lecture six
“ and now, the end is . ”
near; and so I face my final curtain.
Aldol -like reactions
1,3-aminoalcohols R 1
OH NH 2
1 2 3
R 2
R
1NC
Me Me
O i. base
ii.
HO
Me Me
R
1N reduce
HO
Me Me
R
1NH
2the reaction
pKa of the alpha hydrogens of acetonitrile is about 25 (the same as alpha to an ester)
The reductioon can be achieved with LiAlH4 or TM-catalysed hydrogenation
MeO
N Me HO Me
venlafaxine antidepressant
©Buena Vista 2005
MeO
N Me HO Me
C–N amine
MeO
NH
2HO
MeO
CN HO
FGI reduction
1,3-N,O (ish) MeO
CN O
retrosynthesis
Remember: when we are performing the synthesis of 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 work out the mechanism for this reaction).
Aldol -like reactions
1,3-amino ketones R 1 R 2
O N
1
2
3
R 3 R 3
R
1O NR
32R
2C–C Mannich
R
1O
R
2O H
H R
3H N R
3retrosynthesis
NMe O O
HO
atropine deadly nightshade
© MMIII-MMVIII - William H. Baird
NMe O
O Ph HO
NMe OH NMe O
NMe O CO
2H
CO
2H CHO
CHO
MeNH
2CO
2H
CO
2H O C–O
ester
FGI
reduction
FGI
decarbonylation
2 x 1,3-NO 2 x Mannich
retrosynthesis
CHO
CHO
MeNH2
CO2H
CO2H O
N Me
OH
CO2H
CO2H OH
CO2H
O CO2H N
HO Me CO2H
OH CO2H Me N
Me N
CO2H
HO2C
O Me N
O
amine condensation
Mannich reaction
Mannich reaction
synthesis
1,3-dicarbonyl compounds
Claisen -type condensations
R 1 R 2 O O
1
2
3
R
1Me O
X R
2O
R
1R
2O X O
R
1R
2O O
the reaction
©Buena Vista 2005
Ph
N
tazadolene antidepressant
Ph
N
several steps
O
Ph O
O
O Ph 1,3-diCO
retrosynthesis
synthesis
O
N H
N Ph Cl
O
N
Ph O
O
Ph O
enamine formation
hydrolysis
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.
1,5-dicarbonyl compounds
Michael addition
R 1 O
R 2 O
1
2
3
4
5
the reaction
O
HO
2C
O
HO
2C 1,5-diCO
the reaction
O
HO
2C
O
HO
2C 1,5-diCO
EtO
2C O
EtO
2C
O
EtO
2C
CO
2Et
i. KOH ii. H
+, heat
O
CO
2H
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...
N
NH O
O
Et rogletimide
sedative
N
NH O
O Me
N
CO
2Et CO
2Et Me
N
CO
2Et Me
CO
2Et N
CO
2Et Br Me
C–N imide
1,5-diCO
C–C
retrosynthesis
The real synthesis uses acrylamide instead of ethyl acrylate; this allows a simple final cyclisation step.
R
1Me
O
Me
steroid skeleton
©www.sporting-heroes.net
O
Me O
O Me O Me
O
O
O Me
Me O
1,5-diCO C=C
retrosynthesis
The Robinson annelation
O
O Me
O
base
O Me O Me
O
O Me O Me
O
O Me O O
base
base Me
Me O
O O O
Me O O
base
base
Me O
O OH base Me O
O OH O
Me O
The Robinson annelation
alkene disconnection
C C R 2
R 1 R 3 R 4
valuable
intermediate
O
OH OH
H H
Br
Br
HO HO H
OH
Aldol condensation
R
1R
2O
R
1O
R
2C=C
reagents
R
1Me
O O
R
2R
1R
2O
Wittig reaction
R
1R
4R
3R
2C=C R
1R
4R
3R
2! !
R
3R
2O
R
1R
4PPh
3I guess it could be argued that the synthons should be a double +ve and a double –ve but this looks confusing
Wittig reaction
R
1R
4Br H
PPh
3R
1R
4PPh
3H
base
R
1R
4PPh
3R
1R
4PPh
3R
2R
3O PPh
3O
R
1R
4R
3R
2R
1R
4R
3R
2O PPh
3simplification!
Cl
OH Me Me
Me OH
phenaglycol
tranquilliser
retrosynthesis I
Cl
OH Me Me
Me OH
Cl
Me
Me Me FGI
dihydroxylation
Cl
O Me Me Ph
3P
Me Cl
PPh
3Me Me O
Me
C=C C=C
retrosynthesis II
Cl
OH Me Me
Me OH
Cl
Me Me Me
FGI dihydroxylation
Cl
OH Me Me
Me Cl
Me Me OH
Me
3 possible Grignards 3 possible Grignards
retrosynthesis III
Cl
OH Me Me
Me OH
Cl
OEt Me OH
O
Cl
Me OH Cl N
O Me CN
C–C
FGI
C–C
umpolung
R
O
! +
R
O
! –
reverse polarity
example
R Br R MgBr
C N
R C N
O Ph
OH Ph R Mg
umpolung
! + ! – ! – ! +
This is not a true example of umpolung but is just meant to aid us understanding the concept of polarity reversal
R O
electrophile
HS SH
S S
R H
BuLi S S
R H
nucleophile H
dithianes
Curiously, the 5-membered dithioacetal ring (dithiolane) cannot be used in this reaction and fragments on treatment with strong base
Some interesting uses of this kind of chemistry have been reported by the group of Amos B Smith III
