Chem 634 Aldol Chemistry
Reading: CS-B 2, CK 4–5
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•  Problem Set 3 due Fri, 11/6, by 5pm to my mailbox.
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•  This week: Wed, 10/28, 10:30-12 (as usual)
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Fall 2015 Seminar Series
219 Brown Laboratory 4:00 pm, October 28, 2015
Discovery of Telcagepant (MK-0974): The First Orally
Bioavailable Calcitonin Gene-Related Peptide (CGRP)
Receptor Antagonist for Migraine Treatment.
DANIEL PAONE Ph.D.
GlaxoSmithKline, Discovery
Partnerships with Academia
http://www.dpac.gsk.com/team.html
Calcitonin gene-related peptide (CGRP) is a 37 amino acid neuropeptide that has been implicated in
the pathogenesis of migraine. Since CGRP receptor antagonists promote normalization of dilated blood
vessels through a non-vasoconstrictive mechanism, this class of compounds would prove effective in the
relief of migraine without the adverse cardiovascular effects that are sometimes associated with existing
therapies. Our research program targeted non-peptide, small molecule CGRP receptor antagonists with
favorable pharmacokinetic profiles that would result in the first oral drug in this class. Core truncation
of a high-throughput screening lead followed by extensive SAR studies provided potent derivatives with
improved oral bioavailabilities. Further refinement resulted in Telcagepant (MK-0974), ultimately providing the optimal blend of potency and pharmacokinetic profiles. This compound showed efficacy in
a capsaicin-induced dermal vasodilation pharmacodynamic assay in rhesus and advanced to Phase III
clinical trials for the treatment of acute migraine. Clinical efficacy will be summarized and the synthetic
chemistry developed to access these compounds will also be described.
Basic Aldol Reaction
O
R
R1 +
O
O
H
R3
OH
R3
R
R1
"anti" aldol
(+/-)
O
+
R
OH
R3
R1
"syn" aldol
(+/-)
Three Types of Aldol Reactions
1) Open
O
H
+
H
OM
O
OM
R
MO
O
R
R
M= K+, Cs+, NR4+
Typically not used, poor DS.
2) Closed transition state
O
H
+
H
OM
O
O
M
O
O
M
R
R
M= Li, B, Al, Zn
High DS
R
Three Types of Aldol Reactions
3) Lewis Acid (Mukiyama Aldol)
LA
O+
+
O
M
LA
O
O
R
M= SiR3, or SnR3
LA= Lewis Acid
M
MO
O
R
Stereoselection in Closed
Aldol Transition States
Z-Enolates: Syn Aldol
R3
OH O
OM
O
H
+
R2
R3
R1
R1
R2
H
syn
2
O R
R3
O
M
O
R2
R3
H
H
R1
H
O
M
OH O
R3
H
R2
R1
favored
O
H
syn
R2
O
M
O
H
H
R3
R1
R1
R3
R2
O
M
OH O
R3
H
R1
R1
R2
anti
disfavored
Zimmerman-Traxler Model
JACS 1957, 79, 1920
Enantiomeric Transition States
2
O R
R3
O
M
O
R3
H
H
R1
OH O
O
M
R3
H
H
R2
R1
R2
R1
syn
O
M
R2 O
O
M
R3
H
R1
R2
H
R3
H
R1
OH O
O
H
R3
R1
R2
syn
E-Enolates: Anti Aldol
OM
O
R3
O
H
H
OH O
R1
R3
R2
R1
R2
anti
O
M
R3
H
+
H
O
H
R3
R2
H
R1
O
M
OH O
R3
R2
R2
R1
anti
favored
O
H
H
R3
R1
O
M
O
H
H
R2
R1
disfavored
R3
O
M
OH O
R3
R2
R1
R1
R2
syn
Counter Ions in Aldol Reactions
Short M-O Bonds Promote Tightest Closed TS = Highest DS
M-­‐O Bond Bond Length B-­‐O 1.4 Å Zr-­‐O 1.5 Å Li-­‐O 1.95 Å Al-­‐O 1.9 Å Mg-­‐O 2.1 Å Selective
Often Used
Not Often Used
Non-selective
Counter Ions in Aldol Reactions
Another Consideration: Lithium Aldol Reactions are Reversible
O
Me
Ph
O
Me
Ph
O
OLi
LDA
Me
Ph
Ph
Me
OH
Ph
Me
Ph
Ph
O
Ph
PhCHO, –78 °C;
wait 60 seconds,
then H+
OLi
LDA
OLi
PhCHO, –78 °C;
wait 5 seconds,
then H+
Me
O
OH
Ph
Ph
Me
PhCHO
Ph
O
PhCHO
OLi
Me
OLi
Ph
Ph
Me
Boron aldols not reversible.
Heathcock JOC 1980, 45, 1066
Boron Enolates
General Lewis Acid Mediated Enolate Formation:
X
LA
O
H
R
LA-X
LA
O+
H
R
- BHX
O
R
B
With Boron:
X
O
R
LA= R2BX
H
R2B
R2B
O+
H
R
- BHX
O
R
B
Question: What about E vs. Z selectivity?
Patterson TL, 1992, 33, 7223
E-Boron Enolates
O
Me
OBCy2
Cy2BCl
Me
Me
Et3N
Me H H
H
Me
Me
E boron enolate
kinetic
Large Alkyl Groups
Bound Anion
iPr
B
iPr
Me
H
Cl
Me
O
H
O
Cl
B
H
Small Base
iPr
Me
H
Me
H
Et3N:
H
iPr
OBCy2
H
O
Cl
B
Z-Boron Enolates
O
Me
Me
OBBu2
Bu2BOTf
iPr
Me H H
Me
2NEt
Me
Me
H
Z boron enolate
kinetic
Disassoicated Anion
Small Alkyl Groups
TfO
Bu
iPr
Me
H
B
Bu
Bu
iPr
H
O
iPr
H
Large Base
N
Me
B
TfO
Bu
O
iPr
H
iPr
H
Me
H
Et H
iPr
TfO
OBBu2
Me
O
B Bu
Bu
Example
O
Me
Ph
Bu2BOTf
iPr2NEt
Ph
OBBu2
Me
Z
O
PhCHO
Me Bu
O
B
Ph
H
H Bu
Ph
OH O
H2O
Ph
Ph
Me (+/-)
>97:3 syn
82%
Evans JACS, 1981, 103, 3099
Evans' Chiral Auxiliary Aldol Rxns
not chelated in Aldol TS;
coordination site on B needed
for aldehyde
O
O
O
O
Me
N
Bu2BOTf
iPr2NEt
(or Et3N)
Bn
O
Me
N
O
BBu2
O
PhCHO
Bn
both amide and
Bu2BOTf give Z-enolate
Me Bu
O
O
B
Ph
H
H Bn
Bu
N
H
O O
favored
Me Bu
O
B
Ph
Bn Bu
H
H
O
O
OH
N
Ph
Me
Bn
>98:2 dr
O
vs.
H
N
O O
anti-periplanar dipoles
dipole of
=
indicated bond
Bn group inside
JACS 1981, 103, 2127
Evans' Chiral Auxiliary Aldol Rxns
OH O
R
OH O
N
R
R1
OMe
HN
Me
O
LiO
O
O
H
R1
OH
LiBH4
Ti(O
B
R2
OH
R
R1
n)
4
AlMe3
OH O
R
OH O
R
R1
OH
OBn
R1
OMe
N
Me
JACS 1981, 103, 2127
Felkin Control α-Chiral Aldehydes
O
R
OBCy2
H
Me
R1
O
Me
H
H
O
R
+ H
R
R1
Me
(E)
Cy
B Cy
H
+
OH O
Me Me
major
Felkin control aldol
OH O
R
R1
Me
Me
R away from enolate
R1
Me
favored
2,3-anti-3,4-syn
"Felkin"
R away from enolate
R
Me
Me
H
Cy
B Cy
R1
O
H
O
H
OH O
R
R1
Me
Me
Roush JOC 1991, 56, 451
Felkin Control α-Chiral Aldehydes
O
R
OBBu2
H
Me
+
Me
OH O
R
R1
H
Me
(Z)
R1
Cy
B Cy
H
O
H
OH O
R
R1
Me
Me
Me
"Felkin"
R away from enolate
R away from enolate
Me
H
R
H
Cy
B Cy
R1
O
H
Me
O
Me
major
"anti-Felkin" aldol
O
R
H
Me
R1
Note: These are
all Felkin control
models. “AntiFelkin” is a
historical
misnomer in this
case.
OH O
R
R1
Me Me
favored
2,3-syn-3,4-anti
"anti-Felkin"
Roush JOC 1991, 56, 451
Mukaiyama Aldol
OSiMe3
O
+
R
weak nuc.
O
H
R1
weak elect.
Low Temp
OSiMe3
R1
R
However, with Lewis Acid:
OSiMe3
R
BF3-OEt2
Low Temp
O
+
H
R1
then H+
O
R
OSiR3
R1
Mukaiyama Aldol
BF3
BF3
O
H
OSiMe3
O
R1
H
R1
much stronger electrophile
Lewis acid lowers LUMO
R
R3Si
R
O+
OBF3
R1
Si
migration
O
R
OSiR3
R1
Features of Mukaiyama Aldol
1) Open TS - better Felkin control
OTMS
O
+
H
BF3-OEt2
OtBu
OH O
Cy
OtBu
Me
Me
94:6
(vs 60:40 w/ Lithium)
Cy
H
H
Nuc
O
Me
Features of Mukaiyama Aldol
2) Lewis Acid Activation of Ketals
OMe
R1
+
OMe
OSiR3
OMe
R
R1
LA
Me
O+
R1
H
+
OSiR3
R
O+ Me
LA
OMe O
R1
R
Features of Mukaiyama Aldol
3) Asymmetric Mukaiyama Aldol - many, many examples
OTMS
O
Ph
+
H
OH O
cat 1
OPh
PrOH/H2O
Me
I
Ph
Me
95:5 dr
99% ee
Kobayashi
OtBu
O
Zr
OtBu
O
I
OPh
1
See Carreira 4.4 for review of this chemistry.
Vinylogous Aldol – The Michael Rxn (1,4 addition)
OX
R
+
O
O
X
O-
O
R
O
X
1,5 carbonyls
R
Michael Reactions can be Highly Diastereoselective
O
OLi
tBuO
Me
+
Me
O
tBu
tBuO
E
Me
O
tBu
Me
anti >95:5
syn but lower selectivity
tBu
Me
Me
O
H
H
O
Li
OtBu
Heathcock JOC, 1990, 55, 157
Mannich Reaction
Aldol with Imines:
OM
R
+
N
O
R2
R1
imine often generated in situ from:
HN
R2
R1
R
O
RNH2 +
H
R
Good way to install nitrogen centers.
Many asymmetric examples.
Allyl Metallation- Alternative to Aldol
O
R
1)
+
M
H
OH
[LA]
R
BR2
allyl boranes
2)
SiR3
or
allyl silanes or stannanes
SnR3
OH
O3
R
H
O
Allyl Boranes
OH
Me
BR2
R'CHO
R'
Me
anti
(E)-crotyl borane
R'
O
R
OH
R'CHO
Me
BR2
(Z)-crotyl borane
H
B
R
H
Z
R'
Me
syn
Me
H
Allyl Silanes and Stannanes
O
R'
OH
BF3-OEt2
H
Me
SnBu3
R'
Me
major
4:1
R3Sn
O
50:1
BF3
H
R'
Both E and Z give syn.
E gives higher selectivity.
H
Me
Keck JOC, 1994, 59, 7889.
Combined Michael Aldol Reactions (Robinson Annulation)
OH
OH
Me
O
+
N
H
O
Me
O
Me
O
O
aldol
Me
O
(cat)
O
Me
O
78% ee
OH
via
N+
O
Me
Note: general phenomena = "organocatalysis"
Midterm 1
•  Average: 120 (out of 200)
•  Letter grades are advisory only.
•  Work on your arrow-pushing mechanisms!