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Metal catalysed asymmetric epoxidation of olefin
s
First report: chiral molybdenum peroxo complexessqualene
MoO
(acac) 2
t , 2
BuOOH
O
di-isopropyl tartrate
ee
S Otsuka
et al
,^ Tetrahedron Lett.
^1979
N
N N^
N
R^
R
R
R
Cl
ee
CO^2
Me CONH
Cl^
Cl
O
Ar^
O I
1 , toluene, 0
o^ C
J T Groves
et al
,^ J. Am. Chem. Soc.
^1983
,^^105
Iron porphyrin complexes act as mimics for cytochrome P450 enzymes
R =
Fe 1
vs.
M
Chiral centres close to metal centreSimple to prepare - substituted salicylaldehyde plus chiral diamine
N N
N
N
R* R*
R* R*
O^
N O
1 R N
1 R
2 R
3 R
3 R
2 R
Metal salen complexes as catalysts for AE reactions
M
Advantages of metal salen catalysed AE:
Relatively stable to oxidation: range of co-oxidants extended
(E N Jacobsen, T Katsuki)
Achiral metal salen catalysed epoxidations: J K Kochi
et al
,^ J. Am. Chem. Soc.
^1985
,^^107
Manganese salen catalysed asymmetric epoxidation - mechanism and stereochemistr
y
as seen on the previous slide, dialkyl substituted olefins react with retention of configuration (concerted), whereasacyclic aryl substituted olefins react with loss of geometric purity, suggesting a stepwise radical mechanism
OAc Mn
O Mn
O Mn (^1) R
2 R
O Mn (^1) R
2 R
O Mn (^1) R
2 R
1 R
2 R
O
model explains why trans/trisubstituted olefins are poorly reactive (steric hindrance in side-on approach)
alkyl substituents:
concerted
aryl substituents:
radical
O Mn Ar^
2 R
Ar^
2 R
O
O^
N O
NMn
t^ Bu
tBu
H
H^
O
L^ R
SR t^ Bu
t^ Bu
electron rich olefins are most selective, because their transition state is further along the reaction coordinate
Jacobsen,
J. Am. Chem. Soc
.,^1998
,^^120
Tetrahedron
,^1994
,^^50
Process-scale application of manganese salen catalysed asymmetric epoxidation
O
C^ F^2
5
O
CF^2
5
O
O
CF^2
5
OH
N^
O
No additive, x = 1:
Isoquinoline-
N -oxide, x = 0.2:
2-piperidoneKO
t Bu
SB potassiumchannel activator
x mol% cat., NaOCl
Tetrahedron Lett.,
^1996
,^^37
, 3895; increase in rate/selectivity of epoxidations with
N -oxide additives: Jacobsen,
Tetrahedron,
^1994
,^^50
additive
ee , 12 h, quant. 95%
ee , 2 h, quant.
Asymmetric Epoxide Ring Opening
•^
Asymmetric ring opening of racemic terminal epoxides
O
R
O
R^
R^
Nu
HO
kinetic resolution
•^
Desymmetrization of meso-epoxides
O^
HO
Nu
Catalytic asymmetric ring-opening of meso-epoxides
Asymmetrically substituted
cis
-epoxides are achiral compounds with a meso-plane of symmetry: opening at either
carbon produces enantiomeric products. A range of catalysts have been applied to this problem:
azide as nucleophile
1
O O
2% cat-
1a, TMS-N
3
EtO, r.t.^2
O
HO
N^3
ee
halide as nucleophile
(^2)
O
E^
E
OTMS Br
5% cat-
2 , TMS-N
3
(NB allyl azide by-product!)
E = CO
Et 2
allyl bromide
ee
O
TBSO
TBSO
OH tSBu
10% cat-
t^3 , BuSH
4 Å sieves, toluene, r.t.
ee
thiol as nucleophile
3
Ph^
Ph O^
Ph^
Ph HO
OCOPh
ee
benzoate as nucleophile
4
5% cat-
ent
- 1b
, r.t.
phenolate as nucleophile
5
O
20% cat-
3 , ArOH
4 Å sieves, toluene, r.t.
70%87%^
ee
OH OAr
Ar = 4-MeO-Ph
cyanide as nucleophile
6
N O
10% cat
4 , TMSCN
CHCl
oC, 7 days!
N
NC
OTMS
ee
COCF
3
COCF
3
see next slide for catalyst structures and references
Kinetic resolution of racemic epoxides by catalytic asymmetric ring-openin
g
Meso-epoxides are necessarily a small subset of all possible epoxides. Broader applicability needs a wider rangeof substrates - but these will all be chiral. Since terminal epoxides are very cheap, a resolution process is viable:
Reviews of asymmetric epoxide ring opening (meso- and resolution modes):
Acc. Chem. Res
.,^2000
,^^33
Tetrahedron
,^1996
,^^52
Cl^
O
reactions can be run neat; now 1000kg process (Chirex)
0.25 mol% cat-
1b
0.7 eq. H
O, DCM, r.t 2
Cl^
O^
Cl
OH
OH
ee
ee
Jacobsen,
Science
,^1997
,^^277
J. Org. Chem
.,^1998
,^^63
, 6776; Tetrahedron Lett.,
,^^40
polymer-supported catalyst:
J. Am. Chem. Soc
.,^1999
,^^121
other nucleophiles can also be used: BocHN
volatile - distilled
water soluble
OH
C^ H^4
9
O
2.2 eq.
4% cat-
1b TBME, r.t.
BocHN
O^
C^ H^4
9 OH
ee
Jacobsen,
J. Am. Chem. Soc.
,^1999
,^^121
also with azide:
J. Am. Chem. Soc.
,^1996
,^^118
Mechanism
Jacobsen
J. Am. Chem. Soc
.^1996
,^^118
•^
Catalyst
activates both nucleophile and electrophile
CrCl
Cr N^3
N^3 Cr O
O Cr N
3
Cr
O^
N^3
Cr
O^
N^3
•^
Tethered dimeric salens give increased rates:
J. Am. Chem. Soc
.^1998
,^^120
Evolution of Asymmetric Dihydroxylation
Pyridine, tertiary amines accelerates dihydroxylation by OsO
-^
Chiral pyridines (Sharpless 1979): poor affinity for OsO
4
•^
Chiral diamines: bind too tightly to OsO
, forming stable chelates - so cannot be used 4
catalytically
(but can give
excellent enantioselectivities)
NMe
2 NMe
2
Ph^
Ph NH^
HN
N^
N
Ar
Ar
Ar
Ar
NR^
NR
H H
Snyder
Corey
Tomioka
(R = neohexyl)
Hirama
Quinidine / quinuclidine derivatives.....
Et
N
OR
H
H N
MeO
H
H N
OMe N
Et RO
O
Cl
DHQ
DHQD
R = H, CLB
R = H, CLB
CLB =
Sharpless:
Good ee obtained using NMO co-oxidant (Upjohn) system. But…..ee often lower for catalytic reaction than stoichiometric.Mechanistic studies showed this to be due to a two-cycle catalytic mechanism……
Catalytic Cycles for Cis-Dihydroxylation
O OsO O^
O
O OsNR
O 3
O O
R^
R
OsNR
3 O O^
O
O^
R
R HO 2 R^
R
OH
OH
OsNR
3 O O^
OH
OH
OOsO^ O
O
O^
R
R R^
R
O OsO^
O O O
R R
R R
R^
R
OH
OH
Os O
O
O^
R
R
NR
co-oxidant
co-oxidant- NR
first cycle
highly enantioselective
second cycle
low enantioselectivity
HO^2 HOHO
co-oxidant
To avoid second cycle: With NMO acetone/water system, add alkene slowly (inconvenient) Better: use biphasic (
tBuOH/H
O), ferricyanide co-oxidant system: co-oxidant is in different phase to osmate ester, thus 2
preventing second cycle
Structural effects in asymmetric dihydroxylation reaction
s
trans-disubstituted olefins
(all reactions shown carried out with (DHQD)
-PHAL; figure in parentheses is 2
ee
cis-disubstituted olefins
Ph^
Ph OH
OH
Ph^
CO
Me 2
OH
OH
C^ H^4
OH 9
OH
Cl
HO^ Ph
OH
trisubstituted olefins HO
OH
tetrasubstituted olefins
HO
OH
1,1-disubstituted olefins
Ph
OH
OH
TBDPSO
OH OH
OH
OH
terminal olefins*
C^ H^6
17 Ph
Ph
OH
OH OH
OH
OH
OH
MeO
* - an alternative anthraquinone-derived spacer offers superior ee's for terminal olefins and those bearing onlyalkyl substituents. See
Angew. Chem., Int. Ed. Engl
.,^1996
,^^35
R^
R'^
R^
R'
OH
OH
O^
O OMe R^
R'
O^
O
R^
R'
R^
R'
OAc
X
R^
R'
OAc Br
R^
R'
O
Epox
ides
vi
a cata
lyt
ic asymmetr
ic d
ihydroxy
lat
ion
X^ +
K B Sharpless
et al
,^ Tetrahedron
, 1^9
^48
AD-mix
α^ or
β
ee K CO 2
MeC(OMe) , MeOH 3
3
TMSClor TMSBr
Yield 83-98% over 2 steps(no chromatography)
