Synthetic Methods DOI: 10.1002/anie.201407680 An Unusual Ring-Contraction/Rearrangement Sequence for Making Functionalized Di- and Triquinanes** Chinta Nagaraju and Kavirayani R. Prasad* Dedicated to Professor Ganesh Pandey on the occasion of his 60th birthday Abstract: A novel ring contraction/rearrangement sequence leading to functionalized 2,8-oxymethano-bridged di- and triquinane compounds is observed in the reaction of various substituted 1-methyl-4-isopropenyl-6-oxabicylo[3.2.1]octan-8- ones with Lewis acids. The reaction is novel and is unprece- dented for the synthesis of di- and triquinane frameworks. Creating molecular complexity from simple molecules is of great significance in organic synthesis. [1] Molecular rearrange- ments hold a special place in the formation of unusual carbon–carbon and carbon–heteroatom bond-forming reac- tions. Some rearrangements, whether engineered or observed serendipitously, have played significant roles in designing novel molecular architectures, including the synthesis of natural products and their analogues. [2] Synthesis of di- and triquinanes is one of the classics in organic synthesis and a number of strategies were developed for the synthesis of di- and triquinane compounds, which include ring-expansion/ rearrangement and ring-contraction/rearrangement sequen- ces. [3] During the course of the synthesis of the natural products annuionones A, B, and E (1–3 ; see Scheme 1), which possess a 6-oxabicyclo[3.2.1]octane framework, we encoun- tered an unusual ring-contraction/rearrangement sequence leading to functionalized di- and triquinane frameworks, and is the subject of this communication. In our investigations on the total synthesis of 1–3 and their analogues, we required an efficient synthesis of the substi- tuted 6-oxabicyclo[3.2.1]octan-8-one 4 in an enantioselelec- tive fashion (Scheme 1). We anticipated the synthesis of 4 from the corresponding 1,5-dimethyl-4-isopropenyl-6- oxabicyclo[3.2.1]octan-8-ol (5a) by the oxidation of the alcohol and olefin isomerization. Formation of 5a was envisaged by a gold-mediated reaction sequence involving the 5-exo-dig intramolecular hydroalkoxylation of the pri- mary alcohol in the functionalized alkynol 6 to give the exocyclic enol ether intermediate 7a, isomerization of 7a to the oxocarbenium ion 7b, and an intramolecular ene reaction of the alkene in 7b with the oxocarbenium ion. [4] Synthesis of the required 6 was planned to arise from the addition of alkynyl Grignard/lithium reagents to the aldehyde 8a, the synthesis of which starts with geraniol as established by the group of Yamamoto [5] (Scheme 1). At the outset, a series of propargyl alcohols (9a–i ) were synthesized from the enantiopure silyloxy aldehyde 8a by the addition of alkynyl lithium/Grignard reagents (Scheme 2). [6] AuCl 3 -catalyzed reaction of 9a–i cleanly furnished the 1- methyl-4-isopropenyl-6-oxabicyclo[3.2.1]octan-8-ols 5a–i, with various substitutions at the 5-position, in 81–93 % yield. Oxidation of 5a–i afforded the corresponding 5- substituted 1-methyl-4-isopropenyl-6-oxabicyclo[3.2.1]octan- 8-ones 10a–i in excellent yields. By using the same synthetic sequence, the 1-methyl-4-(1-phenylvinyl)-6-oxabicyclo- [3.2.1]octan-8-ones ( Æ)-10j and ( Æ)-10 k, with methyl and pentenyl substitution at the 5-position, were synthesized from the aldehyde ( Æ)-8b in good yields. Interestingly, the quaternary carbon center present in the substrates 9a–k is essential for AuCl 3 -catalyzed formation of the substituted 1- methyl-6-oxabicyclo[3.2.1]octan-8-ols 5a–k. The structurally similar compound 9l, which lacks the quaternary carbon center, produced an unidentifiable mixture of products in the reaction with AuCl 3 (Scheme 3). Scheme 1. Retrosynthesis for 1,5-dimethyl-4-isopropenyl-6-oxabicyclo- [3.2.1]octan-8-ol by gold-catalyzed cyclization. [*] C. Nagaraju, Prof. Dr. K. R. Prasad Department of Organic Chemistry, Indian institute of Science Sir C. V. Raman Av., Bangalore 560 012 (India) E-mail: prasad@orgchem.iisc.ernet.in [**] C.N. thanks the Council of Scientific and Industrial Research (CSIR), New Delhi for a research fellowship. We thank K. Durga Prasad and Prof. T. N. Guru Row of the Solid State and Structural Chemistry Unit (SSCU), IISc for their kind help in X-ray crystal structure analysis. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201407680. A ngewandte Chemi e 10997 Angew. Chem. Int. Ed. 2014, 53, 10997 –11000  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim