Combinatorial Synthesis by Nature: Volatile Organic Sulfur-Containing Constituents of Ruta chalepensis L. by Sina Escher* a ), Yvan Niclass a ), Matthijs van de Waal b ), and Christian Starkenmann* a ) a ) Firmenich SA, Corporate R&D Division, P.O. Box 239, CH-1211 Geneva 8 (phone: þ 41227803477; fax: þ 41227803334; e-mail: christian.starkenmann@firmenich.com) b ) Firmenich SA, Perfumery Division, P.O. Box 239, CH-1211 Geneva 8 Ongoing interest in discovering new natural fragrance and flavor ingredients prompted us to examine a solvent extract of sulfurous-sweaty smelling Ruta chalepensis L. (Rutaceae) plant material more closely. Twenty-one sulfur-containing constituents of similar structures were identified by GC/MS techniques. Amongst them, 14 have never been described to occur in nature. The compounds 1 – 18 belong to a family of natural flavor and fragrance molecules having a 1,3-positioned O,S moiety in common. The identities of the natural constituents were confirmed by comparison with synthetic reference samples, and the organoleptic properties of the latter were studied. The relative and absolute configurations of the four stereoisomers of 4-methyl-3-sulfanylhexan-1-ol (5) were established by stereoselective synthesis. The natural isomers consisted of a 65 :35 mixture of (3R,4S)-5 and (3S,4S)-5. 1. Introduction. – Recently, we isolated 1-methoxyhexane-3-thiol (1) from a steam distillate of freshly harvested Salvia sclarea L. plants [1]. This exceedingly powerful thiol imparts herbaceous, pungent, and repulsive tonalities which are key to the fragrance of natural clary sage. Guided by strongly resembling odors, we later identified 1 also in a solvent extract of Ruta chalepensis L. together with 4-methoxy-2- methylbutane-2-thiol (2), 1-methoxy-4-methylpentane-3-thiol ( 3), and 1-methoxyhep- tane-3-thiol (4)[1].The Ruta plant extract then available excluded further analysis, but our continuing interest in new sulfurous fragrance and flavor chemicals [2] prompted us to re-investigate more closely the chemical composition of this intriguing natural scent. R. chalepensis L. (Rutaceae) is a perennial herb flowering from April to July and having more or less developed woody parts below. It grows wild in dry, often rocky regions of the Mediterranean area [3][4]. It is an ancient medical plant still used in traditional medicine [5]. A closely related species, Ruta graveolens L., is cultivated for commercial production of rue oil. Chemical compositions referring to steam distillates of aerial parts of R. chalepensis L. vary considerably. Thus, essential oils of Turkish [6] and of Sicilian [7] origin had high percentages of alkan-2-ones, notably nonan-2-one and undecan-2-one, respectively, whereas the main components of an essential oil of Greek origin [8] were 1-methyloctyl acetate and monoterpene hydrocarbons. Argentinean oil [9] was reported to contain mostly undecan-2-one, nonan-2-one, and 1-methyloctyl acetate. The plant material for our re-investigation of R. chalepensis L. was collected in May 2003 south of the city wall of San Gimignano, Italy, from the same habitat as described CHEMISTRY & BIODIVERSITY – Vol. 3 (2006) 943 # 2006 Verlag Helvetica Chimica Acta AG, Zürich