Synthesis of Monoterpene Piperidines from the Iridoid Glucoside Antirrhinoside Henrik Franzyk,* Signe M. Frederiksen, and Søren Rosendal Jensen Department of Organic Chemistry, The Technical University of Denmark, DK-2800 Lyngby, Denmark Received May 27, 1997 X Synthesis of five novel piperidine monoterpene alkaloids (17-21) using the iridoid glucoside antirrhinoside (4) as a synthon is described. Two strategies for their preparation were investigated: the first possible pathway involved an intermediate diol, 13, from which the piperidine ring was expected to be constructed via reaction of its ditosylate with an amine; the second strategy involved a double reductive amination as the key step to the piperidine ring, which proved successful. The stereochemistry of C-5 and C-9 in the obtained piperidine monoterpenes was the same as that reported for R-skytanthine (3), a known isolate from Skytanthus acutus (Apocynaceae). Monoterpene alkaloids have been the subject of much interest because they often exhibit pharmacological activity. 1 The piperidine alkaloids especially, from Skytanthus acutus and Tecoma stans 2 have been studied intensively, and tecomanine (1) has been shown to have hypoglycemic activity. 3-5 Also, incarvilline (2) and related compounds from Incarvillea sinensis 6-9 sused in the Chinese traditional medicine to treat rheumatism and to relieve painshave been investigated. Advanced synthetic pathways to such compounds have been reported; for example, (+)-1 has been syn- thesized enantioselectively. 10,11 Moreover, (+)-R-skytan- thine (3) has been prepared by cyclization of an inter- mediate cyclopentanoid ditosylate with methylamine, 12 and a hydroxylated 3-azabicyclo[4.3.0]nonane, racemic isooxyskytanthine, has been prepared using a photocy- clization step. 13 Recently, a Mitsunobu-type cyclization has been employed for the formation of the piperidine ring in 3. 14 Finally, there have been several reports 15-19 on the synthesis of simple 3-azabicyclo[4.3.0]nonanes. The biological activity known for some natural pip- eridine monoterpenes encouraged us to synthesize enantiomerically pure analogues. Utilizing the chirality already present in the iridoid aglucone, steps involving expensive chiral catalysts or reagents, as well as separations of racemates, may be avoided. Previously, one of us has reported 20 on the conversion of antirrhi- noside (4) into the pyridine 5. As a part of our current investigation of 4 as a synthon for cyclopentanoids, we have synthesized five novel piperidine monoterpenes with the same stereochemistry at C-5 and C-9 as 2 and 3, but lacking the methyl group at C-4. Results and Discussion Multigram amounts of antirrhinoside (4) can readily be obtained from Antirrhinum majus L. (Scrophulari- aceae). The commercial varieties “White Wonder” and “Bright Eyes” are preferred because of their high content (1.5% of fresh wt) of 4 and the presence of only small amounts of the closely eluting antirrhide (6) and 5-glu- cosylantirrhinoside (7). Isolation was performed by reversed-phase chromatography of the H 2 O-soluble part of the crude EtOH extract as earlier described. 21 In the present work utilizing 4 as a synthon for cyclopentanoids, our first goal was to make a syntheti- cally useful intermediate. Since our primary aim was piperidines, tosylation 22 or mesylation 23 of the diol 13 (see Scheme 1) and subsequent treatment with an appropriate amine seemed the most straightforward method for achieving this. Previously, a SnCl 2 -catalyzed reaction of 4 has been reported 24 to yield the 5,6-monoisopropylidene deriva- tive 10 directly in 49% yield. However, in our hands this reaction gave a complex mixture of products. Attempts with mild ketalization methods 25-27 (as 4 degraded under conditions using strong acids) showed that the sugar 4′,6′-diol moiety was reacting faster (with 8 as an isolable intermediate) than the aglucone 5,6- diol. This problem was overcome by first preparing the diisopropylidene derivative (9) using pyridinium p- toluenesulfonate (PPTS) and 2,2-dimethoxypropane in Me 2 CO 27 and subsequently removing the 4′,6′-isopro- pylidene group by heating at 60 °C in dilute HOAc. Thus, a 72% overall yield of 10 was obtained. Now, to avoid the inherent problem of cyclobutane formation 28 during NaBH 4 reduction of the aglucone of 5,6-isopro- pylidene antirrhinoside (10), hydrogenation of 11 was performed prior to enzymatic cleavage by -glucosidase, * Author to whom correspondence should be addressed. Phone: +45 45252103. Fax: +45 45933968. E-mail: okhf@pop.dtu.dk. X Abstract published in Advance ACS Abstracts, October 1, 1997. 1012 J. Nat. Prod. 1997, 60, 1012-1016 S0163-3864(97)00264-4 CCC: $14.00 © 1997 American Chemical Society and American Society of Pharmacognosy