Umpolung: Carbonyl Synthons

William D. Shipe

Organic Supergroup Meeting

Princeton University

February 4, 2004

Umpolung - The Carbonyl Group

R

O

R'

normal reactivity

R

O

R'

inverted reactivity umpolung

O OH

O O

O

OH

O

O

Seebach ACIEE 1979 239

odd number of carbonsbetween functional groups

even number of carbonsbetween functional groups

Umpolung - Carbonyl Synthons

Polarity inversion is an old concept, but vigorous research in the area is of relatively recent origin.

The concept of synthons, or functional group equivalents, has spurred research.

Synthons: structural units within a molecule which are related to possible synthetic operations

Corey Pure Appl. Chem 1967 19

1. homoenolates2. α-electrophiles3. acyl anions

R

O

R

O O

Umpolung - Carbonyl Synthons

Corey Pure Appl. Chem 1967 19

umpolung: pole reversal; reversion of polarity; turn-over

Inversion reactions described as "symmetrization of reactivity"

"charge affinity inversion"Evans Acc. Chem. Res. 1974 147

suggested the German word umpolung as a concise expression for the conceptSeebach Chem. Ind. 1974 687

(http://dictionaries.travlang.com/GermanEnglish/)

R'

O

SiR3

TBS

O

MgBr

Li

R'

OMgBr

SiR3

Br

R'

R3SiO MgBr

OTBS

OMeOCO2

MeOCO2

Br

R'

OSiR3

R''

Homoenolates

Corey et al. Org. Lett. 2002 2441

R''X

+

in THF;–78 °C, 2h; 82%

TAS-F, THF-DMF–35 °C to 0 °C, 3h; 90%

4 steps(±)-δ-araneosene

Kuwajima et al. Chem. Commun. 1979 708

RO OTMS

PhNH

O

SnBu3

TiCl4, CH2Cl2

2 BuLi

RO

OR'

OH

RO OTMS

Li

TiCl4

O

NPh

Li

H

O

R'

–TMSCl

TMSO

OR TiCl4

RO

O TiCl3

PhNH

O

E

Homoenolates

E+

Goswami et al. JACS 1980 5973

Kuwajima et al. JACS 1986 3745

OR

OTMS

SnCl4

OR

OTMS

OR

OCl3Sn

ZnCl2, Et2O

OR

OTMS

OR

OZnO

RO

OR

OCl2Sn

OR

O

Homoenolates

Kuwajima et al. Organometallics 1985 641

mercury, copper, silver, and gold homoenolates have also been synthesized

2

Nakamura, Kuwajima et al. JACS 1984 3368Nakamura, Kuwajima et al. JACS 1987 8056

when the zinc reagent contains two homoenolates bound to each zinc atom, only one of the homoenolates can be transferred; the second is unreactive

OR

OTMS

ZnCl2, Et2O

H

O H

OR

OR

OZnEt2O

O OR

Zn Oi-Pr

O

2 TMSClCu(I), HMPA, THF

O

H

O H

OR

Oi-PrO

OTMSRO

O

Homoenolates

Kuwajima Pure and Applied Chem. 1988 115

2 +

Nakamura, Kuwajima et al. JOC 1986 4323Nakamura, Kuwajima et al. JACS 1989 6257

HMPA, CuBr•Me2S, BF3•Et2O 80-85%

> 97 : 3 diastereoselectivitycortisone and adrenosterone intermediate

O

MeO2CORO

H

Zn( OEt)2

O

OO

O

OO

H

H

OOH

OHC(CH3)3

OORO

H

OCO2Me

O

O

O CO2Me

RO

Homoenolates

HMPA, CuBr•Me2S, TMSCl 65%

hν

bilobalide

Crimmins et al. JACS 1993 3146

Reviews on Homoenolates:Crimmins, Nantermet Org. Prep. and Proc. Int. 1993 41-81Werstiuk Tetrahedron 1983 205

ONH2

R

OR'

X

NO

OH2N

R

OR'

Nu

NO

NO

Cl

AgBF4

HNMe2

OHO

OOO

H

α-Electrophiles

Nu-

Eschenmoser, Woodward et al. in Vitamin B12 synthesisSee Classics In Total Synthesis, p. 134

H3O+ (mild)

NH2

R

ON

R

O

Pt(III)2

H2O

R

O

Pt(III)2

R

N

RO

O

R

H

PtH3N OH2N O

ONO2

PtH3N NHH2N NH

ONO2

t-But-Bu

R

O

R

ON

α-Electrophiles

Matsumoto et al. JACS ASAP

2+

+

+

• π-coordination of triple bond to the Pt(III) atom• nucleophilic attack of water• ketonyl–Pt(III) complexes react with amines to give α-amino substituted ketone• with 1° amines, further reaction occurs

H

O

TBSO

TBSO

O

O

OH

O

O

O

TBSO

MeO

H

O

O

HO

H

α-Electrophiles

Moeller et al. JACS 2003 36

RVC anodecarbon cathode0.4 M LiClO4

MeOH/CH2Cl2 (1:4)2,6-lutidine, RT15–20 mA, 2.2 F/mole

TsOH, RTRVC = reticulated vitreous carbon

Anodic Oxidative Cyclization:

alliacol A

Ar

O

H

CN

Ar

OOH

ArAr

O

CNAr

OHH

Ar

O

CNH

Ar

OH

CN

Ar

OH

CNAr

OH

Ar

O

H

Ar

O

Acyl Anions

a benzoin

1a. Benzoin condensation: Cyanide ion catalyzed addition• cyanide ion catalyzed dimerization of aromatic and heterocyclic aldehydes to form α-ketols• nitrile-stabilized anions can also add to α,β-unsaturated ketones, esters, and nitriles• the reaction requires aprotic solvents (most preferably DMF)• cyanide ion catalysis fails with aliphatic aldehydes because they undergo aldol condensations under the strongly basic conditions

Lapworth J. Chem. Soc. 1903 995

O

O

NC Li

O

NO

OMeOH

OMe

H

OH

HNO

OMeOH

OMe

HO

O

Acyl Anions1b. Protected cyanohydrins

• can serve as reagents for annulation

Stork et al. JACS 1974 5272Kraus et al. Tet. Lett. 2000 21

+ THF–78 to rt

85%

A. G. Myers et al. JACS 1997 6072 a dynemicin A intermediate

Acyl Anions2. Thiazolium salt catalyzed addition

cat. thiazolium salt,Et3N, DMF

• in the presence of base, quaternary thiazolium salts are converted to the ylide, which acts as catalyst (5-10 mol %)• aliphatic, aromatic, and heterocyclic aldehydes add to α,β-unsaturated ketones, esters, and nitriles• Et3N or NaOAc are preferred bases• DMF, dioxane, or even alcohols can function as solvent

S

N

HO

N

NNH2

Cl

vitamin B1 (thiamine)

S

N

HO

ClS

N

HO

Br

S

N

HO

I

O

HR+

O

X

O

RO

X

S

N

HO

Bn

H

Cl

O

RO

X

S

N

HO

Bn

OR

OHX

S

N

HO

Bn

S

N

HO

Bn

S

N

HO

Bn

OHR

OX

O

HR

O

X

S

N

HO

BnO

RH

S

N

HO

BnOH

R

Acyl Anions2. Thiazolium salt catalyzed addition (mechanism)

base

+

Breslow Chemistry and Industry 1956 R.28Breslow Chemistry and Industry 1957 893Breslow JACS 1957 1762Breslow JACS 1958 3719Breslow JACS 1959 3080Stetter ACIEE 1976 639

O

BzOS

N

HO

Bn

O

H

HN

O

O

BzO O

Acyl Anions2. Thiazolium salt catalyzed addition (example)

Tius Org. Lett. 1999 649

cat. Et3N, dioxane 60%

2 equiv.

3 steps

formal total synthesisof roseophilin

Acyl Anions3. Dithianes

Corey, Seebach ACIEE 1965 1075Corey, Seebach ACIEE 1965 1077Seebach, Groebel Synthesis 1977 357Page, Van Niel, Prodger Tetrahedron 1989 7643

• usually formed from corresponding aldehydes by thioacetalization• R = primary, secondary, and tertiary alkyl, allyl, benzyl, aryl, and O-containing groups

• with alkyl halides: 70-90% yield from protected formaldehyde, two alkylations can be done in a single reaction mixture without isolation of intermediates• with epoxides: 70% yield to give mercaptals of β-hydroxy ketones or aldehydes• with ketones and aldehydes: 70-90% yield to give mercaptals of α-hydroxy ketones or aldehydes• with imines: 70% yield to give mercaptals of α-amino ketones or aldehydes• with CO2: 70-75% yield to give mercaptals of α-keto carboxylic acids

• biggest drawback: removal of dithiane 1. hydrolysis 2. alkylative or oxidative hydrolysis 3. reductive desulfurization (Raney Ni)

S S

R H

n-BuLi, THFS S

R

E+

S S

R E

Acyl Anions3. Dithianes

S S

R H

n-BuLi, THFS S

R

The 1,3-dithiane grouping was carefully chosen:

S S

R

SS

R

+

1,2-dithianes undergo a fragmentation reaction.

MeS SMe

R

Dimethyl thioacetals are susceptible to carbene formation.R

MeS+ SMe

O

O

BnO2C

O O

CHOCO2Bn

OTMS S S

H O

O

BnO2C

O O

CO2BnHO

S S

OH

O

O

BnO2C

O

O

O

CO2Bn

OH

OH

O

O

BnO2C

O O

CO2BnTMSO

S S

OH

Acyl Anions

Nicolaou et al. in zaragozic acid A synthesisSee Classics In Total Synthesis, p. 701

3. Dithianes (example)

n-BuLi, THF, –40 °C; thenaldehyde, –78 °C, 5 min

30% 34%

+

1. 2% HCl in MeOH, CH2Cl2 (76%)2. Hg(ClO4)2, CaCO3, THF-H2O (72%)

facile hyrolysis is perhaps assistedby nearby -OH group

H

NN

RO

R'H

H R

NN

H R'

O

H R

NN

R

NHN

OH

R'H

n-BuLi

H R

NHN

R

O

OH

R'

Acyl Anions4. t-Butyl hydrazones

• formed by condensation of t-butyl hydrazine with aldehydes or ketones• with methyl hydrazones, N-alkylation can be a problem; t-butyl group directs reaction along desired C-alkylation pathway• can add to: aldehydes/ketones (40-95%) alkyl halides (15-83%) Michael acceptors (methyl crotonate, methyl acrylate, acrylonitrile)• acidic hydrolysis (oxalic acid) gives ketones

H2O, taut.

Baldwin et al. 1983 JCSCC 1040Baldwin et al. 1984 JCSCC 1095

H3O+

NOH

Cl

Cl

1 N NaOH

Acyl Anions5. Oximes

• formed by condensation of aldehydes or ketones with hydroxylamine• base causes an inversion of polarity by deprotonation of the N-hydroxyl• can be cleaved by oxidation, reduction, or hydrolysis

100 °C

NO

Cl

Cl Cl

NO

Cl

NO

Cl

NOH

Eschenmoser et al. Helv. Chim. Acta 1958 2103

NaOH

Br

NOH

NO

NOH

OH

Acyl Anions5. Oximes (example)

a β-ionone derivative intense blue color

Eschenmoser et al. Chimia 1965 538

R

NO2

O

R'

R

NO2

R'

O

R

OR'

O

Acyl Anions6. Nitronate anions (Henry reaction)

Henry reaction:Henry Compt. Rend. 1895 1265Rosini Comp. Org. Synth. 1991 321

base Nef

(Henry)

Nef reaction:Nef Liebigs Ann. Chem. 1894 263Petrini Tetrahedron 2004 1017

R

NO O

R

NO O

EtO

O

NO2

CO2Et

EtO

O

NO2

OEt

O

EtO

O

OOEt

O

Acyl Anions6. Nitronate anions (example)

1. NaOEt2. O33. aq. HCl

67%

Cappon et al. Recl. Trav. Chim. Pays-Bas 1991 158

BnMe3NOH 79%

OBuLi

OR Li

O

Li

R

O R

OLiO

R

OLi

O

H+

R

OHO

Acyl Anions7. Metalated enol derivatives

• metalation of a protected enol, followed by reaction with an electrophile• after hydrolysis, a net nucleophilic acylation has occurred

• big advantage: enol ether products are hydrolyzed under very mildly acidic conditions

• in addition to reactivity with ketones and aldehydes, lithio vinyl ethers are alkylated by primary iodides or allylic halides; acylated by aromatic acids (0.5 equiv.) or nitriles; silylated to give acylsilanes

O

RO ORR OH

Li

O OHOEt H3O+

O O

R OH

OHO

Acyl Anions7. Metalated enol derivatives

• aliphatic or aromatic esters add 2 equiv. of reagent to give bis-adducts• such products are difficult to access without nucleophilic acylation

Review: Lever Tetrahedron 1976 1943

–78 °C

Funk, Shipe unpublished results

O

OOEt

Li

O

O

–H2O

O

HOOEt

O

OEt

Acyl Anions7. Metalated enol derivatives (example)

In total synthesis of nicandrenones:Corey, Stoltz, Kano JACS 2000 9044

hydrolysis

Umpolung - Carbonyl Synthons

R

O

R'

normal reactivity

R

O

R'

inverted reactivity umpolung

Umpolung provides flexibility in synthetic planning: • Michael acceptors vs. homoenolates • enolates vs. α-electrophiles • carbonyls vs. acyl anions

R

O

R

O O

R

O

R

O O

Ph

Ph Li

N PhPh

O OPh

Ph

Umpolung - Carbonyl Synthons

+

Walborsky JOC 1974 608

1. 0 °C, 10 min2. H3O+

+

46% 4%

An interesting ring expansion was observed when a cyclopropyllithium reagent wastreated with an isocyanide. Provide a plausible mechanism for the formation of thetwo products.

RLi NR'

NR'

Li

R

R'NH2

H3O+

NR'

E

R

OE

R

Acyl Anions

8. Metallo aldimines

+ E+

+• can be regarded as masked acyl anion equivalents• less efficient with Grignard reagents and aryllithiums• fails with less basic anions like acetylides• vinyl and propenyllithium undergo complicated side reactions

Walborsky et al. JOC 1974 600Walborsky et al. JACS 1969 7778Walborsky et al. JACS 1970 6675

Ph

Ph Li

N

Ph

PhN

Li

RPh

PhN

Li

R

H3O+

H3O+

Ph

PhOH

H

Ph

Ph

HO

PhPh

O OPh

Ph

Mechanism Problem

+

Walborsky JOC 1974 608

1. 0 °C, 10 min2. H3O+

+

46% 4%

An interesting ring expansion was observed when a cyclopropyllithium reagent wastreated with an isocyanide. Provide a plausible mechanism for the formation of thetwo products.