Eudesmanolides synthesis

Oltra and Cuerva have reported a unified strategy for the synthesis of the eudesmanolides that relies on the collidine-chlorotrimethylsilane reagent... 

Vol. 5, p. 76). Related studies have shown that the butenolide derivative (319) can be used as an annulating agent in the construction of linear tricyclic y-lactones [cf. (322) and (323)] and it is expected that this methodology may be applied to the synthesis of naturally occurring eudesmanolides." ... 

A sultone analog of 107 (4-Me(eq)) instead of 3-Me(eq))] is the key intermediate of the first enantioselective total synthesis of the antileukemic l,10-ji ( ti-eudesmanolides, (—)-eriolanin and (—)-eriolangin <2001EJ03669, 2006EJ01144>. 

This reaction has been used in a total synthesis of the eudesmanolide frullanolide (4), equation (II) . 

Transannular cyclizations generally contribute to the enhancement of molecular rigidity and structural complexity, two properties often associated with biological activity of small molecules [114]. In this scenario, we found that the Cp2TiCl-mediated transannular cychzation of 1,10-epoxycostunolide, a homo chiral material accessible in (multi)gram quantities, provides a straightforward way for the enantiospecific synthesis of eudesmanolides such as (-i-)-reynosin (18) (Scheme 23) and (-i-)-3a-hydroxyreynosin [47]. 

In the synthesis of functionalized eudesmanolides only the product with a /i-onentated hydroxy group was found after oxidation of the selenide with peracetic acid37. 

The original Shapiro reaction involves the preparation of unfiinctionalized alkenes from ketone tosyl-hydrazones by quenching of the in situ generated alkenyllithium reagents with water. Recent applications of this reaction in natural product synthesis include the synthesis of 9(0)-methanoprostacyclin (Scheme 12), the in vitro conversion of humulene to A ( -capnellene (Scheme 13), the synthesis of die basic skeleton of isoadsirene (equation S2) ° and the total synthesis of the eudesmanolides rothin A and rothin B (equation 53). ... 

The structural elucidation and total synthesis of sesquiterpenoid lactones such as the germacranolides [cf. (310)] and eudesmanolides [cf. (311)] continues to be a very... 

Titanocene-catalysed transannular cyclisation OF EPOXYGERMACROLIDES enantospecific synthesis of EUDESMANOLIDES... 

TITANOCENE-CATALYSED TRANSANNULAR CYCLISATION OF EPOXYGERMACROLIDES ENANTIOSPECIFIC SYNTHESIS OF EUDESMANOLIDES... 

Eudesmanolides (such as (3)) constitute a large family of natural sesquiterpenoids, with more than 500 members described to date.tl] Their pharmacological properties include antifungal, anti-inflammatory, and antitumor activities among others,[2] but many of them are scarce in nature. To facilitate their chemical synthesis, a novel procedure has recently been developed that provides satisfactory overall yields.[3] Our method is based on the titanocene-catalyzed cyclization of epoxygermacrolides (such as (2)) easily prepared by selective epoxidation of accessible germacrolides such as ( I )-l 1 (5,13-dihydrocostunolidc (1)[4]. 

Arborescin (586), a metabolite of Artemisia arborescens, has been synthesized (Scheme 59) from the eudesmanolide derivative (421) previously used in the synthesis of vulgarin " cf. p. 128). 

A furan-containing chiral alcohol reacted with p-chloroethanesulfonyl chloride, through an intramolecular Diels-Alder cyclization, to form the endo sultone isomer after thermal equilibration, as shown in the following scheme. The sultone was further converted into a substituted cyclohexene, which was a key intermediate in the total synthesis of 1,10-seco-eudesmanolides eriolanin and eriolangin <04AG(E)5991>. 

There are countless synthetic examples of the aldol condensation. In one example taken from Massanet s synthesis of eudesmanolides, diketone 134 was converted to the enolate anion with LDA. In a second step, methyl pyruvate was added to give a 98% yield of 135 and 136 in about a 1 1 ratio. 

Synthesis of 6,12-sesquiterpenolides This section describes the synthesis of sesquiterpenes bearing a lactone moiety between C(6) and C(12). The transformation of the A-ring in santonin to give eudesmanolides, guaianolides, and elemanolides, as well as the modification of the lactone ring is described. Some microbiological transformations of santonin and its derivatives are also described. 

The same authors have developed an alternative metiiod for the synthesis of 6)8-eudesmanolides from santonin (Scheme 15) [26]. The epimerization process at C(6) consisted of the LiAlH4 reduction of the trans-6oc- actone moiety in compound 122, followed by selective protection of the hydroxyl groups at C(3) and C(12), oxidation of C(6) to give compound 128, and stereoselective reduction of the carbonyl group by attack with sodium borohydride from the less hindered a-side. Re-lactonization was achieved by oxidation, after prior deprotection of the C(12)-hydroxyl group, with RuH2(Ph3P)4 or tetra- -propylammonium... 

The biotransformations of 6)8-eudesmanolides functionalized at C(3), obtained from santonin, with Curvularia lunata and Rhizopus nigricans cultures have been also studied (Schemes 17 and 18) [27]. Rhizopus nigricans was more active in the biotransformation processes against these substrates. It is noteworthy that incubation of compound 109 with Rhizopus nigricans produced epimerization at C(4) and, in decreasing order, hydroxylation at C(8), C(l), or C(4). The authors attributed this epimerization to the participation of the hydroxyl group at C(3), and noticed that microbial functionalization at C(8) could provide access to the synthesis of 8,12-eudesmanolides. 

Artemisin (2) is an 8-hydroxy-functionalized eudesmanolide that is isolated from Artemisia maritima and is closely related to santonin, and is a compound that has been successfully used by our group in several syntheses of sesquiterpenolides functionalized at C(8) or C(9). For example, artemisin (2) has been transformed into the cytotoxic compounds artapshin (147) and dihydro-8a-hydroxybalchanin (148) [28] in a synthetic sequence (Scheme 19) in which the transformation of the A ring was achieved in a similar way to that described previously in the synthesis of dihydrosantamarin (see Scheme 8). 

Pioneering work in the synthesis of 8,12-eudesmanolides from santonin was carried out by Yamakawa and coworkers [47], These authors reported an allylic oxidation, with Cr(VI)-based oxidants, of methyl 3-oxoeudesm-1,4,6-trienoate (291) to give the corresponding 8-oxo-compound 294. Compound 291 was prepared from santonin (1) in a multi-step synthesis in 20% overall yield. Subsequent allylic oxidation of 291 with chromium reagents proceeded in low yield and the 8-oxo-compound (294) obtained in this way presented further difficulties when reduction of the carbonyl group at C(8) into a hydroxyl group was attempted. 

Two e -eudesmanolides, ewr-3-oxodiplophyllin (358) and e -5-(3-hydroxydiplophyllolide (362), occur in European Chiloscyphus polyanthos, together with the previously known ewr-diplophyllin (355) and ent-diplophyllolide (356) (72). The structures of the lactones (358) and (362) were based on spectroscopic correlation with the co-metabolites (355,356). The stereochemistry of (362), including the center containing the tertiary hydroxyl group, was based on its positive Cotton effect and on biogenetic considerations. ( )-3-Oxodiplophyllin (358) has been reported as an intermediate in the synthesis of yomongin (399), the 1,2-dehydroderivative of (358), before its isolation from a liverwort (Scheme 48) 100). 

Metz P, Stolting J, Lage M, Krebs B. A short and highly stereoselective synthesis of the 1,10-seco-eudesmanolide ivan-gulin. Awgew. Chem. Int. Ed 1994 33 2195 2197. 

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