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Synthesis and Biological Activity of Platensimycin
Presented by
Marie-Christine Brochu
First Seminar
University of Ottawa
April 3rd 2008
2
Presentation Outline
1) Platensimycin Biological Activity
2) 10 Synthesis of Platensimycin
1- Nicolaou (racemic) 6- Kaliappan (enantioselective)
2- Nicolaou (enantioselective) 7- Mulzer (racemic)3- Snider (racemic) 8- Corey (enantioselective)4- Nicolaou (racemic) 9 - Ghosh (enantioselective)5- Yamamoto (enantioselective) 10- Nicolaou (enantispecific)
3) Brief overview of different strategies to access the cage like structure of Platensimycin
3
IntroductionO
O
MeO
HN
OH
OHHO2C
Platensimycin1
- Isolated from a strain of a Streptomyces Platensis (a soil bacterium collected in South-Africa) by a Merck research group in New Jersey
- Platensimycin represents a new class of antibiotics because it operates through a new mechanism of action
- It is a selective inhibitor of FabF, an elongation-condensing enzyme involved in the bacterial fatty acid biosynthesis
Wang et al. Nature 2006, 441, 358.
4
Platensimycin biological activity
Häbich, D., Nussbaum, F. V. ChemMedChem 2006, 1, 951.
S
O
ACPn S
O
ACPn
FabIFabKFabL
reduct ion
elongation
HO2CS
ACP
Omalonyl-ACP
CO2
FabBFabF
O
n S
O
ACP
FabG
reduct ion
OH
n S
O
ACP
FabAFabZ elimination
enoyl-ACP acyl-ACP
-ketoacyl-ACP-hydroxyacyl-ACP
5
Platensimycin biological activity
S
O
ACPn
acyl-ACP
HO2CS
ACP
Omalonyl-ACP
HS
Closed FabF
S
O
n
O
SACP
OO
+
+
O
n S
O
ACP
-ketoacyl-ACP
Open FabF
HS
Closed FabF
-- CO2
O
O
MeO
HN
OH
OHHO2CPlatensimycin
block the malonyl-ACPbinding site
Häbich, D., Nussbaum, F. V. ChemMedChem 2006, 1, 951.
6
Nicolaou’s First Racemic Total SynthesisRetrosynthetic Analysis
Nicolaou, K. C., Li, A. Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.
TBSO
O
O
H
OMOM
OMOM
NH2
CO2Me
O
O
MeO
HO+
O
HO
O
O
O
O
O
O
MeO
HN
OH
OHHO2C
O
O
O
MeO
HO
radicalcyclization
acidicetherification
cycloisomerizationO
EtO
4Nicolaou's
intermediate
2 3
3 5 6
67
8
1Platensimycin
7
Nicolaou’s First Racemic Total Synthesis
Nicolaou, K. C., Li, A. Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.
O
EtO
a) LDA,
Br
OTBS
b) LDA, Br
O
EtO
OTBSa) DIBAL-H, MePh, -78 to -20°C, 2h
then 2N aq HCl, MeOH, 2h
b) TBSCl, imidazole,DMF, 22°C, 20 min
O
TBSO89%
over 2 steps84%
over 2 steps
[CpRu(MeCN)3]PF6acetone, 22°C, 1.5h
O
TBSO
a) LiHMDS, TMSCl,THF, -78°C, 2h
O
92%, dr = 1:1
b) Pd(OAc)2MeCN, 22°C
TBSO
1N HCl aq / THF (1:1)22°C, 2h
O
O68%
over 2 steps
85%
8 9
10116
THF, -78 to 22°C, 6h
THF, -78 to 22°C, 13h
7
8
Ru-Catalyzed Enyne Cycloisomerization
RuLn
R
OTBS
R
OTBS
RuLn-2
R
OTBSH
RuLn-2
RuLn-2
R
OTBS
H
OTBS
+
+
+
+
710
12
13
14
15
Trost, B. H., Surivet, J.-P., Toste, F. D. J. Am. Chem. Soc., 2004, 126, 15592.
9
Nicolaou’s First Racemic Total Synthesis
Nicolaou, K. C., Li, A. Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.
O
O
H
SmI2, HFIP,THF/HMPA (10:1), -78°C
1 minute
O
O-
O
HO
46% yielddr = 2:1
inseparableO
HO
O
O
TFA / DCM (1.8:1), 0°C, 1.5 h
87% (based on the correctdiastereoisomer)overall yield from 6 = 27%
6 16 5
54
10
Nicolaou’s First Racemic Total Synthesis
Nicolaou, K. C., Li, A. Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.
O
O
a) KHMDS, MeI, THF / HMPA (5:1)-78 to -10°C, 2h
I
O
O
MeB
O
O
O
O
Me
BO
O
O
O
MeO
H
O
O
MeO
HO
70% over 2 steps
85% E/Z = 6:1
95%95%
b) KHMDS, THF / HMPA (5:1)-78 to -10°C, 2h
Grubbs 2nd genDCM, 40°C, 6h
Me3NO, THF,65°C, 2h
NaClO2, 2-methyl-2-butene,NaH2PO4, tBuOH / H2O (1:1)22°C, 15 min
3
4 17
18
19
11
Nicolaou’s First Racemic Total Synthesis
Nicolaou, K. C., Li, A. Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.
OH
OH
NO2NaH, MOMCl,THF, 0-22°C, 1.5 h
OMOM
OMOM
NO2
H2, Pd/C,MeOH / EtOAc (10:1)22°C, 12 h
OMOM
OMOM
NH2
OMOM
OMOM
NHBoc
OMOM
OMOM
NHBoc
CO2Me
82% 99%
99%54%83%
Boc2O,40°C, 4h
a) nBuLi (1 equiv), TMSCl,-78°C, 15 min
b) nBuLi (2.2 equiv), MeOC(O)CN,THF, -78°C, 30 min
c) 1N aq HCl, 22°C, 30 min
1,2-dichlorobenzene,205°C, mwave, 5 min
OMOM
OMOM
NH2
CO2Me
20 21 22
23242
12
Nicolaou’s First Racemic Total Synthesis
Nicolaou, K. C., Li, A. Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.
OMOM
OMOM
NH2
CO2Me
O
O
MeO
HO +
HATU, Et3N,DMF, 22°C, 26 h
O
O
MeO
HN
MOMO
OMOMMeO2C
85%
O
O
MeO
HN
OH
OHHO2C
i) LiOH, THF / H2O (4:1)45°C, 2h
ii) 2N HCl aq, THF / H2O (3:1)45°C, 10 h
90%
1 equiv 2 equiv3 2
25
1
13
Nicolaou’s First Racemic Total SynthesisAn Overview
O
O4
- First total Synthesis of Platensimycin ever reported (paper published on September 29th 2006, 4.5 months after Merck published in Nature)
- They access the core of Platensimycin via radical cyclization followed by etherification in acidic condition
10 steps11% overall yield
Nicolaou, K. C., Li, A. Edmonds, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.
O
HO
46% yielddr = 2:1
inseparable
O
O
TFA
87% (based on the correctdiastereoisomer)overall yield from 6 = 27%
O
O
SmI2, HFIP,THF/HMPA, -78°C
1 minute
6 5 4
14
Nicolaou’s First Enantioselective Formal SynthesisRetrosynthesis Analysis
Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942.
O
HO
O
O
etherif ication
O
O
congugateradical addition
O
O
O
O
H
get this aldehyde asa sole enantiomer
65 4
6
6
2 strategies:1) asymmetric cycloisomerization2) cyclodearomatization
15
Nicolaou’s First Enantioselective Formal Synthesis1st Approach: Asymmetric Cycloisomerization
Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942.
O O
OHCO2Me
[{Rh(cod)Cl}2],(S)-binap, AgSbF6,DCE, 22°C, 1.5 h
O
CO2MeO
H
O
O
H
EtO
8 steps 5 steps
O
HO
39% yieldsingle diastereoisomer
O
O
TFA
87%overall yield from 6 = 34%
O
O
SmI2, HFIP,THF/HMPA, -78°C
1 minute
46%
91% (ee > 95%)
40%
826
27 6
6 54
16
Nicolaou’s First Enantioselective Formal Synthesis2nd Approach: Cyclodearomatization
Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942.
O
O
N
O
Br
TBSO
Me
O
O
O
OTBS
O
O
OTBS
TMS
O
H
O
mechanismnext slide
O
HO
46% yielddr = 2:1
inseparable
O
O
TFA
87% (based on the correctdiastereoisomer)overall yield from 6 = 27%
O
O
SmI2, HFIP,THF/HMPA, -78°C
1 minute
6 5 4
b) MeLi
2 steps
87% 3 steps61%
28
30 31 6Ph
Me
HO
a) LDA, LiCl
2 steps, 67%
17
Cyclodearomatization mechanism
O
O
OTBS
TMS
NaOH in MeOH,0-22°C, 1h
O
O
OH
TMS
IAcO
OAc
O
O
O
TMS
I
OAc
+
- AcOH
O
- AcO-
- PhI
TMS
+O
O
O
O
O
O
O
H
1N HCl aq./THF (1:1),40°C, 3h
31 32 33
34356
18
Nicolaou’s First Enantioselective Formal Synthesis
12 steps6% overall yield
Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942.
O
OHCO2Me
O
O
H
asymmetric cycloisomerisation
O
O
OTBS
TMS
O
H
O
cyclodearomatization
O
O
O
O
31
26
6 6
4 4
10 steps10 % overall yield
19
Snider’s and Nicolaou’s Racemic Formal Synthesis
OBr
congugateradical addition
O
selective reductionetherification
O
O
HO
O
O
etherification
O
O
congugateradical addition
R R R
steps
36 37 38
6 5 4
Zou, Y., Chen, C. H., Taylor, C. D., Foxman, B. M., Snider, B. B. Org. Lett. 2007, 9 (9), 1825.
20
Snider’s Racemic Formal Synthesis
Zou, Y., Chen, C. H., Taylor, C. D., Foxman, B. M., Snider, B. B. Org. Lett. 2007, 9 (9), 1825.
OMe
O
O
O
H
Br
1 step
86%, dr = 1.5:1
O
O
HAIBN, Bu3SnH,benzene, reflux, 3h
84%
OO
a) L-Selectride (4 equiv)THF, -78 to 25°C, 2h
b) TFA/DCM (1.5:1)0°C, 2h, then K2CO3,MeOH, 25°C, 30 min
OHOO
O
3 steps
73%
74%
39
4041
4142
4
7 steps23% overall yield
21
Snider’s Racemic Formal Synthesis
Zou, Y., Chen, C. H., Taylor, C. D., Foxman, B. M., Snider, B. B. Org. Lett. 2007, 9 (9), 1825.
OMe
O
OMe
OK
K, NH3/Et2O,t -BuOH anh LiBr
OMe
OLi
Br
Br
OMe
OBr
conc. HClTHF
O
OBr
39
40
43 44
45
22
Nicolaou’s Racemic Formal Synthesis
Nicolaou, K. C., Tang, Y., Wang, Chem. Commun. 2007, 1922.
O
EtO
O
O
Br
N
N+N C6F5
BF4-
Et3N
O
OH
Br
7 steps 3 steps
OH
Br
SS
Bu3SnH, AIBN,benzene, reflux
OH
SS
O
SSa) L-selectride,THF, -20°C, 1h
SS
O
1 step
O
O
Stettermechanismnext slide
42%
64%
66%
86%41%85%
b) TFA/DCM (2:1),0°C, 1h
8
46 4748
4949504
23
Stetter’s reaction mechanism
O
N
N+N C6F5
BF4- Et3N+
N
NN C6F5
+ Et3N+H
O
Br
N
NN C6F5
O
O-
Br
N+N
N
F5C6
PT
O
OH
Br
N+N
N
F5C6
-
O-
Br
OH
N+ N
N
F5C6
PT
OH
Br
O-
N+ N
N
F5C6
O
Br
ON
NN C6F5
+
46
47
51 52
5354
24
Snider’s and Nicolaou’s Racemic Formal Synthesis
Nicolaou15 steps8 % overall yield
Snider7 steps
23 % overall yield
OBr
O
SS SS
OBr
OO OH
O
O
OMe
O
O
O
H
Br
1 step
O
EtO
O
O
Br
O
OH
Br
Stetter rxn
39
40
40 42
48
46 4748
49
25
Yamamoto’s Enantioselective Formal SynthesisRetrosynthetic Analysis
Li, P., Payette J. N., Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9534.
O
O
diastereoselectiveRobinson annulation
CHO
O
O
OCHO
O
OO
Baeyer-Villigeroxydation/rearrangement
O
enantioselectiveDiels-Alder
CO2Me
+
455
55
5657
58
59
26
Yamamoto’s Enantioselective Formal Synthesis
Li, P., Payette J. N., Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9534.
CO2Me+
DCM, -78°C, 14hCO2Me
92% yield99% ee
endo/exo > 1
i) LDA, THF, -78°Cii) PhNO, -78°C, 2h
iii) LiOH, dioxane/H2O,30°C, 20h O
75%
OO
H2O2, NaOHEt2O/H2O
0°C to rt, 45 min
OO
i) CuBr.Me2S, THF/DMS,-40°C to rt 2h
ii) HNTf2 (4.5 mol%)DCE, 70°C, 45 min
MgBr
68%81% (dr = 10:1)
N+B
O
PhPh
H
Tf
TfF
F
F
F
F
-
A
A (2 mol%)58
59 60 57
5661
OHONa
O
4N H2SO4
27
Yamamoto’s Enantioselective Diels-Alder Reaction
N+ OB
H
OH
ORR
vs N+ OB
H
OH
OR
R
[1,5] sigmatropicrearrangement
TS disfavoredSteric interaction between
R and phenyl in red
TS favored
Payette J. N., Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9536.
28
Yamamoto’s Enantioselective Formal Synthesis
Li, P., Payette J. N., Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9534.
OO
i) DIBAL-H, toluene,-78°C, 30 min
ii) Et2AlCN, BF3.OEt2,20 min
OCN
OCN +
OCN
OCN
OCN +
LiHMDS, THF-78°C to rt,
30 min
86% (dr = 2:3)
85-95% (dr = 1:1)62a 62b
62b 62a 62b
61
29
Yamamoto’s Enantioselective Formal Synthesis
10 steps5 % overall yield
Li, P., P. J. N., Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9534.
OCN
a) DIBAL-H, nBuLi-78 to 0°C, 25 min
b) NaH, THF,0°C, 20 min
EtOP
OEtO
O
O
O
O
O
ONaIO4 (2.02 equiv)RuCl3 (3.5 mol%)
CH3CN/H2O (6:1)rt, 3h
65% (2 steps)59%
27% recovered SM
O
O
O
CHO
O
O
O
O
+O
O
NH
CO2H
(1 equiv)
DMF, rt, 5 days
i)
ii) 2N NaOH aq0°C to rt, 40 min
95% yield (dr = 5:1)
62a
63
55
5555
4 64
30
Kaliappan’s Enantioselective Formal SynthesisModel Study Preparation
Kaliappan, K. P., Ravikumar, V. Org. Lett. 2007, 9, 2417.
O
O
Wieland-Miescherketone
4 steps
O
SPhO
Claisen
O3 steps
O
TBSO TBSO
1) Bu3SnH, AIBN,tBuOH, reflux, 12h
2) PTSA, DCM,rt, 6h
O
OO
1) L-selectride, THF,-78°C to rt, 2h
2) TFA, DCM0°C, 2h
59%62%
49%
56%30%
69 7071
72737374
12 steps3% overall yield
31
Mulzer’s Racemic Formal SynthesisRetrosynthetic Analysis
Mulzer, J., Tiefenbacher, K. Angew. Chem. Int. Ed. 2007, 46, 8074.
* References cited in the previous paper
OMe
O
OMe
CO2H
a) SOCl2, DMF, toluene, rt, 3hb) TMSCHN2, THF
SiO2, Hexanes/EtOAc (10:1),rt, 12h
OO
O
O
O
Br
HOH
O
O
compound knownin the litterature*
O
O59% (over 3 steps)
c) TFA, -20°C, 1h
78mechanism next slide
475 76
77
7779
4 steps
87%
32
Mechanism OMe
O
O
SOCl2, DMF,toluene, rt, 3h
OMe
OClOHO
TMS N+
N
- OMe
OTMS
N+
NCl-
SiO2
OMe
O
N+
N
-
TFA
OMe
O
N+
O+
O
Me
N
- N2
O
O
+ H2O
- MeOH- H+
79
7777
80 81 82
83
84
33
Mulzer’s Racemic Formal Synthesis
Mulzer, J., Tiefenbacher, K. Angew. Chem. Int. Ed. 2007, 46, 8074.
* References cited in the previous paper
O
O
O
O
O HO
O
O
MeMgITHF, -78°C, 4h
NBS, (BzO)2,CCl4, reflux, 1.5 h
O
HO
Br
75%
NaOMe, THF,0°C, 30 min
O
OH
80%
78% (brsm, dr: 1.3:1)
[Ir(cod)Py(PCy3)]PF6,H2 (1 bar), DCM, o/n
HIO3.DMSO, DMSOcyclohexene, 50°C, 8h
60%
77 85
76
75
864
71% (brsm)
34
Corey’s Enantioselective Formal SynthesisRetrosynthetic Analysis
O
O
OTIPSO
O OBr
OH
MEMO
OH
OMEMOMe
O
O O
OMe
O
O O
enantioselectiveconjugate addition
OH
OMe
4 7587 88
88899091
Lalic, G., Corey, E. J. Org. Lett. 2007, 9 (23), 4921.
35
Corey’s Enantioselective Formal Synthesis
Lalic, G., Corey, E. J. Org. Lett. 2007, 9 (23), 4921.
OH
OMe PhI(O2CCF3)2
HOOH
MeCN, 0°C, 2h
O
OMe
O O
BF3KMe
(S)-BINAP[Rh(cod)2]BF4
O
OMe
O OMe
PhMe, H2O,, rt
80% 96% (94% ee)
OMEM
OH
Me
6 steps78%
a) TIPSCl, imidazole,DCM, rt, 12 h
b) Br2, DCM, -78°Ca) TBAF, THF,
, 130°C
mechanismnext slide
OTIPS
O
O
O
Br
O
O
2 steps
9190 89
8884%
754
essential for reactivity
Et3N
88%58%
12 steps26 % overall yieldenantioenriched
36
Corey’s Enantioselective Formal Synthesis
O
O
O
OBr
OTIPS
OO
Br Br
OTIPS
Br+OO
OTIPS
O+
BrO
TIPS
F-
92
75
93 94
95
OOO
37
Ghosh’s Enantiospecific Formal SynthesisRetrosynthetic Analysis
O
H
Me
H
EtO2C
OMe
O
CO2Me
OMe
O
OMeEtO2C
H
Diels-Alder
O
Me
Me
(+)-carvone
96a 97a 97
9899
OO
H
O
Ghosh, A., Xi, K. Org. Lett. 2007, 9, 4013.
38
Ghosh’s Enantiospecific Formal Synthesis
O i) Hg(OAc)2, THF/H2Oii) NaBH4, MeOH
O
HO
mCPBA, DCM
OO
H
O
HO HO
O
O
HO
O
OO
O
O
O
O
H
Me
H
EtO2C
OMe
O
CO2Me
OMe
OO
H
O
50% (2 steps)
17 steps
19%
99
98
98 97 97
100
100 101 103 98
Ghosh, A. K., Xi, K. Org. Lett. 2007, 9, 4013.
39
Oxymercuration/Reductive-Alkylation Mechanism
Me
O
Me
O
Hg(OAc)2
OH
NaBH4Me
O OH
rt
Me
Me
O OHMe OH
Me
O
AcOHg HHg99
109 110
111100
40
Ghosh’s Enantiospecific Formal Synthesis
O
H
Me
H
EtO2C
OMe
O
OMeEtO2C
H
O
OMeEtO2C
H
O
H
Me
H
EtO2C
MeO
+
O
CO2Me
OMe
Mixture (1:1)
PhCl, BHT,Seal Tube,200°C
O
CO2MeMeO
39% yield
SM, 92b,recovered in 38% yield
97a
97a96a
97b 97b96b
O
OMeEtO2C
H
96a
20 steps4% overall yield
Ghosh, A. K., Xi, K. Org. Lett. 2007, 9, 4013.
41
Nicolaou’s Enantiospecific Formal Synthesis
O
O
O
OO
O
Stetter rxn orradical cyclisation
O
(R)-(-)-carvone
S
N+Et
Me
HO
Br-
Et3N, EtOH, 80°C, 18h
65% (1:5)inseparable
O
HSmI2, MeOH23°C, THF, 2 min
57%only one stereoisomer
O
H
OSm
O
HH
HO
O
O
O
OH
O
H+
OH
H
O
7 steps
17%
99 104 104 86a
10486a 86b
104 105 106 106
O
ONicolaou, K. C., Li, A., Edmons, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.
42
Nicolaou’s Enantiospecific Formal Synthesis
O
HO
H
DIAD, ArCO2HPPh3, benzene,
rt, 2h
O
O
H
Ar
Ar = p-NO2C6H4
KOH,MeOH
O
H
O
HO
H
O
HO
H+
67%
91% (1:1.1)seperable
O
HO
KOH,MeOH
O
HO
H
108b
O
H
O
46%
4 steps
O
O
106 107 108a 108b 108a
4 4
14 steps1.3 % overall yield
Nicolaou, K. C., Li, A., Edmons, D. J. Angew. Chem. Int. Ed. 2006, 45, 7086.
43
Conclusion
O
O
O
O
diastereoselective Robinson annulation
CHO
O
O
OTIPS
OBr
OH
MEMO
O
O
O
CO2Me
OMe
O
OMeEtO2C
H
Diels-Alder
Corey's approach
radical cyclization
etherification
Nicolaou, Snider, Kaliappan
Yamamoto
radical cyclization and etherification
Ghosh
OMe
CHN2O
O
HO
Br
Mulzer's approach
44
AnknowledgmentGroup members:
Pr. Louis BarriaultSteve ArnsFrancis BarabéÉric BeaulieuAnik ChartrandAnna Chkrebtii Christiane GriséGeneviève L. BétournayPatrick LévesqueDaniel NewburyJason PoulinMaxime RiouCatherine Séguin
45
Yamamoto’s Enantioselective Formal Synthesis
Li, P., P. J. N., Yamamoto, H. J. Am. Chem. Soc., 2007, 129, 9534
O
OHC
H
H
Me
O
Me HO
OHC
Me H
H
HO
Me
Si faceattack
favored
Re faceattack
unfavored
O H
H
Me
O
Me H
NHO2C
O H
H
Me
O
Me H
NHO2C
L-prolinematcheddr = 5:1
D-prolinemismatched
dr = 3:1
65 66
67 68
46
Antibacterial Agents Introduction
5 main mechanisms of action:
1) Inhibition of cell metabolism
2) Inhibition of bacterial cell wall synthesis
3) Interactions with the plasma membrane
4) Disruption of protein synthesis
5) Inhibition of nucleic acid transcription and replication
Patrick, G. L. An Introduction to Medicinal Chemistry, 3rd ed, Oxford University Press, 2005, pp 379-439
47
Inhibition of cell metabolism
N
H2N NH2
N
SNH2
O O
Prontosil
H2N
SNH2
O O
metabolism
bacteria in thesmall intestine
NH
SNH
O O
R1
R2
sulfonamides analoguesR1 = acyl groupR2 can be varied to improvepharmacokinetics of the drug
S
H2N
NH
NN
OMe
OMe
O O
Sulfadoxine
Fanisdar, sulfadoxine + pyrimethaminetreatment of malaria
H2N
SN
-O O
N
NAg+
Silver sulfadiazine
In a cream used to preventinfection of burns
S
NH
NH
S
NO O
Succinyl sulfathiazoleintestinal infections
Application in medicine:
- treatment of urinary tract infections- eye lotions- treatment of infections of mucous membranes- treatment of gut infections
O
HO2C
Patrick, G. L. An Introduction to Medicinal Chemistry, 3rd ed, Oxford University Press, 2005, pp 379-439
48
Inhibition of cell metabolism
HN
NH2N
O
NH
N
O P
O-
O
O P
O-
O
O-PABA
DihydropteroateSynthetase
HN
NH2N
O
NH
NHN
CO2H
CO2HH2N
H CO2H
HN
NH2N
O
NH
NHN
HN
O
CO2H
H CO2HDihydrofolate
DihydrofolateReductase
HN
NH2N
O
NH
HN
HN
HN
O
CO2H
H CO2HTetrahydrofolate
(coenzyme F)
Inhibition bysulfonamides
Inhibition bytrimethoprim
NADPH
Important enzyme cofactorfor the synthesis of pyrimidine
nucleic acid bases
N
N
MeO OMe
OMe
NH2
H2N
Trimethoprim
SH2NO
O
HNN O
Me
Sulfamethoxazole
N
NS
NH2
H2N
NHR
OO
Sulfonesantileprosy
Patrick, G. L. An Introduction to Medicinal Chemistry, 3rd ed, Oxford University Press, 2005, pp 379-439
49
Inhibition of cell metabolismResistance
- Sulfonamides are reversible inhibitor of dihydropteroate synthetase, so
resistance by synthesizing more PABA
- Resistance by mutations, modifications of the dihydropteroate
synthetase which result in less affinity for sulfonamides or modifications of
the cell membrane which result in less permeability to the sulfonamides
HN
NH2N
O
NH
N
O P
O-
O
O P
O-
O
O-PABA
DihydropteroateSynthetase
HN
NH2N
O
NH
NHN
CO2H
Inhibition bysulfonamides
Patrick, G. L. An Introduction to Medicinal Chemistry, 3rd ed, Oxford University Press, 2005, pp 379-439
50
Barton Radical Decarboxylation Mechanism
O
O
O N
S
SnBu3
O
O
O N
SBu3Sn
O
O
O
N
SBu3Sn
-
- CO2
O
O
O
H
Bu3Sn HOO
OO
O
O
O
- Bu3Sn
1,3 H-shift
O
O
OH SnBu3
- Bu3Sn
O
O
O 30
31 32
33 34
33 36
51
Nicolaou First Enantioselective Total Synthesis1st Approach: Asymmetric Cycloisomerization
Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942
O
OTBS
prepared as describedpreviously
OTMS
OTBS
a) TMSOTf, Et3N,DCM, 0°C, 10 min
b) n-BuLi, MeOC(O)CN,-78 to -40°C, 1h
O
OH
CO2MeCO2Me
[{Rh(cod)Cl}2],(S)-binap, AgSbF6,DCE, 22°C, 1.5 h
O
CO2MeO
H
(CH2OH)2,CH(OMe)3, PPTS,benzene, 60°C, 3h
O
CO2MeO
O
a) 0.6 N LiOH aq, THF,0°C, 1h
b) EDC.HCl, DCM, 22°C, 2h
N+
SH-O
O
O
O
O
O
H
1N HCl aq / THF (1:1)40°C, 20 min
61% over 4 steps 91% (ee > 95%)
90%
c) Bu3SnH, h, benzene,22°C, 30 min
49% over 3 steps90%
7
2627 28
29306
a) IBX, NPO, DMSO,22°C, 1h
b) 1N HCl aq / THF (1:2)0°C, 1h
52
Nicolaou First Enantioselective Total SynthesisAsymmetric Cycloisomerization Approach
O
HO
39% yieldsingle diastereoisomer
O
O
TFA
87%overall yield from X = 34%
O
O
SmI2, HFIP,THF/HMPA, -78°C
1 minute
34 35 4
12 steps5.6% overall yieldenantioenriched
Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942
4
O
O
53
Nicolaou First Enantioselective Total SynthesisCyclodearomatization Approach
Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942
O
OOH
O
NH
Ph
Me
OH
Me
+ NPh
Me
OHMe
O
O
O
LDA, LiCl,-78 to 0°C 1.5h
Br
TBSO
NPh
Me
OHMe
O
O
O
OTBS
Me
O
O
O
OTBS
N
NTf2
ClKHMDS, THF,-78 to 0°C
OTf
O
O
OTBS
TMSCH2MgCl, LiCl,Pd(PPh3)4, THF,22°C, 30 min
O
O
OTBS
TMS
a) NaOH in MeOH,0-22°C, 1h (100%)
b) PhI(OAc)2, TFE10°C, 20 min (68%)
O
H
O c) 1N HCl aq./THF (1:1),40°C, 3h, 90%
quant.
87% (de=85%)diastereomerically pureafter recrystallization
91%92%94%
40
41
PivCl, Et3N,CH3CN, 0°C, 1h
42
43
44
MeLi, THF,-78 to -25°C,40 min
2945286
54
Nicolaou First Enantioselective Total SynthesisCyclodearomatization Approach
O
HO
46% yielddr = 2:1
inseparable
O
O
TFA
87% (based on the correctdiastereoisomer)overall yield from X = 27%
O
O
SmI2, HFIP,THF/HMPA, -78°C
1 minute
6 5 4
9 steps10.5 % overall yieldenantioenriched
Nicolaou, K. C., Edmonds, D. J., Li, A. Tria, G. S. Angew. Chem. Int. Ed. 2007, 46, 3942
O
O
4
55
Snider Racemic Formal Synthesis
Zou, Y., Chen, C. H., Taylor, C. D., Foxman, B. M., Snider, B. B. Org. Lett., 2007, 9 (9), 1825
OMe
O
i) K, NH3/Et2O, t-BuOH, -78°C, 15 minii) LiBr, 30 miniii) 2,3-dibromopropene, 2hiiii) conc HCl/THF, 30 min
O
O
H
Br
+
O
O
H
Br
86% (10:7)
O
O
H
Br
1:2 HClconc/THF0-25°C, 30 min
O
O
H
Br
+
O
O
H
Br
4:3
5246a 46b
46b46b 46a
56
Snider Racemic Formal Synthesis
Zou, Y., Chen, C. H., Taylor, C. D., Foxman, B. M., Snider, B. B. Org. Lett., 2007, 9 (9), 1825
O
O
H
Br
OMe
O
last slide
70%
AIBN, Bu3SnH,benzene, reflux, 3h
O
O
H
84%O
O
H
Br
AIBN, Bu3SnH,benzene, reflux, 3h
O
O
H
81%
O
O
HO
O
H10% KOH in MeOH25°C, 5h
4:1
52 46a 47a
46b47b
47b 47a
57
Snider Racemic Formal Synthesis
Zou, Y., Chen, C. H., Taylor, C. D., Foxman, B. M., Snider, B. B. Org. Lett., 2007, 9 (9), 1825
O
O
H O
O
L-Selectride (4 equiv)THF, -78 to 25°C, 2h
OH
HO
OH
OH
+
90% (1:1)
OH
HO
OH
OH
+
i) TFA/DCM (1.5:1)0°C, 2h
ii) K2CO3, MeOH,25°C, 30 min
O
HO
O
OH
+
39% 42%
i) Tf2O, Pyr, DCM-78°C to -5°C,15 min
ii) iPrOH,-5 to 25°C, 15 min
E2
H
O O
OTf
H
1M HCl
E1
E2 = 90%E1 = 84%
47a
47a53a 53b
53a 53b48a 48b
55
54
58
Snider Racemic Formal Synthesis
O
O 4
7 steps (+ 2 recuperation steps)32 % overall yield
racemic
Zou, Y., Chen, C. H., Taylor, C. D., Foxman, B. M., Snider, B. B. Org. Lett., 2007, 9 (9), 1825
OSeO2 (3 equiv)dioxane, wave110°C, 10 min
O
HO
+
O
O
O
HO
MnO2, DCM,25°C, 1day
O
O94%83% 7%
O CrO3.3,5-dimethylpyrazole,DCM, -25°C, 20h
O
O
+
O
O
75% (4:1)
OSeO2 (8 equiv)dioxane, wave140°C, 30 min
O
O
O
HO
+
59% 27%
55 56 4 56 4
55 4 57
55 58 56
59
Nicolaou Racemic Formal Synthesis
Nicolaou, K. C., Tang, Y., Wang, J. Chem. Commun., 2007, 1922
O
EtO
IOPMB
a) LDA
b) LDA
BrBr
O
EtO
Br
OPMB
i) DIBAL-Hii) HCl
O
PMBO
Br
a) LDA, TMSClb) IBX, NMO
O
PMBO
Br
a) DDQb) DMP
O
O
Br
N
N+N C6F5
BF4-
Et3N
O
OH
Br
62% (2 steps) 92%
77% (2 steps)90% (2 steps)64%
57 58
59
606147a
60
Nicolaou Racemic Formal Synthesis
O
O4
15 steps5 % overall yieldracemic
Nicolaou, K. C., Tang, Y., Wang, J. Chem. Commun., 2007, 1922
O
OH
Br
HSSH
BF3.Et2O OH
Br
SSa) TMSOTf, Et3Nb) IBX, NMO O
H
Br
SS
AIBN,Bu3SnH O
H
SS
O
SSL-selectride
SSSS+
Dess-Martin
HO
HOTFA, DCM
SS
O
Dess-Martin
O
O
80% 82% (2 steps) 86%
91% (1:1)90%85%
47a 62 49 50
5063a 63b
514
61
Mulzer Racemic Formal SynthesisRetrosynthetic Analysis
Mulzer, J., Tiefenbacher, K. Angew. Chem. Int. Ed., 2007, 46, 8074
* References cited in the previous paper
OMe
O
a) NaBH4, EtOHb) DMF, PCl5
OMe
CO2H
54% (over 3 steps)
H2, Pd/C,EtOH
OMe
CO2H
a) SOCl2, DMF, toluene, rt, 3hb) TMSCHN2, THF
SiO2, Hexanes/EtOAc (10:1),rt, 12h
99%
OO
O
O
O
Br
HOH
O
O
compound knownin the litterature*
O
O
59% (over 3 steps)
c) AgO c) TFA, -20°C, 1h
4 76 77 78
79
80 8178
62
Mulzer Racemic Formal Synthesis
O
O
Mulzer, J., Tiefenbacher, K. Angew. Chem. Int. Ed., 2007, 46, 8074
O
O
O
O
O HO
O
O
MeMgITHF, -78°C, 4h
NBS, (BzO)2,CCl4, reflux, 1.5 h
O
HO
Br
75%
NaOMe, THF,0°C, 30 min
O
OH
80%90% (dr: 1:2)
Pd/C (5%), KOH, EtOHH2 (1 barr), 3h
HClO3.DMSO, DMSOcyclohexene, 50°C, 8h
60%
7882
77
76
8376
12 steps7 % overall yieldenantioenriched
63
Corey Enantioselective Synthesis of the Core Retrosynthetic Analysis
O
O
OTIPSO
O OBr
OH
MEMO
OH
OMEMOMe
O
O O
OMe
O
O O
enantioselectiveconjugate addition
OH
OMe
4 7684 85
85868788
Lalic, G., Corey, E. J. Org. Lett. 2007, 9 (23), 4921
64
Corey Enantioselective Synthesis of the Core
OH
OMe PhI(O2CCF3)2
HOOH
MeCN, 0°C, 2h
O
OMe
O O
BF3KMe
(S)-BINAP[Rh(cod)2]BF4
O
OMe
O OMe
PhMe, H2O,Et3N
80% 96% (94% ee)
a) NaBH4, MeOHb) MEMCl, DIPEA, DCM
OMEM
OMe
O OMe
a) TsOH, Me2O, 0°Cb) DIBAL-H, DCM, 0°Cc) Et3SiH, (CF3CO)2O,
DCM, -20°C
OMEM
OMe
Me79% over5 steps
OMEM
OH
Me
PhSH,Cs2CO3DMF, 170°C
99%
88 87 86
899085
Lalic, G., Corey, E. J. Org. Lett. 2007, 9 (23), 4921
65
Corey Enantioselective Synthesis of the Core
OMEM
OH
Me
a) TIPSCl, imidazole,DCM, rt, 12 h
b) Br2, DCM, -78°C OMe
Br
OTIPS
a) TBAF, THF,, 130°C O
O
Me
84% 88%
[Rh(cod)2]BF4(R,R)-DIOP,H2, 600 psi, DCM,-78°C
OMe
72%O
a) TMSOTf, Me3N, DCMb) IBX, MPO, DMSOOMe
O
80%
85 84 76
904
O
O4
12 steps26 % overall yieldenantioenriched
Lalic, G., Corey, E. J. Org. Lett. 2007, 9 (23), 4921
66
Ghosh Enantiospecific Formal SynthesisRetrosynthetic Analysis
O
H
Me
H
EtO2C
OMe
O
CO2Me
OMe
O
OMeEtO2C
H
Diels-Alder
O
H
Me
OH
TBDPSO
O
Me
Me
(+)-carvone
91a 92 92
9495
67
Ghosh Enantiospecific Formal Synthesis
O i) Hg(OAc)2, THF/H2Oii) NaBH4, MeOH
O
HO
mCPBA, DCM
OO
H
OO
O
HO HO
O
O
HO
HOHO
O
HO
O
OO
O
O
O
O
O
O95
96 97
96 9899
100 101 97
68
Ghosh Enantiospecific Formal Synthesis
O
H
Me
O
O
Me
a) (CF3CO)2O, UHP,DCM, 0°C, 5h
b)K2CO3, MeOH O
H
Me
OHO
80% yieldover 2 steps
a) TBSCl, imidazole
O
H
Me
OTBSb) Cp2TiMe2,
toluene
O
H
Me
OTBS9-BBN, THF
O
H
Me
OTBSH
OHO
H
Me
OTBSH
OH
+
81% yield over 3 stepsdr = 2:1
O
H
Me
OTBSH
OH
a) TBDPSCl,imidazole
O
H
Me
OHH
TBDPSOb) DDQ cat.
THF/H2O (9:1)
91% yieldover 2 steps
Swern Ox.
O
H
Me
OH
TBDPSO
96%
101 10210390%
103 104a 104b
104a 105 94
69
Petasis Olefination Mechanism
TiMe
Me
-elimination
Ti CH2- CH4Ti+ CH2
-
Ti+ CH2- +
O
R2R1
O
Ti CH2
R1
R2Ti O
CH2
R2R1+Cp
Cp
70
Ghosh Enantiospecific Formal Synthesis
O
H
Me
OH
TBDPSO
PO
MeO
MeO
O
O
Ph
n-BuLi, -78°C -20°C
O
H
Me
H
TBDPSO
RO
O
O
H
Me
H
TBDPSO RO
O+
93% yieldE/Z = 3.2:1
can be separated by f lash chromatography
O
H
Me
H
TBDPSO
RO
O DIBALDCM, -78°C
O
H
Me
H
TBDPSO
HO
86%95% of the chiral auxiliary
recovered
a) DHP, PPTS
b) TBAF, THF O
H
Me
H
HO
THPO
99% over 2 steps
94
106
107a 107b
107a108 109
71
Ghosh Enantiospecific Formal Synthesis
LiHMDS
PO
EtO
EtO
O
OEt
c) CSA, EtOHO
H
Me
H
HO
EtO2C
O
H
Me
H
EtO2C
65% over 3 steps
E/Z = 5:1a) Dess-Martin
OMe
b) Ph3P=CHOMeTHF, -78°C
77% over 2 stepsE/Z = 1:1
can't be separated
O
H
Me
H
HO
THPO
a) Swern Ox.b)
109 110 92
72
Ghosh Enantiospecific Formal Synthesis
O
H
Me
H
EtO2C
OMe
O
OMeEtO2C
H
O
OMeEtO2C
H
O
H
Me
H
EtO2C
MeO
+
O
CO2Me
OMe
Mixture (1:1)
PhCl, BHT,Seal Tube,200°C
O
CO2MeMeO
39% yield
SM, 92b,recovered in 38% yield
92a
92a91a
92b 92b91b
73
Nicolaou Enantiospecific Formal Synthesis Retrosynthetic Analysis
OO
O O
O
O
Me
O
O
O
O
O
selective reductionetherification
Stetter rxn orradical cyclisation
radical cyclisation
O
(R)-(-)-carvone
4 111 112
95114 112
74
Nicolaou Enantiospecific Formal Synthesis
O
a) CeCl3, THF, 0°C-rt, 4h
BrMg O
O
b) PCC, DCM, SiO2, 2hO
OO
90%(R)-(-)-carvone
i) Hg(OAc)2,THF/H2Ort, 0.5h
OH
O
O
O
HO
O
O
O
+
61% (1:1)20% SM recovered
HO
Me
O
O
O
Me
O
O
O
HO
(1:6)
ii) NaBH4,20°C, 45 min
114 116a 116b
75
Oxymercuration/Reductive-Alkylation Mechanism
Me
O
O
O
Me
O
O
O
Hg(OAc)2
OH
NaBH4Me
O
O
O
OH
rt
Me
Me
O
O
O
OHMe OH
Me
O
O
O
AcOHg HHg
114 117 118
119116
76
Nicolaou Enantiospecific Formal Synthesis
Me OH
O
O
O
HO Me
O
O
O
+
Martin's sulfurane
O
O
O1) i) LiI, TMSCl, HMDS,
DCM, -35°C-rt, 3hii) PhSeCl
DCM, -78°C, 0.5h
O
O
O
2) H2O2 aq. 30%,Py,DCM, 0°C, 1.5 h
36% yield from
SO
O
F3CCF3
CF3
F3C
Martin's sulfurane
DCM, rt, 12h
O
O
O
O
O
HAcOH/H2O (5:1),80°C, waves,
65 min
85%
116a 116b114 117
113117
77
Martin’s Sulfurane Dehydration Mechanism
PhS
O
PhO
F3CPh
CF3
F3C CF3Ph
R
OH
PhS
O
PhO
R
F3C CF3Ph
HHH
H
HH
++
OH
F3C CF3Ph
RH
H
+ 2 + SPhPh
O
OH
F3C CF3Ph
Martin, J. C., Arhart, R. J. J. Amer. Chem. Soc. 1971, 93, 4327
78
Conversion of Ketones to Enones by Selenoxyde Syn Elimination
O
O
O
LiI, TMSCl, HMDS,DCM, -35°C-rt, 3h
TMSO
O
O
formation of the mostsubstituted silyl enol ether
electrophilic quenchwith PhSeCl
PhSeCl, DCM,-78°C, 0.5h
O
O
OPhSe
H2O2 aq. 30%,Py,DCM, 0°C, 1.5 h
selenium oxydation
O
O
OPhSe
O
H
elimination
O
O
O
114 118 119
120117
79
Nicolaou Enantiospecific Formal Synthesis
O
O
H
O
O
H
O
HO
H
+
S
N+
EtMe
HO
Br-
O
O
H
Et3N, EtOH, 80°C, 18h
65% (1:5)inseparable
O
O
HSmI2, MeOH23°C, THF, 2 min
57%only one stereoisomer
O
H
OSm
O
HH
HO
stereoselectivity explanation
113 111a 111b
113 121a
122 121a
80
Nicolaou Enantiospecific Formal Synthesis
O
O
H
KOH, MeOH
O
O
H
O
O
H+x decomposition ofstarting material
O
HO
H
KOH, MeOH
O
HO
H
O
HO
H+x resistant to epimerization
111b 111a 111b
121a 121b 121a
81
Nicolaou Enantiospecific Formal Synthesis
O
HO
H
DIAD, ArCO2HPPh3, benzene,
rt, 2h
O
O
H
Ar
O
Ar = p-NO2C6H4
KOH,MeOH
O
HO
H
KOH,MeOH
O
HO
H
O
HO
H+
67%91% (1:1.1)seperable
O
HO
H
i) L-selectride, THF,-78°C-rt, 2h
ii) 1N HCl aq.0°C-rt, 2h
HO
H
O
PCC, DCM,rt, 1.5h
O
H
O
80% 95%
121a 122 123a 123b 123a
123b124 111
a) TMSCl, LiI,HMDS, DCM
b) Pd(OAc)2,CH3CN
O
H
O
4
+
O
O
125
90%, 2:1
