umpolung

1

Umpolung reactivityUmpolung reactivity

Special Topic 27/02/09Anne Fournier

2

The synthetic problem

X

d2

a1

X

d4a3

d2

a1

X

d4a3

d2a1

d2

a1

X

1,3-disubstitution

X

d4a3

d0

d2

a1a5

X

d4a3

d2

a1

d4a3

d2

a1

d2

a1 1,2-disubstitution

X

a1

d2a3

d4

X

X

d4

a3

X = halogen, O, N

d = donor (-)

a = acceptor (+)

Heteroatoms impose an alternating acceptor and donor reactivity pattern

1,4-disubstitution

X

a1

d2a3

d4

X

d2a3

X

X

a1 a1

d2a3

a1d2

a3d4

An odd number of carbons between functional groups

An even number of carbons between functional groups

3

Definition

X

d4a3

d0

d2

a1a5

X

d5

a2d1

d3

a0

a4

Umpolung

« usual » reactivity:

C2n= donor, C2n+1= acceptor

Umpolung reactivity:

C2n= acceptor, C2n+1= donor

Umpolung is any process by which donor and acceptor reactivity of an atom are interchanged (reversal in

polarity).

Reactivity enables us to construct new bonds which are difficult to construct or cannot be achieved by « usual » reactivity, particulary the construction of 1,2

or 1,4-difunctionality.

Seebach ACIEE 1979, 239

4

Carbonyl UmpolungPatterns of Carbonyl Reactivity

RR'

O

+_ _

+

"usual" reaction polarity

RR'

O

+

__

+

umpolung reaction polarity

R Nu

O

RE

O

R'

R Nu

O R'

acyl bonding

alpha bonding

beta bonding

acyl transfer reactionFriedel-Craft reaction

enolate anion alkylationaldol and Claisen reactions

conjugate additionsMichael reactions

R E

O

RNu

O

R'

R E

O R'

5

Carbonyl UmpolungCarbonyl Umpolung intermediates

RR'

O

+

__

+

umpolung reaction polarity

R E

O

RNu

O

R'

R E

O R'

R

O

acyl anion

d1 synthon

R

O

+

homoenolate

-electrophile

d3 synthon

a2 synthon

R

O_

_

carbonyls vs. acyl anionsenolates vs. a-electrophilesMichael acceptors vs. homoenolates

Application Strategy

..

..

6

Carbonyl Umpolung

Masked Acyl Anion Equivalents

Lapworth JACS 1903, 995.

• Must use aromatic or heteroaromatic aldehydes; aliphatic aldehydes tend to undergo an aldol condensation

• Cannot selectivity cross couple of two different aldehydes

1a. Benzoin Condensation:1a. Benzoin Condensation:

CN

Ar

O

Ar CN

O

H

Ar CN

OH

_

Ar

OH

Ar

O

NCAr

O

R

OH

NCAr

Ar

OH

O

Ar

O

H

H

Nucleophilic attack of cyanide

Deprotonation (umpolung)

Acyl anion equivalent

Addition of aldehyde

Proton transferRegeneration of catalyst

Benzoin CN_

Ar

O

d1

Ar

OH

a1

1,2-substitution

..

....

_

_

cyanohydrin

Cyanide ionCyanide ion Catalyzed Addition Catalyzed Addition

7

Carbonyl Umpolung


Johnson JACS 2005, 1833

1b. Cyanide ion Catalyzed Cross Silyl-Benzoin Reaction1b. Cyanide ion Catalyzed Cross Silyl-Benzoin Reaction

R1 SiR3

O

R2 H

O

R3Si CN

O

R1

M-CN

R1 CN

OSiR3

_


R1

R2

O

OSiR3

Only product

R1

R1

O

OH

Not observed

18-Crown-6

..

Kinetic control, regiosepecific, (but need to make acyl silane), lower yields often result from aliphatic aldehydes (improvement with La(CN)3 catalyst)

[1,2]-Brook

Rearrangement

8

Carbonyl Umpolung


(a) Breslow JACS 1958,3719. (b) Enders Acc. Chem. Res. 2004, 534.

2. 2. N-Heterocyclic CarbenesN-Heterocyclic Carbenes Catalyzed Acyloin Formation Catalyzed Acyloin Formation

S

NR2

R3

R1

H

- H

Base

S

NR2

R3

R1

S

NR2

R3

R1

R H

O

O

S

NR2

R3

R1

OH

R

S

NR2

R3

R1

O

R

OHR4

R4 H

OR

R4

O

OH


umpolung

..

S

NR2

R3

R1

OH

R

..

..

S

NR2

R3

R1

OH

R

OR4

ylides or nucleophilic carbenesthiazolium salts

acyloin

Breslow intermediate

R

Effective for aliphatic and (hetero)aromatic aldehydes

Applicable to acylsilanes

9

Carbonyl Umpolung


3. Recent Progress in Asymmetric Benzoin Reactions3. Recent Progress in Asymmetric Benzoin Reactions

Ar H

O

Ar

Ar

O

OH

cat. (10mol%)KOtBu (10mol%)

8-83%

ee = 80-95%

O N

NN

Ph

tBu

Ar = Ph, m-Me-Ph, p-Me-Ph, p-MeO-Ph, m-Cl-Ph, p-F-Ph, p-Cl-Ph, p-Br-Ph, o-Furyl, o-Naphtyl

Triazolium salt

cat.

Enders ACIEE, 2002, 1743

10

Carbonyl Umpolung


4. Stetter Reaction: Generation of 1,4-dicarbonyls4. Stetter Reaction: Generation of 1,4-dicarbonyls

General reaction

R1 X

O

R3 R5

OR2

R4

R1

R5

O

O

R4

R2 R3

Nuc. cat.

polar solvent

R1

O

d1R5

O

R4

R2

R3

a3

X = H or SiR3

Nuc. cat. = CN- or NHCs

1,4-disubstitution

Scope includes unsaturated esters, nitriles, ketones and aldehydes(a) Stetter ACIEE 1976, 639.(b) Scheidt JACS 2004, 126, 2314

11

Carbonyl Umpolung


Rovis JACS, 2002, 10298

5a. Recent Advancements in Asymmetric Stetter Reactions5a. Recent Advancements in Asymmetric Stetter Reactions

H

O

R1

X CO2R2

cat. (20mol%), KHMDS (20mol%)xylenes, rt, 24h.

63-95%X

O

CO2R2

R1

5

6

7

8

ee = 82-97%

R1 = 6-Me, 8-Me, 8-MeOR2 = Me, EtX = O, S, NMe, CH2

OMe

NN

N

O

BF4

cat.

Aromatic substrates

Aliphatic substrates

O

CO2Etcat. (20mol%), KHMDS (20mol%)

xylenes, 25°C, 24h.

81%

O

CO2Et

ee = 95%

NN

N

Bn

Ph

BF4

cat.

Enantioselective intramolecular Stetter reaction

12

Carbonyl Umpolung


Rovis JACS, 2004, 8876

5b. Quaternary Stereocenters via Asymmetric Stetter5b. Quaternary Stereocenters via Asymmetric Stetter

O

X R

EWG

X

O

R

EWG

cat. (20mol%), Et3N (2eq.)

PhMe, 25°C, 24h.

55-96%

Aromatic substrates

O

EWG

R

Aliphatic substrates

cat. (20mol%), KHMDS

PhMe, 25°C, 24h.

63-90%

O

R

EWG

ee = 89-99%

X = O, S, CH2R = Et, Me, Ph

ee = 84-99%

R = Me, n-Bu

F

NN

N

O

BF4

cat.

F

F

F

F

Opposite stereochemistry

13

Carbonyl Umpolung


R1 SiEt3

O

H R2

O

O

P

OO

H

Ar Ar

O

O

Me

Me

R1

R2

O

OSiEt3

n-BuLi (5-20mol%)THF, 0.5h.

(5-20mol%)

Ar = 2-FPh

65-88% 41-91% ee

Ar Ar

6. 6. MetallophosphitesMetallophosphites as Umpolung Catalyst: The Enantioselective Cross Silyl Benzoin Reaction as Umpolung Catalyst: The Enantioselective Cross Silyl Benzoin Reaction

Johnson JACS 2004, 3070

14

Carbonyl Umpolung


(a) Corey, Seebach ACIEE 1965 1075 (b) Corey, Seebach ACIEE 1965 1077

7a. Anions of 7a. Anions of 1,3-Dithianes1,3-Dithianes (Corey-Seebach reaction) (Corey-Seebach reaction)

R H

O

HS SH

Lewis Acid (cat.)

S S

R H

BuLi

THF, -30°C

S S

R Li

Acyl Anion equivalent

E+S S

R E

R E

O

Cleavage

• Usually formed from corresponding aldehydes by thioacetalization

• R = primary, secondary and tertiary alkyl, allyl, benzyl, aryl, and O-containing groups

• Biggest drawback: removal of dithiane1. HgCl2, H2SO4, H2O 2. NaIO4 or m-CPBA 3. MeX (X = I, OTs,…)

15

Carbonyl Umpolung


7b. Anions of 1,3-Dithianes (Corey-Seebach reaction)7b. Anions of 1,3-Dithianes (Corey-Seebach reaction)

16

Carbonyl Umpolung

Unmasked Acyl Anion Equivalents

Zirconium Zirconium mediated or catalysed Umpolung reactionsmediated or catalysed Umpolung reactions

R

[Cp2ZrHCl]

R

ZrCp2

Cl

COR ZrCp2

O

Cl

R'

O

OH

R R R''

O

R'CHO

Lewis acid PdCl2(PPh3)2

R''X

-ketol


(Acyzirconocene chloride)

R' = alkyl, alkenyl R''X = phenyl, benzyl, allyl halides,acid chlorides, allyl acetates

ketone or -diketone

(a) Hanzawa ACIEE 1998, 1696

(a) Hanzawa TL 1998, 6249

(a) Guan Curr. Org. Chem. 2008, 1406

17

Carbonyl Umpolung


(a) Hanzawa TL 1998, 8141

(b) Hanzawa ACIEE, 1999, 2395

(c) Hanzawa T 2002, 8141

Zirconium mediated or catalysed Umpolung reactionsZirconium mediated or catalysed Umpolung reactions

R ZrCp2Cl

O

R3 O

R2

R4 R1

R

O

O

R1

R2

R4R3

R3

O

R

R1

R2

R4

OH

Pd(OAc)2 (5mol%)monophosphine (10mol%)

toluene

Pd(OAc)2 (10mol%)BF3.OEt2 (1eq)

Et2O-THF

1,2-addition 1,4-addition (generation of 1,4-dicarbonyls)

18

Carbonyl Umpolung

Acyl Anion Equivalents

A Summary A Summary (Acyl anions are the most sought umpolung reagents) (Acyl anions are the most sought umpolung reagents)

1,3-Dithianes (stoichiometric synthesis, pre-functionalization)

Cyanohydrin derivatives (stoichiometric synthesis, pre-functionalization)

Isonitriles, Nitronates anions, t-Butyl hydrazones, Vinyl thioether anions,…

Metal cyanides (catalytic formation, direct)

Nucleophilic carbenes (catalytic formation, direct)

Metallophosphites (catalytic formation, direct)



Acylzirconocene chloride

19

Carbonyl Umpolung-Electrophile Equivalents

R

R'

O

X

Nu R

R'

O

Nu

-halogenation of ketones

or

Hell-Volhardt-Zelinski reaction

-Electrophile equivalent

X = Cl, Br or I

+

-

1. 1. -Halo Carbonyl Substitution-Halo Carbonyl Substitution

CH3COCH2Cl NaCH(CO2Et)2 CO2Et

O CO2Et

1.

2. 2 BrCH(CO2Et)2

Na2CO3 (EtO2C)2C=C(CO2Et)2

20

Carbonyl Umpolung-Electrophile Equivalents

R1

R2

OSiR3

R1

R2

OSiR3

.

very reactive

porous C anode15-20 mA

CH2Cl2/CH3OH0.4M LiClO4

2. Anodic Oxidation of Silyl Enol Ethers2. Anodic Oxidation of Silyl Enol EthersAnodic oxidative cyclization

OTBS

TBSOO

RVC anodecarbon cathode

0.4 M LiClO4

MeOH/CH2Cl2 (1:4)2,6-lutidine, RT

15-20mA, 2,2F/mole

O

TBSOO

MeO

H

TsOH, RT

O

TBSOO

H

OOH

O

O

Allicacol A Moller JACS 2003,

36

21

Carbonyl UmpolungHomoenolate Equivalents

1. The Tautomerism Problem1. The Tautomerism Problem

M

OO

M

• Enolates

• tautomerism is generally not a problembecause oxyanionic tautomer still acts ascarbon nucleophile

O MO

M

• Homoenolates

• tautomerism is a much larger problembecause it is often irreversible andoxyanioic tautomer rarely acts as acarbon nucleophile

22


OO

Br

OO

M

O

R1. RX

2. H3O+

M

Homoenolate equivalent

NO

Ph

CH3 O

O

(CH2)3MgBr

69%

Synthesis of enantiopure 4-substituted quinolizidines

2. The Acetal Approach2. The Acetal Approach

Bosch JOC 2003, 1919

O

O N

Ph

OH

CH3

H2, Pd/Caq. HCl

66%

N

H

CH3

23

Carbonyl Umpolung

Homoenolate Equivalents

Kuwajima Chem. Comm. 1979, 708

R' SiR3

O

M

M = Li or MgBrR'

OM

R'

MOSiR3

R3Si

R''X

R' R''

OSiR3


3. Silyl Enol Ethers of Ketones3. Silyl Enol Ethers of Ketones

TBS

OLi

Br

THF, -78°C, 2h82%

OTBS

MeOO2C

Br

TAS-F, THF-DMF-35°C to 0°C, 3h

90%

O

MeOO2C4 steps

Synthesis of ()-δ-Araneosene

Corey Org. Lett. 2002, 2441

24


(a) Nakamura, Kuwajima JACS 1977, 7360

(b) Nakamura, Kuwajima JACS 1986, 3745

-hydroxyesters

4a. Cyclopropane Ring Opening : Titanium Homoenolates4a. Cyclopropane Ring Opening : Titanium Homoenolates

RO OTMS

R = Et, Me, iPr

TiCl4

CH2Cl2

RO OTMSTiCl3

Cl TMSO

TiCl4OR

- TMSCl

RO

TiCl3OR'COR''

RO

R'

O

OH


O

O

or/and

R''

R'

R''

Homoaldols Reactions of Titanium Homoenolates

lactones

25


OTMS

OR

2 ZnCl2

Et2O

RO

O Zn OEt2

ORO

2 TMSCl

4b. Zinc Homoenolates: Preparation4b. Zinc Homoenolates: Preparation

Nakamura, Organometallics, 1985, 641

EtO

IOZn-Cu

Benzene/DMA60°C, 3-4h EtO

O ZnI

Yoshida, TL, 1985, 5559

• Cyclopropane Ring Opening

• Direct Oxidative Addition

26

Carbonyl Umpolung

RO

O Zn OEt2

ORO

2 TMSCl

O

Cu(I), HMPA, THF

RO

OTMS

O

Homoenolate Equivalents

4b. Zinc Homoenolates: Reactivity4b. Zinc Homoenolates: Reactivity

• Copper-Catalyzed Conjugate Additions

Kuwajima JACS 1984, 3368

• Catalytic Homo-Reformatsky Reactions

OTMS

OEt

1.2 eq RCHOcat. ZnX2

CH2Cl2, RTEtO

O

R

OTMS

Nakamura, Kuwajima JACS 1987, 8056

27


4b. Zinc Homoenolates: Reactivity4b. Zinc Homoenolates: Reactivity

• Palladium Coupling Reactions

R1O

O Zn

OR1

O

0.5 eq

R2 Cl

O5mol% PdCl2(PPh3)2

Et2O, RTR1O

R2

O

O

Nakamura JOC, 1987, 8056

28

Thank you

for

your attention

umpolung

Documents

Transcript of umpolung