of 254
science
.sciencemag.org/content/
367/6477
/
559
/suppl/DC1
Supp
lementary
Material
s
for
Catalyst
-
controlled doubly enantioconvergent coupling of
racemic alkyl nucleophiles and electrophiles
Haohua
Huo
,
Bradley J.
Gorsline
,
Gregory C.
Fu
*
*
Corresponding author.
Email: gcfu@caltech.edu
Published
31 January
20
20
,
Science
367
,
559
(20
20
)
DOI:
10.1126/science.
aaz3855
This PDF file
includes:
Materials and Methods
Supplementary Text
Figs. S1 and S2
Tables S1 to S5
Spectral Data
References
S
1
Table of Contents
I.
General Information
S
2
II.
Preparation of
Chiral Ligand
s
S
3
II
I
.
Preparation of
Electrophiles
S
5
IV.
Preparation of Nucleophiles
S
1
4
V
.
Enantioconvergent
Couplings
S
28
VI
.
E
ffect of Reaction Parameters
S
70
VII
.
Functional
-
Group Compatibility
S
7
3
VIII
.
Derivatization of Coupling Products
S
7
4
IX
.
Assignment of Absolute Configuration
S
8
3
X
.
1
H
-
NMR and
13
C
-
NMR Spectra; Stereoselectivity
Analysis
S
88
X
I
.
References
S
251
S
2
I
.
General Information
All reactions were performed under an atmosphere of dry nitrogen or
argon
.
CH
2
Cl
2
and
THF
were purified and dried using a solvent
-
purification system that contained activated
alumina
under argon
;
THF
was
further dried
using
fresh
ly
activated 4
Å
MS
.
NiCl
2
glyme
(>97%, Strem),
NiBr
2
glyme
(>97%, Strem),
z
inc powder
(
100 mesh,
99.9
% metal
s
basis,
Alfa
Aesar
),
1,5
-
b
is(diphenylphosphino)pentane
(
97%
,
Sigma
-
Aldrich
)
,
LiCl (
anhydrous, beads, −10
mesh, 99.998% trace metals basis,
Sigma
-
A
ldrich
),
and all c
ommercial
ly available
alkyl iodide
s
(
Acros
, Alfa Aesar, Oakwood,
and Sigma
-
Aldrich
) were
used as received.
1
H
and
13
C NMR data were collected on a
Bruker
4
00 MHz
,
a Varian 500 MHz
,
or a Varian
300 MHz
spectrometer at ambient temperature.
19
F NMR data were collected on a Varian 300
MHz
spectrometer at ambient temperature.
HPLC analyses
were c
arried out on an Agilent
1100 series system with Daicel CHIRALPAK® or Daicel CHIRALCEL® columns (4.6 × 250 mm,
particle size 5 μm).
SF
C analyses
were carried out on an Agilent
1260
Infinity II
system with
Daicel CHIRALPAK® or Daicel CHIRALCEL® columns (4.
6 × 250 mm,
particle size 5 μm).
FT
-
IR measurements were carried out on a Thermo Scientific Nicolet iS
5 FT
-
IR
spectrometer
equipped with an
iD5 ATR
a
ccessory
.
H
RMS were acquired using an
A
gilent
6220
TOF
-
LCMS
system
.
Optical rotation data we
re obtained
with a Jasco P‐2000
polarimeter at 589 nm and at
2
2
24
°C, using a 100 mm path‐length cell in the solvent and at the
concentration indicated.
GC analyses were obtained on an Agilent 6890N GC.
Flash column chromatography was
performed using silica gel (Si
liaFlash
®
P60, particle size 40
-
63
μm
, Silicycle).
S
3
II. Preparation of
Chiral Ligand
s
The yields have not been optimized.
General Procedure 1 (GP-1) (
22
).
In
an oven-dried round-bottom flask equipped with a stir
bar, ZnCl
2
(0.20 equiv) was
melt
ed by a propane flame under
high vacuum
and
cooled under
nitrogen
. Chlorobenzene (7 mL/mmol of isoquinoline-1-carbonitrile) was added, followed by
isoquinoline-1-carbonitrile (1.0 equiv, as a soli
d under a positive flow
of nitrogen)
and
the
aminoalcohol (1.2 equiv, dissolv
ed in chlorobenzene (1.0 mL/mmo
l of aminoalcohol)
). The
resulting mixture
was heated at 140 °C for
48 h. Next, the mixture
was allowed to
cool to room
temperature, and
it was
concentrated under
reduced pressure
.
The
residu
e was added
to
CH
2
C
l
2
/H
2
O (3/2; for
H
2
O: 4.0 mL/mmol of isoquinoline-1-carbonitrile), and the mixture
was
filtered through a sintered funnel that
contained celite.
The resulting
solution was
extracted
three times with C
H
2
Cl
2
(4.0
mL
/mmol of isoquinoline-1-carbonitril
e),
and
the combined organic
layers
were washed with brine, dried (Na
2
SO
4
), filter
ed, and
concentrated under
reduced
pressure
. The residue was
pu
rified by flash
chromatography
on silica g
el to
provide the pure
product.
(
S
)-2-(Isoquinolin-1-yl)-4-neopentyl-4,5-dihydrooxazole
.
The title compound was
synthesized according to
GP-1
from isoquinoline-1-carbonitrile (4.19 g, 27.2 mmol)
and
(
S
)-2-
amino-4,4-dimethylpentan-1-o
l
(
3
4
) (4.27 g, 32.6 mmol).
The product was
purified by flash
chromatography
on silica gel
(1:10
1:4 EtOAc/hexanes) to
afford the
product
as
a pale-
yellow solid (5.20
g, 71%), which was
recrystallized
in hexanes
to
provide the ligand
as
colorless
needles
(3.88
g, 53%, >99% ee)
.
HPLC
analysis: The
ee was determined via HPLC on a CHIRALPAK
A
D
-
H
column (10.0%
2
-
PrOH in hexanes, 1.0 mL/min with t
r
=
10.2 min (
(
R
)
-
L
1
)
, t
r
=
9.4 min
(
(
S
)
-
L
1
).
1
H NMR (
4
00 MHz,
CDCl
3
)
δ 9.3
7
9.23
(
m
, 1H), 8.65 (d,
J
= 5.5 Hz, 1H), 7.91
7.85 (m, 1H),
7.77 (dd,
J
= 5.6, 0.9 Hz, 1H), 7.76
7.66 (m, 2H), 4.71 (dd,
J
= 9.6, 8.0 Hz, 1H), 4.
64
4.53
(
m
, 1H),
4.11 (
t
,
J
= 8.
4
Hz, 1H), 2.05 (dd,
J
= 13.9, 5.0 Hz, 1H), 1.59 (dd,
J
= 14.0, 7.6 Hz, 1H), 1.08 (s,
9
H).
13
C NMR (
101
MHz,
CDCl
3
)
δ 161.3
, 146.
4, 141.
7, 136.
7, 130.3
, 128.
4, 127.5, 127.3
, 12
7
.
0, 123.2,
73.7, 65.2
,
50.
7, 30.4, 30.0
.
FT
-
IR (
film
)
: 2952, 2900, 2865, 1363, 1131, 998, 830, 751 cm
-
1
.
HRMS (ESI
-
MS
)
m/z
[M+H
]
+
calcd for
C
17
H
2
1
N
2
O
:
269.1648
, found:
269.1650
.
[
]
2
4
D
=
3
2.7
(
c
1.0, CHCl
3
).
S
4
(3a
S
,8a
R
)
-
2
-
(
I
soquinolin
-
1
-
yl)
-
3a,8a
-
dihydro
-
8
H
-
indeno[1,2
-
d
]oxazole
. The title
compound was synthesized according to
GP
-
1
from
isoquinoline
-
1
-
carbonitrile (
5.00
g,
32.5
mmol) and
(1
S
,2
R
)
-
1
-
amino
-
2,3
-
dihydro
-
1
H
-
inden
-
2
-
ol
(
5.82
g,
39.0
mmol)
.
The
product
was
purified by flash chromatography on silica gel (
1:10
1:1
EtOAc/hexanes
)
to afford the
pro
duct
as a black solid (6.00 g, 65%), which was r
ecrystalliz
ed in
EtOAc/
hexane
s to provide the ligand
as
white
needles (
2.33
g,
25
%
, >99% ee
).
SFC analysis: The ee was determined via SFC on a CHIRALCEL OD
-
3 column (15.0%
2
-
PrOH in supercritical CO
2
,
2.5
mL/min) with t
r
=
15.6
min ((
S,R
)
-
L
2
), t
r
=
16.3
min ((
R,
S
)
-
L
2
).
1
H NMR (400 MHz, CDCl
3
) δ 9.21 (dq,
J
= 8.3, 1.0 Hz, 1H), 8.64 (d,
J
= 5.5 Hz, 1H), 7.87
7.80
(m, 1H), 7.78
7.60 (m, 4H), 7.38
7.27 (m, 3H), 5.99 (dd,
J
= 8.0, 0.8 Hz, 1H), 5.63 (ddd,
J
= 8.2,
4.9, 3.5 Hz, 1H), 3.66
3.51 (m, 2H).
13
C NMR (
101
MHz,
CDCl
3
)
δ 162.4, 146.2, 141.7, 141.6, 139.9, 136.6, 130.3, 128.6, 128.4, 127.5,
127.4, 127.3, 126.9, 125.5, 125.4, 123.3, 82.7, 77.8, 39.7.
FT
-
IR (
film
)
: 3052,
2982, 2917, 1615, 1130, 1020, 1003, 832, 749, 644 cm
-
1
.
HRMS (ESI
-
MS
)
m/z
[M+
Na
]
+
calcd for
C
19
H
14
N
2
O
Na
:
309.0998
, found:
309.1001
.
[
]
22
D
=
47
.7
(
c
1.0, CHCl
3
).