)
2.55 (br d,
J
= 10.0 Hz, 1H)
2.62 (d,
J
= 11.3 Hz, 1H)
2.22 (br s, 1H)
2.30 (s, 1H)
–
2.15 (dq,
J
= 15.3, 4.1 Hz, 1H)
2.08 (br d,
J
= 15.0 Hz, 1H)
2.04 (d,
J
= 14.7 Hz, 1H)
2.01
–
1.44 (m, 13H)
1.98
–
1.86 (m, 6H)
–
1.86
–
1.71 (m, 3H)
–
1.71
–
1.56 (m, 3H)
3
4
5
6
7
8
10
11
12
13
14
15
17
N
N
H
H
2
9
H
H
2 HSO
4
–
S
14
Table S2
.
1
3
C NMR data for authentic vs synthetic (
±
)
-
sparteine
bis
-
sulfate (D
2
O).
Carbon
Number
(±)
-
1
·2 H
2
SO
4
literature
δ ppm (101 MHz, D
2
O)
3
(±)
-
1
·2 H
2
SO
4
recorded
δ ppm (101 MHz, D
2
O)
Δ δ
6
66.5
66.5
0.0
11
63.2
63.2
0.0
10
57.2
57.1
–
0.1
2
56.5
56.5
0.0
15
55.0
55.0
0.0
17
49.0
48.9
–
0.1
9
32.0
32.0
0.0
12
31.3
31.3
0.0
7
29.1
29.1
0.0
5
26.8
26.8
0.0
3
22.7
22.7
0.0
4
22.5
22.5
0.0
14
22.4
22.4
0.0
8
21.9
21.9
0.0
13
21.5
21.5
0.0
3
4
5
6
7
8
10
11
12
13
14
15
17
N
N
H
H
2
9
H
H
2 HSO
4
–
S
15
Preparation of
(±)
-
lupinine (
21
):
An oven dried N
2
flushed 25 mL flask was charged with methyl ester
S1
(50.0 mg, 237
μ
mol, 1.0 equiv) and THF (2.4 mL, 0.1 M) after which the flask was equipped with a reflux
condenser that had been purged with N
2
. The solution was heated to reflux
in an oil bath
and then
lithium aluminum hydride (1.0 M in THF, 1.32 mL, 1.32 mmol, 5.6 equiv) was added dropwise.
The solution was refluxed for 3 hours under N
2
. Upon completion, the reaction was cooled to
ambient temperature, and quenched by a dropwise addition of a saturated solution of Rochelles
salt (10 mL). The reaction mixture was extracted with DCM (5 x 20 mL). The combined organic
layers were dried over a
nhydrous Na
2
SO
4
, filt
ered, and concentrated under reduced pressure. The
crude product was purified via SiO
2
column chromatography [20 g SiO
2
, 20 mm column diameter,
eluted with 35% 2 M NH
3
in MeOH/65% ACN] to yield (±)
-
lupinine (
21
) as a white crystalline
solid (26.9 mg, 67% yield).
Characterization data match previously reported data.
2
(±)
-
Lupinine (21):
1
H NMR (500 MHz, CDCl
3
):
δ
5.43 (s, 1H), 4.16 (ddd,
J
= 10.7, 4.7, 1.7 Hz, 1H), 3.69 (d,
J
=
10.7 Hz, 1H), 2.86
–
2.78 (m, 2H), 2.23
–
2.08 (m, 2H), 2.01 (td,
J
= 12.8, 3.0 Hz, 1H), 1.90
–
1.69
(m, 4H), 1.65
–
1.49 (m, 6H), 1.26 (qt,
J
= 13.5, 4.5 Hz, 1H).
13
C NMR (101 MHz, CDCl
3
):
δ
66.2, 65.2, 57.3, 57.2, 38.2, 31.6, 29.9, 25.8, 24.8, 23.1.
FTIR (NaCl, thin film):
2985, 2941, 2859, 1466, 1445, 1421, 1268, 1262
cm
-
1
.
HRMS:
(FI
-
TOF)
m/z: [M+H
+
]
calc’d for C
10
H
19
NO
H
+
169.1461, found 169.1462.
TLC
(35% 2 M NH
3
in MeOH/65% ACN),
R
f
:
0.39 (KMnO
4
).
M.P.
47.9
–
51.1 °C.