total syntheses of platensimycin - unc.edu · isolation of platensimycin • merck, 2006 ......
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Total Syntheses of Platensimycin
Adam M. Azman9 May 2007
OHNH
OH
HO
O
O
O
O
Me
Me
1
Antimicrobial Agents• Antibiotic refers to drugs derived wholly or partially from microorganisms
– Antimicrobial agents can be synthetic• 190 million doses of antimicrobials administered each day
– 133 million courses prescribed to non-hospitalized patients each year• First antibiotic discovered by Alexander Fleming in late 1920s (penicillin)
– Followed by sulfonamides in late 1930s• Penicillin not really mass produced until 1940s (WWII)• Many new antibiotics isolated in 1940s (streptomycin, tetracycline,
vancomycin)• As resistance began to occur, synthetic antimicrobial agents prepared in
1960s (amoxicillin, meticillin)• No really new classes of antimicrobial agents since cephalosporins in 1960s• Most disrupt biosynthesis of cell wall, DNA, or proteins
N
S
OOH
O
HN
R
O
the penicillins
Cl
O OO
O
O
O OH
OHOH
OH NH2
Cl
OH
NHO
HN
NH
H2NO
HN
OHOH
HN
ONHCH3
O
O
HO
HO2C
OOH
N
HHO
vancomycin
N
S
OO
HO
O
HN
MeO
OMe
meticillin
NHO
N
HO OH
OH2N
NH2
NH2
H2N
O
O
O
HN
OH
OH
OH
OH
O
H
streptomycin
2
Antimicrobial Resistance• CDC: “one of the world’s most pressing public health problems”• Causes:
– Random mutation (bacteria can reproduce as often as every half hour)– Misuse of antimicrobials
• Not taking full dosing regimen• Taking antimicrobials for viral infections (cold, flu, cough/sore throat (except strep
throat))
• Mechanism– Mutation
• Change in the antimicrobial target (i.e. DNA replication enzyme) such that bacteria can still replicate DNA, and antimicrobial agent cannot bind to enzyme
– Destruction or Inactivation• Enzyme in bacteria modifies or degrades antimicrobial agent before it reaches target
– Efflux• Keeps intracellular concentration of antimicrobial low by pumping antimicrobial out of
cell– Genetic Transfer
• DNA from a resistant bacteria are transferred into non-resistant bacteria (making them resistant, too)
3
Isolation of Platensimycin• Merck, 2006 – Antisense RNA silencing of whole-cell Staphyloccocus
aureus– Bacteria makes less FabF enzyme – more sensitive to chemicals targeting that
enzyme
• Screen of 250,000 natural product extracts led to platencimycin• Isolated from Streptomyces platensis, a bacterium recovered from South
African soil sample (2-4 mg/L fermentation broth)• Active against Meticillin Resistant Staph. aureus (MRSA) & Vanomycin
Resistent Enterococcus (VRE)• Various NMR, MS to determine structure• X-ray of 6’-bromo derivative established absolute stereochemistry
6'
OHNH
OH
HO
O
O
O
O
Me
Me
Active confirmiationof platensimycin
4
Biology• Targets fatty-acid biosynthesis
– FAB organized differently in bacteria (many enzymes from discrete genes) and humans (multifunctional protien encoded from single gene)
• Targets β-ketoacyl-ACP (acyl-carrier-protein) synthase, AKA FabF
• Platensimycin binds only to enzyme w/ attached acyl group – short lived (milliseconds)
– Merck created acyl-enzyl mimic by substituting cysteine with glutamine
S
O
ACPm
FabBFabF
FabH HO
O
S
O
ACPacyl-ACP
malonyl-ACP(C2 donor)elongation
CO2
O
S
O
ACPn
β-ketoacyl-ACP
FabG
reduction
OH
S
O
ACPn
β-hydroxyacyl-ACP
FabAFabZ
elimination
S
O
ACPn
FabIFabKFabL
reduction
OHNH
HO
OH
O
O
5
Timeline – Reception to Publication
MERCK Isolation, Nature, 69 days(3 articles in this issue)
MERCK Isolation, JACS, 131 daysNICOLAOU Racemic Total Synthesis,
ACIEE, 8 days
NICOLAOU Asymmetric Total Synthesis,ACIEE, 71 days
SNIDER Racemic Formal Synthesis, Org. Lett., 29 days
NICOLAOU Racemic Formal Synthesis,Chem. Commun., 17 days
6
Nicolaou’s Racemic Total Synthesis• Retro:
2' 4'6'
1'
OHNH
OH
HO
O
1 2
O3
10
O16 15 148
115
6
7
O19
Me17
Me18
Amide BondFormation
OHNH2
OH
HO
O
1 2
O3
10
O 14
6
7
O
Me
MeHO
DoubleAlkylation
10
O 14
11 6
7
O
MeKetyl Radical Cyclization/Etherif ication
7
6
O
14
1110
O
H
Cycloisomerization
7
6
O
1110
TBSO
7
6
OEt
O
DoubleAlkylation
OHNO2
OH
7
Nicolaou’s Racemic Total Synthesis• Multi-cycle:
7
6
OEt
O
1) LDA,
Br
10 OTBS
14BrH2) LDA,
7
6
OEt
O
14H
10
TBSO
1) DIBAL-H, PhMe-78 °C → rtthen HCl, MeOH-20 °C → rt
2) TBSClimid., DMF84% - 2 steps
92%
97%
O
H
TBSO
RuNCMeMeCN
NCMe
TBSO
PF6-
cat.
acetone92%
1:1 dr
O
1) LiHMDS, TMSClTHF, -78 °C
2) Pd(OAc)2, MeCN68% - 2 steps TBSO
O
1 N HCl/THF
7
6
14
10H
O
O
85%
SmI2
F3C CF3
OH
THF, -78 °C → rt
THF, -78 °C → rt
THF/HMPA (10:1)-78 °C, 1 min46%, ~2:1 dr
HO
OTFA
CH2Cl20 °C87%
10
O 14
6
7
O
Me
8
10
O 14
6
7
O
Me
1) KHMDS, MeITHF/HMPA (5:1)-78 °C → -10 °C88%
10
O 14
6
7
O
Me
2) KHMDSallyl iodideTHF/HMPA (5:1)-78 °C → -10 °C79%
Me2
B1
O
O
G2
CH2Cl2, 40 °C85%, ~6:1 E/Z
10
O 14
6
7
O
Me
Me
B1
O
O
1) Me3NOTHF, 65 °C, 95%
2) NaClO22-methyl-2-buteneNaH2PO4tBuOH/H2O (1:1)95%
10
O 14
6
7
O
Me
Me1HO
O
Nicolaou’s Racemic Total Synthesis
9
Nicolaou’s Racemic Total Synthesis• Aromatic Amine:
OMOM
NHBocOMOM
nBuLi, TMSCl, -78 °C
thennBuLi, MeOC(O)CNTHF, -78 °C,
then1 N aq. HCl54%
OMOM
NHBocOMOM
MeO
O
205 °C
1,2-dichlorobenzeneμwave, 5 min, 83%
OMOM
NH2
OMOM
MeO
O
OMOM
NH2
OMOM
Boc2O
40 °C99%
OMOM
NO2
OMOM
H210% Pd/C (0.1 eq.)
MeOH/EtOAc (10:1)99%
OH
NO2
OH
NaHMOMCl
THF, 0 °C → rt82%
10
Nicolaou’s Racemic Total Synthesis• End Game:
OMOM
NH2
OMOM
MeO
O10
O 14
6
7
O
Me
Me1HO
O
HATU, Et3N
DMF, 85% OMOM
NH
OMOM
MeO
O
O
O
O
Me
Me
OHNH
OH
HO
O1
O
10
O 14
6
7
O
Me
Me
LiOHTHF:H2O (4:1)45 °C
then2 N aq. HClTHF:H2O (3:1)45 °C ~90%
11
Snider’s Racemic Formal Synthesis• Retro:
OHNH
OH
HO
O1
O
10
O 14
6
7
O
Me
Me
10
O 14
6
7
O
MeNicolaou's Intermediate
HO OH
10
O14
6
7
O10
6
7
14
CH2O
O
10
6 7
O
OMe
Etherification
Elimination
AllylicOxidation
ReductiveAlkylationRadical
Cyclization
12
Snider’s Racemic Formal Synthesis• Tricycle:
10
6 7
O
OMe
10
6 7
O
OH
Br
10
6 7
O
OH
14
Br
1:2 con'c HCl/THF0 °C → rt
AIBN, nBu3SnHPhH, Δ
AIBN, nBu3SnHPhH, Δ
106 7
O
OH
14
10
6 7
O
OH
14
10% KOH in MeOH
51%
35%
57% cis43% trans
84%
81%
20% cis80% trans
K, NH3,LiBr
2,3-dibromopropeneEt2O, tBuOH, -78 °C
thenHCl/THF
13
Snider’s Racemic Formal Synthesis• Multi-cycle:
10
6 7
O
OH
14
10
6
7
14CH2
O
O
10
O14
6
7
O
L-SelectrideTHF, -78 °C → rt
99%, 1:1 dr
HO OH
HOOH
H
H
H
H
TFH/CH2Cl20 °C
thenK2CO3/MeOH
OMe OH
OMe
OH
H
H
H
H
Tf2O, PyrCH2Cl2-78 °C → -5 °C
thenMe2CHOH-5 °C → rt
Tf2O, PyrCH2Cl2-78 °C → -5 °C
thenMe2CHOH-5 °C → rt
(inseparable)
39% frommixture
42% frommixture
10
O 14
6
7
Me
6
10
O 147
Me
OTf
H
1 M HClor
silica gel
(not isolated)
90% fromaxial OH84% from
equatorial OH
NaBH4EtOH
-78 °C-0 °C87%
10
O14
6
7OH
H
L-SelectrideTHF, -78 °C → rt
83%TFH/CH2Cl20 °C
thenK2CO3/MeOH
90% frompure diol
14
Snider’s Racemic Formal Synthesis• Interception of Nicolaou’s Multi-cycle:
10
O 14
6
7
Me
CrO3•3,5-dimethylpyrazole
CH2Cl2, -25 °C75%
4:1 mixture regioisomersfavoring desired product
(inseparable)
SeO2 (8 eq.)dioxane
μwave 140 °C 30 min59% dienone
27% allylic alcohol
SeO2 (3 eq.)dioxane
μwave 110 °C 10 min83% allylic alcohol7% desired enone
MnO2CH2Cl294% desired enone
10
O 14
6
7
MeO
Me
OMe
O
O
OH
OMe
O
7 steps, 32% overall yield
15
Nicolaou’s Racemic Formal Synthesis• Retro:
OHNH
OH
HO
O1
O
10
O 14
6
7
O
Me
Me10
O
6
7
O
Me
Same commonintermediate
10
HO14
6
7
O
H 7
6
10
O
HHO
14
Etherification
Radical Cyclization
O
O
Br
Stetter Reaction
7
6
OEt
ODoubleAlkylation
16
Nicolaou’s Racemic Formal Synthesis• Tri-cycle:
7
6
OEt
O
1) LDA
THF-HMPA (5:1)-78 °C → 0 °C, 75%
2) LDA
THF-HMPA (5:1)-78 °C → 0 °C, 87%
IOPMB
BrBr
DIBAL-HPhMe-78 °C → 0 °C
then1 N aq. HCl92%
1) LDA, TMSClTHF-78 °C → 0 °C
2) IBX, MPODMSO77% (2 steps)
1) DDQCH2Cl2-H2O (9:1)95%
2) DMP, NaHCO3CH2Cl295%
7
6
OEt
O
Br
14
10
OPMB
O
Br
OPMB
O
Br
O
H
N
N+NC6F5
BF4-
Et3N
CH2Cl245 °C, 64%
HSCH2CH2SHBF3•OEt2
CH3OH, 80% O
Br
H
SS 1) TMSOTf, Et3NCH2Cl2
2) IBX, MPODMSO82% (2 steps)
O
Br
H
SS
n-Bu3SnH, AIBN
PhH, Δ, 86% 7
6
10
HO
14
SS
O
Br
OPMB
7
6
10
O
O
14
Br
singlediastereomer
H
OI
O
O OH
N+MeO O-
IBXMPO
17
Nicolaou’s Racemic Formal Synthesis• Interception of multi-cycle:
7
6
10
HO
14
SS L-Selectride
THF, -20 °C91%, 1:1 dr
HHO
SS
7
6
10
HHO
14
SS
DMP (1.2 eq.), Pyr.
CH2Cl2, 99%
10
HO14
6
7H
SS
TFA
CH2Cl20 °C, 90% O
Me
SSDMP (8 eq)
CH3CN-CH2Cl2-H2O (9:1:1)85%
10
O 14
6
7
Me
O
18
Nicolaou’s Asymmetric Total Synthesis• Retro:
OHNH
OH
HO
O1
O
10
O 15 14
6
7
O
Me
Me
10
O 14
6
7
O
Mesame old
intermediateKetyl radicalcyclization/
Etherification
7
6
15
14
10H
O
O
Cyclodearomatization
Cycloisomerization
7
6
14
O
10
HO
7
6
OH
10
15
14
TMSO
O
OH
15O
14
O
O
AsymmetricAlkylation
1015 OH
OO
O
Kumadacoupling
19
Nicolaou’s Asymmetric Total Synthesis• Asymmetric Cycloisomerization Strategy:
7
6
15
14
O
10
OTBS
1) TMSOTf, Et3NCH2Cl2, 0 °C
2) nBuLi, MeOC(O)CNTHF, -78 °C → -40 °C
7
6
OEt
O
(From RacemicTotal Synthesis)
OTMS
OTBS
MeO O
1) IBX, MPODMSO67% (3 steps)
2) 1 N aq. HCl/THF0 °C, 91%
O
OH
MeO O
[{Rh(cod)Cl}2] (5 mol %)(S)-BINAP (11 mol %)
AgSbF6 (20 mol %)
dichloroethene, 91%
7
6
14
10H
O
O
HOCH2CH2OHCH(OMe)3, PPTS
PhH, 60 °C, 90%
O
O
O CO2MeCO2Me
1) LiOHTHF, 0 °C
2) EDC•HCl
CH2Cl2
N+-O
HS
O
O
OO
O
NS
hν , nBu3SnH
PhH, 49% (3 steps)
1) 1 N aq HCl/THF, 90%
2) SmI2, (F3C)2CH(OH)THF-HMPA (10:1)-78 °C, 1 min, 39%
3) TFA/CH2Cl20 °C, 87%
O
O
Me
(From RacemicTotal Synthesis)
OHNH
OH
HO
O1
O
10
O 14
6
7
O
Me
Me7
6
14
Me
10
O
O
O
20
1015 OH
OO
O
MeHN
Me
OH
Ph
PivCl, Et3NMeCN, 0 °C
then
Et3NTHF, 100%
N
OO
O
Me
Me
Ph
OH
LDA, LiCl
-78 °C → 0 °C87%
TBSO
Br
15 N
O
O
O
Me
Me
Ph
OH10
7
6
OTBS
MeLi
THF-78 °C → -25 °C
91%
15 O
Me14
O
O
10
76
OTBS KHMDS
THF-78 °C → 0 °C
92%
NCl
NTf2
OTfO
O
OTBS
TMS MgClLiClcat. [Pd(PPh3)4]THF, 94%
2) NaOH in MeOH0 °C → rt, 100%
PhI(OAc)2
tetraf luoroethylene-10 °C, 68%
7
6
O
1)
15
1410
O
O
1 N aq HCl/THF
40 °C, 90%
O
O
H
(From RacemicTotal Synthesis)
OHNH
OH
HO
O1
O
10
O 14
6
7
O
Me
Me
14
• Cyclodearomatization Strategy:Nicolaou’s Asymmetric Total Synthesis
O
O
OH
TMS