Supporting Information
Palladium-Catalyzed Decarbonylative Dehydration for the Synthesis of
a
-Vinyl Carbonyl Compounds and Total Synthesis of (
)-
Aspewentins A, B, and C**
Yiyang Liu, Scott C. Virgil, Robert H. Grubbs,* and Brian M. Stoltz*
anie_201505161_sm_miscellaneous_information.pdf
1
Table of Contents
Materials and Methods
2
Preparation of Carboxylic Acid Substrates
4
Palladium
-Catalyzed Decarbonylative Dehydration of Ca
rboxylic Acids
18
Spectroscopic Data for Pd
-Catalyzed Decarbonylative Dehydration Products
21
Total Synthesis of (
–)-
Aspewentin A, B, C, and Related Compounds
26
Comparison of Synthetic and Natural Aspewentin A (Table S1)
41
Comparison of Synthetic and Natural Aspewentin B (Table S2)
42
Com
parison of Synthetic and Natural Aspewentin C (Table S3)
43
Methods for the Determination of Enantiomeric Excess (Table S4)
44
References
45
1
H NMR,
13
C NMR, and IR Spectra for New Compounds
46
Representative Chiral HPLC, SFC, and GC Traces
124
Supporting Information for Liu, Virgil, Grubbs, and Stoltz
2
Materials and Methods
Unless otherwise stated, reactions were performed in flame-dried glassware under a nitrogen
atmosphere
using dry, deoxygenated solvents,
or under vacuum without the use of solvents.
Solvents were dried by passage through an activated alumina column under
argon.
1
Reaction
progress was monitored by
thin-layer chromatography (TLC) or
1
H NMR analysis of the crude
reaction mixture.
TLC
was performed using E. Merck silica gel 60 F254 precoated glass plates
(0.25 mm) and
visualized by UV fluorescence quenching,
p
-anisaldehyde,
phosphomolybdic
acid,
or KMnO
4
staining. Silicycle Silia
Flash
® P60 Academic Silica gel (particle size 40
−
63
nm) was used for flash chromatography.
1
H NMR
and
13
C NMR
spectra were recorded on a
Varian Inova 500
(500
MHz
and 126 MHz, respectively)
or
a Bruker
CryoProbe
Prodigy 400
spectrometer (400 MHz and 101 MHz, respectively)
and are reported relative to residual CHCl
3
(
δ
7.26 ppm
and
δ
77.16 ppm, respectively).
Data for
1
H NMR are reported as follows: chemical
shift (
δ
ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as
follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m =
multiplet, br s = broad singlet, br d = broad doublet, app = apparent. Data for
13
C NMR are
reported in terms of chemical shifts (
δ
ppm). IR spectra were obtained by use of a Perkin Elmer
Spectrum BXII spectrometer using thin films deposited on NaCl plates and reported in frequency
of absorption (cm
-1
).
Optical rotations
were measured with a Jasco P
-2000 polarimeter operating
on the sodium D-line (589 nm), using a 100 mm path-length cell and are reported as: [
α
]
D
T
(concentration in g/100 mL, solvent).
Analytical chiral GC was performed with an
Agilent 6850
GC utilizing a
G-TA (30 m x 0.25
mm) column (1.0 mL/min carrier gas flow).
Analytical
chiral
HPLC was performed with an Agilent 1100 Series HPLC utilizing a Chiralpak (AD-H or AS) or
Chiralcel (OD-H, OJ-H, or OB-H)
columns (4.6 mm x 25 cm) obtained from Daicel Chemical
Supporting Information for Liu, Virgil, Grubbs, and Stoltz
3
Industries, Ltd.
Analytical
chiral
SFC was performed with a Mettler SFC supercritical CO
2
analytical chromatography system utilizing Chiralpak (AD
-H, AS-H or IC) or Chiralcel (OD
-H,
OJ-H, or OB-H) columns (4.6 mm x 25 cm) obtained from Daicel Chemical In
dustries, Ltd.
High resolution mass spectra (HRMS) were provided by the California Institute of Technology
Mass Spectrometry Facility using a JEOL JMS
-600H High Resolution Mass Spectrometer
(EI+
or FAB+), or obtained with an Agilent 6200 Series TOF using
Agilent G1978A Multimode
source in
electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), or
mixed ionization mode (MM:
ESI
-APCI).
Reagents were purchased from Sigma-Aldrich, Acros Organics, Strem, or Alfa Aesar and
used as
received unless otherwise stated.
i
-Pr
2
NH
was distilled from calcium hydride prior to
use. (
S
)-
t
-BuPHOX was prepared by a known method.
2
List of Abbreviations:
9-BBN
– 9-borabicyclo(3.3.1)nonane,
Ac
– acetyl,
Cy
– cyclohexyl, Bz
– benzoyl,
DBU
– 1,8-
Diazabicycloundec-7-ene, DIBAL
– diisobutylaluminium hydride, ee
– enantiomeric excess,
HPLC
– high-performance liquid chromatography,
LDA
– lithium diisopropylamide,
MTBE
–
methyl
tert
-butyl ether,
LiHMDS
– lithium hexamethyldisilazide,
NMP
–
N
-methylpyrrolidone,
SFC
– supercritical fluid chromatography, TLC
– thin-layer chromatography,
TEMPO
– 2,2,6,6-
Tetramethylpiperidin-1-yloxy,
TFA
–
trifluoroacetic acid,
THF
–
tetrahydrofuran, Ts
–
p
-
toluenesulfonyl
Supporting Information for Liu, Virgil, Grubbs, and Stoltz
4
Preparation of Carboxylic Acid Substra
tes
3-(1-(Ethoxycarbonyl)-2-oxocyclopentyl)propanoic acid
(8a).
A flame
-dried
100 mL round-
bottom flask
was charged with a magnetic stir bar,
anhydrous
MeCN (30 mL),
β
-keto ester
SI-1
(2.9 mL, 20 mmol, 1 equiv),
tert
-butyl acrylate (3.0 mL, 20.6 mmol,
1.02 equiv), and DBU (0.15
mL,
1 mmol,
0.05 equiv). The light yellow reaction mixture was stirred at 23 °C
. After 12 h,
TLC analysis indicated complete consumption of starting material.
Solvents were evaporated,
and the
crude residue
was purified by flash column chromatography
on silica gel
(10
→
16
→
25%
EtOAc
in hexanes) to afford a colorless oil
(5.22 g). To a solution of this oil (1.42
g) in
CH
2
Cl
2
(4 mL) was added trifluoroacetic acid (4 mL). The reaction mixture was stirred at
23 °C for 30
min and concentrated under reduced pressure. Removal of remaining trifluoroacetic acid by
azeotropic evaporation from toluene (5 mL x 5) afforded carboxylic acid
8a
(1.14
g, 92% yield
over 2 steps) as a
viscous
colorless oil.
R
f
= 0.1 (25% EtOAc in hexanes);
1
H NMR (500 MHz,
CDCl
3
)
δ
7.86 (br
s, 1H), 4.17 (q,
J
= 7.1 Hz, 2H), 2.59 (ddd,
J
= 16.3, 10.2, 5.7 Hz, 1H), 2.53–
2.36 (m, 3H), 2.30 (dt,
J
= 19.0, 8.0 Hz, 1H), 2.19 (ddd,
J
= 14.2, 10.2, 5.7 Hz, 1H), 2.09–1.92
(m, 3H), 1.89 (dt,
J
= 13.1, 7.4 Hz, 1H), 1.25 (t,
J
= 7.1 Hz, 3H);
13
C NMR (126 MHz,
CDCl
3
)
δ
214.7, 178.6, 171.1, 61.8, 59.2, 38.0, 34.0, 29.6, 28.2, 19.7, 14.2;
IR (Neat Film, NaCl)
2979,
1713, 1408, 1158, 1028 cm
-1
; HRMS (MM:
ESI
-APCI–)
m/z
calc’d for C
11
H
15
O
5
[M–H]
–
:
227.0925, found 227.0925.
1.
tert
-butyl
acrylate
(1.02
equiv)
DBU
(5
mol%),
MeCN,
23
°
C
2.
TFA/CH
2
Cl
2
, 23
°
C
(92%
yield
over
2 steps)
O
O
OEt
O
OH
8a
O
O
OEt
SI-1
Supporting Information for Liu, Virgil, Grubbs, and Stoltz
5
Methyl (
R
)-3-(1-methyl-2-oxocyclohexyl)propanoate
(SI-3).
Synthesis of
SI-3
was
based on a
literature procedure.
3
A 100 mL round-bottom flask was charged with a magnetic stir bar, 2
-
methylcyclohexanone (
SI-2
, 3.7 mL, 30.6 mmol, 1
equiv), (
S
)-phenylethylamine (3.71 g, 30.6
mmol, 1 equiv),
p
-toluenesulfonic acid hydrate (58 mg, 0.306 mmol, 0.01 equiv), and toluene
(30 mL).
The flask was equipped with a Dean-Stark trap filled with toluene and a reflux
condenser. The reaction mixture
was heated at reflux for 3.5 h. The Dean-Stark trap
was
replaced with a distillation head, and the toluene was distilled
off
under
reduced pressure. The
residue was cooled to 60 °C under nitrogen and methyl acrylate (3.4 mL, 36.7 mmol, 1.2 equiv)
was ad
ded. The reaction mixture was stirred at 60 °C for 12 h. After cooling to ambient
temperature, the reaction mixture was quantitatively transferred to a 250 mL round
-bottom flask
by rinsing with THF (50 mL total).
Aqueous
20%
acetic acid (30 mL) was added and the
solution was stirred at 23 °C for 5 h.
THF was evaporated under reduced pressure and 1N HCl
(11 mL) was added.
The biphasic mixture was extracted with Et
2
O (25 mL x 3). The combined
organic layers were washed with H
2
O and brine, dried over Na
2
SO
4
, filtered, and concentrated
under reduced pressure. The residue was purified by flash column chromatography on silica gel
(5
→
6
→
10
→
12%
EtOAc
in hexanes)
to afford
δ
-keto ester
SI-3
(4.96 g, 81% yield over 2 steps)
as a
light
brown
oil. R
f
= 0.4 (16%
EtOAc in hexanes);
1
H NMR (500 MHz,
CDCl
3
)
δ
3.66 (s,
3H), 2.46–2.26 (m, 3H), 2.22–2.10 (m, 1H), 2.11–1.98 (m, 1H), 1.93–1.67 (m, 6H), 1.67–1.54
(m, 1H), 1.07 (d,
J
= 2.7 Hz, 3H);
13
C NMR (126 MHz,
CDCl
3
)
δ
215.4, 174.2, 51.8, 48.0, 39.4,
O
1.
(
S
)-phenylethylamine
(1
equiv)
p
-TsOH
•
H
2
O (1
mol%)
toluene,
reflux
2. methyl
acrylate
(1.2
equiv)
neat,
60
°
C;
then
AcOH,
THF
(81%
yield
over
2 steps)
O
OMe
O
SI-2
SI-3
(91%
ee)
Supporting Information for Liu, Virgil, Grubbs, and Stoltz
6
38.8, 32.6, 29.1, 27.6, 22.5, 21.1;
IR (Neat Film, NaCl) 2936, 2865, 1740, 1705, 1437, 1378,
1304, 1197, 1172, 1123, 988
cm
-1
; HRMS (ESI-APCI+)
m/z
calc’d for C
11
H
19
O
3
[M+H]
+
:
199.1329, found 199.1325; [
α
]
D
25
+31.5 (
c
3.00, EtOH, 91% ee).
(
R
)-3-(1-Methyl-2-oxocyclohexyl)propanoic acid
(8b).
To a solution of
SI-3
(2.37 g, 11.9
mmol, 1.0 equiv) in MeOH (11 mL) was added
aqueous
2N NaOH
(7.8 mL, 15.5 mmol, 1.3
equiv). The reaction mixture was stirred at 23 °C for 2 h, then MeOH was evaporated under
reduced pressure. The aqueous layer was
washed
with Et
2
O (10 mL
x 1),
acidified with
1N HCl
(25 mL), and extracted with Et
2
O (25 mL x 3).
The combined organic layers were dried over
Na
2
SO
4
, filtered, and concentrated under reduced pressure to a wet residue. The residue was
redissolved in CH
2
Cl
2
, dried over Na
2
SO
4
, filtered, and concentrated under reduced pressure to
afford
carboxylic acid
8b
(2.14 g, 95% yield) as a light yellow viscous oil. R
f
= 0.1 (25% EtOAc
in hexanes);
1
H NMR (500 MHz,
CDCl
3
)
δ
2.43–2.31 (m, 3H), 2.22 (ddd,
J
= 16.8, 13.2, 5.2 Hz,
1H), 2.06–1.96 (m, 1H), 1.89–1.68 (m,
6H), 1.66–1.56 (m, 1H), 1.08
(s, 3H);
13
C NMR (126
MHz,
CDCl
3
)
δ
215.5, 179.7, 48.0, 39.3, 38.8, 32.4, 29.1, 27.5, 22.6, 21.1;
IR (Neat Film, NaCl)
2936, 1706, 1455, 1312, 1224, 1124, 1097, 902, 856
cm
-1
; HRMS (ESI-APCI–)
m/z
calc’d for
C
10
H
15
O
3
[M–H]
–
: 183.1027, found 183.1034; [
α
]
D
25
+36.0 (
c
4.77, EtOH).
O
OH
O
8b
O
OMe
O
SI-3
(91%
ee)
2N
NaOH,
MeOH
(95%
yield)
Supporting Information for Liu, Virgil, Grubbs, and Stoltz
7
3-(1-Ethyl-2-oxocyclohexyl)propanoic acid
(8c).
Using 2-ethylcyclohexanone (
SI-4
)
as staring
material,
the procedure for
the
synthesis of
8b
was followed to provide carboxylic acid
8c
(3.85
g, 85% yield over 3 steps) as a white solid. m.p. 60–62 °C;
R
f
= 0.1 (25% EtOAc in hexanes);
1
H NMR (500 MHz,
CDCl
3
)
δ
2.45–2.26 (m, 3H), 2.23–2.12 (m, 1H), 1.93–1.58 (m, 9H), 1.54–
1.43 (m, 1H), 0.77 (t,
J
= 7.8 Hz,
3H);
13
C NMR (126 MHz,
CDCl
3
)
δ
215.1, 179.9, 51.1, 39.2,
35.8, 28.9, 28.8, 27.3, 27.2,
20.8, 7.8;
IR (Neat Film, NaCl) 2939, 2868,
1704, 1455, 1423, 1312,
1229, 1127, 1091 cm
-1
; HRMS (ESI-APCI–)
m/z
calc’d for C
11
H
17
O
3
[M–H]
–
: 197.1183, found
197.1187.
3-(1-Allyl-2-oxocyclohexyl)propanoic acid
(8d).
Basic hydrolysis of known
δ
-keto ester
SI-5
4
(2.24 g, 10.0
mmol, 1.0
equiv) afforded carboxylic acid
8d
(2.04 g, 97% yield) as a viscous
colorless oil. R
f
= 0.1 (25% EtOAc in hexanes);
1
H NMR (500 MHz,
CDCl
3
)
δ
10.52 (br
s, 1H),
5.64 (dq,
J
= 17.0, 7.7 Hz, 1H), 5.11–5.02 (m, 2H),
2.44–2.28 (m, 4H), 2.28–2.20 (m, 1H), 2.16
(ddd,
J
= 16.4, 11.2, 5.1 Hz, 1H), 1.96 (ddd,
J
= 15.8, 11.2, 5.0 Hz, 1H), 1.88–1.65 (m, 7H);
13
C
NMR (126 MHz,
CDCl
3
)
δ
214.4, 179.7, 133.1, 118.7, 50.9, 39.2, 39.1, 36.2, 29.5, 28.7, 27.1,
20.8;
IR (Neat Film, NaCl) 2937, 2866, 1704, 1419, 1312, 1221, 1126, 995, 917 cm
-1
; HRMS
(ESI-APCI–)
m/z
calc’d for C
12
H
17
O
3
[M–H]
–
: 209.1183, found 209.1190.
O
OH
O
8c
O
1.
benzylamine
(1
equiv)
p
-TsOH
•
H
2
O (1
mol%)
toluene,
reflux
2. methyl
acrylate
(1.2
equiv)
neat,
60
°
C;
then
AcOH,
THF
3. 2N
NaOH,
MeOH
(85%
yield
over
3 steps)
SI-4
O
OH
O
8d
O
OMe
O
SI-5
2N
NaOH,
MeOH
(97%
yield)
Supporting Information for Liu, Virgil, Grubbs, and Stoltz
8
2-Methylallyl 1-(3-methoxy-3-oxopropyl)-2-oxocyclohexane-1-carboxylate
(SI-7).
A flame
-
dried 100 mL round-bottom flask was charged with a magnetic stir bar, MeCN (30 mL),
β
-keto
ester
SI-6
(3.32 g,
16.9
mmol, 1.0
equiv),
methyl
acrylate (1.6
mL,
17.3
mmol, 1.02 equiv), and
DBU (0.25 mL,
1.69 mmol,
0.1
equiv). The light yellow reaction mixture was stirred at 23 °C.
After 14
h, TLC analysis indicated complete consumption of starting material. Solvents were
evaporated, and the crude residue was purified by flash column chromatography on silica gel
(8
→
16%
EtOAc
in hexanes) to afford
ester
SI-7
(4.69 g, 98% yield) as a colorless oil. R
f
= 0.4
(16% EtOAc in hexanes);
1
H NMR (500 MHz,
CDCl
3
)
δ
4.96 (d,
J
= 16.1 Hz, 2H), 4.54 (s, 2H),
3.65 (s,
3H), 2.54–2.34 (m, 4H), 2.30–2.15 (m,
2H), 2.06–1.89 (m, 2H), 1.82–1.74 (m, 1H), 1.73
(s, 3H),
1.71–1.57 (m, 2H), 1.54–1.43 (m, 1H);
13
C NMR (126 MHz,
CDCl
3
)
δ
207.4, 173.6,
171.5, 139.2, 114.2, 68.8, 60.2, 51.8, 41.1, 36.4, 29.8, 29.5, 27.6, 22.6, 19.7;
IR (Neat Film,
NaCl) 2948, 2867, 1738, 1715, 1436, 1307, 1176, 1135, 990, 907 cm
-1
; HRMS (ESI-APCI+)
m/z
calc’d for C
15
H
23
O
5
[M+H]
+
: 283.1540, found 283.1533.
Methyl (
R
)-3-(1-(2-methylallyl)-2-oxocyclohexyl)propanoate
(SI-8).
In a nitrogen-filled
glove box, a 250 mL Schlenk flask was charged with a magnetic stir bar, Pd
2
(dba)
3
(32 mg,
O
O
O
SI-6
methyl
acrylate
(1.02
equiv)
DBU
(10
mol%)
MeCN,
23
°
C
(98%
yield)
O
O
O
CO
2
Me
SI-7
O
O
O
CO
2
Me
O
OMe
O
SI-7
SI-8
(91%
ee)
[Pd
2
(dba)
3
] (0.5
mol%)
(
S
)-
t
-BuPHOX
(1.25
mol%)
MTBE,
0.1
M,
40
°
C
(89%
yield)
Supporting Information for Liu, Virgil, Grubbs, and Stoltz
9
0.035 mmol, 0.005 equiv), (
S
)-
t
-BuPHOX (34 mg, 0.0875 mmol, 0.0125 equiv), and MTBE (40
mL).
The solution was stirred at ambient temperature for 30 min. Then additional MTBE (21
mL) and
SI-7
(1.98 g, 7.0 mmol, 1.0
equiv) were added via syringe. The syr
inge was rinsed with
MTBE (3 mL x 3) to ensure complete transfer of
SI-7
.
The Schlenk flask was sealed and
taken
out of
the glove box. The reaction mixture was
stirred at 40 °C for
28 h, then concentrated under
reduced pressure. The
crude residue was purified by flash column chromatography
on silica gel
(6
→
10%
EtOAc
in hexanes) to afford
δ
-keto ester
SI-8
(1.49 g, 89% yield) as a colorless oil. R
f
= 0.5 (16% EtOAc in hexanes);
1
H NMR (500 MHz,
CDCl
3
)
δ
4.83 (s, 1H), 4.65 (s, 1H), 3.64 (s,
3H), 2.47 (dt,
J
= 14.0, 6.5 Hz, 1H), 2.42–2.27 (m, 4H), 2.15–2.06 (m, 1H), 2.02–1.92 (m, 1H),
1.91–1.65 (m, 7H), 1.64 (s, 3H);
13
C NMR (126 MHz,
CDCl
3
)
δ
214.4, 174.2, 141.9, 115.4, 51.8,
51.0, 42.9, 39.4, 36.7, 30.5, 28.9, 27.2, 24.5,
20.9;
IR (Neat Film, NaCl) 2943, 2865, 1738, 1699,
1436, 1374, 1173, 1128, 1080,
895 cm
-1
; HRMS (ESI-APCI+)
m/z
calc’d for C
14
H
23
O
3
[M+H]
+
:
239.1642, found 239.1633; [
α
]
D
25
+9.0 (
c
1.00, CHCl
3
, 91% ee).
(
R
)-3-(1-(2-Methylallyl)-2-oxocyclohexyl)propanoic acid
(8e).
Basic hydrolysis of
δ
-keto
ester
SI-8
(1.49 g, 6.25 mmol, 1 equiv) afforded carboxylic acid
8e
(1.39 g, 99% yield) as a
white solid. m.p. 81–82 °C;
R
f
= 0.1 (25% EtOAc in hexanes);
1
H NMR (500 MHz,
CDCl
3
)
δ
4.82 (s, 1H), 4.64 (s, 1H), 2.54–2.43 (m, 1H), 2.43–2.27 (m,
4H), 2.15 (ddd,
J
= 16.4, 10.8, 5.5
Hz, 1H), 1.96–1.69 (m,
7H), 1.69–1.63 (m, 1H), 1.62 (s, 3H);
13
C NMR (126 MHz,
CDCl
3
)
δ
214.7, 179.9,
141.7, 115.5, 51.0, 43.0, 39.3, 36.7, 30.1, 28.9, 27.1, 24.4, 20.9;
IR (Neat Film,
O
OH
O
8e
O
OMe
O
SI-8
(91%
ee)
2N
NaOH,
MeOH
(99%
yield)
Supporting Information for Liu, Virgil, Grubbs, and Stoltz
10
NaCl) 3074, 2940, 2866, 1704, 1455, 1312, 1219, 1128, 896 cm
-1
; HRMS (ESI-APCI–)
m/z
calc’d for C
13
H
19
O
3
[M–H]
–
: 223.1340, found 223.1345; [
α
]
D
25
+5.4 (
c
1.00, CHCl
3
).
4,4-Dimethyl-5-oxo-5-phenylpentanoic acid
(8f).
A flame
-dried
100
mL round-bottom flask
was charged with a magnetic stir
bar, THF (26
mL), and cooled to 0 °C. A solution of
n
-
butyllithium in hexanes (2.5 M,
5.7
mL,
14.3
mmol, 1.1 equiv) was added, followed by dropwise
addition of diisopropylamine (2.0
mL,
14.3
mmol, 1.1 equiv). The
light yellow
solution was
stirred at 0 °C for 10 min, then cooled to
–78 °C in a dry ice-acetone bath.
Isobutyrophenone
(
SI-9
,
2.0 mL,
13
mmol, 1.0
equiv) was added dropwise. The orange-red solution was stirred at
the same temperature for 30 min, and methyl 3
-bromopropionate (1.7
mL,
15.6
mmol, 1.2 equiv)
was added dropwise. The
dry ice-acetone bath was removed, and the yellow
reaction mixture
was warmed
to
0 °C and stirred
for an additional
2 h.
The reaction was quenched with half
saturated aqueous NH
4
Cl solution
(30 mL)
and extracted with Et
2
O (30 mL x 2). The combined
organic layers were washed with H
2
O and brine, dried over Na
2
SO
4
, filtered, and concentrated
under reduced pressure. The crude residue was purified by flash column chromatography on
silica gel (5%
EtOAc
in hexanes) to afford a colorless oil
(1.20
g), which was subjected to basic
hydrolysis
to provide
carboxylic acid
8f
(0.93
g, 32% yield over 2 steps) as a viscous colorless
oil. R
f
= 0.1 (25% EtOAc in hexanes);
1
H NMR (400 MHz,
CDCl
3
)
δ
7.69–7.65 (m, 2H), 7.50–
7.45 (m, 1H), 7.43–7.37 (m, 2H), 2.36–2.29 (m, 2H), 2.13–2.07 (m, 2H), 1.34 (s, 6H);
13
C NMR
(101 MHz, CDCl
3
)
δ
208.2, 179.7, 138.6, 131.3, 128.4, 127.8, 47.2, 35.3, 29.9, 26.0;
IR (Neat
O
OH
O
8f
O
1. LDA
(1.1
equiv),
then
methyl
3-bromopropionate
(1.2
equiv)
THF,
−
78
→
0
°
C
2.
2N
NaOH,
MeOH
(32%
yield
over
2 steps)
SI-9
Supporting Information for Liu, Virgil, Grubbs, and Stoltz
11
Film, NaCl) 2972, 1709, 1597, 1444, 1303, 1200, 962, 719, 700 cm
-1
; HRMS (ESI-APCI–)
m/z
calc’d for C
13
H
15
O
3
[M–H]
–
: 219.1027, found 219.1035.
4-(Butoxycarbonyl)-4-ethyloctanoic
acid
(8g).
A
flame-dried 50 mL round-bottom flask was
charged with a magnetic stir bar, THF (10 mL), and cooled to 0 °C. A solution of
n
-butyllithium
in hexanes (2.5 M, 2.4 mL, 6.09 mmol, 1.1 equiv) was added, followed by dropwise addition of
diisopropylamine (0.93 mL, 6.65 mmol, 1.2 equiv). The light yellow solution was stirred at 0 °C
for 10 min, then cooled to
–78 °C in a dry ice-acetone bath.
Butyl ester
SI-10
(1.11 g,
5.54
mmol, 1.0
equiv) was added dropwise. The solution was stirred at the same temperature for 40
min, and
allyl bromide
(0.58
mL,
6.65
mmol, 1.2 equiv) was added dropwise.
After stirring at
–
78 °C for 1 h, the dry ice-acetone bath was removed, and the yellow reaction mixture was
warmed to
23 °C and stirred
for an additional
1 h. The reaction was quenched with half
saturated aqueous NH
4
Cl solution
(10 mL)
and extracted with hexanes
(30 mL x 2). The
combined organic layers were washed with H
2
O, dried over Na
2
SO
4
, filtered, and concentrated
under reduced pressure. The crude residue was purified by flash column chromatography on
silica gel (3%
Et
2
O
in hexanes) to afford
the allylated ester as
a colorless oil
(1.24 g, R
f
= 0.8
(10% Et
2
O in hexanes)), which was used directly in the next reaction.
A solution of 9-BBN in THF (0.5 M, 10 mL, 5.0 mmol, 1.1 equiv) was added to a 50 mL
round-bottom flask containing the
allylated ester
(1.24 g, 4.5 mmol, 1.0 equiv) at 0 °C. After
10
min, the ice bath was removed, and the reaction mixture was stirred for another 3 h. Water (10
O
n
-Bu
O
CO
2
H
8g
O
n
-Bu
O
SI-10
1. LDA
(1.1
equiv),
allyl
bromide
(1.2
equiv)
THF,
−
78
→
23
°
C
2.
9-BBN
(1.1
equiv),
THF,
0
°
C
then
H
2
O,
NaBO
3
•
H
2
O
3. NaClO
2
(2
equiv),
NaClO
(2
mol%)
TEMPO
(7
mol%),
pH
6.7,
MeCN/H
2
O,
35
°
C
(71%
yield
over
3 steps)
Supporting Information for Liu, Virgil, Grubbs, and Stoltz
12
mL) was added to the reaction mixture, followed by careful portionwise addition of sodium
perborate hydrate (1.78 g, 17.8 mmol, 4.0 equiv)
to oxidize the organoborane
intermediate
to
the
corresponding
alcohol.
The biphasic mixture was
stirred for 40 min,
and
extracted with EtOAc
(25
mL x 3). The combined organic layers were dried over Na
2
SO
4
, filtered, and concentrated
under reduced pressure. The crude res
idue was purified by flash column chromatography on
silica gel (16
→
25%
EtOAc
in hexanes) to afford
the desired primary alcohol as
a colorless oil
(1.14 g, R
f
= 0.4 (25% EtOAc in hexanes)), which was used directly in the next reaction.
Oxidation of the
primary alcohol to the corresponding carboxylic acid was carried out
following a literature procedure.
5
A 100 mL round-bottom flask was charged with a magnetic
stir bar, the
primary alcohol
(517 mg, 2.0 mmol, 1.0 equiv), TEMPO
(22 mg, 0.14 mmol, 0.07
equiv), MeCN
(10 mL), H
2
O
(2 mL), and
aqueous
phosphate buffer
(0.33
M in NaH
2
PO
4
and
0.33
M in Na
2
HPO
4
, 7.5 mL), and stirred at 20 °C for 5 min. Solid NaClO
2
(452 mg, 4.0 mmol,
2.0 equiv)
was added to the flask and the reaction mixture was stirred for 2
min when the solid
dissolved. A solution of NaClO (0.26 wt%, 1.1 mL, 0.04 mmol, 0.02 equiv) was added, and the
reaction mixture immediately turned dark red. The flask was placed in a pre
-heated 35 °C oil
bath and stirred
for
14 h. TLC analysis showed complete consumption of
the alcohol. To the
reaction mixture was added
H
2
O (15 mL)
and
2N NaOH (4 mL) to bring the solution’s pH to 10.
The biphasic mixture was poured into an
ice-cold
solution of Na
2
SO
3
(610 mg) in H
2
O (10 mL),
stirred for 30 min,
and
extracted with Et
2
O (30 mL x 1). The ethereal layer was back-extracted
with 0.7N NaOH (8 mL x 2).
The
alkaline
aqueous layers were combined and acidified with 6N
HCl (12 mL), and extracted with EtOAc (25 mL
x 3).
The combined EtOAc extracts were
washed
with H
2
O, dried over Na
2
SO
4
, filtered, and concentrated under reduced pressure
to a
liquid/solid mixture. The
mixture
was
dissolved in Et
2
O and solid impurities were filtered off.
Supporting Information for Liu, Virgil, Grubbs, and Stoltz
13
The filtrate was concentrated and purified
by flash column chromatography
on silica gel (5%
MeOH
in CH
2
Cl
2
) to afford
carboxylic acid
8g
(485 mg, 71% yield over 3 steps) as a viscous
colorless oil. R
f
= 0.3
(25% EtOAc in hexanes);
1
H NMR (500 MHz,
CDCl
3
)
δ
10.27 (br
s, 1H),
4.07 (t,
J
= 6.6 Hz, 2H), 2.29–2.19 (m, 2H), 1.95–1.85
(m, 2H), 1.64–1.55 (m, 4H), 1.55–1.49
(m, 2H), 1.43–1.33 (m, 2H), 1.33–1.23 (m, 2H), 1.20–1.05 (m, 2H), 0.93 (t,
J
= 7.4 Hz, 3H),
0.89 (t,
J
= 7.4 Hz, 3H), 0.79 (t,
J
= 7.5 Hz, 3H);
13
C NMR (126 MHz,
CDCl
3
)
δ
179.9, 176.7,
64.4, 48.8, 34.0, 30.8, 29.3, 28.6, 27.2, 26.2, 23.3, 19.3, 14.1, 13.8, 8.4;
IR (Neat Film, NaCl)
2961, 2875, 1716, 1458, 1207, 1133, 947 cm
-1
; HRMS (ESI-APCI–)
m/z
calc’d for C
15
H
27
O
4
[M–H]
–
: 271.1915, found 271.1923.
3-Allyl-1-benzyl-3-ethylpiperidin-2-one
(SI-12).
A flame
-dried
100 mL
round-bottom flask
was charged with a magnetic stir bar, THF (15 mL), diisopropylamine (1.0 mL, 7.08 mmol, 1.1
equiv), and cooled to 0 °C. A solution of
n
-butyllithium in hexanes (2.5 M, 2.8 mL, 7.08 mmol,
1.1 equiv) was added dropwise. The light
yellow solution was stirred at 0 °C for 10 min, then
cooled to
–78 °C in a dry ice-acetone bath. A solution of benzyl lactam
SI-11
(1.40 g, 6.44
mmol, 1.0 equiv) in THF (5
mL) was added dropwise. The
dark greenish yellow
solution was
stirred at
–78 °C
for 20 min, and allyl bromide (0.67
mL,
7.73
mmol, 1.2 equiv) was added
dropwise.
The
color of the
reaction mixture immediately turned into light yellow. T
he dry ice-
acetone bath was removed, and the yellow reaction mixture was warmed to 23 °C and stirred
for
an additional 1 h. The reaction was quenched with
half saturated
aqueous NH
4
Cl solution
(20
mL) and extracted with
EtOAc
(25
mL x
3). The combined organic layers were washed with
N
Ph
O
SI-11
N
Ph
O
SI-12
LDA
(1.1
equiv)
THF,
−
78
→
23
°
C
then
allyl
bromide
(1.2
equiv)