Lewis Base Catalysis: the Aldol Reaction (Scott Denmark)

45 Pages·2014·3 MB·English

by  Thomas Blaisdell

Lewis
 Base
 Catalysis:
 the
 Aldol

Reaction
 (Scott
 Denmark)

Tom
 Blaisdell

Friday,
 January
 17th
 2014

Topic
 Talk
Scott
 E.
 Denmark

1975
 -­‐
 S.B.
 in
 Chemistry
 –
 MIT
 (Richard
 H.
 Holm
 and
 Daniel
 S.
 Kemp)

1980
 -­‐
 D.Sc
 in
 Chemistry
 -­‐
 ETH
 Zurich
 (Albert
 Eschenmoser)

1980
 -­‐
 Assistant
 Professor
 -­‐
 University
 of
 Illinois

1986
 -­‐
 Associate
 Professor
 -­‐
 University
 of
 Illinois

1987
 -­‐
 Professor
 -­‐
 University
 of
 Illinois

1991
 -­‐
 Reynold
 C.
 Fuson
 Professor
 of
 Chemistry
 -­‐
 UIUC

Main
 Research
 Interests:

•  Lewis
 Base
 Activation
 of
 Lewis
 Acids

•  Palladium-­‐Catalyzed
 Cross-­‐Coupling
 of
 Organosilicon
 Compounds

•  Tandem
 Cycloaddition
 Chemistry
 of
 Nitroalkenes

•  Asymmetric
 Phase
 Transfer
 Catalysis/Chemoinformatics

Aldol
 Chemistry:
 Mid-­‐1990s
 to
 mid-­‐2000s
The
 Aldol
 Reaction

•  One
 of
 the
 most
 ubiquitous
 reactions
 in
 organic
 chemistry

•  Provides
 numerous
 selectivity
 challenges
 (chemo-­‐,
 site-­‐,
 enantio-­‐
 and

diastereoselectivity)

•  “…continues
 to
 serve
 as
 a
 platform
 for
 the
 demonstration
 of
 conceptual

advances
 in
 the
 ^ield
 [of
 organic
 chemistry]”
The
 Aldol
 Reaction

OTMS O OH
H
TiCl
4 82%
Ph
3:1 syn:anti
PhCHO
Mukiyama, T. Chem. Lett. 1973, 9, 1011
O OB(nBu)2 O O OH
Me
PhCHO
N N Ph >500:1 syn:anti
O O
Me
Evans, D. J. Am. Chem. Soc. 1981, 103, 2127
Formation
 of
 Enoxyborinates
 and
 Enoxysilanes

OB(nBu) OTMS
2
R R
1 1
R R
2 2
Enoxyborinates Enoxysilanes
•  Most
 stable
 and
 widely
 used
 enolates

•  Allowed
 for
 identi^ication
 of
 which
 carbonyl
 was
 acting
 as
 the

nucleophile
 (site
 and
 chemoselectivity)

•  Both
 have
 unique
 reactivity
 (diastereo-­‐
 and
 enantioselectivity)
Enoxyborinates

•  Coordination
 of
 the
 aldehyde
 to
 the
 boron
 is
 necessary

•  Proceeds
 through
 a
 predictable
 chair-­‐like
 transition
 state

PhCHO
OB(nBu) O OH
2 CH Cl
2 2
Me 77% yield
Et Et Ph
Et O >97:3 syn/anti
H 2 Me
-78-0 °C
>97:3 Z/E
Et nBu
H
B
O nBu
H
O
Ph
Me
nHex
B
O PhCHO O OH
CH Cl
2 2
Ph 4:96 syn/anti
Et O
2
-78-0 °C
cPent
H
B
O nHex
O
Ph
H
Evans,
 D.
 J.
 Am.
 Chem.
 Soc.
 1981,
 103,
 3099-­‐3111
Enoxysilanes

•  Unlike
 boron,
 the
 silicon
 atom
 is
 not
 lewis
 acidic
 enough
 to
 bind
 and

activate
 the
 aldehyde.

•  Cannot
 form
 a
 six-­‐membered
 transition
 state

•  Requires
 a
 secondary
 Lewis
 acid
 for
 activation
 and
 therefore
 undergo

an
 open
 transition
 state

PhCHO
OTMS O OH
BF -OEt
3 2
Me 62% yield
Et Et Ph
CH Cl 60:40 syn/anti
H 2 2 Me
-78 °C
>99:1 Z/E
OTMS PhCHO O OH
SnCl
2
82% yield
Ph
70:30 anti/syn
TMSCl
CH Cl
2 2
-78 °C
Heathcock,
 C.
 Tetrahedron
 Le7.
 1984,
 25,
 5973-­‐5976

Mukiyama,
 T.
 Chem.
 Le7.,
 1987,
 463-­‐466
Enoxysilanes

OTMS NH PhChO O OTMS
NH Sn(OTf)2 (20 mol %)
EtS + EtS Ph
EtCN
Me Me
77%
92:8 syn/anti
20 mol %
95:5 e.r.
Ph
O CO H
OTMS 2 O OTMS
O O PhChO
Me +
nBu nBu Ph
O O EtCN Me
B
H 97%
20 mol % 93:7 syn/anti
97:3 e.r.
Mukiyama,
 T.
 Chem.
 Le7.,
 1990,
 1455-­‐1458

Yamamoto.
 J.
 Am.
 Chem.
 Soc.
 1991,
 113,
 1041-­‐1042

Nelson,
 Tetrahedron
 Asymmetry,
 1998,
 9,
 357-­‐389

Denmark’s
 Approach

•  Combining
 the
 inherient
 properties
 of
 both
 enoxyborinates
 and

enoxysilanes

–  Enoxyborinates:
 Predictable
 six-­‐membered
 TS
 to
 control

diasteroselectivity

–  Enoxysilanes:
 Able
 to
 establish
 asymmetric
 control

1.  Enoxysilacyclobutanes

Si
O
tBu
R

Me
2.  Lewis
 base
 catalysis
 as
 a
 means
 of
 activating
 the
 metal
 center

  LB*
ML
n
O
R
Me