Synthesis of N -[(3 S)-2,6-dioxo-1-(2-phenylethyl)-3-piperidinyl]-(2 S)-2-methylbutanamide (( - )-julocrotine)

Article abstract of DOI:10.1021/np200234e

The total synthesis of ( - )-julocrotine (1) starting from l-glutamic acid in 41% overall yield is described. The methodology utilizes protection, deprotection, and regioselection (carbonyl differentiation via oxazolidinone) protocols, and glutarimide ring formation is the key step.

Full text of DOI:10.1021/np200234e

1
Supporting Information
Synthesis of N-[(3S)-2,6-Dioxo-1-(2-phenylethyl)-3-
piperidinyl]-(2S)-2-methyl-butanamide (1) ((-)-Julocrotine)
Luciano L. Silva § and Antonio C. Joussef §*
Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis,
SC 88040-900, Brazil.

2
Content
S1.
S2.
S3.
S4.
S5.
S6.
S7.
S8.
S9.
1H NMR spectrum (CDCl3, 400 MHz) of (4S)-5-Oxo-4-
[[(phenylmethoxy)carbonyl]amino]-5-[(2-phenylethyl)amino]-pentanoic Acid (5)
13C NMR spectrum (CDCl3, 100 MHz) of (4S)-5-Oxo-4-
[[(phenylmethoxy)carbonyl]amino]-5-[(2-phenylethyl)amino]-pentanoic Acid (5)
IR spectrum of (4S)-5-Oxo-4-[[(phenylmethoxy)carbonyl]amino]-5-[(2-
phenylethyl)amino]-pentanoic Acid (5)
1H NMR spetrum (CDCl3, 400 MHz) Methyl (4S)-5-Oxo-4-
[[(phenylmethoxy)carbonyl]amino]-5-[(2-phenylethyl)amino]-pentanoate (6)
13C NMR spectrum (CDCl3, 100 MHz) of Methyl (4S)-5-Oxo-4-
[[(phenylmethoxy)carbonyl]amino]-5-[(2-phenylethyl)amino]-pentanoate (6)
IR spectrum of Methyl (4S)-5-Oxo-4-[[(phenylmethoxy)carbonyl]amino]-5-[(2-
phenylethyl)amino]-pentanoate (6)
1H NMR spectrum (CDCl3, 400 MHz) of Phenylmethyl (3S)-[2,6-Dioxo-1-(2-
phenylethyl)-3-piperidinyl]-carbamate (7)
13C NMR spectrum (CDCl3, 100 MHz) of Phenylmethyl (3S)-[2,6-Dioxo-1-(2-
phenylethyl)-3-piperidinyl]-carbamate (7)
COSY spectrum (CDCl3, 400 MHz) of Phenylmethyl (3S)-[2,6-Dioxo-1-(2-
phenylethyl)-3-piperidinyl]-carbamate (7)
S10. IR spectrum of Phenylmethyl (3S)-[2,6-Dioxo-1-(2-phenylethyl)-3-piperidinyl]-
carbamate (7)
S11. 1H NMR spectrum (CDCl3, 400 MHz) of N-[(3S)-2,6-Dioxo-1-(2-phenylethyl)-3-
piperidinyl]-(2S)-2-methyl-butanamide (1)

3
S12.
13C NMR spectrum (CDCl3, 100 MHz) of N-[(3S)-2,6-Dioxo-1-(2-phenylethyl)-3-
piperidinyl]-(2S)-2-methyl-butanamide (1)
S13. COSY spectrum (CDCl3, 400 MHz) of N-[(3S)-2,6-Dioxo-1-(2-phenylethyl)-3-
piperidinyl]-(2S)-2-methyl-butanamide (1)
S14. IR spectrum of N-[(3S)-2,6-Dioxo-1-(2-phenylethyl)-3-piperidinyl]-(2S)-2-methyl-
butanamide (1)

4
S1. 1H NMR (CDCl3, 400 MHz) of (4S)-5-Oxo-4-[[(phenylmethoxy)carbonyl]amino]-5-[(2-phenylethyl)amino]-pentanoic Acid (5)
ID.ESP
O
O
3
7
2
HO
N
4
6
H
NH9
8
12
O
O
12
6
7
9
8
2
4a 4b
3a 3b
7.18 0.90
0.91
6.0
2.07
5.0
1.00
2.10
3.5
2.02
1.04 1.03
2.5 2.0
8.0
7.5
7.0
6.5
5.5
4.5
4.0
3.0
1.5
1.0
0.5

5
S2. 13C NMR (CDCl3, 100 MHz) of (4S)-5-Oxo-4-[[(phenylmethoxy)carbonyl]amino]-5-[(2-phenylethyl)amino]-pentanoic Acid (5)
O
O
3
7
2
1
5
HO
N
4
6
H
NH
10
O
O
12
6
4
7
12
2
3
1
5
10

6
S3. IR of (4S)-5-Oxo-4-[[(phenylmethoxy)carbonyl]amino]-5-[(2-phenylethyl)amino]-pentanoic Acid (5)
O
O
HO
N
H
NH
O
O

7
S4. 1H NMR (CDCl3, 400 MHz) of Methyl (4S)-5-Oxo-4-[[(phenylmethoxy)carbonyl]amino]-5-[(2-phenylethyl)amino]-pentanoate (6)
O
O
13
7
3
2
O
N
H
8
4
6
NH9
O
O
12
13
12
6
7
4a 4b
3a 3b
2
8
9
9

8
S5. 13C NMR (CDCl3, 100 MHz) of Methyl (4S)-5-Oxo-4-[[(phenylmethoxy)carbonyl]amino]-5-[(2-phenylethyl)amino]-pentanoate (6)
O
O
3
13
7
2
1
5
O
N
4
6
H
NH
10
3
O
4
6
O
12
7
12
2
13
1
5
10

9
S6. IR of Methyl (4S)-5-Oxo-4-[[(phenylmethoxy)carbonyl]amino]-5-[(2-phenylethyl)amino]-pentanoate (6)
O
O
O
N
H
NH
O
O

10
S7. 1H NMR (CDCl3, 400 MHz) of Phenylmethyl (3S)-[2,6-Dioxo-1-(2-phenylethyl)-3-piperidinyl]-carbamate (7)
9
H
N
O
4
5
3
12
O
O
N
O
7
8
12
8, 5a
7
4b
9
5b
3
4a

11
S8. 13C NMR (CDCl3, 100 MHz) of Phenylmethyl (3S)-[2,6-Dioxo-1-(2-phenylethyl)-3-piperidinyl]-carbamate (7)
H
N
O
10
4
5
3
12
6
2
O
O
N
O
7
8
5
8
3
4
7
6
12
2
10

12
S9. COSY (CDCl3, 400 MHz) of Phenylmethyl (3S)-[2,6-Dioxo-1-(2-phenylethyl)-3-piperidinyl]-carbamate (7)
9
H
12
N
O
4
5
3
12
8, 5a
O
O
N
O
7
4b
4a
9
5b
3
7
8

13
S10. IR of Phenylmethyl (3S)-[2,6-Dioxo-1-(2-phenylethyl)-3-piperidinyl]-carbamate (7)
H
N
O
O
O
N
O

14
S11. 1H NMR spectrum (CDCl3, 400 MHz) of N-[(3S)-2,6-Dioxo-1-(2-phenylethyl)-3-piperidinyl]-(2S)-2-methyl-butanamide (1)
14
13
14
H
4
13
N
5
11
3
12
O
O
N
O
8
7
8
7
12a,4b
12b
11
3
9
5a, 5b
4a

15
S12. 13C NMR (CDCl3, 100 MHz) of N-[(3S)-2,6-Dioxo-1-(2-phenylethyl)-3-piperidinyl]-(2S)-2-methyl-butanamide (1)
14
H
13
10
N
4
11
3
2
5
12
6
O
O
N
O
7
8
11
12
5
8
3
7
14
13
4
2
10
6

16
S13. COSY (CDCl3, 400 MHz) of N-[(3S)-2,6-Dioxo-1-(2-phenylethyl)-3-piperidinyl]-(2S)-2-methyl-butanamide (1)
14
13
8
7
14
5a,5b
4a
12a, 4b
12b
9
9
3
11
H
N
4'
13
5
11
3
12
O
O
O
N
7
8

17
S14. IR of N-[(3S)-2,6-Dioxo-1-(2-phenylethyl)-3-piperidinyl]-(2S)-2-methyl-butanamide (1)
H
N
O
O
N
O