tetracyclines - university of north carolina at chapel hill total synthesis of a tetracycline-like...
TRANSCRIPT
The Tetracyclines
Michael EllisNovember 30, 2005
-Prepared from the cultures of several species of Streptomyces-Once an enormously effective treatment for a wide range of bacterial infections-Mode of action is binding to the 30S ribosome of the bacteria, preventing attachment of the aminoacyl tRNA to the RNA-ribosome complex-Decades of clinical use have led to the emergence of widespread bacterial resistance-Analogs generally prepared via semisynthesis-First total synthesis of a tetracycline-like molecule reported by Woodward and a group from Pfizer-Synthetic approaches by Woodward, Shemyakin, Muxfeldt, Stork, and Myers
OH O OH O
OH
O
NH2
NMe2HH
OH
OHMe
(-)-tetracycline
D C B A456
12
-R1-R4 can be substituted or removed without effecting a substantial decrease in antimicrobial activity
-Configuration at C-5a and C-4 are crucial for activity
-Hypothesized that the principal active center is the C-11, C-12 diketone system of rings B and C
Structure-Activity Relationships
OH O OH O
OH
O
NH2
NMe2HH
R4
R1
OH
R3R2
6 5 4
11 12
OH O OH O
OH
O
NH2
NMe2HH
OH
OHMe
(-)-tetracycline
D C B A456
1211
Woodward’s Approach
OH O OH O
OH
O
NH2
NMe2HH
OH
D C B A456
1211
6-demethyl-6-deoxytetracycline
OMe
Cl
O
O
OH
OMe
Cl
O
O
OH
H
H HR
R is equatorial
OMe
OMe
O
“The most formidable synthetic problems posed by the structure are concentratedin ring A: every carbon of the atom skeleton of that ring bears at least one substituent, and three of the four asymmetric centers of the molecule fall in the consecutive chain C4, C4a, C12a.” - Woodward
Korst, J. J.; Johnston, J. D.; Butler, K.; Bianco, E. J.; Conever, L. H.; Woodward, R. B. J. Am. Chem. Soc. 1968, 90, 439.
OMe
OMe
O 1. NaH,
DMF, 60 oC
2.
Me OMe
O
OMe
O
Cl OMe
O O
OMe
OMe
O
OMe
O
1.
dioxane, 60 oC,
Triton B
2. AcOH, H2SO4,
3. H2SO4, MeOH55% for 2 steps
OMe
O
OMe
O
OMe
O
87% for 3 steps
Resolution possible atthis point
10% Pd/C, AcOH,
H2 (200 psi)
OMe
OMe
O
O
OOMe OH
O
OMe
O
93%
H2SO4, MeOH
OMe OMe
O
OMe
O
95%
NaOH, H2O,
OMe OH
O
OH
O
I2, AcOH,
12 oC; Cl2
OMe OH
O
OH
OCl
95% for 2 steps
OMe OH
O
OH
OCl
HF
OMe
OH
OCl
O
67%
1. H2SO4, MeOH
2. NaH, MeO2C-CO2Me
DMF; MeOH
MgOMe, Ph-Me,
OnBu
H
O
O
45%
OMe
Cl
O
O
OH
CO2nBu
52%
OMe
Cl
O
O
OH
HCl, AcOH
90 oC
OMe
Cl
O
O
OH
NMe2H H
CO2nBu
NaBH4, MeOCH2CH2OMe,
H2O, -70 oC
OMe
Cl
O
OH
OH
NMe2H H
CO2nBu
53% for 2 steps
Me2NH,
-10 oC
OMe
Cl
O
OH
OH
CO2Me
OMe
OMe
OCl
O
:BH
OMe
OMe
OCl
ONaOMe
Cl
O OHOMe
Cl
O O
OMe
OMe
OCl
ONa
O
OMeO
MeO
OMe
OMe
OCl
O O
O
OMe
H
:B
OMe
OMe
ONaCl
O O
O
OMe
OMe
Cl
O
CO2Me
O
OOMe
Cl
O
CO2Me
OH
OH
OMe
Cl
O O
:B
H
OMe
Cl
O ONa O
OMeO
MeO
OMe
Cl
O OH
CO2Me
OH
OMe
Cl
O O
CO2Me
O
OMe
Cl
O
OH
OH
NMe2H H
CO2nBu
p-TSA, Ph-Me
OMe
Cl
O OH
H H
O
O
NMe2
90%
HCO2H,
Zn dust
OMe
Cl
O OH
NMe2H H
CO2H
81%
10% Pd/C, Et3N,
EtOH, H2 (40 psi)
OMe O OH
NMe2H H
CO2HCl
O
Et3N, 0 oC
OMe O OH
NMe2H H
O
O
O
Me
Me
EtO N Me
O O MeMe
Mg
CH3CN OMe O OH
NMe2H H
OH
R
R = CO2Et
O
NtBu
NaH, DMF,
122 oC
OMe O OH
NMe2H H
O
OH O
NtBu
15% for 4 steps30% recoverable
HBr, 100 oC
OH O OH
NMe2H H
O
OH O
NH2
(CeCl3)-7H2O, DMF,
MeOH, ph = 10.4
OH O OH
NMe2H H
O
O O
NH2
OH
6.4% + 10% RSM
Me
Me
OH O OH OH
OH
O
NH2
NMe2HH
OHMe
12a-deoxytetracycline
D C B A456
1211
OH O OH
HOH
MeH
OOH
MeO
OO
R O
OOHOOH
OO
OEt
Me
Stork’s Approach
Stork, G.; La Clair, J. L.; Spargo, P.; Nargund, R. P. Totah, N. J. Am. Chem. Soc. 1996, 118, 5304.
O
OOH
CHCl3
O
OOH
(quant.)
OOH
OHMe1. MeMgBr, THF
-78 oC to rt
2. p-xylene
78% for 2 steps
1. EtOCHBrCH2Br,
Ph-NMe2, CH2Cl2
2. nBu3SnH, AIBN, C6H6
OOH
O
OEt
Me
89% for 2 steps
HSCH2CH2CH2SH
BF3-OEt2, CH2Cl2
0 oC OOH
OHMe
S
S TFAA; DME
HO O
O O
OOH
Me
S
SO
OO
O
1. PhI(OTfA)2,
CH2Cl2, MeOH
2. 5% HCl, THF
81% for 2 steps
OOH
Me O
OO
O
O
piperidine, AcOH,
4 A MS, C6H6, 0 oC to rt
97% for 3 steps45% for 10 steps
OOH
Me O
OO
O
S
S O1. PhI(OTfA)2, MeOH
2. HCl, H2O
I PhTfAO
TfAO S
S
IOTfAPh
+S
S
+
I
PhOTfA
MeOHTfAO-
S
S
I
PhOTfA
MeO
H+
H+ transfer
S
HS
I
PhOTfA
MeO+
S
HS
I
PhOTfA
MeO+
MeOH
H+ transferOMe
OMe
OOH
Me O
OO
O
ON
OBn
MeO
O
NMe2
1. NaHMDS, THF
2. -78 oC to -20
oC
3. Pd(PPh3)4
OOH
Me O
O
95% for 3 steps
H
O
NR
OBn
NMe2
R = CO2Me
Bu3SnOCH3
Ph-Me, 60 oC
97%
OOH
Me OH
R R
H H
R = CO2Me
NMe2
N
O
OBn
OOH
Me O
OO
OMe
ON
OH
MeO
O
Me
1. NaHMDS, THF
2. -78 oC to -20
oC
OOH
Me O
O
75% for 2 steps
H
O
NR
OH
R = CO2Me
R
DBU, 4 A MS,
C6H6
OOH
Me OH
R
H HNMe2
NO
OBnOH
89%
R = CO2Me
OH O OH OH
NMe2HHMe
OH
NO
OBn
OOH
Me OH
R R
H H
R = CO2Me
NMe2
N
O
OBn
TMSCN, KCN,
18-crown-6, CH2Cl2TMSO
R R
H HNMe2
NO
OBn
Me
OTMS
OKH, THF,
-78 oC to 50
oC
R
OH O OH
NMe2HHMe
OH
NO
OBn
OH O OH OH
NMe2HHMe
OH
NO
OBn
Pd black, H2 (1 atm),
THF, MeOH
59%
OH O OH OH
OH
O
NH2
NMe2HHMe
OH
94%
Myers’ Approach
OH O OH O
OH
O
NH2
NMe2HH
OH
Me
(-)-6-deoxytetracycline
and analogs…
O OH O
OH
O
NH2
NMe2HH
OH
R X
H
O
R-
OPh
O O
NMe2H
OR
X
N
O
OBnCO2H
Charest, M. G.; Lerner, C. D.; Brubaker, J. D.; Siegel, D. R. Myers, A. G. Science 2005, 308, 395.
CO2H
Alcaligenes
eutrophus
OHOH
CO2H
79%, >95% ee90-g batch
m-CPBA,
EtOAc
OHOH
CO2HO
1. TMSCHN2
2. TBSOTf, Et3NOTBS
O
CO2MeTBSO
NO
OBn
Me2N
nBuLi, THF, -78
oC
83% 70% for 2 steps
TBSO
O
TBSO
O
N
O
NMe2
OBn
1. LiOTf, Ph-Me, 60 oC
2. TFA, CH2Cl2
73% 62%
TBSO O
NMe2H
OH
NO
OBnHO
21% for 7 steps
TBSO
O
TBSO
O
N
O
NMe2
OBn
1. LiOTf, Ph-Me, 60 oC
2. TFA, CH2Cl2TBSO O
NMe2H
OH
NO
OBnHO
TBSO
TBSOO
Li
NO
O
OBn
SN2'
Me2N+
H:B
TBSO
TBSOO
Li
NO
O
OBn
Me2N+ -
Sommelet-Hauser
Rearrangement
TBSO O
NMe2H
OH
NO
OBn
1. HCl, MeOH2. IBX, DMSO
3. TBSOTf, 2,6-lutidine
O
NMe2H
OR
NO
OBnO
66% for 3 steps10% for 11 steps
R = TBS
74%
TBSO O
NMe2H
OH
NO
OBnHO
PPh3, DEAD,
Ph-Me, NBSH
TBSO O
NMe2H
OH
NO
OBnHO
1. CBr4, PPh3
2. PhSH, Et3N
TBSO O
NMe2H
OH
NO
OBnPhS
Me Me
Cl
ClNOS
O O
1.
2. P(OMe)3, MeOH,
70 oC
87% for 2 steps
TBSO O
NMe2H
OH
NO
OBn
HO
76% for 2 steps
1. BnO2CCl, DMAP
2. TBAF, AcOH
3. IBX, DMSO
4. TBSOTf, Et3N O
NMe2H
OR
NO
OBnO
BnO2CO
85% for 4 steps12% for 15 steps
R = TBS
O
NMe2H
OR
NO
OBnO
BnO2CO
OBoc
Et
CO2Ph
LDA, TMEDA,
THF, -78 oC to 0
oC
BocO O OH O
NMe2HH
OR
Me
NO
OBn
OR'
79%
R = TBS
R' = CO2Bn
1. HF, CH3CN
2. H2, Pd, THF, MeOH
OH O OH O
OH
O
NH2
NMe2HH
OH
Me OH
(-)-doxycycline90%
8% for 18 steps
TBSO O
NMe2H
OH
NO
OBnPhS
Me Me
Cl
ClNOS
O O
1.
2. P(OMe)3, MeOH,
70 oC TBSO O
NMe2H
OH
NO
OBn
HO
[O]*
TBSO O
NMe2H
OH
N
O
OBnS
OPh
-
+TBSO O
NMe2H
OH
NO
OBn
OS
PhMislow-Evans
Rearrangement
:P(OMe)3
O
NMe2H
OR
NO
OBnO
R = TBS
Et
CO2Ph
OBoc
N
Me
CO2Ph
OBn
Me
CH2Br
CO2Ph
CH2Br
CO2Ph
OMe
1. LDA, TMEDA,
-78 oC to 0
oC
2. HF, CH3CN
3. H2, PdOH O OH O
OH
O
NH2
NMe2HH
OH
Me
(-)-6-deoxytetracycline69% for 3 steps7% for 14 steps
1. LDA, TMEDA,
-78 oC to 0
oC
2. H2, Pd(OH)2
3. HCl, MeOH
pyridone derivative50% for 3 steps5% for 14 steps
HN
O O OH O
OH
O
NH2
NMe2HH
OH
Me
Me
1. nBuLi, -100
oC
to -70 oC
2. HF, CH3CN
3. H2, Pd
1. nBuLi, -100
oC
to 0 oC
2. HF, CH3CN
3. H2, Pd
4. BBr3, CH2Cl2
-78 oC to rt
O OH O
OH
O
NH2
NMe2HH
OH
Me
10-deoxysancycline68% for 3 steps7% for 14 steps
O OH O
OH
O
NH2
NMe2HH
OH
Me
OH
pentacycline derivative56% for 4 steps6% for 15 steps