2014-2015 Autumn Term

6. Functional Group Interconversion

Sky and Water IMaurits Cornelis Escher, 1938

Dr. Pere Romea Department of Organic Chemistry

Organic Synthesis

Carbon Backbone & Functional Groups

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

Functional groups

Functional Group Interconversion (FGI)

I. Nucleophilic Substitutions

Electrophilic Additions to C=C

Addition-Eliminations on Carboxylic Acids and Derivatives

II. Reductions

III. OxidationsMechanism!!!

Carbon backbone

(Chapters 2–4 )

2Pere Romea, 2014

Nucleophilic Substitutions

The nucleophilic substitutions involve

the interconversion of functional groups bound to sp3 carbonis

Csp3

Nucleophile Leaving group

RX

Electrophile

Chap. 15

X+ Nu

Nu+ X

3Pere Romea, 2014

Nucleophilic Substitutions

Two model mechanisms, called SN1 i SN2,

are used to explain the nucleophilic substitutions

Unimolecular (SN1) or bimolecular (SN2) nucleophilic substitution?

X+ Nu

Nu+ X

A slightly different model, called SN2’, may be useful in substitutions on allylic substrates

+ Nu + XX Nu

4 Pere Romea, 2014

Nucleophilic Substitutions and FGI

5

There are three main sources to carry out FGI through nucleophilic substitutions: sulfonates, alcohols, and alkyl halides

NuR–OSO2R’ R–NuSulfonates

R–OH R–NuNu

Alcohols

R–NuR–XNuAlkyl halides

X: I, Br, Cl

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 C–C bond forming reactions and FGI

R X

R Y

R SR

R OH

R OR

RO R

O

R SH

Y

RSHor RS

H2Sor HS

H2Oor OH

ROHor RO

O R

O

RR

NR

R N3

R NH2

NH3

N3

CN

R

6Pere Romea, 2014

Nucleophilic Substitutions and FGI

R–OSO2R’ R–NuNuSulfonates

R–OH R–NuNu

Alcohols

R–NuR–XNuAlkyl halides

X: I, Br, Cl

7

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

Pere Romea, 2014

Alcohols and Sulfonic Esters

Conversion of alcohols into sulfonic esters

– Primary and secondary ROH OK, but the reaction is sensitive to steric hindrance

– The reaction does not affect the C–O 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

OH

MeMe

H

TsCl, pyr

Me

Me

Mesyl chlorideTosyl chloride

Triflic Anhidride

MsCl

TsCl

Tf2O

MeSO2Clp-MePhSO2Cl(CF3SO2)2O

MesylateTosylateTriflate

OH+ RSO2Cl or (RSO2)2O

OSO2R

pyridine

CH2Cl2 or Et2O0 °C – rt

8 Pere Romea, 2014

Sulfonic Esters and Alkyl Halides

Conversion of sulfonate into alkyl halides

SN2

X

OH X X: Cl, Br, I

OH

Pr

1) MsCl, Et3N, CH2Cl22) LiCl, DMF

Cl

Pr83%

PhOH

1) TsCl, pyr, CH2Cl22) LiBr, DMF

89%Ph

PhBr

Ph

TBDPSO OH1) MsCl, Et3N, CH2Cl2

2) Lil, acetone

94%

TBDPSO I

9 Pere Romea, 2014

Alcohols and Alkyl Halides

Conversion of alcohols into alkyl halides

R–OH

R–OSO2R’

R–X

X–

Sulfonates

Alcohols

Alkyl halidesX: I, Br, Cl

?

R’SO2Cl

10 Pere Romea, 2014

Alcohols and Alkyl Halides

Conversion of alcohols into alkyl halides

OH X X: Cl, Br, I

11

HCl conc

HCl/ZnCl2 (Lucas reagent)PCl3SOCl2, 1,4-dioxaneSOCl2, non nucleophilic solvent

Tert

Prim & SecPrim & SecPrim & SecPrim & Sec

SN1 (racemization)

SN2 (inversion)SN2 (inversion)SN2 + SN2 (retention)SN2 (inversion)

HBr conc

HBr conc, ∆PBr3

Tert

PrimPrim & Sec

SN1 (racemization)

SN2 SN2 (inversion)

P/I2 Prim & Sec SN2 (inversion)

Reagents & Conditions Alcohols Mechanism

Pere Romea, 2014

Alcohols and Alkyl Halides

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

SN1

H

Br

OH OH2

Br

Br

Br86% 14%

OHH

OH2Br

BrsingleSN2

OHH

OH2Cl

Cl

single12Pere Romea, 2014

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

Ph3P + E–Nu Ph3PNu

EPh3P E + Nu

Ph3P E + Ph3P + HE

Alkoxyphosphonium salt

HHO

HO

Ph3PH

O + Nu Ph3P=O +H

Nu

Alkoxyphosphonium salt13 Pere Romea, 2014

Alcohols and Alkyl Halides

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

Ph3P + Br–Br Ph3PBr

BrPh3P Br

+ Br

– Br

HHOPh3P Br Ph3P

– HBr

HO+

Br

– Ph3P=O

HBr

SN2

OHBrPBr3Br

Br

+ +

11% 26% 63%

Ph3P/Br2Br

90%

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

OO ROH

Ph3P, Br2

85%

OO RBr

OH

OMe

OBn

Ph3P, I2

ImidazoleEt2O, rt

I

OMe

OBn96%14

Alcohols and Alkyl Halides

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

Ph3P + Cl–CCl3 Ph3P ClH

HO– CCl3 Ph3P

HO

Cl

– Ph3P=O

HCl

– HClcarbon tetrachloride

Ph3P + ClCCl3

O

Cl Cl

ClCCl3

Cl

O

hexachloroacetone

OHPh3P/Cl2

Cl

92%

OH ClPh3P/CCl4

70%

OH ClPh3P/CCl3COCCl3

99%

15 Pere Romea, 2014

Nucleophilic Substitutions and FGI

R–OH R–Nu

R–OSO2R’ R–Nu

R–NuR–XNu

Nu

NuSulfonates

Alcohols

Alkyl halidesX: I, Br, Cl

16 Pere Romea, 2014

Carbon Nucleophiles

R C CHR CN

R X R OH

+ C + 2 C

R NH2 R OH R H R Me

O O O

Amine 1 Carboxylic Acid Aldehyde Methyl ketone

Red LiAlH4

Red DIBALH

Hydrolisis H3O+

Hydration cat Hg2+, H2O

Attention! Alkyl halides are very useful forthe construction of C–C bonds

17 Pere Romea, 2014

Nitrogen Nucleophiles: Primary Amines

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

NH3R X

R NH3 X R NH2

– HX

+ HX

R XR2 NH2 X R2 NH

– HX

+ HXR NH2

R XR3 NH X R3 N

– HX

+ HXR2 NH

R XR4 N XR3 N

Primary Amine

Secondary Amine

Tertiary Amine

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

NH NCO2Et

CO2EtBr1)

2) NaHCO3

CO2Et

H2N

CO2Et

NH

R

1) RCH2Cl

2) NaHCO3

R: C15H3118 Pere Romea, 2014

Nitrogen Nucleophiles: Primary Amines

Potassium phthalimide, PhthNK

N

O

O

KBr

Ph N

O

O

Ph NaOH

95%H2N Ph

Potassium phthalimide, pKa 8.3

SN2Gabriel synthesis of amines

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

Azide, N3–

BuI NaN3

DMSO, Δ BuN3

90%

BuNH2

OTBDPSOH

O O1) MsCl, Et3N

2) NaN3, DMF

85%

OTBDPS

O O

N319

Nitrogen Nucleophiles: Primary Amines

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

HOH

HN3

Ph3P, N N CO2EtEtO2C

HN3 o (PhO)2PON3,

HO PPh3N3

HN3 + O=PPh3

N NCO2Et

EtO2C

Ph3P

N NCO2Et

EtO2C

Ph3P

HOH

N NCO2Et

EtO2C

Ph3PN

EtO2CN

H

CO2Et

HO PPh3 +

NEtO2C

NH

CO2Et HN3(PhO)2P

N3

O

N(PhO)2PO

EtO2CN

H

CO2EtN

H

EtO2CN

H

CO2Et+ N3N3 +

DPPA

20 Pere Romea, 2014

Nitrogen Nucleophiles

R NH2R N R1

O

H

R N3

Amine 1Amide Azide

R OH

R X R OSO2R'

Reduction LiAlH4, H2 cat, Ph3P/H2O

Mitsunobu Ph3P/DEAD/ HN3 or DPPA

SN2 N3

–SN2

Phthalimide

N OHO

Bn

O O

N N3O

Bn

O O

N NH

O

Bn

O O

Ph3P, DEAD, HN3

97%

CH2Cl2, 0 °C

1) H2, Pd/C, THF/MeOH/TFA, ta

97%

2) PhCOCl, Et3N, CH2Cl2, 0 °CPh

O

21

Oxygen Nucleophiles: Alcohols

The most simple nucleophile: H2O / OH–

X OHH2O, OH–

X: Cl, Br, I

This is a rare transformation in which...

... tertiary halides, R3C–X, react with H2O (solvolysis) through SN1 and

... the secondary and primary ones, R2CH–X i RCH2–X, with OH–/H2O through SN2

In both situations E1 and E2 eliminations are competing reactions

Me

NC

Cl2

hν

NC

Cl

NC

OHK2CO3

H2O

85%Radical chlorination

No eliminations can occur at this benzylic position

22 Pere Romea, 2014

Oxygen Nucleophiles: Ethers

Alkoxydes, RO–: Williamson Synthesis

Only on 1ary substrates to avoid E2 eliminations

SN2

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

1) NaH, THF

2) BnCl, Δ

95%

O

O

O

BnO

O

OH

O

O

O

HO

O

OH

NO2

OHNO2

OBuBuBr, K2CO3

H2O

80%

HX

HRO

RO–

X: Cl, Br, I

R1 OR2 R1 O

ArO + MeX o BnX+ XCH2R

2

23 Pere Romea, 2014

Oxygen Nucleophiles: Esters

Carboxilates, RCO2–

SN2

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

OO

OBr

O

OBr

BrOK 18-crown-6+

95%

O

O

O

O

OCO2H O

O

O

O

OCO2Me

MeI, KF

84%

DMF

Attention: interconversion of carboxílic acids and derivatives

why KF?

HX

HRCO2

RCO2–

X: Cl, Br, I, OSO2R

24

Mitsunobu conditions: Ph3P / DEAD / RCO2H

Oxygen Nucleophiles: Esters

SN2H

OHH

RCO2Ph3P, N N CO2EtEtO2C

RCOOH

N NCO2Et

EtO2C

Ph3P

N NCO2Et

EtO2C

Ph3P

HOH

N NCO2Et

EtO2C

Ph3PN

EtO2CNH

CO2Et

HO PPh3+

RCO2H

NH

EtO2CNH

CO2EtRCO2

HRCO2

CO2MeOH

OCO2Me

PhCO2

O

Ph3P, DEAD

89%

PhCO2H25Pere Romea, 2014

Configuration inversion

Oxygen Nucleophiles

HOH

HRCO2

HOSO2R'

HHO

HOH

HRCO2

HHO

Hidrolysis OH–

Mitsunobu Ph3P/DEAD/RCO2H

Hidrolysis OH–

SN2 RCO2

–

MeOH

PhOH

PhO

O

O2NPh

OH

KOH

99% overall

p-O2NPhCO2H

Ph3P, DEAD

26 Pere Romea, 2014

Phosphorus Nucleophiles: in Route to Wittig Reactions

R1CH2–X + PR3

X

R1CH2–PR3 R1CH–PR3 R1CH PR3

B

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

phosphinephosphonium salt

phosphorus ylide

Attention: Wittig reaction

BrOEt

O

Ph3P + Ph3POEt

O

Br

NaOH Ph3POEt

O

BrOPhPh3P + Ph3P

OPhBr

BuLi Ph3POPh

Ph3P OPhAttention: no E2 occurs27

Phosphorus Nucleophiles: in Route to Wittig Reactions

Phosphites are also good nucleophiles and react with alkyl halides:

Michaelis-Arbuzov reaction

alkylphosphonatephosphitealkyltrialkoxyphosphonium halide

Attention:Horner-Wadsworth-Emmons reaction

(R2CHO)3P + R1–XH O

RR

POCHR2

OCHR2R1

X(R2CHO)2

PR1

O

BrOEt

O

(EtO)3P + (EtO)2POEt

OEtO

O

EtBr

Δ(EtO)2P

OEt

OO

(EtO)2POEt

OO

(EtO)2POEt

OO

28Pere Romea, 2014

Sulfur Nucleophiles: Thiols

The easiest option is troublesome ...

R–X + HS R SH R S S RRR–X–H

+H

Bri-Pr

Hi-Pr SAcH

AcSCs

DMF

84%

1) Thiourea

2) NaOH

80%

C10H21HS

C10H21Br

thioacetate

thiourea

H S

H S

X H H SH

H2N NH2

S

S

O

O

NH2

NH2 NaOH

NaOH

or LiAlH4

29 Pere Romea, 2014

Sulfur Nucleophiles: Thioethers

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

R1–SH + OH R1 S S R2R1X–R2

NaOHSH S S

Br

95%

N

O

HO

Me

OMeN

O

MsO

Me

OMeN

O

BnS

Me

OMe

MsCl, Et3N

CH2Cl2100%

BnSH, K2CO3

CH3CN

80%

Weinreb AmideO

BnS

EtMgBr

30 Pere Romea, 2014

Carbon Backbone & Functional Groups

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

Functional groups

Functional Group Interconversion (FGI)

Mechanism!!!

Carbon backbone

(Chapters 2–4 )

Chap. 19I. Nucleophilic Substitutions

Electrophilic Additions to C=C

Addition-Eliminations on Carboxylic Acids and Derivatives

II. Reductions

III. Oxidations

31Pere Romea, 2014

Hydroboration of C=C

Borane, BH3, as a reacting species

HBH

HH

HBH

H BHH2

RXR

HB

X

HH

RR

Lewis Acid

Lewis Base

H3B· SMe2

H3B· OEt2 H3B· THF

HOMO Cyclic transition state4 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

LUMO

syn Addition

CC

π

H BHH

CCCC

B HH

HCC

BH2HBH3

δ+

δ+δ−

δ−

32 Pere Romea, 2014

Hydroboration of C=C

Additions of BH3 to olefins produce boranes

R

RBH2 R

B

H

R RB

R

R

BH3R R

Alkylborane Dialkylborane Trialkylborane

BH2+ BH3

B+ BH32

H

B+ BH33

B+ BH3

H

– The appropriate choice permits to obtain a wide array of alkylboranes

9-BBN

ThxBH2

Sia2BH

33Pere Romea, 2014

Hydroboration of C=C

– Steric effects rule the reactivity

H

H

R

H

H

H

R

R

H

R

R

H

R

H

R

H

> >> R

H

R

R

> R

H

R

R

>

... the regioselectivity,

BH3

Sia2BH

9-BBN

94

99

99.9

80

98

98.5

99

99.5

57

97

99.8

... and the stereoselectivity

% atack Bto the less substituted

carbon atom

BR2

HBR2

HR2BH

BH3

9-BBN

+

72

97

28

334

Hydroboration of C=C

Protonolysis: synthesis of alkanes

Trialkylborane Alkane

BH3R RB3

RCO2H RH

3Δ

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

R

BRR

HO O

R

BO R

R

HO

R

BRROHO–

OR

BORRO

HO3 ROH

– BO33

Borate

– The migration does not produce the inversion of the configuration

Hidrolysis

OHH

1) B2H6

2) H2O2, OH–

85%

It looks likean anti-Markovnikov hydration

with a syn stereochemistry

35 Pere Romea, 2014

Hydroboration of C=C

Hidroboration of alkynes

Alquè Z

R2R1L2B H L2B

R1 R2

H

RCO2H

Δ

H

R1 R2

H

H2O2, OH– HO

R1 R2

H

R1

O R2

H2O (HO)2B

R1 R2

H

Vinilboronic acid

OB

OH1)

2) H2OB

OH

OH

Br

Pd(0) cat

75%

Suzuki Coupling36 Pere Romea, 2014

The moneychanger and his wifeMarinus Claesz van Reymerswaele, 1539

2014-2015 Autumn Term

6. Functional Group Interconversion

Dr. Pere Romea Department of Organic Chemistry

Organic Synthesis

Carboxylic Acids and Derivatives

Carboxylic acids

R1 L

O

R1 OH

O

Derivatives of carboxylic acids

R1 Cl

O

R1 O

O

R1 OR2

O

R1 N

O

R2

O

R2

R3R1 N3

O

R1 SR2

O

Acid chloride Anhydride Acyl azide Thioester Ester Amide

All these FG participate in reactions that can be understood using

the addition-elimination mechanism

R1 C N Nitrile

2 Pere Romea, 2014

Addition-Elimination Mechanism

Addition-elimination mechanism

R1 L

O

Nu

R1 L

ONu

R1 Nu

O

+ L

EliminationAddition

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 ...

Trigonal Planar

Tetrahedral Trigonal Planar

3 Pere Romea, 2014

Addition-Elimination Mechanism

Activation with a Lewis Acid, LA, ...

R1 L

O

R1 L

OLA

LA

NuH

R1 L

OHNuLA

R1 LH

ONuLA

R1 Nu

OLA

R1 Nu

O–LA–LH

EliminationAdditionActivation

Remember: Fischer esterification

Activation with a Lewis Base, B, ...

R1 L

O

R1 B

O

NuH

R1 B

ONu

R1 Nu

O–B–L

B EliminationAdditionActivation

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

4 Pere Romea, 2014

Addition-Elimination Processes

R1 Cl

O

R1 O

O

R1 OR2

O

R1 N

O

R2

O

R2

R3

R2CO2–

R2OH

R2R3NH

R2OH

R2R3NH

R2CO2–

Chap. 16

R1 OH

O

H2O

H2O

H2O

H2O

Very easy

Easy

Moderate

Difficult

Chap. 10

5 Pere Romea, 2014

Addition-Elimination Processes

R1 Cl

O

R1 O

O

R1 OR2

O

R1 N

O

R2

O

R2

R3

R2CO2–

R2OH

R2R3NH

R2OH

R2R3NH

R2CO2–

R1 OH

O

?

Chap. 16

?

?

?

Chap. 10

6 Pere Romea, 2014

Acid Chlorides from Carboxylic Acids

Via SOCl2 o PCl5

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.

NN

O

O Bn

O

HOCO2Na

NN

O

O Bn

O

HOCOCl

(COCl)2

83%

OH

O

Cl

OSOCl2

85%

PCl5

93%O2N

OH

O

O2N

Cl

O

7 Pere Romea, 2014

Anhydrides from Carboxylic Acids

Regioselectivity in the nucleophilic attacks to anhydrides

R1 O R1

O O

Nu

Regioselectivity is not a problem for

the symmetric anhydrides

In mixed anhydrides the R2 group must prevent

the nucleophilic attack

R1 O R2

O O

Nu

Yamaguchi Method

The mixed anhydrides are usually prepared quantitatively from acid chlorides or other anhydrides.They are not isolated.

R1 O

O O

Nu

Cl

ClCl

R1 O

O O

Nu

O

O

PMBO

PMBO

OPO

(OMe)

O

HBnO

HO

O

OBnH

95%

8

O

OH

PMBO

PMBO

OPO

(OMe)

O

O

PMBO

PMBO

OPO

(OMe)

O Cl

Cl Cl

Et3N, DMAPTHF–PhMe, rt

Cl

O Cl

Cl Cl

NuPere Romea, 2014

Esters from Carboxylic Acids and Derivatives

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

R1 OR2

O

R1 L

O

+ HOR2

R1 O

O

+ R2–Xb) a)

Addition-elimination Processes

– Fischer Esterification

– Using coupling agents as carbodiimides

– Acylation with acid chlorides or anhydrides

SN2 Processes

HRCO2

HHCH2N2RCO2H

HX

HRCO2RCO2

–

X: Cl, Br, I, OSO2R

Mitsunobu

HOH

HRCO2

Ph3P, DEADRCOOH

9Pere Romea, 2014

Esters through SN2 Transformations

Synthesis of methyl esters by reaction with diazomethane

HCH

N NHCH

N NHCH

N N

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

– N2

H

HH

R O

O

SN2

The best leaving group

OHOO

O

OMeOO

OCH2N2

Et2O

95%

PhOH + CH2N2 PhOMe PrOH + CH2N2 PrOMepKa 10 pKa 16

Acid-base H

HH

R O

O

H

HCH

N N R O

O

N N

10 Pere Romea, 2014

Esters through Addition-Elimination Transformations

Fischer esterification

A problem

R1 O

O

H + HOR2

R1 O

O

HH

R1 OH

OH

R1 OH

OH

HO R2

R1 OH

OHOH

R2

R1 O

OHO R2

HH R1 O

R2OH

–H

R1 OR2

O

Activation

– Reversible reaction catalyzed by H+

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

R1 O

O

H + HOR2R1 O

O

R2+ H2O

H

11

solventOH

O

+ MeOH OMe

OHCl cat

Δ

95%

OH

O

+ HO Cl O

O

ClTsOH cat

Δ

85%–H2O azeotropic

Pere Romea, 2014

Esters through Addition-Elimination Transformations

Esterification with carbodiimides

R1 O

O

H + HOR2R1 O

O

R2R N C N R+ + R

N NR

O

H HCarbodiimide

C NR

HNR

R1 O

O

H

R N C N R

R1 O

O

R1 O NR

O NHR

R OH

R1 O

O

R2 + R N NR

O

H HGood leaving group– Neutral and aprotic apolar medium

– DMAP is usually used as catalyst

OH

H

H

O

TBSO OMe

O

H

H

O

TBSO OMe

O

HO

O

+

N C N

DMAP cat, CH2Cl297%

DCC: DiCiclohexylCarbodiimide

12 Pere Romea, 2014

Esters through Addition-Elimination Transformations

Acylation with acid chlorides and anhydrides

R1 Cl

O

R1 O

O

R1

O

oR1 O

O

R2R2OH

R3NGood leaving groups

O

O

O

O

O

AcHO

O

O

O

O

O

AcO

OPh

PhCOClpyr, DMAP cat

CH2Cl285%

OH

CO2Me

OH

OH

OAc

CO2Me

OAc

OAc

Ac2OEt3N, DMAP cat

CH2Cl295%

13 Pere Romea, 2014

Esters through Addition-Elimination Transformations

Acylation with mixed anhydrides

O

OH

PMBO

PMBO

OPO

(OMe)

O

O

PMBO

PMBO

OPO

(OMe)

O Cl

Cl Cl

Et3N, DMAPTHF–PhMe, ta

Cl

O Cl

Cl Cl

Nu

O

O

PMBO

PMBO

OPO

(OMe)

O

HBnO

HO

O

OBnH

95%

Mixed anhydrides are usually prepared quantitatively from acid chlorides or other anhydrides. They are not isolated.

Yamaguchi Method

R1 O

O O

Nu

Cl

ClCl

R1 O

O O

Nu

Me

O2N

Shiina MethodJ. Org. Chem. 2004, 69, 1822

Ph OH

OTBSO

+ HO Ph Ph O

OTBSO

Ph

O

O

Me

X

O Me

XX: NO2

Et3N, DMAP cat, CH2Cl2

92% 14Pere Romea, 2014

Lactones in Natural Products

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

OOMe

OOH

HO

O

HOOMe

OH

OHO

H

O

O

O

OH

O

O O

O

OH

O

OHHO

O

O

OH

OMe

NMe2

O

MeO MeO

OMe

O OH

O

OH

O

OMe

N

H

O

Octalactin A (8)

Erythromycin A (14)

Bafilomycin A (16)

Scytophycin C (20)

O (C)nHO (C)n

O

O

L

?Campagne, J. -M.

Chem. Rev. 2006, 106, 911 & 2013, 113, PR115Pere Romea, 2014

Lactones in Natural Products

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

Cyclization of γ- and ∂-hydroxy acids is straightforward …

OH

O

OH

O

O O

OH

OH

O

O

γ δ

Very easy Very easy

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 (C)n

OH(C)n

O

O

Lk1inter

(C)nO(C)nL

O O

OH

O

O

O

O

k2inter

k2intrak1

intra

monòmer dímer

vintra >> vinter

vintra = k1intra [S] vinter = k1

inter [S]2

si k1intra � k1

inter vintra

vinter

1

[S]=

Per a vintra >> vinter [S] 0High 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

OH

OO

HOOCO

O

O

O

OO

O

OO

Cl

O Cl

Cl

1) PhMe, DMAP, 60 °C[S] = 30 mM

78%

Cl

1) Et3N, THF, rt

O OHO

O

OHO

O

O

OOMe Me

X XX: NO2

Et3N, DMAP, CH2Cl2, 40 °C[S] = 2.7 mM

O OO

O

O

O

42%

17 Pere Romea, 2014

Amides through Addition-Elimination Transformations

The retrosynthetic analysis of amides also shows two options …

b) a)

R1 NR2

O

R1 L

O

+ HNR2R3

R1 NR3

O

+ R2–X

R3

Addition-elimination processes

– Acylation with acid chlorides and anhydrides

– Via coupling agents: carbodiimides, HATU

SN2 Processes

No very common, but N-substitutions using

sterically unindexed alkyl halides are useful options.

Attention with E2

N

O

H N

O

MeNaH, MeI

Benzè

18 Pere Romea, 2014

Amides through Addition-Elimination Transformations

Acylation with acid chlorides and anhydrides

Good leaving groupsR1 Cl

O

R1 O

O

R1

O

oR1 N

O

R2

R3N

R2R3NH

R3

Cl

O

N

OMe

Me+ Me2NH2

2 eq Me2NH

85%

Cl

NH2

O

HOHN

O

HOO

Ac2O, pyr

90%19

OH

O

NH2

O1) SOCl2

2) NH3 excess

70%

Pere Romea, 2014

Amides through Addition-Elimination Transformations

Synthesis of amides by using carbodiimides

Good leaving group– Neutral and aprotic apolar medium

– DMAP is usually used as catalyst

CarbodiimideR1 O

O

H + HNR2R3R1 N

O

R2R N C N R+ + R

N NR

O

H HR3

R1 O NR

O NHR

R2 NH

R1 N

O

R2 + RN N

R

O

H H

R3

R3C N

R

HNR

R1 O

O

H

R N C N R

R1 O

O

NHO

R2

O H

Boc

NRO

R1

O H

H NN

R2

O H

BocDCC

HO

ROR1

TFAN

NR2

O H

HHO

ROR1

Coupling Deprotection

Peptide synthesis20 Pere Romea, 2014

Amides through Addition-Elimination Transformations

21

Occasionally, O-acylisourea intermediates are not stable enough or produce the epimerization of the Cα center.

Then, the addition of N-hydroxy derivatives transforms such intermediates into less reactive active esterswith a beneficial effect on the overall efficiency

R1 O NR

O NHRHOXt

R1 OXt

O

R2 NH

R3

R1 NR2

O

R3

RN N

R

O

H H

HOXt

NNN

OHN N

NN

OH

N

O

O

OH

HOBt HOAt HOSu

HOXt

Pere Romea, 2014