J. Chem. Soc., Perkin Trans. 1, 1998 2253 Ring closing metathesis guided synthesis of (R)-(2)-muscone Vijayendra P. Kamat, a, Hisahiro Hagiwara,* ,b Toshio Suzuki b and Masayoshi Ando a Faculty of Engineering a and Graduate School of Science and Technology, b Niigata University, 8050, 2-nocho, Ikarashi, Niigata 950-2181, Japan A concise synthesis of the valuable perfumery compound (R)-(2)-muscone 1 in its natural form by making use of the ring closing olefin metathesis (RCM)-aided macrocyclis- ation route has been achieved. (R)-Muscone 1, the precious and exotic perfumery ingredient, isolated from the male musk deer Moschus moschiferus, 1 is perhaps the only perfumery compound to receive wide attention ever since its chemical constitution was established. 2 Because of the exorbitant price that the natural product fetched, several groups concentrated their efforts in syn- thesising racemic muscone. The literature covering various aspects of macrocyclic musk and related compounds has been excellently reviewed. 3 Being a macrocyclic natural product, muscone in racemic form was synthesized earlier by several routes 4 including a variety of procedures based on acyloin condensation, frag- mentation of tosylhydrazones derived from α,β-epoxy ketones, photochemical reaction involving bridged bicyclic ketones, novel one carbon homologation and ring enlargement proto- cols. Similarly, there have been reports on the synthesis of (R)-muscone 1 involving key reactions like free radical macro- cyclization, 5 diastereoselective conjugate addition to a cyclic α,β-unsaturated ester of (R,R)-cyclohexane-1,2-diol followed by a Dieckman condensation reaction 6 and asymmetrically catalysed macrocyclisation of an ω-alkynal 7 followed by a hydroxy group directed cyclopropanation of the resulting cyclic (15S)-allyl alcohol. 8 In recent years, olefin metathesis has advanced to a widely applicable synthetic method with the development of stable transition metal based catalyst systems. 9 The ring closing olefin metathesis (RCM) guided synthetic protocol continues to yield spectacular success in the synthesis of complex bio-active natural products. 10 Among various catalysts available, the ruthenium alkylidenes and the molybdenum alkylidenes are the most frequently used initiators for olefin metathesis. 11 In principle, muscone could be obtained by RCM of an appropriate diene substrate which in turn should be obtainable using readily available starting materials. This has indeed been realized in practice and we describe herein an efficient synthesis of the natural product (R)-(2)-muscone 1 by employing an RCM reaction as shown in Scheme 2. Although, several reports on the synthesis of racemic 4 and optically active muscone have O 1 On leave from Goa University, Goa, 403 206, India. appeared in the literature, 8 none of them utilized an RCM protocol for effecting macrocyclization leading to the natural product 1. Among the RCM catalysts, we selected bis(tricyclohexyl- phosphine)benzylidene ruthenium( ) dichloride 2 as the initiator for the metathesis after considering its commercial availability, excellent functional group tolerance and the reported retention of catalytic activity even under reaction conditions which did not include rigorous exclusion of moisture and oxygen. 9 The key diene substrate 9 was prepared via the initial Grignard reaction involving (R)-(1)-citronellal 4 ‡ and 1-bromodec-9-ene which in turn was prepared by reacting dec-9-en-1-ol with carbon tetrabromide in the presence of triphenylphosphine using acetonitrile as solvent. In an attempt to effect a short synthesis of the natural product 1, the keto diene 6 was exposed to ruthenium alkylidene 2 under the RCM reaction conditions. 10 However, we could only isolate the corresponding acyclic dimeric compound 3 derived from 6 as a product of intermolecular metathesis in the form of a waxy solid (Scheme 1). The dimerization of 6 in the present PCy 3 Ru PCy 3 Ph Cl Cl 2 OH O (CH 2 ) 8 (CH 2 ) 8 O O H O 5 6 1- Bromodec-9-ene(1 equiv.) Mg (1.2 equiv.), Et 2 O (62%) Jones reagent, acetone 0 °C (80%) 2 (5 mol%) CH 2 Cl 2 , 45 °C, 21 h (83%) 4 3 Scheme 1 ‡ Commercially available (R)-(1)-citronellal from Tokyo Kasei Kogyo Co., Ltd. was used. Published on 01 January 1998. Downloaded on 28/10/2014 17:02:50. View Article Online / Journal Homepage / Table of Contents for this issue