Embed Size (px)
Citation preview
Molecular Molecular things you things you
wantwant
Molecular Molecular things you things you
havehave
??chemistschemists
Molecular Molecular things you things you
wantwant
Molecular Molecular things you things you
havehave
Nam LeNam Le
Synthesis Requires Two ThingsSynthesis Requires Two Things
1. a library of reactions1. a library of reactions
2. a strategy or plan for combining2. a strategy or plan for combining known reactions to reachknown reactions to reach the desired target moleculethe desired target molecule
3. and a little luck always helps3. and a little luck always helps
goalgoal
(a desired molecular structure)(a desired molecular structure)
goalgoal
subgoal-subgoal-1a1a
subgoal-subgoal-1b1b
subgoal-subgoal-2a2a
subgoal-subgoal-2b2b
subgoal-subgoal-3a3a
subgoal-subgoal-3b3b
Work the problem Work the problem from the final goal from the final goal toward the reactants.toward the reactants.
Have a library of Have a library of reactions that reactions that connect a goal to a connect a goal to a subgoal.subgoal.
Work the problem Work the problem from the final goal from the final goal toward the reactants.toward the reactants.
Have a library of Have a library of reactions that reactions that connect a goal to a connect a goal to a subgoal.subgoal.
OH
O
Br
BrBr
Br
Using your Using your knowledge of knowledge of each reaction each reaction select the best select the best pathway as your pathway as your solution to the solution to the synthetic synthetic problem.problem.
Work the problem Work the problem from the final goal from the final goal toward the reactants.toward the reactants.
Have a library of Have a library of reactions that reactions that connect a goal to a connect a goal to a subgoal.subgoal.
OH
O
Br
BrBr
Br
Using your Using your knowledge of knowledge of each reaction each reaction select the best select the best pathway as your pathway as your solution to the solution to the synthetic synthetic problem.problem.
OO
H3C
OH
CH3
H3C
HO
OH
CH3
CH3
CH3
OH
CH3
OCONH2
CH3
DiscodermolideDiscodermolide
The result of biological studies stimulated considerable interest in The result of biological studies stimulated considerable interest in discodermolide as a possible discodermolide as a possible immunosuppressantimmunosuppressant. .
Subsequently studies demonstrated discodermolide is a potent Subsequently studies demonstrated discodermolide is a potent cell growth inhibitory agent, which arrests cell development at the cell growth inhibitory agent, which arrests cell development at the M phase by binding and stabilizing mitotic spindle microtubules. M phase by binding and stabilizing mitotic spindle microtubules. Thus, the ability of (+)-Thus, the ability of (+)-1 1 to inhibit cell growth was suggested to to inhibit cell growth was suggested to resemble the clinically proven resemble the clinically proven anticanceranticancer agent Taxol. agent Taxol.
OO
H3C
OH
CH3
H3C
HO
OH
CH3
CH3
CH3
OH
CH3
OCONH2
CH3
DiscodermolideDiscodermolide
isolated from a isolated from a marine spongemarine sponge
OO
H3C
OH
CH3
H3C
HO
OH
CH3
CH3
CH3
OH
CH3
OCONH2
CH3
DiscodermolideDiscodermolide
Some problems with pharmaceuticals from natural Some problems with pharmaceuticals from natural sources:sources:Quantities can be very limited.Quantities can be very limited.
More active structural variants are not available from More active structural variants are not available from nature.nature.
The isolation process can be very expensive.The isolation process can be very expensive.
Industrial production can destroy valuable Industrial production can destroy valuable ecosystems.ecosystems.
DiscodermolideDiscodermolide
Some problems with pharmaceuticals from natural Some problems with pharmaceuticals from natural sources:sources:Quantities can be very limited.Quantities can be very limited.
More active structural variants are not available from More active structural variants are not available from nature.nature.
The isolation process can be very expensive.The isolation process can be very expensive.
Industrial production can destroy valuable Industrial production can destroy valuable ecosystems.ecosystems.
CH3
O
CH3
OCONH2
CH3
OO
H3C
OH
CH3
H3C
HO
OH
CH3
CH3
CH3
OH
CH3
OCONH2
CH3
DiscodermolideDiscodermolide
isolated from a isolated from a marine spongemarine sponge
OO
H3C
OH
CH3
H3C
HO
OH
CH3
CH3
CH3
OH
CH3
OCONH2
CH3
DiscodermolideDiscodermolide
chemical chemical synthesissynthesis
available available chemicalchemicalss
OO
H3C
OH
CH3
H3C
HO
OH
CH3
CH3
CH3
OH
CH3
OCONH2
CH3
DiscodermolideDiscodermolide
chemical chemical synthesissynthesis
OO
H3C
OTBS
CH3
OTBSO CH3
OTBS
CH3
O
CH3
O
PMP
XPMBO
H3C
X
OH
CH3
CH3
OO
H3C
OTBS
CH3
OTBSO CH3
OTBS
CH3
O
CH3
O
PMP
XPMBO
H3C
X
OH
CH3
CH3
N
OH O
OCH3
CH3
PMBO
HO OCH3
O
commerciallcommercially availabley available
H O
H
OHH
H
.
1. BH3
2. H2O2/OH H
OH .
H H
H
H
Pd/C
.
H H
H HPd.
H
OH PCC O
C XC
R OHH Br
R Br ..
General Scheme of a new reaction:General Scheme of a new reaction:
R1 C C HNa NH2
R1 C C
R1 C C CH2 RR CH2 Br
R1 C C
A+ HB B H + A
Example. :Example. :
H H
muscalure, the sex muscalure, the sex attractant of the attractant of the common houseflycommon housefly
H O
H
OHH
H
.
1. BH3
2. H2O2/OH H
OH .
H H
H
H
Pd/C
.
H H
H H .Pd
H
OH PCC O
C XC
R OHH Br
R Br ..
H2/Pd
6 11
6
11
Br
H
Br
6
1. 2. NH2
H O
H
OHH
H
.
1. BH3
2. H2O2/OH H
OH .
H H
H
H
Pd/C
.
H H
H H .Pd
H
OH PCC O
C XC
R OHH Br
R Br ..
General Reaction Scheme of a new General Reaction Scheme of a new reaction:reaction:
C O
H
H BrC O
H
H
+
Br
CBr
+
OHH
R OHH Br
R Br ..
A+ HB B H + A
Work the problem from the Work the problem from the final goal toward the final goal toward the reactants.reactants.
Have a library of reactions that Have a library of reactions that connect a goal to a subgoal.connect a goal to a subgoal.
Using your knowledge of each Using your knowledge of each reaction select the best pathway as reaction select the best pathway as your solution to the synthetic your solution to the synthetic problem.problem.
Problems in synthetic Problems in synthetic chemistrychemistry
H O
H
OHH
H
.
1. BH3
2. H2O2/OH H
OH .
H H
H
H
Pd/C
.
H H
H H .Pd
H
OH PCC O
C XC
R OHH Br
R Br ..
from compounds containing 2 carbon atoms or less
OH
OHH /H2O H /H2O
??
H O
H
OHH
H
.
1. BH3
2. H2O2/OH H
OH .
H H
H
H
Pd/C
.
H H
H H .Pd
H
OH PCC O
C XC
R OHH Br
R Br ..
from compounds containing 2 carbon atoms or less
OH
H /H2O
H2/Pd
Br
1.
HBr
2. NH2
from compounds containing 2 carbon atoms or less
OH
H /H2O
H2/Pd
Br
1.
HBr
2. NH2
H O
H
OHH
H
.
1. BH3
2. H2O2/OH H
OH .
H H
H
H
Pd/C
.
H H
H H .Pd
H
OH PCC O
C XC
R OHH Br
R Br ..
from compounds containing 2 carbon atoms or less
OH
OH
H /H2OH /H2O
H O
H
OHH
H
.
1. BH3
2. H2O2/OH H
OH .
H H
H
H
Pd/C
.
H H
H H .Pd
H
OH PCC O
C XC
R OHH Br
R Br ..
from compounds containing 2 carbon atoms or less
OHH /H2O
H
Br
OH
HBr
1. BH3 2. H2O2/OH
H2/Pd
H O
H
OHH
H
.
H H
H
H
Pd/C
.
H H
H H .Pd
H
OH PCC O
C XC
R OHH Br
R Br ..
from compounds containing 2 carbon atoms or less
OH
H
Br
OH
HBr
1. BH3 2. H2O2/OH
H2/PdH
Br
H /H2O
H2/Pd
from compounds containing 2 carbon atoms or less
OH
H
Br
OH
HBr
1. BH3 2. H2O2/OH
H2/PdH
Br
H /H2O
H2/Pd
H O
H
OHH
H
.
1. BH3
2. H2O2/OH H
OH .
H H
H
H
Pd/C
.
H H
H H .Pd
H
OH PCC O
C XC
R OHH Br
R Br ..
from compounds containing 2 carbon atoms or less
H
O
H O
H
OHH
H
.
H H
H
H
Pd/C
.
H H
H H .Pd
H
OH PCC O
C XC
R OHH Br
R Br ..
from compounds containing 2 carbon atoms or less
H
O
H
Br
OH
HBr
1. BH3 2. H2O2/OH
H2/Pd
H2/Pd
OHPCC
1. BH3 2. H2O2/OH
1. BH3
2. H2O2/OH H
OH .
H O
H
OHH
H
.
H H
H
H
Pd/C
.
H H
H H .Pd
H
OH PCC O
C XC
R OHH Br
R Br ..
from compounds containing 2 carbon atoms or less
H
O
H
Br
OH
HBr
1. BH3 2. H2O2/OH
H2/PdH
Br
H2/Pd
OHPCC
1. BH3 2. H2O2/OH
