Chiral 1,2-Dihydropyridines and 2,5-Dihydrophridium Salt Equivalents. Synthesis of (+)-Anatabine and a Chiral Benzomorphane

Sodium bomhydride reduction of readily available chiral pyridinium salts (2a-b) in alkaline medium led to 1,Zdihydropyridines (3a-b) which spontaneously cyclized to give 2.5-dihydropyridinium salt equivalents (4a-b).Use of these intermediates for a short synthesis of the tobacco alkaloid (+)-anatabine and of the benzomorphane derivative ((+)-14) is repred.Alkaloids containing six-membered nitrogen heterocycles are abundant in nature and many of them exhibit interesting biological activities.Accordingly, the search for practical and general approaches allowing regio-and stereocontrolled synthesis of highly functionalized derivatives of these heterocycles bas gained continued attention.Among others, a set of powerful strategies makes use of the versatile synthetic potential of dihydmpyridine intermediates as an effective method for their con~uuction.~In earlier studies, we demonstrated that a variety of c h i d dihydropyridine intermediates (or dihydropyridinium salt equivalents) can be successfully used for asymmetric syntheses of such Our e m y into this field was greatly facilitated by the finding that the Zicke's synthesis of pyridinium salts could be easily extended to asymmetric series using various c h i d primary mines3 as starting material.In this paper we report details of the sequence4depicted in Scheme 1 by way of its application to a synthesis of (+)-matabhe and of a chiral benzomorphane derivative according to Scheme 2 and Scheme 3, respectively.Treatment of Zincke's salt (la)5 (Scheme 1) with 1.1 equivalent of (R)-(-)-phenylglycinol in refluxing n-butanol overnight gave, after simple extraction, pure salt (Za) in nearly 90% yield.Since (R)-(-)-phenylglycinol is now made available by a very convenient procedure,6 c h i pyridinium salt (Za) could be mutinely prepared in our laboratory in I00 g scale.Synthesis of 4-substituted salts (2c-d) met with no special difficulties by using this procedure.Zincke's salt (lb) proved to be sensitive to bases and was prepared in refluxing methanol, while the dioxolane protection was needed for the preparation of salt (Id) since 4-acetylpyridine was not nuclwphilic enough to react with l-chloro-2,4-dinirnbemne.bedicated to Prof. Arnold Brossi on the occasion of his 70th anniversary.