H2O2

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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Revisiting the Cleavage of Evans Oxazolidinones with LiOH/H2O2 Gregory L. Beutner,* Benjamin M. Cohen, Albert J. DelMonte, Darryl D. Dixon, Kenneth J. Fraunhoffer, Andrew W. Glace, Ehrlic Lo, Jason M. Stevens, Dale Vanyo, and Christopher Wilbert Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States

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ABSTRACT: The use of LiOH/H2O2 for cleavage of Evans oxazolidinones is an essential but often overlooked part of using these ubiquitous chiral auxiliaries in synthetic routes. These conditions were disclosed in the literature more than 30 years ago and have found widespread use with little change. During studies focused on the synthesis of a drug candidate, we discovered the evolution of oxygen under the LiOH/H2O2 conditions for cleavage of an Evans auxiliary. We find this phenomenon to be general and tied to the fact that the initially formed peracid is not stable under the reaction conditions. The peracid is rapidly reduced by the excess H2O2 present in the reaction mixture, leading to the release of a stoichiometric amount of oxygen. This can present a significant risk for maintaining proper inertion in the presence of the flammable organic solvent, and we propose options for safely executing this chemistry at multikilogram scale. KEYWORDS: chiral auxiliary, oxazolidinone, safety, peracid

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Scheme 1. Use of LiOH/H2O2 for Removal of Oxazolidinones

lthough asymmetric catalysis has made tremendous strides in modern organic synthesis, chiral auxiliaries remain widely used for the preparation of enantioenriched compounds. Many auxiliary-based methods exist, and a few have entered into the common parlance of the field. The use of Evans oxazolidinones, first reported as chiral auxiliaries in the early 1980s, has become a go-to methodology for the robust installation of stereocenters α, β, and, in some cases, further removed from a carbonyl group.1 The use of this chemistry is common not only in academic settings but also in industrial research and manufacturing,2 as evidenced by its consistent appearance in numerous publications and patents over the last 30 years (Figure 1).3 An early example of a highly selective reaction with Evans oxazolidinone 1 was alkylation via intermediacy of a metalloenolate, enabling the synthesis of diastereomerically enriched product 2 (Scheme 1, eq 1).4

The removal of chiral auxiliaries is a necessary but often overlooked and much maligned part of their use. In the case of Evans oxazolidinones, numerous methods exist for conversion of oxazolidinone 2 into an array of functional groups. The simplest transformation, cleavage of 2 to regenerate carboxylic acid 4, can be accomplished using hydrogen peroxide as a nucleophile under strongly basic conditions (Scheme 1, eq 2).5 The reaction is believed to directly generate percarboxylate 3, which can then be converted to acid 4 in an aqueous workup with a reductant such as sodium bisulfite. One competing side reaction commonly observed in this process arises from hydrolysis at the carbamate carbonyl rather than the amide carbonyl, leading to formation of the undesired hydroxyamide 5. As part of efforts focused on developing a large-scale manufacturing route to compound 6 (Scheme 2, eq 1),6 we Received: March 20, 2019

Figure 1. Citations for the use of chiral oxazolidinones since 1982. © XXXX American Chemical Society

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DOI: 10.1021/acs.oprd.9b00124 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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Scheme 2. Evans Oxazolidinone Sequence in the Synthesis of 6

Table 1. Variation of Conditions for the Preparation of 9 from 8

elected to employ the Evans oxazolidinone strategy to install the stereocenter adjacent to the carboxylic acid in 7. We found that under the original Evans conditions for removal of the auxiliary from 8, up to 4.6 HPLC area percent (AP) hydroxyamide 10 was formed (Scheme 2, eq 2). Although this impurity was significantly reduced during the crystallization of 9, it amounted to a measurable loss in yield at a late stage of the synthesis, and we wanted to clearly understand the factors that controlled its formation. These studies, combined with investigations of the safety of the process, led us to uncover some unexpected findings about this widely used reaction, most notably the generation of significant amounts of oxygen during the reaction itself. In this paper, we provide answers to fundamental questions about how this reaction works and why the original reaction conditions are still in such widespread use without change after nearly 40 years. Finally, we propose alternatives supported by these findings for scalable and safer ways to execute it in the future. Following the original Evans conditions for the removal of the oxazolidinone from 8, a good yield and 96% selectivity for the desired product 9 versus hydroxyamide 10 was observed (Table 1, entry 1). To start, we decided to systematically reevaulate these reaction conditions, making straightforward variations of the solvent and base to look for trends that may relate to the underlying mechanism. Not surprisingly, examination of solvent effects as well as the identity of the base demonstrated that lithium hydroxide in THF gave optimal selectivity for the desired acid 9. Biphasic conditions gave no conversion, while among water-miscible solvents THF was clearly optimal in terms of selectivity (entries 1−6). Attempts to use weaker bases, such as lithium carbonate or potassium phosphate, gave little conversion (entries 7 and 8). Consideration of hydroxide bases showed that lithium gave optimal selectivity (entries 1 and 9−11). Of greater interest were the dramatic rate differences between the hydroxides. Reactions using sodium and potassium hydroxide were slowest, requiring more than 3 h to reach >99% conversion. The reaction employing lithium hydroxide reached >99% conversion in about 90 min. When tetrabutylammonium hydroxide (TBAOH) was used, by contrast, the reaction

entry

base

equiv of H2O2

solvent

temp (°C)

conv.a

9:10b

1 2 3 4 5 6 7 8 9 10 11 12 13c 14 15

LiOH·H2O LiOH·H2O LiOH·H2O LiOH·H2O LiOH·H2O LiOH·H2O Li2CO3 K3PO4 NaOH KOH TBAOH LiOH·H2O LiOH·H2O LiOH·H2O LiOH·H2O

4.6 4.6 4.6 4.6 4.6 4.6 4.6 4.6 4.6 4.6 4.6 4.6 4.6 3.5 2.5

THF DCE PhCH3 MeOH MeCN NMP THF THF THF THF THF THF THF THF THF

24 24 24 24 24 24 24 24 24 24 24 42 7 24 24

>99 0.0 0.0 >99 92.9 >99 3.2 4.5 92.3 88.6 >99 >99 >99 >99 >99

96.0:4.0 NA NA 63.9:36.1 13.7:86.3 78.5:21.5 95.5:4.5 94.6:5.4 89.3:10.7 63.3:36.7 93.9:6.1 95.0:5.0 97.4:2.6 94.4:5.6 92.1:7.9

a

Determined from HPLC AP of 8, 9, and 10 adjusted for UV response factors. bDetermined from HPLC AP of 9 and 10 adjusted for response factors. cThe reaction required 6 h to reach >99% conversion.

took less than 5 min to achieve full conversion, although with significantly decreased selectivity compared with the reaction using LiOH under otherwise identical conditions (entry 1 vs 11). Having determined that LiOH in THF was optimal in terms of yield and selectivity, attention turned to the reaction conditions with these reagents. Decreasing the reaction temperature led to lower levels of hydroxyamide, but this approach for improving the conditions was limited because of phase separation and the risk of freezing the aqueous layer (entries 1, 12, and 13). Varying the charge of LiOH from 1.2 to 2.0 equiv led to little change in the amount of hydroxyamide formed. In contrast, lowering the amount of H2O2 charged led to a loss in selectivity (entries 1, 14, and 15). This confirms that the large excess of H2O2 used in the original Evans report5 contributes to minimization of hydroxyamide formation and improved yields of the desired carboxylic acid product. The most interesting result came from varying the concentration of water in the system by adjusting the THF:H2O ratio while keeping the overall reaction volume constant. This had a notable effect on both the reaction rate and selectivity. From the kinetic profile of the reaction, the consumption of the starting material appeared to be a firstorder process, and the data could be fitted to an exponential decay (Figure 2a). Plotting kobs versus the H2O concentration clearly showed that “drier” reaction conditions lead to a slower reaction but give improved selectivity compared with those using higher levels of water (Figure 2b). Our final optimized conditions used significantly less water than the original Evans report (9.5 vs 14.5 M,7 respectively) in an effort to boost the B



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Figure 2. Variation of (a) the reaction rate and (b) the selectivity with [H2O]. In (b), the levels of 10 as HPLC AP are shown.8

selectivity at the cost of the reaction rate. However, since selectivity is generally not a major issue in the hydrolysis of less hindered oxazolidinones, the high rates afforded by the “wet” conditions of the original Evans report make those conditions the obvious choice in most cases. In the process of monitoring these reactions by HPLC, we were surprised to observe an intermediate species at early time points in a reaction with a relatively high water concentration of 15.7 M (Figure 3a). The level and lifetime of this intermediate decreased rapidly as the water content was reduced (Figure 3b). Attempts to observe this intermediate by NMR spectroscopy failed, but HRMS analysis of the peak was consistent with the lithium salt of peracid 11. On the basis of the proposed mechanism of the reaction, we believe the percarboxylate to be the direct product of cleavage of oxazolidinone 8. Although it seems reasonable that it should persist under the strongly oxidizing reaction conditions, our data suggest that it was only a short-lived intermediate. 13C NMR analysis of reaction mixtures before the reductive workup confirmed that the product existed as the lithium carboxylate by comparison to authentic lithium carboxylate prepared in THF from isolated 9. This result immediately raised the question of what was reducing the peracid9 under these strongly oxidizing reaction conditions. In order to address concerns about oxidation of the solvent, it was found that running reactions in THF-d8 did not affect the lifetime of the peracid intermediate as determined by HPLC monitoring. Addition of 1 mol % BHT to the stream

Figure 3. Observation and kinetic behavior of peracid intermediate 11.8

also had no effect, suggesting that the decomposition is not a radical process. Varying the overall reaction concentration or the concentration of LiOH also had no effect on the level or kinetics of peracid decomposition. The only factors that affected it appeared to be the water content (Figure 3b) and hydrogen peroxide concentration, with larger amounts of H2O2 leading to faster consumption of peracid 11. Although changing the concentration of H2O2 at a fixed water content of 15.7 M changed the rate of peracid decomposition and product formation (Figure 4), it did not have a measurable effect on the rate of consumption of oxazolidinone 8, consistent with these being chemically and kinetically distinct steps. Decomposition of peracid 11 clearly occurs after the rate-determining carbon−nitrogen bond cleavage in 8. C



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Figure 4. Effect of the H2O2 concentration on the yield of peracid intermediate 11 at 15.7 M H2O in THF.8

Figure 5. Effect of [H2O2] on the flow rate and total volume of O2.

In parallel to these investigations of the minimization of hydroxyamide 10, an assessment of the safety of the overall process was underway. Thermal analysis did not present any significant risks to running the process at scale, but some offgassing was observed. Follow-up on this observation revealed that the gas being formed was O2. Measurement of the oxygen level showed that it exceeded our acceptable safety limit in the reactor headspace and therefore presented a significant safety risk that required implementation of some control strategy. Although there has been incidental mention of oxygen offgassing during this auxiliary cleavage reaction in the literature,10 there was a clear lack of quantitation and understanding of this O2 generation. It is well-known that the decomposition of hydrogen peroxide under basic conditions leads to oxygen, but we found that the rate of H2O2 decomposition even at high pH is quite low compared with the maximum observed during the reaction of 8 (0.006 vs 0.32 L min−1per kg of 8) and cannot be the only source of the rapid formation of the large amount of oxygen observed.11 It was at this point that our two parallel investigations into this reaction merged. A thorough search of the literature revealed that in 1970, Simamura and co-workers had studied the decomposition of peracids in the presence of hydrogen peroxide and found that it proceeds rapidly under basic conditions.12 It was proposed that hydrogen peroxide acts as a reductant and forms oxygen along with the corresponding carboxylic acid. To confirm the role of H2O2 in the reduction of peracid 11, the O2 flows from two reactions with 8 using different amounts of hydrogen peroxide were measured using a mass flow meter and compared (Figure 5). The O2 flow rates were significantly higher in the case of the higher H2O2 concentration.13 The higher O2 flow rates correspond to the conditions that show lower levels of the peracid intermediate by HPLC, consistent with a mechanism in which peracid 11 is reduced by hydrogen peroxide. Quantitation of the amount of O2 formed showed that slightly more than 1 equiv of O2 was formed in the process. Additionally, titration of residual hydrogen peroxide at the end of the reaction showed that 2 equiv had been consumed,14 confirming the dual role of hydrogen peroxide as both a nucleophile for generation of and subsequent reductant for peracid intermediate 11. Examination of other oxazolidinones 12−14 under identical conditions showed that generation of stoichiometric amounts of O2 was not unique to our substrate and that it is likely a general phenomenon in this reaction (Figure 6).

Figure 6. Common oxazolidinones 12−14 demonstrating similar O2 generation.

With these data in hand, we propose the following general mechanism to explain the H2O2-mediated cleavage of oxazolidinones 2 and the formation of the corresponding hydroxyamides 5 (Figure 7). Deprotonation of H2O2 leads to

Figure 7. General mechanism for cleavage of oxazolidinones 2.

LiOOH (15), which is the active nucleophile in the desired reaction. This equilibrium lies far to the right because of the large pKa difference between H2O and H2O2 (14 vs 10 in H2O, respectively). The data presented here are consistent with Evans proposal that percarboxylate 3 arises from attack of LiOOH while hydroxyamide 5 arises from attack of hydroxide. In fact, exposure of oxazolidinone 8 to LiOH in the absence of H2O2 leads to rapid and exclusive formation of hydroxyamide 10. After attack of the hydrogen peroxide anion, the initially formed peracid 3 exists as the lithiated peracid (pKa ∼ 8)15 under the reaction conditions (pH > 10). This percarboxylate then undergoes a disproportionation with undissociated H2O2, as per Simamura’s proposal, to form carboxylate 4, 1 equiv of O2, and 1 equiv of H2O. This is consistent with increased rates of peracid consumption and oxygen evolution as the concentration of H2O2 is increased. Examination of the mechanism demonstrates that the formation of carboxylate 4 consumes 2 equiv of H2O2, consistent with our titration D



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scalable process. However, the increased levels of hydroxyamide 10 formed under these conditions were not optimal in terms of yield and proved difficult to handle under the current crystallization conditions. Although the lower yield and higher levels of hydroxyamide 10 observed in the initial runs were a major drawback in this case, we note that substrate 8 is peculiar in its propensity to form the hydroxyamide, so these results should not preclude the success of this CSTR strategy with more well-behaved oxazolidinones. The other option, in which LiOH was slowly added to the batch so as to control the reaction rate and therefore the O2 flow rate, achieved superior results (Figure 8). Again, this

studies. Any remaining H2O2 is then quenched during the reductive aqueous workup. So how do we use this information to minimize the generation of O2 and move the reaction toward conditions where we maintain low O2 levels for safer implementation at scale? The original Evans conditions employ a large excess of H2O2 (4.6 equiv), which has clear benefits in terms of selectivity for the desired acid. However, these conditions also accelerate peracid reduction and therefore O2 release. One idea was to run the reaction with less than 2 equiv of H2O2, in essence starving the reaction of H2O2, thereby preventing the in situ reduction of the peracid and release of O2. While this may be a feasible approach that should be investigated with other substrates, the issue with substrate 8 was that even small decreases in the amount of H2O2 led to unacceptably high levels of hydroxyamide (see Table 1, entry 1 vs entries 14 and 15). The remaining options were engineering controls that would minimize the instantaneous amount of O2 released from the system. These options would not reduce the total amount of O2 generated but would control the O2 offgassing rate. By doing so, the flow of N2 through the headspace of the reactor would be sufficient to dilute the O2, reducing the potential safety liabilities of high O2 concentrations. To achieve this, we examined running the reaction in a continuous fashion, minimizing the amount of material undergoing reaction at any point in time when the system is running at steady state. A second option was to run the reaction in semibatch mode with slow addition of LiOH, again reducing the instantaneous O2 offgassing rate. In the case of a continuous process, it was quickly decided to investigate this option with continuous stirred tank reactor (CSTR) technology to avoid potential issues with pressure buildup that could arise in a plug flow reactor.16 The main obstacle in the development of a CSTR process was the rate of the reaction (90 min to >99% conversion), which would necessitate a fairly complex multitank setup to achieve high conversion because of the long residence time required. Returning to our initial work on alternative reaction conditions (Table 1), we focused on TBAOH as a potential option because of its extremely high reaction rate. Using TBAOH/ H2O2 and the understanding of the process that we had built through these investigations, we were quickly able to devise a single-tank CSTR system and provide a proof of concept for this strategy (Scheme 3). If the O2 level ever exceeded a safe value in the CSTR reactor, the flow could be stopped, and maintaining the N2 flow through the reactor would return the system to a safe state, minimizing potential liabilities while preserving product quality and meeting our requirements for a

Figure 8. Semibatch mode synthesis of 9.

system had the feature that if the O2 level exceeded a safe operating level, the flow of LiOH could be stopped to allow the N2 flow through the reactor to return the system to a safe operating state. In the end, this semibatch slow addition process under the original batch-mode conditions was chosen for subsequent scale-up. It has been safely executed at >100 kg scale, and the details of the additional engineering concerns surrounding its implementation will be disclosed in a subsequent paper. In summary, we hope that this work lends clarity and confidence to the safe use of LiOH/H2O2 as a method for removal of Evans oxazolidinones and synthesis of enantiopure carboxylic acids. Starting from a question about impurity control, we were able to combine traditional physical organic chemistry with process safety studies to come to a deeper understanding of this necessary part of employing Evans oxazolidinones in synthetic routes. The generation of significant amounts of O2 during a reaction presents a major

Scheme 3. Synthesis of 9 in a CSTR Reactor

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Teflon line with a diaphragm pump. The base of the Teflon line was maintained at the 100 mL volume mark of the 250 mL reactor to maintain a 20 mL residence time. Three HPLC pumps were then used to charge reagent solutions to the 250 mL reactor. Pump 1 delivered hydrogen peroxide (30 wt % in H2O, 145.6 mmol, 6.5 equiv, 0.26 mL/min). Pump 2 delivered a solution of 10.0 g of 8 in 100 mL of THF (22.40 mmol, 2.0 mL/min). Pump 3 delivered tetrabutylammonium hydroxide solution (55 wt % in H2O, 35.83 mmol, 1.6 equiv, 0.30 mL/ min). The pumps were started sequentially and allowed to run for 60 min before the diaphragm pump was started to remove reaction mixture to the 1 L quench tank. Assay of the final quenched reaction mixture at the end of the addition showed >99% conversion and an in-process yield of 80%. The lower aqueous layer was then removed, and 35 mL of DMAc was added. The solution was then distilled at 50 mmHg with a 40 °C jacket to remove the bulk of the THF. The solution was then heated to 70 °C for slow addition of 28 mL of water. Upon completion of the addition a suspension had formed, and the mixture was cooled to 20 °C. An additional 18 mL of water was added, and the resulting slurry was aged for 1 h at 20 °C. The suspension was filtered, washed with 30 mL of 1:1 DMAc/water, and dried under N2/vacuum sweep to obtain 4.8 g of 9 as a white solid (68% yield). Final solids contained 1.0 AP hydroxyamide 10.

safety concern, especially when unanticipated. The original Evans conditions, which remain in widespread use, derive clear benefits in terms of reaction rate and selectivity from the use of a significant excess of H2O2 under highly aqueous conditions. However, it is these conditions, specifically the use of a large excess of H2O2, that favor rapid generation of O2. A number of options are suggested that allow the chemistry to be run with control over the amount and rate of O2 generation from the reaction that should find application at all scales. However, this work also highlights the need for continued research into robust methods for removal of chiral auxiliaries if they are to remain a part of pharmaceutical synthesis in the future.17 In a more general sense, the lesson we took away from this work is that there is always value in asking fundamental questions about chemical processes, no matter how established they are. The consideration and contribution of data typically obtained in a process safety evaluation can provide additional insights for unexpected issues and have an impact that goes far beyond the specific process under investigation.

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EXPERIMENTAL SECTION Batch-Mode Preparation of (R)-2-((1s,4S)-4-(6-Fluoroquinolin-4-yl)cyclohexyl)propanoic Acid (9). To an 1800 L glass-lined reactor under a nitrogen sweep were charged 254.1 kg of THF and 57.0 kg (127.7 mol, LR) of 8 followed by 127.0 kg of THF. To the mixture was charged 66.9 kg (590 mol, 4.6 equiv) of a 30% w/w solution of hydrogen peroxide in water followed by 2.0 kg of water. The mixture was heated to 25 °C, and a solution of 8.7 kg of LiOH·H2O (207 mol, 1.6 equiv) in 57.3 kg of water was charged over 4 h while the temperature was maintained at 25 °C and the oxygen content at

H2O2

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