Intramolecular epoxide activation

Oxidatively generated oxocarbenium ions have been used for intramolecular epoxide activation. Cascade reactions to form oligotetrahydrofuran products that demonstrated a strong preference for the exo-cyclization pathway were achieved in good yields when disubstituted epoxides were used as substrates. High stereoselectivity was observed in these reactions, with complementary diastereomers being formed from diastereomeric (g) epoxides.257... 

Addition of the reagent derived from lithiation of optically active iodide 66 to the previously prepared, racemic ketone a-44 gave the expected 1 1 mixture of diastereomeric adducts 67 and 68. In contrast to our earlier model studies, intramolecular epoxide opening proceeded to completion without the addition of a Lewis acid (Figure 20). While diastereomers 67 and 68 were readily separable by chromatography, an unequivocal determination of relative stereochemistry by spectroscopic methods was not possible. Each isomer was therefore carried... 

It is concluded that (62) arises by a radical pathway as already postulated, but that (63) and (145) spring from an ionic process. Lewis acid complexation of (9) by FeCls is believed to create successively the tertiary cation (150) and the alkene (151) by selective deprotonation (Scheme 22). Next, intramolecular epoxidation to (152) followed by rearrangement delivers (63). The alkene (151) is also assumed to be the precursor to the dihydropyran (149). Protonation of (151) produces the hydroperoxide (153) that evolves stepwise to (148) and (149). The antimalarial activity of (9) is ascribed to (153). 

Epoxide opening reactions have also been employed in the synthesis of southern half fragments. For example, the synthesis of optically active model system 82 by Barret and Capps [125] includes addition of a lithio-dithiane to ketone 81 and a subsequent intramolecular epoxide opening as key steps. Chirality was introduced in this case by a known yeast mediated reduction of ethyl 2-oxocyclohexane-carboxylate to afford optically active 80. 

As a further extension of push-pull dipole cycloaddition chemistry, the Rh (I I)-catalyzed cycHzation/cycloaddition cascade was applied toward the hexacyclic framework of the kopsifoline alkaloids. The kopsifolines 14 are structurally intriguing compounds, related to and possibly derived from an aspidosperma-type alkaloid precursor 12. A possible biogenetic pathway to the kopsifolines from 12 could involve an intramolecular epoxide-ring opening followed by loss of H2O as shown in Scheme 4. The interesting biological activity of these compounds, combined with their... 

Table 5.2 Intramolecular epoxIde-openIng reactions of epoxy aryl halides using phosphine-based active copper.

In addition to the activity, the selectivity of the two zincates was also different in some cases [12]. In a representative example, addition of LiZnMes to aryl iodide 17 resulted in intramolecular epoxide ring-opening reaction in 86% yield with 96% en o-selectivity. In sharp contrast, when Li2Zn(SCN)Me3 was used, the selectivity changed and the exo-product became the major one (Eq. 12). Dihydroindole 18 and tetrahydroquinoline 19 stmctures exist widely in natural products and pharmaceuticals. Hence, combining the complementary results obtained with zincate-wa and zincate-i a would provide an efficient and practically useful protocol for preparation of aryl zincates as well as for further derivatization ... 

The suggested reaction mechanism involves a nucleophilic attack of the imine nitrogen at the activated triple bond, followed by a proton exchange, to give a benzimidazolinium system which, by intramolecular attack at the carbonyl group, leads to an epoxide that ring opens to the observed product. For the ethyl derivative (R = Et) a tub conformation could be established by X-ray crystallographic analysis.33... 

As mentioned earlier, the McDonald group was able to extend their epoxide-domino-cyclization strategy to 1,5,9-triepoxides [10]. Indeed, they were successful in converting precursor 1-143 into the tricyclic product 1-146 in 52 % yield after hydrolysis (Scheme 1.36) [41]. As a possible mechanism of this polyoxacyclization it can be assumed that, after activation of the terminal epoxide by BF3, a sequence of intramolecular nucleophilic substitutions by the other epoxide oxygens takes place, which is induced by a nucleophilic attack of the carbonate oxygen, as indicated in 1-144 to give 1-145. 

Metal alkoxides undergo alkoxide exchange with alcoholic compounds such as alcohols, hydro-xamic acids, and alkyl hydroperoxides. Alkyl hydroperoxides themselves do not epoxidize olefins. However, hydroperoxides coordinated to a metal ion are activated by coordination of the distal oxygen (O2) and undergo epoxidation (Scheme 1). When the olefin is an allylic alcohol, both hydroperoxide and olefin are coordinated to the metal ion and the epoxidation occurs swiftly in an intramolecular manner.22 Thus, the epoxidation of an allylic alcohol proceeds selectively in the presence of an isolated olefin.23,24 In this metal-mediated epoxidation of allylic alcohols, some alkoxide(s) (—OR) do not participate in the epoxidation. Therefore, if such bystander alkoxide(s) are replaced with optically active ones, the epoxidation is expected to be enantioselective. Indeed, Yamada et al.25 and Sharp less et al.26 independently reported the epoxidation of allylic alcohols using Mo02(acac)2 modified with V-methyl-ephedrine and VO (acac)2 modified with an optically active hydroxamic acid as the catalyst, respectively, albeit with modest enantioselectivity. 

Another example of this cooperative catalysis has been presented by Konsler et al.101 in the course of their asymmetric ring-opening (ARO) study. They found that the ARO of mew-epoxides with TMS-N3, catalyzed by Cr salen compound 132, showed a second-order kinetic dependence on the catalyst.102 They then proposed that there might be cooperative, intramolecular bimetallic catalysis taking place, with one metal activating the substrate mew-epoxide and... 

In order to assess whether intramolecular cooperativity could occur within the dendrimeric [Co(salen)]catalyst the HKR of racemic l-cyclohexyl-l,2-ethenoxide was studied at low catalyst concentrations (2xl0 " M). Under these conditions the monomeric [Co(salen)] complex showed no conversion at all, while the dendritic [G2]-[Co(salen)]catalyst gave an impressive enantiomeric excess of 98% ee of the epoxide at 50% conversion. Further catalytic studies for the HKR with 1,2-hexen-oxide revealed that the dendritic catalysts are significantly more active than a dimeric model compound. However, the [Gl]-complex represents already the maximum (100%) in relative rate per Go-salen unit, which was lower for higher generations [G2] (66%) and [G3] (45%). 

Benedetti, E Berti, R Fabrissin, S. Gianferrara, T. Intramolecular ring opening of epoxides by bis-activated carbanions. The influence of ring size on reactivity and selectivity. J. Org. Chem. 1994, 59, 1518-1524. 

The proposed catalytic cycle for this reaction begins with the initial attack of the in situ generated thiazolylidene carbene on the epoxyaldehyde followed by intramolecular proton transfer (Scheme 28, XXXII-XXXIII). Isomerization occurs to open the epoxide forming XXXIV which undergoes a second proton transfer forming XXXV. Diastereoselective protonation provides activated carboxylate intermediate XXXVI. Nucleophilic attack of the activated carboxylate regenerates the catalyst and provides the desired P-hydroxy ester. 

We have observed intramolecular reactions of septanose species under a variety of reaction conditions using a number of starting materials. Figure 10 shows the putative reactive intermediates 190-193 that were present during iodoglycosidation of the D-xylose-derived oxepine 143, epoxidation of the oxepine 142, and TMS-triflate activation of septanosyl fluorides 72 and 75, respectively. Products 194-197 were obtained in a range of yields depending on whether or not other nucleophiles were present in the reaction. All of the intermediates are electrophilic and therefore... 

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