V-Acyliminium

V-Acyliminium ions act as dienophiles in [4 + 2] cycloaddition reactions with conjugated dienes13, while A-acylimimum ions that (can) adopt an x-cis conformation are able to act as heterodienes in an inverse electron demand Diels-Alder process with alkenes or alkynes3 (see Section D. 1.6.1.1.). 

A possible side reaction in A-acyliminium chemistry is caused by deprotonation, giving rise to the formation of an enamide. Though this tautomerization is in principle reversible in acid media, this is not always the case. The enamide may react as a nucleophile with the /V-acyliminium ion still present, to produce dimers14. 

These side reactions may occur if the /V-acyliminium ion is not trapped quickly enough by a nucleophile. So problems may arise with relatively poor nucleophiles or if there is too much steric hindrance, while in the case of intramolecular reactions, unfavorable stereoelectronic factors or intended formation of medium- or large-sized rings may play a role. The reaction conditions, such as the nature of the (acidic) catalyst and the solvent, may also be of importance. 

If the AM 1 -hydroxyalkyl)amide is not stable enough for isolation it is still possible to perform the amidoalkylation in a one-pot reaction. Thus the amide and the carbonyl compound (or the oxoamide) are treated with an acid catalyst in the presence of the carbon nucleophile, so that the equilibrium amount of the (hydroxyalkyl)amide is converted in situ into the /V-acyliminium ion, which is subsequently attacked by the nucleophile. This principle is often applied in the total synthesis of alkaloids -8. 

The synthesis of precursors for the generation of the enantiomerically pure mono- and trans-dioxygenated /V-acyliminium ions of type 335,36 and 643 is achieved by reduction of the corresponding optically active imides. 

Thus, enantiomerically pure (S)35- or (R)36-acetoxysuccinimide derivatives of type 1, easily prepared from (S)- or (R)-malic acid, are diastereoselectively reduced with sodium borohydride in methanol at lower temperature to yield 85 % of an 11 1 mixture of diastereomeric hy-droxylactams of type 2, from which the enantiomerically pure chiral /V-acyliminium ions 3 are generated. 

A -( 1-Chloro- or bromoalkyl)amides are generally moisture-sensitive, unstable compounds, which are often directly used without further purification. Standard Lewis acids such as boron trifluoride-diethyl ether, aluminum(lll) chloride, zinc(II) chloride, tin(IV) chloride and titani-um(IV) chloride are used to generate the /V-acyliminium ion, although sometimes a catalyst is not necessary. 

Formation of C — C bonds via cyclization of 71-nucleophiles with cyclic /V-acyliminium intermediates usually proceeds with still higher stereoselectivity than in the case of the acyclic congeners, owing to the stereochemical restrictions of the favorable transition state. 

Cyclic (V-Acyliminium Ions with the Acyl Group Outside the Ring... 

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. 

The stereoselective total synthesis of (+)-epiquinamide 301 has been achieved starting from the amino acid L-allysine ethylene acetal, which was converted into piperidine 298 by standard protocols. Allylation of 297 via an. V-acyliminium ion gave 298, which underwent RCM to provide 299 and the quinolizidine 300, with the wrong stereochemistry at the C-l stereocenter. This was corrected by mesylation of the alcohol, followed by Sn2 reaction with sodium azide to give 301, which, upon saponification of the methyl ester and decarboxylation through the Barton procedure followed by reduction and N-acylation, gave the desired natural product (Scheme 66) <20050L4005>. 

The final method for constructing epidithiodiketopiperazine motifs relied on the nucleophilic thiolation of /V-acyliminium ions. Access to alpha-oxidized diketopi-perazine structures was central to this approach, and key developments were made in this regard. Schmidt first demonstrated the feasibility of this ionization approach in 1973 by conversion of proline anhydride to its diacetate using Pb(OAc)4 [42], Hydrolysis of the acetates, ionization of the hemiaminals with zinc chloride in the presence of hydrogen sulfide, and oxidation with iodine provided the epidisulfide of interest. In 1975, Matsunari reported access to alpha-methoxy diketopiperazines,... 

The key precept for any strategy would involve complete stereochemical control and precision in the degree of sulfidation. Accordingly, we envisioned that the epipolysulfides could arise from the ionization of a C15 hemiaminal derivative and subsequent cyclization of a polysulfane onto the resultant /V-acyliminium ion. The polysulfane would be derived from the corresponding thiol accessed by regioselective functionalization of the Ca(Trp) position. 

Scheme 6.236 /V-Acyliminium ion-based cyclizations leading to fused pyridones.

The W-acyliminium ion can be characterized by FTIR spectroscopy as well.9 The starting carbamate 1 exhibited an absorption at 1694 cm 1 due to the carbonyl stretching, while the V-acyliminium ion 2 generated by the cation pool method exhibited an absorption at 1814 cm 1. The higher wave number observed for the cation is consistent with the existence of a positive charge at the nitrogen atom adjacent to the carbonyl carbon. The shift to higher wave number is also supported by DFT (density functional theory) calculations. 

This view has been challenged with more recent evidence indicating that AT-[(acyloxy)methyl] derivatives of both primary and secondary amides (8.170, Fig. 8.21) undergo decomposition by the same mechanisms, namely a) an acid-catalyzed process involving protonation followed by formation of an /V-acyliminium species (Fig. 8.21, Reaction a) b) a pH-independent heterolytic cleavage forming the same /V-acyliminium species (Fig. 8.21, Reaction b) and c) a base-catalyzed pathway, which for /V-[(acyloxy)methyl] derivatives of AT-methylamides is the normal mechanism (Fig. 8.21, Reaction c), but for AT-[(acyloxy)methyl] derivatives of primary amides involves substrate deprotonation followed by /V-acy limine formation (Fig. 8.21, Reaction d) [218],... 

V-Acyliminium ions are even more reactive toward alkenyl and allylic silanes. N-Acyliminium ions are usually obtained from imides by partial reduction. The partially reduced /V-acylcarbinolamincs can then generate acyliminium ions. Intramolecular examples of such reactions have been observed. 

Sordo et al. [144] explained the stereoselectivity on the basis of torquoelectronic effects. Low-temperature infrared spectroscopy was also used to identify the reactive intermediates [145]. Two mechanisms were proposed to explain the product distribution in the (3-lactam formation reaction. The ketene mechanism was observed in a low temperature infrared spectroscopy study [145], while the acylation of imine mechanism was believed to be involved in some [122]. Both mechanisms were supported by evidences. It had been hypothesized that cycloaddition of the imine occurs from the least hindered side of the ketene, and this process generates zwitterionic intermediates conrotatory cyclization of these intermediates then produce cis- and //Y/ .v-[S-lactanis. Acylation of the imine by the acid chloride to form /V-acyliminium chloride also produced zwitterionic intermediates (Scheme 10). 

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