Kinetic Resolution of β-Hydroxy Carbonyl Compounds via

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

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Kinetic Resolution of β‑Hydroxy Carbonyl Compounds via Enantioselective Dehydration Using a Cation-Binding Catalyst: Facile Access to Enantiopure Chiral Aldols Sushovan Paladhi,†,‡,∥ In-Soo Hwang,†,∥ Eun Jeong Yoo,§ Do Hyun Ryu,† and Choong Eui Song*,† †

Department of Chemistry, Sungkyunkwan University, Suwon 16419, Korea Department of Chemistry, A.N.S. College, Barh, Patna 803213, India § Department of Chemistry, Kangwon National University, Chuncheon 24341, Korea ‡

S Supporting Information *

ABSTRACT: A practical and highly enantioselective nonenzymatic kinetic resolution of racemic β-hydroxy carbonyl (aldol) compounds through enantioselective dehydration process was developed using a cation-binding Song’s oligoethylene glycol (oligoEG) catalyst with potassium fluoride (KF) as base. A wide range of racemic aldols was resolved with extremely high selectivity factors (s = up to 2393) under mild reaction conditions. This protocol is easily scalable. It provides an alternative approach for the syntheses of diverse biologically and pharmaceutically relevant chiral aldols in enantiomerically pure form. For example, racemic gingerols could participate in this kinetic resolution with superb efficiency (s > 240), affording both enantiomerically pure gingerols and corresponding shogaols simultaneously in a single step. The dramatic effectiveness of such kinetic resolution process can be ascribed to systematic cooperative hydrogen-bonding catalysis in a densely confined supramolecular chiral cage in situ generated from the chiral catalyst, substrate, and KF. he synthesis of chiral β-hydroxy carbonyl (aldol) scaffolds is of particular importance due to their structural presence in a wide range of natural products and bioactive molecules. Conventionally, asymmetric catalytic aldol reaction is one important method to obtain chiral β-hydroxy carbonyl moieties.1 Recently, a plethora of direct and indirect strategies including enzymes, catalytic antibodies, and small molecules have been developed for catalytic stereoselective aldol reactions with both high efficiency and stereoselectivity.1 Despite these impressive advances, another efficient way to obtain chiral aldol moieties would be to use kinetic resolution of racemate aldol substrates. The main advantage of such kinetic resolution process is to allow facile access to chiral molecules with absolute enantiopurity since this process can give any arbitrarily high enantiomeric excesses of recovered substrates simply by proceeding to higher conversions.2 Thus, this method provides an alternative way to obtain chiral aldols that are hard to obtain in enantiomerically pure form otherwise. In principle, aldols can be resolved either via retro-aldol pathway or via enantioselective dehydration mechanism.3 A few successful examples for kinetic resolution of racemic aldols via retro-aldol reaction catalyzed antibody aldolases4 and small molecule catalysts5 have been reported. Enantioselective dehydration was also adapted for the kinetic resolution of racemic β-hydroxy carbonyl compounds.6 The efficiency of

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© XXXX American Chemical Society

kinetic resolution was characterized by the selectivity factor (i.e., the ratio of the reaction rate of the fast-reacting enantiomer over that of the slow-reacting enantiomer). However, the selectivity factors achieved are too low for synthetic use (s = 1.2−33) (Scheme 1, eq 1). Recently, we have developed a new type of easily accessible 1,1′-bi-2-naphthol (BINOL)-based organocatalysts (Song’s oligo EGs, 1)7 bearing phenols and polyether units for asymmetric cation-binding catalysis (Figure 1). Ether oxygens act as Lewis base to coordinate metal ions such as K+, thus generating a soluble chiral anion in a confined chiral space. Moreover, terminal phenol groups are capable of simultaneously activating the electrophile by hydrogen bonding interaction, resulting in a well-organized transition state with excellent stereoinduction. This concept for ambiphilic activation using Song’s chiral oligoEGs 1 as an evolved cation-binding catalytic system has been successfully applied to several challenging catalytic asymmetric reactions.7 In particular, Song’s oligoEGs catalyst 1 has been successfully applied to an effective kinetic resolution of β-sulfonyl ketones7e and β-halogenated ketones7k via β-elimination. Thus, we envisioned that such a strategy might Received: February 14, 2018

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DOI: 10.1021/acs.orglett.8b00547 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 1. Kinetic Resolution of β-Hydroxy Carbonyls via Different Mechanisms

Table 1. Optimization of Reaction Conditions

entry

catalyst

solvent

time (h)

conv. (%)a

ee (%)b

sc

1 2 3d 4e 5 6 7 8 9

(S)-1a (S)-1b (S)-1b (S)-1b (S)-1b (S)-1b (S)-1b (S)-1b (S)-1b

toluene toluene toluene toluene o-xylene CH2Cl2 1,4-dioxane THF CH3CN

48 3 5.5 30 2.5 4.5 3 3 3

41 50 48.3 48.7 49 48 n.r. n.r. n.r.

56 >99.5 93.1 92.1 95 85

16 >2393 1990 219 665 65

a

Figure 1. Chiral Song’s oligoEGs catalyst 1.

The conversion was determined by 1H NMR analysis of the reaction mixture after a specific time. bThe ee value was determined by HPLC analysis (see Supporting Information). The absolute configuration of unreacted (S)-2a was assigned by comparing measured value of optical rotation and the retention time of HPLC with literature data. c Selectivity factor (s) = rate of fast reacting enantiomer/rate of slow reacting enantiomer. Selectivity factors were calculated by methods of Fiaud: s = ln[(1 − conv.)(1 − ee(R)‑2a)]/ln[(1 − conv.)(1 + ee(R)‑2a)].10 d Catalyst (S)-1b (5 mol %) and KF (0.6 equiv) are used. eCatalyst (S)-1b (1 mol %) and KF (1.2 equiv) are used.

enable enantioselective dehydration of β-hydroxy carbonyl compounds. Herein, we report the successful development of a kinetic resolution of racemic aldols to deliver enantiomerically pure aldols via enantioselective β-elimination process catalyzed by Song’s oligoEGs catalyst 1. Selectivity factors achieved with this new protocol were unprecedentedly high (s = up to ca. 2300) for a wide range of racemic aldols. The utility of this protocol was highlighted by demonstrating that biologically and pharmaceutically important gingerols were successfully subjected to this protocol on a preparative scale (Scheme 1, eq 2). We initiated this study by examining the kinetic resolution of racemic β-hydroxy ketone 2 in the presence of Song’s chiral oligoEGs 1 as catalyst and KF as a base at room temperature (Table 1). Gratifyingly, all examined reactions proceeded exclusively via β-elimination pathway, thus providing (R)-2a and enone 3a as shown in Table 1. In all cases, any retro-aldol product (i.e., benzaldehyde or acetophenone) was not observed.8 Furthermore, suitable acidity for phenolic protons of chiral oligoEGs 1 (Table 1, entry 1 vs entry 2) is crucial to achieving catalytic activity and enantioselectivity.7 Although (S)-1a showed some promising catalytic performance, observed activity and selectivity factor were unsatisfactory for further use. To our delight, however, introduction of electron-withdrawing substituent CF3 (catalyst (S)-1b) at the 3,3′-position of the binaphthyl scaffold resulted in a dramatic increase in the catalytic activity and enantioselectivity.9 Using 10 mol % of catalyst 1b, racemic β-hydroxy ketone 2a was perfectly resolved after 3 h, providing enantiomerically pure β-hydroxy ketone (R)-2a (50% yield and >99.5% ee, s = >2393) and the corresponding enone.

Even with reduced catalyst loading of 1b (1−5 mol %), the reaction proceeded smoothly with almost perfect selectivity factors (Table 1, entries 3 and 4). In further experiments, different solvents were examined with catalyst (S)-1b as the optimal catalyst (Table 1, entries 5−9). Toluene proved to be the optimal choice. Polar solvents were found to be much worse in terms of reaction rates and selectivity factors. In particular, negligible conversions were observed in THF, dioxane, and CH3CN (Table 1, entries 7−9). Further optimization of reaction conditions on KF loading or concentration did not improve catalytic results (see Supporting Information). With optimized reaction conditions (Table 1, entries 2 and 3) in hand, substrate scope of our protocol was investigated. As shown in Scheme 2, a diverse array of racemic β-hydroxyketones 2a−2r derived from acetophenone with various aldehydes were successfully resolved with excellent selectivity factors (s = up to 2393), affording enantiomerically enriched aldols and corresponding dehydration products. Regardless of electronic or steric nature of the aromatic ring, all aromatic substrates 2a−2i were resolved with great success (s = 53 to 2393). Heteroaromatic substrates 2j−2l also fitted well under the present protocol with high selectivity factors. Furthermore, to our delight, the high selectivity could be extended to traditionally challenging aliphatic substrates 2m−2r (s = 48 to 1985). Of note, sterically demanding tertiary butyl substrate 2q was also perfectly resolved (s = 1985). In addition to a wide range of aldol acceptor parts, different aldol donor structures also tolerated our catalytic protocol with high selectivity factors (Scheme 3). All substrates underwent βelimination smoothly to afford highly enantioenriched unreacted B

DOI: 10.1021/acs.orglett.8b00547 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Scope of Kinetic Resolution with Respect to the Aldol Acceptor Part of 2a,b,c

Scheme 3. Scope of Kinetic Resolution with Respect to the Aldol Acceptor Part of 4a,b

a

Unless otherwise indicated, reactions were performed with 4 (0.1 mmol), (S)-1b (5 mol %), and KF (0.6 equiv) in toluene (0.1 M) at 25 °C. bCatalyst (10 mol %) and KF (1.2 equiv) were used.

Scheme 4. Synthetic Utilitya

a

Unless otherwise indicated, reactions were performed with 2 (0.1 mmol), (S)-1b (5 mol %), and KF (0.6 equiv) in toluene (0.1 M) at 25 °C. bThe reaction was carried out at 1 mmol scale. cCatalyst (10 mol %) and KF (1.2 equiv) were used.

(R)-4 and corresponding enones 5. Lastly, this methodology was successfully extended further to include synthetically highly useful β-hydroxythioesters (4k and 4l) that could be easily converted to chiral β-hydroxyaldehydes using Fukuyama reduction protocol.11,12 Of note, chiral β-hydroxyaldehydes are still formidably challenging synthetic targets in modern aldol chemistry.13 It should be also noteworthy that the dehydration reaction of thioesters is part of the metabolic pathway for the synthesis of fatty acids. To demonstrate the synthetic utility and potential large-scale applications of this protocol, kinetic resolution of rac-gingerols was chosen because this reaction could provide direct access to enantiomerically pure gingerols (the major pungent compounds present in rhizomes of ginger) and shogaols (dehydration products of the corresponding gingerols) simultaneously in a single step (Scheme 4). Gingerols and shogaols possess a myriad of pharmacological activities, including anticancer, anti-inflammatory, antioxidant, antimicrobial, antidiabetic, antiallergic, antiaging, antiproliferative potential, and various central nervous system activities.14 Thus, structural modification of gingerols through exploring the relationship between chirality and activity may further enhance their pharmaceutical application potential. However, the lack of a general asymmetric protocol to access both enantiomers of chiral gingerol derivatives has largely hampered their implementation in biological study. Thus, developing a general synthetic method

a Enantiomerically pure (R)-gingerols were also prepared using (R)-1b catalyst. See the Supporting Information for more details.

to access each stereoisomer of gingerol derivatives is highly desirable. Different gingerols (e.g., [6]-, [7]-, [8]-, [9]- and [10]gingerol) were subjected to this protocol at a preparative scale (10 mmol). Gratifyingly, these biologically interesting substrates participated in this kinetic resolution with superb efficiency (s > 240), although the reaction rate was slow. From easily preparable racemic gingerols, both enantiomers of gingerols with extremely high optical purity (>99.9% ee) and their corresponding shogaols could be obtained in a single step. Here again, the resolution proceeded chemoselectively. Thus, zingerone, the retro-aldol product, was not observed. Of note, with selectivity factors obtained with different gingerols, absolute enantiopurity can be achieved after ca. 53% conversion theoretically. Such extreme enantiomeric purities are definitely of great interest in studying biological responses to pure enantiomers of gingerols. In summary, a highly enantioselective biomimetic kinetic resolution of racemic aldols through enantioselective dehydraC

DOI: 10.1021/acs.orglett.8b00547 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

(6) Du, Z.-X.; Zhang, L.-Y.; Fan, X.-Y.; Wu, F.-C.; Da, C.-S. Tetrahedron Lett. 2013, 54, 2828. (7) (a) For a review, see: Oliveira, M. T.; Lee, J.-W. ChemCatChem 2017, 9, 377. (b) Yan, H.; Jang, H. B.; Lee, J.-W.; Kim, H. K.; Lee, S. W.; Yang, J. W.; Song, C. E. Angew. Chem., Int. Ed. 2010, 49, 8915. (c) Yan, H.; Oh, J. S.; Lee, J.-W.; Song, C. E. Nat. Commun. 2012, 3, 1212. (d) Park, S. Y.; Lee, J. W.; Song, C. E. Nat. Commun. 2015, 6, 7512. (e) Li, L.; Liu, Y.; Peng, Y.; Yu, L.; Wu, X.; Yan, H. Angew. Chem., Int. Ed. 2016, 55, 331. (f) Liu, Y.; Ao, J.; Paladhi, S.; Song, C. E.; Yan, H. J. Am. Chem. Soc. 2016, 138, 16486. (g) Vaithiyanathan, V.; Kim, M. J.; Liu, Y.; Yan, H.; Song, C. E. Chem. - Eur. J. 2017, 23, 1268. (h) Kim, M. J.; Xue, L.; Liu, Y.; Paladhi, S.; Park, S. J.; Yan, H.; Song, C. E. Adv. Synth. Catal. 2017, 359, 811. (i) Yu, L.; Wu, X.; Kim, M. J.; Vaithiyanathan, V.; Liu, Y.; Tan, Y.; Qin, W.; Song, C. E.; Yan, H. Adv. Synth. Catal. 2017, 359, 1879. (j) Park, S. Y.; Hwang, I.-S.; Lee, H. J.; Song, C. E. Nat. Commun. 2017, 8, 14877. (k) Tan, Y.; Luo, S.; Li, D.; Zhang, N.; Jia, S.; Liu, Y.; Qin, W.; Song, C. E.; Yan, H. J. Am. Chem. Soc. 2017, 139, 6431. (l) Duan, M.; Liu, Y.; Ao, J.; Xue, L.; Luo, S.; Tan, Y.; Qin, W.; Song, C. E.; Yan, H. Org. Lett. 2017, 19, 2298. (m) Paladhi, S.; Liu, Y.; Kumar, B. S.; Jung, M.-J.; Park, S. Y.; Yan, H.; Song, C. E. Org. Lett. 2017, 19, 3279. (n) Park, S. Y.; Liu, D.; Oh, J. S.; Kweon, Y. K.; Jeong, Y. B.; Duan, M.; Tan, Y.; Lee, J.W.; Yan, H.; Song, C. E. Chem. - Eur. J. 2018, 24, 1020. (8) Remarkably, α-substitution changes the resolution pathway. Thus, α-substituted β-hydroxy ketones were resolved exclusively via retroaldol pathway with reasonable selectivity factors. A comprehensive study on retro-aldolase mimic kinetic resolution of racemic aldols is currently in progress, and the results will be reported elsewhere in due course. (9) We examined two more catalysts (X = H or Ph) having no electronwithdrawing substituents at the 3,3′-position. However, these catalysts were completely inactive in the same reaction conditions, further confirming the importance of suitable acidity for phenolic protons. The importance of the polyether chain was also confirmed unambiguously by replacing the polyether of 1a with the alkyl chain. This catalyst also showed no activity, indicating that the polyether backbone is crucial in achieving the observed catalytic activity. (10) Fiaud, J. C.; Kagan, H. B. Kinetic Resolution. In Topics in Stereochemistry; Eliel, E. L., Wilen, S. H., Ed.; Wiley and Sons, Inc.: New York, 1988; Vol. 18, p 249. (11) Fukuyama, T.; Tokuyama, H. Aldrichimica Acta 2004, 37, 87. (12) Bae, H. Y.; Sim, J. H.; Lee, J.-W.; List, B.; Song, C. E. Angew. Chem., Int. Ed. 2013, 52, 12143. (13) Cross-aldol reactions of aldehydes: (a) Alcaide, B.; Almendros, P. Angew. Chem., Int. Ed. 2003, 42, 858. (b) Denmark, S. E.; Bui, T. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5439. (14) For a review, see: Semwal, R. B.; Semwal, D. K.; Combrinck, S.; Viljoen, A. M. Phytochemistry 2015, 117, 554.

tion process was developed using a cation-binding Song’s oligoEG catalyst with KF as base. A wide range of racemic aldols were resolved with unprecendentedly high selectivity factors (s = up to 2393) under mild reaction conditions. This protocol is easily scalable and provides an alternative approach for syntheses of diverse biologically and pharmaceutically relevant chiral aldols such as gingerols in enantiomerically pure form. The great success of these kinetic resolutions can be ascribed to systematic cooperative hydrogen-bonding catalysis in a densely confined chiral space, which mimics the action of enzymes. Current efforts in our laboratory are focused on detailed mechanistic studies to elucidate the origin of the stereo-outcome. Biological evaluations of chiral gingerols are also in progress. Results will be reported in due course.

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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.8b00547. Experimental details and analytical data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Eun Jeong Yoo: 0000-0003-4027-2441 Do Hyun Ryu: 0000-0001-7615-4661 Choong Eui Song: 0000-0001-9221-6789 Author Contributions ∥

S.P. and I.-S.H. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Korean Research Foundation (Grant No: NRF-2017R1A2A1A05001214 and NRF2016R1A4A1011451).

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REFERENCES

(1) Selected reviews for catalytic asymmetric aldol reactions: (a) Gröger, H.; Vogl, E. M.; Shibasaki, M. Chem. - Eur. J. 1998, 4, 1137. (b) Mahrwald, R. Modern Aldol Reactions; Wiley-VCH: Weinheim, 2004. (c) Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249. (d) Geary, L. M.; Hultin, P. G. Tetrahedron: Asymmetry 2009, 20, 131. (e) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600. (2) (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237. (b) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5. (3) A few reports on lipase-catalyzed kinetic resolution of aldols were also reported. See (a) Nair, M. S.; Joly, S. Tetrahedron: Asymmetry 2000, 11, 2049. (b) Zhang, W.-W.; Wang, N.; Feng, X.-W.; Zhang, Y.; Yu, X.Q. Appl. Biochem. Biotechnol. 2014, 173, 535. (c) Xu, F.; Xu, J.; Hu, Y.; Lin, X.; Wu, Q. RSC Adv. 2016, 6, 76829. (4) (a) Reymond, J. L. Angew. Chem., Int. Ed. Engl. 1995, 34, 2285. (b) Zhong, G.; Shabat, D.; List, B.; Anderson, J.; Sinha, S. C.; Lerner, R. A.; Barbas, C. F., III Angew. Chem., Int. Ed. 1998, 37, 2481. (c) List, B.; Shabat, D.; Zhong, G.; Turner, J. M.; Li, A.; Bui, T.; Anderson, J.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 1999, 121, 7283. (d) Turner, J. M.; Bui, T.; Lerner, R. A.; Barbas, C. F., III; List, B. Chem. - Eur. J. 2000, 6, 2772. (5) Luo, S.; Zhou, P.; Li, J.; Cheng, J.-P. Chem. - Eur. J. 2010, 16, 4457. D

DOI: 10.1021/acs.orglett.8b00547 Org. Lett. XXXX, XXX, XXX−XXX