Organocatalytic asymmetric conjugate addition of diaryloxazolidin-2,4-diones to nitroolefins: an efficient approach to chiral α-aryl-α-hydroxy carboxylic acids

Abstract

The first catalytic asymmetric conjugate addition of diaryloxazolidin-2,4-diones to nitroolefins is described. By employing an L-threonine-based tertiary amine-urea as the catalyst, the reaction proceeded in an excellent enantio- and diastereoselective manner (up to >99% ee and >19 : 1 dr). The adducts could be conveniently transformed to valuable α-aryl-α-hydroxy carboxylic acids, which structurally feature two adjacent hetero-quaternary and tertiary stereogenic centers.

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Introduction

Enantiomeric pure α-aryl-α-hydroxy carboxylic acids, which feature a tertiary alcohol and an aryl group on the α-position of the carboxylic acid, are privileged structural scaffolds in many natural and medicinally important agents.¹ For instance (Fig. 1a), chimonamidine is one of the isolated alkaloids from the seeds of Chimonanthus praecox Link that are employed as folk medicine for the therapy of rheumatoid arthritis in China.^1a Convolutamides A–F are γ-lactam alkaloids from the marine bryozoan Amathia convoluta with cytotoxicity against L1210 murine leukemia and KB human epidermoid carcinoma cells.^1b Other examples include tribulusamide C,^1c mandelamide derivative [inhibitor of hepatitis C virus (HCV) NS5A],^1d IQNP [ligand for the muscarinic acetylcholinergic receptor (mAChR)],^1e and so on.^1f–h Accordingly, the development of synthetic methodologies for the preparation of these valuable entities has attracted great interest of chemists during the past few decades.^2–5 To date, great improvements have been made in the addition of nucleophiles to α-ketoesters.² In addition, the aldol reaction to isatins³ can produce the precursors of α-aryl-α-hydroxy carboxylic acids, namely 3-hydroxy-2-oxindoles; the desired carboxylic acids could be obtained after hydrolysis, but their ortho-substituted amines on the aromatic rings are unavoidable and difficult to modify.

Fig. 1 (a) Representative natural and non-natural products. (b) 5H-Oxazol-4-ones in the build of α-alkyl-α-hydroxy carboxylic acids (eqn (1)) and this work (eqn (2)).

In 2004, Trost and co-workers⁶ introduced 5H-oxazol-4-ones as α-alkyl-α-hydroxy ester surrogates in a highly enantioselective allylic alkylation, thus providing a kind of significant α-alkyl-α-hydroxy carboxylic acids (Fig. 1b, eqn (1)). Since then, catalytic asymmetric reaction of 5H-oxazol-4-ones has been demonstrated as one of the most efficient strategies to build α-alkyl-α-hydroxy carboxylic acids.^7,8 Our group have also successively developed a series of organocatalytic asymmetric reactions of 5H-oxazol-4-ones, including conjugate addition to nitroolefins^8a and vinyl sulfones,^8b Mannich reaction,^8c sulfenylation,^8d alkylation,^8e conjugate addition–protonation^8f and [4 + 2] cycloaddition.^8f All of these works have demonstrated that 5H-oxazol-4-ones cannot be used to construct α-aryl-α-hydroxy carboxylic acids since 5-aryl-substituted 5H-oxazol-4-ones are very unstable and thus inaccessible. Nonetheless, employing feasible surrogates to access the desired α-aryl-α-tertiary hydroxy carboxylic acids could be recognized as plausible tactics in terms of these contributions.

In 2006, the Maruoka group⁴ reported a highly enantioselective phase-transfer-catalyzed alkylation of diaryloxazolidin-2,4-diones, in which the alkylated adducts could be conveniently transformed to α-benzyl-α-aryl-α-hydroxy carboxylic acids with satisfactory results. This pioneering work indicated the possibility of diaryloxazolidin-2,4-diones as the surrogates of α-aryl-α-hydroxy carboxylic esters. However, no other example has yet been reported. It is thus highly desirable to develop new reaction patterns involving diaryloxazolidin-2,4-diones, to afford diverse chiral α-aryl-α-hydroxy carboxylic acids with biological targets. Certainly, the unforeseen reactivity and stereoselectivity of diaryloxazolidin-2,4-diones in the unmet reactions should be the two key challenges. In recent years, we were keen on developing asymmetric organocatalytic reactions to build multitudinous chiral tertiary alcohols.^3d,8,9 As an extension of these ongoing research efforts, herein, we report a highly enantio- and diastereoselective conjugate addition reaction of diaryloxazolidin-2,4-diones to nitroolefins via a hydrogen-bonding catalysis, leading to an efficient approach to a series of valuable α-aryl-α-hydroxy carboxylic acid derivatives, which contain two adjacent hetero-quaternary and tertiary stereogenic centers (Fig. 1b, eqn (2)).

Results and discussion

At the outset, the conjugate addition of diphenyloxazolidin-2,4-dione 1a to nitroolefin 2a was chosen as the model reaction to investigate the reaction conditions (Table 1). The reaction was first conducted in CH₂Cl₂ at 25 °C and in the presence of 10 mol% of L-valine-based tertiary amine-thiourea A as the bifunctional catalyst.¹⁰ It was found that the desired adduct 3a could be obtained in 76% yield within 18 hours, but the enantio- and diastereoselectivity were very poor (entry 1). The reactivity (89% yield) and enantioselectivity (31% ee) were improved by utilizing catalyst B which contains urea instead of thiourea as the H-bonding donor, indicating the feasibility of this bifunctional combination in the stereoselective control (entry 2). Accordingly, a series of L-amino acid-based tertiary amine-urea catalysts (C–G) prepared from diverse L-amino acids were subjected to the reactions (entries 3–7); catalyst F with L-threonine as the chiral skeleton and tert-butyldimethylsilyl (TBDMS) as the protective group of alcohol was found to present the best results, in which 3a was obtained in 92% yield with 66% ee and 60 : 40 dr (entry 6). Noteworthy is that no reaction was detected when catalyst G with a bulkier tert-butyldiphenylsilyl (TBDPS) as the protective group was used (entry 7). Catalyst H bearing 4-fluorophenyl instead of 3,5-di(trifluoromethyl)phenyl as the substituent of urea could slightly increase both the enantioselectivity and diastereoselectivity (68% ee, 68 : 32 dr, entry 8). Afterwards, a range of solvents, including THF, ether, toluene and m-xylene, were screened in succession (entries 9–12). It was found that m-xylene presented the best results, providing 3a in 99% yield with 71% ee and 74 : 26 dr (entry 12). The enantioselectivity was further improved to 87% ee by performing the reaction at −20 °C (entry 14). The additive effect was then evaluated (entries 15–17). 4 Å molecular sieves were found to slightly increase the ee and dr values (entry 15). Similar results were obtained when 10 mol% of NaCl was used (entry 16). Finally, 3a with 94% ee and 92 : 8 dr was attainable when a set of 25 mg of 4 Å molecular sieves and 10 mol% of NaCl were subjected to the reaction (entry 17).

Table 1 Reaction optimization^a

Entry	Cat.	Solvent	T (°C)	t (h)	Yield^b (%)	ee^c (%)	dr^c
a The reaction was carried out with 0.05 mmol of 1a, 0.06 mmol of 2a and 0.005 mmol of catalyst in 0.5 mL solvent. b Isolated yield. c ee value of major diastereomer determined by HPLC methods. d 10 mg 4 Å molecular sieves (MS) were used. e 0.005 mmol of NaCl were used. f 25 mg 4 Å molecular sieves and 0.005 mmol of NaCl was used.
1	A	CH2Cl2	25	18	76	2	56 : 44
2	B	CH2Cl2	25	18	89	31	60 : 40
3	C	CH2Cl2	25	18	93	20	65 : 35
4	D	CH2Cl2	25	18	76	19	62 : 38
5	E	CH2Cl2	25	18	72	28	58 : 42
6	F	CH2Cl2	25	18	92	66	60 : 40
7	G	CH2Cl2	25	30	N.R.	N.A.	N.A.
8	H	CH2Cl2	25	18	95	68	68 : 32
9	H	THF	25	18	85	61	64 : 36
10	H	Et2O	25	18	87	64	65 : 35
11	H	Toluene	25	12	99	65	71 : 29
12	H	m-Xylene	25	12	99	71	74 : 26
13	H	m-Xylene	0	32	64	81	78 : 22
14	H	m-Xylene	−20	60	92	89	89 : 11
15^d	H	m-Xylene	−20	60	91	92	90 : 10
16^e	H	m-Xylene	−20	55	91	92	92 : 8
17^f	H	m-Xylene	−20	55	91	94	92 : 8

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With the optimal reaction conditions in hand, we explored the substrate scope involving both diaryloxazolidin-2,4-diones and nitroolefins (Table 2). First, we examined the viability of aryl nitroolefins (2a–m) with diverse steric and electronic properties by using diphenyloxazolidin-2,4-dione 1a as the nucleophile (entries 1–13). The reactions were completed within 96 hours and gave the corresponding adducts 3a–3m in 88–98% yield with 86–96% ee and 8 : 1 to 19 : 1 dr. The studies showed that the introduction of methoxy as the electron-donating group on the para-, meta- and ortho-position presented a slightly decreased diastereoselectivity (8 : 1 to 16 : 1 dr, entries 8–10). Analogous results were observed for those containing 2-naphthyl (3k) and 2-thienyl (3m) as the aryl groups (7 : 1 and 8 : 1 dr, entries 11 and 13). It was found that the α,β,γ,δ-unsaturated nitroolefin 2n was also suitable for the reaction conditions, providing adduct 3n in good enantio- and diastereoselectivity; after a single recrystallization, 99% ee and 99 : 1 dr of 3n was attainable (entry 14). Nitroolefin 2o containing a cyclohexyl gave the corresponding adduct 3o with a modest ee value yet good dr (50% ee, 15 : 1 dr, entry 15). Furthermore, other diaryloxazolidin-2,4-diones 1 with different aryl groups on the 5-position provided the corresponding adducts 3p–s in 85 − 91 yields with 85–98% ee and 11 : 1 to 14 : 1 dr (entries 16–18). The absolute configurations of the conjugate addition products were assigned based on X-ray crystallographic analysis of a single crystal of 3a.¹¹

Table 2 Substrate scope^a

Entry	1, Ar	2, R	3	Yield^b (%)	ee^c (%)	dr^d
a The reaction was carried out with 0.1 mmol of 1, 0.12 mmol of 2a, 0.01 mmol of catalyst F, 0.01 mmol of NaCl and 50 mg 4 Å MS in 1.0 mL solvent. b Isolated yield. c Determined by HPLC methods; ee in parentheses was obtained after single recrystallization. d Determined by ^1H NMR analysis.
1	1a, Ph	2a, Ph	3a	98	94 (99)	19 : 1
2	1a, Ph	2b, 4-ClPh	3b	92	94	19 : 1
3	1a, Ph	2c, 3-ClPh	3c	96	95	10 : 1
4	1a, Ph	2d, 2-ClPh	3d	92	92	19 : 1
5	1a, Ph	2e, 4-MePh	3e	88	94	18 : 1
6	1a, Ph	2f, 3-MePh	3f	96	90	19 : 1
7	1a, Ph	2g, 2-MePh	3g	95	96	19 : 1
8	1a, Ph	2h, 4-MeOPh	3h	96	91	16 : 1
9	1a, Ph	2i, 3-MeOPh	3i	98	91	14 : 1
10	1a, Ph	2j, 2-MeOPh	3j	95	91	8 : 1
11	1a, Ph	2k, 2-naphthyl	3k	95	86	7 : 1
12	1a, Ph	2l, 2-furyl	3l	90	90	16 : 1
13	1a, Ph	2m, 2-thienyl	3m	92	91	8 : 1
14	1a, Ph	2n, PhCH=CH–	3n	90	78 (>99)	19 : 1
15	1a, Ph	2o, Cy	3o	59	50	15 : 1
16	1b, 4-FPh	2a, Ph	3p	90	98	14 : 1
17	1c, 4-ClPh	2a, Ph	3q	89	91	12 : 1
18	1d, 4-MeOPh	2a, Ph	3r	91	85	11 : 1

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To demonstrate the utility of this methodology, synthetic transformations of conjugate addition products 3 were subsequently processed (Scheme 1a). Using KOH as a base and EtOH/H₂O (3 : 7) as a solvent, the adduct 3a could be readily converted into α-tertiary hydroxyl amide 4 through hydrolysis in 85% yield. Then, the reduction of 4 in the presence of zinc powder and HCl afforded the corresponding amine 5 in good yield and without compromising the ee value. It was found that the amine 5 was able to easily transform to the valuable γ-lactam 6⁵ that is a key chiral scaffold existing in many biologically important molecules, such as chimonamidine,^1a convolutamide A–F,^1b and tribulusamide C^1c (Fig. 1).

Scheme 1 (a) Transformations of the Michael adduct 3a. (b) Plausible transition state.

Although the mechanism towards L-amino acid-based tertiary amine-urea as a catalyst remains to be clarified, a plausible transition-state model is proposed (Scheme 1b), which is different from L-amino acid-based tertiary amine-thiourea^7a due to the entirely distinct enantioselectivity (Table 1, entries 1 and 2). Noteworthy is that similar enantioselectivities were observed when catalysts F (Table 1, entry 6) and H (Table 1, entry 8) respectively with 3,5-bis(trifluoromethyl)phenyl and 4-fluoro-phenyl groups as the urea substituents were used. Therefore, the generated enolate of diaryloxazolidin-2,4-dione after deprotonation would bind to the outside N–H bond of the urea unit, and the ortho C–H bond¹² of the aryl group of urea may not participate in the interaction with the enolate. The R₃NH⁺ arm of the catalyst and another N–H bond of urea can contribute a dual H-bonding mode to interact with nitroolefin. After nucleophilic addition, the conjugate adducts were attainable with the observed stereoselective results.

Conclusions

In summary, we have developed the first catalytic asymmetric conjugate addition of diaryloxazolidin-2,4-diones to nitroolefins. In the presence of an L-threonine-based tertiary amine-urea as the bifunctional catalyst, a series of conjugate adducts were obtained with good to excellent enantio- and diastereoselectivities (up to >99% ee and >19 : 1 dr). This strategy provides an efficient approach to valuable α-aryl-α-hydroxy carboxylic acids which structurally feature two adjacent hetero-quaternary and tertiary stereogenic centers. Further investigation to extend diaryloxazolidin-2,4-diones in novel asymmetric patterns is currently underway.

Acknowledgements

Financial support from the National Science Foundation of China (no. 21072044), Henan Province (14IRTSTHN006, 152300410057) and Henan University is greatly appreciated.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1417451. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00428d

‡ L. J. and X. Z. made equal contributions to this work.

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