Transcript sungkyunkwan university

교과목: 약품합성화학
수강대상: 약학부 4년
수강학기: 2007학년도 1학기
The Logic of Chemical Synthesis
- E.J. Corey and X-M. Cheng -
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The Basis for Retrosynthetic Analysis
1. Multistep Chemical Synthesis
Due to an astronomical number of discrete carbogens,
differing in number and type of constituent atoms, in size, in
topology and in three dimensional (stereo-) arrangement, the
construction of specific molecules by a single chemical step
from constituent atoms or fragments is almost never possible
even for simple structures.
Efficient synthesis, therefore, requires multistep construction
process which utilize at each stage chemical reactions that
lead specifically to a single structure.
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Retrosynthetic Analysis
Retrosynthetic analysis is a problem-solving technique
for transforming the structure of a synthetic target (TGT)
molecule to a sequence of progressively simpler structure
along a pathway which ultimately leads to simple of
commercially available starting materials for a chemical
synthesis.
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Transforms and Retrons
In order for a transform to operate on a target structure to
generate a synthetic predecessor, the enabling structural
subunit or retron for that transform must be present in the
target.
+
Carbo-Diels-Alder Transform
H
H
H
H
H
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Transforms and Retrons
H
H
H
H
Catalytic
H
hydrogenation
Tf.
H
Tf.
H
2
Me
CO2Me
H
Simmons-Smith
H
1
3
Me
CO2Me
Me
CO2Me
+
H
CO2Me
H
CO2Me
MeO2C
4
2, 3, and 4 can be regarded as a partial retrons for D-A Tf.
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Types of Transforms
The most crucial tranforms:
1. simplifying transforms
- disconnecting molecular skeleton (chains (CH) or rings (RG))
- removing or disconnecting functional groups (FG)
- removing or disconnecting stereocenters (ST)
2. non-simplifying transforms
- connecting or rearranging molecular skeleton
- interchanging or transposing functional groups (FGI or FGT)
- Inverting or transferring stereocenters
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FGI Transforms
H2N
Me
Me
O
O
H Conia (Oxo-ene)
FGI
H
CHO
Cyclization
H
H
O
Me
H
NO2
FGI
Ph
Me
Ph
Nef
O
NO2
Me
+
Ph
O
O
FGT Transforms
O
H
TMS
Me
TMS
O
H
O
Me
FGT
Me
+
Me
H
Me
O
Me
H
Me
O
Me
Me
O
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Rearrangement Transforms
H
OH
Oxy-Cope
O
+
Cl
CN
O Rearrangement
H
O
HO
Pinacol
OH
O
2
Rearrangement
FGA Transforms
O
O
MeO2C
CO2Me
CO2Me
Dieckmann
FGA
CO2H
2
H
Ph
H
H
Ph
H
Ph
O
FGA
H
Cyclization
Ph
H
Ph
H
H
Ph
Ph
O
+
Cl
H
H
Cl
C
O
Cl
Cl
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Stereocenters Transforms
Me
RO
RO
RO
Me
RO
OH
+
O
OH
O
O
Ph
Synthesis of (-)-Lentiginosine
(-)-1
BnO
Ph
O
OH
BnO H
Me
Me
Me
Me
Y.H. Jung et. al. Org. Lett. 2006, 8, 4101-4104
RCM
H
N
N
N
BnO
2
OBn
OBn
BnO
3
OBn NHCBz
OBn
4
OBn
OBn
CSI
BnO
Br
Br
5
O
OBn OBn
6
OBn
O
OH
7
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Y.H. Jung et. al. Org. Lett. 2006, 8, 4101-4104
Br
H
BnO
Ph
Br
H
H
OBn
OBn
BnO
Ph
H
H
OBn
OBn
H
O C N SO2Cl
O C N SO2Cl
1,2-anti-tribenzyl ether 6
1,2-syn-tribenzyl ether 9
first inversion
of configuration
H
Bn
Br
H
OBn
O
H
COOBn
N
Ph
SO2Cl
H
Bn
O
Br
H
OBn
COOBn
N
Ph
SO2Cl
H
Transition state B
Transition state A
second inversion
of configuration
OBn
OBn
Br
Br
OBn NHCbz
1,2-anti-product 5a
OBn NHCbz
1,2-syn-product 12
Figure 1. Proposed reaction mechanism of cinnamyl
polybenzyl ethers 6 and 9 with CSI.
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1. Tranform-Based Strategies
Diels-Alder Cycloaddition as T-Goal
+
- Retrosynthetic analysis of Fumagillol
- Retrosynthetic analysis of Ibogamine
- Retrosynthetic analysis of Estron
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Retrosynthetic analysis of Fumagillol
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Retrosynthetic analysis of Fumagillol
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Synthesis of Fumagillol
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Synthesis of Fumagillol
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Retrosynthetic analysis of Ibogamine
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Retrosynthetic analysis of Estrone
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2. Enantioselective Transforms as T-Goals
D-(-)-diethyltartrate
'O'
Sharpless Asymmetric Epoxidation
R2
R1
(CH3)3COOH(TBHP)
R2
R1
O
R3
OH
OH
Ti(O-ipr)4
R3
CH2Cl2, -23oC
'O'
L-(+)-diethyltartrate ((+)-DET)
H
HO
C
COOR
HO
C
COOR
H
R
OH
AE
R
O
OH
(+)-DET
* This reactions are effective for the kinetic resolution of racemic allylic alcohols.
R
R'
OH
AE
(+)-DET
R
R'
OH
+
R
O
R'
OH
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Enantioselective Transforms as T-Goals
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3. Mechanistic Transform Application
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4. T-Goal Search using Tactical Combinations of Transforms
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4. T-Goal Search using Tactical Combinations of Transforms
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