Iminium ion-vinylsilane cyclizations

Iminium ion-vinylsilane cyclizations closely related to the one described here have been used to prepare indolizidine alkaloids of the pumiliotoxin A and elaeokanine families, indole alkaloids, amaryllidaceae alkaloids, and the antibiotic (+)-streptazolin. The ability of the silicon substituent to control the position, and in some cases stereochemistry, of the unsaturation in the product heterocycle was a key feature of each of these syntheses. 

Towards electrophiles, the reactivity of vinylsilanes is similar to that of the corresponding alkene. However, incorporating a silicon substituent at the vinylic carbon of a ir-nucleophile markedly affects the cyclization outcome. Specifically, iminium ion-vinylsilane cyclizations occur cleanly to substitute, preferentially with retention of double-bond configuration, the iminium ion carbon for the silyl substituent. Both endocyclic and exocyclic modes of intramolecular electrophilic substitution have been demonstrated (Scheme 35). 

Mannich-type cyclizations of vinylsilanes have found considerable application in the area of alkaloid total synthesis. Cyclizations that occur in the exocyclic mode with respect to the vinylsilane nucleophile have been widely employed to assemble 3-alkylidenepiperidine substructures with high stereocontrol. Overman and coworkers have made extensive use of the acid-promoted conversion of bicyclic oxazolidines to alkylideneindolizidines in their total syntheses of pumiliotoxin A alkaloids (Scheme 36). - " - An illustration of the mild nature of iminium ion-vinylsilane cyclizations is provided in the conversion of (101) to (102), the penultimate precursor of (-i-)-pumiliotoxin A. This conversion was accomplished in 71% yield by heating (101) at 80 C in a methanolic pyridine-pyridinium tosylate buffer (pH 4.5). More strongly acidic conditions had to be avoided since they led to competitive solvolysis of the allylic benzyl ether functionality of the pumiliotoxin A side chain. To the limits of detection by high... 

The stereocontrolled formation of exocyclic double bonds by stereospecific iminium ion-vinylsilane cyclizations has also been employed by Overman and coworkers as the key step in total syntheses of Co-rynanthe alkaloids. - The crucial cyclization step in the synthesis of ( )-(19Z)-isositsirikine is shown in equation (10). The (Z)-vinylsilane (103) cyclizes in 1 1 methanol-water to provide, in essentially quantitative yield, the (Z)-ethylideneindoloquinolizidine (104). 

The use of iminium ion-vinylsilane cyclizations for forming azacyclic rings other than six-membered has received little attention. Examples of forming azepines containing either endocyclic or exocyclic unsaturation are shown in Scheme 40. 

A variety of tetrahydropyridines have been prepared with complete regiocontrol by the reaction of 4-(trimethylsilyl)-3-butenylamines with aldehydes and acid (Scheme 43). This reaction, although ostensibly an iminium ion-vinylsilane cyclization, is believed to occur by the pathway illustrated in equation (11), in which ring formation ensues from the allylsilane sigmatropic isomer. Consistent with this mechanism pathway, either the ( )- or (Z)-vinylsilane amine stereoisomer can be employed. 

The enantioselective total synthesis of streptazolin (609), a neutral lipophilic antibiotic isolated from cultures of Streptomyces viridochromogenes, utilizes a tandem iminium ion— vinylsilane cyclization of the tartrate-derived 607 together with intramolecular acylation as a way of achieving high stereoselectivity. Heating a mixture of 570 and ( )-4-bromo-4-(tri-methylsilyl)-3-buten-l-amine (605) followed by dehydration with acetyl chloride provides the imide (606) in reproducible yields of 90%. Reduction of 606 with sodium borohydride affords 607, which is refluxed in trifluoroacetic acid to provide, after careful purification, the single bicyclic adduct 608 in 74% yield. This is then transformed in four steps to the desired streptazolin (609) [196] (Scheme 134). 

An elegant application of vinylsilane chemistry reported this year is the clean and stereospecific iminium ion-vinylsilane cyclization to dendrobatid toxin 25 ID shown in Scheme and a spiroannulation synthesis has been described in which the final stage is Lewis-acid-catalysed cyclization of (111) to (112)/ °... 

An iminium ion-vinylsilane cyclization (Scheme 6) provides the basis for a very short synthesis of dendrobatid toxin 25 ID (85) as reported by Overman and Bell. A related iminium ion cyclization [(86) (87)] is a key step in a... 

Overman, L. E., and K. L. Bell Enantiospecific total synthesis of dendrobatid toxin 25ID. A short chiral entry to the cardiac-active pumiliotoxin A alkaloids via stereospecific iminium ion — vinylsilane cyclizations. J. Amer. Chem. Soc. 103, 1851— 1852 (1981). 

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