The First Synthesis of (S)-(+)-Cacalol

The first synthesis of (S)-(+)-cacalol (1) was achieved by a combination of the BF 3 •Et 2 O-mediated reaction of (S)-4,5-epoxy-(2E)pentenoate (7) with 3,4-dimethoxytoluene to give (S)-4-aryl-5-hydroxy-(2E)pentenoate (5) and consecutive conversion of (S)-5 into (S)-1.Cacalol (1) is one of the major components isolated from the root of Cacalia decomposita, a compositae widely distributed in the northern part of Mexico.Extracts from the root have been used for the treatment of diabetes and other diseases, 1 and were recently reported to possess antihyperglycemic activity. 2Through a series of revisions, 3 the structure of cacalol (1) was established to be 5,6,7,8tetrahydro-3,4,5-trimethylnaphto[2,3-b]furan-9-ol by unambiguous synthesis. 4he absolute stereochemistry of C(5)-position of 1 was confirmed to be (S)-configuration by means of X-Ray analysis of its methyl ether (2) 5 and chemical correlation. 6The furotetralin ring structure of 1 appeared to give reasonable opportunity to develop analogue from the standpoint of a medicinal chemistry effort and total synthesis of (±)-1 was undertaken.Several syntheses of (±)-1 have been reported, 7 however, the chiral synthesis of (S)-1 was not reported so far.We now describe the first synthesis of (S)-(+)-1.(Scheme 1)Our retrosynthetic strategy of (S)-1 is illustrated in Scheme 1 and involves asymmetric synthesis of chiral tetralin intermediate ((S)-3) which could be obtained based on the intramolecular Friedel-Crafts acylation strategy from (S)-4-arylpentanoic acid (4).This chiral carboxylic acid ((S)-4) could be derived from (S)-4-aryl-5-hydroxy-(2E)-pentenoate (5).On the other hand, we previously reported the reaction of (±)-4,5-epoxy-(2E)-pentenoate (7) and 3,4-dimethoxytoluene in the presence of BF 3 •Et 2 O to give (±)-5 (46% yield) as a major product and (±)-2-aryl-5-hydroxy-(2E)-penenoate (6) (18% yield) as a minor product. 8When the optically active (S)-7 instead of (±)-7 is applied in the above-mentioned reaction, optically active (S)-5 is presumably obtained.Because the reaction of (R)-7 and anisole afforded (R)-4-aryl-5hydroxy-(2E)-pentenoate (8) (47% yield) along with the nucleophilic inversion at C(4)-position. 9 In order to confirm this assumption, BF 3 •Et 2 O-mediated reaction of (S)-7 possessing 93% enantiomeric excess (ee) 9 and 3,4-dimethoxytoluene was carried out, and the obtained mixture of 5 and 6 was subjected HETEROCYCLES, Vol.65, No. 2, 2005