Synthesis of Novel C ₂-Symmetric Sulfur-Based Catalysts: Asymmetric Formation of Halo- and Seleno-Functionalized Normal- and Medium-Sized Rings

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

Abstract

The synthesis of novel, highly functionalized, C ₂-symmetric sulfur-based catalysts is developed and their catalytic applications are explored in asymmetric bromo-, iodo- and seleno-functionalizations of alkenoic acids. This protocol provides the corresponding normal- and medium-sized bromo, iodo and selenolactones in up to 98% yield and 83% stereoselectivity.

Key words

alkenoic acids - organosulfur catalysts - asymmetric catalysis - halolactones - selenolactones

The group 16 donor atoms sulfur (S), selenium (Se) and tellurium (Te) act as Lewis bases. The Lewis base catalyzed halogenation of organic substrates, in which an n–σ* interaction between a Lewis base chalcogenide and a Lewis acidic halogen source leads to an electrophilic halogen species, has been well documented in the literature.[1] Denmark et al. established a variety of chiral and achiral Lewis bases, such as selenides and sulfides, for the activation of halogens.[2] In recent decades, various research groups have been involved in the development of catalytic halocyclization reactions by utilizing chalcogenide-based catalysts.[3] [4] In 2012, Yeung and co-workers reported the synthesis of medium-ring-sized seven-membered bromolactones using a sulfur-based organocatalyst.[5] However, catalytic asymmetric halogenation of medium-sized rings has not yet been explored. In contrast to the enantioselective halogenation of five- and six-membered rings,[6] enantioenriched medium-sized halolactones are rare, despite their potential applications in the synthesis of biologically relevant molecules.[7]

Sulfide-catalyzed electrophilic bromination of various substrates has been achieved. Yeung and co-worker reported the triphenylphosphine sulfide catalyzed bromocyclization of amides to afford oxazolidines and oxazines.[8] Similarly, Mukherjee and Tripathi described selective oxidation of secondary alcohols with NBS using a thiourea derivative as the catalyst.[9] Moreover, Denmark and Burk accomplished the iodolactonization of alkenoic acids with N-iodosuccinimide catalyzed by the Lewis base, n-Bu₃P=S.[3c]

Numerous methodologies have been reported for the catalytic, enantioselective bromofunctionalization of alkenes.[1d] [6c] [10] In 2010, Yeung et al. developed a thiocarbamate which acts as a Lewis base for the enantioselective bromofunctionalization of alkenes. This sulfur-based catalyst has been employed in the cyclization of various disubstituted alkenes to obtain enantioenriched halolactones, 3-bromopyrrolidines, and 3,4-dihydroisocoumarins.[10h,11]

Our group has also been actively involved in selenium-catalyzed halocyclizations of alkenoic acids, where selenium plays a vital role in the transformation.[12] Inspired by our recent development of the regioselective synthesis of medium-sized bromo/iodolactones and bromooxepanes using a catalytic amount of a monoselenide (Scheme [1a]),[12b] herein we present our results on the stereoinduction of normal- and medium-size rings (Scheme [1b]). Studies on catalytic, enantioselective, chalcogenide-catalyzed medium-sized halogenation reactions are still lacking. Furthermore, the cyclization of linear-chain alkenoic acids is not a favorable process due to enthalpic and entropic factors.[12b] Substrates with an alkyl chain possess a high degree of flexibility that brings a negative entropy change during intramolecular cyclization reactions.[13] Therefore, significant research is still required for the preparation of new chiral Lewis bases and diverse structural analogues.

Scheme 1 Chalcogenide-catalyzed halogenation with formation of medium-sized rings

In continuation of our studies on organochalcogen chemistry,[12] [14] we rationalized that the Lewis base sulfur would be able to activate a halogen for the synthesis of highly strained, medium-sized rings. Thus, we have designed a range of novel C ₂-symmetric sulfur-based chiral catalysts for the synthesis of enantioenriched bromolactones. Initially, the bromolactonization of 4-phenyl-4-pentenoic acid (1a) was carried out using 1.2 equivalents of NBS and 5 mol% of the chiral catalyst in dichloromethane at –78 °C. We screened thiophene dicarboxylates such as (–)-menthol-based cat 1 and found that it catalyzed the bromolactonization reaction, however, no enantioselectivity was observed (Scheme [2]).

Scheme 2 Catalyst screening

Further, we attempted to incorporate a nitrogen-based chiral scaffold to make an effective chiral catalyst and chose various cinchona alkaloid as skeletons. However, the resulting catalysts, quinine cat 2 and cinchonine cat 3 (Scheme [2]), had no effect on the enantioselectivity and only racemic mixtures were obtained. Surprisingly, changing the skeleton to dihydroquinine (DHQN) cat 4 (Scheme [2]) resulted in an enantioselectivity (ee) of 31%. To further improve the enantioselectivity, we explored the impact of the ligand on the structure of the catalyst. Two sites in the catalyst were tuned: (i) the ester and amide units, and (ii) the O-alkoxy substituents on the hydroquinine unit, which was accomplished by demethylation followed by alkylation. The C ₂-symmetry of the scaffold also simplified the catalyst design and modification. Moreover, different substituents have been introduced to tune the steric hindrance. The catalyst was modified by demethylation using sodium ethylthiolate followed by incorporation of different alkyl chains such as n-butyl, n-hexyl, tert-butyl, iso-butyl, 2-butane and 2-methylpropane[15] (Scheme [3]). Similarly, the azide formed from the O-mesylated derivative of DHQN followed by azide reduction and hydrolysis provided 9-amino-(9-deoxy)-epi-cinchona alkaloids (DHQN-NH₂).[16] Thus, the alkoxy or amine derivative of the cinchona alkaloid was treated with 2,5-thiophenedicarbonyl dichloride under basic conditions to afford catalysts cat 5–9 and cat 10–12, respectively. These bifunctional sulfur-based catalysts were then subjected to the asymmetric bromocyclization reaction.

Scheme 3 Synthesis of modified catalysts

Table 1 Optimization of the Reaction Conditions^a

Entry	Cat.	Solvent	Time (h)	Yield (%)b	ee (%)c
1	cat 5	CH2Cl2	16	88	36
2	cat 5	toluene	20	75	15
3	cat 5	CHCl3	28	85	34
4	cat 5	hexane	30	80	45
5	cat 5	toluene/CH2Cl2 (1:1)	35	87	38
6	cat 5	CHCl3/toluene (1:1)	32	85	62
7	cat 5	CHCl3/toluene (1:2)	10	81	44
8	cat 5	CHCl3/hexane (1:1)	24	90	60
9	cat 5	CHCl3/hexane (1:2)	31	97	83
10	cat 6	CHCl3/hexane (1:2)	88	92	60
11	cat 7	CHCl3/hexane (1:2)	68	87	55
12	cat 8	CHCl3/hexane (1:2)	80	89	66
13	cat 9	CHCl3/hexane (1:2)	50	92	45
14	cat 11	CHCl3/hexane (1:2)	40	85	52

^a All reactions were carried out with 1a (0.1 mmol), NBS (0.12 mmol) and the chiral catalyst (5 mol%) in 2 mL of solvent at –78 °C in a 10 mL Schlenk tube under nitrogen. The reaction progress was monitored by TLC.

^b Yield of isolated 2a.

^c Enantiopurity was determined by HPLC analysis using a ChiralPak IC-3 column.

When the reaction of 1a and NBS was conducted with C ₂-symmetric sulfur-based cat 5 (5 mol%) in dichloromethane (CH₂Cl₂), the desired bromolactone 2a was obtained in 88% yield with poor enantioselectivity (36% ee) within 16 hours (Table [1], entry 1). Next, various solvent systems were explored to improve the selectivity of the reaction. We observed that among several solvents, including dichloromethane, chloroform and toluene, the reaction in the less polar solvent hexane proceeded with modest enantioselectivity (45% ee) (entries 2–4). On varying the polarity with mixed solvent systems, CHCl₃/hexane (1:2) showed the highest efficiency with an optimum 83% ee being obtained (entries 5–9). The nonpolar solvent mixture reduced the noncatalyzed reaction and strengthened the polar interaction among the alkenoic acid, NBS, and the catalyst, resulting in enhancement of the enantioselectivity. The hexyl substitution on the quinolone moiety of thiophene dicarboxylate cat 6, under the same conditions, gave a lower enantioselectivity (entry 10). Similarly, reactions with cat 7, cat 8 and cat 9 occurred with low enantioselectivity (entries 11–13). Furthermore, screening the efficient isopinocampheylamine/cinchonine framework, endeavoring to increase the acidity of the carboxylate in cat 10–12 by replacement with an amide functional group, however, resulted in a racemic mixture for cat 10, moderate 52% ee for cat 11 (entry 14), and 43% ee for cat 12, respectively. Also, the use of additives failed to improve the stereoselectivity.

Having optimized the catalyst and reaction conditions, we next investigated the substrate scope. A broad range of 4-phenyl-4-pentenoic acids containing aromatic substituents on the olefin was converted into the corresponding bromolactones with high yields and good to moderate enantioselectivities (Figure [1]). In particular, better results were obtained with the substrates 1b and 1c having electron-rich methyl and methoxy groups at the para positions of the aromatic rings, with the lactones 2b and 2c being obtained with 82% and 66% ee, respectively. Electron-deficient fluoro-, chloro-, and difluoro-substituted substrates 1d–f provided bromolactones 2d–f with good enantioselectivities (43–66%). The X-ray crystal structure of 4-fluorophenyl γ-lactone 2d is shown in Figure [1]. Biphenyl-substituted alkenoic acid 1g provided bromolactone 2g with moderate selectivity (27% ee).

Figure 1 Scope of catalytic enantioselective halo/seleno lactonization

When N-iodosuccinimide (NIS) was used as the halogen source, γ-iodolactone 2h was formed with 31% enantiomeric excess. By utilizing this protocol, five-membered selenolactone 2i [17] was also prepared with 13% enantioselectivity and 62% yield. Furthermore, when 5-phenyl-5-hexanoic acid was subjected to the bromocyclization with NBS in the presence of 5 mol% of chiral catalyst 5 in CHCl₃/hexane (1:1) at –60 °C, the desired product 2aa was obtained with 34% ee.

Next, the synthesis of various seven-membered bromo- and iodolactones was explored starting from the corresponding alkenoic acids (Figure [2]). Bromolactone 3a with a phenyl ring attached was obtained as a racemic mixture using the developed protocol. Lactones 3b–i having an additional heteroatom in the chain were obtained in good to excellent yields (22–82%) and moderate to low enantiomeric excesses, which can be attributed to the reduction of transannular strain in the presence of the heteroatom. Electron-withdrawing Cl and NO₂ substituents on the aromatic rings yielded products 3d,e with low enantioselectivities (<20%). Interestingly, electron-donating Me and OMe substituents induced slightly higher enantioselectivities (>30%) in products 3f,g. Polyaromatic bromolactone 3h containing a naphthyl ring was obtained with 14% ee.

Figure 2 Scope of the enantioselective formation of seven-membered bromo/iodolactones

We speculate that the halocyclization reaction proceeds through a rigid transition state model, in which the olefin–olefin halogen exchange[18] and the transannular strain in the ring[13] could be suppressed through Lewis basic sulfur[1] or via hydrogen bond activation. The n-butyl moiety on the quinine scaffold leads to a pocket in which the carboxylic acid of the substrate was deprotonated by the quinine nitrogen of cat 5 to form an ion pair (Scheme [4]). Cat 5 serves as a bifunctional catalyst by interacting with both the carboxylate nucleophile and the NBS electrophile, facilitating 5-exo cyclization to form desired five- to seven-membered halolactones.

Scheme 4 Proposed working model

In conclusion, we have developed a novel C ₂-symmetric sulfur-based chiral catalyst for the enantioselective bromolactonization of alkenoic acids.[19] This protocol allows for the asymmetric synthesis of γ-, δ- and ω-lactones and selenolactones. Further mechanistic studies and investigations of this class of catalysts in another asymmetric electrophilic cyclization reactions are underway.

• References and Notes

• 1a Mellegaard-Waetzig SR, Wang C, Tunge JA. Tetrahedron 2006; 62: 7191
• 1b Ahmad SM, Braddock DC, Cansell G, Hermitage SA. Tetrahedron Lett. 2007; 48: 915
• 1c Castellote I, Morón M, Burgos C, Alvarez-Builla J, Martin A, Gómez-Sal P, Vaquero JJ. Chem. Commun. 2007; 1281
• 1d Zhang W, Xu H, Xu H, Tang W. J. Am. Chem. Soc. 2009; 131: 3832
• 1e Cao L, Ding J, Yin G, Gao M, Li Y, Wu A. Synlett 2009; 1445
• 1f Lewis Base Catalysis in Organic Synthesis, 1^st ed. Vedejs E, Denmark SE. Wiley-VCH; Weinheim: 2016
• 1g Perin G, Barcellos AM, Peglow TJ, Nobre PC, Cargnelutti R, Lenardão EJ, Marini F, Santi C. RSC Adv. 2016; 6: 103657
• 1h Sancineto L, Mangiavacchi F, Tidei C, Bagnoli L, Marini F, Gioiello A, Scianowski J, Santi C. Asian J. Org. Chem. 2017; 6: 988
• 2a Denmark SE, Beutner GL. Angew. Chem. Int. Ed. 2008; 47: 1560
• 2b Denmark SE, Kalyani D, Collins WR. J. Am. Chem. Soc. 2010; 132: 15752
• 2c Denmark SE, Burk MT. Org. Lett. 2012; 14: 256

Electrophilic halogenation catalyzed by Lewis basic chalcogens:
• 3a Mellegaard SR, Tunge JA. J. Org. Chem. 2004; 69: 8979
• 3b Snyder SA, Treitler DS. Angew. Chem. Int. Ed. 2009; 48: 7899
• 3c Denmark SE, Burk MT. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 20655
• 3d Snyder S, Treitler AD. S, Brucks AP. J. Am. Chem. Soc. 2010; 132: 14303
• 3e Chen F, Tan CK, Yeung Y.-Y. J. Am. Chem. Soc. 2013; 135: 1232
• 3f Sawamura Y, Nakatsuji H, Sakakura A, Ishihara K. Chem. Sci. 2013; 4: 4181
• 3g Ke Z, Tan CK, Chen F, Yeung Y.-Y. J. Am. Chem. Soc. 2014; 136: 5627
• 3h Kawato Y, Kubota A, Ono H, Egami H, Hamashima Y. Org. Lett. 2015; 17: 1244
• 3i Ke Z, Tan CK, Liu Y, Lee KG. Z, Yeung Y.-Y. Tetrahedron 2016; 72: 2683
• 3j See JY, Yang H, Zhao Y, Wong MW, Ke Z, Yeung Y.-Y. ACS Catal. 2018; 8: 850

Catalytic halocyclization reactions by sulfur-based catalysts:
• 4a Dowle MD, Davies DI. Chem. Soc. Rev. 1979; 8: 171
• 4b Cardillo G, Orena M. Tetrahedron 1990; 46: 3321
• 4c French AN, Bissmire S, Wirth T. Chem. Soc. Rev. 2004; 33: 354
• 4d Ranganathan S, Muraleedharan KM, Vaish NK, Jayaraman N. Tetrahedron 2004; 60: 5273
• 4e Laya MS, Banerjee AK, Cabrera EV. Curr. Org. Chem. 2009; 13: 720
• 4f Montana AM, Batalla C, Barcia JA, Montana AM, Batalla C. Curr. Org. Chem. 2009; 13: 919
• 4g Chung W.-j, Vanderwal CD. Angew. Chem. Int. Ed. 2016; 55: 4396
• 5 Cheng YA, Chen T, Tan CK, Heng JJ, Yeung Y.-Y. J. Am. Chem. Soc. 2012; 134: 16492

For reviews on enantioselective halofunctionalization, see:
• 6a Denmark SE, Kuester WE, Burk MT. Angew. Chem. Int. Ed. 2012; 51: 10938
• 6b Tan CK, Yeung Y.-Y. Chem. Commun. 2013; 49: 7985
• 6c Cheng YA, Yu WZ, Yeung Y.-Y. Org. Biomol. Chem. 2014; 12: 2333
• 7a Boye AC, Meyer D, Ingison CK, French AN, Wirth T. Org. Lett. 2003; 5: 2157
• 7b Saito B, Fu GC. J. Am. Chem. Soc. 2007; 129: 9602
• 7c Kambe N, Iwasaki T, Terao J. Chem. Soc. Rev. 2011; 40: 4937
• 7d Shiina I. Chem. Rev. 2007; 107: 239
• 7e Gao W.-C, Xiong Z.-Y, Pirhaghani S, Wirth T. Synthesis 2019; 51: 276
• 8a Wong Y.-C, Ke Z, Yeung Y.-Y. Org. Lett. 2015; 17: 4944
• 8b Ke Z, Wong Y.-C, See JY, Yeung Y.-Y. Adv. Synth. Catal. 2016; 358: 1719
• 9a Tripathi CB, Mukherjee S. J. Org. Chem. 2012; 77: 1592
• 9b Tripathi CB, Mukherjee S. Angew. Chem. Int. Ed. 2013; 52: 8450
• 9c Tripathi CB, Mukherjee S. Synlett 2014; 25: 163
• 10a Zhang W, Zheng S, Liu N, Werness JB, Guzei IA, Tang W. J. Am. Chem. Soc. 2010; 132: 3664
• 10b Murai K, Matsushita T, Nakamura A, Fukushima S, Shimura M, Fujioka H. Angew. Chem. Int. Ed. 2010; 49: 9174
• 10c Zhou L, Chen J, Tan CK, Yeung YY. J. Am. Chem. Soc. 2011; 133: 9164
• 10d Castellanos A, Fletcher SP. Chem. Eur. J. 2011; 17: 5766
• 10e Jiang X, Tan CK, Zhou L, Yeung YY. Angew. Chem. Int. Ed. 2012; 51: 7771
• 10f Hennecke U. Chem. Asian J. 2012; 7: 456
• 10g Zhang W, Liu N, Schienebeck CM, Decloux K, Zheng S, Werness JB, Tang W. Chem. Eur. J. 2012; 18: 7296
• 10h Tan CK, Le C, Yeung YY. Chem. Commun. 2012; 48: 5793
• 10i Zhou L, Tay DW, Chen J, Leung GY, Yeung YY. Chem. Commun. 2013; 49: 4412
• 10j Fujioka H, Murai K. Heterocycles 2013; 87: 763
• 10k Armstrong A, Braddock DC, Jones AX, Clark S. Tetrahedron Lett. 2013; 54: 7004
• 10l Tan CK, Yu WZ, Yeung Y.-Y. Chirality 2014; 26: 328
• 10m Zheng S, Schienebeck CM, Zhang W, Wang H.-Y, Tang W. Asian J. Org. Chem. 2014; 3: 366
• 10n Tay DW, Leung GY, Yeung YY. Angew. Chem. Int. Ed. 2014; 53: 5161
• 10o Tan CK, Er JC, Yeung Y.-Y. Tetrahedron Lett. 2014; 55: 1243
• 10p Denmark SE, Burk MT. Chirality 2014; 26: 344
• 10q Chen T, Foo TJ. Y, Yeung Y.-Y. ACS Catal. 2015; 5: 4751
• 10r Samanta RC, Yamamoto H. J. Am. Chem. Soc. 2017; 139: 1460
• 10s Gieuw MH, Ke Z, Yeung YY. Chem. Rec. 2017; 17: 287

Catalytic asymmetric bromolactonization:
• 11a Zhou L, Tan CK, Jiang X, Chen F, Yeung Y.-Y. J. Am. Chem. Soc. 2010; 132: 15474
• 11b Tan CK, Zhou L, Yeung Y.-Y. Org. Lett. 2011; 13: 2738
• 11c Chen J, Zhou L, Yeung Y.-Y. Org. Biomol. Chem. 2012; 10: 3808
• 11d Chen J, Zhou L, Tan CK, Yeung Y.-Y. J. Org. Chem. 2012; 77: 999
• 12a Balkrishna SJ, Prasad CD, Panini P, Detty MR, Chopra D, Kumar S. J. Org. Chem. 2012; 77: 9541
• 12b Verma A, Jana S, Durga Prasad C, Yadav A, Kumar S. Chem. Commun. 2016; 52: 4179
• 12c Balkrishna SJ, Kumar S, Kumar A, Panini P, Kumar S. Proc. Natl. Acad. Sci., India Sect. A: Phys. Sci. 2016; 86: 589
• 13 Illuminati G, Mandolini L. Acc. Chem. Res. 1981; 14: 95
• 14a Kumar S, Yan J, Poon J.-F, Singh VP, Lu X, Ott MK, Engman L, Kumar S. Angew. Chem. Int. Ed. 2016; 55: 3729
• 14b Prasad ChD, Sattar M, Kumar S. Org. Lett. 2017; 19: 774
• 14c Rathore V, Upadhyay A, Kumar S. Org. Lett. 2018; 20: 6274
• 15a Li H, Wang Y, Tang L, Deng L. J. Am. Chem. Soc. 2004; 126: 9906
• 15b Liu X, Li H, Deng L. Org. Lett. 2005; 7: 167
• 15c Choudhury AR, Mukherjee S. Org. Biomol. Chem. 2012; 10: 7313
• 16 Cassani C, Martín-Rapún R, Arceo E, Bravo F, Melchiorre P. Nat. Protoc. 2013; 8: 325
• 17a Khokhar SS, Wirth T. Eur. J. Org. Chem. 2004; 4567
• 17b Khokhar SS, Wirth T. Angew. Chem. Int. Ed. 2004; 43: 631
• 17c Niu W, Yeung Y.-Y. Org. Lett. 2015; 17: 1660
• 18a Brown RS, Nagorski RW, Bennet AJ, McClung RE. D, Aarts GH. M, Klobukowski M, McDonald R, Santarsiero BD. J. Am. Chem. Soc. 1994; 116: 2448
• 18b Neverov A, Brown RS. J. Org. Chem. 1996; 61: 962
• 18c Brown RS. Acc. Chem. Res. 1997; 30: 131
• 18d Denmark SE, Burk MT, Hoover AJ. J. Am. Chem. Soc. 2010; 132: 1232
• 19 Catalyst Preparation To a stirred solution of 2,5-thiophenedicarbonyl dichloride (1.0 equiv, 1.0 mmol, 209 mg) in CH₂Cl₂ (20 mL) at 0 °C were added dropwise the alkyl derivative of the cinchona alkaloid (2.1 equiv, 2.1 mmol) and Et₃N (4.0 equiv, 4.0 mmol) in CH₂Cl₂ (15 mL) using a dropping funnel. After the addition was complete, the mixture was stirred for 6 h at 0 °C to room temperature. After completion of the reaction, saturated NaHCO₃ solution (20 mL) was added to the mixture. The resulting solution was extracted with CH₂Cl₂ (3 × 20 mL) and the combined organic layer washed with brine (20 mL), dried over Na₂SO₄ and concentrated on a rotary evaporator under vacuum. The resulting solid was purified by column chromatography with CH₂Cl₂/MeOH (10:1). 2-{(1S)-(6-Butoxyquinolin-4-yl)[(2S)-5-ethylquinuclidin-2-yl]methyl} 5-{(1S)-(6-Butoxyquinolin-4-yl)[(2S,4S,5R)-5-ethylquinuclidin-2-yl]methyl} Thiophene-2,5-dicarboxylate (Cat 5) White solid; yield: 576 mg (66%); mp 147–150 °C; [α]_D ¹⁹.⁴ +24.9 (c 0.33, CHCl₃). IR (plate): 1722, 1715, 1620, 1596, 1530, 1507, 1462, 1448, 1362, 1320, 1241 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.69 (d, J = 4.49 Hz, 2 H), 8.00 (d, J = 9.15 Hz, 2 H), 7.79 (s, 2 H), 7.41–7.35 (m, 6 H), 6.67 (d, J = 1.48 Hz, 2 H), 4.17–4.08 (m, 4 H), 3.43–3.38 (m, 2 H), 3.06 (q, J = 12.64 Hz, 2 H), 2.69–2.64 (m, 2 H), 2.36 (d, J = 12.96 Hz, 2 H), 1.87–1.71 (m, 12 H), 1.66–1.62 (m, 2 H), 1.58–1.49 (m, 6 H), 1.45–1.40 (m, 2 H), 1.37–1.25 (m, 4 H), 0.98 (t, J = 7.35 Hz, 6 H), 0.83 (t, J = 7.25 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 160.3, 157.7, 147.2, 144.6, 142.8, 138.8, 133.7, 131.8, 126.7, 122.4, 118.3, 101.8, 75.7, 68.1, 59.0, 58.5, 42.8, 37.3, 31.2, 28.5, 27.7, 25.3, 23.6, 19.3, 13.8, 12.0. HRMS (ESI): m/z [M + H]⁺ calcd for C₅₂H₆₄N₄O₆S: 873.4618; found: 873.4619. Halolactones 2 and 3 To a solution of alkenoic acid (1.0 equiv, 0.1 mmol) and catalyst cat 5 (0.05 equiv, 0.005 mmol, 4.6 mg) in a mixture of CHCl₃ (2 mL) and hexane (4 mL) at –78 °C in the dark under N₂ was added N-bromosuccinimide (NBS) (1.2 equiv, 0.12 mmol, 21 mg) or N-iodosuccinimide (NIS). The resulting mixture was stirred at –78 °C and the reaction progress monitored by TLC. After completion, the reaction was quenched with saturated Na₂SO₃ (2 mL) at –78 °C and then warmed to room temperature. The solution was diluted with H₂O (3 mL) and extracted with CH₂Cl₂ (3 × 5 mL). The combined extracts were washed with brine (5 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography using hexane/EtOAc to yield the corresponding halolactone. (R)-5-(Bromomethyl)-5-phenyldihydrofuran-2(3H)-one (2a) Colorless oil; yield: 24.7 mg (97%); [α]_D ²⁰.⁵ –13.95 (c 0.66, CHCl₃); 83% ee. ¹H NMR (400 MHz, CDCl₃): δ = 7.40–7.32 (m, 5 H), 3.72 (d, J = 11.31 Hz, 1 H), 3.67 (d, J = 11.31 Hz, 1 H), 2.85–2.74 (m, 2 H), 2.58–2.47 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 175.5, 140.7, 128.8, 128.6, 124.9, 86.4, 41.0, 32.3, 29.0. HPLC (Daicel ChiralPak IC-3, i-PrOH/hexane = 25:75, 0.6 mL/min, 214 nm): t ₁ = 21.8 (minor), t ₂ = 25.0 (major). 3-(Bromomethyl)-4,5-dihydrobenzo[c]oxepin-1(3H)-one (3a) White semi-solid; yield: 20.7 mg (81%); [α]_D ²⁶.¹ –3.5 (c 0.2, CHCl₃); racemic. ¹H NMR (400 MHz, CDCl₃): δ = 7.70 (dd, J = 7.5, 0.7 Hz, 1 H), 7.47 (td, J = 7.5, 1.1 Hz, 1 H), 7.35 (t, J = 7.5 Hz, 1 H), 7.20 (d, J = 7.5 Hz, 1 H), 4.30–4.17 (m, 1 H), 3.55 (dd, J = 10.8, 6.1 Hz, 1 H), 3.47 (dd, J = 10.8, 5.4 Hz, 1 H), 3.05–2.95 (m, 1 H), 2.83–2.75 (m, 1 H), 2.20–2.10 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.4, 137.7, 133.0, 131.2, 130.3, 128.8, 127.6, 77.1, 32.8, 32.6, 29.4. HPLC (Daicel ChiralPak IC-3, i-PrOH/hexane = 25:85, 0.6 mL/min, 214 nm): t ₁ = 25.0 (minor), t ₂ = 29.1 (major).