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The AD Catalytic Cycle
R
R
R
H2O
high e.e.
HO
R
OH
Os(VIII)
C
O
O Os O
O
O
O
O Os O
Os(VIII) O
Primary
Cycle
L*
B
R
[O]
L*
A
Secondary
R
Cycle
R
R
O
R
R
R
R
Os(VI)
L*
R
O
Os O
O
L* Os(VI)
H2O
R
R
O
O
Os O
O
O
R
low e.e.
HO
Chem. Rev. 1994, 94, 2483-2547
Sean Parris, Olefin Bisfunctionalisation
OH
Shutting Down the Secondary Cycle
R
R
R
O
+ L*
O
Os O
O
L* Os(VI)
R
R
R
+ L*
HO
O
OH
O Os O
O
Os(VIII)
Organic Phase
Aqueous Phase
O
2 OH
2 H2O
2
HO Os OH
HO
OH
O
Os(VI)
O
2
HO Os O
HO
O
O
Os(VIII)
2 OH
3
2 Fe(CN)6
Sean Parris, Olefin Bisfunctionalisation
2 H2O 4
2 Fe(CN)6
2 OH
The Cinchona Alkaloids
(DHQ)2PHAL
“AD-a”
Sean Parris, Olefin Bisfunctionalisation
The AD-Mix Mnemonic
Works best for:
• trans alkenes
• terminal olefins quite bad
• with aromatic ring to sit in
“attractive area”
Sean Parris, Olefin Bisfunctionalisation
Which Ligand System?
Sean Parris, Olefin Bisfunctionalisation
Racemic Dihydroxylation – Beyond Upjohn
Upjohn (NMO, OsO4) can be slow & prone to
over-oxidation
J. Eames, H. Mitchell, A. Nelson, P. O’Brien, S. Warren, P. Wyatt, Perkin 1 1999, p1095
Sean Parris, Olefin Bisfunctionalisation
Sharpless Asymmetric Aminohydroxylation (AA)
Sean Parris, Olefin Bisfunctionalisation
Sharpless Asymmetric Aminohydroxylation (AA)
Sharpless et al. Angew. Int. 1997 438
Sean Parris, Olefin Bisfunctionalisation
AA –Mechanism
Review: McLeod et al, Perkin 1, 2002, 2733
Sean Parris, Olefin Bisfunctionalisation
AA – Standard Conditions?
Review: P. O’Brien, Angew. Int, 1999, 326
Sean Parris, Olefin Bisfunctionalisation
Competing Dihydroxylation
• First turnover of catalyse is AD
• Can reduce AD with slow addition of substrate
Sean Parris, Olefin Bisfunctionalisation
AA – Best Substrates
Cinnamates best using
(DHQ)2PHAL (as drawn)
(DHQ)2AQN (regioisomer)
a,b-unsat’d
(DHQ)2PHAL (as drawn)
effect ligand unknown
Sean Parris, Olefin Bisfunctionalisation
AA – More Substrates
-Styrenes, a,b-unsat’d esters & vinyl arenes only work with
acetamide & carbamate
- Other egs where DHQ vs DHQD give regioisomers in similar
ee of opposite stereoinduction!
Sean Parris, Olefin Bisfunctionalisation
Sharpless Aminohydroxylation – Further Work

a,b-unsat’d amides & carboxylic acids found to be good substrates
for a racemic AH (Angew. 1997, p2751; Angew. 2001 3455) because
exist solely in “secondary cycle”

Start to develop a AA using the secondary cycle only which places
far more stringent requirements on the ligand, with only partial
success: 50-70% ee for AD, 25-60% ee for AA (Angew. 2002, 474)

Muniz et al got around the problem of a racemic AH for
acrylamindes by using chiral substrate (Tet. Asymm. 2005, 3492)

Hergenrother et al found could change regioselectivity in AA of
styrenes by controlling pH with modest ee (Org. Let. 2003, 281)
Sean Parris, Olefin Bisfunctionalisation
Other Aminhydroxylations - TA
Tethered Aminohydroxylation (TA)
• Stereochemistry comes from allylic alcohol
• Stereoinduction requires cyclic system
Donohoe et al, JACS 2002, 12934
Sean Parris, Olefin Bisfunctionalisation
Tethered Aminohydroxylation
Sean Parris, Olefin Bisfunctionalisation
Tethered Aminohydroxylation - Mechanism
Sean Parris, Olefin Bisfunctionalisation
Diamination to Conjugated Dienes
(1) disfavour 3 (2) favour Nu addn to give diamine
(3) amine souce that won’t react with other species
Sean Parris, Olefin Bisfunctionalisation
Question Time – Predict the Products
O
R
N
H
N
H
2 Products
R
Sean Parris, Olefin Bisfunctionalisation
Diamination – Initial Results
Conditions are modified Wacker conditions
- Regioselectivity of first complexation
- Unsymmetric ureas (solubility also a problem)
- needs chloride Pd pre-catalyst
Sean Parris, Olefin Bisfunctionalisation
Question Time – Wacker Oxidation
O
PdCl2, CuCl2
R
H2O, O2
Sean Parris, Olefin Bisfunctionalisation
R
Diamination – Further Results
- Benzoquinone (method A) is
superior oxidant
- best for symmetric dienes
Sean Parris, Olefin Bisfunctionalisation
Enatioselective Diboronation of Olefins
50-98%
50-96% ee
• Works for terminal & di-substiuted alkene, not tri subst
• Works best for trans alkenes
• Tolerates protected alcohols
Morken et al, JACS 2003, 8702; JOC 2005 9538
Sean Parris, Olefin Bisfunctionalisation
Enatioselective Diboronation of Olefins
Morken et al, JOC 2005 9538
Sean Parris, Olefin Bisfunctionalisation
Carbohyroxyltion of Olefins
One-pot diboronation-Suzuki cross coupling
Morken et al, Org. Lett. 2004, 131
Sean Parris, Olefin Bisfunctionalisation
Diboronation Mechanism
Sean Parris, Olefin Bisfunctionalisation
Regioselective Aminoacetoxylation
• Racemic addition
• Requires adjacent ether in substrate
• Interesting IIII reagent oxidises Pd-C bond…
Stahl et al, JACS 2006, 7179
Sean Parris, Olefin Bisfunctionalisation
Regioselective Aminoacetoxylation
Sean Parris, Olefin Bisfunctionalisation
Hydroxysulfenation
AcO
Sean Parris, Olefin Bisfunctionalisation
SR
Hydroxysulfenation
• R1 = Ar, alk
• R1=R2 = c-hex, Ar
• R3 = Ar, Cy
• Complete diastereoselectivity
• can also replace S-Ar with Si-iPr, SePh & SnBu
Taniguchi, JACS 2006, 7876
Sean Parris, Olefin Bisfunctionalisation
Hydroxysulfenation
Sean Parris, Olefin Bisfunctionalisation
Hydroxysulfenation
Sean Parris, Olefin Bisfunctionalisation