SELECTIVITY
SELECTIVITY
Science 1983, 219, 245
Chemoselectivity
preferential reactivity of one functional group (FG) over another
- Chemoselective reduction of C=C over C=O:
H2,
Pd/C
O
O
- Chemoselective reduction of C=O over C=C:
O
OH
NaBH4
O
O
+
NaBH4, CeCl3
OH
only
- Epoxidation:
MCPBA
+
OH
OH
O
O
(2 : 1)
VO(acac)2,
tBuOOH
OH
OH
O
exclusively
Regioselectivity
- Hydration of C=C:
1) B2H6
2) H2O2, NaOH
OH
R
R
OH
R
1) Hg(OAc)2, H2O
2) NaBH4
- Friedel-Crafts Reaction:
O
RCOCl,
AlCl3
R
+
R
O
O
SiMe3
RCOCl,
AlCl3
R
OH
1
SELECTIVITY
- Diels-Alder Reaction:
R
R
O
O
R
+
+
O
major
O
R
minor
O
R
+
+
R
O
minor
major
O
O
+
O
H
OAc
O
O
H
OAc
O
O
OAc
O
O
OAc
OAc
Raney Ni, H2
+
O
H
SPh
O
O
H
O
O
SPh
H
O
Change in mechanism:
SPh
PhSH, H+
R
R
R
SPh
PhSH, (PhCO2)2
Stereochemistry:
Relative stereochemistry: Stereochemical relationship between two or more stereogenic centers
within a molecule
H
H
HO
cholesterol
H
enantiomers
same relative stereochemistry
H
OH
syn: on the same side ( cis)
anti: on the opposite side (trans)
- differences in relative stereochemistry lead to diastereomers.
Diastereomers= stereoisomers which are not mirror images; usually have different physical
properties
2
SELECTIVITY
Absolute Stereochemistry: Absolute stereochemical assignment of each stereocenter (R vs S)
Cahn-Ingold-Prelog Convention (sequence rules)
- differences in absolute stereochemistry (of all stereocenters within the molecule) leads to
enantiomers.
- Reactions can "create" stereocenters
O
Ph
MeMgBr
HO
H
Ph
MeMgBr
CH3
H
H 3C
OH
Ph
H
O
enantiomers
(racemic product)
Ph
H
HO
CH3
Ph
H
MeMgBr
Diastereomeric transition states- not necessarily equal in energy
Me
Me
Me
N
O
Ph
Zn
O
CH3 CH3
Zn
Me
N
O
O
CH3 CH3
H
Zn
H 3C
H
Zn
Ph
H 3C
HO
Ph
CH3
HO
CH3
H
H
Ph
Diastereoselectivity
CH3MgBr
Ph
CH3
Ph
CHO
HO
+
CH3
Ph
H
H OH
anti
syn
Diastereomers
Cram Model (Cram's Rule): empirical
O
O
M
S
R
O
S
M
H 3C
Nu
H
CH3MgBr
CH3MgBr
L
R
L
favored
H
Ph
3
SELECTIVITY
4
Felkin-Ahn Model
S O
O M
L
R
L
Nu
Nu
M R
S
disfavored
favored
Chelation Control Mode
M
OR
O
O
R
S
M
HO
OR
CH3MgBr
CH3MgBr
M
S
favored
Nu
M
R
S
OR
R
HO
TBSO
O
TBSO
MgBr
relative stereochemical control
H O
H O
OBn
OBn
Stereospecific
Stereochemictry of the product is related to the reactant in a mechanistically defined manner; no
other stereochemical outcome is mechanistically possible.
i.e.; SN2 reaction- inversion of configuration is required
Br2
H
H 3C
Br
Br2
H
meso
H
CH3
Br
CH3 Br
+
H
CH3
Br
CH3
H
Br
H
CH3 Br
enantiomers (racemic)
Stereoselective
When more than one stereochemical outcome is possible, but one is formed in excess (even if that
excess is 100:0).
CH3
H2, Pd/C
H
H
α-pinene
O
only isomer
O
O
H
H
O
H
+
CH3
H
not observed
O
O
LDA, CH3I
N
O
S
N
O
+
S
N
O
S
(96 : 4)
Diasteromers
Diastereoselective
Enantiospecific
OXIDATIONS
Oxidations
Carey & Sundberg: Chapter 12 problems: 1a,c,e,g,n,o,q; 2a,b,c,f,g,j,k; 5; 9 a,c,d,e,f,l,m,n; 13
Smith: Chapter 3
March: Chapter 19
I. Metal Based Reagents
1. Chromium Reagents
2. Manganese Rgts.
3. Silver
4. Ruthenium
5. other metals
II Non-Metal Based Reagents
1. Activated DMSO
2. Peroxides and Peracids
3. Oxygen/ ozone
4. others
III. Epoxidations
Metal Based Reagents
Chromium Reagents
- Cr(VI) based
- exact stucture depends on solvent and pH
- Mechanism: formation of chromate ester intermediate
Westheimer et al. Chem Rev. 1949, 45, 419
JACS 1951, 73, 65.
HO
R2CH-OH
HCrO4
-
R
R
H+
Cr
C O
O-
R
O-
O
R
+ HCrO3- +
H+
H
+ H2O
Jones Reagent (H 2CrO4, H2Cr2O7, K2Cr2O7)
J. Chem. Soc. 1946 39
Org. Syn. Col. Vol. V, 1973, 310.
- CrO3 + H2O → H2CrO4 (aqueous solution)
K2Cr2O7 + K2SO4
- Cr(VI) → Cr(III)
(black)
(green)
- 2°- alcohols are oxidized to ketones
R2CH-OH
Jones
reagent
R
acetone
R
O
- saturated 1° alcohols are oxidized to carboxylic acids.
Jones
reagent
RCH2-OH
acetone
O
R
hydration
H
HO OH
Jones
reagent
R
acetone
H
O
R
OH
- Acidic media!! Not a good method for H+ sensitive groups and compounds
5
OXIDATIONS
1) Jones,
acetone
SePh
OH
6
SePh
CO 2CH 3
2) CH2N2
Me 3Si
Me 3Si
JACS 1982, 104, 5558
H17C 8
H17C 8
O
O
O
OH
Jones
acetone
O
O
O
JACS 1975, 97, 2870
O
Collins Oxidation (CrO3•2pyridine)
TL 1969, 3363
- CrO3 (anhydrous) + pyridine (anhydrous) → CrO 3•2pyridine↓
- 1° and 2° alcohols are oxidized to aldehydes and ketones in non-aqueous solution (CH 2Cl2)
without over-oxidation
- Collins reagent can be prepared and isolated or generated in situ. Isolation of the reagent
often leads to improved yields.
- Useful for the oxidation of H+ sensitive cmpds.
- not particularly basic or acidic
- must use a large excess of the rgt.
CrO3•(C 5H5N)2
OH
ArO
H
CH 2Cl 2
O
O
ArO
O
JACS 1969, 91, 44318.
O
O
CrO3 catalyzed (1-2 mol % oxidation with NaIO6 (2.5 equiv) as the reozidant in wet aceteonitrile.
oxidized primary alcohols to carboxylic acids.
Tetrahedron Lett. 1998, 39, 5323.
Pyridinium Chlorochromate (PCC, Corey-Suggs Oxidation)
TL 1975 2647
Synthesis 1982, 245 (review)
CrO3 + 6M HCl + pyridine → pyH+CrO3 Cl- ↓
- Reagent can be used in close to stoichiometric amounts w/ substrate
- PCC is slighly acidic but can be buffered w/ NaOAc
PCC, CH 2Cl 2
OHC
HO
JACS 1977, 99, 3864.
O
O
O
PCC, CH 2Cl 2
OH
O
CHO
TL, 1975, 2647
OXIDATIONS
- Oxidative Rearrangements
Me
OH
Me
PCC, CH 2Cl 2
JOC 1977, 42, 682
O
Me
Me
PCC, CH 2Cl 2
JOC 1976, 41, 380
OH
O
- Oxidation of Active Methylene Groups
PCC, CH 2Cl 2
O
O
O
JOC 1984, 49, 1647
PCC, CH 2Cl 2
O
O
O
- PCC/Pyrazole PCC/ 3,5-Dimethylpyrazole
JOC 1984, 49, 550.
NH
NH
N
N
- selective oxidation of allylic alcohols
OH
OH
PCC, CH 2Cl 2
H
3,5-dimethyl
pyrazole
H
HO
H
O
H
(87%)
Pyridinium Dichromate (PDC, Corey-Schmidt Oxidation)
TL 1979, 399
- Na2Cr2O7•2H2O + HCl + pyridine → (C5H5N)2CrO7 ↓
PDC
PDC
CHO
CH 2Cl 2
OH
DMF
1° alcohol
-allylic alcohols are oxidized to α,β-unsaturated aldehydes
CO 2H
7
OXIDATIONS
- Supported Reagents
Comprehensive Organic Synthesis 1991, 7, 839.
PCC on alumina : Synthesis 1980, 223.
- improved yields due to simplified work-up.
PCC on polyvinylpyridine : JOC, 1978, 43, 2618.
CH 2 CH
cross-link
N
CH 2 CH
R2CH-OH
R2C=O
CH 2 CH
CrO3, HCl
N
N
Cr(III)
N
Cr(VI)O3 •HCl
8
partially
spent
reagent
to remove Cr(III)
1) HCl wash
2) KOH wash
3) H2O wash
CrO3/Et2O/CH2Cl2/Celite
Synthesis 1979, 815.
- CrO3 in non-aqueous media does not oxidized alcohols
- CrO3 in 1:3 Et2O/CH2Cl2/celite will oxidized alcohols to ketone and aldehydes
C 8H17
C 8H17
CrO3
Et2O/CH 2Cl 2/celite
(69%)
HO
Synthesis 1979, 815
O
H2CrO7 on Silica
- 10% CrO3 to SiO2
- 2-3g H2CrO3/SiO2 to mole of R-OH
- ether is the solvent of choice
Manganese Reagents
Potassium Permanganate
KMnO4/18-Crown-6
JACS 1972 94, 4024.
(purple benzene)
O
O
O
K+
O
MnO 4O
O
- 1° alcohols and aldehydes are oxidized to carboxylic acids
- 1:1 dicyclohexyl-18-C-6 and KMnO4 in benzene at 25°C gives a clear purple solution as high
as 0.06M in KMnO4.
O
JACS 1972, 94, 4024
CO 2H
CHO
Synthesis 1984, 43
CL 1979, 443
CHO
OXIDATIONS
9
Sodium Permanganate
TL 1981, 1655
- heterogeneous reaction in benzene
- 1° alcohols are oxidized to acids
- 2° alcohols are oxidized to ketones
- multiple bonds are not oxidized
Barium Permanganate
(BaMnO4)
TL 1978, 839.
- Oxidation if 1° and 2° alcohols to aldehydes and ketones- No over oxidation
- Multiple bonds are not oxidized
- similar in reactivity to MnO2
Barium Manganate
BCSJ 1983, 56, 914
Manganese Dioxide
Review: Synthesis 1976, 65, 133
- Selective oxidation of α,β-unsatutrated (allylic, benzylic, acetylenic) alcohols.
- Activity of MnO2 depends on method of preparation and choice of solvent
- cis & trans allylic alcohols are oxidized at the same rate without isomerization of the double
bond.
OH
OH
HO
HO
MnO 2, CHCl3
J. Chem. Soc. 1953, 2189
JACS 1955, 77, 4145.
(62%)
O
HO
- oxidation of 1° allylic alcohols to α,β-unsaturated esters
OH
MnO2,
ROH, NaCN
CO 2R
OH
CO 2Me
JACS1968, 90, 5616. 5618
MnO 2, Hexanes
MeOH, NaCN
Manganese (III) Acetate
α-hydroxylation of enones
Synthesis 1990, 1119
TL 1984 25, 5839
O
O
Mn(OAc)3, AcOH
AcO
Ruthenium Reagents
Ruthenium Tetroxide
- effective for the conversion of 1° alcohols to RCO2H and 2° alcohols to ketones
- oxidizes multiple bonds and 1,2-diols.
OXIDATIONS
Ph
OH
O
H
O
JOC 1981, 46, 3936
RuO4, NaIO4
OH
CH 3
CO 2H
Ph
CCl 4, H2O, CH3CN
OH
Ph
RuO4, NaIO4
10
Ph
CCl 4, H2O, CH3CN
CO 2H
H
96% ee
CH 3
94%ee
HO
RuO2, NaIO4
O
TL 1970, 4003
CCl 4, H2O
O
O
O
O
Tetra-n-propylammonium Perruthenate (TPAP, nPr4N+ RuO4-)
Aldrichimica Acta 1990, 23, 13.
Synthesis 1994, 639
- mild oxidation of alcohols to ketones and aldehydes without over oxidation
OH
O
TPAP
MeO 2C
MeO 2C
OSiMe 2tBu
OSiMe 2tBu
O
N+
-O Me
TL 1989, 30, 433
(Ph3P)4RuO2Cl3
RuO2(bipy)Cl2
- oxidizes a wide range of 1°- and 2°-alcohols to aldehydes and ketones without oxidation of
multiple bonds.
OH
CHO
CHO
OH
JCS P1 1984, 681.
H
H
Ba[Ru(OH)2O3]
-oxidizes only the most reactive alcohols (benzylic and allylic)
(Ph3P)3RuCl2 + Me3SiO-OSiMe3
- oxidation of benzylic and allylic alcohols
TL 1983, 24, 2185.
Silver Reagents
Ag2CO3 ( Fetizon Oxidation)
also Ag2CO3/celite
- oxidation of only the most reactive hydroxyl
O
OH
Synthesis 1979, 401
O
Ag 2CO 3
O
OH
OH
O
O
OH
O
OH
Ag 2CO 3, C 6H6
O
O
O
JACS 1981, 103, 1864.
mechanism: TL 1972, 4445.
OXIDATIONS
- Oxidation of 2° alcohol over a 1° alcohol
OH
OH
Ag2CO3, Celite
OH
JCS,CC 1969, 1102
(80%)
O
Silver Oxide (AgO2)
- mild oxidation of aldehyde to carboxylic acids
AgO 2, NaOH
RCHO
CHO
RCO 2H
CO 2H
AgO 2
JACS 1982, 104, 5557
Ph
Ph
Prevost Reaction Ag(PhCO2)2, I2
Ag(PhCO 2)2, I2
AcO
OAc
AcOH
AcO
Ag(PhCO 2)2, I2
OH
AcOH, H 2O
Other Metal Based Oxidations
Osmium Tetroxide OsO 4
review: Chem. Rev. 1980, 80, 187.
-cis hydroxylation of olefins
old mechanism:
O
OH
Os
O O
OH
O
OsO 4, NMO
osmate ester
intermediate
cis stereochemistry
- use of R 3N-O as a reoxidant
TL 1976, 1973.
OsO 4, NMO
O
O
O
OH
O
OH
OH
OH
TL 1983, 24, 2943, 3947
Stereoselectivity:
OsO 4
R3
R2
RO
H
R4
OsO 4, NMO
HO H
R2
HO
R3
RO
H R4
11
OXIDATIONS
- new mechanism: reaction is accelerated in the presences of an 3° amine
R1
R1
O
O O
R2
Os
O
O
[2+2]
R3N
R1
R2
O Os
O
12
O
Os O
O
O
R2
O
NR3
[O]
[3+2]
OsO2
R1
O
O
R2
O
[O]
hydrolysis
R1
Os O
R2
+
O
HO
OH
OsO4
- Oxidative cleavage of olefins to carboxylic acids.
JOC 1956, 21, 478.
- Oxidative cleavage of olefins to ketones & aldehydes.
OH
CHO
CHO
OH
OsO 4, NMO
O
O
NaIO4
OH
O
H2O
O
O
O
O
O
O
OAc
O
OAc
OAc
JACS 1984, 105, 6755.
Substrate directed hydroxylations:
-by hydroxyl groups
Chem. Rev. 1993, 93, 1307
HO
OsO4,
pyridine
O
HO
HO
O
HO
+
O
HO
HO
HO
3:1
HO
OsO4,
pyridine
O
HO
O
TMSO
TMSO
HO
CH3
HO
CH3 OH
OsO4, Et2O
HO
OH
CH3
CH3
+
OH
CH3
(86 : 14)
- by amides
AcO
AcO
OH
MeS
OsO4
MeS
OH
HN
O
OAc
CH3 OH
HN
O
OAc
OXIDATIONS
- by sulfoxides
••
••
OMe
O
OsO4
S
OMe OH
O
S
OH
1) OsO4
2) Ac2O
S
HN
OAc
(2 : 1)
••
••
O
13
O
S
O
AcO
O
HN
(20 : 1)
- by sulfoximines
O
Ph S
O
Ph S
OH
MeN
MeN
OsO4, R3NO
O
OH
∆
OH
OH
OH
OH
CH3
Raney nickel
H 3C
OH
OH
OH
CH3
- By nitro groups
PhO2S
PhO2S
1) OsO4
N
NHR
N
+
2) acetone, H
N
NHR
N
O2N
O2N
N
N
N
O
N
O
N
N
HO
HO
NHR
N
NHR
N
N
N
N
O
N
O
- OsO4 bis-hydroxylation favors electon rich C=C.
OsO4
X
OH
OH
X
+
OH
OH
X= OH
= OMe
= OAc
= NHSO2R
- Ligand effect:
80 : 20
98 : 2
99 : 1
60 : 40
OsO4
OH
K3Fe(CN)6, K2CO3
MeSO2NH2, tBuOH/H2O
OH
OH
OsO4 (no ligand)
Quinuclidine
DHQD-PHAL
X
4:1
9:1
> 49 : 1
+
X
(directing effect ?)
(directing effect ?)
OH
OH
OH
OXIDATIONS
Chem. Rev. 1994, 94, 2483.
Sharpless Asymmetric Dihydroxylation (AD)
- Ligand pair are really diastereomers!!
14
dihydroquinidine ester
N
"HO
Ar
OH"
H
H
R3
OR'
R2
R3 OH
0.2-0.4% OsO4
R2
R1
acetone, H 2O, MNO
80-95 % yield
20-80 % ee
OH
R1
H OR'
"HO
Ar
OH"
MeO
Ar =
N
dihydroquinine ester
N
R'= p-chlorobenzoyl
Mechanism of AD:
L
HO
OH
O
O
H 2O
O
O
Os
O
O
O
O
First Cycle
(high enantioselectivity)
O
Os
O
O
Second Cycle
(low enantioselectivity)
[O]
[O]
O
O
Os
O
O
L
Os
O
L
O
O
O
O
Os
O
O
O
O
R 3N
HO
OH
H 2O, L
- K3Fe(CN)6 as a reoxidant gives higher ee's- eliminates second cycle
TL 1990, 31, 2999.
- Sulfonamide effect: addition of MeSO2NH2 enhances hydrolysis of Os(VI) glycolate
(accelerates reaction)
- New phthalazine (PHAL) ligand's give higher ee's
N
Et
Et
O
H
Et
N
N N
N
N
O
H
O
H
OMe
MeO
O
H
MeO
N
OMe
N
N
N
(DHQ)2-PHAL
(DHQD)2-PHAL
JOC 1992, 57, 2768.
Et
N N
OXIDATIONS
15
- Other second generation ligands
N
Et
Et
O
H
MeO
Et
N
Ph
O
N
N
H
N
OMe
Ph
N
N
O
H
O
OMe
N
N
PYR
IND
Proposed catalyst structure:
O
H
O
O
Os
N
MeO
N
Os
"Bystander
quinoline
(side wall)
Asymmetric
Binding
Cleft
O
N
H
H
N
N
O
N
N
N
O
Phthalazine
Floor
OMe
OMe
OMe
O
Corey Model: JACS 1996, 118, 319
Enzyme like binding pocket;
[3+2] addition of OsO4 to olefin.
N
O
O
Os O
N O
O
N
H
N N
O
O
N
DHQL
Rs
RM
RL
H
DHQ
RL large and flat,
i.e Aromatics work particularly well
OXIDATIONS
Olefin
Preferred Ligand
ee's
PYR, PHAL
30 - 97 %
PHAL
70 - 97 %
IND
20 - 80 %
PHAL
90 - 99.8 %
PHAL
90 - 99 %
PHAL, PYR
+ MeSO2NH2
20 - 97 %
R1
R2
R1
R1
R2
R2
R1
R2
R3
R1
H
R2
R3
R1
R4
"AD-mixes" commercially available pre-mix solutions of Os, ligand and reoxidant
AD-mix α
(DHQ)2PHAL, K 3Fe(CN)6, K2CO3, K2OsO4 (0.4 MOL % Os to C=C)
AD-mix β
(DHQD)2PHAL, K 3Fe(CN)6, K2CO3, K2OsO4
O
HO
O
Campthothecin
N
N
O
OMe
N
OMe
OMe
AD
(DHQD)2PYR
O
N
N
O
94 % ee
O
O
OH
OH
OH
- Kinetic resolution (not as good as Sharpless asymmetric epoxidation)
H
Ph
tBu
Ph
H
tBu
H
Ph
H
Ph
AD mix α
30% conversion
Ph
H
OH
OH
tBu
tBu
olefins with axial
dissymmetry
H
Ph
+
OH
OH
+
tBu
(4 : 1)
tBu
enriched
16
OXIDATIONS
17
Asymmetric Aminohydroxylation TL 1998, 39, 2507; ACIEE 1996, 25, 2818, 2813,
preparation of α-aminoalcohols from olefin. Syn addition as with the dihydroxylation
regiochemistry can be a problem
O
Ph
O
N
Na
CO2Me
Ph
O
OH
Cl
Ph
O
NH
+
CO2Me
Ph
K2OsO6H4 (cat)
Ligand
CO2Me
Ph
N
OH
O
Ph
O
Ligand= PHAL
AQN
4:1
1:4
Molybdenum Reagents
MoOPH [MoO5•pyridine (HMPA)]
JOC 1978, 43, 188.
- α-hydroxylation of ketone, ester and lactone enolates.
O
OR'
R
O
+
Mo
O
L
R
O
H
R
R
Pd(OAc) 2,
CH 3CN, 80° C
HO
H
R
O
H
R
- CO 2
O
O Pd
-
TL 1984, 25, 2791
Tetrahedron 1987, 43, 3903
O
OH
2
HO
CO
H
OH
JACS 1989, 111, 8039.
Pd2(DBA) 3•CHCl 3,
CH 3CN, 80° C
OH
O
R
R
Pd(0)
O
H
H
(Tsuji Oxidation)
O
O 2 CO
OH
R'
OH
L
Palladium Reagents
Pd(0) catalyzed Dehydrogenation (oxidation) of Allyl Carbonates
Tetrahedron 1986, 42, 4361
R
O
THF, -78°C
O
H
O
O
Oxidation of silylenol ethers and enol carbonates to enones
O
OTMS
Pd(OAc) 2,
CH 3CN
O
O
O
OTIPS
Ph
O
Pd(OAc) 2,
CH 3CN
(NH 4)2Ce(NO 3)6
DMF, 0°C
O
O
Ph
TL 1995, 36, 3985
R
Oppenauer Oxidation
OXIDATIONS
Organic reactions 1951, 6, 207
Synthesis 1994, 1007
OiPr
+O Al
R1R2CHOH
(CH3)2C=O
OiPr
OiPr
+O Al
O OiPr
H
R1
R2
O
R1
18
+ Al(OiPr)3
R2
Nickel Peroxide
Chem Rev. 1975, 75, 491
Thallium Nitrate (TNN, Tl(NO 3)3•3H2O
Pure Appl. Chem. 1875, 43, 463.
Lead Tetraacetrate Pb(OAc)4
Oxidations in Organic Chemistry (D), 1982, pp 1-145.
Non-Metal Based Reagents
Activated DMSO Review: Synthesis 1981, 165; 1990, 857.
Me
Me
S+
S+
+ E
O-
Me
E
O
Organic Reactions 1990, 39, 297
Nu:
Nu
S
Me
Me
+
+ E-O
Me
E= (CF3CO)2O, SOCl2, (COCl)2, Cl2, (CH3CO)2O, TsCl, MeCl, SO3/pyridine, F 3CSO2H,
PO5, H3PO4, Br2
Nu:= R-OH, Ph-OH, R-NH2, RC=NOH, enols
Swern Oxidation
- trifluoroacetic anhydride can be used as the activating agent for DMSO
O
Me
Me
(COCl) 2
S + O-
CH 2Cl 2, -78°C
Me
R2CH-OH Me
Me
Me
-CO, -CO 2
Cl -
Me
S + Cl
Me
O
R
R
S+ O
Cl
S+ O
Et3N:
Me
R
S
+
O
Me
R
H
B:
O
Cl
O
DMSO, (COCl) 2
OH
Moffatt Oxidation (DMSO/DCC)
O
JACS 1965, 87, 5661, 5670.
Me
C 6H11
S + O-
CF 3CO 2H,
Pyridine
Me
+
C 6H11 N C
TL 1988, 29, 49.
CH 2Cl 2, Et3N
N C 6H11
OH
CO 2Me
O
Me
NH
S
+
O C
R2CH-OH
Me
R
O
H
R
B:
C 6H11
CHO
DCC/ DMSO
CO 2Me
CF 3CO 2H,
Pyridine
JACS 1978, 100, 5565
O
S
SO3/Pyridine
S+ O
N
Me
R
R
Me
S
JACS 1967, 89, 5505.
CO 2Me
HO
H
CONH 2
H
HO
OH
OH
CO 2Me
H
SO 3, pyridine,
DMSO, CH 2Cl 2
CONH 2
H
HO
O
JACS 1989, 111, 8039.
OXIDATIONS
Corey-Kim Oxidation
(DMS/NCS)
19
JACS 1972, 94, 7586.
O
Me
Me
S:
+
S + Cl
N Cl
Me
Me
O
N-Chlorosuccinimide
(NCS)
Acc. Chem. Res. 1980, 13, 419
••
••
••
O O
singlet
"ene" reaction
H
O
Tetrahedron 1981, 37, 1825
hν
•• ••
•O O •
•• ••
triplet
••
Oxygen & Ozone
Singlet Oxygen
Ph3P:
H
O
O
O
OH
Tetrahedron 1981, 1825
1) O2, hν, Ph2CO
2) reduction
Ozone
HO
Comprehensive Organic Synthesis 1991, 7, 541
O
O 3, CH 2Cl 2
O
O
-78°C
O
Ph3P:
O O
NaBH 4
+
O
O
H
Jones
OH
RCOOH
Other Oxidations
Mukaiyama Oxidation
BCSJ 1977, 50, 2773
O
R
PrMgBr
CH OH
R
N
R
N
N
N
R
O
CH O MgBr
O
R
THF
R
OH
Cl
MeO
CH 3
O
O
NH
O
O
SEt
SEt
MeO
N
Cl
O
N N
N
O
MeO
CH 3
OHC
O
NH
OEt
O
tBuMgBr, THF
(70%)
SEt
SEt
MeO
JACS 1979, 101, 7104
OEt
OXIDATIONS
20
O
OH
tBuMgBr, THF
O
N
N
N
N
O
O
O
Dess-Martin Periodinane
JOC 1983, 48, 4155.
- oxidation conducted in CHCl3, CH3CN or CH2Cl2
- excellent reagent for hindered alcohols
- very mild
JACS 1992, 113, 7277.
OAc
OAc
AcO
••
I
O
OAc
R
R2CH-OH
I
O
+
+ 2 AcOH
O
R
O
O
HO
Dess-Martin
O
JOC 1991, 56, 6264
(99%)
RO
RO
Chlorite Ion
-oxidation of α,β-unsaturated aldehydes to α,β−unsaturated acids.
Tetrahedron 1981, 37, 2091
NaClO 2,
NaH2PO 4
OBn
- HClO2
OBn
OBn
OH
H
tBuOH, H 2O
CHO
CO 2H
-O-Cl-O
Selenium Dioxide
- Similar to singlet oxygen (allylic oxidation)
1) SeO2
2) NaBH 4
OAc
OAc
OH
Phenyl Selenium Chloride
O
OLi
PhSeCl
O
SePh
H2O 2
Ph
Se
O-
THF
O
- PhSeOH
H
- PhS-SPh will do similar chemistry however a sulfoxide elimination is less facile than a
selenoxide elinimation.
Peroxides & Peracids
- R3N: → R3N-O
- sulfides → sulfoxides → sulfones
-Baeyer-Villiger Oxidation- oxidation of ketones to esters and lactones via oxygen insertion
Organic Reactions 1993, 43, 251
Comprehensive Organic Synthesis 1991, vol 7, 671.
OXIDATIONS
21
m-Chloroperbenzoic Acid, Peracetic Acid, Hydrogen peroxide
O
O
H
O
O 2N
O
O
O
H
O
R1
R2
O
O
HO
O
NO 2
Cl
R1
H
Ar
O
C R2
O
R1
O
+
R2
ArCO2H
Ar
O
O
- Concerted R-migration and O-O bond breaking. No loss of stereochemistry
- Migratory aptitude roughly follows the ability of the group to stabilize positive charge:
3° > 2° > benzyl = phenyl > 1° >> methyl
JACS 1971, 93, 1491
O
O
mCPBA
O
HO
O
CO2H
O
CHO
O
HO
O
O
CO2H
HO
OH
PGE1
O
O
CH3
O
mCPBA
Tetrahedron Lett. 1977, 2173
Tetrahedron Lett. 1978, 1385
CH3
(80 %)
CH3
CH3
Oxone (postassium peroxymonosulfate)
Tetrahedron 1997, 54, 401
oxone
RCHO
RCOOH
acetone (aq)
Oxaziridines
reviews: Tetrahedron 1989, 45, 5703; Chem. Rev. 1992, 92, 919
O
N C
R
R3
R2
- hydroxylation of enolates
O
R
O
Base
R
R'
O
_
R
R'
O
O
PhSO2
O
R
Ph
N
R
R'
+ PhSO2N=CHPh
HO
Ph
O
_
R'
O
R'
_
NSO2Ph
R
+ PhSO2N=CHPh
Ph
R'
NHSO2Ph
By-product
supresed by using
bulkier oxaziradine
such as camphor
oxaziradine
OXIDATIONS
22
Asymmetric hydroxylations
O
O
NaN(SiMe3)2, THF
MeO 2C
HO
Tetrahedron 1991, 47, 173
MeO 2C
OMe
OMe
N
Ar
MeO
O
SO 2 O
MeO
KN(SiMe3)2
CO2Me
(67% ee)
O
O
OH
CO2Me
OH
O
OH
OH
N
SO2 O
MeO
MeO
MeO
O
OH
OH
(>95% ee)
- hydroxylation of organometallics
R-Li or R-Mg → R-OH
JACS 1979, 101, 1044
- Asymmetric oxidation of sulfides to chiral sulfoxides.
JACS 1987, 109, 3370.
Synlett, 1990, 643.
Remote Oxidation (functionalization)
Barton Reaction
Comprehensive Organic Synthesis 1991, 7, 39.
NOCl, CH2Cl2
pyridine
OH
hν
O
NO
- NO
•
O
•
OH
H
•
•NO
JACS 1975, 97, 430
OH
OH
NO
N
N
ketone
oxidation state
HO
C5H11
perhydrohistricotoxin
Epoxidations
Peroxides & Peracids
- olefins → epoxides
Tetrahedron 1976, 32, 2855
- α,β-unsaturated ketones, aldehydes and ester → α,β-epoxy- ketones, aldehydes and esters
(under basic conditions).
O
(CH 2)n
tBuOOH
triton B, C6H6
O
O
(CH 2)n
JACS 1958, 80, 3845
OXIDATIONS
O CO 2Me
CO 2Me
mCPBA, NaHPO3
TL 1988, 23, 2793
O
O
H
H
O
O
Henbest Epoxidation- epoxidation directed by a polar group
OH
OH
OH
mCPBA
+
O
OAc
O
10:1 diastereoselection
OH
OAc
mCPBA
+
O
O
1:4 diastereoselection
O
Ph
O
NH
Ph
NH
"highly selective"
mCPBA
O
Ar
O
H
H
O
proposed transition state:
-OH directs the epoxidation
O
O
H
- for acyclic systems, the Henbest epoxidation is often less selective
Rubottom Oxidation:
JOC 1978, 43, 1588
O
OTMS
LDA, TMSCl
TMSO
mCPBA
O
H2O
O
OH
Sharpless Epoxidation
tBuOOH w/ VO(acac)2, Mo(CO)6 or Ti(OR) 4
Reviews:
Comprehensive Organic Synthesis 1991, vol 7, 389-438
Asymmetric Synthesis 1985, vol. 15, 247-308
Synthesis, 1986, 89.
Org. React. 1996, 48, 1-299.
Aldrichimica Acta 1979, 12, 63
review on transition mediated epoxidations: Chem. Rev. 1989, 89, 431.
- Regioselective epoxidation of allylic and homo-allylic alcohols
- will not epoxidize isolated double bonds
- epoxidation occurs stereoselectively w/ respect to the alcohol.
23
OXIDATIONS
- Catalysts: VO(acac)2; Mo(CO)6; Ti(OiPr)4
- Oxidant: tBuOOH; PhC(CH3)2OOH
VO(acac)2
tBuOOH
OH
OH
O
OH
OH
(CH2)n
O
(CH2)n
ring size
5
6
7
8
9
VO(acac)2
>99%
>99
>99
97
91
MoO2(acac)2
-98
95
42
3
mCPBA
84
95
61
<1
<1
Acyclic Systems:
L
M
1,3-interaction
O
R3
A1,2-strain
tBu
O
O
R1
R3
L
Rc
Rt
R1
Rt
R2
Rc
O
O
M
R2
L
A1,3-strain
Major influences:
A1,2-Strain between Rg and R1
A1,3 -strain between R2 and Rc
1,3-interactions between L and R1
O
L
(Rg and R2)
(R1 and Rc)
(L and R2)
VO(acac)2,
tBuOOH
O
OH
+
O
OH
OH
(4 : 1)
tBu
CH3
H
O
L
M
H
H
L
O
O
M
L
O
O
L
tBu
O
H 3C
H
H
H
24
OXIDATIONS
VO(acac)2,
tBuOOH
O
OH
+
O
OH
OH
(19 : 1)
tBu
L
H 3C
H
H
H 3C
O
H
M
L
H
O
O
O
H 3C
H
O
M
L
L
H
O
tBu
CH3
SiMe3
SiMe3
VO(acac)2,
tBuOOH
O
OH
SiMe3
+
OH
O
OH
(> 99 : 1)
- Careful conformational analysis of acyclic systems is needed.
Homoallylic Systems
L
L
O
O
OH
V
OtBu
O
OH
dominent stereocontrol element
Titanium Catalyst structure:
RO2C
OR
Ti
CO2R
O
O
O
RO
O
OR
O
Ti
OR
OR
O
OR
CO2R
O
OR
Ti
CO2R
O
O
O
RO
O
OR
O
CO2R
Ti
O
RO
Ti
O
O
CO2R
O
CO2R
O
O
tBu
OR
Disfavored
O
O
tBu
OR
Ti
O
Favored
O
CO2R
25