Retrosynthetic Analysis. E.J Coreys definition of retrosynthetic analysis: it is a problem solving technique for transforming the structure of synthetic target molecule (TM) to a sequence of progressively simpler structures along the 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

Disconnection: the reverse operation to a synthetic reaction, the imagined cleavage of a bond,

Functional Group Interconversion (FGI): the process of converting one functional group into another by substitution, addition, elimination, reduction, or oxidation.

Each structure thus derived from TM then itself becomes a TM for further

analysis. Repetition of the process eventually produces a tree of intermediates having chemical structures in the nodes and possible chemical transformations as pathways from bottom to TM. One should avoid excessive branching and proliferation of useless pathways. Strategies for control and guidance are of the utmost importance.

Synthetic Strategies: Choosing the way along the retrosynthetic tree, synthetic planning. Synthetic Tactics: How a specific bond or set of bonds at a given site can be efficiently created.

Tactics of synthesis. Retron The minimal substructural element in a target structure which keys the direct application of a disconnection to generate a synthetic precursor. For instance, in Diels-Alder reaction the retron, a minimal keying element, is 6-membered ring with a -bond:

+

Synthon An idealised fragment, usually cation or anion, resulting from a disconnection. May or may not be an intermediate in the corresponding reaction. Reagent compound used in practice for a synthon.

Synthon

Reagent

O+

O-

O

Cl

S

S Li

Disconnections

Basic Guidelines: 1. Use disconnections corresponding to known reliable reactions, choose disconnection corresponding to the highest yielding reaction.

baa

bPhCH2

PhCH2

+

-

+

+

-

+

Ph

Ph

+

-CH2

CH2

-

+

+

+

2. Disconnect C-C bond according to the present FGs in the molecule, few examples:

R R' R C R'

R OH O H+

R C

R RC+

R

O

R'

OH

R C

OC

+

R'

OH

+

R

O

NO2R C

O

NO2R

O

NO2

a. C-C bond with no neighbouring functional groups

++

b. C-C bond with one oxygen substituent

++ +

c. Allylic C-C bond

+

d. C-C bond with two oxygen substituents in positions 1,3

++

e. C-C bond with two heteroatom substituents in positions 1,2 or 1,4. Umpolung methods.

a ba b+

+ - +- +-

3. Aim for simplification: a) Disconnect C-X bond (RCO-X)

O

O

O OH

O

OQuadrone

b) disconnect in the middle of the molecule

CHO OCHO

Ph3P+

MgBr*CuBr O O

O

O

O

O

OHOH

O

O

OHEtO

O

IEtO

-+protection neededC9 C7

C9:EtMgBr.CuBr

+ +

C7:1. LiAiH4

2. MsCl3. LiAlH4

KMnO4 1.EtOH/H+

2.BH3/THF

1. TsCl

2. NaI

Tetrahedron Lett. 1981, 22, 5001

Faranal, Pharaoh's ant trail pheromone

c) disconnect at a branch point d) use symmetry

OHMgBr MgBr

O

O

OH

OH

OH

O

O

O

O

OH

OH

OHOH OH

OH

O

O

OMe

OMe

MeO

MeCOOEt + +

K.C.NicolaouAngew. Chem. Int. Ed. 2001, 40, 761( )-Hybocarpone

SET

+-

e) disconnect rings from chain

N

OH

OMe

OMe

BrMgN

O

+

f) use rearrangements

OO

O O

OH +O O

OEt

O

O O

O

OH O

OOH

O

O

Claisen

O

H

H

Oxy-Cope OHO

Cl CN+

4. Carbocyclic Rings:

If one or more 6-membered carbocyclic unit present in the molecule consider a set of

disconnection available for construction of 6-membered rings: Diels-Alder, Robinson annulation, aldol, Dieckmann, internal SN2, Birch reduction, etc. Some types of Diels-Alder disconnections:

O

O O

O

XY

XY

O

O

O

O

OR

OR

O

+ +

+ +

++

5. Examples of cleavage of C-C bond as a retrosynthetic reconnection

O OO OH CO2H

O CO2H

O CO2Me

OTsNHN O

O

OHBr

Me

OH

HOTs

O

H

H

OMe

O

OMe

OH

O OO

NOH

CO2Me

AcOH/H2O

h

h

MeOH

Base

ZnBr2

t-BuOK

1. O3

2. NaBH4

NOCl

H2O

Examples of effective disconnections:

OH

OH

OH

OHBr

Tago K and Kogen H Tetrahedron, 2000, 56, 8825

+

Plaunotol

OH Geraniol

Key stepOH

OHBrO OH

P

Br

CO2MeO

(RO)2

THF, -78 oC, t-BuOK18-crown-6, 30 min. R = Et mixture E:Z

R = CF3CH2 exclusively E

OOOH

HOH

OH

OH OH Tetracyclic Tigliane ring system

Phorbol

ClaisenO OH

anioniccyclisation

Ovaska TV et al, Org. Lett. 2001, 3, 115

MeLi cat., Ph2O, heat

O

NMe

O

O

O

COOH

COOH

O MeHN

Tropinone

+ +MeNH2

Robinson, 1917, yield 17%Willstatter, 1902, 19 steps, yield 0.75%

Functional Group Interconversion (FGI): Classification of functional groups by oxidation state of carbon atoms: Oxidation state of carbon in alkanes (cycloalkanes ) is 0, the carbon in the fragment C-H is approximated as carbanion

Oxidation level 1 (alkane 2e): C-X (X = Hal, OH, OR, OAc, OTs, NR2, NO2, SR, etc); C=C Oxidation level 2 (alkane 4e): C=X (X = O, NR); CXY (X, Y = Hal, OR, SR); C=C-X (X = Hal, OR, OSiR3); CC; X-C-C-Y; epoxides. Oxidation level 3 (alkane 6e): COOH, COX (X = OR, Hal, OCOR, NR2);CN, C=C-C=O, C=C-CC

C C C +.- e - e

H

H

H

O H

H

O

O

O H

- 2 e- 2 e - 2 e

CH

+C

+C

2+O

2-C

3+O

2-O H

_

O H

_

L e v e l 0 L e v e l 1L e v e l 2 L e v e l 3

H

HH

H

- 2 e

HH

- 2 e

C C

H H

C

C

H H

C C

.. ..

L e v e l 0 L e v e l 1

L e v e l 2

Based on this classification FGI can be divided into two groups: Type 1. Isohypsic transformations with no change to the oxidation level of carbon Type 2. Non-isohypsic transformations, where carbon atom is either reduced or oxidised.

In general, on the same oxidation level any functional group interconversion can be performed in more or less easy way. However, transformations between levels can be achieved only on certain derivatives.

Type 1 (no change in oxidation state), Level 1. The most common functions resulting from C-C bond construction are alcohol (Grignard addition to carbonyl compounds, aldol reaction, etc) and olefin (Wittig and related processes, croton condensation, olefin methathesis, etc). In addition, FGI of type 2 often lead to alcohols and olefines (reduction of carbonyl compounds, partial hydrogention)

Conclusion: in practice all functions of oxidation level 1 are synthetically equivalent as they can be easily transformed into each other.

OR'R O

R'R

R'Obut OH

RO

R

HalHal Hal???

but

R OHR OSO2R'

R Hal

R+

sythones

R X R YY

X = Hal, OTs, OMs, OTfY = OR', OCOR', SR', NR'2, N3, NO2

XR R'

R R' R R'+

H

-HX

HHX

HXH+

HX

Markovnikov anti-Markovnikov

Type 1 (no change in oxidation state), Level 2. The main functional groups are carbonyl compounds (aldehydes and ketones) and alkynes. Formation of synthetic equivalents of carbanions:

Formation of vinyl derivatives.

In organic synthesis vinyl halides can play a dual role: as electrophiles in reaction with organocuprates and as nucleophiles when transformed themselves into organometallic derivatives. Compounds having two functional groups of level 1 which react as a whole belong to level 2 (1,2-disubstituted compounds, oxiranes, allylic systems)

X

OH

-H+ X

O O

-X- +Y-

O

Y

OH

Y+H+

Formation of epoxides in a C-C bond forming procedure (apart from epoxidation of olefines):

O + CH2 SMe2- + O

Formation of allylic systems:

O MgX+OH

O OHH-

NBS Br

O

H

1) TMSOTf, 2) Base

Or LDA, heat

OH

CHO OBase OTMS

H C Li+

TMSCl

RLi

XO

X = Hal, OR, OCOR

Type 1 (no change in oxidation state), Level 3. The main functional group that allows formation of any other derivative on the same level is acid halide. This is a typical electrophile used to make derivatives of carboxylic acids and in Friedel-Crafts C-C bond forming reactions.

O

X

Et3NO

Polyfunctional compounds of level 3 are ,-unsaturated aldehydes and ketones good Michael acceptors:

O HX OXX = OH, Hal, SR. NR2, etc

Type 2 transformations. Availability of methods to go from alcohol to carboxylic acid derivatives and back makes alkohol, carbonyl and carboxyl functions synthetically equivalent.

OH O OH

O

[O] [O]

OR

O

[H-]O

[H-]OH

Other important kind of transformations interconversion of nitrogen containing functions.

R

O

OH

RCN

R

O

NR2

R NH2

R NR2

NR2 NR2

R HalR NO2

R N3

R NH2

R NH2

NO2-

N3-[H]

RNH2 RNO2[O]

R NO2 OMeOMe

R

Conclusions: 1. Many functional groups, especially on the same level of oxidation, can be considered as

synthetically equivalent so their retrosynthetic interconversions can be planned. 2. As any functional group can be removed, retrosynthetically we can put a functional group

in any position of alkane or cycloalkane chain and that would allow assembly of a given C-C fragment. Unfortunately, reverse is not achievable as yet.

Example:

Cl

NH2OH

O H

Cl

O

Cl

ONO2

Cl

PhO

O HNO2

ClHNH

O

N+

NO

Ph

HBr

GABAB receptor agonist(R)-balcofen hydrochloride

HCl.

E.J.Corey, F-Y Zhang, Org. Lett, 2000, 2, 4257

MeNO2

cat.

mCPBA

NiCl2/NaBH4 5N HCl TM

Catalyst

Retrosynthetic Analysis.Tactics of synthesis.DisconnectionsBasic Guidelines:Examples of effective disconnections:Conclusions: