Studies toward the total synthesis of quartromicin D3.

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 endo and two exo 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 endo spirotetronate subunits, the synthesis of the exo spirotetronate subunits has remained much more challenging. In order to address this problem, a new conformationally constrained chiral dienophile II-28 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 II-28f and acyclic (Z)-1,3-diene I-14 provided cycloadduct in 70% yield with 5:1 diastereoselectivity favoring the desired exo-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 II-49, which was further oxidized to exo-alpha-hydroxy aldehyde I-39. Thus, the new conformationally constrained dienophile II-28f afforded a preparatively useful pathway for the development of a direct and step-wise efficient synthesis of the targeted exo-spirotetronate subunits of the quartromicins. The enantiomerically pure endo and exo spirotretronate subunits were then elaborated in order to explore possible sequence for synthesis of the macrocyclic ring system of the quartromicins. Exo-bromo-spirotetronate subunit III-12/III-25 was successfully coupled with endo-bromo-spirotetronate subunit III-24/III-21 under cerium-mediated conditions to produce the bromotetronate-substituted horizontal fragment III-22 (Scheme III. 7, p. 83) and bromotetronate-substitute vertical bis-spirotetronate subunit III-43 (Scheme III. 9, p. 85). Unfortunately, dimerization of the advanced intermediate III-22 failed to produce the desired macrocyclic core of the quartromicins. Dimerization of an analogous vertical fragment IIII-43 via an aldol reaction is proposed as an alternative strategy to complete the total synthesis of the quartromicins.Ph.D.Biological SciencesOrganic chemistryPure SciencesVirologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/126267/2/3238063.pd