Advanced Retrosynthesis.

General overview.
1. Introduction: summary on disconnections and normal carbonyl reactivity. Definition of disconnection, FGI (functional group interconversion), synthon and reagent, synthetic strategies and tactics. Examples of one-group and two-group disconnections. Revision of normal carbonyl reactivity. 2.

2-Group disconnections: unnatural reactivity patterns and other strategies

2.1. Synthetic strategies for 1,2-difunctionalysed compounds 2.1.1. Use of available starting materials 2.1.2. Difuctionalisation of alkenes 2.1.3. -Functionalisation of carbonyl compounds 2.1.4. Radical coupling 2.1.5. Umpolung strategies: 2.1.5.1. Cyanide anion + electrophilic carbonyl 2.1.5.2. Cyanohydrins, benzoin condensation 2.1.5.3. Dithians(thioacetal) nucleophile + electrophilic carbonyl 2.1.5.4. Nitroalkane nucleophile + electrophilic carbonyl 2.1.5.5. Imidoyl nucleophile + electrophilic carbonyl 2.1.5.6. Alkyne nucleophile + electrophilic carbonyl Functional group interconversion: amine synthesis Synthetic strategies for 1,4-difunctionalised compounds 2.3.1. Acyl equivalent + Michael acceptor 2.3.2. Homoenolate + electrophilic carbonyl 2.3.3. Additional umpolung strategies: 2.3.3.1. Enolate + -functionalised carbonyl compound 2.3.3.2. Enolate + ,-unsaturated nitrocompound (Michael-type acceptors 2.3.3.3. Epoxide based transformations 2.3.4. Functional group addition (retrosynthetic technique of introducing a required functional group to facilitate a certain chemical transformation) Synthetic approaches to cyclic systems 2.4.1. Cycloadditions 2.4.2. Conventional methods of acyclic chemistry 2.4.3. Other methods Reconnection strategies 2.5.1. Ozonolysis of cycloalkenes 2.5.2. Baeyer-Villiger rearrangement 2.5.3. Beckmann and related rearrangements

2.2. 2.3.

2.4.

2.5.

3.

Summary of retrosynthetic strategies; some guidelines for retrosynthetic analysis; useful synthons.

1. Introduction: summary on disconnections.

Retrosynthesis analysis 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. (E.J Corey)

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.

Two main Synthetic Strategies:

1) Strategic disconnection approach

MeO HO N MeO O Salutaridine

MeO HO N

MeO OH Reticuline MeO

MeO HO N R Tl(OCOCF3)3 DCM, -78- -20oC, 20 h R = CF3COO 11% R = CH3COO 23% MeO OH JACS, 1975, 97, 1239 JOC, 1981, 46, 4623 HO N R O LiAlH4

MeO

MeO HO N MeO OH 1N HCl 1h

MeO

O N MeO Thebaine

2) Strategic structure approach

Tetracyclic Tigliane ring system Claisen HO OH O H OH OH OH MeLi cat., Ph2O, heat anionic cyclisation

OH

Phorbol Ovaska TV et al, Org. Lett. 2001, 3, 115 3-Carene

Pseudopterosin A H

O OH

OAc OH
Menthol

OAc OAc

Corey E.J JACS, 1989, 111, 5472

OH

OH OH TM

OH

H O

H O

H O

O OH

OAc

OH

OAc OAc Me OH
(S)-(-)-limonene

Corey E.J JACS, 1998, 120, 12777

Synthetic Tactics. Disconnection of molecules according to the present FGs in the molecule: a) C-C bond with no functional group present:
R = R' R R R' R R' R MgX CuI + Hal R' Cl + Na Wurtz reaction

b) One-group disconnections based on normal carbonyl reactivity. Normal carbonyl reactivity:

ACCEPT electrons at the C=O carbon O R Nu DONATE electrons to the -carbon via the enolate O R E R' R E O R' R' R OH Nu R' R ACCEPT electrons at the -carbon of the enone O Nu R' R O Nu R'

Synthetic planning should show an analysis of the problem followed by synthetic solution. Alcohols
Analysis OH OH R1 R
3

Synthesis R1 R2 + R3 R2 R1 O R2 1. R3MgBr 2. H3O+ R1 OH R

3

R2

Carbonyl compounds brunched at -carbon.

Analysis O R O R + Synthesis O O 1. LDA 2. RBr O R

Carbonyl compounds branched at -carbon.

Analysis O O + R R Synthesis: Michael addition O 1. RLi CuI 2. H3O+ R O

Combination of the last two synthetic approaches allows the introduction of two new groups:
O 1. RLi CuI R O 2. R'X X = Hal, OTs, etc O R' R

c) Two-group disconnections based on normal carbonyl reactivity. 1,3-Difunctionalised compounds

X R2 R
1

O R1

X R2 R1

+ R2

X = Br (NaBr); EtO (EtONa) O R1 R2 O R3 R2 R1 R2 + OH R3 R1 R2 O R3 O + OH R3 O H + R3

O R1

O EtO + R3

1,5-Difunctionalised compounds
Analysis O R1 R
2

R3

O R4 R
1

O + R
2

R3

O R4

R3

O R4 FGI

R3 HO

O R4 HO

R3

O R4

Synthesis O R4 1. LDA 2. O
3

OH O R3 R4

R3

O R4

H R 3. H3O+ O R1 R2 1. LDA 2. Cl O

O R1 R OEt
2

O OEt

1. NaOMe 2. R3 3. H3O+ O R4 R1

O
2

R3

O R4

Examples of retrosynthetic disconnections. The synthetic planning can be based on a key disconnection, on a key intermediate or, in more complex systems, on the combination of both. Functional group interconversions (FGI) are frequently used to prepare molecule for the intended disconnection step.
a O O OEt b a O O O OEt OEt O OEt 1,6-diester (see later in the course)

EtO

OEt

O FGI

O OEt +

Br

O EtO

OAc

FGI EtO

O EtO

O + OEt

2.

2-Group disconnections: unnatural reactivity patterns and other strategies

Unnatural or reversed polarity carbonyl reactivity reverses the normal patterns attributable to carbonyl compounds.
Normal polarity: O + Nu (1,2-addition) Reversed polarity (umpolung): E O E

Nu

(1,4-addition to enones)

E (via enolate)

Nu

2.1.
X R1 Y R2

Synthetic strategies for 1,2-difunctionalysed compounds.

1,2-Difunctionalised compounds cannot be prepared by the type of disconnections used for 1,3- and 1,5-difunctionalised compounds.

O + O O

O + O

?
OEt O

?
EtO

2.1.1. Use of available starting materials In view of the fact that construction of 1,2-difunctional skeletons is not always a straightforward process, sometimes it is more convenient to disconnect to precursors with 1,2functionalisation already present in the molecule rather than cut 1,2-relationship. X X e.g. X + R2 + R2 or R1 R2 R
R1
1

A selection of commercially available 1,2-difunctionalised compounds:

O HO OH H O Glyoxal R CO2H OH Hydroxy acids O H OH Glycol H2N OH Ethanolamine OH HO O Pyruvic acid HO2C HO CO2H OH H2N NH2 Diaminocyclohexane O CH3 O O H3C CH3

O Oxalic acid R CO2H NH2 Amino acids

Diacetyl

Tartaric acid

2.1.2. Difuctionalisation of alkenes and opening of epoxides (revision)

Alkenes: R1 R2 R1 R2 OsO4 or KMnO4/NaOH OsO4 TsNClNa (Chloramin-T) Br2/H2O (HOBr) R1 R2 R1 R2 OH OH R1 R2 R1 R2 H2O2 HCOOH R1 R2 R1 R2 OH OH Br Br

OH NHTs

Br2

R1 R2 Epoxides: R1 O R2

R1 R2

OH Br

SiCl4

R1 R2

OH H Cl

R1 O R2 OH

LDA

R1

OH

R2

R1 O R2

OH

RLi

R1 R2 R

OH

2.1.3. -Functionalisation of carbonyl compounds

O R1 X R2 Attention to regioselectivity of enolisation R1 O R2 X R1 O R2

A selection of synthetic equivalents for X :

Br , Cl RS RSe Br2, Cl2, NBS RSCl, RS-SR RSeCl, RSe-SeR =O -OH SeO2; NO (HONO)

O ; OsO4 O Dimethyl dioxirane

Amines can be introduced by FGI, e.g. from halocarbonyl compounds via azides followed by reduction:
O R1 Br R2 O N3 R1 N3 R2 H2 R1 Pd/C O R2 NH2

Examples:
O Br2, H+ Br O via more stable enolate

However, in basic conditions an excess of reagent can lead to haloform reaction:

O R CH3 Br 2, NaOH R O CBr3 NaOH R O ONa + CHBr 3

Carboxylic acids are readily halogenated in the presence of PBr 3:

O OH PBr3 O Br Br Br2 O Br Br H2O O OH

Application in synthesis:
Analysis HO OH O O O 1. LDA 2. TMSCl O O O SiMe3 OH O Synthesis

Strategies 2.1.4 and 2.1.5 are based on disconnection between the two FGs. 2.1.4. Radical coupling
X R1 Y Radical coupling is only good when two identical molecules are being coupled (R1 = R2, X = Y) or when the reaction proceeds intramolecularly. R2 R1 X + Y R2

Pinacol reaction:
R1 O R2 1. Mg 2. H3O+ R2 O Mg R1 O R2 HO R1 R1 R2 Mg R1 R1 OH R2 R2 R1 O Mg R1 R2 O

R1

R1 O

R2

R2 R1 R1 O O Mg R2

H3O+

R2 HO

OH R2

Acyloin condensation:
O R1 OR2 Na/xylene R1 NaO R1 ONa H3O+ OH R1 O R1

The reaction is used to make cyclic acyloins. Yields for 6,7 membered rings - 50-60%, for 10-20 membered rings - 60-95%

2.1.5. Umpolung strategies

X R1 Y O Ph O Me Ph O + O Me R2 R1 X + Y R2

The type of disconnection shown here requires acyl-anion Me-C=O which does not exist, and moreover, cannot be made by deprotonation of the corresponding aldehyde MeCHO. The reversal of normal carbonyl reactivity (umpolung) is required here. A number of synthetic equivalents of acyl-anion have been developed to carry out this reaction scheme.

2.1.5.1.

Cyanide anion + electrophilic carbonyl

Analysis OH R CO2H FGI R OH CN R OH + CN

Synthesis O R H

NaCN R

O CN

H3O+ R

OH CO2H

Note: CN is an ambident nucleophile.

Strategies 3.1.5.2 and 3.1.5.3 are based on replacing the carbonyl oxygen with an anionstabilising groups:
O R synthon R Z Z' Z, Z' - anion stabilising groups

2.1.5.2.

Cyanohydrins, benzoin condensation

+H+; H+ H CN Ph O Ph OH Ph benzoin CN O OH Ph H HO Ph H O CN Ph

O Ph H

CN Ph H

O Ph

OH Ph CN

The reaction works well only on aromatic aldehydes, however, cyanohydrins of aliphatic aldehydes can be protected as silyl ethers and after deprotonation reacted in a similar way with different carbonyl compounds.
O H TMS-CN OSiMe3 H CN R1 1. OH 2. H3O+ O OH R R1 BuLi OSiMe3 CN R O R1

Me3SiO

O CN R

2.1.5.3.

Dithians (thioacetal) nucleophile + electrophilic carbonyl

BuLi RX S S BuLi

S S commecially available S R R2 S

S R

S R

S R2 R1 O

H3O+ R1 O S R R2 O Ph H + S R1 OH

Hg2+ R

O R1 OH R2 S

Note: RX PhX, instead

SH

SH

Ph S

2.1.5.4.

Nitroalkane nucleophile + electrophilic carbonyl

Na2CO3 O H2C N O O O pKa = 11 OEt O H2C N O

O H3C N O

pKa ~ 10, compare with

Nitro groups are rarely desirable themselves, however they can undergo useful FGIs:
R1 NH2 R2 LiAlH4 or Zn/HCl or H2/Pd/C R1 NO2 R2 Nef NaOH; H2SO4 or TiCl3 R1 O R2

Synthetic application:
2. 1. NaOH Me NO2 2. Br H2/Pd/C O NH2 R O2N is a synthetic equivalent for synthones O NO2 1. NaOH O OEt 3. H3O+ LiAlH 4 OH NH2 R or H2N O NO2 TiCl 3 O O R

2.1.5.5.

Imidoyl nucleophile + electrophilic carbonyl

R1 R N C Li = O C R1

Preparation: a) From isonitriles R N C R1Li R N C Li b) From amides via chloroimines PCl5 toluene, Li cat C10H8 THF, 78oC R1 R N C Li R N C R1 E R N C E t-Bu N C is commercially available R1 H3O+ R1 O C E

R N C

R HN O

R1

N Cl

R1

Example: 1. EtLi t-Bu N C t-Bu N C Li

1.

2. H3O+

OH

2.1.5.6.
Analysis HO R1 O R2

Alkyne nucleophile + electrophilic carbonyl

Synthesis HO + R1 R2 R2 R2 O H 1. BuLi 2. O R1 H R1 OH Hg2+ R2 H+, H2O R2 R1 OH O

=
O H R1

2.2 Functional group interconversion, amine synthesis

H R H Level 0 H -2e H R H Level 1 OH -2e R H Level 2 O -2e O R OH Level 3

=
R OSO 2R'

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 Based on the oxidation level of carbon, the two main types of FGIs can be identified: 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:
Y R R Hal R
+

R OH

sythones

X = Hal, OTs, OMs, OTf Y = OR', OCOR', SR', NR'2, N 3, NO 2

However, transformations between levels can be achieved only on certain derivatives:

R OH R O R O R R' R'O O R'

but

Other important kind of transformations interconversion of nitrogen containing functions. With amines, alkylation usually produce mixtures:
MeI RNH2 RNHMe + RNMe2 + RNMe3 I

Alternative strategies are based on reduction of other nitrogen-containing FGs: Primary amines: Primary amines at primary carbon
RX CN RCN LiAlH4 RCH2NH2

Primary amines at primary or secondary carbon

RX N3 RN3 1. Base RCH2NO2 R = H, Alk Phthalimide ROH PPh 3, DEAD R N O 2. R'X R' R LiAlH 4 or H2/Pd/C RNH2 R' NH2 R NH2NH2

LiAlH 4 NO2 or H2/Pd/C or Zn/NCl O

RNH2

Mitsunobu reaction

Primary amines at secondary or tertiary carbon

R1 R2 OH R3 NaCN H2SO4 R1 R2 R3 NC R1 R2 R3 O NCH H+ R1 R2 NH2 R3 Ritter reaction

The Ritter reaction with alkylnitriles produces secondary amines

Secondary amines:
Reductive amination R1 O R2 R2 RNH2 R1 NR NaBH3CN or NaBH4 R1 NHR R2

If hydroxylamine (NH2OH) is used in the place of RNH2, reduction of the corresponding oxime gives primary amine.

Secondary and tertiary amines:

O R Cl R1 N H R2 R O N R2 R1 LiAlH 4 or BH3 THF R N R2 R1

The method is also suitable for the preparation of primary amines (R1 = R2 = H).

2.3. Synthetic strategies for 1,4-difunctionalised compounds

Approaches the synthesis of 1,4-difunctionalised compounds share a lot of common features with methods of preparation of 1,2-analogues discussed in the part 2.1. Again, there are a few commercially available derivatives but in this case the strategies are mainly based on disconnection between the FGs.
X R1 Y R2 e.g. Me O 2,5-Hexanedione O Me Me 2,5-Hexanediol OH Me OH Succinimide O H N O

2.3.1. Acyl equivalent + Michael acceptor

O R1 O R2 R1 Acyl-anion O + O R2 R2 = O

This approach is closely related to the synthesis of 1,5-dicarbonyl derivatives via addition of enolates to ,-unsaturated carbonyl compounds. However this time, acyl-anion synthons are employed as nucleophiles. A selection of such reagents has been discussed in the section 2.1.5. Umpolung Strategies.
O CN R R OH S CN S R R NO2 NR' R

Examples:
O Ph Regioselectivity issues: NO2 R1 R O 1,4-addition 1,4-addition O R1 R O OTMS R
1

+ H

Cat. KCN O DMF Ph

O O

R1

S NO2 R O OH S S 1,2-addition 1,4-addition Et S S O Et Et Et S R S O O R S

CN

2.3.2. Homoenolate + electrophilic carbonyl

O R1 O O R1 = R2 O R1 O or H R1 OEt R2 R1 O O + O R2

homoenolate, this is not a resonanse stabilised enolate

Ester homoenolates (Zn and Ti):

O OEt O R OH OEt [O] R O Br Br O OEt O OEt Zn BrZn O OEt Reformatsky type organozinc reagent 1. RCHO 2. H3O+

Ketone or aldehyde homoenolates: Preparation of ketone or aldehyde homoenolates requires a different approach as the carbonyl group must be either protected or masked (latent) in the anionic reagent.
Protection: Br O R OH OH Br O TsOH R O Mg Et2O MgBr O R O 1. R1CHO 2. H3O
+

OH R1 O Ph R

Latent functionality: Br Mg Et2O Ar BrMg

Ph 1. PhCHO HO Ar 2. H3O + Ar reveal O 3; Me 2S

HO O Ar

2.3.3. Additional umpolung strategies:

O R1 O R2 O O R1 R2 R1 O + O

R2

standard enolate electrophilic centre in -position to carbonyl group

2.3.3.1.

Enolate + -functionalised carbonyl compound

O R1 O R2 Br R1 O O R2

O R1 O R2

1. LDA 2. TMS 3. NBS LDA

Note: -bromoketone can be protected as ketal first to prevent enolisation during the reaction

Illustrative example: OSiR3 OSiR3 1. (Me3Si)2NLi, (LiHMDS) 2. O I Bn 2N O Bn 2N O O

2.3.3.2.

Enolate + ,-unsaturated nitrocompound (Michael-type acceptors)

H2C O H2C CH3

H2C

N O

N O

C O

Nitroalkanes are acyl-anion equivalents, they resemble enolates but have one carbon atom less Nitroalkenes resemble ,-unsaturated carbonyl compounds (Michael acceptors) but have one carbon atom less.

N O

N O

O O

NH2 R

R N O O

O R

Nitroalkenes can be viewed as reagents for carbonyl and nitrogen based functionalities

Examples:
1. base Me NO2 2. RCHO R OH NO2 R NO2 1. EtO2C

CO2Et

2. H3O+

EtO2C R H2/Pd

CO2Et NO2

LiAlH4

HO R

OH NH2

, H3O+ HO2C R NO2

TiCl3 (Nef) EtO2C R CO2Et O

EtO2C R

CO2Et NH2

2.3.3.3.
OH R1

Epoxide based transformations

OH + R1 OH R1 O R2

R2 O O

R1

Epoxide can be viewed as a synthetic equivalent to synthon

a) Opening of epoxides with enolates of -dicarbonyl compounds:

1. O EtO O EtONa EtO O O R 2. H3O+ EtO O O R OH O

In general, epoxides are opened by nucleophiles at the less hindered side (SN2 type) b) Opening of epoxides with enamines catalysed by acids:
O N H H2O N R H+ R OH OH

H3O+ R

OH

In acid, the reaction proceed via intermediate R The opening occures at the side with more stable cation (SN1 type) c) Epoxides can be opened with a variety of nucleophiles and are often used for the synthesis of a wide range of alcohols:

Nucleophiles include CN, dithiane anions, Grignar reagents, e.g.:

O R + PhMgBr 2. H3O+ Ph OH R

Use of alkynyl anions:

H R1 However: O Ph + Ph Li BF3 Et2O Ph major The product can be further converted into 1,4-difunctionalised compound Ph Ph OH O Hg 2+, H2O Ph Ph OH BuLi or Na, NH3 R1 1. R 2. H3O+ Ph OH + Ph minor R1 R O OH

OH Ph

Note: other usefull transformations of alkynes include chemo- and stereoselective reduction: H2, Pd/C R1 R2 H2, Pd/C, BaSO4 (Lindlar catalyst) R1 Na, NH3(l) R1 R2 R2

R1

R2

2.3.4. Functional group addition (retrosynthetic technique of introducing a required functional group to facilitate a certain chemical transformation) Alkynyl-anions have already proved to be useful reagents for acyl-anion synthons, In addition, synthetic versatility of alkyne functionality can be further exploited in organic synthesis.
OH R1 R2 OH FGI HO R1 R2 OH HO R1 R2 OH

There is no reagent corresponding to this synthon, therefore the synthesis has to proceed stepwise Synthesis: H H BuLi H 1. O Li OLi H Ph Li 2. H3O+ HO Ph OH H2 Ph Pd/C OH 1. O H 2 x BuLi OH OH

2. H3O+

Unfunctionalised alkanes as target structures: Functional Group Addition (FGA) strategy employed in the example above to facilitate the construction of the required structural arrangement can be further extended to retrosynthetic analysis of target molecules with few or no functional groups. FGA is a retrosynthetic technique, the corresponding synthetic procedure is functional group removal. FG
C C C C

Conditions for FG removal

H2/Pd a) TsCl, MsCl LiAlH4, BH3 b) Barton reaction (radical Bu3SnH) a) NaBH4 and then as with OH group b) Kizhner reduction(NH2NH2) c) Clemence reduction( Zn/Hg; HCl) Ranney Ni Radical Bu3SnH HNO2 diazotisation

OH

C=O

SH Br NH2

2.4. Synthetic approaches to cyclic systems.

2.4.1. Cycloadditions Some types of Diels-Alder disconnections:
O + O O O + O OR RO + O O CO2R O CO2R O + CO2R CO2R

2.4.2. Conventional methods of acyclic chemistry For the construction of ring systems a set of conventional disconnections can be considered, including intramolecular SN2, Robinson annulation, aldol, Dieckmann, etc. Intramolecular reactions are usually favoured kinetically over intermolecular rections. This factor is greatest for 3- and 5-membered ring formation, and to lesser extent for 6- and 7membered cycles. On the other hand, thermodinamic factors strongly favour formation of 6membered rings. Taking both kinetic and thermodinamic factors into account, 5-,6- and 7membered rings are easy to make, 3-membered rings are also easy to make but often break down under the conditions of their formation, while 4-membered rings are very difficult to make and require different synthetic approaches.

Some examples of cyclisation reactions:

Cl Cl Cl base O CO2Et CO2Et NaOEt Cl Cl CO2Et

CO2Et CO2Et

base O O O O

OH

2.4.3. Other methods

OMe Li, NH3 t-BuOH Birch reduction McMurry coupling OMe O O TiCl3, Zn/Cu

CH2 H2C

[Ru] (Grubbs) or [Mo] (Schrock)

Ring Closing Alkene Metathesis

[Ru] R1 + R2 R1

R2 + R1

R1 + R2

R2 Cross Metathesis

2.5. Reconnection strategies

In retrosynthetic analysis, open chain 1,6-difunctionalised compounds can be linked to appropriate cyclic precursors. In this case, the term disconnection is applied to reconnection strategies, which can also be used to make compounds with two functional groups related to each other as 1,5-, 1,7- and others. 2.5.1. Ozonolysis of cycloalkenes Functional groups with 1,6-relationship are too far apart for any conventional disconnection strategies. However, it is known that ozonolysis of cyclohexene creates two functional groups which are exactly 1,6-related.

Me2S O3 OH OH NaBH 4 O3 KMnO4

O O

O CO2H

Similar transformation can be also achieved in an indirect way:

O OsO4, NMO or KMnO4 NMO: O N O OH OH NaIO4 or Pb(OAc)4 O

This strategy requires synthetic access to 6-membered unsaturated rings. The best way to make such precursors is Diels-Alder cycloaddition reaction (see above in the course):
The reaction is stereospecific

2.5.2. Baeyer-Villiger rearrangement Another type of reconnection strategies is hydrolysis of lactones:

O HO O Lactone OH O O

The required lactones can be prepared from cyclic ketones by a ring expansion reaction, the Baeyer-Villiger rearrangement:

O F3C

O O O OH O

H3O+ MeMgBr

HO

COOH OH

HO

Mechanism: O O H+ OH HO HO O CF3 H O O O CF3

H O

OH O O O CF3 O +
o o o

TS:

+ H H + O O O O CF3

The reaction is regioselective. Migration order: 3 > 2 ~ Ar >1 . The group better capable to stabilise carbocation in the transition state migrates preferentially.

2.5.3. Beckmann and related rearrangements Analogously, a reconnection strategy for 6-amino acids is hydrolysis of lactams:
O H2N O Lactam OH NH O

Lactams can be prepared from cyclic ketones by the Beckmann rearrangement:

O NH2OH N OH 1. PCl5 2. H3O+ O NH H2N CO2H

Reaction mechanism:
N OH Cl Cl4P N O PCl3 Cl N H O H

N OH2

NH O

NH H O

Usually, the group positioned anti to oxime is migrating.

A related process which involves addition of hydrazoic acid to carbonyl compounds catalysed by sulphuric acid is called Schmidt reaction:
H N N N O H+ OH H N N N H N N N HO H N N N H2O H+ H N N N

N N N N

H2O

NH O

Synthetic application:

O Ac n-Oct Analysis n-Oct Pine sawfly's sex attractant C-X Wittig FGI available SM O B-V O O reconnect. OH n-Oct O OH FGI n-Oct OH

Synthesis OH CrO3 H2SO4 aq 79% O n-Oct OH Ph3P-CH2 Wittig 66% n-Oct OH H2 Pd/C 100% O MCPBA B-V 80% O n-OctLi O 70% OH n-Oct OH

AcCl, Py

OAc n-Oct

3.

Summary of retrosynthetic strategies; some guidelines for retrosynthetic analysis; useful synthons.
3.1. Elementary retrosynthetic analysis
Target (parent) structure

Offspring synthons

Offspring reagents

Transformation type One-group disconnection Two-group disconnection (heterolytic) Two-group disconnection (homolytic) Electrocyclic disconnection Reconnection Rearrangement Functional group interconversion (FGI)

Target molecule

Synthons
OH

Reagents and reaction conditions

O + C2H5MgBr 1) 0oC (THF) 2) NH4Cl/H2O 1) 78oC rt (THF) 2) NH4Cl/H2O

OH

+ C2H5 O H OH O OH

O + OH O OH CO2Me

+ CH3CHO

OLi

COOEt COOEt CO2Me synthones reagents

1) Na/Me3SiCl toluene, 2) H2O (benzene, )

+ CO2Me CHO CHO NH O OH O S S CrO3/H2SO4; acetone HgCl2; acetonitrile Ph Ph OH O OH 1) LDA; THF; -78oC 2) Me3SiCl 3) O O H2; Pd/C N MeO2C O3/Me 2S CH2Cl2; 78oC OH H2SO4;

Functional group addition (FGA) Special case of FGI - Functional group removal (FGR)

Ph O

Ph OH

3.2. Guidelines for synthetic planning Retrosynthetic analysis: 1. Use disconnections corresponding to known reliable reactions with the highest yields. 2. Disconnect C-C bond according to the FGs present in the molecule, take into account and exploit the relationship between the FGs. Correlate synthons with appropriate synthetic equivalents. 3. Employ Functional Group Interconversions (FGI), including Functional Group Removal (FGR), as necessary to get useful FGs, use Functional Group Addition (FGA) to install a required FG. 4. Aim for simplification: disconnect C-X bonds, disconnect rings from chains, use symmetry, disconnect at a branch point, separate into equal sized pieces, use rearrangements. 5. Try to find a key disconnection that would bring a considerable simplification to the structure or reveal simple starting materials. 6. Whenever possible, plan a convergent synthesis. Synthesis: 1. 2. 3. 4. 5. 6. Write the synthetic sequence, including reagents. Check for mutually incompatible FGs. Check compatibility between FGs and reagents. Take into account problems of regioselectivity and chemoselectivity. Use protecting groups to resolve these problems. Make sure you make the right TM: check for length of carbon chain, size of rings, position of substituents, nature and position of FGs, removal of protecting groups.

General note: retrosynthetic analysis is a problem solving technique that require a broad knowledge of various synthetic methodologies, so integrate all the material acquired from different courses.

3.3. Summary of synthons and synthetic equivalents used in the course. Table 1. Some natural synthons Synthon
Br N3 RO RS R R R' R' R R''
R

Synthetic equivalent
NaBr NaN3 RONa made from ROH RSNa made from RSH Hal Hal = Br, I alkyl, allylic or benzylic R R' MgHal or cuprate for alkyl, allylic or benzylic Michael addition R R' MgHal or cuprate for R vinyl or aryl R' Michael addition R'' R M M = Li, MgHal O O or R OR' OLi R or R O R' O or R O R NR' 2 O

alkyl, allylic or benzylic alkyl, allylic or benzylic vinyl or aryl

R'

OH R O R O R O R R'

or R R R Methyl acetoacetate or dimethyl malonate are often used as starting materials O R

Hal OSiMe3

Table 2. Some unnatural synthons Synthon

Br+ O or HO+ RS+
2+

Synthetic equivalent
Br2 SeO2 or dimethyl dioxirane RSCl or RSSR S R R R ; R' N ; ; R NO2 Li S Li CN (KCN) O R Br ; O R NO2 R O R NO2

O R

acyl anion O HO O R OH R NH2 R

Li

after reduction (LiAlH4 or H2/Pd-C)

O RO O R R homoenolate and homoenolate O R O MgBr RO

ZnBr or R MgBr

Avoid this type of disconnection as the corresponding reactions require transition metal catalysis.