Joullie synthesis ustiloxin

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. 

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). 

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... 

In the meantime, Joullie published the first total synthesis of ustiloxin Joullie s synthesis employed an S Ar approach to the crucial tertiary alkyl-aryl ether linkage I probably should have stood up for myself in my... 

Subsequent to Wandless s AAA approach to ustiloxin D being published, Joullie reported a second-generation synthesis. JouUie s second-generation route employed Wandless s method to prepare the p-hydroxydopa residue 30, which as explained earher, is close to perfect. To generate the crucial aUcyl-aryl ether, JouUie developed a novel Cu-promoted coupling of the dopa-derived phenol 31 with a o-serine derived aziridine 32. This reaction proceeds with excellent stereocontrol to generate just one diastereomer of the alkyl-aryl ether adduct 33 (Scheme 6). 

Sharpless has noted that the regiochemical outcome with cinnamyl esters is coupled to the ligand system employed [237]. Thus, when AQN ligands (314), were used, benzylic alcohols were preferentially obtained, rather than the benzylic amines observed with PHAL ligands (311). This selectivity trend was utilized by Joullie in the synthesis of the potent microtubule assembly inhibitor ustiloxin D (356, Scheme 9.45) [238]. Under optimized conditions, cinnamyl ester 354 was converted selectively into the desired benzylic alcohol 355 (58% yield). This constitutes one of the structurally more complex substrates to have successfully been employed in catalytic asymmetric aminohydroxylation [238, 239]. 

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