Chiral Bifunctional Selenide Catalysts for Asymmetric Iodolactonizations

Abstract

1,1′-Bi-2-naphthol (BINOL)-derived chiral bifunctional sulfide and selenide catalysts that possess a hydroxy group are known to be effective catalysts for enantioselective bromolactonizations. When applied to asymmetric iodolactonizations of 4-pentenoic acids, these catalysts yield chiral γ-butyrolactone products that are important compounds in medicinal chemistry. Although chiral bifunctional selenides have shown good catalytic performances in enantioselective iodolactonizations, reactions with BINOL-derived chiral sulfide catalysts unexpectedly gave iodolactonization products in nearly racemic forms. The roles of chalcogenide moieties and hydroxy groups on bifunctional catalysts were investigated, and the importance of both a selenide moiety and a hydroxy group on chiral bifunctional selenide catalysts to achieve enantioselective iodolactonizations was clarified. An optimized chiral bifunctional selenide catalyst was applied to the asymmetric synthesis of chiral γ-butyrolactones and phthalides. Furthermore, the utility of chiral bifunctional selenides was also demonstrated in the catalytic enantioselective desymmetrizing iodolactonization of α,α-diallyl carboxylic acids.

Introduction

The development of effective chiral catalysts for asymmetric halolactonizations of alkenyl carboxylic acids is an important research project in the field of asymmetric catalysis,^1–7) because the resultant optically active lactone products are important compounds in medicinal chemistry and in natural products chemistry.^8–12) Among the catalytic asymmetric halolactonizations using well-designed chiral catalysts, the reaction of 4-pentenoic acid derivatives 1 to give γ-butyrolactone products 2 has often been utilized as a benchmark reaction to examine the performance of chiral catalysts^13–21) (Fig. 1). In this context, we have recently developed 1,1′-bi-2-naphthol (BINOL)-derived chiral bifunctional chalcogenide catalysts for enantioselective bromolactonizations.^22–30) When our chiral bifunctional sulfide catalyst (S)-3 was submitted to the bromolactonization of alkenyl carboxylic acid 1 as a benchmark reaction, the corresponding γ-butyrolactone product 2 (X = Br) was obtained in a highly enantioselective manner via the formation of a highly organized transition-state structure.²⁸⁾ The related chiral bifunctional selenide catalyst (S)-4 also served as an effective catalyst for the bromolactonization.²⁶⁾ To expand the utility of our chiral bifunctional chalcogenide catalysts for asymmetric halolactonizations, we drew out an iodolactonization of 1 under the influence of our chiral bifunctional chalcogenides in this work. Surprisingly, however, asymmetric iodolactonization using chiral sulfide catalyst (S)-3 provided γ-butyrolactone product 2 (X = I) in an almost racemic form. On the other hand, the reaction with chiral bifunctional selenide catalyst (S)-4 gave iodolactonization product 2 (X = I) in good enantioselectivity. Herein, we report the details of these unexpected tendencies between BINOL-derived chiral sulfide catalysts and selenide catalysts^31,32) in the enantioselective iodolactonizations of alkenyl carboxylic acids.

Fig. 1. Effects of Chiral Bifunctional Chalcogenide Catalysts in Asymmetric Halolactonizations

Results and Discussion

Our initial aim was to compare the effects of chiral sulfide catalysts (S)-3 and selenide catalysts (S)-4 in the asymmetric iodolactonization of 4-phenyl-4-pentenoic acid 1a^13,16,18) (Table 1). When a reaction of 1a with N-iodosuccinimide (NIS) in dichloromethane was performed at −78 °C for 24 h in the absence of a catalyst, iodolactonization product 2a was obtained in only an 8% yield. BINOL-derived chiral sulfide catalysts (S)-3, which were effective in the bromolactonization of 1a, were used for iodolactonization with NIS. Although the reaction provided 2a in moderate to good yields, almost no enantioselectivity was observed. On the other hand, the reactions using selenide catalysts (S)-4 gave an optically active iodolactonization product 2a with moderate to good levels of enantioselectivity. Among the examined BINOL-derived selenide catalysts, phenyl-substituted catalyst (S)-4d yielded product 2a in a higher level of enantioselectivity (82 : 18 er). Several control experiments were performed to clarify the roles that the chalcogenide moiety and the hydroxy group exert on bifunctional catalysts. When iodolactonization was performed under the influence of hydroxy-protected sulfide catalyst (S)-5, the reaction was sluggishly promoted to give product 2a in a 27% yield and no enantioselectivity. On the other hand, hydroxy-protected selenide catalyst (S)-6 moderately promoted the iodolactonization of 1a to provide 2a in a 69% yield but in very low enantioselectivity. We also examined the reactions under the influence of simple BINOL (S)-7 and BINOL derivative (R)-8. Event in the reactions using the BINOL derivatives without a chalcogenide moiety, the iodolactonizations were moderately promoted, probably via the hydrogen-bonding activation of NIS.³³⁾ In these reactions, the target iodolactonization products 2a were obtained as racemates in moderate yields. These results could indicate that iodolactonizations using sulfide catalysts (S)-3 are promoted mainly by the effects of the hydroxy group on (S)-3, and that the sulfide catalysts (S)-3 cannot form an organized transition-state, as shown in Fig. 1. Based on the results in Table 1, we concluded that both the selenide moiety and the hydroxy group on the chiral bifunctional selenide catalysts (S)-4 are essential to achieve efficient enantioselective iodolactonizations.

Table 1. Effect of Chiral Chalcogenide Catalysts

To further explore the effect of the various functional groups on the reaction, we have carried out density functional theory (DFT) computations on some small model systems. We use the r²SCAN-3c method in combination with the solvation effect of dichloromethane incorporated using a continuum solvation model. First, in the absence of a catalyst, NIS reacts with 1a to give 2a with a concerted transition-state structure (Fig. 2); the calculated barrier for this reaction is 42 kJ mol⁻¹. If the NIS reagent is replaced by the NIS-methanol hydrogen-bonded complex, the barrier is lowered to 37 kJ mol⁻¹. To put this in perspective, the barrier for uncatalyzed bromination by NBS has a calculated barrier of 36 kJ mol⁻¹; we have in our preliminary experimental study found this reaction to proceed with good yield. Thus, our DFT barriers are qualitatively consistent with the catalytic effect of the OH groups in (S)-3, (S)-4, (S)-7, and (R)-8. Next, we discuss the effect of the sulfide and selenide moieties. The proposed mechanism involves the abstraction of iodine by the chalcogenide to form a reactive intermediate. We have examined the complexation energy of NIS with dimethyl sulfide and dimethyl selenide as an indicator for the ease of forming the iodinated chalcogenide intermediate. For the sulfide, the complexation energy is 48 kJ mol⁻¹. In comparison, the binding with the selenide is stronger (54 kJ mol⁻¹). This is consistent with the stronger catalytic effect of (S)-6 than that of (S)-5. Overall, our results show a correlation between the observed catalytic activities and the calculated thermochemical quantities. To further rationalize the enantioselectivity would necessitate a thorough sampling of the conformational space of the catalytic transition-state structure, which we would consider in a separate study.

Fig. 2. Model Systems Used in Our DFT Computations, and Key Calculated Thermochemical Quantities

To improve enantioselectivity in the iodolactonization of 4-phenyl-4-pentenoic acid 1a catalyzed by chiral bifunctional selenide (S)-4d, we next examined the effect of other iodinating reagents (Table 2). In a pleasing development, the reactions using N-iodophthalimide (NIP) and 1,3-diiodo-5,5-dimethylhydantoin (DIH) improved both the yields and the enantioselectivities. In particular, the iodolactonization of 1a with DIH under the influence of catalyst (S)-4d provided γ-butyrolactone product 2a in high levels of yield and enantioselectivity (92 : 8 er).^34,35) The absolute configuration of 2a was confirmed by comparison with reported data.^16,18)

Table 2. Effect of Iodinating Reagents

With the optimum catalyst and iodinating reagent in hand, we investigated the substrate generality for an asymmetric iodolactonization of 1 with DIH under the influence of chiral bifunctional selenide catalyst (S)-4d³⁶⁾ (Table 3). A series of aryl-substituted 4-pentenoic acids 1 were applied to enantioselective iodolactonization in an effort to obtain corresponding γ-butyrolactone products 2. First, the effects of the functional groups at the para position of the aryl unit on 1 were examined. The iodolactonizations of halo-substituted substrates 1b and 1c gave products 2b and 2c in good yields and in good to high enantioselectivities. Methyl- and trifluoromethoxy-substituted substrates 1d and 1e were also applied to the reaction to obtain 2d and 2e in high yields and good enantioselectivities. Unfortunately, the iodolactonization with trifluoromethyl-substituted substrate 1f gave product 2f in low enantioselectivity. The aryl-substituted substrates 1 bearing functionalities at the meta- and ortho-positions were also examined. Although the meta-substituted products 2g and 2h were obtained in good levels of enantioselectivity, the ortho-substituted product 2i was obtained in only moderate enantioselectivity. Heteroaromatic-substituted substrate 1j was also applied to iodolactonization and provided 2j in good levels of yield and enantioselectivity. The reaction with alkyl-substituted substrate 1k gave product 2k in moderate levels of yield and enantioselectivity.

Table 3. Substrate Scope in the Asymmetric Iodolactonization of 4-Pentenoic Acids 1

The chiral bifunctional selenide catalyst (S)-4d could also be applied to the asymmetric iodolactonizations of o-vinylbenzoic acid derivatives 9 to provide chiral phthalide products 10^24,37,38) (Table 4). The reactions of substrates 9 were performed in a solvent mixture of dichloromethane–toluene, which provided better enantioselectivity for the iodolactonizations of substrates 9 by comparison with dichloromethane solvent. The target 3,3-disubstituted phthalide products 10 were obtained in high yields and in moderate to good levels of enantioselectivity.

Table 4. Catalytic Asymmetric Synthesis of 3,3-Disubstituted Phthalides 10 via Iodolactonization

To demonstrate the further potential of our BINOL-derived chiral bifunctional chalcogenide catalysts for iodolactonizations, we next examined catalytic enantioselective desymmetrizing iodolactonization of α,α-diallyl carboxylic acid 11a,^29,39,40) which provided α-quaternary lactone 12a with an all-carbon quaternary stereocenter^41–45) (Table 5). When desymmetrizing iodolactonizations of 11a with NIS in dichloromethane were performed at −78 °C for 24 h under the influence of sulfide catalysts (S)-3c and 3d, the target α-quaternary γ-butyrolactone product 12a was obtained in an almost racemic form (entries 1 and 2). On the other hand, the desymmetrizations of 11a using chiral bifunctional selenide catalysts (S)-4c and 4d provided 12a in moderate enantioselectivities (entries 3 and 4). These trends between sulfide catalysts (S)-3 and selenide catalysts (S)-4 agreed with that seen in the iodolactonization of substrate 1a, as shown in Table 1. The reaction conditions for the desymmetrizing iodolactonization of 11a using selenide catalyst (S)-4c were further optimized to improve the enantioselectivity (entries 5–7). The highest enantioselectivity was observed in the reaction of 11a with DIH in a dichloromethane-toluene mixed solvent (entry 7).

Table 5. Optimization of the Reaction Conditions in the Desymmetrizing Iodolactonization of 11a^a)

Entry	Catalyst	Iodinating reagent	Yield (%)b)	erc)
1	(S)-3c	NIS	97	52 : 48
2	(S)-3d	NIS	66	50 : 50
3	(S)-4c	NIS	62	72 : 28
4	(S)-4d	NIS	80	63 : 37
5	(S)-4c	NIP	96	81 : 19
6	(S)-4c	DIH	93	82 : 18
7d)	(S)-4c	DIH	93	86 : 14

a) Reaction conditions: 11a (0.10 mmol), iodinating reagent (0.12 mmol), catalyst (10 mol %, 0.010 mmol), CH₂Cl₂ (2.0 mL), −78 °C, 24 h. b) Yield of isolated product 12a. c) The enantiomeric ratio (er) was determined via HPLC analysis on a chiral stationary phase. d) The reaction was performed in a CH₂Cl₂–toluene mixed solvent (1.0 mL each).

Selected substrates 11 were submitted to chiral selenide-catalyzed desymmetrizing iodolactonizations under the optimized reaction conditions (Table 6). The target α-quaternary γ-butyrolactone products 12 were obtained in good to high yields and in good levels of enantioselectivity. It should be mentioned that products 12 were obtained in a highly diastereoselective fashion in all cases listed in Table 6.

Table 6. Substrate Scope in the Desymmetrizing Iodolactonization of α,α-Diallyl Carboxylic Acids 11

The synthetic utility of optically active γ-butyrolactone product 12a was demonstrated in a transformation to α-quaternary ester 13²⁹⁾ (Chart 1). The compound 12a was treated with potassium carbonate in methanol to give a methyl ester 13 that would possess epoxide as a useful functional group. It is noteworthy that this transformation proceeded with a complete retention of the stereochemistry.

Chart 1. Synthesis of Optically Active α-Quaternary Ester 13

Conclusion

We reported the unexpected tendencies between chiral sulfide catalysts and selenide catalysts during asymmetric iodolactonizations. BINOL-derived chiral bifunctional selenides bearing a hydroxy group served as efficient catalysts in enantioselective iodolactonizations of 4-pentenoic acids to give optically active γ-butyrolactone products in good enantioselectivities. Unexpectedly, however, the reactions using related chiral sulfide catalysts provided the iodolactonization products as racemates. The roles of the chalcogenide moiety and of the hydroxy group on the BINOL-derived bifunctional catalysts were investigated, and we concluded that both the selenide moiety and the hydroxy group on chiral bifunctional selenide catalysts are essential in order to achieve an efficient enantioselective iodolactonization. The utility of BINOL-derived chiral bifunctional selenide catalysts was further demonstrated in the asymmetric syntheses of chiral phthalides and α-quaternary lactones via enantioselective iodolactonizations. Further applications of chiral bifunctional selenide catalysts to other asymmetric transformations are currently underway by our group.

Experimental

General Procedure for Asymmetric Iodolactonizations

A solution of alkenyl carboxylic acid substrate [1, 9, or 11] (0.10 mmol) and chiral selenide catalyst [(S)-4d or (S)-4c] (10 mol %, 0.010 mmol) in dichloromethane (2 mL) [or dichloromethane (1 mL)–toluene (1 mL)] was cooled to −78 °C. After stirring for 10 min at −78 °C, 1,3-diiodo-5,5-dimethylhydantoin (DIH) (0.12 mmol) was added to the cooled reaction solution. The reaction mixture was stirred for 24 h at −78 °C. After 24 h, the reaction mixture was quenched with saturated aqueous Na₂SO₃ (4 mL) at −78 °C and stirred for 10 min at −78 °C. The quenched reaction mixture was diluted with dichloromethane (2 mL) and water (2 mL). The mixture was then warmed to room temperature. The organic materials were extracted with dichloromethane three times (5 mL × 3). The combined extracts were dried over Na₂SO₄ and concentrated. [The ¹H-NMR analysis of the crude reaction mixture was performed at this stage to confirm diastereoselectivities of products 12.] The residue was purified by flash column chromatography on silica gel (hexane/ethyl acetate as eluent) to give iodolactonization product [2, 10, or 12]. The enantioselectivities of the products were determined by HPLC analysis on a chiral stationary phase.

Acknowledgments

This work was supported by JSPS KAKENHI Grant Numbers JP19K05480 (for S.S.) and JP21J20978 (for R.N.), by the Cooperative Research Program of “Network Joint Research Center for Materials and Devices” (20211315 for S.S.), and Tokyo Ohka Foundation for the Promotion of Science and Technology (21111 for B.C.). B.C. acknowledges computer time from the RIKEN Information Systems and Cybersecurity (ISC, Q21266), Japan. This work was the result of using research equipment shared in the MEXT Project for promoting public utilization of advanced research infrastructure (Program for supporting introduction of the new sharing system) Grant Numbers JPMXS0422500320 and JPMXS0422300120. R.N. thanks JSPS for a research fellowship (DC1).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

References and Notes

• 1) Denmark S. E., Kuester W. E., Burk M. T., Angew. Chem. Int. Ed., 51, 10938–10953 (2012).
• 2) Hennecke U., Chem. Asian J., 7, 456–465 (2012).
• 3) Tan C. K., Yeung Y.-Y., Chem. Commun., 49, 7985–7996 (2013).
• 4) Murai K., Fujioka H., Heterocycles, 87, 763–805 (2013).
• 5) Zheng S., Schienebeck C. M., Zhang W., Wang H.-Y., Tang W., Asian J. Org. Chem., 3, 366–376 (2014).
• 6) Kristianslund R., Tungen J. E., Hansen T. V., Org. Biomol. Chem., 17, 3079–3092 (2019).
• 7) Egami H., Chem. Pharm. Bull., 68, 491–511 (2020).
• 8) Ward R. S., Nat. Prod. Rep., 16, 75–96 (1999).
• 9) Lepoittevin J.-P., Berl V., Giménez-Arnau E., Chem. Rec., 9, 258–270 (2009).
• 10) Alibés R., Figueredo M., Eur. J. Org. Chem., 2009, 2421–2435 (2009).
• 11) Kitson R. R. A., Millemaggi A., Taylor R. J. K., Angew. Chem. Int. Ed., 48, 9426–9451 (2009).
• 12) Mao B., Fañanás-Mastral M., Feringa B. L., Chem. Rev., 117, 10502–10566 (2017).
• 13) Ning Z., Jin R., Ding J., Gao L., Synlett, 2009, 2291–2294 (2009).
• 14) Whitehead D. C., Yousefi R., Jaganathan A., Borhan B., J. Am. Chem. Soc., 132, 3298–3300 (2010).
• 15) Zhou L., Tan C. K., Jiang X., Chen F., Yeung Y.-Y., J. Am. Chem. Soc., 132, 15474–15476 (2010).
• 16) Veitch G. E., Jacobsen E. N., Angew. Chem. Int. Ed., 49, 7332–7335 (2010).
• 17) Nakatsuji H., Sawamura Y., Sakakura A., Ishihara K., Angew. Chem. Int. Ed., 53, 6974–6977 (2014).
• 18) Klosowski D. W., Hethcox J. C., Paull D. H., Fang C., Donald J. R., Shugrue C. R., Pansick A. D., Martin S. F., J. Org. Chem., 83, 5954–5968 (2018).
• 19) Nishikawa Y., Hamamoto Y., Satoh R., Akada N., Kajita S., Nomoto M., Miyata M., Nakamura M., Matsubara C., Hara O., Chem. Eur. J., 24, 18880–18885 (2018).
• 20) Arai T., Horigane K., Watanabe O., Kakino J., Sugiyama N., Makino H., Kamei Y., Yabe S., Yamanaka M., iScience, 12, 280–292 (2019).
• 21) Chan Y.-C., Wang X., Lam Y.-P., Wong J., Tse Y.-L. S., Yeung Y.-Y., J. Am. Chem. Soc., 143, 12745–12754 (2021).
• 22) Nishiyori R., Tsuchihashi A., Mochizuki A., Kaneko K., Yamanaka M., Shirakawa S., Chem. Eur. J., 24, 16747–16752 (2018).
• 23) Tsuchihashi A., Shirakawa S., Synlett, 30, 1662–1666 (2019).
• 24) Okada M., Kaneko K., Yamanaka M., Shirakawa S., Org. Biomol. Chem., 17, 3747–3751 (2019).
• 25) Nakamura T., Okuno K., Kaneko K., Yamanaka M., Shirakawa S., Org. Biomol. Chem., 18, 3367–3373 (2020).
• 26) Nishiyori R., Maynard J. R. J., Shirakawa S., Asian J. Org. Chem., 9, 192–196 (2020).
• 27) Okuno K., Nakamura T., Shirakawa S., Asian J. Org. Chem., 10, 655–659 (2021).
• 28) Nishiyori R., Okada M., Maynard J. R. J., Shirakawa S., Asian J. Org. Chem., 10, 1444–1448 (2021).
• 29) Hiraki M., Okuno K., Nishiyori R., Noser A. A., Shirakawa S., Chem. Commun., 57, 10907–10910 (2021).
• 30) Okuno K., Hiraki M., Bun C., Shirakawa S., Bull. Chem. Soc. Jpn., 95, 52–58 (2022).
• 31) Singh F. V., Wirth T., Catal. Sci. Technol., 9, 1073–1091 (2019).
• 32) Liao L., Zhao X., Synlett, 32, 1262–1268 (2021).
• 33) Hexafluoroisopropanol (HFIP)-promoted halolactonizations, see: Qi C., Force G., Gandon V., Labœuf D., Angew. Chem. Int. Ed., 60, 946–953 (2021).
• 34) When the iodolactonization of 1a was performed with 0.6 equivalent of DIH under the influence of catalyst (S)-4d, iodolactonization product 2a was obtained in a 75% yield with a 92 : 8 er. See also, Chart S1 in Supplementary Materials.
• 35) When the iodolactonization of 1a using DIH (1.2 equiv) and catalyst (S)-4d was performed in the presence of I₂ (0.3 equiv) as an additive, iodolactonization product 2a was obtained in a 99% yield with a 94 : 6 er. See also, Chart S1 in Supplementary Materials.
• 36) Part of the catalyst (S)-4d (approx. 40%) could be recovered after the iodolactonizations.
• 37) Han X., Dong C., Zhou H.-B., Adv. Synth. Catal., 356, 1275–1280 (2014).
• 38) Egami H., Asada J., Sato K., Hashizume D., Kawato Y., Hamashima Y., J. Am. Chem. Soc., 137, 10132–10135 (2015).
• 39) Hennecke U., Wilking M., Synlett, 25, 1633–1637 (2014).
• 40) Wilking M., Daniliuc C. G., Hennecke U., Synlett, 25, 1701–1704 (2014).
• 41) Corey E. J., Guzman-Perez A., Angew. Chem. Int. Ed., 37, 388–401 (1998).
• 42) Christoffers J., Mann A., Angew. Chem. Int. Ed., 40, 4591–4597 (2001).
• 43) Denissova I., Barriault L., Tetrahedron, 59, 10105–10146 (2003).
• 44) Peterson E. A., Overman L. E., Proc. Natl. Acad. Sci. U.S.A., 101, 11943–11948 (2004).
• 45) Trost B. M., Jiang C., Synthesis, 2006, 369–396 (2006).