Enantioselective synthesis of α-methyl-β-cyclopropyldihydrocinnamates

Article abstract of DOI:10.1021/acs.joc.5b02296

α- and β-substitution of dihydrocinnamates has been shown to increase the biological activity of various drug candidates. Recently, we identified enantio- and diastereopure α-methyl-β-cyclopropyldihydrocinnamates to be important pharmacophores in one of our drug discovery programs and endeavored to devise an asymmetric hydrogenation strategy to improve access to this valuable framework. We used high throughput experimentation to define stereoconvergent Suzuki-Miyaura cross-coupling conditions affording (Z)-α-methyl-β-cyclopropylcinnamates and subsequent ruthenium-catalyzed asymmetric hydrogenation conditions affording the desired products in excellent enantio- and diastereoselectivities. These conditions were executed on multigram to kilogram scale to provide three key enantiopure α-methyl-β-cyclopropyldihydrocinnamates with high selectivity.

Full text of DOI:10.1021/acs.joc.5b02296

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Article
Enantioselective Synthesis of #-Methyl-#-Cyclopropyldihydrocinnamates
Melodie Christensen, Andrew Nolting, Michael Shevlin, Mark Weisel, Peter E. Maligres, Joshua Lee, Robert K
Orr, Christopher W. Plummer, Matthew Thomas Tudge, Louis-Charles Campeau, and Rebecca Tamra Ruck
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02296 • Publication Date (Web): 07 Jan 2016
Downloaded from http://pubs.acs.org on January 11, 2016
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Enantioselective Synthesis of αꢀMethylꢀβꢀ
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Cyclopropyldihydrocinnamates
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Melodie Christensen,*,† Andrew Nolting, *,† Michael Shevlin,† Mark Weisel,† Peter E. Maligres,†
Joshua Lee,† Robert K. Orr,† Christopher W. Plummer,‡ Matthew T. Tudge,† LouisꢀCharles
Campeau,† Rebecca T. Ruck †
† Department of Process and Analytical Chemistry, Merck Research Laboratories, Rahway, New
Jersey 07065, United States
‡ Department of Discovery Chemistry, Merck Research Laboratories, Kenilworth, New Jersey
07033, United States
ABSTRACT
αꢀ and βꢀsubstitution of dihydrocinnamates has been shown to increase the biological activity of
various drug candidates. Recently, we identified enantioꢀ and diastereopure ꢀmethylꢀβꢀ
α
cyclopropyldihydrocinnamates to be important pharmacophores in one of our drug discovery
programs and endeavored to devise an asymmetric hydrogenation strategy to improve access to
this valuable framework. We used high throughput experimentation to define stereoconvergent
SuzukiꢀMiyaura crossꢀcoupling conditions affording (Z)ꢀαꢀmethylꢀβꢀcyclopropylcinnamates and
subsequent rutheniumꢀcatalyzed asymmetric hydrogenation conditions affording the desired
products in excellent enantioꢀ and diastereoselectivities. These conditions were executed on
multigram to kilogram scale to provide three key enantiopure
cyclopropyldihydrocinnamates with high selectivity.
αꢀmethylꢀβꢀ
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INTRODUCTION
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Dihydrocinnamate derivatives represent an important class of compounds in the field of drug
discovery and development that are widely used as building blocks in the synthesis of drug
candidates. In addition, dihydrocinnamate moieties have been observed in several compounds of
biological interest. This observation may be explained by their unique structure, comprised of an
aromatic ring and carboxylate group spaced by a two carbon aliphatic chain, which can lead to
specific spatial interactions with biological targets.1 Recent examples in the literature indicate
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that
αꢀ and βꢀ substitution of dihydrocinnamate moieties can further increase biological activity
in drug candidates.2
Recently,
αꢀmethylꢀβꢀcyclopropyldihydrocinnamates were found to be important
pharmacophores in one of our drug discovery programs. Their initial access route was fraught
with long linear sequences, low yields, and requisite chiral chromatography – a bottleneck that
quickly came to limit the discovery and development of new promising drug candidates. To
overcome this challenge we embarked towards the discovery of a novel, efficient, enantioꢀ and
diastereoselective synthesis centered around asymmetric hydrogenation of tetra substituted
cinnamate esters (Scheme 1).
Scheme 1. Asymmetric hydrogenation approach
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We immediately recognized that both the stereoselective synthesis of the tetra substituted
cinnamate esters and the subsequent asymmetric hydrogenation3 would pose substantial
challenges, particularly in the presence of the hydrogenation labile cyclopropyl substituents.4
Even though recent progress has been made in the asymmetric hydrogenation of tetra substituted
enamides,5 αꢀdehydroamino acid derivatives,6 βꢀdehydroamino acid derivatives7 and unsaturated
carboxylic acids;8 fewer examples can be found around the asymmetric hydrogenation of
unsaturated esters,9 enones10 and unfunctionalized olefins11 lacking strong coordinating
functional groups. We therefore brought to bear the power of high throughput experimentation
(HTE) to rapidly scan across reaction space and identify promising conditions for the
development of these two key transformations.
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Herein, we describe the utilization of HTE to define both a stereoselective SuzukiꢀMiyaura
crossꢀcoupling as well as an asymmetric hydrogenation affording the desired products in
excellent enantioꢀ and diastereoselectivities.
RESULTS & DISCUSSION
Preparation of (Z)-α-methyl-β-cyclopropylcinnamates. The initial strategy to access αꢀ
methylꢀβꢀcyclopropyldihydrocinnamates intercepted Meldrum’s acid derivative 3, installing the
βꢀsubstituent via conjugate addition. The overall racemic synthesis was five linear steps followed
by a challenging chiral separation, affording the desired products in less than 10% overall yield
(Scheme 2). In addition, attempts to install the desired functionality using copper catalyzed
conjugate addition to α,βꢀunsaturated esters failed to produce any of the desired product.
Scheme 2. Original route for the synthesis of α,βꢀdisubstitutedꢀdihydrocinnamates
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Our first step towards accessing chiral
α
,βꢀdisubstitutedꢀdihydrocinnamates via asymmetric
hydrogenation was to investigate the synthesis of geometrically pure (Z)ꢀα,βꢀdisubstitutedꢀ
cinnamates, as we recognized that the olefin geometry would define the relative stereochemistry
at the ꢀ and βꢀ positions. In addition, we aimed to design a synthesis that would allow for
α
introduction of a variety of aryl substituents. Our strategy to obtain the (Z)ꢀcinnamate centered
on a crossꢀcoupling reaction between an appropriate aryl nucleophile and a (Z)ꢀvinyl halide or
sulfonate, assuming the geometry could be preserved under the appropriate reaction
conditions.6a,12 This modular route would allow for introduction of a high degree of diversity to
support any future structure activity research (Scheme 3).
Scheme 3. Retrosynthetic analysis for preparation of α,βꢀdisubstitutedꢀdihydrocinnamates
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Execution of our planned synthesis began through alkylation of methyl 3ꢀcyclopropylꢀ3ꢀ
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oxopropanoate (6) with methyl iodide to afford αꢀsubstitutedꢀβꢀketoester 7, which, on treatment
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with KHMDS at ꢀ20 °C in the presence of tosyl anhydride provided enol tosylate 8 in good yield,
albeit in a 1:1 E:Z ratio. Further optimization via screening of base and temperature
combinations provided either stereoisomer with good selectivity. Deprotonation with NaHMDS
at ambient temperature provided 95:5 selectivity for the desired (Z)ꢀenol tosylate 8 (Table 1).
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Table 1. Selective synthesis of the (Z)ꢀenol tosylate
Entry
Base
Temperature
E/Z
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2
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7
KHMDS
LiHMDS
LiHMDS
NaH
ꢀ20 °C
ꢀ20 °C
rt
50/50
70/30
5/95a
20/80
80/20
5/95b
30/70
rt
NaHMDS
NaHMDS
NaOtBu
ꢀ78 °C
rt
ꢀ20 °C
aSignificant impurity generation observed. b58% isolated yield.
(Z)ꢀenol tosylate 8 was then subjected to a series of conditions via HTE in order to develop the
optimal SuzukiꢀMiyaura conditions. Upon evaluating 24 ligands in 8 base and solvent
combinations, we found Pd(OAc)2/ XPhos or SPhos with K3PO4 as base in a mixture of
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acetonitrile and water afforded the highest yield of desired product (Figure 1).13 Crucially,
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cinnamate ester 10 was generated as a single observable stereoisomer.
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BnO
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BnO
B(OH)2
Pd(OAc)2
Ligand
Base
OTs O
(Z)
O
(Z)
OMe
OMe
Solvent, 25 °C
Me
Me
(Z)-10
(Z)-8
95:5 Z:E
Figure 1. HTE results for SuzukiꢀMiyaura couplinga,b
aConditions: 1.0 equiv enol tosylate, 1.1 equiv boronic acid, 10 mol% Pd(OAc)2, 20 mol%
ligand, 3 equiv 1.0M aq base, 0.1M, 25 °C, 3 h. bAssay yields as determined by UPLCꢀMS at
210 nm using 1,2,3,5ꢀtetramethoxybenzene as an internal standard.
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To further study this key coupling reaction we subjected (E)ꢀenol tosylate 8 to the optimized
Suzuki conditions and were surprised to again isolate exclusively the (Z)ꢀSuzuki product 10
(Scheme 4). This finding indicates an unexpected isomerization of either the reactant or product,
most likely through a conjugate addition/elimination process.14,15 In order to test for a base
catalyzed addition/elimination mechanism of the starting material, we treated the (E)ꢀ and (Z)ꢀ
enol tosylates independently with aqueous K3PO4 in acetonitrile, and observed no isomerization
of either. In addition, the Suzuki reaction rates from both enol tosylate stereoisomers were
similar. This leads us to suspect that palladium reinsertion and/or ligand effects may play a role
in the isomerization. Two recent literature reports attribute the occurrence of isomerization under
SuzukiꢀMiyaura conditions to palladium or ligand effects; further experiments are underway to
confirm such effects in our system.6a,16
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Scheme 4. Formation of (Z)ꢀSuzuki product from both (E)ꢀ and (Z)ꢀ enol tosylates
Development of Asymmetric Hydrogenation Conditions. With tetra substituted (Z)ꢀ
βꢀcyclopropylcinnamate 10 in hand, we began HTE efforts to study the asymmetric
hydrogenation to (S,R)ꢀ ꢀmethylꢀβꢀcyclopropyldihydrocinnamate 11. To our knowledge,
αꢀmethylꢀ
α
asymmetric hydrogenation of tetra substituted unsaturated esters bearing potentially
hydrogenationꢀlabile cyclopropyl moieties have not been previously reported.3,4,9 We focused
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our initial evaluation on two transition metal precursors previously shown to catalyze the
asymmetric hydrogenation of tetra substituted olefins, (NBD)2RhBF4 and (Meꢀallyl)2Ru(COD)/
HBF4.6, 9 The screen design incorporated 24 chiral phosphine ligands and two solvents, 2MeTHF
and MeOH. The permutations of these factors resulted in a 96ꢀexperiment array, which was
placed in a 500 psi H2 atmosphere at 60 °C overnight.
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In general, rhodium catalysts gave low conversion to product due to significant substrate
decomposition. Given that cyclopropylalkenes are known substrates for rhodium catalyzed
cycloadditions, it is likely that rhodium catalyzed cyclopropane ring opening was responsible for
the observed decomposition.17 While most ruthenium catalysts gave low conversion to the
product, the combination of (Meꢀallyl)2Ru(COD)/ HBF4 and Josiphos J010ꢀ118 in MeOH
afforded 83% conversion and 94% ee for the (R,S)ꢀenantiomer of dihydrocinnamate 11,
providing a promising hit for future investigation (Figure 2).
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Rh or Ru Precursor BnO
Ligand
HBF4-Et2O
BnO
500 psi H2
(R)
(Z)
(S)
CO2Me
CO2Me
Solvent, 60 °C
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Me
Me
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(Z)-10
(S,R)-11
Figure 2. HTE results for asymmetric hydrogenationa,b
aConditions: 20 mol% metal precursor, 21 mol% ligand, 40 mol% HBF4ꢀEt2O, 0.02M, MeOH,
500 psi H2, 60 °C, 20 h. bScatter plot of % ee against % conversion as determined by chiral SFC
at 210 nm. See supplemental information for list of ligands screened.
We then screened a broader collection of commercially available chiral phosphine ligands in
combination with (Meꢀallyl)2Ru(COD)/ HBF4 in MeOH with the goal of improving on our initial
lead and developing optimal conditions. Five highꢀperforming catalyst systems were identified
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that afforded excellent conversions and enantioselectivities for the (R,S)ꢀenantiomer of
dihydrocinnamate 11 (Table 2). Notably, all the ligands that furnished highꢀperforming catalysts
were members of the Josiphos and JoSPOphos ligand families.19 Three of these ligands displayed
structural similarity in having biaryl phosphine substituents on the sterogenic center (Figure 3).
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Table 2. Best results from chiral phosphine ligand screen
Entrya
Ligandb
J010ꢀ1
J506ꢀ1
J502ꢀ1
J688ꢀ1
J301ꢀ1
J212ꢀ1
Convc
84
%eec
94
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2
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100
100
99
96
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100
94
90
aConditions: 20 mol% (Meꢀallyl)2Ru(COD), 21 mol% ligand, 40 mol% HBF4ꢀEt2O, 0.02M,
MeOH, 500 psi H2, 60 °C, 20 h. bSee Figure 3 for ligand structures. cAs determined by chiral
SFC at 210 nm.
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F
F
F
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P
P
P
P
P
P
Fe
Fe
Fe
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F
F
F
J010-1
J506-1
J502-1
O
H
P
P
P
O
P
P
P
Fe
Fe
Fe
O
J688-1
J301-1
J212-1
Figure 3. Selected ligands from asymmetric hydrogenation screening
We subjected the most promising chiral ligands, Josiphos J502ꢀ1 and JoSPOphos J688ꢀ1, to
comparative loading studies (Table 3). In order to achieve optimal catalyst loadings, we
increased the substrate concentration from 0.02M to 0.2M and the reaction temperature from 60
°C to 80 °C. Each system catalyzed full conversion to product at 2 mol% loading, with the J502ꢀ
1 bound catalyst giving slightly higher product enantioselectivity (Table 3, entry 3). Bearing in
mind that a precious metal recovery step could potentially be implemented to offset the cost of
high catalyst loading, enantiomeric ligand J502ꢀ2 was selected to synthesize desired (S,R)ꢀ
methylꢀβꢀcyclopropyldihydrocinnamate 11.
αꢀ
Table 3. Loading study and comparison of J502ꢀ1 and J688ꢀ1.
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Entrya
% Rub
J502ꢀ1
J688ꢀ1
Convc
100
100
100
91
%eec
98
Convc
100
100
100
97
%eec
96
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10
5
98
97
2
98
97
1
98
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0.5
58
98
67
97
aConditions: (Meꢀallyl)2Ru(COD), ligand, HBF4.Et2O, 0.2M, MeOH, 500 psi H2, 80 °C, 20 h. bA
ratio of 1.05:1 Ligand/Ru and 2:1 HBF4/Ru was used. cAs determined by chiral HPLC at 210 nm.
The cationic ruthenium/ J502ꢀ2 complex proved proficient in catalyzing the asymmetric
hydrogenation of three
αꢀmethylꢀβꢀcyclopropylcinnamate analogs on multigram to kilogram
scales, affording excellent enantioselectivities of products 11a-11c (Scheme 5). Moreover, this
improved route afforded 11a in 36% overall yield from βꢀketoester 6, a fourꢀfold improvement
over the original route. This improvement in chemistry enabled rapid advancement of several
candidates into toxicology studies.
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Scheme 5. Kilogram and multigram syntheses of αꢀmethylꢀβꢀcyclopropyldihydrocinnamates
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R
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B(OH)2
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R
R
(Me-allyl)2Ru(COD)
J502-2
HBF4-Et2O
500 psi H2
Pd(OAc)2
XPhos
OTs
a
(R)
aq K3PO4
(S) CO2Me
Me
(Z)
(Z)
CO2Me
CO2Me
MeCN, 30 °C
CH2Cl2/ MeOH, 80 °C
Me
(Z)-8
Me
(Z)-10b
(S,R)-11
OBn
Ar:
BnO
1 kg
200 g
98% ee
80% IY
295 g
>99% ee
75% IY
HO
F
98% ee
88% IY
(S,R)-11a
(S,R)-11b
(S,R)-11c
aConditions used for preparation of (Z)-10c: Pd(dppf)Cl2 CH2Cl2, aq Cs2CO3, dioxane, 100 °C.
.
bIsolated yields from Suzuki crossꢀcouplings: (Z)-10a: 74%, (Z)-10b: 83%, (Z)-10c: 63%.
CONCLUSIONS
We have developed a facile route to enantiopure
αꢀmethylꢀβꢀcyclopropyldihydrocinnamates
bearing hydrogenationꢀlabile cyclopropyl substituents. Upon identifying conditions for (Z)ꢀ
selective enol tosylate formation, we leveraged HTE to discover stereoconvergent (Z)ꢀselective
SuzukiꢀMiyaura crossꢀcoupling as well as a cationic rutheniumꢀcatalyzed asymmetric
hydrogenation conditions. The developed conditions were mild enough to leave the cyclopropyl
ring intact and general enough to be implemented in the multigram to kilogram scale syntheses
of three enantiopure
αꢀmethylꢀβꢀcyclopropyldihydrocinnamate intermediates.
EXPERIMENTAL
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General Methods. Unless otherwise mentioned, all chemicals were purchased from commercial
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sources and used without further purification. Reactions were monitored by reversedꢀphase
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UPLCꢀMS. H and 13C spectra were recorded on a 500 MHz NMR spectrometer. H NMR
chemical shifts were determined relative to CDCl3 as the internal standard at δ 7.26 ppm. 13C
NMR shifts were determined relative to CDCl3 at δ 77.16 ppm. Mass spectra were recorded on a
highꢀresolution mass spectrometer in the EI, FAB or ESI modes, Xevo G2ꢀQTof. Enantiomeric
excess (ee) values were determined by chiral SFC.
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Methyl 3ꢀcyclopropylꢀ2ꢀmethylꢀ3ꢀoxopropanoate (7). To a clean dry vessel equipped with a
mechanical stirrer, thermocouple probe and nitrogen inlet/outlet adapter was added solid K2CO3
(11.6 kg, 84 mol) followed by THF (50 L). The mixture was aged at room temperature for 30
min. Methyl 3ꢀcyclopropylꢀ3ꢀoxopropanoate (5.5 kg, 39 mol) was then added dropꢀwise over 30
min. The solution was aged for 30 min at room temperature. MeI (6.5 kg, 46 mol) was added
dropꢀwise over 15 min keeping the internal temperature below 22 °C. The reaction was then aged
at room temperature for 30 min then heated to 40 °C for 48 h. The reaction was cooled to room
temperature and the batch concentrated under vacuum to 25 L. The resulting slurry was filtered
and the wet cake was rinsed with THF (90 L). The solution was then concentrated under vacuum
to 10 L, followed by addition of MTBE (40 L) and water (50 L). The organic layer was separated
and washed with fresh water (50 L). The organic layer was separated and concentrated under
reduced pressure to 25 L. The resulting 5.5 kg of methyl 3ꢀcyclopropylꢀ2ꢀmethylꢀ3ꢀ
oxopropanoate was carried through to the next step as a 22.6 wt% solution in 94% assay yield.
1H NMR (500 MHz, CDCl3): δ 3.76 (s, 3 H), 3.68 (q, J = 7.1 Hz, 1 H), 2.10ꢀ2.03 (m, 1 H), 1.43
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(d, J = 7.2 Hz, 3 H), 1.12ꢀ1.05 (m, 2 H), 0.98ꢀ0.92 (m, 2 H). C NMR (500 MHz, CDCl3): δ
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205.8, 171.1, 53.5, 52.3, 19.3, 12.8, 11.7, 11.6. HRMS (ESI) m/z calcd for C8H12O3 (M + H)
157.0865, found 157.0863.
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(Z)ꢀMethyl 3ꢀcyclopropylꢀ2ꢀmethylꢀ3ꢀ(tosyloxy)acrylate ((Z)-8). 1M NaHMDS (44 kg, 49 mol)
was added slowly to the methyl 3ꢀcyclopropylꢀ2ꢀmethylꢀ3ꢀoxopropanoate solution (5.5 kg, 35
mol) over 2 h at room temperature. The mixture was aged for 3 h. Meanwhile tosyl anhydride
(13 kg, 40 mol) was dissolved in THF (70 L). The tosyl anhydride solution was added slowly
over 5 h at room temperature and the batch was aged for 1 h. AcOH was added to adjust the
batch pH to 7. Water (60 L) was then added over 30 min and the batch aged for 30 min. EtOAc
(111 L) was added to mixture. The layers were separated and the organic layer washed with
brine twice. The organic solution was then concentrated to 10 L and the solvent switched to IPA,
under vacuum, until the volume reached 10 L with no residual EtOAc. The solution was heated
to 45 °C, seeded and aged for 3 h at 45 °C. The slurry was then cooled to 10 °C over 5 h and
aged at 15 °C for 8 h. The slurry was filtered and the wet cake was washed with cold IPA (15
L). The wet cake was dried over vacuum to give 6.4 kg of (Z)ꢀmethyl 3ꢀcyclopropylꢀ2ꢀmethylꢀ3ꢀ
(tosyloxy)acrylate in 59% isolated yield. 1H NMR (500 MHz, CDCl3): δ 7.8 (d, J = 8.3 Hz, 2 H),
7.3 (d, J = 8.1 Hz, 2 H), 3.61 (s, 3 H), 2.49 (s, 3 H), 2.04 (s, 3 H), 1.65ꢀ1.57 (m, 1 H), 0.77ꢀ0.65
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(m, 4 H). C NMR (500 MHz, CDCl3): δ 167.1, 151.0, 144.9, 134.3, 129.6, 128.0, 121.4, 51.8,
21.6, 15.1, 12.9, 6.9. HRMS (ESI) m/z calcd for C15H18O5S (M + H) 311.0953, found 311.0950.
(E)ꢀMethyl 3ꢀcyclopropylꢀ2ꢀmethylꢀ3ꢀ(tosyloxy)acrylate ((E)-8). To a clean dry vessel equipped
with a mechanical stirrer, thermocouple probe and nitrogen inlet/outlet adapter was added methyl
3ꢀcyclopropylꢀ2ꢀmethylꢀ3ꢀoxopropanoate (100 mg, 0.640 mmol) followed by THF. The solution
was then cooled to ꢀ78 °C. A 1M solution of NaHMDS (0.700 mL, 0.700 mmol) was added
dropꢀwise over 10 min keeping internal temperature below ꢀ70 °C. Once all the base was added,
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the reaction was aged at ꢀ78 °C for 20 min. Meanwhile tosyl anhydride (209 mg, 0.640 mmol)
was taken up in THF (2.0 mL) and added to the reaction solution over 5 min keeping the internal
temperature below ꢀ70 °C. The reaction was then allowed to warm to room temperature
overnight to give a 80:20 mixture of E:Z tosylate. The reaction was quenched by adding pH 7
buffer and EtOAc. The layers were separated and the organic layer was washed with pure water
and then brine. The organic layer was concentrated and purified by silica gel chromatography to
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give 115 mg of (E)ꢀmethyl 3ꢀcyclopropylꢀ2ꢀmethylꢀ3ꢀ(tosyloxy)acrylate in 57% yield. H NMR
(500 MHz, CDCl3): δ 7.86 (d, J = 8.2 Hz, 2 H), 7.37 (d, J = 8.1 Hz, 2 H), 3.80 (s, 3 H), 2.49 (s, 3
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H), 2.30ꢀ2.20 (m, 1 H), 1.75 (s, 3 H), 0.76ꢀ0.62 (m, 2 H), 0.69ꢀ0.63 (m, 2 H). C NMR (500
MHz, CDCl3): δ 169.2, 157.6, 146.5, 134.5, 129.8, 127.9, 122.5, 51.9, 21.7, 14.8, 14.1, 7.1.
HRMS (ESI) m/z calcd for C15H18O5S (M + H) 311.0953, found 311.0956.
(Z)ꢀMethyl 3ꢀ(3ꢀ(benzyloxy)phenyl)ꢀ3ꢀcyclopropylꢀ2ꢀmethylacrylate ((Z)-10a). A mixture of
acetonitrile (6.0 L) and water (1.2 L) was charged to a vessel equipped with a mechanical stirrer,
thermocouple probe, nitrogen inlet/outlet adapter and a dual compression fitting adapter fitted
with a fritted glass sparge tube and an outlet tube. The mixture was degassed by sparging with N2
for 15min. K3PO4 (1.9 kg, 9.0 mol) followed by (3ꢀ(benzyloxy)phenyl)boronic acid (0.75 kg, 3.3
mol) were added as a solids as the sparging was continued (a slight exotherm was observed).
Then 2ꢀdicyclohexylphosphinoꢀ2’,4’,6’ꢀtriisopropylbiphenyl (43 g, 0.090 mol), (Z)ꢀmethyl 3ꢀ
cyclopropylꢀ2ꢀmethylꢀ3ꢀ(tosyloxy)acrylate (0.93 kg, 3.0 mol), and palladium(II) acetate (20 g,
0.090 mol) were charged as solids into the flask while the sparging was continued. The reaction
mixture was stirred for 2 h at 30 °C at which point HPLC showed 80% conversion. The mixture
was stirred for 30 min more at 30 °C. Then additional 2ꢀdicyclohexylphosphinoꢀ2’,4’,6’ꢀ
triisopropylbiphenyl (21 g, 0.045 mol) and palladium(II) acetate (10 g, 0.045 mol) were added.
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The mixture was stirred for 1 h at 25 °C at which point HPLC showed > 99% conversion. The
mixture was evaporated under vacuum at 30 °C for 1 h. CPME (1.5 L) was added and the batch
evaporated. Then CPME (1.5 L), heptane (1.5 L) and water (3.0 L) were added and the mixture
was filtered. The organic phase was separated and washed with water (1.5 L), 0.5M aq NaOH
(1.5 L) and water (1.5 L). The solution was dried over MgSO4 (90 g), treated with Darco G60
(45 g) for 15min and filtered through a plug of silica (1.5 kg) and MgSO4 (90 g). The cake was
rinsed with 3:7 CPME/heptane (9.0 L). The filtrate was evaporated at 25 °C to ca 1L of an amber
oil which was purified by silica gel chromatography to give 0.71 kg of (Z)ꢀmethyl 3ꢀ(3ꢀ
(benzyloxy)phenyl)ꢀ3ꢀcyclopropylꢀ2ꢀmethylacrylate in 74% isolated yield. 1H NMR (500 MHz,
CDCl3): δ 7.47 (d, J = 7.5 Hz, 2 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.35 (d, J = 7.2 Hz, 1 H), 7.25 (t, J
= 7.7 Hz, 1 H), 6.89 (dd, J = 2.4, 5.8 Hz, 1 H), 6.68 (s, 1 H), 6.61 (d, J = 7.5 Hz, 1 H), 5.10 (s, 2
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H), 3.48 (s, 3 H), 2.21 (s, 3 H) 1.93ꢀ1.84 (m, 1 H), 0.81ꢀ0.73 (m, 2 H), 0.39ꢀ0.34 (m, 2 H). C
NMR (500 MHz, CDCl3): δ 170.2, 158.0, 149.0, 140.3, 137.0, 128.5, 128.4, 127.9, 127.5, 121.3,
115.0, 113.4, 69.8, 51.2, 15.5, 14.6, 5.7. HRMS (ESI) m/z calcd for C21H22O3 (M + H) 323.1647,
found 323.1656.
(Z)ꢀMethyl 3ꢀ(4ꢀ(benzyloxy)phenyl)ꢀ3ꢀcyclopropylꢀ2ꢀmethylacrylate ((Z)-10b) To a clean dry
vessel equipped with a mechanical stirrer, thermocouple probe and nitrogen inlet/outlet adapter
were added (Z)ꢀmethyl 3ꢀcyclopropylꢀ2ꢀmethylꢀ3ꢀ(tosyloxy)acrylate (151 g, 0.486 mol), (4ꢀ
(benzyloxy)phenyl)boronic acid (126 g, 0.534 mol), palladium(II) acetate (5.45 g, 0.0243 mol)
and 2ꢀdicyclohexylphosphinoꢀ2’,4’,6’ꢀtriisopropylbiphenyl (11.6 g, 0.0243 mol). Acetonitrile
(1206 mL) was added and the slurry was sparged with N2 for 10 min. Then degassed 2.0M aq
K3PO4 (729 mL, 1.46 mol) was added via cannula over 10 min. The resulting black solution was
stirred for 2 h at 25 °C. The reaction was quenched with sat NH4Cl (600 mL) then diluted with
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EtOAc (1500 mL) and water (300 mL). Upon 30 min agitation the resulting mixture was filtered
and phases separated. The aqueous layer was backꢀextracted with EtOAc (450 mL). The organic
layers were combined and washed with water, then dried over Na2SO4 and evaporated under
vacuum. The crude compound was dissolved in MeOH and treated with 5 wt % charcoal. Upon
agitation for 4 h, the slurry was filtered over solka floc and the solvent was removed. 500 mL of
heptane was added and the solvent removed. The compound was dried under vacuum and
purified by silica gel chromatography to give 108 g of (Z)ꢀmethyl 3ꢀ(4ꢀ(benzyloxy)phenyl)ꢀ3ꢀ
cyclopropylꢀ2ꢀmethylacrylate in 83% isolated yield. 1H NMR (500 MHz, CDCl3): δ 7.47 (d, J =
7.6 Hz, 2 H), 7.41 (t, J = 7.4 Hz, 2 H), 7.35 (d, J = 7.9 Hz, 1 H), 6.93 (q, J = 8.7, 4.3 Hz, 4 H),
5.10 (s, 2 H), 3.40 (s, 3 H), 2.19 (s, 3 H) 1.92ꢀ1.85 (m, 1 H), 0.81ꢀ0.75 (m, 2 H), 0.40ꢀ0.33 (m, 2
H). 13C NMR (500 MHz, CDCl3): δ 170.5, 157.6, 148.7, 137.0, 131.3, 129.7, 128.5, 127.9,
127.6, 126.0, 113.8, 69.9, 51.2, 15.7, 14.6, 5.5. HRMS (ESI) m/z calcd for C21H22O3 (M + H)
323.1643, found 323.1653.
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(Z)ꢀmethyl 3ꢀcyclopropylꢀ3ꢀ(2ꢀfluoroꢀ3ꢀhydroxyphenyl)ꢀ2ꢀmethylacrylate ((Z)-10c). To a clean
dry vessel equipped with a mechanical stirrer, thermocouple probe and nitrogen inlet/outlet
adapter was added (Z)ꢀmethyl 3ꢀcyclopropylꢀ2ꢀmethylꢀ3ꢀ(tosyloxy)acrylate (200 g, 0.644 mol),
(2ꢀfluoroꢀ3ꢀhydroxyphenyl)boronic acid (110 g, 0.705 mol) and Cs2CO3 (231 g, 0.709 mol)
followed by degassed dioxane (2000 mL) and degassed H2O (200 mL). Added
Pd(dppf)Cl2.CH2Cl2 (21 g, 0.026 mol) and agitated the mixture at 100 °C for 1h. TLC showed
the reaction was completed. The mixture was poured into water and extracted with EtOAc. The
organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was
purified by silica gel chromatography to obtain 102 g of (Z)ꢀmethyl 3ꢀcyclopropylꢀ3ꢀ(2ꢀfluoroꢀ3ꢀ
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hydroxyphenyl)ꢀ2ꢀmethylacrylate in 63% isolated yield. H NMR (500 MHz, CDCl3): δ 6.94ꢀ
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6.85 (m, 2 H), 6.40 (dt, J = 2.5, 4.2, 1.7 Hz, 2 H), 5.59 (bs, 1 H), 3.45 (s, 3 H), 2.20 (s, 3 H)
1.96ꢀ1.88 (m, 1 H), 0.83ꢀ0.76 (m, 2 H), 0.37ꢀ0.30 (m, 2 H). 13C NMR (500 MHz, CDCl3): δ
169.2, 148.8ꢀ147.0 (d, J = 234.1 Hz), 144.6, 143.3 (d, J = 14.1 Hz), 127.5, 126.9 (d, J = 15.0 Hz),
123.5 (d, J = 4.6 Hz), 121.3 (d, J = 2.8 Hz), 116.2 (d, J = 2.0 Hz), 51.4, 15.4, 14.6, 5.8. HRMS
(ESI) m/z calcd for C14H15FO3 (M + H) 251.1083, found 251.1091.
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(2S,3R)ꢀmethyl 3ꢀ(3ꢀ(benzyloxy)phenyl)ꢀ3ꢀcyclopropylꢀ2ꢀmethylpropanoate ((S,R)-11a). In a
nitrogenꢀfilled glove box with O2 < 5 ppm, (COD)Ru(Meꢀallyl)2 (17 g, 0.053 mol) and Josiphos
SLꢀJ502ꢀ2 (30 g, 0.056 mol) were charged to the precatalyst preparation vessel, followed by
anhydrous degassed CH2Cl2 (500 mL). Upon 30 min agitation, HBF4ꢀEt2O (17 g, 0.106 mol) was
added drop wise over 20 min in order to control gas evolution and the precatalyst solution was
aged for 30 min. Meanwhile, methyl (Z)ꢀmethyl 3ꢀ(3ꢀ(benzyloxy)phenyl)ꢀ3ꢀcyclopropylꢀ2ꢀ
methylacrylate (1.0 kg, 3.1 mol) was dissolved in MeOH (5.0 L) and the solution was degassed
for 2 h. The precatalyst solution was transferred to the reaction vessel, which was purged with
argon three times. The headspace exchanged with H2 six times. The reaction vessel was
pressurized with 500 psi H2 and agitated at 80 °C. The reaction was sampled after 40 h to give
100% conversion and cooled to room temperature. Three batches were combined for isolation
(workꢀup basis 3.3 kg (Z)ꢀmethyl 3ꢀ(3ꢀ(benzyloxy)phenyl)ꢀ3ꢀcyclopropylꢀ2ꢀmethylacrylate). The
solvent was switched to MeOH at 50 °C under reduced pressure. MeOH (16 L) was added and
the mixture heated to 50 °C. Upon a 60 min hold, the mixture was cooled to 45 °C, seeded and
cooled to 25 °C over 4 h. Water (6.6 L) was added over 4 h and the slurry was aged at 25 °C for
10 h. The batch was filtered and the wet cake washed with a mixture of MeOH (4.0 L) and water
(1.0 L). The wet cake was dried under vacuum at 45 °C for 30 h to obtain 2.9 kg (2S,3R)ꢀmethyl
3ꢀ(3ꢀ(benzyloxy)phenyl)ꢀ3ꢀcyclopropylꢀ2ꢀmethylpropanoate in 88.2% isolated yield with 98%
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ee. 1H NMR (500 MHz, CDCl3): δ 7.49 (d, J = 7.4 Hz, 2 H), 7.41 (t, J = 7.3 Hz, 2 H), 7.35 (d, J =
7.1 Hz, 1 H), 7.25 (t, J = 8.0 Hz, 1 H), 6.89 (d, J = 8.2 Hz, 1 H), 6.81 (s, 1 H), 6.79 (d, J = 7.5 Hz,
1 H), 5.10 (s, 2 H), 3.78 (s, 3 H) 2.88ꢀ2.77 (m, 1 H), 1.98, (t, J = 9.8 Hz, 1 H), 1.13ꢀ1.02 (m, 1
H), 0.98 (d, J = 6.8 Hz, 3 H), 0.64ꢀ0.55 (m, 1 H), 0.40ꢀ0.31 (m, 1 H), 0.31ꢀ0.22 (m, 1 H), 0.07ꢀ
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0.00 (m, 1 H). C NMR (500 MHz, CDCl3): δ 176.6, 158.8, 144.8, 137.0, 129.3, 128.5, 127.9,
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127.6, 120.7, 114.8, 112.4, 70.0, 54.6, 51.5, 45.9, 16.2, 16.0, 6.4, 3.3. [α]D +111 (c 1.3,
MeOH). HRMS (ESI) m/z calcd for C21H24O3 (M + H) 325.1804, found 325.1790.
(2S,3R)ꢀmethyl 3ꢀ(4ꢀ(benzyloxy)phenyl)ꢀ3ꢀcyclopropylꢀ2ꢀmethylpropanoate ((S,R)-11b). In a
nitrogenꢀfilled glove box with O2 < 5 ppm, (COD)Ru(Meꢀallyl)2 (6.0 g, 0.019 mol) and Josiphos
SLꢀJ502ꢀ2 (10.4g, 0.019 mol) were charged to the precatalyst preparation vessel, followed by
anhydrous degassed CH2Cl2 (100 mL). Upon 15 min agitation, HBF4ꢀEt2O (6.0 g, 0.037 mol)
was added drop wise in order to control gas evolution and the precatalyst solution was aged for
20 min. Meanwhile, (Z)ꢀmethyl 3ꢀ(4ꢀ(benzyloxy)phenyl)ꢀ3ꢀcyclopropylꢀ2ꢀmethylacrylate (200 g,
0.620 mol) was dissolved in MeOH (2200 mL) and the solution was purged with N2 (5 x 80 psi).
The precatalyst solution was transferred to the reaction vessel and rinsed with MeOH (100 mL).
The reactor was sealed and the headspace exchanged with H2 (3 x 500 psi). The reaction vessel
was pressurized with 500 psi H2 and agitated at 80 °C. The reaction was sampled after 19 h to
give 97% conversion, cooled to room temperature and dropped from the vessel. The vessel was
rinsed with MeOH (800 mL), which was combined with the batch and concentrated under
vacuum to 1000 mL total volume. The slurry was filtered the wet cake dried under vacuum at 45
°C for 16 h to obtain 139 g (2S,3R)ꢀmethyl 3ꢀ(4ꢀ(benzyloxy)phenyl)ꢀ3ꢀcyclopropylꢀ2ꢀ
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methylpropanoate in 80.1% isolated yield with 98% ee. H NMR (500 MHz, CDCl3): δ 7.48 (d,
J = 8.7 Hz, 2 H), 7.42 (t, J = 7.4 Hz, 2 H), 7.3 (d, J = 1.5 Hz, 1 H), 7.11 (d, J = 4.5 Hz, 2 H), 6.98
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(d, J = 4.5 Hz, 2H), 5.19 (s, 2 H), 3.78 (s, 3 H), 2.86ꢀ2.76 (m, 1 H), (t, J = 10 Hz, 1 H), 1.12ꢀ1.02
(m, 1 H), 0.98 (d, J = 6.8 Hz, 3 H), 0.62ꢀ0.55 (m, 1 H), 0.39ꢀ0.32 (m, 1 H), 0.30ꢀ0.23 (m, 1 H),
0.06ꢀ0.00 (m, 1 H). 13C NMR (500 MHz, CDCl3): δ 176.7, 157.4, 137.1, 135.5, 128.8, 128.5,
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127.9, 127.5, 114.6, 114.3, 70.0, 53.7, 51.5, 46.1, 16.3, 15.8, 6.4, 3.3. [α]D +150 (c 0.54,
MeOH). HRMS (ESI) m/z calcd for C21H24O3 (M + H) 325.1804, found 325.1815.
(2S,3R)ꢀmethyl 3ꢀcyclopropylꢀ3ꢀ(2ꢀfluoroꢀ3ꢀhydroxyphenyl)ꢀ2ꢀmethylpropanoate ((S,R)-11c). In
a nitrogenꢀfilled glove box with O2 < 5 ppm, (COD)Ru(Meꢀallyl)2 (3.8 g, 0.012 mol) and
Josiphos SLꢀJ502ꢀ2 (6.7 g, 0.012 mol) were charged to the precatalyst preparation vessel,
followed by anhydrous degassed MeOH (80 mL). Upon 10 min agitation, HBF4ꢀEt2O (3.8 g,
0.024 mol) was added drop wise in order to control gas evolution and the precatalyst solution
was aged for 30 min. Meanwhile, methyl (Z)ꢀmethyl 3ꢀcyclopropylꢀ3ꢀ(2ꢀfluoroꢀ3ꢀ
hydroxyphenyl)ꢀ2ꢀmethylacrylate (295 g, 1.18 mol) was dissolved in MeOH (1910 mL) and the
solution was purged with N2 (5 x 80 psi). The precatalyst solution was transferred to the reaction
vessel and rinsed with MeOH (80 mL). The reactor was sealed and the headspace exchanged
with H2 (3 x 500 psi). The reaction vessel was pressurized with 500 psi H2 and agitated at 80 °C.
The reaction was sampled after 20 h to give 100% conversion, cooled to room temperature and
dropped from the vessel. The batch was concentrated down to an oil and purified by silica gel
chromatography to obtain 222 g methyl (2S,3R)ꢀmethyl 3ꢀcyclopropylꢀ3ꢀ(2ꢀfluoroꢀ3ꢀ
1
hydroxyphenyl)ꢀ2ꢀmethylpropanoate in 74.7% isolated yield with > 99% ee. H NMR (500
MHz, CDCl3): δ 7.00 (t, J = 8.3 Hz, 1 H), 6.90 (dt, J = 1.6, 6.6 Hz, 1 H), 6.74 (dt, J = 1.6, 6.3 Hz,
1 H), 3.78 (s, 3 H), 2.99ꢀ2.91 (m, 1 H), 2.31, (t, J = 10 Hz, 1 H), 1.20ꢀ1.10 (m, 1 H), 0.98 (d, J =
6.8 Hz, 3 H), 0.62ꢀ0.54 (m, 1 H), 0.38ꢀ0.32 (m, 1 H), 0.32ꢀ0.25 (m, 1 H), 0.07ꢀ0.00 (m, 1 H). 13C
NMR (500 MHz, CDCl3): δ 176.7, 150.5ꢀ148.6 (d, J = 236.4 Hz), 143.7 (d, J = 15.3 Hz), 130.5
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(d, J = 12.8 Hz), 124.4 (d, J = 3.7 Hz), 120.2 (d, J = 4.3 Hz), 115.2 (d, J = 1.8 Hz), 51.7, 48.3,
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45.02, 45.00, 16.0, 15.3, 6.5, 3.0. [α]D +126 (c 1.10, MeOH). HRMS (ESI) m/z calcd for
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C14H17FO3 (M + H) 253.1240, found 253.1242.
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ASSOCIATED CONTENT
Supporting Information
This material is available free of charge via the Internet at http://pubs.acs.org.
NMR spectra for all new compounds, chiral SFC traces of compounds 11aꢀ11c, list of chiral
phosphine ligands screened in asymmetric hydrogenation.
AUTHOR INFORMATION
Corresponding Authors. melodie.christensen@merck.com, andrew_nolting@merck.com
Present Addresses 126 E Lincoln Ave, Rahway, New Jersey 07065, United States
ACKNOWLEDGMENT
We would like to thank Alexey Makarov and Lisa Frey for analytical and separations support.
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