13-Lactaranolides

Recently, several papers have reported the isolation of new lactarane lactones, possessing the methyl group at C-3 either cis or trans to H-2, and the lactone carbonyl group either at C-5 (5-lactaranolides. Tables 11-13) or at C-13 (13-lactaranolides, Tables 16-17). Differentiation between these structural alternatives on the basis of spectroscopic data alone has been often risky, especially when only a single isomer is at hand. Therefore, chemical correlations, synthesis of the possible isomers, and molecular mechanics calculations have always been performed in order to corroborate spectroscopic informations. 

The same authors assigned the structure 11.1 to a new polyunsaturated 5-lactaranolide sesquiterpene isolated from an ethanol extract of L. vellereus (56). 

The new lactone 16.6, one of the few known natural 13-lactaranolides, has recently been isolated from L. vellereus (87). The simulated C-NMR spectra of compound 16.6 suggested that the configuration at C-3 was opposite to that of isomeric lactaroscrobiculide A (16.2). This stereochemistry was established unequivocally by correlation of sesquiterpene 16.6 with 3-deoxy-3-epi-lactarorufin A (11.20), as shown in Scheme 10 (87). 

Lactaranolides constitute the largest group of sesquiterpenoids isolated from Lactarius species. Thus part 11 includes more than 90 compounds, of which ca. 30 were isolated from extracts of Lactarius, the... 

Three examples of 8-keto-5-lactaranolides (11.1, 11.2, 11.4) as well as three examples of epoxy-derivatives (11.2, 11.14, 11.57) were isolated. 

Structure elucidation of 5-lactaranolides other relevant chemical transformations involved the conversion of the lactone into the furan ring and addition reactions to double bonds (hydrogenation, hydroboration, epo-xidation, osmylation). A brief account of these reactions will be included in the chapter on chemical conversions of Lactarius sesquiterpenes. 

Lactaranolide derivatives included in Part 12 are produced by silica gel degradation of velutinal esters (7.28, 7.30), methylvelutinal (7.17) or free velutinal itself (for a discussion of these transformations see the chapter on chemical interconversions of Lactarius sesquiterpenes). The compounds upon acidification underwent aromatization to form furanoid derivatives (see Part 18). Under these conditions dehydration reactions took place and also dienes were formed (72). 

With respect to the aliphatic moiety (cyclopentene ring, plus protons at C-3, C-4, and C-12), 8,9-secofuranolactaranes gave NMR spectra resembling those of 8,9-seco-5-lactaranolide sesquiterpenes (Part 14) in addition, the two protons on the furan ring exhibited the characteristic couple of signals at 57.20-7.36. Remarkably, when a carbonyl group is attached to C-7, as in compounds 19.1 and 19.3, the signal of H-13 is shifted downfield to 57.95. 

Scheme 18 is the Me2AlCl catalyzed ene cyclisation of 8,9-seco-furanolactarane and 8,9-seco-5-lactaranolide sesquiterpenes exemplified by compound 14.1 to the corresponding lactarane sesquiterpenes such as 11.10 98). Lactone (11.10) exhibited the unusual cis configuration between H-8 and H-9. The emergence of this stereorelationship could be anticipated by examining the Dreiding models of the two possible transition states 25.5 and 25.6 (Scheme 19). In fact, unfavourable steric interactions developing between the C-3 methyl group and the bulky >C=0 -Al- complex are minimized in the transition state 25.6, which eventually collapses to lactone 11.10 98).

Oxidative hydroboration 91) of lactone 11.49 afforded a mixture of four lactarorufins (Scheme 20), in which diols 11.30 and 11.33, arising from a attack of diborane, largely predominated (more than 90%). The same type of stereoselectivity was observed for other addition reactions, i.e. epoxidation, osmylation, hydrogenation (775), (704), 43) to 2,9, 3,4- or 6,7-double bond of lactaranolides and marasmanes. Apparently, the tricyclic structures of these substrates provided enough conformational and steric bias to direct approach of reagents from the same side as the bridgehead protons H-2 and H-9. However, when the double bond was located in a different position, exceptions were observed 98). 

As expected, Pd catalysed hydrogenation of the C3-C4 double bond of lactone 16.15 (Scheme 7) afforded the dihydroderivative 16.17 in which the C-3 methyl group was trans to H-2 (94). Comparison of the NMR data of compound 16.5, readily prepared from 16.17, with those of natural lactone 16.6 (Scheme 6) definitely proved the stereostructure of the latter sesquiterpene (94). Compound 16.6 was also synthesized from 5-lactaranolide 11.28 according to the reaction sequence shown in Scheme 6, which is a nice example of a general strategy for moving the carbonyl group of lactaranolides from C-5 to C-13 (94). 

Ether formation from the corresponding 3,8-furanolactarane or 3,8-lactaranolide diol was performed using different procedures. Thus... 

Upon exposure to LiAl(O Bu)3H (2.5 equiv) in refluxing toluene, ketone 26.103 smoothly rearranged to a 10 1 mixture of 26.105 and 26.106 via the intermediate alkoxide 26.104. The tricyclic ether 26.105 was then converted to Schore s ketone 26.76, thereby completing a formal total synthesis of racemic furanether B (18.8). In addition, de Groot et al. explored an alternative conversion of 26.76 to 18.8 via the isomeric lactaranolides 26.97 and 26.110, which could be obtained in fair yield using the Pummerer-induced cyclization reaction of sulfoxide 26.108 as a key reaction (Scheme 36). 

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