Iminium acyliminium

Intramolecular Mannich reactions of iminium 1 and acyliminium ions (see Section D.1.4.5.) with electron-rich double bonds are important reactions in the synthesis of naturally occurring alkaloids. In general, the iminium ions are not isolated but produced as intermediates. 

Reactivity of A -Acyliminium Ions vs. Iminium and Oxonium Ions... 

Alkylations of 6-methoxycarbonyl six-membered cyclic (V-acyliminium ions show a strong preference for the formation of m-products. This is explained by the A0-3 strain between the substituent and the (V-mcthoxycarbonyl group of the iminium ion, forcing the substituent into an axial position. Stereoelectronically preferred axial attack by the nucleophile then leads to the 2,6-d.v-disubstituted piperidine derivatives. 

M-Acyliminium cyclizations of optically active mono- and di-oxygenated hydroxylactam derivatives have been used in the synthesis of a number of natural products. In case of a five-membered lactam the oxygen function adjacent to the iminium carbon directs attack of the internal nucleophile from the least hindered side, opposite to the substituent. In the examples given the size of the newly formed ring is determined by the electronic bias of the alkene substituent. 

Certain A-acyliminium precursors, with the nucleophile tethered to the carbon atom adjacent to the iminium carbon, give rise to cw-fused hydroindole derivatives. 

Gas phase reactivity toward allyltrimethylsilane was used to compare the reactivity of several cyclic A-acyliminium ions and related iminium ions.203 Compounds with endocyclic acyl groups were found to be more reactive than compounds with exocyclic acyl substituents. Five-membered ring compounds are somewhat more reactive than six-membered ones. The higher reactivity of the endocyclic acyl derivatives is believed to be due to geometric constraints that maximize the polar effect of the carbonyl group. 

Entries 11 to 13 are examples of iminium ion and acyliminium ion reactions. Note that in Entries 11 and 12, vinyl, rather than allylic, silane moieties are involved. Entries 14 and 15 illustrate the synthesis of (3,-y-unsaturated ketones by acylation of allylic silanes. 

However, a better known version of the 2-aza-Cope rearrangement is that carried out by using 2-aza-l,5-hexadienes 619 (equation 269) and particularly their iminium ion counterparts, usually N-acyliminium cations 620 (equation 270)365,366 (for reviews, see also Reference 367). Aza-Cope rearrangement of the norbomene ester 621 leads to tetrahydropyridine ester 622 when allowed to stand in solution at room temperature for... 

Upon addition of boron trifluoride etherate, acetoxylactam 8 eliminates an acetoxy group to produce A-acyliminium ion 9. The indo-lizidinone 10 is formed diastereomerically pure in an iminium-ion-ini bated cyclization reaction of the Overman type ending in a vinyl-silane.14... 

The formation of activated iminium intermediates derived from nitrogen heterocycles has been reported by Comins and co-workers.163,163a The activation of pyridine derivative with phenyl chloroformate provides pyridinium salt, which smoothly reacts with the zinc homoenolate (Equation (94)).163 163a 164 The reaction of unsaturated amide with Ph jC 1 BI 4 produces iV-acyliminium ions, which react with PhaZn in CH2CI2 producing the desired a--substituted amine (Equation (95)).165... 

We used this method as the key sequence in the synthesis of ( )-lycopodine (78). The intramolecular isomiinchnone cycloadduct 81 was envisaged as the precursor of the key Stork intermediate 79 (via 80) [42]. The heart of our synthetic plan was the formation of the latter intermediate by a Pictet-Spengler cyclization of the N-acyliminium ion derived from 81. Central to this strategy was the expectation that the bicyclic iminium ion originating from 81 would exist in a chair-like conformation [42,43]. Cyclization of the aromatic ring onto the iminium ion center should take place readily from the axial position. The readily available heptenoic acid 82 would serve as the precursor for the a-dia-zoimide, the direct progenitor of the isomiinchnone dipole. This extension of the tandem cycloaddition-cationic 1-cyclization protocol to the formal synthesis of ( )-lycopodine (78) is outlined below. 

SCHEME 3.14 Previous examples of oxidative iminium and acyliminium ion formation. 

Speckamp and Hiemstra (1985) proposed a similar approach to anatoxin-a synthesis by applying their previous work on A -acyliminium chemistry. The use of a carbomethoxy group on the nitrogen, inside an alkyl group, would enhance the electrophilicity of the iminium ion owing to the electron-attracting... 

A comprehensive kinetic study examining the reactivity of N-acylimines/N-acyliminium salts versus imines/iminium salts has not, to date, been published. Spectral data ( C NMR), however, would suggest... 

An efficient enantiodivergent synthesis of levorotatory (lS,2/ ,8aS>l,2-dihydroxyindolia e (62a) and its antipode (62b) has been developed starting from commercially available o-isoascoibic acid (61 Scheme 27). This strategy illustrates the complementary use of iminium and IV-acyliminium ion inter-... 

Compared with the simple iminium ions, the enhanced reactivity of acyliminium salts opens up a greatly enlarged spectrum of counter-nucleophiles, which now includes alkenes and aromatic compounds possessing no donor substituents (see Section 4.2.2.2.2). 

As mentioned previously, acyliminium ions are electrophilic enough to react intramolecularly even with nonactivated alkenic ir-systems. These cyclization reactions have been recognized and elaborated as valuable tools in the stereoselective total synthesis of quinolizidine, indolizidine and pyrrolizidine alkaloids. A typical example from Speckamp s laboratory is the highly stereospecific acid-catalyzed cyclization of (81) to (83 Scheme 40), presumably via the corresponding acyliminium ion (82). Analogously, other more complex natural products, such as the antiulcerogenically active alkaloid ma-trine (85), can be built up with high stereocontrol (Scheme 41), with an enol ether function as a more electron-rich nucleophile for the intermediate iminium ion (84). ... 

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