Chiral Bifunctional Selenide Catalysts for Asymmetric Iodolactonizations

1,1 ′ -Bi-2-naphthol (BINOL)-derived chiral bifunctional sulﬁde and selenide catalysts that possess a hy droxy 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.


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 * To whom correspondence should be addressed. e-mail: seijishirakawa@nagasaki-u.ac.jp

Regular Article
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 hydrogenbonding 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.
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 r 2 SCAN-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.
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-5,5dimethylhydantoin (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) 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)-4d 36) (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.
The chiral bifunctional selenide catalyst (S)-4d could also be applied to the asymmetric iodolactonizations of ovinylbenzoic 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.
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.
The synthetic utility of optically active γ-butyrolactone product 12a was demonstrated in a transformation to α-quaternary ester 13 29) (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.

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 BINOLderived 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.
[The 1 H-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.