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 O + O Cl O S S Li

Reagent

Disconnections Basic Guidelines:

1. Use disconnections corresponding to known reliable reactions, choose disconnection corresponding to the highest yielding reaction.
a Ph Ph + -

+ +

- CH + CH

+ PhCH2 b PhCH2 -

+ +

2. Disconnect C-C bond according to the present FGs in the molecule, few examples:
a. C-C bond with no neighbouring functional groups R R' R C

R'

b. C-C bond with one oxygen substituent R OH R C

c. Allylic C-C bond R C

+

d. C-C bond with two oxygen substituents in positions 1,3 O R OH R' R O C

O + C

R'

e. C-C bond with two heteroatom substituents in positions 1,2 or 1,4. Umpolung methods. O R C + NO2 a R NO2 O a b b R O +

NO2

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

O O Quadrone O O

O OH

b) disconnect in the middle of the molecule

CHO Faranal, Pharaoh's ant trail pheromone EtMgBr.CuBr C9: C9

Ph3P+

C7

CHO protection needed

MgBr*CuBr

O C7: O 1. LiAiH4 O 2. MsCl 3. LiAlH4 O 1. TsCl 2. NaI EtO I KMnO4 HO HO

O 1.EtOH/H+ 2.BH3/THF O EtO HO

Tetrahedron Lett. 1981, 22, 5001

c) disconnect at a branch point d) use symmetry

MeCOOEt OH
OH O O OH

MgBr

MgBr

OMe O

HO OH O

OH

OH

OH O OH

SET

MeO OMe O

OH

(+)-Hybocarpone -

K.C.Nicolaou Angew. Chem. Int. Ed. 2001, 40, 761

e) disconnect rings from chain

OMe
HO N

OMe

+
N

BrMg

f) use rearrangements
O Claisen O O O O O O O HO O O O O O OEt

OH O

HO

H Oxy-Cope H O OH O

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

+
O O O

X Y OR

X Y

+
O

OR

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

O O O HO

CO2H

h O AcOH/H2O CO2H

h O MeOH CO2Me

CO2Me

Base TsNHN O O

ZnBr2 O

Br Me H

OH

OTs t-BuOK

H OH OMe 1. O3 2. NaBH4 OMe O OH O

NOCl O H2O

NOH O

Examples of effective disconnections:

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

Br

OH

OH Key step
(RO)2

Geraniol

O P Br

CO2Me

OH Br OH

OH

THF, -78 t-BuOK 18-crown-6, 30 min.

oC,

R = Et mixture E:Z R = CF3CH2 exclusively E

HO

OH

Tetracyclic Tigliane ring system anionic cyclisation

H OH O OH OH O

Claisen

OH

Phorbol

MeLi cat., Ph2O, heat Ovaska TV et al, Org. Lett. 2001, 3, 115

MeHN NMe

COOH

+
O

MeNH2

O COOH

Tropinone Willstatter, 1902, 19 steps, yield 0.75%

Robinson, 1917, yield 17%

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

-e

-e

C+

O 2 e 2 e 2 e

O H

H
+
C

+
C O H

2+
C O

2C

3+
O

2O H

2 e

..
C C C C C H H H H

..
C

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

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-CC-Y; epoxides. Oxidation level 3 (alkane 6e): COOH, COX (X = OR, Hal, OCOR, NR2);CN, C=C-C=O, C=C-CC

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. R O R' R O R'O but Hal R' R OH ??? Hal R O

but

Hal

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) R OSO2R' R OH R Hal R
+

R X

R Y

sythones

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

-HX R X H HX X R' R R'

R'

H H

Markovnikov

anti-Markovnikov

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

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:
O HC Base O
TMSCl

OTMS

RLi

Li

Formation of vinyl derivatives.

O X

X = Hal, OR, OCOR

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
CH2 + SMe2

-H+

X O

-XO
O

+YO

+H+ OH

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

Formation of allylic systems:

OH O

MgX H-

OH

NBS

Br

O H

1) TMSOTf, 2) Base Or LDA, heat

HO

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 Et3N O

Polyfunctional compounds of level 3 are ,-unsaturated aldehydes and ketones good Michael acceptors:
O HX X O X = 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.
[O] [O] O OR O [H-] O [H-] OH OH

OH

Other important kind of transformations interconversion of nitrogen containing functions.

RCN OH R NR2 NO2R Hal N3[O] R N3 O NR2 NR2 R NO2 [H] R NH2 R NH2 R NR2 R NH2

O R

RNH2 R NO2

RNO2 R OMe OMe

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:

HO O H

NH2. HCl

GABAB receptor agonist (R)-balcofen hydrochloride

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

H N N O Ph
+

Br

Catalyst

Cl

O MeNO2 Cl NiCl2/NaBH4 H cat.

NO2

PhO mCPBA Cl O H

NO2

Cl

HN O

5N HCl Cl

TM