Asymmetric Cycloaddition of ortho-Hydroxyphenyl Substituted para

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Asymmetric Cycloaddition of ortho-Hydroxyphenyl Substituted paraQuinone Methides and Enamides Catalyzed by Chiral Phosphoric Acid Guo-Hui Yang, Qun Zhao, Zhi-Pei Zhang, Han-Liang Zheng, Li Chen, and Xin Li J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00749 • Publication Date (Web): 28 May 2019 Downloaded from http://pubs.acs.org on May 28, 2019

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The Journal of Organic Chemistry

Asymmetric Cycloaddition of ortho-Hydroxyphenyl Substituted paraQuinone Methides and Enamides Catalyzed by Chiral Phosphoric Acid Guo-Hui Yang, Qun Zhao, Zhi-Pei Zhang, Han-Liang Zheng, Li Chen, Xin Li* State key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 (China). E-mail: [email protected]

Abstract: A BINOL-based chiral phosphoric acid was employed as an efficient catalyst in enantioselective cycloaddition of ortho-hydroxyphenyl substituted para-quinone methides and enamides, which gave rise to acetamido-substituted tetrahydroxanthenes with three adjacent stereogenic centers in high yields (up to 99%) and excellent stereoselectivities (up to > 99:1 dr and up to 98% ee).

Introduction Para-quinone methides (p-QMs), which containing electrophilic character at the δ-position for the zwitterionic resonance structure of a cyclohexadiene moiety in para-conjugation with a carbonyl group, are excellent reactive intermediates in many chemical and biological processes.1 In 2013, pioneered by Fan, the first enantioselective 1,6-conjugate addition reaction of malonates to p-QMs was reported using phase-transfer catalysis.2 In 2014, Jørgensen described an αalkylation of aldehyde by employing p-QMs as alkylating agents catalyzed by enamine.3 From then on, the one-step 1,6-conjugate addition of p-QMs and various nucleophilic reagents had been well developed in many catalytic modes (Scheme 1a), such as phase transfer catalysis,2,4

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amine catalysis,3,5 transition metals catalysis,6 Brønsted acids catalysis,7 N-heterocyclic carbenes,8 organophosphorus catalysis,9 and so on10. On the other hand, Enders and coworkers developed an enantioselective cascade oxa-Michael/1,6-addition reaction of ortho-hydroxyphenylsubstituted pQMs and isatin-derived enoates in 2016,5c which opened up an important strategy for the asymmetric synthesis of complex skeleton by using p-QMs as building blocks (Scheme 1b). Over the next two years, a number of similar series reactions have been reported.11 Although mentioned above endeavors have been paid in this area, there is still greater room to overcome several limitations, such as harsh reaction conditions, larger catalyst loadings or longer reaction times. Therefore, the exploration of highly efficient strategies for the meaningful reactions of orthohydroxyphenyl substituted p-QMs under mild conditions is still a great challenge and highly desirable. Scheme 1. Different ways for the Addition of p-QMs.


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Figure 1. Examples of biological chiral chroman compounds with three consecutive stereocenters Chroman compounds, including chiral 4H-chromene derivatives, are a kind of privileged scaffold widespread existing in many bioactive molecules, natural products and pharmaceutically compounds.12 For example, psiguadials B−D (Figure 1), which skeletons have three consecutive stereocenters, exhibited potent cytotoxicity against the HepG2 human hepatoma cancer cell line.12e,f Because of their extensive applications,13 much attention has been focused on enantioselective synthesis of chiral chroman type skeletons. As a result, numerous practical routes have been established,14 including bicyclic construction, C−C cross coupling reactions and so on. On the other hand, enamides have been employed as highly reactive nucleophiles in various cycloaddition reactions based on its stable ketone enol surrogates.15 Recently, Schneider described the cycloaddition reactions between ortho-hydroxy benzhydryl alcohol and enamides, which accessed to the chroman skeleton compounds with excellent diastereoselectivities and enantioselectivities15c. To our best knowledge, the cascade reaction between ortho-hydroxyphenyl substituted p-QMs and enamides haven't been reported yet. We speculated that the privileged chiral chroman skeletons could be generated via cycloaddition of ortho-hydroxyphenyl substituted p-QMs and enamides (Scheme 1c). Guided by our ongoing interest in the enantioselective synthesis using p-QM building blocks,7d, 10a, 11d and 11f herein, we reported a chiral phosphoric acid catalyzed cycloaddition of ortho-hydroxyphenyl substituted p-QMs and enamides. It is valuable to note that the resulted chiral acetamidotetrahydroxanthenes could be translated into chiral 4H-chromenes by further deacetylation.

Results and discussion For our initial investigations, we selected the reaction of ortho-hydroxyphenyl substituted pQM 1a and enamine 2a as the model substrates with 5 mol% chiral phosphoric acid catalyst A1 in dichloromethane at room temperature. To our delight, the reaction could be completed in ten minutes, and transformed into product 3a almost quantitative with 95:5 dr and 48% ee (Table 1, entry 1). For the purpose of improving the enantioselectivity, we next evaluated the phosphoric acid catalysts with different substituents and skeletons (Table 1, entries 2-10). As showed in Table 1, we found that catalyst A3, which containing large hindrance substituent on the naphthalene ring, showed the best enantioselectivity (95% yield, 96:4 dr and 96% ee). When the catalyst loading was reduced to 2 mol%, the yield and ee value of 3a were almost maintained but required prolonging the reaction time from 10 min to 60 min (Table 1, entry 11). Further reducing the ACS Paragon Plus Environment


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catalyst loading to 1 mol% resulted in longer reaction time and lower product yield (Table 1, entry 12). Then some solvents were screened with 2 mol% A3, in which the initial used dichloromethane was determined as the best reaction medium (Table 1, entries 11 and 13-17). Collectively, the best result with satisfactory yield and stereoselectivity was obtained by conducting the reaction at room temperature in dichloromethane with 2 mol % of A3. Under the optimized conditions, the chiral chroman skeleton product 3a was obtained in 93% yield with 95:5 dr and 96% ee (Table 1, entry 11). Table 1. Reaction optimization.a

entry

cat./ 5 mol %

solvent

time

yield/%b

drc

eed

1

A1

CH2Cl2

10 min

96

95:5

48

2

A2

CH2Cl2

10 min

99

90:10

47

3

A3

CH2Cl2

10 min

95

96:4

96

4

A4

CH2Cl2

10 min

98

97:3

93

5

A5

CH2Cl2

24 h

74

77:23

10

6

A6

CH2Cl2

10 min

91

89:11

43

7

A7

CH2Cl2

10 min

87

90:10

3

8

A8

CH2Cl2

10 min

93

87:13

15

9

B1

CH2Cl2

10 min

92

96:4

96

10

C1

CH2Cl2

10 min

trace

/

/

11e

A3

CH2Cl2

60 min

93

95:5

96

12 f

A3

CH2Cl2

150 min

68

95:5

96

13 e

A3

THF

60 min

trace

/

/

14 e

A3

CHCl3

60 min

28

92:8

87

15 e

A3

Et2O

60 min

16

91:9

96


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16 e

A3

toluene

60 min

85

82:18

94

17e

A3

c-hexane

60 min

60

81:19

88

The reactions were conducted with 1a (0.1 mmol), 2a (0.1 mmol), cat. (5 mol%), in 1 ml CH2Cl2 at room temperature. b Isolated yield of the product. c,d Determined by HPLC analysis. e Using 2 mol% A3. f Using 1 mol% A3.

a

With the optimized reaction conditions in hand, we then surveyed the scope of the reaction. Firstly, different substituted ortho-hydroxyphenyl p-QMs were investigated by conducting the reaction with 2a. As shown in Table 2, both electron-donating and electron-withdrawing substituents on the R1 or R2 position of phenyl ring were well tolerated in this asymmetric cycloaddition reaction. And the corresponding products 3a-3i were afforded in 73-99% yields, 82:18-96:4 dr and 92-98% ee. The results indicated that the diastereoselectivities of halogen substituted substrates (F, Cl and Br) are lower than the others substituted substrates (Me and MeO). Table 2. The Substrate Scope of the p-QMs.a

The reactions were conducted with 1 (0.1 mmol), 2a (0.1 mmol), A3 (2 mol%), in 1 ml CH2Cl2 at room temperature for 60 min; isolated yield; the dr values were determined by 1H NMR; the ee values were determined by HPLC analysis. b At room temperature for 20 min. c The reactions were conducted with 5 mol% A3 at -20 oC for 180 min. a



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Further exploration of the reaction scope focused on varying the R’ substituents on the aryl moiety of enamides 2. As shown in Table 3, the electronic nature and relative position of the substituents had little influence on neither the yields nor the enantioselectivities (3j-3p, 79–99% yield and 92–98% ee). However, for the product of 3n (R3 = R5 = H, R4 = MeO), only 64:36 dr was obtained. Moreover, we found that the methodology can work with chromane type enamides, in which corresponding products 3q and 3r were obtained with very good yields and stereoselectivities with 5 mol% catalyst at -20 oC. In addition, enamine without benzene ring was also tolerated in this strategy that gave the desired product 3s with 99:1 dr and 81% ee. Finally, we also examined the chain enamine. To our delight, the desired product 3t was delivered in 83% yield with 90:10 dr and 93% ee under the standard conditions. The absolute configuration of 3a was determined by X-ray diffraction analysis.16 The configurations of other products were tentatively assigned by referring to that of 3a. Table 3. The Substrate Scope of Enamides.a


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The reactions were conducted with 1a (0.1 mmol), 2 (0.1 mmol), A3 (2 mol%), in 1 ml CH2Cl2 at room temperature for 60 min; isolated yield; the dr values were determined by 1H NMR; the ee values were determined by HPLC analysis. b At room temperature for 20 min. c The reactions were conducted with 5 mol% A3 at -20 oC for 180 min. a

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To probe the efficiency of current studied asymmetric cycloaddition reaction, a large scale reaction of 1a and 2a was investigated under only 1 mol% catalyst loading (Scheme 2). To our delight, the product 3a was obtained without any loss of reactivity and stereoselectivity (96% yield, 95:5 dr and 96% ee). Further de-acetylation of 3a by 6 N hydrochloric acid solution afforded 4 with 84% yield. Treating 4 with aluminum trichloride dissolved in toluene acquired 5 in 41% yield with retentive 97% ee (Scheme 2). Scheme 2. Large Scale Reaction and Transformation of Product.

Scheme 3. Plausible Reaction Pathways.



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Based on previous study15a,c,d and 11f and X-ray result,16 the plausible reaction pathway was proposed. As shown in Scheme 3, in Path A, the OH group of chiral phosphoric acid A3 activates p-QM and carbonyl activates N-H group of enamine, the Si face of the p-QM is attacked by the activated enamine in 1,6-addition affording intermediate. The following intramolecular oxygen attack on C=N double bond completed the cyclization process, which gave the motive product. Otherwise, enlightened by Schneider’s works on the enantioselective addition of enamides to in situgenerated ortho-quinone methides15a,c, Path B was also proposed. Since the calculated isomerization energy between p-QM 1a and o-QM 1a’ is only 7.0 kcal/mol,17 which indicated that 1a could convert to 1a’ easily under room temperature. Furthermore, when using the hydroxy protected substrate 1, no reaction happened. Based on the above analysis, the Path B is more reasonable. However, Path A can not be totally ruled out.

Conclusion


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In summary, we have developed an enantioselective cascade reaction between orthohydroxyphenyl substituted p-QMs and enamides catalyzed by a chiral phosphoric acid. The reaction is very efficient and mild, in which most reactions can be completed in less than an hour with only 2 mol% catalyst loading at room temperature. As a result, a series of acetamidosubstituted tetrahydroxanthenes were obtained in high yields (up to 99%) with excellent diastereoselectivities (up to >99:1 dr) and enantioselectivities (up to 98% ee).

General Information Commercial reagents and solvents were used as received without further purification, unless otherwise stated. 1H NMR, 13C NMR spectra were recorded on a Bruker Avance 400 (400 MHz) spectrometer. And 19F NMR were reported on a Bruker Avance (376 MHz) spectrometer. Chemical shifts for protons are reported in ppm and are referenced to the NMR solvent peak (CDCl3: δ 7.26, DMSO-d6: δ 2.50). Chemical shifts for carbons are reported in ppm and are referenced to the carbon resonances of the NMR solvent. The following abbreviations were used to designate chemical shift multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. All first-order splitting patterns were assigned on the basis of the appearance of the multiplet. Splitting patterns that could not be easily interpreted were designated as a multiplet (m). The diastereomeric excess were determined by NMR analysis and the enantiomeric excesses were determined by HPLC analysis, which employed a chiral stationary phase column specified in the individual experiment, by comparing the samples with the appropriate racemic mixtures. Mass spectra were obtained using an electrospray ionization (ESI) mass spectrometer. The ortho-hydroxyphenyl-substituted para-quinone methides (p-QMs) 1a−1i are known compounds that prepared according to the reported literature procedures.5c, 6d, 18a,b The enamides 2a−2l are known compounds that prepared according to the reported literature procedures.15, 18c,d,e And we added some relevant proton NMR spectra in SI. Procedures for the derivatization. The compound 1a (1.5 mmol), 2a (1.6 mmol, 1.1 equiv) and catalyst A3 (1 mol%) were added to a 50 mL glass reactor, and then 10 mL CH2Cl2 was added. The reaction was stirred at room temperature for 60 min. The mixture was chromatographed on a silica gel column eluted with PE:EA = 5:1 to afford the desired product 3a. The compound 3a (0.2 mmol) was dissolved in 3 mL CH2Cl2, and 6 N THF solution (3 mL) was added. The reaction was stirred at room temperature for 60 min. The mixture was chromatographed on a silica gel column eluted with PE:EA = 10:1 to afford the desired product 4 in 84% yield. The compound 4 (0.17 mmol ) was dissolved in 10 mL toluene, AlCl3 (6.0 equiv) was added in batches at 0 oC. The reaction mixture was allowed to be cooled to room temperature, quenched the reaction with water 6 hours later, and extracted with EtOAc (3 × 15 mL). The organic phase was separated, dried over MgSO4 and concentrated under reduced pressure. The obtained crude product was chromatographed on a silica gel column eluted with PE:EA = 10:1 to afford the desired product 5 in 41% yield. Characterization of products N-((6aR,7S,12aS)-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6,6a,7-tetrahydro-12aH-benzo[c]xanthenACS Paragon Plus Environment


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12a-yl)acetamide (3a)

White foam, Yield: 46.3 mg, 93%, 1H NMR (400 MHz, Chloroform-d) δ 7.68 (dd, J = 7.7, 1.6 Hz, 1H), 7.26 (td, J = 7.1, 1.6 Hz, 1H), 7.20 (m, 2H), 7.15 – 7.09 (m, 1H), 6.97 (m, 3H), 6.81 – 6.68 (m, 2H), 5.75 (s, 1H), 5.12 (s, 1H), 3.84 (ddd, J = 9.4, 6.2, 3.3 Hz, 1H), 3.76 (d, J = 8.8 Hz, 1H), 2.97 (t, J = 7.0 Hz, 2H), 2.07 (dtd, J = 15.0, 7.6, 3.3 Hz, 1H), 1.76 (dq, J = 14.2, 6.1 Hz, 1H), 1.70 (s, 3H), 1.41 (s, 18H). 13C NMR (100 MHz, Chloroform-d) δ 168.7, 152.6, 152.4, 137.6, 136.9, 135.9, 133.8, 130.4, 129.3, 128.8, 127.7, 126.9, 125.8, 125.3, 124.6, 120.8, 116.9, 86.8, 43.7, 37.1, 34.5, 30.5, 25.4, 24.2, 23.0. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C33H39NO3Na 520.2822; Found 520.2827. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. Major isomer: t1 = 5.75 min, t2 = 7.22 min; Minor isomer: t1 = 6.44 min, t2 = 8.15 min. [α]D25 -18.4 (c 1.0, CHCl3).

N-((6aR,7S,12aS)-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-9-methyl-5,6,6a,7-tetrahydro-12aHbenzo[c]xanthen-12a-yl)acetamide (3b)

Semisolid, Yield: 48.1 mg, 94%, 1H NMR (400 MHz, Chloroform-d) δ 7.63 (dd, J = 7.6, 1.6 Hz, 1H), 7.29 – 7.11 (m, 3H), 6.92 (d, J = 11.6 Hz, 3H), 6.84 (d, J = 8.3 Hz, 1H), 6.62 – 6.55 (m, 1H), 5.68 (s, 1H), 5.11 (s, 1H), 3.76 (m, 2H), 2.96 (q, J = 6.4 Hz, 2H), 2.14 (s, 3H), 2.09 – 1.98 (m, 1H), 1.74 (m, 1H), 1.58 (s, 3H), 1.40 (s, 18H). 13C NMR (100 MHz, Chloroform-d) δ 168.5, 152.2, 150.1, 137.6, 136.8, 135.7, 134.2, 130.8, 129.9, 129.1, 128.6, 128.4, 126.7, 125.7, 125.1, 123.4, 116.7, 86.6, 43.9, 37.5, 34.4, 30.4, 25.9, 24.0, 23.7, 20.6. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C34H41NO3Na 534.2979; Found 534.2982. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 1:19), 1.0 mL/min. Major isomer: t1 = 5.58 min, t2 = 6.06 min; Minor isomer: t1 = 8.11 min, t2 = 11.86 min. [α]D25 -12.4 (c 0.5, CHCl3).

N-((6aR,7S,12aS)-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-9-methoxy-5,6,6a,7-tetrahydro-12aHbenzo[c]xanthen-12a-yl)acetamide (3c)

Semisolid, Yield: 52.2 mg, 99%, 1H NMR (400 MHz, Chloroform-d) δ 7.64 (dd, J = 7.5, 1.6 Hz, 1H), 7.32 – 7.09 (m, 3H), 6.95 (s, 2H), 6.89 (d, J = 8.9 Hz, 1H), 6.70 (dd, J = 8.9, 3.0 Hz, 1H), 6.28 (d, J = 3.0 Hz, 1H), 5.72 (s, 1H), 5.11 (s, 1H), 3.80 (td, J = 7.6, 7.1, 3.3 Hz, 1H), 3.73 (d, J = 8.4 Hz, 1H), 3.60 (s, 3H), 2.95 (t, J = 6.8 Hz, 2H), 2.04 (s, 1H), 1.79 – 1.74 (m, 1H), 1.65 (s, 3H), 1.40 (s,18H). 13C NMR (100 MHz, Chloroform-d) δ 168.7, 153.6, 152.4, 146.6, 137.6, 136.9, 135.9, 133.7, 129.2, 128.7, 126.8, 125.8, 125.2, 125.1, 117.6, 115.0, 114.0, 86.7, 55.8, 44.2, 37.2, 34.5, 30.5, 25.6, 24.2, 23.3. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C34H41NO4Na 550.2928; Found 550.2933. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 1:19), 1.0 mL/min. Major isomer: t1 = 13.13 min, t2 = 19.35 min; Minor isomer: t1 = 15.37 min, t2 = 27.17 min. [α]D25 -29.6 (c 1.0, CHCl3).

N-((6aR,7S,12aS)-9-chloro-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6,6a,7-tetrahydro-12aHbenzo[c]xanthen-12a-yl)acetamide (3d)

Semisolid, Yield: 50.6 mg, 95%, 1H NMR (400 MHz, Chloroform-d) δ 7.65 (dd, J = 7.7, 1.4 Hz, 1H), 7.32 – 7.15 (m, 3H), 7.12 – 7.01 (m, 1H), 6.97 – 6.86 (m, 3H), 6.64 (d, J = 2.0 Hz,lk 1H), 5.81 (s, 1H), 5.16 (s, 1H), 3.83 (dt, J = 9.3, 4.4 Hz, 1H), 3.66 (d, J = 9.8 Hz, 1H), 2.94 (td, J = 8.6, 7.8, 5.5 Hz, 2H), 2.05 (m, 1H), 1.79 (s, 3H), 1.74 – 1.67 (m, 1H), 1.42 (s, 18H). 13C NMR (100 MHz, Chloroform-d) δ 168.8, 152.6, 151.4, 137.0, 136.7, 136.0, 132.6, 129.5, 129.3, 128.9, 127.6, 126.9, 125.7, 125.3, 125.2, 118.1, 87.0, 43.4, 36.6, 34.4, 30.4, 24.6, 24.3, 22.2. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C33H38ClNO3Na 554.2432; Found 554.2436. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 3:97), 1.0 mL/min. Major isomer: t1 = 8.93 min, t2 = 10.53 min; Minor isomer: t1 = 15.63 min, t2 = 23.32 min. [α]D25 -36.4 (c 1.0, CHCl3).

N-((6aR,7S,12aS)-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-9-fluoro-5,6,6a,7-tetrahydro-12aHbenzo[c]xanthen-12a-yl)acetamide (3e)

Semisolid, Yield: 51.1 mg, 99%, 1H NMR (400 MHz, Chloroform-d) δ 7.67 (dd, J = 7.6, 1.6 Hz, 1H), 7.31 – 7.15 (m, 3H), 6.96 – 6.88 (m, 3H), 6.80 (dt, J = 8.8, 4.1 Hz, 1H), 6.35 (dd, J = 9.5, 3.0 Hz, 1H), 5.81 (s, 1H), 5.15 (s, 1H), 3.86 (ddd, J = 9.2, 5.2, 3.5 Hz, 1H), 3.67 (d, J = 10.0 Hz, 1H), 3.07 – 2.87 (m, 2H), 2.15 – 1.98 (m, 1H), 1.80 (s, 3H), 1.74 (ddd, J = 14.5, 6.9, 4.6 Hz, 1H), 1.42 (s, 18H). 13C NMR (100 MHz, Chloroform-d) δ 168.9, 157.1 (d, J = 237.8 Hz), 152.7, 148.8, 137.3, 136.8, 136.1, 132.8, 129.4, 128.9, 127.0, 126.8 (d, J = 7.0 Hz), 125.8, 125.3, 117.7 (d, J = 8.1 Hz), 115.8 (d, J = 23.3 Hz), 114.5 (d, J = 23.6 Hz), 87.0, 43.6, 36.5, 34.5, 30.5, 24.6, 24.4, 22.2. HRMS (QFT-ESI) m/z: [M+Na]+ ACS Paragon Plus Environment

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calcd for C33H38FNO3Na 538.2728; Found 538.2732. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 3:97), 1.0 mL/min. Major isomer: t1 = 10.80 min, t2 = 12.18 min; Minor isomer: t1 = 21.89 min, t2 = 33.12 min. [α]D25 -22.6 (c 1.0, CHCl3).

N-((6aR,7S,12aS)-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-10-methyl-5,6,6a,7-tetrahydro-12aHbenzo[c]xanthen-12a-yl)acetamide (3f)

Semisolid, Yield: 48.1 mg, 94%, 1H NMR (400 MHz, Chloroform-d) δ 7.66 (dd, J = 7.5, 1.6 Hz, 1H), 7.29 – 7.13 (m, 3H), 6.95 (s, 2H), 6.78 (s, 1H), 6.58 (s, 2H), 5.74 (s, 1H), 5.10 (s, 1H), 3.79 (ddd, J = 9.6, 6.3, 3.3 Hz, 1H), 3.70 (d, J = 8.8 Hz, 1H), 2.94 (d, J = 7.0 Hz, 2H), 2.26 (s, 3H), 2.04 (qt, J = 8.0, 3.1 Hz, 1H), 1.80 – 1.70 (m, 1H), 1.69 (s,3H), 1.40 (s, 18H). 13C NMR (100 MHz, Chloroform-d) δ 168.7, 152.3, 137.6, 137.5, 136.8, 135.7, 133.9, 130.0, 129.2, 128.6, 126.8, 125.8, 125.2, 121.7, 121.4, 117.2, 86.7, 43.3, 37.1, 34.4, 30.5, 25.3, 24.2, 22.9, 21.1. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C34H41NO3Na 534.2979; Found 534.2982. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 3:97), 1.0 mL/min. Major isomer: t1 = 7.40 min, t2 = 8.60 min; Minor isomer: t1 = 13.71 min, t2 = 16.33 min. [α]D25 -2.4 (c 1.0, CHCl3).

N-((6aR,7S,12aS)-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-10-methoxy-5,6,6a,7-tetrahydro-12aHbenzo[c]xanthen-12a-yl)acetamide (3g)

Semisolid, Yield: 49.1 mg, 93%, 1H NMR (400 MHz, Chloroform-d) δ 7.66 (dd, J = 7.7, 1.5 Hz, 1H), 7.31 – 7.12 (m, 3H), 6.94 (s, 2H), 6.60 (d, J = 8.5 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.37 (dd, J = 8.6, 2.6 Hz, 1H), 5.73 (s, 1H), 5.10 (s, 1H), 3.76 (s, 4H), 3.68 (d, J = 8.7 Hz, 1H), 2.96 (t, J = 7.0 Hz, 2H), 2.11 – 1.97 (m, 1H), 1.75 (dt, J = 14.0, 6.3 Hz, 1H), 1.68 (s, 3H), 1.40 (s, 18H). 13C NMR (100 MHz, Chloroform-d) δ 168.7, 159.2, 153.2, 152.2, 137.4, 136.8, 135.8, 134.1, 131.0, 129.2, 128.7, 126.8, 125.7, 125.1, 116.5, 108.0, 101.3, 86.9, 55.3, 43.0, 37.3, 34.4, 30.4, 25.4, 24.1, 22.9. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C34H41NO4Na 550.2928; Found 550.2933. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 3:97), 1.0 mL/min. Major isomer: t1 = 9.96 min, t2 = 12.60 min; Minor isomer: t1 = 21.66 min, t2 = 23.96 min. [α]D25 -2.4 (c 1.0, CHCl3).

N-((6aR,7S,12aS)-10-chloro-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6,6a,7-tetrahydro-12aHbenzo[c]xanthen-12a-yl)acetamide (3h)

Semisolid, Yield: 42.0 mg, 79%, 1H NMR (400 MHz, Chloroform-d) δ 7.95 (dd, J = 7.7, 1.5 Hz, 1H), 7.60 – 7.43 (m, 3H), 7.26 (d, J = 2.2 Hz, 1H), 7.22 (s, 2H), 6.98 (dd, J = 8.3, 2.2 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.12 (s, 1H), 5.42 (s, 1H), 4.12 (dt, J = 9.2, 4.0 Hz, 1H), 3.92 (d, J = 10.2 Hz, 1H), 3.37 – 3.01 (m, 2H), 2.35 (dtd, J = 13.9, 7.2, 6.8, 3.6 Hz, 1H), 2.09 (s, 3H), 2.04 – 1.94 (m, 1H), 1.69 (s, 18H). 13C NMR (100 MHz, Chloroform-d) δ 168.9, 153.5, 152.6, 137.1, 136.7, 136.0, 132.8, 132.5, 130.9, 129.3, 128.9, 127.0, 125.8, 125.3, 124.1, 120.8, 116.8, 87.2, 42.9, 36.5, 34.42, 30.4, 24.4, 24.3, 22.0, 19.2. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C33H38ClNO3Na 554.2432; Found 554.2435. The enantiomeric excess was determined by HPLC with an IF column at 210 nm (2-propanol/hexane 3:97), 1.0 mL/min. Major isomer: t1 = 10.14 min, t2 = 11.34 min; Minor isomer: t1 = 13.33 min, t2 = 16.48 min. [α]D25 -41.8 (c 1.0, CHCl3).

N-((6aR,7S,12aS)-10-bromo-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6,6a,7-tetrahydro-12aHbenzo[c]xanthen-12a-yl)acetamide (3i)

Semisolid, Yield: 42.1 mg, 73%, 1H NMR (400 MHz, Chloroform-d) δ 7.68 (dd, J = 7.6, 1.6 Hz, 1H), 7.32 – 7.17 (m, 3H), 7.14 (d, J = 2.0 Hz, 1H), 6.94 – 6.91 (m, 2H), 6.84 (dd, J = 8.3, 2.0 Hz, 1H), 6.48 (dd, J = 8.2, 1.1 Hz, 1H), 5.83 (s, 1H), 5.15 (s, 1H), 3.85 (dd, J = 9.9, 4.7 Hz, 1H), 3.61 (d, J = 10.3 Hz, 1H), 3.09 – 2.67 (m, 2H), 2.14 – 2.01 (m, 1H), 1.83 (s, 3H), 1.76 – 1.67 (m, 1H), 1.41 (s, 18H). 13C NMR (100 MHz, Chloroform-d) δ 169.0, 153.7, 152.7, 137.1, 136.7, 136.1, 132.8, 131.3, 129.4, 129.0, 127.1, 125.9, 125.4, 124.7, 123.7, 120.4, 119.8, 87.3, 43.0, 36.5, 34.5, 30.5, 24.4, 22.0. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C33H38BrNO3Na 598.1927; Found 598.1930. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 2:98), 1.0 mL/min. Major isomer: t1 = 8.86 min, t2 = 9.71 min; Minor isomer: t1 = 11.13 min, t2 = 13.27 min. [α]D25 -44.8 (c 1.0, CHCl3).

N-((6aR,7S,12aS)-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-methyl-5,6,6a,7-tetrahydro-12aHbenzo[c]xanthen-12a-yl)acetamide (3j)



Page 12 of 22

Semisolid, Yield: 50.7 mg, 99%, 1H NMR (400 MHz, Chloroform-d) δ 7.57 (t, J = 4.6 Hz, 1H), 7.13 (d, J = 4.7 Hz, 2H), 7.11 – 7.04 (m, 1H), 6.95 (t, J = 3.7 Hz, 3H), 6.73 (td, J = 7.4, 1.3 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 5.78 (s, 1H), 5.11 (s, 1H), 3.84 (ddd, J = 9.3, 5.7, 3.3 Hz, 1H), 3.71 (d, J = 9.3 Hz, 1H), 2.75 (td, J = 7.0, 6.6, 3.8 Hz, 2H), 2.25 (s, 3H), 2.15 – 2.04 (m, 1H), 1.86 – 1.64 (m, 4H), 1.40 (s, 18H). 13C NMR (100 MHz, Chloroform-d) δ 168.7, 152.7, 152.3, 137.5, 136.7, 135.8, 135.2, 133.7, 130.2, 130.2, 127.5, 126.5, 125.3, 124.8, 123.5, 120.6, 116.8, 87.0, 43.4, 36.3, 34.4, 30.4, 24.3, 22.9, 22.4, 19.7. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C34H41NO3Na 534.2979; Found 534.2983. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 2:98), 1.0 mL/min. Major isomer: t1 = 9.67 min, t2 = 11.57 min; Minor isomer: t1 = 17.82 min, t2 = 20.81 min. [α]D25 -48.8 (c 1.0, CHCl3).

N-((6aR,7S,12aS)-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-methoxy-5,6,6a,7-tetrahydro-12aHbenzo[c]xanthen-12a-yl)acetamide (3k)

Semisolid, Yield: 52.2 mg, 99%, 1H NMR (400 MHz, Chloroform-d) δ 7.32 (d, J = 7.9 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.97 (d, J = 3.0 Hz, 3H), 6.81 (d, J = 8.1 Hz, 1H), 6.74 (t, J = 7.4 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 5.77 (s, 1H), 5.11 (s, 1H), 3.84 (d, J = 1.3 Hz, 4H), 3.74 (d, J = 9.4 Hz, 1H), 2.78 (t, J = 7.3 Hz, 2H), 2.10 – 1.94 (m, 1H), 1.75 (m, 4H), 1.41 (s, 18H). 13C NMR (100 MHz, Chloroform-d) δ 168.7, 157.0, 152.7, 152.3, 138.5, 135.7, 133.9, 130.3, 127.5, 127.3, 125.8, 125.4, 124.9, 120.6, 117.5, 116.8, 109.7, 86.7, 55.5, 43.3, 36.5, 34.4, 30.5, 24.3, 21.9, 19.3. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C34H41NO4Na 550.2928; Found 550.2932. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 3:97), 1.0 mL/min. Major isomer: t1 = 9.67 min, t2 = 11.84 min; Minor isomer: t1 = 15.18 min, t2 = 26.11 min. [α]D25 -30.0 (c 1.0, CHCl3).

N-((6aR,7S,12aS)-4-bromo-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6,6a,7-tetrahydro-12aHbenzo[c]xanthen-12a-yl)acetamide (3l)

Semisolid, Yield: 54.8 mg, 95%, 1H NMR (400 MHz, Chloroform-d) δ 7.69 – 7.63 (m, 1H), 7.52 (dd, J = 7.8, 1.2 Hz, 1H), 7.16 – 7.05 (m, 2H), 6.94 (d, J = 6.9 Hz, 3H), 6.83 – 6.71 (m, 2H), 5.73 (s, 1H), 5.12 (s, 1H), 3.84 – 3.63 (m, 2H), 2.90 (t, J = 6.9 Hz, 2H), 2.06 (ddq, J = 13.5, 6.4, 4.0, 3.6 Hz, 1H), 1.79 (dq, J = 12.8, 6.2 Hz, 1H), 1.65 (s, 3H), 1.40 (s, 18H). 13C NMR (100 MHz, Chloroform-d) δ 168.7, 152.3, 152.2, 139.8, 136.5, 135.9, 133.6, 132.9, 130.5, 128.0, 127.8, 125.4, 125.1, 125.1, 124.1, 121.0, 116.9, 86.5, 43.5, 36.7, 34.4, 30.4, 27.0, 24.1, 22.7. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C33H38BrNO3Na 598.1927; Found 598.1930. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 2:98), 1.0 mL/min. Major isomer: t1 = 15.03 min, t2 = 19.38 min; Minor isomer: t1 = 23.88 min. [α]D25 -24.0 (c 1.0, CHCl3).

N-((6aR,7S,12aS)-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methyl-5,6,6a,7-tetrahydro-12aHbenzo[c]xanthen-12a-yl)acetamide (3m)

Semisolid, Yield: 44.5 mg, 87%, 1H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 8.0 Hz, 1H), 7.09 (td, J = 7.7, 7.1, 1.8 Hz, 1H), 7.03 – 6.96 (m, 2H), 6.97 – 6.90 (m, 3H), 6.75 (td, J = 7.4, 1.2 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 5.72 (s, 1H), 5.10 (s, 1H), 3.87 – 3.63 (m, 2H), 3.01 – 2.67 (m, 2H), 2.29 (s, 3H), 1.74 (dd, J = 13.9, 6.1 Hz, 1H), 1.68 (s, 3H), 1.62 (s, 1H), 1.39 (s, 18H). 13C NMR (100 MHz, Chloroform-d) δ 168.6, 152.6, 152.2, 138.4, 136.6, 135.8, 134.7, 133.8, 130.2, 129.7, 127.6, 127.6, 125.7, 125.2, 124.5, 120.6, 116.8, 86.3, 43.6, 37.1, 34.4, 30.4, 25.2, 24.1, 23.0, 21.1. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C34H41NO3Na 534.2979; Found 534.2982. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 2:98), 1.0 mL/min. Major isomer: t1 = 10.03 min, t2 = 12.11 min; Minor isomer: t1 = 20.14 min, t2 = 27.19 min. [α]D25 -4.8 (c 1.0, CHCl3).

N-((6aR,7S,12aS)-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-methoxy-5,6,6a,7-tetrahydro-12aHbenzo[c]xanthen-12a-yl)acetamide (3n)

Semisolid, Yield: 41.2 mg, 79%, 1H NMR (400 MHz, Chloroform-d) δ 7.56 (d, 8.7 Hz, 1H), 7.21 – 6.56 (m, 8H), 5.74 (s, 1H), 5.12 (s, 1H), 3.78 (m, 4H), 3.77 – 2.79 (m, 3H), 1.87 – 1.55 (m, 4H), 1.41 (s, 18H). 13C NMR (100 MHz, Chloroform-d) δ 168.7, 168.7, 159.7, 159.7, 152.6, 152.6, 152.3, 151.8, 139.5, 138.5, 135.8, 135.5, 133.9, 130.8, 130.4, 130.1, 130.0, 129.4, 127.8, 127.7, 127.3, 127.2, 126.8, 125.3, 124.5, 123.6, 121.4, 120.7, 117.3, 116.9, 113.7, 113.4, 113.0, 112.9, 87.8, 86.8, 55.3, 43.7, 42.4, 38.7, 37.2, 34.5, 34.5, 30.6, 30.5, 25.7, 24.2, 23.4, 20.3. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C34H41NO4Na 550.2928; Found 550.2932. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 2:98), 1.0 mL/min. Major isomer: t1 = 17.14 min, t2 = 19.93 min; Minor isomer: t1 = 30.80 min, t2 = 47.07 min. [α]D25 -34.4 (c 1.0, CHCl3)


Page 13 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


N-((6aR,7S,12aS)-3-bromo-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,6,6a,7-tetrahydro-12aHbenzo[c]xanthen-12a-yl)acetamide (3o)

Semisolid, Yield: 57.1 mg, 99%, 1H NMR (400 MHz, Chloroform-d) δ 7.52 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 7.2 Hz, 2H), 7.19 – 7.09 (m, 1H), 6.94 (m, 3H), 6.81 (dt, J = 13.1, 7.5 Hz, 2H), 5.70 (s, 1H), 5.13 (s, 1H), 3.75 (m, 2H), 2.95 (m, 2H), 2.04 (ddd, J = 16.5, 8.2, 5.4 Hz, 1H), 1.77 (dt, J = 13.9, 6.6 Hz, 1H), 1.60 (s, 3H), 1.40 (s, 18H).13C NMR (100 MHz, Chloroform-d) δ 168.7, 152.4, 152.1, 139.3, 136.6, 136.0, 133.9, 131.9, 130.7, 130.0, 128.0, 127.8, 125.0, 123.8, 122.8, 121.1, 116.9, 86.4, 43.9, 37.6, 34.5, 30.5, 25.9, 24.0, 23.6. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C33H38BrNO3Na 598.1927; Found 598.1930. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 1:99), 1.0 mL/min. Major isomer: t1 = 24.53 min, t2 = 29.96 min; Minor isomer: t1 = 57.93 min. [α]D25 28.2 (c 1.0, CHCl3).

N-((6aR,7S,12aS)-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methoxy-5,6,6a,7-tetrahydro-12aHbenzo[c]xanthen-12a-yl)acetamide (3p)

Semisolid, Yield: 42.2 mg, 80%, 1H NMR (400 MHz, Chloroform-d) δ 7.18 – 7.12 (m, 2H), 7.07 (dd, J = 8.1, 6.7 Hz, 1H), 6.97 – 6.89 (m, 3H), 6.89 – 6.81 (m, 2H), 6.34 (s, 1H), 5.16 (s, 1H), 4.51 (d, J = 5.7 Hz, 0H), 3.80 (s, 1H), 3.23 (ddd, J = 11.8, 5.7, 4.1 Hz, 1H), 2.75 (dd, J = 8.3, 4.6 Hz, 2H), 2.05 (s, 2H), 1.71 – 1.53 (m, 1H), 1.43 (s, 18H). 13C NMR (100 MHz, Chloroform-d) δ 168.7, 158.1, 152.6, 151.7, 138.0, 135.6, 130.8, 130.1, 130.1, 127.8, 127.2, 123.7, 121.4, 117.3, 114.3, 111.2, 87.8, 55.4, 42.4, 38.6, 34.5, 30.6, 28.5, 24.2, 20.6. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C34H41NO4Na 550.2928; Found 550.2933. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 3:97), 1.0 mL/min. Major isomer: t1 = 14.55 min, t2 = 27.82 min; Minor isomer: t1 = 10.81 min, t2 = 12.87 min. [α]D25 -54.6 (c 1.0, CHCl3).

N-((6aS,7S,12aS)-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-6a,7-dihydro-6H,12aH-chromeno[4,3b]chromen-12a-yl)acetamide (3q)

Semisolid, Yield: 48.0 mg, 96%, 1H NMR (400 MHz, Chloroform-d) δ 7.59 (dd, J = 7.7, 1.7 Hz, 1H), 7.30 – 7.21 (m, 1H), 7.09 (td, J = 7.6, 7.0, 1.8 Hz, 1H), 7.01 (s, 2H), 6.99 – 6.83 (m, 3H), 6.76 – 6.63 (m, 2H), 6.09 (s, 1H), 5.16 (s, 1H), 4.40 (dd, J = 11.7, 2.0 Hz, 1H), 4.07 (dd, J = 11.7, 2.6 Hz, 1H), 3.93 – 3.78 (m, 2H), 1.91 (s, 3H), 1.42 (s, 19H). 13C NMR (100 MHz, Chloroform-d) δ 169.2, 154.4, 152.8, 152.5, 136.1, 132.7, 130.9, 130.0, 127.6, 126.2, 126.0, 124.9, 123.0, 121.3, 120.9, 117.0, 116.8, 83.0, 65.9, 41.3, 36.7, 34.5 , 30.5, 24.6. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C32H37NO4Na 522.2615; Found 522.2618. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 2:98), 1.0 mL/min. Major isomer: t1 = 13.79 min, t2 = 16.82 min; Minor isomer: t1 = 24.95 min, t2 = 30.06 min. [α]D25 -38.8 (c 1.0, CHCl3).

N-((6aS,7S,12aS)-7-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-fluoro-6a,7-dihydro-6H,12aHchromeno[4,3-b]chromen-12a-yl)acetamide (3r)

Semisolid, Yield: 45.0 mg, 87%, 1H NMR (400 MHz, Chloroform-d) δ 7.58 – 7.50 (m, 1H), 7.10 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 6.99 – 6.92 (m, 3H), 6.76 (td, J = 7.5, 1.3 Hz, 1H), 6.70 (dd, J = 7.9, 1.8 Hz, 1H), 6.65 – 6.56 (m, 4H), 6.01 (s, 1H), 5.16 (s, 1H), 4.46 – 4.27 (m, 1H), 4.08 (dd, J = 11.7, 2.3 Hz, 1H), 3.84 (m, 2H), 1.90 (s, 3H), 1.41 (s, 18H). 13 C NMR (100 MHz, Chloroform-d) δ 169.1, 164.1 (d, J = 247.5 Hz), 155.8 (d, J = 13.0 Hz), 152.8, 152.2, 136.2, 132.6, 130.1, 127.8, 125.9, 124.6, 121.2, 119.2, 116.9, 108.7 (d, J = 22.4 Hz), 104.1 (d, J = 24.9 Hz), 82.8, 66.4, 41.2, 36.8, 34.5, 30.5, 24.5. 19F NMR (376 MHz, Chloroform-d) δ -109.97. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C32H36FNO4Na 540.2521; Found 540.2522. The enantiomeric excess was determined by HPLC with an IA column at 210 nm (2-propanol/hexane 2:98), 1.0 mL/min. Major isomer: t1 = 12.07 min, t2 = 14.86 min; Minor isomer: t1 = 18.50 min, t2 = 20.22 min. [α]D25 -32.8 (c 1.0, CHCl3).

N-((4aR,9S,9aR)-9-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,2,3,4,9,9a-hexahydro-4aH-xanthen-4ayl)acetamide(3s)

Colorless oil, Yield: 27.0 mg, 60%, 1H NMR (400 MHz, Chloroform-d) δ 7.22 (ddd, J = 8.5, 7.2, 1.7 Hz, 1H), 7.08 (dd, J = 7.7, 1.6 Hz, 1H), 7.03 – 6.93 (m, 2H), 6.90 (s, 2H), 5.43 (s, 1H), 5.12 (s, 1H), 3.86 (s, 1H), 2.80 (ddd, J = 11.9, 4.4, 1.9 Hz, 1H), 2.52 (dd, J = 14.0, 4.0 Hz, 1H), 2.05 (ddd, J = 14.0, 10.9, 5.9 Hz, 1H), 1.80 (m, 1H), 1.70 (m, 1H), 1.64 – 1.56 (m, 2H), 1.54 – 1.45 (m, 1H), 1.37 (s, 19H), 1.24 (s, 3H). 13C NMR (100 MHz, Chloroform-d) δ 168.7, 152.1, ACS Paragon Plus Environment


Page 14 of 22

151.8, 135.9, 135.3, 132.1, 128.3, 124.6, 120.9, 120.6, 117.9, 86.4, 45.1, 42.0, 35.1, 34.5, 30.7, 30.3, 24.8, 24.1, 22.1. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C29H39NO3Na 472.2822; Found 472.2826. The enantiomeric excess was determined by HPLC with an OX column at 210 nm (2-propanol/hexane 3:97), 1.0 mL/min. Major isomer: t1 = 9.49 min; Minor isomer: t1 = 15.28 min. [α]D25 -52.0 (c 1.0, CHCl3).

N-((2S,4S)-4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-phenylchroman-2-yl)acetamide (3t)

Semisolid, Yield: 39.1 mg, 83%, 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.42 (d, J = 7.1 Hz, 2H), 7.31 (m, 3H), 7.13 (t, J = 7.7 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 6.87 (s, 1H), 6.78 (s, 2H), 6.72 (t, J = 7.5 Hz, 1H), 6.50 (d, J = 7.7 Hz, 1H), 3.29 (dd, J = 12.7, 4.9 Hz, 1H), 3.07 (t, J = 13.1 Hz, 1H), 2.59 (dd, J = 13.3, 5.0 Hz, 1H), 1.81 (s, 3H), 1.32 (s, 18H). 13C NMR (100 MHz, DMSO-d6) δ 168.9, 153.8, 152.6, 142.0, 139.3, 133.6, 128.7, 128.1, 127.9, 127.5, 125.7, 125.5, 124.3, 120.1, 116.1, 87.1, 34.5, 30.4, 23.7, 20.8, 14.1. HRMS (QFT-ESI) m/z: [M+Na]+ calcd for C31H37NO3Na 494.2666; Found 494.2668. The enantiomeric excess was determined by HPLC with an OX column at 210 nm (2-propanol/hexane 3:97), 1.0 mL/min. Major isomer: t1 = 18.34 min, t2 = 23.24 min; Minor isomer: t1 = 10.42 min, t2 = 14.11 min. [α]D25 -45.6 (c 1.0, CHCl3).

(R)-2,6-di-tert-butyl-4-(5,7-dihydro-6H-benzo[c]xanthen-7-yl)phenol (4)

Dark green solid, Yield: 73.7 mg, 84%, 1H NMR (400 MHz, Chloroform-d) δ 7.66 (dd, J = 7.7, 1.3 Hz, 1H), 7.19 (td, J = 7.6, 1.4 Hz, 1H), 7.13 – 6.98 (m, 4H), 6.95 (m, 3H), 6.87 – 6.81 (m, 1H), 4.95 (s, 1H), 4.43 (s, 1H), 2.80 – 2.52 (m, 2H), 2.25 – 1.98 (m, 2H), 1.29 (s, 18H). 13C NMR (100 MHz, Chloroform-d) δ 152.6, 150.8, 142.1, 136.2, 136.0, 135.0, 130.6, 129.8, 127.5, 127.3, 127.2, 126.5, 124.9, 124.5, 123.1, 121.4, 116.5, 111.1, 45.5, 34.4, 30.5, 28.3, 25.7. HRMS (ESI) m/z: [M+H]+ calcd for C31H35O2 439.2632; Found 439.2632. [α]D25 3.2 (c 1.0, CHCl3).

(R)-4-(5,7-dihydro-6H-benzo[c]xanthen-7-yl)phenol (5)

Green solid, Yield: 22.5 mg, 41%, 1H NMR (400 MHz, Chloroform-d) δ 7.76 (dd, J = 7.7, 1.3 Hz, 1H), 7.30 (td, J = 7.6, 1.3 Hz, 1H), 7.21 (td, J = 7.4, 1.4 Hz, 1H), 7.19 – 7.09 (m, 5H), 7.02 – 6.88 (m, 2H), 6.77 – 6.69 (m, 2H), 4.77 (s, 1H), 4.57 (s, 1H), 2.78 (ddq, J = 30.9, 15.5, 7.6, 7.1 Hz, 2H), 2.33 – 2.05 (m, 2H). 13C NMR (100 MHz, Chloroform-d) δ 154.4, 150.6, 141.9, 138.3, 136.0, 130.4, 129.8, 129.7, 127.7, 127.6, 127.3, 126.5, 124.1, 123.3, 121.5, 116.7, 115.5, 110.5, 44.9, 28.1, 25.6. HRMS (ESI) m/z: [M-H]- calcd for C23H17O2 325.1234; Found 325.1238. The enantiomeric excess was determined by HPLC with an AD column at 210 nm (2-propanol/hexane 1:9), 1.0 mL/min. Isomer: t1 = 9.49 min, t2 = 11.34 min; [α]D25 25.6 (c 1.0, CHCl3).

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. AUTHOR INFORMATION Corresponding Author E-mail: [email protected] Author Contributions Yang, G.-H. and Zhao, Q. contributed equally.


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Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We are grateful to the NNSFC (Grant No. 21390400) for financial support. REFERENCES (1) (a) Jansen, R.; Gerth, K.; Steinmetz, H.; Reinecke, S.; Kessler, W.; Kirschning, A.; Müller, R. Elansolid A3, a Unique p-Quinone Methide Antibiotic from Chitinophaga sancti. Chem. - Eur. J. 2011, 17, 7739-7744. (b) Messiano, G. B.; da Silva, T.; Nascimento, I. R.; Lopes, L. M. X. Biosynthesis of antimalarial lignans from Holostylis reniformis. Phytochemistry 2009, 70, 590596. (c) Itoh, T. Polymerizations and polymers of quinonoid monomers. Prog. Polym. Sci. 2001, 26, 1019-1059. (d) Dehn, R.; Katsuyama, Y.; Weber, A.; Gerth, K.; Jansen, R.; Steinmetz, H.; Höfle, G.; Müller, R.; Kirschning, A. Molecular Basis of Elansolid Biosynthesis: Evidence for an Unprecedented

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ortho-Quinone Methides with 3-Methyl-2-Vinylindoles. Angew. Chem., Int. Ed. 2015, 54, 54605464. (i) Liu, K.-G.; Jiang, X.-H. Regioselective and Enantioselective Domino Aldol–Oxa-Michael


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Reactions to Construct Quaternary (Chroman) Stereocenters. Eur. J. Org. Chem. 2015, 6423-6428. (j) Hsiao, C.-C.; Liao, H.-H.; Rueping, M. Enantio- and Diastereoselective Access to Distant Stereocenters Embedded within Tetrahydroxanthenes: Utilizing ortho-Quinone Methides as Reactive Intermediates in Asymmetric Brønsted Acid Catalysis. Angew. Chem., Int. Ed. 2014, 53, 13258-13263. (15) Selected examples related to this work: (a) Kretzschmar, M.; Hodík, T.; Schneider, C. Brønsted Acid Catalyzed Addition of Enamides to ortho-Quinone Methide Imines—An Efficient and Highly Enantioselective Synthesis of Chiral Tetrahydroacridines. Angew. Chem., Int. Ed. 2016, 55, 9788-9792. (b) Zhang, M.-M.; Yu, S.-W.; Hu, F.-Z.; Liao, Y.-J.; Liao, L.-H.; Xu, X.-Y.; Yuan, W.C.; Zhang, X.-M. Highly enantioselective [3+2] coupling of cyclic enamides with quinone monoimines promoted by a chiral phosphoric acid. Chem. Commun. 2016, 52, 8757-8760. (c) Saha, S.; Schneider, C. Brønsted Acid-Catalyzed, Highly Enantioselective Addition of Enamides to In Situ-Generated

ortho-Quinone

Methides:

A

Domino

Approach

to

Complex Acetamidotetrahydroxanthenes. Chem. Eur. J. 2015, 21, 2348-2352. (d) Saha, S.; Schneider, C. Directing Group Assisted Nucleophilic Substitution of Propargylic Alcohols via o-Quinone Methide Intermediates: Brønsted Acid Catalyzed, Highly Enantio- and Diastereoselective Synthesis of 7-Alkynyl-12a-acetamido-Substituted Benzoxanthenes. Org. Lett. 2015, 17, 648-651. (16)

CCDC:

1879324.

This

data

can

be

obtained

free

of

charge

via

www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033. See Supporting Information for more details. (17) For the details of the calculation, see Supporting Information. (18) Selected examples for the synthesis of substrates : (a) Li, Z.-J.; Wang, W.-H.; Jian, H.; Li, W.-J.; Dai, B.; He, L. Synthesis of 9-phenol-substituted xanthenes by cascade O-insertion/1,6conjugate addition of benzyne with ortho-hydroxyphenyl substituted para-quinone methides. Chinese Chemical Letters 2019, 30, 386-388. (b) Duan, C.; Ye, L.; Xu, W.- Q .; Li, X.-Y.; Chen, F.; Zhao, Z.-G.; L, X.-F. Organocatalytic cascade 1,6-conjugate addition/annulation/tautomerization of functionalized para-quinone methides: Access to chiral 2-amino-4-aryl-4H-chromenes. Chinese Chemical Letters 2018, 29, 1273–-1276. (c) Baokun Qiao, Cao, H.-Q.; Huang,Y.-J.; Zhang, Y.; Nie, J.; Zhang, F.-G.; Ma, J.-A. Pd(II)-Catalyzed Phosphorylation of Enamido C(sp2 )‒H Bonds: A General Route to β-Amido-vinylphosphonates. Chin. J. Chem. 2018, 36, 809-814. (d) Xu, Y.-H.;



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Zhang, Q.-C.; He, T.; Meng, F.-F.; Loh T.-P. Palladium-Catalyzed Direct Alkynylation of NVinylacetamides. Adv. Synth. Catal. 2014, 356, 1539-1543. (e) Guan, Z.-H.; Zhang, Z.-Y.; Ren, Z.-H.; Wang, Y.-Y.; Zhang, X.-M. Synthesis of Enamides via CuI-Catalyzed Reductive Acylation of Ketoximes with NaHSO3. J. Org. Chem. 2011, 76, 339-341.


Asymmetric Cycloaddition of ortho-Hydroxyphenyl Substituted para

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