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
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Chemoselectivity
reactivity towards nucleophiles
reacivity towards metal-hydride
LiAlH(O-t-Bu)3
LiAlH(OMe)3
LiAlH(O-t-Bu)3
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LiBH(CH2CH3)3 Rt, 2 min
(LiAlH4)
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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
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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
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How to reduce esters and amides to aldehydes
tetrahedral intermediate stable at -78?
stable cyclic tetrahedral intermediate
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Making ketones from Weinreb amides (esters)
DIBALH
tetrahedral intermediate stabilized by
cooordination of the second oxygen atom to the
magnesium atom
H
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How to reduce carboxylic acids to alcohols
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Other synthetically important reduction protocols
Narasaka 1984
Evans 1988
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Reductions in an industrial scale are crucial
transformations
Glaxo anti-asthma Drugs
H2, Pd-C
sulbutamol
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Glaxo anti-asthma Drugs
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Selective Reduction Hypothesis
NaBH4
NaBH4
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Combination of BH3 with catalytic NaBH4 (Brown,
Yoon 1968)
Route a
Route b
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Selective Reduction Results
chemoenzymatic process
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Mechanism (1)
?
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Mechanism (2) catalytic cycle
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Mechanism (3) catalytic cycle
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Mechanism (4) catalytic cycle
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Synthetic Applications
K. Mori, T. Takigawa, T. Matsuo, Tetrahedron, 1979
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Commercial Production of Grams-to-Tons of Chiral
HGB Synthon Corporation

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has been playing an important role in