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The Logic of Chemical Synthesis

- E.J. Corey and X-M. Cheng -

교과목 : 약품합성화학수강대상 : 약학부 4 년수강학기 : 2007 학년도 1 학기

The Basis for Retrosynthetic Analysis

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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.

Retrosynthetic Analysis

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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.

Transforms and Retrons

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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.

H

H

H

H

H

+

Carbo-Diels-Alder Transform

Transforms and Retrons

H

H

H

H

H

H

H

H

HCatalytic

hydrogenationTf.

Simmons-Smith

Tf.

12 3

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CO2Me

CO2MeMe

HCO2Me

CO2MeMe

H

+Me

MeO2C

CO2Me

4

2, 3, and 4 can be regarded as a partial retrons for D-A Tf.

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Types of Transforms

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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

H

MeH FGI

O

H

MeH Conia (Oxo-ene)

Cyclization

O

H

CHO

O

MePh

O FGI

NefO

MePh

NO2

O

Me+

NO2

Ph

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H

HMe

Me

O

OMe

FGTH

HMe

Me

O

OMe

TMS

Me

TMS

+Me

Me

O

O

FGT Transforms

Rearrangement Transforms

H

HO

Oxy-Cope

Rearrangement

OH O Cl CN+

O Pinacol

Rearrangement

HO OH O

2

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FGA Transforms

O

Ph Ph

H H

FGA

O

Ph Ph

H H

CO2MeDieckmann

Cyclization

Ph Ph

H H

CO2MeMeO2C

Ph

CO2H2

H

H

O FGAH

H

O

Cl

Cl

+Cl

ClC O

Stereocenters Transforms

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(-)-1N

BnO

BnO HN

BnO OBn

RCM HN

BnO OBn

Br

NHCBz

OBn

OBn

Br

OBn

OBn

OBnO

BnO

OBn

OBn

OH

CSI

2 3 4

5 6 7

O

RO RO

OH

OH

RO

O

OH

O

Me

Ph MeMe

RO

+OO

Me

Ph MeMe

Synthesis of (-)-Lentiginosine Y.H. Jung et. al. Org. Lett. 2006, 8, 4101-4104

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H

BnO

H

C NO

O

H

Bn SO2ClN

COOBn

Ph

Br

OBnH

Br

OBnH

HPh

SO2Cl

OBn

Transition state A

1,2-anti-tribenzyl ether 6

Br

NHCbz

OBn

OBn

1,2-anti-product 5a

BnO

H

C NO

O

H

Bn SO2ClN

COOBn

Ph

Br

OBnH

Br

OBnH

Ph

SO2Cl

OBn

Transition state B

1,2-syn-tribenzyl ether 9

Br

NHCbz

OBn

OBn

1,2-syn-product 12

H

H

first inversion of configuration

second inversion of configuration

Figure 1. Proposed reaction mechanism of cinnamyl polybenzyl ethers 6 and 9 with CSI.

Y.H. Jung et. al. Org. Lett. 2006, 8, 4101-4104

1. Tranform-Based Strategies

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Diels-Alder Cycloaddition as T-Goal

+

- Retrosynthetic analysis of Fumagillol

- Retrosynthetic analysis of Ibogamine

- Retrosynthetic analysis of Estron

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

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R2R1

OHR3

(CH3)3COOH(TBHP)

Ti(O-ipr)4

CH2Cl2, -23oC

R3

R2

OH

R1

O

D-(-)-diethyltartrate

L-(+)-diethyltartrate ((+)-DET)

'O'

'O'

HO

HO C

C

COOR

COOR

H

H

R OHAE

(+)-DET

R OHO

* This reactions are effective for the kinetic resolution of racemic allylic alcohols.

R R'AE

(+)-DETOH

R R'

OH

R R'

OH

O+

Sharpless Asymmetric Epoxidation

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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