Total Synthesis of (±)-Filiforminol and (±)-Bromoether A

Abstract

±)-Filiforminol and (±)-bromoether A, marine halogenated sesquiterpenes, were synthesized in a concise manner from 3-methylcyclopent-2-en-l-one using copper-catalyzed conjugate addition and subsequent methylation, epoxidation, and spontaneous cyclization as key synthetic steps.A number of halogenated sesquiterpenes with the cuparane or the rearranged cuparane skeleton have been isolated from the red alga Laurencia and also from the sea hare Aplysia species. 1 Among them, filiforminol (1) was iso]ated from the red alga L. filiformis 2 and bromoether A (2) was isolated from L. grandulifera 3 and L. nana. 4 These sesquiterpenes represent a new structural type, and some of them also show important biological activity, such as antifungal and antibiotic properties.The relative stereochemistry was determined on the basis of the 1 H NMR chemical shifts and NOE data. The chemical shift of the 2-methyl doublet (d = 0.68) of the trans isomer was shielded relative to that of the methyl doublet (d = 1.03) of the cis isomer. 9 Strong NOE to the 2-H was observed after irradiation of the 3-methyl group in the trans isomer while no NOE was observed in the cis isomer. O OH Br H O Br Br H 2 1The structural uniqueness and the interesting bioactivities prompted us to investigate the total synthesis of these natural products 5 and in this report we describe a stereocontrolled synthesis of (±)-filiforminol and (±)-bromoether A.The structural features include a trichothecane-like skeleton 6 with two vicinal methyl groups in trans orientation. Our approach to filiforminol involves opening of epoxide compound 3, which is derived from debromoallolaurinterol (4) resulting from demethylation of compound 5. Compound 5 can be prepared from readily available 3-methylcyclopent-2-en-1-one (7) using copper-catalyzed conjugate addition of Grignard reagent and subsequent methylation, followed by methylenation. The retrosynthetic scheme based on this strategy is shown in Scheme 1.Our synthesis started with 3-methylcyclopent-2-en-1-one (7) (Scheme 2). A conjugate addition of the Grignard reagent 8 derived from 2-bromo-5-methylanisole 7 in the presence of cuprous ions in THF at 0°C produced the enolate. Subsequent addition of excess iodomethane in HMPA at 0°C and warming to room temperature gave the desired trans-3-(2-methoxy-4-methylphenyl)-2,3-dimethylcyclopentanone (6) and cis isomer 9 in a ratio of 2.8:1 along with nonmethylated compound 10. 8 OH OH OMe O OMe M OMe O O OH Br H O 3 + 4 5 6 7

Stereocontrolled Synthesis of Adjacent Acyclic Quaternary‐Tertiary Motifs: Application to a Concise Total Synthesis of (−)‐Filiformin

“…Deprotection of the methyl ether using NaSEt13 gave 3‐hydroxylaurene ( 11 ) and subsequent addition of catalytic amounts of TFA14 led to clean cyclization to give debromofiliformin as a single diastereoisomer in 60 % yield over two steps. Finally, bromination completed the synthesis of (−)‐filiformin in a total of just nine steps, 98:2 d.r., and >99:1 e.r.…”

Marine natural products

“…143 Filiforminol 170 from L. filiformis 144 and the corresponding bromoether 171 from L. glandulifera 145 and L. nana 146 have been synthesized as racemates. 147 Chondriamide C 172 is an additional indole alkaloid that was isolated together with 3-indoleacrylamide 173 from Chondria atropurpurea: both displayed anthelmintic activity. 148 The structure of martefragin A 174, which is an inhibitor of lipid peroxidation that was isolated from Martensia fragilis, 149 was determined by X-ray crystallographic analysis and confirmed by synthesis.…”

Laurencia Filiformis: Phytochemical Profiling by Conventional and HPLC-NMR Approaches

“…(Karachi, Pakistan) [34]. The total synthesis of 2 was achieved in 1998 [35]. Allolaurinterol (3) was isolated as a yellow oil as the major constituent of L. filiformis forma heteroclada.…”