ALKYNE-IMINIUM ION CYCLIZATIONS

E)-1-BENZYL-3-(1-I0D0ETHYLIDENE)-PIPERIDINE NUCLEOPHILE-PROMOTED ALKYNE-IMINIUM ION CYCLIZATIONS... 

H. Arnold, L. E. Overman, M. J. Sharp and M. C. Witschel 111 (E)-1-BENZYL-3-(1-IODOETHYLIDENE)-PIPERIDINE NUCLEOPHILE-PROMOTED ALKYNE-IMINIUM ION CYCLIZATIONS... 

Alkyne-Iminium-promoted Cyclizations. Another reaction of TMS-Br with alkynes is the intramolecular alkyne-iminium ion cyclization, which has heen used to prepare piperidines of various substitution patterns. 

An N-acyliminium ion was utilized as the electrophile in a key step of Hiemstra s enantioselective synthesis of the unnatural enantiomer of gelse-dine (148, Scheme 11.24) [123]. In this synthetic endeavor it was discovered that treatment with iodide promotes the participation of the allene as the nucleophile to give the cyclized vinyl iodide 147 in 42 % yield. This finding is related to Overman s previous investigations of halide-promoted iminium ion cyclizations with alkynes as the nucleophilic cyclization terminators (cf. 149 150) [124]. The allene cyclization step (145 146—>147) afforded a rapid route to the skeleton of gelsedine (148), thus enabling the total synthesis of this natural product [123]. 

A plausible mechanism for this new alkyne aza-Prins cyclization is outlined in Scheme 27. Thus, reaction of the homopropargyl tosyl amine with an aldehyde promoted by ferric halide generates the W-sulfonyl iminium ion. This intermediate evolves to the corresponding piperidine, via the vinyl carbocation. Ah initio theoretical calculations support the proposed mechanism. 

The usefulness of nucleophile-promoted Iminium Ion-alkyne cyclizations derives from the ready availability of alkynylamines and the subsequent transformations of the cyclization products made possible because of their vinylic functionality (e.g., equations 1 and 2). Equation 2 illustrates use of this chemistry to elaborate an exocyclic tetrasubstituted double bond with complete stereooontrol. Net "reductive iminium ion alkyne cyclizations can be accomplished by dehalogenation of vinyl halide cyclization products. The conversion illustrated in equation 3 is a key step in an efficient, practical synthesis of the cardiotonic frog alkaloid pumiliotoxin A. ... 

Successful cyclization reactions of alkynes with weakly electrophilic iminium ions requires the presence of strong external nucleophiles. The only study to date which addresses the nature of useful cyclization promoters indicates that nonbasic nucleophiles with nucleophilic constants T)-Mel > 5.8 are required. ... 

The first example of a successful iminium ion-alkyne cyclization appeared in 1977. The 4-alkynyl-amine (88) was cyclized in acidified aqueous formaldehyde to a mixture of indoloquinolizidine ketones which could be equilibrated in base to provide the more stable epimer (89) in 49% yield. Not surprisingly, the six-membered ring was formed exclusively. 

The utility of stereospecific nucleophile-induced iminium ion-alkyne cyclizations that proceed in the exocyclic mode was recently demonstrated by Overman and coworkers in efficient enantioselective total syntheses of the Dendrohatid alkaloids (+)-pumiliotoxin A and (-i-)-allopumiliotoxin 323BThe piperidine ring and 6-alkylidene side chain of these alkaloids were stereospecifically generated in good... 

The pronounced sensitivity of alkynes to cyclization in the presence of external nucleophiles is illustrated in studies of formaldiminium ion (99) in which an alkyne and alkene compete as intramolecular ir-nucleophiles. While cyclization of (99) in water afforded 4-hydroxypiperidine (98) in 73% yield, cyclization in the presence of 10 equiv. of Nal gave vinyl iodide (100) in 76% yield (Scheme 34). It has been suggested that the mechanism of these nucleophile-promoted iminium ion-alkyne cyclizations probably involves rate-determining attack of the nucleophile on a ir-complex or bridged cation produced from reversible interaction of the iminium ion and alkyne groups. ... 

In other reactions that proceed via an acyliminium ion, 0-vinyl iV,0-acetals rearrange smoothly to -((V-acylamino)aldehydes at 0 °C in CH2CI2 in the presence of TMSOTf with moderate to high diastereoselectivities (eq 78). However, TMSOTf failed to promote aprotic alkyne-iminium cyclizations, which are readily enhanced by TMSCl, TMSBr, or SiClq. On the other hand, TMSOTf assists in the addition of enols to heteroaromatic imines or hydroxyaminal intermediates. ... 

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