Addition of Metal-H bonds to Carbonyl Groups - PowerPoint PPT Presentation

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Addition of Metal-H bonds to Carbonyl Groups

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Addition of Metal-H bonds to Carbonyl Groups Group 13 Hydride-Donor Reagents Chemoselectivity reactivity towards nucleophiles = reacivity towards metal-hydride LiAlH ... – PowerPoint PPT presentation

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Title: Addition of Metal-H bonds to Carbonyl Groups


1
Addition of Metal-H bonds to Carbonyl Groups
Group 13 Hydride-Donor Reagents
2
Chemoselectivity
reactivity towards nucleophiles
reacivity towards metal-hydride
LiAlH(O-t-Bu)3
LiAlH(OMe)3
LiAlH(O-t-Bu)3
3
LiBH(CH2CH3)3 Rt, 2 min
(LiAlH4)
4
How to reduce esters to alcohols
tetrahedral intermediate
How to reduce amides to amines
tetrahedral intermediate
does not happen -NR2 is not eliminated in this
step
5
Borane can also reduce amides to amines
tetrahedral intermediate collapses to iminium ion
only reactive towards protonated imines at pH
67, essentially unreactive towards carbonyl
groups
6
How to reduce esters and amides to aldehydes
tetrahedral intermediate stable at -78?
stable cyclic tetrahedral intermediate
7
Making ketones from Weinreb amides (esters)
DIBALH
tetrahedral intermediate stabilized by
cooordination of the second oxygen atom to the
magnesium atom
H
8
How to reduce carboxylic acids to alcohols
9
Other synthetically important reduction protocols
Narasaka 1984
Evans 1988
10
Reductions in an industrial scale are crucial
transformations
Glaxo anti-asthma Drugs
H2, Pd-C
sulbutamol
11
Glaxo anti-asthma Drugs
12
Selective Reduction Hypothesis
NaBH4
NaBH4
13
Combination of BH3 with catalytic NaBH4 (Brown,
Yoon 1968)
Route a
Route b
14
Selective Reduction Results
chemoenzymatic process
15
Mechanism (1)
?
16
Mechanism (2) catalytic cycle
17
Mechanism (3) catalytic cycle
18
Mechanism (4) catalytic cycle
19
Synthetic Applications
K. Mori, T. Takigawa, T. Matsuo, Tetrahedron, 1979
20
Commercial Production of Grams-to-Tons of Chiral
HGB Synthon Corporation

21
has been playing an important role in
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