Reduction of Cyclic Ethers

Reduction of cyclic ethers with metal hydrides... 

Stepwise two-electron-transfer reduction of cyclic ethers and lactones with alkalide K, K (15-crown-5)2 07COC1126. 

As attractive as the transannular bridging of bis(thiolactones) to bicyclic bis(oxepane) frameworks is, our inability to convert the disulfide bridging product (see 25, Scheme 5) to a mmv-fused bre-vetoxin-type bis(oxepane) (see 28) necessitated the development of a modified, stepwise strategy. This new stepwise approach actually comprises two very effective methods for the construction of cyclic ethers the first of these is the intramolecular photo-induced coupling of dithioesters, and the second is the reductive cyclization of hydroxy ketones. We will first address the important features of both cyclization strategies, and then show how the combination of the two can provide an effective solution to the problem posed by trans-fused bis(oxepanes). 

The reaction processes shown in Scheme 8 not only accomplish the construction of an oxepane system but also furnish a valuable keto function. The realization that this function could, in an appropriate setting, be used to achieve the annulation of the second oxepane ring led to the development of a new strategy for the synthesis of cyclic ethers the reductive cyclization of hydroxy ketones (see Schemes 9 and 10).23 The development of this strategy was inspired by the elegant work of Olah 24 the scenario depicted in Scheme 9 captures its key features. It was anticipated that activation of the Lewis-basic keto function in 43 with a Lewis acid, perhaps trimethylsilyl triflate, would induce nucleophilic attack by the proximal hydroxyl group to give an intermediate of the type 44. 

These reductions of lactols with Et3SiH 84b in combination of BE3 -OEt2, TfOH, or TMSOTf 20 have become standard reactions for synthesis of cyclic ethers [62-69]. Thus even co-hydroxyketones such as 1837 cyclize readily with excess EtsSiH 84b in the presence of TMSOTf 20, in high yields, via the lactols 1838, to give cyclic ethers such as the substituted oxepane 1839 in 90% yield [65] (Scheme 12.18). 

Reduction of cyclic five-membered ethylene monothioketals with calcium in liquid ammonia cleaves the bond- between carbon and sulfur and yields alkyl -mercaptoethyl ethers (7-88%) [795]. Cyclic five-membered ethylene dithioketals (ethylenemercaptoles) afford, analogously, alkyl -mercaptoethyl thioethers (yields 85%) [795]. 

Asymmetric reduction of cyclic ketones. Prochiral cyclic ketones arc reduced to (R)-alcohols in 75-96% ee by a chiral hydride obtained by refluxing a mixture of lithium aluminum hydride, (— )-N-methylephedrine (I equiv.), and 2-ethylaminopyridine (2 cquiv.) in ether for 3 hours. Reduction of prochiral acychc ketones with this hydride also results in (R)-alcohols, but only in moderate yield. 

Reductive cleavage of cyclic ethers This complex is effective for reductive cleavage of cyclic ethers. The order of reactivity is epoxide > oxetane > tetrahydrofurane>tetrahydropyrane>oxepane. It is less effective for cleavage of acyclic ethers, except for methyl ethers. The reaction involves formation of a complex of the ethereal oxygen with aluminum r-butoxide followed by Sn2 displacement with lithium triethylborohydride. Steric and electronic Victors are involved, but yields are >90% in favorable cases. 

The enantioselective reduction of cyclic conjugated enones may be best accomplished using a complex of LAH with (11) to which EAP has been added.Optimum conditions for these reductions involve treatment of the ketone with 3 equiv of a 1 1 2 complex of LAH-(—)-(ll)-EAP in ether at —78 °C for 3 h (Table 3). However, under these conditions, acetophenone is reduced to the (R)-alcohol in only 54% ee. 

Entry 9 in Table 15 illustrates another synthetically useful stereocontrolled reduction of cyclic oxime ethers (isoxazolines) to alicyclic amino alcohols using LAH. The stereoselectivity obtained is further enhanced by the incorporation of a 4a-hydroxy group which, upon reduction, affords almost entirely the erythro isomer (equation High diastereoselectivity in the reductive cleavage of isoxazolines has... 

Such a phenol keto-tautomer equivalent strategy was used for conjugate reduction of cyclic enones (equation 5). The quinone monoketals 9 and para-quinol ethers 10 were used as precursors to keto-tautomer equivalents of substituted phenols, namely enones 11, which were prepared by action of bis(2,6-di-fert-butyM-methylphenoxy)methylaluminium (MAD), followed by addition of lithium tri-iec-butyl borohydride (L-Selectride). The enones 11 obtained are reasonably stable at a freezer temperature without aromatization. ... 

Brown reported that the reagent used for the reductive cleavage of cyclic ethers, a lithium triethylborohydride-aluminum fert-butoxide complex (from lithium... 

An enantioselective synthesis of (-)-nonactic acid and (+)-8-epi-nonactic acid using a microbial reduction step (baker s yeast) was reported <97SL159>. A highly enantiotopic-plane selective C-H oxidation of cyclic ethers (up to 82% ee) was achieved by using a (R.R)-(salen)manganese(Hl) complex as a catalyst <97SL836>. 

Lithium triethylborohydride reducing agent, mild nucleoside chemistry Tris (trimethylsilyl) silane reducing agent, mild reductive cleavage of cyclic ethers... 

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