Parallel kinetic resolution of aziridines via chiral phosphoric acid-catalyzed apparent hydrolytic ring-opening

Abstract

We report a chiral phosphoric acid catalyzed apparent hydrolytic ring-opening reaction of racemic aziridines in a regiodivergent parallel kinetic resolution manner. Harnessing the acyloxy-assisted strategy, the highly stereocontrolled nucleophilic ring-opening of aziridines with water is achieved. Different kinds of aziridines are applicable in the process, giving a variety of enantioenriched aromatic or aliphatic amino alcohols with up to 99% yields and up to >99.5 : 0.5 enantiomeric ratio. Preliminary mechanistic study as well as product elaborations were inducted as well.

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Introduction

Enantiopure β-amino alcohols are frequently encountered in natural products and synthetic molecules¹ which display diverse bioactivities and excellent potential for pharmaceutical use (Scheme 1a).² In addition, these units are frequently used as chiral auxiliaries and ligands in asymmetric synthesis.³ Due to the significant importance of such essential structural motifs, considerable attention has been paid to their enantioselective construction,⁴ and a variety of methods have been reported.⁵ The catalytic asymmetric hydrolytic ring-opening of aziridines⁶ provides an inherently efficient and atom-economical approach for the construction of chiral β-amino alcohols. Nonetheless, water is a rather inert nucleophile that is difficult to activate and control,⁷ rendering the method a daunting challenge. In 2014, Feng and co-workers realized a chiral magnesium(II)-catalyzed direct asymmetric ring-opening of meso-aziridine with H₂O as the nucleophile (Scheme 1b),⁷ⁱ and this is to the best of knowledge, the only work on non-enzymatic catalytic enantioselective hydrolytic ring-opening of aziridines reported so far.⁸ In organocatalysis, List and co-workers reported a chiral phosphoric acid catalyzed aziridine ring-opening reaction using carboxylic acid as the nucleophile,⁹ which can be considered as an indirect version of asymmetric hydrolysis. In this context, the development of direct asymmetric hydrolytic ring-opening of aziridines (Scheme 1c), especially in organocatalysis, is highly demanded.

Scheme 1 Enantioselective construction of amino alcohols via enantioselective hydrolytic ring-opening of aziridines.

Recently, Christmann et al. reported a unique catalytic asymmetric halohydroxylation of unactivated alkenes using water as the nucleophile.¹⁰ In their strategy, an intramolecular assisting group is designed to activate H₂O as a nucleophile by forming a temporally covalent interaction. We wondered whether a similar idea would facilitate the hydrolytic ring-opening of aziridines. To our delight, in the preliminary experiment, racemic aziridine (±)-1a′ successfully transformed into the corresponding products 2a′ and 3a′ in the presence of 4 equivalents of water and 10 mol% of chiral phosphoric acid C1 (ref. 11a) as the catalyst. The relationship between yields and ee is indicative of a parallel kinetic resolution process. When the acyl group was sterically substituted (3,5-di-tert-Bu), the enantioselectivity of the reaction was significantly improved, given the approach highly promising to be further optimized (Scheme 2).

Scheme 2 Preliminary study on the hydrolytic parallel kinetic resolution.

Parallel kinetic resolution (PKR) is a unique type of resolution,^12,13 in which the conversions of both enantiomers of a racemate proceed at similar rates, giving two separable chiral compounds as the products. This relatively uncommon class of reaction has considerable potential compared to traditional kinetic resolution (KR).¹⁴ However, it is a complicated task for one catalyst to accurately discriminate the enantiomers in a racemic mixture, yielding the two products in different directions according to their configurations. Therefore, in sharp contrast to the traditional resolution, much less successful examples have been reported on PKR.¹⁵ Most of the studies developed so far in this field involve metal catalysis,¹⁶ whilst examples of catalytic PKRs in enantioselective organocatalysis are, however, very limited.^10,17

Chiral phosphoric acids (CPAs),^14k,18 as an important class of organocatalysts, have been widely studied in asymmetric catalysis for their broad spectrum and efficient catalytic characteristics. Though, reports on CPA-catalyzed PKR are scarce. In 2010, List and co-workers reported CPA-catalyzed kinetic resolution of homoaldols via intramolecular transacetalization,¹⁹ wherein partial PKR was observed when the substrate was linear aliphatic substituted homoaldol; the group later reported a stereodivergent PKR in racemic diol acetalization²⁰ and epoxide ring-opening²¹ with CPA as a catalyst. In 2011, Ding and co-workers demonstrated the CPA catalyzed Baeyer–Villiger oxidation of racemic cyclobutanones to form regioisomeric lactones in optically enriched forms.²² In 2019, Zheng and co-workers developed an efficient PKR of acyclic aliphatic syn-1,3-diol derived acetals in the presence of CPA.^17e Very recently, Terada and co-workers reported a unique dynamic parallel kinetic resolution of the α-ferrocenyl cation initiated by the CPA catalyst.^17f Although handful of examples were reported as mentioned, such a challenging field is still in its infancy, and new strategies as well as systematic development are highly desirable. Herein, we are glad to disclose a CPA-catalyzed asymmetric hydrolytic ring-opening of racemic aziridines via regiodivergent PKR, providing a new approach for the synthesis of chiral β-amino alcohols.

We commenced the investigation by using racemic aziridine 1a as a model substrate (Table 1). A variety of BINOL-derived CPA catalysts were evaluated (entries 2–7), and C7 (ref. 11b) was found to be the superior one, giving 2a with 99 : 1 enantiomeric ratio (er) and 3a with >99.5 : 0.5 er (entry 6). Notably, decreasing the catalyst loading from 10 mol% to 5 mol% resulted in almost the same outcomes in an acceptable reaction time (14 h, entry 7). The solvents were further screened and it was found that CH₂Cl₂ remains to be the optimal one. Ultimately, catalyst C7 in 5 mol% loading, together with CH₂Cl₂ as the solvent showed the best performance, giving 2a and 3a in excellent yields and enantioselectivities.

Table 1 Optimization of the reaction conditions^a

Entry	Cat.	Solv.	Cat. (mol%)	Ratio 3/2	er 2	er 3	Time (h)
a Unless otherwise noted, reactions were performed on a 0.05 mmol scale in 1.0 mL solvent at rt; >95% conversion was achieved after the indicated time; ratios were determined by ^1H NMR analysis of the crude mixture; ers were determined by HPLC; Ar = 3,5-(t-Bu)2-4-MeO-C6H2. b The reactions were sluggish and substrates were not fully consumed.
1	C1	CH2Cl2	10	1.12	98 : 2	94 : 6	2
2	C2	CH2Cl2	10	1.11	90 : 10	87.5 : 12.5	48
3	C3	CH2Cl2	10	1.07	99 : 1	96 : 4	14
4	C4	CH2Cl2	10	0.98	72 : 28	72.5 : 27.5	4
5	C5	CH2Cl2	10	1.09	97 : 3	95 : 5	2
6	C7	CH2Cl2	10	1.04	99 : 1	>99.5 : 0.5	3
7	C7	CH2Cl2	5	1.03	99 : 1	>99.5 : 0.5	14
8	C7	Toluene	5	0.94	97 : 3	98.5 : 1.5	16
9^b	C7	Et2O	5	1.01	95 : 5	99 : 1	>72
10^b	C7	EtOAc	5	1.02	95 : 5	97 : 3	>72

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With the optimized conditions in hand, the substrate scope of this parallel kinetic resolution was assessed. Different racemic aryl substituted aziridines were evaluated (Table 2). Aziridines bearing both electron-withdrawing or -donating groups in para or meta positions on the phenyl ring proceeded smoothly and the corresponding products 2 and 3 were obtained in excellent yields and enantioselectivities (entries 2–11). Ortho-position-substituted racemic starting materials were also well tolerated under optimal conditions, providing excellent PKR performances, albeit a slower reaction rate was observed possibly due to steric hindrance (entries 12–14). The electronic properties of substituents on the phenyl rings of aziridines have a great impact on their reaction activities, for the electron-deficient substituents require a prolonged reaction time. It is worth noting that a sterically hindered 1-naphthyl derivative was feasible, giving the corresponding 2p in 45% yield with 97 : 3 er and 3p in 46% yield with 93.5 : 6.5 er (entry 16). Indene-derived aziridine 1s was also compatible, although with lower enantioselectivity (90 : 10 er, entry 19). Alcoholysis of 2a produced its amino alcohol derivative, of which the absolute configuration was unambiguously determined by X-ray crystallography (see Scheme 4a and ESI†).²³

Table 2 Scope of the aromatic aziridines^a

Entry	R		2			3		Time (h)
			Yield (%)	er		Yield (%)	er
a Unless otherwise noted, reactions were performed on a 0.1 mmol scale in 2 mL CH2Cl2 at rt for the indicated time; yields are of isolated products; ers were determined by HPLC; Ar = 3,5-(t-Bu)2-4-MeO-C6H2. b N-Mesyl aziridine was used as a substrate. c C6 was used as the catalyst. d ers are determined after derivatization. e Yields and ers are determined after derivatization. f 10 mol% catalyst was used. g C3 was used as the catalyst.
1	C6H5	2a	48	99 : 1	3a	50	>99.5 : 0.5	14
2	4-F-C6H4	2b	49	99.5 : 0.5	3b	50	>99.5 : 0.5	14
3	4-Cl-C6H4	2c	43	99 : 1	3c	53	96 : 4	14
4	4-Br-C6H4	2d	46	98 : 2	3d	48	95 : 5	46
5^b	4-CF3-C6H4	2e	46	98 : 2	3e	51	97 : 3	48
6^c	4-Me-C6H4	2f	43	98 : 2	3f	48	90.5 : 9.5	5
7	3-F-C6H4	2g	49	97.5 : 2.5	3g	45	>99.5 : 0.5	48
8	3-Cl-C6H4	2h	47	97.5 : 2.5	3h	48	>99.5 : 0.5	60
9	3-Br-C6H4	2i	46	98 : 2	3i	48	>99.5 : 0.5	72
10	3-MeO-C6H4	2j	46	97.5 : 2.5	3j	45	98 : 2	12
11	3-Me-C6H4	2k	46	99 : 1	3k	45	99.5 : 0.5	12
12	2-F-C6H4	2l	48	99 : 1	3l	48	99 : 1	72
13^b	2-Cl-C6H4	2m	46	98.5 : 1.5	3m	50	97.5 : 2.5	46
14^b	2-Br-C6H4	2n	45	99.5 : 0.5	3n	52	95.5 : 4.5	70
15^b	2-Me-C6H4	2o	46	99.5 : 0.5	3o	47	99 : 1	5
16^c	1-Naphthyl	2p	45	97 : 3	3p	46	93.5 : 6.5	14
17^f	2-Naphthyl	2q	46	90 : 10	3q	44	91 : 9	12
18^g	4-Phenyl	2r	44	99 : 1	3r	46	98 : 2	12
19		2s	48	90 : 10	3s	47	90 : 10	16

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Encouraged by the satisfactory results obtained, we further broaden the substrate scope for PKR to alkyl-substituted aziridines, for their products, aliphatic amino alcohols, were found to be more common units in bioactive molecules. However, as the aliphatic aziridines are not electronically biased as aromatic ones, such substrates are relatively inert and hard to be activated for the transformation. As expected, aliphatic aziridine rac-1t as a substrate under the standard conditions resulted in a sluggish reaction. Therefore, several kinds of catalysts that are more electron-deficient were further screened (see the ESI†).²⁴ Gratifyingly, C6 (R = 2,4-(CF₃)₂C₆H₃)^24c as a catalyst was found to be satisfactory, resulting in 2t and 3t in excellent yield and high enantioselectivity (see the ESI†). Various kinds of alkyl-substituted aziridines reacted smoothly under the modified catalytic system, and a range of aliphatic chiral amino alcohols were synthesized (Table 3). Et, n-Pr, i-Pr and Bn substituted aziridines were well tolerated, providing the secondary alcohol products 2t–2w with 90 : 10 er to 95 : 5 er and the primary alcohol products 3t–3w with 90 : 10 er to 93 : 7 er (entries 1–4). Aziridines with terminal hydroxyl groups protected by silyl, benzyl and acyl-groups were amendable as well, and corresponding products were obtained in excellent yield and good to excellent enantioselectivity (entries 5–7). In addition, aziridine with an azide substitution was also applicable, which provided a convenient site for further derivatization (entry 8). It is noteworthy that the hydrolyses are all highly regioselective, although there is no electron effect provided by the aromatic ring as before in the examples in Table 2.

Table 3 Scope of the aliphatic aziridines^a

a Unless otherwise noted, reactions were performed on a 0.1 mmol scale in 2 mL CH₂Cl₂ at rt for the indicated time; yields are of isolated products; ers were determined by HPLC; Ar = 3,5-(t-Bu)₂-4-MeO-C₆H₂. b C7 was used as the catalyst.

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To further understand the mechanism of this developed reaction, control experiments were conducted (Scheme 3). Reaction employing Bn- instead of acyl-protected 2,3-aziridinyl alcohol was performed under the standard conditions, and no reaction took place, implying that the presence of an acyloxy moiety as an assisting group is crucial for the reaction to occur (Scheme 3a). When racemic constitutional isomers rac-2a or rac-3a were subjected to the standard conditions, no resolution was observed, which rules out the mechanisms involving interconversion between products (Scheme 3b). An isotopic labeling experiment was performed by using H₂¹⁸O instead of H₂O (Scheme 3c), and the transformation resulted in an installation of both isomers with the ¹⁸O atom exclusively on the carbonyl group (see the ESI†). The outcome demonstrated that the addition of water proceeds via the assistance of acyloxyl but not a direct nucleophilic addition. Furthermore, enantiopure aziridine substrate 1o was subjected to the standard conditions. As anticipated, the reaction with (R)-C6 exclusively generated 2o, while the catalyst (S)-C6 with opposite configuration selectively afforded the corresponding product 3o (Scheme 3d). The performance of aziridine rac-1ae with two identical methyl substituents was evaluated, and this resulted in products 2ae and 3ae in almost racemic form. In contrast, when we subjected the disubstituted aziridine rac-1af with different substituents (methyl and n-propyl groups) to the reaction, the products 2af and 3af were both obtained with significantly increased er values (Scheme 3e). These results suggested that the steric difference at the carbon in the small ring distal to the acyloxy group is essential for the catalyst to discriminate substrates.

Scheme 3 Preliminary study of the mechanism: (a) reaction of substrate without assisting group. (b) Products interconversion experiment. (c) Isotopic labeling experiment. (d) Reactions with enantiopure substrate. (e) Steric effect studies. (f) Proposed mechanism.

On the basis of these results from the control experiments, a plausible reaction mechanism for the parallel kinetic resolution process is proposed (Scheme 3f). First, aziridine and H₂O are both activated by CPA, and the two ends are connected by a double nucleophilic attack sequence throughout the carbonyl group in the substrate. During the course, the critical intermediates, racemic cyclic hemi-orthoesters (INT and ent-INT) containing three stereocenters are formed with excellent diastereoselectivity. Afterwards, the resulting two enantiomers of hemi-orthoester are regiodivergently protonated by CPA, leading to the corresponding final products.

Furthermore, transformations of the obtained products from this approach were presented for the elaboration of its synthetic utility (Scheme 4). Alcoholysis of isomer 3a readily provided 1,3-dihydroxy-2-amino compound 4a. Selective tosylation of 4a followed by treatment with Et₃N regenerated a terminal aziridine 6a in 86% yield and 97.5 : 2.5 er. Reduction of 6a with LiAlH₄ successfully afforded β-N-tosylaminoalcohol 7a in 95% yield and 99 : 1 er. In addition, treatment of 6a with t-BuOK gave aza-Payne rearrangement product 8a. The γ-N-tosylated amino alcohol 9a could be obtained by further transformation of 8a with LiAlH₄ in 92% yield with maintained enantiopurity (Scheme 4a). Compound 9a is of interest as an intermediate in the synthesis of fluoxetine, which is a drug for treating depression and other disorders.²⁵ Through the azide–alkyne cycloaddition, 2aa was transformed into a triazole (4aa) with almost complete retention of the stereochemical integrity (Scheme 4b).

Scheme 4 Transformations of the product: (a) derivatizations of 3a. (b) Azide–alkyne reaction of 2aa. (c) Reactions of 1o.

As shown in Scheme 4c, treatment of the reaction mixture containing products 2o and 3o after the PKR with p-NsCl and Et₃N resulted in a selective transformation, in which the primary alcohol 3o could be readily converted into terminal aziridine 6o with high efficiency, while the secondary alcohol 2o remained. However, when DMAP was additionally employed, the secondary alcohol 2o could be transformed into enantioenriched aziridine 1o′ as well. The obtained internal aziridine appeared to be one of the enantiomers of the starting materials in the PKR reaction, and this one-pot procedure resulted in a formal traditional KR of racemic aziridine 1o. Enantioenriched aziridines provided by the transformations mentioned above are synthetically useful for their propensity to undergo ring-opening reactions to give a series of functionalized molecules. For instance, by treatment of NaN₃, chiral azido amide 7o could be regioselectively obtained in 97% yield with 97.5 : 2.5 er.

Conclusions

In summary, we reported an intriguing CPA-catalyzed asymmetric hydrolytic ring-opening of racemic aziridines via regiodivergent PKR. A wide array of aromatic and aliphatic aziridines were well compatible, providing amino alcohol derivatives in generally excellent yield and enantioselectivities. Preliminary mechanistic studies indicate that such a PKR process may have proceeded via the formation of cyclic hemi-orthoester intermediates and a subsequent regiodivergent resolution. In addition, facile and versatile transformations of the enantioenriched products demonstrated the utilities of the method in asymmetric synthesis. Further study on the mechanism as well as the applications of this methodology are underway.

Data availability

All experimental data and detailed procedures are available in the ESI.†

Author contributions

J. L. performed the main part of the experiments, and prepared the ESI† and manuscript. Y.-Y. D. participated in the synthesis of substrates, compound characterization, and ESI† preparation. Y.-S. H. and Y. L. participated in the synthesis of substrates and discussion. S.-Z. L. and Y.-Y. L. participated in the discussion and helped with the optimization of the manuscript. Y.-M. C. conceived and directed the project. All authors discussed the results and commented on the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the financial support from the National Key R&D Program (2022YFD1700403) and the 2115 Talent Development Program of China Agricultural University.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure, spectral data, NMR-data, and HPLC-data. CCDC 2244430. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3sc03899h

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