Inspired by ORGANIC CHEMISTRY, by Clayden, Greevs, Warren and Wothers 1.

1

Inspired by ORGANIC CHEMISTRY, by Clayden, Greevs, Warren and Wothers

Molecola da sintetizzare "Target""

Ph Ph

OH

1,5-difenilpentan-1-olo

Ph Ph

OH

Ph Ph

OH

sintoni

PhBr Mg, Et2O

PhBrMg Ph

O

Ph Ph

OMgBrH2O/H+

Ph Ph

OH

Ph

O

PhPh? Br

reagenti XMg


2


P X + Y

Ph O Ph

O

Ph OH Cl Ph

O

+ repellente degli insetti

NH2

O

O2N

Cl

O

O2N

H2N

+AMELFOLIDEmedicinale per learitmie cardiache

HONH

O

O

N HOCl

O

O

H2NN+

H2NN

O

O

O

+

DIAMINOZIDEfitofarmaco, impedisce lo sviluppodi alcune pianteInspired by ORGANIC CHEMISTRY, by Clayden, Greevs, Warren and Wothers

3


The Nobel Prize in Chemistry 1990"for his development of the theory and methodology of organic synthesis"

Elias James Corey

USA

Harvard University Cambridge, MA, USA

b. 1928


4


Retrosynthtic AnalysisDuring the first half of this century most syntheses were developed by selecting an appropriate starting material, after a trial and error search for commercially available compounds having a structural resemblance to the target of synthesis. Suitable reactions were then sought for elaboration of the chosen starting material to the desired product. Synthetic planning in most instances was strongly dependent on an assumed starting point. In the fall of 1957 I came upon a simple idea which led to an entirely different way of designing a chemical synthesis. In this approach the target structure is subjected to a deconstruction process which corresponds to the reverse of a synthetic reaction, so as to convert that target structure to simpler precursor structures, without any assumptions with regard to starting materials. Each of the precursors so generated is then examined in the same way, and the process is repeated until simple or commercially available structures result.


5


This “retrosynthetic” or “antithetic” procedure constitutes the basis of a general logic of synthetic planning which was developed and demonstrated in practice over the ensuing decade. In an early example, retrosynthetic planning for the tricyclic sesquiterpene longifolene (1) (Chart I) produced several attractive pathways for synthesis, one of which was selected and validated by experimental execution. The basic ideas of retrosynthetic analysis were used to design many other syntheses and to develop a computer program for generating possible synthetic routes to a complex target structure without any input of potential starting materials or intermediates for the synthesis. The principles of retrosynthetic analysis have been summarized most recently in the textbook, “The Logic of Chemical Synthesis” which was written for advanced undergraduate and graduate students of chemistry.


6

Inspired by ORGANIC CHEMISTRY, by Clayden, Greevs, Warren and Wothers Inspired by ORGANIC CHEMISTRY, by Clayden, Greevs, Warren and Wothers

7


The retrosynthetic way of thinking about chemical synthesis also provided a logical and efficient way to teach synthetic planning to intermediate and advanced students, a good example of the intimate link between teaching and research in an academic setting. A brief synopsis of the retrosynthetic planning of syntheses will now be given.Retrosynthetic (or antithetic) analysis is a problem-solving technique for transforming the structure of a synthetic target (TGT) molecule to a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. The transformation of a molecule to a synthetic precursor is accomplished by the application of a transform, the exact reverse of a synthetic reaction, to a target structure.


8


Each structure derived antithetically from a TGT then itself becomes a TGT for further analysis. Repetition of this process eventually produces a tree of intermediates having chemical structures as nodes and pathways from bottom to top corresponding to possible synthetic routes to the TGT. Such trees, called EXTGT trees since they grow out from the TGT, can be quite complex since a high degree of branching is possible at each node and since the vertical pathways can include many steps. This central fact implies the need for strategies which control or guide the generation of EXTGT trees so as to avoid explosive branching and the proliferation of useless pathways. Each retrosynthetic step requires the presence of a target structure of a keying structural subunit or retron which allows the application of a particular transform. For example, the retron for the aldol transform consists of the subunit HO-C-C-C=O, and it is the presence of this subunit which permits transform function, e.g. as follows:


9


Transforms vary in terms of their power to simplify a target structure. The most powerful of simplifying transforms, which reduce molecular complexity in the retrosynthetic direction, occupy a special position in the hierarchy of all transforms. Their application, even when the appropriate retron is absent, may justify the use of a number of non-simplifying transforms to generate that retron. In general, simplifying transforms function to modify structural elements which contribute to molecular complexity:molecular size, cyclic connectivity (topology), stereocenter content, element and functional group content, chemical reactivity, structural instability, and density of complicating elements.


10


HN

HOO

NH2

HO

O

O

Cl

O O+

PARACETAMOLO

Cl

Cl

O CO2H

Cl

Cl

OCO2H erbicida

sintone sintone

Cl

Cl

OHCO2HX

reagente reagente

X = Cl, Br, OTs

O

O

Cl

O OSintone

O

11


Cl

Cl

O CO2H

Cl

Cl

CO2H

sintone sintone

O

reagenti ?1. La disconnessione deve fare riferimento a meccanismiaffidabili

+

S

Cl

Cl

ClS

Cl

SH

Cl

Cl

Cl

2. In presenza di un eteroatomo, la disconnessioneva praticata adiacente allo stesso

+ base

+

O

OEt

NH

R

R = C15H31 CETABEN etil estere (farmaco antilipidi del sangue)

BrR O

OEt

H2NR

O

H2N

+

OEt

Clorobenzide, antizecche

12


OHN

O

OO

NH

O

OMe

ICI-D7114antiobesità

HN

O

O Ph

Ph

a

bcd

aO Ph OH

PhX+

sintoni reagenti

b

O

HNPh

HO

HNPh

X

reagentisintoni

←Importante intermedio

13


c NHPhO

d Ph

OHN

NH2PhO

X

Ph

OH2N

X

reagentisintoni

reagentisintoni

a

OH

PhX+

b

HO

HNPh

X

Alchilazione di un fenolo in presenza di ungruppo amminico basico ! CHEMOSELETTIVITA'

c

d

NH2PhO

X

PhO

H2NX

+

HN

O

O Ph

Ph

a

bcd

14


HN

O

O Ph

Ph

a

bcd3. Nel caso di disconnessioni alternative è meglio scegliere il percorso che non pone problemi di CHEMIOSELETTIVITA' (nella sintesi è meglio introdurre dopo i gruppi reattivi - nella retrosintesi disconnettere prima i gruppi reattivi)

BrO

O Ph

f

ee

BrO

O Ph

BrO

OH

PhBr+

sintoni

reagenti

f

O

O Ph

Br

HO

O Ph

BrBr

sintoni

+ reagenti

15


HO

O Ph O

HO

Ph

OH

HO

PhCl

sintoni

reagenti

OH

HO

PhCl O

HO

PhBr

Br

O

O

Ph

Br

Ph NH2O

O

Ph

HNPh

HN

O

O Ph

Ph

a

bcd

bis alchilante

alchilante

16


Interconversione di gruppi funzionli

N

NH

N

O

OFORNINA antiipertensivo

HN

NH

N

O

N

NH2

N

O

Cl

b

a

Disconnessione ammidica: Disconnessione amminica

a b

HN

NH2

O

Cl

?

NH2

N

O

Cl

???

17


NH2

O

OH

N

Cl

+

NH

N

O

OH SOCl2

NH

N

O

Cl HN

FGI

18


NH2 NH

R

?NH2NH

R

>>

1. R ingombrante

CO2Et

H2N

CO2Et

NH

R Br

R

CO2Et

NR

R Br

R

X

2. R elettronatrattore

3. FGI trasformare l'ammina in un derivato meno reattivo prima della disconnessione

R NH

R'

FGIR N

HR'

O

R NH2 R'

O

Cl+

sinteticamente, il derivato meno reattivo precede l'ottenimento dell'ammina

19


R NH2 R'

O

Cl+ R N

HR'

O

R NH

R'

LIAlH4

(BH3)

R NH

R'

FGI

R N R' R NH2 R'O+

R NH2 R'O+H+

H2OR N R' R N

HR'

NaBH4

(H2/cat)

20


Studioso della Chimica Organica, diede il suo nome a derivati di aldeidi con ammine, lavorò nell'allora Laboratorio Chimico della Università in Via San Francesco da PaolaNato a Francoforte nel 1834 da una antica famiglia israelita, morì nel 1915. Tedesco, allievo di Wohler, uomo di grande cultura e di idee liberali, profugo dalla sua terra, fu Professore di Chimica all'Università di Torino. Prima di approdare in Italia, a Pisa, a Firenze e poi a Torino, fu costretto a continui spostamenti in Laboratori chimici europei molto avanzati, Goettingen, Berna, per le sue idee (frequentava ambienti di impostazione politica avanzata per i tempi).

21


NPh

N

OOMe

F

OCFENTANIL antidolorifico

NPh

N

OOMe

F

NPh

HN

OOMe

F

Cl

NPh

HN

F

FGI

NPh

N

F

NPh

H2N

F

O

22


NPh

H2N

F

O

+ H+

H2O NPh

N

F

rid

NPh

HN

F

+O

OMe

Clprodotto

23


F3C

HN FENFLURAMMINA farmaco anoressizzante

F3C

HN FGI

F3C

HN

O

F3C

NH2

O

Cl

FGI

F3C

NH

F3C

O

NH2OH

24


Ph

Ph HNTERODILINA calcio-antagonista

Ph

Ph HN FGI

Ph

Ph N

Ph

PhH2NO

FGI !!!!

Ph O

Ph HN

25


O

OH

Ph

a b b O

OH

Pha

O

OH

Ph

OHOH

Ph

NaH OBr

+ O

OH

Ph

+O

Ph

O

OH

Ph

Disconnessione di due gruppi (di tipo 1,2)

1

2

La relazione spaziale 1,2 è presente in molti composti di interesse farmacologicoper esempio nei 2-AMMINOALCOLI

PhNH

OH

N1

2

O

PhH2N N

Feniramidolo rilassante della muscolatura

26


O NH

OH

PROPRANOLOLO farmaco beta-bloccante anti-ipertensivo (ZENECA)

O

O

Cl

O NH

OH

O

HN

OH

OO

O

O

Cl+

O

O

Cl O

O

27


R

OH

sintone

O R

reagente

R

O

sintone

RCl

reagente

O

OH+ O

HO

H

H

H+ OH

Cl Cl

ON

O

H2N

N

O

MOXNIDAZOLO antiparassitario

HOHN

H2NN

O

O O

O

N

OO

HN

O

O

Cl+ N

O NH2NH2O

28


N

O N

NAFIMIDONE farmaco anti-convulsioni

1 2

HN

O N

sintone

O

Cl

reagente

imidazolo

29


Disconnessione 1,3

Nu

O

Nu

O1,3

sintone

O

reagente

"accettore di Michael" alchene nucleofilo, coniugazione con CO, CN, NO2

12

3

12

3

Ph SCO2Me

Ph SCO2Me

Ph SH CO2Me

N

Ph

O N

Ph

O

NH

Ph

O

Mimetico dell’Atropina

OH

O N

O

30


Sconnessioni C C

H + base

X

H H

LindlarNa

NH3liqH

H

OH

FGI

Lindlar

OH OH

H+base O

HBr

Intermedio per la sintesi dell’aroma di garofano

31


(CH2)9O

O

(CH2)9O

O

FGI

(CH2)9

OH

feromone farfalla dei piselli (pea-moth)

(CH2)9

OH

CH3 (CH3 I)

(CH2)8

OH

(CH2)8

OHBr

Protezione OH

32


OEt

O O

EtO OEt

O OO

EtO

O

reagente sintone reagente sintone

O

intermedio sintesi -carotene

O

Br OEt

O O

PhO P(OBu)2

P(OBu)2

O

O

C PC S

BELFOSIL farmaco Ca2+ bloccante

PhOCH2OH P(OBu)2

CH2OHP(OBu)2

O

O

FGI

PhO

O

OEt

O OEt

PhO

O

OEt

O OEt

Br

? CH2OH

CH2OH

?OTs

OTs

33


Ph OH Ph OH

Uso dei reattivi di Grignard nelle sconnessioni C C

PhOsintoni reagenti

profumo del Lillà

MgBr

PhOH

a

bc

profumo della Peonia

a

b

c

Ph O

Ph O

MgIPh

O

BrMgAccessibilità al chetone ?

a: acetacetica [MeCOCH2COOEt + EtBr]b: Grignard [PhCH2CH2Br + CH3CH2CHO] poi oxc: aldolica [PhCHO + CH3COCH3] poi H2/Pd

MgBr

34


R1 R3

OH

R2 R1R3MgX

O

R2R1

OH

R2R1

R2MgX

O

R1

O

R2

FGI

R1

OH

R2 R1 R2

OH

R2 R1R2MgX

O

OR'

Doppia Disconnessione

Ph N

OH

Ph

2 X2PhMgBr +

EtO N

O

EtO HN

O

35


Sintoni "donatori" o -; Sintoni "accettori" o +

R

d a

OH

a1R

OH

a2R a3

OH

R

O

d2

R

O

R

O

R

O

R

O

12

12

312

1

OFGI

OOH OOH

O O

Condensazione aldolica: gruppi funzionali in relazione 1,3

O OH1

2

3

O OH1

23

O

d2

O

a1

36


Non tutto è sempre così semplice in sintesi !!

H

O

H

O

OH

FGI

H

O

OH O H

O

+??

O

BrOEt

O

Zn

OEt

BrZnOOEt

O

OH

37


EtO2C

HO

MeO

EtO2C

HO

MeO

EtO2C

CO2Et

O

MeO

EtO2C

CO2Et

Br

Farnaco antagonista del TROMBOXANO, anticoagulante (ICI)

38


F

O

HN

CINFLUMIDE rilassante muscolare

F

O

H2NCl

F

O

OH

FGI

HOF O

OH

O

EtO OEt

OO

39


N O

O

N

DOXPICOMINA analgesico

N OH

OH

N

FGI

N O

O

N EtO

EtO 1

23

N O

O

HN

EtO

EtOFGI

N O

O

EtO

EtO

OH

N O

O

EtO

EtO

O

Knoevenagel

40


R1

R

OH

NH2

12

3

FGI

R1 CN

R

OH1

23 R1 CN

R

OH

R1

O CN

Raldolica nitrile: relazione 1,3addizione nitrile: relazione 1,2

C N analogo azotato del C=O

R

CN B:

R

CNO

CN

R

OH

R

OH

NH2

41


R1

O CN

R1

OH

CN

LiAlH4

R1

OH

NH212cianidrina

Me

NMe

HO

MeO

VENLAFAXINA antidepressivo

NH2HO

MeO

FGI CN

HO

MeO

CN

OMeO

+ Br

MeO

+ CN

aldolica nitrile: relazione 1,3addizione nitrile: relazione 1,2

42


H3C H

OHO

+ H2C=O H

OOH

HH

H H

HO

H

OOH

HO

HO

H2C=OHO

H

OHOH

HO

HO

H

pentaeritrolo

Cannizzaro O O

H H

H2COOH +

43


Reazione di MANNICH [aldeide o chetone enolizzabile, ammina secondaria e formaldeide]

O

Me2NH, H2C=O

H2O/cat. HCl

O

NMe2

MeI

O

NMe3H

OH

O

NMe3

OE1cB

H H

O

N Me

Me

H

O NMe

HMe H+

HO NMe

Me HCl

H2O NMe

MeCH2 N

O

HCl

HO

H+

O

NMe2

44


Disconnessione di MANNICH

HO NR2

R1

R2

FGI

O NR2

R1

R2

Mannich

O HNR2

R1

R2

H2C=O

ClHO NM2 Cl O NM2

MgCl

O

HNM2 + H2C=O+

CLOBUTINOLO antitosse

45


MeO

HO

Ph NMe2

XFGI

Ph NMe2

O

MeO

O

Ph NMe2

analogo della NISOXETINA antidepressivo

Ph

O

HNM2 + H2C=O+

46


Disconnessione di CLAISEN

N

Ph

TAZADOLENEanalgesico non opiaceo

O

Ph

O

intermedio

1

2 3

O

Ph

O

O

NH

O

+

N

O

PhCOCl

OPh

OPh NH2

H2/cat

OPh

N Ph

OHPh

HN Ph

OHPh

NH2

H2O

NH2 Br Br

Ph

+ N

Ph

N

O

O

Cl

enammina

O

N+

O H2O/H+

47


R1 R2

OH O

12

3 R1 R2

O O

R1 R2

O

R12N R2

O

12

3 R12NH + H2C=O +

R2

O

R1 NH2

OH

123

R2

R1 CN

OH

R2

R1 CN

O

R2

R1 R2

O O

12

3 R1 R2

O O

R1 R2

O O

OEt

Sconnessione 1,3

48


Relazioni 1,5 Addizione di Michael

O

HO2C

12

34

5

O

HO2C

sintone d2 sintone a3

EtO OEt

O O

O

O

EtO OEt

O O

EtO

O

CO2Et

EtO2C

KOH/H2O

H+/

O

HO2C

49


N

NH

O

O

ROGLETIMIDE sedativo

N

CO2Et

CO2Et

N

CO2Et

CO2Et1

5

N

CO2Et

N

CO2Et

Br

N

CO2Et EtBr

base N

CO2Et

base

CONH2

N

CO2Et

CONH2

50


R

OHa1

Ra3

OH

R

O

d2

R

O

R

O

R

O

1

2

3 1

21

adispari dpari

Le proprietà di "donatore" o "accettore" si alternano procedendo lungo la catena a

partire dal gruppo C=O. Questo spiega la facilità delle disconnessioni per formare

composti 1,3 ed 1,5 funzionalizzati. Derivano da sintoni a1 + d2 e a3 + d2.

Reagenti corrispondenti a sintoni a2 e d1 sono più rari e qundi composti con

relazioni funzionali 1,2 ed 1,4 richiedono più impegno retrosintetico.

R

OHa2

R

O1

2C N

d1

KCN

Composti 1,2-bifunzionali

R1

OH

OH

R2 FGI

R1R2

R1 OR2

PPh3

FGIR2

XWITTIGadd el

51


Cl

OH

OH

12

Cl

CO2Et

OH

2FGI

Cl

CN

OH

21

ClCN

OCl

Ac2O

AlCl3

Cl

O

FENAGLICODOLO farmaco tranquillante

52


Composti 1,4-bifunzionali

R1R2

O

O

1

2

34

R1 R2

O

O

R1

O

? "polarità chimica inversa"R2

O

Br

R1R2

O

O

1

2

34

R1R2

O

O

? "polarità chimica inversa"

R2

OR1

R2

O

O

1

2

34

R1R2

O

O

R2

O

Cl

? "polarità chimica inversa"

Se riesco a disconnettere "fuori" dalla relazione 1,4.............

OEt

O

O

1

2

34 FGI OH

O

O

O

O

O

+

Inspired by ORGANIC CHEMISTRY, by Clayden, Greevs, Warren and Wothers 1.

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Transcript of Inspired by ORGANIC CHEMISTRY, by Clayden, Greevs, Warren and Wothers 1.