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Home , Aldehyde, Alkoxide, Chromate ester, Chromic acid, Chromium trioxide, Citronellol

Key words: oxidations using and reagents, cleavage of double bonds with and tetroxide, oxidations with aluminum isopropoxide, peracids, Introduction Broader definition of oxidation and reduction respectively refer to the loss and gain of electrons, or an increase in oxidation number (oxidation) Definition and a decrease in oxidation number (reduction). In organic , the gain of or loss of is often referred to as oxidation. In practice, a series of functional groups have been qualitatively identified in the order of increasing . Then, oxidation is referred to as the conversion of one higher in the sequence to another lower in the list. Conversion within a group are neither oxidation nor reduction. It is summarized in following table.

This module has been organized based on the reagent that are used for oxidation reactions oxidation Table summarizing O functional groups RH CO arranged according 2 to oxidation state. OH ROH O O RCl CCl4 RNH2 etc. R R R NH2

Cl

C Cl C Cl

Cl Cl

C C etc.

Cl Cl

C C

OH OH

etc. reduction I. Oxidation of For oxidation of to corresponding carbonyl compounds, generally alcohols using Cr(VI) reagents such as K2Cr2O7, Jones reagent, PCC etc., are employed. Cr(VI) reagents  Oxidation of alcohols to carbonyl compound occurs via Cr(VI) monoester. Mechanism is as follows.

OH O

CrO3

R1 R2 R1 R2

O HO H O O Cr O O O Cr O + + H2CrO3 R1 C H 1 1 2 O R C H R R R2 R2 Example for chromium based oxidation Oxidation of fused aromatic system is generally carried 4mmol CrO3 out using CrO3 reagent 60 min, rt Juaristi M. et al, Can.J.Chem., O 1984, 62, 2941 O 80% PCC (pyridinium chlorochromate) is other efficient reagent used widely for oxidation of primary and secondary alcohols. E J Corey and W Suggs in 1975 suggested PCC as . PCC is Reagent can be used in slightly acidic but can be buffered with NaOAc close to stoichiometric O amounts with substrate HN Cl Cr O

O O

OH H HO H

O 1,6-Hexanediol Hexanedial (68%) Corey E J & Suggs W, Tet.Lett., 1975, 16, 2647 OH O

Benzhydrol Benzophenone (100%)

OH O

4-tertbutylcyclohexanol 4-tertbutylcyclohexanone (97%) Corey and Suggs used H OH following method for O preparation of PCC. R R

100g (1mol) CrO3 is added to conc. HCl, R rapidly with stirring over R 5 min time. Homogenous Presqalene Presqalene (78%) obtained is R : (CH ) CCH(CH )CH CH C(CH )=CHCH CH - cooled to 00C. To this, 3 3 3 2 2 3 2 2 1mol of is added. Yellow- OH O obtained is filtered H and dried in vacuum. This solid is PCC and is not hygroscopic. It can be stored at room Citronellol (82%) temperature. PCC is used particularly for the oxidation of to aldehyde. It does not have any effect on C=C or any other easily oxidizable functional groups.

In this reaction, double O PCC, DCM bond is not affected. OH H

Geraniol Geranial

PCC is used in aprotic solvents, usually, . As no water is present in the reaction mixture, no aldehyde hydrate is formed which is oxidized to in presence of Cr(VI)

PCC, dry CHCl3, Agarwal S; Tiwari H anhy. AcOH, rt, 1h O P; Sharma J P, OH Tetrahedron, 1990, 46, H 1-Hexanol 1-Hexanal (89%) 4417  Another similar oxidant is PDC (pyridiniumdichromate)

H O 1.5eq PDC OH DCM, 250 C O O 90%

O O

NH O Cr O Cr O HN

O O

pyridiniumdichromate

Since PDC is less acidic than PCC it is often used to oxidize alcohols that may be sensitive to . In methylene chloride solution, PDC oxidizes primary and secondary alcohols in roughly the same fashion as PCC, but much more slowly. However, in DMF solution saturated primary alcohols are oxidized to carboxylic acids.

In both solvents allylic alcohols are oxidized efficiently to conjugated enals and enones respectively. Stanfield C F, et al, J. examples Org. Chem., 1981, 46, 4797

3.5eq PDC 1.5eq PDC COOH DMF, 250 C DCM, 250 C CHO OH

83% 92%

1.5eq PDC, OH DCM, 250C, 24h O O CHO

90% Corey E J & Schmidt COOH G, Tet.Lett., 1979, OH O O 20(5), 399 3.5eq PDC, DMF, 250C, 7-9h

H H

85% can be  Collins reagent is the mixture of chromium prepared and isolated or trioxide with pyridine in dichloromethane. generated in situ. It is used to selectively oxidize primary alcohols to aldehyde, and will Isolation of reagent often tolerate many other functional groups in the molecule. to improved yields. CrO3-2Py R H R DCM OH O

It can be used as an alternative to Jones reagent and PCC in oxidation of secondary alcohols. Moreover, Collins reagent is especially useful for oxidations of acid sensitive compounds. This complex is both difficult and dangerous to prepare, as it is very hygroscopic and can inflame during its preparation. It is required to be used in a sixfold excess in order to complete the reaction. examples O one of the steps in the O synthesis of O O prostaglandin F2α CrO3-2Py DCM, 00C employs Collin’s reagent as oxidant H OH AcO Corey E J, JACS, 1969, AcO O 91, 5675 one of the steps in OH synthesis of longifolene O employs Collin’s reagent H CrO -2Py, DCM, 3 H as oxidant rt, 15min

McMurry J E, JACS, OH 1972, 94, 7132 H O 100% one of the steps in synthesis of triquinacene employs Collin’s reagent as oxidant CrO3-2Py, DCM Woodward RB, JACS, H O 1964, 86, 3162 OH 74% Jones described for the  Jones reagent is used for the oxidation of primary and first time a convenient secondary alcohols to carboxylic acids and , respectively, that do and safe procedure for a not contain acid sensitive group. chromium (VI) based oxidants, that paved way for some further developments such as Collins Reaction and pyridinium dichromate. It is chromium oxide, and . A mixture of or dichromate and dilute sulfuric acid can also be used.

CrO3, aq.H2SO4 O acetone R OH R OH

OH CrO3, aq.H2SO4 O acetone

R R' R R' O Mechanism : O H2SO4 H2O HO Cr OH or Cr O O with O dilute H2SO4 in situ forms chromic acid . O O H2SO4 H2O Chromic acid and HO Cr O Cr OH Na2Cr2O7 alcohol then through O O chromate gives carbonyl compound in Dichromic acid .. presence of (water H2O O OH O H in this case). VI VI R' HO Cr OH + HO Cr O The intramolecular R R'

reaction occurs by way O H O R .

.. . . of β-elimination through O O . cyclic transition state. + H O ..Cr IV 3 R R' HO O O VI OH can form O HO Cr OH H2O hydrates in presence of O R OH water and further R H H oxidized to carboxylic

. .. .

. O . acid in presence of H .. O OH O VI H2O Cr(VI) reagents. HO Cr O + .. IVCr -H3O R OH HO O O R The Jones reagent is The oxidation of primary allylic and benzylic alcohols gives aldehydes. prepared by adding Some alcohols such as benzylic and allylic alcohols give aldehydes that chromium trioxide to do not form hydrates in significant amounts; these can therefore be dilute sulfuric acid in selectively oxidized with unmodified Jones Reagent to yield aldehydes. acetone and is added to the alcohol at 0-25oC. K2Cr2O7, H2SO4 CHO OH 0 H2O, acetone, 0-25 C

The excess Cr(VI), if any is remained, is destroyed CrO , H SO , H O, in the reaction workup 3 2 4 2 O acetone, 0-250C by adding . OH H

For the synthesis of aldehydes, the Collins Reaction or use of more modern although more expensive chromium (VI) reagents such as PCC and PDC can be an appropriate choice. Tertiary alcohols cannot be oxidized by this reagent. It is a powerful oxidizing reagent and exhibits only poor chemoselectivity. OH CrO3, aq.H2SO4 O 0 oxidation of secondary H2O, acetone, 0-25 C alcohol gives whereas primary alcohol is oxidized to aldehyde OH CHO COOH first and then to CrO3, aq.H2SO4 0 (O) carboxylic acid. H2O, acetone, 0-25 C

H H Jones reagent, acetone, Panda J; Ghosh S & 00C - rt, 1h Ghosh S, ARKIVOC, O O 2001(viii), 146 H H H OH O MnO2 is used widely as oxidant in organic synthesis. II. Oxidation using It oxidizes allylic alcohols to corresponding aldehydes or ketones.

Mn reagents O MnO2 R OH (a) Mn(IV) reagent R H

The configuration of double bond is preserved in the reaction. Also, acetylenic alcohols and benzylic alcohols are oxidized under similar conditions.

Applications of MnO2 are numerous. These include many kinds of reactions such as oxidation, aromatization, oxidative coupling, and oxidation.

Activity of MnO2 S S depends upon method of MnO2, DCE preparation and choice 2 2 1 R R1 R of solvent R N N

1,2- are cleaved by MnO2 to dialdehydes or diketones.

OH MnO2, DCM, O Ph rt, 24h Ph 2 Ph H OH MnO , rt, 5d CH OH 2 examples 2 Pet.

vit.A Taylor R J K; et al,

Acc. Chem. Res., 2005, CHO 38, 851.

retinal (80%) oxidation of benzylic and 10eq. MnO2, DCM, rt, 24h allylic alcohol with OH CHO MnO2 in mild condition 84%

10eq. MnO , Aoyama T; et al, O 2 O CHO OH DCM, rt, 24h Synlett, 1998, 35. O O 95% dehydration is also 10eq. MnO2, accomplished in good DCM, rt, 24h yields + NH N N

1,2,3,4-tetrahydroisoquinoline 3,4-dihydro- (8%) -isoquinoline (83%) More examples

Oxidation of allylic OH COOMe alcohol to corresponding ester in MnO2, hexane methanolic solvent. MeOH, NaCN E J Corey; N W Gilman; B E Ganem, JACS, 1968, 90, 5616

N N O

MnO2, 1,4-dioxane

Husinec S; et al, COOMe COOMe Tet.Lett., 2011, 52, COOMe COOMe

2733 45% (b) Mn (VII) reagents Manganese can function as oxidant when it is in +7 oxidation state.

KMnO4 is one such oxidant. It is a very strong oxidizing agent. side chains on aromatic rings are oxidized to carboxylic acid group. This method is more generally applied to , however, longer side chains can also be cleaved. Tertiary alkyl groups are not oxidized and are usually accompanied by ring cleavage.

KMnO4 is also used to oxidize primary alcohol and aldehyde to corresponding carboxylic acid. Protected hydroxy aldehydes are oxidized to corresponding carboxylic

acids with KMnO4 buffered with mixture of tBuOH and aq. NaH2PO4 Abiko A; Roberts J C;

Takemasa T & KMnO , 5min CHO 4 COOH Masamune S, Tet.Lett., tBuOH -5%NaH2PO4 O O O OSiMe tBu 1986, 27, 4537 O O O OSiMe2tBu 2

Ph Ph 97%

Jefford C W; Li Y;

Wa n g Y, Org. Syn., KMnO4, CuSO4 DCM, 6-8h, 250C 1998, 9, 462

HO O

HO

O

In this reaction KMnO4 first oxidizes primary alcohol to corresponding carboxylic acid which subsequently cyclizes to give a . More examples

O KMnO4, MnO2 solv. free, 6h oxidation using KMnO4 supported on MnO2 under heterogenous and 85% solvent free conditions O S KMnO4, MnO2 S O Shaabani A; et al, Tet., DCM, 29h 2004, 6, 11415.

72%

OH KMnO4, MnO2, )))) O solv. free, 2h 30min

H H 64% This reaction is also used Dilute of KMnO4 convert into diols. as a qualitative test for the presence of double or KMnO4 triple bonds in a molecule, since the HO OH reaction decolourises the Dihydroxylation of alkenes using alkaline KMnO4 is a stereoselective syn solution. It addition of two hydroxyl groups across a double bond. is sometimes referred to The reaction is believed to proceed through a cyclic permanganate ester as Baeyer's reagent. intermediate.

O OK O OK OH Mn Mn

O O O O OH

Though the presence of such an intermediate can not be confirmed by actual isolation. But, some of them are detectable spectroscopically also 18 - use of Mn O4 in the reaction to formation of 1,2-diols in which both the oxygen atoms were labeled. So, it can be concluded that both of 18 - them are coming from Mn O4 , and hence the presence of an intermediate cyclic permanganate ester can be confirmed. Under acidic conditions, the double bond is cleaved to give a carboxylic acid.

D J Sam; H E + Simmons, JACS, 1972, KMnO4, H 17 94, 4024 17 COOH

O

KMnO4, DC-18[C]-6 Synthesis, 1984, 43, COOH 443 NaMnO4, sodium permanganate is similar oxidant to KMnO4. It oxidizes primary alcohol to acid and secondary alcohol to ketones but does not have any effect on multiple bonds.

OH O

Menger F M and Lee NaMnO4 .H2O, DCM,410C, 24h C, Tet.Lett., 1981, 22, 1655.

HO HO H H

5α-Androstan-17β-ol 5α-Androstan-17-one (84%) III. Oxidation using OsO4 is primarily used in cis dihydroxylation of olefins. Os reagent Os(VIII) reagent OH OsO4 hydrolysis

OH

O O 0 OH 1. OsO4, THF, 25 C, 48h 2. H2S

p-electrons of olefins act Mechanism of reaction goes through the formation9 of0% 5O-Hmembered cyclic as a and ester intermediate. forms favorable 5- membered ring as cyclic osmate ester by attacking OsO . This is considered 4 O O O O OH HO O as the origin of cis hydrolysis stereoselectivity. Os Os + Os O O O HO O This osmate ester upon O OH hydrolysis liberates cis and reduced osmium species. OsO4 is toxic and is used in catalytic amounts in reaction. It can be reoxidized using co-oxidant such as NMO, K3Fe(CN)6, etc.

NMO = N-methyl morpholine

O OH OsO , NMO O 4 O O OH OH

OH

OCOCH3 OCOCH3

OH OsO4-NMO tBuOH/ THF/ H2O HO (10:3:1) HO OH

O O 78%

The use of NMO in catalytic OsO4 reactions was first reported for the introduction of corticoid (an α-ketol) in a (as shown above). OsO4 is also used for oxidative cleavage of olefin. It forms carbonyl compound. H

O O O O O O OsO4, NMO O Oxidative cleavage of O O olefins using OsO4 -

NaIO4 in presence of 2,6- O O lutidine O O OCO2CH2Ph OCO2CH2Ph Yu W; Mei Y; Kang Y; Hua Z and Jin Z, Org.Lett., 2004, 6, 3217.

0.02eq OsO4, 4eq NaIO4, 2eq 2,6-lutidine, 3h, O dioxane-water (3:1) O O O CHO

OTBS OTBS 81% Oxidation of primary and secondary alcohol with ketone in the presence of metal to corresponding aldehyde or ketone is known as Oppenauer I V. . oxidation

OH O O OH Al(iPrO)3 + +

R1 R2 R1 R2

The reaction is completely reversible and can be driven to completion according to Le Chatlier’s principle by addition of excess of ketone.

In the first step of the iPrO OiPr mechanism, alcohol, Al OH O and acetone -iPrOH O O coordinates to form a + Al(iPrO)3 + R1 R2 complex. This complex R1 H then, via a six-membered R2 chair like transition state transfers hydride from α- iPrO OiPr iPrO OiPr of the alcohol to the Al Al O alcoholysis O O O carbonyl carbon of acetone O to give the desired ketone R1 R2 1 H R H 1 2 as product. R2 R R six membered T.S. . In 1937, Oppenauer Oppenauer oxidation has many advantages. discovered this reaction.  mild reaction conditions.  most functional groups are tolerated (If substrate contains basic . Reaction is reverse of then use of alkoxide is necessary instead of Al- Meerwein-Ponndorf- isopropoxide). Verley reduction.  in order to achieve reasonable reaction rate, stiotiometric amount of Al-alkoxide to be used (Al-isopropoxide, Al-tertbutoxide, Al-phenoxide can be used).  wide range of substrates are oxidized.  secondary alcohols are oxidized faster than primary alcohols. Due to this secondary alcohols can be oxidized chemoselectively over primary ones.  over oxidation to carboxylic acid does not happen.  oxidation of 1,4 and 1,5-diols yields .  acetone is most often used as an oxidant but aromatic and aliphatic aldehyde are suitable as oxidants due to low reduction potential.  addition of protic acid dramatically increases the rate of oxidation.  oxidation can be conducted using heterogenous . It has advantage over homogenous catalysis as product can be separated easily from a reaction mixture. O O Synthetic applications 1. Al(OiPr) , 3 TsOH, Et2O OH reflux, 5h OH 18h, rt

N O Syntheses of Estrone HO 2. 1% HCl, 00C O from tetracyclic diol 78% O

HO Estrone Syntheses of linearly 1. 1.7eq Al(OiPr)3 fused triquinane dry tol, reflux, (4+2) acetone, 9h (±)-hirsutene. 2. 10% HCl, 250C

OH O 47%

H H H

COMe

( )-Hirsutene

O O syntheses of hormone Al(OiPr)3 acetone H H

H H H H

HO O Progesterone Syntheses of steroid derivative OBz OBz 18.1eq p-quinone Oppenauer oxidation 1.6eq Al(OtBu)3 tol., 1h, using strong oxidant H H p-quinone H H H H acetone, HO O or N-methylpyridinone gives over oxidation OH O

Cl3CCHO trichloroacetaldehyde Al2O3, CCl4 on alumina is used as oxidant.

HO HO secondary alcohol gets readily oxidized over primary.

p-quinone oxidation of Al(OiPr)3 tol., 45 min cholesterol using H H

p-quinone H H H H HO O Oxidation of Carveol:

OH O 1mol% cat. 1.2eq tBuCHO Ooi T; Otsuka H; tol., 210C, 1h Miura J; Ichikawa H; Maruoka K; Org. Lett., 2002, 4, 2669. 94% Catalyst: 3mol% cat. 1.2eq acetone SO2C8F17 tol., 210C, 2h N OH O AlMe 80% O

Mello R; Martinez-Ferrer J; Asensio G; Slena M, JOC, 2007, 72, 9376. OH O 3eq 3-nitrobenzaldehyde 10mol% AlMe3, tol., rt, 0.5h

>99%

OH O 3eq 3-nitrobenzaldehyde Graves C R; Zeng B 10mol% AlMe3, tol., rt, 0.5h S; SonBinh T N,

JACS, 2006, 128, S S 12596. >99%

OH O 1.2eq 2,4-dinitrobenzaldehyde 10mol% AlMe3, tol., rt, 1h

88%

O OH O F C H 3 H EtOAlEt2, Mello R; Martinez- DCM, rt, 18h Ferrer J; Asensio G; Slena M, JOC, 2007, 72, 9376. H H 26% H Al(OiPr)3, tol., reflux, 6h Raggio M L; Watt D H S, JOC, 1976, Vol.41, N O No.10, 1873. H H

HO β-Sitosterol

H

H

H H

O 24-Ethylcholest-4-en-3one (71%) V. Ozonolysis involves the cleavage of olefins with ozone. It forms either carbonyl compound or carboxylic acid depending on work up procedure.

1 3 R R O O 1. O3 2. Zn/ H2O +

1 2 3 4 R2 R4 R R R R

Ozonolysis is an oxidative cleavage (like permanganate). But, it is comparatively mild reaction and no overoxidation is seen.

R1 R2 O O O , DCM Me S 3 R1 R2 2 R1CHO + R2CHO O H H H H

example O

0 1. O3, MeOH, -78 C oxidation of eugenol to 2. Me2S corresponding aldehyde

O O

OH OH Reductive work up forms aldehydes and ketones while in oxidative work up aldehydes are further oxidized to corresponding alcohol.

H R' O O O , DCM 3 H R'

O R R" R R"

reductive work up oxidative work up work up of NaBH4 PPh3/ Me2S H2O2

O O

R OH R H R OH + + +

OH O O

R' R" R' R" R' R" Overall result is that double bond is replaced by an ozonide ring. Ozone is high energy Ozonolysis is a two step reaction. form of oxygen, produced when UV First step is 1,3-dipolar addition of ozone across the double bond, to give light or electrical molozonide. It rapidly undergoes rearrangement to give ozonide. discharge passes R2 O through oxygen gas. O O O O O O O retro R1 1,3- 1,3-cycloaddition + R1 R 3 R4 Lewis structure has R1 R3 central oxygen R2 R4 O R2 R 4 positively charged and molozonide each outer oxygen has R3 ½ negative charge. O O O O O 1,3-cycloaddition 1 3 acidic work up R R + O O O 1 2 3 4 R 2 R4 R R R R

ozonide

Second step is work up. Oxidative work up can be done by aqueous acid O while reductive work up by and water or dimethyl or Pd-H2. O O More details on Molozonide or primary ozonide has peroxy linkage which makes it ozonolysis reaction unstable and it undergoes rapid rearrangement to give ozonide. On the other hand, ozonide is stable but is rarely isolated. It is reduced with mild reducing agents to give aldehydes or ketones.

S O O O O + S O

O O3

O O

H H + O O

H CHO H H

1. O3 2. Me2S CHO

CHO H H CHO H Ozonolysis does not afford information about stereochemistry of alkene. Thus, 1 and 2 give same carbonyl compound.

R1 R3 O O R1 R4

Key facts about O3 O3 + ozonolysis 1 2 3 4 R2 R4 R R R R R2 R3

1 2 Ozonolysis is mainly used to determine the position of a double bond in an alkene.

1. O3 2. Me S 2 CHO CHO

O

O 1. O3 2. Me2S

O

1. O3 2. Me2S CHO

CHO 0 O3/ O2, 0 C O 5%H2O/ acetone AcO H AcO H

81%

H 0 H Schiaffo C E & O3/ O2, 0 C Dussault P H, JOC, 5%H2O/ acetone 2008, 73, 4688. O O O 100% VI. Epoxidation Epoxidation is a reaction in which C=C of an olefin is converted to an (or oxirane), a cyclic ether.

O peracid

Commonly used reagents are peracid or peroxyacid, , etc., Addition of oxygen to C=C is syn stereoselective epoxidation of O perbenzoic acid 0 using perbenzoic acid CHCl3, 0 C

Styrene

The reaction is an example of a concerted process (all bonding changes occur in one step) R3 R1 R3 1 R O R R O O R3 R4 O O

O 1 2 H O 2 H R R R2 R4 R RCOOH R4 Since the reaction is concerted the stereochemistry of the alkene is preserved in the product. For example if the alkyl groups of the alkene are cis then they are also cis in the epoxide.

H

O H mCPBA, DCM,Na2CO3, J.Chem. Edu., 2001, 78. H 00C, 20 min H

H3CO

H3CO

O Dubois G; Murphy A O 2eq CH3CO3H, 0.25 mol% cat., and Stack T D P, MeCN, 5 min, 00C OEt Org.Lett., 2003, 5, 2469. OEt O Ethyl sorbate 87%

III Catalyst: [{(Phen)2(H2O)Fe }2(µ-O)](ClO4)4 Epoxidation of an olefin is distereoselective reaction. The reagent attacks alkene from less hindered face.

O H H only important Si Ph conformer has H H eclipsing double bond SiMe2Ph SiMe2Ph

mCPBA attacks the less hindered face

O O

mCPBA +

OH OH OH

95 : 5

Villa de P A L; Sels B F; O De Vo s D E and Jacobs P O 2mmol H2O2, 2mg cat., MeCN, 380C, 24h O A, JOC, 1999, 64, 7267. O

O 94%

Catalyst: PW4O24[(C4H9)4N]3-Amberlite IRA900 Sharpless The Sharpless Epoxidation is an enantioselective and distereoselective epoxidation epoxidation of allylic alcohols. The stoichiometric oxidant is a , usually tert-

butylhydroperoxide in the presence of catalyst Ti(O-isopropoxide)4. K. Barry Sharpless won It allows the enantioselective epoxidation of prochiral allylic alcohols. The the 2001 Nobel prize in is achieved by adding an enantiomerically enriched Chemistry for his work tartrate derivative. on asymmetric oxidations. 3 3 R tBuOOH, Ti(OiPr)4, R (+)-DET, DCM, O 0 0 R2 OH 3A MS, -20 C R2 OH

R1 R1

The stereochemistry of the resulting epoxide is determined by the diastereomer of the chiral tartrate diester. Usually diethyl tartrate or diisopropyl tartrate are employed in the reaction.

Assymetric Assymetric epoxidation epoxidation O O (-)-DET OH OH (+)-DET OH Advantages: tBuOOH O Ph OH 5mol% Ti(OiPr)4 can be converted 7.5mol% (+)-DIPT Ph OH -200C, 3h into diols, aminoalcohols 89% (>98%ee) or . The formation of chiral epoxides is a very OH tBuOOH O important step in the 5mol% Ti(OiPr)4 OH synthesis of natural 7.4mol% (+)-DIPT -200C, 0.75h products. 95% (91%ee) Can be carried out with many primary and O secondary allylic alcohols. tBuOOH Ph OH Ph OH 120mol% Ti(OiPr)4 High enantiomeric 150mol% (-)-DET 0 excesses > 90%. -20 C, 5h Ph Ph The products of the 90% (94%ee) Sharpless Epoxidation are predictable using the It can be used for preparation of intermediates in natural product synthesis, Sharpless Epoxidation such as in the synthesis of Lekotriene C-1. model.

COOCH3 tBuOOH, Ti(OiPr)4, COOCH3 The reagents are (+)-DIPT, DCM, 0 commercially available -20 C, 48h and relatively cheap. O OH OH

80% (95%ee) Robinson A and HO HO tBuOOH, Ti(OiPr)4, Aggarwal V K, (-)-DET, DCM, -200C, 5h Angew. Chem. Int. O Ed. 2010, 49, 6673. 75% (97%ee)

HO OBn

Ghosh A K and Liu C,

Org. Lett. 2001, 3, 635. tBuOOH, Ti(OiPr)4, (-)-DET, 4A0MS, DCM, -230C, 20.5h

O

HO OBn

90% Additional/Practice Problems

OH 1.5mol CrO3 H (1) 6h, rt Cl Cl O 78% Zou J D; Xu Z N, Tet.Lett., 2002, 43, 6095

(2) PCC, SiO2, DCM rt, 90min

OH O

d,l- d,l- Luzzio F A, et al, J Chem. Edu., 1999, 76, 974.

(3) O O HO O O PCC, acetone, Al2O3 O DCM, reflux, 4h

AcO AcO

3-Acetoxy-17-- 3-Acetoxy-17-ethylene-dioxyestra- dioxyestra-1,3,5(10)-trien-11-ol 1,3,5(10)-trien-11-one (79%) McNab H, et al, Org. Biomol. Chem., 2010, 8, 4383

OH O (4) PCC, DCM rt, 1h

N N

O O 1,2-dihydro-1-hydroxypyrrolizin-3-one Pyrrolizine-1,3-dione (68%)

(5) OH 2 mol% PCC, 1.05eq H5IO6 O MeCN, 00C-rt, 2h

Ph Ph

89%

(6) OH 2 mol% PCC, 1.05eq H5IO6 O MeCN, 00C-rt, 2h Hunsen M, Tet.Lett., 2005, 46, 1651 Ph Ph

96% Jones reagent, acetone, 00C (7) OBn OBn O CHO OH PDC, DCM, rt Neral : Geranal = 7:1 (84%) OH H

NHBoc NHBoc 80% Jones reagent, (8) acetone, 00C

CHO OH Neral : Geranal = 7:1 (84%)

OH Na2Cr2O7, conc. H2SO4 (9) DMSO, 700C, 30 min CHO Rao Y S; Filler R, J.Org. Chem., 1974, 39, 82% 3304

Na2Cr2O7, dil. H2SO4 (10) OH silica gel, rt, 1h O

α-Fenchol 98 % Singh R P; Subbarao H N; Dev S, Tetrahedron, 1979, 35, 1789 (11) OH O MnO2, alumina DCM

O O

benzoin benzil

Crouch R D; Holden M S; Burger J S, J.Chem. Edu., 2001, 78, 951 OH O O OH

Al(OtBu)3 (12) xylene

N

H H O H H O H H

OMe (13) 1. O3, MeOH, p-TsOH AcO AcO 2. NaHCO3, Me2S AcO CHO + OMe OMe CHO MeO 1 : 3

(14) O3, NaHCO3, O O O O DCM, iPrOH, OR O O -780C OHC + HOO HOO OHC OR (15)

Ac2O, Et3N O O O O DCM + 73% OHC ROOC

ROOC OHC

3.6 : 1 Taber D F & Nakajima K, JOC, 2001, 66, 2515.