The AD Catalytic Cycle

1
The AD Catalytic Cycle
Chem. Rev. 1994, 94, 2483-2547
2
Shutting Down the Secondary Cycle
3
The Cinchona Alkaloids
(DHQ)2PHAL AD-a
4
The AD-Mix Mnemonic

• Works best for
• trans alkenes
• terminal olefins quite bad
• with aromatic ring to sit in
• attractive area

5
Which Ligand System?
6
Racemic Dihydroxylation Beyond Upjohn
Upjohn (NMO, OsO4) can be slow prone to
over-oxidation
J. Eames, H. Mitchell, A. Nelson, P. OBrien, S.
Warren, P. Wyatt, Perkin 1 1999, p1095
7
Sharpless Asymmetric Aminohydroxylation (AA)
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Sharpless Asymmetric Aminohydroxylation (AA)
Sharpless et al. Angew. Int. 1997 438
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AA Mechanism
Review McLeod et al, Perkin 1, 2002, 2733
10
AA Standard Conditions?
Review P. OBrien, Angew. Int, 1999, 326
11
Competing Dihydroxylation

• First turnover of catalyse is AD
• Can reduce AD with slow addition of substrate

12
AA Best Substrates
Cinnamates best using (DHQ)2PHAL (as
drawn) (DHQ)2AQN (regioisomer)
a,b-unsatd (DHQ)2PHAL (as drawn) effect ligand
unknown
13
AA More Substrates

• Styrenes, a,b-unsatd esters vinyl arenes only
  work with acetamide carbamate
• Other egs where DHQ vs DHQD give regioisomers in
  similar ee of opposite stereoinduction!

14
Sharpless Aminohydroxylation Further Work

• a,b-unsatd 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)

15
Other Aminhydroxylations - TA
Tethered Aminohydroxylation (TA)

• Stereochemistry comes from allylic alcohol
• Stereoinduction requires cyclic system

Donohoe et al, JACS 2002, 12934
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Tethered Aminohydroxylation
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Tethered Aminohydroxylation - Mechanism
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Diamination to Conjugated Dienes
(1) disfavour 3 (2) favour Nu addn to give
diamine (3) amine souce that wont react with
other species
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Question Time Predict the Products
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Diamination Initial Results

• Conditions are modified Wacker conditions
• - Regioselectivity of first complexation
• Unsymmetric ureas (solubility also a problem)
• needs chloride Pd pre-catalyst

21
Question Time Wacker Oxidation
22
Diamination Further Results

• Benzoquinone (method A) is superior oxidant
• best for symmetric dienes

23
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
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Enatioselective Diboronation of Olefins
Morken et al, JOC 2005 9538
25
Carbohyroxyltion of Olefins
One-pot diboronation-Suzuki cross coupling
Morken et al, Org. Lett. 2004, 131
26
Diboronation Mechanism
27
Regioselective Aminoacetoxylation

• Racemic addition
• Requires adjacent ether in substrate
• Interesting IIII reagent oxidises Pd-C bond

Stahl et al, JACS 2006, 7179
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Regioselective Aminoacetoxylation
29
Hydroxysulfenation
30
Hydroxysulfenation

• R1 Ar, alk
• R1R2 c-hex, Ar
• R3 Ar, Cy
• Complete diastereoselectivity
• can also replace S-Ar with Si-iPr, SePh SnBu

Taniguchi, JACS 2006, 7876
31
Hydroxysulfenation
32
Hydroxysulfenation