Development of a Kilogram-Scale Process for the Enantioselective Synthesis of 3-Isopropenyl-cyclohexan-1-one via Rh/DTBM-SEGPHOS-Catalyzed Asymmetric Hayashi Addition Enabled by 1,3-Diol Additives

Article abstract of DOI:10.1021/acs.oprd.7b00253

The development of a scalable process for the Rh-catalyzed asymmetric 1,4-addition of (isopropenyl)pinacolboronate to 2-cyclohexen-1-one is reported. High-throughput ligand screening and initial optimization studies identified DTBM-SEGPHOS as an effective ligand along with a heptane/MeOH mixed solvent system. An inhibitory effect of the pinacol byproduct was identified, which could be mitigated by the addition of a 1,3-diol such as neopentyl glycol (npg). This process was demonstrated on 1 kg scale with 0.6 mol % Rh, producing (S)-1 in 82% yield and 99.6% ee, and was successfully scaled up at a vendor on 100 kg scale.

Full text of DOI:10.1021/acs.oprd.7b00253

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Full Paper
Development of a Kilogram-Scale Process for the Enantioselective
Synthesis of 3-Isopropenyl-cyclohexan-1-one via Rh/DTBM-SEGPHOS-
Catalyzed Asymmetric Hayashi Addition Enabled By 1,3-Diol Additives
Eric M. Simmons, Boguslaw Mudryk, Andrew G. Lee, Yuping Qiu, Thomas M. Razler, and Yi Hsiao
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00253 • Publication Date (Web): 25 Aug 2017
Downloaded from http://pubs.acs.org on August 26, 2017
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Development of a KilogramꢀScale Process for the
Enantioselective Synthesis of 3ꢀIsopropenylꢀcyclohexanꢀ
1ꢀone via Rh/DTBMꢀSEGPHOSꢀCatalyzed Asymmetric
Hayashi Addition Enabled By 1,3ꢀDiol Additives
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Eric M. Simmons,* Boguslaw Mudryk,* Andrew G. Lee, Yuping Qiu, Thomas M. Razler and Yi
Hsiao
Chemical & Synthetic Development, BristolꢀMyers Squibb Company, One Squibb Drive,
New Brunswick, New Jersey 08903, United States
* To whom correspondence should be addressed. Eꢀmail: eric.simmons@bms.com,
bmudryk@comcast.net
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ABSTRACT
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The development of a scalable process for the Rhꢀcatalyzed asymmetric 1,4ꢀaddition of
(isopropenyl)pinacolboronate to 2ꢀcyclohexenꢀ1ꢀone is reported. Highꢀthroughput ligand
screening and initial optimization studies identified DTBMꢀSEGPHOS as an effective ligand
along with a heptane/MeOH mixed solvent system. An inhibitory effect of the pinacol byꢀ
product was identified, which could be mitigated by the addition of a 1,3ꢀdiol such as neopentyl
glycol (npg). This process was demonstrated on 1 kg scale with 0.6 mol % Rh, producing (S)ꢀ1
in 82% yield and 99.6% ee, and was successfully scaled up at a vendor on 100 kg scale.
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Key Words: Hayashi 1,4ꢀAddition, RhꢀCatalyzed, DTBMꢀSEGPHOS, Pinacol Inhibition,
Neopentyl Glycol
INTRODUCTION
As part of an ongoing drug development program, we required access to multiꢀkilogram
quantities of (S)ꢀ3ꢀisopropenylꢀcyclohexanꢀ1ꢀone ((S)ꢀ1) with high levels of enantioenrichment
(>98% ee). Though several multiꢀstep routes to 1 have previously been reported, starting from
chiral pool material1 or utilizing an enzymatic resolution,2 we sought to directly access (S)ꢀ1 in a
single step through the asymmetric 1,4ꢀaddition of a suitable isopropenyl nucleophile (3) to 2ꢀ
cyclohexenꢀ1ꢀone (2) (Scheme 1).3 A search of the literature revealed three previous
enantioselective syntheses of 1 via asymmetric 1,4ꢀaddition to 2 utilizing organosilicon (3a),4
organomagnesium (3b),5 and organoboron (3c)6 nucleophiles. While all of these methods
generate 1 with high enantioselectivity (92ꢀ98% ee),4ꢀ6 they suffer either from high catalyst
loading of an expensive metal (3 mol % Rh),4,6 the use of a nonꢀcommercially available ligand5
or isopropenyl nucleophile,4 or cryogenic reaction conditions (ꢀ78 °C) with slow addition of the
nucleophile.5
The method reported by Lalic and Corey6 for an asymmetric conjugate addition to generate 1
was the most attractive for a process that would need to be conducted a multiꢀkilogram scale
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because of the mild reaction conditions and use of a commerciallyꢀavailable, airꢀstable
organoboron nucleophile (3c). On the other hand, the principal drawbacks of this methodology
were the high catalyst loading (3 mol % Rh) and long reaction time (72 h), both of which were
deemed unsuitable for scaleꢀup. With these considerations in mind, we sought to use the
Lalic/Corey conditions as a starting point to develop a scalable process for the asymmetric
conjugate addition7 of a suitable organoboron nucleophile8,9 to 2 under mild conditions that
utilize a low loading of the rhodium catalyst. In this report, we describe the successful
development and execution of an efficient, kilogramꢀscale process for the asymmetric conjugate
addition of (isopropenyl)pinacolboronate (3d) to 2, which provides 1 with high enantioselectivity
(>99% ee) with a catalyst loading of 0.6 mol % Rh. This process is the first reported synthesis of
1 to utilize 3d as a nucleophile, and generates 1 with the highest enantioselectivity reported to
date, with a commensurate fiveꢀfold reduction in the amount of rhodium catalyst required as
compared to existing methods.
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Scheme 1. Synthesis of 1 via asymmetric conjugate addition of isopropenylmetal nucleophiles to
2ꢀcyclohexenꢀ1ꢀone
RESULTS AND DISCUSSION
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Ligand Screening with 3c and 3d. We began our studies by investigating the Rhꢀcatalyzed
asymmetric addition of potassium isopropenyltrifluoroborate (3c) to 2, which was previously
developed by Lalic and Corey6. It was hypothesized that the high catalyst loading (3 mol % Rh)
employed in the original study could potentially be overcome through the identification of a
suitable chiral ligand and Rh precursor that led to the generation of a more active and/or more
stable catalyst than the reported Rh/BINAP system.6 Toward this goal, we conducted a
microscale highꢀthroughput ligand survey10 with a broad range of chiral ligands utilizing the
reaction conditions shown in Figure 1.11 Disappointingly, while numerous chiral ligands gave
high conversion to the ketone product (1) using 3c, low enantioselectivity (<75% ee) was
observed in all cases.12 However, we were encouraged by a parallel ligand survey conducted
with commerciallyꢀavailable (isopropenyl)pinacolboronate (3d),13 which revealed that this
nucleophile in combination with the bulky, electronꢀrich bisphosphine ligand DTBMꢀ
SEGPHOSꢀR and toluene as solvent led to the generation of (R)ꢀ1 with >90% ee.14 This
promising preliminary hit prompted us to pursue further reaction development with 3d as the
nucleophile.
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Figure 1. top) Conditions for the highꢀthroughput ligand survey for the asymmetric addition of
3c and 3d to 2 bottom) Results for reactions conducted in toluene for the ligand survey with
(isopropenyl)pinacolboronate (3d). aArea percent (AP) and absolute enantiomeric excess (abs ee)
based on gas chromatography (GC) analysis with a chiral stationary phase using FID.
Initial Reaction Optimization with 3d. With the identification of DTBMꢀSEGPHOS as an
effective ligand for the asymmetric addition of 3d to 2, we set out to optimize the reaction
conditions to enable the preparation of hundreds of kilograms of compound 1.15 We began by
investigating a broad range of solvents to assess their effect on the rate and enantioselectivity of
this transformation. While the enantioselectivity was uniformly high (≥94% ee) in all solvents
examined, nonꢀpolar solvents such as heptane gave the lowest levels of enone byꢀproduct 4
(Table 1). This impurity is believed to form from 1 by isomerization of the exocyclic doubleꢀ
bond, presumably through the intermediacy of a tetraꢀsubstituted alkene that was not detected in
the reaction mixture.16 Interestingly, these studies also revealed that MeOH gave a dramatically
higher level of 1 after 2 h relative to all of the other solvents that were investigated, a finding
which warranted further study.
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Table 1. Effect of solvent on reaction rate, enantioselectivity and byꢀproduct formation for the
Rh/DTBMꢀSEGPHOSꢀcatalyzed addition of 3d to 2a
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1 (2 h) 1 (17 h) 1 (ee)
4
(AP)
1:4
Ratio
Solvent
AP
AP
(%)
Heptane
Cyclohexane
Toluene
F3-Toluene
p-Xylene
Anisole
CPME
47.9
44.7
38.0
28.2
42.3
33.9
45.5
44.4
52.4
38.0
14.1
41.4
58.1
11.8
84.9
28.5
74.7
73.2
64.3
58.4
70.6
61.9
75.7
72.6
81.5
70.2
35.8
68.8
62.9
24.0
83.0
61.0
96.4
97.1
96.8
96.4
97.0
96.8
96.2
97.1
96.8
97.1
95.1
96.3
96.7
94.0
96.2
96.5
0.5
0.4
1.2
1.5
1.5
1.5
1.6
2.2
6.0
3.8
5.9
1.8
3.5
3.2
15.3
38.2
99:1
99:1
98:2
97:3
98:2
98:2
98:2
97:3
93:7
95:5
86:14
97:3
95:5
88:12
84:16
61:39
2-MeTHF
Dioxane
THF
DCE
iPAc
DMF
MeCN
MeOH
iPrOH
aArea percent (AP) and enantiomeric excess (ee) based on gas chromatography (GC) analysis
with a chiral stationary phase using FID.
We questioned whether we could simultaneously take advantage of the high product stability
afforded by nonꢀpolar solvents, as well as the reaction rate acceleration that was observed with
MeOH, through the use of a mixed solvent system. Indeed, it was found that reactions conducted
in 2ꢀMeTHF, toluene and heptane were all significantly accelerated with the use of 10% MeOH
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as coꢀsolvent. Of the three mixed solvent systems, the fastest reaction rates and the lowest levels
of 4 were observed with 90:10 heptane:MeOH, thus we selected heptane as the nonꢀpolar coꢀ
solvent component moving forward. EtOH, iPrOH, tꢀAmOH and TFE were also examined as
protic coꢀsolvents in combination with heptane, but none of these alcohols led to superior
reaction performance as compared with MeOH. Similarly, we examined a range of amine bases17
and inorganic bases,18 but none of the bases surveyed offered any advantages over DIPEA.
Finally, we determined that [Rh(cod)2]BF4,19 [Rh(nbd)2]BF4,19b [Rh(cod)OH]2 and
[Rh(cod)Cl]220 could be used interchangeably as Rh precursors, and we elected to move forward
with [Rh(cod)Cl]2 due to its cost advantage and greater air stability as compared to the other Rh
sources.21
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Effects of Pinacol and B(OMe)3 on Reaction Rate. On multiꢀgram scale, the
[Rh(cod)Cl]2/DTBMꢀSEGPHOS catalyst system in 90:10 heptane:MeOH delivered modest
conversion when the catalyst loading was decreased to less than 1.8 mol % Rh. This presented a
significant economic burden due to the high costs of both [Rh(cod)Cl]2 and DTBMꢀSEGPHOS.
Furthermore, we consistently observed that the rate of conversion of enone 2 slowed
dramatically as the reaction progressed, hinting at either catalyst decomposition or product/byꢀ
product inhibition during the course of the reaction. To probe the latter possibility, we conducted
a series of reactions at reduced catalyst loading (1 mol % Rh) that were spiked with various
species that were either present in the initial reaction mixture in low levels, or which were
potentially generated during the course of the reaction. While the addition of B(OH)3, 1,5ꢀ
cyclooctadiene (COD) and chloride (in the form of TEACl) had no impact on the reaction rate,
reactions that were conducted with added pinacol, MeOꢀB(pin) or HOꢀB(pin) (data not shown)
were all found to be significantly slower compared to a typical reaction (Figure 2). Taken
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together, these results point to a buildup of pinacol in the reaction mixture as the key factor
responsible for the observed decrease in reaction rate. Theoretically, one molecule of pinacol is
potentially liberated for every molecule of 1 that is formed.
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0.5 mol % [Rh(cod)Cl]2
1.1 mol % DTBM-SEGPHOS-S
1.0 equiv DIPEA, additive
O
2
O
Me
B(pin)
3d
+
Me
10 vol 90:10 Heptane:MeOH
4 vol H2O, 50 °C
( )-1
S
(1.1 equiv)
Figure 2. Spiking experiment demonstrating the inhibitory effect of pinacol on reaction rate.
aArea percent (AP) based on gas chromatography (GC) analysis with a chiral stationary phase
using FID. bAdditive amounts: Boric acid (B(OH)3) – 1.5 equiv; 1,5ꢀcyclooctadiene (1,5ꢀCOD) –
0.1 equiv; tetraethylammonium chloride (TEACl) – 0.1 equiv; 2ꢀmethoxyꢀ4,4,5,5ꢀtetramethylꢀ
1,3,2ꢀdioxaborolane (MeOꢀB(pin)) – 1.5 equiv; pinacol – 1.5 equiv; trimethyl borate (B(OMe)3)
– 1.5 equiv.
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Interestingly, the spiking experiments revealed an unexpected positive effect of added
B(OMe)3 on the reaction rate. Subsequent experiments revealed that B(OMe)3 was uniquely
effective among borate additives. B(OEt)3, B(OiPr)3 B(OnꢀBu)3, B(OtꢀBu)3 and B(OPh)3 either
had less of a positive impact on reaction rate or led to an increase of the isomerized enone byꢀ
product 4. The use of B(OMe)3 as a stoichiometric additive was initially pursued further in hopes
of capitalizing on its accelerating effect on reaction rate, which did enable a modest reduction in
the catalyst loading;22 however, this approach was abandoned once it was determined that
B(OMe)3 led to unacceptable product losses during workup (vide infra).
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The observation of an inhibitory effect of pinacol on the reaction rate led us to consider that
there may be one (or more) alternative isopropenylboron species generated in situ that is the
actual nucleophilic transmetallation partner with the Rh/DTBMꢀSEGPHOS catalyst under our
optimized reaction conditions.23 We hypothesized that two species could potentially be present,
isopropenylboronic acid (3e) and methyl isopropenylboronate (3f). As shown in Scheme 2,
hydrolytic cleavage of the pinacol group of 3d would liberate 3e, while alternatively a
methanolic cleavage of 3d would give rise to 3f. It was unclear a priori which of 3e or 3f would
be favored under the reaction conditions; however, we hypothesized that both of these species
would undergo a more rapid transmetallation step due to significantly reduced steric congestion
around the boron atom as compared to 3d.24 Assuming that transmetallation from 3d is slow
under the reaction conditions, the inhibitory effect of pinacol would arise from an increasingly
disfavored equilibrium for formation of the more reactive organoboron species (3e or 3f) from
3d as the concentration of free pinacol increases.
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Scheme 2. Potential equilibria between isopropenylboron species in the Rh/DTBMꢀSEGPHOSꢀ
catalyzed addition of 3d to 2
Reaction Rate Acceleration by Diol Additives. With a working hypothesis to explain the
inhibitory effect of pinacol, we considered that the use of an alternative isopropenylboron
nucleophile with reduced steric demand as compared to 3d, such as 3e or 3f, would be
advantageous. An initial evaluation of the reactivity of 3e25 was conducted during the course of
our studies employing B(OMe)3 as a stoichiometric additive, and we were pleased to find that
under otherwise identical reaction conditions we could obtain higher overall conversion of 2 with
3e as compared to 3d, with no difference in enantioselectivity (>99% ee). The higher conversion
and identical enantioselectivity with 3e are consistent with the hypothesis that 3d is not the true
reactive organoboron species, and must first be converted to 3e (or 3f) through a disfavored
equilibrium process prior to undergoing transmetallation.
Encouraged by these preliminary results, we decided to reꢀexamine the dual solvent system to
determine whether a 90:10 heptane:MeOH mixture was the optimal composition with 3e as the
nucleophile. As with 3d, the use of heptane as the nonꢀpolar solvent gave higher yield and lower
impurity levels relative to more polar solvents;26 however, we found that the use of MeOH and
EtOH as the protic coꢀsolvent component gave very similar results.27 This finding prompted us to
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evaluate a number of alcohols, as well as several diols, as potential replacements for MeOH as
coꢀsolvent. As shown in Figure 3, there was minimal difference among the alcohol coꢀsolvents
evaluated, but both ethylene glycol and propylene glycol gave significantly higher levels of 1
after 3 h. In all cases, the enantioselectivity was uniformly high (>99% ee) and the level of enone
byꢀproduct 4 was <2 area percent (AP) based on gas chromatography (GC) analysis.
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0.40 mol % [Rh(cod)Cl]2
0.88 mol % DTBM-SEGPHOS-S
O
2
O
OH
B
1.0 equiv DIPEA
1.2 equiv B(OMe)3
Me
OH
+
Me
8-9 vol Heptane,
1-2 vol alcohol or diol
3 vol H2O, 50 °C
3e
(1.1 equiv)
(S)-1
Figure 3. Effect of alcohol and diol coꢀsolvents on reaction rate (all reaction conditions formed 1
with >99% ee and gave <2AP 4)
We followed up on the exciting finding of reaction rate acceleration by stoichiometric diol
additives by evaluating an extended set of diols (Figure 4). Among the diol additives investigated,
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1,3ꢀpropanediol and 2ꢀmethylꢀ1,3ꢀpropanediol, in conjunction with 1.1 equiv B(OMe)3, led to
the most pronounced increase in reaction rate, while also giving high enantioselectivity (>99% ee)
and good impurity control (<2AP 4). It was subsequently discovered that with both 2ꢀmethylꢀ
1,3ꢀpropanediol as well as 2,2ꢀdimethylꢀ1,3ꢀpropanediol (neopentyl glycol, npg), the addition of
B(OMe)3 was no longer necessary, obviating any concerns over losses of 1 during workup and
enabling us to fully capitalize on the dramatic rate acceleration afforded by the use of diol
additives.
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0.35 mol % [Rh(cod)Cl]2
0.77 mol % DTBM-SEGPHOS-S
O
2
O
OH
B
1.0 equiv DIPEA
1.1 equiv B(OMe)3
Me
OH
+
Me
alcohol (2 equiv) or diol (1 equiv)
10 vol Heptane
3e
(1.1 equiv)
3 vol H2O, 50 °C
(S)-1
Figure 4. Effect of alcohol and diol additives on reaction rate (all reaction conditions formed 1
with >99% ee and gave <2AP 4)
In parallel with the finding that the use of 2ꢀmethylꢀ1,3ꢀpropanediol or neopentyl glycol as a
stoichiometric additive led to significantly faster reactions with isopropenylboronic acid (3e), we
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discovered that both diols also led to faster reactions and higher conversions with
(isopropenyl)pinacolboronate (3d). This key finding provided a path forward for the
development of reaction conditions that could enable a reduction of the catalyst loading below
the 1.8 mol % Rh limit previously encountered with 3d as the nucleophile, which became critical
in light of the limited stability of 3e 28 that precluded its use on scale. We hypothesize that the
pronounced rate enhancement observed with 1,3ꢀdiols, relative to other diols and alcohols, arises
from a combination of three key factors (Scheme 3): 1) a more favorable equilibrium constant
for diol exchange with pinacol,29,30 leading to a higher concentration of the corresponding
(isopropenyl) diol boronate (e.g. 3g) 2) high solubility of the (isopropenyl) diol boronate in
heptane, and 3) faster transmetallation with Rh relative to 3d.31
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Scheme 3. Possible factors contributing to the pronounced rate enhancement observed with 1,3ꢀ
diol additives (e.g. neopentyl glycol) in the Rh/DTBMꢀSEGPHOSꢀcatalyzed addition of 3d to 2
After several additional rounds of optimization, it was ultimately determined that even with
diol additives, the use of 5ꢀ10% MeOH as coꢀsolvent led to further acceleration of the reaction
rate and higher overall conversion of 2.32 Similar to our initial optimization studies with 3d in the
absence of diol additives, heptane again proved superior to other nonꢀpolar coꢀsolvents (toluene,
iPAc, 2ꢀMeTHF, dioxane) in terms of reaction rate, overall conversion of 2 and impurity profile.
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As a final modification to the reaction conditions, we found that the DIPEA loading could be
reduced to 0.5 equiv, with minimal impact on the reaction rate or impurity profile. With these
optimized conditions (Scheme 4), we were able to reduce the catalyst loading to 0.3 mol %
[Rh(cod)Cl]2 (0.6 mol % Rh), representing a threeꢀfold reduction as compared to our original
conditions without the diol additive and a fiveꢀfold reduction as compared to the previously
reported conditions with isopropenyltrifluoroborate (3c).6
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Scheme 4. Final optimized reaction conditions for the synthesis of (S)ꢀ1 via asymmetric addition
of 3d to 2
Process Development with 3d on Kilogram Scale. With the optimal reaction conditions
identified, control of several key parameters was critical to the success of the reaction on large
scale. Unligated [Rh(cod)Cl]2 was found to promote the racemic background reaction,33 thus it
was critical that all of the [Rh(cod)Cl]2 was complexed with the DTBMꢀSEGPHOS ligand prior
to start of the reaction to ensure high enantioselectivity.9 In practice, this was achieved by
targeting a ligand to metal ratio (L/M) of ≥1.05 and conducting the catalyst formation in a
separate, smaller reaction vessel to minimize losses of the Rh and ligand during charging. While
[Rh(cod)Cl]2 and DTBMꢀSEGPHOS are both poorly soluble in MeOH, the resulting Rh/DTBMꢀ
SEGPHOS complex has excellent solubility in MeOH and the ligation is complete within 1 hour
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at RT.34 Efficient inertion of the reaction vessels (≤300 ppm headspace O2)35 was also found to
be critical for achieving high enantioselectivity, and the use of both vacuum/nitrogen swings and
subꢀsurface N2 sparging were effective for the removal of oxygen. On gram scale, the catalyst
solution could be conveniently transferred to the main reaction vessel by syringe, while on
kilogram scale (20 L vessel) and in production the catalyst transfer was achieved by applying a
slight positive N2 pressure to the catalyst preparation vessel (Figure 5).
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Figure 5. Experimental setup for 1 kg scale (20 L) reaction top) Overall setup bottom left)
Catalyst preparation bottom right) Catalyst transfer. See the Supporting Information for details.
Upon completion of the reaction, the biphasic mixture was split and the organic layer was
washed with 1 N HCl to remove DIPEA. A subsequent water wash resulted in almost complete
removal of residual 2, while the combined loss of 1 to the aq. layers was typically 5ꢀ6%. The
resulting organic stream was concentrated under reduced pressure to remove heptane and provide
the crude product, which could be purified by distillation (bp 70ꢀ75 °C/5 Torr) to provide 1 as a
colorless liquid with >99% ee. With the initial reaction conditions not employing diol additives,
the isolated yield of 1 was around 75ꢀ77%, with ~6% loss to the distillation residue. As described
earlier, the addition of B(OMe)3 allowed for reduced catalyst loadings, but the losses to the aq.
layers were more than double that of the original conditions (13% vs. 6%), leading us to abandon
the use of B(OMe)3 as an additive.
Following the identification of the dramatic rate acceleration afforded by 1,3ꢀdiol additives,
both 2ꢀmethylꢀ1,3ꢀpropanediol and neopentyl glycol were evaluated as stoichiometric additives
on scale. While both diols enabled a threeꢀfold reduction in the catalyst loading to 0.3 mol %
[Rh(cod)Cl]2 and 0.63 mol % DTBMꢀSEGPHOS, we ultimately selected neopentyl glycol based
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on the faster reaction rate relative to 2ꢀmethylꢀ1,3ꢀpropanediol. Although the use of
stoichiometric diol additives also led to higher losses to the aq. phases under our original workup
conditions, the increased loss could be mitigated by implementing a backꢀextraction of the
original aq. layer with heptane (2 x 2 vol). On 1 kg scale, the product loss to the heptane distillate
was 2.7% and the losses to the forerun and pot residue during the product distillation were both
1.6%, with an additional 5ꢀ6% estimated to be lost to the vacuum. The isolated yield after
concentration and distillation was 82%, ca. 5% higher as compared to the original process
without the diol additive. More importantly, the reduced catalyst loading made possible by the
neopentyl glycol additive enabled us to realize a cost savings of nearly 50% for this process as
compared to our initial optimized conditions.
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Production of (S)-1 on 100 kg Scale. As shown in Table 2, the optimized Rh/DTBMꢀ
SEGPHOS process using neopentyl glycol additive was successfully scaled up at a vendor. Five
105 kg batches were run, leading to the production of >600 kg of (S)ꢀ1 with 82% average yield
and 99.4ꢀ99.5 % ee. While this chemistry was being scaled up, we discovered in the lab that the
crude (nonꢀdistilled) 1 could be used in the downstream chemistry without any comprimise to
quality. Based on these findings, the five production batches were telescoped directly into the
subsequent step, with all telescoped batches successfully performing as expected and without an
imact to quality. Importantly, by eliminating the isolation of 1, the yield losses to the vacuum,
forerun and pot during the product distillation were obviated.
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Batch
2
(AP)
1
(AP)
ee
(%)
4
(AP)
Yield
(%)
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7
8
9
1
2
3
4
5
0.32
0.35
0.44
0.34
0.46
88.8
86.2
90.5
90.0
92.2
99.5
99.5
99.4
99.5
99.4
1.37
1.61
0.96
1.30
1.22
86
83.6
86
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89.2
77
Table 2. Scaleꢀup of the Rh/DTBMꢀSEGPHOSꢀSꢀcatalyzed asymmetric addition of 3d to 2 to
generate (S)ꢀ1
CONCLUSION
In summary, we have identified DTBMꢀSEGPHOS as a uniquely effective ligand for the Rhꢀ
catalyzed asymmetric 1,4ꢀaddition of (isopropenyl)pinacolboronate (3d) to 2ꢀcyclohexenꢀ1ꢀone
(2) to generate 3ꢀisopropenylꢀcyclohexanꢀ1ꢀone (1) with >99% ee. During the course of our
reaction optimization studies, we identified a pronounced inhibitory effect of the pinacol byꢀ
product, which was ultimately overcome through the addition of neopentyl glycol to the process.
This key 1,3ꢀdiol additive enabled a subsequent threeꢀfold reduction in catalyst loading to 0.6
mol % Rh, and the resulting optimized process was successfully scaled up to 100 kg scale to
produce >600 kg of (S)ꢀ1 with 82% average yield and 99.4ꢀ99.5 % ee. The demonstrated utility
of 1 as a starting material in the synthesis of biologically active compounds1 and complex natural
products2,3d and analogs,36 hints at the potential application of this methodology in future
complex molecule syntheses. Additionally, the observation that the optimized Hayashi
conditions were successful (>99% ee) with both 3d as well as isopropenylboronic acid (3e)
suggests that the dramatic reaction rate acceleration afforded by 1,3ꢀdiol additives might
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ultimately prove to be general for Hayashi additions with a range of organoboron nucleophiles,
and could potentially be more broadly applicable to other transitionꢀmetal catalyzed processes
involving organoboron species.
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EXPERIMENTAL SECTION
General Information. All operations were performed under a nitrogen atmosphere. Starting
materials, reagents and solvents were used as received from the commercial vendors. Quoted
yields are for isolated material, and are corrected for potency. Chiral GC analysis was performed
using a Supelco AlphaDEX 120 column (30 m x 0.25 mm x 0.25 µm), front inlet at 200 °C, split
ratio 30:1, helium carrier gas with constant flow 1.9 mL/min (40 cm/s), oven program: 80 °C for
0 min, then 2 °C/min to 110 °C for 0 min, then 20 °C/min to 220 °C (20.5 min run time), front
detector: FID, 250 °C, 35/350/30 hydrogen/air/makeup (He), 20 Hz acquisition, auto zero on.
Synthesis of (S)-1 via Rh/DTBM-SEGPHOS-S-cat. addition of (2-isopropenyl)
pinacolboronate (3d) to 2-cyclohexen-1-one (2)
Catalyst preparation: An inerted 500 L reactor was charged with methanol (38 kg, 0.45 vol)
and agitation was begun. Four vacuum/N2 backfill cycles were performed and then nitrogen was
sparged subsurface for 30ꢀ60 min or until ≤300 ppm oxygen was detected in the headspace.
[Rh(cod)Cl]2 (1.59 kg, 0.0030 equiv, 0.3 mol %) and Sꢀ(+)ꢀDTBMꢀSEGPHOS (8.02 kg, 0.0063
equiv, 0.63 mol %) were charged sequentially to the reactor and then vacuum/N2 backfill cycles
were performed four times or until ≤300 ppm oxygen level was detected in the headspace. The
resulting mixture was stirred 20 °C for 30ꢀ60 min prior to transfer to the main reactor. Reaction:
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An inerted 2000 L reactor was charged with water (310 kg, 3.0 vol) and 2,2ꢀdimethylꢀ1,3ꢀ
propanediol (neopentylglycol, 123 kg, 1.10 equiv) and agitation was begun. Four vacuum/N2
backfill cycles were performed and the mixture was stirred at 20 °C for 30ꢀ60 min. 2ꢀ
Cyclohexenꢀ1ꢀone (2, 103 kg, 1070 mol), (2ꢀisopropenyl)pinacolboronate (3d, 198 kg, 1.10
equiv), DIPEA (69.5 kg, 0.50 equiv), and heptane (597 kg, 8.55 vol) were sequentially charged
to the reactor. After the charges were complete, four vacuum/N2 backfill cycles were performed
and then nitrogen was sparged subsurface through the agitated biphasic mixture for 30ꢀ60 min or
until ≤300 ppm oxygen was detected in the headspace. The catalyst slurry prepared above was
transferred via the bottom valve of the 500 L reactor into the 2000 L reactor by applying a
positive pressure of nitrogen. After the transfer was complete, four vacuum/N2 backfill cycles
were performed and then nitrogen was sparged subsurface through the agitated biphasic mixture
for 30ꢀ60 min or until ≤300 ppm oxygen was detected in the headspace. The mixture was heated
to 58 °C and agitated at 100 RPM for 20ꢀ24 h under nitrogen. Reaction progress was monitored
by GC analysis of the organic phase of a composite sample that was taken from the agitated
mixture. After 24 h, the reaction was judged to be complete (≤1.0 RAP 1 in the organic phase)
and the reaction mixture was cooled to 25 °C. The phases were separated and transferred to
HDPE tanks for workup. Workup: An inerted 3000 L reactor was charged with the organic layer
from above, followed by water (527 kg, 5 vol). The biphasic mixture was agitated at 25 °C and
then the phases were separated. The remaining organic phase was sequentially washed with a 1
N HCl solution (582 kg, 0.55 equiv), followed by water (255 kg, 2.5 vol). The organic phase was
transferred to HDPE tanks and then the original aqueous layer was charged back to the reactor.
Two backꢀextractions with heptane (2 x 2 vol) were performed at 35 °C. The organic phases were
combined and polished filtered via a bag filter back to the cleaned reactor (cleaned using
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MeOH). Concentration: The combined organic phases were concentrated at 50 °C and 50ꢀ100
mbar to approximately 8 vol to give 581 kg of a heptane solution of 1 (22.2 wt % potency, 86%
corrected yield, 99.4% ee). This solution was used in the subsequent step without further
purification.
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ASSOCIATED CONTENT
Supporting Information
Additional scaleꢀup details and NMR spectra for compounds 1 and 3g are provided in the
Supporting Information (PDF)
The Supporting Information is available free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: eric.simmons@bms.com
*Eꢀmail: bmudryk@comcast.net
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS: We would like to thank Dr. David Kronenthal and Dr. Robert
Waltermire for their support of this work. We are grateful to Fred Roberts for assistance with
chiral GC analysis. We would like to acknowledge Dr. Gregory Beutner for helpful discussions
throughout the course of this work, and Dr. Steven Wisniewski for providing a critical reading of
this manuscript.
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REFERENCES
(1) Santos Pisoni, D. d.; Sobieski da Costa, J.; Gamba, D.; Petzhold, C. L.; César de Amorim Borges,
A.; Ceschi, M. A.; Lunardi, P.; Saraiva Gonçalves, C. A. Eur. J. Med. Chem. 2010, 45, 526.
(2)
(3)
Horn, E. J.; Silverston, J. S.; Vanderwal, C. D. J. Org. Chem. 2016, 81, 1819.
(a) Suzuki, M.; Suzuki, T.; Kawagishi, T.; Noyori, R. Tetrahedron Lett. 1980, 21, 1247; (b)
Kende, A. S.; Jungheim, L. N. Tetrahedron Lett. 1980, 21, 3849; (c) Boccara, N.; Maitte, P. Bull. Soc.
Chim. Fr. 1972, 1448; (d) Piers, E.; Keziere, R. J. Can. J. Chem. 1969, 47, 137.
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(4)
Nakao, Y.; Chen, J.; Imanaka, H.; Hiyama, T.; Ichikawa, Y.; Duan, W.ꢀL.; Shintani, R.; Hayashi,
T. J. Am. Chem. Soc. 2007, 129, 9137.
(5)
(6)
(7)
(8)
Robert, T.; Velder, J.; Schmalz, H.ꢀG. Angew. Chem. Int. Ed. 2008, 47, 7718.
Lalic, G.; Corey, E. J. Tetrahedron Lett. 2008, 49, 4894.
Howell, G. P. Org. Process Res. Dev. 2012, 16, 1258.
(a) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829; (b) Tian, P.; Dong, H.ꢀQ.; Lin, G.ꢀQ.
ACS Catalysis 2012, 2, 95.
(9)
has been conducted on 27 kg scale using 2 mol % Rh/BINAP, see: Brock, S.; Hose, D. R. J.; Moseley, J.
D.; Parker, A. J.; Patel, I.; Williams, A. J. Org. Process Res. Dev. 2008, 12, 496.
(10)
(11)
(12)
discrepency between these results and the high enantioselectivity reported by Lalic and Corey is due to
the low solubility of BINAP resulting in inefficient Rh ligation under the conditions for in situ catalyst
generation employed in our ligand survey.
(13)
(14)
The rhodiumꢀcatalyzed asymmetric 1,4ꢀaddition of an arylboronic acid to an α,βꢀunsaturated ester
Schmink, J. R.; Bellomo, A.; Berritt, S. Aldrichimica Acta 2013, 46, 71.
For details, see the Supporting Information.
In this set of experiments, both BINAPꢀR and BINAPꢀS gave <25% ee. We suspect that the
CAS 126726ꢀ62ꢀ3
In comparison, this ligand and solvent system afforded 1 with 54% ee in the ligand survey with
3c as the nucleophile.
(15)
Our early optimization studies utilized DTBMꢀSEGPHOSꢀR, which was the enantiomer used in
our initial ligand screen. These experiments were conducted before it was determined that the (S)ꢀ1
correlated with the desired enantiomer of the downstream API.
(16)
Enone 4 could also be formed via a transfer hydrogenation process that would presumably
involve the intermediacy of the fully saturated and diene analogs of 4. While these species were not
observed in the reaction mixture, we cannot definitively rule out this alternative isomerization pathway.
We thank a reviewer for this suggestion.
(17)
(18)
(19)
Taylor, S. H. J. Chem. Soc. A 1971, 2334.
(20) (a) Chatt, J.; Venanzi, L. M. J. Chem. Soc. 1957, 4735; (b) Ashfeld, B. L.; Judd, A. S. In
Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons, Ltd: 2001.
(21) While we are not aware of any studies explicitly comparing the stability of various rhodium
precurors, we note that in the originally reported syntheses of [Rh(cod)2]BF4 and [Rh(nbd)2]BF4 these
complexes are described as “moderately” or “reasonably” airꢀstable (see references 19a and 19b). In
contrast, the original report of the synthesis of [Rh(cod)Cl]2 indicates that this complex is stable in warm
concentrated HCl (see reference 20a), and it has been described as being “quite airꢀstable” (see reference
20b).
Pyridine, 2,6ꢀlutidine, Cy2NMe, nꢀBu3N, iBu3N, PMP, DBU, TMG.
K3PO4, K2CO3, KOH, NaOH, Cs2CO3, TMAOAc, TMAOH.
(a) Green, M.; Kuc, T. A.; Taylor, S. H. J. Chem. Soc. D 1970, 1553; (b) Green, M.; Kuc, T. A.;
(22)
[Rh(cod)Cl]2 and 1.1 mol % DTBMꢀSEGPHOS (1.0 mol % total Rh).
(23) For studies on the transmetallation from organoboron compounds to Rh, see: (a) Hayashi, T.;
Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052; (b) Zhao, P.; Incarvito, C.
D.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 1876.
The addition of 2.5 equiv B(OMe)3 led to >98% conv. of 2 within 24 h using 0.5 mol %
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(24)
Transmetallation from aryl(pinacol)boronate esters to Pd has been shown to be significantly
slower relative to the corresponding transmetallation with arylboronic acids, see: (a) Carrow, B. P.;
Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2116; (b) Fyfe, J. W. B.; Fazakerley, N. J.; Watson, A. J. B.
Angew. Chem. Int. Ed. 2017, 56, 1249.
(25)
Isopropenylboronic acid (CAS 14559ꢀ87ꢀ6) was obtained from Biogene Organics Inc. (part
number R9993I).
(26)
90:10 Toluene:MeOH, 90:10 MTBE:MeOH and 90:10 2ꢀMeTHF:MeOH gave 15ꢀ20% lower
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yield and 1ꢀ3 GCAP higher 4 relative to 90:10 Heptane:MeOH under otherwise identical conditions.
(27)
The effect of water vol was also investigated at this stage with a 90:10 Heptane:MeOH mixture.
A slight decrease in reaction rate was observed upon increasing water from 3 vol to 4 vol or 5 vol, but
there was no impact on enantoselectivity or impurity profile. However, in the absence of water the
reaction was extremely sluggish and gave slightly lower enantioselectivity as well as elevated impurity
levels.
(28)
Isopropenylboronic acid is known to be unstable in the solid state and has been reported to be a
pyrophoric solid, see: (a) Boldrini, G. P.; Lodi, L.; Tagliavini, E.; Trombini, C.; UmaniꢀRonchi, A. J.
Organomet. Chem. 1987, 336, 23; (b) Li, J.; Burke, M. D. J. Am. Chem. Soc. 2011, 133, 13774.
(29)
diols, see: Roy, C. D.; Brown, H. C. J. Organomet. Chem. 2007, 692, 784.
(30) Isopropenyl neopentyl glycol boronate (3g) is observed in the reaction mixture throughout the
For studies on the relative stability of boronate esters and rates of transesterification with various
course of the reaction of 3d and 2 with added neopentyl glycol. An authentic sample of 3g was prepared
by condensation of isopropenyl boronic acid (3e) with neopentyl glycol. See the Supporting Information
for details.
(31)
For a comparison of the reactivity of arylboron nucleophiles in Niꢀcatalyzed SuzukiꢀMiyaura
couplings, see: Zhang, N.; Hoffman, D. J.; Gutsche, N.; Gupta, J.; Percec, V. J. Org. Chem. 2012, 77,
5956.
(32)
It is hypothesized that the beneficial effect of the MeOH coꢀsolvent in reactions with diol
additives may be due to enhanced mass transfer between the aqueous and organic phases. In 0.1 L and 0.5
L reactors, a stir rate of 400ꢀ600 RPM was typically employed; however, the effect of stir rate on reaction
performance was not systematically investigated.
(33)
(34)
Itooka, R.; Iguchi, Y.; Miyaura, N. J. Org. Chem. 2003, 68, 6000.
During initial process development in the lab, catalyst formation was monitored by 31P NMR. For
details, see the Supporing Information.
(35) For laboratory scale experiments, it was found that reactions conducted in vessels with smaller
headspace consistently gave higher enantioselectivity than reactions conducted in vessels with larger
headspace. This is likely due to both the total amount of O2 and the molar ratio of O2/catalyst being lower
in vessels with smaller headspace at equivalent O2 concentrations (which were measured using a
Teledyne O2 analyzer).
(36)
Tokuyasu, T.; Masuyama, A.; Nojima, M.; McCullough, K. J.; Kim, H.ꢀS.; Wataya, Y.
Tetrahedron 2001, 57, 5979.
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