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
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lecture six
“.”
and now, the end is near; and so I face my final curtain.
Aldol-like reactions
1,3-aminoalcohols
R1
OH NH2
1 2 3
R2
R1
NC
Me Me
O
i. base
ii.
HO
Me Me
R1
N reduce
HO
Me Me
R1
NH2
the 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
NMe
MeHO
venlafaxineantidepressant
©Buena Vista 2005
MeO
NMe
MeHO
C–N
amine
MeO
NH2HO
MeO
CN
HO
FGIreduction
1,3-N,O
(ish)
MeO
CN
O
retrosynthesisRemember: 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
R1 R2
O N
1
2
3
R3 R3
R1
O NR32
R2
C–C
Mannich
R1
O
R2
O
HHR3
HN
R3
retrosynthesis
NMe O
O
HO
atropinedeadly nightshade
© MMIII-MMVIII - William H. Baird
NMe O
O Ph
HO
NMe OH NMe O
NMe O
CO2H
CO2H
CHO
CHO
MeNH2
CO2H
CO2H
O
C–O
ester
FGI
reduction
FGIdecarbonylation
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
NMe
NMe
CO2H
HO2C
O
NMe
O
amine
condensation
Mannich
reaction
Mannich
reaction
synthesis
1,3-dicarbonyl compounds
Claisen-type condensations
R1 R2
O O
1
2
3
R1 Me
O
X R2
O
R1 R2
O X O
R1 R2
O O
the reaction
©Buena Vista 2005
Ph
N
tazadoleneantidepressant
Ph
N
several
steps
O
Ph
O
O
O
Ph
1,3-diCO
retrosynthesis
synthesis
O
NH
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
R1
O
R2
O
1
2
3
4
5
the reaction
O
HO2C
O
HO2C1,5-diCO
the reaction
O
HO2C
O
HO2C1,5-diCO
OEtO2C
EtO2C
O
EtO2C
CO2Et
i. KOH
ii. H+,
heat
O
CO2H
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
rogletimidesedative
N
NH
O
O
Me
N
CO2Et
CO2EtMe
N
CO2Et
Me
CO2Et
N
CO2Et
BrMe
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.
R1
Me
O
Me
steroid skeleton
©www.sporting-heroes.net
O
MeO
O
OMe
Me
O
O
O
Me
Me
O
1,5-diCO
C=C
retrosynthesis
The Robinson annelation
O
O
Me
O
base
O
OMe
Me
O
O
OMe
Me
O
O
OMe
O
base
base
Me
OMe
OO
O
OMe
O
base
base
OMe
OHO
base
OMe
OHO
O
MeO
The Robinson annelation
alkene disconnection
C C
R2
R1 R3
R4
valuable intermediate
O
OHOH
H H
Br
Br
HO
HHO
OH
Aldol condensation
R1 R2
O
R1
O
R2
C=C
reagents
R1 Me
O O
R2 R1 R2
O
Wittig reaction
R1
R4 R3
R2 C=C R1
R4 R3
R2
! !
R3
R2
O
R1
R4
PPh3
I guess it could be argued that the synthons should be a double +ve and a double –ve but this looks confusing
Wittig reaction
R1 R4
BrH
PPh3
R1 R4
PPh3H
base
R1 R4
PPh3
R1 R4
PPh3
R2 R3
OO PPh3
R1
R4R3R2
R1
R4R3
R2
O PPh3
simplification!
Cl
OH
Me Me
Me OH
phenaglycoltranquilliser
retrosynthesis ICl
OH
Me Me
Me OH
Cl
Me
Me
Me
FGIdihydroxylation
Cl
O
Me
Me
Ph3P
Me
Cl
PPh3
Me
Me
O
Me
C=C C=C
retrosynthesis II
Cl
OH
Me Me
Me OH
Cl
Me
Me
Me
FGIdihydroxylation
Cl
OH
Me Me
Me
Cl
Me
Me OH
Me
3 possible Grignards 3 possible Grignards
retrosynthesis IIICl
OH
Me Me
Me OH
Cl
OEt
Me OH
O
Cl
Me OH
NCl
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
BuLiS S
RH
nucleophile
H
dithianesCuriously, 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
OOMeOMe
Me
MeO
MeOH O OH O
Me
Me
OH
MeMeOH
O
(+)-tedanolideanti-carcinogen
OOMeOMe
Me
MeO
MeOH O OH O
Me
Me
OH
MeMeOH
O
remove reactive
functionality
split molecule
umpolung
retrosynthesis
J. Am. Chem. Soc. 2007, 129, 10957
synthesis
OPMe
Me
Me
OP OO
Me
OOMe
Me
Me
OP
MeMeOP
PO
SS
the only way to improve is practice
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