Catalyst-Controlled Regio- and Stereoselective Bromolactonization with Chiral Bifunctional Sulfides

Published as part of the Cluster Organosulfur and Organoselenium Compounds in Catalysis

Abstract

Highly regioselective 5-exo bromolactonizations of stilbene-type carboxylic acids bearing electron-withdrawing substituents are achieved for the first time via the use of chiral bifunctional sulfide catalysts possessing a urea moiety. The chiral phthalide products are obtained in moderate to good enantioselectivities as the result of 5-exo cyclizations.

Catalytic asymmetric reactions with modularly designed organocatalysts are recognized as one of the most effective methods to produce important chiral molecules in highly enantioenriched form.[1] Various types of chiral organocatalysts have been designed and applied to highly stereoselective transformations over the past two decades. Among these organocatalysts, chiral amines and phosphines are some of the most widely utilized catalysts in catalytic asymmetric synthesis. By comparison with an inordinate number of reactions using chiral amine and phosphine catalysts, examples of efficient asymmetric reactions with chiral sulfide catalysts have remained limited and under-developed.[2] [3] In this context, we became interested in the design of effective chiral sulfide catalysts and successfully developed bifunctional catalysts (S)-4 for highly enantioselective bromolactonizations with stilbene-type carboxylic acids 1 (Scheme [1]).[4] [5] [6] In previous work, we selectively synthesized 3,4-dihydroisocoumarin products 3 via 6-endo cyclization under optimized reaction conditions with selected substrates, and 5-exo products 2 were not formed.[6] During the course of an extension of the substrate scope for the asymmetric bromolactonization of 1, we found that 5-exo cyclization products 2, which possess a phthalide structure as an important structural motif,[7] [8] could be selectively obtained in reactions with stilbene-type carboxylic acids 1 bearing electron-withdrawing substituents (Scheme [1]). Herein, we report catalyst-controlled regio- and stereoselective 5-exo bromolactonizations of compounds 1 with bifunctional chiral sulfides (S)-4.

Table 1 Catalyst Optimization^a

Entry	Cat.	Regioselectivity(2a:3a)b	Yield of 2a (%)c	er of 2a d,e
1	(S)-4a	5.3:1	76	76:24
2	(S)-4b	3.2:1	67	75:25
3	(S)-4c	7.1:1	84	82:18
4	(S)-4d	8.5:1	86	82:18
5	(S)-5a	2.3:1	59	49:51
6	(S)-5b	1.1:1	39	50:50
7	nonef	1.8:1	7	(50:50)

^a Reaction conditions: 1a (0.10 mmol), NBS (0.12 mmol), catalyst (10 mol%, 0.010 mmol), CH₂Cl₂ (2.0 mL), 0 °C, 24 h.

^b Regioselectivities were confirmed via ¹H NMR analysis of the crude reaction mixture.

^c Yield of isolated product 2a.

^d Determined by HPLC analysis on a chiral stationary phase.

^e Enantioselectivities of product 3a were low (lower than 59:41 er).

^f The reaction was performed without a catalyst.

Asymmetric bromolactonization of 1a possessing a trifluoromethyl group was selected as a model reaction in an attempt to develop an effective catalyst for the 5-exo-selective cyclization. Yeung reported that the 5-exo cyclization product 2a was preferentially obtained in the bromolactonization of 1a, with or without catalysts, in low to moderate regioselectivities (2a:3a = 2:1 to 4:1).[5] Our original aim was to improve the regioselectivity via the use of bifunctional sulfide catalysts (S)-4 (Table [1]). An attempted reaction of 1a with N-bromosuccinimide (NBS) in CH₂Cl₂ under the influence of phenylurea-type bifunctional catalyst (S)-4a at 0 °C for 24 hours provided bromolactonization product 2a in a good yield but with moderate levels of regio- and enantioselectivity (Table [1], entry 1). Encouraged by this result, a fine-tuning of the urea moiety on catalyst (S)-4 was performed to improve the regioselectivity. Although the introduction of an arylurea possessing electron-donating groups on the catalyst (4b) caused a reduction in regioselectivity (Table [1], entry 2), catalysts bearing electron-deficient aryl­ureas (4c and 4d) improved the levels of both the regio- and enantioselectivity (Table [1], entries 3 and 4). A higher level of regioselectivity was observed in the reaction with catalyst (S)-4d (Table [1], entry 4). To establish the importance of the urea moiety on catalysts (S)-4, we also examined the reactions with related BINOL-derived catalysts (S)-5a and 5b. Although these catalysts promoted the bromolactonization of 1a, the 5-exo cyclization product was obtained only in low levels of regio- and enantioselectivity (Table [1], entries 5 and 6). Additionally, the reaction without a catalyst proceeded slowly under the reaction conditions with low regio­selectivity (Table [1], entry 7). These results clearly suggested that the urea moiety of catalysts (S)-4 was essential for obtaining good levels of regio- and enantioselectivity in the present 5-exo bromolactonization.[9]

Table 2 Effect of Different Brominating Reagents^a

Entry	X–Br	Regioselectivity (2a:3a)b	Yield of 2a (%)c	er of 2a d,e
1	NBS	8.5:1	86	82:18
2	NBP	13:1	90	71:29
3	DBH	15:1	89	80:20
4	DBI	18:1	92	82:18
5	NBA	3.3:1	71	70:30
6	Br2	1:11	8 (77)f	50:50

^a Reaction conditions: 1a (0.10 mmol), brominating reagent (0.12 mmol), catalyst (S)-4d (10 mol%, 0.010 mmol), CH₂Cl₂ (2.0 mL), 0 °C, 24 h.

^b Regioselectivities were confirmed via ¹H NMR analysis of the crude reaction mixture.

^c Yield of isolated product 2a.

^d Determined by HPLC analysis on a chiral stationary phase.

^e Enantioselectivities of product 3a were low (lower than 59:41 er).

^f The yield in parentheses refers to the isolated yield of product 3a.

We also examined the effect of different brominating reagents under the influence of optimized catalyst (S)-4d (Table [2]). The levels of regio- and enantioselectivity for product 2a depend significantly on the structure of the brominating reagent. Reactions with brominating reagents possessing 5- and 6-membered ring structures generally gave the target 5-exo cyclization product 2a in good to high levels of regioselectivity and with moderate to good levels of enantioselectivity (Table [2], entries 1–4). On the other hand, N-bromoacetamide (NBA), an acyclic brominating reagent, gave product 2a with lower levels of regio- and enantioselectivity (Table [2], entry 5). Interestingly, the 6-endo cyclization product 3a was obtained in good regioselectivity when the reaction was performed with bromine (Br₂) as the brominating reagent, although almost no enantioselectivity was observed (~50:50 er) (Table [2], entry 6).[10] Among these brominating reagents, the highest level of regioselectivity for 2a was observed with dibromoisocyanuric acid (DBI), and the highest levels of enantioselectivity were achieved with NBS and DBI (Table [2], entries 1 and 4).[11]

With the optimum catalyst (S)-4d and reaction conditions in hand, we next studied the substrate scope for the 5-exo-selective bromolactonization of 1 (Scheme [2]).[12] Both NBS and DBI were examined as possible brominating reagents that could provide generality for each substrate. First, we investigated the effect that an electron-withdrawing group (EWG) at the para-position of 1 exerted on an aromatic ring (Ar). The application of stilbene-type carboxylic acids 1 bearing a variety of EWGs produced highly regioselective reactions and products 2a–d in moderate to good levels of enantioselectivity. In general, the reactions with DBI provided higher levels of regioselectivity with slightly lower levels of enantioselectivity than those of the reactions with NBS. The reactions of compounds 1 possessing EWGs at the meta- and ortho-positions were also examined, and products 2e–g were obtained with high levels of regio­selectivity. On the other hand, the reactions with simple substrate 1h (Ar = Ph), without an EWG, produced bromolactonization products 2h and 3h with low levels of regioselectivity, and 6-endo cyclization product 3h was the major product even under the optimum reaction conditions for 5-exo cyclization. It should be noted that a completely regio­selective reaction to produce 3h in a highly enantioselective manner was achieved with catalyst (S)-4a under low reaction temperature conditions.[6] These opposite trends in regioselectivity can be explained by the nature of the substrates (Figure [1]). When the reaction was performed with a simple substrate, 1h (Ar = Ph), 6-endo cyclization was favored due to stabilization by the cationic nature of the benzylic carbon of the phenyl group (A in Figure [1]). On the other hand, the introduction of an EWG on the aryl moiety (Ar) destabilized the cationic nature of the benzylic carbon. As a result, 5-exo cyclization was favored slightly more than 6-endo cyclization (B in Figure [1]). This trend for the production of 5-exo bromolactonization products 2 was enhanced by the reactions using urea-type bifunctional sulfide catalysts (S)-4, due to the formation of a well-organized intermediate (C in Figure [1]).[6] The substituent effects on the other aromatic ring (Y) of 1 were also examined to produce 2i–l (Scheme [2]). Even with the introduction of EWGs to another aromatic ring (Y), the reactions proceeded with good levels of regioselectivity to give 2i and 2j. The products 2k and 2l possessed electron-donating groups and were obtained in good levels of regio- and enantioselectivity.

In summary, we have successfully achieved hitherto unknown, highly regioselective 5-exo bromolactonizations of stilbene-type carboxylic acids 1 bearing EWGs under the influence of urea-type chiral bifunctional sulfide catalysts (S)-4. The target chiral phthalide products 2 were obtained with moderate to good levels of enantioselectivity. The bifunctional design of catalysts (S)-4 with a urea moiety was essential in obtaining good levels of regio- and enantioselectivity for the reported 5-exo bromolactonization.

• References and Notes


For reviews on organocatalysis, see:
• 1a Dalko PI, Moisan L. Angew. Chem. Int. Ed. 2001; 40: 3726
  CrossrefPubMedSearch in Google Scholar
• 1b Dalko PI, Moisan L. Angew. Chem. Int. Ed. 2004; 43: 5138
  CrossrefPubMedSearch in Google Scholar
• 1c MacMillan DW. C. Nature 2008; 455: 304
  Search in Google Scholar
• 1d Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications. Dalko PI. Wiley-VCH; Weinheim: 2013
  Search in Google Scholar

For reviews on chiral sulfide catalysts, see:
• 2a Aggarwal VK. Synlett 1998; 329
  Thieme Connect
• 2b Aggarwal VK, Winn CL. Acc. Chem. Res. 2004; 37: 611
  CrossrefPubMedSearch in Google Scholar
• 2c McGarrigle EM, Myers EL, Illa O, Shaw MA, Riches SL, Aggarwal VK. Chem. Rev. 2007; 107: 5841
  CrossrefPubMedSearch in Google Scholar
• 2d Gómez Arrayás R, Carretero JC. Chem. Commun. 2011; 47: 2207
  CrossrefPubMedSearch in Google Scholar
• 2e Luo J, Liu X, Zhao X. Synlett 2017; 28: 397
  Thieme ConnectSearch in Google Scholar

For recent examples of chiral sulfide catalysts, see:
• 3a Wu H.-Y, Chang C.-W, Chein R.-J. J. Org. Chem. 2013; 78: 5788
  CrossrefPubMedSearch in Google Scholar
• 3b Ke Z, Tan CK, Chen F, Yeung Y.-Y. J. Am. Chem. Soc. 2014; 136: 5627
  CrossrefPubMedSearch in Google Scholar
• 3c Ke Z, Tan CK, Liu Y, Lee KG. Z, Yeung Y.-Y. Tetrahedron 2016; 72: 2683
  CrossrefSearch in Google Scholar
• 3d Liu X, An R, Zhang X, Luo J, Zhao X. Angew. Chem. Int. Ed. 2016; 55: 5846
  CrossrefPubMedSearch in Google Scholar
• 3e Li Q.-Z, Zhang X, Zeng R, Dai Q.-S, Liu Y, Shen X.-D, Leng H.-J, Yang K.-C, Li J.-L. Org. Lett. 2018; 20: 3700
  CrossrefPubMedSearch in Google Scholar
• 3f Cao Q, Luo J, Zhao X. Angew. Chem. Int. Ed. 2019; 58: 1315
  CrossrefPubMedSearch in Google Scholar
• 3g Okada M, Kaneko K, Yamanaka M, Shirakawa S. Org. Biomol. Chem. 2019; 17: 3747
  CrossrefPubMedSearch in Google Scholar

For reviews on catalytic asymmetric halolactonization, see:
• 4a Chen G, Ma S. Angew. Chem. Int. Ed. 2010; 49: 8306
  CrossrefPubMedSearch in Google Scholar
• 4b Tan CK, Zhou L, Yeung Y.-Y. Synlett 2011; 1335
  Thieme Connect
• 4c Castellanos A, Fletcher SP. Chem. Eur. J. 2011; 17: 5766
  CrossrefPubMedSearch in Google Scholar
• 4d Denmark SE, Kuester WE, Burk MT. Angew. Chem. Int. Ed. 2012; 51: 10938
  CrossrefPubMedSearch in Google Scholar
• 4e Hennecke U. Chem. Asian J. 2012; 7: 456
  CrossrefPubMedSearch in Google Scholar
• 4f Tan CK, Yeung Y.-Y. Chem. Commun. 2013; 49: 7985
  CrossrefPubMedSearch in Google Scholar
• 4g Murai K, Fujioka H. Heterocycles 2013; 87: 763
  CrossrefSearch in Google Scholar
• 4h Tan CK, Yu WZ, Yeung Y.-Y. Chirality 2014; 26: 328
  CrossrefPubMedSearch in Google Scholar
• 4i Zheng S, Schienebeck CM, Zhang W, Wang H.-Y, Tang W. Asian J. Org. Chem. 2014; 3: 366
  CrossrefSearch in Google Scholar
• 4j Cheng YA, Yu WZ, Yeung Y.-Y. Org. Biomol. Chem. 2014; 12: 2333
  CrossrefPubMedSearch in Google Scholar
• 4k Tripathi CB, Mukherjee S. Synlett 2014; 25: 163
  Thieme ConnectSearch in Google Scholar
• 4l Sakakura A, Ishihara K. Chem. Rec. 2015; 15: 728
  CrossrefPubMedSearch in Google Scholar
• 4m Gieuw MH, Ke Z, Yeung Y.-Y. Chem. Rec. 2017; 17: 287
  CrossrefPubMedSearch in Google Scholar
• 4n Kawato Y, Hamashima Y. Synlett 2018; 29: 1257
  Thieme ConnectSearch in Google Scholar
• 4o Kristianslund R, Tungen JE, Hansen TV. Org. Biomol. Chem. 2019; 17: 3079
  CrossrefPubMedSearch in Google Scholar
• 5a Chen J, Zhou L, Tan CK, Yeung Y.-Y. J. Org. Chem. 2012; 77: 999
  CrossrefPubMedSearch in Google Scholar
• 5b Chen T, Yeung Y.-Y. Org. Biomol. Chem. 2016; 14: 4571
  CrossrefPubMedSearch in Google Scholar
• 6 Nishiyori R, Tsuchihashi A, Mochizuki A, Kaneko K, Yamanaka M, Shirakawa S. Chem. Eur. J. 2018; 24: 16747
  CrossrefPubMedSearch in Google Scholar

For reviews on phthalides, see:
• 7a Beck JJ, Chou S.-C. J. Nat. Prod. 2007; 70: 891
  CrossrefPubMedSearch in Google Scholar
• 7b Karmakar R, Pahari P, Mal D. Chem. Rev. 2014; 114: 6213
  CrossrefPubMedSearch in Google Scholar

For examples of catalytic asymmetric synthesis of chiral phthalides, see:
• 8a Kitamura M, Ohkuma T, Inoue S, Sayo N, Kumobayashi H, Akutagawa S, Ohta T, Takaya H, Noyori R. J. Am. Chem. Soc. 1988; 110: 629
  CrossrefSearch in Google Scholar
• 8b Everaere K, Scheffler J.-L, Mortreux A, Carpentier J.-F. Tetrahedron Lett. 2001; 42: 1899
  CrossrefSearch in Google Scholar
• 8c Lei J.-G, Hong R, Yuan S.-G, Lin G.-Q. Synlett 2002; 927
• 8d Tanaka K, Nishida G, Wada A, Noguchi K. Angew. Chem. Int. Ed. 2004; 43: 6510
  CrossrefPubMedSearch in Google Scholar
• 8e Chang H.-T, Jeganmohan M, Cheng C.-H. Chem. Eur. J. 2007; 13: 4356
  CrossrefPubMedSearch in Google Scholar
• 8f Tanaka K, Osaka T, Noguchi K, Hirano M. Org. Lett. 2007; 9: 1307
  CrossrefPubMedSearch in Google Scholar
• 8g Luo J, Wang H, Zhong F, Kwiatkowski J, Xu L.-W, Lu Y. Chem. Commun. 2012; 48: 4707
  CrossrefPubMedSearch in Google Scholar
• 8h Zhong F, Luo J, Chen G.-Y, Dou X, Lu Y. J. Am. Chem. Soc. 2012; 134: 10222
  CrossrefPubMedSearch in Google Scholar
• 8i Luo J, Jiang C, Wang H, Xu L.-W, Lu Y. Tetrahedron Lett. 2013; 54: 5261
  CrossrefSearch in Google Scholar
• 8j Luo J, Wang H, Zhong F, Kwiatkowski J, Xu L.-W, Lu Y. Chem. Commun. 2013; 49: 5775
  CrossrefPubMedSearch in Google Scholar
• 8k Liu R, Jin R, An J, Zhao Q, Cheng T, Liu G. Chem. Asian J. 2014; 9: 1388
  CrossrefPubMedSearch in Google Scholar
• 8l Han X, Dong C, Zhou H.-B. Adv. Synth. Catal. 2014; 356: 1275
  CrossrefSearch in Google Scholar
• 8m Parmar D, Maji MS, Rueping M. Chem. Eur. J. 2014; 20: 83
  CrossrefPubMedSearch in Google Scholar
• 8n Egami H, Asada J, Sato K, Hashizume D, Kawato Y, Hamashima Y. J. Am. Chem. Soc. 2015; 137: 10132
  CrossrefPubMedSearch in Google Scholar
• 8o Gelat F, Coffinet M, Lebrun S, Agbossou-Niedercorn F, Michon C, Deniau E. Tetrahedron: Asymmetry 2016; 27: 980
  CrossrefSearch in Google Scholar
• 8p Kong L, Zhao J, Cheng T, Lin J, Liu G. ACS Catal. 2016; 6: 2244
  CrossrefSearch in Google Scholar
• 8q Liu W, Hu Z.-P, Yan Y, Liao W.-W. Tetrahedron Lett. 2018; 59: 3132
  CrossrefSearch in Google Scholar
• 8r Cabrera JM, Tauber J, Krische MJ. Angew. Chem. Int. Ed. 2018; 57: 1390
  CrossrefPubMedSearch in Google Scholar
• 9 For the reaction with catalyst (S)-4d at low temperature and the reaction with another different catalyst, see Schemes S1 and S2 in the Supporting Information.
• 10 The reaction with bromine (Br₂) may proceed via a non-catalyzed reaction pathway (background reaction pathway). For a reaction using another reactive brominating reagent, see Scheme S3 in the Supporting Information.
• 11 For other control experiments, see Scheme S4 in the Supporting Information.
• 12 Asymmetric Bromolactonizations; General Procedure A solution of substrate 1 (0.10 mmol) and catalyst (S)-4d (10 mol%, 0.010 mmol) in CH₂Cl₂ (2 mL) was cooled to 0 °C. After stirring for 10 min, N-bromosuccinimide (NBS) (0.12 mmol) was added and the resulting mixture was stirred for 24 h at 0 °C. The mixture was quenched with saturated aqueous Na₂SO₃ (4.0 mL) at 0 °C, stirred for 10 min at 0 °C, diluted with CH₂Cl₂ (2 mL) and H₂O (2 mL) and then warmed to room temperature. The organic materials were extracted with CH₂Cl₂ (3 × 5 mL) and the combined extracts dried over Na₂SO₄ and concentrated. (The ¹H NMR analysis of the crude reaction mixture was performed at this stage to determine the regioselectivity of the bromolactonization products.) The residue was purified by flash column chromatography on silica gel (hexane/EtOAc as eluent) to give product 2. The enantioselectivity of the product 2 was determined by HPLC analysis on a chiral stationary phase. Compound 2a⁵ Yield: 31.9 mg (86%); colorless oil; [α]_D ²¹ +4.4 (c = 0.87, CHCl₃); 82:18 er; HPLC (Daicel Chiralpak IC-3, hexane/2-propanol = 10:1, flow rate = 0.5 mL/min, 230 nm): t _R = 59.3 min (major) and 68.8 min (minor). IR (neat): 1769, 1324, 1286, 1167, 1124, 1114, 1067, 1018 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.85 (d, J = 7.2 Hz, 1 H), 7.67–7.71 (m, 2 H), 7.53–7.60 (m, 5 H), 5.96 (d, J = 6.4 Hz, 1 H), 5.16 (d, J = 6.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.9, 146.0, 140.1, 134.1, 131.1 (q, J = 32.1 Hz), 130.2, 129.0, 126.5, 126.0 (q, J = 2.5 Hz), 125.7 (m), 123.7, 123.6 (q, J = 272 Hz), 82.1, 51.8.

• References and Notes


For reviews on organocatalysis, see:
• 1a Dalko PI, Moisan L. Angew. Chem. Int. Ed. 2001; 40: 3726
  CrossrefPubMedSearch in Google Scholar
• 1b Dalko PI, Moisan L. Angew. Chem. Int. Ed. 2004; 43: 5138
  CrossrefPubMedSearch in Google Scholar
• 1c MacMillan DW. C. Nature 2008; 455: 304
  Search in Google Scholar
• 1d Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications. Dalko PI. Wiley-VCH; Weinheim: 2013
  Search in Google Scholar

For reviews on chiral sulfide catalysts, see:
• 2a Aggarwal VK. Synlett 1998; 329
  Thieme Connect
• 2b Aggarwal VK, Winn CL. Acc. Chem. Res. 2004; 37: 611
  CrossrefPubMedSearch in Google Scholar
• 2c McGarrigle EM, Myers EL, Illa O, Shaw MA, Riches SL, Aggarwal VK. Chem. Rev. 2007; 107: 5841
  CrossrefPubMedSearch in Google Scholar
• 2d Gómez Arrayás R, Carretero JC. Chem. Commun. 2011; 47: 2207
  CrossrefPubMedSearch in Google Scholar
• 2e Luo J, Liu X, Zhao X. Synlett 2017; 28: 397
  Thieme ConnectSearch in Google Scholar

For recent examples of chiral sulfide catalysts, see:
• 3a Wu H.-Y, Chang C.-W, Chein R.-J. J. Org. Chem. 2013; 78: 5788
  CrossrefPubMedSearch in Google Scholar
• 3b Ke Z, Tan CK, Chen F, Yeung Y.-Y. J. Am. Chem. Soc. 2014; 136: 5627
  CrossrefPubMedSearch in Google Scholar
• 3c Ke Z, Tan CK, Liu Y, Lee KG. Z, Yeung Y.-Y. Tetrahedron 2016; 72: 2683
  CrossrefSearch in Google Scholar
• 3d Liu X, An R, Zhang X, Luo J, Zhao X. Angew. Chem. Int. Ed. 2016; 55: 5846
  CrossrefPubMedSearch in Google Scholar
• 3e Li Q.-Z, Zhang X, Zeng R, Dai Q.-S, Liu Y, Shen X.-D, Leng H.-J, Yang K.-C, Li J.-L. Org. Lett. 2018; 20: 3700
  CrossrefPubMedSearch in Google Scholar
• 3f Cao Q, Luo J, Zhao X. Angew. Chem. Int. Ed. 2019; 58: 1315
  CrossrefPubMedSearch in Google Scholar
• 3g Okada M, Kaneko K, Yamanaka M, Shirakawa S. Org. Biomol. Chem. 2019; 17: 3747
  CrossrefPubMedSearch in Google Scholar

For reviews on catalytic asymmetric halolactonization, see:
• 4a Chen G, Ma S. Angew. Chem. Int. Ed. 2010; 49: 8306
  CrossrefPubMedSearch in Google Scholar
• 4b Tan CK, Zhou L, Yeung Y.-Y. Synlett 2011; 1335
  Thieme Connect
• 4c Castellanos A, Fletcher SP. Chem. Eur. J. 2011; 17: 5766
  CrossrefPubMedSearch in Google Scholar
• 4d Denmark SE, Kuester WE, Burk MT. Angew. Chem. Int. Ed. 2012; 51: 10938
  CrossrefPubMedSearch in Google Scholar
• 4e Hennecke U. Chem. Asian J. 2012; 7: 456
  CrossrefPubMedSearch in Google Scholar
• 4f Tan CK, Yeung Y.-Y. Chem. Commun. 2013; 49: 7985
  CrossrefPubMedSearch in Google Scholar
• 4g Murai K, Fujioka H. Heterocycles 2013; 87: 763
  CrossrefSearch in Google Scholar
• 4h Tan CK, Yu WZ, Yeung Y.-Y. Chirality 2014; 26: 328
  CrossrefPubMedSearch in Google Scholar
• 4i Zheng S, Schienebeck CM, Zhang W, Wang H.-Y, Tang W. Asian J. Org. Chem. 2014; 3: 366
  CrossrefSearch in Google Scholar
• 4j Cheng YA, Yu WZ, Yeung Y.-Y. Org. Biomol. Chem. 2014; 12: 2333
  CrossrefPubMedSearch in Google Scholar
• 4k Tripathi CB, Mukherjee S. Synlett 2014; 25: 163
  Thieme ConnectSearch in Google Scholar
• 4l Sakakura A, Ishihara K. Chem. Rec. 2015; 15: 728
  CrossrefPubMedSearch in Google Scholar
• 4m Gieuw MH, Ke Z, Yeung Y.-Y. Chem. Rec. 2017; 17: 287
  CrossrefPubMedSearch in Google Scholar
• 4n Kawato Y, Hamashima Y. Synlett 2018; 29: 1257
  Thieme ConnectSearch in Google Scholar
• 4o Kristianslund R, Tungen JE, Hansen TV. Org. Biomol. Chem. 2019; 17: 3079
  CrossrefPubMedSearch in Google Scholar
• 5a Chen J, Zhou L, Tan CK, Yeung Y.-Y. J. Org. Chem. 2012; 77: 999
  CrossrefPubMedSearch in Google Scholar
• 5b Chen T, Yeung Y.-Y. Org. Biomol. Chem. 2016; 14: 4571
  CrossrefPubMedSearch in Google Scholar
• 6 Nishiyori R, Tsuchihashi A, Mochizuki A, Kaneko K, Yamanaka M, Shirakawa S. Chem. Eur. J. 2018; 24: 16747
  CrossrefPubMedSearch in Google Scholar

For reviews on phthalides, see:
• 7a Beck JJ, Chou S.-C. J. Nat. Prod. 2007; 70: 891
  CrossrefPubMedSearch in Google Scholar
• 7b Karmakar R, Pahari P, Mal D. Chem. Rev. 2014; 114: 6213
  CrossrefPubMedSearch in Google Scholar

For examples of catalytic asymmetric synthesis of chiral phthalides, see:
• 8a Kitamura M, Ohkuma T, Inoue S, Sayo N, Kumobayashi H, Akutagawa S, Ohta T, Takaya H, Noyori R. J. Am. Chem. Soc. 1988; 110: 629
  CrossrefSearch in Google Scholar
• 8b Everaere K, Scheffler J.-L, Mortreux A, Carpentier J.-F. Tetrahedron Lett. 2001; 42: 1899
  CrossrefSearch in Google Scholar
• 8c Lei J.-G, Hong R, Yuan S.-G, Lin G.-Q. Synlett 2002; 927
• 8d Tanaka K, Nishida G, Wada A, Noguchi K. Angew. Chem. Int. Ed. 2004; 43: 6510
  CrossrefPubMedSearch in Google Scholar
• 8e Chang H.-T, Jeganmohan M, Cheng C.-H. Chem. Eur. J. 2007; 13: 4356
  CrossrefPubMedSearch in Google Scholar
• 8f Tanaka K, Osaka T, Noguchi K, Hirano M. Org. Lett. 2007; 9: 1307
  CrossrefPubMedSearch in Google Scholar
• 8g Luo J, Wang H, Zhong F, Kwiatkowski J, Xu L.-W, Lu Y. Chem. Commun. 2012; 48: 4707
  CrossrefPubMedSearch in Google Scholar
• 8h Zhong F, Luo J, Chen G.-Y, Dou X, Lu Y. J. Am. Chem. Soc. 2012; 134: 10222
  CrossrefPubMedSearch in Google Scholar
• 8i Luo J, Jiang C, Wang H, Xu L.-W, Lu Y. Tetrahedron Lett. 2013; 54: 5261
  CrossrefSearch in Google Scholar
• 8j Luo J, Wang H, Zhong F, Kwiatkowski J, Xu L.-W, Lu Y. Chem. Commun. 2013; 49: 5775
  CrossrefPubMedSearch in Google Scholar
• 8k Liu R, Jin R, An J, Zhao Q, Cheng T, Liu G. Chem. Asian J. 2014; 9: 1388
  CrossrefPubMedSearch in Google Scholar
• 8l Han X, Dong C, Zhou H.-B. Adv. Synth. Catal. 2014; 356: 1275
  CrossrefSearch in Google Scholar
• 8m Parmar D, Maji MS, Rueping M. Chem. Eur. J. 2014; 20: 83
  CrossrefPubMedSearch in Google Scholar
• 8n Egami H, Asada J, Sato K, Hashizume D, Kawato Y, Hamashima Y. J. Am. Chem. Soc. 2015; 137: 10132
  CrossrefPubMedSearch in Google Scholar
• 8o Gelat F, Coffinet M, Lebrun S, Agbossou-Niedercorn F, Michon C, Deniau E. Tetrahedron: Asymmetry 2016; 27: 980
  CrossrefSearch in Google Scholar
• 8p Kong L, Zhao J, Cheng T, Lin J, Liu G. ACS Catal. 2016; 6: 2244
  CrossrefSearch in Google Scholar
• 8q Liu W, Hu Z.-P, Yan Y, Liao W.-W. Tetrahedron Lett. 2018; 59: 3132
  CrossrefSearch in Google Scholar
• 8r Cabrera JM, Tauber J, Krische MJ. Angew. Chem. Int. Ed. 2018; 57: 1390
  CrossrefPubMedSearch in Google Scholar
• 9 For the reaction with catalyst (S)-4d at low temperature and the reaction with another different catalyst, see Schemes S1 and S2 in the Supporting Information.
• 10 The reaction with bromine (Br₂) may proceed via a non-catalyzed reaction pathway (background reaction pathway). For a reaction using another reactive brominating reagent, see Scheme S3 in the Supporting Information.
• 11 For other control experiments, see Scheme S4 in the Supporting Information.
• 12 Asymmetric Bromolactonizations; General Procedure A solution of substrate 1 (0.10 mmol) and catalyst (S)-4d (10 mol%, 0.010 mmol) in CH₂Cl₂ (2 mL) was cooled to 0 °C. After stirring for 10 min, N-bromosuccinimide (NBS) (0.12 mmol) was added and the resulting mixture was stirred for 24 h at 0 °C. The mixture was quenched with saturated aqueous Na₂SO₃ (4.0 mL) at 0 °C, stirred for 10 min at 0 °C, diluted with CH₂Cl₂ (2 mL) and H₂O (2 mL) and then warmed to room temperature. The organic materials were extracted with CH₂Cl₂ (3 × 5 mL) and the combined extracts dried over Na₂SO₄ and concentrated. (The ¹H NMR analysis of the crude reaction mixture was performed at this stage to determine the regioselectivity of the bromolactonization products.) The residue was purified by flash column chromatography on silica gel (hexane/EtOAc as eluent) to give product 2. The enantioselectivity of the product 2 was determined by HPLC analysis on a chiral stationary phase. Compound 2a⁵ Yield: 31.9 mg (86%); colorless oil; [α]_D ²¹ +4.4 (c = 0.87, CHCl₃); 82:18 er; HPLC (Daicel Chiralpak IC-3, hexane/2-propanol = 10:1, flow rate = 0.5 mL/min, 230 nm): t _R = 59.3 min (major) and 68.8 min (minor). IR (neat): 1769, 1324, 1286, 1167, 1124, 1114, 1067, 1018 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.85 (d, J = 7.2 Hz, 1 H), 7.67–7.71 (m, 2 H), 7.53–7.60 (m, 5 H), 5.96 (d, J = 6.4 Hz, 1 H), 5.16 (d, J = 6.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.9, 146.0, 140.1, 134.1, 131.1 (q, J = 32.1 Hz), 130.2, 129.0, 126.5, 126.0 (q, J = 2.5 Hz), 125.7 (m), 123.7, 123.6 (q, J = 272 Hz), 82.1, 51.8.

• Supplementary Material