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.