Functional Group Transformations

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Functional Group Transformations
Chem 313Spring Semester 2009
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Oxidation Reactions
1. Use of Cr(VI)-based reagents CrO3, H2CrO4,
Cr2O72-, CrO3/acetone ....
pyridine-chromium trioxide
pyridinium chlorochromate (PCC)
pyridinium dichromate (PDC)

• CrO3 etc./H2O/H in aqueous solvents RCH2OH ?
  RCOOH RCHOHR' ? RCOR'
• CrO3-pyridine reagents in organic solvents
  (usually CH2Cl2) v. good for RCH2OH ? RCHO,
  especially PDC
• PDC in DMF RCH2OH ? RCOOH

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Oxidation Cr(VI) Reagents
Many examples from CHEM 111, synthetic
laboratory etc.!

• pyridine-based Cr reagents oxidation of alcohols
  containing acid-sensitive groups.

Mechanism complicated overall
stoichiometry 2Cr(VI) 3RCHOHR' ? 2Cr(III)
3RCOR' 6H
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Cr(VI) Reagents Mechanism (cont.)
i. H2CrO4 via formation of chromate ester from
alcohol
then Cr(IV) RCHOHR ? Cr(II) RCOR Cr(II)
Cr(VI) ? Cr(III) Cr(V) Cr(V) RCHOHR ?
Cr(III) RCOR
via corresponding Cr(IV) and Cr(V) esters!
ii. for pyridine-based reagents, possible
abstraction of proton by base from activated
ester
Compare with E2 reaction!
Problem with use of Cr-based oxidants toxicity
and environmental hazard of Cr on industrial
scale!
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Non-metallic Reagents Dess-Martin Oxidation
- Rely on conversion of 1, 2 alcohol into
activated ester followed by elimination!
a. Dess-Martin Periodinane
Preparation
Oxidation of I(1) to I(V), then
esterification/ nucleophilic addition!
IBX Iodoxybenzoic acid
Example
98

• Relies on oxidizing power of I(V).
• Very easy to carry out.
• By-product from oxidant is very easily removed
  and recycled!

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Dess-Martin Oxidation - Mechanism

• Alcohol is activated by attachment of redox
  active leaving group by SN reaction on I(V)!

• Activated alcohol has been detected.
• Reduction of I(V) to I(III).
• Decomposition pathway of ester to ketone unknown.

Reduction product is recycled!
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Swern Oxidation
DMSO-(COCl)2

• Oxalyl chloride DMSO (lt-30 C)
• alcohol (lt-30 C)
• 3 amine

• Very easy reaction to carry out
• By-products easily removed
• however, 1st and 2nd steps require low
  temperature (usually lt -30 C)

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Swern Oxidation - Mechanism
Key step is activation of DMSO by oxalyl chloride
i. activation of DMSO
formation of chlorosulfonium salt
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Swern Oxidation Mechanism (cont.)
ii. Activation of alcohol by conversion of
leaving group to O atom
The activated alcohol is unstable above 30 C
therefore add alcohol to chlorosulfonium salt
below this temperature!
iii. Elimination
The activated alcohol unstable above 30 C
therefore add base below this temperature!
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Swern Oxidation Related Reactions
DMSO-Trifluoroacetic anhydride (TFAA)

• trifluoroacetic anhydride DMSO (lt-30 C)
• alcohol (lt-30 C), then to room temperature.

Mechanism Key step is activation of DMSO by TFAA
i. activation of DMSO
ii. and iii. as for Swern CF3COO- acts as base
to convert active ester into ketone!
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Swern Oxidation Related Reactions (cont.)
DMSO-DCC

• Dicyclohexylcarbodiimide (DCC) DMSO (0 C -room
  temperature) together with alcohol and catalytic
  protic acid

Mechanism Key step is activation of DMSO by
DCC/H
i. activation of DMSO
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DMSO-DCC Oxidation Mechanism (cont.)
ii. formation of active ester
dicyclohexylurea

• Dicyclohexylurea by-product difficult to remove
• activated alcohol is sulfoxonium derivative

iii. elimination

• Other bases in reaction mixture may also be
  effective (e.g. DCC
• -OCOCF3 etc. )

DCC widely used in peptide coupling, other
reactions!
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Epoxidation of Alkenes Use of Peracids
a. Peracids - usually m-chloroperbenzoic acid
(m-CPBA)

• transfer of non-carboxyl O

• Stereochemistry
• Geometry of double bond 'preserved' in epoxide
  completely stereoselective!
• presence of adjacent -OH (or other H-bond donor
  group) in 5- or 6-membered ring induces
  epoxidation on 'same side'
• otherwise, epoxidation from least-hindered face

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Peracid Epoxidation of Alkenes Mechanism
'butterfly' TS

• 'concerted' reaction no intermediates!
• completely stereoselective with respect to alkene
  geometry

• electronic effects
• more highly-substituted alkenes epoxidized more
  rapidly
• does not react with electrophilic ('electron
  deficient') alkenes

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Epoxidation of Electrophilic Alkenes -
Nucleophilic Reagents
b. H2O2/OH- ROOH/OH-, other bases

• pKa H2O2 ? 7.8
• HOO- ROO- good nucleophiles, weak bases

• Stereochemistry
• Geometry of double bond generally 'preserved' in
  epoxide highly stereoselective!
• epoxidation from least-hindered face

Mechanism nucleophilic addition, then ring
closure!

• isolated double bonds not affected!

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Transition Metal Catalyzed Epoxidation of Alkenes
c. ROOH Ti(IV), Mo(VI), V(V) etc.

• Excess of alkyl hydroperoxide is required
• Only small amount (?10 mol) of metal catalyst
  required.
• 'Electron deficient' double bonds not epoxidized
  
• More substituted double bonds preferentially
  epoxidized

• Mo(CO)6 Mo(0) is oxidized by the (CH3)3COOH to
  catalytically active Mo(VI) species!

Especially useful for allylic alcohols!
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Sharpless Asymmetric Epoxidation of Alkenes
Use of (CH3)3COOH Ti(O-i-Pr)4- L-()-
('natural') and D-(-)-('unnatural') diethyl
tartrate (DET)

• yield 90
• ee 91

• yield 95
• ee 91

• Reaction is selective for allylic alcohols.
• Only small amount (?10 mol) of Ti catalyst and
  DET ligand required.
• Reaction best conducted at low temperature in
  non-polar solvent (CH2Cl2 or toluene) with 4 Å
  molecular sieves to absorb water.
• epoxy alcohols can be converted into many other
  useful products

ee enantiomeric excess ee of 96 - 4 of the
product is racemic (R,S) 96 is enantiomerically
pure (either R or S)
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Asymmetric Epoxidation (cont.)

• yield 77 ee 93

• yield 87 ee 97

Empirical model

• -OH to 'south-east' corner of plane
• 'Natural' DET from 'underNeath' 'unnatural' from
  'top'

• A remarkable reaction! how does it work?

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Asymmetric Epoxidation (cont.)
Via dimeric Ti(IV) species with ligated
(CH3)3COOH and allylic alcohol - simplified
presentation
E -COOEt

• Reaction is faster in presence of coordinated
  chiral ligand
• 'ligand acceleration'!
• (CH3)3COOH is 'activated' by coordination to
  'oxophilic' Ti(IV)

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Asymmetric Epoxidation (cont.)
Actual structures of dimeric Ti(IV) species with
ligated (CH3)3COOH and allylic alcohol (not for
examination!)
E -COOEt

• Ti(IV) is octahedral 6 coordinate
• Dimer structure emphasizes steric effects
• Peroxide enters from front lower 'south-east'
  quadrant, displacing axial (CO of ester) and
  equatorial (O-i-Pr) ligands
• allylic alcohol displaces axial (O-i-Pr) ligand

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Asymmetric Epoxidation (cont.)
Examples of use Synthesis of naturally-occurring
polyols
AE Asymmetric Epoxidation MH metal hydride
reduction R" protecting groups

• Use of either L-()- or D-(-) DET to vary
  absolute configuration at epoxide
• Use free OH to direct hydride reduction of
  epoxide

Preparation of ()-Amphotericin B polyene ether
antibiotic
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Asymmetric Epoxidation Polyol Synthesis (cont.)
this product used as one component in synthesis
of amphotericin B
Very widely used reactions Preparation of
L-glucose many other (un)natural products!
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Dihydroxylation of Alkenes
Use of KMnO4/OH-, OsO4 McMurry Ch. 7 CS B
Ch. 12
Os(VIII)
osmate ester Os(VI)

• Features
• Addition to double bond completely
  stereoselective concerted!
• Osmate ester is not isolated, but cleaved under
  reductive hydrolytic conditions to diol.

However OsO4 is expensive and toxic!
? Use catalytic amount of OsO4 in presence of a
cheaper oxidant providing that a catalytic cycle
can be maintained
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Dihydroxylation of Alkenes Catalytic Cycle
Depending upon oxidant, can use as little as 1
mol (0.01 equivalents) of OsO4!
65
(?)
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Ligand Acceleration of Dihydroxylation
Criegee discovered that pyridine or tertiary
amine ligands accelerates the reaction of OsO4
Remarkable effect Use chiral amine to obtain
enantiomerically-enriched diols! Use
naturally-occurring chiral amines cinchona
alkaloids. dihydroxylation is now 'asymmetric
'AD' reaction!
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Cinchona trees and bark
Cinchona ledgeriana
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Isolation of Quinine
The first of the cinchona alkaloids
1819 Runge 1820 Pelletier and Caventou
Concentrated an alcoholic extract ? white powder
1903 Rabe
Deduces correct structure
quinine
cinchona alkaloid
World supply Bark of Cinchona ledgeriana (to
11 dry weight)
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Asymmetric Dihydroxylation
Asymmetric dihydroxylation -AD use of cinchona
alkaloids
dihydroquinine DHQ
dihydroquinidine DHQD
quinine
Attach to 'spacers' via hydroxyl group to
'enhance' chirality
phthalazine PHAL
Indoline IND
Diphenylpyrimidine PYR
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Asymmetric Dihydroxylation (cont.)
Chiral amine ligands
dihydroquinine (DHQ)2-PHAL
dihydroquinidine (DHQD)2-DPYR
(DHQD)2- PHAL (DHQ)2-DPYR DHQD-IND DHQ-IND,
others
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Asymmetric Dihydroxylation Catalytic Cycle
Conditions

• Use K3Fe(CN)6 as oxidant with
• 1 mol (0.01 equivalents) of
• Os(VI) salt usually K2OsO2(OH)4
• and 1 mol (0.01 equivalents) of
• ligand in mixture of organic solvent
• - usually tert-butyl alcohol - and
• water in presence of K2CO3.
• ii. Additive may be added to assist
• in hydrolysis of osmate ester in
• catalytic cycle usually
• CH3SO2NH2.

Sharpless asymmetric dihydroxylation reaction
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Asymmetric Dihydroxylation - Examples
(DHQ)2-PHAL 93 ee
(DHQD)2- PHAL 94 ee
(DHQ)2-DPYR 92 ee
(DHQD)2- DPYR 87 ee
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Asymmetric Dihydroxylation Examples (cont.)
(DHQ)2-PHAL gt99.5 ee
(DHQD)2- PHAL 99.8 ee
(DHQ)2-PHAL gt97 ee
(DHQD)2- PHAL gt97 ee
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Asymmetric Dihydroxylation Examples (cont)
(DHQ)2-PHAL 95 ee
(DHQD)2- PHAL 98 ee
For (Z)-alkenes, reactions are not so effective
(DHQ)2-IND 59 ee
(DHQD)2- IND 72 ee
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Asymmetric Dihydroxylation Chiral Alkenes
Chiral alkenes diastereotopic faces - intrinsic
preference to react at one of the two
diastereotopic faces in absence of chiral
catalyst
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Asymmetric Dihydroxylation Empirical Model
Check!
(DHQ)2-PHAL
Good for monosubstituted, (E)-disubstituted,
trisubstituted alkenes
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Asymmetric Dihydroxylation Examples in Synthesis
Juvenile hormone bis-epoxide analogue
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Why Synthesis? Natural Products
Why carry out synthesis?
1. To confirm the structure of a natural product
- Normally, structures established by means of
NMR spectroscopy, X-ray crystallography,
other techniques! - but there are exceptions
especially when stereochemistry is complex!
JUVENILE HORMONE Stereochemistry established by
total synthesis - prevents maturation of larva of
the silk moth
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Asymmetric Dihydroxylation Examples in
Synthesis (cont.)
(S)-propranolol antidepressant
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THE END