Asymmetric synthesis of 1H-pyrrol-3(2H)-ones from 2,3-diketoesters by combination of aldol condensation with benzilic acid rearrangement

Abstract

An efficient two-step protocol for the asymmetric synthesis of 1H-pyrrol-3(2H)-one derivatives in 99% ee from conveniently accessed 2,3-diketoesters has been developed.

---

2,2-Disubstituted 1H-pyrrol-3(2H)-ones that possess a chiral center at the 2-position occur widely in natural products,¹ and they are also fundamental units which have been used to build molecules with significant biological activities (Fig. 1).² Due to their importance, a variety of methods for their synthesis have been developed. Cycloaddition strategies are among the most efficient ways used to access the key 1H-pyrrol-3(2H)-ones.³ However, general highly enantioselective addition methods are rare: one begins with chiral starting materials,⁴ and the other employs catalytic asymmetric cycloaddition.⁵ Although progress is being made in this area, the narrow substrate scope of reported methods suggests the need for more general enantioselective processes.

Fig. 1 Selected natural products containing the 1H-pyrrol-3(2H)-one unit or its analogue with a tetrasubstituted carbon stereocenter.

Pioneering work by Wasserman and coworkers⁶ demonstrated wide applications of vicinal tricarbonyl compounds (VTCs) in the synthesis of natural products and synthetic intermediates. Our group has applied VTCs in the synthesis of functionalized furans⁷ and pyrroles⁸ and demonstrated their convenient uses as hydrates.^8b We also reported the first diastereoselective⁹ and enantioselective¹⁰ nucleophilic addition reactions of VTC compounds. Based on our understanding of the VTC chemistry and reported benzilic acid rearrangement reactions,¹¹ an enantioselective strategy for the synthesis of 1H-pyrrol-3(2H)-ones starting from 2,3-diketoester hydrates was designed as shown in Scheme 1. The mixed asymmetric aldol reaction with VTCs has been unexplored. The enamine formation step is known,¹² although not in this system. To form the chiral key intermediate 3, a chiral secondary amine-catalyzed aldol reaction was predicted to have the potential to achieve this goal.

Scheme 1 A designed strategy for the asymmetric synthesis of 1H-pyrrol-3(2H)-ones.

The Hajos–Parrish–Eder–Sauer–Wiechert reaction, the first example of asymmetric enamine catalysis, was reported 50 years ago.¹³ However this powerful reaction was relatively unexplored until List and coworkers¹⁴ discovered proline-catalyzed enantioselective intermolecular aldol reaction. Explosive progress ensued during which various organocatalysts were developed to realize the asymmetric aldol reaction.¹⁵ Many types of carbonyl substrates have been successfully utilized in aldol reactions, including various aromatic aldehydes, aliphatic aldehydes and activated ketones that include 2-ketoesters. However, 2,3-diketoesters, which are unique and highly activated ketones, have not been investigated. Herein, we present the two-step asymmetric synthesis of 1H-pyrrol-3(2H)-ones that takes unique advantage of the 2,3-diketoester framework to couple an L-proline catalyzed aldol reaction with the benzilic acid rearrangement.

Vicinal tricarbonyl compounds easily absorb water to form their corresponding hydrates that can be dehydrated by heating under vacuum. However, the VTC hydrates were used directly in this study due to their convenience in handling. Based on our initial hypothesis, benzyl 2,2-dihydroxy-3-oxobutanoate hydrate 1a and cyclohexanone 2a were selected for the aldol reaction. Of all the organocatalysts we examined,¹⁶L-proline was found to be optimal for diastereoselectivity and enantio control.¹⁷ The aldol product was formed in 74 : 26 d.r., and the major diastereoisomer 3a was conveniently isolated by simple chromatography in 68% yield with 99% ee. All attempts to increase diastereoselectivity with alternative catalysts, lowering reaction temperatures, use of 1a in its anhydrous form, and changing solvents were unsuccessful.¹⁶ However, the good yield of the major diastereomer, its ease of isolation, and its excellent enantiomeric excess made this transformation very promising.

With the optimal reaction conditions in hand, we set out to explore the substrate generality of the L-proline catalyzed aldol reactions. Using hydrated 2,3-diketoesters, the effect of different groups on the ester was investigated first (Table 1, entries 1–3). The size of the group did not significantly affect yield or stereoselectivity of products. The major diastereomers were isolated in moderate yields with 99% ee, and the minor diastereomers were also obtained with high ee's. Then 2,3-diketoesters with different groups on the keto side were investigated: replacing the methyl group with ethyl or benzyl gave similar results (Table 1, entries 4 and 5). However, changing the methyl group bound to the keto group to aryl resulted in a significant increase in the d.r. of the aldol products (Table 1, entries 6–12) up to 89 : 11 (Table 1, entries 7 and 8). The effects of different substituents on the aromatic ring were also investigated showing that electron-withdrawing groups favored this process (Table 1, entry 10). An electron-donating para-substituted methoxy group, however, strongly inhibited the aldol process (Table 1, entry 9). Dihydro-2H-thiopyran-4(3H)-one (2b) worked well in this process as an alternative to cyclohexanone from which the major diastereoisomer 3m was obtained in 56% isolated yield with 99% ee (Table 1, entry 13) (Scheme 2).

Table 1 Substrate scope of L-proline catalyzed aldol reactions of 2,3-diketoesters with cycloketones^a

Entry	R^1	R^2	X	Time (h)	Ratio 3/4^b	Yield^c^,^d (ee) of 3	Yield^c^,^d (ee) of 4
a Reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), L-proline (20 mol%), DCM (5.0 mL), r.t. 24–96 h. b Determined by ^1H NMR spectroscopy or HPLC analysis of the reaction mixture. c Yield of the isolated product after column chromatography. d The ee value was determined by HPLC using a chiral stationary phase.
1	Me	Bn	CH2	24	74/26	3a/68% (99%)	4a/24% (97%)
2	Me	Me	CH2	32	79/21	3b/60% (99%)	4b/16% (97%)
3	Me	Cy	CH2	48	77/23	3c/67% (99%)	4c/20% (98%)
4	Et	Me	CH2	32	77/23	3d/65% (99%)	4d/19% (97%)
5	Bn	Bn	CH2	48	73/27	3e/59% (99%)	4e/21% (98%)
6	C6H5	Et	CH2	32	81/19	3f/51% (99%)	4f/12% (98%)
7	p-ClC6H4	Et	CH2	48	89/11	3g/58% (99%)	4g/7% (94%)
8	p-BrC6H4	Et	CH2	48	89/11	3h/56% (99%)	4h/6% (95%)
9	p-OMeC6H4	Et	CH2	96	85/15	3i/25% (99%)	4i/4% (98%)
10	p-CNC6H4	Et	CH2	42	84/16	3j/70% (99%)	4j/13% (96%)
11	2-Naphthyl	Et	CH2	54	79/21	3k/45% (99%)	4k/12% (97%)
12	2-Thienyl	Et	CH2	48	88/12	3l/67% (99%)	4l/9% (92%)
13	Me	Bn	S	48	76/24	3m/56% (99%)	4m/17% (89%)

---

Scheme 2 L-Proline catalyzed aldol reaction of benzyl 2,2-dihydroxy-3-oxobutanoate (1a) with cyclohexanone (2a).

The high efficiency and broad generality of the aldol reaction that gave, without exception, the major diastereomers with 99% ee's was evident throughout investigations of substrate scope. A limitation that did appear was that ketone ring sizes other than six, especially cyclopentanone and cycloheptanone, gave intractable mixtures of products.

The high enantio control in these aldol condensation reactions prompted us to investigate the subsequent benzilic acid rearrangement reaction. Initially, we attempted to combine the aldol reaction and the benzilic acid rearrangement reaction in one pot. As shown in Table 2, without adding any additives, 6a was obtained in only 32% yield and 30% ee (Table 2, entry 1). Various additives were examined from which we discovered that by using 20 mol% trifluoroacetic acid the yield of 6a increased significantly. However, 6a was always obtained in only moderate enantiomeric excess no matter what solvent was used (Table 2, entries 2–6) reflecting the uniform conversions of each aldol product diastereomer (3a and 4a) to 1H-pyrrol-3(2H)-one 6a in inverse enantiomeric excesses. This result indicated that a two-step procedure to synthesize 1H-pyrrol-3(2H)-ones in which the major diastereomer from the aldol condensation is used for the benzilic acid rearrangement would be successful.

Table 2 Investigation of a one-pot enantioselective synthesis of 1H-pyrrol-3(2H)-one derivatives^a

Entry	Additive	Solvent	Yield^b (%)	ee^c (%)
a Reaction conditions: (1) 1a (0.10 mmol), 2a (0.20 mmol), L-proline (20 mol%), solvent (0.50 mL), r.t. 24 h; (2) 5a (0.11 mmol), CF3COOH (20 mol%), 65 °C, 24 h. b Yield of the isolated product after column chromatography. c The ee value was determined by HPLC using a chiral stationary phase.
1	—	MeCN	32	30
2	CF3COOH	MeCN	82	31
3	CF3COOH	DCM	67	47
4	CF3COOH	CHCl3	64	41
5	CF3COOH	DCE	72	44
6	CF3COOH	Toluene	55	41

---

With chromatographic isolation of the major diastereomers from the asymmetric aldol reactions, we examined the benzilic acid rearrangement of these compounds with aniline. By using trifluoroacetic acid as an additive and DCM as the solvent at 65 °C for 24 h, the rearrangement product 6a was isolated in 87% yield with 99% ee (Table 3, 6a). Anilines with halogen atoms (F, Cl, Br, I) all gave the 1H-pyrrol-3(2H)-ones in high yield with 99% ee (Table 3, 6b–6e). Anilines with both electron-donating groups (Me, OMe) and electron-withdrawing groups (CN, NO₂) gave the corresponding products in good yields without loss of enantioselectivity (Table 3, 6f–6i). Hexadecylamine, which was chosen as a representative aliphatic amine, gave 6j in 46% yield with 99% ee (Table 3, 6j). The presence of a sulfur atom on the cyclic aliphatic ring (3m), gave the benzilic acid rearrangement product 6k in 91% yield with 99% ee (Table 3, 6k). Different groups on the ester all gave the corresponding 1H-pyrrol-3(2H)-one products in good yields with 99% ee (Table 3, 6l–6m). By changing the substituent from methyl to ethyl on the keto side, a significant decrease of the product yield was observed (Table 3, 6n) and was further limited with other alkyl substituents. However, by replacing the methyl group with phenyl, 6o was obtained in 73% yield with 99% ee (Table 3, 6o). Lastly, the effects from various aryl groups were studied from which the benzylic acid rearrangement products were obtained in moderate to good yields with 99% ee (Table 3, 6p–6t).

Table 3 Benzylic acid rearrangement reactions leading to 1H-pyrrol-3(2H)-ones^a

a Reaction conditions: 3 (0.10 mmol), 5 (0.11 mmol), DCM (0.50 mL), CF₃COOH (20 mol%), 65 °C, 24 h; yields refer to isolated yields after column chromatography; the ee value was determined by HPLC using a chiral stationary phase.

---

The synthetic utility of the present methodology involving the L-proline catalyzed aldol reaction was examined on a 10 mmol scale.¹⁶ Under the optimized reaction conditions, the aldol products were formed in 74 : 26 d.r. The major diastereoisomer was isolated in 61% yield (1.86 g) with 99% ee. The minor diastereoisomer was obtained in 21% yield (0.63 g) with 98% ee. These separated aldol products were then used to perform the benzylic acid rearrangement. Products 6d and 7d were obtained in 82% yield (2.19 g) and 84% yield (0.77 g) respectively, both with excellent enantiomeric excess.

The relative and absolute configurations of 3g and 6c were assigned (R,S)-3g and R-6c based on their single-crystal X-ray diffraction analysis (Fig. 2).¹⁸

Fig. 2 X-ray structures of 3g and 6c.

Reduction of 6d with 4.0 equiv. NaBH₄ gave 8d as the sole diastereomer in 81% yield with 99% ee. The configuration of 8d was determined by NOESY experiments. In addition, 6d is conveniently oxidized to 9d in 65% yield with 98% ee, and this process provides convenient access to nearly optically pure indolin-3-ones (Scheme 3).

Scheme 3 Reduction and oxidation of 1H-pyrrol-3(2H)-one 6d.

In summary, we have developed a two-step method for the highly enantioselective synthesis of 1H-pyrrol-3(2H)-ones. 2,3-Diketoesters have been employed for the first time in asymmetric aldol reactions. By combining the L-proline catalyzed aldol reaction with the benzylic acid rearrangement, 1H-pyrrol-3(2H)-ones are obtained in moderate yields but with notably excellent enantiomeric excess (99% ee for all (R,S)-products). Efforts are underway to examine additional applications of 2,3-diketoesters in highly enantioselective catalytic reactions.

Qiang Sha acknowledges China Scholarship Council (CSC) for his financial support. We acknowledge U.S. National Science Foundation (CHE-1212446), The Welch Foundation, and the University of Texas at San Antonio for supporting this research. The HRMS used in this research was supported by a grant from the National Institutes of Health (G12MD007591).

Notes and references

1. For selected examples, see: (a) W. H. Pearson, Y. Mi, I. Y. Lee and P. Stoy, J. Am. Chem. Soc., 2001, 123, 6724; (b) K. Amada, T. Kurokawa, H. Tokuyama and T. Fukuyama, J. Am. Chem. Soc., 2003, 125, 6630; (c) R. M. Williams, J. H. Cao, H. Tsujishima and R. J. Cox, J. Am. Chem. Soc., 2003, 125, 12172; (d) A. Karadeolian and M. A. Kerr, J. Org. Chem., 2010, 75, 6830; (e) D. B. Zhang, D. G. Yu, M. Sun, X. X. Zhu, X. J. Yao, S. Y. Zhou, J. J. Chen and K. Gao, J. Nat. Prod., 2015, 78, 1253.
2. For selected examples, see: (a) M. Brüggemann, A. I. McDonald, L. E. Overman, M. D. Rosen, L. Schwink and J. P. Scott, J. Am. Chem. Soc., 2003, 125, 15284; (b) M. Mucedda, D. Muroni, A. Saba and C. Manassero, Tetrahedron, 2007, 63, 12232; (c) B. N. Reddy and C. V. Ramana, Chem. Commun., 2013, 49, 9767; (d) S. Han, K. C. Morrison, P. J. Hergenrother and M. Movassaghi, J. Org. Chem., 2014, 79, 473; (e) A. B. Smith III, L. D. Cantin, A. Pasternak, L. Guise-Zawacki, W. Q. Yao, A. K. Charnley, J. Barbosa, P. A. Sprengeler, R. Hirschmann, S. Munshi, D. B. Olsen, W. A. Schleif and L. C. Kuo, J. Med. Chem., 2003, 46, 1831; (f) A. B. Smith III, A. K. Charnley and R. Hirschmann, Acc. Chem. Res., 2011, 44, 180.
3. (a) M. A. Gomaa, J. Chem. Soc., Perkin Trans. 1, 2002, 341; (b) J. Huang, Y. J. Liang, W. Pan, Y. Yang and D. W. Dong, Org. Lett., 2007, 9, 5345; (c) I. Kim and K. Kim, Org. Lett., 2010, 12, 2500; (d) P. X. Zhou, Z. Z. Zhou, Z. S. Chen, Y. Y. Ye, L. B. Zhao, Y. F. Yang, X. F. Xia, J. Y. Luo and Y. M. Liang, Chem. Commun., 2013, 49, 561; (e) Z. K. Wang, X. H. Bi, P. Q. Liao, X. Liu and D. W. Dong, Chem. Commun., 2013, 49, 1309; (f) Z. J. Zhang, Z. H. Ren, Y. Y. Wang and Z. H. Guan, Org. Lett., 2013, 15, 4822; (g) S. R. Mothe, M. L. Novianti, B. J. Ayers and P. W. H. Chan, Org. Lett., 2014, 16, 4110; (h) X. Sun, P. H. Li, X. L. Zhang and L. Wang, Org. Lett., 2014, 16, 2126; (i) N. Li, T. Y. Wang, L. Z. Gong and L. M. Zhang, Chem. – Eur. J., 2015, 21, 3585.
4. (a) A. B. Smith III, H. Liu, H. Okumura, D. A. Favor and R. Hirschmann, Org. Lett., 2000, 2, 2041; (b) N. Gouault, M. L. Roch, C. Cornée, M. David and P. Uriac, J. Org. Chem., 2009, 74, 5614; (c) R. Spina, E. Colacion, B. Gabriele, G. Salerno and J. Martinez, J. Org. Chem., 2013, 78, 2698.
5. (a) J. X. Liu, Q. Q. Zhou, J. G. Deng and Y. C. Chen, Org. Biomol. Chem., 2013, 11, 8175; (b) Q. Yin and S. L. You, Chem. Sci., 2011, 2, 1344; (c) M. Rueping, S. Raja and A. Núñez, Adv. Synth. Catal., 2011, 353, 563; (d) A. Parra, R. Alfaro, L. Marzo, A. Moreno-Carrasco, J. L. Garcia Ruano and J. Aleman, Chem. Commun., 2012, 48, 9759; (e) Y. L. Zhao, Y. Wang, J. Cao, Y. M. Liang and P. F. Xu, Org. Lett., 2014, 16, 2438; (f) C. Guo, M. Schedler, C. G. Daniliuc and F. Glorius, Angew. Chem., Int. Ed., 2014, 53, 10232; (g) R. R. Liu, S. C. Ye, C. J. Lu, G. L. Zhuang, J. R. Gao and Y. X. Jia, Angew. Chem., Int. Ed., 2015, 54, 11205.
6. H. H. Wasserman and H. Parr, Acc. Chem. Res., 2004, 37, 687.
7. P. Truong, X. F. Xu and M. P. Doyle, Tetrahedron Lett., 2011, 52, 2093.
8. (a) P. Truong, M. D. Mandler and M. P. Doyle, Tetrahedron Lett., 2015, 56, 3042; (b) Q. Sha, H. Arman and M. P. Doyle, Org. Lett., 2015, 17, 3876.
9. P. Truong, C. S. Shanahan and M. P. Doyle, Org. Lett., 2012, 14, 3608.
10. P. Truong, P. Y. Zavalij and M. P. Doyle, Angew. Chem., Int. Ed., 2014, 53, 6468.
11. (a) D. Askin, R. A. Reamer, T. K. Jones, R. P. Volante and I. Shinkai, Tetrahedron Lett., 1989, 30, 671; (b) D. Askin, R. A. Reamer, D. Joe, R. P. Volante and I. Shinakai, Tetrahedron Lett., 1989, 45, 6121; (c) M. J. Fisher, K. Chow, A. Villalobos and S. J. Danishefsky, J. Org. Chem., 1991, 56, 2900; (d) H. H. Wasserman, D. S. Ennis and C. B. Vu, Tetrahedron Lett., 1991, 32, 6039.
12. For selected examples, see: (a) W. Schrader, P. P. Handayani, J. Zhou and B. List, Angew. Chem., Int. Ed., 2009, 48, 1463; (b) L. Ren, T. Lei and L. Z. Gong, Chem. Commun., 2011, 47, 11683; (c) Y. M. Deng, L. Liu, R. G. Sarkisian, K. Wheeler, H. Wang and Z. H. Xu, Angew. Chem., Int. Ed., 2013, 52, 3663; (d) Y. M. Deng, S. Kumar, K. Wheeler and H. Wang, Chem. – Eur. J., 2015, 21, 7874.
13. H. Pracejus, Justus Liebigs Ann. Chem., 1960, 634, 23.
14. B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc., 2000, 122, 2395.
15. For selected reviews on organocatalyst catalysed aldol reactions, see: (a) M. Movassaghi and E. N. Jacobsen, Science, 2002, 298, 1904; (b) B. List, Acc. Chem. Res., 2004, 37, 548; (c) C. Allemann, R. Gordollo, F. R. Clemente, P. H. Cheong and K. N. Houk, Acc. Chem. Res., 2004, 37, 558; (d) S. Saito and H. Yamamoto, Acc. Chem. Res., 2004, 37, 570; (e) M. Gruttadauria, F. Giacalone and R. Noto, Chem. Soc. Rev., 2008, 37, 1666; (f) J. Seayad and B. List, Org. Biomol. Chem., 2005, 3, 719; (g) S. Mukherjee, J. W. Yang, S. Hoffmann and B. List, Chem. Rev., 2007, 107, 5471; (h) P. Melchiorre, M. Marigo, A. Carlone and G. Bartoli, Angew. Chem., Int. Ed., 2008, 47, 6138; (i) D. W. C. Macmillan, Nature, 2008, 455, 304; (j) S. Bertelsen and K. A. Jørgensen, Chem. Soc. Rev., 2009, 38, 2178; (k) B. M. Trost and C. S. Brindle, Chem. Soc. Rev., 2010, 39, 1600; (l) A. Moyano and R. Rios, Chem. Rev., 2011, 111, 4703; (m) C. M. Marson, Chem. Soc. Rev., 2012, 41, 7712.
16. See the ESI† for details.
17. This finding is consistent with results of Jørgensen and Maruoka for aldol reactions with 2-ketoesters (50 mol% proline with up to 99% ee): (a) A. Bøgevig, N. Kumaragurubaran and K. A. Jørgensen, Chem. Commun., 2002, 620; (b) O. Tokuda, T. Kano, W.-G. Gao, T. Ikemoto and K. Maruoka, Org. Lett., 2005, 7, 5103.
18. CCDC 1417169 (3g) and 1417170 (6c).

---

Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, optimization of reaction conditions, HPLC and spectral data for all new compounds. CCDC 1417169 (3g) and 1417170 (6c). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5cc07780j

---