A Unified Synthetic Strategy for Dendrodolides E, F, G, I, J, and L

Abstract

Au nified synthetic strategy has been developed for the total synthesis of the dendrodolide family,e mploying Jørgensen asymmetric epoxidation, Keck allylation, Brown allylation, Yamaguchi esterification,a nd ring-closing metathesis as key reactions. IntroductionIn recent years, many naturally occurring macrolides with different ring sizes have been isolated from fungal metabolites. These compounds play important roles in biochemical fields due to their variousb iological properties.[1] Many of them and their synthetic derivatives have been provent ob eb eneficial to human cells. Some 10 and 12-membered lactones and their derivatives, such as stagonolides, [2] recefeiolide, [3] cladospolides, [4] patulolides, [5] sporiolides, [6] and balticolid, [7] have anticancer,a ntibacterial, antiviral, antifungal, and cytotoxic activities.Recently,t he class of 12-membered macrolides named dendrodolides (Figure1)w ere isolated from Dendrodochium Sp.,afungus associated with the sea cucumber Holothurian nobilis Selenka, which wasc ollected from the South China Sea by Zhang and coworkers.[8] Thes tructures of these dendrodolides were elucidated by means of spectroscopic analysis and single crystal X-ray diffraction. The absolute configurations were assigned using the modified Mosher method, excitation-coupled circulard ichroism (ECCD), electronic solution and solid-state circular dichroism (ECD), supported by time dependent density functional theory (TDDFT) ECD calculations, andX -ray analysis. The dendrodolides have different levels of growth-inhibiting activity against SMMC-7721 and HCT116 cells in in vitro bioassays.Intramolecular ring-closing metathesis [9] is au seful tool for construction of macrolactones through CÀCb ondf ormation. It gives interesting results about the geometry of the newly formed doubleb ond and has been studied earlier.T he geometry of the double bond depends on the ring size and protecting groups present in substrates. As part of our ongoing research in exploring ring-closing metathesis reaction for macrolides synthesis, [10] herein we report the total synthesis of dendrodolides E, F, G, I, J, and L. Results and DiscussionAccording to our retrosynthetic analysis of dendrodolides as shown in Scheme 1, the macrolactones could be synthesized by ring-closing metathesis of the corresponding di and triolefinic esters 14-18.T hese di and triolefinic esters 14-18 could be prepared from the coupling of corresponding alcohols 19-23 with ak nown acid 24 [10a] under Yamaguchi esterification conditions. These two fragments could be derived from commerciallya vailable achiral starting materials trans-crotanaldehyde (25)a nd 1,3-propaned iol (26,Scheme 1). The synthesis of alcohol fragments 19 and 20 began with the enantioselective epoxidation of trans-crotanaldehyde (25) [11] with 2-[bis(3,5-bis(trifluoromethyl)phenyl)(trimethylsilyloxy)methyl]pyrrolidine as the chiral catalysttoa ffordt he chiral epoxide, which was followed by two-carbon Wittig olefination to form a,b-unsaturated epoxy ester 27 in ...

Marine natural products

“…has been accomplished from a commercially available substrate by a convergent strategy 338 and other dendrolides (F, G, I, J and L 337 ) have also been synthesised via a unied strategy employing ring-closing metathesis. 339 A unied strategy was also employed in the total synthesis of luteoalbusins A and B, 340 indole diketopiperazines isolated from sediment-derived Acrostalagmus luteoalbus. 341 In addition to the new compound talaromycin C, 296 purpactins A, 342 C 342 and penicillide 343 exhibited potent antifouling activity against settlement of Balanus amphitrite larvae 296 as did altertoxin I, a metabolite of both terrestrial 344 and marine 345 Alternaria alternata.…”

Marine-Derived Macrolides 1990–2020: An Overview of Chemical and Biological Diversity

“…derived from sea cucumber Holothuria nobilis Selenka in the South China Sea [ 143 ]. Dendrodolide K was obtained from a commercially available substrate by a convergent strategy, and the dendrolides F, G, I, J, and L were synthesized via a unified strategy employing ring-closing metathesis [ 144 , 145 ].…”

Total Synthesis of Kanamienamide

“…With the key fragments 2 , 5 , and 6 in hand, we began the assembly by first coupling acid 5 and amine 6 under the HATU condition, yielding diene 4 in an 80% yield. The ring-closing metathesis reaction , of diene 4 using the Grubbs’ second generation catalyst (20 mol %) in refluxing dichloromethane furnished the 11-membered macrolactone smoothly ( E / Z > 95:5 by 1 H NMR). The crude product was subjected to hydrogenation with the Pd–C catalyst in ethyl acetate, furnishing the saturated macrolactone 23 in a 67% yield over two steps.…”