Total Synthesis of Marine Eicosanoid (−)‐Hybridalactone

Abstract

(-)-Hybridalactone (1) is a marine eicosanoid isolated from the red alga Laurencia hybrida. This natural product contains cyclopropane, cyclopentane, 13-membered macrolactone and epoxide ring systems incorporating seven stereogenic centers. Moreover, this compound has an acid-labile skipped Z,Z-diene motif. In this paper, we report on the total synthesis of (-)-hybridalactone (1). The unique eicosanoid (-)-hybridalactone (1) was synthesized starting from optically active γ-butyrolactone 2 in a linear sequence comprising 21 steps with an overall yield of 21.9%. A key step in the synthesis of (-)-hybridalactone (1) is the methyl phenylsulfonylacetate-mediated one-pot synthesis of the cis-cyclopropane-γ-lactone derivative. This reaction provided an efficient and stereoselective access to cis-cyclopropane-γ-lactone 12. Further elaboration of the latter compounds through desulfonylation, epoxidation, oxidation, Wittig olefination and Shiina macrolactonization afforded (-)-hybridalactone.

Applications of Wittig Reaction in the Total Synthesis of Natural Macrolides

“…[119] For the first time, total synthesis of hybridalactone was performed relied on the reported results by Corey's group. [120] (-)-Hybridalactone 82, a marine eicosanoid, was isolated from the red alga Laurencia hybrida. This natural product includes cyclopropane, cyclopentane, 13-membered macrolactone and epoxide ring systems including seven stereogenic centers.…”

Progress in the Chemistry of Organic Natural Products 102

“…These can be roughly divided into six subgroups, namely: (1) those with a 6,12epoxy, also known as laurenan-type acetogenins ; (2) those with a 7,13epoxy, also known as lauthisan-type acetogenins (835)(836)(837)(838)(839)(840)(841)(842)(843)(844)(845)(846)(847)(848)(849)(850)(851); (3) those with a 4,7:6,12-bisepoxy (852-862); (4) those with a 6,12-epoxy and a second epoxy system between C-7 and either C-9, C-10 or C-11 (863)(864)(865)(866)(867)(868)(869); (5) those with a 7,13-epoxy and a second epoxy system between C-6 and either C-9 or C-10 (870-886); and (6) those with a 4,10:9,13-bisepoxy (887-889) functionality. These can be roughly divided into six subgroups, namely: (1) those with a 6,12epoxy, also known as laurenan-type acetogenins ; (2) those with a 7,13epoxy, also known as lauthisan-type acetogenins (835)(836)(837)(838)(839)(840)(841)(842)(843)(844)(845)(846)(847)(848)(849)(850)(851); (3) those with a 4,7:6,12-bisepoxy (852-862); (4) those with a 6,12-epoxy and a second epoxy system be...…”

“…The sphingosine derivative 1037 was obtained from a Hawaiian Laurencia nidifica specimen [836], while the fatty acid amide 1039, designated as papillamide, was isolated from a Japanese Laurencia papillosa [842]. Hybridalactone (1038), an unusual C 20 fatty acid-derived metabolite containing a cyclopropane and a macrolactone ring, was isolated from Laurencia hybrida and its structure, including the absolute stereochemistry, was established on the basis of analysis of its spectroscopic data, X-ray diffraction analysis, molecular mechanics calculations, chemical derivatizations, and total synthesis [837][838][839][840][841]. A number of fatty acid derivatives (1040 and 1042-1047) have been isolated from species of Laurencia [822,843,844].…”

Nonhalogenated organic molecules from Laurencia algae

“…Among these, an unusual a,b-unsaturated aldehyde 156 was identified from Japanese L. undulata and L. papillosa (Suzuki et al 1987a;Basavaiah and Hyma 1996), and three fatty acid derivatives 157-159 were characterized from British L. hybrida (Higgs 1981;Bernart and Gerwick 1988;Higgs and Mulheirn 1981;Hickmann et al 2011;Ota et al 2012). Compound 157 was named 11-formyl-undeca-(5Z,8E,10E)-trienoic acid, but its structure was drawn as (8Z) (Higgs 1981).…”

“…Compound 159, possibly derived from 158 in biogenesis, represented the first marine-derived oxylipin containing a cyclopropane and a macrolactone ring, and its structure and relative/absolute configuration were extensively elucidated by spectroscopic methods including X-ray diffraction, molecular mechanics calculations, chemical derivation, and total synthesis (Higgs and Mulheirn 1981;Hickmann et al 2011;Ota et al 2012). Three nitrogen-containing constituents were identified from Hawaiian L. nidifica (160) (Cardellina and Moore 1978), Japanese L. papillosa (161) (Maru et al 2010), and Chinese L. cartilaginea (162) (Xu et al 2005).…”