Org. Biomol. Chem. 7(9), 2009, 1858-1867 Application of Nazarov cyclization to access [6-5-6] and [6-5-5]tricyclic core embedded New Heterocycles : An easy entry to structures related to Taiwaniaquinoids† Ritesh Singh, a Maloy Kumar Parai b and Gautam Panda *a Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow-226001, UP, India Tel: 91-522-2612411-18, Ext. 4385, 4469; Fax: 91-522-2623405 E-mail: gautam.panda@gmail.com; gautam_panda@cdri.res.in A concise and general route to synthesize new class of [6-5-6] tricyclic core embedded polyheterocycles has been accomplished using diastereoselective Nazarov cyclization with an overall yield of 35-40%. Versatility of this synthetic route has also been demonstrated by accessing a variety of [6-5-5] tricyclic core incorporated polycycles. It was observed that the efficiency of cyclization depends upon the impact of polarization on the reacting systems. Amongst the various Lewis and Bronsted acids screened for cyclization, Triflic acid was found to be the most effective catalyst. Introduction [6-5-6]ABC tricyclic skeleton, which is rather uncommon, has been known to be found in several natural products, among which members of taiwaniaquinoids holds special mention (Fig 1). 1a-c Taiwaniaquinol B, isolated from Taiwanese pine tree Taiwania cryptomerioide, is one such 6-nor-5(6ﾆ7)abeo- abietane type diterpenoid containing the uncommon fused [6-5- 6] tricyclic carbon skeleton. 2 Several members of the taiwaniaquinoids have shown activity as aromatase inhibitors and are currently under evaluation for their potential as drug leads in the treatment of estrogen-dependent cancers. 3,4 Thus, the distinctive [6-5-6] fused ring system has received considerable attention by synthetic organic chemists, and several total synthesis of such norditerpenoids has appeared in the last few years. 5 Nazarov reaction 6 is considered as one of the most versatile reactions to construct cyclopentenone fused carbocycles. Although the concept of polarized Nazarov substrate 7 i.e. divinyl ketone 1 has been exploited to construct simple functionalized cyclopentenone 3 via intermediate 2 under mild reaction conditions (Scheme 1), its utilization for the construction of [6- 5-6] tricyclic skeleton fused heteropolycycles is rather limited. 8 Trauner et al utilized the Nazarov chemistry efficiently to synthesize several members of Taiwaniaquinoid family containing [6-5-6] tricyclic skeleton including Taiwaniaquinol B using trimethylsilyl triflate(TMSOTf) in nitromethane. 9 Fillion et al reported synthesis of Taiwaniaquinol B, applying domino acylation/alkylation as a key step. 5a Approaches based on palladium catalyzed alkylation 5b and intramolecular Heck reactions 5c-e to assemble the [6-5-6] tricyclic skeleton containing natural products have also been well delineated by several groups. How ever, as such, no general and efficient method to assemble heterocycles with hetroatom impregnated [6-5-6] tricyclic skeleton is reported so far. Therefore, a mild and expedient method for the construction of heteroatom embedded [6-5-6] tricyclic skeletons is highly desirable. In the quest for attaining novel molecules with interesting properties, we envisaged to encompass the polarized Nazarov concept to access diversified [6-5-6] tricyclic skeletons. Further cognizing the fact that the cis ring fusion preferences in the cyclic systems could direct the protonation in diastereoselective Nazarov product, 10,11 we endeavored to design a new class of polarized Nazarov substrate 4 by casting H CHO O O Taiwaniaquinol A H O OH HO OMe Taiwaniaquinol B OHC OH OH OMe Taiwaniaquinol D CHO OH OH Diachroanal B X H H O designed 6,5,6/6,5,5 tricyclic embedded molecule X=O,S,N aromatic/ Heteroaromatic A B C A B C Fig 1 Representative natural [6-5-6] tricyclic skeleton and our designed novel ]6-5-6]/[6-5-5] skeleton embedded polycycles R R O R O-LA R O R R 1 3 D E E D E D H D=electron donating group E=electron withdrawing group, LA=Lewis Acid vinyl nucleophile vinyl electrophile X O R X LA-O R X R vinylic nucleophile vinylic electrophile 5 , 6 membered heteroaromatic/aromatics H+/ LA O H H X=O,S,N 4 5 2 6 Lewis Acid LA=Lewis Acid Scheme 1 A general Polarized Nazarov Reaction and our designed polarized substrate 4 aromatics/heteroaromatics 12 as vinyl nucleophiles to access a variety of novel benzene annulated [6-5-6]/[6-5-5] tricylic heteropolycycles 6 via intermediate 5.