Roccellaric acid

Hydrolysis of the amide, followed by reductive ozonolysis furnished 44 (99.5 0.5 mixture of 44a and 44b), which can be alkenylated to 45 via the aldehyde 44b. Halolactonization could be achieved to the frans-disubstituted lactone 46 via the iodonium ion 51 (Fig. 2), being preferred to 52 because of lesser allylic 1,3-strain [24]. Methylation of 46 gave rise to a 3 1 1 mixture of 47-49, which can be easily separated by chromatography. Deprotection followed by oxidation furnished (-)-roccellaric acid (1) [25], (-)-dihydropro-tolichesterinic acid (4) and the dimethylated acid 50 in pure form. 

Acyloxazolidinones of acyclic dicarboxylic acids can be used in the stereoselective synthesis of y-butyrolactones, which has been applied to one of the shortest syntheses of (-)-roccellaric acid (1) reported to date (Scheme 16) [49]. 

Alternatively, the thiophenyl group could be reduced in 147 under retention of configuration to 149, which was further converted to roccellaric acid (1) in very high yield (Scheme 23). 

The uses of chiral 3-carbon synthons are many and have been discussed in several reviews and other sources 18-23). Molecules that have been prepared from isopropylidene glyceraldehydes include various trialkoxynitrobutanes such as 35 and 36 24), Corey lactone variants 37 and 38 (25,26), nucleoside analogs 39-42 (27), verrucarinolactone isomers 43-46 (25), the enantiomers of roccellaric acid 47 (29), rubrenolide 48 30) and (+)-laurencin 49 (37). 

Cp2TiCl-mediated 5-exo-trig cyclizations have been intensively exploited by Roy et al. for the total synthesis of ( )-dihydroprotolichesterinic and ( )-roccellaric acids, ( )-sesamin, ( )-dihydrosesamin, ( )-acuminatin, ( )-eudesmin, ( )-lariciresinol, ( )-pinoresinol, ( )-piperitol, ( )-acumi-natin methyl ether, (zh)-sanshodiol methyl ether, ( )-piperitol methyl ether, ( )-pinoresinol monomethyl ether, ( )-lariciresinol monomethyl ether, and ( )-lariciresinol dimethyl ether [ 100-103]. Moreover, this group has very recently reported the enantioselective synthesis of (-)-sesamin (Scheme 19), (-)-dihydrosesamin, (-)-acuminatin, and (-)-methyl piperitol by radical cyclization of chiral epoxides initiated by Cp2TiCl [104]. 

Allylic alcohol 846 is instrumental in controlling the stereochemistry in the synthesis of (+ )-roccellaric acid (864) [231] (Scheme 115). The key step is an Ireland-Claisen rearrangement of propionate 861, which produces 862 as a mixture of isomers (epimeric at the methyl group). The minor diastereomer is removed at the lactone stage (863). Debenzylation and oxidation of the alcohol to an acid furnishes the natural product. 

B Roccellaric acid very thin rectangular lamellae... 

Deriv Methyl roccellarate, needles (MeOH), mp 40-41 °C, [a]o + 25 (CHCI3), from roccellaric acid with ethereal CHjNj StL Roccellaria mollis (Hampe) Zahlbr. 

Mulzer J, Salimi N, Hartl H (1993) First asymmetric synthesis of (+)- and (-)-roccellaric acid and dihyd-roprotolichesterinic acid. Tetrahedron Asymmetry 4 457-471... 

Mulzer et al. 553) synthesized (-)-nephromopsinic acid by the addition of a chiral allylic bromide to tetradecanal (see Scheme 36). The same group 628, 666) also described total syntheses of (-)- and (+)-roccellaric acid and (-)-dihydroprotolichesterinic acid and secured the relative configuration of (+)-roccellaric acid by an X-ray analysis. One route started from (2S,3E)-l,2-isopropylidene-5-0-benzyl-3-pentene-1,2,5-triol (42) (see Scheme 37). The second route included the ozonisation of methyl-(2RS,3R,4E)-3-benzyloxy-5-hydroxy-oxolan-3-one and subsequent condensation with tridecyltriphenylphosponium bromide (see Scheme 38). Finally they synthesized (-t-)-roccellaric acid and (-l-)-dihydroprotolichesterinic acid from D-glucose as the chiral pool (552) (see Scheme 39). 

Scheme 38. Synthesis of (-)-roccellaric acid and (-)-dihydroprotolichesterinic acid via (4S,2E)-l-0-benzyl-2-pentene-l,4-diol...

Scheme 39. Synthesis of (+)-roccellaric acid and (+)-dihydroprotolichesterinic acid...

Total syntheses of racemic protolichesterinic and roccellaric acids were achieved with the use of a tungsten-7i-ally complex in the key step (see Scheme) (Chen M-J, Liu R-S (1998) Efficient Total Syntheses of ( )-Protolichesterinic Acid and ( )-Roccellaric Acid via Tungsten-7t-allyl Complexes. Tetrahedron Letters 39 9465). 

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