Crystallization-Induced Diastereomer Transformations of Brominated Arylacetic and Arylpyruvic Acids

Abstract

Enantiopure halogenated carboxylic acid derivatives are valuable building blocks for the synthesis of stereochemically complex and pharmaceutically relevant molecules. Crystallization-induced diastereomer transformations (CIDTs) are commonly used to access these compounds, but most methods rely on covalently attached chiral auxiliaries, limiting options for downstream manipulations of the carbonyl. We report the CIDT of diastereomeric salt pairs of α-bromo arylacetic and β-bromo arylpyruvic acids. The salts were obtained with high diastereoselectivities via direct filtration of the reaction mixture, and a salt break facilitated recovery of the enantiopure acid and chiral amine in high yields. The carboxylic acid products underwent additional manipulations to produce a variety of synthetically useful enantiopure building blocks.

Graphical Abstract

Carboxylic acid derivatives containing an α-stereogenic center are ubiquitous in natural products and small molecule drug targets.^1–4 These compounds have also proved invaluable in asymmetric synthesis and are commonly used as catalysts,⁵ ligands,^6,7 and resolving agents⁸ (Figure 1a). α-Halo carboxylic acids are particularly useful as they provide direct access to a range of substitution at the α-chiral center via nucleophilic halide displacement.⁹ Due to their synthetic utility, catalytic asymmetric reactions for the generation of α-halo carboxylic acid derivatives have been developed and new methods for the efficient asymmetric synthesis of α-halo carboxylic acids would be advantageous.^10–13 The resolution of chiral carboxylic acids by diastereomeric salt pairs using an enantiopure amine is an established and practical method with an inherent 50% maximum yield of the desired enantiomer.⁸ Crystallization-induced diastereomer transformations (CIDTs) are an appealing alternative when feasible: a maximum theoretical yield of 100% is possible due to the in situ substrate epimerization that funnels the mixture to a single diastereomer via a dynamic crystallization process.^14,15 Racemic α-halo carboxylic acids are commonly bound covalently to chiral auxiliaries to form diastereomeric mixtures of esters or amines that undergo CIDT processes using catalytic quantities of halide to induce epimerization (Figure 1b). There are several examples of this method in the literature;^16–18 however, the CIDT of diastereomeric salt pairs of α-halo carboxylic acids, obtained using a chiral amine as resolving agent, is comparatively underdeveloped.^19,20 This type of CIDT carries the advantage of non-covalent auxiliary attachment, circumventing the additional steps required for auxiliary attachment and removal. Additionally, the resultant carboxylic acid is readily manipulated to various carbonyl products. CIDTs of racemic α-halo carboxylic acids have been used for the synthesis of specific compounds en route to small molecule drug targets, but the development of a broader substrate scope is typically outside the remit of those studies.^19–21 Herein we report a CIDT platform for the asymmetric synthesis of a selection of α-bromo carboxylic acid salts (Figure 1b). After salt break, the enantioenriched acid is obtained and the chiral amine is reisolated. The halogen and carbonyl functional handles lend themselves to facile downstream manipulations allowing for the rapid synthesis of a variety of enantioenriched building blocks.

Figure 1.

a) Usefulness of α-stereogenic carboxylic acids. b) CIDT approach to accessing α-chiral carboxylic acids.

We began our investigation by exploring the CIDT of α-bromo phenylacetic acid derivative 1a. The aryl halide functional handle on this compound was projected to provide access to a variety of additional aryl derivatives through catalyzed cross-coupling reactions. For our initial screens, we selected two chiral bases as resolving agents: (S)-1-phenylethan-1-amine (A1) and (S)-diphenyl(pyrrolidin-2-yl)methanol (A2). Both of these chiral amines have been used in classical resolutions of racemic carboxylic acids,^8,22 and α-bromo acids are known to undergo racemization in the presence of quaternary ammonium bromide salts at elevated temperatures.^19,20,23 To that end, tetraethylammonium bromide (TEAB) was initially selected as an epimerization catalyst (entries 1–4), but tetrabutylammonium bromide (TBAB) was later preferred due to its increased solubility in the solvents listed. We first combined carboxylic acid 1a with an equimolar amount of A1 and catalytic quantities of TEAB (condition I), then screened a range of solvents, temperatures, and concentrations (Table 1). All reactions were initially homgeneous but became increasingly heterogeneous over time. Using MTBE as the solvent at 50 °C resulted in high diastereoselectivity but poor yield, likely due to high product solubility at elevated temperatures (entry 1). Lowering the temperature to 40 °C increased the yield but resulted in a complete loss in diastereoselectivity (entry 2). Similarly, using MeCN as the solvent resulted in low yields or unsatisfactory diastereomeric ratios (entries 3–4). Upon switching to chiral amine A2, low diastereomeric ratios but increased yields were initially observed when 2-MeTHF, MeCN, or THF were employed as solvent (entries 5–7). Filtrate analysis revealed some decomposition in reactions carried out at 40 °C, likely due to increased propensity of the secondary amine to react with the α-bromo acid to form the corresponding α-amino acid. Thus, the temperature was lowered for the remaining trials. We found that the addition of a small amount of water as an antisolvent²⁴ was crucial for selective precipitation, permitting isolation of the desired salt as a single diastereomer in good yield using a 98:2 THF:H₂O solvent mixture (entry 8). Analysis of the filtrate in all cases revealed a diastereomeric ratio of 1:1, consistent with a dynamic resolution process.

Table 1.

Optimization of α-bromo arylacetic acid CIDT.^a

entry	I or II	solvent	temp (°C)	conc. (M)	drb	yield %c
1	I	MTBE	50	0.2	>20:1	4
2	I	MTBE	40	0.2	1.4:1	60
3	I	MeCN	40	0.2	>20:1	8
4	I	MeCN	40	0.4	12:1	48
5	II	2-MeTHF	40	0.15	1:1	66
6	II	MeCN	30	0.15	1.6:1	75
7	II	THF	30	0.15	1:1	64
8	II	98:2 THF:H2O	30	0.15	>20:1	67

^aAll reactions were carried out on 0.10 mmol scale.

^bThe diastereomeric ratio values were determined by ¹H NMR spectroscopic analysis of the solid obtained by vacuum filtration of the crude reaction mixtures.

^cYields refer to isolated yields obtained from product filtration.

With optimized reaction conditions in hand, we explored additional substitutions of the aryl ring in the CIDT of α-halo carboxylic acids (Scheme 1). Structural modifications typically change the physical properties of a compound, often resulting in the need for substrate-specific optimization of reaction conditions for CIDT processes.^25–27 We were pleased to find our optimized conditions could be applied to additional substrates with no alterations. Both p-chlorophenyl and p-fluorophenyl substituents were tolerated in good yields and excellent diastereoselectivity (2b, 2d), as well as p-trifluoromethylphenyl (2c). Additionally, an unsubstituted phenyl substrate was isolated as a single diastereomer in modest yield (2e). A salt break of this substrate afforded enantioenriched (S)-1e and the optical rotation of this compound was used to assign the absolute stereochemistry of the α-bromo acid salts by comparison with a literature value.²⁸

Scheme 1.

Scope of brominated arylacetic and arylpyruvic acid CIDT.

We were interested in exploring whether this method could be applied to β-bromo arylpyruvic acids to access additional functionality. Due to the enhanced acidity of these substrates, we hypothesized that a slight excess of chiral base would be sufficient to promote epimerization of the α-stereocenter, obviating the need for the exogenous bromide catalyst. By using 1.05 equivalents of A2 and conducting the CIDT at room temperature, p-Me β-bromo arylpyruvic acid salt 4a was isolated in high yield and diastereomeric ratio. With minimal adjustments to solvent and concentration, p- and m-bromo adducts 4b and 4c were also isolated in moderate yield and high diastereoselectivity. To the best of our knowledge, these are the first CIDTs of arylpyruvic acids.

All reactions were carried out on 0.10 mmol scale. Yields refer to isolated yields and are the average of at least two trials. The diastereomeric ratio values were determined by ¹H NMR spectroscopic analysis of the solid obtained by vacuum filtration of the crude reaction mixtures. ^aReaction performed at 23 °C with 1.05 equiv A2 and no TBAB. See the Supporting Information for solvent and concentration.

The CIDT of 1a was conducted on 3.5 mmol scale and subsequent salt break afforded (S)-1a in good yield and high enantiomeric ratio. The chiral amine A2 was re-isolated in quantitative yield (Scheme 2a). Enantioenriched 1a underwent acid catalyzed esterification to afford methyl ester 5a in high yield with no loss in optical purity. This product underwent stereospecific S_N2 reactions with thiophenol and 1,2-phenylene diamine to afford α-thio ester 5b and quinoxalinone 5c, respectively, in excellent yields. The latter product was subjected to a Suzuki arylation,²⁹ affording biaryl adduct 5d in good yield and high enantiomeric ratio. Additionally, α-keto acid adduct 4a was converted to α-hydroxy esters 6a via a sodium borohydride-mediated reduction, followed by acid-catalyzed esterification. While the reduction proceeded with poor diastereoselectivity (dr 2:1), both diastereomers were isolated in moderate yield. The minor diastereomer (epi-6a) was converted to glycidic ester 6b via base-mediated intramolecular cyclization. The stereochemistry of the β-bromo arylpyruvicacid products 4a-c was assigned by comparing the optical rotation of glycidic ester 6b to a literature value.³⁰

Scheme 2.

Gram-scale CIDT and synthetic manipulations of α-bromo arylacetic and β-bromo arylpyruvic acids. a) i. Bu₄NBr (10 mol %), 98:2 THF/H₂O, 30 °C, 24 h ii. MeOH, H₂O, H₂SO₄, Et₂O iii. Aqueous NaOH, DCM. b) CH(OMe)₃ (1.5 equiv), H₂SO₄ (15 mol %), MeOH, rt, 8 h. c) Thiophenol (1.2 equiv), ⁱPr₂NEt (1.0 equiv), PhMe, rt, 3 h. d) 1,2-phenylene diamine (2.5 equiv), CHCl₃, rt, 48 h. e) PdCl₂(PPh₃)₂ (10 mol %), 4-chlorophenyl boronic acid (1.5 equiv), Na₂CO₃ (1.5 equiv), THF, 66 °C, 16 h. f) i. NaBH₄ (2.2 equiv), THF, −78 °C, 1.5 h ii. CH(OMe)₃ (1.5 equiv), H₂SO₄ (15 mol %), MeOH, rt, 16 h g) K₂CO₃ (1.5 equiv), MeOH, rt, 2 h. The er values were determined by HPLC analysis using a chiral stationary phase. The diastereomeric ratio values were determined by ¹H NMR spectroscopic analysis.

CONCLUSION

In summary, we have developed CIDTs enabling the isolation of diastereomerically pure brominated arylacetic and arylpyruvic acid salt pairs using (S)-diphenyl(pyrrolidin-2-yl)methanol as the resolving agent. A salt break afforded the enantioenriched carboxylic acids in good yield and high enantiomeric ratio and facilitated the quantitative recovery of the chiral amine. The α-bromo arylacetic and β-bromo arylpyruvic acids were further elaborated to synthesize various pharmaceutically relevant chiral building blocks such as α-thio esters and α-hydroxy esters.

Supplementary Material

ASSOCIATED CONTENT:

Supporting Information. Experimental procedures, compound characterization.

Data Availability Statement

The data underlying this study are available in the published article and its online supplementary material.