Facial selectivity epoxidation

The second C-C bond forming step (step C), while occurring after the first irreversible ee determining step (step B), can affect the observed enantioselective outcome of the reaction. If the radical intermediate collapses without rotation (k3 Ict, k5 ke), then the observed ee would be determined by the first C-C bond forming step (ki vs. k2), that is the facial selectivity (Scheme 1.4.6). However, if rotation is allowed followed by collapse, then the rate of both trans pathways (Ic and k ) will proportionally effect the observed ee of the cis epoxide (ks vs. ks). Should bond rotation be permissible, the diastereomeric nature of the radical intermediates 9a and 9b renders the distinct possibility of different observed ee s for frany-epoxides and dy-epoxides. 

Klein showed that axial reaction of the parent methylenecyclohexane 37 is preferred in hydroboration [106], The experimental data on the parent methylenecyclohexanone 37a accumulated by Senda et al. [107] and the more recent systematic studies by Cieplak et al. [108, 109] on jr-facial selectivities of 3-substituted methylene-cyclohexanes 37 have characterized the intrinsic features of the facial selection of methylenecyclohexanes. That is, axial preference of unsubstituted and 3-substituted methylenecyclohexanes was observed in oxymercuration [107] and epoxidation reactions [110], There is also an increase in the proportion of axial attack with increase in the electronegativity of the remote 3-equatorial... 

Jones and Vogel investigated the snbstitnent effect of a 5,6-bis(methoxycarbonyl) group in bicyclo[2.2.2]octene (48i) [117]. The substituent effect of a single 5-exo substituent on the facial selectivities of bicyclo[2.2.2]octenes 48b-48h was also characterized by our group [118]. Epoxidation and dihydroxylation of the olefin moiety of 5-exo-substituted... 

This notion is also snpported by the following experimental observations. Because substitution of a cyano gronp on the cyclopropane ring lowers the energy of the Walsh orbital of the cyclopropyl group, the resultant attennation of the interaction of the olefin orbital with the Walsh orbital, if this interaction is indispensable, would reduce the facial selectivity. However, substitution of a cyano gronp on the cyclopropyl group, as in ejco-cyano 59c and endo-cymo 59d, essentially does not modify the syn-preference in dihydroxylation and epoxidation, but even increases the syn preference (59c (98 2) and 59d (>99 <1)) in the case of dihydroxylation. 

However, the low facial selectivity in epoxidations of unsymmetrical alkylidene- and cy-cloalkylidenecyclopropanes can be a serious drawback. Thus, both 2-cyclopropylidenebicy-clo[2.2.1]heptane (10)48 and 10,15-dicyclopropylidenetrispiro[3.1.3.1.3.1.]pentadecan-5-one (U)4<). so produced mixtures of stereoisomeric cyclobutanones on epoxidation and rearrangement of the resulting oxaspiropentanes. 

A selective and reactive oxidizing agent. Will epoxidize a,3-unsaturated carbonyl compounds. In epoxidation reactions, there is a strong steric influence directing the facial selectivity ... 

The order of redox potentials for oxidation of (4) (F>C1 Br) has been reported and found most consistent with a detectable resonance contribution through the a-framework. The most difficult oxidation of (5) (despite the fluoro substituent being one carbon atom more removed from the double bond) is consistent with the Whiffer effect (cr-hyperconjugative destabilization proceeding through two pathways is more than double tiie same effect through one pathway), in consonance with the AMI prediction. The facial selectivity of epoxidation and diazetidme formation from (4) proved to be hi... 

Hyperconjugation appears to be the dominant factor governing the diastereoselectivity of the hydrochlorination of 5-substituted 2-methyleneadamantanes 3 (Table 2)36. However, the product distribution for epoxidation suggests that the stereochemical course of electrophilic additions not mediated by carbocations is most likely regulated by direct field effects36. Note that, unlike in the previous reactions, the facial selectivity in this case reflects the preference for the nucleophilic attack on the corresponding carbocation. 

Consider the reactions A-F. Assume that the Sharpless epoxidations proceed with complete a-facial selectivity regardless of substrate. Select the best answer among the following choices regarding the stereochemical outcome of each of the reactions. 

Reactions B, C, E and F lead to mixtures of diastereomers. Reaction D affords a single enantiomer since the Sharpless epoxidation proceeds with complete n-facial selectivity. 

The facial selectivity required for an asymmetric epoxidation can be achieved with manganese complexes to provide sufficient induction for synthetic utility (Scheme 9.10).98-103 This manga-nese(III) salen complex 5 can also use bleach as the oxidant rather than an iodosylarene.104,105 The best selectivities are seen with cA-alkenes. 

There are four main factors that control the enantioselectivity in the sulfur ylide-mediated epoxidation (1) selectivity for one sulfide lone pair (2) control of ylide conformation (3) control of facial selectivity and (4) the reversibility of anti-betaine formation. 

To explain the enantioselectivity obtained with semi-stabilized ylides (e.g., benzyl-substituted ylides), the same factors as for the epoxidation reactions discussed earlier should be considered (see Section 10.2.1.10). The enantioselectivity is controlled in the initial, non-reversible, betaine formation step. As before, controlling which lone pair reacts with the metallocarbene and which conformer of the ylide forms are the first two requirements. The transition state for antibetaine formation arises via a head-on or cisoid approach and, as in epoxidation, face selectivity is well controlled. The syn-betaine is predicted to be formed via a head-to-tail or transoid approach in which Coulombic interactions play no part. Enantioselectivity in cis-aziridine formation was more varied. Formation of the minor enantiomer in both cases is attributed to a lack of complete control of the conformation of the ylide rather than to poor facial control for imine approach. For stabilized ylides (e.g., ester-stabilized ylides), the enantioselectivity is controlled in the ring-closure step and moderate enantioselectivities have been achieved thus far. Due to differences in the stereocontrolling step for different types of ylides, it is likely that different sulfides will need to be designed to achieve high stereocontrol for the different types of ylides. 

For the epoxidation of y-oxygenated vinyl sulfoxides 260 and 262, with sodium terf-butyl peroxide, an even greater reversal in stereoselectivity was observed. Epoxidation of260 gave the anti isomer 261, whereas 262 gave the syn isomer 263 (Scheme 67).139 This remarkable reversal of facial selectivity may be understood in terms of a mismatched situation and underlines that a chiral sulfinyl functionality is an extremely powerful chiral controller. 

The epoxy alctrfiol (97), a key intermediate in the synthesis of maytansine, has been prepared through Ti-catalyzed epoxidadon of (95 equation S6). The alcohol (95) exists predominantly in confoimation (162), with the allylic hydrogen at C-4 and the ir-bond very nearly eclipsed. The oxygens of the alcohol and silyl ether which are located below the plane the ir bond complex with Ti this complex blocks the approach of the epoxidizing reagent fitom the a-fu and hence the P-epoxide is fmmed. It is of interest to note that the ir-facial selectivity resulting fiom this route is the opposite of the ir-facial selectivity observed in MCPBA epoxidadon (see equadon 33). 

Different facial selectivities also exist in the epoxidation of norbornadiene, to give the epoxide 4 and diepoxide 5, respectively, where appreciable differences in nonbonded steric interactions in the two diastereomeric transition states would not be expected. 

Schreiber and co-workers48 have developed a mathematical model that allows calculation of the enantiomeric purity of products of reactions exhibiting enantiocontrol and diastereoselection. Application of this model to the Sharpless epoxidation of 10 using the relative facial selectivities obtained34 for 9 leads to the expectation that the enantiomeric excess of the epoxide products 11 should increase with the progress of the reaction. Within the limits of detection, this was experimentally observed (Table 6)48. 

Freccero, M., Gandolfi, R., Sarzi-Amade, M., Rastelli, A. Facial Selectivity in Epoxidation of 2-Cyclohexen-1-ol with Peroxy Acids. A Computational DFT Study. J. Org. Chem. 2000, 65, 8948-8959. 

As discussed in the preceding section, the -substituent protrudes into the open quadrant (Fig. 1) and chiral E-substituents have Httle effect on the stereoselectivity of the epoxidation. Thus, most E-allyHc alcohols show standard facial selectivity. Even a densely functionalized substrate such as 9 [42] and 10 [43] can be epoxidized with high enantioselectivity. 

Terminal olefins represent another challenging substrate class. For olefins such as styrene, cis-trans partitioning leads to diminished catalyst enantioselec-tivity (60-70% ee). A viable solution was reported through an efficient low-temperature Mn(salen) epoxidation protocol employing N-methylmorpholine N-oxide and ra-CPBA [77]. Improved enantioselectivities were attainable for most substrates under low-temperature conditions, but the effect was especially pronounced in the case of terminal olefins. Epoxidation of styrene, for instance, occurred rapidly to afford the epoxide in 86% ee using catalyst 22g (Scheme 8). Deuterium-labelling experiments revealed that the improved enantioselectivity derived from enhancement of olefin facial selectivity in initial C-0 bond formation as well as suppression of deleterious cis-trans partitioning. 

In some cases, a simple tosylation can be equally regioselective, especially when one of the hydroxyl substituents is more sterically hindered then the other. This approach served as a key step in an expeditious approach towards naproxen 217 (Scheme 55). The primary alcohol function of the optically active diol 214, of 98% ee, was selectively activated with tosyl chloride [135]. The resulting to-sylate, upon treatment with NaH, underwent smooth cycHzation to the epoxide 215. Hydrogenolysis proved to be highly facial selective, delivering the primary alcohol 216 in high enantiopuxity. A final Jones oxidation then furnished naproxen of 96% ee. 

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