Evolution of the Total Syntheses of Ustiloxin Natural Products and Their Analogues

Abstract

Ustiloxins A-F are antimitotic heterodetic cyclopeptides containing a 13-membered cyclic core structure with a synthetically challenging chiral tertiary alkyl-aryl ether linkage. The first total synthesis of ustiloxin D was achieved in 31 linear steps using an S N Ar reaction. An nOe study of this synthetic product showed that ustiloxin D existed as a single atropisomer. Subsequently, highly concise and convergent syntheses of ustiloxins D and F were developed by utilizing a newly discovered ethynyl aziridine ring-opening reaction in a longest linear sequence of 15 steps. The approach was further optimized to achieve a better macrolactamization strategy. Ustiloxins D, F and eight analogues (14-MeO-ustiloxin D, four analogues with different amino acid residues at the C-6 position, and three (9R, 10S)-epi-ustiloxin analogues) were prepared via the second generation route. Evaluation of these compounds as inhibitors of tubulin polymerization demonstrated that variation at the C-6 position is tolerated to a certain extent. In contrast, the S configuration of the C-9 methylamino group and a free phenolic hydroxyl group are essential for inhibition of tubulin polymerization. Antimitotic agentsAntimitotic agents have long been of interest to scientists and physicians, even before their precise mechanism of action could be articulated. Most of these compounds interfere with microtubule assembly and functions thus resulting in mitotic arrest of eukaryotic cells. There are a number of natural and synthetic compounds that interfere with tubulin function to inhibit the formation of microtubules. 1 Such antimitotic agents exhibit a broad range of biological activities and can be used for medicinal and agrochemical purposes, acting as anticancer, antifungal, or anthelmintic agents. Moreover, tubulin binding compounds are valuable for understanding basic mechanisms involved in the dynamics of the microtubule network. 2 Mitotic arrest is of importance in cancer chemotherapy, since tubulin is an established chemotherapeutic target. In addition to the widely used vinca alkaloids and taxoids, many other antimitotic agents are currently in clinical or preclinical development. 3 Newer potential targets NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript that may cause mitotic arrest are in development as well. Although cancer chemotherapy is a very important goal being extensively investigated, the mechanism of action of the naturally occurring peptides that inhibit tubulin polymerization remains a challenging problem. Attempts to establish a relationship among the tubulin binding peptides have only had limited success. [4][5][6][7][8] As a result, the mechanism of action of peptidic antimitotic agents is not completely elucidated and deserves further investigation. UstiloxinsThe first peptide shown to interact with tubulin was phomopsin A (Error! Reference source not found.). [9][10][11][12][13] Since then, a number of peptides and depsipeptides were found to disrupt cellular microtubules. These compo...

A twist of nature – the significance of atropisomers in biological systems

“…Structurally, it is a simple cyclodepsipeptide comprised of four amino acid residues (namely glycine, valine, and derivatives of isoleucine and tyrosine), however the atropisomeric nature of the alkyl-aryl ether bond posed a number of synthetic challenges, including how best to selectively induce axial chirality without impacting pre-existing point-chiral elements, while maintaining functional group tolerance. 101 The atropisomerism of this molecule was assigned using 1 H-1 H NOESY, and found to only be naturally present in the syn form. The first successful approach in the generation of ustiloxin D was a linear total synthesis consisting of 31 steps, with an 82% yield on average for each step.…”

“…98 Similar in structure to the previously identified phomopsin family, these molecules were found to have inhibitory activity on brain tubulin, 99, 100 though had much lower cytotoxic potential than many other antimitotic agents. 101 The recent total synthesis of the ustiloxins has allowed for SAR studies to be conducted on a variety of analogues, which has served the dual purpose of revealing key interactions of the relatively ambiguous mode of inhibition, and allowing the production of more effective antimitotic drugs. 101,102 Ustiloxin D (Figure 13, Compound 50) was used as an initial synthetic target, given its simple structure and that it demonstrated the highest biological activity of all members of the ustiloxin family.…”

“…101 The recent total synthesis of the ustiloxins has allowed for SAR studies to be conducted on a variety of analogues, which has served the dual purpose of revealing key interactions of the relatively ambiguous mode of inhibition, and allowing the production of more effective antimitotic drugs. 101,102 Ustiloxin D (Figure 13, Compound 50) was used as an initial synthetic target, given its simple structure and that it demonstrated the highest biological activity of all members of the ustiloxin family. Structurally, it is a simple cyclodepsipeptide comprised of four amino acid residues (namely glycine, valine, and derivatives of isoleucine and tyrosine), however the atropisomeric nature of the alkyl-aryl ether bond posed a number of synthetic challenges, including how best to selectively induce axial chirality without impacting pre-existing point-chiral elements, while maintaining functional group tolerance.…”

Synthesis of Ranolazine Metabolites and Their Anti-myocardial Ischemia Activities

“…Selective oxidation of the terminal hydroxyl group of A3 with sodium hypochlorite and TEMPO afforded CVT-4784. 26) As shown in Chart 3, the preparation of metabolite CVT-2514 started from pyrocatechol. One hydroxyl group was selectively protected with benzyl to afford compound A4.…”

Synthesis of Aib-containing cyclopeptides via the ‘azirine/oxazolone method’

“…Filtration and evaporation of the solvent gave a colorless oil, which was dissolved in CH 2 Cl 2 and washed with 1 M NaOH and 2 M HCl (2 ×). The organic phase was dried over Na 2 SO 4 and filtered, the solvent evaporated, and the residue crystallized by addition of 1710m, 1660s (br), 1550s, 1540s, 1530s, 1455m, 1385m, 1265m (br), 1235m (br) (24). To a solution of 23 (500 mg, 0.65 mmol) in MeOH (2 ml) and DMF (1 ml) under argon was added 50 mg Pd/C (10%).…”