Oxidative carbocation formation

This project arose from a desire to find a tmique application for some methodological work that my group had developed on oxidative carbocation formation. This process (Scheme 1) showed that oxocarbenium and acyliminium ions could be formed from oxidative cleavage reactions of homobenzylic ethers and amides, respectively. Cychzation reactions ensued when a nucleophilic group was incorporated into the cationic fragment. 

The cyclic phosphonium salts 140,141,143,145, and 146 so obtained are evidence for the mechanism of the oxaphospholic cyclization and especially for the main role of the tertiary carbocation formation during the process. The additional data which support this assumption, come from the investigation of the same reaction, but with different substrate, i.e., dimethyl(l,2-hexadienyl)phosphine oxide 147. In this case, the reaction mechanism involved formation of secondary carbocation that gives oxaphosphole product 148 only in 10% yield (Scheme 60) [124],... 

Carbocation formation is initiated by epoxide ring opening in squalene oxide, giving a tertiary carbocation, and this is transformed into the four-ring system of the protosteryl cation by a series of electrophilic addition reactions (see Box 8.3). 

An interesting feature of this reaction was the appearance of another, more polar, product on ozonolysis of 46. The compound was determined to be 6-a-hydroxy-f-steroid 48. This compound can be formed from the reduction of a ketone 49 by sodium borohydride, a product often observed on ozonolysis of ethers.51 This type of ketone formation has been rationalized by the type of mechanism shown in Scheme 11.13 and tends to occur in reactions in which carbocation formation at the site of oxidation is relatively favorable.51 Limiting the time of ozonolysis has the effect of suppressing the formation of the ketone, demonstrating the ability to control the formation of products by controlling the time of ozonolysis. 

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. 

General acid catalysis in the hydrolysis of 81 is quite facile. This reaction, as discussed in Section Benzylic epoxides and arene oxides and shown in Scheme 39, involves proton transfer to the epoxide oxygen concerted with epoxide C-O bond breaking to form a carbocation 83. For primary ammonium ions with pKa < 8, only the acid form of the amine is reactive, and carbocation formation is irreversible,... 

The primary approach was a development of the classical system investigated by Johnson [57], which involves initiation of carbocation formation following solvolysis of a sulfonate ester. In this scenario, once cyclization has occurred, the newly formed carbocation can be captured by either elimination or attack of a nucleophile. At an entry level, in an attempt to catalyze the cyclization of the acyclic sulfonate ester 35 two haptens, 36 and 37, were utilized in a bait-and-switch strategy (Scheme 8) [58]. HPLC assay revealed that four antibodies (4C6,16B5, 1C9, and 6H5) elicited to the N-oxide hapten 36 and one antibody, 87D7, elicited to the N-methylammonium hapten 37 were initiation catalysts, i.e., they catalyzed the solvolysis of the sulfonate ester bond of 35. A remarkable feature of antibody catalysis of this reaction is the narrow product distribution observed. Of all the possible products 38 to 42 inferred from the work of Johnson, only the cy-clized products 38 and 39 were detected, a testimony to the antibodies exquisite binding of a putative cyclic transition state as programmed by the haptens 36 and 37. 

SCHEME 1 Carbocation formation via oxidative carbon-carbon bond cleavage. 

PCC oxidation conditions are often also used with secondary alcohols, because the relatively nonacidic reaction conditions minimize side reactions (e.g., carbocation formation Sections 7-2, 7-3, and 9-3) and often give better yields than does the aqueous chromate method. Tertiary alcohols are unreactive toward oxidation by Cr(VI) because they do not carry hydrogens next to the OH function and therefore cannot readily form a carbon-oxygen double bond. 

The key initiation step in cationic polymerization of alkenes is the formation of a carbocationic intermediate, which can then interact with excess monomer to start propagation. We studied in some detail the initiation of cationic polymerization under superacidic, stable ion conditions. Carbocations also play a key role, as I found not only in the acid-catalyzed polymerization of alkenes but also in the polycondensation of arenes as well as in the ring opening polymerization of cyclic ethers, sulfides, and nitrogen compounds. Superacidic oxidative condensation of alkanes can even be achieved, including that of methane, as can the co-condensation of alkanes and alkenes. 

Since the results of our experiments with isolated rat liver fractions supported a reaction sequence Initiated by microsomal oxidation of the nitrosamine leading to formation of a carbonium ion, the results of the animal experiment suggested that in the intact hepatocyte, one of the earlier electrophilic intermediates (II, III or V, Figure 1) is intercepted by nucleophilic sites in DNA (exemplified here by the N7 position of guanine) before a carbocation is formed. 

Alkanes are formed when the radical intermediate abstracts hydrogen from solvent faster than it is oxidized to the carbocation. This reductive step is promoted by good hydrogen donor solvents. It is also more prevalent for primary alkyl radicals because of the higher activation energy associated with formation of primary carbocations. The most favorable conditions for alkane formation involve photochemical decomposition of the carboxylic acid in chloroform, which is a relatively good hydrogen donor. 

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