Organocatalytic, Chemoselective, and Stereospecific House–Meinwald Rearrangement of Trisubstituted Epoxides

Abstract

We present a novel method for the chemoselective House–Meinwald rearrangement of trisubstituted epoxides under mild conditions with the use of simple perfluorinated disulfonimides as Brønsted acid catalysts. We isolated the α-quaternary aldehyde products in yields of 27–97% using catalyst loadings as low as 0.5 mol% on a scale of 1 mmol. In addition, we show the stereospecific rearrangement using an enantioenriched substrate, which makes this method suitable for applications in total synthesis of natural products.

Numerous drugs and biologically active natural products possess all-carbon quaternary stereogenic centers.[1] The construction of such centers is often a complex endeavor and needs much synthetic effort.[2] A simple synthetic approach for the construction of chiral quaternary carbons is the stereospecific House–Meinwald rearrangement of asymmetric epoxides to the corresponding α-chiral carbonyls.[3] Since epoxidation is one of the most important reactions in organic synthesis and can be performed with an outstanding level of enantioselectivity,[4] the epoxidation–rearrangement sequence describes a powerful tool for the construction of α-chiral quaternary carbonyls. In particular, quaternary carbaldehydes are versatile building blocks in organic synthesis and many groups have used the sequence of ‘asymmetric epoxidation – House–Meinwald rearrangement’ to form quaternary carbaldehydes, e.g., in the total synthesis of cuparene,[5] lyngbyatoxin A,[6] and furanoterpene.[7] However, the House–Meinwald rearrangement of trisubstituted epoxides to α-quaternary carbaldehydes remains challenging in terms of chemoselectivity for the alkyl shift versus hydrogen shift. Stoichiometric amounts of Lewis acids are typically used, which makes it therefore an attractive target for organocatalysis using mild conditions.[8]

The metal-based epoxide rearrangements have the drawback that the catalysts are often moisture-sensitive and the reaction has to be carried out under Schlenk conditions. In addition, high catalyst loading or even a stoichiometric amount of the Lewis acid is required. In general, Lewis acids based on V,[9] Fe,[10] Co,[11] Cu,[12] Pd,[13] In,[14] Er,[15] Ir,[16] and Bi[17] complexes promote the hydrogen shift, whereas Lewis acids based on B,[18] Al,[19] Si,[20] and Cr[21] favor alkyl migration (Scheme [1]). To the best of our knowledge, there is only one report of the chemoselective rearrangement of trisubstituted epoxides using an organocatalyst based on a silicon-thiourea Lewis acid.[20] However, this catalyst has to be prepared in situ and is moisture-sensitive. Hence, the Brønsted acid catalyzed rearrangement of trisubstituted epoxides using non-Schlenk conditions is an open challenge and such catalysts have been rarely used in the rearrangement of disubstituted[22] or tetrasubstituted epoxides.[23] Here, we present a novel method using simple and cheap Brønsted acids for the chemoselective alkyl migration of trisubstituted epoxides under mild conditions.

We chose 1-phenylcyclohexene oxide (1) as test substrate to identify the ideal Brønsted acid catalysts and the optimal reaction conditions (Table [1]). We chose CH₂Cl₂ as solvent since it was used in other reports of Brønsted acid catalyzed House–Meinwald rearrangements,[22a] [23a] and we tested a series of simple and commercially available sulfonic acids (entries 1–4). Using 5 mol% sulfonic acid and dichloromethane as solvent, we observed full conversion but no chemoselectivity. Moreover, besides the formation of 1-phenylcyclopentane carbaldehyde (2) and 2-phenyl cyclohexanone (3), we observed the formation of various dimerization and polymerization side products via GC–MS analysis that may occur from the subsequent aldol addition of the formed 2-phenyl cyclohexanone.

Table 1 Optimization of Reaction Conditions^a

Entry	Catalyst	Solvent	Temp (°C)	Time (h)	Conv. (%)b	Yield of 2 (%)b	Yield of 3 (%)b
1	H2SO4	CH2Cl2	22	2	full	19	21
2	MsOH	CH2Cl2	22	2	full	33	39
3	p-TsOH	CH2Cl2	22	2	full	32	36
4	TfOH	CH2Cl2	22	2	full	24	28
5c	MsNH2	CH2Cl2	22	16	7	3	2
6c	p-TsNH2	CH2Cl2	22	16	7	2	3
7c	TfNH2	CH2Cl2	22	16	71	39	13
8	Ms2NH	CH2Cl2	22	2	18	15	1
9	p-Ts2NH	CH2Cl2	22	2	16	13	1
10d	Tf2NH	CH2Cl2	22	0.5	full	67	22
11	(C6F5SO2)2NH	CH2Cl2	22	20	25	21	< 1
12	(C6F5SO2)2NH	CH2Cl2	40	20	57	47	2
13	(C6F5SO2)2NH	CHCl3	61	5	full	81	3
14	(C6F5SO2)2NH	(CH2Cl)2	83	1	full	82	3
15d	(C6F5SO2)2NH	(CH2Cl)2	83	2	full	81	4
16e	(C6F5SO2)2NH	(CH2Cl)2	83	4	> 95	72	10
17	none	(CH2Cl)2	83	16	< 1	n.d.f	n.d.f

^a Reaction conditions: 0.2 mmol scale, 5 mol% catalyst, 2 mL solvent.

^b Determined by ¹H NMR with 0.1 eq. p-nitrobenzaldehyde as internal standard.

^c 10 mol% of catalyst was used.

^d 2.5 mol% of catalyst was used.

^e 1 mol% of catalyst was used.

^f n.d. = not determined

Using organic sulfonic acids, we observed full epoxide conversion and small amounts of side products. However, the chemoselectivity was still low with a slightly higher preference for 2-phenyl cyclohexanone (3, entries 2–4). As these sulfonic acids have low pK _a values (pK _a = 10.0 (MsOH),[24] 8.5 (p-TsOH),[24] 7.6 (H₂SO₄),[24] and 0.7 (TfOH),[25] all in MeCN) and since it is known that the acidity of Brønsted acids can be crucial for substrate activation,[26] we investigated the less acidic corresponding sulfonamides. However, even with an increase to 10 mol% catalyst loading and a reaction time of 16 h, we observed low conversions of around 5% using MsNH₂ and p-TsNH₂ (entries 5 and 6). With more acidic TfNH₂, the conversion increased to 71% with a 3:1 ratio of aldehyde/ketone (entry 7). We reasoned that these catalysts were not acidic enough (pTsNH₂, pK _a = 27.0 in MeCN),[24] we therefore synthesized a series of bis-sulfonimides as they have pK _a values between sulfonic acids and sulfonamides (p-Ts₂NH, pK _a = 12.0 in MeCN).[24] Using 5 mol% bis(methanesulfonyl)imide, we observed a conversion of 18%, but high chemoselectivity for the aldehyde over the ketone (15:1; entry 8). The use of bis-para-toluene sulfonimide did not improve conversion or chemoselectivity (entry 9). We tested bistriflilimide that has an even lower pK _a value than triflic acid (pK _a in (CH₂Cl)₂ –11.9 and –11.4, respectively).[25] Thus, we decided to decrease the catalyst loading to 2.5 mol% and shorten the reaction time to 30 min. We obtained full conversion but a decrease of the chemoselectivity to 3:1 compared to the other disulfonimides employed (entry 10). However, we observed smaller amounts of side products than when using triflic acid, which indicates that not only the acidity of the catalysts is crucial but also the nature of the Brønsted acid. Since bisperfluorinated phenyl sulfonimide is on the acidity scale between p-Ts₂NH and Tf₂NH ((C₆F₅SO₂)₂NH, pK _a = 5.1 in MeCN),[24] we employed this Brønsted acid and observed 25% conversion after 20 h and an excellent selectivity of 40:1 favoring carbaldehyde formation (entry 11). Additionally, we only observed traces of side products. To improve the conversion, we warmed the reaction to 40 °C and obtained 57% conversion and 47% aldehyde formation (entry 12). The change to chloroform as solvent allowed us to run the reaction at 61 °C. We achieved full conversion with 81% carbaldehyde formation after 5 h reaction time (entry 13). To enable even higher reaction temperature, we used 1,2-dichloroethane as solvent at 83 °C. We obtained the same results even after 1 h (entry 14), and therefore decreased the catalyst loading to 2.5 mol% (entry 15) and then to 1 mol% (entry 16). With 2.5 mol% catalyst, the selectivity was marginally smaller, but we still observed 81% carbaldehyde formation after 2 h. Using 1 mol% catalyst, we obtained almost full conversion after 4 h with 72% carbaldehyde formation but also 10% of the ketone, which means a slight loss of reactivity as well as selectivity. The catalyst is crucial for the reaction as we isolated unchanged pure starting material in a blind reaction after 16 h reaction time (entry 17).

With the optimized reaction conditions in hand (cf. entry 15), we focused on the rearrangement of various substrates (Scheme [2]).[27] The substrates are easily accessible via either Suzuki coupling using 1-bromocyclohexene or Grignard reaction using cyclohexanone derivatives followed by subsequent elimination. For the epoxidation, we chose either the well-established m-CPBA procedure developed by Prileschajew[28] or the in situ formation of dimethyl dioxirane (see the Supporting Information for further details).[29] Under our conditions, the House–Meinwald rearrangement proceeded with low catalyst loading and we isolated 67% of 1-phenylcyclopentane carbaldehyde (2). In addition, we observed the formation of 2-phenyl cyclohexanone (3) and some dimerization products in very small amounts via GC–MS; however, we were not able to isolate these compounds. Using more electron-rich substrates, we isolated the toluyl-substituted derivatives 4 and 5 in 69% and 59%, respectively. The para-toluyl-substituted derivative 6 was isolated in 27% and we further observed 54% of the corresponding ketone. We reasoned that this is due to the stabilization of the benzylic cation intermediate and a lower rate of the rearrangement. The halogen-substituted aldehydes 7–9 were isolated in yields ranging from 47% to 61% using 5 mol% (C₆F₅SO₂)₂NH and longer reaction times up to 72 h. The para-(trifluoromethyl)phenyl-substituted aldehyde 10 was isolated in 72%, whereas the meta- and ortho-substituted derivatives did not react under the standard reaction conditions. Thus, we tested Tf₂NH as catalyst again, but we only observed decomposition of the epoxides and isolated neither the aldehyde nor the ketone. To obtain aldehydes 11–13, we employed Tf₂NH as catalyst since the conversion using (C₆F₅SO₂)₂NH was low even at higher catalyst loading and longer reaction time.[30] We isolated 11,[31] 12,[32] and 13 [33] in good yields ranging from 73% to 82%. The House–Meinwald rearrangement to furnish aldehyde 14 has been known for many years using an excess of boron trifluoride.[34] [18a] Thus, it is worth mentioning that we isolated 14 in 93% using 1 mol% catalyst in only 15 min. We explored the scope of our protocol using simple 1-methyl-substituted cyclohexene oxide. Since the stabilization of the cationic intermediate via a π-system is lacking, we used more acidic Tf₂NH and isolated 15 in 46% yield. With the use of 1-phenyl-1,2-cycloheptene oxide, we obtained 1-phenylcyclohexane carbaldehyde (16) in 41% yield. The use of an open-chain epoxide furnished ketone 17 in very good yield of 89%. This result appears to be similar to that using the para-toluyl-substituted substrate due to the strong stabilization of the cationic intermediate and lower rate of the rearrangement.

To establish the stereospecific nature of the rearrangement, we synthesized enantioenriched epoxide 18 via Shi epoxidation.[35] We used only 0.5 mol% Tf₂NH for the House–Meinwald rearrangement and isolated 97% of the enantioenriched aldehyde (R)-14 [36] after 15 min with virtually the same enantiomeric ratio (Scheme [3]). This means a turnover number of 200 and a turnover frequency of 800 h^–1, which underlines that our method is a powerful alternative to metal-based epoxide rearrangements of trisubstituted epoxides, where usually stoichiometric amounts of Lewis acids are used.

In summary, we report a novel strategy for the synthesis of various α-quaternary carbaldehydes via chemoselective House–Meinwald rearrangement of trisubstituted epoxides. The reaction is catalyzed by simple and easily accessible disulfonimides using catalyst loadings as low as 0.5 mol%. It provides facile access to several new carbaldehydes. In addition, we validated the stereospecificity of the reaction using an enantioenriched substrate. This makes our method suitable for applications in total synthesis of natural products.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Chiara E. Campi and Dr. Madison J. Sowden for fruitful discussions.

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• 31 1-(4-Benzoic Acid Methyl Ester)cyclopentanecarbaldehyde (11) Via Method B and 2 h reaction time; yield 191 mg (0.822 mmol, 82%); R_f = 0.25 (n-hexane/ethyl acetate, 20:1). ¹H NMR (400 MHz, CDCl₃): δ = 9.41 (s, 1 H), 8.03–8.00 (m, 2 H), 7.37–7.29 (m, 2 H), 3.91 (s, 3 H), 2.60–2.49 (m, 2 H), 1.95–1.86 (m, 2 H), 1.83–1.62 (m, 4 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 200.2, 166.9, 145.7, 130.1, 127.8, 64.1, 52.3, 32.7, 24.4 ppm. IR (ATR): 2952 (w), 2873 (w), 1716 (s), 1608 (w), 1435 (m), 1275 (s), 1186 (m), 1018 (m), 770 (m), 706 (m) cm^–1. HRMS (ESI): m/z calcd for C₁₄H₁₆O₃Na⁺: 255.0991; found: 255.0991 [M + Na]⁺.
• 32 1-(4-Cyanophenyl)cyclopentanecarbaldehyde (12) Via Method B and 2 h reaction time; yield 146 mg (0.733 mmol, 73%); R_f = 0.20 (n-hexane/ethyl acetate, 20:1). ¹H NMR (400 MHz, CDCl₃): δ = 9.39 (s, 1 H), 7.64 (dd, J = 8.7, 1.9 Hz, 3 H), 7.36 (dd, J = 8.7, 1.9 Hz, 3 H), 2.56–2.49 (m, 2 H), 1.93–1.84 (m, 4 H), 1.82–1.63 (m, 6 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 199.7, 145.9, 132.6, 128.6, 118.7, 111.2, 64.1, 32.7, 24.3 ppm. IR (ATR): 3364 (m), 2954 (m), 2874 (w), 2235 (m), 1607 (m), 1403 (m), 833 (s), 566 (s) cm^–1. HRMS (ESI): m/z calcd for C₁₃H₁₃NONa⁺: 222.0889; found: 222.0890 [M + Na]⁺.
• 33 1-(4-Nitrophenyl)cyclopentanecarbaldehyde (13) Via Method B and 2 h reaction time; yield 160 mg (0.730 mmol, 75%); R_f = 0.22 (n-hexane/ethyl acetate, 10:1). ¹H NMR (400 MHz, CDCl₃): δ = 9.43 (s, 1 H), 8.21 (dd, J = 8.9, 2.1 Hz, 2 H), 7.43 (dd, J = 8.9, 2.1 Hz, 2 H), 2.61–2.53 (m, 2 H), 1.98–1.89 (m, 2 H), 1.85–1.65 (m, 5 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 199.6, 148.0, 147.2, 128.7, 124.0, 64.1, 33.0, 24.4 ppm. IR (ATR): 3108 (w), 3080 (w), 2944 (m), 1720 (s), 1595 (m), 1513 (s), 1347 (s) 1317 (m), 1108 (m), 851 (m), 748 (m), 696 (s) cm^–1. HRMS (ESI): m/z calcd for C₁₂H₁₃NO₃Na⁺: 242.0787; found: 242.0790 [M + Na]⁺.
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• 36 Ethyl-(3R)-(3-phenyl-3-formyl-1-pyrrolidinecarboxylate) ((R)-14) Via Method B on a 1.5 mmol scale with 0.5 mol% catalyst and 15 min reaction time; yield 360 mg (1.46 mmol, 97%); R_f = 0.22 (n-hexane/ethyl acetate, 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 9.45 (s, 1 H), 7.44–7.37 (m, 2 H), 7.36–7.30 (m, 1 H), 7.24–7.17 (m, 2 H), 4.47–4.35 (m, 1 H), 4.22–4.09 (m, 2 H), 3.70–3.47 (m, 2 H), 3.35 (td, J = 10.7, 6.9 Hz, 1 H), 2.81 (br s, 1 H), 2.21 (q, J = 10.7 Hz, 1 H), 1.63 (br s, 1 H), 1.31–1.24 (m, 3 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 198.0, 155.1, 136.3, 129.4, 128.3, 127.4, 106.3, 61.4, 50.2, 44.8, 30.8, 14.9 ppm. IR (ATR): 2989 (w), 2878 (w), 2809 (w), 1718 (m), 1694 (s), 1419 (s), 1380 (m), 1354 (m), 1341 (m), 1103 (m), 1024 (m), 888 (w), 769 (m), 759 (m), 699 (m) cm⁻¹. HRMS (ESI): m/z calcd for C₁₄H₁₇NO₃Na⁺: 270.1100; found: 270.1102 [M + Na]⁺. HPLC: Chiralpak IC (n-hexane/2-propanol, 70:30 v/v, 1 mL/min, 30 min run time), fraction 1: t _R = 11.59 min, fraction 2: t _R = 14.65 min.

Corresponding Author

Publication History

Received: 18 October 2023

Accepted after revision: 22 November 2023

Accepted Manuscript online:
22 November 2023

Article published online:
05 January 2024

© 2023. Thieme. All rights reserved

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• References and Notes

• 1a Fuji K. Chem. Rev. 1993; 93: 2037
  CrossrefSearch in Google Scholar
• 1b Overman LE, Peterson EA. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 11943
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• 2 Li C, Ragab SS, Liu G, Tang W. Nat. Prod. Rep. 2020; 37: 276
  CrossrefPubMedSearch in Google Scholar
• 3a House HO. J. Am. Chem. Soc. 1955; 77: 3070
  CrossrefSearch in Google Scholar
• 3b House O, Wasson L. J. Am. Chem. Soc. 1956; 78: 4394
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• 3c Meinwald J, Labana SS, Chadha MS. J. Am. Chem. Soc. 1963; 85: 582
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• 4a Xia Q.-H, Ge H.-Q, Ye C.-P, Liu Z.-M, Su K.-X. Chem. Rev. 2005; 105: 1603
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• 4b Davis RL, Stiller J, Naicker T, Jiang H, Jørgensen KA. Angew. Chem. Int. Ed. 2014; 53: 7406
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• 4c Zhu Y, Wang Q, Cornwall RG, Shi Y. Chem. Rev. 2014; 114: 8199
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• 6 Vital P, Tanner D. Org. Biomol. Chem. 2006; 4: 4292
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• 7 Bando T, Shishido K. Chem. Commun. 1996; 1357
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• 8 Jung ME, D'Amico DC. J. Am. Chem. Soc 1995; 117: 7379
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• 9 Martínez F, Del Campo C, Llama EF. J. Chem. Soc., Perkin Trans. 1 2000; 1749
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• 10 Suda K, Baba K, Nakajima S.-i, Takanami T. Tetrahedron Lett. 1999; 40: 7243
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• 11 Liu W, Leischner T, Li W, Junge K, Beller M. Angew. Chem. Int. Ed. 2020; 59: 11321
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• 15 Procopio A, Dalpozzo R, De Nino A, Nardi M, Sindona G, Tagarelli A. Synlett 2004; 2633
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• 17 Anderson AM, Blazek JM, Garg P, Payne BJ, Mohan RS. Tetrahedron Lett. 2000; 41: 1527
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• 27 (C₆F₅SO₂)₂NH-Catalyzed Rearrangement of Trisubstituted Epoxides 1.0 mmol epoxide was dissolved in 10 mL (CH₂Cl)₂, and 12.0 mg (0.025 mmol, 2.5 mol%) (C₆F₅SO₂)₂NH was added. The reaction mixture was heated to 83 °C for the indicated time, then cooled to room temperature and quenched with 10 mL saturated NaHCO₃ solution. The aqueous phase was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic phases were dried over MgSO₄, and the solvent was removed under reduced pressure. Purification by column chromatography afforded the product.
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• 30 Tf₂NH-Catalyzed Rearrangement of Trisubstituted Epoxides 1.0 mmol epoxide was dissolved in 10 mL CH₂Cl₂, and 7.0 mg (0.025 mmol, 2.5 mol%) Tf₂NH was added. The reaction mixture was stirred at room temperature for the indicated time and then quenched with 10 mL saturated NaHCO₃ solution. The aqueous phase was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic phases were dried over MgSO₄, and the solvent was removed under reduced pressure. Purification by column chromatography afforded the product.
• 31 1-(4-Benzoic Acid Methyl Ester)cyclopentanecarbaldehyde (11) Via Method B and 2 h reaction time; yield 191 mg (0.822 mmol, 82%); R_f = 0.25 (n-hexane/ethyl acetate, 20:1). ¹H NMR (400 MHz, CDCl₃): δ = 9.41 (s, 1 H), 8.03–8.00 (m, 2 H), 7.37–7.29 (m, 2 H), 3.91 (s, 3 H), 2.60–2.49 (m, 2 H), 1.95–1.86 (m, 2 H), 1.83–1.62 (m, 4 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 200.2, 166.9, 145.7, 130.1, 127.8, 64.1, 52.3, 32.7, 24.4 ppm. IR (ATR): 2952 (w), 2873 (w), 1716 (s), 1608 (w), 1435 (m), 1275 (s), 1186 (m), 1018 (m), 770 (m), 706 (m) cm^–1. HRMS (ESI): m/z calcd for C₁₄H₁₆O₃Na⁺: 255.0991; found: 255.0991 [M + Na]⁺.
• 32 1-(4-Cyanophenyl)cyclopentanecarbaldehyde (12) Via Method B and 2 h reaction time; yield 146 mg (0.733 mmol, 73%); R_f = 0.20 (n-hexane/ethyl acetate, 20:1). ¹H NMR (400 MHz, CDCl₃): δ = 9.39 (s, 1 H), 7.64 (dd, J = 8.7, 1.9 Hz, 3 H), 7.36 (dd, J = 8.7, 1.9 Hz, 3 H), 2.56–2.49 (m, 2 H), 1.93–1.84 (m, 4 H), 1.82–1.63 (m, 6 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 199.7, 145.9, 132.6, 128.6, 118.7, 111.2, 64.1, 32.7, 24.3 ppm. IR (ATR): 3364 (m), 2954 (m), 2874 (w), 2235 (m), 1607 (m), 1403 (m), 833 (s), 566 (s) cm^–1. HRMS (ESI): m/z calcd for C₁₃H₁₃NONa⁺: 222.0889; found: 222.0890 [M + Na]⁺.
• 33 1-(4-Nitrophenyl)cyclopentanecarbaldehyde (13) Via Method B and 2 h reaction time; yield 160 mg (0.730 mmol, 75%); R_f = 0.22 (n-hexane/ethyl acetate, 10:1). ¹H NMR (400 MHz, CDCl₃): δ = 9.43 (s, 1 H), 8.21 (dd, J = 8.9, 2.1 Hz, 2 H), 7.43 (dd, J = 8.9, 2.1 Hz, 2 H), 2.61–2.53 (m, 2 H), 1.98–1.89 (m, 2 H), 1.85–1.65 (m, 5 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 199.6, 148.0, 147.2, 128.7, 124.0, 64.1, 33.0, 24.4 ppm. IR (ATR): 3108 (w), 3080 (w), 2944 (m), 1720 (s), 1595 (m), 1513 (s), 1347 (s) 1317 (m), 1108 (m), 851 (m), 748 (m), 696 (s) cm^–1. HRMS (ESI): m/z calcd for C₁₂H₁₃NO₃Na⁺: 242.0787; found: 242.0790 [M + Na]⁺.
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• 36 Ethyl-(3R)-(3-phenyl-3-formyl-1-pyrrolidinecarboxylate) ((R)-14) Via Method B on a 1.5 mmol scale with 0.5 mol% catalyst and 15 min reaction time; yield 360 mg (1.46 mmol, 97%); R_f = 0.22 (n-hexane/ethyl acetate, 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 9.45 (s, 1 H), 7.44–7.37 (m, 2 H), 7.36–7.30 (m, 1 H), 7.24–7.17 (m, 2 H), 4.47–4.35 (m, 1 H), 4.22–4.09 (m, 2 H), 3.70–3.47 (m, 2 H), 3.35 (td, J = 10.7, 6.9 Hz, 1 H), 2.81 (br s, 1 H), 2.21 (q, J = 10.7 Hz, 1 H), 1.63 (br s, 1 H), 1.31–1.24 (m, 3 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 198.0, 155.1, 136.3, 129.4, 128.3, 127.4, 106.3, 61.4, 50.2, 44.8, 30.8, 14.9 ppm. IR (ATR): 2989 (w), 2878 (w), 2809 (w), 1718 (m), 1694 (s), 1419 (s), 1380 (m), 1354 (m), 1341 (m), 1103 (m), 1024 (m), 888 (w), 769 (m), 759 (m), 699 (m) cm⁻¹. HRMS (ESI): m/z calcd for C₁₄H₁₇NO₃Na⁺: 270.1100; found: 270.1102 [M + Na]⁺. HPLC: Chiralpak IC (n-hexane/2-propanol, 70:30 v/v, 1 mL/min, 30 min run time), fraction 1: t _R = 11.59 min, fraction 2: t _R = 14.65 min.

• Supplementary Material
• Primary Data