Development of a Kilogram-Scale Process for the Enantioselective

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Development of a Kilogram-Scale Process for the Enantioselective Synthesis of 3-Isopropenyl-cyclohexan-1-one via Rh/DTBM-SEGPHOSCatalyzed 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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Organic Process Research & Development

Development of a Kilogram-Scale Process for the Enantioselective Synthesis of 3-Isopropenyl-cyclohexan1-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 Chemical & Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States

* To whom correspondence should be addressed. E-mail: [email protected], [email protected]

ACS Paragon Plus Environment


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TOC Figure


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ABSTRACT 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.

Key Words: Hayashi 1,4-Addition, Rh-Catalyzed, DTBM-SEGPHOS, Pinacol Inhibition, Neopentyl Glycol

INTRODUCTION As part of an ongoing drug development program, we required access to multi-kilogram quantities of (S)-3-isopropenyl-cyclohexan-1-one ((S)-1) with high levels of enantioenrichment (>98% ee). Though several multi-step 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 1,4-addition of a suitable isopropenyl nucleophile (3) to 2cyclohexen-1-one (2) (Scheme 1).3 A search of the literature revealed three previous enantioselective syntheses of 1 via asymmetric 1,4-addition to 2 utilizing organosilicon (3a),4 organomagnesium (3b),5 and organoboron (3c)6 nucleophiles. While all of these methods generate 1 with high enantioselectivity (92-98% ee),4-6 they suffer either from high catalyst loading of an expensive metal (3 mol % Rh),4,6 the use of a non-commercially 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 multi-kilogram scale



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because of the mild reaction conditions and use of a commercially-available, air-stable 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 scale-up. 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, kilogram-scale 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 five-fold reduction in the amount of rhodium catalyst required as compared to existing methods.

Scheme 1. Synthesis of 1 via asymmetric conjugate addition of isopropenylmetal nucleophiles to 2-cyclohexen-1-one

RESULTS AND DISCUSSION


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Ligand Screening with 3c and 3d. We began our studies by investigating the Rh-catalyzed 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 high-throughput 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 (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 high-throughput 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 DTBM-SEGPHOS 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, non-polar solvents such as heptane gave the lowest levels of enone by-product 4 (Table 1). This impurity is believed to form from 1 by isomerization of the exocyclic doublebond, presumably through the intermediacy of a tetra-substituted 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 by-product formation for the Rh/DTBM-SEGPHOS-catalyzed addition of 3d to 2a

Solvent

1 (2 h) 1 (17 h) 1 (ee) AP AP (%)

4 (AP)

1:4 Ratio

Heptane

47.9

74.7

96.4

0.5

99:1

Cyclohexane

44.7

73.2

97.1

0.4

99:1

Toluene

38.0

64.3

96.8

1.2

98:2

F3-Toluene

28.2

58.4

96.4

1.5

97:3

p-Xylene

42.3

70.6

97.0

1.5

98:2

Anisole

33.9

61.9

96.8

1.5

98:2

CPME

45.5

75.7

96.2

1.6

98:2

2-MeTHF

44.4

72.6

97.1

2.2

97:3

Dioxane

52.4

81.5

96.8

6.0

93:7

THF

38.0

70.2

97.1

3.8

95:5

DCE

14.1

35.8

95.1

5.9

86:14

iPAc

41.4

68.8

96.3

1.8

97:3

DMF

58.1

62.9

96.7

3.5

95:5

MeCN

11.8

24.0

94.0

3.2

88:12

MeOH

84.9

83.0

96.2

15.3

84:16

iPrOH

28.5

61.0

96.5

38.2

61:39

a

Area 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 non-polar 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 2-MeTHF, toluene and heptane were all significantly accelerated with the use of 10% MeOH



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as co-solvent. 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 non-polar cosolvent component moving forward. EtOH, iPrOH, t-AmOH and TFE were also examined as protic co-solvents 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 Effects of Pinacol and B(OMe)3 on Reaction Rate. On multi-gram scale, the [Rh(cod)Cl]2/DTBM-SEGPHOS 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 DTBM-SEGPHOS. 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/byproduct 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, 1,5cyclooctadiene (COD) and chloride (in the form of TEACl) had no impact on the reaction rate, reactions that were conducted with added pinacol, MeO-B(pin) or HO-B(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.

O + 2

Me

B(pin)

3d (1.1 equiv)

0.5 mol % [Rh(cod)Cl] 2 1.1 mol % DTBM-SEGPHOS-S 1.0 equiv DIPEA, additive 10 vol 90:10 Heptane:MeOH 4 vol H 2O, 50 °C

O

Me

( S )-1

Figure 2. Spiking experiment demonstrating the inhibitory effect of pinacol on reaction rate. a

Area 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; 1,5-cyclooctadiene (1,5-COD) – 0.1 equiv; tetraethylammonium chloride (TEACl) – 0.1 equiv; 2-methoxy-4,4,5,5-tetramethyl1,3,2-dioxaborolane (MeO-B(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(On-Bu)3, B(Ot-Bu)3 and B(OPh)3 either had less of a positive impact on reaction rate or led to an increase of the isomerized enone byproduct 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). 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/DTBM-SEGPHOS 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/DTBM-SEGPHOScatalyzed 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 re-examine 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 non-polar 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 co-solvent 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 co-solvent. As shown in Figure 3, there was minimal difference among the alcohol co-solvents 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 by-product 4 was 99% ee and gave 99% ee) and good impurity control (99% ee and gave 99% ee. With the initial reaction conditions not employing diol additives, the isolated yield of 1 was around 75-77%, 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 1,3-diol additives, both 2-methyl-1,3-propanediol and neopentyl glycol were evaluated as stoichiometric additives on scale. While both diols enabled a three-fold reduction in the catalyst loading to 0.3 mol % [Rh(cod)Cl]2 and 0.63 mol % DTBM-SEGPHOS, we ultimately selected neopentyl glycol based



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on the faster reaction rate relative to 2-methyl-1,3-propanediol. 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 back-extraction 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 5-6% 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. Production of (S)-1 on 100 kg Scale. As shown in Table 2, the optimized Rh/DTBMSEGPHOS 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 99.4-99.5 % ee. While this chemistry was being scaled up, we discovered in the lab that the crude (non-distilled) 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 (%)

1

0.32

88.8

99.5

1.37

86

2

0.35

86.2

99.5

1.61

83.6

3

0.44

90.5

99.4

0.96

86

4

0.34

90.0

99.5

1.30

89.2

5

0.46

92.2

99.4

1.22

77

Table 2. Scale-up of the Rh/DTBM-SEGPHOS-S-catalyzed asymmetric addition of 3d to 2 to generate (S)-1

CONCLUSION In summary, we have identified DTBM-SEGPHOS as a uniquely effective ligand for the Rhcatalyzed asymmetric 1,4-addition of (isopropenyl)pinacolboronate (3d) to 2-cyclohexen-1-one (2) to generate 3-isopropenyl-cyclohexan-1-one (1) with >99% ee. During the course of our reaction optimization studies, we identified a pronounced inhibitory effect of the pinacol byproduct, which was ultimately overcome through the addition of neopentyl glycol to the process. This key 1,3-diol additive enabled a subsequent three-fold 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 99.4-99.5 % 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 1,3-diol 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 transition-metal catalyzed processes involving organoboron species.

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 30-60 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 S-(+)-DTBM-SEGPHOS (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 30-60 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 2,2-dimethyl-1,3propanediol (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 30-60 min. 2Cyclohexen-1-one (2, 103 kg, 1070 mol), (2-isopropenyl)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 30-60 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 30-60 min or until ≤300 ppm oxygen was detected in the headspace. The mixture was heated to 58 °C and agitated at 100 RPM for 20-24 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 back-extractions 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 50-100 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.

ASSOCIATED CONTENT Supporting Information Additional scale-up 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 *E-mail: [email protected] *E-mail: [email protected]

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) Horn, E. J.; Silverston, J. S.; Vanderwal, C. D. J. Org. Chem. 2016, 81, 1819. (3) (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. (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) Robert, T.; Velder, J.; Schmalz, H.-G. Angew. Chem. Int. Ed. 2008, 47, 7718. (6) Lalic, G.; Corey, E. J. Tetrahedron Lett. 2008, 49, 4894. (7) Howell, G. P. Org. Process Res. Dev. 2012, 16, 1258. (8) (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) The rhodium-catalyzed asymmetric 1,4-addition of an arylboronic acid to an α,β-unsaturated ester 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) Schmink, J. R.; Bellomo, A.; Berritt, S. Aldrichimica Acta 2013, 46, 71. (11) For details, see the Supporting Information. (12) In this set of experiments, both BINAP-R and BINAP-S gave 98% conv. of 2 within 24 h using 0.5 mol % [Rh(cod)Cl]2 and 1.1 mol % DTBM-SEGPHOS (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.



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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 14559-87-6) was obtained from Biogene Organics Inc. (part number R9993I). (26) 90:10 Toluene:MeOH, 90:10 MTBE:MeOH and 90:10 2-MeTHF:MeOH gave 15-20% lower yield and 1-3 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.; Umani-Ronchi, A. J. Organomet. Chem. 1987, 336, 23; (b) Li, J.; Burke, M. D. J. Am. Chem. Soc. 2011, 133, 13774. (29) For studies on the relative stability of boronate esters and rates of transesterification with various 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 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 Ni-catalyzed Suzuki-Miyaura 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 co-solvent 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 400-600 RPM was typically employed; however, the effect of stir rate on reaction performance was not systematically investigated. (33) Itooka, R.; Iguchi, Y.; Miyaura, N. J. Org. Chem. 2003, 68, 6000. (34) 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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Development of a Kilogram-Scale Process for the Enantioselective

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