supplementary material synthesis of (+)-l-733,060, (+)-cp ... · 7 210 200 190 180 170 160 150 140...

Supplementary Material

Synthesis of (+)-L-733,060, (+)-CP-99,994 and (2S,3R)-3-Hydroxypipecolic Acid:

Application of an Organocatalytic Direct Vinylogous Aldol Reaction

Sunil V. Pansare* and Eldho K. Paul

Department of Chemistry Memorial University

St. John’s, NL, Canada A1B 3X7 1H and 13C spectra..................................................................................................................2-34 HPLC traces...........................................................................................................................35-37

1

Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012

2

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

EKP-3473D/1EKP-03-90B(CDCl3)

1.02

1.01

1.01

1.00

6.13

0.00

1.55

2.29

2.30

5.08

5.09

5.10

5.18

5.18

5.18

5.19

5.19

5.19

6.18

6.18

6.19

6.19

7.26

7.34

7.35

7.35

7.36

7.36

7.37

7.37

7.37

7.38

7.39

7.39

7.40

7.41

7.41

7.42

7.42

7.42

7.43

7.43

7.44

OHOO

Ph

CDCl3, 500 MHz1 (anti)


3

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

EKP-03-90B

73.0

976

.64

77.0

677

.49

86.6

1

123.

2312

6.06

128.

5612

8.79

138.

28

152.

85

173.

05

OHOO

Ph

CDCl3, 75 MHz1 (anti)


4

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

EKP-3421D/1EKP-03-38C(CDCl3)

1.03

1.03

1.02

1.00

1.02

5.59

-0.0

0

1.61

2.77

2.78

4.70

4.72

5.15

5.16

5.16

5.17

5.17

5.17

6.12

6.12

6.13

6.13

7.16

7.17

7.17

7.18

7.26

7.31

7.31

7.32

7.34

7.35

7.35

7.36

7.36

7.36

7.37

7.37

7.38

7.38

7.39

7.40

7.40

7.40

7.40

7.41

7.41

7.42

OHOO

Ph

CDCl3, 500 MHz1 (syn)


5

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

EKP-03-38B

-0.0

0

75.7

276

.60

77.0

277

.44

86.8

5

123.

0112

6.72

128.

8012

9.01

137.

66

153.

00

172.

40

OHOO

Ph

CDCl3, 75 MHz1 (syn)


6

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

EKP-3554A/1EKP-04-41A(CDCl3)

0.27

1.06

1.39

1.94

1.24

1.00

5.74

-0.0

01.

921.

931.

931.

941.

942.

262.

272.

282.

282.

292.

302.

422.

442.

452.

452.

462.

462.

472.

472.

522.

532.

542.

552.

562.

57

4.68

4.68

4.69

4.69

4.70

4.70

4.70

4.71

4.72

5.12

5.13

7.26

7.30

7.31

7.31

7.32

7.32

7.33

7.33

7.34

7.36

7.37

7.38

7.38

7.39

OHOO

Ph

CDCl3, 500 MHz

1aanti (major) + syn (minor)


7

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

EKP-04-41AEKP-04-41A(CDCl3) 0.

00

20.6

824

.02

28.4

828

.59

73.4

476

.60

77.0

277

.44

83.2

483

.41

126.

0212

6.95

128.

1312

8.64

128.

7312

8.75

138.

3113

8.39

176.

8317

7.61

OHOO

Ph

CDCl3, 75 MHz

1aanti (major) + syn (minor)


8

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)


2.16

2.42

0.38

3.01

1.12

0.12

1.00

6.29

0.00

2.22

2.22

2.23

2.24

2.25

2.25

2.27

2.40

2.41

2.44

2.45

2.45

2.47

2.47

2.49

2.49

2.50

2.51

2.52

2.89

2.91

4.82

4.83

4.83

4.84

4.84

4.84

4.85

4.86

5.51

5.53

5.72

5.73

7.26

7.42

7.42

7.43

7.43

7.43

OSO2CH3OO

Ph

CDCl3, 500 MHz

1banti (major) + syn (minor)


9

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

EKP-04-57A

0.00

22.0

924

.22

27.7

427

.91

38.9

739

.27

76.6

177

.04

77.4

680

.31

80.3

882

.81

84.3

4

126.

8512

7.53

129.

1412

9.18

129.

6212

9.98

133.

4613

3.70

175.

9817

6.07

OSO2CH3OO

Ph

CDCl3, 75 MHz

1banti (major) + syn (minor)


10

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

EKP-3735C/1EKP-05-28A(CDCl3)

2.34

0.23

2.31

1.00

1.12

0.12

6.18

-0.0

01.

981.

981.

981.

992.

002.

002.

002.

002.

012.

012.

012.

022.

022.

032.

042.

052.

062.

072.

072.

082.

082.

082.

092.

092.

092.

102.

102.

112.

112.

112.

122.

352.

362.

372.

382.

382.

392.

392.

402.

402.

402.

412.

412.

412.

422.

432.

432.

432.

442.

452.

462.

462.

484.

594.

604.

674.

684.

684.

694.

694.

714.

894.

907.

277.

357.

367.

367.

377.

377.

397.

407.

407.

407.

417.

417.

427.

427.

437.

44

N3OO

Ph

CDCl3, 500 MHz

2syn (major) + anti (minor)


11

-0.0

0

22.3

024

.62

28.0

028

.10

67.5

668

.45

76.5

977

.01

77.4

381

.19

81.4

0

127.

2112

7.80

128.

9612

9.10

129.

1212

9.26

134.

5113

4.60

176.

1717

6.38

N3OO

Ph

CDCl3, 75 MHz

2syn (major) + anti (minor)


12

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

EKP-3622A/1EKP-04-45C(CDCl3)

0.99

1.06

1.01

1.02

1.02

1.00

1.00

0.96

3.05

2.05

-0.0

0

1.68

2.01

2.02

2.13

2.13

2.14

2.14

2.15

2.37

2.38

2.40

2.41

2.41

2.42

2.70

2.71

2.72

4.08

4.67

4.67

5.85

7.27

7.33

7.35

7.35

7.36

7.37

7.41

7.42

7.42

7.43

7.44

CDCl3, 500 MHz

NH

OH

PhO

cis 3


13

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

EKP-04-45CEKP-04-45C -0

.00

26.0

626

.68

61.8

7

66.2

3

76.6

177

.03

77.4

6

127.

0312

8.68

129.

15

137.

85

172.

28

CDCl3, 75 MHz

NH

OH

PhO

cis 3


14

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

EKP-3552B/1EKP-04-32C(CDCl3)

0.98

1.04

1.05

1.02

1.01

1.00

1.00

0.96

3.04

1.98

0.00

1.46

1.46

1.47

1.47

1.61

2.05

2.16

2.16

2.17

2.17

2.18

2.40

2.43

2.44

2.44

2.45

2.72

2.73

2.74

2.76

4.09

4.10

4.10

4.69

4.70

5.70

7.26

7.35

7.36

7.36

7.38

7.39

7.39

7.40

7.43

7.43

7.44

7.44

7.44

7.45

7.46

CDCl3, 500 MHz

NH

OH

PhO

trans 3


15

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

EKP-04-32CEKP-04-32C -0

.00

26.0

526

.68

61.9

3

66.2

8

76.5

977

.01

77.4

4

126.

9812

8.77

129.

23

137.

80

172.

13

CDCl3, 75 MHz

NH

OH

PhO

trans 3


16

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)


1.10

1.42

1.70

1.59

1.05

1.00

1.01

1.02

1.81

4.02

0.00

1.49

1.51

1.52

1.70

1.70

1.71

1.71

1.87

1.89

2.02

2.02

2.02

2.03

2.04

2.05

2.05

2.81

2.81

2.83

2.83

3.19

3.19

3.20

3.78

3.78

3.86

3.86

7.25

7.25

7.26

7.26

7.27

7.27

7.28

7.32

7.34

7.34

7.35

7.36

CDCl3, 500 MHz

NH

OH

Ph

3a


17

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

EKP-04-47AEKP-04-47A(CDCl3) 0.

00

19.9

0

31.9

8

47.4

6

65.0

2

68.9

2

76.5

977

.01

77.4

4

126.

5912

7.27

128.

45

142.

02

CDCl3, 75 MHz

NH

OH

Ph

3a


18

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

EKP-3591B/1EKP-04-51B(CDCl3)

9.29

1.08

1.11

3.13

1.02

1.02

1.04

1.00

1.86

2.00

2.02

0.00

1.37

1.58

1.66

1.67

1.68

1.70

1.70

1.72

1.77

1.77

1.78

1.78

1.80

1.81

1.83

1.83

1.84

1.84

3.01

3.01

3.03

3.04

3.06

3.07

3.98

3.99

4.00

4.01

4.01

4.02

4.03

4.07

4.08

4.09

4.10

4.11

5.31

5.33

7.26

7.26

7.28

7.32

7.32

7.33

7.33

7.35

7.44

7.46

7.46

CDCl3, 500 MHz4

N

OH

Ph

O OtBu


19

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

EKP-04-51BEKP-04-51B -0

.00

23.0

727

.70

28.3

2

39.4

5

59.2

5

70.0

5

76.5

977

.01

77.4

479

.89

127.

1912

8.37

138.

43

155.

39

CDCl3, 75 MHz4

N

OH

Ph

O OtBu


20

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

EKP-3591A/1EKP-04-52D(CDCl3)

CDCl3, 500 MHz

N

O

Ph

O OtBu

CF3

CF3

4a


21

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

EKP-04-52DEKP-04-52D -0

.00

24.1

825

.85

28.4

0

39.2

4

55.4

4

69.1

5

76.5

977

.01

77.4

478

.69

80.1

3

117.

8712

1.33

121.

3812

1.43

121.

4812

5.09

127.

0712

7.15

127.

2112

8.29

128.

3312

8.70

130.

9513

1.39

131.

8313

2.28

137.

9914

1.00

155.

29

CDCl3, 75 MHz

N

O

Ph

O OtBu

CF3

CF3

4a


22

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)


1.08

1.20

1.06

1.20

1.03

1.01

1.00

1.03

1.01

1.00

1.00

1.86

2.00

2.00

1.97

0.98

-0.0

01.

521.

541.

541.

701.

701.

711.

711.

731.

731.

741.

771.

771.

861.

89

2.20

2.20

2.21

2.84

2.85

2.87

3.27

3.28

3.28

3.68

3.68

3.84

3.85

4.12

4.15

4.51

4.53

7.25

7.25

7.26

7.28

7.28

7.30

7.32

7.33

7.36

7.37

7.38

7.44

7.69

CDCl3, 500 MHz

NH

O

Ph

CF3

CF3

(+)-L-773,060


23

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

EKP-04-53B

0.00

20.2

8

28.3

5

46.9

4

64.1

6

70.0

776

.61

77.0

477

.11

77.4

6

121.

1912

1.24

121.

2912

1.48

125.

0912

6.81

127.

2812

7.45

127.

5012

8.20

130.

6613

1.10

131.

5413

1.98

141.

1214

1.38

CDCl3, 75 MHz

NH

O

Ph

CF3

CF3

(+)-L-773,060


24

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

EKP-3608A/1EKP-04-62B(CDCl3)

9.30

2.06

2.05

1.00

0.98

0.92

2.02

0.85

2.02

-0.0

01.

371.

391.

431.

451.

491.

641.

901.

911.

921.

931.

941.

951.

961.

971.

97

2.44

2.45

2.45

2.46

3.30

3.30

3.31

3.32

3.33

3.34

3.35

4.08

5.66

7.20

7.22

7.26

7.28

7.30

7.34

7.36

7.37

CDCl3, 500 MHz

N

O

Ph

O OtBu5


25

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

EKP-04-62BEKP-04-62B -0

.00

22.8

7

28.2

8

37.3

440

.15

66.3

4

76.6

177

.03

77.4

580

.76

125.

4012

7.63

128.

94

135.

61

155.

01

205.

51

CDCl3, 75 MHz

N

O

Ph

O OtBu5


26

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

EKP-3735B/1EKP-05-24D(CDCl3)

9.64

2.07

2.31

1.07

1.09

1.05

0.93

1.05

1.00

1.21

2.12

2.03

0.00

1.36

1.37

1.48

1.65

1.66

1.67

1.67

1.68

1.69

1.77

1.78

1.79

1.86

1.87

1.88

3.14

3.16

3.19

3.21

3.99

3.99

4.00

4.02

4.03

5.19

5.20

7.25

7.26

7.27

7.28

7.28

7.28

7.30

7.30

7.31

7.32

7.33

7.33

7.43

7.43

7.44

7.44

CDCl3, 500 MHz

N Ph

O OtBu

NH2

6


27

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

EKP-3630A/1EKP-04-72C(CDCl3)

9.11

1.36

1.22

3.04

0.95

1.00

2.99

2.03

0.98

0.87

0.94

0.98

3.67

2.09

1.90

-0.0

0

1.41

1.42

1.52

1.54

1.62

1.63

1.63

1.76

1.76

1.78

1.78

1.81

1.82

2.96

2.96

3.04

3.04

3.05

3.06

3.06

3.71

3.79

3.82

3.85

3.87

3.94

3.96

5.47

6.80

6.80

6.82

6.87

6.89

6.90

7.19

7.20

7.20

7.21

7.21

7.21

7.22

7.25

7.25

7.26

7.26

7.26

7.26

7.29

7.30

7.31

7.31

7.31

7.32

7.33

7.57

7.59

CDCl3, 500 MHz6a

N

HN

PhOCH3

O OtBu


28

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

EKP-04-72CEKP-04-72C -0

.00

24.3

626

.80

28.4

3

39.5

1

46.6

1

55.0

657

.26

76.5

977

.01

77.4

479

.60

110.

13

120.

3912

6.89

128.

0612

8.09

129.

2212

9.53

139.

19

155.

2715

7.54

CDCl3, 75 MHz6a

N

HN

PhOCH3

O OtBu


29

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)


1.04

1.14

2.02

1.15

1.00

1.94

1.01

0.94

2.92

1.04

1.00

0.92

0.96

0.97

0.94

5.11

0.00

1.38

1.40

1.57

1.59

1.60

1.60

1.60

1.62

1.77

1.90

1.91

1.92

1.93

1.94

1.95

2.12

2.81

2.81

2.82

2.82

3.25

3.25

3.26

3.26

3.27

3.28

3.28

3.28

3.39

3.42

3.44

3.45

3.65

3.68

3.87

6.66

6.68

6.78

6.79

6.80

6.80

6.81

6.96

6.98

7.12

7.14

7.16

7.20

7.20

7.21

7.21

7.23

7.25

7.25

7.25

7.26

7.26

7.27

7.28

7.29

7.29

7.30

CDCl3, 500 MHz

NH

HN

PhOCH3

(+)-CP-99,994


30

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

EKP-04-74A

20.3

8

28.2

4

46.7

747

.81

54.7

254

.78

64.0

0

76.6

577

.07

77.5

0

109.

81

119.

9812

6.33

126.

5612

7.82

128.

1612

8.30

129.

61

142.

49

157.

62

CDCl3, 75 MHz

NH

HN

PhOCH3

(+)-CP-99,994


31

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

EKP-3770D/1EKP-05-35B(CDCl3)

2.77

4.42

2.37

0.30

1.00

1.00

0.30

1.34

0.31

1.00

6.08

0.67

0.00

1.80

1.81

1.82

1.83

1.84

1.84

1.84

1.85

1.85

1.86

2.01

2.02

2.02

2.03

2.03

2.04

2.04

2.09

2.11

2.12

2.13

2.13

2.14

2.15

2.15

2.16

2.16

2.17

2.74

2.74

2.75

2.77

2.78

3.13

3.14

3.15

3.16

3.16

3.17

3.18

3.19

3.80

3.81

3.83

3.84

4.35

4.36

4.38

4.39

5.21

5.22

5.22

5.23

5.24

5.25

5.25

5.54

5.55

5.98

5.99

7.26

7.28

7.29

7.30

7.31

7.31

7.33

7.34

7.34

7.35

7.36

7.37

7.37

7.39

7.41

7.42

7.42

7.48

7.49

CDCl3, 500 MHz

N Ph

O CF3

O

O

CH3

8 (rotamers)


32

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

EKP-05-35B

0.00

21.0

521

.13

23.4

723

.85

24.9

4

38.8

241

.08

41.1

341

.18

41.2

3

55.5

357

.67

70.5

772

.39

76.6

577

.07

77.4

9

110.

8611

4.67

118.

4812

2.30

127.

7612

7.97

128.

0212

8.74

128.

9013

5.04

135.

38

155.

7715

6.25

156.

7215

7.20

169.

6316

9.71

CDCl3, 75 MHz

N Ph

O CF3

O

O

CH3

8 (rotamers)


33

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.5f1 (ppm)

EKP-05-46B3-Hydroxy pipecolic acid

2.08

2.03

1.02

1.00

0.99

1.00

1.63

1.64

1.66

1.69

1.69

1.70

1.71

1.72

1.75

1.76

1.77

1.88

1.89

1.90

1.91

1.92

1.93

1.94

1.95

1.96

1.97

2.89

2.93

2.94

2.97

2.99

3.32

3.33

3.33

3.36

3.37

3.38

3.60

3.61

4.44

4.72

D2O, 500 MHz

NH

OH

COOH

(2S,3R)-3-Hydroxypipecolic acid


34

-100102030405060708090100110120130140150160170180190200210f1 (ppm)

EKP-05-46B3-Hydroxy pipecolic acid 15

.88

28.7

0

43.5

7

62.2

464

.10

172.

28

D2O, 75 MHz

NH

OH

COOH

(2S,3R)-3-Hydroxypipecolic acid


35

AD-H 99 hex 1ipa 210nm 90 min

Time5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00

AU

0.0

1.0e-1

2.0e-1

3.0e-1

4.0e-1

5.0e-1

6.0e-1

7.0e-1

8.0e-1

9.0e-1

1.0

1.1

1.2

1.3

1.4

1.5

1.6

1.7

EKP-05-65A Sm (SG, 20x4) Diode Array Range: 1.855

AreaArea%

1.9595.332.73

Area26052.82

1275896.0036516.55

Height42958

185287848598

Time26.2833.9935.75

33.991275896

26.2826053

35.7536517

5

N

O

Ph

O OtBu

minor

major

N

O

Ph

O OtBu

5


36

AD-H 99 hex 1ipa 210nm 60 min

Time5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00 50.00

AU

0.0

1.0e-1

2.0e-1

3.0e-1

4.0e-1

5.0e-1

6.0e-1

7.0e-1

8.0e-1

9.0e-1

1.0

1.1

1.2

1.3

1.4

EKP-05-25B (Recemic) Sm (SG, 20x4) Diode Array Range: 1.546

AreaArea%

0.5352.6346.84

Area10471.55

1035272.94921369.69

Height23461

15356661273964

Time12.6734.7036.25

34.701035273

12.6710472

36.25921370

Recemic

N

O

Ph

O OtBu

N

O

Ph

O OtBu

5 racemic


37

OD-H 90 hex 10ipa 210nm 60 min

Time2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00

AU

0.0

1.0e-1

2.0e-1

3.0e-1

4.0e-1

5.0e-1

6.0e-1

7.0e-1

8.0e-1

9.0e-1

1.0

1.1

EKP-05-72A(3rd run) Sm (SG, 20x4) Diode Array Range: 1.211

AreaArea%

1.071.44

94.782.71

Area5400.147273.15

478479.5913663.85

Height2136239599

120636930785

Time3.624.926.279.75

6.27478480

4.9272733.62

54009.75

13664

NH

HN

PhOCH3

(+)-CP-99,994

minor

major


supplementary material synthesis of (+)-l-733,060, (+)-cp ... · 7 210 200 190 180 170 160 150 140...

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