Chem 634 Fall 2013
Alkene Synthesis and Oxidation
Prof. Donald Watson
"
Assistant Professor"
"
"
Alkene Synthesis Methods Already Discussed
1) E1 and E2 - Can be used, but often results in poor selectivity.
2) Aldol Condensations
O
R
Me
+
O
H
H+
R1
O
R
R1
3) Cross-Coupling Reactions (i.e. Heck/Suzuki/Stille)
4) Seguza, Selenium oxidations
Alkene Synthesis from Carbonyl Substrates
Wittig Reaction – Non-Stabilized Ylides
H
R
X
X= Br, I
R
base
PPh3
R
PPh3
•  If R can not conjugate ylide = non-stabilized ylide.
•  These generally cannot be isolated and are generated in situ.
Wittig Reaction – Non-Stabilized Ylides
General Reaction:
O
PPh3
R2
H
PPh3
R2
H
R'
H
Ph3P O
R2
Ph3P O
Ph3P O
R'
may be
intermediate or
transition state
R2
+
R'
R2
R'
alkene + PPh3O
What about stereochemistry of alkene and intermediates?
Vedejs, JACS, 1988, 110, 3940
Vedejs, JACS, 1988, 110, 3948
Wittig Reaction – Non-Stabilized Ylides
Augment: For non-stablized ylides, as they are reactive, there is an early TS where CC bond formation proceeds P-O bond formation.
Need to be gauche
Need to be gauche
Ph3P
Ph3P O
R2
O
vs.
C
R'
R2
R2
R'
R'
H
(trans)
-Ph3PO
R'
R2
H
H
favored
O PPh3
R2
PPh3
C
H
disfavored
R'
O
O PPh3
R'
R2
-Ph3PO
R2
R'
(cis)
Vedejs, JACS, 1988, 110, 3940
Vedejs, JACS, 1988, 110, 3948
Wittig Reaction – Non-Stabilized Ylides
Example:
:B
H
Me
H
Me
Me
O
Bu
PPh3
KHMDS
Me
Me
Bu
88%
Me
High (Z) selectivity w/ K+ or Na+
(Rough, TL, 1997, 38, 8785)
Rough, TL, 1997, 38, 8785
Wittig Reaction – Stabilized Ylides
Conjugating groups stabilize ylide:
R
O
PPh3, base
O
X
O
PPh3
R
R
PPh3
stablized ylide
•  These reagents are often isolatable.
Other examples:
O
RO
PPh3
etc.
•  Basic mechanism is the same as for non-stabilized ylides, but with one
significant difference.
Wittig Reaction – Stabilized Ylides
Argument: Because ylide is less reactive, transition state is later, allowing for
more fully developed P–O bond. This leads to eclipsed transition states
where C–C and P–O bond formation is more concerted.
Need to be eclipsed
Need to be eclipsed
Ph3P
O
O
vs.
C
R2
H
R'
H
C
R2
R'
H
H
disfavored
favored
O PPh3
R'
R2
(trans)
-Ph3PO
R'
PPh3
R2
O PPh3
R'
R2
-Ph3PO
R2
R'
(cis)
Vedejs, JACS, 1988, 110, 3940
Vedejs, JACS, 1988, 110, 3948
Wittig Reaction – Stabilized Ylides
Examples:
O
RO
OMe
Ph3P
RO
O
H
O
OMe
70%
Bio Org. Med. Chem. Lett, 2000,10, 2101
Also works with more substitution (depending on size of groups).
Me
OTBSH
TBSO
O
MeO2C
OTBS
PPh3
TBSO
CO2Me
Me
trans
Horner-Wadsworth-Emmons (HWE)
O
P
RO
RO
R' +
O
R2
H
(R'= CO2R, COR, CN, vinyl, aryl, not allyl)
(R= Me, Et, etc.)
R2
R'
(E)
O
+ RO P O
RO
(water soluble)
Two reason for HWE over Standard Wittig:
•
Water soluble byproduct
•
Better reactivity
Horner-Wadsworth-Emmons (HWE)
Preparation of Reagents (Arbuzou Reaction):
P(OMe)3
R'
Br
R'
OMe
OMe
P
O
-MeBr
Br
Me
OMe
OMe M+B–
R'
P
O
- BH
H
isolated
R'
OMe
OMe
P
M+
O
deprotonation usually
done in situ
Horner-Wadsworth-Emmons (HWE)
MeO
MeO
NaH (or similar);
then RCHO
O
P
O
MeO
MeO
CO2R
Stereochemical
Model:
O
P
Na+
CO2R
Na+
MeO OMe
O P
O
MeO OMe
O P
O
+
RO2C
R
cyclization
fast (RDS)
RO2C
(E)
favored
H
highly stablized anion
RO2C
R
R
MeO OMe Na+
P O
O
O
–
MeO P ONaRO2C
MeO
R
Na+
less stable anions
R
slow
Na+
MeO OMe
P O
O
RO2C
R
developing steric
interactions
O
–
MeO P ONa
MeO
RO2C
R
(Z)
Ando JOC, 1999, 64, 6815
Still-Genarri
Consider Intermediates more closely, which is more kinetically accessible?
O
(RO)2P
O
E
E
C
R
R
R
H
H
H
RO2C
O
P(OR)2
C
vs
H
MeO OMe
O P
O
O
Na+
vs
MeO OMe
O P
O
RO2C
Na+
R
kinetically favored
TL 1983, 24, 4405
Still-Genarri
So if we can make k1 the rate determining step (by making k3 >> k-1),
we can the trans intermediate become irrelevant.
RO
RO
O
P
O
KHMSD (or similar);
then RCHO
RO
RO
CO2R
K+
R
K+
RO OR
O P
O
+
RO2C
R
H
k1
k-1
CO2R
RO OR
O P
O
RO2C
O
P
K+
R
kinetically favored
k2
R
RO2C
(E)
O
–
RO P OK
RO
RO OR
P O
O
RO2C
k3
K+
R
K+
RO OR
P O
O
RO2C
R
O
–
RO P OK
RO
RO2C
(Z)
favored
R
Still-Genarri
O
O
P
F3CH2CO
OR
OCH2CF3
O
R'
O
O
H
KHMDS
18-C-6
O
R'
O
O
K+
CO2R
O
(Z)
4:1
O
O
O
O
O
O
18-crown-6
K·18-crown-6+
50:1
more nucleophilic
K•18-C-6+
E
O
R
O
P(OCH2CF3)2
F3CH2CO OCH CF
2
3
O P
O
RO2C
H
fast
F3CH2CO OCH2CF3
P O
O
R
RO2C
R
H
more electrophlic
•
•
•
potassium has low oxygen affinity
make even lower with crown-ether
CF3 groups on phosphanite make P more electronegative
TL 1983, 24, 4405
Ando Modification of Still-Genarri
O
O
Also gives (Z) alkene
P
OR
PhO
OPh
EWG
Ando JOC, 1998, 63, 8411
Still-Genarri
Example:
R
O
O
O
R
P
O
(OCH2CF3)2
R'CHO
KHMDS, 18-C-6
-100°C
R
O
O
O
R
R'
7:1 (Z:E)
Julia-Lythgoe Reaction
BuLi
R'
R'
SO2Ph
SO2Ph
R2CHO
R'
SO2Ph
R2
OH
O
Me
Cl
R'
SO2Ph
R2
OAc
Na/Hg
(e- reduction)
-SO2, Ph–
R'
R2
OAc
R'
R2
(E)
•  Will discuss mech of Na/Hg when we talk about Birch reduction.
•  This process requires 3 steps
•  Also Na/Hg is very harsh!
Modified Julia
N
R
HO
SH
S
DIAD, PPh3
N
S
S
O O
R
mCPBA
N
S
S
R
KHMDS
tol., R'CHO
R'
R
(E)
TL 1991, 32, 1175
Modified Julia
O
S
S
O O
S
R
S
O O
R'
R
R'
R'
R'
O
O
R
N
S
H
N
KHMDS
N
S
O
O
O
R
N
S
O
O
S
R
N
S
S
O
O
N
-SO2
OH
S
R
R'
(E)
TL 1991, 32, 1175
Synlett 1998, 26
Peterson Olefination
R'
Li
TMS
H+
OLi
RCHO
then
H+
SiMe3
R
R'
OH
SiMe3
R
R'
R
R'
TMSOH
usually poor E/Z selectivity
Organometallic Methods for Alkene Synthesis
Tebbe and Petasis Reagents
Cp
Cp Ti
Cl Al Me
Me
Cp2Ti CH2
-AlMe2Cl
Tebbe Reagent
Cp2Ti
-MeH
O
Me
Me
Petasis Reagent
O
O
O
R
OR'
O
R
Cp2Ti
CH2
+
O
CR2
[2+2]
Cp2Ti
H2C
OR'
O
CR2
retro
[2+2]
Cp2Ti
H2C
O
+
CR2
JACS 1978, 100, 3611
JACS 1980, 102, 3275
JOC 1985, 50, 2386
Takai Olefination
H
R
CrCl2
O
CHX3
R
X
X= Cl, Br, I
(E) - major
Takai JACS 1986, 108, 7408
Example:
CHO
O
O
Si
R R
CrCl2
CHI3
I
O
O
Si
R R
E/Z = 6:1
JACS 2000, 122, 11090
Via Enol Triflates
O
R
OTf
Tf2O
Et3N
Pd0, R3SnH
R
H
R
Stille, Suzuki, etc.
Olefin Metathesis
NAr
Mo
RO
OR
Schrock Catalyst (MIT)
L
Cl
Ru
Cl
PCy3 R' R'= Ph, etc.
Grubbs Catalyst (Cal Tech)
Schrock, Grubbs, and Chauvin Nobel 2005
L=
R
N R
N
GII
or
PCy3
GI
General Mechanism
M
R
R''
R'
2+2
M
R
R''
M
R'
R
R''
R'
“Chauvin Mechanism”
Note: Katz, Casey, & Ziegler also made important early contributions
Ring Closing Metathesis
BOC
GII
BOC N
O
R3SiO
Bn
OBn
H2C CH2 (Gas evolution)
O
N
O
N
OTBS
GI
0.005M
O
O
NR2
Bn
JACS 1999, 121, 5653 (Crimmins)
Alkene Oxidation
Epoxidations - Preacids
O
H
H
R
R
Cl
O
mCPBA
H
R
O
H
R
mCPBA
R
O
H
H
R
O
O
H
R
super facial addition
OH
Relative Rates
>
Rel. Rates:
>
>
Nuc
Me
mCPBA
Me
Me O
Me
Me
Me
Directed Epoxidations
OH
OH
mCPBA
O
Ar
O
syn 10:1
H
O
O
H
O
Compare:
OAc
OAc
mCPBA
O
trans 4:1
JCS 1957, 1958
Acylic Stereocontrol
R
OH
H
mCPBA
Me
R
O
OH
H
OH
Me
H
H
Me
H
vs.
R
Me
R
H
OH
mCPBA
mCPBA
OH
H
Me
O
O
R
Me
H
favored
OH
R
Vanadyl Acetylacetonate
Me
O
VO(acac)2
O
O
V
Me
O
O
Me
Me
Me
Me
Me
Vo(acac)2
OH
Me
Me
OH
Me
tBuOOH
O
Vanadyl Acetylacetonate
-OH directed; Relative Rates
OH
vs.
200
:
1
OR
O V O
O
O
[V]
O
O
General Review on substrate directed reactions:
Evans, Hoveyda, Fu Chem. Rev. 1993, 93, 130
Dimethyldioxirane (DMSO)
HO
O
Me
O
O
S
OK
O O
O
Me
Me
R1
R2
O R2
R1
Me
dioxirane
(co-distill with acetone)
H
O
O
OK
Me
O
S
Me
O O
Review: Denmark, Synlett, 1999, 847
Sharpless Asymmetric Epoxidation (SAE)
tBuOOH
Ti(OiPr)4
R
OH
trans best allylic
alcohol required
HO
CO2Et
HO
CO2Et
3Å MS, -20°C
diethyl tartrate
Sharpless Nobel 2001
R
OH
O
60-90%
90 to >98% ee
Jacobsen- Katsuki Epoxidation
O
cat. 1
R1
R2
NaOCl
R1
N
R2
N
Mn
t-Bu
O
>95% ee
Cl
t-Bu
O
t-Bu
t-Bu
1
Works best for cis alkenes, with R1 = Ar.
Jacobsen, JACS, 1990, 112, 2801
Shi Epoxidation
from fuctose
Me
Me
R2
R3
R1
di or tri-sub alkenes
O
O
O
O
Me
O
Me
KHSO5
(cat)
R2
R3
R1 O
>95% ee
JACS, 1997, 119, 11224
Ozonolysis
Me
Me
O
O3
then PPh3
or Me2S
Me
Me
O
Me
H
Me
Mechanism:
O
Me
Me
O
O
O
Me
Me
Me
Me
O O
Me
Me
O
O
O
Me
Me
Me
Me
PR3
Me
ozonide
O
O
O
Me
+
Me
Me
Me
O
Me
Me
carbonyl oxide
Me
O
PPh3O
Modifications
O3
then NaBH4
OH
OH
O
O3
MeOH, TsOH MeO
then Ac2O,
OMe
Et3N
steps
OMe
H
OMe
OMe
O
OMe
OH
R
O
B
OMe
OAc
Schreiber TL 1982, 23, 3867
Dihydroxylation
OH
OsO4 (cat)
K3Fe(CN)6
tBuOH/H O
2
O O
Os
O O
3+2
Sharpless Nobel 2001
O
Os
O
O
O
H2O
(+/-)
OH
OH
OH
O
Os
O
HO
HO
ox.
OsO4
Sharpless JOC 1990, 55, 766
Sharpless Asymmetric Dihydroxylation (SAD)
(DHQD)2PHAL (1%)
O
Bu
OEt
K3Os2(OH)4 0.2%
K3Fe(CN)6
K2CO3
tBuOH/H O
2
OH O
Bu
OEt
OH
active catalyst
O
O
*
R3N Os
O
O
alpha face (DHQD)
>95% ee
Rs
RL
OMe
"pseudo enantiomers"
Et
OR
vs. H
N
N
R= H, DHDQ
$, dihydroquinidine
Et
OMe
OR
N N
Rm
H
beta face (DHQ)
R=
N
N
R= H, DHQ
$, dihydroquinine
(DHQD)2PHAL
(DHQ)2PHAL
Chem Rev 1994, 94, 2483
Electrophilic Reactions
Dibromination:
Me
Me
Me
Me
Br2
Br
Me
Me
Me
Me
Me
Br
OH
Br
Me
Br Me
Me
Br
Hydroxybromination:
Br2
R
DMSO
H2O
R
Br
R
OH2
Stereoselectivity
Me
Br
Br2
Me
Me
Me
Br
Me >94:6
Me
Br
H
Br
vs.
H
Br
Br
H
both axial
H
Iodolactonization
OH
R
O
I2, KI
NaHCO3
RO
H
O
O H
B
R
H
I
H
O
I
H
Wacker Oxidation
Pd(II) = electrophilic
O
PdCl2 (cat)
R
H2O, CuCl2 (cat)
O2
R
OH
PdCl2
R
PdCl2
R
PdCl
B-H
H2O
Cl
PdII
H
CuCl
- HCl
O2
Pd(0)
Cu(II)Cl2
Cl
H
HO H
R
Pd
2 Cu(II)Cl2
- CuCl
PdCl2
Rubottom Oxidation
R3Si
OTBS
m-CPBA
O
O
O
OSiR3
next oxidation
α to ketone
Allylic Oxidation
O
R
R-
R
OH
CrO3
O
Via
R
OH
O Cr O
O
R
H
B
O Cr
Allylic Oxidation
O
OH
SeO2
+
or
SeO2 + t-BuOOH
(cat)
Sharpless JACS, 1973, 95, 7917
O
Se
O
O
H
OH
O
Me
Me
Me
t-BuOOH
-SeO2
Me
O
Me
Me
Me
Se
Se
Se
"ene"
Me
HO
H O
H
2nd Oxidation
Me
OH
Me
Me
O
Me