The Vinylogous Aldol Reaction: Application in Synthesis

37 Pages·2005·2.04 MB·English

The Vinylogous Aldol Reaction:
Application in Synthesis
Audrey Chan
Literature Presentation
11/16/04
Lead References: Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929-1972.
Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Synlett. 1999, 9, 1333-1350.
Outline
- Relevance of vinylogous aldol additions in natural products
- Non-directed vinylogous aldol additions
-Vinylogous aldol reaction of metal dienolates
- Kinetic vs. Thermodynamic conditions
- γ-selectivity with amides, carboxylic acids, aldehydes and ketones.
- Diastereoselective vinylogous aldol reactions
- Vinylogous Mukaiyama aldol
- Siloxyfurans
- Schlessinger's chiral auxillaries
- Catalytic, enantioselective vinylogous aldol reactions
- Carreira's Ti(IV) and Cu(I) catalysts
- Evans' Cu(II) catalyst
The Aldol Reactions
aldol coupling
OH O ML
O n
O
+
R
H
R1 R R1 H
Aldol Adduct enolate
homoaldol coupling
O
O
R1 M O
R +
H
R R
1 H
OH
homoenolate
Homoaldol Adduct
vinylogous aldol
coupling
ML
OH O n
O O
R +
H
R1 R R1 H
Vinylogous Aldol Adduct
dienolate
Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G.; Synlett. 1999, 9, 1333-1350.
The Vinylogous Aldol Reaction in Nature
Euphoperfolianes
O
O
AcO
AcO
O
AcO O
AcO
AcO AcO O AcO AcO O
H
H H+
Jatrophane structure
O
AcO
OH
AcO
O
AcO AcO
Both Euphorperfoliane
A and B isolated
Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929-1972.
The Vinylogous Aldol Reaction In Nature
Yohimbine and Reserpine
N N
N N
H H
H H
MeO C MeO C
2 2
O OH
H+
N
N
H H H N
N
O H H
H
OMe
MeO C H
2
OMe MeO2C
OMe
OH
Reserpine OMe Yohimbine
Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929-1972.
Nondirected Vinylogous Aldol Additions
- In a nondirected aldol reaction, the nucleophilic species (enolate or enol) is generated in a substoichiometric way in
situ, namely, in the presence of its complimentary electrophilic carbonyl partner.
- Nondirected vinylogous aldol reactions are rare since VAR adducts rarely survive reaction conditions (strong
acid/base catalysis)
- Reaction conditions favor higher conjugation such as crontonatization and polymerization
Example:
O
O
Me O
TsOH Me Me
C H , Δ
6 6
H
O
O
OH
O
H+ O O
H
This is the first intramolecular vinylogous aldol reaction reported
Gaidamovich, N.N.; Torgov, I.V. Izv. Acad. Nauk. SSSR 1964, 1311.
Nondirected Vinylogous Aldol Reaction
Cycloaromatization and Crotonization
H SO
2 4
+
O
O
O
A 1:1 B
O O
H
H O
O O 2 B
H O
H
H OH2
O O OH HO H O
H 2
H+ H
A
Kinetic vs. Thermodynamic Control of the Vinylogous Aldol Reaction
RCHO O Me
Kinetic
low temp Control
X
O Me shorter rxn time
R OH
X Me
Base O Me α-alkylation
or
X OH
O Me
O R
X
RCHO
Themo
X
R=OH, OR, NR , H Control
2 High temp
+
longer rxn time
O Me OH
X R
γ-alkylation
Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929-1972.
Kinetic vs. Thermodynamic Control of dienolates of Amides
Li
Me O Me O Me O OH Me O
LDA RCHO
Me Me Me + Me
Me N -78oC N THF, -5oC N R N
Me Me Me Me
HO R
A B
R -5oC, 5 min -5oC to rt overnight
A:B A:B
Ph 80:20 0:100
O
88:12 0:100
O
OMe
82:18 0:100
OMe
Prn 100:0 13:87
100:0 15:85
N
Majewski, M.; Mpango, G.B.; Thomas, M.T.; Wu, A.; Snieckus, V. J. Org. Chem. 1981, 46, 2029-2045.
Dienolates of Unsaturated Carboxylic Acids
Vinylogous Aldol Selectivity Highly dependent on Metal(s)
Me O Me OM Me O
1
Me OH OM OH
2
PhCHO, THF, -78oC
Me O
O OH Me
OH Me
CO H
2 OH
O Ph
Ph
CO H Ph OH
2 Ph Me
A B C D
M M Relative Yields
1 2
A B C D
Li SnBu - - - 100
3
Li Li 19 27 - 54
Na Li 5 44 5 46
K Li 54 24 - 22
K K 100 - - -
- Formation of the γ-alkylated vinylogous aldol adduct is favored with more ionic character counterions.
- The cis regioselectivity of the γ-alkylated product is because the trans-γ-alkylated product is destabilized
by allylic strain between the β-methyl and the oxygen atom of the carboxyl.
Cainelli, G.; Cardillo, G.; Contento, M.; Trapani, G.; Umani-Ronchi, A. J. Chem. Soc. Perkin Trans. 1 1973, 400-404.