Chem 634
Enolate Formation and Alkylation
Part 2
Announcements
John Wriston Memorial Lecture
101 Brown Laboratory
October 23, 2015, 4pm
Directing Biosynthesis with Modular Architecture in Terpenoid
Cyclases
OPO3PO33–
geranylgeranyl diphosphate
OPO3PO34–
OPO3PO33–
H
ent-copalyl diphosphate
H
taxadiene
David W. Christianson Ph.D.
University of Pennsylvania
Department of Chemistry
http://www.chem.upenn.edu/profile/david-w-christianson
**Refreshments 3:45
Terpenoid cyclases catalyze the most complex chemical reactions in biology, in that on average,
two-thirds of the carbon atoms in an isoprenoid substrate undergo changes in bonding and/
or hybridization during a multi-step cyclization cascade typically proceeding through multiple
carbocation intermediates. Although the substrate pool for these enzymes is limited to only a
handful of linear isoprenoids, more than 70,000 terpenoid natural products have been identified to date. This exquisite chemodiversity arises in part from the promiscuity of terpenoid
biosynthesis, i.e., the ability of a cyclase to generate multiple products – sometimes utilizing
different active sites that have evolved in different domains of a common protein fold. Crystal
structures of terpenoid cyclases reveal modular architectures and catalytic strategies for carbocation generation, stabilization, and manipulation. Correlation of terpenoid cyclase structures
and product arrays sets the foundation for understanding the biosynthetic code that directs
the chemistry of carbon-carbon bond formation. As we decipher this code, we enable synthetic
biology approaches for the large-scale generation of terpenoid natural products useful as pharmaceuticals, fragrances, flavorings, and fuels.
Crystal structures of taxadiene synthase and ent-copalyl diphosphate synthase reveal identical
protein folds. However, the active site of taxadiene synthase is in the α domain (blue), where it
catalyzes the metal-dependent ionization and cyclization of geranylgeranyl diphosphate; the
active site of ent-copalyl diphosphate synthase is at the interface of the β and γ domains (green
and yellow, respectively), where it catalyzes the protonation-dependent cyclization of geranylgeranyl diphosphate.
Enolate Stereochemistry
Cyclic Enolates – Substrate Control
O
OLi
Me
O
Me
LDA
EtI
Me
Et
O
vs.
Et
Me
(0.9 equiv)
Me
Me
Me
Me
Me
Me
Me
Me
Me
major
Me
Me
Me
minor
Cyclic Enolates – Substrate Control
H
Me
Me
Me
Me
OLi
t-Bu "locks" conformation
OLi
H
H Me
Me
Me
Me
Me
Me
Me Me
H
"half-chair"
OLi
Cyclic Enolates – Substrate Control
I
H
H
Me
I
:
H
t-Bu
Me
OLi
H
Me C H
t-Bu
H
HOMO
Et
t-Bu
O
Me
O
chair
"chair-like"
"axial attack"
O
H
:
t-Bu
Me
OLi
H
H
Me
I
H
t-Bu
H
Me C H
I
"boat-like"
higher in energy
O
tBu
Me
Et
twist boat
Consider Role of Steric Interaction
OLi
O
EtI
Me
Et
Me
major
=
EtI
Me
Me
H
O
Et
H LiO
EtI
EtI
Me
H
LiO
=
Me
Et
H
EtI
H
O
developing 1,3 diaxial
interaction
Exocyclic Stereocontrol
MeO
O
MeO
OLi
LDA
EtI
Me
MeO
Me
O
Et
MeO
O
Et
vs.
Me
90
Me
:
10
Exocyclic Stereocontrol
Et–I
H
H
OLi
OMe
developing 1,3
interactions
Me
H
H
Me
OLi
OMe
Et–I
transition states all that
is important!!
H
H
Me
Et
OMe
O
H O
H
OMe
Et
Me
Note GS are ~ same energy
Cyclopentanones
Prostaglandin Synthesis (Corey)
O
O[Cu]
[Cu]
R
TBSO
R'
OSnPh3
Ph3SnCl
HMPA
(in situ)
R
TBSO
R'
O
I
TBSO
(Tin most conf. stable, also Zn)
R
R
TBSO
trans
”Acyclic” Stereocontrol
Seebach-Frater alkylation
note: "anti" aldol product
LDA
OH O
Me
OEt
OH O
OH O
vs.
MeI
Me
Me
OEt
OEt
Me
Me
95
:
Me–I
Me =
H
O
Li
O Li
OEt
Me–I
favored
5
Seebach Alkylation
O
O
Ph
O
H
HO
O
O
H+
OH
tBu
LiO
LDA
tBu
O
O
Ph
MeI
O
tBu
O
tBu
O
H+
HO
Ph
Me
OH
Me
Ph
O
Chiral Auxiliaries For Controlling Alkylation Stereochemistry
Read Carreira Chapter 3
General concept:
O
R
R
O
E+
N *
LDA
N *
X
OLi
R
O
HN *
R
diastereoselective
N *
E
(high de)
remove
HN *
O
R
X
E
chiral
enantioenriched (high ee)
most common with amides
Early Examples
Ph
R
O
OMe
Al Meyers
(Acc. Chem. Res. 1978, 11, 375)
N
OH
O
R
N
D. Evans
(TL, 1980, 21, 4233)
Sonnet
(JOC, 1980, 45, 3137 )
Work Horse: Evans Oxazolidinones
O
HN
O
R
N-acyl oxazolidinone
O
Ph
R
N
X
X = Cl, etc.
Li
O
LDA
O
O
O
N
O
Ph
E+
R
O
O
R
N
O
O
E
Ph
Ph
very high de
(typically >90%)
Z only
blocks back face
HN
X , Ph
X
"hot" electrophiles only
O
O
related:
E = MeI, EtI,
HN
O
Ph
Me
cheap
"pseudo-enantiomer"
O
Me
Me
Evans JACS 1982, 104, 1737
Utilization of Products
note: other enant. of chiral auxiliary
gives other enant. of products!
O
O
R
N
O
H2O2
O
E
R
LiOH
OH
E
R
LAH
or
NaBH4
LiOBn
LiSEt
O
R
R
OH
E
O
R
E
SEt
E
OBn
Myers’ Auxiliary
Me
OH
O
N
Me
Me
LDA
R
OH
OLi
N
Me
R
(+)-pseudoephedrine
E+
cis
Me
de > 95%
OH
O
N
Me
R
Et
E = lots of 1º things!
including:
R
I
R
Andy Myers JACS, 1994, 116, 9361
Model for Stereoselection
R–X
LiO
Me
Me Me
N
H H
LiO
Ph
H
Myers JACS, 1994, 116, 9361
Reactions with Epoxides
Note: for
O
R
LiO
Me
lower face preferred
Me Me
N
H H
Ph
O H
O Li
R
Myers JACS, 1994, 116, 9361
Utilization of Myers Products
O
R
R'
R'Li
E
Me
OH
LiNH2
BH3
O
R
N
Me
E
H2SO4 or
Bu4NOH or
FeCl3
R
O
LiAlH(OEt)3
HO
R
HO
R
E
O
E
R
H
E
With Ketones
Ph
O
+
H2N
Ph
H
OMe
OMe
N
-H2O
cyclic only
Me
O
H
Li
LDA
Ph
N
Ph
Br
N
OMe
H
H2O
O
Assumed that lithium atom is highly solvated and large.
Al Meyers JACS, 1976, 98, 3032
SAMP / RAMP
OMe
N
NH2
MeO
SAMP
N
NH2
RAMP
1-amino-2-methoxymethylpyrrolidine
O
Me
SAMP
Me
N
N
Me
OMe
Me
hydrazone
OMe
Me
O3
or
Me
same face
N
Me
60 ºC, -H2O
1. LDA
2. nPrI
N
H+
O
Me
Me
Me
Model
Stereoselection model:
blocks top face
N
L
L Li
N
O
Me
Me
E+
H
Me
Enantioselective Enolate Alkylations
Tin Enolates
O
OSnBu3
Me
2.5% cat.
Me
Ph
BnBr or RX
R = MeI, BnBr, Allyl-X, etc
93% ee
tin enolate
cat.
N
N
Cr
tBu
O
tBu
O
tBu
tBu
"Cr salen"
Doyle & Jacobsen
JACS, 2005, 127, 62 / ACIE 2007, 46, 3701
Mechanism not clear
Doyle & Jacobsen
JACS, 2005, 127, 62 / ACIE 2007, 46, 3701
Nickel Enolates
S
S
O
N
R
S
(MeO)3CH
5% cat.
BF3OEt2
2,6-lutidine
cat =
O
R
N
S
MeO
OMe
Model:
(o-tolyl)2
P
OTf
Ni
P
OTf
(o-tolyl)2
Ar
Ar
P* P
Ar
Ni Ar
S
O
S
N
blocks top face
R
O
+
MeO
Me
H
D. Evans JACS, 2005, 127, 10506