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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. a-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 + a-functionalised carbonyl compound

2.3.3.2. Enolate + a,b-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

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.

addition, elimination, reduction, or oxidation. Each structure thus derived from TM then itself becomes a TM

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
MeO
HO
N
MeO

O

Salutaridine

MeO N HO MeO
MeO
N
HO
MeO

OH

Reticuline

MeO

HO

MeO

N
N

OH

Tl(OCOCF 3 ) 3

R DCM, -78- -20 o C, 20 h

R

= CF3COO 11%

R

= CH3COO 23%

JACS, 1975, 97, 1239 JOC, 1981, 46, 4623

MeO

HO

MeO

N R
N
R

O

MeO MeO HO 1N HCl O N N 1 h MeO MeO OH Thebaine
MeO
MeO
HO
1N HCl
O
N
N
1 h
MeO
MeO
OH
Thebaine

LiAlH 4

2) Strategic structure approach

Tetracyclic Tigliane ring system

O
O
OH
OH
O
O

Claisen

anionic

cyclisation

OH HO H OH O OH OH
OH
HO
H
OH
O OH
OH

Phorbol

MeLi cat., Ph 2 O, heat
MeLi cat., Ph 2 O, heat

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

3-Carene

Pseudopterosin A

H O O OAc OH OAc OAc OH Menthol Corey E.J JACS, 1989, 111, 5472
H
O
O
OAc
OH
OAc OAc
OH
Menthol
Corey E.J JACS, 1989, 111, 5472
OH
OH
H
H

O

OH H O
OH
H
O
H O OH O OAc OH OAc OAc OH Me
H
O
OH
O
OAc
OH
OAc OAc
OH
Me

Corey E.J JACS, 1998, 120, 12777

OH OH H O
OH
OH
H
O
(S)-(-)-limonene
(S)-(-)-limonene

TMH O OH H O H O OH O OAc OH OAc OAc OH Me Corey

Synthetic Tactics.

Disconnection of molecules according to the present FGs in the molecule:

a) C-C bond with no functional group present:

R

R'molecule : a) C-C bond with no functional group present : R R = R' R

R = R'

bond with no functional group present : R R' R = R' R R' Cl +

R R'

Cl + R MgX CuI R
Cl
+
R
MgX CuI
R

Na

+ Hal

Wurtz reaction

R'R R' Cl + R MgX CuI R N a + Hal Wurtz reaction b) One-group

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

Normal carbonyl reactivity:

ACCEPT electrons at the C=O carbon

O R R' Nu
O
R
R'
Nu

R

OH

R'ACCEPT electrons at the C=O carbon O R R' Nu R OH Nu DONATE electrons to

Nu

DONATE electrons to the a-carbon via the enolate

O R R' E
O
R
R'
E

O

R R'
R
R'

E

ACCEPT electrons at the b-carbon of the enone

R

O Nu R'
O
Nu
R'

R

O

Nu

R'at the b -carbon of the enone R O Nu R' R O Nu Synthetic planning

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

Alcohols

Analysis OH R 1 3 R
Analysis
OH
R 1
3
R

Synthesis

O 1. R 3 MgBr 1 R R 2 2. H 3 O + Synthesis
O 1. R 3 MgBr
1
R
R 2
2. H 3 O +
Synthesis

1. LDA

O

O 1. R 3 MgBr 1 R R 2 2. H 3 O + Synthesis 1.

2. RBr

OH

R 1 R 2
R 1
R 2

+

R R 2 2. H 3 O + Synthesis 1. LDA O 2. RBr OH R

R 3

R 2

R 1

Carbonyl compounds brunched at a-carbon.

Analysis

O O

O 2. RBr OH R 1 R 2 + R 3 R 2 R 1 Carbonyl

R

O 2. RBr OH R 1 R 2 + R 3 R 2 R 1 Carbonyl

R

+

O

OO 2. RBr OH R 1 R 2 + R 3 R 2 R 1 Carbonyl

O 2. RBr OH R 1 R 2 + R 3 R 2 R 1 Carbonyl
O 2. RBr OH R 1 R 2 + R 3 R 2 R 1 Carbonyl
O 2. RBr OH R 1 R 2 + R 3 R 2 R 1 Carbonyl
OH 3 R
OH
3
R

R

R 2

Carbonyl compounds branched at b-carbon.

Analysis

O O R
O
O
R
Synthesis: Michael addition O 1. RLi CuI + R 2. H 3 O +
Synthesis: Michael addition
O
1. RLi
CuI
+
R
2. H 3 O +
O R
O
R

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

O

approaches allows the introduction of two new groups: O 1. RLi CuI O R 2. R'X
1. RLi CuI
1. RLi
CuI
O
O

R

2. R'X X = Hal, OTs, etc
2. R'X
X = Hal, OTs, etc

O

groups: O 1. RLi CuI O R 2. R'X X = Hal, OTs, etc O R'

R'

R

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

1,3-Difunctionalised compounds

O X

2 R O OH 1 R R 3 2 R O O R 1 R
2
R
O OH
1
R
R 3
2
R
O O
R 1
R 3
2
R
O X 2 R O OH 1 R R 3 2 R O O R 1
1,5-Difunctionalised compounds Analysis O R 3 O R 1 R 4 R 2
1,5-Difunctionalised compounds
Analysis
O
R 3
O
R 1
R 4
R 2
X O R R 1 R 2 X = Br (NaBr); EtO (EtONa)
X
O
R
R 1
R 2
X = Br
(NaBr); EtO
(EtONa)

O

d+ 1
d+
1

R 2

O OH O + 1 R R 3 H d+ R 3 2 R O
O
OH O
+
1
R
R 3
H d+
R 3
2
R
O
O O
+
1
EtO
R 3
R
R 3
d+
2
R
O
R 3
O
R 3
O
+
1
R
R 4
R 4
2
R
FGI
R 3
O
O
R 3
HO
R 4
HO
R 4

Synthesis

R

O

R 4 O 1 R 2
R 4
O
1
R 2
1. LDA 2. O H R 3
1. LDA
2. O
H
R 3

3. H 3 O +

1. LDA

2. O Cl OEt
2. O
Cl
OEt
OH O R 3 R 4 O O R 1 OEt 2 R
OH
O
R 3
R 4
O
O
R 1
OEt
2
R

Examples of retrosynthetic disconnections.

D

R 1 OEt 2 R Examples of retrosynthetic disconnections. D O R 3 R 4 1.

O

R 3 R 4
R 3
R 4

1. NaOMe

2. O 1 R 4 R 3 R
2. O
1
R
4
R 3
R

3. H 3 O +

O R 3 O 2 R
O
R 3
O
2
R

R 4

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 b
O
O
b

OEt

a

for the intended disconnection step. a O O b OEt a O O OEt O OEt
O O
O
O

OEt

O

OEt O
OEt
O

OEt

1,6-diester

(see later in the course)

EtO OEt
EtO
OEt

FGI

O OAc FGI EtO
O
OAc
FGI
EtO

O

OEt 1,6-diester (see later in the course) EtO OEt F G I O OAc FGI EtO
O O EtO
O
O
EtO
O O + OEt O O EtO OEt
O
O
+
OEt
O O
EtO
OEt

Br

OEt 1,6-diester (see later in the course) EtO OEt F G I O OAc FGI EtO

+

O

OEt 1,6-diester (see later in the course) EtO OEt F G I O OAc FGI EtO

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:

d-

O

attributable to carbonyl compounds. Normal polarity: d- O N u (1,4-addition to enones) d+ E Nu
attributable to carbonyl compounds. Normal polarity: d- O N u (1,4-addition to enones) d+ E Nu

Nu (1,4-addition

to enones)

d+ E
d+
E

Nu

(1,2-addition)

(via enolate)

Reversed

polarity

(umpolung):

E O E Nu
E
O
E
Nu

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

R 1

X

R 2 R 2

Y

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

used for 1,3- and 1,5-difunctionalised compounds. O O + ? OEt O O O + O

O

O

+
+
? OEt
?
OEt

O

O O + O O O ? EtO
O
O
+
O
O
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 1,2- functionalisation already present in the molecule rather than cut 1,2-relationship.

e.g.

X R 2 R 1
X
R 2
R 1

Y

X

R + +

Y

than cut 1,2-relationship. e.g. X R 2 R 1 Y X R + Y R 2

R

2

or

R

X

1
1

Y

+

e.g. X R 2 R 1 Y X R + Y R 2 or R X

R 2

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

O

O OH

H

H H

available 1,2-difunctionalised compounds: O O OH H H O HO O H CH 3 HO O
O HO
O
HO
available 1,2-difunctionalised compounds: O O OH H H O HO O H CH 3 HO O

OH

CH 3

HO

O O

OH O Glycol Pyruvic acid H 2 N HO 2 C CO 2 H OH
OH
O
Glycol
Pyruvic acid
H 2 N
HO 2 C
CO 2 H
OH
HO
OH
Ethanolamine Tartaric acid
Oxalic acid R CO 2 H
Oxalic acid
R
CO 2 H

NH 2

Amino acids

Glyoxal R CO 2 H
Glyoxal
R
CO 2 H

OH

Hydroxy acids

H 3 C CH 3 O O Diacetyl H 2 N NH 2
H 3 C
CH 3
O
O
Diacetyl
H 2 N
NH 2

Diaminocyclohexane

2.1.2.

Difuctionalisation of alkenes and opening of epoxides (revision)

Alkenes: R OsO 4 1 or R 2 KMnO 4 /NaOH R OsO 4 1
Alkenes:
R
OsO 4
1
or
R
2
KMnO 4 /NaOH
R
OsO 4
1
TsNClNa
R
2
(Chloramin-T)
R
1
Br
2 /H 2 O
(HOBr)
R
2

Epoxides:

R 1 SiCl 4 O R 2 OH R 1 RLi O R 2
R
1
SiCl 4
O
R
2
OH
R
1
RLi
O
R
2
R OH R 1 1 H 2 O 2 HCOOH R OH R 2 2
R
OH
R
1
1
H
2 O 2
HCOOH
R
OH
R
2
2
R
R
OH
1
Br 2
1
R 2
NHTs R
2
R
OH
1
R 2
Br

R

R

OH 1 Cl 2 OH R 1 OH R 2 R
OH
1
Cl
2
OH
R
1
OH
R 2
R

H

R 1 O
R
1
O

R 2

LDA

R R OH 1 Cl 2 OH R 1 OH R 2 R H R 1
R OH 1 R OH 2 R Br 1 Br R 2
R
OH
1
R
OH
2
R
Br
1
Br
R 2
R 1 R 2
R 1
R 2

OH

2.1.3. aa-Functionalisation of carbonyl compounds

O R 2 R 1
O
R 2
R 1
aa -Functionalisation of carbonyl compounds O R 2 R 1 Attention to X regioselectivity of enolisation

Attention to

X regioselectivity

of enolisation

O O R 2 R 1 R 1 X
O
O
R 2
R 1
R 1
X

R 2

of enolisation O O R 2 R 1 R 1 X R 2 A selection of

A selection of synthetic equivalents for X :

Br , Cl RS RSe
Br
, Cl
RS
RSe

Br 2 , Cl 2 , NBS 2 , Cl 2 , NBS

RSCl, RS-SRfor X : Br , Cl RS RSe Br 2 , Cl 2 , NBS RSeCl,

RSeCl, RSe-SeRX : Br , Cl RS RSe Br 2 , Cl 2 , NBS RSCl, RS-SR

=O SeO 2 ; NO (HONO) -OH O ; OsO 4 O
=O
SeO 2 ; NO
(HONO)
-OH
O ; OsO 4
O

Dimethyl dioxirane

Amines can be introduced by FGI, e.g. from a-halocarbonyl compounds via azides followed by reduction:

O R 1
O
R 1

Br

R 2

O N 3 R 1
O
N 3
R 1

N 3

R 2

H 2

compounds via azides followed by reduction: O R 1 Br R 2 O N 3 R

Pd/C

O R 2 R 1 NH 2
O
R 2
R 1
NH 2

Examples:

O

Examples: O Br 2 , H + O Br via more stable enolate However, in basic

Br 2 , H +

Examples: O Br 2 , H + O Br via more stable enolate However, in basic

O

Examples: O Br 2 , H + O Br via more stable enolate However, in basic

Br

via more stable enolate

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

O R CH 3
O
R CH 3

Br 2 , NaOH

O R CBr 3
O
R CBr 3

NaOH

haloform reaction: O R CH 3 Br 2 , NaOH O R CBr 3 NaOH R

R

O

reaction: O R CH 3 Br 2 , NaOH O R CBr 3 NaOH R O

ONa + CHBr 3

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

O O O PBr 3 Br 2 O H 2 O OH Br Br OH
O
O
O
PBr 3
Br 2
O H 2 O
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
SiMe 3

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

2.1.4. Radical coupling

X R 1
X
R 1

Y

R 2

X R 1
X
R 1

+

two FGs. 2.1.4. Radical coupling X R 1 Y R 2 X R 1 + Y

Y

R 2

Radical coupling is only good when two identical molecules are being coupled (R 1 = R 2 , X = Y) or when the reaction proceeds intramolecularly.

Pinacol reaction:

R 1 R 2 1. Mg O 2. H 3 O + R 1 R
R 1
R 2
1. Mg
O 2. H 3 O +
R 1
R 2
R 1
O
Mg
O
R 2
R 1
H 3 O +
R
1
R 2
O
Mg O
R 1 OH R 2 HO R 2
R
1
OH
R 2
HO
R 2

R 1

R 2 R 1 O Mg R 1 OH R 2 HO R 2
R 2
R 1
O
Mg
R
1
OH
R 2
HO
R 2

R 1

R 2

R 2 O Mg O R 1 OH R 2 HO R 2 R 1 R

R 1

R 2 R 1 O O Mg
R
2
R
1
O
O
Mg

R 2

R 2 O Mg O R 1 OH R 2 HO R 2 R 1 R

Acyloin condensation:

O R 1
O
R 1

Na/xylene

Acyloin condensation : O R 1 Na/xylene OR 2 R 1 R 1 NaO ONa H

OR 2

R 1 R

R

1

NaO

ONa

H 3 O +

: O R 1 Na/xylene OR 2 R 1 R 1 NaO ONa H 3 O

R

OH 1 R 1
OH
1
R 1

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 R 1
X
R 1

Y

R 2

Ph

O

- 60-95% 2.1.5. Umpolung strategies X R 1 Y R 2 Ph O O M e

O

Me

X

2.1.5. Umpolung strategies X R 1 Y R 2 Ph O O M e X R

R 1 1

+

Umpolung strategies X R 1 Y R 2 Ph O O M e X R 1

Y

R 2

Phstrategies X R 1 Y R 2 Ph O O M e X R 1 +

O Me + O
O
Me
+
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 R CO 2 H Synthesis O NaCN R H
OH FGI
R
CO 2 H
Synthesis
O NaCN
R
H
OH OH + R CN R OH H 3 O + R CN R CO
OH
OH
+
R
CN
R
OH
H 3 O +
R
CN
R
CO 2 H
R H OH OH + R CN R OH H 3 O + R CN R

CN

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

R synthon
R
synthon

Z

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

R

Z'

the carbonyl oxygen with an anion- stabilising groups: O R synthon Z Z, Z' - anion

2.1.5.2. Cyanohydrins, benzoin condensation

2.1.5.2. Cyanohydrins, benzoin condensation O CN +H + ; -H + O H Ph CN Ph

O CN

+H + ; -H + O H Ph CN
+H + ; -H +
O
H
Ph
CN
Ph H
Ph
H
H O OH Ph Ph CN
H
O
OH
Ph
Ph
CN

Ph

O OH Ph H CN
O
OH
Ph
H
CN

Ph

O

OHCN Ph H H O OH Ph Ph CN P h O OH Ph H CN

Ph

benzoin

H HO O Ph Ph CN
H
HO
O
Ph
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 TMS-CN H Me 3 SiO R 1 O R CN
O
TMS-CN
H
Me 3 SiO
R 1
O
R
CN
OSiMe 3 H
OSiMe 3
H

CN

1. OH -

O TMS-CN H Me 3 SiO R 1 O R CN OSiMe 3 H CN 1.

2. H 3 O +

BuLi OSiMe 3 CN O OH R 1
BuLi
OSiMe 3
CN
O
OH
R 1

R

R

R 1 R 1

O

- 2. H 3 O + BuLi OSiMe 3 CN O OH R 1 R R

2.1.5.3. Dithians (thioacetal) nucleophile + electrophilic carbonyl

BuLi RX S S S S S S commecially R available H 3 O +
BuLi
RX
S
S
S
S
S
S
commecially
R
available
H 3 O +
S
S
S
S
R 1
R 1
R
R O
OH
R 2
R 2
Note: RX PhX, instead
O
Ph
+

H

BuLi

R O OH R 2 R 2 Note: RX PhX, instead O Ph + H BuLi
S S R R 2 R 1 O
S
S
R
R 2
R 1
O

Hg 2+

SH SH
SH
SH

R

O

OHO Ph + H BuLi S S R R 2 R 1 O Hg 2 +

R 2

S S
S
S

Ph

2.1.5.4. Nitroalkane nucleophile + electrophilic carbonyl

O Na 2 CO 3 H 3 C N O pK a ~ 10, compare
O
Na 2 CO 3
H 3 C
N
O
pK a ~ 10, compare with
O H 2 C N O O O OEt
O
H 2 C
N
O
O
O
OEt

pK a = 11

H 2 C

O N
O
N

O

Nitro groups are rarely desirable themselves, however they can undergo useful FGIs:

LiAlH 4 or Zn/HCl or R Nef R 1 NH 2 1 NO 2 O
LiAlH 4 or
Zn/HCl or
R
Nef
R 1
NH 2
1
NO 2
O
NaOH; H2SO4 or
R 1
R
R 2
2
H2/Pd/C
TiCl3
R 2
Synthetic application:
2.
O
1. NaOH
O
NO 2 1. NaOH
Me
NO 2
OEt
2.
Br
3. H 3 O +
NO 2
H 2 /Pd/C
TiCl 3
LiAlH 4
O
OH
O
NH 2
NH 2
O

O 2 N

R

2 /Pd/C TiCl 3 LiAlH 4 O OH O NH 2 NH 2 O O 2

is a synthetic equivalent for synthones

R R

2 O O 2 N R is a synthetic equivalent for synthones R R O or

O

or

H

2 N

R is a synthetic equivalent for synthones R R O or H 2 N 2.1.5.5. Imidoyl

2.1.5.5. Imidoyl nucleophile + electrophilic carbonyl

1 R R 1 R N C = O C Li Preparation: a) From isonitriles
1
R
R 1
R
N
C
=
O
C
Li
Preparation:
a) From isonitriles
R
N
C
R
N
C
t-Bu
N
C
is commercially available
1
1
1
R
1 Li
R
E
R
H
R
3 O +
R
N
C
R
N
C
R
N
C
O
C
Li
E
E
b) From amides via chloroimines
Li
PCl 5
R
HN
R 1
R
N
R 1
R 1
cat C 10 H 8
R
N
C
O toluene, D
Li
Cl THF, -78 o C
1.
O
Example:
O
1. EtLi
t-Bu
N
C
t-Bu
N
C Li
OH
2. H 3 O +

2.1.5.6.

Alkyne nucleophile + electrophilic carbonyl

=

Analysis

HO O R R 1 2
HO
O
R
R
1
2

HO

+ electrophilic carbonyl = Analysis HO O R R 1 2 HO R 1 O R

R 1

O R 1
O
R 1

H

O + R 2 R 2 =
O
+
R 2
R 2
=

Synthesis

R 1 H 1. BuLi O 2. R 2 H R 1 R 2
R 1
H 1. BuLi
O
2.
R
2
H
R 1
R 2

OH

Hg 2+

R 1 H 1. BuLi O 2. R 2 H R 1 R 2 OH Hg

H + , H 2 O

R 1 OH O
R 1
OH
O

R

2

2.2 Functional group interconversion, amine synthesis

R

H H H Level 0
H
H
H
Level 0

-2e

interconversion, amine synthesis R H H H Level 0 -2e R H -2e O -2e OH

R

H

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

R

O OH Level 3
O
OH
Level 3

Oxidation level 1 (alkane – 2e):

C-X (X = Hal, OH, OR, OAc, OTs, NR 2 , NO 2 , 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, OSiR 3 ); C C; X-C-C-Y; epoxides.

Oxidation level 3 (alkane – 6e):

COOH, COX (X = OR, Hal, OCOR, NR 2 ); 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

OH

R OSO 2 R' R Hal R + sythones
R
OSO 2 R'
R
Hal
R +
sythones

Y

R

X

R X R Y

R

Y

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

transformations between levels can be achieved only on certain derivatives: R OH R O but R

OH

R

transformations between levels can be achieved only on certain derivatives: R OH R O but R

O but

R

O
O

R'

transformations between levels can be achieved only on certain derivatives: R OH R O but R

R R' NO 2 However, transformations between levels can be achieved only on certain derivatives: R OH R

R'O

Other important kind of transformations – interconversion of nitrogen containing functions. With amines, alkylation usually produce mixtures:

RNH 2

MeI

With amines, alkylation usually produce mixtures: RNH 2 MeI RNHMe + RNMe 2 + R N

RNHMe

+

RNMe 2

+

usually produce mixtures: RNH 2 MeI RNHMe + RNMe 2 + R N M e 3

RNMe 3

I I

Alternative strategies are based on reduction of other nitrogen-containing FGs:

Primary amines:

Primary amines at primary carbon

RX

CN
CN

RCN

LiAlH 4 L i A l H 4

RCH 2 NH 2

Primary amines at primary or secondary carbon

N 3 RX RN 3 1. Base RCH 2 NO 2 2. R'X
N 3
RX
RN 3
1. Base
RCH 2 NO 2
2. R'X

R = H, Alk

Phthalimide

ROH

LiAlH 4
LiAlH
4

or H 2 /Pd/C

RNH 2

R' LiAlH 4 NO 2 or H 2 /Pd/C R or Zn/NCl
R'
LiAlH 4
NO
2
or H 2 /Pd/C
R or Zn/NCl
R' NH 2 R O NH 2 NH 2 N
R'
NH 2
R
O
NH 2 NH 2
N

Ror H 2 /Pd/C R or Zn/NCl R' NH 2 R O NH 2 NH 2

PPh 3 , DEAD

O

RNH 2

Primary amines at secondary or tertiary carbon

R 2

R 1 R 3
R 1
R 3

OH

NaCN R 1 R 2 H 2 SO 4 R 3
NaCN
R 1
R 2
H 2 SO 4
R 3

NC

carbon R 2 R 1 R 3 OH NaCN R 1 R 2 H 2 SO

R 2

R O 1 NCH R 3
R
O
1
NCH
R 3

H +

NaCN R 1 R 2 H 2 SO 4 R 3 NC R 2 R O

Mitsunobu reaction

R 2

R 1 R 3
R 1
R 3

NH 2

Ritter reaction

The Ritter reaction with alkylnitriles produces secondary amines

Secondary amines:

Reductive amination

R 1 RNH 2 O R 2
R 1
RNH 2
O
R 2
R 1 R 2
R 1
R 2

NR

NaBH 3 CN R 1 or NaBH 4 R 2
NaBH 3 CN
R 1
or NaBH 4
R 2

NHR

If hydroxylamine (NH 2 OH) is used in the place of RNH 2 , reduction of the corresponding oxime gives primary amine.

Secondary and tertiary amines:

R

O

Clgives primary amine. Secondary and tertiary amines: R O R 1 R 2 N H R

R 1 R 2 N H
R
1
R 2
N
H

R

O N R 1
O
N R 1

R 2

LiAlH 4

or BH 3 THF 3 THF

R

N
N

R 2

R 1

The method is also suitable for the preparation of primary amines (R 1 = R 2 = 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 R 1
X
R 1

Y

R

2

e.g.

O Me
O
Me

O

Me

2,5-Hexanedione

OH Me Me OH
OH
Me
Me
OH

2,5-Hexanediol

H

N O O Succinimide
N
O
O
Succinimide

2.3.1. Acyl equivalent + Michael acceptor

O R 1
O
R 1

O

R 2

O R 1
O
R 1

Acyl-anion

+

R 2 = O O
R 2
=
O O

R 2

This approach is closely related to the synthesis of 1,5-dicarbonyl derivatives via addition of enolates to a,b-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

R Examples:
R
Examples:
in the section 2.1.5. Umpolung Strategies . O R Examples: CN R OH CN R NO

CNin the section 2.1.5. Umpolung Strategies . O R Examples: R OH CN R NO 2 in the section 2.1.5. Umpolung Strategies . O R Examples: R OH CN R NO 2

R

OH

section 2.1.5. Umpolung Strategies . O R Examples: CN R OH CN R NO 2 NR'

CN

R R

NO 2

Umpolung Strategies . O R Examples: CN R OH CN R NO 2 NR' R R

NR'

R

Strategies . O R Examples: CN R OH CN R NO 2 NR' R R Ph

R

Strategies . O R Examples: CN R OH CN R NO 2 NR' R R Ph

Ph

O

. O R Examples: CN R OH CN R NO 2 NR' R R Ph O

H

+

Regioselectivity issues:

O

CN R NO 2 NR' R R Ph O H + Regioselectivity issues: O Cat. KCN

Cat. KCN

2 NR' R R Ph O H + Regioselectivity issues: O Cat. KCN DMF Ph O

DMF

Ph

O O
O
O

R 1

Et

S S 1,2-addition 1,4-addition Et S S
S
S
1,2-addition
1,4-addition
Et
S
S

O

Et

NO 2

R 1 NO 2
R 1
NO 2
O R
O
R

OH S

1,4-addition Et S S O Et NO 2 R 1 NO 2 O R OH S

R

S

1,4-addition Et S S O Et NO 2 R 1 NO 2 O R OH S

O

R 1

O

Et S S O Et NO 2 R 1 NO 2 O R OH S R

R 1,4-addition

R 1
R 1

1,4-addition

OTMS

Et O S O S
Et
O
S
O
S

R

Et S S O Et NO 2 R 1 NO 2 O R OH S R

R

O CN

2.3.2. Homoenolate + electrophilic carbonyl

O R 1
O
R 1

O

R 1
R 1

O

=

O

R 2

R

R

2 O or H 1
2
O
or
H
1
O R 1 O OEt R 1
O
R 1
O
OEt
R 1

+

R 2 O
R 2
O

- homoenolate, this is not a resonanse stabilised enolate

Ester homoenolates (Zn and Ti): O Br O Br - OEt
Ester homoenolates (Zn and Ti):
O
Br
O
Br -
OEt

OEt

BrZn O OEt Reformatsky type
BrZn
O
OEt
Reformatsky type

Zn

1.

RCHO

Br - OEt OEt BrZn O OEt Reformatsky type Z n 1. RCHO 2. H 3

2. H 3 O +

R

O OEt Reformatsky type Z n 1. RCHO 2. H 3 O + R O OH

O OH
O
OH

OEt

[O]

R

O O
O
O

organozinc reagent

OEt

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 R Mg MgBr R Br R OH OH O O O O O TsOH
Br
R
Mg
MgBr
R
Br
R
OH OH
O
O
O
O
O TsOH
Et 2 O

Latent functionality:

BrMg Br Mg Et 2 O Ar
BrMg
Br
Mg
Et 2 O
Ar
1. PhCHO 2. H 3 O + Ar
1. PhCHO
2. H 3 O +
Ar
Ph HO
Ph
HO

Ar

1. R 1 CHO

2. H 3 O + reveal
2.
H 3 O +
reveal
Ar 1. PhCHO 2. H 3 O + Ar Ph HO Ar 1. R 1 CHO

O 3 ; Me 2 S

OH

R R 1 O Ph HO O
R
R 1
O
Ph
HO
O

Ar

2.3.3.

Additional umpolung strategies:

O

R 1 O R 2
R 1
O
R 2

R

O

O

1
1
O R 2 R 1 - standard enolate
O
R 2
R 1
- standard enolate

+

O R 1 O R 2 R O O 1 O R 2 R 1 -

O

R 2

-

electrophilic centre in a-position to carbonyl group

2.3.3.1. Enolate + a-functionalised carbonyl compound

O 1. LDA R 1 2. TMS
O
1. LDA
R 1
2. TMS

O

R 2 R

3. NBS

LDA

carbonyl compound O 1. LDA R 1 2. TMS O R 2 3. NBS LDA O
O Br R 1 O R 2
O
Br
R 1
O
R 2

R 1 1

O

R 1 2. TMS O R 2 3. NBS LDA O Br R 1 O R

O

R 2

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

Illustrative example:

OSiR 3

during the reaction Illustrative example: O S i R 3 O 1. (Me 3 Si) 2

O

1. (Me 3 Si) 2 NLi, (LiHMDS)

O S i R 3 O 1. (Me 3 Si) 2 NLi, (LiHMDS) 2. I Bn
2. I Bn 2 N O
2. I
Bn 2 N
O
OSiR 3 O Bn 2 N O
OSiR 3
O
Bn 2 N
O

2.3.3.2. Enolate + a,b-unsaturated nitrocompound (Michael-type acceptors)

H 2 C O H 2 C N N O O O O N N
H 2 C
O
H 2 C
N
N O
O
O
O
N
N O
O
O
NH 2 R
NH 2
R
R N O O
R
N O
O
H 2 C C CH 3 O
H 2 C
C CH 3
O

O

Nitroalkanes are acyl-anion equivalents, they resemble enolates

but have one carbon atom less

Nitroalkenes resemble a,b-unsaturated carbonyl compounds (Michael acceptors) but have one carbon atom less.

O

(Michael acceptors) but have one carbon atom less. O Nitroalkenes can be viewed as reagents for

Nitroalkenes can be viewed as reagents for

R carbonyl and nitrogen based functionalities

Examples:

Me

NO 2

1. base OH 2. RCHO R
1. base
OH
2. RCHO
R

NO 2

Examples: Me NO 2 1. base OH 2. RCHO R NO 2 R N O 2

R

Examples: Me NO 2 1. base OH 2. RCHO R NO 2 R N O 2

NO 2

2. H 3 O +

2 1. base OH 2. RCHO R NO 2 R N O 2 2. H 3

EtO 2 C

R

H CO 2 Et NH 2
H
CO 2 Et
NH 2
EtO 2 C CO 2 Et NO 2 R 2 /Pd D, H 3 O
EtO 2 C
CO 2 Et
NO 2
R
2 /Pd
D, H 3 O +
HO 2 C
NO 2
R

LiAlH 4

2 Et NO 2 R 2 /Pd D, H 3 O + HO 2 C NO

TiCl 3 (Nef) 3 (Nef)

1. EtO 2 C CO 2 Et HO OH NH 2 R EtO 2 C
1.
EtO 2 C
CO 2 Et
HO
OH
NH 2
R
EtO 2 C
CO 2
Et
O
R

2.3.3.3. Epoxide based transformations

OH R 1
OH
R 1

O

R 2

OH R 1
OH
R 1

O Epoxide can be viewed as

OH R 1 O R 2 OH R 1 O Epoxide can be viewed as R

R 1

a synthetic equivalent to synthon

+

R

R 2 O OH 1
R 2
O
OH
1

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

O O EtONa EtO
O
O
EtONa
EtO
O O
O
O

EtO

OH 1. R O R O 2. H 3 O + EtO O
OH
1.
R
O
R
O
2. H 3 O +
EtO
O

In general, epoxides are opened by nucleophiles at the less hindered side (S N 2 type)

b) Opening of epoxides with enamines catalysed by acids:

O O N N N R H H + -H 2 O R OH OH
O
O
N
N
N
R
H
H +
-H 2 O
R
OH
OH
In acid, the reaction proceed via intermediate
R

H 3 O +

acid, the reaction proceed via intermediate R H 3 O + O R OH The opening
O R OH
O
R
OH

The opening occures at the side with more stable cation (S N 1 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 + PhMgBr R Use of alkynyl anions: H BuLi or R 1 Na, NH
O
+ PhMgBr
R
Use of alkynyl anions:
H BuLi or
R 1
Na, NH 3

However:

Ph

O

of alkynyl anions: H BuLi or R 1 Na, NH 3 However: Ph O + Ph

+

Ph

OH Ph R 2. H 3 O + 1. O OH R R 1 R
OH
Ph
R
2. H 3 O +
1.
O
OH
R
R 1
R
R 1
2. H 3 O +
Ph
Li
BF 3 Et 2 O
OH
+ Ph
Ph
Ph
major
minor

OH

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

Ph

Ph Hg 2+ , H 2 O OH
Ph
Hg 2+ , H 2 O
OH
Ph Ph O
Ph Ph
O

OH

Note: other usefull transformations of alkynes include chemo- and stereoselective reduction:

of alkynes include chemo- and stereoselective reduction: R 1 R 2 H 2 , Pd/C R

R 1

R 2

H 2 , Pd/C

and stereoselective reduction: R 1 R 2 H 2 , Pd/C R 1 R 2 H

R

1
1

R 2

H 2 , Pd/C, BaSO 4 (Lindlar catalyst)

Pd/C R 1 R 2 H 2 , Pd/C, BaSO 4 (Lindlar catalyst) Na, NH 3

Na, NH 3 (l) 3 (l)

2 , Pd/C, BaSO 4 (Lindlar catalyst) Na, NH 3 (l) R 1 R 1 R

R 1

R 1 R 2
R 1
R 2

R 2

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 R 2 R 1 OH
OH
R 2
R 1
OH

FGI

further exploited in organic synthesis. OH R 2 R 1 OH FGI HO R 2 OH
HO R 2 OH R 1
HO
R 2
OH
R 1
HO R 2 R 1 OH
HO
R 2
R 1
OH

There is no reagent corresponding to this synthon, therefore the synthesis has to proceed stepwise

Synthesis:

BuLi H H Li OLi
BuLi
H
H
Li
OLi
1. O H Li H OH O 2. H 3 O + 1. HO H
1.
O
H
Li
H
OH
O 2. H 3 O +
1.
HO
H 2
H
Ph
OH
2. H 3 O +
Ph
Pd/C

2 x BuLi

BuLi H H Li OLi 1. O H Li H OH O 2. H 3 O

Ph

OH

BuLi H H Li OLi 1. O H Li H OH O 2. H 3 O

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

functional group removal . FG Conditions for FG removal C C C C H 2 /Pd

C

C

group removal . FG Conditions for FG removal C C C C H 2 /Pd O

C

H 2 /Pd

OH

 

a) TsCl, MsCl – LiAlH 4 , BH 3

b)

Barton reaction (radical Bu 3 SnH)

 

a) NaBH 4 and then as with OH group

C=O

b) Kizhner reduction(NH 2 NH 2 )

c) Clemence reduction( Zn/Hg; HCl)

SH

Ranney Ni

Br

Radical Bu 3 SnH

NH 2

HNO 2 diazotisation

2.4. Synthetic approaches to cyclic systems.

2.4.1. Cycloadditions

Some types of Diels-Alder disconnections:

O O + O O
O
O
+
O
O
Some types of Diels-Alder disconnections: O O + O O + CO 2 R CO 2
+
+
CO 2 R CO 2 R + O O CO 2 R CO 2 R
CO 2 R
CO 2 R
+
O
O
CO 2 R
CO 2 R
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 S N 2, 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 CO 2 Et NaOEt Cl Cl Cl O base CO Et 2 CO
Cl
Cl
CO 2 Et
NaOEt
Cl
Cl
Cl
O
base
CO
Et
2
CO
Et
2
CO 2 Et

CO 2 Et 2 Et

O
O

O

base O OH
base
O
OH

2.4.3. Other methods

2 CO 2 Et CO 2 Et O O base O OH 2.4.3. Other methods O
O
O

OMe

Li, NH 3 t-BuOH
Li, NH 3
t-BuOH

Birch reduction

OMe

Other methods O OMe Li, NH 3 t-BuOH Birch reduction OMe O O TiCl 3 ,
O O TiCl 3 , Zn/Cu McMurry coupling
O O
TiCl 3 , Zn/Cu
McMurry coupling
Birch reduction OMe O O TiCl 3 , Zn/Cu McMurry coupling CH 2 H 2 C
CH 2 H 2 C + R 1 R 2
CH 2 H 2 C
+
R 1
R 2

[Ru] (Grubbs)

CH 2 H 2 C + R 1 R 2 [ R u ] ( G

or [Mo] (Schrock)

R 2 [ R u ] ( G r u b b s ) or [Mo]

Ring Closing Alkene Metathesis

[Ru]

s ) or [Mo] (Schrock) Ring Closing Alkene Metathesis [Ru] R 2 R 1 + R
R 2 R 1
R 2
R 1

+

R 1
R
1

R 1

+

R 2 2
R
2
2

R

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.

OH
OH

O 3

OH O 3 OH NaBH 4 Me 2 S O 3 KMnO 4 O O O

OH

NaBH 4

Me 2 S O 3 KMnO 4
Me 2 S
O 3
KMnO 4
O O O CO 2 H
O
O
O
CO 2 H

Similar transformation can be also achieved in an indirect way:

transformation can be also achieved in an indirect way: OsO 4 , NMO or KMnO 4
transformation can be also achieved in an indirect way: OsO 4 , NMO or KMnO 4

OsO 4 , NMO

or KMnO 4 NMO: O N
or KMnO 4
NMO: O
N

OH

NaIO 4

way: OsO 4 , NMO or KMnO 4 NMO: O N OH NaIO 4 O OH

O

OH

or Pb(OAc) 4

O O
O
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

(see above in the course): The reaction is stereospecific 2.5.2. Baeyer-Villiger rearrangement Another type of

2.5.2. Baeyer-Villiger rearrangement

Another type of reconnection strategies is hydrolysis of lactones:

OH HO
OH
HO

O

O O
O
O

Lactone

O O O

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

H 3 O + HO COOH MeMgBr OH HO
H 3 O +
HO
COOH
MeMgBr
OH
HO

H O

HO

H 3 O + HO COOH MeMgBr OH HO H O HO O TS: O F

O TS:

O

F 3 C O OH
F 3 C
O
OH
O Mechanism:
O
Mechanism:

O

MeMgBr OH HO H O HO O TS: O F 3 C O OH O Mechanism:
O O O OH HO O
O
O
O
OH
HO
O
O O CF 3 H d+ H O d+ O CF 3 O O d+
O O
CF 3
H d+
H
O d+
O
CF 3
O O
d+

H +

CF 3

OH H O O O CF 3
OH
H
O
O O
CF 3
O
O

The reaction is regioselective. Migration order: 3 o > 2 o ~ Ar >1 o . 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:

H 2 N

for 6-amino acids is hydrolysis of lactams: H 2 N O O H O NH Lactam

O

OH

O NH
O
NH

Lactam

O O O

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

O N

NH 2 OH

ketones by the Beckmann rearrangement : O N NH 2 OH O H 1. PCl 5

OH 1. PCl 5

rearrangement : O N NH 2 OH O H 1. PCl 5 2. H 3 O
rearrangement : O N NH 2 OH O H 1. PCl 5 2. H 3 O

2. H 3 O +

Reaction mechanism:

N N OH Cl 4 P Cl N OH 2
N
N
OH Cl 4 P Cl
N
OH 2
O NH O PCl 3 Cl NH O H
O
NH
O PCl 3
Cl
NH O
H

H 2 N

Cl 4 P Cl N OH 2 O NH O PCl 3 Cl NH O H
H O H N NH O
H
O
H
N
NH
O

CO 2 H

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 HO OH + H H N N
H
N
N
N
H
N
N
N
HO
OH
+
H
H
N
N
N

reaction : H N N N H N N N HO OH + H H N

N

H H 2 O N N NH O
H
H 2 O
N
N
NH
O

N

O
O

H

+

N N N H 2 O N Synthetic application: O Ac n-Oct Analysis OH OH
N
N
N
H 2 O
N
Synthetic application:
O Ac
n-Oct
Analysis
OH
OH
FGI
n-Oct
n-Oct
Pine sawfly's sex attractant
C-X

available

SM

FGI

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

O

reconnect. O
reconnect.
O
Wittig OH n-Oct O
Wittig
OH
n-Oct
O

Synthesis

OH

O B-V O reconnect. O Wittig OH n-Oct O Synthesis O H O CrO 3 MCPBA

O

CrO 3

O reconnect. O Wittig OH n-Oct O Synthesis O H O CrO 3 MCPBA H 2

MCPBA

O Wittig OH n-Oct O Synthesis O H O CrO 3 MCPBA H 2 SO 4

H 2 SO 4 aq

79%

B-V

80%

O O
O
O

n-OctLi

O CrO 3 MCPBA H 2 SO 4 aq 79% B-V 80% O O n -OctLi

70%

O OH Ph 3 P-CH 2 n-Oct H 2 n-Oct n-Oct OH Pd/C OH OH
O
OH
Ph 3 P-CH 2
n-Oct
H 2
n-Oct
n-Oct
OH
Pd/C
OH
OH
Wittig
66%
100%

AcCl, Py

O O n -OctLi 70% O OH Ph 3 P-CH 2 n-Oct H 2 n-Oct n-Oct
OAc n-Oct
OAc
n-Oct

3.

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

3.1. Elementary retrosynthetic analysis

Target (parent)

structure

retrosynthetic analysis Target (parent) structure Offspring synthons Offspring reagents Transformation

Offspring synthons

Offspring reagents

Transformation

Target molecule

Synthons

Reagents and reaction conditions

type

One-group

OH

OH

 
OH

OH

 

O

O

disconnection

 
disconnection   + 2 H 5 MgBr 1) 0 o C (THF) 2) NH 4 Cl/H

+

2 H 5 MgBr

1) 0 o C (THF) 2) NH 4 Cl/H 2 O

 

+

C

C 2 H 5

2 H 5

C

Two-group

O OH

O

OH

   

disconnection

(heterolytic)

 
disconnection (heterolytic)   O + + H OLi 1) - 78 o C 2) NH 4
O + + H
O
+
+
H

OLi

1) -78 o C

2) NH 4 Cl/H 2 O

rt (THF)

 

CH 3 CHO

 

OH

Two-group

disconnection

(homolytic)

O

O

OH

Two-group disconnection (homolytic) O OH O O H C O O E t COOEt 1) Na/Me
O
O
O

O

OH

C O O E t COOEt

COOEt

COOEt

1) Na/Me 3 SiCl

toluene, D 2) H 2 O

Electrocyclic

CO CO

CO

CO

2

Me

+

+

 

CO 2 Me

synthones

 

disconnection

 
disconnection   (benzene, D )
disconnection   (benzene, D )

(benzene, D)

2

Me

MeO 2 C

reagents

Reconnection

CHO CHO

CHO

CHO

 
Reconnection CHO CHO   O 3 /Me 2 S CH 2 Cl 2 ; - 78
Reconnection CHO CHO   O 3 /Me 2 S CH 2 Cl 2 ; - 78

O 3 /Me 2 S CH 2 Cl 2 ; -78 o C

   
 

Rearrangement

N H O

NH O

Rearrangement N H O N O H H 2 SO 4 ; D  
N O H
N O H

N OH

H 2 SO 4 ; D

 

Functional group

 

OH

OH
 

interconversion

O
O

CrO 3 /H 2 SO 4 ; acetone

 

(FGI)

(FGI) HgCl 2 ; acetonitrile

HgCl 2 ; acetonitrile

S S

S

S

Functional group

Ph

Ph

 

Ph

 

addition (FGA)

addition (FGA) Ph H 2 ; Pd/C
Ph

Ph

Ph

H 2 ; Pd/C

OH

 

OH

Special case of FGI - Functional group removal (FGR)

O

O

OH

O

O
O
 

1) LDA; THF; -78 o C 2) Me 3 SiCl 3) O O

1) LDA; THF; -78 o C 2) Me 3 SiCl 3) O O
 

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

R

Br -

N 3 -

RO -

RS -

alkyl, allylic or benzylicSynthetic equivalent R Br - N 3 - R O - R S - R '

R'

alkyl, allylic or benzylic R R' R vinyl or aryl R'
alkyl, allylic or benzylic
R
R'
R
vinyl or aryl
R'

R''

NaBr NaN 3 RONa made from ROH RSNa made from RSH Hal

Hal = Br, I alkyl, allylic or benzylic R R' MgHal alkyl, allylic or benzylic
Hal = Br, I
alkyl, allylic or benzylic
R
R'
MgHal
alkyl, allylic or benzylic
or cuprate for
Michael addition
R
R'
MgHal
R
vinyl or aryl
R'
or cuprate for
Michael addition
 

R''

R

R R M M = Li, MgHal

R

R R M M = Li, MgHal

M

M = Li, MgHal

R

OH R'
OH
R'

R

O

R R M M = Li, MgHal R OH R' R O O R O R

O

R O R
R
O
R

R

O

R R M M = Li, MgHal R OH R' R O O R O R

R'

 

O

O

O

O

or or  

or

or

or

or or  
or or  
 

R

OR'

OLi

or

R

Hal

OSiMe 3

Hal OSiMe 3 or

or

R

O

NR' 2

R

 

R

  R R   R

R

 
R

R

Methyl acetoacetate or dimethyl malonate are often used as starting materials

R

O

2 R   R R   R Methyl acetoacetate or dimethyl malonate are often used as

Table 2. Some “unnatural” synthons

Synthon

Synthetic equivalent

R

Br + O 2+ or RS +

HO +

O

acyl anionSynthetic equivalent R Br + O 2 + or RS + HO + O HO O

HO O

R Br + O 2 + or RS + HO + O acyl anion HO O

Br 2 SeO 2 or dimethyl dioxirane RSCl or RSSR

S R R R ; R' N NO 2 ; S Li Li CN -
S
R
R R
;
R'
N
NO 2 ;
S
Li
Li
CN - (KCN)

;

R

S R R R ; R' N NO 2 ; S Li Li CN - (KCN)

Li

 

O

O

NO 2

R

R R Br ; R

R

R R Br ; R

Br

;

R

R R Br ; R

OH

O

R

R R

R

R R

NH 2

NH 2
 

NO 2

NO 2
 

after reduction (LiAlH 4 or H 2 /Pd-C)

R

R

 
O RO O R
O
RO
O
R

homoenolate

homoenolate

R

a n d and

R   O RO O R homoenolate homoenolate R a n d O O R O
O
O

O

R

O RO
O
RO

MgBr

or

ZnBr R
ZnBr
R

MgBr

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