Lewis Acids Promoted 3 + 2 Cycloaddition of Oxaziridines and Cyclic

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Lewis Acids Promoted 3+2 Cycloaddition of Oxaziridines and Cyclic Allylic Alcohols through Carbonyl Imine Intermediates Erbao Zhao, Feilong Zhou, and Yujun Zhao J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00246 • Publication Date (Web): 14 Mar 2019 Downloaded from http://pubs.acs.org on March 14, 2019

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The Journal of Organic Chemistry

Lewis Acids Promoted 3+2 Cycloaddition of Oxaziridines and Cyclic Allylic Alcohols through Carbonyl Imine Intermediates Erbao Zhao,a,b,† Feilong Zhou,b,† Yujun Zhao b,c* a

Nano Science and Technology Institute, University of Science and Technology of

China, Suzhou, Jiangsu 215123, China b

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,

Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai 201203, China c

School of Pharmacy, Yancheng Teachers University, Yancheng, Jiangsu, China,

224007 † Equal

contribution

KEYWORDS: Isoxazolidine, 3+2 Cycloaddition, Carbonyl imine, Oxaziridine, Allylic alcohol, Allylic cation, Oxocarbenium.

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ABSTRACT: Syntheses of isoxazolidines through the carbonyl imine intermediates are currently limited to mono-substituted olefin substrates. Herein, we reported syntheses of novel bicyclic isoxazolidine-containing compounds through 1,3-dipolar cycloaddition reactions using cyclic allylic alcohols as substrates, which are challenging in previous reports. Generally, the reaction yields range from good to high and the reaction substrates tolerate various functional groups including the cyclopropyl and amine groups. Mechanistic studies suggest that an allylic cation and a carbonyl imine intermediates are involved and responsible for the observed stereochemistry and diastereoselectivity.

HO R3 O N R1

R2

H

O N SnCl4 o

-78 C

R2

N

O

R1

R2

R1 R3 35 examples Up to 99% yield


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INTRODUCTION Isoxazolidines are unique five-membered heteocycles featuring a labile N-O bond in a saturated oxazole ring.1-2 Several methods have been reported for the synthesis of isoxazolidine-containing compounds and most of them are based on 1,3-dipolar cycloaddition reactions of oxaziridines/nitrones with olefines or cyclization of hydroxylamines.2-13 Recently, Yoon's group reported a practical method for preparation of isoxazolidines from the oxaziridines and olefines (Scheme 1, equation 1),14 via a challenging and less-well studied carbonyl imines intermediates.10, 15-16 Previous Work: O N Ph

Ns

Lewis Acid

R Ns

H

N

O

Ns N O

Ph R

Ph

(1)

(I) HO R3

This Work: O N R1

R2

H

O N Lewis Acid

R2

N

O

R1

R2 (2)

R1 R3

(II)

Scheme 1: Proposed synthesis of bicyclic isoxazolidines (2) in comparison with Yoon's methods (1). Although computational studies suggested that the carbonyl imines, formed through the C-N cleavage of N-sulfonyl oxaziridines, are significantly higher in energy than the isomeric nitrones formed through C-O cleavage,17-18 yet the 1,3-dipolar cycloaddition reaction involving the carbonyl imine intermediates proceeded smoothly. Generally, the reaction yields and diastereoselectivity for such a transformation are high for terminal mono-substituted olefins. However, the reported



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reaction yields for disubstituted olefines is low (ca. 20%) in Partridge et. al.’s study.14 Although this issue is minor, it may limit the applications of synthesizing more versatile 1,2-isoxazolidine-containing compounds from multiple substituted olefin substrates. Further improvement of the synthetic method is warranted. In view of the biological activities of several classes of isoxazolidine-containing compounds2,

19-22

including natural alkaloids (-)-Flueggine A, (+)-Virosaine B, and Zetekitoxin AB,23-26 we are interested in developing a practical method to synthesize versatile isoxazolidine-containing compounds. In this paper, we report our studies of a reaction between N-sulfonyl oxaziridines ("Davis oxaziridines") and cyclic allylic alcohols (Scheme 1, equation 2), which affords novel isoxazolidine-containing bicyclic compounds in good to high yields in a single step. RESULTS AND DISCUSSION We firstly screened suitable reaction conditions for the oxaziridine 1a and the allylic alcohol 2a (Table 1). In the presence of 0.1 equiv. of TiCl4, we obtained a mixture 3a and 4a with a 47% yield at room temperature (Table 1, entry 1). The reaction yield decreased either at -78 oC (entry 2) or in the presence of 1.0 equiv. of TiCl4 (entry 3). We also screened additional Lewis acids suitable for this transformation (entries 4-7) and found SnCl4 that gave a 99% yield of 3a and 4a with a ratio of 44:56. Structures of 3a/4a have been determined by X-ray crystallography studies (Supporting Information). Additionally, a less amount of SnCl4 (entry 8), the absence of molecular sieve (entry 9), or a shorter reaction time (entry 10) were all detrimental to the reaction yields. In summary, the best reaction condition for this


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transformation is to use a stoichiometric amount of SnCl4 in the presence of molecular sieve 4Å, toluene as the solvent, and an optimal reaction temperature at -78 oC. Table 1: Screening of reaction conditions

Cl

Ph

Ts N O

OH

Acids Ph

H

Ph

H

Toluene

1a (1.0 eq)

a

Ts H N O

Ts H N O

2a (1.5 eq)

3a Cl

Entry

Acid

MS 4Å

Eq.

T(oC)

1

TiCl4

Yes

0.1

2

TiCl4

Yes

3

TiCl4

4

4a

Cl

Time (h)

Yield (%)a

3a:4ab Ratioc

rt

12

47

62:38

0.1

-78

12

70% in all cases with 4k, 4l, and 4n-4p as the major isomers (entries 1-6). When 1m was used as the substrate, a region-isomer 3x was also obtained as a single isomer in a 31% yield.27-28 Unfortunately, para-electron-withdrawing group substitutions on the 3-aryl group were detrimental for this transformation with no products isolated (SI Scheme S2).

Table 3: Substrate scope of substituted toluenesulfonyl-1,2-oxaziridines



R

O N

SnCl4 1.0 eq. 4Å MS

Cl OH Ts

-78 oC, Toluene

1l-1q (1.0 eq.)

2a (1.5 eq.)

Entry

R

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R

H

3k-3q

Produc t

Reactant

Ts H N O

Ts H N O

R

Cl

Yield(%) a

H

4k-4q

Cl

3:4 ratiob

3+4

Me

1

2

Me

3c

1k

3k+4k

80

44:56

1l

3l+4l

86

34:66

1m

3m+4m

57

37:63

1n

3n+4n

76

37:63

1p

3p+4p

70

43:57

1q

3q+4q

78

58:42

Me

4 F

5 Cl

6 Br

O

H

Ts N H

Me

a

Cl

3x

Isolated yield; b Ratio of isomers determined by 1H NMR of the crude products; c Isomer

3x was isolated in 31% yield, its structure was determined by X-ray crystallography studies.

In order to explore the substrate compatibility of the allylic alcohols, we tested the reaction of 1a with a small library of cyclic allylic alcohols 2b-2n and the results are


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summarized in Table 4. In general, the R group of 2 tolerates various functional groups including aromatic and aliphatic groups. When the R groups were phenyl, halogen substituted phenyl, alkly substituted phenyl, CF3-substituted phenyl, and N-Ts-substituted phenyl (entries 1-3, 5-8), the desired products 5b/6b-5d/6d and 5f/6f-5i/6i were obtained in good to high yields. When meta position of phenyl was an isopropyl group (entry 9), a moderate yield of 5j/6j was obtained likely because of the steric repulsion of the isopropyl group. Table 4: Substrate scope of allylic alcohols

Ph

O N

OH R Ts

-78 oC, Toluene

1a (1.0 eq.)

Ts H N O

SnCl4 1.0 eq. 4 Å MS

Ph

2b-2n (1.5 eq.)

Entry

R

1

H

Ts H N O R

5b-5n

Ph

H

R 6b-6n

Reactant

Product

Yield(%)a 5+6(%)

5:6 ratiob

2b

5b+6b

92

48:52

2c

5c+6c

99

38:62

2d

5d+6d

93

43:57

2e

5e+6e

37

68:32

2f

5f+6f

84

50:50

2g

5g+6g

73

37:63

2h

5h+6h

67

28:72

2i

5i+6i

62

47:53

F

2

Br

3 4 Me

5

Me

Me

6 7 8

F3C

N Ts



9 10 11

a

MeO

Ph

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2j

5j+6j

45

22:78

2k

---

0

---

2l

5l+6l

94

61:39

12

Me

2m

5m+6m

83

29:71

13

Et

2n

5n+6n

94

63:37

Isolated yield; b Ratio of isomers determined by 1H NMR of the crude products; Unfortunately, we only obtained 5e/6e with a 37% yield and 5e was the major

isomer. No product was found when 2k was used (entry 10). When the R were aliphatic groups (entries 11-13), the desired cyclization products 5l/6l-5n/6n were obtained in high yields. Again, two isomers were obtained in all these cases and the diastereoselectivity was poor. We also tried 3-alkyl groups substituted 1,2-oxaziridines as the reaction substrates and most of these efforts were futile (SI Scheme S2), which suggested the aromatic aryl groups may function as cation stabilization groups for this transformation. It is well known that the cyclopropyl group can stabilize a carbenium cation, we therefore study whether the 3-cyclopropyl substituted 1,2-oxaziridine 7 is a suitable substrate, and the results are summarized in Table 5. Interestingly, all cyclic allylic alcohols reacted with 7 smoothly and the anticipated products 10a/11a, 10c/11c, 10d/11d, 10h/11h, and 10l/11l - 10n/11n were obtained, while additional compounds 8/9 were also observed in all cases. To simplify the data analysis, the crude reaction products were treated with AgSF6 to facilitate the removal of Cl atoms. Upon treatment of the


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silver salt, the anticipated cyclization products were isolated with good to high yields (Entries 1-7). Again, moderate isomer ratios of 10/11 were obtained, ranging from 69:31 to 21:79. The relative stereochemistry of the cyclization product 11a was further confirmed by X-ray crystallography studies. It is noteworthy to point out that 3-cyclopropyl-1,2-oxaziridine type substrate was found inactive in previous reports,14 which suggests that a distinct reaction mechanism is probably involved. Table 5: Reaction with 3-cyclopropyl substituted 1,2-oxaziridine 7 Ts H N Cl O

Ts N O 7 (1.0 eq.)

OH R

H

SnCl4 1.0 eq. 4 Å MS -78 oC, Toluene

2a, 2c, 2d 2h, 2l-2n (1.5 eq.)

Ts H N Cl O H

R

8

9

Ts H N O

Ts H N O

H

R

H

R AgSbF6

10a, 10c, 10d, 10h, 10l-10n 11a, 11c, 11d, 11h, 11l-11n

R

10a, 10c, 10d, 11a, 11c, 11d, 10h, 10l-10n 11h, 11l-11n

Entry

R

1

Reactant

Products

Yield(%)a 10+11

10:11 ratiob

2a

10ac+11a

99

65:35

2c

10c+11c

99

65:35

2d

10d+11d

99

69:31

2h

10h+11h

72

21:79

2l

10l+11l

80

33:67

Cl

2 Br

3

4 5

F3C

Ph

6

Et

2m

10m+11m

63

59:41

7

Me

2n

10n+11n

81

66:34



a

Isolated yield;

b

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Ratio of isomers determined by 1H NMR of the crude products; c

The structure of 11a has been confirmed by X-ray crystallography studies To investigate the reaction mechanism, we synthesized 12a-12e to react with 1a (Table 6). Table 6: Model reactions to probe reaction mechanism Y O N

Ph

Z Toluene, -78 °C X 12a-12e 2a, 2d, 2m (1.5 eq.)

Ts

1a (1.0 eq.)

Entry

Reactant

1

Ts H N O

SnCl4 1.0 eq. 4 Å MS

Ph

H

Ts H N O R

3a/5d/5m

Ph

H

R

4a/6d/6m

Yield(%)a

Isomer ratiob

83

29:71

80

24:76

12b

42

43:57

2a

99

44:56

75

39:61

12d

63

30:70

2d

93

43:57

99

42:58

Reactant

Product

2m HO

2

12a

5m+6m

OH

3 Cl

4c HO Ar Ar

5c

12c

3a+4a

OH Ar

6c Cl

7 HO Ph

5d+6d

Ph

8

12e OH

a

Isolated yield; b Ratio of isomers determined by 1H NMR of the crude products for


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3a:4a, 5d:6d, and 5m:6m; c Ar is a 4-Cl phenyl group. Interestingly, three different substrates 2m, 12a, and 12b (entries 1-3) gave the same products 5m/6m in 83%, 80%, and 42% yields respectively with no significant differences of isomer ratios. Similarly, substrates 2a, 12c, and 12d (entries 4-6) gave the same products 3a/4a in 99%, 75%, and 63% yields respectively with no significant differences of isomer ratios. The same trend was also observed for substrates 2d and 12e (entries 7-8). Because the same products were obtained from different reaction substrates, we hypothesized that common intermediates were involved for all of these transformations. It has been previously demonstrated that an allylic cation could be generated from allylic alcohols and allylic chlorides in the presence of acids,29-33 we therefore postulate that allylic cationic intermediates are involved in our reactions. Based on our data, we proposed the following reaction mechanism for such a transformation (Scheme 3). R HO

R1

SnCl4

2

R HO Cl4Sn

O N R' 13

R1

R

R

R H +

14 + O SnCln N R'

R1

R1 = Ar, cyclopropyl

O

N

R1 R' 15

R H R1

O

N

R1 O

R'

N R' O 18

-H+

R H R1

N

R'

16'

16

H

H

H N

O R' 17

Scheme 3: Proposed reaction mechanism In the presence of SnCl4, oxaziridine 13 opens up and generates a carbonyl imine



intermediate 15, which is in line with the observed arrangement of N-O-C sequences in the final products. The N atom of the carbonyl imine intermediate 15 attacks the allylic cation 14, in situ formation from the allylic alcohol 2, from a less hindered site furnishing the intermediates 16 and 16'. Subsequently, the olefine electron flows into the oxocarbenium of 16 and 16' furnishing a stabilized carbenium 17. The oxocarbenium of 16 and 16' approach the olefine from the same side of the N group, which leads to the cis stereochemistry of the fused ring system. However, the benzylic stereogenic center of 17 epimizes because both E/Z oxocarbenium can be possible active electrophiles. Finally, elimination of a proton from 17 yields the desired final products 18 as a mixture of two isomers where R1 is one of aryl groups. When R1 is a cyclopropyl group, similar reaction mechanism is observed except that 17 is likely to be quenched by Cl anions. Subsequent elimination is facilitated by treatment of AgSbF6 and 18 is obtained as a mixture of two isomers. Our data shown that the 3-phenyl and 3-cyclopropyl groups (not 3-cyclohexyl nor 3-methyl group) substituted oxaziridines are the only reactive substrates. These experimental observations are consistent with the proposed reaction mechanism, which indicates that a carbocation stabilization group is required for such a transformation. CONCLUSIONS In conclusion, we have reported a novel 1,3-dipolar cycloaddition reactions of the oxaziridines and the cyclic allylic alcohols, which are challenging substrates with low reactivities in precedent reports. In our reaction conditions, the yields range from good to high and the activities of the substrates decorated with various functional


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groups are robust. Mechanistic studies suggested that an allylic cation and a carbonyl imine intermediates are involved and responsible for the observed stereochemistry and diastereoselectivity. We consider that our practical method may be applied to obtain diverse bicyclic compounds embedded with isoxazolidine moieties, which are of potential interests for future studies. EXPERIMENTAL SECTION General Methods. Unless otherwise stated, reagents were purchased from commercial

suppliers

and

used

as

received

without

further

purification:

2-Cyclohexen-1-one (Energy), dichloromethane (J&K, Super Dry, with molecular sieves), SnCl4 (Energy), BF3.OEt2 (Aladdin), TiCl4 (Aladdin), AgSbF6 (TCI), AgBF4 (Energy). Proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) spectroscopy were performed on Bruker Advance NMR 400 and 500, Chemical shifts of 1H NMR spectra are reported as δ in units of parts per million (ppm) downfield from SiMe4 (δ= 0.0) and relative to the signal of CDCl3 (δ = 7.26, singlet). Multiplicities were given as: s (singlet); d (doublet); t (triplet); q (quartet); dd (doublet of doublets); dt (doublet of triplets); and m (multiplets). The number of protons for a given resonance is indicated by nH. Coupling constants are reported as J values in Hz. Carbon nuclear magnetic resonance spectra (13C NMR) are reported as proton-decoupled carbon data and δ in units of parts per million (ppm) downfield from SiMe4 (δ = 0.0) and relative to the signal of CDCl3 (δ = 77.23, triplet). Fluorine nuclear magnetic resonance spectra (19F NMR) are reported as δ in units of parts per million (ppm) downfield from CFCl3 (δ = 0) and relative to the



signal of PhCF3 (δ = -63.72). Low resolution mass spectrum analysis was performed on The LTQ linear ion trap mass spectrometer (Finnigan) and Thermo DFS (Thermo Fisher Scientific). High-resolution mass spectral analysis (HRMS) was performed on UHPLC-QTOF (Agilent Corporation) and Thermo DFS (Thermo Fisher Scientific). Melting points (mp) were measured on DSC Q2000 (V24.11 Build 124). Known 1,2-oxaziridines34-35 and allylic alcohols29 were prepared according to literature procedures. Synthesis of 1, 2-Oxaziridines A round-bottom flask equipped with a magnetic stirring bar was charged with TsNH2 (17.15 mmol, 1.0 equiv.), aldehyde (18.87 mmol, 1.1 equiv.), and toluene. To this mixture, BF3·OEt2 (0.28 mmol, 0.016 equiv.) was added.36 The mixture was allowed to heat to 120 oC and stirred for overnight. The resulting mixture was concentrated in vacuo. The crude was used directly for the next m-CPBA oxidation. In a second 100 ml round-bottom flask equipped with a magnetic stirring bar was charged with m-CPBA (3.76 mmol, 1.1 equiv.) and dichloromethane at 0 oC followed by addition of KOH (11.98 mmol, 3.5 equiv.).34 After 10 min, the crude material from the first step (3.42 mmol, 1.0 equiv.) was added as a dichloromethane solution at 0 oC. The mixture was allowed to warm up to room temperature and stirred for 15 min. The mixture was filtered and concentrated in vacuo. The residual crude materials were purified by flash column chromatography to yield the desired products. 3-Phenyl-2-(m-tolylsulfonyl)-1, 2-oxaziridine (1b): a white solid (0.18 g, 20% yield). 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 1.6 Hz, 2H), 7.63 – 7.39 (m, 7H),


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5.51 (s, 1H), 2.51 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 139.8, 135.9, 134.5, 131.4, 130.5, 129.6, 129.2, 128.8, 128.3, 126.5, 76.3, 21.3. HRMS (ESI): m/z calculated for C14H14NO332S [M+H]+ : 276.0689, Found [M+H]+ : 276.0689. 3-Phenyl-2-(o-tolylsulfonyl)-1, 2-oxaziridine (1c): a yellow solid obtained (0.74 g, 41% yield). 1H NMR (400 MHz, CDCl3): δ 8.32 – 7.99 (m, 1H), 7.61 (dd, J = 7.6, 1.4 Hz, 1H), 7.55 – 7.38 (m, 7H), 5.57 (s, 1H), 2.87 (s, 3H).

13C{1H}

NMR (100 MHz,

CDCl3): δ 140.3, 135.0, 133.4, 133.0, 131.4, 131.1, 130.7, 128.8, 128.3, 126.5, 75.7, 21.0. HRMS (ESI): m/z calculated for C14H14NO332S [M+H]+ : 276.0689, Found [M+H]+ : 276.0688. Methyl 4-((3-phenyl-1, 2-oxaziridin-2-yl)sulfonyl)benzoate (1f): a yellow solid obtained (0.63 g, 57% yield). 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 8.37 Hz, 2H), 8.06 (d, j = 8.37 Hz, 2H), 7.4 - 7.33 (m, 5H), 5.46 (s, 1H), 3.92 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 164.3, 137.6, 135.0, 130.5, 129.4, 129.2, 128.3, 128.0, 127.8, 127.3, 126.9, 125.5, 124.9, 75.3, 51.8. HRMS (EI): m/z calculated for C15H13NO532S: 319.0509, Found: 319.0508. 2-((4-Fluorophenyl)sulfonyl)-3-phenyl-1, 2-oxaziridine (1g) : a white solid obtained (730 mg, 68% yield). 1H NMR (400 MHz, CDCl3): δ 8.08 (m, 2H), 7.55 – 7.37 (m, 4H), 7.38 – 7.28 (m, 2H), 5.50 (s, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 166.7 (d, JC-F = 257 Hz), 132.3 (d, JC-F = 10 Hz), 131.5, 130.7 (d, JC-F = 3 Hz), 130.2, 128.7, 128.8, 128.3, 116.9 (d, JC-F = 22 Hz), 76.5. HRMS (EI): m/z calculated for C13H10NO3F32S: 279.0360, Found: 279.0363.



2'-Isopropyl-3, 4-dihydro-[1, 1'-biphenyl]-1(2H)-ol (2j): To a solution of the corresponding 1-bromo-2-isopropylbenzene (5.7 mmol, 1.0 equiv.) in anhydrous THF at -40 oC, n-buthyllithium (6.8 mmol, 1.2 equiv. 1.6 M in hexane) was added. The reaction mixture was stirred for 30 min before 2-Cyclohexen-1-one (1.0 g, 8.5 mmol, 1.5 equiv.) was added via a syringe. The reaction mixture was allowed to stir at -40 oC for overnight before quenching with saturated aqueous solution of NH4Cl. The aqueous layer was extracted with ethyl acetate (3 × 50 ml), and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residual crude material was purified by flash column chromatography to give the final product as yellow oil (1.94 g, 75 % yield). 1H NMR (400 MHz, CDCl3): δ 7.60 (dd, J = 7.9, 1.5 Hz, 1H), 7.35 (dd, J = 7.8, 1.5 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.14 (ddd, J = 7.9, 7.1, 1.5 Hz, 1H), 5.99 (ddd, J = 9.9, 4.6, 2.9 Hz, 1H), 5.91 – 5.85 (m, 1H), 2.22 – 2.07 (m, 2H), 2.07 – 1.94 (m, 2H), 1.85 (m, 2H), 1.65 (m, 1H), 1.30 – 1.13 (m, 6H). 13C{1H} NMR (125 MHz, CDCl3): δ 147.1, 143.3, 133.7, 129.4, 127.4, 126.4, 125.1, 72.6, 37.7, 28.7, 27.0, 24.8, 24.7, 19.3. HRMS (EI): m/z calculated for C15H20O: 216.1509, Found: 216.1511. General procedures for reactions between the oxaziridines and the allylic alcohols To a dry round-bottom flask equipped with a magnetic stirring bar, the oxaziridine (0.2 mmol, 1.0 equiv.), 4Å MS (87 mg), the allylic alcohol (0.3 mmol, 1.5 equiv.), and anhydrous toluene (5 mL) were added. The solution was cooled to -78 oC followed by addition of SnCl4 (0.2 mmol, 1.0 equiv. 1.0 M solution in CH2Cl2) via a


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syringe. The reaction mixture was allowed to proceed at -78 oC for another 12 h before filtration and concentration in vacuo. The residual crude material was purified by flash column chromatography. In each case, the cyclization compounds were obtained as two pairs of enantiomers, and the name of only one enantiomer of each pair was shown as follows. (3S, 3aR, 7aS)-4-(4-Chlorophenyl)-3-phenyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydro benzo[c]isoxazole (3a) / (3S, 3aS, 7aR)-4-(4-Chlorophenyl)-3-phenyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydro benzo[c]isoxazole (4a) : White solid (3a + 4a = 92 mg, 99 % yield). 3a: 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 6.97 (m, 5H), 6.79 (d, J = 7.3 Hz, 2H), 6.72 – 6.60 (m, 2H), 5.90 (s, 1H), 5.65 (d, J = 9.5 Hz, 1H), 4.83 (m, 1H), 4.23 (m, 1H), 2.43 (s, 4H), 2.33 – 2.20 (m, 1H), 2.13 (m, 1H), 1.96 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 145.1, 139.8, 135.4, 134.3, 133.0, 132.2, 129.7, 129.3, 128.8, 128.1, 127.8, 127.8, 127.4, 126.9, 86.4, 76.7, 58.6, 47.5, 25.7, 23.1, 21.8. HRMS (EI): m/z calculated for C26H24O3N35Cl32S: 465.1160, Found: 465.1161, mp: 161.5 oC. 4a: 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.23 – 6.99 (m, 5H), 6.99 – 6.78 (m, 2H), 6.83 – 6.61 (m, 2H), 6.04 (s, 1H), 4.72 (d, J = 9.9 Hz, 1H), 4.61 (m, 1H), 3.65 (t, J = 8.6 Hz,1H), 2.44 (m, 5H), 2.23 – 2.07 (m,1H), 2.07 – 1.85 (m, 1H).

13C{1H}

NMR (100 MHz, CDCl3): δ 145.2, 137.9,

136.7, 134.1, 132.5, 132.2, 129.7, 128.3, 128.1, 128.0, 127.7, 127.7, 127.6, 89.0, 59.7, 51.2, 25.3, 24.2, 21.8. HRMS (EI): m/z calculated for C26H24O3N35Cl32S: 465.1160, Found: 465.1161, mp: 184.8 oC.



Page 20 of 54

(3S, 3aR, 7aS)-4-(4-Chlorophenyl)-3-phenyl-1-(m-tolylsulfonyl)-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (3b) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)3-phenyl-1-(m- tolylsulfonyl)-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (4b) : White solid (3b + 4b = 74 mg, 80% yield). 3b: 1H NMR (400 MHz, CDCl3): δ 7.89 – 7.80 (m, 2H), 7.51 – 7.38 (m, 2H), 7.09 – 6.91 (m, 5H), 6.83 – 6.77 (m, 2H), 6.75 – 6.69 (m, 2H), 5.95 – 5.87 (m, 1H), 5.66 (d, J = 9.5 Hz, 1H), 4.58 (m, 1H), 4.24 (t, J = 8.7 Hz, 1H), 2.43 (m, 5H), 2.20 – 2.08 (m, 1H), 2.00 (m, 1H).

13C{1H}

NMR (125

MHz, CDCl3): δ 139.9, 136.2, 135.5, 135.0, 134.5, 132.5, 129.6, 129.1, 128.9, 128.3, 128.0, 127.6, 127.1, 126.6, 86.6, 58.7, 47.6, 29.9, 26.9, 23.2. HRMS (EI): m/z calculated for C26H24O3N35Cl32S: 465.1160, Found: 465.1164. 4b: 1H NMR (400 MHz, CDCl3): δ 7.89 – 7.80 (m, 2H), 7.51 – 7.38 (m, 2H), 7.17 – 7.09 (m, 1H), 7.09 – 6.91 (m, 4H), 6.90 – 6.83 (m, 2H), 6.75 – 6.69 (m, 2H), 6.04 (m, 1H), 4.86 (m, 1H), 4.73 (d, J = 9.8 Hz, 1H), 3.56 (t, J = 8.6 Hz, 1H), 2.43 (m, 5H), 2.20 – 2.08 (m, 1H), 2.00 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 139.5, 138.1, 136.7, 135.1, 135.0, 134.2, 132.7, 130.2, 129.0, 128.5, 128.1, 127.9, 127.9, 127.7, 127.0, 89.2, 60.0, 53.6, 51.2, 25.6, 24.3, 21.5. HRMS (EI): m/z calculated for C26H24O3N35Cl32S: 465.1160, Found: 465.1164. (3S, 3aR, 7aS)-4-(4-Chlorophenyl)-3-phenyl-1-(o-tolylsulfonyl)-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (3c) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)3-phenyl-1-(o-tolylsulfonyl)-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (4c): White solid (3c + 4c = 36 mg, 39 % yield). 3c: 1H NMR (400 MHz, CDCl3): δ 7.49 (t, J = 7.5 Hz, 2H), 7.42 – 7.20 (m, 2H), 7.13 - 6.90 (m, 5H), 6.90 – 6.73 (m, 2H), 6.69


Page 21 of 54 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


(d, J = 8.2 Hz, 2H), 5.92 (d, J = 4.3 Hz, 1H), 5.78 (d, J = 9.6 Hz, 1H), 4.94 (m, 1H), 4.34 (t, J = 8.9 Hz, 1H), 2.74 (s, 3H), 2.56 – 2.21 (m, 2H), 2.16 (m, 1H), 1.97 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 139.9, 139.7, 135.4, 134.7, 134.4, 133.9, 132.3, 131.8, 131.5, 128.6, 128.3, 128.3, 128.0, 127.9, 127.5, 126.3, 85.8, 56.8, 46.5, 25.8, 23.2, 20.8. HRMS (EI): m/z calculated for C26H24O3N35Cl32S: 465.1160, Found: 465.1157. 4c: 1H NMR (400 MHz, CDCl3): δ 8.10 (m, 1H), 7.42 – 7.20 (m, 1H), 7.13 (m, 2H), 7.09 – 6.90 (m, 3H), 6.90 – 6.73 (m, 2H), 6.69 (d, J = 8.2 Hz, 2H), 6.77 (d, J = 8.2 Hz, 2H), 6.04 (d, J = 4.1 Hz, 1H), 4.87 – 4.77 (m, 1H), 4.74 (d, J = 10.2 Hz, 1H), 3.81 (t, J = 8.7 Hz, 1H), 2.74 (s, 3H), 2.56 – 2.21 (m, 2H), 2.16 (m,1H), 1.97 (m, 1H). 13C{1H}

NMR (125 MHz, CDCl3): δ 139.8, 138.0, 136.8, 134.3, 134.2, 124.1, 132.8,

132.6, 128.2, 127.9, 127.8, 127.7, 127.1, 126.3, 89.7, 59.0, 51.5, 25.3, 24.7, 20.9. HRMS (EI): m/z calculated for C26H24O3N35Cl32S: 465.1160, Found: 465.1157. (3S, 3aR, 7aS)-4-(4-Chlorophenyl)-3-phenyl-1-(phenylsulfonyl)-1, 3, 3a, 6, 7, 7a-hexahydrobenzo

[c]isoxazole

(3d)

/

(3S,

3aS,

7aR)-4-(4-Chloro

phenyl)-3-phenyl-1-(phenylsulfonyl)-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (4d) : White solid (3d + 4d = 80 mg, 90 % yield). 3d: 1H NMR (400 MHz, CDCl3): δ 8.13 – 7.94 (m, 2H), 7.74 – 7.61 (m, 1H), 7.55 (t, J = 7.7 Hz, 2H), 7.13 – 6.89 (m, 5H), 6.87 – 6.74 (m, 2H), 6.74 – 6.58 (m, 2H), 5.92 (t, J = 4.3 Hz, 1H), 5.65 (d, J = 9.4 Hz, 1H), 4.94 – 4.76 (m, 1H), 4.23 (s, 1H), 2.38 (d, J = 5.1 Hz, 1H), 2.27 (m 1H), 2.13 (m, 1H), 2.05 – 1.90 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 137.9, 136.5, 135.3, 134.1, 132.6, 129.7, 129.2, 129.0, 128.4, 128.1, 128.1, 127.8, 127.7, 127.6,



126.9, 89.0, 59.8, 51.4, 31.9, 29.7, 29.4, 25.4, 24.2, 22.7, 14.1. HRMS (EI): m/z calculated for C25H22O3N35Cl32S: 451.1003, Found: 451.1004. 4d: 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 7.3, 1.4 Hz, 2H), 7.78 – 7.61 (m, 1H), 7.56 (t, J = 8.4, 7.1 Hz, 2H), 7.13 (m, 1H), 7.08 – 6.99 (m, 4H), 6.90 – 6.83 (m, 2H), 6.77 – 6.69 (m, 2H), 6.04 (dd, J = 5.0, 3.3 Hz, 1H), 4.73 (d, J = 9.8 Hz, 1H), 4.61 (ddd, J = 11.7, 7.2, 4.8 Hz, 1H), 3.60 (t, J = 8.6 Hz, 1H), 2.56 – 2.24 (m, 2H), 2.14 (m, 1H), 1.99 (m, 1H).

13C{1H}

NMR (125 MHz, CDCl3): δ 136.6, 135.5, 134.3,

133.2, 133.0, 132.9, 131.5, 128.6, 128.2, 128.0, 128.0, 127.8, 127.4, 127.1, 127.0, 126.9, 126.7, 126.7, 126.5, 126.4, 125.9, 88.0, 85.4, 58.7, 57.6, 50.1, 46.5, 24.7, 24.6, 24.4, 23.1. HRMS (EI): m/z calculated for C25H22O3N35Cl32S: 451.1003, Found: 451.1002. (3S, 3aR, 7aS)-4-(4-Chlorophenyl)-1-((4-methoxyphenyl)sulfonyl)-3-phenyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (3e) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)1-((4-methoxyphenyl)sulfonyl)-3-phenyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (4e) : White solid (3e + 4e = 87 mg, 91 % yield ). 3e: 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.8 Hz, 2H), 7.08 – 6.90 (m, 2H), 6.90 – 6.83 (m, 5H), 6.80 (d, J = 7.3 Hz, 2H), 6.70 – 6.62 (d, J = 8.58 Hz, 2H), 5.96 – 5.85 (m, 1H), 5.64 (d, J = 9.4 Hz, 1H), 4.81 (ddd, J = 10.6, 7.8, 4.8 Hz, 1H), 4.23 (t, J = 8.8 Hz, 1H), 3.86 (d, J = 2.0 Hz, 3H), 2.50 – 2.18 (m, 1H), 2.11 (m, 1H), 1.98 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 164.2, 138.1, 136.9, 134.3, 132.7, 131.6, 128.4, 128.2, 128.1, 127.9, 127.5, 126.7, 114.4, 89.1, 59.9, 55.9, 51.3, 25.5, 24.3. HRMS (EI): m/z calculated for C26H24O4N35Cl32S: 481.1109, Found: 481.1105.


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4e: 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.8 Hz, 2H), 7.17 – 7.08 (m, 1H), 7.08 – 6.90 (m, 2H), 6.90 – 6.83 (m, 4H), 6.80 (d, J = 7.3 Hz, 2H), 6.77 – 6.71 (d, J = 8.58 Hz, 2H), 6.03 (t, J = 4.1 Hz, 1H), 4.71 (d, J = 9.8 Hz, 1H), 4.58 (ddd, J = 11.7, 7.2, 4.8 Hz, 1H), 3.86 (d, J = 2.0 Hz, 3H), 3.64 (t, J = 8.7 Hz, 1H), 2.50 – 2.18 (m, 1H), 2.11 (m, 1H), 1.98 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 164.2, 140.0, 135.6, 134.5, 132.4, 132.0, 129.0, 128.3, 128.0, 127.9, 127.7, 127.6, 127.1, 114.5, 86.5, 58.8, 55.9, 47.6, 26.0, 23.2. HRMS (EI): m/z calculated for C26H24O4N35Cl32S: 481.1109, Found: 481.1105. Methyl-4-(((3S,

3aR,

7aS)-4-(4-chlorophenyl)-3-phenyl-3a,

6,

7,

7a-

tetrahydrobenzo[c]isoxazol- 1(3H)-yl)sulfonyl)benzoate (3f) / Methyl-4-(((3S, 3aS,

7aR)-4-(4-chlorophenyl)-3-phenyl-3a,

6,

7,

7a-tetrahydrobenzo[c]isoxazol-1(3H)- yl)sulfonyl)benzoate (4f): White solid (3f + 4f = 70 mg, 69 % yield). 3f: 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 8.2 Hz, 2H), 8.10 (d, J = 8.2 Hz, 2H), 7.10 – 6.86 (m, 5H), 6.80 (d, J = 7.6 Hz, 2H), 6.67 (d, J = 8.2 Hz, 2H), 5.93 (d, J = 4.3 Hz, 1H), 5.69 (d, J = 9.3 Hz, 1H), 4.89 (m, 1H), 4.26 (t, J = 8.8 Hz, 1H), 3.95 (s, 3H), 2.58 – 2.35 (m, 1H), 2.35 – 2.21 (m, 1H), 2.12 (m, 1H), 2.03 – 1.85 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 165.7, 140.2, 139.9, 135.2, 135.0, 134.4, 132.4, 130.3, 129.4, 129.0, 128.2, 128.1, 128.1, 127.7, 127.1, 86.7, 58.7, 53.6, 52.9, 47.7, 25.9, 23.1. HRMS (EI): m/z calculated for C27H24O5N35Cl32S: 509.1058, Found: 509.1056. 4f: 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 8.5 Hz, 2H), 7.14 (td, J = 5.9, 5.4, 2.6 Hz, 1H), 7.10 – 7.01 (m, 4H), 6.93 – 6.82 (m, 2H), 6.81



– 6.68 (m, 2H), 6.05 (t, J = 4.2 Hz, 1H), 4.74 (d, J = 9.8 Hz, 1H), 4.64 (m, 1H), 3.96 (s, 3H), 3.65 (t, J = 8.6 Hz, 1H), 2.44 (m, 1H), 2.24 – 2.05 (m, 1H), 2.00 (m, 1H). 13C{1H}

NMR (125 MHz, CDCl3): δ 165.7, 139.5, 138.0, 136.5, 135.1, 134.2, 132.8,

130.2, 129.8, 128.7, 128.4, 128.2, 128.0, 127.8, 127.2, 89.3, 59.9, 52.9, 51.4, 25.5, 24.3. HRMS (EI): m/z calculated for C27H24O5N35Cl32S: 509.1058, Found: 509.1056. (3S, 3aR, 7aS)-4-(4-Chlorophenyl)-1-((4-fluorophenyl)sulfonyl)-3-phenyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (3g) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)1-((4-fluorophenyl)sulfonyl)-3-phenyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c] isoxazole (4g): White solid (3g + 4g = 43 mg, 46 % yield ). 3g: 1H NMR (400 MHz, CDCl3): δ 8.05 (dd, J = 8.6, 5.1 Hz, 2H), 7.21 (td, J = 8.6, 2.7 Hz, 2H), 7.14 (h, J = 4.2 Hz, 1H), 7.07 (d, J = 4.4 Hz, 3H), 7.01 – 6.92 (m, 1H), 6.81 (d, J = 7.6 Hz, 2H), 6.68 (d, J = 8.5 Hz, 2H), 5.93 (d, J = 4.3 Hz, 1H), 5.70 (d, J = 9.5 Hz, 1H), 4.96 – 4.80 (m, 1H), 4.28 (t, J = 8.8 Hz, 1H), 2.58 – 2.21 (m, 2H), 2.13 (m, 1H), 2.10 – 1.88 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 166.3 (d, JC-F = 255 Hz), 140.0, 136.8, 134.6, 132.5, 132.4 (d, JC-F = 10 Hz), 132.3 (d, JC-F = 3 Hz), 129.1, 128.5, 128.4, 128.3, 127.8, 127.2, 116.7 (d, JC-F = 23 Hz), 86.8, 58.8, 47.8, 26.0, 23.2. 19F NMR (471 MHz, CDCl3): δ -103.0. HRMS (EI): m/z calculated for C25H21O3N35ClF32S: 469.0909, Found: 469.0909. 4g: 1H NMR (400 MHz, CDCl3): δ 8.05 (dd, J = 8.6, 5.1 Hz, 2H), 7.21 (td, J = 8.6, 2.7 Hz, 2H), 7.14 (h, J = 4.2 Hz, 1H), 7.07 (d, J = 4.4 Hz, 3H), 7.01 – 6.92 (m, 1H), 6.87 (d, J = 8.2 Hz, 2H), 6.75 (d, J = 8.3 Hz, 2H), 6.05 (t, J = 3.9 Hz, 1H), 4.74 (d, J = 9.9 Hz, 1H), 4.63 (m, 1H), 3.68 (t, J = 8.6 Hz, 1H), 2.58 – 2.21 (m, 2H), 2.13 (m, 1H),


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2.10 – 1.88 (m, 1H).

13C{1H}

NMR (125 MHz, CDCl3): δ 166.4 (d, JC-F = 255 Hz),

138.1, 136.8, 134.3, 132.9, 132.7 (d, JC-F = 10 Hz), 131.6 (d, JC-F = 3 Hz), 128.5, 128.7, 128.2, 128.0, 127.7, 127.8, 116.6 (d, JC-F = 23 Hz), 89.4, 60.0, 52.5, 25.5, 24.4.

19F

NMR

for

(471

MHz,

CDCl3):

δ

-102.8.

HRMS

(EI):

m/z

calculated

C25H21O3N35ClF32S: 469.0909, Found: 469.0909. (3S, 3aR, 7aS)-4-(4-Chlorophenyl)-1-((4-chlorophenyl)sulfonyl)-3-phenyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (3h) / (3S, 3aS, 7aR)-4-(4-Chloro phenyl)-1-((4-chlorophenyl)sulfonyl)-3-phenyl-1,

3,

3a,

6,

7,

7a-hexahydrobenzo[c] isoxazole (4h) : White solid (3h + 4h = 30 mg, 30 % yield ). 3h: 1H NMR (400 MHz, CDCl3): δ 8.02 – 7.91 (m, 2H), 7.55 – 7.46 (m, 2H), 7.10 – 6.90 (m, 5H), 6.84 – 6.77 (m, 2H), 6.74 – 6.61 (m, 2H), 5.92 (m, 1H), 5.69 (d, J = 9.4 Hz, 1H), 4.86 (m, 1H), 4.26 (t, J = 8.8 Hz, 1H), 2.54 – 2.33 (m, 1H), 2.33 – 2.18 (m, 1H), 2.12 (m, 1H), 2.05 – 1.87 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 140.7, 139.7, 135.1, 134.8, 134.3, 132.3, 130.6, 129.4, 128.8, 128.1, 127.9, 127.5, 126.9, 86.5, 58.5, 47.5, 25.8, 22.9. HRMS (EI): m/z calculated for C25H21O3N35Cl232S: 485.0614, Found: 485.0616. 4h: 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.21 – 7.01 (m, 5H), 6.88 (d, J = 8.1 Hz, 2H), 6.75 (d, J = 8.1 Hz, 2H), 6.05 (t, J = 4.0 Hz, 1H), 4.74 (d, J = 9.8 Hz, 1H), 4.63 (p, J = 5.3 Hz, 1H), 3.68 (t, J = 8.6 Hz, 1H), 2.62 – 2.29 (m, 2H), 2.23 – 2.06 (m, 1H), 1.98 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 140.9, 137.8, 136.5, 134.0, 133.9, 132.6, 131.0, 129.3, 128.5, 128.2,



128.0, 127.8, 127.7, 127.6, 89.2, 59.7, 51.2, 25.3, 24.1. HRMS (EI): m/z calculated for C25H21O3N35Cl232S: 485.0614, Found: 485.0616. (3S, 3aR, 7aS)-1-((4-Bromophenyl)sulfonyl)-4-(4-chlorophenyl)-3-phenyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (3i) / (3S, 3aS, 7aR)-1-((4-bromophenyl) sulfonyl)-4-(4-chlorophenyl)-3-phenyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c] isoxazole (4i): White solid (3i + 4i = 37 mg, 35 % yield). 3i: 1H NMR (500 MHz, CDCl3): δ 7.81 (dq, J = 9.1, 2.2 Hz, 2H), 7.64 – 7.58 (m, 2H), 7.13 - 6.93 (m, 5H), 6.83 – 6.76 (d, J = 8.5 Hz, 2H), 6.70 – 6.63 (d, J = 8.5 Hz, 2H), 5.85 (ddd, J = 5.1, 3.4, 1.4 Hz, 1H), 5.62 (d, J = 9.4 Hz, 1H), 4.79 (ddd, J = 10.6, 7.8, 4.8 Hz, 1H), 4.18 (t, J = 8.7 Hz, 1H), 2.45 – 2.13 (m, 2H), 2.05 (m, 1H), 1.91 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 139.9, 135.5, 135.4, 134.4, 132.5, 132.4, 130.8, 129.5, 129.0, 128.2, 128.1, 127.7, 127.1, 86.7, 88.7, 47.7, 29.9, 25.9, 23.1. HRMS (EI): m/z calculated for C25H21O3N79Br35Cl32S: 529.0109, Found: 529.0096. 4i: 1H NMR (500 MHz, CDCl3): δ 7.81 (dq, J = 9.1, 2.2 Hz, 2H), 7.64 – 7.58 (m, 2H), 7.13 – 7.03 (m, 1H), 7.03 – 6.93 (m, 4H), 6.93 – 6.84 (m, 2H), 6.76 – 6.70 (m, 2H), 5.97 (dd, J = 5.3, 3.0 Hz, 1H), 4.66 (d, J = 9.8 Hz, 1H), 4.55 (ddd, J = 11.6, 7.2, 4.7 Hz, 1H), 3.61 (t, J = 8.6 Hz, 1H), 2.45 – 2.13 (m, 2H), 2.05 (m, 1H), 1.91 (m, 1H). 13C{1H}

NMR (125 MHz, CDCl3): δ 138.0, 136.6, 134.6, 134.2, 133.8, 132.5, 131.2,

129.6, 128.7, 128.3, 128.2, 127.8, 127.7, 89.3, 59.9, 51.5, 29.9, 25.4, 24.3. HRMS (EI): m/z calculated for C25H21O3N79Br35Cl32S: 529.0109, Found: 529.0096. (3R, 3aS, 7aR)-4-(4-Chlorophenyl)-1-(methylsulfonyl)-3-phenyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (3j) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)-1-(methyl


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sulfonyl)-3-phenyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (4j): White solid (3j + 4j = 20 mg, 25 % yield). 3j: 1H NMR (400 MHz, CDCl3): δ 7.26 – 7.19 (m, 2H), 7.19 – 7.10 (m, 1H), 7.08 – 6.97 (m, 2H), 6.96 – 6.85 (m, 2H), 6.73 – 6.66 (m, 2H), 5.94 (dd, J = 5.7, 3.4 Hz, 1H), 5.81 (d, J = 9.6 Hz, 1H), 4.80 (ddd, J = 10.8, 7.9, 5.0 Hz, 1H), 4.28 (t, J = 8.9 Hz, 1H), 3.22 (s, 3H), 2.53 – 2.35 (m, 1H), 2.36 – 2.21 (m, 1H), 2.12 (m, 1H), 1.95 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 137.9, 136.8, 134.2, 132.8, 128.7, 128.4, 128.2, 128.1, 127.9, 127.1, 90.1, 58.4, 51.5, 37.8, 25.1, 24.7. HRMS (EI): m/z calculated for C20H20O3N35Cl32S: 389.0847, Found: 389.0846. 4j: 1H NMR (400 MHz, CDCl3): δ 7.19 – 7.10 (m, 2H), 7.08 – 6.97 (m, 3H), 6.96 – 6.85 (m, 2H), 6.79 (d, J = 8.6 Hz, 2H), 6.05 (d, J = 4.9 Hz, 1H), 4.87 (d, J = 10.4 Hz, 1H), 4.74 – 4.65 (m, 1H), 3.85 – 3.73 (m, 1H), 3.22 (s, 1.6H), 3.18 (s, 1.4H), 2.53 – 2.35 (m, 1H), 2.36 – 2.21 (m, 1H), 2.12 (m, 1H), 1.95 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 139.9, 135.4, 134.6, 133.4, 128.7, 128.4, 128.1, 127.9, 127.7, 127.1, 86.9, 57.2, 47.6, 38.2, 25.8, 23.2. HRMS (EI): m/z calculated for C20H20O3N35Cl32S: 389.0847, Found: 389.0846. (3R,

3aS,

7aR)-4-(4-Chlorophenyl)-3-(o-tolyl)-1-tosyl-1,

7a-hexahydrobenzo[c]isoxazole

(3k)

/

(3S,

3aS,

3,

3a,

6,

7,

7aR)-4-(4-chlorophenyl)-

3-(o-tolyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (4k): White solid (3k + 4k = 74 mg, 80 % yield). 3k: 1H NMR (400 MHz, CDCl3): δ 7.96 – 7.84 (m, 2H), 7.34 (dd, J = 8.1, 4.1 Hz, 2H), 7.19 – 7.07 (m, 1H), 7.06 – 6.82 (m, 2H), 6.81 – 6.71 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 6.60 – 6.49 (m, 2H), 5.93 (t, J = 4.6 Hz, 1H), 5.46 (d, J = 7.6 Hz, 1H), 4.98 – 4.83 (m, 1H), 4.06 (t, J = 7.7 Hz, 1H), 2.44 (m, 5H),



2.18 (m, 1H), 2.09 – 1.92 (m, 1H), 1.76 (d, J = 17.7 Hz, 3H).

Page 28 of 54

13C{1H}

NMR (125

MHz, CDCl3): δ 145.2, 137.5, 135.4, 134.9, 133.3, 133.2, 132.8, 131.9, 129.9, 129.6, 128.0, 127.6, 127.1, 127.0, 126.6, 90.1, 58.4, 51.5, 37.8, 25.1, 24.7. HRMS (EI): m/z calculated for C27H26O3N35Cl32S: 479.1316, Found: 479.1314. 4k: 1H NMR (400 MHz, CDCl3): δ 7.96 – 7.84 (m, 2H), 7.52 (d, J = 7.7 Hz, 1H), 7.34 (dd, J = 8.1, 4.1 Hz, 2H), 7.19 – 7.07 (m, 1H), 7.06 – 6.82 (m, 3H), 6.81 – 6.71 (m, 2H), 6.67 (d, J = 7.6 Hz, 1H), 6.11 (t, J = 4.2 Hz, 0.57H), 5.09 (d, J = 9.7 Hz, 0.57H), 4.54 (ddd, J = 11.7, 7.4, 4.8 Hz, 0.57H), 3.62 (t, J = 8.6 Hz, 0.57H). 2.44 (m, 5H), 2.18 (m, 1H), 2.09 – 1.92 (m, 1H), 1.76 (d, J = 17.7 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.3, 140.3, 136.5, 134.6, 133.8, 133.2, 132.2, 130.0, 129.9, 129.8, 129.4, 128.3, 127.7, 127.4, 127.0, 126.4, 83.6, 60.1, 51.1, 25.9, 24.5, 24.3, 21.9, 19.3. HRMS (EI): m/z calculated for C27H26O3N35Cl32S: 479.1316, Found: 479.1314. (3R, 3aS, 7aR)-4-(4-Chlorophenyl)-3-(m-tolyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexa hydrobenzo[c] isoxazole (3l) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)-3-(m- tolyl)-1tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (4l): White solid (3l + 4l = 80 mg, 86 % yield). 3l: 1H NMR (400 MHz, CDCl3): δ 8.00 – 7.82 (m, 2H), 7.34 (t, J = 8.5 Hz, 2H), 7.05 – 6.78 (m, 4H), 6.78 – 6.59 (m, 3H), 6.45 (s, 1H), 5.91 (d, J = 4.5 Hz, 1H), 5.58 (d, J = 9.3 Hz, 1H), 4.81 (ddd, J = 10.3, 7.6, 4.6 Hz, 1H), 4.18 (t, J = 8.7 Hz, 1H), 2.55 – 2.31 (m, 4H), 2.31 – 2.18 (m, 1H), 2.18 – 1.73 (m, 5H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.3, 138.2, 137.7, 136.8, 134.5, 132.7, 132.3, 129.8, 129.4, 129.0, 128.7, 128.3, 128.1, 127.9, 127.6, 124.4, 88.9, 59.9, 51.5, 25.7, 24.2,


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21.9, 21.2. HRMS (EI): m/z calculated for C27H26O3N35Cl32S: 479.1316, Found: 479.1316. 4l: 1H NMR (400 MHz, CDCl3):δ 8.00 – 7.82 (m, 2H), 7.34 (t, J = 8.5 Hz, 2H), 7.05 – 6.78 (m, 4H), 6.78 – 6.59 (m, 3H), 6.54 (s, 1H), 6.03 (t, J = 4.0 Hz, 1H), 4.66 (d, J = 9.7 Hz, 1H), 4.54 (ddd, J = 11.8, 7.4, 4.9 Hz, 1H), 3.52 (t, J = 8.9 Hz, 1H), 2.55 – 2.31 (m, 4H), 2.31 – 2.18 (m, 1H), 2.18 – 1.73 (m, 5H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.2, 140.1, 137.1, 135.4, 134.5, 133.4, 133.4, 129.9, 129.4, 128.9, 128.5, 127.9, 127.2, 127.8, 124.8, 86.4, 58.9, 47.7, 26.0, 23.1, 21.9, 21.2. HRMS (EI): m/z calculated for C27H26O3N35Cl32S: 479.1316, Found: 479.1316. (3R, 3aS, 7aR)-4-(4-Chlorophenyl)-3-(p-tolyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexa hydrobenzo[c]isoxazole (3m) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)- 3-(p-tolyl)1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (4m): White solid (3m + 4m = 55 mg, 57 % yield). 3m: 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 7.9 Hz, 2H), 7.33 (dd, J = 8.2, 3.9 Hz, 2H), 6.98 (d, J = 8.2 Hz, 1H), 6.86 (m, 3H), 6.79 – 6.59 (m, 4H), 5.91 (d, J = 4.3 Hz, 1H), 5.58 (d, J = 9.3 Hz, 1H), 4.80 (m, 1H), 4.15 (t, J = 8.6 Hz, 1H), 2.43 (m,5H), 2.21 (m, 3H), 2.09 (m, 1H), 2.05 – 1.88 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.3, 138.4, 138.1, 134.4, 133.3, 132.6, 132.2, 129.8, 129.4, 128.2, 128.0, 127.8, 127.1, 88.9, 58.9, 47.6, 25.5, 24.2, 21.9, 21.2. HRMS (EI): m/z calculated for C27H26O3N35Cl32S: 479.1316, Found: 479.1314. 4m: 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 7.9 Hz, 2H), 7.33 (dd, J = 8.2, 3.9 Hz, 2H), 6.98 (d, J = 8.2 Hz, 1H), 6.86 (m, 3H), 6.79 – 6.59 (m, 4H), 6.02 (t, J = 4.0 Hz, 1H), 4.68 (d, J = 9.7 Hz, 1H), 4.55 (m, 1H), 3.57 (t, J = 8.6 Hz, 1H), 2.43 (m,5H),



2.21 (m, 3H), 2.09 (m, 1H), 2.05 – 1.88 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.3, 140.0, 137.7, 134.4, 133.7, 132.5, 132.3, 129.9, 128.9, 128.1, 127.9, 127.8, 127.8, 86.3, 58.9, 51.2, 23.1, 21.9, 21.2. HRMS (EI): m/z calculated for C27H26O3N35Cl32S: 479.1316, Found: 479.1314. (3R, 3aS, 7aR)-4-(4-Chlorophenyl)-3-(4-fluorophenyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (3n) / (3S, 3aS, 7aR)-4-(4-chlorophenyl)-3-(4fluorophenyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (4n): White solid (3n + 4n = 74 mg, 76 % yield). 3n: 1H NMR (400 MHz, CDCl3): δ 7.90 (dd, J = 8.1, 6.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.11 – 6.99 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.83 – 6.58 (m, 5H), 6.03 (t, J = 4.0 Hz, 1H), 4.71 (d, J = 9.9 Hz, 1H), 4.63 (m, 1H), 3.63 (t, J = 8.7 Hz, 1H), 2.43 (s, 5H), 2.12 (m, 1H), 1.93 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 162.4 (d, JC-F = 247 Hz), 145.3, 139.8, 134.3, 133.2, 132.6, 131.4 (d, JC-F = 3 Hz), 129.9, 129.4 (d, JC-F = 8 Hz), 128.1, 128.3, 128.2, 128.2, 114.5 (d, JC-F = 21Hz), 85.9, 58.7, 47.5, 25.9, 23.2, 21.9.

19F

NMR (471 MHz, CDCl3): δ

-114.0. HRMS (EI): m/z calculated for C26H23O3N35ClF32S: 483.1066, Found: 483.1067. 4n: 1H NMR (400 MHz, CDCl3): δ 7.90 (dd, J = 8.1, 6.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.11 – 6.99 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.83 – 6.58 (m, 5H), 5.94 (d, J = 4.4 Hz, 1H), 5.65 (d, J = 9.5 Hz, 1H), 4.93 – 4.77 (m, 1H), 4.22 (d, J = 8.8 Hz, 1H), 2.43 (s, 5H), 2.12 (m, 1H), 1.93 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 162.9 (d, JC-F = 247 Hz), 145.5, 138.1, 134.1, 132.9, 132.7 (d, JC-F = 3 Hz), 132.4, 129.9, 129.7 (d, JC-F = 8 Hz), 129.7, 128.0, 127.8, 127.1, 115.2 (d, JC-F = 21 Hz), 88.6, 59.8,


Page 30 of 54

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51.3, 25.4, 24.4, 21.9.

19F

NMR (471 MHz, CDCl3): δ -113.2. HRMS (EI): m/z

calculated for C26H23O3N35ClF32S: 483.1066, Found: 483.1067. (3S, 3aR, 7aS)-3, 4-Bis(4-chlorophenyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydro benzo[c]isoxazole (3p) / (3S, 3aS, 7aR)-3, 4-Bis(4-chlorophenyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (4p): White solid (3p + 4p = 70 mg, 70 % yield). 3p: 1H NMR (400 MHz, CDCl3): δ 8.01 – 7.83 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.09 – 6.97 (m, 2H), 6.96 – 6.87 (m, 2H), 6.71 (dd, J = 10.1, 7.7 Hz, 4H), 5.93 (ddd, J = 5.1, 3.4, 1.4 Hz, 1H), 5.62 (d, J = 9.4 Hz, 1H), 4.91 – 4.73 (m, 1H), 4.21 (d, J = 8.7 Hz, 1H), 2.50 – 2.19 (m, 5H), 2.11 (m, 1H), 1.90 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.4, 139.8, 134.2, 134.1, 133.9, 133.2, 132.7, 129.9, 129.4, 129.4, 129.3, 128.2, 127.7, 127.1, 85.7, 58.7, 47.7, 25.9, 23.2, 21.9. HRMS (EI): m/z calculated for C26H23O3N35Cl232S: 499.0770, Found: 499.0772. 4p: 1H NMR (400 MHz, CDCl3): δ 7.90 (t, J = 7.8 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 7.11 – 6.83 (m, 6H), 6.75 (d, J = 8.7 Hz, 2H), 6.03 (d, J = 4.8 Hz, 1H), 4.75 – 4.52 (m, 2H), 3.62 (t, J = 8.6 Hz, 1H), 2.44 (s, 6H), 2.11 (t, J = 7.6 Hz, 1H), 1.95 (s, 1H). 13C{1H}

NMR (125 MHz, CDCl3): δ 145.5, 138.0, 135.6, 134.5, 133.1, 132.5, 129.9,

129.9, 129.8, 129.2, 128.5, 128.3, 128.1, 127.8, 88.5, 59.8, 51.6, 25.4, 24.5. HRMS (EI): m/z calculated for C26H23O3N35Cl232S: 499.0770, Found: 499.0772. (3S, 3aR, 7aS)-3-(4-Bromophenyl)-4-(4-chlorophenyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (3q) / (3S, 3aS, 7aR)-3-(4-bromophenyl)-4-(4chlorophenyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (4q): White solid (3q + 4q = 85 mg, 78 % yield). 3q: 1H NMR (400 MHz, CDCl3): δ 7.90 (t, J =



Page 32 of 54

7.7 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.06 (t, J = 8.5 Hz, 2H), 6.93 (d, J = 7.9 Hz, 2H), 6.78 – 6.61 (m, 3H), 5.93 (t, J = 4.4 Hz, 1H), 5.60 (d, J = 9.4 Hz, 1H), 4.81 (td, J = 9.5, 7.8, 4.8 Hz, 1H), 4.71 – 4.55 (m, 1H), 2.44 (s, 5H), 2.11 (m, 1H), 2.02 – 1.80 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.5, 139.8, 136.1, 134.1, 134.1, 132.7, 130.6, 129.9, 129.7, 129.4, 129.3, 128.2, 127.1, 122.1, 85.7,

59.7,

47.7,

25.9,

23.1,

21.9.

HRMS

(EI):

m/z

calculated

for

C26H23O3N79Br35Cl32S: 543.0265, Found: 543.0268. 4q: 1H NMR (400 MHz, CDCl3): δ 7.90 (t, J = 7.7 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.06 (t, J = 8.5 Hz, 2H), 6.93 (d, J = 7.9 Hz, 2H), 6.78 – 6.61 (m, 3H), 6.03 (t, J = 4.1 Hz, 1H), 4.71 – 4.55 (m, 2H), 3.61 (t, J = 8.6 Hz, 1H), 2.44 (s, 5H), 2.11 (m, 1H), 2.02 – 1.80 (m, 1H).

13C{1H}

NMR (125 MHz, CDCl3):

δ 145.4, 138.0, 134.8, 134.1, 133.2, 132.4, 131.4, 129.9, 129.8, 129.5, 128.3, 128.1, 127.8, 122.6, 88.5, 58.7, 51.5, 25.4, 24.3, 21.9. HRMS (EI): m/z calculated for C26H23O3N79Br35Cl32S: 543.0265, Found: 543.0268. (3R,

3aR,

7aR)-4-(4-Chlorophenyl)-3-(p-tolyl)-2-tosyl-2,

3,

3a,

6,

7,

7a-hexahydrobenzo [d]isoxazole (3x): White solid (30 mg, 31% yield). 1H NMR (400 MHz, CDCl3): δ 7.78 – 7.70 (m, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.18 – 7.11 (m, 2H), 7.11 – 7.00 (m, 4H), 6.74 – 6.66 (m, 2H), 5.67 (t, J = 4.0 Hz, 1H), 4.80 (td, J = 5.2, 4.8, 2.7 Hz, 1H), 4.06 (d, J = 3.9 Hz, 1H), 3.46 (m, 1H), 2.52 (s, 3H), 2.32 (s, 3H), 2.12 – 1.99 (m, 3H), 1.73 – 1.61 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 144.8, 138.5, 137.8, 137.7, 134.3, 133.2, 131.0, 129.9, 129.5, 129.4, 128.4, 128.1, 127.1,


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127.0, 69.7, 52.7, 22.9, 22.0, 21.3, 20.8. HRMS (EI): m/z calculated for C27H26O3N35Cl32S: 479.1316, Found: 479.1321, mp: 172.5 oC. (3S, 3aR, 7aS)-4-(4-Fluorophenyl)-3-phenyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexa hydrobenzo[c]isoxazole (5b) / (3S, 3aS, 7aR)-4-(4-fluorophenyl)-3-phenyl-1tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (6b) : White solid (5b + 6b = 82 mg, 92 % yield). 5b: 1H NMR (400 MHz, CDCl3): δ 7.96 – 7.88 (m, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.06 – 6.97 (m, 1H), 6.94 (dd, J = 8.2, 6.7 Hz, 2H), 6.83 – 6.76 (m, 2H), 6.74 – 6.65 (m, 4H), 5.87 (td, J = 3.5, 1.7 Hz, 1H), 5.64 (d, J = 9.5 Hz, 1H), 4.83 (ddd, J = 10.6, 7.8, 4.8 Hz, 1H), 4.23 (t, J = 8.9 Hz, 1H), 2.43 (s, 4H), 2.27 (dddd, J = 18.1, 12.0, 5.1, 2.8 Hz, 1H), 2.12 (dq, J = 13.9, 4.8 Hz, 1H), 1.97 (dtd, J = 13.0, 10.4, 5.3 Hz, 1H).

13C{1H}

NMR (100 MHz, CDCl3) δ 161.8 (d, JC-F = 245 Hz), 145.3,

137.7 (d, JC-F = 3 Hz), 135.7, 134.5, 133.4, 129.9, 129.9, 129.5, 128.4, 127.7, 127.4 (d, JC-F = 8 Hz), 114.8 (d, JC-F = 21 Hz), 86.6, 58.9, 47.9, 26.0, 23.2, 21.9. 19F NMR (471 MHz, CDCl3): δ -116.2. HRMS (EI): m/z calculated for C26H24O3NF32S: 449.1455, Found: 449.1453. 6b: 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 7.7 Hz, 2H), 7.17 – 6.97 (m, 4H), 6.93 (t, J = 7.5 Hz, 1H), 6.86 – 6.73 (m, 2H), 6.69 (d, J = 7.1 Hz, 1H), 6.59 (t, J = 8.5 Hz, 1H), 5.99 (t, J = 4.1 Hz, 1H), 4.72 (d, J = 9.9 Hz, 1H), 4.61 (m, 0.1H) 3.64 (t, J = 8.7 Hz, 1H), 2.43 (d, J = 2.8 Hz, 5H), 2.12 (m, 1H), 2.05 – 1.89 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 161.9 (d, JC-F = 245 Hz), 145.4, 137.0, 135.8 (d, JC-F = 3 Hz), 134.4, 132.5, 129.9, 129.9, 128.5, 128.3, 128.1 (d, JC-F = 8 Hz), 128.0, 127.6, 127.4, 114.5 (d, JC-F = 21 Hz), 89.3, 60.0, 51.6, 25.6, 24.4, 22.0.



19F

NMR (471 MHz, CDCl3): δ -115.9. HRMS (EI): m/z calculated for

C26H24O3NF32S: 449.1455, Found: 449.1453. (3S, 3aR, 7aS)-4-(4-Bromophenyl)-3-phenyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydro benzo[c]isoxazole (5c) / (3S, 3aS, 7aR)-4-(4-Bromophenyl)-3-phenyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydro benzo[c]isoxazole (6c) : White solid (5c + 6c = 102 mg, 99 % yield). 5c: 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.18 – 7.08 (m, 2H), 7.03 (dd, J = 9.8, 5.3 Hz, 1H), 6.94 (t, J = 7.5 Hz, 2H), 6.80 (d, J = 7.3 Hz, 2H), 6.66 – 6.55 (m, 2H), 5.91 (d, J = 4.5 Hz, 1H), 5.64 (d, J = 9.4 Hz, 1H), 4.83 (ddd, J = 11, 7.8, 4.8 Hz, 1H), 4.21 (t, J = 8.7 Hz, 1H), 2.43 (s, 3H), 2.40 – 2.32 (m, 1H), 2.34 – 2.20 (m, 1H), 2.11 (m, 1H), 2.04 – 1.91 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 145.1, 135.4, 133.2, 130.8, 129.7, 129.3, 128.9, 128.1, 127.8, 127.4, 127.3, 86.3, 58.6, 47.4, 25.8, 23.0, 21.7. HRMS (EI): m/z calculated for C26H24O3N79Br32S: 509.0655, Found: 509.0655. 6c: 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.13 (m, 1H), 7.08 – 6.97 (m, 6H), 6.73 – 6.62 (m, 2H), 6.04 (t, J = 4.1 Hz, 1H), 4.71 (d, J = 9.8 Hz, 1H), 4.65 – 4.50 (m, 1H), 3.62 (t, J = 8.5 Hz, 1H), 2.43 (s, 5H), 2.13 (m, 1H), 1.97 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 145.2, 138.4, 136.7, 134.2, 132.3, 130.7, 129.7, 128.3, 128.1, 128.1, 127.9, 127.7, 120.7, 89.0, 59.7, 51.2, 25.4, 24.2, 21.7. HRMS (EI): m/z calculated for C26H24O3N79Br32S: 509.0655, Found: 509.0655. (3S, 3aR, 7aS)-3, 4-Diphenyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (5d) / (3S, 3aS, 7aR)-3, 4-diphenyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydro


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benzo[c]isoxazole (6d): White solid (5d + 6d = 80 mg, 93 % yield).

5d 1H NMR

(400 MHz, CDCl3): δ 8.00 – 7.86 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.11 – 6.95 (m, 4H), 6.91 (dd, J = 8.4, 6.8 Hz, 2H), 6.83 – 6.73 (m, 4H), 5.93 (ddd, J = 5.0, 3.3, 1.4 Hz, 1H), 5.66 (d, J = 9.5 Hz, 1H), 4.82 (ddd, J = 10.8, 7.8, 4.9 Hz, 1H), 4.35 – 4.15 (m, 1H), 2.44 (s, 4H), 2.28 (dddt, J = 18.0, 10.7, 5.4, 3.0 Hz, 1H), 2.13 (dq, J = 13.8, 4.7 Hz, 1H), 1.98 (dtd, J = 13.0, 10.6, 5.4 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 150.2, 141.3, 135.7, 135.2, 133.3, 129.9, 129.4, 128.2, 128.0, 127.8, 127.7, 126.9, 125.8, 86.5, 59.0, 47.4, 26.0, 23.3, 21.8. HRMS (EI): m/z calculated for C26H25O3N32S: 431.1550, Found: 431.1551. 6d: 1H NMR (400 MHz, CDCl3): δ 8.00 – 7.86 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.11 – 6.95 (m, 4H), 6.91 (dd, J = 8.4, 6.8 Hz, 2H), 6.83 – 6.73 (m, 4H), 6.06 (ddd, J = 5.1, 3.3, 1.4 Hz, 1H), 4.93 – 4.74 (m, 1H), 4.62 (ddd, J = 11.6, 7.2, 4.8 Hz, 1H), 3.72 (t, J = 8.6 Hz, 1H), 2.57 – 2.24 (m, 5H), 2.15 (m, 1H), 2.12 – 1.93 (m, 1H). 13C{1H}

NMR (125 MHz, CDCl3): δ 145.2, 139.6, 137.0, 135.3, 132.3, 129.8, 128.2,

128.1, 127.9, 127.6, 127.4, 126.5, 89.2, 60.0, 51.2, 25.6, 24.2, 21.9. HRMS (EI): m/z calculated for C26H25O3N32S: 431.1550, Found: 431.1551. (3S, 3aR, 7aS)-3-Phenyl-4-(p-tolyl)-1-tosyl-1,3,3a,6,7,7a-hexahydrobenzo[c] isoxazole (5e) / (3S, 3aS, 7aR)-3-phenyl-4-(p-tolyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexa hydrobenzo[c]isoxazole (6e): White solid (5e + 6e = 36 mg, 37 % yield). 5e: 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.05 – 6.96 (m, 1H), 6.91 (dd, J = 8.4, 6.8 Hz, 2H), 6.82 (dd, J = 18.1, 7.7 Hz, 4H), 6.66 (d, J = 8.1 Hz, 2H), 5.94 – 5.79 (m, 1H), 5.65 (d, J = 9.7 Hz, 1H), 4.78 (ddd, J = 11.0, 7.8,



5.0 Hz, 1H), 4.19 (t, J = 8.9 Hz, 1H), 2.44 (s, 3H), 2.24 (m 5H), 2.11 (ddd, J = 17.6, 9.4, 4.7 Hz, 1H), 1.94 (ddt, J = 16.9, 11.2, 5.6 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 145.3, 137.3, 136.8, 136.6, 135.3, 132.4, 129.9, 128.6, 128.1, 128.0, 127.8, 127.7, 127.4, 126.8, 89.2, 60.2, 51.4, 25.7, 24.2, 22.0, 21.2. HRMS (EI): m/z calculated for C27H27O3N32S: 445.1706, Found: 445.1704. 6e: 1H NMR (400 MHz, CDCl3): δ 7.92 (dd, J = 8.1, 5.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.14 – 7.03 (m, 1H), 7.01 (d, J = 4.3 Hz, 3H), 6.91 (t, J = 7.6 Hz, 1H), 6.87 – 6.75 (m, 1H), 6.75 – 6.62 (m, 3H), 6.01 (t, J = 4.2 Hz, 1H), 4.84 – 4.68 (m, 1H), 4.55 (m, 1H), 3.65 (t, J = 8.5 Hz, 1H), 2.44 (s, 5H), 2.20 (m, 3H), 2.14 – 1.90 (m, 2H). 13C{1H}

NMR (100 MHz, CDCl3): δ 145.3, 138.5, 136.5, 136.0, 135.0, 133.5, 130.0,

129.5, 128.8, 128.3, 128.2, 127.5, 126.5, 125.8, 86.6, 59.1, 47.5, 26.0, 23.5, 22.0, 21.1. HRMS (EI): m/z calculated for C27H27O3N32S: 445.1706, Found: 445.1704. (3S, 3aR, 7aS)-3-Phenyl-4-(m-tolyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydro benzo[c]isoxazole (5f) / (3S, 3aS, 7aR)-3-Phenyl-4-(m-tolyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (6f) : White solid (5f + 6f = 74 mg, 84 % yield). 5f : 1H

NMR (400 MHz, CDCl3): δ 8.02 – 7.83 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.06 –

6.97 (m, 1H), 6.96 – 6.83 (m, 5H), 6.78 (dd, J = 7.6, 1.6 Hz, 2H), 6.60 (d, J = 7.6 Hz, 1H), 6.44 (s, 1H), 5.89 (ddd, J = 5.1, 3.2, 1.3 Hz, 1H), 5.62 (d, J = 9.5 Hz, 1H), 4.80 (ddd, J = 10.8, 7.9, 4.9 Hz, 1H), 4.21 (t, J = 8.8 Hz, 1H), 2.44 (s, 4H), 2.31 – 2.19 (m, 1H), 2.19 – 2.04 (m, 4H), 2.06 – 1.91 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 145.0, 141.2, 137.2, 135.7, 135.2, 133.3, 129.7, 129.3, 128.0, 127.8, 127.7, 127.4,


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127.3, 127.2, 126.8, 122.7, 86.4, 58.8, 47.5, 25.9, 23.1, 21.7, 21.2. HRMS (EI): m/z calculated for C27H27O3N32S: 445.1706, Found: 445.1709. 6f: 1H NMR (400 MHz, CDCl3): δ 7.99 – 7.87 (m, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.12 – 6.97 (m, 4H), 6.97 – 6.64 (m, 4H), 6.54 (s, 1H), 6.05 (t, J = 4.3 Hz, 1H), 4.74 (d, J = 9.7 Hz, 1H), 4.59 (ddd, J = 11.6, 7.2, 4.7 Hz, 1H), 3.69 (t, J = 8.6 Hz, 1H), 2.45 (s, 4H), 2.09 (s, 1H), 2.02 (s, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ 145.1, 139.2, 137.1, 137.0, 132.3, 129.7, 129.6, 129.3, 128.1, 127.8, 127.7, 127.7, 127.5, 127.1, 127.0, 123.6, 89.1, 59.9, 51.1, 25.5, 24.1, 21.7, 21.1. HRMS (EI): m/z calculated for C27H27O3N32S: 445.1706, Found: 445.1709. (3S, 3aR, 7aS)-3-Phenyl-4-(o-tolyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydro benzo[c]isoxazole (5g) / (3S, 3aS, 7aR)-3-Phenyl-4-(o-tolyl)-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (6g) : White solid (5g + 6g = 65 mg, 73 % yield). 5g: 1H NMR (400 MHz, CDCl3): δ 8.01 – 7.82 (m, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.12 – 7.05 (m, 1H), 7.01 – 6.94 (m, 3H), 6.94 – 6.83 (m, 2H), 6.82 – 6.76 (m, 2H), 5.66 (t, J = 4.2 Hz, 1H), 5.50 (d, J = 9.5 Hz, 1H), 4.79 (ddd, J = 11, 7.7, 4.7 Hz, 1H), 4.19 (t, J = 8.8 Hz, 1H), 2.43 (m, 4H), 2.29 – 2.16 (m, 1H), 2.16 – 2.07 (m, 1H), 2.07 – 1.94 (m, 1H), 1.65 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 135.7, 133.3, 130.9, 131, 129.7, 129.3, 127.7, 127.6, 126.3, 125.2, 86.0, 59.2, 51.5, 48.4, 21.7, 20.1. HRMS (EI): m/z calculated for C27H27O3N32S: 445.1706, Found: 445.1710. 6g: 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.07 – 6.99 (m, 1H), 6.95 (t, J = 7.4 Hz, 2H), 6.90 – 6.73 (m, 5H), 6.69 (d, J = 7.5 Hz, 1H), 5.74 (d, J = 4.1 Hz, 1H), 4.80 (d, J = 9.6 Hz, 1H), 3.32 (s, 1H), 2.54 –



2.26 (m, 5H), 2.24 – 1.96 (m, 5H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.0, 139.8, 135.8, 135.0, 134.6, 131.9, 129.8, 129.6, 128.9, 128.8, 128.2, 127.7, 126.8, 125.1, 88.0, 60.1, 51.4, 25.6, 23.7, 21.7, 19.9. HRMS (EI): m/z calculated for C27H27O3N32S: 445.1706, Found: 445.1710. (3S, 3aR, 7aS)-3-phenyl-1-tosyl-4-(4-(trifluoromethyl)phenyl)-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (5h) / (3S, 3aS, 7aR)-3-phenyl-1-tosyl-4-(4(trifluoromethyl) phenyl)-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (6h): White solid (5h + 6h = 67 mg, 67 % yield). 5h: 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 7.04 – 6.96 (m, 1H), 6.89 (t, J = 7.6 Hz, 2H), 6.82 (d, J = 8.1 Hz, 2H), 6.79 – 6.73 (m, 2H), 6.09 – 5.96 (m, 1H), 5.63 (d, J = 9.2 Hz, 1H), 4.87 (ddd, J = 10.1, 7.8, 4.7 Hz, 1H), 4.28 (t, J = 8.7 Hz, 1H), 2.43 (s, 4H), 2.35 – 2.22 (m, 1H), 2.13 (dq, J = 14.3, 4.9 Hz, 1H), 2.01 (ddt, J = 13.5, 9.5, 5.0 Hz, 1H).

13C{1H}

NMR (125 MHz, CDCl3): δ 145.2, 143.2,

136.7, 134.8, 133.3, 130.6, 130.0, 129.5, 128.7 (q, JC-F = 32 Hz), 128.3, 128.1, 127.9, 126.2, 124.8 (q, JC-F = 4 Hz), 124.3 (q, JC-F = 272 Hz), 86.5, 58.9, 47.8, 26.1, 23.1, 22.0.

19F

NMR (471 MHz, CDCl3): δ -62.5. HRMS (EI): m/z calculated for

C27H24O3NF332S: 499.1424, Found: 499.1425. 6h: 1H NMR (400 MHz, CDCl3): δ 8.00 – 7.90 (m, 2H), 7.37 (dd, J = 8.1, 4.9 Hz, 2H), 7.28 (s, 2H), 7.16 (d, J = 8.2 Hz, 1H), 7.07 – 6.98 (m, 3H), 6.91 (t, J = 7.8 Hz, 2H), 6.85 (d, J = 8.1 Hz, 1H), 6.82 – 6.76 (m, 1H), 6.14 (d, J = 4.6 Hz, 1H), 4.80 – 4.61 (m, 1H), 4.30 (t, J = 8.5 Hz, 1H), 3.70 (t, J = 8.7 Hz, 1H), 2.46 (m, 5H), 2.17 (m, 1H), 2.03 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.5, 145.4, 135.4, 134.5,


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132.5, 130.0, 129.9, 129.6, 128.9 (q, JC-F = 32 Hz), 128.7, 128.4, 127.7, 126.9, 124.9 (q, JC-F = 3 Hz), 124.4 (q, JC-F = 271 Hz), 89.2, 59.8, 51.5, 25.6, 24.6, 22.0. 19F NMR (471 MHz, CDCl3): δ -62.8. HRMS (EI): m/z calculated for C27H24O3NF332S: 499.1424, Found: 499.1425. N, 4-Dimethyl-N-(4-((3S, 3aR, 7aS)-3-phenyl-1-tosyl-1, 3, 3a, 6, 7,7a-hexahydro benzo[c]isoxazol-4-yl)phenyl)benzenesulfonamide (5i) / N, 4-Dimethyl-N-(4-((3S, 3aS, 7aR)-3-phenyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexa hydrobenzo[c]isoxazol -4-yl)phenyl)benzenesulfonamide (6i) : White solid (5i + 6i = 76 mg, 62 % yield). 5i: 1H

NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.1 Hz, 2H), 7.37 (dd, J = 11.5, 8.1 Hz,

4H), 7.24 (m,2H), 6.99 (t, J = 7.3 Hz, 1H), 6.92 (td, J = 7.5, 5.2 Hz, 3H), 6.81 (d, J = 7.5 Hz, 2H), 6.74 – 6.61 (m, 2H), 6.49 (t, J = 1.9 Hz, 1H), 5.84 (s, 1H), 5.53 (d, J = 9.3 Hz, 1H), 4.78 (s, 1H), 4.09 (s, 1H), 3.49 (s, 1H), 3.01 (s, 3H), 2.44 (d, J = 13.5 Hz, 7H), 2.25 (s, 1H), 2.10 (m, 1H), 2.03 – 1.87 (m, 1H).

13C{1H}

NMR (125 MHz,

CDCl3): δ 145.2, 145.1, 143.9, 141.3, 136.5, 133.8, 133.2, 129.7, 129.6, 129.5, 129.0, 128.6, 128.1, 128.0, 127.9, 125.4, 124.7, 85.9, 60.5, 58.0, 38.0, 32.0, 29.9, 28.1, 21.8, 21.9, 19.2. HRMS (EI): m/z calculated for C34H34O5N232S2: 614.1904, Found: 614.1903. 6i: 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.0 Hz, 2H), 7.40 – 7.30 (m, 5H), 7.22 (d, J = 8.1 Hz, 2H), 7.12 – 6.99 (m, 5H), 6.81 (t, J = 7.7 Hz, 1H), 6.74 – 6.66 (m, 2H), 6.59 (dt, J = 8.1, 1.4 Hz, 1H), 5.96 (t, J = 4.1 Hz, 1H), 4.72 (d, J = 9.9 Hz, 1H), 4.57 (ddd, J = 11.6, 7.1, 4.7 Hz, 1H), 3.59 (t, J = 8.6 Hz, 1H), 2.91 (s, 3H), 2.43 (m, 8H), 2.12 (m, 1H), 1.99 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 145.3, 143.6,



141.2, 140.7, 136.7, 134.4, 133.6, 132.2, 129.7, 129.7, 129.3, 128.6, 128.2, 128.0, 127.9, 125.4, 125.3, 124.4, 89.0, 59.8, 50.8, 38.0, 25.4, 24.1, 21.7, 21.6. HRMS (EI): m/z calculated for C34H34O5N232S2: 614.1904, Found: 614.1903. (3S, 3aR, 7aS)-4-(2-Isopropylphenyl)-3-phenyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexa hydrobenzo [c]isoxazole (5j) / (3S, 3aS, 7aR)-4-(2-isopropylphenyl)-3-phenyl-1tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (6j) : White solid (5j + 6j = 44 mg, 45 % yield). 5j: 1H NMR (400 MHz, CDCl3): δ 7.94 – 7.86 (m, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.21 – 7.14 (m, 1H), 7.08 (ddd, J = 7.4, 4.4, 3.0 Hz, 3H), 7.01 (td, J = 7.6, 1.4 Hz, 1H), 6.95 – 6.89 (m, 2H), 6.54 (td, J = 7.4, 1.4 Hz, 1H), 5.79 – 5.67 (m, 1H), 5.61 (d, J = 7.7 Hz, 1H), 5.47 (d, J = 9.3 Hz, 1H), 4.86 (q, J = 7.4 Hz, 1H), 4.02 (t, J = 8.6 Hz, 1H), 2.93 – 2.74 (m, 1H), 2.41 (s, 4H), 2.35 – 2.22 (m, 1H), 2.11 (m, 1H), 1.34 – 1.20 (m, 4H), 1.00 (d, J = 6.7 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.7, 145.1, 139.9, 135.9, 133.4, 131.0, 129.9, 129.5, 129.4, 128.5, 128.2, 128.1, 126.8, 125.1, 124.9, 86.6, 59.1, 49.9, 29.8, 26.5, 25.0, 24.6, 22.8, 21.9. HRMS (EI): m/z calculated for C29H31O3N32S: 473.2019, Found: 473.2018. 6j: 1H NMR (400 MHz, CDCl3): δ 7.97 – 7.70 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.08 – 6.91 (m, 5H), 6.78 (dq, J = 6.7, 2.2, 1.6 Hz, 3H), 6.67 (dd, J = 7.3, 1.1 Hz, 1H), 5.74 (ddd, J = 4.7, 3.1, 1.2 Hz, 1H), 4.86 (d, J = 9.3 Hz, 1H), 4.39 (ddd, J = 9.2, 7.4, 5.8 Hz, 1H), 3.18 (t, J = 8.4 Hz, 1H), 2.80 (s, 1H), 2.59 – 2.23 (m, 5H), 2.23 – 1.95 (m, 2H), 1.00 (d, J = 6.9 Hz, 6H). 13C{1H} NMR (125 MHz, CDCl3): δ 146.0, 145.2, 138.9, 135.9, 131.8, 130.0, 129.7, 128.7, 128.4, 128.3, 127.9, 127.5, 125.3, 125.0, 87.8, 60.5, 51.8, 29.9, 29.7, 25.6, 23.6, 21.9. HRMS (EI): m/z calculated for


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C29H31O3N32S: 473.2019, Found: 473.2018. (3S,

3aR,

7aS)-4-Phenethyl-3-phenyl-1-tosyl-1,

3,

3a,

6,

7,

7a-hexa

hydrobenzo[c]isoxazole (5l) / (3S, 3aS, 7aR)-4-phenethyl-3-phenyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (6l) : White solid (5l + 6l = 94 mg, 94 % yield). 5l: 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.0 Hz, 2H), 7.32 (q, J = 9.2, 7.6 Hz, 4H), 7.17 (d, J = 7.4 Hz, 3H), 7.12 (d, J = 7.0 Hz, 2H), 6.84 (d, J = 7.3 Hz, 1H), 5.66 (d, J = 5.0 Hz, 1H), 5.42 (d, J = 8.1 Hz, 1H), 4.68 (d, J = 5.6 Hz, 1H), 3.34 (t, J = 8.0 Hz, 1H), 2.44 (m, 3H), 2.32 (m, 2H), 2.17 (m, 2H), 1.83 (m, 2H), 1.52 – 1.33 (m, 2H). 13C{1H}

NMR (125 MHz, CDCl3): δ 145.0, 141.9, 135.7, 134.2, 133.5, 129.9, 129.5,

129.4, 128.9, 128.8, 127.5, 128.4, 128.4, 128.3, 128.3, 126.5, 126.4, 125.9, 86.1, 59.1, 49.4, 36.6, 34.3, 27.4, 21.9, 21.4. HRMS (EI): m/z calculated for C28H29O3N32S: 459.1863, Found: 459.1863. 6l: 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 8.0 Hz, 2H), 7.49 (dd, J = 6.7, 2.9 Hz, 2H), 7.40 (dd, J = 5.1, 1.8 Hz, 3H), 7.37 – 7.28 (m, 4H), 7.19 – 7.07 (m, 3H), 6.71 – 6.59 (m, 2H), 5.59 (d, J = 4.4 Hz, 1H), 4.83 (d, J = 10.4 Hz, 1H), 4.49 (m, 1H), 3.16 (t, J = 8.8 Hz, 1H), 2.44 (s, 3H), 2.40 – 2.31 (m, 1H), 2.31 – 2.21 (m, 3H), 2.07 (m, 1H), 1.88 (m, 2H), 1.69 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.2, 141.6, 137.1, 133.8, 133.6, 129.9, 129.8, 129.4, 129.0, 128.9, 128.4, 128.3, 128.0, 127.9, 126.5, 125.9, 89.3, 60.3, 50.5, 37.5, 34.5, 26.1, 24.0, 21.9.

HRMS (EI): m/z

calculated for C28H29O3N32S : 459.1863, Found: 459.1863. (3S, 3aR, 7aS)-4-Methyl-3-phenyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (5m) / (3S, 3aS, 7aR)-4-methyl-3-phenyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexa



Page 42 of 54

hydrobenzo[c]isoxazole (6m): White solid (5m + 6m = 61 mg, 83 % yield). 5m: 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.3 Hz, 2H), 7.43 – 7.26 (m, 7H), 5.52 (s, 1H), 4.80 (d, J = 11 Hz, 1H), 4.51 – 4.38 (m, 1H), 2.90 (t, J = 8.9 Hz, 1H), 2.52 – 2.39 (m, 3H), 2.37 – 2.14 (m, 1H), 2.01 (m, 2H), 1.86 (m, 1H), 0.95 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.2, 137.0, 132.4, 130.1, 130.0, 129.8, 129.3, 128.7, 128.5, 128.2, 124.4, 89.1, 60.4, 52.8, 26.1, 23.9, 22.4, 21.9. HRMS (EI): m/z calculated for C21H23O3N32S: 369.1393, Found: 369.1393. 6m: 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.3 Hz, 2H), 7.43 – 7.26 (m, 7H), 5.58 (d, J = 4.4 Hz, 1H), 5.44 (d, J = 8.3 Hz, 1H), 4.68 (m, 1H), 3.32 (t, J = 8.0 Hz, 1H), 2.52 – 2.39 (m, 3H), 2.37 – 2.14 (m, 1H), 2.01 (m, 2H), 1.86 (m, 1H), 0.95 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.0, 135.6, 133.4, 130.5, 129.9, 129.8, 129.4, 128.8, 128.7, 128.2, 126.7, 85.9, 59.5, 51.0, 27.0, 22.8, 21.8, 21.4. HRMS (EI): m/z calculated for C21H23O3N32S: 369.1393, Found: 369.1393. (3S,

3aR,

7aS)-4-Ethyl-3-phenyl-1-tosyl-1,

3,

3a,

6,

7,

7a-hexahydro

benzo[c]isoxazole (5n) / (3S, 3aS, 7aR)-4-ethyl-3-phenyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (6n): White solid (5n + 6n = 72 mg, 94 % yield).5n: 1H

NMR (400 MHz, CDCl3): δ 7.87 (dd, J = 17.9, 8.3 Hz, 2H), 7.41 (dd, J = 6.7, 3.0

Hz, 1H), 7.36 – 7.29 (m, 5H), 7.24 (m, 1H), 5.52 (s, 1H), 4.79 (d, J = 10.4 Hz, 1H), 4.46 (ddd, J = 12.0, 7.3, 4.8 Hz, 1H), 3.05 (t, J = 8.8 Hz, 1H), 2.44 (d, J = 11.5 Hz, 4H), 2.38 – 2.11 (m, 2H), 2.09 – 2.02 (m, 1H), 1.88 (m, 1H), 1.39 – 1.26 (m, 1H), 0.66 (dt, J = 19.0, 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 144.8, 136.2,1


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33.3, 129.2, 129.1, 127.1, 127.4, 124.3, 122.9, 86.0, 59.3, 49.0, 28.2, 27.2, 23.1, 21.3, 12.1. HRMS (EI): m/z calculated for C22H25O3N32S: 383.1550, Found: 383.1544. 6n: 1H NMR (400 MHz, CDCl3): δ 7.87 (dd, J = 17.9, 8.3 Hz, 2H), 7.41 (dd, J = 6.7, 3.0 Hz, 1H), 7.36 – 7.29 (m, 5H), 7.24 (m, 1H), 5.61 (s, 1H), 5.44 (d, J = 8.4 Hz, 1H), 4.68 (td, J = 7.9, 4.1 Hz, 1H), 3.40 (t, J = 8.1 Hz, 1H), 2.44 (d, J = 11.5 Hz, 4H), 2.38 – 2.11 (m, 2H), 2.09 – 2.02 (m, 1H), 1.88 (m, 1H), 1.39 – 1.26 (m, 1H), 0.66 (dt, J = 19.0, 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 144.9, 136.9, 135.7, 132.4, 129.8, 129.7, 129.6, 128.7, 128.6, 128.4, 89.2, 60.2, 51.0, 27.8, 26.0, 23.7, 21.7, 11.7. HRMS (EI): m/z calculated for C22H25O3N32S: 383.1550, Found: 383.1544. (3R, 3aR, 7aS)-4-(4-Chlorophenyl)-3-cyclopropyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo [c]isoxazole (10a) / (3R, 3aS, 7aR)-4-(4-chlorophenyl)-3-cyclo propyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (11a): White solid (10a+ 11a = 86 mg, 99 % yield). 10a: 1H NMR (400 MHz, CDCl3): δ 7.92 (dd, J = 22.9, 7.9 Hz, 2H), 7.39 (dd, J = 16.2, 7.9 Hz, 2H), 7.25 (q, J = 10.1, 8.9 Hz, 3H), 7.09 (d, J = 8.1 Hz, 1H), 6.26 (t, J = 4.2 Hz, 1H), 4.64 (ddd, J = 11.1, 7.3, 4.2 Hz, 1H), 3.86 (t, J = 8.1 Hz, 1H), 3.66 (t, J = 9.3 Hz, 1H), 2.65 – 2.18 (m, 5H), 2.18 – 1.60 (m, 2H), 0.71 – 0.48 (m, 1H), 0.42 (m, 1H), 0.21 (m, 1H), -0.18 (m, 1H), -0.54 (m, 1H). 13C{1H}

NMR (125 MHz, CDCl3): δ 145.2, 139.8, 134.3, 133.1, 129.2, 129.7, 128.9,

127.5, 127.2, 92.7, 60.0, 48.0, 24.7, 24.1, 21.9, 14.0, 4.0, 3.1. HRMS (EI): m/z calculated for C23H24O3N35Cl32S: 429.1160, Found: 429.1157, mp: 181.6 oC. 11a: 1H NMR (400 MHz, CDCl3): δ 7.92 (dd, J = 22.9, 7.9 Hz, 2H), 7.39 (dd, J = 16.2, 7.9 Hz, 2H), 7.25 (q, J = 10.1, 8.9 Hz, 3H), 7.09 (d, J = 8.1 Hz, 1H), 5.96 (d, J =



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4.1 Hz, 1H), 4.43 (dt, J = 11.4, 5.2 Hz, 1H), 3.19 (t, J = 7.8 Hz, 1H), 3.03 (t, J = 8.9 Hz, 1H), 2.65 – 2.18 (m, 5H), 2.18 – 1.60 (m, 2H), 0.71 – 0.48 (m, 1H), 0.42 (m, 1H), 0.21 (m, 1H), -0.18 (m, 1H), -0.54 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 144.1, 140.4, 133.5, 133.5, 132.7, 129.9, 129.3, 128.9, 128.6, 127.0, 90.2, 59.4, 44.9, 25.1, 24.1, 21.2, 12.3, 4.2, 4.2. HRMS (EI): m/z calculated for C23H24O3N35Cl32S: 429.1160, Found: 429.1157. (3S,

3aS,

7aR)-4-(4-Bromophenyl)-3-cyclopropyl-1-tosyl-1,

3,

3a,

6,

7,

7a-hexahydrobenzo [c]isoxazole (10c) / (3R, 3aS, 7aR)-4-(4-bromophenyl)-3-cyclo propyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (11c): White solid (10c + 11c = 94 mg, 99 % yield). 10c: 1H NMR (400 MHz, CDCl3): δ 7.92 (dd, J = 22.9, 7.9 Hz, 2H), 7.39 - 7.25 (m, 3H), 7.15 (d, J = 8.3 Hz, 2H) 7.00 (d, J = 8.0 Hz, 1H), 6.26 (t, J = 4.2 Hz, 1H), 4.64 (ddd, J = 11.1, 7.3, 4.2 Hz, 1H), 3.86 (t, J = 8.1 Hz, 1H), 3.66 (t, J = 9.3 Hz, 1H), 2.65 – 2.18 (m, 5H), 2.18 – 1.60 (m, 2H), 0.71 – 0.48 (m, 1H), 0.42 (m, 1H), 0.21 (m, 1H) -0.18 (m, 1H), -16 (m, 1H).

13C{1H}

NMR (125

MHz, CDCl3): δ 145.2, 140.3, 134.4, 132.5, 129.9, 129.7, 129.0, 128.2, 121.2, 92.7, 60.0, 48.0, 29.9, 24.7, 24.1, 14.1, 4.0, 3.1. HRMS (EI): m/z calculated for C23H24O3N79Br32S: 473.0655, Found: 473.0659. 11c: 1H NMR (400 MHz, CDCl3): δ 7.92 (dd, J = 22.9, 7.9 Hz, 2H), 7.39 (dd, J = 16.2, 7.9 Hz, 3H), 7.15 (d, J = 8.3 Hz, 2 H) 7.00 (d, J = 8.0 Hz, 1H), 5.96 (d, J = 4.1 Hz, 1H), 4.43 (dt, J = 11.4, 5.2 Hz, 1H), 3.19 (t, J = 7.8 Hz, 1H), 3.03 (t, J = 8.9 Hz, 1H), 2.65 – 2.18 (m, 5H), 2.18 – 1.60 (m, 2H), 0.71 – 0.48 (m, 1H), 0.42 (m, 1H), 0.21 (m, 1H) -0.18 (m, 1H), -16 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.1,


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141.9, 133.7, 133.5, 131.5, 129.9, 129.3, 127.5, 120.9, 90.2, 59.4, 44.9, 25.2, 23.4, 21.9, 12.3, 4.2, 4.2. HRMS (EI): m/z calculated for C23H24O3N79Br32S: 473.0655, Found: 473.0659. (3S, 3aR, 7aS)-3-Cyclopropyl-4-phenyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydro benzo[c]isoxazole (10d) / (3S, 3aS, 7aR)-3-cyclopropyl-4-phenyl- 1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (11d): White solid (10d + 11d = 84 mg, 99 % yield). 10d : 1H NMR (400 MHz, CDCl3): δ 7.93 (dd, J = 23.0, 8.3 Hz, 2H), 7.40 (dd, J = 16.5, 8.0 Hz, 2H), 7.29 (m, 2H), 7.27 – 7.19 (m, 2H), 7.14 (m, 1H), 6.42 – 6.19 (m, 1H), 4.65 (ddd, J = 11, 7.3, 4.3 Hz, 1H), 3.90 (t, J = 8.1 Hz, 1H), 3.67 (dd, J = 10.0, 8.8 Hz, 1H), 2.63 – 2.25 (m, 5H), 2.10 – 1.96 (m, 1H), 1.95 – 1.74 (m, 1H), 0.65 0.54 (m, 1H), 0.44-0.33 (m, 1H), 0.10 (m, 1H), -0.23 (m, 1H), -0.48 – -0.71 (m, 1H). 13C{1H}

NMR (100 MHz, CDCl3): δ 144.9, 141.2, 135.2, 132.4, 129.7, 129.5, 128.2,

128.0, 127.3, 127.1, 92.7, 60.0, 47.9, 31.4, 24.7, 23.9, 13.9, 3.8, 2.7. HRMS (EI): m/z calculated for C23H25O3N32S: 395.1550, Found: 395.1549. 11d : 1H NMR (400 MHz, CDCl3): δ 7.93 (dd, J = 23.0, 8.3 Hz, 2H), 7.40 (dd, J = 16.5, 8.0 Hz, 2H), 7.29 (m, 2H), 7.27 – 7.19 (m, 2H), 7.14 (m, 1H), 5.97 (t, J = 4.1 Hz, 1H), 4.43 (ddd, J = 11.1, 6.7, 4.4 Hz, 1H), 3.22 (t, J = 7.7 Hz, 1H), 3.05 (t, J = 8.9 Hz, 1H), 2.63 – 2.25 (m, 5H), 2.10 – 1.96 (m, 1H), 1.95 – 1.74 (m, 1H), 0.65 - 0.54 (m, 1H), 0.44-0.33 (m, 1H), 0.10 (m, 1H), -0.23 (m, 1H), -0.48 – -0.71 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 144.9, 141.7, 134.3, 133.5, 129.7, 129.1, 128.3, 127.0, 126.5, 125.6, 90.2, 59.4, 44.7, 25.1, 23.9, 21.7, 12.1, 4.0, 3.8. HRMS (EI): m/z calculated for C23H25O3N32S: 395.1550, Found: 395.1549.



Page 46 of 54

(3S, 3aR, 7aS)-3-Cyclopropyl-1-tosyl-4-(4-(trifluoromethyl)phenyl)-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (10h) / (3S, 3aS, 7aR)-3-cyclopropyl-1-tosyl-4-(4(trifluoromethyl) phenyl)-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (11h): White solid (10h + 11h = 93 mg, 72 % yield). 10h: 1H NMR (400 MHz, CDCl3): δ 7.90 (dd, J = 24.0, 7.9 Hz, 2H), 7.52 (d, J = 7.5 Hz, 2H), 7.37 (dd, J = 17.1, 7.7 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 6.34 (s, 1H), 4.65 (ddd, J = 11.0, 7.1, 4.2 Hz, 1H), 3.91 (s, 1H), 3.64 (t, J = 9.3 Hz, 1H), 2.64 – 2.22 (m, 5H), 2.02 (m, 1H), 1.83 (m, 1H), 0.60 (m, 1H), 0.40 (m, 1H), 0.17 (m, 1H), -0.28 (m, 1H), -0.65 (m, 1H).

13C{1H}

NMR (125 MHz, CDCl3): δ 145.6, 145.3, 133.7, 133.5, 130.8, 129.7, 129.4, 127.7 (q, JC-F = 32 Hz), 126.1, 125.44 (q, JC-F = 3 Hz), 124.41 (q, JC-F = 272 Hz), 24.4, 126.1, 125.44, 90.2, 59.4, 45.0, 25.2, 23.4, 21.9, 12.3, 4.4, 4.1. 19F NMR (471 MHz, CDCl3): δ -62.37. HRMS (EI): m/z calculated for C24H24O3NF332S: 463.1424, Found: 463.1424. 11h: 1H NMR (400 MHz, CDCl3): δ 7.90 (dd, J = 24.0, 7.9 Hz, 2H), 7.52 (d, J = 7.5 Hz, 2H), 7.37 (dd, J = 17.1, 7.7 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 6.04 (t, J = 4.0 Hz, 1H), 4.53 – 4.33 (m, 1H), 3.24 (t, J = 7.6 Hz, 1H), 3.01 (t, J = 8.9 Hz, 1H), 2.64 – 2.22 (m, 5H), 2.02 (m, 1H), 1.83 (m, 1H), 0.60 (m, 1H), 0.40 (m, 1H), 0.17 (m, 1H), -0.28 (m, 1H), -0.65 (m, 1H).

13C{1H}

NMR (125 MHz, CDCl3): δ 145.3, 145.0,

134.5, 132.4, 130.0, 129.8, 129.45 (q, JC-F = 32 Hz), 129.4, 126.9, 125.42 (q, JC-F = 3 Hz), 124.37 (q, JC-F = 272 Hz), 92.7, 60.0, 48.0, 24.7, 24.2, 21.9, 14.0, 4.1, 3.1. 19F NMR (471 MHz, CDCl3): δ -62.42. HRMS (EI): m/z calculated for C24H24O3NF332S: 463.1424, Found: 463.1424.


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(3S, 3aR, 7aS)-3-Cyclopropyl-4-phenethyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexa hydrobenzo

[c]isoxazole

(10l)

/

(3S,

3aS,

7aR)-3-Cyclopropyl-

4-phenethyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydro benzo [c]isoxazole (11l) : White solid (10l + 11l = 85 mg, 80 % yield). 10l: 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 7.1 Hz, 2H), 7.22 (d, J = 7.3 Hz, 1H), 7.13 – 7.10 (m, 2H), 5.56 (d, J = 4.2 Hz, 1H), 4.27 (ddd, J = 11.5, 6.9, 4.6 Hz, 1H), 3.37 (s, 1H), 3.18 (t, J = 9.1 Hz, 1H), 2.80 – 2.61 (m, 1H), 2.63 – 2.48 (m, 2H), 2.47 (s, 3H), 2.33 (m, 2H), 2.12 (m, 2H), 2.04 – 1.80 (m, 1H), 1.80 – 1.66 (m, 1H), 0.93 (m, 1H), 0.78 – 0.44 (m, 3H), 0.24 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.1, 141.9, 133.5, 132.6, 129.8, 129.8, 129.7, 129.2, 129.4, 128.6, 128.6, 128.4, 128.4, 126.1, 126.1, 123.9, 92.8, 60.6, 48.6, 37.8, 34.5, 26.3, 23.6, 21.9, 14.3, 4.5, 4.2. HRMS (EI): m/z calculated for C25H29O3N32S : 423.1863, Found: 423.1864. 11l: 1H NMR (400 MHz, CDCl3): δ 7.90 – 7.85 (m, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 10.0 Hz, 2H), 7.25 – 7.21 (m, 1H), 7.19 – 7.14 (m, 2H), 5.87 – 5.67 (m, 1H), 4.57 – 4.44 (m, 1H), 3.70 (dd, J = 9.9, 8.9 Hz, 1H), 3.16 (t, J = 8.2 Hz, 1H), 2.81 – 2.73 (m, 1H), 2.64 (m, 1H), 2.46 (s, 4H), 2.38 – 2.20 (m, 1H), 2.09 (m, 1H), 2.03 – 1.94 (m, 1H), 0.96 – 0.73 (m, 1H), 0.59 (m, 2H), 0.38 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.0, 142.1, 134.0, 133.8, 129.8, 129.2, 129.2, 128.6, 128.6, 128.5, 126.1, 126.1, 125.1, 90.4, 60.0, 46.5, 38.6, 34.9, 25.8, 22.8, 21.9, 12.0, 4.9, 4.5, 4.1. HRMS (EI): m/z calculated for C25H29O3N32S : 423.1863, Found: 423.1864. (3S, 3aR, 7aS)-3-Cyclopropyl-4-ethyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydro benzo[c]isoxazole (10m) / (3S, 3aS, 7aR)-3-Cyclopropyl-4-ethyl-1-tosyl-1, 3, 3a, 6,



7, 7a-hexahydro benzo[c]isoxazole (11m): White solid (10m + 11m = 58 mg, 63 % yield). 10m: 1H NMR (400 MHz, CDCl3): δ 7.90 – 7.82 (m, 2H), 7.35 (d, J = 8.1 Hz, 2H), 5.70 (d, J = 4.7 Hz, 1H), 4.49 (ddd, J = 10.3, 7.3, 4.6 Hz, 1H), 3.73 (t, J = 9.5 Hz, 1H), 3.17 (t, J = 8.2 Hz, 1H), 2.46 (s, 3H), 2.33 – 2.07 (m, 2H), 2.06 – 1.83 (m, 4H), 1.01 (t, J = 7.4 Hz, 3H), 0.89 – 0.72 (m, 1H), 0.64 – 0.50 (m, 2H), 0.42 – 0.33 (m, 1H), 0.26 (m, 1H). 13C NMR{1H} (125 MHz, CDCl3): δ 145.0, 135.1, 133.5, 129.8, 129.2, 123.2, 90.3, 59.5, 46.5, 29.4, 25.7, 22.9, 21.8, 21.8, 12.6, 11.9, 5.0, 3.9. HRMS (EI): m/z calculated for C19H25O3N32S: 347.1550, Found: 347.1543. 11m: 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 7.7 Hz, 2H), 5.52 (s, 1H), 4.28 (td, J = 7.1, 3.6 Hz, 1H), 3.15 (t, J = 9.0 Hz, 1H), 2.57 – 2.49 (m, 1H), 2.47 (s, 3H), 2.13 (td, J = 15.7, 15.2, 7.6 Hz, 2H), 2.03 – 1.88 (m, 2H), 1.79 – 1.62 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H), 0.72 – 0.62 (m, 1H), 0.60 (s, 1H), 0.47 (m, 2H), 0.22 (m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 145.0, 135.8, 132.7, 129.8, 129.6, 121.9, 92.8, 60.6, 49.0, 29.1, 25.5, 24.0, 21.9, 14.4, 13.3, 4.4, 4.2. HRMS (EI): m/z calculated for C19H25O3N32S: 347.1555, Found: 347.1543. (3S, 3aR, 7aS)-3-Cyclopropyl-4-methyl-1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydro benzo[c]isoxazole (10n) / (3S, 3aS, 7aR)-3-cyclopropyl-4-methyl- 1-tosyl-1, 3, 3a, 6, 7, 7a-hexahydrobenzo[c]isoxazole (11n) : White solid (10n + 11n = 67 mg, 81 % yield). 10n: 1H NMR (400 MHz, CDCl3): δ 7.86 (dd, J = 23.2, 7.9 Hz, 2H), 7.33 (t, J = 8.9 Hz, 2H), 5.65 (d, J = 4.7 Hz, 1H), 4.46 (ddd, J = 11.3, 7.3, 4.4 Hz, 1H), 3.69 (t, J = 9.5 Hz, 1H), 3.12 – 3.04 (m, 1H), 2.43 (d, J = 5.7 Hz, 3H), 2.27 – 1.97 (m, 2H), 1.97 – 1.80 (m, 1H), 1.76 (s, 3H), 1.64 (s, 1H), 0.87 (m, 2H), 0.70 – 0.40 (m, 1H),


Page 48 of 54

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0.40 – 0.15 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 144.8, 132.5, 130.1, 129.6, 129.5, 123.8, 92.5, 60.3, 51.0, 29.7, 25.1, 23.4, 22.8, 14.3, 4.4, 4.0. HRMS (EI): m/z calculated for C18H23O3N32S: 333.1393, Found: 333.1393. 11n: 1H NMR (400 MHz, CDCl3): δ 7.86 (dd, J = 23.2, 7.9 Hz, 2H), 7.33 (t, J = 8.9 Hz, 2H), 5.49 (s, 1H), 4.25 (dq, J = 11.5, 5.5, 5.0 Hz, 1H), 3.18 – 3.10 (m, 1H), 2.43 (d, J = 5.7 Hz, 3H), 2.23 – 2.16 (m, 1H), 2.23 – 1.97 (m, 2H), 1.97 – 1.80 (m, 1H), 1.76 (s, 3H), 1.64 (s, 1H), 0.87 (m, 2H), 0.70 – 0.40 (m, 1H), 0.40 – 0.15 (m, 2H). 13C{1H}

NMR (100 MHz, CDCl3): δ 144.7, 133.6, 130.1, 129.6, 129.0, 125.1, 90.1,

59.3, 48.1, 25.4, 23.6, 22.6, 21.7, 11.6, 4.8, 3.8. HRMS (EI): m/z calculated for C18H23O3N32S: 333.1393, Found: 333.1393. ASSOCIATED CONTENT Supporting Information Spectroscopic and analytical data as well as the original copy of 1H and

13C

NMR

spectra of all new compounds and X-ray crystallographic data (CIF files) of compounds 3a, 3x, 4a, and 11a (CCDC codes: 1900624, 1900626, 1900625, and 1900627). This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author Email: [email protected]

for Y. Zhao

Notes The authors declare no competing financial interest.



ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China grants 81673295 and 81872724 for financial support. We also thank Shanghai Institute of Materia Medica start-up grant and K. C. Wong Education Foundation for financial support. We also thank Dr. Chao-Yie Yang (University of Michigan, Ann Arbor) for proof reading. REFERENCES 1.

Giomi, D.; Cordero, F. M.; Machetti, F., 4.03 - Isoxazoles. In Comprehensive

heterocyclic chemistry III, Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K., Eds. Elsevier: Oxford, 2008; pp 365-485. 2.

Berthet, M.; Cheviet, T.; Dujardin, G.; Parrot, I.; Martinez, J., Isoxazolidine: A

privileged scaffold for organic and medicinal chemistry. Chem. Rev. 2016, 116 (24), 15235-15283. 3.

Gini, A.; Segler, M.; Kellner, D.; Mancheno, O. G., Dehydrogenative TEMPO-mediated

formation of unstable nitrones: easy access to N-carbamoyl isoxazolines. Chem. - Eur. J. 2015, 21 (34), 12053-12060. 4.

Bloch, R., Additions of organometallic reagents to C=N bonds: reactivity and selectivity.

Chem. Rev. 1998, 98 (4), 1407-1438. 5.

Cardona, F.; Goti, A., The discovery of novel metal-induced reactions of nitrones: Not

only electrophiles and reagents for [3+2] cycloadditions. Angew. Chem., Int. Ed. 2005, 44 (48), 7832-7835. 6.

Gothelf, K. V.; Jorgensen, K. A., Catalytic enantioselective 1,3-dipolar cycloaddition

reactions of nitrones. Chem. Commun. 2000,

(16), 1449-1458.


Page 50 of 54

Page 51 of 54 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


7.

Gothelf, K. V.; Jorgensen, K. A., Asymmetric 1,3-dipolar cycloaddition reactions. Chem.

Rev. 1998, 98 (2), 863-909. 8.

Huisgen, R.; Ohta, A.; Geittner, J., 1,3-Dipolar cycloadditions .76. Cycloadditions of

diazomethane to substituted butadienes. Chem Pharm Bull 1975, 23 (11), 2735-2743. 9.

Huisgen, R., 1,3-Dipolar cycloadditions. 76. Concerted nature of 1,3-dipolar

cycloadditions and the question of diradical intermediates. J. Org. Chem. 1976, 41 (3), 403-419. 10. Huisgen, R., 1,3-Dipolar cycloadditions. past and future. Angew. Chem., Int. Ed. 1963, 2 (10), 565-598. 11. Stanley, L. M.; Sibi, M. P., Enantioselective copper-catalyzed 1,3-dipolar cycloadditions. Chem. Rev. 2008, 108 (8), 2887-2902. 12. Williamson, K. S.; Michaelis, D. J.; Yoon, T. P., Advances in the chemistry of oxaziridines. Chem Rev 2014, 114 (16), 8016-36. 13. Davis, F. A., Recent applications of N-sulfonyloxaziridines (Davis oxaziridines) in organic synthesis. Tetrahedron 2018, 74 (26), 3198-3214. 14. Partridge, K. M.; Guzei, I. A.; Yoon, T. P., Carbonyl imines from oxaziridines: Generation and cycloaddition of N-O=C dipoles. Angew. Chem., Int. Ed. 2010, 49 (5), 930-934. 15. Huisgen, R., Kinetics and mechanism of 1,3-dipolar cycloadditions. Angew. Chem., Int. Ed. 1963, 2 (11), 633-645. 16. Buchi, G.; Ayer, D. E., Light catalyzed organic reactions. IV. The oxidation of olefins with nitrobenzene J. Am. Chem. Soc. 1956, 78 (3), 689-690.



17. Porter, K. E.; Rzepa, H. S., MNDO SCF MO study of the relative stability of carbonyl imines (R2C=O+N-R). J. Chem. Res., Synop. 1983,

(10), 262-263.

18. Altmann, J. A.; Rzepa, H. S., An ab initio SCF-MO study of the relative stability of carbonyl imines (R2C=O-NR). J. Mol. Struct.: THEOCHEM 1987, 149 (1), 33-38. 19. Rescifina, A.; Chiacchio, M. A.; Corsaro, A.; De Clercq, E.; Iannazzo, D.; Mastino, A.; Piperno, A.; Romeo, G.; Romeo, R.; Valveri, V., Synthesis and biological activity of isoxazolidinyl polycyclic aromatic hydrocarbons: potential DNA intercalators. J. Med. Chem. 2006, 49 (2), 709-715. 20. Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.; Pistarà, V.; Rescifina, A.; Romeo, R.; Valveri, V.; Mastino, A.; Romeo, G., Enantioselective syntheses and cytotoxicity of N,O-nucleosides. J. Med. Chem. 2003, 46 (17), 3696-3702. 21. Loh, B.; Vozzolo, L.; Mok, B. J.; Lee, C. C.; Fitzmaurice, R. J.; Caddick, S.; Fassati, A., Inhibition of HIV-1 replication by isoxazolidine and isoxazole sulfonamides. Chem. Biol. Drug Des. 2010, 75 (5), 461-474. 22. Ravi Kumar, K. R.; Mallesha, H.; Basappa; Rangappa, K. S., Synthesis of novel isoxazolidine derivatives and studies for their antifungal properties. Eur. J. Med. Chem. 2003, 38 (6), 613-619. 23. Zhao, B.-X.; Wang, Y.; Zhang, D.-M.; Huang, X.-J.; Bai, L.-L.; Yan, Y.; Chen, J.-M.; Lu, T.-B.; Wang, Y.-T.; Zhang, Q.-W.; Ye, W.-C., Virosaines A and B, Two new birdcage-shaped securinega alkaloids with an unprecedented skeleton from flueggea virosa. Org. Lett. 2012, 14 (12), 3096-3099. 24. Zhao, B.-X.; Wang, Y.; Zhang, D.-M.; Jiang, R.-W.; Wang, G.-C.; Shi, J.-M.; Huang,


Page 52 of 54

Page 53 of 54 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


X.-J.; Chen, W.-M.; Che, C.-T.; Ye, W.-C., Flueggines A and B, two new dimeric indolizidine alkaloids from flueggea virosa. Org. Lett. 2011, 13 (15), 3888-3891. 25. Fuhrman, F. A.; Fuhrman, G. J.; Mosher, H. S., Toxin from Skin of Frogs of the Genus Atelopus: Differentiation from Dendrobatid Toxins. Science 1969, 165 (3900), 1376-1377. 26. Yotsu-Yamashita, M.; Kim, Y. H.; Dudley, S. C.; Choudhary, G.; Pfahnl, A.; Oshima, Y.; Daly, J. W., The structure of zetekitoxin AB, a saxitoxin analog from the Panamanian golden frog

Atelopus zeteki: A potent sodium-channel blocker. Proc. Natl. Acad. Sci. 2004,

101 (13), 4346-4351. 27. Partridge, K. M.; Anzovino, M. E.; Yoon, T. P., Cycloadditions of N-sulfonyl nitrones generated by lewis acid catalyzed rearrangement of oxaziridines. J . Am. Chem. Soc. 2008, 130 (10), 2920-2921. 28. Michaelis, D. J.; Ischay, M. A.; Yoon, T. P., Activation of N-sulfonyl oxaziridines using Copper(II) catalysts: aminohydroxylations of styrenes and 1,3-dienes. J. Am. Chem. Soc. 2008, 130 (20), 6610-6615. 29. Zhou, F. L.; Zhao, E. B.; Yan, Z. Q.; Chen, D. H.; Zhao, Y. J., Synthesis of 3,4-diarylsubstituted hexahydro-1H-indoles. Tetrahedron Letters 2018, 59 (19), 1871-1874. 30. Markezich, R. L.; Willy, W. E.; McCarry, B. E.; Johnson, W. S., Direct formation of the steroid nucleus by a nonenzymic biogenetic-like cyclization. Preparation of the cyclization substrate. J. Am. Chem. Soc. 1973, 95 (13), 4414-4416. 31. McCarry, B. B.; Markezich, R.; Johnson, W. S., Direct formation of the steroid nucleus by a nonenzymic biogenetic-like cyclization. Cyclization and proof of structure and configuration of products. J. Am. Chem. Soc. 1973, 95 (13), 4416-4417.



Page 54 of 54

32. Morton, D. R.; Gravestock, M. B.; Parry, R. J.; Johnson, W. S., Acetylenic bond participation in biogenetic-like olefinic cyclizations in nitroalkane solvents. Synthesis of the 17-hydroxy-5.beta.-pregnan-20-one system. J. Am. Chem. Soc. 1973, 95 (13), 4417-4418. 33. Morton, D. R.; Johnson, W. S., Acetylenic bond participation in biogenetic-like olefinic cyclizations in nitroalkane solvents. Facile total synthesis of dl-testosterone benzoate. J. Am. Chem. Soc. 1973, 95 (13), 4419-4420. 34. Tan, S. W. B.; Chai, C. L. L.; Moloney, M. G., Mimics of pramanicin derived from pyroglutamic acid and their antibacterial activity. Org. Biomol. Chem. 2017, 15 (8), 1889-1912. 35. Ghosh, A.; Mandal, S.; Chattaraj, P. K.; Banerjee, P., Ring expansion of donor–acceptor cyclopropane via substituent controlled selective N-transfer of oxaziridine: synthetic and mechanistic insights. Org. Lett. 2016, 18 (19), 4940-4943. 36. Stark, D. G.; O’Riordan, T. J. C.; Smith, A. D., Synthesis of Di-, Tri-, and Tetrasubstituted

Pyridines

from

(Phenylthio)carboxylic

2-[Aryl(tosylimino)methyl]acrylates. Org. Lett. 2014, 16 (24), 6496-6499.


Acids

and

Lewis Acids Promoted 3 + 2 Cycloaddition of Oxaziridines and Cyclic

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