a total synthesis of (+)-negamycin through isoxazolidine ... · 2 a total synthesis of...
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A Total Synthesis of (+)-Negamycin through Isoxazolidine AllylationRoderick W. Bates, Rab’iah Nisha Khanizeman, Hajime Hirao, Yu Shan Tay and Patcharaporn Sae-Lao
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371
roderick@ntu.edu.sg
1H and 13C NMR spectra. All apectra were recorded in CDCl3 unless stated otherwise.
compound page
phthalimide 3 2
hydroxylamine 4 3
hydroxylamine 5 4
methoxyisoxazolidine 6a 5
allyl isoxazolidine 7a 6
carboxylic acid 9 7
hydrazide 11 8
azide 12 9
negamycin 1 10
silyl ether 2b 11
hydroxylamine 3b 12
hydroxylamine 4b 13
hydroxylamine 5b 14
isoxazolidines 6b 15
allyl isoxazolidine 7b 17
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2014
3
-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)
R01080F2ECA400 CDCl3 MAY-27
102030405060708090100110120130140150160170180f1 (ppm)
Phth-Cl-13CPhth-Cl-13C, CDCl3, AV400, JAN-15-2014
19.3
2
35.9
637
.70
38.4
441
.16
41.2
2
76.9
277
.23
77.5
582
.26
85.0
6
118.
8112
3.79
123.
8212
8.67
128.
7912
9.15
132.
1613
2.27
132.
3713
2.75
134.
7613
4.80
164.
39
ClO
O
ON
phthalimide 3
4
ClO
hydroxylamine 4
H2N
5
-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
CBZ-Cl-02ECA400SL CDCl3 JAN-15-2014
30405060708090100110120130140150160170f1 (ppm)
CBZ-Cl-13C-2ECA400SL CDCl3 JAN 16-2014
34.8
1
43.9
3
67.9
2
76.7
777
.09
77.2
977
.41
83.9
0
118.
5812
8.47
128.
4812
8.49
128.
6512
8.70
128.
7112
8.72
128.
7312
8.74
132.
8613
5.41
157.
82
ClO
HN
OO
hydroxylamine 5
6
-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)
OECA400SL CDCl3 MARCH-11
3035404550556065707580859095100105110115120125130135140145150155160165170f1 (ppm)
MeO-13C
39.0
739
.25
39.3
243
.63
44.6
744
.79
56.0
356
.29
68.5
5
76.8
877
.20
77.4
077
.52
80.0
780
.80
90.2
991
.21
128.
3412
8.52
128.
6912
8.80
128.
8313
5.62
145.
71
157.
03
MeOCl
ON
methoxyisoxazolidines 6a
O
O
7
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
RSAK1RSAK1, 1HAV 400 MHz CDCl3 JULY-17
2030405060708090100110120130140150160170f1 (ppm)
RSAK1-13CRSAK1-13CAV 400 MHz CDCl3 JULY-17
36.73
39.14
44.54
58.67
68.25
76.88
77.20
77.52
80.17
118.41
128.48
128.57
128.75
133.79
135.92
157.70
ClON
allyl isoxazolidine 7a
O
O
8
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)
CHECK COOHCHECK COOH, AV400, CDCl3, AUG-12-2013
2030405060708090100110120130140150160170180190200f1 (ppm)
COOH-13ECA400SL CDCl3 AUG-12-2013
37.5
938
.95
44.2
8
55.7
4
68.4
6
76.7
777
.09
77.4
179
.93
128.
4512
8.60
128.
7013
5.50
157.
37
174.
68
ClON
O
O
OHO
carboxylic acid 9
9
-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)
R01277F2ECA400SL CDCl3 APRIL 30
102030405060708090100110120130140150160170180190f1 (ppm)
R01273F2-13CECA400 CDCl3 APRIL17
14.2
8
21.1
3
36.9
337
.20
39.7
944
.05
44.5
056
.90
57.6
360
.48
66.7
166
.87
68.2
268
.45
76.7
877
.09
77.3
077
.41
80.0
680
.26
128.
4612
8.51
128.
6112
8.65
128.
6912
8.77
128.
8213
5.09
135.
2513
5.49
157.
65
167.
8017
0.54
ClON
Cbz
NH
ON
O
MeO
hydrazide 11
10
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
R02015F2R02015F2, AV 400, CDCl3 JULY-15
30405060708090100110120130140150160170180f1 (ppm)
AZIDE-13CAZIDE-13C, CDCl3, AV400, JAN-15-2014
N3ON
Cbz
NH
ON
O
MeO
azide 12
11
1.21.41.61.82.02.22.42.62.83.03.23.43.63.84.04.24.44.64.85.05.2f1 (ppm)
R02023F2-CONC-3R02023F2-CONC-3 BBF01 CDCl3 AUG-02
30405060708090100110120130140150160170180f1 (ppm)
R02023F2-CONC-13CR02023F2-CONC-13C BBF01 CDCl3 AUG-02
39.5
941
.16
43.8
444
.94
45.2
2
60.8
9
65.7
8
170.
85
177.
09
spectra recorded in D2O
NH2OHNH2
NH
ONMe
HO
O
negamycin 1
12
-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
ys-61-crudeJ400SL cdcl3 16oct13
-20-100102030405060708090100110120130140150f1 (ppm)
ys-grignard OTBS-crudeJ400SL cdcl3 16oct13 13C
-5.3
5-5
.32
18.3
3
25.7
525
.93
37.6
7
66.6
071
.18
76.7
977
.11
77.4
3
117.
40
134.
53
OTBSOH
silyl ether 2b
13
-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)
ys-63-pJ400SL cdcl3 17oct13
-100102030405060708090100110120130140150160170180f1 (ppm)
ys-mitsunobu OTBS-pJ400SL cdcl3 17oct13 13C
-5.5
7
18.2
2
25.7
6
34.6
4
64.1
5
76.7
977
.11
77.4
3
87.2
8
117.
9612
3.45
129.
1813
3.28
134.
35
163.
89
OTBSO
O
ON
hydroxylamine 3b
14
-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
ys-66-crudeJ400SL cdcl3 21oct13
-90-80-70-60-50-40-30-20-100102030405060708090f1 (ppm)
ys-NH2+OTBS-crudeJ400SL cdcl3 21oct13 13C
-75.
15
-51.
48
-43.
89
-35.
26
-6.1
2
6.91
7.23
7.55
14.2
2
46.9
9
65.1
3
OTBSO
hydroxylamine 4b
H2N
15
-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)
ys-68-pJ400SL cdcl3 24oct13
-100102030405060708090100110120130140150160170f1 (ppm)
ys-cbz+OTBS-pJ400SL cdcl3 13C 24oct13
-5.3
0
18.3
5
26.0
0
34.4
1
64.1
867
.53
76.9
177
.23
77.5
5
85.5
2
117.
46
128.
3912
8.48
128.
6813
4.21
135.
88
157.
58
OTBSO
HN
OO
hydroxylamine 5b
16
-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)
ys-71-p-F2J400SL cdcl3 31oct13
253035404550556065707580859095100105110115120125130135140145150155160165f1 (ppm)
ys-ozonolysis OTBS-F2J400SL cdcl3 01nov13
36.5
2
56.1
0
62.0
9
68.9
2
76.9
177
.23
77.5
581
.70
91.5
0
128.
5912
8.97
135.
3513
5.59
157.
95
MeOOH
ON
O
O
isoxazolidines 6b
17
-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
ys-71-p-F3J400SL cdcl3 31oct13
253035404550556065707580859095100105110115120125130135140145150155160165f1 (ppm)
ys-ozonolysis OTBS-pJ400SL cdcl3 13C 31oct13
36.6
2
56.1
3
62.1
2
68.4
3
76.7
777
.09
77.4
182
.14
91.3
6
128.
2512
8.59
128.
73
157.
22
MeOOH
ON
O
O
isoxazolidines 6b
18
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
ys-73-p-f1-c6d6J400SL c6d6 08nov13
The 1H spectrum was recorded in C6D6 to give better resolution of the signals
OHON
O
O
allyl isoxazolidine 7b
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