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