Asymmetric Synthesis of cis-3,4-Dihydrocoumarins via [4 + 2

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Asymmetric Synthesis of cis-3,4-Dihydrocoumarins via [4+2] Cycloadditions Catalyzed by Amidine-Derivatives Jing-Hai Jin, Xiang-Yu Li, Xiaoyan Luo, John Stephen Fossey, and Wei-Ping Deng J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 25 Apr 2017 Downloaded from http://pubs.acs.org on April 25, 2017

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The Journal of Organic Chemistry

Asymmetric Synthesis of cis-3,4-Dihydrocoumarins via [4+2] Cycloadditions Catalyzed by Amidine-Derivatives Jing-Hai Jin,a Xiang-Yu Li,a Xiaoyan Luo,a John S. Fosseyb and Wei-Ping Deng*,a a

School of Pharmacy and Shanghai Key Laboratory of New Drug Design, East China University

of Science and Technology, 130 Meilong Road, Shanghai 200237, China b

School of Chemistry, University of Birmingham, Edgbaston, Birmingham, West Midlands B15

2TT, United Kingdom

ABSTRACT: A highly efficient chiral amidine derivative-catalyzed tandem Michael addition/lactonisation of carboxylic acids and o-quinone methides (o-QMs) has been developed, which enables the asymmetric synthesis of cis-3,4-dihydrocoumarins bearing contiguous tertiary stereogenic centers in high yields with excellent stereoselectivities. Coumarins are common structural motifs that are found in a variety of natural products and pharmaceuticals.1 Among them, 3,4-dihydrocoumarin derivatives exhibit important biological activities, and have been employed as antihypertensive (Figurer 1, I),2c anti-tumor (Figure 1, II),2a, anti-oxidation2b (Figure 1, III) and anti-platelet aggregation2d (Figure 1, IV) agents et al as shown in Figure 1. Consequently, the coumarin skeleton has long been employed as versatile building block for the synthesis of a series of new 3,4-dihydrocoumarin derivatives in a variety of drug discovery scenarios.2

ACS Paragon Plus Environment


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Figure 1. Biologically active molecules with 3,4-dihydrocomarin skeletons: I-antihypertensive agent; II-anti-tumor agent; III-anti-inflammatory/antioxidant agent; IV-platelet aggregation inhibitor The synthesis of 3,4-dihydrocoumarins and their derivatives has attracted considerable attention and numerous synthetic approaches have been developed for the stereo-controlled synthesis of structurally diverse dihydrocoumarins.3,4 However, most reported synthetic routes rely upon transition metal catalysis.4 Despite the great progress of organocatalysis over the last decades,5 more efficient and practical methods for the construction of 3,4-dihydrocoumarins, especially bearing contiguous stereogenic centers, via organocatalysis are still rare. Recently, o-QMs6 have been successfully employed in the asymmetric organocatalytic synthesis of 3,4-dihydrocoumarins.7 For example, Lectka and co-workers demonstrated efficient construction of trans-dihydrocoumarin skeletons via formal [4+2] cycloaddition of o-QMs with silyl ketene acetals catalyzed by a chiral phase transfer catalyst (PTC) (Scheme 1a).8 In 2009, Lv et al reported chiral N-heterocyclic carbene (NHC)-catalyzed formal [4+2] annulation of o-QMs and ketenes to form cis-3,3,4-trisubstitued dihydrocoumarins (Scheme 1b). However, when oQMs bearing a cinnamyl group were employed as substrate, low to moderate diastereoselectivity (dr up to 3:1) was observed.9 In 2015, Scheidt and co-workers developed a dual activation strategy where chiral NHCs efficiently catalyzed asymmetric cycloadditons of o-QMs, generated


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in situ, with acyl imidazoles for the synthesis of 3-substituted dihydrocoumarin adducts (Scheme 1c).10 The organocatalytic α-functionalization of carboxylic acids via C1-ammonium enolates as key reactive species is widely used in organic synthesis, making carboxylic acids ideal starting materials.11 For example, Romo and co-workers first described nucleophile-catalyzed aldollactonisation (NCAL) reactions of carboxylic acids in 2001.12 After that, reports from the groups of Smith,13 Ye14 and others15 have also demonstrated organocatalytic α-activation of carboxylic acids and subsequent cyclization as a versatile strategy to form heterocycles such as lactones and lactams. Based on recent developments in amidine- and isothiourea-based nucleophilic organocatalysts originally introduced by Birman,16 we envisioned that chiral amidine derivativecatalyzed intermolecular Michael addition/lactonisation of carboxylic acids via C1-ammonium enolates with o-QMs would offer an alternative methodology for the synthesis of 3,4dihydrocoumarin derivatives. Here in, we report a chiral amidine-catalyzed, highly cis-selective, formal [4+2] cycloaddition of carboxylic acids and o-QMs to deliver 3,4-disubstitued dihydrocoumarin derivatives in high yields and excellent enantioselectivities (Scheme 1d).



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Scheme 1. The synthesis of dihydrocoumarins via organocatalytic enantioselective [4+2] cycloaddition of o-QMs Initially, o-QM bearing a cinnamyl group 1a and phenyl acetic acid 2a were chosen as the model substrates with DIPEA as base in DCM at room temperature under nitrogen. To begin with, achiral DMAP was used as a catalyst in a control reaction. Pleasingly, 1a and 2a reacted smoothly to give the desired cycloadduct 3aa in 90% yield with cis/trans diastereoisomer ratio of 55:45 (Table 1, entry 1). Next, chiral nucleophilic catalysts, derivatives of amidine-based catalysts introduced by Birman16 adopted by us in our prior work17, were probed for their suitability to affect the same transformation with asymmetric control, Np-PIQ(C-1a), AnPIQ(C-1b) and Fc-PIP(C-2) (Figure 2). Interestingly, these catalysts offered corresponding product 3aa in high yields and excellent enantioselectivities (97-99% ee for cis-enantiomer, Table 1, entries 2-4), however in moderate diastereoselectivities (66:34-76:24 dr). Since cis-3,4dihydrocoumarins are not well-studied, and that they offer a potential new platform for


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biologically active molecule discovery, we decided to focus our attention on optimization for enantio- and cis-selectivities. Table 1. Optimization of conditions of the organocatalyzed [4+2] cycloaddition of 1a with 2a to give 3,4-dihydrocoumarin 3aaa

entry

base

catalyst

solvent

yielde (%)

drf

1

DIPEA

DMAP

DCM

95

55:45

-

2

DIPEA

C-1a

DCM

96

76:24

97/56

3

DIPEA

C-1b

DCM

97

66:34

97/87

4

DIPEA

C-2

DCM

81

70:30

99/78

5

DIPEA

C-3a

DCM

97

76:24

98/70

6

DIPEA

C-3b

DCM

99

78:22

96/64

7b

Et3N

C-3b

CHCl3

99

84:16

98/93

b,c

Et3N

C-3b

CHCl3

99

88:12

98/95

9b,d

Et3N

C-3b

CHCl3

99

89:11

>99/91

10b,d

Et3N

C-3a

CHCl3

68

89:11

99/98

11b,d

Et3N

C-1a

CHCl3

85

82:18

>99/83

12b,d

Et3N

C-2

CHCl3

76

78:22

>99/77

b,d

Et3N

C-4

CHCl3

86

84:16

98/72

8

13

eeg (%)

14b,d Et3N CHCl3 99 81:19 -98/-85 C-5 a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), base (0.2 mmol), PivCl (0.2 mmol), solvent (2 mL); then base (0.4 mmol), catalyst (0.02 mmol), 4Å MS, under an N2 atmosphere at room temperature; b base (0.05 mmol) was used in step two; c The reaction was performed at 0 °C; d The reaction was performed at -20 °C; e Total isolated yield of cis- and trans-isomers; f Determined by chiral HPLC analysis; g Determined by chiral HPLC analysis; the ee of the cis-isomer followed by that of the trans-isomer; the minus ee value means the opposite enantiomer was obtained as the major product.

Accordingly, having observed that catalyst C-1a, with a smaller substituent at the 6-position than C-1b and C-2, gave a higher ratio of cis-product, we envisioned that reducing the steric bulk at the 6-position could serve to further enhance the cis-selectivity. Compounds C-3a and C-3b, bearing a proton at the 6-position (Figure 2), were next investigated as catalysts. Although the



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diastereoselectivities were comparable to that using C-1a (Table 1, entries 2, 5, 6), considering relative higher diastereoselectivity and availability of catalyst, we chose the more easy-to-access C-3b for further optimization of reaction conditions.

Figure 2. Amidine- (C-1a, C-1b, C-2, C-3a, C-3b, C-4) and isothiourea (C-5)-based catalysts for stereoselectivity optimization of the [4+2] cycloaddition of 1a with 2a Screening of solvents and bases was carried out (see Supporting Information for the details), and the combination of chloroform and Et3N was found to give the optimal result in terms of both yield and stereoselectivity, affording 3aa in 99% yield with 84:16 dr and 98/93% ee (Table 1, entry7). Moreover, lowering the reaction temperature to 0 °C or -20 °C (Table 1, entries 8 and 9), led to the formation of 3aa in 99% yield with extremely high enantioselectivity (>99% ee for cisisomer) at -20 °C (Table 1, entry 9). Finally, other chiral amidine- and isothiourea-based catalysts16 (Figure 2) were tested at -20 °C (Table 1, entries 10-14). Interestingly, C-1a (Np-PIQ), C-2 (Fc-PIP), C-3a and C-4 gave the product in lower yields (68-86%) at -20 °C (Table 2, entries 10-13), possibly due to the steric influence of the phenyl group at the 2-positon, although in excellent stereoselectivities. Finally, C-3b with benzyl group at 2-position was chosen as the optimal catalyst for this transformation. Table 2. Scope of carboxylic acids in the synthesis of 3,4-dihydrocoumarinsa


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entry

substrat 2 (R1)

yieldb (%)

drc

eed (%)

1

2a (Ph)

99 (3aa)

89:11

>99

2

2b (4-FPh)

95 (3ab)

87:13

>99

3

2c (4-ClPh)

99 (3ac)

87:13

>99

4

2d (4-BrPh)

99 (3ad)

88:12

>99

5

2e (4-CF3Ph)

90 (3ae)

59:41

99

6

2f (2-ClPh)

97 (3af)

88:12

>99

7

2g (4-MeOPh)

98 (3ag)

91:9

99

8

2h (4-MePh)

98 (3ah)

91:9

>99

9

2i (3-MeOPh)

99 (3ai)

88:12

>99

10

2j (2-MePh)

87 (3aj)

91:9

98

11

2k (3,4-diMeOPh)

99 (3ak)

87:13

>99

12

2l (2-Thienyl)

98 (3al)

70:30

97

13

2m (1-Naphthyl)

95 (3am)

87:13

99

14

2n (2-Naphthyl)

97 (3an)

87:13

>99

2o (3-Indolyl) 80 (3ao) 95:5 99 15 a Reaction conditions: The same reaction conditions as for entry 22 in Table 1; b Total isolated yield of cis- and trans-isomers; c Determined by 1H-NMR spectroscopy; d Determined by chiral HPLC analysis; the ee value of the transisomer is shown in the Supporting Information.

With the optimal conditions in hand, the substrate scope of this formal [4+2] cycloaddition was explored (Table 2). The reaction was found to be tolerant for both electron-withdrawing or donating substitutions on phenyl acetic acids. To begin with, phenyl acetic acids with electronwithdrawing groups (Cl, Br, F, CF3) afforded dihydrocoumarins 3ab-3af in excellent yields (9099%) with good diastereoselectivites (59:41-88:12 dr) and excellent enantioselectivities (99>99% ee) (Table 2, entries 2-6). In the case of electron-donating groups (Me, MeO), the corresponding

cycloadducts

3ag-3ak

were

generated

in

87-99%

yields

with

high

diastereoselectivites (87:13-91:9 dr) and excellent enantioselectivities (98->99% ee) (Table 2, entries 7-11). Additionally, heteroaromatic carboxylic acids also worked efficiently in this transformation, providing the desired products 3al-3an in 80-98% yields with 70:30-87:13 dr and



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97->99% ee (Table 2, entries 12-14). Interestingly, the cycloaddition of indole-3-acetic acid 2o and o-QM 1a gave desired product 3ao in 80% yield with excellent diastereoselectivity (95:5 dr) and 99% ee for major isomer (Table 2, entry 15). Notably, we failed to separate diastereoisomers via column chromatography except for the cases of 3af and 3ao. The scope of o-QMs was next investigated. Different o-QMs 1b-1e reacted smoothly with 4methylphenyl acetic acid 2h providing access to structurally diverse dihydrocoumarins in high yields (78-92%) with good diastereoselectivities (87:13-95:5 dr) and excellent enantioselectivities (99->99% ee) (Table 3, entries 1-4). While indole-3-acetic acid 2o offered desired dihydrocoumarins in moderate yields (30-65%) with high diastereo- and excellent enantioselectivities (91:9-96:4 dr, 98->99% ee) (Table 3, entries 5-11). We envisioned that Nprotected indole-3-acetic acid may increase the yield of the desired dihydrocoumarins. As expected, using N-methyl protected indole-3-acetic acid 2p offered the corresponding cycloaddition product 3gp in 80% yield with 95:5 dr and 99% ee (Table 3, entry 12). Compared to 2o, the reaction of o-QMs with 1-methyl-1H-Indole-3-carboxylic acid 2p offered dihydrocoumarins in increased yields with similar selectivity (Table 3, entries 8 vs 12 and 5 vs 13). Notably, two diastereoisomers could be separated via column chromatography when using indole-3-acetic acids as the starting material (Table 3, entries 5-13). Table 3. Scope of o-QMs in the synthesis of 3,4-dihydrocoumarinsa

entry

substrate 1 (R2)

substrate 2 (R1) yieldb (%)

drc

eed (%)

1

1b (4-ClPh)

2h (4-MePh)

82 (3bh)

91:9

99

2

1c (4-MeOPh)

2h (4-MePh)

90 (3ch)

91:9

>99

3

1d (1-Naphthyl)

2h (4-MePh)

78 (3dh)

87:13

>99

4

1e (i-Pr)

2h (4-MePh)

92 (3eh)

95:5

>99


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5

1b (4-ClPh)

2o (3-Indolyl)

60 (3bo)

95:5

99

6

1f (4-BrPh)

2o (3-Indolyl)

65 (3fo)

92:8

99

7

1c (4-MeOPh)

2o (3-Indolyl)

60 (3co)

96:4

>99

8

1g (2-MeOPh)

2o (3-Indolyl)

30 (3go)

92:8

99

9

1d (1-Naphthyl)

2o (3-Indolyl)

38 (3do)

91:9

99

10

1h (2-Thienyl)

2o (3-Indolyl)

61 (3ho)

94:6

99

11

1e (i-Pr)

2o (3-Indolyl) 64 (3eo) 95:5 98 2p (N-Me-380 (3gp) 95:5 99 12 1g (2-MeOPh) Indolyl) 2p (N-Me-313 1b (4-ClPh) 90 (3bp) 97:3 99 Indolyl) a Reaction conditions: The same reaction conditions as for entry 22 in Table 1; b Total isolated yield of cis- and trans-isomers; c Determined by 1H-NMR spectroscopy; d Determined by chiral HPLC analysis; the ee value of the trans-isomer is shown in the Supporting Information.

The absolute stereochemistry of compound 3bp was determined by single crystal X-ray diffraction analysis as (7S,8S). (see the Supporting Information) A proposed catalytic cycle for this reaction, similar to that postulated by Smith,13f is depicted in Scheme 2. Initially, the carboxylic acid reacts with pivaloyl chloride to form a mixed anhydride A, which is followed by the formation of acyl ammonium intermediate B. Then, deprotonation of the intermediate B generates enolate C that further reacts with o-QM 1 via asymmetric Michael addition to form cis-intermediate D, because the benzyl group blocks the siface of the intermediate C. Finally, intermediate D undergoes intramolecular lactonisation to afford the desired cis-dihydrocoumarin 3.


ba se

cy cli za l ae ich on M diti ad

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tio n


Scheme 2. Proposed catalytic cycle for the formation of 3 CONCLUSION In summary, we have developed a novel chiral amidine derivative-catalyzed [4+2] cycloaddition of o-QMs with carboxylic acids as stable and easy-to-access starting materials. This protocol provides an efficient and highly stereoselective entry to a series of structurally diverse 3,4-dihydrocoumarins bearing two contiguous tertiary stereogenic centers, with relevance and importance for the drug discovery community as well as the wider synthetic chemistry arena. EXPERIMENTAL SECTION General Information 1

H NMR spectrums were recorded on a Bruker DPX 400 MHz spectrometer in CDCl3.

Chemical shifts were reported in ppm with the internal TMS signal at 0.0 ppm as a standard. The spectrums’ multiplicities are interpreted as: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, brs = broad singlet, coupling constant(s) J are reported in Hz and relative integrations are reported.

13

C NMR (100 MHz) spectrums were recorded on a Bruker DPX 400 MHz


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spectrometer in CDCl3 and are proton decoupled. Chemical shifts are reported in ppm with the internal chloroform signal at 77.16 ppm as a standard. Diastereomeric ratios were determined from crude 1H NMR spectroscopy interpretation or by analysis of HPLC traces. Enantiomer ratios were determined by analysis of HPLC traces, obtained by using chiralpak IF, IA, IB, AD, AS-H or chiralcel OD-H columns with n-hexane and i-propanol as solvents. (Chiralpak IF, IA, IB, AD, AS-H and chiralcel OD-H columns were purchased from Daicel Chemical Industries, LTD.) Mass spectrums were recorded on TOF mass Finigann MAT8401 spectrometer. Solvents were dried and distilled following usual protocols. Ortho-quinone methides 1 were prepared according to literature procedures 18. Based on the 1H NMR data of the cis-3bp determined by single crystal X-ray diffraction analysis, the coupling constant of the doublet peak at δ 4.58 ppm is 5.2 Hz. All of the other major products’ 1H NMR data showed the coupling constant of the doublet peak around 4 ppm is around 5.2 Hz. Based on the 1H NMR data, all of the other major products were deduced as 3,4-cis-configuration. General procedure for the preparation of 3,4-dihydrocoumarin 3 To a solution of the corresponding commercial available carboxylic acid (2.0 eq.) in CHCl3, triethylamine (2.0 eq.) was added followed by dropwise addition of pivaloyl chloride (2.0 eq.) at 0 °C, under a nitrogen atmosphere. After 0.5 h, triethylamine (0.5 eq.), catalyst C-3b (20 mol%) and ortho-quinone methide (1.0 eq.) were added at -20 °C. Once starting material was consumed (monitored by TLC), the mixture was concentrated and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 4/1) to afford the corresponding product. (7S,8S)-7-Phenyl-8-((E)-styryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6-one (3aa)



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Yellow solid, total yield (cis- and trans-isomers): 36.7 mg, 99%; 1H NMR (400 MHz, CDCl3) δ 7.38-7.16 (m, 10H, major + minor), 6.71 (s, 1H, major), 6.66 (s, 1H, minor), 6.65 (s, 1H, minor), 6.61 (s, 1H, major), 6.32-6.22 (m, 1H, major + minor), 6.11 (dd, J = 15.8, 7.6 Hz, 1H, minor), 6.03 (dd, J = 15.8, 8.4 Hz, 1H, major), 5.98 (d, J = 1.9 Hz, 2H, major), 5.96 (d, J = 2.4 Hz, 2H, minor), 4.20 (d, J = 5.6 Hz, 1H, major), 4.03 (d, J = 6.7 Hz, 1H, minor), 3.95 (t, J = 7.1 Hz, 1H, minor), 3.87 (dd, J = 8.2, 5.7 Hz, 1H, major);

13

C NMR (100 MHz, CDCl3) δ (major + minor)

168.5, 168.4, 147.8, 145.6, 145.5, 144.7, 144.6, 136.4, 136.3, 134.1, 134.0, 133.4, 129.9, 129.0, 128.7, 128.7, 128.6, 128.2, 128.2, 128.1, 128.0, 127.9, 126.6, 125.5, 118.0, 116.2, 107.6, 107.1, 101.9, 99.3, 99.2, 51.2, 51.2, 45.9, 45.8; HRMS (EI-TOF) calcd for C24H18O4 [M]+: 370.1200, found: 370.1204 ; HPLC (Chiralpak IF, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 17.59 min (cis-major), 19.73 min (cis-minor), 21.07 min (trans-minor), 24.09 (trans-major). (7S,8S)-7-(4-Fluorophenyl)-8-((E)-styryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6-one (3ab) White solid, total yield (cis- and trans-isomers): 36.9 mg, 95%; 1H NMR (400 MHz, CDCl3) δ 7.35-7.12 (m, 7H, major + minor), 7.06-6.95 (m, 2H, major + minor), 6.70 (s, 1H, major), 6.66 (s, 2H, minor), 6.62 (s, 1H, major), 6.29 (d, J = 15.8 Hz, 1H, minor), 6.24 (d, J = 15.8 Hz, 1H, major), 6.08-5.96 (m, 3H, major + minor), 4.20 (d, J = 5.5 Hz, 1H, major), 3.97 (d, J = 7.6 Hz, 1H, minor), 3.91 (t, J = 7.7 Hz, 1H, minor), 3.83 (dd, J = 8.4, 5.6 Hz, 1H, major); 13C NMR (100 MHz, CDCl3) δ (major + minor) 168.3, 163.7, 161.2, 147.9, 145.6, 145.5, 144.7, 136.2, 134.2, 134.0, 131.7, 131.6, 130.1, 130.0, 128.8, 128.7, 128.2, 127.8, 126.6, 125.2, 118.0, 116.3, 116.1, 115.8, 115.6, 115.4, 107.4, 107.0, 102.0, 99.3, 99.2, 50.6, 50.4, 46.2, 45.8; HRMS (EI-TOF) calcd for C24H17FO4 [M]+: 388.1105, found: 388.1110; HPLC (Chiralpak IA, hexane/i-PrOH =


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80/20, 0.8 mL/min, 220 nm) tR = 17.13 min (cis-minor), 19.03 min (cis-major), 32.23 min (transminor), 36.87 min (trans-major). (7S,8S)-7-(4-Chlorophenyl)-8-((E)-styryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6-one (3ac) Yellow solid, total yield (cis- and trans-isomers): 40.1 mg, 99%; 1H NMR (400 MHz, CDCl3) δ 7.32-7.24 (m, 7H, major + minor), 7.18 (d, J = 8.4 Hz, 2H, major), 7.12 (d, J = 8.4 Hz, 2H, minor), 6.70 (s, 1H, major), 6.65 (s, 2H, minor), 6.62 (s, 1H, major), 6.30 (d, J = 15.8 Hz, 1H, minor), 6.24 (d, J = 15.8 Hz, 1H, major), 6.09-5.95 (m, 3H, major + minor), 4.18 (d, J = 5.5 Hz, 1H, major), 3.96 (d, J = 7.6 Hz, 1H, minor), 3.92 (t, J = 7.6 Hz, 1H, minor), 3.83 (dd, J = 8.3, 5.7 Hz, 1H, major);

13

C NMR (100 MHz, CDCl3) δ (major + minor) 168.2, 168.0, 147.9, 145.5,

145.4, 144.8, 136.2, 134.3, 134.1, 134.0, 132.7, 131.3, 129.7, 129.2, 128.8, 128.7, 128.2, 127.6, 126.6, 125.0, 117.9, 116.2, 107.4, 107.0, 102.0, 99.3, 99.2, 50.7, 50.6, 46.1, 45.6; HRMS (EITOF) calcd for C24H17ClO4 [M]+: 404.0810, found: 404.0812; HPLC (Chiralpak IF, hexane/iPrOH = 100/5, 0.8 mL/min, 220 nm) tR = 37.39 min (cis-major), 44.95 min (cis-minor), 55.89 min (trans-minor), 58.07 min (trans-major). (7S,8S)-7-(4-Bromophenyl)-8-((E)-styryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6-one (3ad) Yellow solid, total yield (cis- and trans-isomers): 44.5 mg, 99%; 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.4 Hz, 2H, major), 7.42 (d, J = 8.5 Hz, 2H, minor), 7.33-7.20 (m, 5H, major + minor), 7.12 (d, J = 8.4 Hz, 2H, major), 7.06 (d, J = 8.4 Hz, 2H, minor), 6.70 (s, 1H, major), 6.65 (s, 2H, minor), 6.61 (s, 1H, major), 6.30 (d, J = 15.8 Hz, 1H, minor), 6.24 (d, J = 15.8 Hz, 1H, major), 6.08-5.95 (m, 3H, major + minor), 4.17 (d, J = 5.5 Hz, 1H, major), 3.93 (q, J = 7.5 Hz,



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2H, minor), 3.82 (dd, J = 8.2, 5.7 Hz, 1H, major); 13C NMR (100 MHz, CDCl3) δ (major + minor) 168.1, 168.0, 147.9, 145.5, 145.4, 144.8, 136.1, 134.6, 134.3, 134.0, 133.2, 132.1, 131.7, 131.6, 130.0, 128.8, 128.7, 128.2, 127.6, 126.6, 125.0, 122.2, 122.0, 117.8, 116.1, 107.4, 107.0, 102.0, 99.3, 99.2, 50.8, 50.6, 46.0, 45.5; HRMS (EI-TOF) calcd for C24H17BrO4 [M]+: 448.0305, found: 448.0302; HPLC (Chiralpak IF, hexane/i-PrOH = 100/5, 0.8 mL/min, 220 nm) tR = 40.64 min (cis-major), 50.56 min (cis-minor), 63.57 min (trans-major + minor). (7S,8S)-8-((E)-Styryl)-7-(4-(trifluoromethyl)phenyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5g]chromen-6-one (3ae) White solid, total yield (cis- and trans-isomers): 39.5 mg, 90%; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.2 Hz, 2H, major), 7.57 (d, J = 8.2 Hz, 2H, minor), 7.39 (d, J = 8.1 Hz, 2H, major), 7.34-7.20 (m, 5H, major; 7H, minor), 6.71 (s, 1H, major), 6.67 (s, 1H, minor), 6.66 (s, 1H, minor), 6.63 (s, 1H, major), 6.30 (d, J = 15.8 Hz, 1H, minor), 6.24 (d, J = 15.7 Hz, 1H, major), 6.09-5.96 (m, 3H, major + minor), 4.27 (d, J = 5.5 Hz, 1H, major), 4.05 (d, J = 7.8 Hz, 1H, minor), 3.97 (t, J = 7.7 Hz, 1H, minor), 3.85 (dd, J = 8.3, 5.6 Hz, 1H, major);

13

C NMR (100 MHz, CDCl3) δ

(major + minor) 167.9, 167.7, 148.0, 145.5, 145.4, 144.9, 144.9, 139.7, 138.3, 136.0, 134.5, 134.3, 130.5, 128.9, 128.8, 128.8, 128.3, 128.3, 127.3, 126.6, 126.6, 126.0, 125.9, 125.5, 125.5, 124.7, 117.8, 116.0, 107.4, 107.0, 102.0, 99.4, 99.3, 51.2, 51.0, 46.1, 45.6.; HRMS (EI-TOF) calcd for C25H17F3O4 [M]+: 438.1073, found: 438.1080; HPLC (Chiralpak IA, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 15.64 min (cis-minor), 18.17 min (cis-major), 32.82 min (transminor), 37.51 min (trans-major). (7S,8S)-7-(2-Chlorophenyl)-8-((E)-styryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6-one (3af)


Page 15 of 34

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White solid, mp: 114-115 °C (for cis-isomer), total yield (cis- and trans-isomers): 39.3 mg, 97%; 1

H NMR (400 MHz, CDCl3) δ 7.52-7.38 (m, 2H, major + minor), 7.30-7.16 (m, 7H, major +

minor), 6.71 (s, 1H, major), 6.67 (s, 1H, minor), 6.66 (s, 1H, major), 6.63 (s, 1H, minor), 6.126.05 (m, 1H, major + minor), 6.04-5.94 (m, 3H, major + minor), 4.85 (d, J = 5.5 Hz, 1H, major), 4.46 (d, J = 9.4 Hz, 1H, minor), 4.04 (t, J = 8.9 Hz, 1H, minor), 3.83 (dd, J = 7.2, 5.6 Hz, 1H, major); 13C NMR (100 MHz, CDCl3) δ (major + minor) 167.9, 167.8, 148.0, 147.8, 145.5, 145.2, 144.7, 136.3, 136.0, 134.2, 133.8, 132.4, 132.2, 132.1, 132.0, 129.6, 129.4, 129.2, 128.7, 128.4, 128.0, 127.8, 126.6, 126.5, 126.5, 125.5, 118.5, 118.2, 116.7, 107.2, 102.0, 101.9, 99.4, 99.2, 48.6, 47.2, 45.4, 44.5; HRMS (EI-TOF) calcd for C24H17ClO4 [M]+: 404.0810, found: 404.0819; HPLC (Chiralpak IA, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 11.06 min (cis-major), 14.19 min (cis-minor), 32.82 min (trans-minor), 35.17 min (trans-major). 1

H NMR (400 MHz, CDCl3) (for cis-3af) δ 7.49-7.41 (m, 2H), 7.30-7.16 (m, 7H), 6.71 (s, 1H),

6.66 (s, 1H), 6.08 (d, J = 15.8 Hz, 1H), 6.04-5.97 (m, 3H), 4.85 (d, J = 5.5 Hz, 1H), 3.83 (dd, J = 7.2, 5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) (for cis-3af) δ 167.8, 147.9, 145.5, 144.7, 136.3, 134.2, 133.8, 132.4, 132.1, 129.6, 129.2, 128.7, 128.0, 126.5, 125.4, 118.2, 107.2, 101.9, 99.4, 47.1, 44.5. 1

H NMR (400 MHz, CDCl3) (for trans-3af) δ 7.40-7.14 (m, 9H), 6.72 (s, 1H), 6.63 (s, 1H), 6.28

(d, J = 15.8 Hz, 1H), 6.08 (dd, J = 15.7, 8.4 Hz, 1H), 5.97 (dd, J = 3.7, 1.3 Hz, 2H), 4.47 (d, J = 9.4 Hz, 1H), 4.06-4.02 (m, 1H);

13

C NMR (100 MHz, CDCl3) (for trans-3af) δ 168.0, 147.9,

145.5, 144.7, 136.3, 134.5, 134.2, 133.8, 130.0, 129.9, 129.2, 128.7, 128.1, 127.4, 127.2, 126.6, 116.7, 107.4, 101.9, 99.2, 48.6, 45.3.



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Page 16 of 34

(7S,8S)-7-(4-Methoxyphenyl)-8-((E)-styryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6one (3ag) Yellow solid, total yield (cis- and trans-isomers):39.2 mg, 98%; 1H NMR (400 MHz, CDCl3) δ 7.36-7.19 (m, 4H, major + minor), 7.15 (d, J = 8.6 Hz, 2H, major), 7.10 (d, J = 8.6 Hz, 2H, minor), 6.85 (d, J = 8.7 Hz, 2H, major), 6.81 (d, J = 8.7 Hz, 2H, minor), 6.70 (s, 1H, major), 6.65 (s, 2H, minor), 6.61 (s, 1H, major), 6.33-6.22 (m, 1H, major + minor), 6.13-6.08 (m, 1H, minor), 6.03 (dd, J = 15.8, 8.4 Hz, 1H, major), 5.98-5.96 (m, 2H, major + minor), 4.15 (d, J = 5.5 Hz, 1H, major), 3.97 (d, J = 6.8 Hz, 1H, minor), 3.92 (t, J = 7.1 Hz, 1H, minor), 3.85 (dd, J = 8.1, 5.8 Hz, 1H, major), 3.79 (s, 3H, major), 3.75 (s, 3H, minor);

13

C NMR (100 MHz, CDCl3) δ (major +

minor) 168.7, 159.2, 147.8, 145.6, 144.6, 136.4, 133.9, 133.4, 131.0, 129.2, 128.7, 128.3, 128.0, 126.6, 126.1, 125.7, 118.1, 114.4, 114.0, 107.6, 107.1, 101.9, 99.3, 99.2, 55.4, 50.4, 46.0, 45.7; HRMS (EI-TOF) calcd for C25H20O5 [M]+: 400.1305, found: 400.1312; HPLC (Chiralpak IA, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 16.90 min (cis-minor), 19.85 min (cis-major), 33.41 min (trans-minor), 39.53 min (trans-major). (7S,8S)-8-((E)-Styryl)-7-(p-tolyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6-one (3ah) Yellow solid, total yield (cis- and trans-isomers):37.7 mg, 98%; 1H NMR (400 MHz, CDCl3) δ 7.31-7.20 (m, 5H, major + minor), 7.16-7.05 (m, 4H, major + minor), 6.70 (s, 1H, major), 6.65 (s, 1H, minor), 6.64 (s, 1H, minor), 6.61 (s, 1H, major), 6.33-6.24 (m, 1H, major + minor), 6.15-6.08 (m, 1H, minor), 6.04 (dd, J = 15.8, 8.4 Hz, 1H, major), 5.98-5.96 (m, 2H, major + minor), 4.16 (d, J = 5.5 Hz, 1H, major), 4.00 (d, J = 6.5 Hz, 1H, minor), 3.94 (t, J = 7.1 Hz, 1H, minor), 3.86 (dd, J = 8.1, 5.8 Hz, 1H, major), 2.33 (s, 3H, major), 2.28 (s, 3H, minor);

13

C NMR (100 MHz,

CDCl3) δ (major + minor) 168.6, 147.8, 145.7, 144.6, 137.7, 136.4, 133.9, 133.3, 131.0, 129.7,


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129.7, 129.3, 128.7, 128.0, 127.9, 126.6, 125.7, 118.1, 107.6, 107.1, 101.9, 99.3, 99.2, 50.8, 45.8, 45.7, 21.2; HRMS (EI-TOF) calcd for C25H20O4 [M]+: 384.1356, found: 384.1364; HPLC (Chiralpak IF, hexane/i-PrOH = 90/10, 0.8 mL/min, 220 nm) tR = 25.06 min (cis-minor), 27.33 min (cis-major), 32.52 min (trans-minor), 34.73 min (trans-major). (7S,8S)-7-(3-Methoxyphenyl)-8-((E)-styryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6one (3ai) Yellow oil, total yield (cis- and trans-isomers): 39.6 mg, 99%; 1H NMR (400 MHz, CDCl3) δ 7.33-7.17 (m, 6H, major + minor), 6.87-6.73 (m, 3H, major + minor), 6.71 (s, 1H, major), 6.65 (s, 1H, minor), 6.65 (s, 1H, minor), 6.62 (s, 1H, major), 6.34-6.25 (m, 1H, major + minor), 6.11 (dd, J = 15.8, 7.5 Hz, 1H, minor), 6.04 (dd, J = 15.8, 8.4 Hz, 1H, major), 5.98 (dd, J = 3.3, 1.3 Hz, 2H, major), 5.96 (dd, J = 3.0, 1.3 Hz, 2H, minor), 4.17 (d, J = 5.6 Hz, 1H, major), 4.01 (d, J = 6.4 Hz, 1H, minor), 3.95 (dd, J = 8.8, 5.0 Hz, 1H, minor), 3.89 (dd, J = 8.4, 5.6 Hz, 1H, major), 3.74 (s, 3H, minor), 3.70 (s, 3H, major);

13

C NMR (100 MHz, CDCl3) δ (major + minor) 168.4, 168.3,

159.9, 159.5, 147.8, 145.6, 145.5, 144.7, 144.7, 137.0, 136.4, 136.3, 135.5, 134.0, 133.3, 129.9, 129.5, 128.7, 128.7, 128.2, 128.1, 126.5, 125.6, 122.2, 120.4, 118.0, 116.1, 115.4, 114.2, 113.8, 113.1, 107.6, 107.1, 101.9, 99.3, 99.2, 55.3, 55.3, 51.2, 51.1, 45.8, 45.7; HRMS (EI-TOF) calcd for C25H20O5 [M]+: 400.1305, found: 400.1314; HPLC (Chiralpak IA, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 21.54 min (cis-minor), 23.79 min (cis-major), 30.21 min (trans-major + minor); (Chiralpak IF, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 23.53 min (cis-major + minor), 30.41 min (trans-minor), 38.48 min (trans-major). (7S,8S)-8-((E)-Styryl)-7-(o-tolyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6-one (3aj)



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Page 18 of 34

Yellow oil, total yield (cis- and trans-isomers): 33.4 mg, 87%; 1H NMR (400 MHz, CDCl3) δ 7.32-7.09 (m, 9H, major + minor), 6.72 (s, 1H, major), 6.71 (s, 1H, minor), 6.63 (s, 1H, major), 6.62 (s, 1H, minor), 6.30 (d, J = 15.8 Hz, 1H, minor), 6.21 (d, J = 15.8 Hz, 1H, major), 6.11-6.06 (m, 1H, minor), 6.05-5.98 (m, 3H, major), 5.98-5.96 (m, 2H, minor), 4.47 (d, J = 5.7 Hz, 1H, major), 4.20 (d, J = 7.6 Hz, 1H, minor), 3.89 (t, J = 7.8 Hz, 1H, minor), 3.83 (dd, J = 8.1, 5.7 Hz, 1H, major), 2.39 (s, 3H, minor), 2.36 (s, 3H, major);

13


minor) 168.5, 147.9, 145.7, 144.7, 136.4, 136.4, 133.8, 132.5, 131.0, 130.8, 130.1, 128.7, 128.5, 128.0, 127.9, 126.5, 126.0, 125.8, 118.2, 107.6, 107.1, 101.9, 99.4, 46.5, 45.7, 44.5, 20.0; HRMS (EI-TOF) calcd for C25H20O4 [M]+: 384.1356, found: 384.1361; HPLC (Chiralpak AS, hexane/iPrOH = 80/20, 0.8 mL/min, 220 nm) tR = 15.09 min (cis-minor), 20.03 min (trans-minor), 24.45 min (cis-major), 28.98 min (trans-major). (7S,8S)-7-(3,4-Dimethoxyphenyl)-8-((E)-styryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6-one

(3ak) Yellow oil, total yield (cis- and trans-isomers): 42.6 mg, 99%; 1H NMR (400 MHz, CDCl3) δ 7.32-7.20 (m, 5H, major + minor), 6.84-6.72 (m, 3H, major + minor), 6.71 (s, 1H, major), 6.67 (s, 1H, minor), 6.65 (s, 1H, minor), 6.62 (s, 1H, major), 6.33-6.26 (m, 1H, major + minor), 6.12 (dd, J = 15.8, 7.5 Hz, 1H, minor), 6.05 (dd, J = 15.8, 8.6 Hz, 1H, major), 5.98 (d, J = 3.7 Hz, 2H, major + minor), 4.15 (d, J = 5.5 Hz, 1H, major), 3.99 (d, J = 6.4 Hz, 1H, minor), 3.96-3.91 (m, 1H, minor), 3.90-3.83 (m, 4H, major), 3.82 (s, 3H, minor), 3.81 (s, 3H, minor), 3.69 (s, 3H, major); 13C NMR (100 MHz, CDCl3) δ (major + minor) 168.7, 149.1, 148.7, 148.6, 148.6, 147.8, 145.6, 145.5, 144.7, 144.6, 136.3, 133.9, 133.3, 128.7, 128.7, 128.2, 128.1, 128.0, 127.9, 126.5, 126.5, 126.5, 125.7, 122.0, 120.4, 118.1, 116.3, 113.1, 111.3, 111.3, 111.0, 107.6, 107.1, 101.9,


Page 19 of 34

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99.2, 99.1, 55.9, 55.9, 55.8, 50.7, 46.0, 45.7; HRMS (EI-TOF) calcd for C26H22O6 [M]+: 430.1411, found: 430.1421; HPLC (Chiralpak IF, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 43.34 min (cis-major), 47.95 min (cis-minor), 52.43 min (trans-major), 55.90 min (transminor). (7R,8S)-8-((E)-Styryl)-7-(thiophen-2-yl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6-one (3al) Yellow oil, total yield (cis- and trans-isomers): 36.9 mg, 98%; 1H NMR (400 MHz, CDCl3) δ 7.34-7.15 (m, 5H, major + minor), 7.02 (d, J = 3.1 Hz, 1H, major), 7.00-6.95 (m,1H, major), 6.88 (dd, J = 4.5, 3.0 Hz, 1H, major), 6.69 (s, 1H, major), 6.68 (s, 1H, minor), 6.66 (s, 1H, major), 6.64 (s, 1H, minor), 6.42 (d, J = 15.8 Hz, 1H, major), 6.34 (d, J = 15.8 Hz, 1H, minor), 6.17 (dd, J = 15.8, 7.1 Hz, 1H, minor), 6.07 (dd, J = 15.7, 8.4 Hz, 1H, major), 5.99 (s, 2H, major + minor), 4.50 (d, J = 5.2 Hz, 1H, major), 4.36 (d, J = 4.6 Hz, 1H, minor), 4.00 (dd, J = 8.2, 5.3 Hz, 1H, major), 3.96-3.92 (m, 1H, minor); 13C NMR (100 MHz, CDCl3) δ (major + minor) 167.4, 167.1, 148.1, 148.0, 145.6, 145.6, 144.9, 144.8, 137.2, 136.3, 136.2, 135.0, 134.8, 133.2, 128.7, 128.2, 128.1, 128.0, 127.8, 126.9, 126.9, 126.7, 126.7, 126.6, 126.0, 125.6, 125.0, 117.5, 115.4, 108.0, 107.2, 102.0, 99.3, 99.2, 47.0, 46.6, 46.4, 45.5; HRMS (EI-TOF) calcd for C22H16O4S [M]+: 376.0764, found: 376.0766; HPLC (Chiralpak IA, hexane/i-PrOH = 90/10, 0.8 mL/min, 220 nm) tR = 21.73 min (cis-minor), 25.69 min (cis-major), 31.03 min (trans-major), 44.35 min (transminor). (7S,8S)-7-(Naphthalen-1-yl)-8-((E)-styryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6one (3am)



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Page 20 of 34

Yellow oil, total yield (cis- and trans-isomers): 39.9 mg, 95%; 1H NMR (400 MHz, CDCl3) δ 8.05-7.72 (m, 3H, major + minor), 7.63-7.47 (m, 3H, major + minor), 7.44 (t, J = 7.8 Hz, 1H, major), 7.33-7.05 (m, 5H, major + minor), 6.77 (s, 1H, major), 6.75 (s, 1H, minor), 6.64 (s, 1H, major), 6.49 (s, 1H, minor), 6.34 (d, J = 15.8 Hz, 1H, minor), 6.12 (d, J = 15.8 Hz, 1H, major), 6.02-5.92 (m, 3H, major + minor), 5.10 (d, J = 5.4 Hz, 1H, major), 4.85 (d, J = 5.0 Hz, 1H, minor), 4.08 (dd, J = 7.0, 5.2 Hz, 1H, minor), 3.98 (dd, J = 7.8, 5.6 Hz, 1H, major);

13

C NMR

(100 MHz, CDCl3) δ (major + minor) 168.6, 168.4, 147.9, 145.7, 145.4, 144.8, 144.7, 136.4, 134.1, 133.8, 131.6, 129.5, 129.5, 128.6, 128.4, 128.0, 126.9, 126.8, 126.6, 126.5, 126.0, 125.7, 125.4, 125.2, 122.9, 122.2, 118.3, 115.8, 107.9, 107.2, 101.9, 99.4, 99.3, 48.1, 46.1, 45.7, 45.0; HRMS (EI-TOF) calcd for C28H20O4 [M]+: 420.1356, found: 420.1361; HPLC (Chiralpak IB, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 15.98 min (cis-major), 21.43 min (transminor), 26.94 min (trans-major), 65.38 min (cis-minor). (7S,8S)-7-(Naphthalen-2-yl)-8-((E)-styryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6one (3an) Yellow oil, total yield (cis- and trans-isomers): 40.8 mg, 97%; 1H NMR (400 MHz, CDCl3) δ 7.84-7.69 (m, 4H, major + minor), 7.51-7.41 (m, 2H, major + minor), 7.35 (dd, J = 8.5, 1.7 Hz, 1H, major + minor), 7.30-7.17 (m, 5H, major + minor), 6.74 (s, 1H, major), 6.68 (s, 1H, minor), 6.65 (s, 1H, minor), 6.62 (s, 1H, major), 6.33 (d, J = 15.8 Hz, 1H, minor), 6.25 (d, J = 15.8 Hz, 1H, major), 6.16 (dd, J = 15.8, 7.6 Hz, 1H, minor), 6.07 (dd, J = 15.8, 8.3 Hz, 1H, major), 5.98 (dd, J = 5.2, 1.2 Hz, 2H, major), 5.95 (dd, J = 9.2, 1.2 Hz, 2H, minor), 4.37 (d, J = 5.6 Hz, 1H, major), 4.20 (d, J = 6.5 Hz, 1H, minor), 4.08 (t, J = 7.1 Hz, 1H, minor), 3.95 (dd, J = 8.2, 5.7 Hz, 1H, major);

13

C NMR (100 MHz, CDCl3) δ (major + minor) 168.5, 168.5, 147.9, 145.7, 145.6,


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144.8, 144.7, 136.4, 136.2, 134.0, 133.5, 133.3, 132.9, 132.8, 131.8, 129.1, 128.9, 128.7, 128.7, 128.5, 128.2, 128.1, 128.0, 127.8, 127.7, 127.5, 127.3, 126.6, 126.5, 126.4, 126.3, 125.6, 118.0, 116.2, 107.6, 107.1, 101.9, 99.3, 99.2, 51.4, 51.3, 46.1, 45.7; HRMS (EI-TOF) calcd for C28H20O4 [M]+: 420.1356, found: 420.1361; HPLC (Chiralpak AD, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 41.50 min (cis-major), 53.18 min (cis-minor), 70.77 min (trans-minor), 78.79 min (trans-major). (7S,8S)-7-(1H-Indol-3-yl)-8-((E)-styryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6-one (3ao) Yellow oil, total yield (cis- and trans-isomers): 32.8 mg, 80%; 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H, major), 8.07 (s, 1H, minor), 7.54 (d, J = 7.9 Hz, 1H, major), 7.35 (d, J = 8.1 Hz, 1H, major), 7.31-7.07 (m, 8H, major + minor), 6.71 (s, 1H, major), 6.65 (s, 1H, major), 6.62 (s, 1H, minor), 6.62 (s, 1H, minor), 6.31-6.24 (m, 1H, major + minor), 6.06 (dd, J = 15.8, 7.9 Hz, 1H, major), 5.98 (d, J = 2.2 Hz, 2H, major), 5.95 (s, 2H, minor), 4.56 (d, J = 5.2 Hz, 1H, major), 4.46 (d, J = 4.9 Hz, 1H, minor), 4.05-3.97 (m, 1H, major);

13


minor) 168.7, 147.7, 145.9, 145.7, 144.7, 144.6, 136.4, 136.3, 136.0, 135.8, 133.7, 132.4, 128.8, 128.7, 128.6, 127.9, 127.1, 126.6, 126.2, 123.9, 122.7, 122.5, 120.2, 120.0, 118.9, 118.6, 118.4, 111.5, 110.1, 107.9, 107.3, 101.9, 99.2, 99.1, 45.1, 44.7, 43.2, 42.5; HRMS (EI-TOF) calcd for C26H19NO4 [M]+: 409.1309, found: 409.1316; HPLC (Chiralpak IA, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 12.04 min (trans-minor), 15.73 min (trans-major), 21.40 min (cis-major), 32.34 min (cis-minor). (7S,8S)-8-((E)-4-Chlorostyryl)-7-(p-tolyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6-one (3bh)



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Yellow oil, total yield (cis- and trans-isomers): 34.3 mg, 82%; 1H NMR (400 MHz, CDCl3) δ 7.28-7.03 (m, 8H, major + minor), 6.70 (s, 1H, major), 6.64 (s, 1H, minor), 6.61 (s, 1H, minor), 6.59 (s, 1H, major), 6.27-6.16 (m, 1H, major + minor), 6.10 (dd, J = 15.8, 7.2 Hz, 1H, minor), 6.06-5.93 (m, 3H, major + minor), 4.16 (d, J = 5.6 Hz, 1H, major), 4.00 (d, J = 6.1 Hz, 1H, minor), 3.94-3.89 (m, 1H, minor), 3.84 (dd, J = 7.8, 5.9 Hz, 1H, major), 2.33 (s, 3H, major), 2.28 (s, 3H, minor); 13C NMR (100 MHz, CDCl3) δ (major + minor) 168.5, 147.9, 145.7, 144.6, 137.8, 137.7, 134.9, 133.7, 132.6, 132.0, 131.0, 129.7, 129.7, 129.3, 129.1, 128.9, 128.8, 127.9, 127.8, 126.5, 117.8, 115.9, 107.6, 107.0, 101.9, 99.3, 99.2, 50.8, 45.9, 45.7, 21.2, 21.2; HRMS (EI-TOF) calcd for C25H19ClO4 [M]+: 418.0966, found: 418.0973; HPLC (Chiralpak IF, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 18.08 min (cis-minor), 19.71 min (cis-major), 25.10 min (transmajor + minor); (Chiralpak IA, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 18.77 min (cis-major + minor), 37.43 min (trans-major), 43.58 min (trans-minor). (7S,8S)-8-((E)-4-Methoxystyryl)-7-(p-tolyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6one (3ch) Yellow oil, total yield (cis- and trans-isomers): 37.3 mg, 90%; 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.6 Hz, 2H, major + minor), 7.16-7.05 (m, 4H, major + minor), 6.81 (d, J = 8.6 Hz, 2H, major + minor), 6.69 (s, 1H, major), 6.64 (s, 2H, minor), 6.61 (s, 1H, major), 6.26-6.19 (m, 1H, major + minor), 5.97-5.95 (m, 2H, major + minor), 5.89 (dd, J = 15.7, 8.4 Hz, 1H, major), 4.14 (d, J = 5.5 Hz, 1H, major), 3.98 (t, J = 6.7 Hz, 1H, minor), 3.86-3.76 (m, 4H, major + minor), 2.32 (s, 3H, major), 2.27 (s, 3H, minor); 13C NMR (100 MHz, CDCl3) δ (major + minor) 168.7, 159.6, 147.7, 145.7, 144.6, 137.7, 133.3, 131.1, 129.8, 129.7, 129.3, 129.2, 127.9, 127.8, 123.4, 118.4, 114.5, 114.1, 107.7, 107.1, 101.9, 99.2, 55.4, 50.9, 45.8, 21.2; HRMS (EI-TOF) calcd for


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C26H22O5 [M]+: 414.1462, found: 414.1470; HLPC (Chiralpak AD, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 25.40 min (cis-major), 33.44 min (cis-minor), 55.57 min (trans-major), 68.21 min (trans-minor). (7S,8S)-8-((E)-2-(Naphthalen-1-yl)vinyl)-7-(p-tolyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5g]chromen-6-one (3dh) Yellow oil, total yield (cis- and trans-isomers): 33.9 mg, 78%; 1H NMR (400 MHz, CDCl3) δ 7.86-7.71 (m, 3H, major + minor), 7.50-7.36 (m, 4H, major + minor), 7.20-7.09 (m, 4H, major + minor), 7.01-6.95 (m, 1H, major + minor), 6.75 (s, 1H, minor), 6.73 (s, 1H, major), 6.70 (s, 1H, major), 6.68 (s, 1H, minor), 6.09-5.92 (m, 3H, major + minor), 4.23 (d, J = 5.6 Hz, 1H, major), 4.07 (t, J = 8.0 Hz, 1H, minor), 3.98 (dd, J = 8.5, 5.4 Hz, 1H, major), 2.33 (s, 3H, major), 2.31 (s, 3H, minor);

13

C NMR (100 MHz, CDCl3) δ (major + minor) 168.9, 168.6, 147.8, 145.7, 144.7,

137.8, 134.6, 134.3, 133.6, 132.7, 131.9, 131.6, 131.1, 131.1, 129.8, 129.7, 129.3, 129.0, 128.6, 128.5, 128.4, 128.4, 126.2, 126.0, 125.7, 125.6, 124.3, 124.2, 124.0, 123.8, 118.2, 116.8, 107.4, 107.1, 101.9, 99.4, 99.3, 51.0, 50.9, 46.5, 46.0, 21.2; HRMS (EI-TOF) calcd for C29H22O4 [M]+: 434.1513, found: 434.1519; HPLC (Chiralpak IA, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 13.40 min (cis-minor), 18.93 min (cis-major), 22.98 min (trans-major), 31.68 min (transminor). (7S,8S)-8-(2-Methylprop-1-en-1-yl)-7-(p-tolyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen6-one (3eh) Yellow solid, mp: 143-144 °C (for cis-isomer), total yield (cis- and trans-isomers): 30.9 mg, 92%; 1

H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 8.1 Hz, 2H, major), 7.03 (d, J = 8.2 Hz, 2H, major),

6.66 (s, 1H, major), 6.63 (s, 1H, minor), 6.58 (s, 1H, minor), 6.55 (s, 1H, major), 5.96 (dd, J = 5.2,



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1.3 Hz, 2H, major), 5.03-4.97 (m, 1H, major), 4.96-4.94 (m, 1H, minor), 4.02 (d, J = 5.4 Hz, 1H, major), 3.93 (dd, J = 10.0, 5.4 Hz, 1H, major), 2.31 (s, 3H, major), 1.69 (d, J = 1.2 Hz, 3H, major), 1.66 (d, J = 1.2 Hz, 3H, minor), 1.55 (d, J = 1.2 Hz, 3H, minor), 1.36 (d, J = 1.2 Hz, 3H, major); 13C NMR (100 MHz, CDCl3) δ (major + minor) 169.1, 147.3, 145.6, 144.5, 137.4, 137.0, 131.4, 129.5, 129.4, 129.1, 120.4, 119.5, 106.7, 101.8, 99.3, 50.3, 41.0, 25.9, 21.2, 18.0; HRMS (EI-TOF) calcd for C21H20O4 [M]+: 336.1356, found: 336.1361; HPLC (Chiralpak AS, hexane/iPrOH = 80/20, 0.8 mL/min, 220 nm) tR = 11.54 min (trans-minor), 22.50 (cis-minor), 24.94 min (cis-major), 34.40 min (trans-major). (7S,8S)-8-((E)-4-Chlorostyryl)-7-(1H-indol-3-yl)-7,8-dihydro-6H-[1,3]dioxolo[4,5g]chromen-6-one (3bo) Yellow oil, total yield (cis- and trans-isomers): 26.6 mg, 60%; 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H, major), 8.03 (s, 1H, minor), 7.53 (d, J = 7.9 Hz, 1H, major), 7.39 (d, J = 8.1 Hz, 1H, major), 7.27-7.16 (m, 4H, major + minor), 7.15-7.09 (m, 3H, major + minor), 6.73 (s, 1H, major), 6.65 (s, 1H, major), 6.22 (d, J = 15.8 Hz, 1H, major), 6.08-5.97 (m, 3H, major + minor), 4.58 (d, J = 5.2 Hz, 1H, major), 4.40 (d, J = 3.7 Hz, 1H, minor), 4.31 (dd, J = 14.2, 7.2 Hz, 1H, minor), 4.07-3.99 (m, 1H, major); 13C NMR (100 MHz, CDCl3) δ (major + minor) 168.5, 147.9, 145.9, 144.6, 135.8, 134.9, 133.6, 132.4, 128.8, 127.8, 127.0, 127.0, 123.8, 122.6, 120.1, 118.7, 118.1, 111.6, 108.0, 107.3, 101.9, 99.3, 44.7, 42.5; HRMS (EI-TOF) calcd for C26H18ClNO4 [M]+: 443.0919, found: 443.0925; HPLC (Chiralpak IB, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 25.16 min (cis-minor), 27.52 min (cis-major), 48.20 min (trans-minor), 56.94 min (transmajor).


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(7S,8S)-8-((E)-4-Bromostyryl)-7-(1H-indol-3-yl)-7,8-dihydro-6H-[1,3]dioxolo[4,5g]chromen-6-one (3fo) Yellow oil, total yield (cis- and trans-isomers): 31.7 mg, 65%; 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H, major), 8.04 (s, 1H, minor), 7.74 (d, J = 7.0 Hz, 1H, minor), 7.53 (d, J = 8.0 Hz, 1H, major), 7.39 (d, J = 8.1 Hz, 1H, major + minor), 7.35 (d, J = 8.4 Hz, 2H, major + minor), 7.247.09 (m, 3H, major + minor), 7.04 (d, J = 8.3 Hz, 2H, major + minor), 6.72 (s, 1H, major), 6.64 (s, 1H, major), 6.27 (d, J = 4.8 Hz, 1H, minor), 6.20 (d, J = 15.9 Hz, 1H, major), 6.09-5.97 (m, 3H, major + minor), 4.58 (d, J = 5.2 Hz, 1H, major), 4.40 (d, J = 3.7 Hz, 1H, minor), 4.05-4.00 (m, 1H, major + minor); 13C NMR (100 MHz, CDCl3) δ (major + minor) 168.5, 147.9, 145.9, 144.6, 135.8, 135.4, 132.5, 131.7, 128.1, 127.1, 127.0, 123.9, 122.6, 121.7, 120.1, 118.6, 118.0, 111.6, 108.0, 107.3, 101.9, 99.3, 44.7, 42.5; HRMS (EI-TOF) calcd for C26H18BrNO4 [M]+: 487.0414, found: 487.0418; HPLC (Chiralpak IB, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 26.60 min (cis-minor), 28.93 min (cis-major), 52.28 min (trans-minor), 80.65 min (trans-major). (7S,8S)-7-(1H-Indol-3-yl)-8-((E)-4-methoxystyryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5g]chromen-6-one (3co) Yellow oil, total yield (cis- and trans-isomers): 26.4 mg, 60%; 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H, major), 7.55 (d, J = 8.0 Hz, 1H, major), 7.37 (d, J = 8.1 Hz, 1H, major), 7.24-7.18 (m, 1H, major + minor), 7.15-7.07 (m, 4H, major + minor), 6.77 (d, J = 8.7 Hz, 2H, major + minor), 6.72 (s, 1H, major), 6.70 (s, 1H, minor), 6.66 (s, 1H, major), 6.63 (s, 1H, minor), 6.23 (d, J = 15.8 Hz, 1H, major), 5.99-5.97 (m, 2H, major), 5.91 (dd, J = 15.8, 8.0 Hz, 1H, major), 4.56 (d, J = 5.1 Hz, 1H, major), 4.39 (d, J = 3.8 Hz, 1H, minor), 4.01 (dd, J = 7.8, 5.3 Hz, 1H, major), 3.79 (s, 3H, minor), 3.77 (s, 3H, major); 13C NMR (100 MHz, CDCl3) δ (major + minor) 168.7, 159.5, 147.7,



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145.9, 144.5, 135.8, 133.1, 129.3, 127.8, 127.2, 123.9, 123.8, 122.5, 120.1, 118.7, 118.7, 114.0, 111.5, 108.2, 107.4, 101.9, 99.2, 55.4, 44.8, 42.6; HRMS (EI-TOF) calcd for C27H21NO5 [M]+: 439.1414, found: 439.1422; HPLC (Chiralpak IB, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 27.86 min (cis-minor), 30.84 min (cis-major), 44.71 min (trans-minor), 132.15 min (transmajor). (7S,8S)-7-(1H-Indol-3-yl)-8-((E)-2-methoxystyryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5g]chromen-6-one (3go) Yellow oil, total yield (cis- and trans-isomers): 13.2 mg, 30%; 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H, major), 8.02 (s, 1H, minor), 7.75 (d, J = 7.3 Hz, 1H,minor), 7.56 (d, J = 7.9 Hz, 1H, major), 7.36 (d, J = 8.1 Hz, 1H, major), 7.32 (d, J = 7.6 Hz, 1H, minor), 7.23-7.07 (m, 5H, major + minor), 6.82 (t, J = 7.8 Hz, 2H, major + minor), 6.73-6.67 (m, 3H, major + minor), 6.27 (dd, J = 15.8, 7.8 Hz, 1H, minor), 6.07 (dd, J = 15.9, 8.5 Hz, 1H, major), 5.98 (d, J = 2.0 Hz, 2H, major), 5.96 (s, 2H, minor), 4.57 (d, J = 5.1 Hz, 1H, major), 4.39 (d, J = 4.1 Hz, 1H, minor), 4.07 (dd, J = 8.4, 5.1 Hz, 1H, major), 3.80 (s, 3H, minor), 3.73 (s, 3H, major); 13C NMR (100 MHz, CDCl3) δ (major + minor) 168.8, 156.8, 147.6, 145.9, 144.5, 135.7, 129.0, 128.8, 127.3, 127.1, 126.6, 125.5, 123.6, 122.5, 120.7, 120.1, 118.8, 118.7, 111.4, 111.0, 108.2, 107.4, 101.8, 100.1, 99.2, 55.5, 45.2, 42.4; HRMS (EI-TOF) calcd for C27H21NO5 [M]+: 439.1414, found: 439.1424; HPLC (Chiralpak IB, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 26.37 min (cis-major), 40.71 min (trans-minor), 46.04 min (cis-minor), 59.36 min (trans-major). (7S,8S)-7-(1H-Indol-3-yl)-8-((E)-2-(naphthalen-1-yl)vinyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5g]chromen-6-one (3do)


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Yellow oil, total yield (cis- and trans-isomers): 17.5 mg, 38%; 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H, major), 8.03 (s, 1H, minor), 7.84-7.69 (m, 3H, major + minor), 7.61 (d, J = 7.8 Hz, 1H, major), 7.49-7.30 (m, 5H, major + minor), 7.24-7.13 (m, 3H, major + minor), 7.04-6.94 (m, 1H, major + minor), 6.76 (s, 2H, major + minor), 6.20 (dd, J = 15.5, 7.4 Hz, 1H, minor), 6.115.96 (m, 3H, major + minor), 4.66 (d, J = 5.2 Hz, 1H, major), 4.39 (d, J = 5.7 Hz, 1H, minor), 4.18 (dd, J = 7.8, 5.4 Hz, 1H, major + minor); 13C NMR (100 MHz, CDCl3) δ (major + minor) 168.6, 147.8, 146.0, 144.6, 135.8, 134.3, 133.6, 131.3, 131.1, 129.4, 128.6, 128.2, 127.1, 126.2, 125.9, 125.6, 124.2, 124.0, 123.7, 122.6, 120.1, 118.5, 118.4, 111.5, 108.1, 107.4, 101.9, 99.4, 45.0, 42.5; HRMS (EI-TOF) calcd for C30H21NO4 [M]+: 459.1465, found: 459.1472; HPLC (Chiralpak IB, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 29.99 min (cis-major), 35.88 min (cis-minor), 60.84 min (trans-minor), 102.63 min (trans-major). (7S,8S)-7-(1H-Indol-3-yl)-8-((E)-2-(thiophen-2-yl)vinyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5g]chromen-6-one (3ho) Yellow oil, total yield (cis- and trans-isomers): 25.3 mg, 61%; 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H, major), 7.61 (d, J = 7.6 Hz, 1H, minor), 7.54 (d, J = 7.9 Hz, 1H, major), 7.38 (d, J = 8.1 Hz, 1H, major), 7.31 (d, J = 7.8 Hz, 1H, minor), 7.21 (d, J = 7.6 Hz, 2H, major + minor), 7.14 (t, J = 7.5 Hz, 1H, major + minor), 7.09 (d, J = 5.0 Hz, 1H, major + minor), 6.92-6.86 (m, 1H, major + minor), 6.81 (d, J = 3.2 Hz, 1H, major + minor), 6.72 (s, 1H, major), 6.66 (s, 1H, major), 6.36 (d, J = 15.6 Hz, 1H, major), 6.00 (d, J = 1.7 Hz, 2H,major), 5.97 (s, 2H, minor), 5.91 (dd, J = 15.6, 7.7 Hz, 1H, major), 4.57 (d, J = 5.2 Hz, 1H, major), 4.39 (d, J = 3.8 Hz, 1H, minor), 4.043.92 (m, 1H, major); 13C NMR (100 MHz, CDCl3) δ (major + minor) 168.5, 147.8, 145.9, 144.6, 141.6, 135.8, 127.5, 127.0, 126.7, 126.1, 125.8, 124.7, 124.0, 122.5, 120.1, 118.6, 118.1, 111.5,



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108.0, 107.3, 101.9, 99.3, 44.6, 42.6; HRMS (EI-TOF) calcd for C24H17NO4S [M]+: 415.0873, found: 415.0881; HPLC (Chiralpak IF, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 20.66 min (trans-minor), 22.36 min (cis-minor), 24.66 min (cis-major), 29.07 min (trans-major). (7S,8S)-7-(1H-Indol-3-yl)-8-(2-methylprop-1-en-1-yl)-7,8-dihydro-6H-[1,3]dioxolo[4,5g]chromen-6-one (3eo) Yellow solid, mp: 195-197 °C (for cis-isomer), total yield (cis- and trans-isomers): 23.1 mg, 64%; 1

H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H, major), 7.58 (d, J = 7.8 Hz, 1H, major), 7.34 (d, J =

8.0 Hz, 1H, major), 7.22-7.10 (m, 2H, major + minor), 6.88 (d, J = 2.3 Hz, 1H, major), 6.67 (s, 1H, major), 6.62 (s, 1H, major), 5.98 (dd, J = 3.2, 1.3 Hz, 2H, major), 5.95 (dd, J = 3.7, 1.3 Hz, 2H, minor), 5.11-5.05 (m, 1H, major), 4.43 (d, J = 4.9 Hz, 1H, major), 4.13 (dd, J = 9.8, 4.9 Hz, 1H, major), 1.68 (s, 3H, minor), 1.66 (d, J = 1.1 Hz, 3H, major), 1.64 (s, 3H, minor), 1.44 (d, J = 1.0 Hz, 3H, major); 13C NMR (100 MHz, CDCl3) δ (major + minor) 169.0, 147.3, 146.0, 144.5, 137.1, 135.6, 127.6, 123.1, 122.4, 120.8, 120.0, 119.6, 118.7, 111.3, 108.4, 106.9, 101.8, 99.2, 42.0, 39.6, 26.0, 18.2; HRMS (EI-TOF) calcd for C22H19NO4 [M]+: 361.1309, found: 361.1315; HPLC (Chiralpak IB, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 28.96 min (cis-minor), 31.45 min (cis-major), 56.53 min (trans-major + minor); (Chiralcel OD, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 20.55 min (cis-major + minor), 34.61 min (trans-major), 44.16 min (trans-minor). (7S,8S)-8-((E)-2-Methoxystyryl)-7-(1-methyl-1H-indol-3-yl)-7,8-dihydro-6H[1,3]dioxolo[4,5-g]chromen-6-one (3gp) Yellow oil, total yield (cis- and trans-isomers): 36.3 mg, 80%; 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.9 Hz, 1H, major), 7.30 (d, J = 8.1 Hz, 1H, major + minor), 7.24-7.15 (m, 3H, major


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+ minor), 7.11 (t, J = 7.4 Hz, 1H, major + minor), 6.95 (s, 1H, major), 6.82 (t, J = 7.5 Hz, 2H, major + minor), 6.74-6.67 (m, 3H, major + minor), 6.07 (dd, J = 15.9, 8.4 Hz, 1H, major), 5.98 (s, 2H, major), 5.96 (s, 2H, minor), 4.56 (d, J = 5.1 Hz, 1H, major), 4.39 (d, J = 4.0 Hz, 1H, minor), 4.06 (dd, J = 8.2, 5.2 Hz, 1H, major), 3.80 (s, 3H, minor), 3.74 (s, 3H, major), 3.72 (s, 3H, major), 3.65 (s, 3H, minor); 13C NMR (100 MHz, CDCl3) δ (major + minor) 168.9, 156.8, 147.6, 145.9, 144.5, 136.6, 128.9, 128.8, 128.1, 127.9, 127.1, 126.7, 125.6, 122.0, 120.7, 119.6, 118.8, 118.7, 111.0, 109.5, 107.4, 106.4, 101.8, 99.2, 55.5, 46.0, 45.2, 42.5, 33.1; HRMS (EI-TOF) calcd for C28H23NO5 [M]+: 453.1571, found: 453.1577; HPLC (Chiralpak IF, hexane/i-PrOH = 90/10, 0.8 mL/min, 220 nm) tR = 52.35 min (cis-minor), 59.33 min (trans-minor), 66.81 min (cis-major), 123.33 min (trans-major). (7S,8S)-8-((E)-4-Chlorostyryl)-7-(1-methyl-1H-indol-3-yl)-7,8-dihydro-6H-[1,3]dioxolo[4,5g]chromen-6-one (3bp) White solid, mp: > 200 °C (for cis-isomer), total yield (cis- and trans-isomers): 41.2 mg, 90%; 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.0 Hz, 1H, major), 7.32 (d, J = 8.2 Hz, 1H, major), 7.287.17 (m, 3H, major + minor), 7.14-7.08 (m, 3H, major + minor), 7.03 (s, 1H, major), 6.72 (s, 1H, major), 6.64 (s, 1H, major), 6.27 (d, J = 2.8 Hz, 1H, minor), 6.23 (d, J = 15.8 Hz, 1H, major), 6.04 (dd, J = 15.9, 7.7 Hz, 1H, major), 5.99 (s, 2H, major), 4.57 (d, J = 5.2 Hz, 1H, major), 4.40 (d, J = 3.4 Hz, 1H, minor), 4.02 (dd, J = 7.5, 5.4 Hz, 1H, major), 3.74 (s, 3H, major), 3.64 (s, 3H, minor); 13C NMR (100 MHz, CDCl3) δ (major + minor) 168.5, 147.8, 145.9, 144.6, 136.7, 135.0, 133.5, 132.4, 128.8, 128.3, 127.8, 127.6, 127.1, 126.7, 122.1, 119.6, 118.8, 118.1, 109.7, 107.3, 106.3, 101.9, 99.3, 44.7, 42.6, 33.1; HRMS (EI-TOF) calcd for C27H20ClNO4 [M]+: 457.1075,



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found: 457.1075; HPLC (Chiralpak IF, hexane/i-PrOH = 80/20, 0.8 mL/min, 220 nm) tR = 25.17 min (cis-minor), 30.86 min (cis-major), 34.02 min (trans-minor), 55.13 min (trans-major). 1

H NMR (400 MHz, CDCl3) (for cis-3bp) δ 7.51 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H),

7.28-7.23 (m, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.12 (t, J = 7.8 Hz, 3H), 7.03 (s, 1H), 6.73 (s, 1H), 6.64 (s, 1H), 6.23 (d, J = 15.8 Hz, 1H), 6.09-5.97 (m, 3H), 4.58 (d, J = 5.2 Hz, 1H), 4.06-4.00 (m, 1H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) (for cis-3bp) δ 168.5, 147.8, 145.9, 144.6, 136.7, 135.0, 133.5, 132.4, 128.8, 128.3, 127.8, 127.6, 127.1, 122.1, 119.6, 118.8, 118.1, 109.7, 107.3, 106.3, 101.9, 99.3, 44.7, 42.6, 33.1. 1

H NMR (400 MHz, CDCl3) (for trans-3bp) δ 7.73 (d, J = 7.9 Hz, 1H), 7.32-7.11 (m, 7H), 6.64

(s, 2H), 6.58 (s, 1H), 6.26 (d, J = 2.7 Hz, 2H), 5.98 (d, J = 6.6 Hz, 2H), 4.40 (d, J = 3.5 Hz, 1H), 4.00 (dd, J = 5.7, 2.9 Hz, 1H), 3.63 (s, 3H); 13C NMR (100 MHz, CDCl3) (for trans-3bp) δ 167.8, 147.8, 145.7, 144.7, 136.8, 134.9, 133.6, 131.0, 129.7, 128.8, 127.8, 126.8, 126.7, 122.4, 119.8, 119.0, 115.8, 109.6, 108.5, 107.9, 101.9, 99.2, 45.3, 43.0, 33.0. ASSOCIATED CONTENT Supporting Information Experimental details, characterization of new compounds, crystallographic data, chiral HPLC chromatograms and NMR spectrums. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author [email protected] Notes


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Asymmetric Synthesis of cis-3,4-Dihydrocoumarins via [4 + 2

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