Org. Lett.: Total Synthesis of salvinorin a

Salvinorin a (1) is a new natural product of crocidoditerpenoids extracted from the leaves of salviadivinorum 1 is the most effective hallucinogen known in nature At the same time, it is also an effective and highly selective activator of κ - opioid receptor (KOR), and is expected to become a leading compound in the treatment of central nervous system diseases Recently, the Peter Metz research group of Dresden University of technology in Germany realized the simple and efficient synthesis of salvinorin a, and relevant articles were published on org Lett (DOI: 10.1021 / ACS Orglett 8b01357) The author is committed to designing a novel synthetic route of salvinorin a (1), and envisages to synthesize some salvinorin a analogues which can not be obtained from natural products and have new functions through this route Reverse synthesis analysis is shown in scheme 1: as a key precursor of natural product 1, olefin 2 can be converted into 1 by selective oxidation; the cyclohexene part of precursor 2 can be constructed by intramolecular Diels alder reaction (IMDA) of triene 3; then, triene 3 may be obtained by chemical selective carbonylation of ketaldehyde 4 and α - position difference isomerization of lactone carbonyl; Intermediate 4 It can be obtained by the cracking of alkenes in known bicyclolactone 5, which can be obtained by D-A reaction of another key molecule (source: org Lett.) in the specific synthesis process, the author first optimized the route from 3-furfural (6) to intermediate 5 (scheme 2) Among them, diene 10 can be obtained in high yield by Liebeskind coupling of vinyl iodine 7 and stantane 8 In addition, the total yield of cycloaddition product 5 can be increased by prolonging the intramolecular Da reaction time of acrylate 11 to 3 days (source: org Lett.) to get unsaturated lactone 5, the author dihydroxylated it to get diastereomeric diols 12 and 13 Then 12 and 13 were cleaved by diol under the action of PIDA and converted to aldehydes and ketones 4 in 88% yield 4 E-vinyl iodide 14 was synthesized by chemical selective Takai olefinization, and then the mixture 16 and 17 were obtained by Horner Wadsworth Emmons olefinization with sodium salt 15 Under the function of DBU, 16 can be completely converted to 17 (scheme 3) (source: org Lett.) next, compound 17 was coupled with vinyl stantane 18 by stile to obtain triene 3 in 93% yield As expected, the trans relationship between diene and amphiphilic in 3 is necessary for the high enantioselectivity of the IMDA reaction After selecting the solvent, temperature and BHT amount, the author found that the target enantiomer 2 could be obtained with 66% separation yield (94% DS) after heating trien3 and 1.2 equivalent BHT in chlorobenzene (sealed tube) at 200 ℃ for 3.5 days Cycloaddition product 2 may be formed by endo chair transition state, diastereomer 22 by exo chair transition state, and secondary product 20 may be formed by C8 difference of 2 to isomerization (scheme 5) (source: org Lett.) prepared the key precursor 2, and the whole synthesis process of salvinorin a (1) entered the final stage Oso 4 obtained diol 23 from the side attacking cyclohexene 2 with less steric hindrance Diol 23 was converted to regional isomer 24 by silylation under the action of tescl, and then oxidized by ley Griffith and separated by column, a single enantiomer 25 was obtained, with a two-step yield of 72% Ketone 25 was dealkylated with acetic acid and TBAF buffer to obtain 2-epi-salviorin B (26) Finally, the author reported that salvinorin a (1) was obtained by Mitsunobu reaction, which was reported by Hagiwara group The yield of this step was 81% (source: org Lett.) Summary: Peter Metz group took the highly enantioselective intramolecular Diels alder reaction as a key step to realize the total synthesis of salvinorin a (1) The synthetic route consists of 18 steps and is one of the shortest routes to construct diterpenoid 1.