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Home , Dioxirane, Hydroperoxide, Organic peroxide, Peroxy acid, Trifluoroperacetic acid

Baran Group Meeting Changxia Yuan 4/5/2014 Commercial available * Inorganic peroxides

Na2O2 CaO2 Li2O2 BaO2 Ni2O3 NiO2 xH2O H2O2(30%) ZnO2 NaBO3 4H2O MgO2 TbO2 SrO2 Na2CO3 1.5H2O

sodium calcium lithium barium nickel nickel(II) zinc sodium magnesium terbium Stronium sodium peroxide peroxide peroxide peroxide peroxide peroxide peroxide perborate peroxide peroxide peroxide percarbonate $ 109/100g $ 27/100g $ 32 /50g $ 146/500g $ 106/5g hydrate $ 350/4L $ 75/1kg tetrahydrate complex $ 30/1g $ 38/100g $ 91/ 2.5kg $ 40/ 1g $94/1kg $ 40/250g

+ (NH4)2S2O8 Na2S2O8 K2S2O8 2K2SO5 KHSO4 K2SO4 5[Bu4N ] SO5] HSO4] SO4]

ammonium sodium potassium Oxone® OXONE® persulfate persulfate persulfate monopersulfate tetrabutylammonium salt $ 39/ 100g $ 87/ 2.5kg $ 70/ 500g compound $ 156/ 25g $ 60/ 1kg

Organic peroxides-1 O CO3H O HOO tBu O O OO O CH2(CH2)9CH3 O H3C(H2C)9H2C O O tBu tBuOOH H2O2 BzOOBz OOH O Cl O tert-Butyl Urea Benzoyl mCPBA Cyclobutane 2-Butanone tert-Butyl Lauoyl $ 81/100g maloyl peroxide peroxide peroxide solution (5-6 M) peroxide $ 92/500g peroxide $ 129/500mL $ 134/1L $ 81/100g $ 47/25mL $ 88/ 250g $ 100/1g Cl O O Cl O Me Me O Me Me Me Me O O O O Ph O O O O OO O Me O Me O Ph O O tBu Cl Ph Me Me Me O Me 2,4-Dichlorobenzoyl Cl tert-Butyl tert-Butyl peracetate solution, Dicumyl tert-Butylperoxy 1,1-Bis(tert-amylperoxy)cyclohexane peroxide, 50% in DBP peroxybenzoate 50% in mineral spirits peroxide 2-ethylhexyl solution, 80% in mineral spirits $ 59/100g $ 86/500mL $ 77/500mL $ 123/500g carbonate $ 74/500g Me $ 77/500mL Me Et O OtBu O O OtBu O Me O O O O OtBu O tBu O O O O O O O OtBu O O O OH Et Me O O O Me Me Me Et O O Me tert-Butyl 1,3-Bis(2-tert-butylperoxyisopropyl) 1,1-Bis(tert-butylperoxy)-3,3,5- 3,6,9-Triethyl- 2,4-Pentanedione 2,2-Di(tert-butylperoxy) monoperoxymaleate trimethylcyclohexane 3,6,9-trimethyl-1,4,7-triperoxonane peroxide solution butane $ 75/5g $ 150/250g $ 78/500mL $ 62/100g $ 45/500mL $ 86/500mL

* Prices are based on Aldrich Inventory (price from other suppliers will not be noted); any resouce less than 10 mg will not be included

Baran Group Meeting Changxia Yuan 4/5/2014

Hydrogen peroxide based oxidants: OTMS Me Me Me Me OH TBHP, MoO2(acac)2 Prep:H2O2 and Mo reagent mixing for the reaction;stable powder H2O2 (NH4)6Mo7O24 4H2O O Application: 1)[Mo] Among the best catalyst for the epoxidations benzene, CF CO H Hydrogen peroxide 3 2 since it is cheap and easy handling; 2)mono and di-subustituted 60 °C, 72 h ammonium heptamolybdate Me Me react very slowly 85% selectively on more hindered Tetrahedron. Lett. 1981, 2595. OH O O H O +[Mo] O Cl Me 2 2 Me Cl 1. TBHP, , CCl4,0°C TBA, K2CO3,THF,6d O 2. 96 °C 44% HO 90% HO Isr. J. Chem. 1984, 134. J. Am. Chem. Soc. 1975, 2281.

O O O O O O Me O Cu(ClO4) 6H2O H TBHP Me OEt OMe Me H2O2 +[Mo] Me OEt O HO HO O NC CH3CN, 80 °C OOtBu tBuOO TBA, K2CO3,THF,4d H Ph Ph OEt OtBu 45% 66% HO 73% O H H 88% some noticeable examples without the base, epoxidation can occur J. Org. Chem. 2010, 5065-5071. J. Am. Chem. Soc. 1992, 7375. OtBu OtBu OtBu OtBu OtBu TBHP: TBHP, TMSN DHQ) Pyr O O Prep:70-90% aqueous solution or anhydrous solution in hydrocarbon 3 2 N3 O N N3 O FeCl (0.1 eq) O (3 mol%) O 3 (Sharpless' Aldrich procedure to prepare anhydrous TBHP) 3 N3 N3 O Application: 1)oxidation of alkenes to ; 2) oxidation of allylic or benzylic or H H R CH2Cl2,0°C R R=H R tBu propargylic positions with SeO2 and TBHP 3)epoxidation widely applied; 4) vicinal OOH can be cleaved by TBHP with MoO ; 5) alcohol can be oxidized by TBHP with R = H, , aryl moderate to high ee 2 32%, 93% ee 35%, 96% ee 90%, racemic tbutyl hydroperoxide Se or Cr compound; 6) can be oxidized to or ; 7) 30-40% yield phosphanes can be oxidized to phphosphine oxide; 8) can be oxidized to N- Org. Lett. 2013, 3832. some noticeable examples oxide or ; 9) Kharasch reaction; 10) peroxy can be made from Antilla has chiral Bronsted catalyzed peroxidation of imine on Angew. Chem. Int. Ed. 2010, 6589. or with TBHP; 12) alkyl halide can be converted to alkyl alcohol from with TBHP. Me tBuOOH, AgOTf Me Br AgOTf Me OH OH Me Me HO O Me CH Cl ,0°C MeOH Me TBHP, VO(acac)2 Br Br 2 2 Me O O TBHP, SeO2 (5% mol) OOH benzene, 40 °C, 50 h 50% tBuOH OH O 78% Tetrahedron Lett. 1983, 543-546. 60% J. Chem. Soc. Perkin. Trans. 1. 1985, 267. Tetrahedron. Lett. 1976, 3157. mCPBA and its families: O H Prep:stable in 85% purity, 100% purity is possible, stored in polyethylene TBHP, CrO3 (5%) Cl O container in fridge O Application: 1) epoxidation of alkenes (electron-riched); 2) B-V reaction; CH2Cl2 O 3) Rubottum oxidation; 4) oxidation of sulfide to sulfoxide (tandemed with sole SeO gave oxidation on both sides 47% (9% sm) 2 meta-chloroperbenzoic acid Mislow-Evans rearrangement); 5) oxidation of selenides and phosphanes and phosphites; Tetrahedron. Lett. 1983, 2321. Baran Group Meeting Changxia Yuan 4/5/2014

mCPBA, EtOAc Persulfate based peroxide reagents: CH2Cl2,Na2CO3 (aq.) OH Application: 1) oxidizing primary and secondary to aldehyde w/o I CO2Me K2S2O8/(NH4)2S2O8 5 -20 °C, 1 hour CO2Me cat.(kinatically slow to acid; 2) oxidizing to aldehyde oxidizing aldehyde or to benzoic acid with metal catalysts; 4)oxidizing aliphatic 65 - 67% potassium/ammonium peroxydisulfate to aldimines or with Cu(II)/Ni(II) as catalyst; 5)oxidizing J. Am. Chem. Soc. 1983, 2908. to peracid under phase transfer condition;

Elbs oxidation: O H OH Cl O Application: 1) oxidation of alcohol at room MeO O 1. K S O MeO O O + Me Me HCl temp for high yield; 2) ketone can be 2 2 8 N prepared in one step from allylic alcohol; 3) Me H Me 2. NaOH forced conditions lead to or meta-chloroperbenzoic acid-2,2,6,6-tetramethylpiperidine from alcohol 40% hydrochloride OH O OH O O Me flavanol based structure through p-hydroxysulfate ester salts O Me H Me 1. mCPBA, TMPHCl Me H Chem. Rev. 1951, 49, 91. 2. hydrazine HO Boyland-Sims oxidation: HO Me Me Me Me Me Me Me Me N 68% N N - N SO3 J. Org. Chem. 1961, 3615. (H4N)O3S OOSO3(NH4) O OSO3K + KOH NO 2 Characterization:Stable at ambient temperature as white crystal; OSO3K Application: epoxidation of alkenes; B-V reaction o/p = 2/1, 22% O J. Org. Chem. 1992, 2266. H O C-H oxidation: O p-Nitrobenzoic peroxide Me OH K2S2O8,NaOAc,Cu(II) PNPBA, CHCl3 MeCN-HOAc, 80 °C reflux, 23 h 80% 69% Angew. Chemie. Engl. 1979, 407. J. Org. Chem. 1986, 3693. Me CO Me O O 2 K2S2O8,Fe(II) O H Me O O NaOAc-HOAc Me Ph O reflux OOH 81% Oxidation of alkenes: Tetrahedron. 1980, 3559. O CO3H Perbenzoic acid NH tButyl 4-benzoylperbenzoate p-Methoxyl NH 2 carbonylperbenzoic acid K S O N 2 2 8 N H SO /HOAc OH 80 °C OH epoxidation/B-V Prep: from corresponding benzoic acid N N 2 4 O Prep: from ester aldehyde which K2S2O8 + reaction/oxidation with tButyl hydrogperoxide. H2O, 80 °C was irradiated with 2 kW high EtOH, H2O HOSO of amine or sulfide N N 2 OH Application: low-temperature initiation pressure Mercury light with O ,as N 91% N 60% extremely like mCPBA (360 nm, compared to reflux of AIBN) of 2 R R Caro's acid stable as mCPBA; adenosine Peroxymonosulfuric acid reaction; Utilization : very similar as mCPBA Chem. Pharm. Bull. 1992, 1656. J. Org. Chem. 1960, 1901. Baran Group Meeting Changxia Yuan 4/5/2014

NO Oxidation of alcohols: 2 O O O O O O (ArSO3)2 (NH ) S O , Cu(II) S O OH 4 2 2 8 X X O O S AcOH, 100 °C O O X=OR,NR2 around 60% ONs O N 96% 2 p-Nitrobenzenesulfonyl peroxide J. Org. Chem. 1990, 1267. J. Org. Chem. 1983, 4914. J. Org. Chem. 1991, 1014.

OH OH Application: Pseudohalogen reagent whose reactivity is comparable to that of chlorine; Na2S2O8 -hydroxy ketone can be made from enol derivatives (OTMS, OAc, NR2) CN O H2O, 60 °C CN CO H 40% 3 Preparation: o-sulfobenzoic anhydride and 30% H2O2 in acetone, stable in Bulll. Acad. Sci. USSR, Div. Chem. Sci. 1984, 2099. acetone; SO H Utilization: epoxidation and hydroxylation have been reported; sometimes the B-V C-H oxidation: 3 reaction gave better result compared to -Boron Etherate O o-Sulfoperbenzoic acid CO2H Na2S2O8 O Ag(I), Cu(II), O Preparation:insuwithKO2 and sulfonyl chloride Me MeCN, 80 °C O Application: epoxidation of alkenes (basic condition epoxidation); 56% S oxidation of benzylic position (few case); oxidative desulfurization of Tetrahedron. Lett. 1985, 2525. O OK thiocarbonyl compounds (sulfuryl urea to urea) H NO2 2KHSO KHSO K SO experiments suggested a radical 5 4 2 4 Potassium oxone o-Nitrobenzeneperoxysulfonate under dimethyldioxirine item K2S2O8 Me 2+ R N HOAc/KOAc H2O, 100 °C R R OH R=H O [Ag] N N 2- 86% S2O8 R=H Ag distribution N N subs. yield(%) O 2-OAc 3-OAc 4-OAc CONHMe anisole 68 0.6 31 63 biphenyl 21 0 79 18 Bis(2,2'-bipyridyl)silver(II) peroxydisulfate Na S O ,K CO naphthalene 95 5 - 63 2 2 8 2 3 Me 4-bromoanisole 100 0 0 35 N one electron oxidant of electron-rich aromatic compounds 4-fluoroanisole 0 0 100 35 H O, 100 °C 2 canbealsoincatalyticversionwithK2S2O8 4-t-Butylanisole 100 0 0 63 R=OMe O 76% R=OH Symmetric peroxide reagents:

Alternate name: DBP; relative unstable; NO2 Ph Application: 1) widely used as ; classic anti-Markovnikov O reaction;Minisci reaction of radical from alkyl halides, dioxane, DMF and even O O O O XPh OO cyclohexane to protonated heteroaromatic compounds; used as benzoyloxylation S O (ArSO3)2 MeOH X Ph X S O of aromatics; used in hydroxylation of enolate O S Ph X Ph O Ar O O X=Se,Te,S 16-98% OMe Ph dibenzoyl peroxide J. Am. Chem. Soc. 1979, 5687. NO2 m-Nitrobenzenesulfonyl peroxide Preparation:potassium carbonate, sulfonyl chloride and hydrogen peroxide; Application: moderate aromatic substitution to give aryl sulfonates, which can be hydrolyzed to

Baran Group Meeting Changxia Yuan 4/5/2014

DMDO and TFDO: (it is worthy to give another group meeting on these two reagents!) H2O2 BF3 Et2O Utilization: B-V reaction using 90% H2O2 and BF3 Et2O, much stronger condition; moderate hydroxylation of arenes with HF as O O Preparation: recent easy Organic Synthesis procedure; hydrogen peroxide- additive Application: Epoxidation of kinds of alkenes! C-H activation of with the Me Me retention of the ; readily oxidize amines and sulfide. MeO C MeO C 2 2 oxidation of vincinal diols: HN 1. H2O2,BF3 OEt2,CH2Cl2 HN OH OH masked during 1.2eqDMDO 2. TMSNCO HO 1.2eqDMDO O oxidation MeO N MeO N H acetone, 0 °C acetone, 0 °C OH NH2 OH O HO O OH OH 98% > 98% ee96% > 98% ee J. Am. Chem. Soc. 1992, 1375. Tetrahedron. Lett. 1993, 4559. J. Org. Chem. 1993, 3600. O O O O Preparation: Guillaume's procedure, stable in fridge for a week; Preparation: phthalic anhydride and H O in O OH O OH 2 2 Utilization: epoxidaton of extreme inert alkenes such as CF3 the presence of NaOH or MgO Me CF3 substituted alkenes;oxidation of hindered phenols such as 2,6-di-t-butyl OH and O- Utilization:epoxidation of alkenes, B-V rxns; ; some magic C-H oxidation methyl(trifluoromethyl) 2+ and oxidation of amine, sulfide and O O Mg 6H2O O monoperoxyphthalic acid O H H 1 eq. TFDO + tBuMe SiOOH Hg(OTf) 2 2 soluable in most , mercury, toxic! 0°C,7min hydroperoxide - mercury triflate H H 86% 13% 1. peroxide, Hg* BrHg OOtBu Tetrahedron. Lett. 1992, 7929. 2. KBr, H2O-CH2Cl2 O O 3 eq. TFDO I OOtBu I OOtBuAgOTf, CH2Cl2 I ,CH Cl 2 2 2 + H CH Cl ,0C,3h H 2 2 >45% OH 63% H 85% H NaI, acetone O O 50% H H J. Org. Chem. 1992, 5052. used in peroxy-mercuration to epoxidation (by Corey) J. Chem. Soc. Perkin. Trans. 1. 1991, 1923. Metal-based peroxides:

oxidizing agent for a variety of functional groups; cheap/safe/convenient alternative readily available, stable red solid. mild oxidizing reagent for NaBO3 4H2O Ce(OH)3O2H to oxidants such as H2O2,MeCO3HormCPBA; In general, not good for functional groups such as alcohol (aldehyde), phenol(to sodium perborate dihydroxylation, B-V reaction though which was reported before; industry level viable cerium(IV) trihydroxide hydroperoxide quinone) and amine (to ) alternative to hydrogen peroxide for the oxidative decomposition of organophsphorus ester wastes

NaBO 4H O OAc 3 2 Prepared in situ with LiOH and H2O2; LiOOH Utlization: cleavage of different kinds of ligands, such as Evan's Ac O, H SO ,reflux 2 2 4 OH lithium hydroperoxide oxazolidones, Davis' sultam auxiliary, and Myer's pseudoephenamine auxiliary; ester can be also cleaved. 59% relative harsh condition Synth. Comm. 1988, 937. Baran Group Meeting Changxia Yuan 4/5/2014

R O Preparation: yellow crystal from Palladium(II) acetate and R m. p. 52 °C w/ detonation; F C O O tBu 3 and TBHP Se Preparation: diphenyl diselenide with 30% H O Pd O OOH 2 2 Utlization: alkenes to methyl ketone O Application:major for B-V reaction; and oxidizing agent for multiple O Pd palladium t-Butyl Peroxide R=HorNO2 TfO O X R functional groups such as hydrazyl imine to cyano groups Trifluoroacetate Benzeneperoxyseleninic acid key intermediate general mechnism: different from Wacker Me Me Me Pd OTf oxidation F C O O tBu Me CHO H2O2, DNPDS OCHO KOH OCHO 3 Pd O R R R + + R CH2Cl2,20°C MeOH O O H2O2 can be used as oxidant for this transformation: 94%, suitable for phenol with EDG groups Varation: Pd(PPh3)4 + aq. H2O2 Tetrahedron. 1987, 2853. Me O [Pd], tBuOOH, benzene O Me Me Black hydrous powder NiO2 Utilization: oxidation of primary alcohols to carboxylic acid in aqueous media, or 50 °C, 12 h Ph O Me Ph O OH oxidize allylic, benzylic alcohol to aldehyde in organic solvent; oxidize phenols to Nickel(II) Peroxide 71% polymeric mixtures and quinones; oxidize alcohol or aldehyde to amide in ammonia solution; oxidize amine to cyano or diazo compounds; dehydrogenation of J. Chem. Soc. Chem. Comm. 1983, 1245. unsaturated hertocycles HMPA Peracid series: Preparation:MoO , 30% hydrogen peroxide with HMPA, free- The sole peroxide which can be generated in situ (industral favored) O O 3 O flowing yellow crystal OH Electrophilic reagent capable of reacting with many functional groups; prepared in situ in Mo Application: common reagent for hydroxylation of enolates; O O O industry for epoxidation of vegetable oil and fatty acid ; broad range of N oxidation N, S, P. OH peracetic acid formation when carrying no acid sensitive groups;(terminal alkenes are sluggish); in O O some cases, different can be observed comparing to mCPBA; oxidation of arenes to phenols in low yield; B-V reaction;amine to , sulfide to sulfone oxydiperoxymolybdenum (Py)-HMPA Me TMS TMS NaOAc, MeCO H not sensitive to equilibration Me 3 compared to Davis' reagent 86% CH Cl ,7°C Me Et 2 2 Me Et O O O OO Ph Ph O 78% O O O O N Mo H Chem. Lett. 1983, 1771. O Mo N 3 O O O O -butenolides, mCPBA is compared worse for this reaction Ph OO Ph H Oxoperoxobis(N-phenylbenzo- OAc OAc Me N hydroxamato)molybdenum(VI) 2 Me RuCl ,MeCO H OH molybdenum (VI) 3 3 Oxidation of primary and secondary alcohols Application: enantioselective epoxidatioin MeCN/H O/CH Cl epoxydation of alkenic alcohols (not common) 2 2 2 of unfunctionalized simple alkenes MeO2C MeO2C O 55% PPh L O L J. Org. Chem. 1993, 2929. O 3 NC Ph (PPh3)2PdO2 23-50 °C Pd Pd O Pd O O L L OTBS PPh3 THF, 0 °C OTBS Ph 95% RuCl3, MeCO3H NC Ph NC NC OAc Peroxylbis(triphenyl- NC Ph NC Me Me 72% NaOAc, AcOH, EtOAc, rt phosphine)palladium TFA O Preparation: Pd(PPh ) and O NH NH 3 4 2 J. Organo. Met. 1975, 115. Ph O 99% Utilization: Mild oxidation of alkenes, NC O sulfur compouns and NC Ph Baran Group Mee Changxia Yuan 4/5/2014

O H Preparation: HO O H in situ with Tf2O and 90% H2O2 or Urea H2O2; Prepared from 90% hydrogen O Application: the strongest organic ; very powerful O peroxide and maleic anhydride F3C O O O epoxidation reagents, more than mCPBA; diols are the subsquently Utilization: for epoxidation; B-V hydrolysis by TFA; B-V reaction is facile; various of heteroatoms can be reaction (most common) no buffer CO2H needed; oxidize amine to nitro group oxidized Peroxymaleic acid -Tetralyl Hydroperoxide H O H unusually stable peroxide but still need Prepared from the tetralin and O Me cautions; for epoxidation, it is faster Utilization: for epoxidation, usua N N Ph OOH comparing to TBHP and higher yield; a mCPBA or TBHP/Mo is superior; TFPAA, H O Me reliable reagent for enantioselective oxidation of aromatics to give ph 2 2 low yield cumyl hydroperoxide sulfoxide formation with Ti(OiPr)4 and CH2Cl2, 23-0 °C diethyl tartrate

76% prepared from diphenylpyrazole, 90% hydrogen peroide (caution!) Me Me and dibromo- 5,5'-dimethylhydantoin OMe OMe Ph Ph 1 fast rate 2 mild reaction 3 stable reagent J. Org. Chem. 1983, 5199. OOH Br NN Utilization: transfer reagents; heteroatom and oxida Miscellaneous peroxides: pyrazolyl peroxide faster N, S oxidation compared to (same magnitude) flavin hydrope 5 O and (two orders) acyclic azo and 10 more than H2O O H stable at -30 °C for years H O H2N N EtO OOH O Prepared from triethylsilane and O , stable for a few minutes at -78 Et3SiOOOH 3 O-ethylperoxycarbonic acid H H Reactivity: very like the combo of (oxidative cleavage of alke hydrogen peroxide-urea triethylsilyl Hydrotrioxide Et3SiH (reduction to alcohol or aldehyde) Preparation: not stable to store; ethyl stable white powder; utilized as anhydrous chloroformate with hydrogen peroxide in situ "hydrogen peroxide" in organic solvent for the O O H Et3SiO3H TBSOTf Utilization: epoxidation of alkenes on biphase standard reactions such as epoxidation, B-V O condition, cheap and evironmentally benign reactions and oxidation reactions Me CH2Cl2 O O MeO O O 48% CF3 H OMe N H OMe O H O F3C 2 Tetrahedron. Lett. 1985, 4485. OH R O 2-Hydroperoxy- hexafluoro-2-propanol R=PhorMe O Preparation: from SO3 and TMSOOTMS using as crude at -30 °C better than HO-OH Me3SiO S O decompose (explose) at rt! Use immediately. Preparation: hexafluoroacetone with 30% or 90% H2O2 Peroxyacetimidic acid (Payne oxidation) Utilization:epoxidation; oxidize aldehyde to acid without O OSiMe3 Application: strong oxidant; B-V oxidant in nonprotic solvent; weak reactivity for epoxidation, to touching alcohol;oxidize sulfide to sulfoxide and alkenes to ketones; sulfides to , pyridine to pyridine-oxide show as solvent can help Bis(trimethylsilyl) epoxidation using other peroxides monoperoxysulfate

H Me Me Ph3COOH oxidant useful for enantioselective metal- N H peroxide triphenylmethyl catalyed epoxidation of allylic alcohols and O CH2Cl2,-30°C Hydroperoxide enantioselective oxidation of sulfides to Cl C O O 3 high yield sulfoxides (moderate to poor result) Trichloroperoxy- O acetamidic acid J. Org. Chem. 1990, 93. O exist in polluted air, easy to Prepared with trichloroacetonitrile NO2 generate peroxy radical; not Me O and 30% H O ;mostofthetime useful comparingtomCPBA 2 2 Peroxyacety which can be substituted by and H O 2 2 common reagents for epoxidation

Baran Group Meeting Changxia Yuan 4/5/2014

Some peroxides contained natural products:

Me Me OH Me HO Me H Me H Me O O O Me Me C H H C16H33 H O 16 33 SR S S Me O O MeO MeO O H OO CO2Me OO CO2Me O Me H O Me Me Me O Me O first cyclic peroxide to be Qinghaosu isolated from marine sources Yingzhaosu A Yingzhaosu C or Chondrillin Plakorin first studied naturally Yingzhaosus A and C both contain a 1,2-dioxane core 1,2,4-trioxane core, artemisinin and its derivatives occurring structure. These compounds have been extensively are a group of that possess the most rapid studied for their potential antimalarial activity action of all current drugs against falciparum

O HO H O H O O Me Me O CO H HO C 2 2 O OMe HO O O O OO Plakinic acid A Prostaglandin G2 OOH Gracilioether A Mycangimycin The first isolated five-membered ring peroxide key intermediates in prostaglandin's show considerable antimalarial activity selectively inhibits the beetle's fungal antagonist which has a big family on the side chain; remarkable biosynthesis from arachidonic acid cytotoxicity against fungal and cancer cell lines within a big family of prostaglandin

HO2C O O O Me H HO HO S N N O H O O OH N S OH N MeO H O CO2H O O H O Dioxetanone N O H H Plakortide G H O O Me O O O Et Et O Me Me CO2H Me Me O Trunculin B Terpenic peroxide Verruculogen O O O OAc moderate antimalarial activity produces severe tremors and acute toxicity Plakortide E Me Me Talaperoxides A collected on the coastal saltmarsh of the South China Sea Baran Group Meeting Changxia Yuan 4/5/2014

Semi-synthesis of Artemisinin-Qinghaosu in industry: Brief History: Malaria is a disease that affects millions of people; Discovery by Keasling of a biosynthetic pathway for artemisinic acid; Initial chemistry path discovered by Amyris; An industrial process was fully implanted to produce 60t in 2014.

Me Me Me Me Me Me Me H H H H H H Arbry H decomposition DOWEX resin O RhCl(PPh3)3 cat. Cu(OSO Ph) H O ,Na MoO 2 2 Me S/C 2000/1 SOCl2,NEt3 2 2 2 4 air O ++ O Me toluene, H /25barMe Me toluene, MeOH Me Me 1,2-butanediol Me H H 2 H H H H H H H H O H CH2Cl2 H O 25 °C 25 °C HO isolation by Me HOOC HOOC Me HOOC Me MeO2C Me MeO2C Me MeO2C Me chromatography 99% 85% O Artemisinic acid Dihydroartemisinic acid (DHAA) Dihydroartemisinic acid methyl ester (DHAM) Linear peroxide of DHAM 23% Artimisinin 90:10 Diastereoselective Photooxidation of artemisinin problems solution problems solution

NiBH4 gives 3:2 d.r. ratio RuCl2[(R)-DTBM-Segphos](DMF)n is catalyst that is Mechanism: Schenck /Hock cleavage/subsequent oxygenation/cyclization Willkinson cat. is good solely favor of inherent diastereoselectivity of artemisinic solvent is initially switched to CH2Cl2 because 1) safety concern: non- based on inherent diastereo- acid (AA) with an appropriately matched chiral ligand, 41% yield from the lead by Amyris with significant impurities selectivity of artemisinic acid, halogenated solvent is forbidden in oxygenation reaction; 2) CH2Cl2 can be Ru is much more affordable Rh is too expensive recycled

S/C is 2000/1 S/C is 8000/1, with more time, 16000/1 sensitizer was changed to tetraphenylporphyrin (TPP) since it is cheap and Aubry reaction is to avoid photochemical equipment highly efficent for photosensitizer

reaction performed at 15 °C showed accumulation of the hydroperoxide, but the d.r. is not perfect with extensive screen The first generation of peroxide is dangeous one-pot procedure was needed, therefore the ester was ochestrated to more activated anhydride ester

Mechanism of photooxidation of artemisinin

H2O Me Me Me O Me H H H H

Hock 3 O2,h Me Me O2 cleavage HO O N. P. Me TFA O H H H2O O H O H H EtO O O O O Me Me Me Me EtO EtO EtO O O O O O O O O concentration of steps Me RuCl2[(R)-dtbm-Segphos](DMF)2 Me Me Me Me Me Hock cleavage H Me S/C >8000/1 H H H H H cyclization H MeOH, Et3N, 22bar / 5-6h O EtOCOCl Hg vapor lamp NaHCO3/H2O Me K2CO3 TPP / air washes O ++ O Me Me Me Me Me isolation by H CH2Cl2, CH2Cl2,THF OOH H Me tworkup by evaporation of H H H H H H H H H O H 20 °C EtO O EtO O -10 °C EtO O solvent switch Me MeOH, extraction using HOOC Me HOOC Mewater wash Me Me Me with heptane/EtOH aq. HCl/CH Cl HOOC 2 2 quant. 55% in all total O 95:5 O O O O O O steps including Artemisinic acid 99% Dihydroartemisinic acid (DHAA) Dihydroartemisinic acid methyl ester (DHAM) Mixed anhydride linear peroxide Artimisinin crystalization of the final product Org. Process Res. Dev. 2014, 18, 417-422