Fructose derived ketone

Among many other methods for epoxidation of disubstituted E-alkenes, chiral dioxiranes generated in situ from potassium peroxomonosulfate and chiral ketones have appeared to be one of the most efficient. Recently, Wang et /. 2J reported a highly enantioselective epoxidation for disubstituted E-alkenes and trisubstituted alkenes using a d- or L-fructose derived ketone as catalyst and oxone as oxidant (Figure 6.3). 

Epoxidation using a chiral fructose-derived ketone is easy to carry out, as it occurs in aqueous conditions. The reactions were performed without any modification of the published procedure. The glassware has to be free of trace metal, which can decompose the oxone the use of a plastic spatula is recommended and the volumes must be measured using glass-graduated cylinders. Table 6.2 gives different examples of epoxides which can be obtained using the method prescribed. 

In order to test these assumptions Heathcock prepared different chiral ketones. Thus, the aldol condensation of the fructose-derived ketone and the acetonide of (/ )-glyceraldehyde gave poor results in the double stereodifferentiation, since an almost equal mixture of the two jyn-aldols 68a and 68b were obtained. However, the reaction with the (5)-aldehyde gave only one syn adduct (69a) (Scheme 9.22) ... 

The breakthrough came already in 1996, one year after Curd s prediction, when Yang and coworkers reported the C2-symmetric binaphthalene-derived ketone catalyst 6, with which ee values of up to 87% were achieved. A few months later, Shi and coworkers reported the fructose-derived ketone 7, which is to date still one of the best and most widely employed chiral ketone catalysts for the asymmetric epoxidation of nonactivated alkenes. Routinely, epoxide products with ee values of over 90% may be obtained for trans- and trisubstituted alkenes. Later on, a catalytic version of this oxygen-transfer reaction was developed by increasing the pH value of the buffer. The shortcoming of such fructose-based dioxirane precursors is that they are prone to undergo oxidative decomposition, which curtails their catalytic activity. 

Many other variations of the basic structure 10 have been explored, including an-hydro sugars and carbocyclic analogs, the latter derived from quinic acid 13 [23-26]. In summary, the preparation of these materials (e.g. 14-16) requires more synthetic effort than the fructose-derived ketone 10. Occasionally, e.g. when using 14, catalyst loadings can be reduced to 5% relative to the substrate olefin, and epoxide yields and selectivity remain comparable with those obtained by use of the fructose-derived ketone 10. Alternative ex-chiral pool ketone catalysts were reported by Adam et al. The ketones 17 and 18 are derived from D-mannitol and tartaric acid, respectively [27]. Enantiomeric excesses up to 81% were achieved in the epox-idation of l,2-(E)-disubstituted and trisubstituted olefins. 

Whereas the chiral TEMPO analog 87 was used to resolve racemic secondary alcohols, the D-fructose-derived ketone 88 [137] proved useful for oxidative resolution of racemic diols (Table 10.13) [138, 139], Persulfate in the form of Oxone, Curox, etc., served as the final oxidizing agent, and the dioxirane generated from the ketone 88 is the chiral active species. Because of the relatively low conversions (except for unsubstituted dihydrobenzoin) at which the ee stated were achieved, the method currently seems to be of less practical value. Furthermore, typically 3 equiv. ketone 88 had to be employed [138, 139]. 

Tu Y, Wang ZX, Shi Y (1996) An efficient asymmetric epoxidation method for irans-olefins mediated by a fructose-derived ketone. J Am Chem Soc 118 9806... 

Optically active a-hydroxy-keto functional units are widespread in natural products and have been frequently used for convenient building blocks in organic synthesis . Adam and coworkers reported that optically active a-hydroxy ketones can be obtained by oxidation of the corresponding silyl enolates with various oxidizing agents in the presence of manganese(in) adducts of optically active Shiff bases °, or with in situ generated dioxirane from a fructose-derived ketone (equation 7) . 

They found that the erythrolthreo-% i,cX N Xtj is X-substituent dependent, acting through H-bonding, which was demonstrated by the TFDO Ic epoxidation of 73. An example of cyclohexene epoxidation by dioxiranes derived from various ketones grafted on solid supports has also appeared <1996MI273>. Shi and co-workers reported <1996JA9806> excellent ee s of asymmetric epoxidation of different /ra t-olefms by fructose-derived ketones 74 before then, only low enantioselectivities (9-20%) have been reported on this type of reaction. 

ASYMMETRIC EPOXIDATION OF trans-p-METHYLSTYRENE AND 1-PHENYLCYCLOHEXENE USING A D-FRUCTOSE-DERIVED KETONE (R,R)-trans-P-METHYLSTYRENE OXIDE AND (R,R)-l-PHENYLCYCLOHEXENE OXIDE... 

The epoxidation procedure described herein utilizes the fructose-derived ketone (1) as catalyst and Oxone" j or H,0, as oxidant. The procedure provides a valuable method for... 

R " = H, alkyl, aryl, substituted alkyl and aryl SIRs = SIMes, SiMe2(t-Bu), SIEts solvent CHoCH. pentane, toluene n = 1-3 chiral oxidant Davis chiral oxaziridine, Shi s D-fructose derived ketone/Oxone, (Salen)manganese(lll)-complexes/NaOCI or PhIO... 

Tu, Y., Wang, Z.-X., Shi, Y. An Efficient Asymmetric Epoxidation Method fortrans-Olefins Mediated by a Fructose-Derived Ketone. J. Am. Chem. Soc. 1996,118, 9806-9807. 

These ketone precursors can also serve as chiral auxiliaries. The dioxirane from the fructose-derived ketone 20 converts trisubstituted and rram-disubstitued alkenes (e.g., 22) to the corresponding epoxides in very good yields and enantioselectivities, but is less effective for terminal and cis-disubstituted substrates. Fortunately, the oxazolidino analog 21 exhibits a complementary scope, providing high enantioselectivities for these latter olefins (e.g., 24). The stereochemical outcome of the reaction has been rationalized on the basis of a spiro transition... 

The ability of non-C2 symmetric ketones to promote a highly enantioselective dioxirane-mediated epoxidation was first effectively demonstrated by Shi in 1996 [114]. The fructose-derived ketone 44 was discovered to be particularly effective for the epoxidation of frans-olefins (Scheme 17 ). frans-Stilbene, for instance, was epoxidized in 95% ee using stoichiometric amounts of ketone 44, and even more impressive was the epoxidation of dialkyl-substituted substrates. This method was rendered catalytic (30 mol %) upon the discovery of a dramatic pH effect, whereby higher pH led to improved substrate conversion [115]. Higher pH was proposed to suppress decomposition pathways for ketone 44 while simultaneously increasing the nucleophilicity of Oxone. Shi s ketone system has recently been applied to the AE of enol esters and silyl enol ethers to provide access to enantio-enriched enol ester epoxides and a-hydroxy ketones [116]. Another recent improvement of Shi s fructose-derived epoxidation reaction is the development of inexpensive synthetic routes to access both enantiomers of this very promising ketone catalyst [117]. 

Shi and co-workers reported in 1996 the enantioselective epoxidation of unfunctionalized alkenes mediated by the fructose-derived ketone 10 (Figure 10.10) [46]. Corresponding oxiranes were obtained with excellent enantioselectivities (Equation 10.23). Yang and co-workers also reported the enantioselective epoxidation of alkenes, employing a cyclic ketone derived from binaphthyldicarboxylic add [47]. 

The methodology described above allows the asymmetric epoxidation of allylic alcohols or cis-substituted conjugated alkenes and the resolution of terminal epoxides. The asymmetric synthesis of trans-di- and trisubstituted epoxides can be achieved with the dioxirane formed from the fructose-derived ketone 64, developed by Shi and co-workers. The oxidizing agent potassium peroxomonosulfate... 

C-H bonds. This strategy has been used in an intramolecular fashion for the oxidation of hydrocarbons (eq 49) and steroids. Fructose-derived ketone 5 has also been used for this purpose in an intermolecular reaction for the desymmetrization and kinetic resolution of 1,2-diols to a-hydroxy ketones (eq 50). There has also been a report of the direct oxidation of hydrocarbons to ketones and lactones by Mn-porph)rin complexes with Oxone. ... 

The D-fructose-derived ketone (25) reacts with Grignard reagents... 

In 1996, Shi made a huge development in this area, reporting the asymmetric epoxidation of alkenes using chiral dioxiranes generated in situ. The epoxidation works well for disubstituted tra s-olefins, and trisubstituted olefins using a fructose-derived ketone as a catalyst and oxone as an oxidant (Scheme 1.9) [26]. 

Besides the secondary amine-catalyzed oxygenation reactions (see Sects. 2.3.1. and 3.2.5.) and phase-transfer catalyzed epoxidations (Chap. 6.) already mentioned, asymmetric epoxidation reactions using the method developed by Shi et al. (530) have found to be highly useful in complex total syntheses (531-535). The Shi epoxidation employs the fructose-derived ketone 629 as an easily available namral... 

Fructose-derived ketone 42 has been shown to be a highly general ketone catalyst (typically 20-30 mol% used) for epoxidation of a wide variety of trans and trisubsti-... 

Dioxiranes for alkene epoxidation may be prepared in situ from a catalytic amount of a ketone and Oxone (potassium peroxymonosulfate triple salt). )V,)V-Dimethyl-and A, A -dibenzylalloxans (20a) and (20b) (Figure 3) have been prepared and used as novel dioxirane catalysts for the epoxidation of a range of di- and tri-substituted alkenes in good to excellent yield. H2O2 (rather than the usual Oxone) has been successfully used as primary oxidant in asymmetric epoxidations with Shi s fructose-derived ketone (21) in acetonitrile. The ketone is converted into the dioxirane, which is responsible for epoxidation and the active oxidant responsible for dioxirane formation is proposed to be peroxyimidic acid formed by combination of H2O2 with acetonitrile. ... 

In 1996, Shi et al. [75] developed a fructose-derived ketone (Epoxone ) 183 as a highly effective asymmetric epoxidation catalyst. Shi s epoxidation is known to be the best for the asymmetric epoxidation of tramolefms and tri-substituted olefins. Shi s ketone is readily available and an efficient and selective oxidant that requires mild conditions. Ketone 183 could be synthesized [88] from inexpensive chiral starting material D-fructose, by ketalization and oxidation (Scheme 9.48). The enantiomer of 183 can be synthesized from L-fructose, which in turn could be obtained from commereially available L-sorbose. Chemists at DSM developed a scalable process for the preparation of Epoxone 183 in large quanities. 

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