Ustiloxins synthesis

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. 

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. 

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...

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... 

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... 

Just as Nathan started his PhD project in Melbourne, Wandless published the second total synthesis of ustiloxin D. The Wandless synthesis employed an AAA approach to the tertiary alkyl-aryl ether 25, but using a simpler substrate (24) than the functionalized isoleucine derivative we had been constructing (8, 9, or 14). Wandless subsequently converted the olefin in the AAA adduct 25 to the p-hydroxyisoleucine residue (i.e., 25—>27, Scheme 4). Though the AAA reaction proceeded with low diastereoselectivity (2 1), and the subsequent conversion of the olefin 25 to the a-amino acid 27 required multiple steps, the hallmark of the Wandless synthesis was the use of an Evans-Suga Al-catalyzed aldol-type reaction to generate the p-hydroxydopa residue... 

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). 

SCHEME 14 Completion of the total synthesis of ustiloxin D via ammonia-Ugi reaction. 

With the successful synthesis of ustiloxin D in hand, it would seem sensible to extend our method to the preparation of the most complex and most active member of the family, ustiloxin A. In fact, my first forays into the ustiloxins involved studies of the preparation of the sulfinylnorvaline moiety. During my ARC postdoctoral fellowship (my first stint at Melbourne) I had been awarded funding to study the biosynthesis of lysobactin, ° another highly functionalized cyclic peptide natural product. Unfortunately, I was not able to reproduce the biosynthetic production of lysobactm through incubation of the lysobacter species, which makes it difficult to undertake a biosynthetic analysis So I needed another project that would deliver results. 

However, these findings were before the development of our current method to perform AAA reaction and complete the macrocycle. Hence, after Aaron had completed the synthesis of ustiloxin D, it seemed the most obvious route to ustiloxin A was to introduce iodine functionality on the dopa moiety at a late stage in the ustiloxin D synthesis, then incorporate the sulfinylnorvaline moiety. However, iodination of protected ustiloxin D 58 or the acyclic precursor 57 resulted in degradation through a retro-aldol reaction and destruction of the p-hydroxydopa residue and/or other pathways. 

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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