Bifunctional Phosphonium Salt Directed Enantioselective

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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Bifunctional Phosphonium Salt Directed Enantioselective Formal [4 + 1] Annulation of Hydroxyl-Substituted para-Quinone Methides with α‑Halogenated Ketones Jian-Ping Tan,†,# Peiyuan Yu,‡,# Jia-Hong Wu,† Yuan Chen,† Jianke Pan,† Chunhui Jiang,†,§ Xiaoyu Ren,† Hong-Su Zhang,† and Tianli Wang*,†

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†

Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, P. R. China ‡ Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen, China § School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, 2 Mengxi Road, Zhenjiang 212003, P. R. China S Supporting Information *

ABSTRACT: A highly diastereo- and enantioselective [4 + 1] cycloaddition of para-quinone methides to α-halogenated ketones was realized by bifunctional phosphonium salt catalysis, furnishing functionalized 2,3-dihydrobenzofurans in high yields and excellent stereoselectivities (>20:1 dr and up to >99.9% ee). Mechanistic observations suggested that the reaction underwent a cascade intermolecular substitution/intramolecular 1,6-addition process. DFT calculations revealed the presence of multiple H-bonding interactions between the catalyst and the enolate intermediate in the stereodetermining transition states.

B

enzo-fused O-heterocyclic skeletons, especially 2,3-dihydrobenzofuran-containing structures, are prominent building blocks not only in many biologically active natural products but also in numerous medicinally important agents (Scheme 1).1

straightforward synthetic methods for producing such ring systems.3−8 Accordingly, the hydroxyphenyl-substituted paraquinone methides (p-QMs) emerged as a potential class of versatile C4-synthons for formal [4 + 1] annulation reactions to access the 2,3-dihydrobenzofuran skeletons, due to their intrinsic reactivity of aromatization as well as the nucleophilicity of their phenolic sites.4 Recently, the research groups of Enders,5 Yuan,6 and Yao7 pioneered to report their utilization of the hydroxyl-containing p-QMs for racemic [4 + 1] cycloadditions with sulfonium and/or ammonium ylides, particularly providing trans-2,3-dihydrobenzofurans with high yields and good diastereoselectivities.8 However, despite these impressive advances, a highly catalytic asymmetric variant of a formal [4 + 1] synthetic strategy using such p-QMs as C4-synthons still constitutes a daunting challenge. It may be due to the fact that the distance and space position between the carbonyl group and acceptor−donor reactive sites (CC bond and phenol group) are not favorable for stereocontrol. To the best of our knowledge, no practical and efficient catalytic system to realize

Scheme 1. Bioactive and Natural Compounds Containing 2,3-Dihydrobenzofuran Skeletons

The broad spectra of their applications make such chiral structural motifs attractive synthetic targets, and many efforts have been devoted to construct such significant architectures over the past decade.2−4 Among several synthetic methods, the [4 + 1] annulation reaction, which uses a suitable C1-synthon and an acceptor−donor containing C4-synthon as building blocks, is considered to be one of the most efficient and © XXXX American Chemical Society

Received: July 23, 2019

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DOI: 10.1021/acs.orglett.9b02560 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Reaction Optimizationa

this objective has been reported to date. Thus, it is highly desirable to develop an efficient catalytic system to fill this void. In this study, we aim to exploit a highly efficient and easily accessible catalytic system to solve the principal stereoinduction problem, and thus offer an alternative approach to access chiral 2,3-dihydrobenzofuran compounds. Over the past decades, peptide-based catalysis, which was particularly influenced by enzymology, has been diffusely investigated as a versatile tool for the asymmetric synthesis of structurally divergent chiral molecules; numerous privileged chiral catalysts/ligands containing peptide active sites have been accordingly developed by chemists.9−11 For instance, peptide-based phosphine catalysis has already been well established and widely applied in asymmetric synthesis in the past years.12 However, despite the past decade of great progress in enantioselective phosphonium salt catalysis,13−15 analogous P-based phosphonium salt catalysts by taking peptide residues as secondary active sites are very limited. Recently, Zhao and co-workers pioneered the development of bifunctional phosphonium salt catalysts derived from amino acids16a,b and further demonstrated their effectiveness in a number of catalytic reactions.16 Very recently, we developed an L-threonine-derived bifunctional phosphonium salt catalyst for the highly enantioselective synthesis of tetrasubstituted aziridines.17a It should be noted that such an amino acid derived phosphonium salt possesses remarkably high tunability, and further, this catalyst with an ion-pairing moiety and peptide backbone that captures essential features of enzymatic active sites with hydrogen-donating characteristics becomes a multifunctional phase-transfer catalyst, which can be advantageous for asymmetric induction.18 Inspired by these advancements, we envisioned that such a powerful dipeptidebased phosphonium salt catalyst may bridge the gap in realizing the stereoinduction and thus direct the guidance of bifunctional hydroxyl-containing p-QMs to a catalytic asymmetric formal [4 + 1] process, which represents a complementary strategy for accessing biologically significant chiral 2,3-dihydrobenzofurans (Figure 1). Herein, we describe the first highly catalytic

entry

cat.

solvent

base

yield (%)b

erc

1 2 3 4 5 6 7 8 9 10d,e,f

none P0 A B C1 C2 D1 D2 D3 D3

toluene toluene toluene toluene toluene toluene toluene toluene toluene PE

Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3

21 62 92 93 86 88 90 94 96 93

− − 52:48 57:43 58:42 60:40 62:38 61:39 77:23 99:1

a Reactions were performed with 1a (0.10 mmol), 2a (0.12 mmol), base (0.40 mmol), and the catalyst (0.02 mmol) in the solvent (1.0 mL) at room temperature. bIsolated yields. cEnantiomeric ratio (er) determined by chiral HPLC. dReaction run at −20 °C for 48 h. e Cs2CO3 (2.0 equiv). fReaction run at 10 mol % catalyst for 72 h. P0 = Ph2Me2P+·I−, and PE = petroleum ether (bp 60−90 °C).

virtually unexplored. According to our previous studies,17a we preferred to select a dipeptide as the basic chiral backbone for our catalyst preparation and further optimization. To our delight, all the bifunctional phosphonium salts examined were effective in promoting this reaction (Table 1, entries 3−9).19 Generally, dipeptide-based phosphonium salts were better than monopeptide-based ones (see Table S1 for details). While the LVal-derived dipeptide phosphonium salt induced relatively low enantioselectivity (entries 3 and 4), the L-Thr-derived phosphonium salts were found to be more favorable in stereoinduction (entries 5−9), and the O-TBDPS-protected LThr-D-tert-Leu-derived phosphonium salt D3 was found to be the best, providing the annulation product in 96% yield with 77:23 er at room temperature (entry 9). To improve the enantioselectivity of this transformation, we further screened the following reaction conditions: base (Table S2), solvent (Table S3), and others (Table S4). Notably, it was found that nonpolar solvents might be favorable to improve the enantioselectivities.19 When the model reaction was performed at −20 °C with 10 mol % of catalyst D3 and 2.0 equiv of Cs2CO3 in petroleum ether, the cyclization product was obtained in 93% yield with 99:1 er (entry 10). With the identified optimized conditions (Table 1, entry 10), the scope of p-QMs was investigated with 2a as the cyclization partner (Scheme 2). The substituents on the phenol ring of pQMs were first investigated. Generally, both electron-donating groups including methyl and methoxyl and electron-withdrawing groups including fluoro, chloro, and bromo at the 4, 5, or 6-position of the phenol ring were perfectly compatible

Figure 1. Asymmetric construction of 2,3-dihydrobenzofurans via bifunctional phosphonium salt-catalyzed formal [4 + 1] annulation.

enantioselective [4 + 1] annulation between hydroxylcontaining p-QMs and α-halogenated ketones by dipeptidederived phosphonium salt catalysis, providing an efficient and complementary way to functionalized 2,3-dihydrobenzofuran derivatives. Moreover, the critical importance of the peptide residue on the catalyst backbone in dictating the stereochemical outcome was elucidated through DFT calculations. We initially evaluated the feasibility of the annulation between hydroxyl-substituted p-QM 1a and α-bromo acetophenone 2a in the presence of cesium carbonate or/and monofunctional phosphonium salt (P0). Unfortunately, the desired products were obtained in very low yields even after 12 h (Table 1, entries 1 and 2). These preliminary results inspired us to search for a more efficient catalytic system for realizing this reaction in an asymmetric manner. It should be noted that employment of αhalogenated ketones in such formal [4 + 1] cyclization is B

DOI: 10.1021/acs.orglett.9b02560 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Substrate Scope of p-QMsa

Scheme 3. Substrate Scope of α-Halogenated Ketonesa

a

Reactions were performed with 1 (0.10 mmol), 2a (0.12 mmol), Cs2CO3 (0.20 mmol), and the catalyst D3 (0.01 mmol) in PE (1.0 mL) at −20 °C for 72 h. Isolated yields provided; er determined by chiral HPLC. PE = petroleum ether (bp 60−90 °C). bThe αchloroketone 2a′ was used as reaction partner. See SI for more details.

a

Reactions were performed with 1a (0.10 mmol), 2 (0.12 mmol), Cs2CO3 (0.20 mmol), and the catalyst D3 (0.01 mmol) in PE (1.0 mL) at −20 °C for 72 h. Isolated yields provided; er determined by chiral HPLC. PE = petroleum ether (bp 60−90 °C). bThe corresponding α-chloroketone 2′ was used as a cyclization partner. See SI for more details.

with the reaction conditions, and the corresponding products 3a−l were obtained in high yields (84−96%) with excellent diastereo- and enantioselectivities (>20:1 dr, 91:9−99:1 er). Substrates bearing substitutents at the 3-position on the phenol ring slightly lowered the enantioselectivities of the reaction (3m and 3n). Notably, naphthol-containing p-QM proved to be an excellent substrate and gave the annulation product 3o with exceptionally high ee (>99.9%). The absolute configurations of the annulation products were assigned based on the X-ray crystal structural analysis of 3a (CCDC1864020). The above optimal conditions were readily extended to reactions utilizing α-halogenated ketones as substrates (Scheme 3). First, different substituents on the aromatic ring of α-bromo ketones were investigated. Both the electronic properties and the positions of the substituents on the aromatic ring did not observably influence the isolated yield and stereoselectivity of the annulation reaction (Scheme 3, 4a−p). Then, the thienyl and naphthyl substituted α-bromoketones were tested and found to be excellent substrates (4q and 4r). It is worth noting that the reaction conditions were also suitable for the cyclic αhalogenated ketones, which afforded the cyclization products with a quaternary stereogenic center in good yields and excellent er values (4s and 4t). Remarkably, the aliphatic α-bromoketone was also well tolerated under the catalytic system and provided the desired product 4u with excellent enantioselectivity (97:3 er). Moreover, the large-scale reaction between p-QM 1a (2.0 mmol) and α-bromoacetophenone 2a was performed under the optimal reaction conditions, and the corresponding product 3a was obtained in 83% yield without any loss of stereoselectivities (Scheme S6); further, the optically enriched product 3a could be

readily derived into 3′-hydroxyl substituted chiral compound 5a in 91% yield via a reduction step. Alternatively, the bulky substituent tert-butyl group could be removed easily, thus affording 5b in 78% yield promoted by AlCl3 (Scheme S7).19 Subsequently, we carried out further experiments to better understand the reaction pathway (see Scheme S8 in SI for more details). As shown in Scheme 4, the p-QMs without a free hydroxyl group at the aromatic ring were examined in their reactions with α-bromoketone 2c, and no reaction took place (eq 1). When the annulation reaction between 1a and 2c was suspended after 24 h, the intermediate 8 generated from intermolecular substitution was successfully isolated in 41% yield, and some of the desired product 4c was also observed with unchanged stereoselectivities; further, only the cyclization product 4c was obtained upon a prolonged reaction time (eq 2). Moreover, we synthesized this intermediate 8 and tested its intramolecular 1,6-addition under the identical reaction conditions, and the sole product 4c was obtained with similar enantioselectivity to that of the cyclization reaction (eq 3). On the basis of these results, a cascade pathway including intermolecular nucleophilic substitution and subsequent intramolecular 1,6-addition might be very likely for our catalytic system (Figure S10). In addition, DFT calculations (see SI for computational details), which mainly focused on the step of intramolecular 1,6C

DOI: 10.1021/acs.orglett.9b02560 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

interactions between the enolate oxygen and the peptide catalyst. One additional hydrogen bond is also present in the catalyst itself (Figure 2b, 2.13 Å), as well as in the TSs (2.14 and 2.16 Å, respectively). This intramolecular hydrogen bond leads to a ten-membered ring (excluding hydrogen) conformation of the catalyst. The three axial hydrogen atoms that bear considerable positive charges (Figure 2b, computed charges shown in blue) are able to interact strongly with the enolate oxygen in the TS. The computed electrostatic potential (ESP) map (Figure 2b, right) also demonstrates that these hydrogen atoms on the catalyst form an electropositive region (blue color in the center of the ESP map), which enables the strong interactions between the phosphonium cation and the enolate. Moreover, some other TSs were also located, but are much higher in energy (Figure S8). To validate our TS model from DFT computations, we further prepared both substitutedbenzyl-assisted phosphonium salts (D1-a and D1-b) and methylated catalysts (D3-a and D3-b). When these phosphonium salts were used as the catalyst, respectively, the reaction became much slower, and the enantioselectivities decreased dramatically (Table S6),19 which also suggested that the enantioselectivity originates from the multiple hydrogenbonding interactions between the dipeptide-based phosphonium catalyst and the key enolate intermediate of the reaction. In conclusion, we have disclosed the first catalytic enantioselective formal [4 + 1] annulation reaction between hydroxyl-substituted p-QMs and α-halogenated ketones by a dipeptide-based bifunctional phosphonium salt catalyst. This method represented a novel and complementary approach for the preparation of optically active 2,3-dihydrobenzofuran derivatives in excellent diastereo- and enantioselectivities.20 Mechanistic study of the reaction intermediate and control experiments indicated that the annulation reaction underwent a cascade pathway including intermolecular nucleophilic substitution and subsequent intramolecular 1,6-addition. Moreover, DFT calculations suggested that the enantioselectivity originates from a triad of hydrogen-bonding interactions in the L-Thrderived dipeptide catalytic system. Further mechanistic studies and applications of this privileged peptide-phosphonium salt to other challenging organic syntheses are underway.

Scheme 4. Preliminary Mechanistic Studies

addition, were performed to probe the origin of the observed stereoinduction. The enolate formed by deprotonation of intermediate 8 was found to be unstable in the absence of a counterion (Figure S5). Thus, the phosphonium catalyst is likely to play a role in stabilizing the enolate, in addition to controlling the enantioselectivity. In the presence of the phosphonium cation, the enantio-determining transition states (TSs) could be located (Figure 2a). TS-(S,S), which leads to the major

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02560. Experimental procedures and compound characterization data (PDF) Accession Codes

CCDC 1864020 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Figure 2. DFT calculations: (a) DFT-optimized transition states that lead to the major (left) and minor (right) enantiomers, respectively. (b) Conformation of the catalyst (phosphonium cation) that features one intramolecular C−H···O hydrogen bond and three axial H atoms with computed charges shown in blue (left) and its ESP map (right). Distances are in Å.

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enantiomer, is slightly more stable than TS-(R,R) by 0.5 kcal/ mol, in agreement with the moderate enantioselectivity (54 ee %) observed at room temperature. Calculations using three different density functionals have been performed to make sure this small difference in energy is consistent (Figure S7). The DFT-optimized TSs featured multiple strong hydrogen-bonding

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Peiyuan Yu: 0000-0002-4367-6866 D

DOI: 10.1021/acs.orglett.9b02560 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

(11) For impressive work of Kudo, see: Akagawa, K.; Kudo, K. Acc. Chem. Res. 2017, 50, 2429 and references therein . (12) For selected reviews on amino acid based bifunctional phosphine catalysis, see: (a) Wang, T.; Han, X.; Zhong, F.; Yao, W.; Lu, Y. Acc. Chem. Res. 2016, 49, 1369. (b) Ni, H.; Chan, W.-L.; Lu, Y. Chem. Rev. 2018, 118, 9344. For selected examples, see: (c) Wang, T.; Yu, Z.; Hoon, D. L.; Phee, C. Y.; Lan, Y.; Lu, Y. J. Am. Chem. Soc. 2016, 138, 265. (d) Wang, T.; Yu, Z.; Hoon, D. L.; Huang, K.-W.; Lan, Y.; Lu, Y. Chem. Sci. 2015, 6, 4912. (e) Wang, T.; Yao, W.; Zhong, F.; Pang, G. H.; Lu, Y. Angew. Chem., Int. Ed. 2014, 53, 2964. (f) Wang, T.; Hoon, D. L.; Lu, Y. Chem. Commun. 2015, 51, 10186. (13) For recent reviews, see: (a) Werner, T. Adv. Synth. Catal. 2009, 351, 1469. (b) Liu, S.; Kumatabara, Y.; Shirakawa, S. Green Chem. 2016, 18, 331. (c) Golandaj, A.; Ahmad, A.; Ramjugernath, D. Adv. Synth. Catal. 2017, 359, 3676. (d) Selva, M.; Noè, M.; Perosa, A.; Gottardo, M. Org. Biomol. Chem. 2012, 10, 6569. (14) For the pioneering work on phosphonium salt catalysis by Maruoka, see: (a) He, R.; Wang, X.; Hashimoto, T.; Maruoka, K. Angew. Chem., Int. Ed. 2008, 47, 9466. (b) He, R.; Ding, C.; Maruoka, K. Angew. Chem., Int. Ed. 2009, 48, 4559. (c) He, R.; Maruoka, K. Synthesis 2009, 2009, 2289. (d) Shirakawa, S.; Kasai, A.; Tokuda, T.; Maruoka, K. Chem. Sci. 2013, 4, 2248. (e) Shirakawa, S.; Koga, K.; Tokuda, T.; Yamamoto, K.; Maruoka, K. Angew. Chem., Int. Ed. 2014, 53, 6220. (15) For the pioneering work on phosphonium salt catalysis by Ooi, see: (a) Uraguchi, D.; Sakaki, S.; Ooi, T. J. Am. Chem. Soc. 2007, 129, 12392. (b) Uraguchi, D.; Ueki, Y.; Ooi, T. J. Am. Chem. Soc. 2008, 130, 14088. (c) Uraguchi, D.; Nakashima, D.; Ooi, T. J. Am. Chem. Soc. 2009, 131, 7242. (d) Uraguchi, D.; Ito, T.; Ooi, T. J. Am. Chem. Soc. 2009, 131, 3836. (e) Uraguchi, D.; Asai, Y.; Ooi, T. Angew. Chem., Int. Ed. 2009, 48, 733. (f) Uraguchi, D.; Kinoshita, N.; Kizu, T.; Ooi, T. J. Am. Chem. Soc. 2015, 137, 13768. (16) For selected examples on bifunctional phosphonium saltcatalyzed asymmetric reactions by Zhao, see: (a) Cao, D.; Zhang, J.; Wang, H.; Zhao, G. Chem. - Eur. J. 2015, 21, 9998. (b) Cao, D.; Chai, Z.; Zhang, J.; Ye, Z.; Xiao, H.; Wang, H.; Chen, J.; Wu, X.; Zhao, G. Chem. Commun. 2013, 49, 5972. (c) Wu, X.; Liu, Q.; Liu, Y.; Wang, Q.; Zhang, Y.; Chen, J.; Cao, W.; Zhao, G. Adv. Synth. Catal. 2013, 355, 2701. (d) Ge, L.; Lu, X.; Cheng, C.; Chen, J.; Cao, W.; Wu, X.; Zhao, G. J. Org. Chem. 2016, 81, 9315. (e) Cao, D.; Fang, G.; Zhang, J.; Wang, H.; Zheng, C.; Zhao, G. J. Org. Chem. 2016, 81, 9973. (f) Wang, H.; Wang, K.; Ren, Y.; Li, N.; Tang, B.; Zhao, G. Adv. Synth. Catal. 2017, 359, 1819. (g) Xia, X.; Zhu, Q.; Wang, J.; Chen, J.; Cao, W.; Zhu, B.; Wu, X. J. Org. Chem. 2018, 83, 14617. (h) Fang, G.; Zheng, C.; Cao, D.; Pan, L.; Hong, H.; Wang, H.; Zhao, G. Tetrahedron 2019, 75, 2706. (i) Zhang, J.; Zhao, G. Tetrahedron 2019, 75, 1697. (j) Pan, L.; Zheng, C.-W.; Fang, G.-S.; Hong, H.-R.; Liu, J.; Yu, L.-H.; Zhao, G. Chem. - Eur. J. 2019, 25, 6306. (17) (a) Pan, J.; Wu, J.-H.; Zhang, H.; Ren, X.; Tan, J.-P.; Zhu, L.; Zhang, H.-S.; Jiang, C.; Wang, T. Angew. Chem., Int. Ed. 2019, 58, 7425. (b) Wen, S.; Li, X.; Lu, Y. Asian J. Org. Chem. 2016, 5, 1457. (18) (a) Kim, S.-K.; Park, Y.-C.; Lee, H. H.; Jeon, S. T.; Min, W.-K.; Seo, J.-H. Biotechnol. Bioeng. 2015, 112, 346. (b) Svedendahl, M.; Hult, K.; Berglund, P. J. Am. Chem. Soc. 2005, 127, 17988. (19) See the Supporting Information (SI) for more details. (20) During our preparation of this manuscript, a single isolated example of a phosphine-catalyzed [4 + 1] cyclization of orthohydroxypara-quinone methides with allenoates was reported, which proceeded with moderate yields (59−89%) and enantioselectivities (0−88% ee); see: Zielke, K.; Kovác,̌ O.; Winter, M.; Pospíšil, J.; Waser, M. Chem. - Eur. J. 2019, 25, 8163.

Tianli Wang: 0000-0002-8431-9048 Author Contributions #

J.-P.T. and P.Y. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS T.W. particularly thanks Prof. Yixin Lu (National University of Singapore) for valuable help and suggestions. Financial support was provided by the National Natural Science Foundation of China (21702139), the “1000-Youth Talents Program” (YJ201702), and the Fundamental Research Funds for the Central Universities. We also acknowledge the comprehensive training platform of the Specialized Laboratory in the College of Chemistry at Sichuan University and the Analytical & Testing Center of Sichuan University for compound testing.

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DOI: 10.1021/acs.orglett.9b02560 Org. Lett. XXXX, XXX, XXX−XXX