Enantioselective Synthesis of Arglabin

Abstract

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.

Synthesis of Biologically Active Guaianolides with a trans‐Annulated Lactone Moiety

“…The first synthesis of 1 was recently accomplished [39] by using furan derivatives as a starting point: cyclopropylcarbaldehyde 118 can be prepared by a two-step sequence involving Cu I -catalyzed asymmetric cyclopropanation and subsequent ozonolysis from methyl-2-furoate (117, X = CO 2 Me; Scheme 22). [3c,29] The chiral trans-substituted allylsilane 119 is accessible from furfuryl alcohol (117, X = CH 2 OH) by enzymatic resolution and functional group transformations.…”

A single-flask synthesis of α-alkylidene and α-benzylidene lactones from ethoxyacetylene, epoxides/oxetanes, and carbonyl compounds

“…The α–alkylidene lactone motif is typically constructed by the condensation of lactone enolates with aldehydes or iminium ions, 4 by transition-metal mediated lactonizations, 5 or by Wittig or Horner-Wadsworth-Emmons-type reactions 6 between phosphorous ylides/phosphonate anions and carbonyl compounds. 1b In the present Letter we describe a useful one-pot assembly α–alkylidene and α–benzylidene lactones from ethoxyacetylene, epoxides/oxetanes, and aldehydes or ketones.…”

An Allenic Pauson–Khand Approach to 6,12-Guaianolides

“…9 While this multi-step process is high yielding, limitations arise when applying this protocol to access a structurally diverse array of natural products. The most common strategies for forming the seven membered ring include: ring expansion of [3.2.0] ring systems, 10 tropone or tropylium cation alkylation, 11 olefin metathesis, 12 intramolecular oxidative or ene cyclizations, 13 and 3,3-sigmatropic rearrangements of 3,3-divinyl cyclopropanes. 14 Finally, the α-methylene butyrolactone moiety is nearly always constructed in the final steps of a synthetic sequence via a multi-step process involving a series of homologations, oxidations, reductions, protections and/or deprotection steps.…”