Diastereoselective and Enantioselective Synthesis of Barbiturate

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Diastereoselective and Enantioselective Synthesis of Barbiturate-fused Spirotetrahydroquinolines via Chiral Palladium(0)/Ligand Complex Catalyzed [4+2] Cycloaddition of Vinyl Benzoxazinanones with Barbiturate-Based Olefins Hong-Wu Zhao, Ning-Ning Feng, Jia-Ming Guo, Juan Du, Wan-Qiu Ding, Li-Ru Wang, and Xiu-Qing Song J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01268 • Publication Date (Web): 18 Jul 2018 Downloaded from http://pubs.acs.org on July 19, 2018

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The Journal of Organic Chemistry

Diastereoselective and Enantioselective Synthesis of Barbiturate-fused Spirotetrahydroquinolines via Chiral Palladium(0)/Ligand Complex Catalyzed [4+2] Cycloaddition of Vinyl Benzoxazinanones with Barbiturate-Based Olefins

Hong-Wu Zhao,* Ning-Ning Feng, Jia-Ming Guo, Juan Du, Wan-Qiu Ding, Li-Ru Wang, Xiu-Qing Song

College of Life Science and Bio-engineering, Beijing University of Technology, No.100 Pingleyuan, Chaoyang District, Beijing 100124, P. R. China

Abstract: Under the catalysis of chiral palladium(0)/ligand complex, the [4+2] cycloaddition between vinyl benzoxazinanones and barbiturate-based olefins proceeded readily and provided barbiturate-fused spirotetrahydroquinolines in up to 96% chemical yield with up to >99:1 dr and 97% ee. The absolute configuration of barbiturate-fused spirotetrahydroquinolines was clearly identified by X-ray single crystal structure analysis. The reaction mechanism was proposed to shed light on the enantioselective formation of barbiturate-fused spirotetrahydroquinolines.

1

ACS Paragon Plus Environment

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INTRODUCTION Chiral barbiturate-fused spirotetrahydroquinolines constitute a class of structurally diverse and complex nitrogen-containing spiroheterocyclic scaffolds, and possess biologically and medicinally important properties such as antibacterial and anticancer activities as illustrated in Figure 1.1 Especially, ETX09142 and PUN-2866073 have been determined as clinic antibacterial candidates. HO

N

H N

O O

N

O

N

O O HN

NH

N N *

O

O

N *

S

O

Anticancer agent

Anticancer agent

O

O

O N

O

HN

HN O

O2N

NH

O

NH H O

N

H O O

N

N

F ETX0914

O

O PNU-286607

Antibacterial agent

Antibacterial agent

Figure 1. Representative bioactive chiral barbiturate-fused spirotetrahydroquinolines Over the past years, intrigued by the biological significances with these chemical entities, many efforts have been invested on their racemic4 and enantiomeric3b,5 synthesis. The previous enantioselective synthetic methodologies for chiral barbiturate-fused spirotetrahydroquinolines mainly involve using chiral substrates and chiral resolutions. However, in this content, the asymmetric catalytic protocols have fully been unexplored to date. So, developing asymmetric catalytic synthetic methodology is highly urgent to synthesize chiral barbiturate-fused spirotetrahydroquinolines enantioselectively. Being robust and versatile building blocks, vinyl benzoxazinanones participate in the catalytic enantioselective construction

of

structurally diverse

and complex nitrogen-containing chiral

heterocycles.6 Upon treatment with palladium(0)/chiral ligand or palladium(0)/chiral N-heterocyclic

2


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carbene,

vinyl

benzoxazinanones

decarboxylate

into

the

reactive

chiral

zwitterionic

palladium-stabilized-π-allyl intermediates easily and efficiently.7 Regarding these zwitterionic intermediates in situ formed, they can be readily and enantioselectively captured by structurally diverse reactants such as sulfur ylides, electron-deficient olefins, isatines and enals in the [4+1]8, [4+2]9 and [4+3]10 cycloadditions, respectively. Surely, these previously disclosed enantioselective catalytic cycloadditions of vinyl benzoxazinanones have functioned as the alternative and important tools for the synthesis of optically active nitrogenous heterocycles. Despite the significant advances in the catalytic enantioselective cycloaddition of vinyl benzoxazinanones, the design and development of novel enantioselective catalytic cycloadditions of vinyl benzoxazinanones remains highly needed for the construction of potentially bioactive chiral barbiturate-fused spirotetrahydroquinolines.

Scheme 1. Representative enantioselective catalytic vinyl benzoxazinanone-involved cycloadditions

3



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Motivated by the previous works, we designed the novel chiral palladium(0)/ligand complex catalyzed [4+2] cycloaddition of vinyl benzoxazinanones with synthetically valuable and versatile barbiturate-based olefins11 for the easily and efficiently enantioselective synthesis of chiral barbiturate-fused spirotetrahydroquinolines. Pleasantly, under the catalysis of chiral palladium(0)/ligand complex, the [4+2] cycloaddition between vinyl benzoxazinanones and barbiturate-based olefins proceeded smoothly and furnished the novel chiral barbiturate-fused spirotetrahydroquinolines in the reasonable chemical yields with high diastereoselectivities and enantioselectivities. To the best of our knowledge, such a work has not been reported in the literature to date.

RESULTS AND DISCUSSION O P N O

Ph

Ph

O P N O

O P N O

Ph

Ph (R,S,S)-L3

(S,S,S)-L2

(R)-L1

O O

PPh2 PPh2

PPh2 PPh2

O O (R)-L5

(R)-L4

Figure 2. Chiral ligands screened in this work. Table 1. Screening of chiral ligandsa

4


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a

entry

ligand

time

yieldb (%)

drc

eec

1

–

3

66

>99:1

0

2

L1

3

56

>99:1

88

3

L2

3

57

>99:1

50

4

L3

3

64

>99:1

60

5

L4

3

trace

–

–

6

L5

3

19

>99:1

80

Unless otherwise noted, reactions were carried out with 1a (0.1 mmol), 2a (0.1 mmol), Pd(PPh3)4 (2.5

mol%) and chiral ligands L1–L5 (10 mol%) in CH2Cl2 (1.0 mL) at room temperature. b Isolated chemical yield. c Determined by chiral HPLC analysis. Initially, in the presence of Pd(PPh3)4, we checked the reactivity and stereoselectivity of axially chiral BINOL-based ligands L1–L3, BINAP-based L4 and biphenyl bisphosphine L5 (Figure 2) in the [4+2] cycloaddition of vinyl benzoxazinanone 1a and barbiturate-based olefin 2a as shown in Table 1. Generally, most of chiral ligands delivered >99:1 dr in the cycloaddition. By comparison, the chemical yield and enantioselectivity of the cycloaddition significantly changed with the tested chiral ligands (entries 2–4 & 6). Without a chiral ligand, the [4+2] cycloaddition furnished product 3aa in 66% chemical yield as a racemate (entry 1). BINOL-based phosphoramidite ligand L1 delivered 3aa in 56% chemical yield with 88% ee (entry 2). Use of ligand L2 bearing the combined axial and central chiralities did not greatly improved the chemical yield and enantioselectivity of 3aa as we expected (entries 2 vs 3). In the case of ligand L3, it contained the opposite axial chirality to that of ligand L2, and delivered 3aa in the comparable chemical yield and enantioselectivity to those obtained with ligand L2 (entries 3 vs 4). Badly, using BINAP-based L4 gave product 3aa only in a trace amount after 3 h (entry 5). Delightfully, biphenyl bisphosphine L5 could furnish 3aa in a higher enantioselectivity though the chemical yield of 3aa

5



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remained lower (entry 6). In view of the chemical yield and enantioselectivity obtained with these tested axially chiral ligands, L1 proved to be the most suitable for the cycloaddition (entry 2). Table 2. Screening of ratio of Pd(PPh3)4/L1a

a

entry

Pd(PPh3)4 /L1(mmol/mmol)

time

yieldb (%)

drc

eec

1

0.0025/0.01

3

56

>99:1

88

2

0.005/0.01

3

68

>99:1

78

3

0.005/0.02

3

66

>99:1

90

4

0.01/0.02

3

61

>99:1

80

5

0.005/0.02

17

59

>99:1

93

6

0.005/0

3

66

>99:1

–

Unless otherwise noted, reactions were carried out with 1a (0.1 mmol), 2a (0.1 mmol), Pd(PPh3)4 and

L1 in CH2Cl2 (1.0 mL) at room temperature. b Isolated chemical yield. c Determined by chiral HPLC analysis. Then, we explored the effect of the molar ratio of Pd(PPh3)4/L1 on the [4+2] cycloaddition of vinyl benzoxazinanone 1a and barbiturate-based olefin 2a as depicted in Table 2. Basically, the different ratios tended to give 3aa in >99% dr (entries 1–6). By comparison, the chemical yield and enantioselectivity highly depended on the used molar ratios. Using 0.0025: 0.01 ratio gave 3aa in 56% chemical yield and 88% ee (entry 1). Meanwhile, the choice of 0.005:0.01 ratio increased the chemical yield, but decreased the enantioselctivity (entries 1 vs 2). Delightfully, the 0.005:0.02 ratio delivered 3aa in excellent enantioselectivity even with the moderate chemical yield (entry 3). In case of the 0.01:0.02 ratio, it 6


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decreased both chemical yield and enantioselectivity as compared with the former case (entries 3 vs 4). In addition, by using the ratio of 0.005:0.02, we prolonged the reaction time for 17 h, and the chemical yield lowered and enantioselectivity improved a little (entries 3 vs 5). In addition, in the absence of L1, loading Pd(PPh3)4 in 0.005 mmol afforded 3aa in 66% chemical yield (entry 6). Obviously, among all the tested ratios, as shown in entry 5, the ratio of 0.005:0.02 behaved more efficiently in terms of enantioselectivity in the cycloaddition. Table 3. Screening of palladium catalystsa

a

entry

palladium catalysts

time

yieldb (%)

drc

eec

1

Pd(PPh3)4

17

59

>99:1

93

2

Pd(OAc)2

17

72

>99:1

96

3

Pd2(dba)3

17

85

>99:1

91

4

Pd(PPh3)2Cl2

17

nrd

–

–

5

[Pd2(dba)3]·CHCl3

17

76

>99:1

96

6e

Pd(OAc)2

17

58

>99:1

92

7f

Pd2(dba)3

17

60

>99:1

96

Unless otherwise noted, reactions were carried out with 1a (0.1 mmol), 2a (0.1 mmol), palladium

catalyst (5 mol%) and L1 (20 mol%) in CH2Cl2 (1.0 mL) at room temperature. b Isolated chemical yield. c Determined by chiral HPLC analysis.

d

No reaction.

e

Pd(OAc)2 (10 mmol%) and L1 (40 mmol%).

f

Pd2(dba)3 (5 mmol%) and L1 (25 mmol%). Moreover, in the presence of L1, we attempted several structurally different palladium catalysts in the [4+2] cycloaddition of vinyl benzoxazinanone 1a with barbiturate-based olefin 2a in CH2Cl2 as outlined 7



Page 8 of 31

in Table 3. With the exception of Pd(PPh3)2Cl2, all the other tested palladium catalysts delivered >99% dr in the cycloaddition (entries 1–3 & 5–7). Normally, the used palladium catalysts influenced the chemical yield and enantioselectivity quite differently. In case of Pd(PPh3)4, it provided 3aa in 59% chemical yield with 93% ee (entry 1). By comparison, use of Pd(OAc)2 led to the increased chemical yield and enantioselectivity (entries 1 vs 2). Moreover, as compared with the former two cases, the employment of 3aa enhanced chemical yield, but lowered the enantioselectivity (entries 1–2 vs 3). Disappointedly, the cycloaddition did not occur at all in the presence of Pd(PPh3)2Cl2 (entry 4). With the use of [Pd2(dba)3]·CHCl3 as the palladium catalyst, the cycloaddition proceeded in 76% chemical yield with 96% ee (entry 5). Unfortunately, under the 1:4 ratio of Pd(OAc)2 and L1, increasing the actual loading of Pd(OAc)2 and L1 lowered the chemical yield and enantioselectivity of 3aa (entries 2 vs 6). Finally, we attempted the increased 1:5 ratio of Pd2(dba)3 and L1 in the cycloaddition, and discovered the chemical yield of 3aa decreased dramatically and the ennatioselectivity with it increased on some extents (entries 3 vs 7). Overall, [Pd2(dba)3]·CHCl3 behaved most efficiently with respect to the enantioselectivity achieved in the cycloaddition. Table 4. Screening of solventsa

entry

solvent

time

yieldb (%)

drc

eec

1

CH2Cl2

17

76

>99:1

96

2

THF

17

76

>99:1

93

3

DCE

17

70

>99:1

93

8


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a

4

Toluene

17

64

>99:1

94

5

MeCN

17

70

>99:1

96

6

CHCl3

17

70

>99:1

95

7

MeOH

17

nrd

-

–

Unless otherwise noted, reactions were carried out with 1a (0.1 mmol), 2a (0.1 mmol),

[Pd2(dba)3]·CHCl3 (5 mol%) and L1 (20 mol%) in solvent (1.0 mL) at room temperature. c

b

Isolated

d

chemical yield. Determined by chiral HPLC analysis. No reaction. Meanwhile, we investigated the solvent effect of a wide range of solvents possessing various palorities on the cycloaddition of vinyl benzoxazinanone 1a and barbiturate-based olefin 2a as outlined in Table 4. Except for the protic MeOH solvent, all the other examined aprotic solvents resulted in excellent diastereoselectivities in the cycloadditon (entries 1–6 vs 7). Using CH2Cl2 as solvent produced 3aa in76% chemical yield with 96% ee (entry 1). In the case of THF solvent, the chemical yield maintained the same as the previous case, but the enantioselectivity decreased (entries 1 vs 2). With regard to DCE, Toluene, MeCN ans CHCl3 as solvents, the chemical yields ranged from 64% to 70% and the enantioselectivities from 93% to 96% (entries 3–6). Badly, in the very polar and protic MeOH solvent, the cycloaddition did not take place at all (entry 7). So, in CH2Cl2 solvent, the cycloaddition performed most efficiently, and furnished product 3aa in the highest chemical yield with excellent diastereoselectivity and enantioselectivity (entry 1). Currently, for the cycloaddition, we determined the optimal reaction conditions as below: 5 mol% [Pd2(dba)3]·CHCl3, 20 mol% L1, 1a/2a/[Pd2(dba)3]·CHCl3/L1 = 1:1:0.05:0.2, CH2Cl2, rt. Table 5. Extension of reaction scopea

9



Page 10 of 31

time

yieldb

(h)

(%)

drc

eec

76

>99:1

96

3

68

>99:1

91

3ac

5

68

>99:1

94

2d (3-MeC6H4, Me)

3ad

3

90

>99:1

88

1a (H,Ts, H)

2e (4-MeOC6H4, Me)

3ae

3

81

>99:1

92

6

1a (H,Ts, H)

2f (4-MeC6H4, Me)

3af

3

74

>99:1

91

7

1a (H,Ts, H)

2g (4-ClC6H4, Me)

3ag

5

78

>99:1

89

8

1a (H,Ts, H)

2h (4-CF3C6H4, Me)

3ah

3

45

>99:1

93

9

1a (H,Ts, H)

2i (3,4,5-tri-MeOC6H2, Me)

3ai

3

84

>99:1

89

10

1a (H,Ts, H)

3aj

3

76

>99:1

90

11

1a (H,Ts, H)

3ak

3

89

>99:1

90

12

1a (H,Ts, H)

3al

48

nrd

–

–

13

1a (H,Ts, H)

2m (C6H5, H)

3am

48

nrd

–

–

14

1b (6-Br,Ts, H)

2a (C6H5, Me)

3ba

3

66

>99:1

58

15

1c (6-Cl,Ts, H)

2a (C6H5, Me)

3ca

5

66

>99:1

66

16

1d (6-Me,Ts, H)

2a (C6H5, Me)

3da

12

74

>99:1

80

17

1e (7-Cl, Ts, H)

2a (C6H5, Me)

3ea

3

85

>99:1

92

18

1f (7-F, Ts, H)

2a (C6H5, Me)

3fa

5

82

>99:1

96

19

1g (H, H, H)

2a (C6H5, Me)

3ga

12

96

>99:1

35

48

nr

d

–

–

d

–

–

1

2

3

4

5

entry

1 (R , R , R )

2 (R , R )

3

1

1a (H,Ts, H)

2a (C6H5, Me)

3aa

3

2

1a (H,Ts, H)

2b (2-MeOC6H4, Me )

3ab

3

1a (H,Ts, H)

2c (2-BrC6H4 , Me)

4

1a (H,Ts, H)

5

2j (

, Me) O

20

1h(H, Bn, H)

2k ( 2l (

, Me) , Me)

2a (C6H5, Me)

3ha

21

1i (H, Ts, Me)

2a (C6H5, Me)

3ia

48

nr

22

1d (6-Me,Ts, H)

2f (4-MeC6H4, Me)

3df

12

63

>99:1

67

23

1d (6-Me,Ts, H)

2g (4-ClC6H4, Me)

3dg

5

66

>99:1

76

24

1d (6-Me,Ts, H)

2c (2-BrC6H4, Me)

3dc

12

62

>99:1

83

25

1e (7-Cl, Ts, H)

2f (4-MeC6H4, Me)

3ef

5

83

>99:1

89

26

1e (7-Cl, Ts, H)

2g (4-ClC6H4, Me)

3eg

5

67

>99:1

94

10


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27 28 29 a

e

1f (7-F, Ts, H)

2g (4-ClC6H4, Me)

3fg

17

83

>99:1

92

1f (7-F, Ts, H)

2c (2-BrC6H4, Me)

3fc

17

77

>99:1

97

48

d

–

–

1i (H, Ts, Me)

2a (C6H5, Me)

3ia

nr

Unless otherwise noted, reactions were carried out with 1 (0.1 mmol), 2 (0.1 mmol), [Pd2(dba)3]·CHCl3 (5

mol%) and L1 (20 mol%) in CH2Cl2 (1.0 mL) at room temperature. b Isolated chemical yield. c Determined by chiral HPLC analysis. d No reaction. e At 40 °C Finally, under the optimal reaction conditions, we widely broaden the reaction scope by diversifying vinyl benzoxazinanones 1 and barbiturate-based olefins 2 as shown in Table 5. In the most cases, the diastereoselectivity of the cycloaddition reached >99:1 (entries 1–11, 14–19 & 22–28). In contrast, the chemical yield and enantioselectivity of the cycloaddition noticeably varied with the used substrates 1 and 2. Concerning the cycloaddition with 1a, most substrates 2 bearing an electron-rich or electron-poor aromatic ring as R4 group and a methyl as R5 group proceeded readily, and afforded products 3aa–3ak in 45–90% chemical yields with 88–96% enantioselectivities (entries 1–11). Remarkably, the substrates 2l with a bulky iso-propyl as R4 group and 2m without a substituent at R5 position exhibited much lower reactivities, and did not undergo the cycloaddition with 1a at all (entries 12–13). So, the chemical nature of R4 and R5 groups in substrates 2 significantly affected their chemical reactivities in the cycloaddition with 1a.

Also, we attempted the [4+2] cycloaddition between 1b–1i and 2a as summarized in Table 5 (entries 14–21). In this context, the substrate 1d with an electron-donating methyl as R1 group behaved better than the substrates 1b–1c bearing an electron-withdrawing halogen group in the cycloaddition and gave higher chemical yield and enantioselectivity (entries 14–15 vs 16). Moreover, the substitution position of R1 group in substrates 1 also influenced the chemical yield and enantioselectivity of the cycloaddition. For example, the substrates 1e–1f having R1 group at C7 position behaved better than the substrates 1b–1d containing R1 group at C6 position, and furnished the higher chemical yields and enantioselectivities 11



(entries 14–16 vs 17–18). Regarding the substrate 1g without any substituent at R2 position, it reacted with 2a to provide 3ga in excellent chemical yield with very low enantioselectivity (entry 19).

Clearly, the replacement of Ts group with benzyl group in the substrates 1 rendered the cycloaddition unsuccessful (entries 1 vs 20). Similarly, the substrate 1i with a methyl at R3 position also failed to react with 2a (entry 21). Therefore, the substrates 1 did not tolerate the wide variation of R2 and R3 groups in the cycloaddition. Lastly, we conducted some crossed cycloadditions by utilizing more reactive substrates 1d–1f and 2c or 2f–2g, and the chemical yield ranged from 62–83%, and enantioselectivity changed from 67–97% (entries 22–28). Lastly, we examined the cycloaddition between 1i and 2a at 40 °C, and still no reaction took place (entry 29). Moreover, the single crystal of 3ac was obtained, and its absolute configuration was determined to be (C-14S, C-18S) by X-ray analysis as presented in Figure 3.12 On the basis of the determined absolute configuration of 3ac, the absolute configurations of the other desired chiral barbiturate-fused spirotetrahydroquinolines were assigned similarly as shown in Table 5.

Figure 3. X-ray single crystal structure of 3ac

(with thermal ellipsoid shown at the 50% probability level)

To account for the enantioselective formation of 3ac, we predicted a reaction mechanism for the [4+2] cycloaddition between 1a and 2c as depicted in Scheme 2 according to previous works.9a–b,9d Both Pathway A and Pathway B include a reversible aza-michael addition and an intramolecular cyclization

12


Page 12 of 31

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sequence. Catalyzed by in situ formed chiral palladium(0)/L1 complex, 1a decarboxylates into a chiral palladium-stabilized zwitterionic intermediate 4. Then, the intermediate 4 conducts the reversible aza-michael addition with 2c to furnish two zwitterionic intermediates Int-I and Int-II. Regarding the intramolecular cyclization, Int-1 in pathway A is kinetically favoured than that of Int-2 in pathway B because of the strong steric repulsion between Ar and Ts groups caused during the intramolecular cyclization of Int-2. Finally, the intramolecular cyclization of the intermediate Int-1 gives cis-3ac as the major product by using the carbon anion on the barbiturate moiety to attack the si face of the palladium-stabilized π-allyl subunit. Commonly, as described in the previous works, the initial reversible aza-michael addition is fast, and the subsequent intramolecular cyclization is slow, and works as a rateand stereochemistry-determining step for the similar [4+2] cycloadditions.7b, 9a

Scheme 2.

Proposed reaction mechanism for the formation of 3ac.

13



In conclusion, we first have established the novel chiral palladium(0)/ligand complex catalyzed [4+2] cycloaddition between vinyl benzoxazinanones and barbiturate-based olefins for the enantioselective synthesis of the potentially bioactive barbiturate-fused spirotetrahydroquinolines. The [4+2] cycloaddition proceeded readily and provided barbiturate-fused spirotetrahydroquinolines in the reasonable chemical yields and enantioselectivities.

EXPERIMENTAL SECTION General information Unless noted otherwise, all reagents were commercially available and used without further purification. All solvents were distilled from the appropriate drying agents immediately before use. Reactions were monitored by TLC carried out on 0.25 mm SDS silica gel coated glass plates (60F254) and compounds were detected with UV light. The melting points of compounds were determined with a melting point instrument. NMR spectra were recorded on 400 MHz instrument and calibrated using tetramethylsilane (TMS) as internal reference. High resolution mass spectra (HRMS) were recorded under electrospray ionization (ESI) conditions on an Orbitrap mass analyzer. Specific optical rotations were measured with a polarimeter. HPLC analysis was performed on Waters equipment using Chiralpak AD (25 cm × 0.46 cm), AD-H (25 cm × 0.46 cm), AS-H (25 cm × 0.46 cm), IC (25 cm × 0.46 cm) and OD-H (25 cm × 0.46 cm) columns. Vinyl benzoxazinanones 1a-1i9a, 9d, 10a and barbiturate-based olefins 2a-2m11b,11d were prepared according to literature procedures. General procedure for enantioselective synthesis of products 3 A mixture of vinyl benzoxazinanone 1 (0.1 mmol, 1.0 equiv), barbiturate-based olefin 2 (0.1 mmol, 1.0 equiv), [Pd2(dba)3]·CHCl3 (0.005 mmol, 5 mol%) and L1 (0.02 mmol, 20 mol%) in 1.0 mL of CH2Cl2

14


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was stirred at room temperature. After the reaction was completed as indicated by TLC plate, the solvent was removed by evaporation and the crude product was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 5:1−6:1) to afford products 3. 3aa: White solid, yield: 40 mg (76%); mp 235–236 °C; dr >99:1; ee = 96%; [α]18 D : 160 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 7.6 Hz, 1H), 7.52–7.47 (m, 3H), 7.29–7.24 (m, 5H),

7.21–7.18 (m, 3H), 6.89 (d, J = 7.6 Hz, 1H), 6.31 (s, 1H), 5.46–5.36 (m, 1H), 5.22 (dd, J = 10.0, 1.2 Hz, 1H), 4.80 (d, J = 16.4 Hz, 1H), 3.32 (s, 3H), 2.80 (d, J = 10.0 Hz, 1H), 2.64 (s, 3H), 2.42 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 170.1, 165.5, 150.1, 144.0, 139.1, 136.6, 134.6, 133.2, 130.5, 129.3, 128.6, 128.1, 127.9, 127.7, 127.5, 126.8, 126.2, 125.6 123.1, 66.3, 65.9, 50.6, 29.1, 28.0, 21.5 ppm; HRMS (ESI) calculated for C29H28N3O5S [M + H]+: 530.1744, found 530.1751; HPLC separation (Chiralpak IC column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (minor) = 14.06 min, tR (major) = 16.73 min. 3ab: White solid, yield: 38 mg (68%); mp 223–224 °C; dr >99:1; ee = 91%; [α]18 D : 240 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 8.0 Hz, 1H), 7.62–7.56 (m, 3H), 7.48 (t, J = 7.6 Hz, 1H),

7.28–7.22 (m, 3H), 7.17 (t, J = 7.6 Hz, 1H), 6.97–6.93 (m, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.63 (s, 1H), 5.48–5.39 (m, 1H), 5.19 (d, J = 9.6 Hz, 1H), 4.72 (d, J = 16.8 Hz, 1H), 3.64 (s, 3H), 3.34 (s, 3H), 2.81 (d, J = 10.0 Hz, 1H), 2.66 (s, 3H), 2.40 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 171.1, 166.1, 154.2, 150.9, 143.7, 136.0, 135.5, 134.6, 130.5, 129.1, 128.8, 128.6, 128.6, 128.1, 128.0, 127.8, 127.1, 125.6, 122.7, 121.5, 109.4, 65.7, 62.0, 55.1, 51.4, 28.8, 27.8, 21.5 ppm; HRMS (ESI) calculated for C30H30N3O6S [M + H]+: 560.1850, found 560.1847; HPLC separation (Chiralpak IC column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (major)

15



= 8.68 min, tR (minor) = 15.20 min. 3ac: White solid, yield: 41 mg (68%); mp 250–251 °C; dr >99:1; ee = 94%; [α]18 D : 188 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.51–7.44 (m, 2H),

7.35–7.26(m, 4H), 7.22–7.19 (m, 1H), 7.10–7.06 (m, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.58 (s, 1H), 5.50–5.40 (m, 1H), 5.24 (dd, J = 10.0, 1.2 Hz, 1H), 4.83 (dd, J = 16.8, 1.2 Hz, 1H), 3.28 (s, 3H), 3.02 (d, J = 10.0 Hz, 1H), 2.58 (s, 3H), 2.43 (s, 3H) ppm;

13

C NMR (100 MHz, CDCl3): δ 169.5, 166.4, 150.0,

144.0, 139.0, 135.7, 134.9, 132.4, 131.4, 130.6, 129.6, 129.3, 127.8, 127.7, 127.5, 127.2, 125.8, 123.6, 120.8, 65.3, 65.1, 49.8, 29.2, 28.0, 21.6 ppm; HRMS (ESI) calculated for C29H27BrN3O5S [M + H]+: 608.0849, found 608.0857; HPLC separation (Chiralpak IC column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (minor) = 12.36 min, tR (major) = 13.69 min. 3ad: White solid, yield: 49 mg (90%); mp 220–221 °C; dr >99:1; ee = 88%; [α]18 D : 142 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 3H), 7.28–7.24 (m, 3H), 7.13

(t, J = 7.6 Hz, 1H), 7.02–6.94 (m, 3H), 6.89 (d, J = 7.6 Hz, 1H), 6.22 (s, 1H), 5.45–5.36 (m, 1H), 5.22 (dd, J = 10.0, 1.2 Hz, 1H), 4.81 (d, J = 16.8 Hz, 1H), 3.32 (s, 3H), 2.82 (d, J = 10.0 Hz, 1H), 2.63 (s, 3H), 2.42 (s, 3H), 2.28 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 170.1, 165.6, 150.1, 144.0, 138.9, 138.2, 136.5, 134.6, 133.3, 130.7, 129.2, 128.7, 128.4, 128.0, 127.7, 127.4, 126.9, 126.7, 125.6, 123.3, 123.0, 66.6, 65.8, 50.3, 29.0, 28.0, 21.5, 21.4 ppm; HRMS (ESI) calculated for C30H30N3O5S [M + H]+: 544.1901, found 544.1899; HPLC separation (Chiralpak IC column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (minor) = 11.72 min, tR (major) = 12.96 min. 3ae: White solid, yield: 45 mg (81%); mp 130–131 °C; dr >99:1; ee = 92%; [α]18 D : 130 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 8.0 Hz, 1H), 7.50–7.46 (m, 3H), 7.28–7.24 (m, 3H), 7.11 (d, J 16


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= 8.4 Hz, 2H), 6.88 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 2H), 6.23 (s, 1H), 5.45–5.35 (m, 1H), 5.22 (d, J = 10 Hz, 1H), 4.79 (d, J = 16.8 Hz, 1H), 3.76 (s, 3H), 3.31 (s, 3H), 2.79 (d, J = 10.0 Hz, 1H), 2.68 (s, 3H), 2.41 (s, 3H) ppm;

13

C NMR (100 MHz, CDCl3): δ 170.1, 165.6, 159.1, 150.1, 144.0, 136.6, 134.6,

133.1, 131.1, 130.6, 129.2, 128.1, 127.7, 127.5, 127.4, 126.7, 125.6, 123.0, 113.9, 66.0, 65.9, 55.2, 50.5, 29.1, 28.1, 21.5 ppm; HRMS (ESI) calculated for C30H30N3O6S [M + H]+: 560.1850, found 560.1854; HPLC separation (Chiralpak AD column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (major) = 8.68 min, tR (minor) = 15.20 min. 3af: White solid, yield: 40 mg (74%); mp 203–204 °C; dr >99:1; ee = 91%; [α]18D : 134 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.0 Hz, 1H), 7.50–7.46 (m, 3H), 7.28–7.24 (m, 3H), 7.06 (s,

4H), 6.88 (d, J = 7.2 Hz, 1H), 6.24 (s, 1H), 5.42–5.36 (m, 1H), 5.22 (d, J = 10.0 Hz, 1H), 4.80 (d, J = 16.8 Hz, 1H), 3.32 (s, 3H), 2.79 (d, J = 10 Hz, 1H), 2.66 (s, 3H), 2.42 (s, 3H), 2.28 (s, 3H) ppm;

13

C NMR

(100 MHz, CDCl3): δ 170.1, 165.6, 150.1, 143.9, 137.6, 136.6, 136.1, 134.6, 133.1, 130.6, 129.2, 128.1, 127.7, 127.4, 126.7, 126.1, 125.6, 123.0, 66.3, 65.8, 50.5, 29.0, 28.0, 21.5, 21.2 ppm; HRMS (ESI) calculated for C30H30N3O5S [M + H]+: 544.1901, found 544.1887; HPLC separation (Chiralpak IC column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (minor) = 16.31 min, tR (major) = 18.86 min. 3ag: White solid, yield: 44 mg (78%); mp 191–192 °C; dr >99:1; ee = 89%; [α]18 D : 126 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 3H), 7.28–7.23 (m, 5H), 7.16

(d, J = 8.0 Hz, 2H), 6.86 (d, J = 7.6 Hz, 1H), 6.32 (s, 1H), 5.44–5.35 (m, 1H), 5.24 (d, J = 9.6 Hz, 1H), 4.78 (d, J = 16.4 Hz, 1H), 3.31 (s, 3H), 2.72 (d, J = 10.0 Hz, 4H), 2.42 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 169.8, 165.2, 150.0, 144.2, 137.8, 136.6, 134.3, 133.7, 132.4, 130.1, 129.3, 128.7, 128.4, 127.8,

17



127.7, 127.3, 126.9, 125.6, 123.3, 65.7, 65.2, 51.2, 29.1, 28.1, 21.5 ppm; HRMS (ESI) calculated for C29H27ClN3O5S [M + H]+: 564.1354, found 564.1350; HPLC separation (Chiralpak AD column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (major) = 6.69 min, tR (minor) = 9.42 min.

3ah: White solid, yield: 27 mg (45%); mp 175–176 °C; dr >99:1; ee = 93%; [α]18 D : 134 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.0 Hz, 1H), 7.54–7.50 (m, 5H), 7.37 (d, J = 7.6 Hz, 2H),

7.29–7.25 (m, 3H), 6.86 (d, J = 7.2 Hz, 1H), 6.45 (s, 1H), 5.46–5.37 (m, 1H), 5.25 (d, J = 10.0 Hz, 1H), 4.79 (d, J = 16.8 Hz, 1H), 3.32 (s, 3H), 2.70 (d, J = 11.6 Hz, 4H), 2.42 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 169.7, 165.0, 150.0, 144.2, 143.4, 136.6, 134.3, 132.2, 129.9, 129.3, 128.5, 127.7, 127.4, 127.0, 126.9, 126.3 (q, J = 270.0 Hz), 125.5, 123.4, 65.9, 65.1, 51.5, 29.1, 28.1, 21.5 ppm; HRMS (ESI) calculated for C30H27F3N3O5S [M + H]+: 598.1618, found 598.1609; HPLC separation (Chiralpak IC column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (minor) = 7.70 min, tR (major) = 8.22 min. 3ai: White solid, yield: 52 mg (84%); mp 213–214 °C; dr >99:1; ee = 89%; [α]18D : 166 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.0 Hz, 1H), 7.51–7.48 (m, 3H), 7.28–7.25 (m, 3H), 6.89 (d, J

= 8.0 Hz, 1H), 6.40 (s, 2H), 6.20 (s, 1H), 5.44–5.35 (m, 1H), 5.23 (d, J = 10.0 Hz, 1H), 4.81 (d, J = 16.8 Hz, 1H), 3.78 (d, J = 8.8 Hz, 9H), 3.32 (s, 3H), 2.81 (d, J = 10.0 Hz, 1H), 2.71 (s, 3H), 2.42 (s, 3H) ppm; 13

C NMR (100 MHz, CDCl3): δ 170.2, 165.4, 153.1, 150.1, 144.1, 136.5, 134.6, 134.5, 133.2, 130.5,

129.3, 128.1, 127.7, 127.0, 126.9, 125.7, 123.2, 103.4, 66.5, 65.8, 60.8, 55.9, 50.3, 29.0, 28.2, 21.5 ppm; HRMS (ESI) calculated for C32H34N3O8S [M + H]+: 620.2061, found 620.2068; HPLC separation (Chiralpak IC column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention

18


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times tR (major) = 28.15 min, tR (minor) = 35.81 min. 3aj: White solid, yield: 44 mg (76%); mp 248–249 °C; dr >99:1; ee = 90%; [α]18D : 126 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 8.11 (d, J = 8.0 Hz, 1H), 7.78–7.70 (m, 4H), 7.55 (d, J = 8.0 Hz, 3H),

7.47–7.45 (m, 2H) ,7.33–7.26 (m, 4H), 6.91 (d, J = 7.6 Hz, 1H), 6.51 (s, 1H), 5.48–5.39 (m, 1H), 5.25 (d, J = 10.0 Hz, 1H), 4.83 (d, J = 16.8 Hz, 1H), 3.35 (s, 3H), 2.85 (d, J = 10.0 Hz, 1H), 2.55 (s, 3H), 2.43 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 170.1, 165.4, 150.0, 144.0, 136.8, 136.6, 134.6, 133.0, 132.9, 130.4, 129.3, 128.3, 128.3, 128.2, 127.8, 127.6, 127.5, 126.8, 126.3, 126.2, 125.6, 125.6, 124.1, 123.1, 66.3, 66.0, 50.9, 29.1, 28.0, 21.5 ppm; HRMS (ESI) calculated for C33H30N3O5S [M + H]+: 580.1901, found 580.1912; HPLC separation (Chiralpak IC column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (major) = 17.32 min, tR (minor) = 18.56 min. 3ak: White solid, yield: 46 mg (89%); mp 166–167 °C; dr >99:1; ee = 90%; [α]18 D : 120 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 7.6 Hz, 1H), 7.51–7.42 (m, 3H), 7.28–7.22 (m, 3H), 7.13 (s,

1H), 6.83 (d, J = 7.6 Hz, 1H), 6.55 (s, 1H), 6.38 (s, 1H), 6.30 (s, 1H), 5.48–5.39 (m, 1H), 5.23 (d, J = 10.0 Hz, 1H), 4.71 (d, J = 16.8 Hz, 1H), 3.34 (s, 3H), 2.92 (s, 3H), 2.56 (d, J = 10.0 Hz, 1H), 2.41 (s, 3H) ppm; 13

C NMR (100 MHz, CDCl3): δ 169.7, 165.3, 152.4, 150.7, 144.2, 141.6, 135.7, 134.4, 132.7, 129.8,

129.3, 128.3, 127.9, 127.8, 127.1, 125.4, 123.1, 111.3, 108.4, 64.0, 61.2, 50.9, 29.1, 28.3, 21.5 ppm; HRMS (ESI) calculated for C27H26N3O6S [M + H]+: 520.1537, found 520.1536; HPLC separation (Chiralpak AS-H column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (minor) = 7.77 min, tR (major) = 9.88 min. 3ba: White solid, yield: 40 mg (66%); mp 195–196 °C; dr >99:1; ee = 58%; [α]18 D : 94 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.4, 1.6 Hz, 1H), 7.54 (d, J = 8.0 19



Page 20 of 31

Hz, 2H), 7.30–7.21 (m, 5H), 7.14 (d, J = 6.8 Hz, 2H), 7.02 (s, 1H), 6.22 (s, 1H), 5.40–5.31 (m, 1H), 5.26 (dd, J = 10.0, 1.2 Hz 1H),4.85–4.80 (m, 1H), 3.32 (s, 3H), 2.81 (d, J = 9.6 Hz, 1H), 2.64 (s, 3H), 2.44 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 169.8, 165.6, 149.9, 144.3, 138.7, 135.7, 135.4, 134.4, 131.1, 129.8, 129.5, 128.8, 128.7, 128.6, 128.2, 127.7, 126.1, 123.9, 120.5, 66.5, 65.6, 50.0, 29.1, 28.1, 21.5 ppm; HRMS (ESI) calculated for C29H27BrN3O5S [M + H]+: 608.0849, found 608.0833; HPLC separation (Chiralpak IC column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (major) = 10.24 min, tR (minor) = 11.45 min. 3ca: White solid, yield: 37 mg (66%); mp 174–175 °C; dr >99:1; ee = 66%; [α]18 D : 84 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.2 Hz, 1H),

7.30–7.21 (m, 5H), 7.14 (d, J = 6.8 Hz, 2H), 6.87 (s, 1H), 6.23 (s, 1H), 5.40–5.31 (m, 1H) 5.26 (d, J = 9.6 Hz, 1H), 4.82 (d, J = 16.4 Hz 1H), 3.32 (s, 3H), 2.78 (d, J = 9.6 Hz, 1H), 2.64 (s, 3H), 2.44 (s, 3H) ppm; 13

C NMR (100 MHz, CDCl3): δ 169.9, 165.6, 149.9, 144.3, 138.7, 135.2, 135.1, 134.4, 132.5, 129.8,

129.5, 128.6, 128.5, 128.2, 128.1, 127.7, 126.1, 125.9, 123.9, 66.5, 65.5, 50.0, 29.1, 28.1, 21.6 ppm; HRMS (ESI) calculated for C29H27ClN3O5S [M + H]+: 564.1354, found 564.1342; HPLC separation (Chiralpak IC column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (major) = 10.36 min, tR (minor) = 11.31 min. 3da: White solid, yield: 40 mg (74%); mp 176–177 °C; dr >99:1; ee = 80%; [α]18 D : 116 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.30–7.20 (m, 5H),

7.19–7.16 (m, 3H), 6.68 (s, 1H), 6.28 (s, 1H), 5.44–5.35 (m, 1H), 5.21 (d, J = 10.0 Hz, 1H), 4.78 (d, J = 16.8 Hz, 1H), 3.32 (s, 3H), 2.76 (d, J = 10.0 Hz, 1H), 2.64 (s, 3H), 2.42 (s, 3H), 2.36 (s, 3H) ppm;

13

C

NMR (100 MHz, CDCl3): δ 170.2, 165.5, 150.1, 143.9, 139.2, 136.6, 134.7, 133.9, 132.8, 130.7, 129.2,

20


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128.8, 128.5, 127.9, 127.8, 127.2, 126.3, 126.1, 122.9, 66.3, 66.0, 50.6, 29.0, 28.0, 21.5, 21.4 ppm; HRMS (ESI) calculated for C30H30N3O5S [M + H]+: 544.1901, found 544.1905; HPLC separation (Chiralpak AD-H column, solvent: hexane/ethanol = 95/5, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (minor) = 11.68 min, tR (major) = 13.13 min. 3ea: White solid, yield: 48 mg (85%); mp 218–219 °C; dr >99:1; ee = 92%; [α]18 D : 110 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 8.02 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.28–7.21 (m, 6H), 7.15 (d, J =7.6

Hz, 2H), 6.81 (d, J = 8.0 Hz, 1H), 6.26 (s, 1H), 5.41–5.32 (m, 1H), 5.24 (dd, J = 10.0, 1.2 Hz, 1H), 4.83 (d, J = 16.8 Hz, 1H), 3.32 (s, 3H), 2.80 (d, J = 9.6 Hz, 1H), 2.64 (s, 3H), 2.42 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 169.9, 165.6, 149.9, 144.4, 138.7, 137.7, 134.5, 133.6, 131.7, 130.0, 129.4, 128.6, 128.1, 127.7, 127.3, 126.8, 126.5, 126.1, 123.6, 66.4, 65.6, 50.1, 29.1, 28.0, 21.5 ppm; HRMS (ESI) calculated for C29H27ClN3O5S [M + H]+: 564.1354, found 564.1355; HPLC separation (Chiralpak IC column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (minor) = 8.77 min, tR (major) = 9.61 min. 3fa: White solid, yield: 45 mg (82%); mp 97–98 °C; dr >99:1; ee = 96%; [α]18D : 148 (c = 0.10, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.79–7.77 (m, 1H), 7.55 (d, J = 7.6 Hz, 2H), 7.28–7.16 (m, 7H), 6.97–6.94 (m, 1H), 6.85–6.81 (m, 1H), 6.28 (s, 1H), 5.42–5.33 (m, 1H), 5.24 (d, J = 10.0 Hz, 1H), 4.84 (d, J = 16.8 Hz, 1H), 3.32 (s, 3H), 2.80 (d, J = 10.0 Hz, 1H), 2.65 (s, 3H), 2.43 (s, 3H) ppm;

13

C NMR (100 MHz,

CDCl3): δ 169.9, 165.5, 162.1 (d, J = 245.0 Hz), 149.9, 144.3, 138.8, 137.9 (d, J = 10.0 Hz), 134.5, 130.2, 129.4, 128.7 (d, J = 3.0 Hz), 128.6, 128.1, 127.7, 126.5 (d, J = 9.0 Hz), 126.1, 123.4, 114.9 (d, J = 25.0 Hz), 113.5 (d, J = 25.0 Hz), 66.4, 65.6, 50.2, 29.1, 28.0, 21.6 ppm; HRMS (ESI) calculated for C29H27FN3O5S [M + H]+: 548.1650, found 548.1650; HPLC separation (Chiralpak IC column, solvent:

21



hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (minor) = 9.31 min, tR (major) = 10.18 min.

3ga: White solid, yield: 36 mg (96%); mp 169–170 °C; dr >99:1; ee = 35%; [α]18 D : 28 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 7.37–7.31 (m, 3H), 7.21–7.12 (m, 4H), 6.84–6.81 (m, 1H), 6.71 (d, J =

7.6 Hz, 1H), 5.70–5.61 (m, 1H), 5.39–5.29 (m, 2H), 4.81 (s, 1H), 4.56 (d, J = 9.6 Hz, 1H), 4.44 (s, 1H), 3.08 (s, 3H), 3.03 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 169.5, 165.1, 150.2, 142.4, 136.4, 135.4, 129.8, 128.8, 127.7, 127.3, 126.6, 122.0, 121.7, 118.6, 114.3, 64.1, 58.4, 48.9, 28.4, 27.8 ppm; HRMS (ESI) calculated for C22H22N3O3 [M + H]+: 376.1656, found 376.1656; HPLC separation (Chiralpak OD-H column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (minor) = 7.36 min, tR (major) = 11.35 min. 3df: White solid, yield: 35 mg (63%); mp 194–195 °C; dr >99:1; ee = 67%; [α]18 D : 118 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.28–7.24 (m, 3H), 7.05

(s, 4H), 6.67 (s, 1H), 6.22 (s, 1H), 5.42–5.35 (m, 1H), 5.21 (dd, J = 10.0, 1.2 Hz, 1H), 4.78 (d, J = 16.8 Hz, 1H), 3.31 (s, 3H), 2.76 (d, J = 10.0 Hz, 1H), 2.66 (s, 3H), 2.42 (s, 3H), 2.36 (s, 3H), 2.27 (s, 3H) ppm; 13

C NMR (100 MHz, CDCl3): δ 170.2, 165.6, 150.2, 143.8, 137.5, 136.5, 136.2, 134.7, 133.9, 132.8,

130.8, 129.2, 129.2, 128.7, 127.7, 127.2, 126.3, 126.1, 122.8, 66.2, 65.9, 50.5, 29.0, 28.0, 21.5, 21.4, 21.0 ppm; HRMS (ESI) calculated for C31H32N3O5S [M + H]+: 558.2057, found 558.2054; HPLC separation (Chiralpak IC column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (major) = 17.67 min, tR (minor) = 19.94 min. 3dg: White solid, yield: 38 mg (66%); mp 111–112 °C; dr >99:1; ee = 76%; [α]18 D : 108 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.30–7.22 (m, 5H), 7.15 22


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(d, J = 8.4 Hz, 2H), 6.65 (s, 1H), 6.30 (s, 1H), 5.43–5.34 (m, 1H), 5.22 (d, J = 10.0 Hz, 1H), 4.76 (d, J = 16.4 Hz, 1H), 3.30 (s, 3H), 2.74 (s, 3H), 2.66 (d, J = 10.0 Hz, 1H), 2.42 (s, 3H), 2.36 (s, 3H) ppm;

13

C

NMR (100 MHz, CDCl3): δ 169.9, 165.1, 150.0, 144.1, 138.0, 136.7, 134.3, 133.9, 133.6, 132.1, 130.2, 129.3, 129.0, 128.6, 127.8, 127.7, 127.1, 126.3, 123.2, 65.8, 65.1, 51.2, 29.1, 28.1, 21.5, 21.4 ppm; HRMS (ESI) calculated for C30H29ClN3O5S [M + H]+: 578.1511, found 578.1490; HPLC separation (Chiralpak IC column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (major) = 11.57 min, tR (minor) = 13.98 min. 3dc: White solid, yield: 38.5 mg (62%); mp 100–101 °C; dr >99:1; ee = 83%; [α]18 D : 146 (c = 0.10, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H) 7.29–7.26(m, 3H), 7.22–7.18 (m, 1H), 7.08–7.05 (m, 1H), 6.79 (s, 1H), 6.55 (s, 1H), 5.48–5.39 (m, 1H), 5.22 (d, J = 10.4 Hz, 1H), 4.80 (d, J = 16.8 Hz, 1H), 3.27 (s, 3H), 2.97 (d, J = 10.0 Hz, 1H), 2.59 (s, 3H), 2.41 (d, J = 12.8 Hz, 6H) ppm;

13

C NMR (100 MHz, CDCl3): δ 169.6,

166.4, 150.1, 143.9, 139.1, 137.0, 135.0, 134.5, 133.0, 132.4, 131.4, 130.8, 129.6, 129.2, 128.5, 127.8, 127.5, 127.4, 126.5, 123.4, 120.8, 65.3, 65.0, 49.9, 29.2, 28.0, 21.6, 21.5 ppm; HRMS (ESI) calculated for C30H29BrN3O5S [M + H]+: 622.1006, found 622.1010; HPLC separation (Chiralpak IC column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (major) = 12.67 min, tR (minor) = 14.34 min. 3ef: White solid, yield: 48 mg (83%); mp 208–209 °C; dr >99:1; ee = 89%; [α]18D : 180 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 7.6 Hz, 2H),

7.22(dd, J = 8.0, 1.6 Hz, 1H), 7.05 (q, J = 8.0 Hz, 4H), 6.81 (d, J = 8.0 Hz, 1H), 6.19 (s, 1H), 5.41–5.32 (m, 1H), 5.24 (d, J = 10.0 Hz, 1H), 4.83 (d, J = 16.4 Hz, 1H), 3.31 (s, 3H), 2.79 (d, J = 10.0 Hz, 1H), 2.66

23



Page 24 of 31

(s, 3H), 2.43 (s, 3H), 2.28 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 169.9, 165.6, 150.0, 144.3, 137.9, 137.8, 135.6, 134.4, 133.5, 131.7, 130.1, 129.4, 129.3, 127.7, 127.3, 126.7, 126.5, 126.1, 123.5, 66.4, 65.5, 50.0, 29.1, 28.0, 21.6, 21.1 ppm; HRMS (ESI) calculated for C30H29ClN3O5S [M + H]+: 578.1511, found 578.1504; HPLC separation (Chiralpak IC column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (minor) = 8.76 min, tR (major) = 9.85 min. 3eg: White solid, yield: 40 mg (67%); mp 233–234 °C; dr >99:1; ee = 94%; [α]18 D : 162 (c = 0.10, CHCl3). 1

H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 2.0 Hz 1H), 7.53 (d, J = 8.4 Hz 2H), 7.29–7.21 (m, 5H), 7.13

(d, J = 8.0 Hz, 2H), 6.79 (d, J = 8.0 Hz, 1H), 6.27 (s, 1H), 5.40–5.31 (m, 1H), 5.25 (dd, J = 10.0, 1.6 Hz, 1H), 4.82 (d, J = 16.4 Hz, 1H), 3.30 (s, 3H), 2.74–2.69 (m, 4H), 2.43 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 169.6, 165.2, 149.8, 144.5, 137.8, 137.4, 134.2, 133.9, 133.8, 130.9, 129.6, 129.5, 128.8, 127.8, 127.7, 127.2, 126.9, 126.5, 123.8, 65.4, 65.3, 50.7, 29.2, 28.1, 21.6 ppm; HRMS (ESI) calculated for C29H26Cl2N3O5S [M + H]+: 598.0965, found 598.0947; HPLC separation (Chiralpak AD column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (major) = 6.28 min, tR (minor) = 8.30 min.

3fg: White solid, yield: 48 mg (83%); mp 127–128 °C; dr >99:1; ee = 92%; [α]18D : 146 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 7.78–7.75 (m, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.28–7.23 (m, 4H), 7.15 (d, J

= 8.4 Hz, 2H), 6.97–6.93 (m, 1H), 6.82–6.79 (m, 1H), 6.30 (s, 1H), 5.41–5.32 (m, 1H), 5.26–5.24 (m, 1H), 4.82 (d, J = 16.4 Hz, 1H), 3.30 (s, 3H), 2.75–2.70 (m, 4H), 2.42 (s, 3H) ppm;

13

C NMR (100 MHz,

CDCl3): δ 169.6, 165.2, 162.2 (d, J = 245.0 Hz), 149.9, 144.5, 138.0 (d, J = 11.0 Hz), 137.5, 134.2, 133.9, 129.8, 129.5, 128.8, 128.0 (d, J = 3.0 Hz), 127.8, 127.7, 126.6 (d, J = 9.0 Hz), 123.6, 114.9 (d, J = 24.0 Hz), 113.6 (d, J = 21.0 Hz), 65.5, 65.3, 50.8, 29.1, 28.1, 21.6 ppm; HRMS (ESI) calculated for

24


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C29H26ClFN3O5S [M + H]+: 582.1260, found 582.1252; HPLC separation (Chiralpak AD column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (major) = 7.31 min, tR (minor) = 8.91 min. 3fc: White solid, yield: 48 mg (77%); mp 180–181 °C; dr >99:1; ee = 97%; [α]18D : 160 (c = 0.10, CHCl3); 1

H NMR (400 MHz, CDCl3): δ 7.72 (dd, J = 9.6, 2.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.0

Hz, 1H), 7.30–7.21 (m, 4H), 7.11–7.07 (m, 1H), 7.05–7.00 (m, 1H), 6.96–6.92 (m, 1H), 6.55 (s, 1H), 5.45–5.38 (m, 1H), 5.25 (dd, J = 10.0, 1.2 Hz 1H), 4.86 (d, J = 16.8 Hz, 1H), 3.28 (s, 3H), 3.01 (d, J = 10.0 Hz, 1H), 2.60 (s, 3H), 2.43 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 169.3, 166.4, 161.9 (d, J = 245.0 Hz), 149.9, 144.4, 138.6, 136.9 (d, J = 11.0 Hz), 134.8, 132.5, 131.3, 130.5 (d, J = 4.0 Hz), 130.4, 129.8, 129.4, 127.8, 127.6, 126.7 (d, J = 8.0 Hz), 123.9, 120.8, 115.0 (d, J = 24.0 Hz), 114.0 (d, J = 21.0 Hz), 65.2, 65.0, 49.5, 29.2, 28.0, 21.6 ppm; HRMS (ESI) calculated for C29H26BrFN3O5S [M + H]+: 626.0755, found 626.0760; HPLC separation (Chiralpak AD column, solvent: hexane/ethanol = 90/10, flow rate = 1.0 mL/min, λ = 254 nm): retention times tR (minor) = 6.22 min, tR (major) = 7.27 min.

ASSOCIATED CONTENT SUPPORTING INFORMATION Copies of NMR for products 3; X-ray single crystal structure analysis data for 3ac; Copies of HPLC spectra

This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

25



Corresponding Author

*E-mail: [email protected]

NOTES

The authors declare no competing financial interest.

ACKNOWLEDGEMENTS We thank Beijing Municipal Commission of Education (No. JC015001200902), Beijing Natural Science Foundation (No. 7102010, No. 2122008, No. 2172003), Basic Research Foundation of Beijing University of Technology (X4015001201101), Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality (No. PHR201008025), Doctoral Scientific Research Start-up Foundation of Beijing University of Technology (No. 52015001200701) for financial supports.

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(11) For selected examples, see: (a) Han, B.; Huang, W.; Ren, W.; He, G.; Wang, J.-h.; Peng, C. Asymmetric Synthesis of Cyclohexane-Fused Drug-Like Spirocyclic Scaffolds Containing Six Contiguous Stereogenic Centers via Organocatalytic Cascade Reactions. Adv. Synth. Catal. 2015, 357, 561–568. (b) Zhao, H. W.; Tian, T.; Li, B.; Yang, Z.; Pang, H. L.; Meng, W.; Song, X. Q.; Chen, X. Q. Diastereoselective Synthesis of Dispirobarbiturates through Et3N-Catalyzed [3 + 2] Cycloaddition of Barbiturate-Based Olefins with 3-Isothiocyanato Oxindoles. J. Org. Chem. 2015, 80, 10380–10385. (c) Dieskau, A. P.; Holzwarth, M. S.; Plietker, B. Fe-catalyzed Allylic C-C-Bond Activation: Vinylcyclopropanes As Versatile a1,a3,d5-Synthons in Traceless Allylic Substitutions and [3 + 2]-Cycloadditions. J. Am. Chem. Soc. 2012, 134, 5048–5051. (d)Zhao, H.-W.; Tian, T.; Pang, H.-L.; Li, B.; Chen, X.-Q.; Yang, Z.; Meng, W.; Song, X.-Q.; Zhao, Y.-D.; Liu, Y.-Y. Organocatalytic [3+2] Cycloadditions of Barbiturate-Based Olefins with 3-Isothiocyanato Oxindoles: Highly Diastereoselective and Enantioselective Synthesis of Dispirobarbiturates. Adv. Synth. Catal. 2016, 358, 2619–2630. (e) Soleimani, E.; Yazdani, H.; Saei, P. Synthesis of spiro 3-bromo-4,5-dihydroisoxazoles via [1,3]dipolar cycloaddition reactions. Tetrahedron Lett. 2015, 56, 1635–1637. (f) Girgis, A. S.; Farag, H.; Ismail, N. S.; George,

R.

F.

Synthesis,

hypnotic

properties

and

molecular

modeling

studies

of

1,2,7,9-tetraaza-spiro[4.5]dec-2-ene-6,8,10-triones. Eur. J. Med. Chem. 2011, 46, 4964–4969.

(12) CCDC 1828461 contains the supplementary crystallographic data for compound 3ac. These data can be obtained free of charge from The Cambridge Crystallographic Data Center via www. ccdc.cam.ac.uk/data_request/cif.

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Diastereoselective and Enantioselective Synthesis of Barbiturate

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