P-hydroxydopa residue

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... 

This elegant route generated the p-hydroxydopa residue 23 in 98% yield and 99% ee, which is rather close to perfect ... 

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). 

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. 

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