Studies toward the total synthesis of quartromicin D3.

Abstract

The quartromicins are a group of structurally complex macrocyclic natural products that display activity against herpes simplex virus type 1 (HSV-1), influenza, and HIV. The quartromicins contain four spirotetronate subunits (two <italic>endo</italic> and two <italic>exo</italic> spirotetronates) connected in an alternating head to tail manner. While previous synthetic studies in the Roush laboratory have led to the development of an efficient pathway to the <italic>endo</italic> spirotetronate subunits, the synthesis of the <italic> exo</italic> spirotetronate subunits has remained much more challenging. In order to address this problem, a new conformationally constrained chiral dienophile <bold>II-28</bold> was designed and synthesized (Scheme II. 6, p.33). This dieneophile was designed to allow the required hydroxyl group to be installed on the a face of cyclohexene moiety during the Diels-Alder reaction. The Lewis acid-catalyzed Diels-Alder reaction between bicyclic dienophile <bold> II-28f</bold> and acyclic (<italic>Z</italic>)-1,3-diene <bold>I-14</bold> provided cycloadduct in 70% yield with 5:1 diastereoselectivity favoring the desired <italic>exo</italic>-isomer (Scheme II. 9, p. 37). The auxiliary unit of the Diels-Alder product was removed by a lithium aluminum hydride reduction to provide diol <bold>II-49</bold>, which was further oxidized to <italic> exo</italic>-alpha-hydroxy aldehyde <bold>I-39</bold>. Thus, the new conformationally constrained dienophile <bold>II-28f</bold> afforded a preparatively useful pathway for the development of a direct and step-wise efficient synthesis of the targeted <italic>exo</italic>-spirotetronate subunits of the quartromicins. The enantiomerically pure <italic>endo</italic> and <italic>exo</italic> spirotretronate subunits were then elaborated in order to explore possible sequence for synthesis of the macrocyclic ring system of the quartromicins. <italic> Exo</italic>-bromo-spirotetronate subunit <bold>III-12/III-25</bold> was successfully coupled with <italic>endo</italic>-bromo-spirotetronate subunit <bold> III-24/III-21</bold> under cerium-mediated conditions to produce the bromotetronate-substituted horizontal fragment <bold>III-22</bold> (Scheme III. 7, p. 83) and bromotetronate-substitute vertical bis-spirotetronate subunit <bold>III-43</bold> (Scheme III. 9, p. 85). Unfortunately, dimerization of the advanced intermediate <bold>III-22 </bold> failed to produce the desired macrocyclic core of the quartromicins. Dimerization of an analogous vertical fragment <bold>IIII-43</bold> via an aldol reaction is proposed as an alternative strategy to complete the total synthesis of the quartromicins.