A prominent member of the widely distributed class of guaianolides is arglabin, [1] which inhibits farnesyl transferase and thus activation of the RAS proto-oncogene, a process that is believed to play a pivotal role in 20-30 % of all human tumors. The natural product shows promising antitumor activity and cytotoxicity against different tumor cell lines (human tumor cell lines IC 50 = 0.9-5.0 mg mL À1 ). [2] Arglabin is isolated from Artemisia glabella and is transformed into the hydrochloride salt of the dimethylamino adduct 1·HCl to increase bioavailability. This compound 1·HCl has been successfully used in Kazakhstan for the treatment of breast, colon, ovarian, and lung cancers. [3,4] The heart of arglabin consists of a cycloheptane ring with five contiguous stereocenters, to which two five-membered rings are trans-annulated. The resulting strain can be released by ring opening of the g-butyrolactone at C-2, which makes arglabin and its derivatives prone to attack by nucleophilesa mode of action that plays an integral role in its biological activity. [2,5] The absence of other control factors should cause the planned epoxidation of 2 described in our retrosynthetic analysis (Scheme 1) to preferably occur from the top face of the tricycle to afford a less-strained but undesirable cis junction between the five-and seven-membered rings. Considering this, we reasoned that a hydroxy function at C-8 could direct a suitable epoxidation reagent to the desired lower face, and subsequently allow the installment of the double bond between C-8 and C-9 by elimination of water. Compound 2 should be accessible from 3 by allylation and subsequent ringclosing metathesis (RCM); the latter requires the formation of a tetrasubstituted double bond within a medium-sized seven-membered ring. Following the strategy developed in our research group for the enantioselective synthesis of trans-4,5-disubstituted g-butyrolactones, [6,7] the allylation of cyclopropane 4 with the allylsilane 5 should lead to the first key intermediate 3.Cyclopropanecarbaldehyde 8 was prepared in diastereoand enantiomerically pure form in two steps from methyl-2-furoate (6) on a 50 g scale (Scheme 2) following an analogous Scheme 1. Retrosynthetic analysis of arglabin. PG = protecting group, TMS = trimethylsilyl.Scheme 2. a) 1. Ethyl diazoacetate (2.67 equiv), Cu(OTf) 2 (0.66 mol %), (R,R)-iPr-box [8] (0.84 mol %), PhNHNH 2 (0.70 mol %), CH 2 Cl 2 , 85-90 % ee; 2. recrystallization (pentane), > 99 % ee, 38%; b) 1. O 3 , CH 2 Cl 2 , À78 8C 2. dimethylsulfide, 94 %; c) CH 3 MgCl, TMSCl, CuI, LiCl, THF, À78 8C, 4 h, 90 %; d) TMSCH 2 MgCl, [Ni(acac) 2 ], Et 2 O, reflux, 16 h, 72 %. Tf = trifluoromethanesulfonyl, acac = acetylacetonate, PMB = para-methoxybenzyl.

The biosynthetic pathways of sesquiterpene lactones are described in conjunction with recent developments in the total syntheses of various biologically active guaianolides. Different strategies towards the 5,7,5‐membered ring system are highlighted. Oxidative diol cleavages, aldol reactions, and intramolecular cyclopropanations were used as key reactions to construct the racemic guaianolide core system. Radical cyclizations, as well as ring closing metathesis, were successfully applied in asymmetric approaches. Biomimetic reactions were also applied as versatile tools for the construction of these highly complex natural products.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

A systematic study of a ring-closing metathesis towards a tetrasubstituted double bond as part of a seven-membered ring in a 5.7.5-tricyclic guaianolide system is described. By combining two techniques, namely sparging an inert gas through the solution together with dielectric heating via microwave irradiation a high-yielding ring-closing metathesis reaction in this particularly challenging case was achieved. The results obtained compare favorably with conventional heating conditions or with microwave irradiation in a closed system. The key aspects seem to be that rapid microwave irradiation diminishes catalyst decay by allowing the required high reaction temperature to be reached quickly and homogeneously and thereby providing enough energy for a successful metathesis reaction, while inert gas sparging is purging off evolving ethylene to shift the equilibrium to the product.

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2,2‐Dimethyl‐propanedioyl dichloride ( l )‐Valinol