Cyclization oxocarbenium ions

A Esterification B Tebbe methylenation C Oxocarbenium ion cyclization D Hydroboration... 

Aubele et al. studied the aqueous Prins cyclization using cyclic unsaturated acetals as oxocarbenium ion progenitors and allylsilanes are used as nucleophiles. Cyclizations proceed efficiently inside Lewis acidic micelles (of cerium salt) in water. A variety of vinyl- and aryl-substituted tetrahydropyrans with excellent stereocontrol was obtained (Eq. 3.26).113... 

Scheme 18 Synthesis of C-glycals based on oxocarbenium ion-enol ether cyclization.

The formation of the products could be explained by hemiacetal formation followed by Prins cyclization and subsequent Ritter amidation. A tentative reaction mechanism to realize the cis selectivity is given in Fig. 20 and could be explained by assuming the formation of an (L )-oxocarbenium ion via a chair-like transition state, which has an increased stability relative to the open oxocarbenium ion owing to electron delocalization. The optimal geometry for this delocalization places the hydrogen atom at C4 in a pseudoaxial position, which favors equatorial attack of the nucleophiles. 

The formation and the hydrolysis of acyclic and cyclic acetals have been studied in rather great detail [91]. Several reviews on this topic are available [92] and some comments have been made [13] concerning the carbohydrate series. We have shown in Schemes 1,2, and 3 that a common feature of this reaction seems to be the intermediacy of an oxocarbenium ion. However, the cyclization of such an intermediate has been questioned more recently [93] in the light of the Baldwin s rules for ring closure [94]. At least for the five-membered ring, an SN2-type displacement mechanism far the protonated form (B) of die hemiacetal (A) (favorable 5-exo-tet cyclization) has been proposed rather than the unfavorable 5-endo-trig cyclization of the oxocarbenium ion (C) (Scheme 5). Except when the formation of the enol ether (D) is structurally impossible, the intermediacy of such a compound remains feasible. 

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... 

The enantioselective synthesis of the C(18)-C(25) segment of lasanolide A 324 can be achieved via an oxonia-Cope-Prins cascade cyclization of a-acetoxy ether 325. The in situ reduction of the oxocarbenium ion intermediate 326 with Bu3SnH prevents the formation of a tetrahydropyran 4-one side product (Scheme 81) <20050L1589>. 

Electrophilic substitutions of alkenyl-, aryl-, and alkynylsilanes with heteroatom-stabilized cationic carbon species generated by the action of a Lewis or Brpnsted acid (acyl cation, oxocarbenium ion, etc.) provide powerful methods for carbon-carbon bond formation. Particularly, intramolecular reactions of alkenylsilanes with oxocarbenium and iminium ions are very valuable for stereoselective construction of cyclic ether and amine units.21-23 For example, the BFj OEt -promoted reaction of (E)- and (Z)-alkenylsilanes bearing an acetal moiety in the alkenyl ligand gives 2,6-disubstituted dihydropyrans in a stereospecific manner (Scheme l).23 Arylsilanes also can be utilized for a similar cyclization.24... 

A diastereoselective ewrfo-cyclization into an oxidatively generated oxocarbenium ion was a key step in a formal synthesis of leucascandrolide A. Exposing 56 to CAN provided cw-tetrahydropyran 57 in high yield and with excellent stereocontrol (Scheme 3.20). This transformation provides further evidence that oxidative electrophile formation is tolerant of several functional groups and can be applied to complex molecule synthesis. The synthetic sequence also utilized a Lewis acid mediated ionization reaction to form an oxocarbenium ion in the presence of the homobenzylic ether (58, 59), illustrating that two carbocation precursors that ionize through chemically orthogonal conditions can be incorporated into the same structure. 

The discovery of w-pentenyl glycosides (NPGs) [12], was derived from an observation made by Mootoo and Fraser-Reid in a completely unrelated project [13], Attempted formation of bromohydrin 5 by reaction of 4 with NBS in 1% aqueous acetonitrile led, instead to bro-momethyl tetrahydrofuran 6 (O Scheme 2) [14]. To rationalize this transformation (4 6), the authors invoked a 5-exo-cyclization [15] of the pyranosidic oxygen in 7 leading to cationic intermediate 8, and thence to oxocarbenium ion 9, that upon capture of H2O led to hemiac-etal 6. The overall result of the process had been a, nonhydrolytic, electrophilic unravelling of the glycosidic-type bond in 4. 

Exo- and endo-cyclic ring closure reactions using 0-nucleophiles transform oxocarbenium ions into cyclic acetals. As an example of an endocyclic cyclization, epoxide ring opening of (96) with lithium dimethyl cuprate, and subsequent treatment of the resulting alcohol with acid, smoothly gives the bicyclic acetal (97), ° a key intermediate in the total synthesis of tirandamycic acid (Scheme 47). ... 

An impressive application is the highly stereocontrolled and enandoselective synthesis of (-)-laure-nyne (113 Scheme 54). The key step is the cyclization of the mixed acetal (110) to give the oxocene (112), with the required endocyclic unsaturation at the correct position. The formation of this eight-mem-bered cyclic ether, instead of the corresponding seven-membered ring with an exocyclic double bond, may be rationalized by an intramolecular ene-type reaction of the intermediate oxocarbenium ion (111). 

Qearly the nature of the Lewis acid affects the outcome of these cyclizations it is not simply a spectator to the cyclization of an oxocarbenium ion. Indeed, the diversity of selectivites suggested many possible roles for the Lewis acid and cast doubt on the generality of the ionization mechanism. The dramatic change in selectivity between 5a-c (6a-c) and 5d (6d) was also inconsistent with a common mechanism either involving ionization or direct displacement... 

In none of the complexation experiments were oxocarbenium ions observed. Thus, we were unable to unambiguously correlate the divergent stereochemical results with a change in mechanism. However, it seems certain that the range of cyclization selectivities is a consequence of the various modes of acetal complexation observed. ether the different modes of complexation reflect different mechanisms remained to be established. 

The absence of oxocarbenium ions in flie complexation spectra does not necessarily rule out their intermediacy in the cyclization reactions they may be present in low concentration or are shortlived intermediates not observed on the NMR timescie. Thus, a test of their viability as reactive intermediates must be indirect, i.e. by using an alternative source of the ions. 

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