Total Synthesis of Neuritogenic Alkynes: Lembehyne B and Key Intermediate of Lembehyne A

Abstract

A new Ti‐catalyzed cross‐cyclomagnesiation of aliphatic and oxygenated 1,2‐dienes with EtMgBr in the presence of Cp2TiCl2 was used in the key stage for the development for the first time original methods for the preparation of racemic and natural neuritogenic alkynes lembehyne B and stereoselective syntheses of (4Z,8Z)‐pentacosa‐4,8‐dien‐1‐ol ‐ the key intermediate in the total synthesis of lembehyne A.

Total Synthesis of Natural Lembehyne C and Investigation of Its Cytotoxic Properties

“…No efficient methods for the formation of the 1 Z ,5 Z ,9 Z -triene moiety in lembehyne C were reported, except for the interesting but laborious approach to unbranched 1,5,9, n -polyenes developed by A. Stark for the total synthesis of an acetogenin, chatenaytrienin-4 . To solve this problem, we resorted to the new Ti-catalyzed cross-cyclomagnesiation of functionally substituted and aliphatic 1,2-diynes, previously developed and which had been used for the total syntheses of lembehynes A and B, 5 Z ,9 Z -dienoic acids, acetogenins, macrodiolides, and some insect pest pheromones. − …”

“…The n-hexane extract was combined with the oily liquid, washed with water (20 mL), and dried over anhydrous Na 2 SO 4 . Evaporation of the solvent, followed by column chromatography of the residue on silica gel, using n-hexane/Et 2 O (95:5) as eluent, gave 8 (9.8 g, 85%) as a yellow liquid oil: 1 H NMR (400 MHz, CDCl 3 ) δ 5.59−5.52 (m, 1H), 5.41−5.35 (m, 1H), 3.38 (t, J = 7.2 Hz, 2H), 2.64 (q, J = 7.1 Hz, 2H), 2.06 (q, J = 7.2 Hz, 2H), 1.38−1.28 (m, 28H), 0.90 (t, J = 6.7 Hz, 3H); 13 Synthesis of Docos-5-en-1-yne (9). To a suspension of a lithium acetylide/ethylenediamine complex (3.1 g, 36.9 mmol) in DMSO (13.6 mL) was added 8 (8.0 g, 22.2 mmol) in DMSO (11.2 mL) at 0 °C.…”

New 1,3-Diynoic Derivatives of Natural Lembehyne B: Stereoselective Synthesis, Anticancer, and Neuritogenic Activity

“…First, racemic 8 and natural lembehyne B ( 10 ) were synthesized according to a previously developed scheme − by the successive addition of lithium trimethylsilylacetylenide to aldehyde 4 , deprotection of the resulting alkyne 7 , oxidation of alcohol 8 , and stereoselective reduction of ketone 9 at the final step. The reactions of natural lembehyne B ( 10 ) with 1-bromo-2-trimethylsilylacetylene or 1-bromo-2-(ω-hydroxyalkyl)­acetylenes in the presence of CuCl afforded the target 1,3-diyne lembehyne B derivatives 11 and 12a–d in high yields.…”

“…Column chromatography was carried out on an Acrus silica gel (0.060–0.200 mm). Aliphatic and oxygenated 1,2-dienes and lembehyne B have been synthesized according to previously developed procedures. − …”

“…Meanwhile, studies along this line were considerably held up by the exceptionally low content of lembehynes in sea sponges and the lack of efficient methods for their total synthesis. Therefore, we developed original stereoselective approaches both for the preparation of key monomers and for the total synthesis of lembehynes A and B − using the Ti-catalyzed cross-cyclomagnesiation of oxygenated and aliphatic 1,2-dienes on treatment with Grignard reagents, which we discovered. − In addition, it was shown for the first time by flow cytometry that lembehyne B can induce early apoptosis in various types of leukemia cells …”