Zeolite NaY-Promoted Cyclization of Farnesal: A Short Route to Nanaimoal Constantinos Tsangarakis, Ioannis N. Lykakis, and Manolis Stratakis* Department of Chemistry, UniVersity of Crete, Voutes 71003, Iraklion, Greece stratakis@chemistry.uoc.gr ReceiVed NoVember 15, 2007 The sesquiterpene nanaimoal was synthesized in 21% overall yield and in a biomimetic manner. As a key step, the acid- catalyzed cyclization of farnesal under zeolite NaY confine- ment conditions was used. The intrazeolite cyclization of farnesal affords as major product a double-bond isomer of nanaimoal, via a novel diastereoselective tandem 1,5-diene cyclization/Prins-type reaction. Nature constructs cyclic terpenes using a variety of enzymes called cyclases. 1 Those enzymes provide a delicate balance of an acidic initiator, a basic amino acid residue to terminate the cyclization sequence, and the perfect conformational control of the confined substrate that allows stereocontrol. As a result, synthetic chemists expend a great deal of effort attempting to mimic the work done by enzymes, as they strive for ever-greater efficiency in their own syntheses. 2 We anticipated that by adsorbing an acyclic terpene within the cavities of an acidic zeolite, the confined environment would provide stereocontrolled cyclization through conformational control. Zeolites, which are mixed silicon/aluminum-based porous materials, catalyze reactions by confining the substrates within “active site” cavities. 3 We have reasoned that acidic zeolites with appropriate cage dimensions of ca. 10 Å, 4 such as faujasites (MX, MY, M ) cation), would be particularly well suited for our purpose. Our initial studies have revealed that the slightly acidic 5 zeolite NaY is a perfect catalyst and host medium, as well, to achieve the clean and good-yielding biomimetic cyclization of small acyclic terpenoids, such as geraniol and its derivatives. 6 The cyclization is catalyzed by Bronsted acidic sites 7 (bridging hydroxyl groups, Al-OH-Si), and since such sites appear only within the cavities of zeolites, 8 we consider the cyclization as occurring intrazeolite. In addition, we reported later on epoxy polyene terpenes undergo under NaY confinement conditions a fast and selective monocyclization, 9 allowing thus a short and good-yielding synthesis of elegansidiol and farnesiferols B-D. We report in this manuscript a novel tandem bi-cyclization pathway promoted by zeolite NaY, which allows the fast and efficient synthesis of the sesquiterpene nanaimoal in a relatively few steps from the naturally occurring farnesal (1). Adsorption of 60 mg of farnesal per 1 g of dry NaY in a hexane slurry and heating to 70 °C for 3 h afforded a mixture of 1a-1c in 82% yield (Scheme 1). The loading level of 1 within NaY was kept low to ensure its quantitative confinement within the zeolite cavities. 10 It is important to emphasize herein, that identical results were obtained by performing the intrazeolite cyclization reaction starting with a mixture of farnesal isomers, either at the C2-C3 or at the C6-C7 double bond. The major product (50% relative yield; 30% isolated yield after column chromatography) was the bicyclic aldehyde 1a 11 obtained as a 92/8 mixture of diastereomers (GC-MS), with the major one shown in Scheme 1. Aldehyde 1a is a double- bond isomer of the naturally occurring nanaimoal (2), 12 a sesquiterpene with a unique carbon skeleton, isolated from the nudibranch Acanthodoris nanaimoensis. The monocyclized 1b (E) and 1c (Z) were formed in 50% relative yield and in ∼4/1 ratio. The relative stereochemistry of the major diastereomer 1a was established by combined DEPT, COSY, HMQC, and NOESY experiments (some representative NOEs for the more stable conformer of the major diastereomer of 1a are shown below). After much experimentation, by monitoring the reaction at several stages, we found that the optimum conditions favoring 1a were 3 h at refluxing hexane. Upon shorter reaction times, (1) (a) Wendt, K. U.; Schulz, G. E.; Corey, E. J.; Liu, D. R. Angew. Chem., Int. Ed. 2000, 39, 2812-2833. (b) Christianson, D. W. Chem. ReV. 2006, 106, 3412-3442. (2) (a) Yoder, R. A.; Johnston, J. N. Chem. ReV. 2005, 105, 4730-4756. (b) Ishibashi, H.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 11122-11123. (3) (a) Sen, S. E.; Smith, S. M.; Sullivan, K. A. Tetrahedron 1999, 55, 12657-12698. (b) Turro, N. J. Acc. Chem. Res. 2000, 33, 637-646. (4) Dyer, A. An Introduction to Zeolite Molecular SieVes; Wiley: Bath, U.K., 1988. (5) Rao, V. J.; Perlstein, D. L.; Robbins, R. J.; Lakshminarasimhan, P. H.; Kao, H-M.; Grey, C. P.; Ramamurthy, V. Chem. Commun. 1998, 269- 270. (6) (a) Tsangarakis, C.; Stratakis, M. AdV. Synth. Catal. 2005, 347, 1280- 1284. (b) Tsangarakis, C.; Stratakis, M. Eur. J. Org. Chem. 2006, 4435- 4439. (7) Tsangarakis, C.; Raptis, C.; Stratakis, M. Unpublished results. (8) Bevilacqua, M.; Montanari, T.; Finocchio, E.; Busca, G. Catal. Today 2006, 116, 132-142. (9) Tsangarakis, C.; Arkoudis, E.; Raptis, C.; Stratakis, M. Org. Lett. 2007, 9, 583-586. (10) Under these low loading level conditions (n ≈ 0.2), neither the reacting farnesal nor any of the products was detected by GC on the supernatant hexane, indicative that all substrate was adsorbed within the zeolite cavities. (11) Engler, T. A.; Ali, M. H.; Takusagawa, F. J. Org. Chem. 1996, 61, 8456-8463. (12) Isolation of nanaimoal: (a) Ayer, S. W.; Hellou, J.; Tischler, M.; Andersen, R. J. Tetrahedron Lett. 1984, 25, 141-144. (b) Ayer, S. W.; Andersen, R. J.; He, C. H.; Clardy, J. J. Org. Chem. 1984, 49, 2653- 2654. 10.1021/jo7024527 CCC: $40.75 © 2008 American Chemical Society J. Org. Chem. 2008, 73, 2905-2908 2905 Published on Web 03/06/2008