Umpolung: Carbonyl Synthons

William D. Shipe

Organic Supergroup Meeting

Princeton University

February 4, 2004
 Umpolung - The Carbonyl Group

O O

R R' R R'

normal reactivity inverted reactivity

umpolung
O
O OH

OH

O
O O

odd number of carbons even number of carbons

between functional groups between functional groups

Seebach ACIEE 1979 239

 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. homoenolates
O O O
2. α-electrophiles
R R
3. acyl anions
 Umpolung - Carbonyl Synthons

Inversion reactions described as "symmetrization of reactivity"

Corey Pure Appl. Chem 1967 19

"charge affinity inversion"

Evans Acc. Chem. Res. 1974 147

suggested the German word umpolung as a concise expression for

the concept
Seebach Chem. Ind. 1974 687

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

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

O OMgBr R3SiO MgBr

MgBr R''X OSiR3

R' SiR3 R'

SiR3
R' R' R''

Kuwajima et al. Chem. Commun. 1979 708

MeOCO2
O Li OTBS Br
+
TBS
Br in THF;
–78 °C, 2h; TAS-F, THF-DMF
82% –35 °C to 0 °C, 3h;
90%

O
4 steps
(±)-δ-araneosene MeOCO2

Corey et al. Org. Lett. 2002 2441

 Homoenolates

O Ph O
2 BuLi N Li E+
Li
PhNH SnBu3 PhNH E
O
Goswami et al. JACS 1980 5973

RO OTMS TiCl4, CH2Cl2 RO OTMS OR TiCl4

TiCl4
TMSO

–TMSCl
O
O
H R' O TiCl3
R'
RO
RO
OH

Kuwajima et al. JACS 1986 3745

 Homoenolates

OR OR

OR SnCl4 OR OTMS O
Cl2Sn
Cl3Sn O O
OTMS
OR

Kuwajima et al. Organometallics 1985 641

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

OR
OR ZnCl2, Et2O
2 O Zn O
OTMS
RO

Nakamura, Kuwajima et al. JACS 1984 3368 when the zinc reagent contains two
Nakamura, Kuwajima et al. JACS 1987 8056 homoenolates bound to each zinc atom,
only one of the homoenolates can be
transferred; the second is unreactive
 Homoenolates
OR
O O
OR ZnCl2, Et2O Et2O Zn O
2 + 2 TMSCl RO
OTMS
OTMS Cu(I), HMPA, THF

O OR

Kuwajima Pure and Applied Chem. 1988 115

O
O H

Zn Oi-Pr OR
O H
OR H
HMPA, CuBr•Me2S,
BF3•Et2O
H
80-85%
O Oi-Pr

Nakamura, Kuwajima et al. JOC 1986 4323 > 97 : 3 diastereoselectivity

cortisone and adrenosterone
Nakamura, Kuwajima et al. JACS 1989 6257
intermediate
 Homoenolates
O
O CO2Me
MeO2C
Zn( OEt)2
OR OR
O O
O O
HMPA, CuBr•Me2S,
H TMSCl H
65%

hν

H
O O O
O CO2Me
O O
O
O OH
C(CH3)3
H OH
RO
O
bilobalide
Crimmins et al. JACS 1993 3146
Reviews on Homoenolates:
Crimmins, Nantermet Org. Prep. and Proc. Int. 1993 41-81
Werstiuk Tetrahedron 1983 205
 α-Electrophiles
O O
Nu-
R' R'
R R
X Nu

O H3O+ (mild)
N O
NH2 O O H2N O O O
N H

HNMe2
AgBF4

O
N
Cl HO O

Eschenmoser, Woodward et al. in Vitamin B12 synthesis

See Classics In Total Synthesis, p. 134
 α-Electrophiles
• 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

2+
ONO2
H2N Pt O O
H2O
H3N O t-Bu
+ R R
H2N Pt NH t-Bu
H3N NH Pt(III)2
ONO2

NH2
O
O
R
N R
R
O Pt(III)2 H O
+ N H N
O R
O
R Matsumoto et al. JACS ASAP
R
 α-Electrophiles
Anodic Oxidative Cyclization:

RVC anode O
TBSO H
carbon cathode
0.4 M LiClO4

MeOH/CH2Cl2 (1:4) TBSO O

TBSO O
2,6-lutidine, RT
15–20 mA, 2.2 F/mole MeO

RVC = reticulated vitreous carbon

TsOH, RT

O O
H

O OH
HO O
O
alliacol A Moeller et al. JACS 2003 36
 Acyl Anions
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

O CN O OH O

Ar H Ar CN Ar CN Ar
H

Ar H

O O OH
OH OH O
Ar Ar Ar
CN H CN H
Ar Ar Ar
a benzoin

Lapworth J. Chem. Soc. 1903 995

 Acyl Anions
1b. Protected cyanohydrins
• can serve as reagents for annulation

Stork et al. JACS 1974 5272

Kraus et al. Tet. Lett. 2000 21

H
O H THF O HN
N –78 to rt O
O + O OMe
OMe 85% OMe
OMe OH
NC Li OH
O OH
O

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

 Acyl Anions
2. Thiazolium salt catalyzed addition

N
NH2
N

N Br N I
N Cl N Cl
HO S S
HO
S HO S
HO
vitamin B1 (thiamine)
• 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

O
cat. thiazolium salt, O
O Et3N, DMF
+ X
R H X R
O
 Acyl Anions
2. Thiazolium salt catalyzed addition (mechanism)
O
Bn Bn
Bn
N Cl R H N O
base N
H
S HO S H R
HO HO S

O
X X
X Bn
Bn OH Bn O
N OH
N N

R R HO S R
HO S O S OH
HO

Breslow Chemistry and Industry 1956 R.28

Bn
Breslow Chemistry and Industry 1957 893
O Breslow JACS 1957 1762
N Breslow JACS 1958 3719
X +
R Breslow JACS 1959 3080
HO S Stetter ACIEE 1976 639
O
 Acyl Anions
2. Thiazolium salt catalyzed addition (example)
Bn
O N O
BzO BzO O
HO S

O
2 equiv.
H
cat. Et3N, dioxane
60%
3 steps

HN

formal total synthesis O

of roseophilin

Tius Org. Lett. 1999 649

 Acyl Anions
3. Dithianes

n-BuLi, THF E+
S S S S S S
R H R R E
• 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)
Corey, Seebach ACIEE 1965 1075
Corey, Seebach ACIEE 1965 1077
Seebach, Groebel Synthesis 1977 357
Page, Van Niel, Prodger Tetrahedron 1989 7643
 Acyl Anions
3. Dithianes

n-BuLi, THF
S S S S
R H R

The 1,3-dithiane grouping was carefully chosen:

S S +
S S
R
R
1,2-dithianes undergo a fragmentation reaction.

MeS SMe MeS

+ SMe
R R
Dimethyl thioacetals are susceptible to carbene formation.
 Acyl Anions
3. Dithianes (example)
HO CO2Bn TMSO CO2Bn
OTMS S S BnO2C OH BnO2C OH
BnO2C
CO2Bn
CHO H
O
+ O
O S S S S
n-BuLi, THF, –40 °C; then O O O O
O O
O
aldehyde, –78 °C, 5 min O O

30% 34%

1. 2% HCl in MeOH,
CH2Cl2 (76%)
2. Hg(ClO4)2, CaCO3,
THF-H2O (72%)
facile hyrolysis is perhaps assisted
by nearby -OH group CO2Bn
BnO2C
O
OH
O
OH
O
Nicolaou et al. in zaragozic acid A synthesis O O
See Classics In Total Synthesis, p. 701
 Acyl Anions
4. 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

n-BuLi
HN N N
N N N

H R H R H R
O

H R'

O
HN
R'
H3O+ N H2O, taut.
H N
R N
R' H
OH R R'
OH H
R
O
Baldwin et al. 1983 JCSCC 1040
Baldwin et al. 1984 JCSCC 1095
 Acyl Anions
5. 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
Cl
Cl Cl
Cl
Cl
1 N NaOH
100 °C
N N
OH N O
O

Cl

Cl

N N
OH O
Eschenmoser et al. Helv. Chim. Acta 1958 2103
 Acyl Anions
5. Oximes (example)
OH O
N N
NaOH

Br

a β-ionone derivative intense blue color

OH
N

OH

Eschenmoser et al. Chimia 1965 538

 Acyl Anions
6. Nitronate anions (Henry reaction)

NO2 O
NO2 base Nef
R' R'
R R
R O
O O
R'

(Henry)
O O O O
N N

R R

Henry reaction: Nef reaction:

Henry Compt. Rend. 1895 1265 Nef Liebigs Ann. Chem. 1894 263
Rosini Comp. Org. Synth. 1991 321 Petrini Tetrahedron 2004 1017
 Acyl Anions
6. Nitronate anions (example)

O CO2Et O O

EtO EtO OEt

BnMe3NOH
NO2 79% NO2

1. NaOEt
2. O3 67%
3. aq. HCl

O O

EtO OEt
O

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

 Acyl Anions
7. Metalated enol derivatives
• metalation of a protected enol, followed by reaction with an electrophile
• after hydrolysis, a net nucleophilic acylation has occurred

Li OLi OH
BuLi H+
O O O
O O R R

R
O
R
Li
R O Li
O

• 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
 Acyl Anions
7. 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

R OH R OH
RO OR

O O

Review: Lever Tetrahedron 1976 1943

Li
OH OH
O O
OEt H3O+ O

–78 °C

Funk, Shipe unpublished results

 Acyl Anions
7. Metalated enol derivatives (example)
Li
O O
OEt

HO
O
OEt

–H2O

O O
hydrolysis

O OEt

In total synthesis of nicandrenones:

Corey, Stoltz, Kano JACS 2000 9044
 Umpolung - Carbonyl Synthons

O O

R R' R R'

normal reactivity inverted reactivity

umpolung

O O O O O O

R R R R

Umpolung provides flexibility in synthetic planning:

• Michael acceptors vs. homoenolates
• enolates vs. α-electrophiles
• carbonyls vs. acyl anions
 Umpolung - Carbonyl Synthons
An interesting ring expansion was observed when a cyclopropyllithium reagent was
treated with an isocyanide. Provide a plausible mechanism for the formation of the
two products.

1. 0 °C, 10 min
Ph Ph O
Ph N 2. H3O+ Ph
O

Ph Li
+ + Ph

46% 4%

Walborsky JOC 1974 608

 Acyl Anions
8. Metallo aldimines

Li E
N
E+
RLi + N N
R' R' R R' R

H3O+

E
R'NH2 + O
• can be regarded as masked acyl anion equivalents R
• 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 600

Walborsky et al. JACS 1969 7778
Walborsky et al. JACS 1970 6675
 Mechanism Problem
An interesting ring expansion was observed when a cyclopropyllithium reagent was
treated with an isocyanide. Provide a plausible mechanism for the formation of the
two products.

1. 0 °C, 10 min
Ph Ph O
Ph N 2. H3O+ Ph
O

Ph Li
+ + Ph

H3O+ 46% 4%

Ph Ph N R
N R Ph
Ph
Li Li

H3O+
Ph Ph HO
OH
Ph Ph
H

Walborsky JOC 1974 608