Epoxide disubstituted

Substrate structure has a dramatic influence on the rate of the Sharpless asymmetric epoxidation. -Disubstituted and trisubstituted allylic alcohols react the most rapidly whereas Z-disubstituted and unsyininetrical disubstituted analogs react much more slowly32. Chemical yields for these substitution patterns are all in the range of 77-87% and enantioselection is in the range of 95% ee except for the slow-reacting Z-disubstituted allylic alcohols that exhibit enantioselectivities in the range of 90 % ee. 

Other methods of generating a-aminoketones in situ are common, if somewhat less general than the methods already described. 2-Nitrovinylpyrrolidine, which is readily available, yields 2,3-bis(3-aminopropyl)pyrazine on reduction and this almost certainly involves ring opening of the intermediate enamine to an a-aminoketone which then dimerizes under the reaction conditions (Scheme 59) (78TL2217). Nitroethylene derivatives have also served as a-aminoketone precursors via ammonolysis of the derived epoxides at elevated temperatures (Scheme 60) (76S53). Condensation of 1,1-disubstituted hydrazine derivatives with a-nitro-/3-ethoxyethylene derivatives has been used in the synthesis of l,4-dialkylamino-l,4-dihydropyrazines (Scheme 61) (77S136). 

Initial studies on the Jacobsen-Katsuki epoxidation reaction identified conjugated eyelie and acyelic cw-disubstituted olefins as the class of olefins best suited for the epoxidation reaetion. " Indeed a large variety of c/s-disubstituted olefins have been found to undergo epoxidation with a high degree of enantioselectivity. 2,2"-Dimethylehromene derivatives are especially good substrates for the epoxidation reaetion. Table 1.4.1 lists a variety of examples with their corresponding reference. 

To date, no effieient and general Mn(III)salen-eatalyst exists that effeets epoxidation of 1,1-disubstituted olefins with good enantioseleetivity. 

During the early development of the Jacobsen-Katsuki epoxidation reaetion, it was elear that trans-disubstituted olefins were very poor substrates (slow reaetion rates, low enantioseleetivity) eompared to cis-disubstituted olefins. The side-on approaeh model originally proposed by Groves for porphyrin epoxidation systems was used to rationalize the differenees observed in the epoxidation of the cis and trans-disubstituted elasses (Seheme 1.4.7). ... 

As with i -substituted allyl alcohols, 2,i -substituted allyl alcohols are epoxidized in excellent enantioselectivity. Examples of AE reactions of this class of substrate are shown below. Epoxide 23 was utilized to prepare chiral allene oxides, which were ring opened with TBAF to provide chiral a-fluoroketones. Epoxide 24 was used to prepare 5,8-disubstituted indolizidines and epoxide 25 was utilized in the formal synthesis of macrosphelide A. Epoxide 26 represents an AE reaction on the very electron deficient 2-cyanoallylic alcohols and epoxide 27 was an intermediate in the total synthesis of (+)-varantmycin. 

Direct deprotonation/electrophile trapping of simple aziridines is also possible. Treatment of a range of N-Bus-protected terminal aziridines 265 with LTMP in the presence ofMe3SiCl in THF at-78 °C stereospecifically gave trans-a, 3-aziridinylsi-lanes 266 (Scheme 5.67) [96]. By increasing the reaction temperature (to 0 °C) it was also possible to a-silylate a (3-disubstituted aziridine one should note that attempted silylation of the analogous epoxide did not provide any of the desired product [81],... 

Jacobsen also showed that 2,2-disubstituted epoxides underwent kinetic resolution catalyzed by (salen)Cr-N3 complex 3 under conditions virtually identical to those employed with monosubstituted epoxides (Scheme 7.34) [64]. Several epoxides in this difficult substrate class were obtained with high ees and in good yields, as were the associated ring-opened products. The kinetic resolution of TBS-... 

Ten years after Sharpless s discovery of the asymmetric epoxidation of allylic alcohols, Jacobsen and Katsuki independently reported asymmetric epoxidations of unfunctionalized olefins by use of chiral Mn-salen catalysts such as 9 (Scheme 9.3) [14, 15]. The reaction works best on (Z)-disubstituted alkenes, although several tri-and tetrasubstituted olefins have been successfully epoxidized [16]. The reaction often requires ligand optimization for each substrate for high enantioselectivity to be achieved. 

In the cyclization of the corresponding cis-epoxides, with the aim of obtaining the corresponding cis-2,3-disubstituted tetrahydropyrans, a similar trend was observed. For these systems, however, the 6-endo pathway was less favored, which was ascribed to difficulties in attaining a TS conformation that would allow for maximum stabilization of the developing p-orbital with the adjacent 7t-system. Alternatively, palladium-catalyzed cyclization of the tetrabutylammonium alkoxide derived from 33b results in the corresponding ris-2,3-disubstituted tetrahydro-pyran in excellent yield and selectivity (90%, dr >99 1), while the ris-epoxide gives stereoisomer 37b (86%, dr 98 2) [112]. 

Figure 6.71 Enantioconvergent hydrolysis of a 2,2-disubstituted epoxide by combined bio- and chemocatalysts.

When gem-disubstituted epoxides (122) are treated with Grignard reagents (and sometimes other epoxides), the product may be 123, that is, the new alkyl group may appear on the same carbon as the OH. In such cases, the epoxide is isomerized to an aldehyde or a ketone before reacting with the Grignard reagent. Halohydrins are often side products. 

While alkylation of terminal epoxides is reliable, attempted alkylations of 1,2-disubstituted epoxides have proved capricious. An unsuccessful approach to the swinholides, which called for the alkylation of cyanohydrin 47 with epoxide 48, is one such example. In the event, alkylation cleanly produced imidate 49, rather than the expected product 50 [27] (Eq. 14). 

Under some circumstances, acid-catalyzed ring opening of 2,2-disubstituted epoxides by sulfuric acid in dioxane goes with high inversion at the tertiary center.116... 

In addition to the enzymatic hydrolysis of esters, there also ample examples where an epoxide has been cleaved using a biocatalyst. As described by the Faber group [19], reaction of the ( )-2,3-disubstituted ds-chloroalkyl epoxide roc-8-40 with a bacterial epoxide hydrolase (BEH), led to the formation of vie-diol (2 ,3S)-8-41 (Scheme 8.11). The latter underwent a spontaneous cydization to give the desired product (2i ,3i )-8-42 in 92 % ee and 76 % yield. The same strategy was used with the homologous molecule rac-8-43, which afforded the THF derivative (2R,3R)-S-4S in 86% ee and 79% yield. 

Scheme 8.11. Enzyme-initiated domino reaction of ( )-disubstituted chloroalklyl epoxides.

Electrophylic halogenation of 9-oxabicyclo[3.3.l]nona-2,6-diene (139), a heteroanalog of 39, in the presence of water and its epoxidation with performic acid results in ring closure to 4,8-disubstituted 2,6-dioxaada-mantane derivatives.168 4,8-Dibromo-2,6-dioxaadamantane is also prepared from the syn-dibromide of 1,5-cyclooctadiene.169... 

The synthesis of a,a-disubstituted amino acids is a difficult task and continues to attract attention. An efficient route that utilizes the ring-opening of an epoxide with azide has been reported <06TL9268>. Treatment of the sulfoxide substituted epoxide 23 with NaN3 provides intermediate azido aldehyde 24. This aldehyde was not isolated but oxidized to the acid and then the azide reduced to provide the a,a-disubstituted amino acid 25. The regioselectivity of this reaction was impressive with only one product reported. 

An additional example of an oxonium ion generated via the acid catalyzed rearrangement has been used to prepare a dihydropyran <06TL6149>. The oxonium ion 54 generated by the reaction of an epoxide with ZrCl4 can be trapped by a nucleophile such as butynol to prepare dihydropyran 55. A variety of mono- and disubstituted epoxides have been used in this reaction. 

For 1,2-disubstituted epoxides, the regiochemical outcome of nucleophilic attack becomes less predictable. However, in the case of epoxy ethers chelation control can be used to deliver the nucleophile preferentially to the epoxide carbon away from the ether moiety. Thus, treatment of epoxy ether 61 with an imido(halo)metal complex, such as [Cr(N-t-Bu)Cl3(dme)], leads to the clean and high-yielding production of the chlorohydrin 64. The regioselectivity is rationalized in terms of initial formation of a chelated species (62), followed by attack at C-3 to form the more stable 5-membered metallacyclic alkoxide 63 <00SL677>. 

Disubstituted oxepanes have also been synthesised by (Bu3Sn>20/Zn(OTf)2-promoted cyclization of hydroxy epoxides via an Sn2 process with exo mode selectivity <00TL7697> and <00TL7701>. 

At first, the reaction was characterized as most effective in the epoxidation of cw-disubstituted olefins.86 Later, the scope of this reaction was expanded to include the highly enantioselective synthesis of hYwiv-dis ubstitutcd8 7 and tri-substituted epoxides,88 as well as certain monosubstituted epoxides.89 The first example of nondirect asymmetric epoxidation of tetrasubstituted olefins has also appeared.90... 

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