Title: Addition of Metal-H bonds to Carbonyl Groups
1Addition of Metal-H bonds to Carbonyl Groups
Group 13 Hydride-Donor Reagents
2Chemoselectivity
reactivity towards nucleophiles
reacivity towards metal-hydride
LiAlH(O-t-Bu)3
LiAlH(OMe)3
LiAlH(O-t-Bu)3
3LiBH(CH2CH3)3 Rt, 2 min
(LiAlH4)
4How 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
5Borane 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
6How to reduce esters and amides to aldehydes
tetrahedral intermediate stable at -78?
stable cyclic tetrahedral intermediate
7Making ketones from Weinreb amides (esters)
DIBALH
tetrahedral intermediate stabilized by
cooordination of the second oxygen atom to the
magnesium atom
H
8How to reduce carboxylic acids to alcohols
9Other synthetically important reduction protocols
Narasaka 1984
Evans 1988
10Reductions in an industrial scale are crucial
transformations
Glaxo anti-asthma Drugs
H2, Pd-C
sulbutamol
11Glaxo anti-asthma Drugs
12Selective Reduction Hypothesis
NaBH4
NaBH4
13Combination of BH3 with catalytic NaBH4 (Brown,
Yoon 1968)
Route a
Route b
14Selective Reduction Results
chemoenzymatic process
15Mechanism (1)
?
16Mechanism (2) catalytic cycle
17Mechanism (3) catalytic cycle
18Mechanism (4) catalytic cycle
19Synthetic Applications
K. Mori, T. Takigawa, T. Matsuo, Tetrahedron, 1979
20Commercial Production of Grams-to-Tons of Chiral
HGB Synthon Corporation
21has been playing an important role in