Total Synthesis of Gukulenin B via Sequential Tropolone Functionalizations

Abstract

The synthesis of functionalized aromatic compounds is a central theme of research for modern organic chemistry. Despite the increasing finesse in the functionalization of fiveand six-membered aromatic rings, their seven-membered-ring sibling, tropolone (2-hydroxy-2,4,6-cycloheptatrien-1-one), remains a challenging target for synthetic derivatization. This challenge primarily emanates from the unique structural and chemical properties of tropolonoid compounds, which often lead to unexpected and undesired reaction outcomes under conditions developed for the functionalizations of other aromatic moieties. Herein, we describe the total synthesis of one of the most complex natural tropolonoids, gukulenin B. Our synthetic route features a series of siteselective aromatic C−H bond functionalizations and C−C bond formations, whose reaction conditions are judiciously tuned to allow uncompromised performance on the tropolone nucleus. The flexibility and modularity of our synthesis are expected to facilitate further synthetic and biological studies of the gukulenin family of cytotoxins. In addition, the methods and tactics developed herein for the functionalization of the tropolone moiety could inspire and enable chemists of multiple disciplines to take advantage of this privileged yet underexplored structural motif.

Metal-catalysed C–H bond activation and borylation

“…Nicolaou and co-workers reported 252 a total synthesis of gukulenin B via sequential tropolone functionalization. In this total synthesis, the authors developed δ-C–H borylation of a tropolone derivative, followed by oxidation and triflate protection, to prepare the right-handed fragment with a 60% yield (Scheme 137).…”

Troponoid Compounds as Therapeutic Agents and as Targets and Templates for Chemical Synthesis

“…In a related vein, very recently, and during the opening stages of a total synthesis of the complex and highly biologically active bis-troponoid natural product gukulenin B ( 64 ) (Figure 9 ), Nicolaou and co-workers demonstrated 65 that an isomer of compound 61 could be engaged, at gram scale, in a Negishi-type cross-coupling reaction with a cyclopentenyl-based organozinc species. Two-metal catalyzed, cross-electrophile couplings of bromotroponoids have also been reported recently.…”

The Palladium-Catalyzed Glycosylation of Halotropones

“…Both synthetically derived and naturally occurring troponoid compounds display a diverse range of biological properties and are re-emerging as systems of interest in the development of, inter alia, new-generation anti-infective agents . A notable and distinct subset of such compounds are those in which this nonbenzenoid aromatic system is linked to or annulated with a monosaccharide residue.…”

“…To that end, and on the basis that halotropones could undergo base-promoted ipso-substitution reactions with oxygen-centered nucleophiles, we began by investigating the transformation shown in Scheme . In pursuing such possibilities, we were also mindful of the capacity (indeed propensity) of halogenated troponoids to undergo ring-contraction reactions at elevated temperatures in the presence of, inter alia, a hydroxide ion. , Accordingly, each of the commercially available tetra- O -acetyl and tetra- O -benzyl derivatives of glucose, namely, 10 (P = Ac and P = Bn, respectively), was treated, in the presence of various bases, with 2-bromotropone ( 11 ) in the hope that the α- and β-anomeric forms, namely, 12 and 13 , respectively, of the anticipated tropolone glucosides could be formed.…”