Supporting Information for:
Synthesis of fluorescent ring-fused 2-pyridone peptidomimetics
K. Syam Krishnan,1 Christoffer Bengtsson,1 James A. D. Good,1 Shamil
Mirkhanov,1 Erik Chorell,1 Lennart B. –Å. Johansson,1 Fredrik Almqvist.*,1,2
1
Umeå University, Department of Chemistry, 901 87 Umeå, Sweden; 2 Umeå Centre for
Microbial Research, Umeå University, 901 87 Umeå, Sweden.
* Corresponding author: Prof. Fredrik Almqvist, Department of Chemistry, Umeå University SE90187 Umeå, Sweden; Fax: (+46)907867655; Email: [email protected]
1
Table of Contents:
Figure S1 – Time-resolved fluorescence decay of 19c
S3
Scheme S1 – Original route towards BODIPY-containing thiazolino 2-pyridones
S4
Scheme S2 – Revised route towards BODIPY-containing thiazolino 2-pyridones
S4
Table S1 - Screened hydrolysis conditions for BODIPY methyl ester 17a
S5
Table S2: LiI halogenolysis of BODIPY methyl esters
S6
NMR Spectra:
Compound 10, 1H NMR and 13C NMR
S7
Compound 12, 1H NMR and 13C NMR
S8
Compound 13, 1H NMR and 13C NMR
S9
Compound 8, 1H NMR and 13C NMR
S10
Compound 14a, 1H NMR and 13C NMR
S11
Compound 14b, 1H NMR and 13C NMR
S12
Compound 14c, 1H NMR and 13C NMR
S13
Compound 15, 1H NMR and 13C NMR
S14
Compound 16, 1H NMR and 13C NMR
S15
Compound 6, 1H NMR and 13C NMR
S16
Compound 17a, 1H NMR and 13C NMR
S17
Compound 17b, 1H NMR and 13C NMR
S18
Compound 17c, 1H NMR and 13C NMR
S19
Compound 18, 1H NMR and 13C NMR
S20
Compound 19a, 1H NMR and 13C NMR
S21
Compound 19b, 1H NMR and 13C NMR
S22
Compound 19c, 1H NMR and 13C NMR
S23
Supplementary References
S24
2
FIGURE S1 - Time-resolved fluorescence decay of 19c dissolved in DMSO at 25 °C [ F (t ) , i.e.
the number of counted photons vs. time]. In the lower graph, the upper curve reveals biphasic
fluorescence decay, while the lower curve displays the instrumental response function. The upper
graph shows the weighted residual obtained by fitting the decay to a sum of exponential
functions.
3
SCHEME S1 – Original route towards BODIPY containing thiazolino 2-pyridones.1
O
O
2,4-dimethyl pyrrole
NEt3, BF3·Et2O, DCE
O
MWI at 140 °C, 3 h
O
F F
B
N
N
O
O
F F
B
N
N
O
DCC, DMAP
DCM, 8 h
S1
O
O
HO
OH
O
O
S3 (82%)
S2 (16%)
S
O
11
N
CO2Me
TFA
F
N
F B
N
S
Overall yield = 11.1%
N
DCE
MWI 120 °C
140 s
O
CO2Me
6 (85%)
SCHEME S2 – Revised route towards BODIPY-containing thiazolino 2-pyridones.
4
TABLE S1 - Screened hydrolysis conditions for BODIPY methyl ester 17a.
Notes/Reference
Time
LCMS
conversion
(isolated
yield)
rt
2h
-
1
Dioxane
rt
16 h
-
NaOH
THF/MeOH
rt
30 min
-
Decomposition.2
4
KOH
THF/MeOH
rt
30 min
-
Decomposition.3
5
K2CO3
DMF
rt
6h
-
6
TMSI
CCl4/CDCl3
rt
6h
-
4
7
TMSI, MWI
CCl4/CDCl3,
60-90
20 min
-
4
8
Me3SnOH
DCE
rt
6h
-
5
9
Me3SnOH, MWI
DCE
80-110
30 min
-
5
10
Mucor javanicus
38
6h
-
38
6h
-
rt
24 h
<16%
6
rt
24 h
-
6
rt
24 h
-
6
rt
24 h
-
40
5h
16%
40
5h
-
6
40
5h
-
Decomposition.6
40
5h
-
6
7
Entry
Hydrolysis
method
Solvent
Temp
(°C)
1
LiOH
THF/MeOH
2
LiOH
3
Candida antartica lipase
B
Et3N (20 eq.), LiBr (20
eq.)
Et3N (20 eq.), LiBr (20
eq.)
Et3N (20 eq.), LiBr (20
eq.)
Et3N (20 eq.), KBr (20
eq.)
Et3N (20 eq.), LiBr (20
eq.)
DABCO (20 eq.), LiBr
(20 eq.)
DBU (20 eq.), LiBr (20
eq.)
DMAP (20 eq.), LiBr (20
eq.)
Acetone
/phosphate buffer
THF/phosphate
buffer
MeCN/H2O
(98/2)
THF/H2O
(98/2)
MeOH/H2O
(98/2)
MeCN/H2O
(98/2)
MeCN/H2O
(98/2)
MeCN/H2O
(98/2)
MeCN/H2O
(98/2)
MeCN/H2O
(98/2)
20
LiCl (15 eq.), MWI
DMF
80
15 min
-
21
LiBr (15 eq.), MWI
DMF
80
15 min
Trace
22
LiBr (15 eq.)
DMF
rt
16 h
-
23
LiBr (15 eq.)
DMF
60
4h
-
24
LiBr (10 eq.), MWI
DMF
90
2h
16%
25
LiBr (10 eq.), MWI
DMF/H2O (90/10)
90
2h
20%
26
LiBr (50 eq.), MWI
DMF
90
70 min
75%
(65%)
11
12
13
14
15
16
17
18
19
5
Complex mixture
of products.6
TABLE S2 - LiI halogenolysis in DMF of BODIPY methyl esters.
Compound
Structure
Conditions
Conversion
Lit.
Yield
MWI,
S4
110 °C,
Lit. Conditions
(i) 0.1 M LiOH (aq),
70%a
88%
THF/MeOH (4:1) 2 h;
(ii) AcOH.1
30 min
(i) LiI, pyridine, MWI,
MWI,
S5
140 °C,
Trace
29%b
10 min
140 °C, 15 min; (ii)
BF3·Et2O, DCE, 80 °C,
15 min.1
MWI,
6
140 °C,
100%a
n/a
-
40%a
n/a
-
50%a
n/a
-
12 min
MWI,
S6
100 °C, 1 h
MWI,
S7
120 °C, 1 h
MWI,
S8
110 °C, 20
(i) LiBr, NEt3, MeCN
80%a
88%
(2 v/v% H2O), 3h (ii)
min
Notes: a = LC-MS conversion; b = removal of BF2 observed. n/a = not available.
6
AcOH.1
1
H NMR spectra of 10 (CDCl3)
13
C NMR spectra of 10 (CDCl3)
7
H NMR spectra of 12 (CDCl3)
13
C NMR spectra of 12 (CDCl3)
8
1
H NMR spectra of 13 (MeOD + CDCl3)
13
C NMR spectra of 13 (MeOD + CDCl3)
9
1
H NMR spectra of 8 (MeOD)
13
C NMR spectra of 8 (MeOD)
10
1
H NMR spectra of 14a (MeOD)
13
C NMR spectra of 14a (MeOD)
11
1
H NMR spectra of 24b (MeOD + CDCl3)
13
C NMR spectra of 14b (MeOD + CDCl3)
12
1
H NMR spectra of 14c (CDCl3)
13
C NMR spectra of 14c (CDCl3)
13
1
H NMR spectra of 15 (MeOD + CDCl3)
13
C NMR spectra of 15 (MeOD + CDCl3)
14
1
H NMR spectra of 16 (MeOD + CDCl3)
13
C NMR spectra of 16 (MeOD + CDCl3)
15
1
H NMR spectra of 6 (CDCl3)
13
C NMR spectra of 6 (CDCl3)
16
1
H NMR spectra of 17a (CDCl3)
13
C NMR spectra of 17a (CDCl3)
17
1
H NMR spectra of 17b (CDCl3)
13
C NMR spectra of 17b (CDCl3)
18
1
H NMR spectra of 17c (CDCl3)
13
C NMR spectra of 17c (CDCl3)
19
1
H NMR spectra of 18 (DMSO-d6)
13
C NMR spectra of 18 (DMSO-D6)
20
1
H NMR spectra of 19a (DMSO-D6)
13
C NMR spectra of 19a (DMSO-D6)
21
1
H NMR spectra of 19b (MeOD + CDCl3)
13
C NMR spectra of 19b (MeOD + CDCl3)
22
1
H NMR spectra of 19c (CDCl3)
13
C NMR spectra of 19c (CDCl3)
23
Supplementary References
(1)
Chorell, E.; Pinkner, J. S.; Bengtsson, C.; Edvinsson, S.; Cusumano, C. K.; Rosenbaum,
E.; Johansson, L. B. Å.; Hultgren, S. J.; Almqvist, F. Chem. Eur. J. 2012, 18, 4522.
(2)
Boldyrev, I. A.; Zhai, X.; Momsen, M. M.; Brockman, H. L.; Brown, R. E.;
Molotkovsky, J. G. J. Lipid Res. 2007, 48, 1518.
(3)
Komatsu, T.; Urano, Y.; Fujikawa, Y.; Kobayashi, T.; Kojima, H.; Terai, T.; Hanaoka,
K.; Nagano, T. Chem. Commun. 2009, 7015.
(4)
Jung, M. F.; Lyster, M. A. J. Am. Chem. Soc. 1977, 99, 968.
(5)
Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S. Angew. Chem. Int. Ed.
2005, 44, 1378.
(6)
Mattsson, S.; Dahlström, M.; Karlsson, S. Tetrahedron Lett. 2007, 48, 2497.
(7)
Wu, X.-A.; Ying, P.; Liu, J.-Y.; Shen, H.-S.; Chen, Y.; He, L. Synth. Commun. 2009, 39,
3459.
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