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. α-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

2.2. Functional group interconversion: amine synthesis

2.3. 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 + α-functionalised carbonyl compound
2.3.3.2. Enolate + α,β-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)

2.4. Synthetic approaches to cyclic systems

2.4.1. Cycloadditions
2.4.2. Conventional methods of acyclic chemistry
2.4.3. Other methods

2.5. Reconnection strategies

2.5.1. Ozonolysis of cycloalkenes
2.5.2. Baeyer-Villiger rearrangement
2.5.3. Beckmann and related rearrangements

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 MeO

N
HO HO
N

MeO MeO
O OH
Salutaridine Reticuline

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

MeO MeO

HO 1N HCl O
N N
1h
MeO MeO
OH Thebaine
2) Strategic structure approach

Tetracyclic Tigliane ring system

Claisen anionic
O cyclisation OH
OH
HO

O
H MeLi cat., Ph2O, heat
OH

OH
O OH
Phorbol

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

Pseudopterosin A

H
O OAc
O
OAc
OH OAc OH

Menthol
Corey E.J JACS, 1989, 111, 5472

OH OH
OH
TM
OH H
H H
O O O

H
O OAc OH
O

OH OAc
OAc
OH
Me
(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'
Cl + Na Wurtz reaction
R

R'
R
MgX CuI + R'
R ≠ R' R Hal

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

Normal carbonyl reactivity:

ACCEPT electrons at the C=O carbon ACCEPT electrons at the β-carbon of the enone
O
OH Nu O Nu
O
R R'
R R' R R'
Nu R R'
Nu

DONATE electrons to the α-carbon via the enolate

O O

R R' R R'
E
E

Synthetic planning should show an analysis of the problem followed by synthetic solution.

Alcohols

Analysis Synthesis
OH
OH O 1. R3MgBr OH
R1 R2
R1 R2 + R1 R2 2. H3O+ R1 R2
3 3
R R
R3

Carbonyl compounds brunched at α-carbon.

Analysis Synthesis
R
O O + O O O
R 1. LDA R
2. RBr
Carbonyl compounds branched at β-carbon.

Analysis Synthesis: Michael addition

O O O O
1. RLi CuI
+ R
2. H3O+ R
R

Combination of the last two synthetic approaches allows the introduction of two new groups:

O O O
1. RLi CuI 2. R'X R'

R X = Hal, OTs, etc R

c) Two-group disconnections based on normal carbonyl reactivity.

1,3-Difunctionalised compounds

X O
O X O δ+
1
R1 R2 R1 R2 R R2

X = Br (NaBr); EtO (EtONa)

O OH O OH O
+
R1 R3 R1 R3 H δ+ R3
R2 R2

O O O
O O
+
R1 R3 EtO δ+ R3
R1 R3
R2 R2

1,5-Difunctionalised compounds

Analysis

R3 O R3
O O R3 O O
1 +
R1 R4 R R4
2
R4
R 2 R
FGI

R3 O
R3 O

R4 HO R4
HO
 Synthesis
1. LDA
O OH O ∆ O
2. O
R4 R3 R4 R3 R4
3
H R
3. H3O+
1. NaOMe
O 1. LDA O O O R3 O
2. O
R1 R1 OEt R1 R4
2. O R3 R4 2
2 R
R2 R
3. H3O+
Cl OEt

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 O O O
a 1,6-diester
OEt
OEt (see later in the course)
OEt OEt
b O

O O O Br
EtO OEt
FGI +
OEt

O OAc O O O
O O
FGI +
EtO EtO EtO 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 Reversed
δ− polarity E
polarity: O Nu O
(1,4-addition (umpolung):
δ+ to enones)

E E Nu
Nu
(via enolate)
(1,2-addition)

2.1. Synthetic strategies for 1,2-difunctionalysed compounds.

X
R2 1,2-Difunctionalised compounds cannot be prepared by the type of disconnections
R1 used for 1,3- and 1,5-difunctionalised compounds.
Y

O O O
+ +

O O O

O
? ?
OEt EtO
O

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 1,2-
functionalisation already present in the molecule rather than cut 1,2-relationship.
e.g. X X X
R2 + R2 or R1 + R2
R1 R 1
Y Y Y

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

O O OH O H3C CH3
OH H CH3
HO H HO
O O
O O OH O
Oxalic acid Glyoxal Glycol Pyruvic acid Diacetyl

R CO2H R CO2H H2N HO2C CO2H

NH2 OH OH HO OH H2N NH2

Amino acids Hydroxy acids Ethanolamine Tartaric acid Diaminocyclohexane
 2.1.2. Difuctionalisation of alkenes and opening of epoxides (revision)

Alkenes:

R1 OsO4 R1 OH R1 H2O2 R1 OH
or
R2 R2 OH R2 HCOOH R2 OH
KMnO4/NaOH

R1 OsO4 R1 OH R1 Br2 R1 Br

R2 TsNClNa R2 NHTs R2 R2 Br
(Chloramin-T)

R1 Br2/H2O R1 OH

R2 (HOBr) R2 Br

Epoxides:

R1 R1 OH R1 LDA R1 OH
SiCl4
O O
H
R2 R2 Cl
R2 R2

OH OH
R1 RLi R1
OH
O
R2 R2 R

2.1.3. α -Functionalisation of carbonyl compounds

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

A selection of synthetic equivalents for X :

Br , Cl Br2, Cl2, NBS =O SeO2; NO (HONO)

RS RSCl, RS-SR -OH O ; OsO4

O
RSe RSeCl, RSe-SeR Dimethyl dioxirane

Amines can be introduced by FGI, e.g. from α−halocarbonyl compounds via azides followed by
reduction:
O O O
N3 H2
R2 R2 R2
R1 R1 R1
Br N3 Pd/C NH2
Examples:
O
O Br2, H+ via more stable
enolate
Br

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

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

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

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

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

O O O 2. TMSCl O O
SiMe3

Strategies 2.1.4 and 2.1.5 are based on disconnection between the two FGs.

2.1.4. Radical coupling

X X R2
R2 +
R1 R1 Y
Y

Radical coupling is only good when two identical molecules are being coupled (R1 = R2, X = Y)
or when the reaction proceeds intramolecularly.

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

R2 R1 R1
H3O+ R2 OH
R1 R2 HO R2
O O
Mg R1
Acyloin condensation:

R1 R1 OH
O Na/xylene H3O+
R1
R1 OR2 R1
NaO ONa
O
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 X R2
R2 +
R1 R1 Y
Y
O O Me
Me +
Ph Ph O
O

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 FGI OH OH
+ CN
R CO2H R CN R

Synthesis
O O OH
NaCN H3O+
R H R CN R 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 anion-
stabilising groups:

O Z
Z, Z' - anion stabilising groups
R R Z'
synthon
 2.1.5.2. Cyanohydrins, benzoin condensation

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

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.

OSiMe3 R R1
O TMS-CN BuLi OSiMe3
H
O
H CN
CN
O
R1
Me3SiO 1. OH− OH
O
R1
CN R 2. H3O+ R

2.1.5.3. Dithians (thioacetal) nucleophile + electrophilic carbonyl

BuLi RX BuLi
S S S S S S
S S
commecially R R2
R
available R1
O
H3O+ Hg2+ O
S S S S R1
R1 R1 R OH
R R R2
O OH
R2 R2

O S
Note: RX ≠ PhX, instead Ph +
SH SH
Ph
H S

2.1.5.4. Nitroalkane nucleophile + electrophilic carbonyl

O Na2CO3 O O
H3C N H2C N H2C N
O O O
O O
pKa ~ 10, compare with pKa = 11
OEt
Nitro groups are rarely desirable themselves, however they can undergo useful FGIs:

R1 LiAlH4 or R1 Nef R1
NH2 Zn/HCl or NO2 O
R2 NaOH; H2SO4 or
R2 H2/Pd/C TiCl3 R2

Synthetic application:

2. O
1. NaOH NO2 O
Me NO2 1. NaOH OEt
2. Br
3. H3O+ NO2

H2/Pd/C TiCl 3
LiAlH 4

O OH O

NH2 NH2 O

R R R
is a synthetic equivalent for synthones or
O2N O H2N

2.1.5.5. Imidoyl nucleophile + electrophilic carbonyl

R1 R1
R N C = O C
Li

Preparation:
a) From isonitriles

R N C R N C t-Bu N C is commercially available

R1Li R1 E R1 H3O+ R1
R N C R N C R N C O C
Li E E

b) From amides via chloroimines

PCl5 Li
R HN R1 R N R1 cat C10H8 R1
R N C
O toluene, ∆ Cl THF, −78oC Li

Example: 1. O
O
1. EtLi
t-Bu N C t-Bu N C
Li OH
2. H3O+
 2.1.5.6. Alkyne nucleophile + electrophilic carbonyl

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

=
R2

=
O R1 H R2 R2
H R2
R1

2.2 Functional group interconversion, amine synthesis

H H O
-2e -2e O -2e
R H R OH R R
H OH
H H

Level 0 Level 1 Level 2 Level 3

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); C≡C; X-C-C-Y;
epoxides.

Oxidation level 3 (alkane – 6e):

COOH, COX (X = OR, Hal, OCOR, NR2); C≡N, C=C-C=O, C=C-C≡C

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:

R OSO 2R' Y
R OH R X R Y
R Hal X = Hal, OTs, OMs, OTf
+ Y = OR', OCOR', SR', NR'2, N 3, NO 2
R sythones

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

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

CN LiAlH4
RX RCN RCH2NH2

Primary amines at primary or secondary carbon

N3 LiAlH 4
RX RN3 RNH2
or H2/Pd/C

1. Base R' LiAlH 4 R'

RCH2NO2 NO2 or H2/Pd/C NH2
2. R'X R or Zn/NCl R
R = H, Alk
O
Phthalimide NH2NH2
RNH2 Mitsunobu reaction
ROH R N
PPh 3, DEAD
O

Primary amines at secondary or tertiary carbon

R1 NaCN R1 R1 O H+ R1
R2 OH R2 NC R2 NCH R2 NH2 Ritter reaction
R3 H2SO4 R3 R3 R3
The Ritter reaction with alkylnitriles produces secondary amines
Secondary amines:

Reductive amination

R1 RNH2 R1 NaBH3CN R1
O NR NHR
R2 R2 or NaBH4 R2

If hydroxylamine (NH2OH) is used in the place of RNH2,

reduction of the corresponding oxime gives primary amine.

Secondary and tertiary amines:

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

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.
OH H
X O O N O
R2 Me Me
R1 e.g. Me Me
O OH
Y
2,5-Hexanedione 2,5-Hexanediol Succinimide

2.3.1. Acyl equivalent + Michael acceptor

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

This approach is closely related to the synthesis of 1,5-dicarbonyl derivatives via addition
of enolates to α,β-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 OH NO2 NR'
CN S S R
R R CN R R

Examples:

O Cat. KCN O
+ O O
Ph H DMF Ph

Regioselectivity issues:
S
NO2 R1 NO2 OH S
O
O S
R1
R 1,4-addition R 1,2-addition R S

OTMS 1,4-addition
1,4-addition
1 Et Et
O R S S Et O
S
O CN O
R1 Et O
S
R
R
 2.3.2. Homoenolate + electrophilic carbonyl

O O R2
R2 +
R1 R1
O O

O O O
= or
R1 R1 H R1 OEt

R2
− homoenolate, this is not a resonanse stabilised enolate
O

Ester homoenolates (Zn and Ti):

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

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:
OH
OH OH Br
R Mg MgBr R 1. R1CHO
Br R
O O R
O O
+
R1
O TsOH Et2O 2. H3O
O

Latent functionality: Ph
Ph
Br BrMg reveal
Mg 1. PhCHO HO HO
O
O 3; Me 2S
Et2O 2. H3O +
Ar Ar Ar Ar
 2.3.3. Additional umpolung strategies:

O O
R2 R2
R1 +
R1
O O

R2
− standard enolate
O
O
− electrophilic centre in α-position to carbonyl group
R1

2.3.3.1. Enolate + α-functionalised carbonyl compound

O 1. LDA O
Br O
R1 2. TMS R1
3. NBS R2
R1
O O
O
LDA
R2 R2

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

Illustrative example:
OSiR3
OSiR3
1. (Me3Si)2NLi, (LiHMDS)

2. I

O
O Bn 2N O Bn 2N O

2.3.3.2. Enolate + α,β-unsaturated nitrocompound (Michael-type acceptors)

H2C O H2C O H2C CH3 Nitroalkanes are acyl-anion

N N C equivalents, they resemble enolates
O O O but have one carbon atom less

O O Nitroalkenes resemble α,β-unsaturated

N N
carbonyl compounds (Michael acceptors)
O O O
but have one carbon atom less.

R
NH2 O Nitroalkenes can be viewed as reagents for
O
N carbonyl and nitrogen based functionalities
R R
O
Examples:

1. base OH 1.
Me NO2 NO2 NO2 EtO2C CO2Et
2. RCHO R R

EtO2C CO2Et LiAlH4

2. H3O+ HO OH
NO2 NH2
R R
TiCl3 (Nef)
H2/Pd ∆, H3O+

EtO2C CO2Et HO2C EtO2C CO2Et

NH2 NO2 O
R R R

2.3.3.3. Epoxide based transformations

OH
OH R2
R2 +
R1
R1 O
O

O OH
Epoxide can be viewed as
R1 a synthetic equivalent to synthon R1

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

R OH
1. O
O O EtONa O O R O
EtO EtO 2. H3O+ EtO 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
O N O
N N R H3O+
H
−H2O H+ R R
OH OH
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 OH
+ PhMgBr
R 2. H3O+ Ph R

Use of alkynyl anions:

1. O
H BuLi or OH
R
R1 Na, NH3 R1 R1 R
2. H3O+
However:
Ph
OH
O Li BF3 Et2O OH
+ +
Ph Ph Ph
Ph Ph
major minor

The product can be further converted into 1,4-difunctionalised compound

Ph Hg 2+, H2O Ph Ph
Ph
OH
OH O

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

Na, NH3(l)
R2
R1

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 FGI HO R2 HO R2
R2
R1
OH R1 OH R1 OH

There is no reagent corresponding to this synthon,

therefore the synthesis has to proceed stepwise

Synthesis: 1. O
BuLi 2 x BuLi
H H H Li H OH
2. H3O+
1. O
OH
HO H2
H Ph
Li OLi Ph
OH
2. H3O+ Ph Pd/C OH
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 Conditions for FG removal

C C C C H2/Pd

a) TsCl, MsCl – LiAlH4, BH3

OH
b) Barton reaction (radical Bu3SnH)

a) NaBH4 and then as with OH group

C=O b) Kizhner reduction(NH2NH2)
c) Clemence reduction( Zn/Hg; HCl)

SH Ranney Ni

Br Radical Bu3SnH

NH2 HNO2 diazotisation

2.4. Synthetic approaches to cyclic systems.

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

O RO

+ +
O
O OR

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 7-
membered cycles. On the other hand, thermodinamic factors strongly favour formation of 6-
membered rings. Taking both kinetic and thermodinamic factors into account, 5-,6- and 7-
membered 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
CO2Et NaOEt CO2Et
Cl Cl

Cl

base O
CO2Et
CO2Et
CO2Et

base

O O O O
OH

2.4.3. Other methods

OMe OMe
O O TiCl3, Zn/Cu
Li, NH3

t-BuOH
McMurry coupling
Birch reduction

CH2 H2C [Ru] (Grubbs)

Ring Closing Alkene Metathesis
or [Mo] (Schrock)

[Ru] R2 R1 R2
+ + + Cross Metathesis
R1 R2 R1 R1 R2

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 O
O
O3 O3
OH
OH NaBH 4 KMnO4
O
CO2H

Similar transformation can be also achieved in an indirect way:

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

NMO:
O N
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 O
OH
HO O
O
Lactone

The required lactones can be prepared from cyclic ketones by a ring expansion reaction,
the Baeyer-Villiger rearrangement:
 H3O+
O HO COOH
O O
F3C O OH MeMgBr
O OH
HO

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

OH H δ+ H
H O O δ+ O
O TS: O
O CF3
O O O CF3
δ+
o o o
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 O
OH
H2N NH
O
Lactam

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

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

Reaction mechanism:

Cl H
N OH N O O H
Cl4P PCl3 N
Cl

N NH NH
H O
OH2 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 H N N N

H H
O OH HO H2O
N N N N N N
H+ H+
H N N N

N N N
N H2O NH
O

Synthetic application:

O Ac
n-Oct Analysis
OH OH
FGI
n-Oct n-Oct
Pine sawfly's sex attractant
C-X

Wittig
O
O OH
FGI B-V reconnect.
O n-Oct
available
SM
O

Synthesis

OH O O
CrO3 MCPBA n-OctLi
B-V O
H2SO4 aq
80% 70%
79%

O OH
Ph3P-CH2 n-Oct H2 n-Oct
n-Oct
OH Wittig OH Pd/C OH
66% 100%

OAc
AcCl, Py
n-Oct
3. Summary of retrosynthetic strategies; some guidelines for
retrosynthetic analysis; useful synthons.

3.1. Elementary retrosynthetic analysis

Target (parent)
Offspring synthons Offspring reagents
structure

Transformation Target molecule Synthons Reagents and reaction

type conditions
One-group OH O
disconnection + 1) 0oC (THF)
+
OH 2) NH4Cl/H2O
C2H5 C2H5MgBr
Two-group
disconnection O O 1) −78oC rt (THF)
OLi
(heterolytic) + H + 2) NH4Cl/H2O
OH CH3CHO
OH
Two-group O O
COOEt 1) Na/Me3SiCl
disconnection toluene, ∆
(homolytic) OH OH COOEt
2) H2O
Electrocyclic CO2Me CO2Me synthones
disconnection + (benzene, ∆)
CO2Me MeO2C reagents
Reconnection CHO O3/Me 2S
CHO CH2Cl2; −78oC
Rearrangement NH
N
OH
O H2SO4; ∆

Functional group OH
interconversion CrO3/H2SO4; acetone
O
(FGI)
HgCl2; acetonitrile
S S

Functional group Ph
Ph Ph Ph
addition (FGA) H2; Pd/C
OH OH
Special case of O O 1) LDA; THF; -78oC
FGI - Functional OH 2) Me3SiCl
group removal 3) O O
(FGR)
 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. Write the synthetic sequence, including reagents.

2. Check for mutually incompatible FGs.
3. Check compatibility between FGs and reagents.
4. Take into account problems of regioselectivity and chemoselectivity.
5. Use protecting groups to resolve these problems.
6. 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 Synthetic equivalent

−
Br NaBr
N3− NaN3
RO− RONa made from ROH
RS− RSNa made from RSH
Hal
alkyl, allylic or benzylic alkyl, allylic or benzylic Hal = Br, I
R R' R R'
MgHal
alkyl, allylic or benzylic or cuprate for
R R' alkyl, allylic or benzylic
R R' Michael addition
MgHal
R vinyl or aryl R or cuprate for
R' vinyl or aryl R' Michael addition
R'' R''
R R M M = Li, MgHal
OH O

R R' R R'
O O O O O
or or
R R OR' R Hal R O R
OLi OSiMe3 NR' 2
or or
O
R R R
R Methyl acetoacetate or dimethyl malonate
are often used as starting materials
O O

R R
Table 2. Some “unnatural” synthons

Synthon Synthetic equivalent

Br+ Br2
O or HO+
2+
SeO2 or dimethyl dioxirane
RS+ RSCl or RSSR
O S R R R
acyl anion ; ; R' N ; R Li
NO2
R S Li Li
O
CN− (KCN)
HO
O O NO2
Br ;
R R R
OH O

R R
NH2 NO2
after reduction (LiAlH4 or H2/Pd-C)
R R
O O
homoenolate
RO RO ZnBr
O
O O or
homoenolate
R R MgBr R MgBr
Avoid this type of disconnection as the corresponding
R and
reactions require transition metal catalysis.