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Home , Manganese dioxide, Osmium tetroxide, Periodate

TETROXIDE 1

1 O R R O O R O OsO4 + NR3 Os O Os NR3 O O NR3 R O OsO4 OH R (3) [20816-12-0] O4Os (MW 254.20) R InChI = 1S/4O.Os OH InChIKey = VUVGYHUDAICLFK-UHFFFAOYSA-N Due to the electrophilic nature of osmium tetroxide, electron- withdrawing groups connected to the double bond re- (cis dihydroxylation of ; osmylation; asymmetric and tard the dihydroxylation.2 This is in contrast to the oxidation diastereoselective dihydroxylation; oxyamination of alkenes) of alkenes by , which preferentially at- Physical Data: mp 39.5–41 ◦C; bp 130 ◦C; d 4.906 g cm−3; tacks electron-deficient double bonds. However, in the presence of - or ozone-like . a tertiary such as , even the most electron-deficient 3 : soluble in water (5.3% at 0 ◦C, 7.24% at 25 ◦C); solu- alkenes can be osmylated by osmium tetroxide (eq 4). The more highly substituted double bonds are preferentially oxidized (eq 5). ble in many organic solvents (toluene, t-BuOH, CCl4, acetone, methyl t-butyl ether). F C OH H2O 3 Form Supplied in: pale yellow solid in ampule, as 4 wt % OH R R = CF F C in water, and as 2.5 wt % in t-BuOH. R OO 3 3 OsO4 py R Os (4) Handling, Storage, and Precautions: vapor is toxic, causing dam- py py O O age to the eyes, respiratory tract, and skin; may cause temporary R O H2O OH blindness; LD50 14 mg/kg for the rat, 162 mg/kg for the mouse. R = F HO Because of its high toxicity and high , it should be –HF handled with extreme care in a chemical fume hood; chemical- resistant gloves, safety goggles, and other protective clothing should be worn; the solid reagent and its should be 1. OsO4, py stored in a refrigerator. (5) 2. Na SO 2 3 HO HO Original Commentary HO OH Under stoichiometric and common catalytic osmylation condi- Yun Gao tions, alkene double bonds are hydroxylated by osmium tetroxide Sepracor, Marlborough, MA, USA without affecting other functional groups such as hydroxyl groups, and carbonyl groups, acetals, triple bonds, Dihydroxylation of Alkenes. The cis dihydroxylation (os- and sulfides (see also Osmium Tetroxide–N-Methylmorpholine mylation) of alkenes by osmium tetroxide to form cis-1,2- N-). (vic-glycols) is one of the most reliable synthetic transformations The cis dihydroxylation can be performed either stoichiometri- 1 (eq 1). cally, if the alkene is precious, or more economically and con- O O veniently with a catalytic amount of osmium tetroxide (or its R1 R3 Os HO OH precursors such as osmium chloride or potassium osmate) in con- O O R1 R3 + OsO4 R1 R3 (1) junction with a cooxidant. In the stoichiometric dihydroxylation, R2 R4 2 4 the product is usually obtained by the reductive hydroly- 2 4 R R R R sis of the osmate ester with a reducing agent such as The reaction has been proposed to proceed through a [3 + 2] or Aluminum Hydride, Sulfide,K2SO3 or Na2SO3, and [2 + 2] pathway to give the common intermediate osmium(VI) KHSO3 or NaHSO3. The reduced osmium species is normally monoglycolate ester (osmate ester), which is then hydrolyzed removed by filtration. Osmium can be recovered as osmium tetrox- ide by oxidation of low-valent osmium compounds with hy- reductively or oxidatively to give the cis-1,2-diol (eq 2). The 4 cis dihydroxylation of alkenes is accelerated by tertiary drogen . In the catalytic dihydroxylation, the osmate such as Pyridine, quinuclidine, and derivatives of dihydroquini- ester is usually hydrolyzed under basic aqueous conditions to dine (DHQD) or dihydroquinine (DHQ) (eq 3). produce the diol and osmium(VI) compounds, which are then reoxidized by the cooxidant to osmium tetroxide to continue the OH catalytic cycle. Normally 0.01% to 2% equiv of osmium tetroxide R R O [3 + 2] O R or precursors are used in the catalytic dihydroxylation. Common + OsO4 Os R (2) R O O cooxidants are metal chlorates, N-Methylmorpholine N-Oxide R OH (NMO), Trimethylamine N-Oxide, , t-Butyl [2 + 2] Hydroperoxide, and Potassium Ferricyanide. has also R been used as cooxidant in dihydroxylation of certain alkenes.5 O O Excess cooxidant and osmium tetroxide are reduced with a re- Os O R ducing agent such as those mentioned above during the workup. O The stoichiometric dihydroxylation can be carried out in almost 2 OSMIUM TETROXIDE

CO Me any inert organic solvent, including most commonly MTBE, 2 CO2Me HO toluene, and t-BuOH. In the catalytic dihydroxylation, in order to O OsO , py O OTBS 4 OTBS OH dissolve the inorganic cooxidant and other additives, a mixture (10) MeO O MeO O of water and an organic solvent are often used. The most com- OBz OBz mon solvent combinations in this case are acetone–water and t- de > 25:1 BuOH–water. Because of the high cost and toxicity of osmium tetroxide, the stoichiometric dihydroxylation has been mostly OH OH OH OH OH replaced by the catalytic version in preparative organic chem- OsO4 OBn OBn (11) istry (see also Osmium Tetroxide–tert-Butyl Hydroperoxide, NMO Osmium Tetroxide–N-Methylmorpholine N-Oxide, and Osmium HO Tetroxide–Potassium Ferricyanide). de = 35:1

Diastereoselective Dihydroxylation. Dihydroxylation of OH HO OH OsO4 OH acyclic alkenes containing an allylic, oxygen-bearing stereocenter (12) proceeds with predictable stereochemistry. In general, regardless MeO2C NMO MeO2C of the double-bond substitution pattern and geometry, the rela- de > 100:1 tive stereochemistry between the pre-existing hydroxyl or alkoxyl group and the adjacent newly formed hydroxyl group of the major diastereomer will be erythro (i.e. anti if the chain is drawn OTBS OH OTBS OH OsO4 in the zig-zag convention) (eq 6).6,7 R R R NMO R OTBS OH OTBS OH OsO4 OH 3 OsO de > 99:1 H R 1 4 4 OsO4 or R R NMO (13) 3 (6) OsO4 1 4 OsO4, NMO R R R (R2)HO OH TBSO OH NMO 2 OH(R ) R R R = CO2Et, CH2OAc In the osmylation of 1,2-disubstituted allylic and TBSO OH de > 99:1 derivatives, cis-alkenes provide higher diastereoselectivity than the corresponding trans-alkenes (eqs 7 and 8).6 Opposite se- lectivities have been observed in the osmylation of (Z)-enoate The diastereoselective osmylation has been extended to 8 and (E)-enoate esters (eqs 9 and 10). High selectivity has also oxygen-substituted allylic silane systems, and the general rule 9 been observed in the osmylation of 1,1-disubstituted and (E)- observed for the allylic system also applies (eq 14).12 10 trisubstituted allylic alcohols and derivatives and bis-allylic High selectivity is also observed in the osmylation of allylsilanes 11 compounds (eqs 11–13). where the substituent on the chiral center bearing the silyl group 13 OH is larger than a methyl group (eq 15). These diastereoselec- OBn tivities have been achieved in both stoichiometric and catalytic BnO dihydroxylations. Slightly higher selectivity has been observed in the stoichiometric reaction than in the catalytic reaction; this may OBn OH OBn OH be due to less selective bis-osmate ester formation in the catalytic BnO OH + BnO OH (7) reaction using NMO as the cooxidant. Use of K3Fe(CN)6 may solve this discrepancy. Several rationales have been proposed for OH OH the observed selectivity.14 The conclusion appears to be that the OsO4 8.0:1.0 osmylation of these systems is controlled by steric bias, rather OsO , NMO 7.0:1.0 4 than by the electronic nature of the allylic system, and osmylation OBn will occur from the sterically more accessible face. The high di- BnO OH astereoselectivity of osmium tetroxide in the dihydroxylation of chiral unsaturated compounds has been applied widely in organic synthesis.8,15 OBn OH OBn OH BnO OH + BnO OH (8) OH OsO OH OH PhMe2Si 4 R OBn OBn OsO4 4.2:1.0 OH OH OH OsO4, NMO 3.1:1.0 de = 97:3 Ac2O (14) CO2Me HO OH O OsO4, py O OsO OTBS CO2Me OTBS OH PhMe2Si 4 R (9) OBn OBn MeO O MeO O OBz OBz OAc OH OH de > 18:1 de = 4.4:1 OSMIUM TETROXIDE 3

SiMe Ph PhMe Si OH PhMe Si OH 1 2 OsO4 2 2 as chiral for the asymmetric dihydroxylation (AD). The + (15) AD can be classified into two types: (a) noncatalytic reaction, R py R R OH OH where stoichiometric amounts of and osmium tetroxide R = Me 34:65 are used, and (b) catalytic reaction, where catalytic amounts of R = i-Pr 67:33 ligand and osmium tetroxide are employed in conjunction with R = Ph 92:8 stoichiometric amounts of cooxidant. Generally, in the stoichio- metric AD systems, chiral chelating diamines are used as chiral groups direct the dihydroxylation of a remote dou- auxiliaries with osmium tetroxide for the introduction of asymme- ble bond in an acyclic system perhaps by prior complexation of try to the diol products.1,19 Although high asymmetric inductions 16 the sulfoxide oxygen with osmium tetroxide (eqs 16 and 17). have been achieved in these systems, the stoichiometric ADs have Chiral sulfoximine-directed diastereoselective osmylation of cy- limited use in practical organic synthesis because of the cost of cloalkenes has been used for the synthesis of optically pure di- both ligand and osmium tetroxide. The discovery of the ligand- 17 hydroxycycloalkanones (eq 18). Nitro groups also direct the accelerated in AD made the transition from stoichio- osmylation of certain cycloalkenes, resulting in dihydroxylation metric to catalytic AD possible.1c,1d,20 In the most effective cat- from the more hindered side of the ring. In contrast, without the alytic system, osmium tetroxide or its precursors and chiral ligands nitro group the dihydroxylation proceeds from the less hindered derived from cinchona alkaloids, dihydroquinidine (DHQD), or 18 side (eq 19). dihydroquinine (DHQ), are used catalytically in the presence of a stoichiometric amount of cooxidant such as NMO or K3Fe(CN)6. O OAc O O Besides alkaloid-derived ligands, other types of ligand have been S 1. OsO4 S 21 Ph Ph (16) designed and used in the catalytic AD with moderate success. 2. Ac2O HN CCl3 AcO HN CCl3 (see also Osmium Tetroxide–N-Methylmorpholine N-Oxide and Osmium Tetroxide–Potassium Ferricyanide). O O de > 20:1 Double Diastereoselective Dihydroxylation. AD of homochiral alkenes gives matched and mismatched diastereos- O OAc O O S 1. OsO4 S electivities due to the steric interaction of the chiral osmium Ph Ph (17) tetroxide–ligand complex with the chiral center in the vicinity 2. Ac2O HN CCl3 AcO HN CCl3 of the alkene double bond. For example, in the noncatalytic 22 O O osmylation of the monothioacetal (eq 20), the ratio of (2S,3R) de > 20:1 to (2R,3S) diastereomers is 2.5:1 with the achiral quinuclidine as ligand, 40:1 with Dihydroquinidine Acetate (DHQD-OAc) Ph Ph O O O as ligand in the matched case, and 1:16 with Dihydroquinine S OH S OH MeN OsO4 MeN heat OH Acetate (DHQ-OAc) as ligand in the mismatched case. OH (18) Me3NO OH OH OsO4 O NHR2 S Ph

N N N 1 N OH OH R O + O (20) S Ph S Ph 1. OsO4, NMO OO OH OH 2. acetone, H+ Quinuclidine 2.5:1 NO DHQD-OAc 40:1 NHR2 2 R1 = DHQ-OAc 1:16 (19) N N SO2Ph R2 = CO Me 2 Diastereoselectivities in the catalytic AD with OsO4–NMO of 1 N N R 2 several α,β-unsaturated uronic acid derivatives are significantly 1. OsO4, NMO NHR 2. acetone, H+ enhanced when the alkenes are matched with the chiral ligands N N DHQ-CLB (dihydroquinine p-chlorobenzoate) and DHQD-CLB 23 N (dihydroquinidine p-chlorobenzoate) (eq 21). Using the chi- R1 N ral ligands (DHQD)2-PHAL and (DHQ)2-PHAL, the double di- astereoselective dihydroxylation of a chiral unsaturated ester has R1 = OH, R2 = H OO been tested using Osmium Tetroxide–Potassium Ferricyanide (eq 22).1c These results show that enhanced diastereoselectivity in the dihydroxylation can be achieved by matching of alkene diastereoselectivity with catalyst enantioselectivity. Double di- Enantioselective Dihydroxylation. The acceleration of os- astereoselective dihydroxylation with a bidentate ligand has also 24 mylation by tertiary amines brought about the use of chiral amines been reported. Kinetic resolutions of racemic alkenes with OsO4 4 OSMIUM TETROXIDE in the presence of a chiral ligand have been demonstrated.25 An nium acetate, trisubstituted alkenes can be oxyaminated with cat- elegant example is the kinetic resolution of the enantiomers of alytic OsO4 and N-chloro-N-metallocarbamates. So far, attempts C76, the smallest chiral fullerene, by asymmetric osmylation in to effect catalytic asymmetric oxyamination have not been the presence of DHQD- and DHQ-derived ligands.26 successful. Osmium tetroxide also catalyzes the oxidation of organic sul- OH OH fides to sulfones with NMO or trimethylamine N-oxide (see OsO4 CO2Me CO2Me + CO2Me (21) Osmium Tetroxide–N-Methylmorpholine N-Oxide). In contrast, R NMO R R OH OH most sulfides are not oxidized with stoichiometric amounts of OsO4. Oxidations of alkynes and alcohols with OsO4 without and R Reagent Ratio in the presence of cooxidants have also been reported.1a,1b How- BnO O OsO4 only 10.3:1 ever, these reactions have not found wide synthetic applications BnO DHQD-CLB 1.3:1 because of the availability of other methods. BnO DHQ-CLB 20.5:1 OMe OBn

BnO O OsO4 only 7.4:1 BnO DHQD-CLB 3.4:1 First Update DHQ-CLB 15.9:1 OMe Timothy J. Donohoe, Robert M. Harris & Majid J. Chughtai

CO2-i-Pr Dyson Perrins Laboratory, Oxford, UK O OsO4 O K3Fe(CN)6 Asymmetric Dihydroxylation Reactions. A substantial amount of work has been reported on the development of the OH OH asymmetric dihydroxylation (AD) reaction as originally described 29 CO2-i-Pr CO2-i-Pr by Sharpless. A greater understanding has emerged of the func- O + O (22) tional group tolerance of the AD reaction and also its applicability O OH O OH towards differing alkene substitution patterns. The mechanism of the AD reaction has been the subject of intense debate especially no ligand 2.8:1 with respect to the question of whether a [2 + 2] or [3 + 2] path- (DHQD)2-PHAL 39:1 (DHQ)2-PHAL 1:1.3 way is followed, and some insightful mechanistic studies have followed from this discussion.30 Two representative examples of the AD process are shown be- Oxyamination of Alkenes and Oxidation of Other Func- low: the first (eq 25)31 helps to define the relative reactivity of the tional Groups. Osmium tetroxide catalyzes the vicinal oxyam- two alkene units within geraniol with respect to asymmetric di- ination of alkenes to give cis-vicinal hydroxyamides with hydroxylation (the electron rich C6,7 alkene reacts first), and the Chloramine-T (eq 23)27 and alkyl N-chloro-N-argentocarbamate, second (eq 26)32 illustrates the compatibility of the AD process generated in situ by the reaction of alkyl N-chlorosodiocarbamate with easily oxidized sulfides. (such as ethyl or t-butyl N-chlorosodiocarbamate) with (I) Nitrate (eq 24).28 cat OsO4, (DHQD)2PHAL OH K3Fe(CN)6 1% OsO4 + TsNClNa·3H2O (23) t-BuOH, 60 ºC NHTs 66–73% OH OH

OH EtOCONClNa OH (25) AgNO , H O Ph 3 2 Ph OH Ph Ph (24) 1% OsO4, MeCN 94% ee, >49:1 regioselectivity 66–69% NHCO2Et

Since chloramine-T is readily available, the former method of- OH cat OsO4, (DHQD)2PHAL fers a practical and direct method for introducing a vicinal hy- SPh SPh Ph Ph droxyl group and a tolylsulfonamide to a double bond. While K3Fe(CN)6 75% OH the sulfonamide protecting group is difficult to remove (and un- 98% ee desirable in some cases), the N-chloro-N-argentocarbamate sys- tem provides an alternative method, since the carbamate group can be easily removed to give free amine. This latter system is also more regioselective and reactive towards electron-deficient HO cat OsO4, (DHQD)2PHAL SS alkenes such as Dimethyl Fumarate and (E)-stilbene than the SS (26) K3Fe(CN)6 Ph H procedures based on chloramine-T. In all of these oxyamina- Ph H 78% tion reactions, monosubstituted alkenes react more rapidly than OH di- or trisubstituted alkenes. In the presence of tetraethylammo- 97% ee OSMIUM TETROXIDE 5

Moreover, Sharpless has recently defined a series of bidentate (eq 29).35,36 The selectivity observed during this oxidation is op- ligands that help to promote a reaction through the ‘second cat- posite to that normally observed under dihydroxylation with more alytic cycle.’33 Addition of citric acid to a dihydroxylation reac- standard (i.e., Upjohn) conditions and is difficult to accomplish tion gives excellent yields of diols from electron deficient alkenes by other means. For example, compare the oxidation of geraniol 35 (eq 27). In addition to lowering the pH of the reaction, the citrate under the action of OsO4/TMEDA (eq 30, oxidation of the C- additive is presumed to chelate to the transition metal throughout 2,3 alkene ensues) with that observed under the action of an AD the reaction so favoring turnover via the second cycle. Dihydrox- mix (eq 25). ylation through this mechanism is commonly believed to destroy any enantioselectivity imparted by the cinchona alkaloid ligands, OH OH OsO4, TMEDA and clearly one consequence of the addition of citric acid to a OH dihydroxylation reaction is, therefore, the formation of racemic then NH2CH2CH2NH2 88% products when chiral amine additives are added. OH dr ≥ 25:1 EtOOC 0.2% OsO4, 1.1 equiv NMO COOEt NHCOCCl3 NHCOCCl3

OsO4, TMEDA OH OH (29) then aq. Na2SO3 EtOOC 80% COOEt (27) OH OH dr ≥ 25:1

Conditions Yield (%) OsO4, TMEDA OH 1. water/acetone/tBuOH (5:2:1) 10 then aq. Na2SO3 74% 2. water/tBuOH (1:1), citric acid (25 mol %) 76

One possible solution to the lack of enantioselectivity observed OH (30) with citric acid additive is the addition of a chiral amino alcohol HO OH (eq 28),34 which performs the same chelating role as the citrate and locks the reaction into the second cycle. However, the chiral There is evidence (NMR, IR, X-ray) that TMEDA forms a (re- backbone of the ligand is then capable of imparting enantiose- active) bidentate complex with the osmium tetroxide whereby the lectivity during a subsequent dihydroxylation reaction. While this diamine ligand increases the electron on both the osmium area clearly has much potential for development, the enantiose- center and also the outlying oxo ligands: this in turn makes them lectivities obtained are not yet competitive with those commonly more electron rich and better hydrogen bond acceptors and so realized with the conventional AD process. to the selectivity observed.36 O The chelating nature of the diamine precludes osmate ester hy- 0.2% OsO4, 2% ligand droysis in situ and means that the oxidation of an alkene requires 1 OR 1.1 equiv NMO, tBuOH/H2O equiv of osmium tetroxide, followed by a step to release the glycol. However, the use of catalytic amounts of transition metal in the di- rected dihydroxylation of allylic amides was shown to be possible HO O (eq 31)37 by using a monodentate amine (quinuclidine, which is released in situ from quinuclidine-N-oxide). These conditions are OR (28) catalytic in osmium but generally exhibit a less powerful directing OH effect than stoichiometric osmium tetroxide and TMEDA.

NHCOCl3 NHCOCl3 TsHN HO O 1.3 equiv QNO·H2O OH COOH (31) OH 5% OsO4 OH Ligand 95% R OH NHTs de = 20:1 Me 48% (ee) 51% (ee)

Et 50% (ee) 48% (ee) In Situ Protection of Diols from Dihydroxylation. Sharp- less recently examined the applicability of Narasaka’s dihydrox- ylation reaction conditions (catalytic osmium tetroxide and NMO Hydrogen Bonding Control During Dihydroxylation. The in the presence of phenylboronic acid). The boronic acid reagent reagent combination of OsO4 and TMEDA produces a complex replaces the water which is normally present in dihydroxylation that acts as a hydrogen bond acceptor and dihydroxylates allylic al- reactions to hydrolyze the osmate ester and liberate the diol.38 In cohols and amides with control of both stereo- and regiochemistry this case, however, the phenyl boronic acid promotes this reaction 6 OSMIUM TETROXIDE forming a cyclic boronate ester in the process (eq 32). Sharpless seen the use of even cheaper amine additives such as triethylamine discovered that these modified conditions could sometimes give (eq 34).41 This ‘triple catalytic’ system is also compatible with different stereoselectivities to that observed under UpJohn con- Sharpless’ chiral ligands and allows oxidation of a range of alkenes ditions and also that conjugated dienes could be dihydroxylated with high enantioselectivity. only once (something that is not possible with the UpJohn reac- tion because overoxidation ensues). The cyclic boronate esters so OH 2% OsO4, 1.5 equiv H2O2, 2 equiv TEA produced are useful protecting groups for the glycol unit and can 6% (DHQD)2PHAL, 5% flavin OH Ph Ph be easily cleaved with aqueous hydrogen peroxide. 75% 95% ee 4% OsO4, 2.2 equiv NMO O O (34) 2.2 equiv PhB(OH)2 Ph B B Ph H 81% O O N NO flavin = N N O 1% OsO4, 1 equiv NMO O Ph Ph Ph 1 equiv PhB(OH)2 (32) Ph 42% B Ph O In another development, Krief has shown that selenoxides (es- pecially aryl/alkyl selenoxides) are capable of replacing amine- as the reoxidant in the dihydroxylation reaction. An asym- Oxidative Cyclization of 1,5-Dienes. The oxidative cycliza- metric process based on (DHQD)2PHAL (named SeOAD) was tion of 1,5-dienes to produce cis- has previously also developed and this gave good to excellent ee’s with a range been reported only with strong oxidants such as KMnO4 and of alkenes.42 RuO4; yields are not usually above 50% probably because of overoxidation of the products. This reaction is an interesting one Aminohydroxylation of Alkenes. Asymmetric aminohy- because addition of oxygen is (syn) stereospecific across both droxylation (AA) reaction is a powerful method for preparing alkenes and also stereoselective for the formation of 2,5-cis- vicinal aminoalcohols in a stereospecific reaction from alkenes ; it is possible to make up to four new chiral centers using osmium catalysis; the use of cinchona based ligands enables and one heterocyclic ring in one step. Recently, there have been the products to be formed with high levels of enantioselectivity.43 reports of osmium tetroxide promoting the same type of oxidative It should be noted, however, that Sharpless’ aminohydroxylation 39 cyclization, using either or amine-oxides as reoxidants reaction does not usually involve the addition of osmium tetrox- 40 (eq 33). The yields for such reactions (especially using amine- ide, rather potassium osmate [K2(OH)4OsO2] is employed as the N-oxides in conjunction with acidic conditions) are very high, and catalyst. There are several reasons for this, such as the ease of this method promises to become a useful way of preparing heav- handling and minimization of the diol side-product. Therefore, ily substituted heterocycles in one step. The role of stereodirect- this review will concentrate only on the recently published exam- 40 ing groups on the 1,5-diene backbone was also probed. Studies ples that use osmium tetroxide as the transition metal additive. The showed clearly that lowering the pH of the reaction was essen- first example shown below is unusual in that oxidation of a silyl tial in promoting oxidative cyclization at the expense of simple enol-ether means that one of the newly formed chiral centers is dihydroxylation. lost as an amino-ketone is formed in situ (eq 35);44 however, good OBn levels of enantioselectivity were observed within these products. 5% OsO4 4 equiv Me3NO, TFA O OBn OTMS O 95% H OH cat OSO4 NHTs HO Chloramine-T (35) (DHQD)2-PYR 45% BnO OBn 85% ee OBn 5% OsO4, 4 equiv Me3NO 6 equiv CSA (33) 84% O Another example shown regards the regio- and stereoselective OBn H H HO OH hydroxyamination of chiral alkenes using a similar reagent com- bination (eq 36);45 in this case the was placed at the least hindered end of the alkene (this is the commonly expected out- New Reoxidants for Dihydroxylation. Bäckvall has intro- come of the AA process, although exceptions are known). There duced some well thought out reoxidants for the dihydroxylation is no need for a chiral ligand here because the facial selectivity is and asymmetric dihydroxylation processes. Hydrogen peroxide set by the steric bias of the bridged ring system. is the terminal oxidant that oxidizes osmium(VI) back to os- mium(VIII) by first oxidizing flavin (the product flavin-OOH in turn oxidizes an amine to its N-oxide in situ; this N-oxide then cat OsO4, Chloramine-T (36) acts conventionally in the dihydroxylation reaction). Originally, 79% OH N-methylmorpholine was the amine of choice and this additive could be added in catalytic amounts. Recent developments have NHTs OSMIUM TETROXIDE 7

Oxidative Cleavage of Alkenes. An alternative to the ox- tetroxide in order to overcome the problems of toxicity and volatil- idative cleavage of alkenes using ozone or the Lemieux–Johnson ity associated with this reagent. Ley has encapsulated osmium protocol has been reported recently. Under the action of catalytic tetroxide in a polyurea matrix forming a stable catalyst that is osmium tetroxide, with oxone as a reoxidant, a variety of substi- completely insoluble in water or organic solvents (eq 39).48 This tuted alkenes were cleaved efficiently to furnish carbonyl com- catalyst is then capable of promoting the dihydroxylation reaction pounds (eq 37).46 Any of the that are produced via this of a range of alkenes using NMO as the reoxidant. The microcap- sequence are immediately oxidized in situ to give the correspond- sules (called Os EnCat) could be stored for long periods of time ing acid; clearly this does not happen for any so produced. without special precautions and could also be reused five times Even electron deficient alkenes such as α,β-unsaturated carbonyl without any loss in activity. compounds could be conveniently oxidized, although the prod- HO Ph ucts then underwent a decarboxylation reaction to produce the Ph 5% Os EnCat (39) corresponding diacid. NMO R R OH O 1% OsO4, 4 equiv Oxone R = Me, Ph, CO2Me 80–85%

OBn OBn Kobayashi has recently encapsulated osmium tetroxide into a O polymer derived from acrylonitrile, butadiene, and polystyrene. This catalyst (called ABS-MC OsO4) has also been used to give 1% OsO4, 4 equiv Oxone HO2C CO2H geminal diols from alkenes using NMO as a reoxidant; it can be easily recovered and then reused (eq 40).49 In addition, Kobayashi has shown that this immobilized catalyst is compatible with con- O O 1% OsO4 ditions for the AD reaction and gives diols with good levels of 2 equiv Oxone (37) enantioselectivity when (DHQD)2PHAL ligands are included in the dihydroxylation reaction. O Ph 5% ABS-MC OsO4 HO Ph The authors postulate that vicinal diols are not produced as 5% (DHQD)2PHAL (40) intermediates during this reaction sequence, primarily because NMO OH the reintroduction of such diols does not to the formation of cleaved products but leaves them unaltered. 81–97%, 84–96% ee

Photoinduced Charge Transfer Osmylation. The reaction Other approaches to immobilization have included the use of of osmium tetroxide with benzenoid derivatives can only be macroporous resins and functionalized silica solids that contain accomplished by irradiation of the mixture. This reaction had pre- residual vinyl groups which can be dihydroxylated as a means of viously been shown to work (with stoichiometric osmium tetrox- anchoring the transition metal to the solid support: the resulting ide) by promotion of charge transfer between the two reactants to osmium(VI) complexes are then reoxidized in situ.50 The AD form an -pair; this can then collapse to form an osmate ester of reaction has also been investigated with polymeric versions of benzene diol. Subsequent dihydroxylation of this intermediate ap- Sharpless’ chiral cinchona based ligands.51 pears to follow a more conventional (and stereoselective) course. The use of catalytic osmium tetroxide (in conjunction with bar- Oxidation of Alcohols and Amines using Osmium Tetrox- ium as a reoxidant) for this reaction is noteworthy, as ide. Recent reports have shown that benzylic amines can be ox- is the formation of both inositol and conduritol derivatives in one- idized to yield nitriles using an oxidizing system that includes pot (eq 38).47 The photoinduced osmylation of mono-substituted catalytic osmium tetroxide. Unfortunately, only benzylic amines arenes was possible although the yields were lower and the amount could be successfully oxidized, with aliphatic derivatives giving of cyclitol-type products reduced. rise to complex reaction mixtures (eq 41).52

1. 1.3% OsO4, hv, 0.22 M Ba(ClO4)2 NH2 2. Ac2O, Et3N, DMAP CN 36% Me3NO (41) cat OsO4 50% OAc OAc AcO OAc OAc There have also been reports of the oxidation of alcohols into + (38) aldehydes and ketones using oxygen and catalytic osmium tetrox- AcO OAc OAc ide in the presence of (eq 42).53 Remarkably, allylic alco- OAc OAc hols are not dihydroxylated at all and the reagent does not lead to any overoxidation to carboxylic acids. This reagent combination Immobilized Forms of Osmium Tetroxide. Several groups will only oxidize activated alcohols (such as benzylic or allylic) have been actively searching for immobilized forms of osmium and is, therefore, a useful alternative to dioxide. 8 OSMIUM TETROXIDE

2% OsO , 1% copper(II) OH 4 O 2-ethylhexanoate OH 1. OsO4 (1 equiv) O TMEDA, CH2Cl2 18% allyl ethyl ether, O2 98% 2. MeOH, HCl

OCH3 OH O 1% OsO4, 1.5% CuCl (42) 5% py, O2 HO OH HO OH 69% OH OH O + O Related Reagents. Periodate–Osmium Tetroxide.

OCH3 OCH3 syn (major) anti (minor) Second Update (43) syn:anti = 99:1 Jung Woon Yang, Sun Min Kim, Joong Suk Oh & Choong

Eui Song HO OCO(CH2)4CH3 Department of Chemistry and Department of Energy Science, Institute of Basic Science, Sungkyunkwan University, Suwon, O Korea O O Dihydroxylation of Alkenes: Synthetic Applications. secosyrin 1

Using Upjohn condition (OsO4-NMO). The utility of the Up- john protocol for the dihydroxylation was recently demonstrated O in the synthesis of bicyclic analogues of pentopyranoses,54a HN 1 or 2 54b 54c X (–)-anisomycin, trisubstituted γ-butyrolactone, 6-bromo- then, Ac2O/pyridine 4-(1,2-dihydroxyethyl)-7-hydroxycoumarine (Bhc-diol) as a photoremovable protecting group,54d 3,4-dihydroxy-2-(3- O O methylbut-2-enyl)-3,4-dihydronaphthalen-1(2H)-one,54e benzo- HN HN [c]pyrano[3,2-h]acridin-7-ones,54f both enantiomers of conduri- X X tol C tetraacetate and of meso-conduritol-d-tetraacetate.54g + (44) Recently, Richarson and coworkers developed a convenient method for in situ generation of NMO from NMM (N- AcO OAc AcO OAc methylmorpholine) using CO and H O . The NMO is quantita- 2 2 2 syn anti tively formed in situ without isolation, and undergoes asymmetric dihydroxylation of alkenes to yield the resulting diols with high X = CCl3; 1. OsO4-TMEDA, 1.2:1 (syn:anti), 92% yield enantioselectivities.55 2. UpJohn, 1:1 (syn:anti), 99% yield

X = CF3; 1. OsO4-TMEDA, >20:1 (syn:anti), 98% yield Using OsO4-TMEDA condition. Dihydroxylation of homoal- 2. UpJohn, 1:1 (syn:anti), 98% yield lylic alcohol using stoichiometric OsO4 with TMEDA (tetram- ethylethylene diamine) as a ligand predominantly provides syn product. The enhanced syn selectivity can be ascribed to the coor- Conversion of a spirodiene to the desired diol was also achieved dination of TMEDA to OsO4, thereby enhancing the electronega- in 60% yield as a single diastereomer by employing Donohoe’s 59 tivity of the oxo-ligand on osmium and favoring hydrogen bonding OsO4-TMEDA complex (eq 46). to the homoallylic OH-group. This methodology was efficiently applied to an enantioselective formal synthesis of (–)-Secosyrin 1, New Cooxidants for Dihydroxylation. In recent studies, sev- 60a 60b 60c a natural product isolated from Pseudomonas syringae, showing eral oxidants, O2, air, NaClO2 (sodium chlorite), NaOCl 56 60d 60e 60f an unusual response in resistant soybean plants (eq 43) . (sodium ), PhSe(O)Bn, Ba(ClO)3, and 60g–i Donohoe et al. also studied the directed dihydroxylation of Me3NO were successfully used as cooxidants in Os- homoallylic trihaloacetamide under OsO4−TMEDA conditions. catalyzed dihydroxylation of olefins. For instance, Donohoe re- In particular, replacement of trichloroacetamide with trifluoroac- ported on the use of Me3NO as a cooxidant in the dihydroxylation etamide as a directing group produced syn selectivity that is re- process, which allows the synthesis of (±)-1-epiaustraline in 14% 57 61 markably enhanced under OsO4-TMEDA conditions (eq 44). overall yield from N-Boc-pyrrole 2,5-methyl diester (eq 47). The Fuchs and coworkers approach to apoptolidin commenced The construction of syn-diol moiety is employed by means of 62 with a hydrogen-bonding directed dihydroxylation of a single (Z)- OsO4-Ba(ClO)3 oxidation (eq 48). allylic hemiacetal by employing Donohoe’s OsO4-TMEDA con- Allylic hydroperoxides can be directly converted to the corre- dition to give Apoptolidin diols in quantitative yield with high syn sponding triols upon treatment with a tiny amount of OsO4 (0.2 selectivity, whereas (E)-allylic acetal (if R = CH3) produced the mol %) in aqueous acetone. Hydroperoxide acts as both a directing opposite selectivity (eq 45).58 group and an internal cooxidant (eq 49).63 OSMIUM TETROXIDE 9

OTBS OR O CO2Me PhO2S OMe OTBS (R = H)

OsO4 (1equiv) TMEDA (1.1 equiv)

CH2Cl2, –78 ºC OTBS OR OTBS OR OHOH O OHOH O CO2Me CO2Me PhO2S + PhO2S OMe OMe OTBS OTBS syn (syn:anti = 9:1) anti (45)

Apoptolidin Diols

OH 1. OsO4, TMEDA OOH OsO (0.2 mol %) –78 to 25 ºC, 2 h OH 4 OH NH NH OH (46) (49) 2. MeOH, HCl, 2 h acetone–H2O (9:1), rt OH 60% yield 30–94% yields

MeO2C OsO (cat.) NBoc 4 Deprotection by Using OsO4/NMO. The selective cleavage CH2Cl2, Me3NO CO2Me of propargyl ethers and tosyl groups can be achieved under OsO4- H catalyzed dihydroxylation conditions. For example, deprotection of the propargyl ethers was achieved by isomerization to the corre- OH sponding allenes with potassium tert-butoxide, followed by cleav- MeO2C age with catalytic amounts of OsO4 and NMO to release the parent NBoc 64a,b N (47) alcohols (eq 50). HO HO CO2Me H HO HO H OH 1-epiaustraline Ph O O OBn O O t-BuOK O O O TBDMS BnO OsO4, NMO O BnO (β:α = 5:1) OMe H O N H H OsO (cat.) OTBDMS 4 Ba(ClO) 3 Ph O OH OBn HN O O O THF–H2O (4:1) O O (50) H rt, 24 h TBDMS BnO O NO BnO 2 OMe 80% yield O H N H O H OTBDMS Deprotection of tosyl groups is highly dependent on the double HN OH (48) OH bond position during the course of dihydroxylation of olefins. For instance, the tosyl group was deprotected to produce alcohol if the O H NO2 numbers of methylene units are less than 2, while the tosyl group was tolerated if the number of methylene units is greater than 2 (eq 51).65 10 OSMIUM TETROXIDE

OsO4 (0.2–10 mol %) sylvaticin through double oxidative cyclization using OsO4 to NMO (1.0 equiv) establish the bis-THF core. Synthesis of the bis-THF fragment R OTs n acetone–H2O began with commercially available tetradecatetraene. Dihydrox- ylation of the tetraene followed by in situ protection selectively OH yielded terminal diene. Mono-dihydroxylation of the terminal di- R OX ene using the Sharpless AD-mix-β produced a diol. The aldehyde n (51) was then generated using , followed by Wittig OH reaction to produce a new diene that contained a long chain alkyl n = 1 or 2; X = H group. The resulting diene underwent double oxidative cycliza- n = >2; X = OTs tion in the presence of OsO4 to produce a single diastereomer of the key bis-THF fragment (eq 53).70

Asymmetric Dihydroxylation: Synthetic Applications. Re- Sharpless “AD-mix-α” cently, the synthesis of d-xylose-protected alkanediol,66a (S)- then 66b − 66c oxybutynin, natural ( ) and unnatural (+) glyceollin I, H C CH(OMe)CH 66d 2 3 l-DOPA, and (R)-Selegiline was realized by using Sharpless CSA asymmetric dihydroxylation as a key step.

Stereoselective Oxidative Cyclization of 1,5-dienes O O Catalyzed by OsO4. There have been reports of osmium Sharpless “AD-mix-β” tetroxide promoting the nonasymmetric oxidative cyclization O O of 1,5-dienes to produce cis-tetrahydrofurans, using either periodate67 or amineoxides68 as reoxidants. Stereoselective 37% yield, >98% ee, >90% de oxidative cyclization of a 1,5-diene to furnish enantioenriched cis-tetrahydrofuran was also reported by Donohoe et al.69 O O Os-catalyzed asymmetric dihydroxylation followed by oxidative cyclization of 1,5-diene was accomplished with Me3NO (TMO) HO 1. NaIO4 as an oxidant under acidic conditions using catalytic OsO4.It OH O O 2. was postulated that the 1,2-diol was tightly bound to Os prior PPh3 59% yield 9 to oxidation of the pendant alkene, leading to cyclization of the conformationally rigid vicinal diol with a high level of stereocontrol. This protocol was successfully applied to a formal 69 synthesis of (+)-cis-solamin (eq 52). 9 O O OsO4 (5 mol %) cinnamic acid Sharpless α Me3NO (5 equiv) “AD-mix- ” O O 11 OH TFA, acetone/H2O

OH OsO4 (5 mol %) OH 9 O O isoprene (5 equiv) HH H H OH OH HO 11 OH TMO, TFA/acetone/H2O, rt OH 77% yield (as a single diastereomer) >90% ee (53) OH (+)-cis-Sylvaticin 10 O OH O H H H O OH OH via Os O H The same group also described a highly stereoselective synthe- 81% yield, >90% ee O sis of pyrrolidines utilizing a OsO4-catalyzed oxidative cycliza- H tion strategy. Preferential mode of cyclization is most likely due to R 5 steps the robust intramolecular coordination of osmium with nitrogen and oxygen atoms of the N-tosylated aminoalcohol (eq 54).71 O Aminohydroxylation of Alkenes. Sharpless’ asymmetric (52) 10 O 9 H H O aminohydroxylation (AA) allows for the catalytic and enantios- OH OH elective synthesis of protected vicinal aminoalcohols in a single 72a (+)-cis-solamin step. This reaction is significant as it applies to the synthesis of a wide variety of biologically active agents and natural products. For The same group further extended this methodology to the enan- example, new monoterpene β-amino alcohols can effectively be tioselective total synthesis of the potent antitumor agent (+)-cis- synthesized from (+)-2-carene, (+)-3-carene, (−)-β-pinene, and OSMIUM TETROXIDE 11

(−)-camphene using commercially available chloramine-T as the can be purified by column chromatography, followed by reduc- 72b nitrogen source. tion with LiAlH4 to give an enantiomerically pure vicinal diamine (eq 56). They also investigated diamination of electron-deficient OH OsO4 (5 mol %) olefins including amides, ketones, and aldehydes as the functional trans-cinnamic acid groups with bis(imido) complex. As a result, the corresponding TMO, CSA (6 equiv) osmaimidazolidines were obtained as a single product in high 73a–c NHTs CH2Cl2, rt chemical yields (84–92%). Ts N H O Os O O NtBu O O THF + Os Ph O t –15 ºC, 56% O N Bu N (54) Ph H H HO Ts OH 61% yield tBu O N O O (56) Os O Aminohydroxylation Reaction using a New Nitrogen Source. N Ph Ph Luxenburger and coworkers reported a base-free, intermolecu- tBu lar asymmetric aminohydroxylation (AA) reaction of olefins with tBuHN CH OH alkyl 4-chlorobenzoyloxycarbamates as a nitrogen source that is 2 LiAlH4, THF, rt 73 94% yield readily prepared. Generally, the reoxidant for an AA reaction is t typically carbamate salt prepared in situ by treatment of NaOH BuHN Ph with t-BuOCl. The addition of a base was mandatory for the pro- motion of the AA reaction. However, Luxenburger’s reagent is Interestingly, the use of monoimidoosmium(VIII) complex in found to be effective under base-free reaction conditions. The reac- combination with dimethyl fumarate provided complicated prod- tion proceeds under neutral conditions and various base-sensitive ucts such as diols and aminoalcohols. On the other hand, bis- and functional substituents were not affected (eq 55). tris(imido)osmium complexes displayed complete chemoselectiv- ity and underwent diamination exclusively (eq 57).76 (DHQD)2PHAL (5 mol %) OsO (4 mol %) 4 t carbamate (1.4 equiv) CO2Me N Bu THF, rt R1 O R + Os O CH3CN:H2O (8:1), rt then, Na2SO3/H2O MeO2C O nitrogen source : Cl tBu O HO CO2Me HN CO2Me RHN + O HO HO R = CO2Et, Cbz, Boc, Fmoc CO2Me CO2Me 11% yield 52% yield

OH NHR t CO2Me N Bu R1 R1 O THF R + R (55) + Os NtBu rt NHR OH MeO2C X 43–96% yields, up to 97% ee tBu regioselectivity (up to 13.4:1) X N CO2Me Os O N (57) CO2Me Applications of Imido-Osmium (VIII) Complex to Diamina- tBu tion and Aminohydroxylation. Imidoosmium(VIII) compounds X = O; 90% yield are versatile reagents that can be used for the transformation of X = tBuN; 92% yield olefins to vicinal diamines or vicinal aminoalcohols. Since the pioneering work of Sharpless in the development of the diamina- tion of olefins,74 Muñiz et al. reported the first example of asym- In particular, this protocol showed a highly chemoselective metric diamination of alkene bearing an (−)-8-phenylmenthol es- diamination of vinyl acrylate. For example, the diaminated prod- ter as a chiral auxiliary with bisimidoosmium complex at −15◦C uct was the sole product with neither diol nor aminoalcohol being to give the corresponding osmaimidazolidine as a 94:6 dr (di- detected. Diamination of the acrylate C=C double bond was ex- astereomeric ratio). The stabilized osmaimidazolidine compound clusive. (eq 58).76 12 OSMIUM TETROXIDE

t O N Bu THF, rt + O Os t O N Bu 92% yield O 100:0 O O Os OsO4 tBu N N tBu (58) N N O O O N N

OMe O Recycling of Osmium by Immobilization of Osmium N Tetroxide. Several groups have been actively searching for im- mobilized forms of osmium tetroxide in order to overcome the problems of toxicity and associated with this reagent. The following are some representative examples of immobi- OMe N lization methods for a catalytic system (OsO4 and/or cinchona alkaloid ligand). macroporous alkaloid resin bearing residual vinyl groups Immobilization of Osmium Tetroxide onto Macroporous (white-colored resin) Resins. Song and coworkers reported simple immobilization of OsO4 onto macroporous resins such as Amberlite XAD-4 (di- O vinylbenzene and styrene copolymer) or XAD-7 (divinylbenzene O Os and acrylate copolymer) bearing residual vinyl groups via osmy- O O lation. The osmylated resins are air-stable, nonvolatile, and much easier to handle than their homogeneous counterpart. Moreover, the resin-bound OsO4 exhibited excellent catalytic activity in the asymmetric dihydroxylation (AD) of olefins. After reaction, the O O recovered osmylated resins could be reused for five consecutive Os OsO4 O reactions without any significant decrease in product yield. The N N O osmylated resin in particular maintained its catalytic efficiency O for almost three cycles even if the catalyst loading of Amberlite N (60) XAD-7 was reduced to 0.2 mol % (eq 59).77 N OMe O O O N Os O O O O Os O O Os O O OMe N O O

XAD-4·OsO4 or XAD-7·OsO4 R RS RM RS M Os-complex of macroporous alkaloid resin (0.1–1 mol %) H H (59) (black-colored resin) RL H (DHQ)2PHAL (0.1–1 mol %) HO OH K3Fe(CN)6/K2CO3 t-BuOH:H2O(v/v=1:1), rt Application of Osmylated Macroporous Resins for Asymmet- Although this approach is highly efficient for recycling the ric Aminohydroxylation. Song and coworkers also examined osmium component, an additional acid-base work-up procedure the utility of osmylated macroporous resins for the asymmetric is required to recover the cinchona alkaloid-derived chiral ligand. aminohydroxylation (AA) of olefins with AcNHBr/LiOH as the For this reason, the same group attempted to develop an immobi- oxidant/nitrogen source. Most of the reactions proceeded with lization method for simultaneous recovery and reuse of both cat- excellent enantioselectivity (>99% ee for trans-cinnamate deriva- alytic components (osmium and cinchona alkaloid-derived chiral tives) and extremely high regioselectivity (>20:1). After reaction, 78 ligand). Addition of OsO4 to macroporous cinchona alkaloid the osmylated resins can be quantitatively recovered and reused resin bearing residual vinyl groups resulted in the formation of in three consecutive reactions without any significant loss of cat- rigid Os-ligand complexes and partially osmylated product onto alytic efficiency (eq 61).79 resins. The catalytic system exhibited excellent activity and enan- tioselectivity (up to 99% ee) in heterogeneous Os-catalyzed AD Macroencapsulation Method for Immobilization of Osmium reactions (eq 60). Tetroxide. Macroencapsulation is a technique for entrapping pre- OSMIUM TETROXIDE 13 cious metals in a polymeric coating of microspheres. Kobayashi Yanada et al. also described the immobilization of OsO4 in and coworkers introduced a phenoxyethoxymethyl-polystyrene ionic liquid [Emim][BF4] applied to several substrates including microencapsulation (PEM-MC) method for the immobilization mono-, di-, and trisubstituted aliphatic olefins as well as aromatic 83 of OsO4. To examine the efficiency of the PEM-MC OsO4, the olefins. AD of olefin was performed using (DHQD)2PHAL as a chi- Song et al. employed 1,4-bis(9-O-quininyl)phthalazine ral ligand and K3Fe(CN)6 as a cooxidant in acetone/H2O. The [(QN)2PHAL] as a chiral ligand for an AD reaction using NMO microencapsulated OsO4 catalyst can be recovered quantitatively in mixtures of [Bmim][PF6] and acetone–H2O. (QN)2PHAL can by simple filtration and reused without loss of activity. However, also be converted into a new ligand bearing highly polar residues microencapsulated OsO4 exhibited somewhat inferior catalytic (four hydroxy groups) during AD reactions. This highly polar activity and enantioselectivity compared with its homogeneous ligand can be strongly immobilized in the ionic liquid phases and R analogue. Interestingly, when using PEM-MC OsO4 and Triton thus minimize Os leaching during the extraction of product. The X-405 as a nonionic phase transfer catalyst, the reaction proceeds recovered ionic liquid phase containing Os and chiral ligand are smoothly and produces the desired product with water as the sole capable to reuse it three times even at a low catalyst loading of solvent.80 Os (0.1 mol %). A distinctive feature of this methodology is that it requires neither structural modification of the ligand nor high 84 XAD-4·OsO or XAD-16·OsO catalyst loading of OsO4 (eq 63). i 4 4 CO2 Pr (4 mol %)

(QN)2PHAL (2.5 mol %) (DHQ)2PHAL (5 mol %) OsO (1 mol %), NMO (1.5 equiv) AcNHBr (1.1 equiv)/LiOH (1.0 equiv) Ph 4 Ph (63) t-BuOH–H2O (1:1), 5 h, 4 ºC Ionic liquid, acetone–H2O (10:1) 92% yield, 98% ee

NHAc i CO2 Pr OH HO (61) OH

OH HO OH >99% ee, >20:1 (regioselectivity), N N N N Ph + 93% yield (XAD-4·OsO4), 90% yield (XAD-16·OsO4) Ph O O H H OH MeO OMe Ley and Malla Reddy independently reported OsO4 microen- capsulated in polymer matrices such as polyurea or polysulfone, N N respectively. Polyurea-microencapsulated OsO4 has proven to be extremely robust and long-term storable. High chemical yield and On the other hand, Afonso and coworkers described an AD excellent enantioselectivity was also achieved using polysulfone- reaction in a biphasic solvent system ([Bmim][PF6]/H2O using microencapsulated OsO4 even without the need for slow addition OsO (0.5 mol %), (DHQD) PHAL (1.0 mol %), and K Fe(CN) 81a,b 4 2 3 6 of olefins. (3 equiv) as a cooxidant at room temperature.85

Immobilization of Osmium Tetroxide into Ionic Immobilization of Osmium Tetroxide onto Sugar. Table sugar Liquids. Room temperature ionic liquids (RTILs) have emerged (sucrose), a disaccharide of glucose and fructose, contains eight as powerful media for the immobilization of catalysts. Several free hydroxyl functional groups that can be used as a new me- research groups have pursued AD reaction by immobilizing OsO4 dia for convenient immobilization methods. Song and coworkers into ionic liquids. In 2002, Yao initially studied the Os-catalyzed demonstrated that the combination of sucrose and highly polar- dihydroxylation under standard Upjohn conditions (OsO4/NMO ized alkaloid ligands generated in situ from (QN)2PHAL during in t-BuOH/H2O) in the presence of RTILs such as 1-butyl-3- the reaction provided a highly simple and efficient approach for methylimidazolium hexafluorophosphate ([Bmim]PF6). Both recycling both catalytic components (OsO4 and chiral cinchona the catalyst and the RTIL can be recycled and reused in the AD alkaloid ligand). The chiral catalyst is strongly bounded into sugar reaction, but with a decrease of catalytic activity due to the Os moiety in aqueous phase and thus isolated chiral diol from organic leaching. 4-dimethylaminopyridine (4-DMAP) as a ligand was layers by extraction with Et2O. 0.1 mol % of Os-catalyst load- added to the reaction mixture for the creation of amine-OsO4 ing was sufficient to reach excellent enantioselectivity (>99% ee) complex in order to prevent Os metal leaching. The resulting (eq 64).86 complex strongly binds to cationic imidazolium moieties of RTIL, which enhances its immobilizability in polar ionic liquids Immobilization of Osmium Tetroxide onto Ionic Polymer (eq 62).82 Support. The incorporation of OsO4 onto short-length PEGy- lated (PEG: Poly(ethylene glycol)) ionic polymers was achieved

N N OsO4 by Janda and coworkers. Immobilized OsO4 exhibited excellent OH catalytic performance and recyclability in the AD reaction. The (2 mol %) OH (62) high recyclability could be attributed to the interaction between NMO, ionic liquid the induced dipole of OsO4 and the of the polymeric scaf- t-BuOH-H2O folds in a manner similar to ionic liquids. Moreover, Os-bounded 14 OSMIUM TETROXIDE

(QN)2PHAL (2.5 mol %) OsO4 (0.1 mol %) NMO, acetone–H2O OH Sucrose

OH >99% ee (Ether Phase) (64) N N N N

OMe OMe OMe OMe H H H H O O O O OsO N NN N N NN N 4

(QN)2PHAL OH HO Total TON = ~3500 HO OH

Sugar Phase

polymer is also able to effectively immobilize a significant amount Recycling of Osmium from Homogeneous Systems. Con- of chiral ligand (eq 65).87 ceptually new methodology for recycling of osmium species from homogeneous systems was developed by Donohoe et al. For ex- ample, the reaction of bis(imino)osmium(VI) complex, which MsO-PEG3-OMe (3 equiv) P is synthesized by mixing trans-stilbene with OsO4, and trans- DMF, 80 ºC, 48 h t stilbene with tert-butyl hydroperoxide ( BuOOH) in CH2Cl2 produced a corresponding osmium(VII) intermediate. This inter- mediate was isolated by column chromatography, which was sub- MsO ◦ NH4BF4 jected to hydrolysis in acetone:H2O (4:1) at 60 C to produce a P (65) PEG3 DMF, rt, 1 h (x3) stilbene diol (87% yield) and liberate bis(imino)osmium(VI) com- plex for reuse (eq 66).91

BF4 BF4 OsO4 P PEG Os PEG3 3 CH CN, rt, 24 h 3 R′′ R N O R′′′ R′ Os P: poly(4-vinylpyridine/styrene) tBuOOH N O recycling system MsO-PEG3-OMe: tri(ethylene glycol) monomesylate monomethyl ether R CH2Cl2, 5 min Os(VI)

R O R′′ acetone–H2O Immobilization of Osmium Tetroxide onto PEG Support. N O (4:1) PEG [Poly(ethylene glycol), molecular weight: 400] can be used R′ Os 60 ºC N O ′′′ as an alternative recyclable medium for the AD reaction. Using R R (DHQD) PHAL ligand, OsO , and NMO in PEG, it was possi- 2 4 Os(VII) ble to reuse the catalytic system for up to five cycles, producing the desired diols in high yields with excellent enantioselectivities 88 without any loss of catalytic activity. R′′ R HO N O + R′ Os (66) Immobilization of Osmium Tetroxide onto Other Supports. HO R′′′ N O Good performance in terms of chemical yield (up to 90%), R enantioselectivity (up to 86% ee), and recyclability of both compo- 60–91% yields Os(VI) nents (OsO4 and chiral ligand) was achieved by employing silica- 89a supported chitosan-OsO4 and wool-OsO4 complex in the AD reaction of olefins.89b,c Fullerene was also shown to serve as a Oxidative Cleavage of Olefins. Oxidative cleavage of olefin support for efficient immobilization of OsO4, which was success- is used widely in organic synthesis. Most oxidative cleavage of fully recovered and recycled several times.90 olefin reactions can be classified into two categories: direct cleav- OSMIUM TETROXIDE 15 age via ; and dihydroxylation of olefin followed by diol Boland and coworkers during a short and efficient total synthe- cleavage. Recently, Borhan and coworkers demonstrated that the sis of several alkanolides, alkenolides, and dihydroisocoumarins. combination of OsO4/Oxone is an effective system for the oxida- For instance, micromolide was synthesized that is potent in vitro tive cleavage of alkenes, where Oxone plays three distinct roles activity against Mycobacterium tuberculosis (H37Rv) (eq 70).95 in this system: (i) reoxidation of Os(VI) to form Os(VIII) species; (ii) promotion of oxidative cleavage to intermediate aldehyde be- OH 1. OsO4, Oxone, DMF, rt ginning with an attack of a peroxomonosulfate ion derived from C8H17 2. H , Lindlar catalyst, hexane, –5 to 0 ºC Oxone into Os(VIII) species; and (iii) oxidation of aldehyde into 3 2 carboxylic acid. The reaction can be considered as an alternative 76% yield over two steps to ozonolysis because the reaction proceeds without the interme- >99% ee 92 diacy of 1,2-diols (eq 67). O O OsO4 (0.01 equiv) (70) Oxone (4 equiv) O O 3 C7H15 1 + R R DMF, 3 h, rt R OH R1 OH Micromolide

O O Due to the high volatility and toxicity of OsO4, the same group Os applied OsEnCatTM40 (microencapsulation of OsO in polyurea) OsO4 [O] 4 O O TM R R to oxidative cleavage of olefins. The OsEnCat 40 catalyst was recovered and reused three times but with a sacrifice of catalytic R R activity (eq 71).96 O O O – O O O O Os Os Oxidative OsEnCatTM 40 (2 mol %) OSO3H Cleavage O O Oxone (4 equiv) O HO SO – O O Ph 3 2 Ph 2 (71) DMF, 12 h, 25 ºC Ph OH R R R R

A catalytic amount of OsO4 in combination with H2O2 in O O DMF has also been shown to efficiently cleave alkenes, producing [O] (67) aldehydes rather than carboxylic acids. Aryl olefins are cleaved R H R OH in good yield, whereas alkyl olefins cleaved moderate yield for di- and tri-substituted alkenes (eq 72).97 OsO4-mediated oxidative cleavage/oxidative lactonization of alkenols with Oxone as the cooxidant in alcoholic solvents pro- OsO4 (1 mol %) duced the corresponding lactones via the formation of aldehydes ′′ 93 R 50% aq. H2O2 (4 equiv) O as a key intermediate (eq 68). R (72) R′ DMF R H O OsO4 (cat.) OH (68) R = Ph, alkyl n Oxone/solvent O R′, R′′ = alkyl or H n Dias et al. reported that the oxidation of N-Boc-protected Borhan and coworkers described the stereoselective total syn- homoallylic alcohols with OsO4 as a catalyst in the presence of thesis of (+)-tanikolide, a natural product isolated from the marine NaIO4 efficiently occurred in Et2O:H2O (1:1) to provide 4-N- cyanobacteria Lyngbya majuscula, using OsO4-mediated tandem Boc-amino-3-hydroxy ketones in high yields (eq 73).98 oxidative cleavage–lactonization of the alkenol in the presence of 94 soluble Oxone (n-Bu4NHSO5) to produce the lactone (eq 69). OH 1. OsO4 (2 mol %) Et2O/H2O (1:1), 2 h 1. OsO4 (1 mol %) R C13H27 2. then NaIO , 18 h OH n-Bu4NHSO5 (4.4 equiv) 4 8 NHBoc OH THF (73%)

2. Pd(OH)2/H2 R = Me, i-Pr, Bn, i-Bu, CH2OBn EtOAc, rt (87%) OH O R (73) O C13H27 OH NHBoc O (69) 80–94% yield (+)-tanikolide Conventional oxidative cleavage of olefin can be achieved by a Similarly, the importance of the tandem oxidative cleavage– two-step sequencing reaction of OsO4-mediated dihydroxylation lactonization reaction using OsO4–Oxone was demonstrated by of olefin, followed by periodate cleavage of diol. The resulting 16 OSMIUM TETROXIDE aldehyde can be reduced to the desired alcohol with sodium boro- of 1-azabicyclo[3.1.0]hexane is reported via dihydroxylation/ hydride in a quantitative yield (eq 74).99 oxidative cleavage/reduction (eq 77).102

O CO2Bn OsO4, NMO O 1. OsO4 (cat.), NMO N acetone–H2O (8:1) rt, 3 h, 57% O 2. NaIO4 3. NaBH O 4 O HO 1. NaIO , H O O HO CO2Bn 4 2 CO2Bn 0 ºC, 30 min, 73% (77) O HO HO N 2. NaBH4, MeOH N (74) rt, 1.5 h, 34% O HO O O l-Hamamelose, which is used as a starting material for the syn- furanofuran lignan thesis of potential glycosidase inhibitors, was also synthesized via dihydroxylation/oxidative cleavage/reduction (eq 78).103 The main drawback of the oxidative cleavage of olefins by HO 1. OsO (cat.)/NaIO OsO4-NaIO4 is the formation of side product such as α-hydroxy 4 4 O acetone-H O (4:1), rt, 2 h ketone derivatives presumably formed via the overoxidation of HO 2 the diol intermediate. Jin and coworkers found that the use O O 2. NaBH4, MeOH, rt, 5 min of 2,6-lutidine in dioxane-H2O enables higher chemical yield of the corresponding aldehydes by suppressing unwanted products HO OH (eq 75).100 HO O

Me OPMB O O OsO , NaIO , 2,6-lutidine 4 4 (78) Me dioxane/H2O 71% yield OBn without 2,6-lutidine: 1 h, 44% yield with 2,6-lutidine: 1 h, 83% yield HO OH O Me OPMB HO HO O HO OH OHC Me (75) HO OH OH OH OBn L -Hamamelose An efficient method for the oxidative cleavage of solid- supported peptide olefins into aldehydes using a combination C–H and Si–H Bond Oxidation. Mayer and coworkers of OsO /NaIO /DABCO system was described by Meldal and 4 4 reported selective C–H bond oxidation of unactivated alkanes, coworkers. The resulting aldehydes are subjected to intermolec- including primary, secondary, and tertiary C–H bonds, using sto- ular N-acylium Pictet–Spengler reactions to furnish pyrroloiso- ichiometric amounts of OsO in aqueous pH = 12.1 solution at quinoline derivatives in high purity (eq 76).101 4 85 ◦C. For example, isobutane can be oxidized to tert-butanol 1 (eq 79). The catalytic version of this reaction using NaIO as R 1. OsO4 (0.01 equiv) 4 3 1 DABCO (5 equiv) a terminal oxidant exhibited unsatisfactory results. The turnover R R 104 NaIO4 (10 equiv) number of OsO4 was only ca. 4. THF:H2O (1:1) pH = 12.1 2. TFA:CH2Cl2 (1:1) – Gly H + OsO4 + H2O + 2 OH HN 3. 0.1 M NaOH (aq) H2O, 85 ºC, 7 d then 0.1 M HCl (aq) O O 2 2– R OH + OsO2(OH)4 (79) R3 R1 The author proposed that the reaction presumably proceeded H (76) via [3+2] mechanism, which is quite similar to [3+2] mechanisms Gly − OH for olefin dihydroxylation. Insertion of OH into OsO4 at pH N − = 12.1 led to the formation of OsO4(OH) species. Addition of O − O C–H bonds into two oxo-groups of OsO4(OH) provided an in- termediate, which can be hydrolyzed by aqueous base, and liber- 2− The 1-azabicyclo[3.1.0]hexane moiety is present relatively ated a corresponding alcohol and reduced osmate [OsO2(OH)4 ] often in biologically active compounds. A new synthetic route (eq 80). OSMIUM TETROXIDE 17

H – H 1. (a) Schröder, M., Chem. Rev. 1980, 80, 187. (b) Singh, H. S., In Organic R – – O R OH – O O RO OH Synthesis by Oxidation with Metal Compounds; Mijs, W. J.; De Jonge, Os O O Os O C. R. H. I., Eds.; Plenum: New York, 1986; Chapter 12. (c) Johnson, O Os O O O OH H2O R. A.; Sharpless, K. B., In Catalytic Asymmetric Synthesis; Ojima, I., OH OH Ed.; VCH: New York, 1993. (d) Lohray, B. B., Tetrahedron: Asymmetry 1992, 3, 1317. (e) Haines, A. H., Comprehensive Organic Synthesis O 2– 1991, 7, 437. HO OH ROH + Os (80) 2. Henbest, H. B.; Jackson, W. R.; Robb, B. C. G., J. Chem. Soc. (B) 1966, HO OH O 803. 3. Herrmann, W. A.; Eder, S.; Scherer, W., Angew. Chem., Int. Ed. Engl. Methane could also be oxidized to methanol at 50 ◦C by uti- 1992, 31, 1345. lizing OsO4 and NaIO4 in D2O. No methane oxidation product 4. Rüegger, U. P.; Tassera, J., Swiss Chem. 1986, 8, 43. was detected using either NaIO4 without OsO4 or OsO4 without 5. Austin, R. G.; Michaelson, R. C.; Myers, R. S., In Catalysis of Organic Reactions; Augustine, R. L., Ed.; Dekker: New York, 1985; p 269. NaIO4. It was observed that the presence of methane noticeably inhibited the further oxidation of methanol, which is a competi- 6. (a) Cha, J. K.; Christ, W. J.; Kishi, Y., Tetrahedron 1984, 40, 2247. (b) tor for methane oxidation. The overoxidation of methanol was Christ, W. J.; Cha, J. K.; Kishi, Y., Tetrahedron Lett. 1983, 24, 3943 and 3947. ca.1000 times slower in methane than in argon (eq 81).105 7. Brimacombe, J. S.; Hanna, R.; Kabir, A. K. M. S.; Bennett, F.; Taylor, I. D., J. Chem. Soc., Perkin Trans. 1 1986, 815. OsO4/NaIO4 CH4 CH3OH + CH2(OH)2 + CO2 (81) 8. DeNinno, M. P.; Danishefsky, S. J.; Schulte, G., J. Am. Chem. Soc. D2O, 50 ºC 1988, 110, 3925. 9. Evans, D. A.; Kaldor, S. W., J. Org. Chem. 1990, 55, 1698. Exposure of silanes (Et3SiH, i-Pr3SiH, Ph3SiH, or PhMe2SiH) 10. 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