Supporting Information for Stanko, Ramirez, de Almenara,
Virgil, and Stoltz
S
1
Supporting Information
-
Experimental Procedures and
Spectroscopic Data
Enantioselective Nickel
-
Catalyzed
a
-
Spirocyclization of Lactones
Allison M. Stanko, Melissa Ramirez, Adrian J
.
de Almenara, Scott C. Virgil, Brian M. Stoltz*
Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering, Division of
Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California
91125, United
States.
*stoltz@caltech.edu
Table of Contents
Materials
and Methods
.....................................................................................
S2
List of Abbreviations
....................................................................................
...
S3
Substrate Preparation
......................................................................................
S
4
Lactam Spirocyclization
.................................................................................
.
S34
General Procedure for Lactone Spirocyclization: Optimization Scale
...........................
..
S
36
Additional
Optimization Experiments
: Automated Reaction Setup
...........................
.....
S
37
General Procedure for Spirocyclization: Isolation Scale
..........................................
...
S
40
Spirocyclization
Procedure at
1.0 mmol Scale
............
.............................................
S41
N
-
Aryl Imine Isolation
....................................................................................
S68
NMR and IR Spectra
......................................................................................
S69
References
................................................................................................
S176
Supporting Information for Stanko, Ramirez, de Almenara,
Virgil, and Stoltz
S
2
Materials and Methods
Unless otherwise stated, reactions were performed in flame
-
dried glassware under an
argon
or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through
an activated alumina column under argon. Reaction progress was monitored by thin
-
layer
chromatography (TLC) or Agilent 1290 UHPLC
-
MS. TLC was performed us
ing E. Merck silica
gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching or
KMnO
4
staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40
–
63
μ
m) was used
for silica gel flash chromatography.
1
H NMR spec
tra were recorded on Varian Inova 500
MHz,Varian Inova 600 MHz, and Bruker 400 MHz spectrometers and are reported relative to
residual CHCl
3
(
δ 7.26
ppm).
13
C NMR spectra were recorded using a Bruker 400 MHz
spectrometer (100 MHz) and are reported relative to residual CHCl
3
(
δ 77.16
ppm)
19
F NMR
spectra were recorded on a Varian Mercury 300 MHz spectrometer (282 MHz) or a Bruker 400
MHz spectrometer (376 MHz) and referenced to an external standard
:
hexafluorobenzene;
19
F
NMR (282 MHz, CDCl
3
)
δ
-
161.64.
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, m = multiplet, br s = broad singlet. Data
for
13
C
NMR
is reported in terms of chemical shifts (
δ
ppm).
Some reported spectra include minor solvent
impurities of water (
δ 1.56
ppm), ethyl acetate (
δ 4.12, 2.05, 1.26
ppm), methylene chloride (
δ
5.30 ppm), acetone (
δ 2.17
ppm), grease (
δ 1.26, 0.8
6
ppm), and/or silicon grease (
δ 0.07
ppm),
which do not impact product assignments.
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. Analytical SFC was performed
Supporting Information for Stanko, Ramirez, de Almenara,
Virgil, and Stoltz
S
3
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 Industries,
Ltd.
High resolution mass spectra (HRMS) were obtained from the
Caltech Mass Spectral Facility
using a JEOL JMST2000 AccuTOF GC
-
Alpha time
-
of
-
flight mass
spectrometer using Field Desorption (FD) ionization
.
The absolute configurations of
13b
,
13c
, and
S26
were determined by X
-
ray crystallography, and all other products were assigned by analogy
.
Reagents were purchased from commercial sources and
used as received unless otherwise stated.
Ni(COD)
2
, SL
-
M001
-
1, SL
-
M009
-
1, and (S,S)
-
BDPP
were purchased from
Strem Chemicals
.
HG
-
II was gratuitously provided by Umicore.
List of Abbreviations
LHMDS
–
lithium hexamethyldisilazane, COD
–
cyclooctadiene,
SFC
–
Supercritical Fluid
chromatography,
DCM
–
methylene chloride, DMF
–
dimethylformamide,
SL
-
M001
-
1
–
(
S,S
)
Fc
-
1,1’
-
Bis(diphenylphosphino)
-
2,2'
-
bis[(
R,R
)
C
-
(
N,N
-
dimethylamino)phenylmethyl]ferrocene,
SL
-
M009
-
1
–
(
S,S
)
Fc
-
1,1’
-
Bis[bis(3,5
-
dimethylphenyl)phosphino]
-
2,2'
-
bis[(
R,R
)
C
-
(
N,N
-
dimethylamino)phenylmethyl]ferrocene
,
(S,S)
-
BDPP
–
(2
S
,4
S
)
-
2,4
-
Bis(diphenylphosphino)pentane, HG
-
II
–
Hoveyda
-
Grubbs Catalyst
®
M720
, LDA
–
lithium
diisopropyl amide
,
EtOAc
–
ethyl acetate
, RBF
–
round bottom flask
, dppe
–
diphenylphosphino
ethane
, IPA =
isopropanol
, min
–
minutes, h
–
hours
Supporting Information for Stanko, Ramirez, de Almenara,
Virgil, and Stoltz
S
4
Substrate Preparation
General Procedure
A
:
LDA Alkylation for the
Synthesis of Substrates
10
a
–
10
c
and
14
A round
-
bottom flask with a stir bar was flame
-
dried and cooled to room temperature under
vacuum. The flask was backfilled with nitrogen, then diisopropylamine (1.1 equiv, freshly distilled
over CaH) and 1/3 of the THF were added via syringe. The flask was
cooled to 0 ºC in an ice bath,
then
n
-
BuLi (2.5 M in hexanes, 1.1 equiv) was added dropwise over
10
min. After stirring at 0 ºC
for 20 min, the flask was cooled to
-
78 ºC, and a solution of
the
lactone
(1 equiv)
in
1/3 of the THF
was added dropwise over 3
0 min. Lastly, a solution of benzyl bromide (1.2 equiv) was added
dropwise over 30 minutes in the last 1/3 of the THF (0.43 M with respect to
γ
-
butyrolactone) The
reaction was stirred at
-
78 ºC until consumption of
the
lactone was observed by TLC. (1
-
3
hours
depending on the substrate) The reaction was quenched at
-
78 ºC with sat. aq. NH
4
Cl, diluted with
EtOAc (1 x reaction volume), then immediately warmed to room temperature. The reaction was
transferred to a separatory funnel and the aqueous phase was extracted with EtOAc (2 x reaction
volume). The combined organics were washed with brin
e (1 x reaction volume), dried over
Na
2
SO
4
, and concentrated. The crude reaction was purified via
silica gel
flash column
chromatography.
Compound
10
a
was prepared via General Procedure A from
γ
-
butyrolactone (1 equiv, 25 mmol,
1.9 mL) and 2
-
cyanobenzyl bromide (1.2 equiv, 30 mmol, 5.88 g) with a reaction time of 3 h. The
residue was purified by silica gel flash column chromatography (30% EtOAc/Hexanes) and then
O
O
CN
O
O
CN
+
Br
R
R
LDA (1.1 equiv)
THF, 0ºC to -78 ºC, 1-3 h
10a-c, 14
n
n = 1, 2
n
O
O
CN
10a
Supporting Information for Stanko, Ramirez, de Almenara,
Virgil, and Stoltz
S
5
recrystallized (4:9 EtOAc/Hexanes, 130 mL) to afford
10
a
as a fluffy white solid (2.02 g, 40%
yield)
1
H NMR
(600 MHz, CDCl
3
)
δ 7.65 (
dd,
J
= 7.8, 1.4 Hz, 1H), 7.56 (td,
J
= 7.6, 1.4 Hz, 1H), 7.43
(d,
J
= 7.8 Hz, 1H), 7.36 (td,
J
= 7.6, 1.2 Hz, 1H), 4.31 (td,
J
= 8.8, 2.5 Hz, 1H), 4.17 (td,
J
= 9.5,
6.5 Hz, 1H), 3.42 (dd,
J
= 14.2, 5.3 Hz, 1H), 3.08 (dd,
J
= 14.2, 8.5 Hz, 1H), 2.95 (dtd,
J
= 11.0,
8.5, 5.3 Hz, 1H), 2.31 (dddd,
J
= 12.8, 8.8, 6.5, 2.4 Hz, 1H), 2.05 (dtd,
J
= 12.7, 10.3, 8.4 Hz, 1H).
13
C NMR
(101 MHz, CDCl
3
)
δ 177.8, 142.
5
, 133.
4
, 133.
1
, 130.
5
, 127.6, 118.
1
, 113.0, 66.6, 40.90,
34.2, 28.1.
IR (NaCl, Thin Film)
2912, 2224, 1769, 1599, 1487, 1450, 1376, 1310, 1260, 1206, 1187, 1154,
1109, 1021, 957, 916, 765
cm
-
1
HRMS(FI)
m/z
: [M + •]
+
:
Calculated for C
12
H
11
NO
2
: 201.07
90
, Found:
201.078
6
Compound
S1
was prepared in 2 steps from commercially available 4
-
bromo
-
2
-
methylbenzonitrile
according to a published procedure. Spectral data matched those reported in the literature.
1
Compound
10
b
was prepared via General Procedure A from
γ
-
butyrolactone (1 equiv, 0.83 mmol,
63 μL) and benzyl bromide
S1
(1.2 equiv, 1.0 mmol, 225.4 mg) with a reaction time of 1 h. The
residue was purified by silica gel flash column chromatography (35% EtOAc/Hexanes) afford
10
b
as a white solid (116.4 mg, 61% yield)
1
H NMR (400 MHz, CDCl
3
)
δ 7.57 (
d,
J
= 8.6 Hz, 1H), 6.92 (d,
J
= 2.5 Hz, 1H), 6.85 (dd,
J
=
8.6, 2.5 Hz, 1H), 4.41
–
4.27 (m, 1H), 4.18 (ddd,
J
= 10.0, 9.1, 6.5 Hz, 1H), 3.85 (s, 3H), 3.37 (dd,
CN
Br
OMe
S1
O
O
CN
10b
OMe
Supporting Information for Stanko, Ramirez, de Almenara,
Virgil, and Stoltz
S
6
J
= 14.0, 5.2 Hz, 1H), 3.07 (dd,
J
= 14.1, 8.1 Hz, 1H), 2.94 (dtd,
J
= 10.9, 8.3, 5.2 Hz, 1H), 2.33
(dddd,
J
= 12.7, 8.7, 6.4, 2.5 Hz, 1H), 2.06 (dddd,
J
= 14.8, 12.7, 10.0, 8.4 Hz, 1H).
13
C NMR (101 MHz, CDCl
3
)
δ 177.9, 163.2, 144.6, 134.7, 118.
6
, 115.8, 113.
7
, 104.
7
, 66.
7
, 55.
8
,
4
1
.
0
, 34.
3
, 28.0.
IR (NaCl, Thin Film)
3060, 2941, 2915, 2884, 2218, 1768, 1605, 1567, 1494, 1462, 1455, 1431,
1375, 1293, 1249, 1209, 1153, 1110, 1072, 1022, 959, 921, 885, 823, 732, 698
cm
-
1
HRMS(FD)
m/z
: [M + •]
+
Calculated for C
13
H
13
NO
3
: 231.0895; Found: 231.0882
Compound
10
c
was prepared via General Procedure A from
γ
-
butyrolactone (1 equiv, 0.5 mmol,
38 μL) and
2
-
(bromomethyl)
-
4
-
fluorobenzonitrile
(1.2 equiv, 0.6 mmol, 128 mg) with a reaction
time of 2.5 h. The residue was purified by silica gel flash column chromatography (30%
EtOAc/Hexanes) afford
10
c
as a white solid (70.6 mg, 64% yield)
1
H NMR (400 MHz, CDCl
3
)
δ 7.67 (
dd,
J
= 8.6, 5.5 Hz, 1H), 7.17 (dd,
J
= 9.1, 2.5 Hz, 1H), 7.13
–
7.03 (m, 1H), 4.35 (td,
J
= 8.8, 2.3 Hz, 1H), 4.19 (ddd,
J
= 10.2, 9.2, 6.4 Hz, 1H), 3.40 (dd,
J
=
14.2, 5.5 Hz, 1H), 3.09 (dd,
J
= 14.2, 8.1 Hz, 1H), 2.95 (dtd,
J
= 11.1, 8.3, 5.5 Hz, 1H), 2.35 (dddd,
J
= 12.7, 8.6, 6.4, 2.3 Hz, 1H), 2.05 (dddd,
J
= 12.7, 11.1, 10.2, 8.5 Hz, 1H).
13
C NMR (101 MHz, CDCl
3
)
δ 177.
5
, 166.
5
, 163.9, 145.9, 145.8, 135.4, 135.3, 118.1, 117.9,
117.
4
, 115.6, 115.
4
, 109.2, 109.
2
, 66.
6
, 40.
7
, 34.2, 34.2, 28.
2
.
19
F NMR (282 MHz, CDCl
3
)
δ
-
106.39
–
-
106.56 (
m).
IR (NaCl, Thin Film)
2911, 2226, 1766, 1607, 1584, 1493, 1376, 1346, 1279, 1243, 1211, 1171,
1153, 1022,
985, 961, 825, 682
cm
-
1
HRMS(FI)
m/z
: [M + •]
+
:
Calculated for C
12
H
10
NO
2
F: 219.069
6
, Found:
219.069
3
O
O
CN
10c
F
Supporting Information for Stanko, Ramirez, de Almenara,
Virgil, and Stoltz
S
7
Compound
14
was prepared via General Procedure A from
d
-
valerolactone
(
1 equiv, 15 mmol,
1.39 mL) and
2
-
cyanobenzyl bromide
(1.2 equiv, 18 mmol, 3.53 g) with a reaction time of 2 h.
The residue was purified by silica gel flash column chromatography (35% EtOAc/Hexanes) afford
14
as a white solid (2.25 g, 80% yield)
1
H NMR (400 MHz, CDCl
3
)
δ 7.63 (
dd,
J
= 7.7, 1.4 Hz, 1H), 7.54 (td,
J
= 7.6, 1.4 Hz, 1H), 7.47
(dd,
J
= 8.0, 1.3 Hz, 1H), 7.34 (td,
J
= 7.6, 1.3 Hz, 1H), 4.38
–
4.24 (m, 2H), 3.49 (dd,
J
= 14.0,
5.8 Hz, 1H), 3.03 (dd,
J
= 14.1, 7.8 Hz, 1H), 2.91
–
2.79 (m, 1H), 2.08
–
1.80 (m, 3H), 1.63 (ddt,
J
= 12.6, 11.1, 7.1 Hz, 1H).
13
C NMR (101 MHz, CDCl
3
)
δ 173.
5
, 143.
4
, 133.1, 13
3
.
0
, 130.
9
, 127.3, 118.
3
, 113.
1
, 68.
5
, 41.2,
35.
6
, 24.4, 22.0.
IR (NaCl, Thin Film)
3448, 3066, 2952,
2874, 2223, 1768, 1731, 1599, 1573, 1485, 1449, 1401,
1351, 1267, 1212, 1155, 1084, 983, 969, 902, 827, 766, 738, 624
cm
-
1
HRMS(
FI
)
m/z
: [M + •]
+
:
Calculated for C
13
H
13
NO
2
: 215.094
4
, Found: 215.094
3
Alkylation/Decarboxylative Protonation Sequence for the Synthesis of
10
d
Preparation of Alcohol
S2
CN
O
O
14
CN
Br
CN
OH
n
-BuLi (1.0 equiv)
BF
3
·Et
2
O (1.0 equiv)
+
O
THF, -78 ºC, 1 h
Br
CN
CBr
4
(2 equiv)
PPh
3
(1 equiv)
imidazole (1.4 equiv)
DCM, 0ºC to
23 ºC (19 h)
S2
S3
Br
CN
+
O
O
O
O
O
O
O
O
NC
Cs
2
CO
3
(1 equiv)
DMF, 23 ºC, 22.5 h
Pd(OAc)
2
(10 mol %)
HCO
2
H (8.0 equiv)
dppe (12 mol%)
4
Å
MS
dioxane, 40 - 60 ºC,
17 h
O
O
NC
10d
S3
S4
S5
Supporting Information for Stanko, Ramirez, de Almenara,
Virgil, and Stoltz
S
8
A 250 RBF with stir bar was flame
-
dried and cooled under vacuum. The flask was opened, charged
with 2
-
bromobenzonitrile as a solid (1 equiv, 12.5 mmol, 2.28 g), and then evacuated and purged
with nitrogen 3x. THF (0.19 M, 67 mL) was added via cannula and
the solution was cooled to
-
78 ºC. Next,
n
-
BuLi
(2.5 M in hexanes, 1 equiv, 12.5 mmol, 5 mL)
was added dropwise over 10
minutes and the reaction was stirred at
-
78 ºC for 15 minutes. Ethylene oxide (
advertised as 2.5
–
3.3 M in THF, assumed 2.5 M, 2
equiv, 25 mmol, 10 mL) was added dropwise over 10 minutes,
followed by BF
3
•Et
2
O (added quickly via syringe, 1 equiv, 12.5 mmol, 1.54 mL). The reaction was
stirred at
-
78 ºC for 1 hour, after which 2
-
bromobenzonitrile was
observed to be
fully consumed
by TLC
. The reaction was quenched at
-
78 ºC by adding sat. NH
4
Cl
(50 mL)
and
EtOAc
(40 mL)
,
warmed to room temperature, and stirred
at room temperature
overnight. (CAUTION
-
ethylene
oxide is a highly carcinogenic and volatile reagent
,
bp ~ 1
1
ºC at 1 atm
. Care
should be exercised
in handling and quenching this reaction
.
)
The reaction mixture was transferred to a separatory
funnel, the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 50 mL).
The combined organics were washed with brine, dried over Na
2
SO
4
, and concentrated. The residue
was purified via column chromatography to afford
S2
as an off
-
white oil (1.02 g, 55% yield)
1
H NMR (500 MHz, CDCl
3
)
δ 7.68 (
dd,
J
= 7.7, 1.4 Hz, 1H), 7.57 (td,
J
= 7.7, 1.4 Hz, 1H), 7.44
(dd,
J
= 7.8, 1.1 Hz, 1H), 7.37 (td,
J
= 7.6, 1.2 Hz, 1H), 3.99 (t,
J
= 6.5 Hz, 2H), 3.15 (t,
J
= 6.5
Hz, 2H).
13
C NMR (101 MHz, CDCl
3
)
δ 142.
9
, 133.0, 132.9, 130.5, 127.
2
, 118.2, 11
3
.
0
, 62.
8
, 37.
9
.
IR (NaCl, Thin Film)
3434, 3068,
2952, 2881, 2224, 1599, 1486, 1449, 1210, 1165, 1099, 1048,
950, 761, 720
cm
-
1
HRMS(FI)
m/z
: [M + •]
+
Calculated for C
9
H
9
NO: 147.0684, Found: 147.068
2
CN
Br
CN
OH
n
-BuLi (1.0 equiv)
BF
3
·Et
2
O (1.0 equiv)
+
O
THF, -78 ºC, 1 h
S2