Epoxidation trisubstituted olefins

CDP840 is a selective inhibitor of the PDE-IV isoenzyme and interest in the compound arises from its potential application as an antiasthmatic agent. Chemists at Merck Co. used the asymmetric epoxidation reaction to set the stereochemistry of the carbon framework and subsequently removed the newly established C-O bonds." Epoxidation of the trisubstituted olefin 51 provided the desired epoxide in 89% ee and in 58% yield. Reduction of both C-O bonds was then accomplished to provide CDP840. 

The combination of (EtO)3SiH/CsF (or KF) provides a convenient reagent for the reduction of esters to alcohols.76,80,83 The yields are in the 70% range. Potassium tetraethoxyhydridosilicate also reduces esters in moderate yields.288 The combination of PM HS/CpiTiCE/n-BuLi reduces esters in high yields even in the presence of an epoxide and a trisubstituted olefin (Eq. 140).289 The reagent combination can reduce a methyl ester in the presence of a tert-butyl ester (Eq. 141).290... 

All the reactions were carried out at 0°C, with the substrate (1 equivalent), ketone (3 equivalents), Oxone (5 equivalents), and NaHCC>3 in CH3CN aqueous EDTA for 2 hours. High enantioselectivity can generally be obtained for trans- and trisubstituted olefins. The favored spiro and planar transition states have been proposed for ketone 130-mediated rrans-stilbene epoxidation (Scheme 4-48). 

Subsequently, high chemoselectivity and enantioselectivity have been observed in the asymmetric epoxidation of a variety of conjugated enynes using fructose-derived chiral ketone as the catalyst and Oxone as the oxidant. Reported enantioselectivities range from 89% to 97%, and epoxidation occurs chemoselectively at the olefins. In contrast to certain isolated trisubstituted olefins, high enantioselectivity for trisubstituted enynes is noticeable. This may indicate that the alkyne group is beneficial for these substrates due to both electronic and steric effects. 

Catalyst Development for the Epoxidation of trans- and Trisubstituted Olefins... 

In 1996, ketone 26 was reported to be a highly effective epoxidation catalyst for a variety of trans- and trisubstituted olefins [53]. Ketone 26 can be readily synthesized from D-fructose by ketalization and oxidation (Scheme 2) [54-56]. The enantiomer of ketone 26 (ent-26) can be obtained by the same methods from L-fructose, which can be obtained from L-sorbose [57, 58]. 

A catalytic amount of ketone 26 was used to investigate the substrate scope of the asymmetric epoxidation. High enantioselectivities can be obtained for a wide variety of trans- and trisubstituted olefins (Table 3, entries 1 ) [54]. Simple trans-olefins, such as franx-7-tetradecene, can be epoxidized in high yield and enantiomeric excess, indicating that this asymmetric epoxidation is generally suitable for frani-olefms. 2,2-Disubstituted vinyl silanes are epoxidized in high ees (Table 3, entries 5, 6) and enantiomerically enriched 1,1-disubstituted epoxides can be... 

The stereochemistry of the resnlting epoxidation products using chiral ketones, such as ketone 26, could provide new insights about the epoxidation transition states. Studies showed that the epoxidation of trans- and trisubstituted olefins with ketone 26 mainly goes through the spiro transition state (spiro A) (Fig. 10). Planar transition state B competes with spiro A to give the opposite enantiomer [53, 54]. Hence, factors that influence the competition between spiro A and planar B will also affect the enantiomeric excess of the resulting epoxides. Spiro A can be further... 

The availability of ketone 26 and its effectiveness toward a wide variety of tmns-and trisubstituted olefins make the epoxidation with this ketone a useful method. Other researchers have used ketone 26 in the synthesis of optically active complex molecules. Some of these studies will be highlighted in this section. 

Asymmetric epoxidation of prochiral olefins is a powerful strategy for the synthesis of enantiomericaUy enriched epoxidesJ Previously, we reported a fructose-derived catalyst (1) that gives high ee for a wide variety of trans- and trisubstituted olefins (Figure 6.5). " Recently, we discovered a new catalyst (2) derived from D-glucose that can epoxidize many c -olefins with high enantioselectivity and no c w/rran -isomerization. ... 

This experimental procedure in section 6.5.7 can be used to epoxidize certain cyclic as well as acychc cw-olefins with good enantioselectivity and no cis/trans-isomerization (Table 6.7). Promising results have also been observed for some terminal olefins with this new glucose-derived catalyst, which complements our previously reported trans- and trisubstituted olefin catalyst 1. 

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. 

These results contradict Jacobsen s earlier mechanistic theories, which would have predicted a top-on" approach for the sterically demanding tetrasubstituted olefins (Figure 1) and thus inferior results compared to the less-substituted olefins, which were assumed to approach from a skewed side-on" disposition. Furthermore, his observation that trisubstituted olefins were epoxidized in an opposite stereochemical sense compared to other olefins required invoking a stepwise mechanism, wherein the radical intermediate is steered by the pendant chiral catalyst [94JOC4378], At the current time, these results fail to coalesce into a clear unified predictive model. 

The substrate scope of this epoxidation was subsequently investigated using a variety of olefins with a catalytic amount of ketone 1 (usually 20-30 mol%). A variety of hms-substituted and trisubstituted olefins have been shown to be effective substrates (Table 10.1),39 and the high ee obtained with hms-7-tetradecene suggests that this epoxidation is quite general for simple trans-olefins (Table 10.1, Entry 5). Various functional groups such as ethers, ketals, esters, and so on are compatible with the epoxidation conditions (Table 10.1). A variety of 2,2-disubstituted vinylsilanes... 

Asymmetric Epoxidation of Representative fram-Substituted and Trisubstituted Olefins by Ketone 1... 

This procedure illustrates a general, one-step method to deoxygenate di- or trisubstituted epoxides to olefins in high yield and with high retention of stereochemistry.8 Reductions are usually... 

To illustrate the utility of the metal salen complexes, several reactions are outlined in Scheme 1. They include the asymmetric epoxidation of unfimctionalized cw-disubstituted and trisubstituted olefins, which are promoted by (salen)Mn complexes." In the case of trani-disubstituted olefins, the simple (salen)Mn complexes do not exhibit the same levels of enantioselectivity as they do with the cis- and trisubstituted derivatives. Promising alternatives include more elaborate (salen)Mn complexes based on the binaphthyl imit, (salen)Cr complexes,and (salen)Ru-based catalysts. Catalysts based on (salen)Co moiety have exhibited amazing levels of selectivity in the hydrolytic kinetic resolution (HKR) of terminal epoxides. The HKR allows access to terminal epoxides and diols with very high enantioselectivities. 

D-Fmctose-derived ketone 50 (also available in its enantiomeric form from L-sorbose) was introduced as a catalyst for the asymmetric epoxidation of trans- and trisubstituted olefins, and as such was successful in the preparation of enantioenriched substituted cycloalkene oxides (Table 5, entries 1-5) <1996JA9806, 1997JA11224, 2001T5213>. 

Yang et al. have applied C2-symmetric chiral dioxiranes, generated in situ from corresponding chiral ketones 75 and Oxone, for asymmetric epoxidation of trans-olefins and trisubstituted olefins (33-87% ee) <1996JA491, 1996JA11311>. 

Catalytic Enantioselective Epoxidation of Unfunctionalized trans-Oleflns and lYisabstituted Olefins. (R)-l is an efficient catalyst for enantioselective epoxidation of unfunctionalized traw-olefins and trisubstituted olefins (eq 3). In a homogenous CH3CN/H2O solvent system, (/ )- reacts with oxone to generate a chiral dioxirane in situ, which can epoxidize /ranr-stilbenes (3a-3e) with high yields (> 90%) and high enantioselectivity (76-91% ee). The enantioselectivity of epoxidation is generally... 

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