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Ni-Catalyzed Enantioselective Desymmetrization: Development of Divergent Acyl and
Decarbonylative Cross-Coupling Reactions
Ángel D. Hernández-Mejías,
1
Alexander M. Shimozono,
1
Avijit Hazra,
2
Sven Richter,
1
Zhengjia T
ong,
1
Neil Langille,
3
Kyle Quasdorf,
4
Andrew
T. Parsons,
3
Matthew S. Sigman,
*
2
Sarah E. Reisman*
1
1.
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical
Engineering Division of Chemistry and Chemical Engineering, California Institute of
Technology Pasadena, California 91125
2. Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, USA
3.
Drug Substance Technologies – Synthetics, Amgen, Inc. 360 Binney St, Cambridge, MA
02142.
4.
Drug Substance Technologies – Synthetics, Amgen, Inc. One Amgen Center Drive,
Thousand Oaks, CA 91320
Supplementary
Information:
2
Table of Contents
General Information
S3
Ni-Catalyzed Doubly Stereoselective Acyl Cross-Coupling:
Preliminary Experiments
S5
Ni-Catalyzed Asymmetric Decarbonylative Alkylation:
Preliminary Experiments
S11
Synthetic Methods:
Ligand Synthesis
S19
Substrate Synthesis
S35
Substrate Scope: Characterization
Ni-Catalyzed Doubly Stereoselective Acyl Cross-Coupling
S40
Ni-Catalyzed Asymmetric Decarbonylative Alkylation
S86
Derivatization: Characterization
S116
Electrochemical Analysis
S124
X-Ray Diffraction Data
S136
Supplementary References
S145
1
H and
13
C NMR Spectral Data
S146
3
General Information
Materials and Methods
Unless otherwise stated, reactions were performed under a N
2
atmosphere using freshly dried
solvents. Tetrahydrofuran (THF) and dichloromethane (DCM) were dried by passing through
activated alumina columns. Anhydrous dimethylacetamide (DMA) was purchased from Millipore-
Sigma and stored over activated 3Aº mol sieves in an N
2
filled glovebox. BF
3
•OEt
2
was purchased
from Millipore-Sigma and stored in an N
2
filled glovebox at –20 ºC. NiCl
2
•DME was purchased
from Millipore-Sigma or Strem chemicals, stored in an N
2
filled glovebox, and used as received.
Mn
powder was purchased from Millipore-Sigma. Commercially available anhydrides (Combi-
Blocks and Ambeed) were purified by filtration through a short plug of silica using methylene
chloride followed by concentration from
n-
heptane (if solid) or distilled over CaH
2
then stored in
an N
2
filled glovebox prior to use. All other reagents were used as received from commercial
vendors. When applicable, 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, p-
anisaldehyde, or KMnO
4
staining. Flash column chromatography was performed as described by
Still et al.
1
using silica gel (230-400 mesh, Silicycle) or automated chromatography system
(Combi-Flash). Purified compounds were dried on a high vacuum line (0.2 torr) to remove trace
solvent. Optical rotations were measured on a Jasco P-2000 polarimeter using a 100 mm path-
length cell at 589 nm. Enantiomeric excess was measured with an Agilent 1260 Infinity II
SuperCritical Fluid Chromatography (SFC)-MS or HPLC-SFC system.
1
H and
13
C NMR spectra
were recorded on a Bruker Avance III HD with Prodigy cyroprobe (at 400 MHz and 101 MHz,
respectively), a Varian 400 MR (at 400 MHz and 101 MHz, respectively), or a Varian Inova 500
(at 500 MHz and 126 MHz, respectively).
1
H and
19
F NMR spectra were also recorded on a Bruker
400 MHz Spectrometer with broadband iProbe (at 400 MHz and 376 MHz, respectively). NMR
data is reported relative to internal CHCl
3
(
1
H, δ = 7.26), CDCl
3
(
13
C, δ = 77.0),
DMSO (
1
H, δ =
2.50),
d
6
-DMSO (
13
C, δ = 39.52), C
6
H
6
(
1
H, δ = 7.16), and C
6
D
6
(
13
C, δ = 128.06). Data for
1
H
NMR spectra are reported as follows: chemical shift (
δ ppm) (multiplicity, coupling constant (Hz),
integration). Multiplicity and qualifier abbreviations are: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad. IR spectra were recorded on a Perkin Elmer Paragon 1000
spectrometer and are reported in frequency of absorption (cm
–1
). HRMS were acquired on an
Agilent 6230 LC-TOF or from the Caltech Mass Spectral Facility using fast-atom bombardment
4
(FAB), electrospray ionization (ESI-TOF), or electron impact (EI).
Abbreviations Used:
AcOH = Acetic acid, AlCl
3
= Aluminum (III) chloride, Bn = benzyl, BOX = bisoxazoline, CO =
carbon monoxide, c = concentration, CHCl
3
= chloroform, DCM = dichloromethane, DMA =
dimethylacetamide, DMAP = 4-dimethylaminopyridine, DMSO = dimethyl sulfoxide, d.r. =
diastereomer ratio, ee = enantiomeric excess, equiv = equivalents, Et
3
N = triethylamine, Et
2
O =
diethyl ether, EtOAc = ethyl acetate, h = hours, HPLC = high-performance liquid chromatography,
HRMS = high-resolution mass spectrometry, Hz = Hertz, m/z = mass to charge ratio, mg =
milligrams, MeCN = acetonitrile, MeOH = methanol, Mn = Manganese, NMR = nuclear magnetic
resonance, Ni = Nickel,
THF
=tetrahydrofuran, Ts = para-tolylsulfonyl
5
Ni-Catalyzed Doubly Stereoselective Acyl Cross-Coupling: Preliminary Investigations.
Figure S1:
Yield
s determined by
1
H NMR analysis relative to tetrachloronitrobenzene as an
internal standard. The dr and ee
were determined using LC-SFC with chiral stationary phase.
O
O
O
H
H
+
Ph
Cl
Me
NiCl
2
DME
(10 mol%)
L1
(22 mol%), Mn (3)
DMBA (0.75)
DMA/THF (3:7, 0.375M)
23 ºC, overnight
O
Ph
Me
CO
2
H
H
H
N
O
O
N
Me
Me
Ph
Ph
L1
1
2
3
entry
yield
3aa
(%)
0
17
39
conditions
none
– 0.75 DMBA
+ 0.5 BF
3
•OEt
2
% ee
83
88
Me
Me
CO
2
H
DMBA
1a
2a
3aa
dr
3.7:1
10:1
6
General Procedure 1 for Doubly Stereoselective Initial Reaction Screening (0.2 mmol scale):
An oven dried 1-dram vial equipped with a shaved 2-dram teflon coated stir bar was brought into
an N
2
- filled glovebox. Concomitantly, in an N
2
- filled glovebox, 1 stock solution containing
anhydride (2.0 equiv, 0.400 mmol) and a portion of THF (0.50 mL). In the reaction vial, the
corresponding amounts of NiCl
2
•DME, ligand, anhydrous DMA, and a portion of anhydrous THF
(0.25
mL) were added and stirred for approximately 5 minutes (red to purple color depending on
ligand employed). Then, the appropriate amount of the stock solution (0.25 mL) was added to the
reaction mixture, followed by the addition of the remaining components benzyl chloride (2.0 equiv,
56.2 mg, 0.400 mmol), BF
3
•OEt
2
and Mn powder (3.0 equiv, 33.0 mg, 0.600 mmol) (yellow
solution). The reaction vial was sealed with a Teflon cap followed by electrical tape, removed from
the glovebox, and stirred on the bench at 1000 rpm. After the appropriate amount of time, the
reaction (dark grey/black slurry) was quenched by dilution with ethyl acetate (fill vial to 60%
capacity) followed by slow addition of 3M HCl (to 90% capacity, vigorous gas evolution noted)
and stirred at 1000 rpm until gas evolution ceased. The organic phase was removed, and the
remaining aqueous phase was extracted with ethyl acetate (3 x 3mL). The combined organic phases
were washed with 1M LiCl (if cosolvent quantities of DMA were employed), dried over a short
plug of Na
2
SO
4
, concentrated under reduced pressure, and analyzed by
1
H NMR with
tetrachloronitrobenzene standard (to measure yield and d.r.) followed by HPLC/SFC to measure
ee. Reaction performance for each “new” screen was evaluated relative to a positive control using
the “best” conditions at a given time.
O
O
O
H
H
+
Ph
Cl
Me
NiCl
2
DME
(XX mol%)
Ligand
(XX mol%),
DMA (XX mol%),
BF
3
•OEt
2
(XX mol%)
THF (0.4 M)
Mn (3)
23 ºC, overnight
O
Ph
Me
CO
2
H
H
H
1 equiv
1a
2 equiv
2a
3aa