lecture six Aldol-like reactions

20 Pages·2008·2.41 MB·English

lecture six
“
and now, the end is
near; and so I face
my final curtain.
.”
Aldol-like reactions
OH NH
2
2
1 1 3
R
2
R
1,3-aminoalcohols
the reaction
i. base Me Me Me Me NH2
NC N reduce
ii.
HO HO
O
R1
R1 R1
Me Me
pKa of the alpha hydrogens of
The reductioon can be achieved with
acetonitrile is about 25 (the
LiAlH4 or TM-catalysed hydrogenation
same as alpha to an ester)
MeO
Me
N
HO
Me
venlafaxine
antidepressant
©Buena Vista 2005
Remembrer: wehen wet arer peroformings the syynthesnis of thesis
this compound that alkylation of the amine with
methyl iodide is probably not the best reaction.
Instead we should do a reductive amination (in reality
they used methanal and formic acid; see if you can
MeO work out the mechanism for this reaction). MeO
Me C–N
N NH
2
HO HO
Me
amine
FGI
reduction
MeO MeO
CN 1,3-N,O CN
HO
O
(ish)
Aldol-like reactions
3 3
R R
O N
1 1 3 2
R R
2
1,3-amino ketones
retrosynthesis
R1 R1
C–C
O
H
N
O NR32 O R3 R3
Mannich H H
R2 R2
© MMIII-MMVIII - William H. Baird
HO
NMe O
O
atropine
deadly nightshade
retrosynthesis
HO
C–O FGI
NMe O
NMe OH NMe O
ester reduction
O Ph
FGI
decarbonylation
CO H CO H
2 2
CHO 2 x 1,3-NO
MeNH O NMe O
2
CHO 2 x Mannich
CO H CO H
2 2
synthesis
CO H CO H
2 amine 2
CHO
condensation N Me
MeNH O OH
2
CHO OH
CO H CO H
2 2
Mannich
reaction
Me Me N Me N Me N
N CO2H CO2H CO2H
HO
Mannich OH O
O reaction
O
HO2C CO2H CO2H
1,3-dicarbonyl compounds
O O
1 1 3 2
R R
2
Claisen-type condensations
the reaction
O O O X O O O
R1 Me X R2 R1 R2 R1 R2
Ph
N
tazadolene
antidepressant
©Buena Vista 2005
retrosynthesis
O
Ph
O O
several 1,3-diCO
N
Ph
steps
O
Ph
synthesis
O
O Ph Cl
N
N enamine
H formation
The chemistry of enamines is quite fascinating.
The last few years have seen an explosion in the
use of proline derivatives for the temporary
formation of chiral enamines.
Ph O Ph O
hydrolysis
O N
1,5-dicarbonyl compounds
O O
R1 1 3 5 R2
2 4
Michael addition
the reaction
O O
1,5-diCO
HO C
2
HO C
2
the reaction
O O
1,5-diCO
HO C
2
HO C
2
Why do malonates prefer 1,4 addition? Might be time to learn
about Hard-Soft Acid-Base theory (or when reactions are
controlled by electrostatics and when they are controlled by
orbital overlap!!) Then again, perhaps not...
O i. KOH O
O ii. H+,
EtO C
2
heat
EtO C
EtO C 2
2
CO Et CO H
2 2
O
NH
Et
N O
rogletimide
sedative
retrosynthesis
Me O Me
CO Et
C–N 2
NH
CO Et
2
imide
N O N
The real synthesis uses acrylamide instead
of ethyl acrylate; this allows a simple final 1,5-diCO
cyclisation step.
Me Br Me
C–C
CO Et
CO Et CO Et 2
2 2
N N