Development of a Zinc-Mediated Approach to a 2,3- cis-Pyrrolidine Arginase Inhibitor

Article abstract of DOI:10.1021/acs.oprd.0c00171

This manuscript outlines the development activities toward a robust synthesis of cis-2,3-pyrrolidine via tandem zinc-enolate cyclization/Negishi coupling that proceeds with high diastereoselectivity. The methodology facilitated a gram-scale delivery of the target API and eliminated the need for costly chiral resolutions and inefficient protecting group manipulations. A series of DFT experiments provided a transition-state model that agrees closely with the experimental observations and provides a more in-depth understanding of the observed selectivity.

Full text of DOI:10.1021/acs.oprd.0c00171

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Full Paper
Development of a Zinc-Mediated Approach
to a 2,3-cis-pyrrolidine Arginase Inhibitor
Thomas W Lyons, Theodore Martinot, Cyndi He, Ji Qi, and Guangxin Shao
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00171 • Publication Date (Web): 09 Jun 2020
Downloaded from pubs.acs.org on June 9, 2020
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Development of a Zinc-Mediated Approach to a 2,3-
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cis-pyrrolidine Arginase Inhibitor
Thomas W. Lyons*†, Theodore A. Martinot†‡, Cyndi Qixin He , Ji Qi , Guangxin Shao⸋
◊
○
AUTHOR ADDRESS †Department of Process Research and Development, Merck & Co.,
◊
Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Department Modeling and
○
Informatics, Merck & Co., Inc., 90 E. Scott Ave., Rahway NJ 07065, USA. Department
of Process Research and Development, Merck &Co., Inc., 126 E. Lincoln Ave, Rahway
⸋
NJ 07065, USA. Department of Synthetic Chemistry, Pharmaron Beijing Co., Ltd. 6
Taihe Rd BDA, Beijing, 100176, China.
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Table of Contents Figure
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HO
OEt
ZnBr
B
OH
Br
LiHMDS
O
N
N
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ZnBr2
tBuXPhos Pd G3
N
HN
CO2Et
CO2Et
CO2H
• High yield Zn-cascade
• High diastereoselectivity
• DFT transition state model
• Multi-gram scale
• High stereoselectivity
• API crystallization
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Abstract
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This manuscript outlines the development activities toward a robust synthesis of a cis-
2,3-pyrrolidine via a tandem zinc-enolate cyclization / Negishi coupling that proceeds with
high diastereoselectivity. The methodology facilitated a gram-scale delivery of the target
API and eliminated the need for costly chiral resolutions and inefficient protecting group
manipulations. A series of DFT experiments provided a transition state model that agrees closely
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with the experimental observations and provides a more in-depth understanding of the observed
selectivity.
KEYWORDS. Arginase inhibitor, zinc, cyclization, Negishi
Introduction
Arginase is a manganese-containing enzyme that catalyzes the hydrolysis of L-arginine
to L-ornithine and urea as part of the urea cycle. In humans, this enzyme is predominantly
found in the liver (ARG I, hepatic arginase), but has also been found within the
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mitochondrial matrix (ARG II, extrahepatic arginase).1-3 By regulating the availability of L-
arginine and L-ornithine, arginase plays an important role in the cellular function of both
normal and cancer cells.4 High levels of arginase activity have been reported in various
types of cancer including breast,5 pancreatic,6 non-small cell lung,7 and prostate cancers.8
Several studies have identified a promising therapeutic link between this metabolic
pathway and cancer.9, 10 Moreover, small molecule arginase inhibitors have been shown
to have significant immune-mediated anti-tumor effects.11, 12 In particular, the combination
of arginase inhibitors with checkpoint inhibitors in mice has led to a decrease in tumor
growth.12 Given these studies and related reports, arginase has become an attractive
target for cancer therapy.
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First Generation Synthesis
As part of a drug discovery program we became interested in robust methods for the
synthesis of compound 7 as an arginase inhibitor to support exploratory safety and toxicity
studies. Initial quantities of 7 were produced via the pyrrole functionalization strategy
shown in Scheme 1. This route utilized a Stille13 coupling of an advanced intermediate
114,15 with allyl tin, followed by an Ir-catalyzed hydroboration of the resulting allyl chain to
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give 3. Subsequent hydrogenation of the heterocycle and Boc cleavage revealed (+/-) 5.
Cbz protection of (+/-) 5 was required to achieve efficient supercritical fluid
chromatography (SFC) separation of the enantiomers of 6. Finally, global deprotection
with HCl and ion exchange chromatography (IEC) produced 7 as a white powder after
lyophilization.16, 17 While this sequence was suitable for small-scale preparation (< 1g) of
7 and related derivatives, it was plagued by low yields and an SFC separation which
necessitated a protecting group change. To alleviate these constraints and provide more
efficient access to 7 we began exploring alternative approaches to the cis-2,3-
disubstituted proline core.18, 19
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Boc
N
O
O
Boc
N
O
O
BH
Pd/C
H2
Boc
N
Boc
N
O
O
O
O
Bu3Sn
O
O
[Ir(cod)Cl]2
dppe, DCM
40%
MeOH
66%
Pd(PPh3)2Cl2,
DMF
Br
64%
B
B
O
O
1
O
O
2
3
(+/-) 4
Cbz
O
H
N
N
O
O
HN
O
1. Cbz-Cl
TEA
1. HCl deprotection
2. IEC separation
O
O
HCl/dioxane
HO
B
2. SFC separation
30 %
OH
OH
6
O
CH2Cl2
99%
B
76%
B
O
7
O
(+/-) 5
Scheme 1. Initial route to 7
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We envisioned a different synthetic sequence, outlined in Scheme 2, that leveraged the
amino-zinc-enolate cyclization reported by Karoyan and Chassaing20-22 simultaneously
with others23-25 to provide access to the desired cis-3-allyl pyrrolidine product 9. This
would involve a Zn-mediated cyclization, followed by an in situ Negishi coupling to afford
the allyl product. This new route provides three key advantages. First, the starting material
is inexpensive and readily synthesized from commercial compounds. Second, the
benzylamine chiral auxiliary provides stereocontrol and obviates the need for SFC
separation. Third, the overall step count is reduced, increasing the efficiency of the
synthesis.
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OR
Deprotection
Hydroboration
Zinc cyclization/
Negishi
HN
O
N
O
N
HO
N
RO2C
CO2R
OH
OH
O
B
B
O
7
8
9
10
Scheme 2. Retrosynthetic Analysis
While the zinc cyclization had been carried out with a number of electrophiles22, 26, 27, 28
,
the in situ Negishi sequence had only been demonstrated with iodobenzene29, 30; the use
of vinyl halides has not been reported. Dialkylbiarylphosphine ligands such as CPhos
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have been shown to be highly effective in the cross-coupling of alkylzinc reagents.31, 32
Thus we began exploring Negishi conditions with that ligand system. We were pleased to
see our initial conditions of 10 mol % CPhos Pd G4 with 1.5 equivalents vinyl bromide
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1
provided 35% isolated yield of the desired product (Scheme 3). The crude H NMR
spectrum indicated an approximately 87:13 ratio of diastereomers. Column
chromatography and further 2D 1H NMR analysis confirmed that the major diastereomer
bore the desired cis-2,3 configuration.33 With this exciting proof-of-concept in hand, we
set about optimizing this reaction.
OEt
ZnBr
Br
O
1. LDA (1.5 equiv.)
THF, –78 °C to 0 °C
N
N
CPhos Pd G4
N
CO2Et
CO2Et
2. ZnBr2 (3 equiv.)
–78 °C to rt
(35%)
11
12
13
Scheme 3. One Pot Zn-Mediated Cyclization.
Zinc-Cyclization Optimization. To further our understanding of this key transformation
we focused on the first cyclization step by quenching the Zn reaction with water rather
than adding a Pd/vinyl bromide solution. This afforded the methyl pyrrolidine product and
the opportunity to interrogate the effects of base, solvent, and ester identity on the
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cyclization. To that end, we examined several organic bases in THF. Our initial base
choice based on literature precendent21 was LDA and provided high conversion and dr.
LiHMDS and KHMDS also provided high conversion to the desired product (R=Et, Table
1, entries 2, 3). The stronger base nBuLi (Table 1, entry 4) led to consumption of 11a, but
was ultimately deleterious to the formation of 14a. The weaker alkoxide bases (Table 1,
entries 5, 7, 8) were ineffective, leaving residual 11a to be observed in the LCMS. Taken
together, these data suggest the alkoxide bases are unable to generate the enolate
sufficiently and nBuLi is too strong a base, which leads to decomposition.
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We also explored other etherial solvents in these reactions including diethyl ether, and
diisopropyl ether. While initial experiments with diethyl ether showed promising
conversions and dr (e.g. Table 1, entry 10), we found these results to be difficult to
reproduce in repeat experiments and ultimately not compatible with the Negishi
conditions. A larger scale of this reaction revealed a biphasic mixture upon addition of the
ZnBr2 solution and warming to 0 °C. This mixture became gelatinous in appearance over
time and was ultimately deleterious to the reaction, resulting in low yield of the desired
Negishi product.34 Other common etherial solvents including 2-Me-THF, diisopropyl ether,
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and CPME resulted in minimal conversion (>10%) and were unsuitable for the Negishi
conditions.
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Interestingly, the choice of ester had a strong influence on the outcome of the reaction.
The benzyl ester substrate 11b (R=Bn, entries 11-14) provided lower conversion and
lower dr relative to 11a (R=Et). Switching to the tBu ester 11c (R=tBu, entries 15, 16)
provided only trace conversion to the desired product, leaving predominantly residual
starting material. In the end, LiHMDS in THF using R=Et provided the most robust
conversion and dr for this reaction, which improved slightly at larger scale; a reaction run
on a 5 g scale gave 95% conversion and 87:13 dr of 14a.
Table 1. Base and Substrate Screen for the Cyclization Reaction a
OR
ZnBr
O
Base
Solvent
1.
(0.95 equiv)
–78°C - 0°C
H2O
N
N
N
CO2R
2. ZnBr2 (3 equiv.)
–78°C to RT
CO2R
11 a-c
12 a-c
14 a-c
Entry
Base
R
Solvent
Conversion
%
dr
Et (11 a)
THF
82
92:8
LDA
1
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Et
THF
THF
THF
THF
THF
THF
THF
Et2O
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
91
98
83
1.2
91
<5
<5
78
94
55
61
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65
<5
<5
87:13
83:17
n/a
LiHMDS
KHMDS
nBuLi
2
3
Et
Et
4
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Et
0
LiOtBu
LiTMP
NaOtBu
KOtBu
LDA
5
Et
85:15
n/a
6
Et
7
Et
Et
n/a
8
92:8
93:7
83:17
75:25
83:17
75:25
n/a
9
Et
LiHMDS
LDA
10
11
12
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14
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16
Bn (11 b)
Bn
LDA
Bn
LiHMDS
LiHMDS
LDA
Bn
tBu (11 c)
tBu
n/a
LDA
a Reaction conversion and dr determined on the basis of the LCAP of the desired product from the
crude reaction mixture. ZnBr2 added as a solid to the reaction mixture.
Using the optimized conditions, we monitored this reaction using in situ IR (ReactIR)
which illustrate the steps of the cyclization. As shown in Figure 1, addition of LiHMDS
leads to rapid formation of the Li-enolate. The disappearance of the ester peak at 1752
cm-1 is followed by formation of a new peak at 1663 cm-1. Addition of ZnBr2 then produces
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the proposed Zn-enolate characterized by a new shift in the IR spectrum to 1680 cm-1
and shown below in the calculated Z-geometry (Figure 1). Conversion to the cyclized
intermediate takes place over several hours at –78 ℃ as indicated by the disappearance of
enolate IR signal and formation of the new alkyl-Zn species 12 in the IR spectrum (Figure 1).
Closely monitoring the formation of the cyclized intermediate 12 via ReactIR or LCMS
enabled high conversion in the subsequent Negishi coupling upon scale-up.
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OEt
Me
ZnBr
O
N
O
1. LiHMDS (1.2 equiv.)
THF, –78°C to 0°C
2. ZnBr2 (3 equiv.)
–78°C to RT
O
Br
Zn
Me
Me
N
H
Me
N
H
CO2Et
(S)
warm to RT
Ph
H
11
12
Z-enolate
Figure 1. Following the cyclization reaction using ReactIR
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Negishi Reaction Optimization. While our initial result with CPhosPd G431 provided
rapid and clean conversion to the desired allyl pyrrolidine, we were interested in exploring
catalyst alternatives that were less expensive and more amenable to larger scale. Thus,
we pursued an extensive screen of known Pd precatalysts in our coupling conditions
using a freshly prepared solution of the alkyl-Zn species. While the complexities of
distributing this zinc solution into micro vial kits resulted in lower overall conversions than
larger scale reactions35, the observed relative performance from the data provided an
adequate guide for appropriate alternatives (Figure 2). These results indicated that a
number of viable replacements for CPhosPd G4 existed, including APhos G2, DTBPF
G3, and tBuXPhos G3. While several Pd precatalysts were competent for this
transformation, we found the cost and ready availability of tBuXPhos to be the most
appealing choice. In addition to catalyst, the high conversion to the cyclized Zn
intermediate 12 was also critical in achieving high yields of 13, highlighting the importance
of in situ monitoring.
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ZnBr
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CO2Et
Negishi Coupling
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o
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)
yst
G
G2 G4
G
h
G3
G
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G
G3 G3
l
G
G
G2 G3
G2
G
G
G
G2
G2 G3
G
G2 G4 G2
G
G2 G3
G2
G
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G3
G3
h 3
a
G
s
s
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i
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s G s G
s
s
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s G
h
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9
h
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F
3
)
l
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h 3
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P
y) 3
A
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y 3
h
u 3
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h
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ca
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(
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u
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p
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p
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t
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J0
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t
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i
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(
B
t
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l
t
t
t
t
h
Cl 2
d
ckP
e
r
T
o
n
u
u
t
t
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D
tt
S
C
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A
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(
n
Q
n
n
Cg
o
e
e
e
ve
e
u
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u
a
a
a
r
r
P
s
r
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e
Da
o
a
r
Ip
ckie B
t
B
t
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u
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B
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-
w
P
R
ta ta
a
D
m
I
yJo
i-
d
e 4
M
S
a
Ja
M
B
C
N
A
t
C
C
P
P
E
P
-
d
P
Figure 2. Investigation of 39 ligand-supported precatalysts for Negishi coupling. Error bars
represent conversion measured over two experiments.
Computational Analysis. To gain insight into the nature of the reaction selectivity, we
undertook a series of DFT experiments that provided a transition state model for the Zn-
mediated cyclization.36 In the cyclization step, two new stereocenters are generated in
the C–C bond formation, leading to four possible diastereomeric pathways in the
presence of the existing chirality from the auxiliary (Figure 3). Initial conformational
analysis showed that to access the trans-ring product, an E configuration of the amino
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zinc enolate is adopted to coordinate to the enolate oxygen and the terminal alkene, giving
rise to the (S,S,S)- and (S,R,R)-pyrrolidine products. The cis-products, on the other hand,
comes from a Z-enolate, where both the enolate oxygen and the nitrogen are on the same
side and can coordinate to zinc.
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Figure 3. Possible diastereomeric pathways of Zn-mediated cyclization and DFT-
optimized transition states of tetrahedral zinc complexes.
The reaction energy profiles for 4-coordinate (tetrahedral) and 6-coordinate (octahedral)
zinc were explored. Previous DFT studies have shown that zinc prefers to be tetrahedral
in the gas-phase, octahedral in aqueous solution, and can adopt either geometry in a
protein environment depending on the type of ligand and solvent accessibility.37 Figure 4
shows the lowest energy tetrahedral and octahedral zinc complexes undergoing
cyclization to the corresponding cis- and trans- products. In both models, the Z-enolate
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12a′-Z is significantly more stable (ΔΔG = 20 kcal/mol) than the E isomer 12a′-E. This
large energy difference partly arises from the absence of nitrogen and alkene coordination
to zinc in the E-enolate, because the enolate oxygen and the nitrogen are trans to each
other and cannot simultaneously coordinate to zinc. To account for the empty
coordination sites, explicit ether molecules are included in the E-enolate pathway.38
Comparing the cis-/trans-determining transition states, formation of the 2,3-trans product
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is highly disfavored (ΔΔG = 11–18 kcal/mol) in both coordination models.
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(A) Tetrahedral zinc model
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Me
Me
O
O
O
Me
Zn
H
H
H
N
Me
Me
Br
O
Ph
Br
O
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MeO
Zn
TSS,S
12a'-ETS
28.0 (17.1)
H
O
H
H
N
Me
Zn
Ph
Me2O
Me
Ph
E-enolate
12a'-E
19.7 (21.4)
N
TSS,R
'-Z
12a TS
MeO2C
Ph
(S)
(S)
H
MeO2C
Ph
(S)
Br
Br
(R)
N
16.6 (15.4)
O
N
Zn
OMe
Z-enolate
12a'-Z
productS,S
14a'-SS
0
productS,R
14a'-SR
N
6.1 (6.9)
Me
8.2 (9.1)
(B) Octahedral zinc model
Me
Me
Me
O
Me
O
Me
Me
O
Me
Me
Me
O
Me
O
O
O
MeO
H
Zn
O
Me
Br
MeO
Me
Ph
TSS,S
12a'-ETS
33.6 (10.9)
Zn
Br
Me
O
O
H
Br
Zn
N
Ph
Me
Me
O
Me
Me
Me
N
Me
O
H
H
H
H
N
Me
Br
O
Me
E-enolate
12a'-E
19.5 (3.2)
O
Zn
MeO2C
(S)
(S)
TSS,R
12a'-ZTS
15.5 (13.8)
MeO2C
(S)
N
(R)
N
Me
Me2O
N
Ph
Z-enolate
12a'-Z
Ph
productS,S
14a'-SS
0
productS,R
14a'-SR
6.1 (6.9)
G (H)
energies in kcal/mol
M06-2X/6-311+G(2d,2p)/SMD(THF) // M06-L/6-31+G(d,p)/SMD(THF)
8.2 (9.1)
Figure 4. Calculated cyclization reaction energy profiles of (A) tetrahedrally and (B)
octahedrally coordinated zinc complexes. (TS = transition state).
A closer examination of the two possible transition states leading to cis-(2S,3R)- and cis-
(2R,3S)-products reveals a 0.8 kcal/mol difference in energy between the two
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diastereomeric TSs (Figure 5). A fine balance of two key interactions, the favorable
phenyl–zinc coordination and the methyl–methylene repulsion (Figure 5, green line),
dictate diastereoselectivity. A similar 12a′-TSZ,S,R is predicted to be 0.8 kcal/mol more
stable than 12a′-TSZ,R,S. These data match nicely with the experimental diastereomeric
ratio of 87:13 and no observable amount of the 2,3-trans product. These interactions are
also in agreement with previously proposed transition state models22, 24 and the reported
loss of dr when the phenyl-zinc interaction is replaced with a cyclohexyl ring.24
Additionally, in both TSs, the methoxy group of the ester points away from the chiral
auxiliary (Figure S1). The computed dr of benzyl and tert-butyl esters are consistent with
experimental observations that varying the ester does not increase cis-(S,R)/(R,S)-
selectivity (Figure 3). This suggests that enolate formation rather than cyclization is the
problematic step in our optimization reactions (Table 1, entries 11-14). Interestingly, while
both the tetrahedral and octahedral zinc models give reasonable and surmountable
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energy barriers (ΔG = 15–16 kcal/mol), the former predicts the wrong cis-
diastereoselectivity (Figure S1, S2), which suggests that an octahedrally coordinated zinc
complex is more likely the operable species.
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Figure 5. Proposed role of chiral auxiliary in the diastereoselectivity of two possible cis-
products.
Optimized Route. The final route provided us with a good yield of 7 and a high level of
purity for toxicity studies (Scheme 4). It began with the nucleophilic displacement of 4-
bromobutene (15) with (S)-methylbenzylamine, an inexpensive source of chirality for this
sequence. The homoallylamine 16 was exposed to the bromoester in the presence of
base to yield the cyclization precursor (11) in 85% yield. Subjecting 11 to the optimized
conditions of LiHMDS and ZnBr2 in THF gave >90% conversion to the alkyl-Zn
intermediate. Addition of vinyl bromide and tBuXPhos Pd G3 to the mixture gave the
desired allyl pyrrolidine 13 in 76% isolated yield, and this reaction was successfully scaled
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to >200 g. Purity upgrade of the desired cis-diastereomer was achieved by crystallization
of the HCl salt (17) in toluene. Attempts were made to carry out this crystallization directly
from the reaction mixture but were ultimately less efficient than the isolation from toluene.
In addition to affording a diastereomeric enrichment of the reaction product, the isolation
of the HCl salt 17 provided a practical crystalline handle in the synthetic sequence among
intermediates that otherwise had poor physical properties. An important challenge in the
synthesis of 7 and related compounds is that intermediates were often oils that could only
be purified using chromatography. Thus, any opportunity to capitalize on key crystalline
intermediates for impurity control provided a significant benefit.39 While the HCl salt could
be used directly in the subsequent coupling, a lower overall conversion was observed
compared to the free base. Therefore, the free base 13 was generated with NaHCO3 and
subsequently subjected to Ir-catalyzed borylation with HBPin to give 18 in 68% yield.
Lower iridium catalyst loading can be employed, but this resulted in longer reaction times
and greater amounts of boronic ester hydrolysis – the major side product of this reaction.
Hydrogenation with Pd(OH)2 cleaved the benzyl group and resulted in partial deprotection
of the boronic acid to give a mixture of 19 and 20. Subjecting this mixture to HCl at 80 °C
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gave full deprotection of the desired compound, which was subsequently purified via ion-
exchange chromatography. Importantly, we have also found crystallization conditions for
7 from IPA/H2O, which were suitable for purging any residual 20 remaining in the reaction.
These crystallization conditions may be suitable for related compounds, which have been
historically difficult to purify.
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OEt
O
O
Br
(1.5equiv)
O
NH2
(1.3 equiv)
N
K2CO3 (4 equiv)
NaI (4 equiv)
1. LiHMDS (1.2 equiv)
–78 °C / THF
2. ZnBr2 (3 equiv)
–78 °C / THF
NH
K2CO3 (2 equiv)
Br
DMF, 50 °C
(85%)
DMF, 90 °C
(53 %)
15
16
11
HCl
N
ZnBr
Br (1.5 equiv)
N
N
N
tBuXPhos Pd G3 (0.1 equiv)
NaHCO3
adjust pH > 7
(62% for 2 steps)
HCl 4M in dioxane
toluene, 20 °C
CO2Et
CO2Et
CO2Et
CO2Et
25-30 °C
(76%)
12
13
7:1 dr
17
> 100:1 dr
13
O
O
O
HO
B
B
O
3 eq.
BH
O
HO
B
OH
B
O
OH
12 M HCl
80 °C
H2
N
HN
DPPM (0.1 equiv)
[Ir(cod)Cl]2 (0.07 equiv)
0-30 °C
Pd(OH)2/C (20% wt)
rt, H2O
HN
HN
CO2Et
CO2H
CO2Et
19
CO2Et
(71% for 2 steps)
(68%)
18
20
7
Scheme 4. Optimized Synthetic Route
Conclusion
In summary, we developed an efficient synthesis to 2,3-cis substituted pyrrolidine 7. This
route features a Zn-mediated cyclization that provided the desired cis configuration in
high yield and dr. Our transition state model suggests a Zn-arene interaction and methyl-
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methylene repulsion are important interactions for dictating the diastereoselectivity. In situ
monitoring enabled high conversion and selectivity for this step. Key to the
stereochemical purity of this route was the crystallization of the HCl salt 17 in toluene,
which provided a diastereomeric upgrade from 87:13 dr to greater than 100:1. The final
API was purified by ion-exchange chromatography in 10.2% overall yield and analyzed
by LCMS with CAD detection and both 1H and 11B NMR. The chiral purity was verified by
SFC. IEC used in the purification of 7 can be substituted for a crystallization from IPA /
H2O. This compares favorably to the previous route, which was 3.8% yield from an
advanced intermediate.
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EXPERIMENTAL SECTION
Materials and Methods. Reactions were performed in scintillation vials with Teflon septa
and kept under a nitrogen atmosphere via a needle unless otherwise specified. Reactions
were monitored by liquid chromatography/mass spectrometry (LCMS) or thin-layer
chromatography (TLC) on silica gel 60 F254 plates (EMD) and visualized with UV light
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(254 nm). IR spectra were obtained using a Metler Toledo ReactIR15 equipped with a
diamond probe and a sampling rate of 1 scan/min (3000 to 650 cm-1). The data was
processed with iC IR 7.0 with standard background subtraction techniques. Flash
chromatography was performed using prepacked RediSep Rf Gold silica gel columns on
a Teledyne Isco CombiFlash Rf automated chromatography system. Organic solutions
were concentrated under reduced pressure on a rotary evaporator. Tetrahydrofuran
(THF), acetonitrile (MeCN), dimethylformamide (DMF), 1.0 M LiHMDS solution in THF,
4M HCl solution in dioxane were purchased from Sigma-Aldrich in Sure-Seal bottles and
used as received. ZnBr2 ampules (99.999%, beads, 10 mesh) were purchased from
Sigma-Aldrich and stored in an inert atmosphere glovebox. For large scale reactions
ZnBr2 (>98%) was purchased from Sigma-Aldrich and dried under vacuum overnight at
80 ℃ before use. Precatalysts tBuXPhos Pd G3 and CPhos Pd G4 as well as [Ir(COD)Cl]2
were purchased from Strem Chemicals and used as received.
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Negishi Catalyst Screen. For this screen two kits containing 24 ligands each were used.
An internally prepared ligand kit (prepared as described below) was used as well as a
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commercially available cross-coupling kit (KitAlysis-24PD, Sigma-Aldrich). The
experiments were set up in an MBraun glovebox (oxygen typically <5ppm). Liquid
chemicals and reagent solutions were dosed using a micropipetter. Stirring was
accomplished with parylene stir bars and a tumble stirrer.
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Internal Ligand Kit. Ligands (0.25 μmol) were dosed into the reactor vials as solutions,
and the solvent was removed by evacuation on a Genevac evaporator. A parylene stir
bar was added to each vial, and the plates were stored in the glovebox or a desiccator.
The 24 microvials containing the precatalysts were placed in an aluminum block. In a
flask, a mixture of 12 was freshly prepared (0.158 M, 3 mL), then combined with 0.7 mL
of vinyl bromide (1.0 M in THF) in a glovebox and 25 μL was dispensed into each of the
precatalysts on the plate. Below each reactor vial in the aluminum 24-well plate was a
0.062 mm-thick silicon rubber gasket. Directly above the glass vial reactor tops was a
0.002 mm Teflon perfluoroalkoxy copolymer resin (PFA) sealing gasket, and above that
were two more 0.062 mm-thick silicon rubber gaskets. The entire assembly was
compressed between an aluminum top and the reactor base with nine evenly placed
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screws. The reaction block was removed from the glovebox and placed on a tumble
stirrer. The tumble stirrer was set to 50% and left at room temperature for 18 h. The
reaction block was removed, and each sample was quenched by the addition of 100 μL
of quenching solution (prepared by mixing 30.8 mg of biphenyl, 100 mL of MeCN, and 33
mL of DMSO). The plate was then resealed and stirred for 20 min. For analysis, a sample
was removed from each reaction vial (25 μL) and diluted with 400 μL of MeCN. The diluted
mixture was filtered and analyzed by LCMS.
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KitAlysis Ligand Kit. In a flask, a mixture of 12 was freshly prepared (0.158 M, 3 mL),
then combined with 0.7 mL of vinyl bromide (1.0 M in THF). In a glovebox 100 μL of the
solution was charged to each of the vials in the kit. The plate was sealed as above, and
the reaction block removed from the glovebox and placed on the tumble stirrer. The
tumble stirrer was set to 50% and left at room temperature for 18 h. The reaction block
was removed, and each sample was quenched by the addition of 400 μL of quenching
solution (prepared by mixing 30.8 mg of biphenyl, 100 mL of MeCN, and 33 mL of DMSO).
The plate was then resealed and stirred for 20 min. For analysis, a sample was removed
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from each reaction vial (25 μL) and diluted with 400 μL of MeCN. The diluted mixture was
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General Procedures. (S)-N-(1-phenylethyl)but-3-en-1-amine (16). Into a 5-L 4-necked
round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was
placed 4-bromobut-1-ene (250.00 g, 1.85 mol, 1.00 equiv) in DMF (2.5 L), (1S)-1-
phenylethan-1-amine (291.73 g, 2.40 mol, 1.30 equiv), K2CO3 (1.03 kg, 7407 mmol, 4.00
equiv) and sodium iodide (1.11 kg, 7.40 mol, 4.00 equiv). The resulting solution was
stirred for 16 h at 90 ℃. The reaction mixture was then cooled to room temperature and
quenched by the addition of water (2.50 L). The solution was transferred to a separatory
funnel and extracted with 3 x 1000 mL of ethyl acetate. The organic layer was washed
with 3 x 1000 mL of 5 % NaCl and dried over anhydrous magnesium sulfate. The solids
were filtered out. The crude product was purified by distillation under reduced pressure
(0.01 atm) and the product-bearing fraction was collected at 85 ℃. This resulted in 172.0
g (53%) of (S)-N-(1-phenylethyl)but-3-en-1-amine as a yellow oil. The spectroscopic data
20
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Ethyl (S)-N-(but-3-en-1-yl)-N-(1-phenylethyl)glycinate (11). Into a 5-L 4-necked round-
bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed
(but-3-en-1-yl)[(1S)-1-phenylethyl]amine (172.00 g, 981.3 mmol, 1.00 equiv) in DMF (1.7
L), ethyl 2-bromoacetate (245.82 g, 1.472 mol, 1.50 equiv), K2CO3 (273.22 g, 1.963 mol,
2.00 equiv). The resulting solution was stirred for 16 h at 50 ℃. The reaction mixture was
then cooled to room temperature and quenched by the addition of water (1.7 L). The
mixture was transferred to a separatory funnel and extracted with 3 x 1000 mL of ethyl
acetate. The organic layer was washed with 2 x 1000 mL of 5% NaCl and dried over
anhydrous magnesium sulfate. The solids were filtered out and the filtrate was
concentrated under reduced pressure. The residue was applied onto a silica gel column
with ethyl acetate/petroleum ether (1:10). This resulted in 220.0 g (85%) of Ethyl (S)-N-
(but-3-en-1-yl)-N-(1-phenylethyl)glycinate as yellow oil. The spectroscopic data matched
that reported in the literature.20
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Ethyl (2S,3R)-3-allyl-1-((S)-1-phenylethyl)pyrrolidine-2-carboxylate (13). Into a 10-L 4-
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1 h, was placed ethyl 2-[(but-3-en-1-yl)[(1S)-1-phenylethyl]amino]acetate (11) (220.00 g,
841.7 mmol, 1.00 equiv) in 2.2 L dry THF (H2O < 0.01%). The mixture was cooled to –78
℃, and LiHMDS (1.00 L, 1 mol/L, 1.2 equiv) was added. The solution was stirred at –78
℃ for 10 min and then allowed to warm to 0 ℃ and stirred at 0 ℃ for 30min. An aliquot
of the reaction mixture was quenched with D2O and analyzed by LCMS to show that the
reaction (enolate formation) was complete. The solution of the lithium enolate was cooled
back down to –78 ℃. In a separate flask, ZnBr2 (568.65 g, 2.52 mol, 3.00 equiv) was
dissolved in THF (1.50 L) and 284 g of 4Å-molecular sieves was added. The solution of
ZnBr2 was added into the solution of the lithium enolate at –78 ℃ over 30 min (exotherm
observed). The solution was warmed to rt and stirred at rt for 1 h. An aliquot of the reaction
mixture was quenched with D2O (11 and 14 have the same mass) and analyzed by LCMS
to show that the reaction (conversion of 11 to 12) was complete. To the mixture was
added vinylbromide in THF (1.263 L, 1.263 mol, 1.50 equiv 1 mol/L) (dried with 4Å-
molecular sieves (43 g)) dropwise at 25 ℃ over 10 min. t-BuXPhos Pd G3 (66.86 g,
84.173 mmol, 0.10 equiv) was added into the mixture at 25 ℃, and the mixture was stirred
at 30 ℃ for 16 h. The reaction mixture was cooled to 0 ℃ with a water/ice bath and was
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quenched by addition of 1000 mL of HCl (1M). The resulting solution was transferred to
a separatory funnel and extracted with 3 x 1000 mL of ethyl acetate. The organic layer
was washed with 2 x 500 mL of 10% NaHCO3. The organic layer was dried over
anhydrous magnesium sulfate. The solids were filtered off and the filtrate was
concentrated under reduced pressure. The residue was applied onto a silica gel column
with ethyl acetate/petroleum ether (1:10). This resulted in 220.0 g (76%) of ethyl (2S,3R)-
1-[(1S)-1-phenylethyl]-3-(prop-2-en-1-yl)pyrrolidine-2-carboxylate as a light yellow oil with
of 7:1. Major diastereomer: 1H NMR (600 MHz, CDCl3) δ 7.39 (s, 5H), 5.63 (m, 1H), 5.01
(d, J = 4.6 Hz, 1H), 4.99 (s, 1H), 4.46 ( s, 1H), 4.22 (s, 1H), 4.09 (m, 1H), 3.85 (d, J = 7.2
Hz, 1H), 3.56 (s, 1H), 2.83 (s, 1H), 2.35 (s, 1H), 2.13 (dt, J = 12.4, 6.0 Hz, 1H), 1.88 (dq,
J = 11.6, 7.1 Hz, 1H), 1.80 (m, 1H), 1.74 (d, J = 6.9 Hz, 1H), 1.15 (t, J = 7.1 Hz, 1H). 13C
NMR (600 MHz, CDCl3) δ 13.92, 19.89, 28.81, 34.38, 40.89, 52.32, 61.79, 64.25, 66.40,
117.49, 129.13, 129.70, 134.47, 136.13, 168.32. Two peaks coincidentally overlap.
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Ethyl (2S,3R)-3-allyl-1-((S)-1-phenylethyl)pyrrolidine-2-carboxylate hydrochloride (17).
Into a 3-L 4-necked round-bottom flask purged and maintained with an inert atmosphere
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of nitrogen, was placed crude ethyl (2S,3R)-1-[(1S)-1-phenylethyl]-3-(prop-2-en-1-
yl)pyrrolidine-2-carboxylate (205.00 g, 713.3 mmol, 1.00 equiv) in toluene (1000 mL). HCl
(200 mL, 4M in 1,4-dioxane) was added to the mixture at 20 ℃ over 10 min. The resulting
solution was stirred for 5 hours at room temperature. The solids were collected by filtration
(13:13A = 1:1 in mother liquor). The solids (dr = 97:3) were slurried with n-hexanes (5
volumes) for 2 h, and were collected by filtration. This resulted in 140 g of ethyl (2S,3R)-
1-[(1S)-1-phenylethyl]-3-(prop-2-en-1-yl)pyrrolidine-2-carboxylate hydrochloride as a
white solid (61%, dr =99.7:0.3). 1H NMR (400 MHz, CDCl3) δ 13.26 (s, 1H), 7.65 (s, 2H),
7.37 (s, 3H), 5.70 – 5.51 (m, 1H), 5.02 – 4.96 (m, 1H), 4.95 (s, 1H), 4.45 (p, J = 6.9 Hz,
1H), 4.05 (dddt, J = 18.0, 10.8, 7.2, 3.6 Hz, 3H), 3.79 (dd, J = 7.1, 4.1 Hz, 1H), 3.50 (tdd,
J = 10.9, 6.6, 3.8 Hz, 1H), 3.23 – 3.07 (m, 1H), 2.35 (ddd, J = 12.3, 3.7 Hz, 1H), 2.11 (dt,
J = 13.7, 6.0 Hz, 1H), 1.90 (dd, J = 11.6, 7.3 Hz, 1H), 1.83 (d, J = 6.9 Hz, 4H), 1.81 – 1.68
(m, 1H), 1.12 (t, J = 7.2 Hz, 3H).
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Ethyl (2S,3R)-3-allyl-1-((S)-1-phenylethyl)pyrrolidine-2-carboxylate (13) from Ethyl
(2S,3R)-3-allyl-1-((S)-1-phenylethyl)pyrrolidine-2-carboxylate hydrochloride (17). Into a
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