annulation of o-quinone methides with Î²-keto acylpyrazoles

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Asymmetric formal [4 + 2] annulation of o-quinone methides with #-keto acylpyrazoles: A general approach to optically active trans-3,4-dihydrocoumarins Liying Cui, Dan Lv, Youming Wang, Zhijin Fan, Zhengming Li, and Zhenghong Zhou J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00234 • Publication Date (Web): 13 Mar 2018 Downloaded from http://pubs.acs.org on March 13, 2018

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The Journal of Organic Chemistry

Asymmetric formal [4 + 2] annulation of o‑ ‑quinone methides with β-keto acylpyrazoles: A general approach to optically active trans-3,4-dihydrocoumarins Liying Cui, Dan Lv, Youming Wang, Zhijin Fan, Zhengming Li, Zhenghong Zhou* Institute and State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, P. R. China. E-mail: [email protected]

Abstract: An asymmetric cascade reaction between β-keto acylpyrazoles and o-quinone methides in

a

formal

[4

+

2]

fashion

to

access

potentially

pharmacological

active

trans-3,4-dihydrocoumarins has been achieved efficiently by using a quinine-based chiral squaramide as the catalyst. The desired products were obtained in high yields with excellent diastereo- and enantioselectivities (up to 96% yield, >19/1 dr and 96% ee) under mild reaction conditions. 3,4-Dihydrocoumarins are found, as an importance structural subunit, in many natural occurring compounds.1 Biological studies reveal that 3,4-dihydrocoumarin derivatives show a wide range of biological activities, thus making them attractive candidates as lead compounds in drug 1 / 29

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discovery.2 Moreover, 3,4-dihydrocoumarins are also useful building blocks in the synthesis of some other important compounds.3 Given the significance of these compounds as important structural scaffolds in natural products and drug candidates, significant efforts have been devoted to the asymmetric synthesis of these fascinating molecules and many methods have been reported in recent years.4 o-Quinone Methides (o-QMs) are considerably more reactive than regular α,β-unsaturated ketones and esters since nucleophilic attack at the external carbon produces an aromatic phenol/phenoxide and this aromatization process of the ring is highly thermodynamically favorable.5 Therefore, among these methods, the asymmetric formal [4+2] annulation between o-QMs and different two-carbon reaction partners represents a powerful approach for the facile construction of 3,4-dihydrocoumarins.6 In 2008, Lectka reported a chiral ammonium fluoride promoted reaction of o-QMs with silyl ketene acetals, affording the desired 3,4-dihydrocoumarin products with ee values range from 72% to 90%.6a Later, NHC catalyzed formal [4+2] cycloaddition of stabilized or in situ generated o-QM with other C2 reaction partners, such as ketenes,6b acrolein,6c acyl imidazoles,6d were also realized with high levels of enantioselectivity. In addition, the synthesis of 3,4-dihydrocoumarin derivatives were also achieved by squaramide catalyzed asymmetric addition of deconjugated butenolides4b or Meldrum’s acid6e to in situ generated o-QM as well as chiral Sc(III) complex catalyzed hetero-Diels–Alder reaction between o-QMs and azlactones.6f Most recently, Deng developed a chiral amidine catalyzed tandem Michael addition/lactonization of carboxylic acids and o-QMs that enables the asymmetric synthesis of cis-3,4-dihydrocoumarins in excellent enantioselectivities.4e Since an aromatic phenoxide intermediate will be generated after the Michael addition of a nucleophile to o-QMs, we envisioned that the introduction of a good acylation unit in the Michael donor will facilitation 2 / 29


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the subsequent intermolecular lactonization to generate 3,4-dihydrocoumarins in a one-pot fashion. Such catalytic transformations will give new and general entries to 3,4-dihydrocoumarins. It is well documented that N-acyl azoles have a high degree of reactivity in nucleophilic reactions and have been considered to be mild acylating agents as alternatives to acyl halides and anhydrides.7 Therefore, β-keto acylpyrazoles are especially deserved to be noticed in the reaction with o-QMs owning to their unique characteristics: (i) The increased electron-withdrawing capability of the acyl pyrazole moiety will enhance activation of the substrate toward deprotonation of the methylene proton; (ii) The facile nucleophilic cleavage of C-N bond enables to access to the desired lactonization product in a one-pot fashion under mild conditions. As a part of our ongoing research on the development of approaches to biorelevant heterocycles,8 We herein report the organocatalyzed [4 + 2] cyclization of β-keto acylpyrazoles and o-QMs, which provide a new access to trans-3,4-dihydrocoumarins in high levels of diastereo- and enantioselectivity. Initially, a model reaction of 1-phenyl-3-(1H-pyrazol-1-yl)propane-1,3-dione (1a) with stable o-quinone methide (2a) was investigated under the catalysis of several of thiourea9 and squaramide-based10 chiral Brønsted bases (Figure 1). The results are summarized in Table 1.

3 / 29



R R

N H

N H

F3C

CF3

Ia, R = Ph b, R-R = (CH2)4

N H

F3C

CF3

NH

N H

N

III

N H N

CF3

N

NH

H N

O

O

O

O CF3

CF3 VI

V CF3

O

O

N H

N H

CF3

N

IVa, R = Ph b, R-R = (CH2)4

OMe N

R N

N H

N

N

N H

NMe2

N H

S

OMe

O

R R

OMe

II

CF3 O

N

CF3

S

S N H

N

N

CF3

CF3

Page 4 of 29

CF3

NH

H N

N

VIIa, R = t Bu b, R = Bn

O VIII

O

Figure 1. Catalyst candidates. Table 1. Catalyst screening a

Entry

Catalyst

Time

Yield (%) b

Ee (%) c

1

Ia

4

72

79

2

Ib

1

73

82

3

II

2

77

–79

4

III

1

63

–76

5

IVa

2

65

89

4 / 29


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6

IVb

1

75

88

7

V

1

92

–94

8

VI

0.5

77

–87

9

VIIa

1

69

–88

10

VIIb

1

81

–73

11

VIII

2

76

–86

a)

All reactions were carried out with β-keto acylpyrazole 1a (0.10 mmol), o-quinone methide 2a

(0.20 mmol) and catalyst (10 mol%) in dichloromethane (1 mL) at 20 °C.

b)

Isolated yield.

c)

Determined by HPLC analysis with a chiral stationary phase. As we anticipated, the desired [2+4] annulation product 3aa could be obtained in 72% yield with >19/1 dr and 79% ee when thiourea Ia containing a (1R,2R)-1,2-diphenylethane-1,2-diamine skeleton was employed (entry 1). Other thioureas, such as (1R,2R)-cyclohexane-1,2-diamine derived thiourea Ib and cinchona alkaloid-based thioureas II, III also proved to be efficient for this reaction, delivering the desired cyclization product 3aa with comparable results as thiourea Ia (entries 2–4 vs. entry 1). To further improve the enantioselectivity of this transformation, we then turn our attention to squaramide-based bidentate hydrogen bond donor catalysts. Generally, much better performances were observed for bifunctional squaramide catalysts III–VIII bearing different chiral diamine backbone and N-substituent (entries 5–11). Eventually, we found the quinine-derived squaramide V to be optimal for this reaction. With this catalyst, 3,4-dihydrocoumarin 3aa was obtained as a single diastereomer in 92% yield with 94% ee (entry 7). For comparison, we attempted to synthesis other β-keto acyl compounds, such as 1-(1H-imidazol-1-yl)-3-phenylpropane-1,3-dione and 1-phenyl-3-(1H-pyrrol-1-yl)propane-1,35 / 29



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dione, and evaluate their reactivity in this transformation. Unfortunately, these two compounds are so reactive that only the dimerization product 3-benzoyl-4-hydroxy-6-phenyl-2H-pyran-2-one could be isolated during their synthesis. Having identified squaramide V as the optimum catalyst for the reaction, other factors, such as solvent, catalyst loading, and reaction temperature, influencing the reaction were thoroughly investigated employing the reaction between 1-phenyl-3-(1H-pyrazol-1-yl)propane-1,3-dione (1a) and o-quinone methide (2a) as the model. The results are listed in Table 2. Table 2. Optimization of reaction conditions a O

O

O

O O Ph

Ph

O

O N

N

V (10 mol%)

+ OCH3

O

O

Solvent, 20 C

O 2a

1a

OCH3

Entry

Solvent

Time

Yield (%) b

Ee (%) c

1

CH2Cl2

1

92

94

2

Toluene

0.4

74

76

3

Ethyl acetate

1

78

88

4

Chloroform

1

77

87

5

1,2-Dichloroethane

0.5

75

94

6

Ether

0.7

95

80

7

Acetonitrile

0.7

95

88

8

THF

1.5

91

88

9d

CH2Cl2

4

94

95

6 / 29


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10 e

CH2Cl2

8

95

94

11 f

CH2Cl2

45

89

91

12 g

CH2Cl2

4

94

95

13 h

CH2Cl2

5

94

92

a)

Unless otherwise specified, all reactions were carried out with β-keto acylpyrazole 1a (0.10

mmol), o-quinone methide 2a (0.20 mmol) and catalyst V (10 mol%) in solvent (1 mL) at 20 °C. b) Isolated yield. c) Determined by HPLC analysis with a chiral stationary phase. d) The reaction was performed at 0 °C.

e)

The reaction was carried out at –20 °C.

f)

The reaction was conducted at –

40 °C. g) The reaction took place at 0 °C with a catalyst loading of 5 mol%. h) The reaction ran at 0 °C with a catalyst loading of 2.5 mol%. A careful examination of the solvents indicated that the asymmetric cascade Michael addition-lactonization could be carried out smoothly in several conventional solvents such as methylene chloride (94% ee), toluene (76% ee), ethyl acetate (88% ee), chloroform (87% ee), 1,2-dichloroethane (94% ee), ether (80% ee), acetonitrile (88% ee) and THF (88% ee) (entries 1– 8). In terms of both yield and ee value, dichloromethane was the best of choice for the reaction. Further investigation showed that there was almost negligible temperature effect when the reaction was carried out at 20 to −40 °C, giving the corresponding 3aa with ee value ranged from 91% to 95% (entries 1 and 9–11). A slightly improved enantioselectivity of 95% ee was observed by performing the reaction at 0 °C (entry 9). Adjusting the catalyst loading demonstrated no appreciable influence on the outcome of the reaction. The use of 5 mol % of catalyst V led to the formation of 3aa with an identical yield and ee value (entry 12). Further decreasing the catalyst loading to 2.5 mol% resulted in a slightly decreased ee value (enry 13). 7 / 29



Page 8 of 29

With the optimal reaction conditions in hand, we set out to explore the scope of this cascade Michael addition-lactonization process. The results are collected in Table 3. Table 3 Substrate scope of squaramide V-catalyzed [4 + 2] annulation reaction

Entry

3 (Ar, R)

Yield (%) b

Ee (%) c

1

3aa (Ph, 4-MeC6H4)

94

95

2

3ba (4-FC6H4, 4-MeC6H4)

93

90

3

3ca (3-FC6H4, 4-MeC6H4)

81

91

4

3da (2-FC6H4, 4-MeC6H4)

86

93

5

3ea (4-ClC6H4, 4-MeC6H4)

96

93

6

3fa (3-ClC6H4, 4-MeC6H4)

90

94

7

3ga (4-BrC6H4, 4-MeC6H4)

96

90

8

3ha (3-BrC6H4, 4-MeC6H4)

93

93

9

3ia (4-MeC6H4, 4-MeC6H4)

75

90

10

3ja (3-MeC6H4, 4-MeC6H4)

74

94

11

3ka (2-MeC6H4, 4-MeC6H4)

80

95

12

3la (2,4-Me2C6H3, 4-MeC6H4)

81

93

13

3ma (3,5-Me2C6H3, 4-MeC6H4)

84

93

14 d

3na (3-MeOC6H4, 4-MeC6H4)

89

94

15

3oa (2-Naph, 4-MeC6H4)

91

90

8 / 29


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16 d

3pa (2-Thienyl, 4-MeC6H4)

93

96

17 e

3ab (Ph, (E)-PhCH=CH)

50

90

18 e

3ac (Ph, (E)-4-BrC6H4CH=CH)

41

94

19 e

3ad (Ph, (E)- 4-MeC6H4CH=CH)

69

94

20 e

3ae (Ph, (E)- 4-MeOC6H4CH=CH)

77

95

a)

Unless otherwise specified, all reactions were carried out with β-keto acylpyrazole 1 (0.10

mmol), o-quinone methide 2 (0.20 mmol) and catalyst V (5 mol%) in dichloromethane (1 mL) at 0 °C for 4 h.

b)

Isolated yield.

c)

Determined by HPLC analysis with a chiral stationary phase.

d)

The catalyst loading is 10 mol%. e) 1.3 Equivalents of o-quinone methide 2 was employed.

First, we submitted various β-keto acylpyrazoles to this reaction. It was found that a broad range of β-keto acylpyrazoles (1) could readily participate in this reaction. Generally, the reaction proceeded smoothly, and the desired annulation products 3 were obtained as single diastereomers in good yields with excellent enantioselectivities (90–96% ee) within 4 h. Both electron-withdrawing and electron-donating substituents on the phenyl group of 1 were readily tolerated regardless of the substitution pattern (entry 2–14). 2-Naphthyl substituted β-keto acylpyrazole 1o worked well to give the 3,4-dihydrocoumarin 3oa in 91% yield with >19/1 d.r. and 90% ee (entry 15). By replacing the phenyl group of the β-keto acylpyrazole 1a with an electron-rich heteroaryl, the reaction also ran smoothly to afford the annulation product 3pa in good yield and excellent enantioselectivity in the presence of 10 mol% of catalyst V (entry 16). Unfortunately, aliphatic β-keto acylpyrazole, such as 1-(1H-pyrazol-1-yl)butane-1,3-dione, was completely inactive under the optimal reaction conditions and failed to generate the corresponding

9 / 29



Page 10 of 29

cyclization product. We next studied the scope of this process in terms of the o-QM to this process. When (E)-2-styryl substituted o-QM 2b was employed, the corresponding cyclization product 3ab was obtained with almost unaltered ee value albeit in a somewhat decreased yield (entry 17). The introduction of either electron-withdrawing or electron-donating substituent on the phenyl ring of the styryl group demonstrated no obvious influence on the stereochemical outcome of the reaction. Again, in all cases studied, the reaction proceeded smoothly and was typically completed within 4 h to afford the corresponding annulation product 3ac–3ae as a single diastereomer in good yields with excellent enantioselectivities (entries 18–20, 94–95% ee). The relative and absolute configuration of the product 3ea is unequivocally established by X-ray analysis (see the Supporting Information), and the remaining configurations are assumed by analogy.11 The

proposed

catalytic

cycle

is

depicted

in

Figure

2.

The

deprotonation

of

1-phenyl-3-(1H-pyrazol-1-yl)propane-1,3-dione (1a) forming a hydrogen-bond-paired enolate A, which nucleophilic attacks the o-QM (2a) with the restoration of aromaticity as the driving force to generate a phenoxide intermediate B. Subsequent lactonization furnishes the final [4+2] annulation product 3aa with the 7S,8R absolute configuration as the predominant enantiomer and accompanied with the release of the pyrazole moiety.

10 / 29


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Figure 2. Proposed catalytic circle. The 3,4-dihydrocoumarin products obtained in these formal [4+2] annulations would find more application

in

organic

synthesis.

For

example,

under

basic

hydrolytic

condition,

3,4-dihydrocoumarin 3aa took place hydrolytic decarboxylation smoothly to give an inseparable mixture of hydroxyl ketone 4 and the related lactol 4’ in good yield. Subsequent methylation of the phenolic hydroxyl group afforded chiral β-diaryl substituted ketone 5, an important type of intermediates for the synthesis of many pharmaceuticals and natural products. It is worth noting that this type of compounds is generally obtained via transition metal catalyzed conjugate addition of organoboron reagents to enone.12 This newly developed process offered an alternative organocatalytic indirect approach to access these synthetic valuable compounds. Moreover, according to a literature procedure,13 the ketone/lactol mixture (4/4’) could be conveniently converted into 2,4-cis-chroman 6, a class of compounds that are found widely in bioactive natural products, without appreciable loss in optical purity via Lewis acid mediated silane reduction 11 / 29



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(Scheme 1). PMP O O

PMP O

O

O

O

NaOH

Ph

THF/H2O, 60 C

O

PMP O

Ph

O

O

OH

78%

3aa, 94% ee (PMP = 4-MeOC6H4)

4

4'

3 CO 2 K , ne eI M ceto a

Et3SiH, BF3.Et2O CH2Cl2, 78 C PMP

PMP O O

O

Ph

O

Ph OH

O

O

OMe 5 65% yield, 91% ee

O

Ph

6 68% yield, 91% ee

Scheme 1 Basic hydrolytic decarboxylation of 3aa and subsequent transformation To overcome the inherent limitation in scope of using stabilized substrates, we have tried application of this reaction to o-quinone methide 2a generated in situ upon the treatment of the corresponding 2-sulfonylalkyl phenol 7 with aqueous sodium hydrocarbonate. Although the reaction ran smoothly to give the corresponding annulation product 3aa, in this case, an obvious decrease both in yield and enantioselectivity was observed. OMe

OMe O + O O

Ts

Ph

O N

V (5 mol%)

N

NaHCO3 H2O/DCM, rt

O O

OH 7 (0.2 mmol)

O

1a (0.24 mmol)

Ph O O 3aa 47% yield, 68% ee

In conclusion, we have developed a highly efficient diastereo- and enantioselective formal [4+2] annulation reaction for the synthesis of dihydrocoumarin derivatives via bifunctional Brønsted base catalysis. Under the catalysis of a chiral quinine-based squaramide, the cascade Michael addition/lactonization of a wide range of β-keto acylpyrazoles and o-QMs took place smoothly to 12 / 29


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deliver the desired dihydrocoumarins in high yields with excellent diastereo- and enantioselectivities. This platform facilitates rapid access to chiral trans-3,4-disubstituted dihydrocoumarins. EXPERIMENTAL SECTION General Information Materials were obtained from commercial suppliers and were used without further purification. NMR spectra were obtained with a 400 MHz spectrometer (1H 400 MHz,

13

C 100.6 MHz) in

CDCl3. The chemical shifts are reported as δ values (ppm) relative to tetramethylsilane. HRMS spectra were recorded with a Q-TOF mass spectrometer, equipped with an ESI source. Optical rotation values were measured with instruments operating at λ = 589 nm, corresponding to the sodium D line at 20 °C. Enantiomeric excesses were determined by HPLC analysis with a chiral stationary phase. General procedure for the chiral squaramide Vb-catalyzed Michael addition reactions A mixture of β-keto acylpyrazoles 1 (0.10 mmol), o-quinone methides 2 (0.20 or 0.13 mmol) and squaramide catalyst V (1.9 mg, 0.004 mmol) in dichloromethane (1 mL) was stirred at 0 °C for 4 h. After the completion of the reaction, the reaction mixture was directly purified by column chromatography on silica gel (100–200 mesh, petroleum ether/ethyl acetate = 2/1) to afford the desired chiral trans-3,4-dihydrocoumarins 3. The title compounds were fully characterized by 1H, 13

C NMR, HRMS and specific rotation data. (7S,8S)-7-Benzoyl-8-(4-methoxyphenyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6-one

(3aa): White solid, m.p. 151–153 °C, 37.8 mg, 94% yield, [α]20D 83.76 (c 0.83, CHCl3), >19/1 dr, 95% ee. 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 7.6 Hz, 2 H), 7.59 (t, J = 7.2 Hz, 1 H), 7.47 (t, 13 / 29



J = 7.6 Hz, 2 H), 7.10 (d, J = 8.8 Hz, 2 H), 7.10 (d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.69 (s, 1 H), 6.32 (s, 1 H), 5.95 (d, J = 1.2 Hz, 1 H), 5.94 (d, J = 1.2 Hz, 1 H), 4.88 (d, J = 7.2 Hz, 1 H), 4.62 (d, J = 6.8 Hz, 1 H), 3.76 (s, 3 H).

13

C NMR (100.6 MHz, CDCl3): δ 193.5, 165.2,

159.1, 147.7, 145.4, 144.7, 135.4, 133.9, 131.3, 128.9, 128.8, 128.7, 116.3, 114.6, 107.5, 101.8, 98.9, 55.3, 55.1, 43.5. HRMS (ESI) m/z calc'd for C24H22NO6 [M+NH4]+: 420.1442, found 420.1435. HPLC analysis (Chiralpak OD-H column, Hexane:2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 15.75 (major) and 63.24 min (minor). (7S,8S)-7-(4-Fluorobenzoyl)-8-(4-methoxyphenyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chro men-6-one (3ba): White solid, m.p. 71–73 °C, 39.1 mg, 93% yield, [α] 20D 86.62 (c 1.30, CHCl3), >19/1 dr, 90% ee. 1H NMR (400 MHz, CDCl3): δ 7.91 (dd, J = 8.8, 5.2 Hz, 2 H), 7.13 (t, J = 8.8 Hz, 2 H), 7.09 (d, J = 8.8 Hz, 2 H), 6.83 (d, J = 8.8 Hz, 2 H), 6.68 (s, 1 H), 6.31 (s, 1 H), 5.95 (d, J = 1.2 Hz, 1 H), 5.94 (d, J = 1.2 Hz, 1 H), 4.83 (d, J = 7.6 Hz, 1 H), 4.62 (d, J = 7.6 Hz, 1 H), 3.76 (s, 3 H). 13C NMR (100.6 MHz, CDCl3): δ 191.9, 166.1 (d, J = 256.7 Hz), 165.10, 159.1, 147.7, 145.2, 144.8, 132.0, 131.5 (d, J = 9.7 Hz), 131.0, 128.9, 116.6, 116.0 (d, J = 22.1 Hz), 114.6, 107.5, 101.8, 98.9, 55.3, 54.8, 43.3. HRMS (ESI) m/z calc'd for C24H21FNO6 [M+NH4]+: 438.1347, found 438.1344. HPLC analysis (Chiralpak OD-H column, Hexane:2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 13.93 (major) and 35.05 min (minor). (7S,8S)-7-(3-Fluorobenzoyl)-8-(4-methoxyphenyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chro men-6-one (3ca): White solid, m.p. 159–161 °C, 34.1 mg, 81% yield, [α] 20D 99.8 (c 1.00, CHCl3), >19/1 dr, 91% ee. 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.0 Hz, 1 H), 7.54 (td, J = 9.2, 2.0 Hz, 1 H), 7.45 (dt, J = 8.0, 5.6 Hz, 1 H), 7.28 (dt, J = 8.0, 2.0 Hz, 1 H), 7.09 (d, J = 8.4 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.69 (s, 1 H), 6.30 (s, 1 H), 5.96 (d, J = 1.2 Hz, 1 H), 5.95 (d, J = 14 / 29


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1.2 Hz, 1 H), 4.81 (d, J = 8.0 Hz, 1 H), 4.63 (d, J = 8.0 Hz, 1 H), 3.77 (s, 3 H). 13C NMR (100.6 MHz, CDCl3): δ 192.4, 165.0, 162.8 (d, J = 247.5 Hz), 159.2, 147.7, 145.3, 144.8, 137.7 (d, J = 6.4 Hz), 130.9, 130.6 (d, J = 7.6 Hz), 129.0, 124.4 (d, J = 3.0 Hz), 121.0 (d, J = 21.4 Hz), 116.6, 115.4 (d, J = 22.6 Hz), 114.7, 107.5, 101.8, 98.9, 55.3, 55.0, 43.3. HRMS (ESI) m/z calc'd for C24H21FNO6 [M+NH4]+: 438.1347, found 438.1343. HPLC analysis (Chiralpak OD-H column, Hexane:2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 13.92 (major) and 63.39 min (minor). (7S,8S)-7-(2-Fluorobenzoyl)-8-(4-methoxyphenyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chro men-6-one (3da): White solid, m.p. 173–175 °C, 36.2 mg, 86% yield, [α] 20D 71.6 (c 1.00, CHCl3), >19/1 dr, 93% ee. 1H NMR (400 MHz, CDCl3): δ 7.72 (dt, J = 7.6, 2.0 Hz, 1 H), 7.54– 7.60 (m, 1 H), 7.21 (t, J = 7.6 Hz, 1 H), 7.17 (dd, J = 7.6, 4.4 Hz, 1 H), 7.10 (d, J = 8.4 Hz, 2 H), 6.83 (d, J = 8.4 Hz, 2 H), 6.71 (s, 1 H), 6.26 (s, 1 H), 5.94 (s, 2 H), 4.87 (d, J = 8.0 Hz, 1 H), 4.58 (dd, J = 7.2, 2.0 Hz, 1 H), 3.77 (s, 3 H). 13C NMR (100.6 MHz, CDCl3): δ 191.5 (d, J = 3.6 Hz), 165.2, 161.4 (d, J = 253.8 Hz), 159.0, 147.7, 145.7, 144.6, 135.7 (d, J = 9.4 Hz), 131.3 (d, J = 1.8 Hz), 130.8, 129.0, 125.0 (d, J = 3.2 Hz), 123.9 (d, J = 11.8 Hz), 116.7 (d, J = 23.8 Hz), 116.2, 114.5, 107.5, 101.8, 99.0, 59.4, 55.2, 43.1. HRMS (ESI) m/z calc'd for C24H21FNO6 [M+NH4]+: 438.1347, found 438.1345. HPLC analysis (Chiralpak OD-H column, Hexane:2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 12.92 (major) and 23.88 min (minor). (7S,8S)-7-(4-Chlorobenzoyl)-8-(4-methoxyphenyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chro men-6-one (3ea): White solid, m.p. 190–192 °C, 41.9 mg, 96% yield, [α] 20D 55.67 (c 1.20, CHCl3), >19/1 dr, 93% ee. 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.4 Hz, 2 H), 7.43 (d, J = 8.4 Hz, 2 H), 7.08 (d, J = 8.8 Hz, 2 H), 6.83 (d, J = 8.4 Hz, 2 H), 6.77 (s, 1 H), 6.30 (s, 1 H), 5.95 15 / 29



(d, J = 1.2 Hz, 1 H), 5.94 (d, J = 1.2 Hz, 1 H), 4.81 (d, J = 8.0 Hz, 1 H), 4.61 (d, J = 7.6 Hz, 1 H), 3.76 (s, 3 H). 13C NMR (100.6 MHz, CDCl3): δ 192.4, 165.0, 159.2, 147.7, 145.2, 144.8, 140.5, 134.0, 130.9, 130.1, 129.2, 128.9, 116.6, 114.7, 107.5, 101.8, 98.9, 55.3, 54.8, 43.3. HRMS (ESI) m/z calc'd for C24H21ClNO6 [M+NH4]+: 454.1052, found 454.1047. HPLC analysis (Chiralpak OD-H column, Hexane:2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength = 220 nm): Rt = 14.37 (major) and 25.72 min (minor). (7S,8S)-7-(3-Chlorobenzoyl)-8-(4-methoxyphenyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chro men-6-one (3fa): White solid, m.p. 65–67 °C, 39.3 mg, 90% yield, [α] 20D 165.28 (c 0.53, CHCl3), >19/1 dr, 94% ee. 1H NMR (400 MHz, CDCl3): δ 7.82 (s, 1 H), 7.74 (d, J = 7.6 Hz, 1 H), 7.54 (d, J = 7.6 Hz, 1 H), 7.39 (t, J = 8.0 Hz, 1 H), 7.09 (d, J = 8.4 Hz, 2 H), 6.84 (d, J = 8.4 Hz, 2 H), 6.67 (s, 1 H), 6.29 (s, 1 H), 5.95 (d, J = 1.2 Hz, 1 H), 5.94 (d, J = 1.2 Hz, 1 H), 4.82 (d, J = 8.4 Hz, 1 H), 4.63 (d, J = 8.4 Hz, 1 H), 3.76 (s, 3 H). 13C NMR (100.6 MHz, CDCl3): δ 192.5, 165.0, 159.1, 147.7, 145.2, 144.8, 137.2, 135.2, 133.8, 130.7, 130.1, 129.0, 128.7, 126.7, 116.6, 114.6, 107.5, 101.8, 98.9, 55.2, 54.8, 43.2. HRMS (ESI) m/z calc'd for C24H21ClNO6 [M+NH4]+: 454.1052, found 454.1054. HPLC analysis (Chiralpak OD-H column, Hexane:2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 16.07 (major) and 97.83 min (minor). (7S,8S)-7-(4-Bromobenzoyl)-8-(4-methoxyphenyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chro men-6-one (3ga): White solid, m.p. 188–190 °C, 46.2 mg, 96% yield, [α] 20D 35.32 (c 0.47, CHCl3), >19/1 dr, 90% ee. 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.8 Hz, 2 H), 7.60 (d, J = 8.8 Hz, 2 H), 7.08 (d, J = 8.4 Hz, 2 H), 6.83 (d, J = 8.4 Hz, 2 H), 6.68 (s, 1 H), 6.30 (s, 1 H), 5.95 (d, J = 0.8 Hz, 1 H), 5.94 (d, J = 0.8 Hz, 1 H), 4.80 (d, J = 8.0 Hz, 1 H), 4.62 (d, J = 7.6 Hz, 1 H), 3.77 (s, 3 H). 13C NMR (100.6 MHz, CDCl3): δ 192.6, 165.0, 159.2, 147.7, 145.3, 144.8, 134.4, 16 / 29


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132.2, 130.9, 130.1, 129.3, 128.9, 116.6, 114.67, 107.5, 101.8, 98.9, 55.3, 54.8, 43.3. HRMS (ESI) m/z calc'd for C24H21BrNO6 [M+NH4]+: 498.0547, found 498.0545. HPLC analysis (Chiralpak IC column, Hexane:2-propanol = 75:25, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 29.11 (major) and 33.93 min (minor). (7S,8S)-7-(3-Bromobenzoyl)-8-(4-methoxyphenyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chro men-6-one (3ha): White solid, m.p. 143–145 °C, 44.8 mg, 93% yield, [α]20D 74.25 (c 1.33, CHCl3), >19/1 dr, 93% ee. 1H NMR (400 MHz, CDCl3): δ 7.97 (s, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.33 (t, J = 8.0 Hz, 1 H), 7.09 (d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.68 (s, 1 H), 6.29 (s, 1 H), 5.95 (d, J = 1.2 Hz, 1 H), 5.94 (d, J = 1.2 Hz, 1 H), 4.80 (d, J = 8.0 Hz, 1 H), 4.63 (d, J = 8.0 Hz, 1 H), 3.77 (s, 3 H). 13C NMR (100.6 MHz, CDCl3): δ 192.4, 165.0, 159.2, 147.7, 145.3, 144.8, 137.4, 136.7, 131.6, 130.8, 130.4, 129.0, 127.1, 123.2, 116.6, 114.7, 107.5, 101.8, 98.9, 55.3, 54.8, 43.2. HRMS (ESI) m/z calc'd for C24H21BrNO6 [M+NH4]+: 498.0547, found 498.0538. HPLC analysis (Chiralpak OD-H column, Hexane:2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 19.56 (major) and 135.20 min (minor). (7S,8S)-8-(4-Methoxyphenyl)-7-(4-methylbenzoyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chro men-6-one (3ia): White solid, m.p. 167–169 °C, 31.2 mg, 75% yield, [α]20D 100.67 (c 0.30, CHCl3), >19/1 dr, 90% ee. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.4 Hz, 2 H), 7.27 (d, J = 8.0 Hz, 2 H), 7.09 (d, J = 8.8 Hz, 2 H), 6.83 (d, J = 8.4 Hz, 2 H), 6.69 (s, 1 H), 6.32 (s, 1 H), 5.94 (d, J = 1.2 Hz, 1 H), 5.93 (d, J = 1.2 Hz, 1 H), 4.86 (d, J = 6.8 Hz, 1 H), 4.60 (d, J = 6.4 Hz, 1 H), 3.76 (s, 3 H), 2.41 (s, 3 H). 13C NMR (100.6 MHz, CDCl3): δ 193.0, 165.3, 159.1, 147.7, 145.4, 145.0, 144.7, 132.8, 131.5, 129.6, 128.9, 128.7, 116.3, 114.6, 107.6, 101.7, 99.0, 55.3, 55.1, 43.6, 21.7. HRMS (ESI) m/z calc'd for C25H24NO6 [M+NH4]+: 434.1598, found 434.1593. HPLC 17 / 29



analysis (Chiralpak OD-H column, Hexane:2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 15.69 (major) and 25.41 min (minor). (7S,8S)-8-(4-Methoxyphenyl)-7-(3-methylbenzoyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chro men-6-one (3ja): White solid, m.p. 122–124 °C, 30.8 mg, 74% yield, [α]20D 103.19 (c 1.13, CHCl3), >19/1 dr, 94% ee. 1H NMR (400 MHz, CDCl3): δ 7.69 (s, 1 H), 7.68 (d, J = 7.6 Hz, 1 H), 7.40 (d, J = 7.6 Hz, 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.10 (d, J = 8.4 Hz, 2 H), 6.84 (d, J = 8.4 Hz, 2 H), 6.69 (s, 1 H), 6.31 (s, 1 H), 5.94 (s, 2 H), 4.87 (d, J = 6.8 Hz, 1 H), 4.61 (d, J = 6.4 Hz, 1 H), 3.76 (s, 3 H), 2.39 (s, 3 H). 13C NMR (100.6 MHz, CDCl3): δ 193.7, 165.3, 159.1, 147.7, 145.4, 144.7, 138.8, 135.4, 134.8, 131.3, 129.2, 128.8, 128.7, 125.9, 116.4, 114.6, 107.5, 101.8, 98.9, 55.2, 55.1, 43.5, 21.3. HRMS (ESI) m/z calc'd for C25H24NO6 [M+NH4]+: 434.1598, found 434.1597. HPLC analysis (Chiralpak OD-H column, Hexane:2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 15.53 (major) and 53.04 min (minor). (7S,8S)-8-(4-Methoxyphenyl)-7-(2-methylbenzoyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chro men-6-one (3ka): White solid, m.p. 120–122 °C, 33.3 mg, 80% yield, [α] 20D 99.0 (c 0.20, CHCl3), >19/1 dr, 95% ee. 1H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 7.6 Hz, 1 H), 7.37 (dt, J = 7.6, 1.2 Hz, 1 H), 7.25 (t, J = 7.6 Hz, 1 H), 7.21 (d, J = 7.6 Hz, 1 H), 7.05 (d, J = 8.8 Hz, 2 H), 6.83 (d, J = 8.4 Hz, 2 H), 6.69 (s, 1 H), 6.30 (s, 1 H), 5.96 (d, J = 1.2 Hz, 1 H), 5.95 (d, J = 1.2 Hz, 1 H), 4.69 (d, J = 7.6 Hz, 1 H), 4.56 (d, J = 7.6 Hz, 1 H), 3.77 (s, 3 H), 2.17 (s, 3 H). 13C NMR (100.6 MHz, CDCl3): δ 197.2, 165.5, 159.1, 147.7, 145.6, 144.7, 138.9, 136.5, 132.0, 131.9, 130.8, 129.0, 127.9, 125.7, 116.6, 114.6, 107.4, 101.8, 99.0, 58.1, 55.3, 43.4, 20.3. HRMS (ESI) m/z calc'd for C25H24NO6 [M+NH4]+: 434.1598, found 434.1599. HPLC analysis (Chiralpak OD-H column, Hexane:2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 11.47 18 / 29


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(major) and 48.96 min (minor). (7S,8S)-8-(4-Methoxyphenyl)-7-(2,4-dimethylbenzoyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]c hromen-6-one (3la): White solid, m.p. 64–66 °C, 34.9 mg, 81% yield, [α] 20D 64.0 (c 0.40, CHCl3), >19/1 dr, 93% ee. 1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 8.0 Hz, 1 H), 7.06 (d, J = 7.6 Hz, 1 H), 7.05 (d, J = 8.4 Hz, 2 H), 7.02 (s, 1 H), 6.83 (d, J = 8.8 Hz, 2 H), 6.69 (s, 1 H), 6.30 (s, 1 H), 5.95 (s, 2 H), 4.70 (d, J = 7.2 Hz, 1 H), 4.55 (d, J = 7.2 Hz, 1 H), 3.77 (s, 3 H), 2.34 (s, 3 H), 2.17 (s, 3 H).

13

C NMR (100.6 MHz, CDCl3): δ 196.5, 165.6, 159.1, 147.7, 145.6, 144.6,

142.7, 139.4, 133.5, 132.9, 131.0, 128.9, 128.5, 126.4, 116.6, 114.5, 107.4, 101.7, 99.0, 57.8, 55.3, 43.5, 21.4, 20.6. HRMS (ESI) m/z calc'd for C26H26NO6 [M+NH4]+: 448.1755, found 448.1750. HPLC analysis (Chiralpak OD-H column, Hexane:2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 9.97 (major) and 14.77 min (minor). (7S,8S)-8-(4-Methoxyphenyl)-7-(3,5-dimethylbenzoyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]c hromen-6-one (3ma): White solid, m.p. 154–156 °C, 36.2 mg, 84% yield, [α]20D 93.0 (c 1.20, CHCl3), >19/1 dr, 93% ee. 1H NMR (400 MHz, CDCl3): δ 7.48 (s, 1 H), 7.22 (s, 1 H), 7.10 (d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.69 (s, 1 H), 6.31 (s, 1 H), 5.94 (s, 2 H), 4.86 (d, J = 7.2 Hz, 1 H), 4.61 (d, J = 6.8 Hz, 1 H), 3.77 (s, 3 H), 2.35 (s, 6 H). 13C NMR (100.6 MHz, CDCl3): δ 193.8, 165.4, 159.1, 147.6, 145.4, 144.6, 138.6 135.7, 135.4, 131.4, 128.8, 126.5, 116.4, 114.6, 107.6, 101.7, 99.0, 55.3, 55.0, 43.5, 21.2. HRMS (ESI) m/z calc'd for C26H26NO6 [M+NH4]+: 448.1755, found 448.1751. HPLC analysis (Chiralpak IC column, Hexane:2-propanol = 75:25, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 30.45 (minor) and 41.54 min (major). (7S,8S)-7-(3-Methoxybenzoyl)-8-(4-methoxyphenyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chr omen-6-one (3na): White solid, m.p. 52–54 °C, 37.2 mg, 86% yield, [α] 20D 141.0 (c 0.53, 19 / 29



CHCl3), >19/1 dr, 94% ee. 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 7.6 Hz, 1 H), 7.38 (d, J = 2.0 Hz, 1 H), 7.37 (t, J = 8.0 Hz, 1 H), 7.13 (dd, J = 8.0, 2.0 Hz, 1 H), 7.10 (d, J = 8.4 Hz, 2 H), 6.84 (d, J = 8.4 Hz, 2 H), 6.69 (s, 1 H), 6.32 (s, 1 H), 5.94 (d, J = 1.2 Hz, 1 H), 5.93 (d, J = 1.2 Hz, 1 H), 4.86 (d, J = 7.2 Hz, 1 H), 4.61 (d, J = 6.8 Hz, 1 H), 3.81 (s, 3 H), 3.76 (s, 3 H). 13C NMR (100.6 MHz, CDCl3): δ 193.4, 165.2, 160.0, 159.1, 147.7, 145.4, 144.7, 136.6, 131.3, 129.8, 128.8, 121.2, 120.6, 116.3, 114.6, 112.7, 107.5, 101.8, 98.9, 55.4, 55.2 (2 C), 43.6. HRMS (ESI) m/z calc'd for C25H24NO7 [M+NH4]+: 450.1547, found 450.1547. HPLC analysis (Chiralpak IC-H column, Hexane:2-propanol = 75:25, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 57.21 (minor) and 61.75 min (major). (7S,8S)-7-(2-Naphthoyl)-8-(4-methoxyphenyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen6-one (3oa): White solid, m.p. 89–91 °C, 41.2 mg, 91% yield, [α]20D 30.15 (c 1.30, CHCl3), >19/1 dr, 90% ee. 1H NMR (400 MHz, CDCl3): δ 8.43 (s, 1 H), 7.86–7.96 (m, 4 H), 7.63 (t, J = 7.2 Hz, 1 H), 7.57 (t, J = 7.2 Hz, 1 H), 7.14 (d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.72 (s, 1 H), 6.32 (s, 1 H), 5.95 (s, 2 H), 5.05 (d, J = 7.2 Hz, 1 H), 4.69 (d, J = 7.2 Hz, 1 H), 3.75 (s, 3 H). 13C NMR (100.6 MHz, CDCl3): δ 193.4, 165.3, 159.1, 147.7, 145.4, 144.7, 135.8, 132.8, 132.4, 131.3, 130.9, 129.8, 129.1, 128.9, 127.8, 127.1, 123.9, 116.5, 114.7, 107.6, 101.8, 99.0, 55.2, 55.1, 43.7. HRMS (ESI) m/z calc'd for C28H24NO6 [M+NH4]+: 470.1598, found 470.1595. HPLC analysis (Chiralpak OD-H column, Hexane:2-propanol = 70:30, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 14.75 (major) and 27.74 min (minor). (7S,8S)-8-(4-Methoxyphenyl)-7-(thiophene-2-carbonyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g] chromen-6-one (3pa): White solid, m.p. 140–142 °C, 38.0 mg, 93% yield, [α]20D 124.8 (c 1.00, CHCl3), >19/1 dr, 96% ee. 1H NMR (400 MHz, CDCl3): δ 7.78 (dd, J = 4.0, 0.8 Hz, 1 H), 7.68 (dd, 20 / 29


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J = 4.8, 0.8 Hz, 1 H), 7.13 (dd, J = 4.8, 4.0 Hz, 1 H), 7.10 (d, J = 8.8 Hz, 2 H), 6.83 (d, J = 8.8 Hz, 2 H), 6.67 (s, 1 H), 6.35 (s, 1 H), 5.95 (d, J = 1.2 Hz, 1 H), 5.94 (d, J = 1.2 Hz, 1 H), 4.68 (d, J = 7.6 Hz, 1 H), 4.66 (d, J = 7.6 Hz, 1 H), 3.76 (s, 3 H), 2.35 (s, 6 H). 13C NMR (100.6 MHz, CDCl3): δ 185.5, 164.8, 159.1, 147.6, 145.3, 144.7, 142.5, 135.5, 133.5, 131.0, 128.9, 128.5, 116.5, 114.6, 107.6, 101.8, 98.9, 56.4, 55.2, 43.6. HRMS (ESI) m/z calc'd for C22H20NO6S [M+NH4]+: 426.1006, found 426.1006. HPLC analysis (Chiralpak AD-H column, Hexane:2-propanol = 75:25, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 27.20 (minor) and 46.83 min (major). (7S,8R)-7-Benzoyl-8-((E)-styryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6-one (3ab): White solid, m.p. 173–175 °C, 19.9 mg, 50% yield, [α]20D 44.18 (c 0.67, CHCl3), >19/1 dr, 90% ee. 1

H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 7.6 Hz, 2 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.50 (t, J = 7.6

Hz, 2 H), 7.23–7.32 (m, 5 H), 6.68 (s, 1 H), 6.61 (s, 1 H), 6.49 (d, J = 16.0 Hz, 1 H), 6.12 (dd, J = 15.6, 7.6 Hz, 1 H), 5.98 (d, J = 1.2 Hz, 1 H), 5.97 (d, J = 1.2 Hz, 1 H), 4.75 (d, J = 6.0 Hz, 1 H), 4.23 (t, J = 7.2 Hz, 1 H).

13

C NMR (100.6 MHz, CDCl3): δ 193.2, 165.1, 147.9, 145.3, 144.8,

135.9, 135.3, 134.0, 133.9, 129.0, 128.7, 128.6, 128.2, 126.6, 126.5, 114.8, 107.1, 101.8, 99.2, 53.4, 42.3. HRMS (ESI) m/z calc'd for C25H22NO5 [M+NH4]+: 416.1492, found 416.1486. HPLC analysis (Chiralpak IC column, Hexane:2-propanol = 75:25, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 25.34 (major) and 31.68 min (minor). (7S,8R)-7-Benzoyl-8-((E)-4-bromostyryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6-on e (3ac): White solid, m.p. 164–166 °C, 19.6 mg, 41% yield, [α]20D 45.11 (c 0.47, CHCl3), >19/1 dr, 94% ee. 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 7.6 Hz, 2 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.50 (t, J = 7.6 Hz, 2 H), 7.41 (d, J = 8.8 Hz, 2 H), 7.17 (d, J = 8.4 Hz, 2 H), 6.68 (s, 1 H), 6.58 (s, 1 H), 6.40 (d, J = 15.6 Hz, 1 H), 6.11 (dd, J = 15.6, 7.6 Hz, 1 H), 5.99 (d, J = 1.2 Hz, 1 H), 5.97 (d, J = 21 / 29



Page 22 of 29

1.2 Hz, 1 H), 4.73 (d, J = 6.0 Hz, 1 H), 4.21 (t, J = 6.8 Hz, 1 H). 13C NMR (100.6 MHz, CDCl3): δ 193.1, 165.0, 147.9, 145.3, 144.8, 135.2, 134.7, 134.1, 132.8, 131.7, 129.0, 128.7, 128.0, 127.4, 122.0, 114.4, 107.1, 101.9, 99.3, 53.2, 42.2. HRMS (ESI) m/z calc'd for C25H21BrNO5 [M+NH4]+: 494.0598, found 494.0589. HPLC analysis (Chiralpak IC-H column, Hexane:2-propanol = 75:25, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 30.34 (major) and 34.78 min (minor). (7S,8R)-7-Benzoyl-8-((E)-4-methylstyryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6-on e (3ad): White solid, m.p. 176–178 °C, 28.5 mg, 69% yield, [α]20D 87.53 (c 0.93, CHCl3), >19/1 dr, 94% ee. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 7.2 Hz, 2 H), 7.62 (t, J = 7.2 Hz, 1 H), 7.49 (t, J = 7.2 Hz, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 7.10 (d, J = 8.0 Hz, 2 H), 6.68 (s, 1 H), 6.60 (s, 1 H), 6.45 (d, J = 15.6 Hz, 1 H), 6.06 (dd, J = 15.6, 7.6 Hz, 1 H), 5.98 (d, J = 1.2 Hz, 1 H), 5.96 (d, J = 1.2 Hz, 1 H), 4.74 (d, J = 6.4 Hz, 1 H), 4.21 (t, J = 6.8 Hz, 1 H), 2.32 (s, 3 H). 13C NMR (100.6 MHz, CDCl3): δ 193.3, 165.2, 147.8, 145.2, 144.7, 138.1, 135.2, 134.0, 133.8, 133.0, 129.3, 128.9, 128.7, 126.4, 125.5, 114.9, 107.1, 101.8, 99.2, 53.4, 42.3, 21.2. HRMS (ESI) m/z calc'd for C26H24NO5 [M+NH4]+: 430.1649, found 430.1652. HPLC analysis (Chiralpak IC-H column, Hexane:2-propanol = 75:25, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 25.61 (major) and 31.20 min (minor). (7S,8R)-7-Benzoyl-8-((E)-4-methoxystyryl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromen-6one (3ae): White solid, m.p. 130–132 °C, 33.0 mg, 77% yield, [α]20D 72.91 (c 1.10, CHCl3), >19/1 dr, 95% ee. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 7.2 Hz, 2 H), 7.61 (t, J = 7.2 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 2 H), 7.24 (d, J = 8.0 Hz, 2 H), 6.82 (d, J = 8.8 Hz, 2 H), 6.68 (s, 1 H), 6.60 (s, 1 H), 6.42 (d, J = 15.6 Hz, 1 H), 5.98 (d, J = 1.2 Hz, 1 H), 5.97 (dd, J = 15.6, 7.6 Hz, 1 H), 5.96 (d, J = 1.2 Hz, 1 H), 4.73 (d, J = 6.4 Hz, 1 H), 4.19 (t, J = 6.8 Hz, 1 H), 3.79 (s, 3 H). 22 / 29


13

C NMR

Page 23 of 29 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


(100.6 MHz, CDCl3): δ 193.4, 165.2, 159.6, 147.8, 145.2, 144.7, 135.3, 134.0, 133.3, 129.0, 128.7, 128.6, 127.7, 124.3, 115.0, 114.0, 107.2, 101.8, 99.2, 55.3, 53.5, 42.4. HRMS (ESI) m/z calc'd for C26H24NO6 [M+NH4]+: 446.1598, found 446.1601. HPLC analysis (Chiralpak IC-H column, Hexane:2-propanol = 75:25, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 46.00 (major) and 50.49 min (minor). Hydrolytic decarboxylation of compound 3aa and the subsequent transformation To a solution of 3aa (242 mg, 0.6 mmol) in tetrahydrofuran (6 mL) was added a solution of sodium hydroxide (64 mg, 1.6 mmol) in water (6 mL), the resulting mixture was stirred at 60 °C for 1 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (3×10 mL). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100–200 mesh, PE/EtOAc = 5/1) to afford 176.2 mg of the desired mixture of hydroxy ketone 4 and lactol 4‘ as a colorless oil in 78% yield (4/4’ = 1.25:1, 4’ dr = 8:1). 1

H NMR (CDCl3): For lactol 4‘ (major): δ 7.69 (dd, , J = 8.0, 1.2 Hz, 2 H), 7.41 (t, J = 7.2 Hz, 2

H), 7.36 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 6.53 (s, 1 H), 6.26 (d, J = 0.8 Hz, 1 H), 5.87 (d, J = 1.2 Hz, 1 H), 5.84 (d, J = 1.2 Hz, 1 H), 4.33 (dd, J = 12.8, 5.6 Hz), 3.80 (s, 3 H), 3.08 (d, J = 2.4 Hz, 1 H), 2.42 (dd, J = 13.6, 5.6 Hz, 1 H), 2.03 (dt, J = 13.2, 2.4 Hz, 1 H); For lactol 4‘ (minor, incomplete data): δ 7.08 (d, J = 8.6 Hz, 2 H), 6.88 (d, J = 8.4 Hz, 2 H), 6.60 (s, 1 H), 6.18 (d, J = 0.4 Hz, 1H), 4.31 (dd, J = 7.2, 6.4 Hz, 1 H), 3.80 (s, 3 H), 3.27 (s, 1 H), 2.63 (dd, J = 13.6, 6.0 Hz, 1 H), 2.45 (dd, J = 13.6, 9.6 Hz, 1 H); For hydroxy ketone 4: 1H NMR (CDCl3): δ 8.01 (dd, J = 8.4, 1.2 Hz, 2 H), 7.59 (t, J = 7.6 Hz, 1 H), 7.47 (t, J = 8.0 Hz, 2 H), 7.25 (d, J = 8.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 7.35 (s, 1 H), 6.49 (s, 1 H); 6.41 (s, 1 H), 5.79 (d, J 23 / 29



= 1.2 Hz, 1 H), 5.78 (d, J = 1.2 Hz, 1 H), 4.95 (dd, J = 10.4, 3.6 Hz, 1 H), 3.87 (dd, J = 18.0, 10.4 Hz, 1 H), 3.79 (s, 3 H), 3.71 (dd, J = 18.0, 3.2 Hz, 1 H). Combined 13C NMR (CDCl3): δ 200.5, 158.4, 158.1, 148.1, 147.0, 146.7, 146.3, 144.0, 141.9 (2 C), 136.3, 135.8 (2 C), 133.8, 129.7, 128.7 (2 C),, 128.5, 128.4, 128.3, 125.2, 124.0, 117.8, 114.0, 108.1, 107.4, 100.9 (2 C), 100.2, 98.9, 97.5, 55.3 (2 C), 45.0, 43.3, 38.4, 36.5. To a solution of ketone (4)/lactol (4‘) mixture (86.6 mg, 0.23 mmol) in acetone (2 mL) was added potassium carbonate (191 mg, 1.38 mmol) and methyl iodide (229 mg, 1.61 mmol). After stirring at room temperature for 48 h, the resulting mixutre was diluted with water (10 mL) and extracted with ethyl acetated (3×5 mL). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100–200 mesh, petroleum ether/ethyl acetate = 15/1) to afford the desired methylation product 5. (S)-3-(6-Methoxybenzo[d][1,3]dioxol-5-yl)-3-(4-methoxyphenyl)-1-phenylpropan-1-one (5): Colorless oil, 58.4 mg, 65% yield, [α]20D –16.44 (c 1.67, CHCl3), 91% ee. 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.2 Hz, 2 H), 7.55 (t, J = 7.2 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H), 7.19 (d, J = 8.4 Hz, 2 H), 6.81 (d, J = 8.4 Hz, 2 H), 6.61 (s, 1 H), 6.50 (s, 1 H), 5.86 (d, J = 1.2 Hz, 1 H), 5.85 (d, J = 1.2 Hz, 1 H), 5.06 (t, J = 7.2 Hz, 1 H), 3.76 (s, 3 H), 3.71 (s, 3 H), 3.65 (dd, J = 16.8, 8.0 Hz, 1 H), 3.59 (dd, J = 16.8, 7.2 Hz, 1 H). HRMS (ESI) m/z calc'd for C24H22NaO5 [M+Na]+: 413.1359, found 413.1362.

13

C NMR (100.6 MHz, CDCl3): δ 198.4, 157.8, 151.7, 146.2, 141.0,

137.0, 135.7, 132.9, 128.8, 128.5, 128.1, 125.4, 113.7, 107.9, 101.0, 95.0, 56.5, 55.1, 44.0, 38.6. HPLC analysis (Chiralpak AD-H column, Hexane:2-propanol = 75:25, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 13.42 (major) and 15.26 min (minor). 24 / 29


Page 24 of 29

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To a solution of ketone (4)/lactol (4’) mixture (86.6 mg, 0.23 mmol) in CH2Cl2 (2 mL) was added successively triethylsilane (401 mg, 3.5 mmol) and BF3.Et2O (131 mg, 0.92 mmol) at – 78 °C. The resulting mixture was stirred at the same temperature for 1.5 h and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (100–200 mesh, petroleum ether/ethyl acetate = 12/1) to give the corresponding cis-chromane 6. (6R,8S)-8-(4-methoxyphenyl)-6-phenyl-7,8-dihydro-6H-[1,3]dioxolo[4,5-g]chromene

(6):

Colorless oil, 56.4 mg, 68% yield, [α]20D 15.93 (c 0.97, CHCl3), >19/1 dr, 91% ee. 1H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 7.2 Hz, 2 H), 7.40 (t, J = 7.2 Hz, 2 H), 7.32 (t, J = 7.2 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 2 H), 6.87 (d, J = 8.4 Hz, 2 H), 6.50 (s, 1 H), 6.24 (s, 1 H), 5.86 (d, J = 1.2 Hz, 1 H), 5.84 (d, J = 1.2 Hz, 1 H), 5.13 (dd, J = 10.8, 1.2 Hz, 1 H), 4.22 (dd, J = 12.0, 5.6 Hz, 1 H), 3.81 (s, 3 H), 2.37 (ddd, J = 13.6, 6.0, 1.2 Hz, 1 H), 2.19 (dt, J = 12.0, 1.2 Hz, 1 H). 13C NMR (100.6 MHz, CDCl3): δ 158.4, 150.2, 146.6, 141.6, 141.1, 136.7, 129.3, 128.5, 128.0, 126.0, 117.7, 114.0, 108.3, 100.8, 98.5, 78.2, 55.2, 42.7, 40.8. HPLC analysis (Chiralpak IC-H column, Hexane:2-propanol = 90:10, flow rate = 1.0 mL/min, wavelength = 254 nm): Rt = 5.27 (minor) and 6.24 min (major).

ACKNOWLEDGMENT. We are grateful to the Key laboratory of Elemento-Organic Chemistry and Collaborative Innovation Center of Chemical Science and Engineering for generous financial support for our programs.

Supporting Information Available: X-ray structure data of compound 3ea, Copies of NMR and HRMS spectra, HPLC analysis. This material is available free of charge via the Internet at http://pubs.acs.org. References 1. a) Asai, F.; Iinuma, M.; Tanaka, T.; Takenaka, M.; Mizuno, M. Phytochemistry, 1992, 31, 25 / 29



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annulation of o-quinone methides with Î²-keto acylpyrazoles

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