Stereoselectivity dioxiranes

D Accolti, L. Fiorentino, M. Fusco, C. Capitelli, F. Curci, R. Stereoselective dioxirane hydroxylations and the synthesis of tripod boronic acid esters. Tetrahedron Lett. 2007, 48, 3575. 

The relative reactivity of a wide series of nucleophiles towards dioxirane, dimethyidioxirane, carbonyl oxide, and dimethylcarbonyl oxide has been examined at various levels of theory. The general trend in reactivity for oxidation by dioxirane was R2S R2SO, R3P > R3N in the gas phase, and R2S R2SO, R3N R3 (R = Me) in solution. A theoretical study of the first oxidation step of [3.2.1]-bridged bicyclic disulfides highlights a highly oriented reaction path was probably responsible for stereoselective attack on the exo face. ... 

Part of the mystique surrounding the often assumed high reactivity of dioxiranes stems from the observation that dioxiranes such as methyl(trifluoromethyl)dioxirane (TFDO) are capable of oxidizing saturated hydrocarbons to their alcohols at relatively low temperatures in high yields and with impressive stereoselectivities (equation 8). 

As already mentioned, the dioxirane epoxidation of an alkene is a stereoselective process, which proceeds with complete retention of the original substrate configuration. The dioxirane epoxidation of chiral alkenes leads to diastereomeric epoxides, for which the diastereoselectivity depends on the alkene and on the dioxirane structure. A comparative study on the diastereoselectivity for the electrophihc epoxidants DMD versus mCPBA has revealed that DMD exhibits consistently a higher diastereoselectivity than mCPBA however, the difference is usually small. An exception is 3-hydroxycyclohexene, which displays a high cis selectivity for mCPBA, but is unselective for DMD . ... 

In regard to the stereoselectivity of the insertion process, Murray and coworkers have shown that the CH oxidation of substituted cyclohexanes by dioxiranes is, like the already discussed epoxidation, highly stereo-controUed . A specific case is c -decalin, which gives only the cis alcohol, as exemplarily displayed in equation 27. A similar stereoselective retention of configuration was also obtained for frawi-decalin and cis- and frawi-dimethylcyclohexanes"°. In fact, complete retention of configuration was demonstrated in the CH oxidation of chiral alkanes ". For example, the optically active (f )-2-phenylbutane was converted by either DMD or TFD" to (5 )-2-phenylbutan-2-ol (equation 28) without any loss of the enantiomeric purity (ep) in the product. 

Two new reactive, very powerful organic peroxides, dimethyldioxirane and methyl(trifluoromethyl)dioxirane (4), have been introduced.81-83 The latter is more reactive and can be used more conveniently.84 85 Acyclic alkanes give a mixture of isomeric ketones on oxidation with methyl(trifluoromethyl)dioxirane,84,85 while cyclohexanone is the sole product in the oxidation of cyclohexane (99% selectivity at 98% conversion).85 With the exception of norbomane, which undergoes oxidation at the secondary C-2 position, highly selective tertiary hydroxylations can be carried out with regioselectivities in the same order of magnitude as in oxidations by peracids.85-87 A similar mild and selective tertiary hydroxylation by perfluorodialkyloxaziridines was also reported.88 Oxidation with dioxiranes is highly stereoselective 85... 

Dimethyldioxirane has also been used as the epoxidizing agent in a key step in the synthesis of A-norsteroids69,70. The reaction occurs in dichloromethane-acetone and is highly regio- and stereoselective as shown in equation 9. Dioxiranes may also be generated in situ, by reaction of potassium monoperoxysulfate (sold commercially as OXONE) and cyclohexanones. In this case, cyclohexene derivatives may be smoothly epoxidized in 40-100% yields (equation 10)71. 

Epoxidation. Oxone decomposes in the presence of a ketone (such as acetone) to form a species, possibly a dioxirane (a), which can epoxidize alkenes in high yield in reactions generally conducted in CH2C12-H20 with a phase-transfer catalyst. An added ketone is not necessary for efficient epoxidation of an unsaturated ketone. The method is particularly useful for preparation of epoxides that are unstable to heat or acids and bases.3 The acetone-Oxone system is comparable to m-chloroperbenzoic acid in the stereoselectivity of epoxidation of allylic alcohols. It is also similar to the peracid in preferential attack of the double bond in geraniol (dienol) that is further removed from the hydroxyl group.4... 

DMD is suitable for the oxidation of most substrates with substances that are resistant to oxidation, however, the more reactive but also more expensive methyl (trifluoromethyl)dioxirane (TFD) is necessary. The oxidation is stereoselective for both dioxiranes and proceeds with complete retention of configuration at the oxidized carbon atom (Scheme 1) [20-22]. The reactivity follows the usual order of electrophilic oxidation-primary < secondary < tertiary < benzylic < allylic C-H bonds. Except for tertiary C-H bonds, which produce the oxidatively inert tertiary alcohols, further oxidation of the primary product (an alcohol) to a ketone or aldehyde (the latter is readily further oxidized to the corresponding acid) is possible, because the a-hydrogen of the alcohol is usually more reactive than that of the unactivated alkane, especially for allylic C-H bonds. 

A concerted, spiro-structured, oxenoid-type transition state has been proposed for C-H oxidation by dioxiranes (Scheme 5). This mechanism is based mainly on the stereoselective retention of configuration at the oxidized C-H bond [20-22], but also kinetic studies [29], kinetic isotopic effects [24], and high-level computational work support the spiro-configured transition structure [30-32], The originally proposed oxygen-rebound mechanism [24, 33] was recently revived in the form of so-called molecule-induced homolysis [34, 35] however, such a radical-type process has been experimentally [36] and theoretically [30] rigorously discounted. 

The explanation for these experimental results, i.e. the lack of label transfer, is that the tetrahedral species (A) resulting from the addition of HSOf to the carbonyl group is capable of epoxidation. Ring closure of (A) is likely to be the rate-determining step in dioxirane formation. This work is important from a synthetic viewpoint, since it is crucial in the development of chiral ketones for the catalytic asymmetric epoxidation and the design of probes of transition state stereoselectivities that the nature of the oxidizing species is understood. 

A very nice example of the oxidation by dioxirane lb where other oxidants failed is the regio- and stereoselective oxidation of C3-C4 enol double bond of quinine methide triterpenes pristimerin 76 and tingenone 77 <1996T10667>. 

In contrast, dioxirane chemistry has increasingly developed. Dioxiranes are approved as very powerful chemo- and stereoselective oxidative reagents. Remarkable progress has been made in developing dioxirane-catalyzed enantio-selective oxidations. 

Major interest has been expressed in the synthesis of chiral sulfoxides since the early 1980s, when it was discovered that chiral sulfoxides are efficient chiral auxiliaries that are able to bring about important asymmetric transformations [22]. Sulfoxides are also constituents of important drugs (e.g., omeprazole (Losec , Priso-lec )) [23]. There is a plethora of routes of access to enantioenriched sulfoxides, and many involve metal-catalyzed asymmetric oxidations [24]. Examples of ruthenium metal-based syntheses of sulfoxides are scarce, presumably due to the tendency of sulfur atoms to bind irreversibly to a ruthenium center. Schenk et al. reported a dia-stereoselective oxidation of Lewis acidic Ru-coordinated thioethers with dimethyl-dioxirane (DMD) (Scheme 10.16) [25[. Coordination of the prochiral thioether to the metal is followed by diastereoselective oxygen transfer from DMD in high yield. The... 

The highly potent antithrombotic (+)-rishirilide B was synthesized in the laboratory of S.J. Danishefsky. One of the tertiary alcohol functionalities was introduced via the Rubottom oxidation of a six-membered silyl dienol ether with dimethyl dioxirane (DMDO). The oxidation was completely stereoselective, and it was guided by the proximal secondary methyl group. Subsequently, the enone was converted to the enedione, which was used as a dienophile in the key intermoiecuiar Dieis-Aider cycioaddition step. 

Stereoselective epoxidations of substituted cyclohexenes with in situ generated dioxiranes have been studied <94TL1577>. The most favorable trans/cis selectivities have been achieved using dioxiranes derived from sterically hindered ketones (Scheme 26). 

In ketone-directed peroxy acid epoxidations of cyclic alkenes the actual epoxidizing agent has been shown by 180-labeling not to involve a dioxirane <94TL6155>. Instead, an a-hydroxy-benzoylperoxide or a carbonyl oxide is believed to be responsible for observed stereoselectivities in the intramolecular epoxidations. The extent of syn-selectivity is greater for ketones than with esters the syn/anti ratios increase when ether is used as solvent rather than CH2C12, the reverse situation for hydroxyl-directed epoxidations. Fused-ring oxiranes can also be prepared from acyclic precursors. Four different approaches are discussed below. 

An alternative method whereby a fused-ring oxirene may be generated is the epoxidation of a cycloalkyne. Curci et al. have employed methyl(trifluoromethyl)dioxirane (TFD) toward that end, and obtained (215) and c -bicyclo[4.4.0]decan-2-one in ca. 7 1 ratio from cyclodecayne (213) <92TL7929>. These products obviously stem from stereoselective 1,5- and 1,6-transannular insertion pathways. The authors conclude that the products of cycloalkyne oxidations may arise directly from trapping of the oxirene intermediates by transannular hydrogen transfer, as shown in Scheme 46. 

Secondary alcohols are oxidized to ketones with high regio- and stereoselectivity on treatment with perfluoro oxaziridine (64a) at room temperature, (Equation (11)) <92TL7245>. Yields are excellent and the reactivity of this oxaziridine is reported to be comparable to that of dioxiranes. 

On the other hand, oxidation of 161 with dimethyl dioxirane gave a 1 9 mixture of diols 165 and 166 (Scheme 31). Surprisingly and inexplicably the major product 166 results from attack on the double bond face syn to the arylsulfonyl moiety. Diol 166 could be converted to monoacetate 167 which underwent stereoselective alkylation with allyl trimethylsilane to yield 168. Similarly, acetate 167 could be converted to a single nitrile 169. Both of these transformations involve axial attack anti to the arylsulfonyl group on an intermediate N-sulfon-ium iminium ion. 

The development of solid-supported chiral oxidants is a challenging area that has yielded interesting results in the development of a chiral supported dioxiran precursor. The preparation of non-racemic epoxides has been extensively studied in recent years since they are important building blocks in stereoselective synthesis. A supported dioxirane precursor based on a-fluorotropinones was shown to promote the epoxidation of alkenes [28, 29]. The reactant was anchored on meso-porous MCM-41 and amorphous silicas. It has shown comparable activity to its homogenous counterpart and good stability on recycling. The enantiomerically enriched version efficiently promotes the enanhoselective epoxidation of alkenes, with ee values up to 80% (Scheme 4.4). 

Epoxidation. Oxone is used to generate dioxirane from a ketone added to the reaction medium. Such dioxiranes epoxidize alkenes stereoselectively. 2-Cyclo-hexenol gives two epoxy alcohols in a ratio of 77 23 (trans cis). 

In the presence of anhydrous zinc chloride as catalyst and in tetrahydrofuran as solvent, the a dioxirane 30 reacts with a glycosyl acceptor [A], to give stereoselectively the corresponding (1-0-glycoside 31 [122,128] (Scheme 14). 

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