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OXIDATIONS 5 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. Reagents 2. Rgts. 3. 4. 5. other metals II Non-Metal Based Reagents 1. Activated DMSO 2. and Peracids 3. / ozone 4. others III. Epoxidations

Metal Based Reagents

Chromium Reagents - Cr(VI) based - exact stucture depends on and pH - Mechanism: formation of chromate intermediate Westheimer et al. Chem Rev. 1949, 45, 419 JACS 1951, 73, 65. HO - - O HCrO4 R Cr R R CH-OH O - + 2 C O O- + HCrO3 + H H+ R R H

+ H2O

Jones Reagent (H2CrO4, 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°- are oxidized to Jones reagent R R2CH-OH O R

- saturated 1° alcohols are oxidized to carboxylic . Jones O HO OH Jones reagent hydration reagent O RCH2-OH acetone R H R H acetone R OH

- Acidic media!! Not a good method for H+ sensitive groups and compounds OXIDATIONS 6

1) Jones, SePh SePh acetone CO2CH3 OH 2) CH2N2

Me3Si Me3Si JACS 1982, 104, 5558 H C H C 17 8 O 17 8 O OH O Jones

O acetone O JACS 1975, 97, 2870 O O

Collins Oxidation (CrO3•2pyridine) TL 1969, 3363 - CrO3 (anhydrous) + (anhydrous) ® CrO3•2pyridine¯ - 1° and 2° alcohols are oxidized to and ketones in non-aqueous solution (CH2Cl2) without over-oxidation - Collins reagent can be prepared and isolated or generated in situ. Isolation of the reagent often 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•(C5H5N)2 H OH JACS 1969, 91, 44318. CH2Cl2 O ArO O ArO O 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/ - PCC is slighly acidic but can be buffered w/ NaOAc

PCC, CH2Cl2

OHC HO JACS 1977, 99, 3864.

O O PCC, CH2Cl2 CHO O O OH TL, 1975, 2647 OXIDATIONS 7 - Oxidative Rearrangements Me OH Me PCC, CH Cl 2 2 JOC 1977, 42, 682 O Me Me

PCC, CH Cl 2 2 JOC 1976, 41, 380 OH O

- Oxidation of Active Methylene Groups

PCC, CH2Cl2

O O O JOC 1984, 49, 1647

PCC, CH2Cl2 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, CH2Cl2

H H 3,5-dimethyl pyrazole H H HO O (87%)

Pyridinium Dichromate (PDC, Corey-Schmidt Oxidation) TL 1979, 399 - Na2Cr2O7•2H2O + HCl + pyridine ® (C5H5N)2CrO7 ¯

PDC PDC

CHO CH Cl DMF CO2H 2 2 OH

-allylic alcohols are oxidized to a,b -unsaturated aldehydes OXIDATIONS 8 - Supported Reagents Comprehensive 1991, 7, 839. PCC on alumina : Synthesis 1980, 223. - improved yields due to simplified work-up. PCC on polyvinylpyridine : JOC, 1978, 43, 2618.

CH CH CH CH 2 CH2 CH R2CH-OH R2C=O 2 cross-link CrO3, HCl partially spent N N N N reagent Cr(III) Cr(VI)O3 •HCl

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 and aldehydes

C 8H17 C 8H17

CrO3 Et2O/CH2Cl2/celite (69%)

HO O Synthesis 1979, 815

H2CrO7 on Silica - 10% CrO3 to SiO2 - 2-3g H2CrO3/SiO2 to mole of R-OH - is the solvent of choice

Manganese Reagents KMnO4/18-Crown-6 (purple ) JACS 1972 94, 4024. O O O + - K MnO4 O O 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 CO2H

CHO Synthesis 1984, 43 CL 1979, 443

CHO OXIDATIONS 9 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 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 BCSJ 1983, 56, 914

Manganese Dioxide Review: Synthesis 1976, 65, 133 - Selective oxidation of a,b -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

MnO2, CHCl3

(62%) J. Chem. Soc. 1953, 2189 JACS 1955, 77, 4145. HO O

- oxidation of 1° allylic alcohols to a,b -unsaturated MnO2, OH ROH, NaCN CO2R

OH CO Me 2 JACS1968, 90, 5616. 5618 MnO2, Hexanes MeOH, NaCN

Manganese (III) Acetate a -hydroxylation of enones Synthesis 1990, 1119 TL 1984 25, 5839 O O

Mn(OAc)3, AcOH AcO

Ruthenium Reagents - effective for the conversion of 1° alcohols to RCO2H and 2° alcohols to ketones - oxidizes multiple bonds and 1,2-. OXIDATIONS 10

RuO , NaIO CO2H Ph OH 4 4 Ph O CCl , H O, CH CN O 4 2 3 JOC 1981, 46, 3936 OH RuO4, NaIO4 Ph OH Ph CO2H CCl4, H2O, CH3CN H CH H CH 3 96% ee 3 94%ee

HO RuO2, NaIO4 O TL 1970, 4003 CCl4, 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 MeO2C MeO2C OSiMe tBu OSiMe2tBu O 2

+ N TL 1989, 30, 433 -O Me

(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 Synthesis 1979, 401 - oxidation of only the most reactive hydroxyl

O O OH Ag2CO3 O

OH OH JACS 1981, 103, 1864. mechanism: TL 1972, 4445. O O O OH Ag2CO3, C6H6 OH O O O OXIDATIONS 11 - Oxidation of 2° alcohol over a 1° alcohol OH Ag2CO3, Celite OH JCS,CC 1969, 1102 OH (80%) O Silver (AgO2) - mild oxidation of to carboxylic acids AgO , NaOH RCHO 2 RCO2H

CO2H CHO AgO2

JACS 1982, 104, 5557 Ph Ph

Prevost Reaction Ag(PhCO2)2, I2 AcO OAc Ag(PhCO2)2, I2

AcOH

AcO OH Ag(PhCO2)2, I2

AcOH, H2O

Other Metal Based Oxidations Tetroxide OsO4 review: Chem. Rev. 1980, 80, 187. -cis hydroxylation of olefins old mechanism:

O OsO4, NMO O OH Os O O OH

osmate ester intermediate cis stereochemistry

- use of R3N-O as a reoxidant TL 1976, 1973.

O OH O OsO4, NMO O OH O OH OH TL 1983, 24, 2943, 3947 Stereoselectivity: OsO4

R3 HO H R2 OsO , NMO 4 R2 HO R RO R4 3 H RO H R4 OXIDATIONS 12 - new mechanism: reaction is accelerated in the presences of an 3° R 1 R1 O R N O R 3 R2 R2 O 1 O O Os O Os R2 O Os O O [2+2] O O O NR3 [O]

[3+2] OsO R1 2 [O] R O 2 O R1 R2 Os O O + OsO4 O HO OH - Oxidative cleavage of olefins to carboxylic acids. JOC 1956, 21, 478. - Oxidative cleavage of olefins to ketones & aldehydes. OH

CHO OH O CHO OsO , NMO NaIO4 H2O 4 O OH O O O O O O O O OAc OAc OAc JACS 1984, 105, 6755.

Substrate directed hydroxylations: Chem. Rev. 1993, 93, 1307 -by hydroxyl groups HO HO OsO , 4 HO HO O pyridine O + O HO HO HO 3:1

HO OsO , O 4 HO pyridine O TMSO TMSO

CH OH OH HO 3 HO CH3 HO CH3 OsO4, Et2O OH + OH

CH3 CH3 (86 : 14) CH3

- by AcO AcO OH MeS MeS OsO4 OH HN HN O O

OAc OAc OXIDATIONS 13 - by •• O OMe •• O OMe OH S OsO4 S

OH (2 : 1) •• •• O OAc O 1) OsO4 S S 2) Ac2O HN O AcO HN O (20 : 1) - by sulfoximines O O O Ph S OH Ph S OH MeN MeN OsO4, R3NO OH D OH OH OH

CH3 Raney

H3C OH OH OH

CH3 - By nitro groups PhO2S N 1) OsO4 PhO2S N N NHR 2) acetone, H+ N NHR O2N O2N N N N N O O

N N HO N NHR HO N NHR N N N N O O

- OsO4 bis-hydroxylation favors electon rich C=C.

OsO4 X + X X OH OH OH OH

X= OH 80 : 20 (directing effect ?) = OMe 98 : 2 = OAc 99 : 1 = NHSO2R 60 : 40 (directing effect ?) - effect:

OsO4 X + OH OH K Fe(CN) , K CO OH OH 3 6 2 3 OH OH MeSO2NH2, tBuOH/H2O

OsO4 (no ligand) 4 : 1 Quinuclidine 9 : 1 DHQD-PHAL > 49 : 1 OXIDATIONS 14 Sharpless Asymmetric Dihydroxylation (AD) Chem. Rev. 1994, 94, 2483. - Ligand pair are really diastereomers!!

dihydroquinidine ester N "HO OH" Ar H H OR'

R3 R3 OH R2 0.2-0.4% OsO4 R2 80-95 % yield R1 20-80 % ee acetone, H2O, MNO OH R1 H OR' Ar "HO OH" MeO N Ar = dihydroquinine ester N R'= p-chlorobenzoyl Mechanism of AD:

L HO OH

O O O H2O Os O O

O O O Os O O First Cycle Second Cycle (high enantioselectivity) (low enantioselectivity) [O] O [O] O Os O O O O L Os O O L

O O O Os O O O

R3N HO OH

H2O, 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 Et N N N N Et N O O N N H H O O H H MeO OMe MeO OMe

N N N N (DHQ) -PHAL (DHQD)2-PHAL 2 JOC 1992, 57, 2768. OXIDATIONS 15 - Other second generation N Et Et Et Ph N N O O N O H H H MeO N N OMe O OMe

Ph N N N PYR IND

Proposed catalyst structure: "Bystander O Os Asymmetric O H N (side wall) MeO N Binding O Os Cleft O N H H N N N N O O

Phthalazine OMe Floor N

OMe OMe

O

Corey Model: JACS 1996, 118, 319 N O O like binding pocket; O Os O N H [3+2] addition of OsO4 to olefin. N O N N O O N

DHQL

Rs R M RL large and flat, i.e Aromatics work particularly well

RL H

DHQ OXIDATIONS 16 Olefin Preferred Ligand ee's

R1 PYR, PHAL 30 - 97 %

R2 PHAL 70 - 97 % R1

R 1 IND 20 - 80 % R2

R2 R1 PHAL 90 - 99.8 %

R2

R3 R 1 PHAL 90 - 99 % H

R2 R3 PHAL, PYR 20 - 97 % R1 + MeSO2NH2 R4

"AD-mixes" commercially available pre-mix solutions of Os, ligand and reoxidant AD-mix a (DHQ)2PHAL, K3Fe(CN)6, K2CO3, K2OsO4 (0.4 MOL % Os to C=C) AD-mix b (DHQD)2PHAL, K3Fe(CN)6, K2CO3, K2OsO4

O HO O Campthothecin N N O

OMe OMe OMe AD N O (DHQD)2PYR N O N O

94 % ee OH O OH OH

- Kinetic resolution (not as good as Sharpless asymmetric epoxidation) H Ph Ph H olefins with axial dissymmetry tBu tBu

H H Ph Ph AD mix a OH Ph OH 30% conversion H OH + + Ph OH tBu H tBu tBu (4 : 1) tBu

enriched OXIDATIONS 17 Asymmetric Aminohydroxylation TL 1998, 39, 2507; ACIEE 1996, 25, 2818, 2813, preparation of a -aminoalcohols from olefin. Syn addition as with the dihydroxylation regiochemistry can be a problem

O O Cl OH Ph O N Ph O NH CO2Me Na + Ph CO2Me Ph CO2Me Ph N O Ph K2OsO6H4 (cat) Ligand OH O Ligand= PHAL 4:1 AQN 1:4

Molybdenum Reagents MoOPH [MoO5•pyridine (HMPA)] JOC 1978, 43, 188. - a -hydroxylation of ketone, ester and enolates.

O O O- O O THF, -78°C + Mo R' R' O R R O L L OH

Palladium Reagents Pd(0) catalyzed Dehydrogenation (oxidation) of Allyl Carbonates (Tsuji Oxidation) Tetrahedron 1986, 42, 4361 O R O CO 2 R Pd(0) R R OH O H H O O H O Pd - CO2 - R Pd(OAc)2, R R R CH CN, 80° C 3 TL 1984, 25, 2791 Tetrahedron 1987, 43, 3903

HO H HO OH O CO H 2 OH JACS 1989, 111, 8039. Pd2(DBA)3•CHCl3, H O OH CH3CN, 80° C H O O

Oxidation of silylenol and carbonates to enones O OTMS Pd(OAc)2, O CH3CN

O

O O Pd(OAc)2, O CH3CN

OTIPS O (NH4)2Ce(NO3)6 DMF, 0°C Ph Ph TL 1995, 36, 3985 OXIDATIONS 18 Synthesis 1994, 1007 Organic reactions 1951, 6, 207

OiPr R1R2CHOH OiPr O O Al O + H + Al + Al(OiPr)3 (CH ) C=O OiPr 3 2 O R1 R2 R1 OiPr R2 Nickel Chem Rev. 1975, 75, 491 (TNN, Tl(NO3)3•3H2O Pure Appl. Chem. 1875, 43, 463. Tetraacetrate Pb(OAc)4 Oxidations in Organic (D), 1982, pp 1-145.

Non-Metal Based Reagents Activated DMSO Review: Synthesis 1981, 165; 1990, 857. Organic Reactions 1990, 39, 297 Me Me Me E + Nu: + S+ O- + E S O Nu S + E-O Me Me Me E= (CF3CO)2O, SOCl2, (COCl)2, Cl2, (CH3CO)2O, TsCl, MeCl, SO3/pyridine, F3CSO2H, PO5, H3PO4, Br2 Nu:= R-OH, Ph-OH, R-NH2, RC=NOH, - trifluoroacetic anhydride can be used as the activating agent for DMSO O Me Me Me (COCl)2 Cl - -CO, -CO2 + S+ O- S+ O Cl S Cl CH Cl , -78°C Me 2 2 Me O Me

Me R Et N: R Me R2CH-OH + R 3 S O O + S Me Me H R B: O O Cl DMSO, (COCl)2 TL 1988, 29, 49.

CH2Cl2, Et3N OH O Moffatt Oxidation (DMSO/DCC) JACS 1965, 87, 5661, 5670. Me C 6H11 Me R + - S O CF CO H, + R R 3 2 Me NH S O Pyridine R2CH-OH O Me + Me S O C H + R Me N C H N C N C H B: 6 11 6 11 C 6H11

CHO OH DCC/ DMSO JACS 1978, 100, 5565 CO2Me CO2Me CF3CO2H, O Pyridine O S S

SO3/Pyridine JACS 1967, 89, 5505. CO2Me CO2Me HO HO H OH H SO3, pyridine, CONH CONH DMSO, CH2Cl2 2 2 JACS 1989, 111, 8039. O H OH H HO OXIDATIONS 19 Corey-Kim Oxidation (DMS/NCS) JACS 1972, 94, 7586. O Me Me S: + N Cl S+ Cl Me Me O N-Chlorosuccinimide (NCS) Oxygen & Ozone Singlet Oxygen Acc. Chem. Res. 1980, 13, 419 Tetrahedron 1981, 37, 1825 • • • • hn • • • O O • • • • •O O • • • • • • triplet singlet

"ene" reaction H H Ph3P: O O O OH O Tetrahedron 1981, 1825

1) O2, hn, Ph2CO HO 2) reduction

Ozone Comprehensive Organic Synthesis 1991, 7, 541 O O Ph P: O3, CH2Cl2 O O 3 O + O -78°C O O NaBH4

H Jones OH

RCOOH

Other Oxidations Mukaiyama Oxidation BCSJ 1977, 50, 2773 O N N N N R R PrMgBr O R CH OH CH O MgBr O R R THF R

OH OHC Cl CH Cl CH 3 O O O 3 O MeO NH MeO NH O N N N N O OEt OEt O O tBuMgBr, THF SEt (70%) SEt SEt SEt MeO MeO

JACS 1979, 101, 7104 OXIDATIONS 20 OH O tBuMgBr, THF

O N N N N O O O

Dess-Martin Periodinane JOC 1983, 48, 4155. JACS 1992, 113, 7277. - oxidation conducted in CHCl3, CH3CN or CH2Cl2 - excellent reagent for hindered alcohols - very mild AcO OAc OAc • • I R CH-OH R I OAc 2 O O + O + 2 AcOH R O O

Dess-Martin O HO (99%) JOC 1991, 56, 6264 RO RO Chlorite -oxidation of a,b -unsaturated aldehydes to a,b- unsaturated acids. Tetrahedron 1981, 37, 2091

NaClO2, - HClO2 NaH2PO4 OBn OBn tBuOH, H2O OBn OH CHO H CO2H -O-Cl-O Dioxide - Similar to singlet oxygen (allylic oxidation)

1) SeO2 2) NaBH 4 OAc OAc

OH Phenyl Selenium Chloride Ph OLi O O O SePh Se PhSeCl H2O2 - PhSeOH O- THF H - -SPh will do similar chemistry however a elimination is less facile than a selenoxide elinimation.

Peroxides & Peracids - R3N: ® R3N-O - sulfides ® sulfoxides ® -Baeyer-Villiger Oxidation- oxidation of ketones to esters and via oxygen insertion Organic Reactions 1993, 43, 251 Comprehensive Organic Synthesis 1991, vol 7, 671. OXIDATIONS 21 m-Chloroperbenzoic , Peracetic Acid, peroxide O H O H

O O2N O O O

Cl NO2 H O O O R C R R R 1 2 1 2 R2 + ArCO2H O R1 O O O Ar HO O Ar 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 HO O O mCPBA O CO2H CHO

O O HO CO H O 2 HO OH

PGE1 O O

CH3 mCPBA O Tetrahedron Lett. 1977, 2173 Tetrahedron Lett. 1978, 1385 (80 %) CH3 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 R N C 3 R R2 - hydroxylation of enolates O _ O O R O R' R R _ R + R' R' R' PhSO2N=CHPh O NSO2Ph O Ph HO Ph N PhSO2 O By- _ O R supresed by using R' bulkier oxaziradine R + PhSO2N=CHPh such as R' oxaziradine Ph NHSO2Ph OXIDATIONS 22 Asymmetric hydroxylations O O NaN(SiMe3)2, THF HO MeO2C Tetrahedron 1991, 47, 173 MeO2C OMe OMe N (67% ee) Ar SO2O MeO O MeO O O OH O OH KN(SiMe3)2 CO2Me CO2Me OH OH

MeO N MeO MeO O OH OH SO 2O (>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) Comprehensive Organic Synthesis 1991, 7, 39. Barton Reaction

NOCl, CH2Cl2 pyridine hn - NO OH O • O NO • OH H •

•NO JACS 1975, 97, 430

OH OH NO N N HO perhydrohistricotoxin ketone C5H11

Epoxidations Peroxides & Peracids - olefins ® Tetrahedron 1976, 32, 2855 - a,b -unsaturated ketones, aldehydes and ester ® a,b -epoxy- ketones, aldehydes and esters (under basic conditions). O O tBuOOH triton B, C6H6 O JACS 1958, 80, 3845 (CH2)n (CH2)n OXIDATIONS 23 O CO Me CO2Me 2

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 + O

10:1 diastereoselection OAc OAc OH mCPBA O + O

1:4 diastereoselection O O Ph NH Ph NH mCPBA "highly selective" O

Ar

O O H proposed transition state: O H -OH directs the epoxidation O

H

- for acyclic systems, the Henbest epoxidation is often less selective

Rubottom Oxidation: JOC 1978, 43, 1588

O OTMS TMSO O O H2O LDA, TMSCl mCPBA 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. OXIDATIONS 24 - Catalysts: VO(acac)2; Mo(CO)6; Ti(OiPr)4 - Oxidant: tBuOOH; PhC(CH3)2OOH VO(acac)2 tBuOOH OH OH O

OH OH

O (CH2)n (CH2)n

ring size VO(acac)2 MoO2(acac)2 mCPBA 5 >99% -- 84 6 >99 98 95 7 >99 95 61 8 97 42 <1 9 91 3 <1

Acyclic Systems: tBu O R L M 1 R3 R 1,3-interaction L t O O R3 Rc Rt R2 O R 1 Rc O A1,2-strain M O R 2 L L A1,3-strain Major influences: A1,2-Strain between Rg and R1 (Rg and R2) A1,3-strain between R2 and Rc (R1 and Rc) 1,3-interactions between L and R1 (L and R2)

VO(acac)2, tBuOOH + O O OH OH OH (4 : 1)

tBu CH 3 H L O H M H O O L O M L O H L H3C O H tBu H OXIDATIONS 25

VO(acac)2, tBuOOH + O O OH OH OH (19 : 1)

tBu H H C L O 3 H M H O O L O H3C H C O 3 H M L H L H O tBu CH3

SiMe SiMe SiMe3 3 3 VO(acac)2, tBuOOH + O O OH OH OH (> 99 : 1)

- Careful conformational analysis of acyclic systems is needed.

Homoallylic Systems L L V OtBu O O O OH OH

dominent stereocontrol element

Titanium Catalyst structure: RO2C OR OR RO CO2R O O Ti Ti O O O OR O OR

OR

CO R CO R OR 2 2 O OR O CO R RO 2 RO CO2R Ti O O O Ti Ti Ti O CO2R O O O CO R O O O O O 2 O O

tBu tBu OR OR Disfavored Favored OXIDATIONS 26 Asymmetric Epoxidation tBuOOH, Ti(OiPr), (+) or (-) Diethyl Tartrate, 3Å molecular sieves Empirical Rule

R1 R2 (+)- DET epoxidation from the bottom (-)- DET epoxidation from the top R3 OH

Catalytic system: addition of molecular sieves to "soak" up any with 3A sieves, 5-10 mol % catalyst is used. Preparation of Allylic Alcohols:

[(CH3)2CHCH2]2AlH Na (MeOCH2CH2O)2AlH2 CO2R' R (DIBAL) R OH (REDAL) R CHO R C C CH2OH R R [(CH3)2CHCH2]2AlH CO2R' OH H2, Lindlar's Catalyst

"In situ" derivatization of water soluble epoxy-alcohol (-)-DIPT O OH

(R)-glycidol OH water soluble O OH (+)-DIPT (S)-glycidol O O O organic soluble OH O S NO2 O

Alkoxide opening of epoxy-alcohol product reduced by use of Ti(OtBu)4 and catalytic conditions

- O O O OH OH OH R from R Ti(OiPr)4

Stoicheometric Catalytic epoxidation: (+)-DET Ti(OiPr)4 tBuOOH O OH OH

stoicheometric: 85% ee catalytic (6-7 mol %) 47% yield >95% ee in situ deriv. with PNB 78% yield 92 % ee >98 %ee after 1 recrystallization (+)-DET R Ti(OiPr)4 R tBuOOH O OH OH yields: 50 - 100 % ee: > 95% OXIDATIONS 27 Ring Opening of Epoxy-Alcohols REDAL OH R OH 1,3- AE O R OH R OH

R OH DIBAL OH 1,2-Diol

Two dimensional amplification

OH OH OH

(+)-DIPT, Ti(OiPr)4, tBuOOH, 3A sieves +

(90 % ee)

O O OH OH OH 95 : 5 major minor

major minor major minor

95 : 5 95 : 5 OH O OH OH O O

O OH O O OH OH

90 % meso 0.25 % (>99.5 % ee) 9.75%

Kinetic Resolution of Allylic Alcohols (+)-DIPT, Ti(OiPr)4, OH tBuOOH, 3A sieves O OH + OH

R R R

CO2R OR O H RO CO2R Ti O Ti O O CO R O O O 2 O

tBu OR OXIDATIONS 28

R3 R4 kinetic resolution R3 R4 R3 R4 -20 °C, 0.5 - 6 days O OH OH + OH R2 R2 R2

R1 R1 R1

40 - 50 % yield 40 - 50 % yield > 99 % ee high ee

Reiterative Approach to the Synthesis of OR OR (+)-DET, Ti(OiPr)4, DIBAL tBuOOH, 3A sieves OR (MeO)2P(O)CH2CO2Me NaH CHO OH CO2Me

OR OR OR OR HO- OH OH acetone, H+ O mCPBA, Ac2O O O OH PhS- HO O Pummerer SPh SPh PhS- CHO OR OR OR HO H O O O DIBAL HO H

OAc O HO H O CHO O O HO H SPh O CHO CH2OH L-glucose

Jacobsen Aysmmetric Epoxidation JACS 1990, 112, 2801; JACS 1991, 113, 7063; JOC 1991, 56, 2296. - Reaction works best for cis C=C conjugated to an aromatic ring

H H H H N N NaOCl N N Mn Mn O O O Cl O O

tBu tBu tBu tBu

O 5 mol % Cat. ,NaOCl, O H2O, CH2Cl2

(98% ee) O

86% ee

O

Methyltrioxoruthenium (MTO) Ru(VII) Sharpless et al. JACS 1997, 117, 7863, 11536. 0.5 mol % MTO Ru (VII), Ph Ph pyridine, CH2Cl2 O 1.5 eq. 30% H2O2 (aq.) OXIDATIONS 29 - Asymmetric epoxidation of olefins Tetrahedron 1989 45 5703 CH3 O2 O Ph S * N N * C6F5 Ph *

Dioxiranes (Murray's Reagent) Reviews: Chem. Rev. 1989, 89, 1187; ACR 1989, 27, 205 Org. Syn. 1996, 74, 91 KHSO5 O O "oxone" O - epoxidation of olefins O OTBS OTBS O TBSO O TBSO O JOC 1990, 55, 2411 TBSO TBSO CH2Cl2, acetone (100%) O

- Asymmetric epoxidation JACS 1996, 118, 491. - oxidation of sulfides to sulfoxides and sulfones - oxidation of to amine-N- - oxidation of aldehydes to carboxylic acids - hydroxylation of enolates

1) LDA OH 2) Cp2TiCl2 H JOC 1994, 59, 2358 O 3) O O O - bis-trifluoromethyldioxirane, much more reactive JACS 1991, 113, 2205. F3C O O F3C - oxidation of alcohols to carbonyl compounds. 1° alcohols give a mixture of aldehydes and carboxylic acids. - Insertion into 3° C-H bonds to give R3C-OH

DCC-H2O2 JOC 1998, 63, 2564 R O O N H R H2O2, MeOH + H C H R N C N R H C O R N N N O R R R