Dr.

Pere Romea
Department of Organic Chemistry

Sky and Water I

Maurits Cornelis Escher, 1938

6. Functional Group Interconversion

Organic Synthesis 2014-2015 Autumn Term

 Carbon Backbone & Functional Groups

The synthesis of an organic compound must pay attention to ...

Carbon backbone Functional groups

(Chapters 24 )
Functional Group Interconversion (FGI)

I. Nucleophilic Substitutions
Electrophilic Additions to C=C
Addition-Eliminations on Carboxylic Acids and Derivatives
II. Reductions
Mechanism!!! III. Oxidations
Pere Romea, 2014 2
 Nucleophilic Substitutions

The nucleophilic substitutions involve

the interconversion of functional groups bound to sp3 carbonis

+ Nu + X
X Nu

Csp3

RX

Electrophile Nucleophile Leaving group

Chap. 15
Pere Romea, 2014 3
 Nucleophilic Substitutions

Two model mechanisms, called SN1 i SN2,

are used to explain the nucleophilic substitutions

+ Nu + X
X Nu

Unimolecular (SN1) or bimolecular (SN2)

nucleophilic substitution?

A slightly different model, called SN2,

may be useful in substitutions on allylic substrates

X + Nu Nu + X

4 Pere Romea, 2014

 Nucleophilic Substitutions and FGI

There are three main sources to carry out FGI

through nucleophilic substitutions: sulfonates, alcohols, and alkyl halides

Nu
Sulfonates ROSO2R RNu

Nu
Alcohols ROH RNu

Alkyl halides Nu
RX RNu
X: I, Br, Cl

5 Pere Romea, 2014

 Nucleophilic Substitutions and FGI

A wide array of structures can be synthesized from sulfonates and alkyl halides through
nucleophilic substitution of X = OSO2R, I, Br, Cl in CC bond forming reactions and FGI
R Y
R R R OH

Y
R H 2O
or OH
R N R OR
ROH
CN or RO
R X
O
N3 O
R N3 O R R
O R
NH3 H 2S
RSH or HS
or RS

R NH 2 R SH

Pere Romea, 2014 R SR 6

 Nucleophilic Substitutions and FGI

How easy is to interconvert sulfonates, alcohols, and alkyl halides?

Nu
Sulfonates ROSO2R RNu

Nu
Alcohols ROH RNu

Alkyl halides Nu
RX RNu
X: I, Br, Cl

7 Pere Romea, 2014

 Alcohols and Sulfonic Esters

Conversion of alcohols into sulfonic esters

pyridine
+ RSO2Cl or (RSO 2 )2O
OH CH 2Cl 2 or Et2O OSO 2R
0 C rt

Mesyl chloride MsCl MeSO2Cl Mesylate

Tosyl chloride TsCl p-MePhSO2Cl Tosylate
Triflic Anhidride Tf2O (CF3SO2)2O Triflate

Primary and secondary ROH OK, but the reaction is sensitive to steric hindrance
OH
TsCl, pyr Me
Me
Me
H Me

The reaction does not affect the CO bond: the configuration of the carbon remains the same
Mesylates and tosylates are largely employed.Triflates are the most reactive sulfonates
Rearrangements of the carbon backbone are not frequent
8 Pere Romea, 2014
 Sulfonic Esters and Alkyl Halides

Conversion of sulfonate into alkyl halides

X
OH SN2 X X: Cl, Br, I

OH 1) MsCl, Et3N, CH2Cl2 Cl

Pr 2) LiCl, DMF Pr
83%

Ph 1) TsCl, pyr, CH2Cl2 Ph

OH Br
2) LiBr, DMF
Ph Ph
89%

1) MsCl, Et 3N, CH 2Cl 2

TBDPSO OH TBDPSO I
2) Lil, acetone
94%
9 Pere Romea, 2014
 Alcohols and Alkyl Halides

Conversion of alcohols into alkyl halides

Sulfonates ROSO2R

RSO2Cl

Alcohols ROH X

?
Alkyl halides
RX
X: I, Br, Cl

10 Pere Romea, 2014

 Alcohols and Alkyl Halides

Conversion of alcohols into alkyl halides

OH X X: Cl, Br, I

Reagents & Conditions Alcohols Mechanism

HCl conc Tert SN1 (racemization)

HCl/ZnCl2 (Lucas reagent) Prim & Sec SN2 (inversion)

PCl3 Prim & Sec SN2 (inversion)
SOCl 2 ,1,4-dioxane Prim & Sec SN2 + SN2 (retention)
SOCl 2 , non nucleophilic solvent Prim & Sec SN2 (inversion)

HBr conc Tert SN1 (racemization)

HBr conc, Prim S N2

PBr3 Prim & Sec SN2 (inversion)

P/I2 Prim & Sec SN2 (inversion)

11 Pere Romea, 2014

 Alcohols and Alkyl Halides

Problem! Too harsh experimental conditions: mixture of mechanisms and transpositions

H Br
OH OH2 Br
SN2 single

OH OH2
H

Br Br
SN1
Br

86% 14% Br

Cl

H Cl
OH OH2

single
Pere Romea, 2014 12
 Alcohols and Alkyl Halides

More selective transformations are required

The most used options are based on the conversion of alcohols into alkoxyphosphonium salts,
highly reactive in SN2 substitutions

E
Ph3P + ENu Ph3P Ph3P E + Nu
Nu

Ph3P E + HO Ph3P O + HE
H H
Alkoxyphosphonium salt

Ph3P O + Nu Ph3P=O + Nu
H H
Alkoxyphosphonium salt
13 Pere Romea, 2014
 Alcohols and Alkyl Halides

Ph3P / X2 : Ph3P / I2, Ph3P / Br2, Ph3P / Cl2

Br Br
Ph3P + BrBr Ph3P Ph3P Br
Br + Br

HBr Ph3P=O
Ph3P Br + HO Ph3P O Br
H H Br H
SN2

This transformation is very useful for secondary alcohols and those systems that easily produce transpositions, as neopentylic alcohols
The control on the configuration is very good.

Br
Br PBr3 Ph3P/Br2
+ + Br OH Br

11% 26% 63% 90%

OMe OMe
Ph3P, Br2 Ph 3P, I 2
O R O R OH I
O O Imidazole
OH Br Et 2O, rt
85% 96%
14 OBn OBn
 Alcohols and Alkyl Halides

Since chlorine (Cl2) is a gas difficult to handle ....

HO
CCl3 H Ph3P=O
Ph3P + ClCCl3 Ph3P Cl Ph3P O Cl
HCl H H
Cl
carbon tetrachloride

O O
Ph3P + Cl CCl3
Cl
CCl3
Cl Cl Cl
hexachloroacetone

Ph3P/Cl2 OH Ph3P/CCl4 Cl
OH Cl
92% 70%

Ph3P/CCl3COCCl3
OH Cl
99%

15 Pere Romea, 2014

 Nucleophilic Substitutions and FGI

Nu
Sulfonates ROSO2R RNu

Nu
Alcohols ROH RNu

Alkyl halides Nu
RX RNu
X: I, Br, Cl

16 Pere Romea, 2014

 Carbon Nucleophiles

O O O

R NH2 R OH R H R Me
Amine 1 Carboxylic Acid Aldehyde Methyl ketone

Red Hydrolisis Red Hydration

LiAlH4 H3O+ DIBALH cat Hg2+, H2O

R CN R C CH

+C +2C

Attention!
Alkyl halides are very useful for R X R OH
the construction of CC bonds

17 Pere Romea, 2014

 Nitrogen Nucleophiles: Primary Amines

The alkylation of ammonia, NH3, is not easy ...

R X HX
NH3 R NH3 X R NH2 Primary Amine
+ HX

R X HX
R NH2 R2 NH2 X R2 NH Secondary Amine
+ HX

R X HX
R2 NH R3 NH X R3 N Tertiary Amine
+ HX

R X
R3 N R4 N X Ammonium Salt

Such an alkylation only becomes efficient when the resulting amine is much less nucleophile than the initial one,
for steric or electronic reasons

CO2Et
CO2Et CO2Et 1) Br CO2Et
1) RCH2Cl
NH N
H2N 2) NaHCO3 R N 2) NaHCO3
R: C15H31 H
18 Pere Romea, 2014
 Nitrogen Nucleophiles: Primary Amines

Potassium phthalimide, PhthNK

O O
Br Ph NaOH
Ph H2N
N K N Ph
95%
O SN2 O
Potassium phthalimide, pKa 8.3 Gabriel synthesis of amines

Azide, N3
The azide anion is an excellent nucleophile that participates in a large number of SN2 processes
The reduction of the azide group affords a primary amine
NaN3
I N3 NH2
Bu Bu Bu
DMSO,
90%
O O O O
1) MsCl, Et3N
OTBDPS OTBDPS
2) NaN3, DMF
OH N3
85% 19
 Nitrogen Nucleophiles: Primary Amines

Mitsunobu conditions: Ph3P / DEAD / HN3 or DPPA [(PhO)2PON3]

Ph3P, EtO2C N N CO2Et

OH N3
H HN3 o (PhO)2PON3, H

Ph3P
CO2Et Ph3P CO2Et
N N N N
EtO2C EtO2C

OH Ph3P CO2Et CO2Et

H N N O PPh3 + N N
EtO2C H EtO2C H
O
(PhO)2PO CO2Et P CO2Et H CO2Et
(PhO)2 N3 HN3
N3 + N N N N N N + N3
EtO2C H DPPA EtO2C H EtO2C H

N3 O PPh3 N3 + O=PPh3
H H
20 Pere Romea, 2014
 Nitrogen Nucleophiles

Reduction Mitsunobu
O
LiAlH4, H2 cat, Ph3P/H2O Ph3P/DEAD/ HN3 or DPPA

R N R1 R NH2 R N3 R OH
H
Amide Amine 1 Azide

SN2 SN2
Phthalimide N3

R X R OSO2R'

O O O O
Ph3P, DEAD, HN3
O N OH O N N3
CH2Cl2, 0 C
Bn 97% Bn

O O O
1) H2, Pd/C, THF/MeOH/TFA, ta
O N N Ph
H 2) PhCOCl, Et3N, CH2Cl2, 0 C
Bn 97% 21
 Oxygen Nucleophiles: Alcohols

The most simple nucleophile: H2O / OH

H2O, OH
X OH
X: Cl, Br, I

This is a rare transformation in which...

... tertiary halides, R3CX, react with H2O (solvolysis) through SN1 and
... the secondary and primary ones, R2CHX i RCH2X, with OH/H2O through SN2
In both situations E1 and E2 eliminations are competing reactions
No eliminations can occur at this benzylic position
Me Cl OH
Cl2 K2CO3
h H2O
NC NC 85% NC
Radical chlorination
22 Pere Romea, 2014
 Oxygen Nucleophiles: Ethers

Alkoxydes, RO: Williamson Synthesis

RO
X RO SN2
H H
X: Cl, Br, I

Only on 1ary substrates to avoid E2 eliminations

... and the most successful deconnections are applied to activated systems

O O O
Ar + XCH2R2 R1 R2 R1 + MeX o BnX

NO2 NO2
O O
OH OBu O O
BuBr, K2CO3 1) NaH, THF
O O O O
H2O H 2) BnCl, H
HO O BnO O
80% 95%

23 Pere Romea, 2014

 Oxygen Nucleophiles: Esters

Carboxilates, RCO2

RCO2
X RCO2 SN2
H H
X: Cl, Br, I, OSO2R

They are usually applied to 1ary substrates to avoid E2 eliminations

O O
OK Br 18-crown-6 O
+
O 95% O
Br Br
why KF?
O O CO2H O O CO2Me
MeI, KF
O O
O DMF O
O O
84%

Attention: interconversion of carboxlic acids and derivatives

24
 Oxygen Nucleophiles: Esters

Mitsunobu conditions: Ph3P / DEAD / RCO2H

Ph3P, EtO2C N N CO2Et

OH
RCOOH
RCO2 SN2
H H

Ph3P
CO2Et Ph3P CO2Et
N N N N
EtO2C EtO2C

OH Ph3P CO2Et CO2Et

H N N N N + O PPh3
EtO2C EtO2C H H

RCO2H
H CO2Et
N N RCO2 RCO2
EtO2C H H

OH PhCO2
Ph3P, DEAD
CO2Me CO2Me
O PhCO2H O
Pere Romea, 2014 25
89%
 Oxygen Nucleophiles

Configuration inversion
SN2 Hidrolysis
RCO2 OH

OH OSO2R' RCO2 HO
H H H H

Mitsunobu Hidrolysis
Ph3P/DEAD/RCO2H OH

OH RCO2 HO
H H H

OH O OH
Ph Ph Ph
Ph 3P, DEAD O2N KOH
p-O2NPhCO 2H MeOH
99% overall

26 Pere Romea, 2014

 Phosphorus Nucleophiles: in Route to Wittig Reactions

Phosphines are excellent nucleophiles because

they are less basic than amines and the phosphorus atom is very polarizable.
Moreover, E2 reactions do not compete with SN2 because they are weak bases
B
R1CH 2X + PR3 R1CH 2PR3 R1CHPR3 R1CH PR3

phosphine X phosphorus ylide

phosphonium salt
Attention: Wittig reaction

O O O
NaOH Ph3P
Ph3P + Br Ph3P
OEt OEt OEt
Br

BuLi Ph3P
Ph3P + Br Ph3P
OPh OPh OPh
Br

Ph3P
Attention: no E2 occurs OPh
27
 Phosphorus Nucleophiles: in Route to Wittig Reactions

Phosphites are also good nucleophiles and react with alkyl halides:
Michaelis-Arbuzov reaction

RR R1 OCHR2 O
(R2CHO)3P + R1X P P
H O OCHR2 (R2CHO)2 R1
X
phosphite alkylphosphonate
alkyltrialkoxyphosphonium halide
Attention:
Horner-Wadsworth-Emmons reaction

O O O O O
EtO
(EtO)3P + Br (EtO)2P (EtO)2P
OEt OEt OEt
EtBr

O O
(EtO)2P
OEt

O O
(EtO)2P
Pere Romea, 2014 28 OEt
 Sulfur Nucleophiles: Thiols

The easiest option is troublesome ...

H RX
RX + HS R SH R S R S R
+H
S

thiourea NH2
H2N NH2 NaOH
H S NH2

O
X H H SH
O
S NaOH
thioacetate H S or LiAlH4

1) Thiourea AcSCs
Br HS
C10H 21 C10H 21 Br H
2) NaOH DMF
i-Pr i-Pr
H SAc
80% 84%

29 Pere Romea, 2014

 Sulfur Nucleophiles: Thioethers

Thiolates are the best option since they are excellent nucleophiles ...

XR2
R1SH + OH R1 S R1 S R2

NaOH Br
SH S S
95%

O O O
MsCl, Et3N BnSH, K2CO3
Me Me Me
N N N
CH2Cl2 CH3CN
HO OMe MsO OMe BnS OMe
100% 80%
Weinreb Amide
O
EtMgBr

BnS

30 Pere Romea, 2014

 Carbon Backbone & Functional Groups

The synthesis of an organic compound must pay attention to ...

Carbon backbone Functional groups

(Chapters 24 )
Functional Group Interconversion (FGI)

I. Nucleophilic Substitutions
Chap. 19
Electrophilic Additions to C=C
Addition-Eliminations on Carboxylic Acids and Derivatives
II. Reductions
Mechanism!!! III. Oxidations
Pere Romea, 2014 31
 Hydroboration of C=C

Borane, BH3, as a reacting species

Lewis Base
R R
H H X R R
H X
B B 2 H B H
H H
H H H B H
H
Lewis Acid
H3B SMe2
H3B OEt2 H3B THF
LUMO
H B H
H +
H H BH2
BH3 H B H
C C C C C C
C C
+ syn Addition
HOMO Cyclic transition state
4 centers, 4 electrons

The regiochemistry for the addition of BH3 to an olefin is controlled by steric as well as electronic factors:
the boron atom binds to the less substituted carbon atom

32 Pere Romea, 2014

 Hydroboration of C=C

Additions of BH3 to olefins produce boranes

R

H
R R R
BH3 BH2 B B
R R R R R
Alkylborane Dialkylborane Trialkylborane

The appropriate choice permits to obtain a wide array of alkylboranes

3 + BH3 B

2 + BH3 B Sia2BH
H

+ BH3 BH2 ThxBH2

H
B
+ BH3
9-BBN
Pere Romea, 2014 33
 Hydroboration of C=C

Steric effects rule the reactivity

H R H H R R
H > H > H > R > R > R
R R R R R R
H H R H H H

... the regioselectivity,

BH3 94 80 99 57
% atack B
Sia2BH 99 98 97 to the less
substituted
99.9 98.5 99.5 99.8 carbon atom
9-BBN

... and the stereoselectivity

R2BH H
+ BR2
H
BR2
BH3 72 28

34 9-BBN 97 3
 Hydroboration of C=C

Protonolysis: synthesis of alkanes

BH3 RCO2H
R R 3 R
B H

3
Trialkylborane Alkane

Conversion of trialkylboranes into alcohols: H2O2/NaOAc, ...

R R R OR
HO
B B R B B 3 ROH
R R O R HO RO R RO OR BO33
HO O HO
Borate

The migration does not Hidrolysis

produce the inversion of the configuration

H
1) B2H6 OH It looks like
an anti-Markovnikov hydration
2) H2O2, OH with a syn stereochemistry
35 85% Pere Romea, 2014
 Hydroboration of C=C

Hidroboration of alkynes
RCO2H H H

R1 R2 Alqu Z

L2B H L2B H H2O2, OH HO H O R2

R1 R2
R1 R2 R1 R2 R1

H2O (HO)2B H

R1 R2
Vinilboronic acid

O
1) B H
O Br
OH
B
2) H2O OH Pd(0) cat
75%

Suzuki Coupling
36 Pere Romea, 2014
 Dr. Pere Romea
Department of Organic Chemistry

The moneychanger and his wife

Marinus Claesz van Reymerswaele, 1539

6. Functional Group Interconversion

Organic Synthesis 2014-2015 Autumn Term

 Carboxylic Acids and Derivatives

Carboxylic acids Derivatives of carboxylic acids

O O

R1 OH R1 L

O O O O O O O
R2
R1 Cl R1 O R2 R1 N3 R1 SR2 R1 OR2 R1 N
R3
Acid chloride Anhydride Acyl azide Thioester Ester Amide

R1 C N Nitrile

All these FG participate in reactions that can be understood using

the addition-elimination mechanism
2 Pere Romea, 2014
 Addition-Elimination Mechanism

Addition-elimination mechanism

O Addition Nu O Elimination O

R1 R1 + L
Trigonal Planar L R1 L Nu

Nu Tetrahedral Trigonal Planar

The requirements for a smooth process are

a) RCOL must be a good electrophile,
b) Nu must be a good nucleophile,
c) L must be a better leaving group than Nu

Remember: The lower the pKa (HL), the better the leaving group

If the system is not reactive enough, it must be activated ...

3 Pere Romea, 2014

 Addition-Elimination Mechanism

Activation with a Lewis Acid, LA, ...

LA LA LA LA
O O HNu O Nu O O O
LA LH LA
R1 L R1 L R1 L R1 LH R1 Nu R1 Nu

Activation Addition Elimination

NuH

Remember: Fischer esterification

Activation with a Lewis Base, B, ...

O O Nu O O
L B
R1 L R1 B R1 B R1 Nu

B Activation NuH Addition Elimination

Remember: synthesis of esters by addition of alcohols to acid chlorides in the presence of DMAP

4 Pere Romea, 2014

 Addition-Elimination Processes

O
H2O
R1 Cl
Very easy
Chap. 16 Chap. 10
R2CO2

O O
R2CO2 H2O
R1 O R2 O
Easy

R2OH R1 OH

R2OH O H2O
R1 OR2 Moderate

R2R3NH

O
R2R3NH H2O
R2
R1 N Difficult
R3
5 Pere Romea, 2014
 Addition-Elimination Processes

O
?
R1 Cl
Chap. 16 Chap. 10
R2CO2

R2CO2
O O
?
R1 O R2 O

R2OH R1 OH

R2OH O ?
R1 OR2

R2R3NH

R2R3NH
O
R2
?
R1 N
R3
6 Pere Romea, 2014
 Acid Chlorides from Carboxylic Acids

Via SOCl2 o PCl5

O O
O O
SOCl2 OH PCl5 Cl
OH Cl
85% O2N 93% O 2N

Via (COCl)2
Useful for systems sensitive to acid media.
It is usually used with the sodium salt (neutral media) or with catalytic amounts of DMF.

O Bn O Bn
O (COCl)2 O
N N N N
CO2Na 83% COCl
HO O HO O

7 Pere Romea, 2014

 Anhydrides from Carboxylic Acids

Regioselectivity in the nucleophilic attacks to anhydrides

O O O O
Regioselectivity In mixed anhydrides
R1 O R1 R1 O R2
is not a problem for the R2 group must prevent
the symmetric anhydrides the nucleophilic attack
Nu Nu
O O Cl O O
The mixed anhydrides are usually prepared quantitatively
from acid chlorides or other anhydrides. R1 O R1 O
They are not isolated.
Cl Cl
Yamaguchi Method
Nu Nu

O O O Cl O O O O O
P P P
(OMe) Cl (OMe) H OBn (OMe)

Cl Cl HO O
BnO
PMBO O Et 3N, DMAP PMBO O O Cl PMBO O H
95%
THFPhMe, rt
PMBO OH PMBO O PMBO O

Cl Cl
Nu
Pere Romea, 2014 8
 Esters from Carboxylic Acids and Derivatives

The retrosynthetic analysis shows two ways of deconnecting the ester group ...

O b) O a) O
+ HOR2 R2 + R2X
R1 L R1 O R1 O

Addition-elimination Processes SN2 Processes

Fischer Esterification X
H
Using coupling agents as carbodiimides RCO2 RCO2
X: Cl, Br, I, OSO2R
H
Acylation with acid chlorides or anhydrides
OH
H
RCOOH RCO2
Ph3P, DEAD H
Mitsunobu

HH
CH2N2
RCO2H RCO2
H
Pere Romea, 2014 9
 Esters through SN2 Transformations

Synthesis of methyl esters by reaction with diazomethane

Diazomethane is a highly volatile (it must be handled in etherial solutions), toxic, and explosive compound ...

H H H
C N N C N N C N N
H H H

The best leaving group

O O O HH
H HH N2
H C N N N N
R O R O R O H
H H SN2
Acid-base

O O
CH2N2
HO O MeO O
Et2O
O O
95%

pKa 10 pKa 16
PhOH + CH2N2 PhOMe PrOH + CH2N2 PrOMe

10 Pere Romea, 2014

 Esters through Addition-Elimination Transformations

Fischer esterification O
H + HOR2
R1 O

A problem

H
H H 2 H
O
H
O O HO O 2 HO O R O
H O
R
H H H R2 R2
R1 O R1 O R1 O R1 OH R1 O H R1 O R1 O
H
Activation
HO R2

O O
H
H + HOR2 R2 + H2O
R1 O R1 O

Reversible reaction catalyzed by H+

Excess of R2OH or removal of H2O are necessary to obtain esters in high yields

O O O O
HCl cat TsOH cat
OH + MeOH OMe OH + HO Cl O Cl

solvent H 2O azeotropic
95%
85%
11 Pere Romea, 2014
 Esters through Addition-Elimination Transformations

Esterification with carbodiimides

O O O
H + R N C N R + HOR2 R2 + R R
R1 O R1 O N N
Carbodiimide H H

O O
H O NHR O O
R1 O R1 O
H R2 + R R
R1 O NR R1 O N N
R N C N R R N C N
R H H
R OH Good leaving group
Neutral and aprotic apolar medium
DMAP is usually used as catalyst

TBSO OMe TBSO OMe

O DCC: DiCiclohexylCarbodiimide O
O

OH O N C N O
H H
+ HO
DMAP cat, CH2Cl2
97%
H 12 H Pere Romea, 2014
 Esters through Addition-Elimination Transformations

Acylation with acid chlorides and anhydrides

O O O O
R2OH
o R2
R1 Cl R1 O R1 R3N R1 O
Good leaving groups

O O
O PhCOCl O
O O pyr, DMAP cat O O
Ac O CH2Cl2 Ac O
HO O
85% O
Ph

CO2Me CO2Me
Ac2O
OH OAc
Et3N, DMAP cat
OH OAc
CH2Cl2
95%
OH OAc

13 Pere Romea, 2014

 Esters through Addition-Elimination Transformations

Acylation with mixed anhydrides O O Cl O O Me

R1 O R1 O
Mixed anhydrides are usually prepared quantitatively
Cl Cl O2N
from acid chlorides or other anhydrides.
They are not isolated. Nu Nu
Yamaguchi Method Shiina Method
J. Org. Chem. 2004, 69, 1822

O O O Cl O O O O O
P P P
(OMe) Cl (OMe) H OBn (OMe)

Cl Cl HO O
BnO
PMBO O Et3N, DMAP PMBO O O Cl PMBO O H
95%
THFPhMe, ta
PMBO OH PMBO O PMBO O

Cl Cl
Nu
Me O O Me

X X
TBSO O TBSO O
X: NO2
Ph OH + HO Ph Ph O Ph
Et3N, DMAP cat, CH2Cl2

Pere Romea, 2014 92% 14

 Lactones in Natural Products

Lactones (cyclic esters) are a common structural motif in natural products

OMe
O
HO
O O OH Scytophycin C (20)
O
H O N O
MeO MeO OH
Octalactin A (8) H
O
O
OMe O

HO OH O OH Bafilomycin A (16)
OH NMe2
O O O OMe
O OH
O O OMe
O OH O
Erythromycin A (14) O OH
HO
HO
OMe

O
HO (C)n L
O (C)n
? O
Campagne, J. -M.
Pere Romea, 2014 15 Chem. Rev. 2006, 106, 911 & 2013, 113, PR1
 Lactones in Natural Products

The size of the ring determines the synthetic method ...

Cyclization of - and -hydroxy acids is straightforward
O O O O
Very easy OH Very easy O
OH O
OH
OH
For 5- and 6-membered rings, both enthalpy and entropy OK !!!

... but as the size of the ring increases, the cyclization mets the selectivity problem
O O O
k1 inter k2inter
L (C)n OH L (C)n O (C)n OH
vintra >> vinter
O
k1intra k2intra vintra = k1intra [S] vinter = k1inter [S]2
O O
vintra 1
O (C)n si k1intra k1inter =
monmer dmer vinter [S]
O O

Per a vintra >> vinter [S] 0

High dilution conditions are required as well as
activation of the carboxylate group compatible with the OH group
16
 Synthesis of Macrolactones

Mixed anhydrides (Yamaguchi and Shiina methods) met these conditions

O Cl
O O
Cl
O O
Cl Cl
O 1) Et3N, THF, rt O

OH O 1) PhMe, DMAP, 60 C O O
[S] = 30 mM
HOOC
O O O
78%

Me O O Me

O X X O
X: NO2
O OH O O O
O O
Et3N, DMAP, CH2Cl2, 40 C
HO [S] = 2.7 mM
O O
O 42%

17 Pere Romea, 2014

 Amides through Addition-Elimination Transformations

The retrosynthetic analysis of amides also shows two options

O b) O a) O
+ HNR2R3 R2 + R2X
R1 L R1 N R1 NR3
R3

Addition-elimination processes SN2 Processes

Acylation with acid chlorides and anhydrides No very common, but N-substitutions using
Via coupling agents: carbodiimides, HATU sterically unindexed alkyl halides are useful options.
Attention with E2

O O
H NaH, MeI Me
N N
Benz

18 Pere Romea, 2014

 Amides through Addition-Elimination Transformations

Acylation with acid chlorides and anhydrides

O O O O
R2R3NH
o R2
R1 Cl R1 O R1 R3N R1 N
Good leaving groups R3

O O
1) SOCl2
OH NH 2
2) NH 3 excess

70%

O O
2 eq Me2NH Me
Cl N + Me2NH2 Cl
Me
85%

O O
Ac2O, pyr H
NH2 N
HO HO
90% O
19 Pere Romea, 2014
 Amides through Addition-Elimination Transformations

Synthesis of amides by using carbodiimides

O O O
H + R N C N R + HNR2R3 R2 + R R
R1 O R1 N N N
Carbodiimide
R3 H H

O O
H O NHR O O
R1 O R1 O
H R2 + R R
R1 O NR R1 N N N
R N C N R R N C N
R R3 H H
R2 NH Good leaving group
Neutral and aprotic apolar medium
R3
DMAP is usually used as catalyst

R2
HO Boc
O H N O H R2 O H R2
N O H N Boc TFA N H
RO H RO N RO N
DCC
R1 R1 O H R1 O H
Coupling Deprotection

Peptide synthesis
20 Pere Romea, 2014
 Amides through Addition-Elimination Transformations

Occasionally, O-acylisourea intermediates are not stable enough

or produce the epimerization of the C center.
Then, the addition of N-hydroxy derivatives transforms such intermediates into less reactive active esters
with a beneficial effect on the overall efficiency

O NHR O O
HOXt
Xt R2
R1 O NR R1 O R1 N
O HOXt R3
R2 NH
R R
N N R3
H H

HOXt
O
N N
N N N OH
N N N
OH OH O
HOBt HOAt HOSu

21 Pere Romea, 2014