1.4- Dihydropyridinium salts, synthesis

The iminium salts of 2,3-dihydropyridines are far more stable than the free bases and have been used extensively in the synthesis of alkaloids. N-Benzyl iminium salt 26, formed from the Polonovski-Potier reaction of V-oxide 25, was transformed into enol ether 27, which is a synthon for the unstable AT-benzvl-l, 2-dihvdropyridine 28 (Scheme 5) <2004LOC168>. The same transformation on a similar iminium salt has been used in the formation of macrocyclic marine alkaloids <1995TL2059>. Carbon nucleophiles, such as the silylenol ethers of esters, have been shown to undergo 1,2-addition rather than 1,4-addition to 2,3-dihydropyridinium salts <1999T14995>. 

A semibiomimetic synthesis of keramaphidin B was also reported utilizing RCM methods (Scheme 8.18) [133]. The keramaphidin B precursor 240 (prepared from dihydropyridinium salt 239 [134,135]) was treated vhth Grubb s catalyst to give the monocyclized 241 and keramaphidin B. 

Further insights into the biosynthesis of manzamines came from the synthetic studies made on the conversion of 3-alkyl-dihydropyridinium salts to the unstable 3-alkyldihydropyridine reported in Fig.(24) [39]. Similar compounds were used in model studies towards a biomimetic synthesis of the alkaloids keramaphidin A and halicyclamine A [40]. 

Grierson, D. S., Harris, M., Husson, H. P. Synthesis and chemistry of 5,6-dihydropyridinium salt adducts. Synthons for general electrophilic and nucleophilic substitution of the piperidine ring system. J. Am. Chem. Soc. 1980,102, 1064-1082. 

Baldwin etal have achieved the keramaphidin synthesis via an intramolecular Diels-Alder reaction of the proposed precursor, macrocyclic dihydropyridinium salt 105a (Scheme 18). Cycloaddition of 105a in a MeOH buffer followed by NaBH4 reduction produced keramaphidin B (107) in 0.2-0.3% yield. This result is the first chemical evidence for the Baldwin and Whitehead s hypothesis. 

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