Ustiloxins

An application of copper-catalyzed propargylic etherification has been reported in the synthesis of ustiloxin D (Equation (63)).248 Here, a quaternary center was generated from the unprecedented reaction of a phenol with an ethynyl aziridine. 

Koiso, Y., Natori, M., Iwasaki, S., Sato, S., Sanoda, R., Fujita, Y., Yaegashi, H., and Sato, Z. (1994). Ustiloxin A phytotoxin and a mycotoxin from false smut balls on rice panicles. Tetrahedron Lett. 33,4157-M160. 

In the final stages of the total synthesis of ustiloxin D, M.M. Joullie and co-workers had to install the amide side-chain onto the already assembled macrocycle.To achieve this goal, the macrocyclic primary alcohol was treated with the Dess-Martin periodinane to generate the corresponding aldehyde, which was subsequently treated with sodium chlorite to afford the carboxylic acid. The carboxylic acid was then coupled with the benzyl ester of glycine to complete the installation of the side-chain in 66% yield for three steps. 

The Sharpless regioreversed asymmetric aminohydroxylation protocol was used as a key step in the total synthesis of ustiloxin D by M.M. Joullie and co-workers.The ( )-ethyl cinnamate derivative was subjected to in situ generated sodium salt of the N-Cbz chloroamine in the presence of catalytic amounts of the anthraquinone-based chiral ligand to afford the desired A/-Cbz protected (2S,3R)-(3-hydroxy amino ester in good yield and with good diastereoselectivity. 

An interesting copper catalyzed phenol opening of aziridine 163 yielded an intermediate, 164, for the synthesis of ustiloxin D <05OL5325>. This reaction is quite unique in that the phenol is reacting at a highly congested carbon and that none of the S 2 addition is observed. 

The Uemura system found appHcation in an approach by Hutton towards members of the ustiloxin family of cycHc peptides. While the oxidation employing DET as ligand showed only Httle selectivity, the desired sulfoxide was obtained with a diastereomeric ratio of greater than 50 1 by changing to the (R)-BINOL ligand [23]. 

Li, R, Evans, C.D. and Joullie, M.M. (2005) A convergent total synthesis of ustiloxin D via an unprecedented copper-catalysed ethynyl aziridine ring-opening by phenol derivatives. Organic Letters, 7, 5325-5327. 

The ustiloxins, isolated from the fungus Ustilaginoidea virens associated with rice plants, show antimitotic properties by inhibiting microtubule formation (7S0, 781). Structurally, they are characterized by the presence of two peptide bonds and one tmusual tertiary alkyl-aryl ether connection. The first total synthesis of ustiloxin D (1205) was achieved in 2002 (782) by Joullie et al., followed by a shorter synthesis by Wandless et al. (783, 784). Later on, its synthesis was conducted again (785) along with ustiloxin F (1206) (786) in a more convergent manner than previously by Joullie et al. (Scheme 15.2). 

Scheme 15.2 Convergent total synthesis of ustiloxin D (1205) and F (1206). Reagents and conditions a) CuOAc (1 mol%), DBU, toluene, 0°C, 90% b) PhSH, CS2CO3, DMF, rt, 78% c) 1202, EDC HC1, HOBt, NaHCOj, DMF, 0°C to rt d) Hj, Pd black, EtOH, rt e) EDC-HCl, HOBt, NaHCOs, DMF, rt f) TFA, EtsSiH, CH2CI2, rt, 8.7% over four steps for 1205 8.8% over four steps for 1206...

Luduena RF, Roach MC, Prasad V, Baneijee M, Koiso Y, Li Y, Iwasaki S (1994) Interaction of Ustiloxin A with Bovine Brain Tubulin. Biochem Pharmacol 47 1593... 

Li Y, Koiso Y, Kohayashi H, Hashimoto Y, Iwasaki S (1995) Ustiloxins, new Antimitotic Cyclic Peptides Interaction with Porcine Brain Tubulin. Biochem Pharmacol 49 1367... 

Tanaka H, Sawayama AM, Wandless TJ (2003) Enantioselective Total Synthesis of Ustiloxin D. J Am Chem Soc 125 6864... 

Sawayama AM, Tanaka H, Wandless TJ (2004) Total Synthesis of Ustiloxin D and Considerations on the Origin of Selectivity of the Asymmetric Allylic Alkylation. J Org Chem 69 8810... 

Li P, Evans CD, Joullie MM (2005) A Convergent Total Synthesis of Ustiloxin D via an Unprecedented Copper-Catalyzed Ethynyl Aziridine Ring-Opening by Phenol Derivatives. Org Lett 7 5325... 

Li P, Evans CD, Forbeck EM, Park H, Bai R, Hamel E, Joullie MM (2006) Total Synthesis and Biological Evaluation of Ustiloxin Natural Products and Two Analogs. Biowg Med... 

Isol. from the false smut balls caused by Ustilaginoidea virens on rice. Powder. Struct, not detd. due to lack of material. Poss. metab. of Ustiloxin A, U-10015. 

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