Rubromycins: Structurally Intriguing, Biologically Valuable, Synthetically Challenging Antitumour Antibiotics

Abstract

Although known for more than 50 years the rubromycin family still constitutes a fascinating class of antitumour antibiotics. They are characterized by a challenging molecular architecture with the central spiroketal unit as the key feature and possess highly attractive biological properties. After a short treatment of the history of their isolation, structural elucidation and biosynthesis, their biological activities will briefly be summarized. This review strongly emphasizes the synthetic efforts aimed at these complex hexacyclic spiroketals. Reactions leading to simple spiroketal model compounds are described, followed by the synthetic approaches to the fully functionalized naphthalene and isocoumarin “wings”. The coupling of these units and their transformations into more advanced spiroketals demonstrate “the state of the art” in this research field. Only Danishefsky and co‐workers have so far completed the total synthesis of a fully functionalized rubromycin derivative; however, their product heliquinomycinone (103) is still only the aglycon of the natural product heliquinomycin (7), and it was prepared as the racemic compound. All these achievements and pitfalls reveal that increased engagement of synthetic organic chemists is required to develop new methods to make rubromycins and their analogues available by a modular approach and with reasonable efficacy. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

New strategies for natural products containing chroman spiroketals

“…This involves the creation of both the ethereal spiroketal bonds through sequential additions of the alcohols under reversible conditions to furnish the thermodynamic diastereomer. While this method has been successfully applied to the synthesis of numerous aliphatic spiroketals, it has been shown that many phenols lack the nucleophilicity needed to undergo this transformation [3]. In light of this diminished reactivity, we chose to take an orthogonal approach predicated upon successful cycloaddition reactions employing exocyclic enol ethers.…”

Total Synthesis of (±)‐γ‐Rubromycin on the Basis of Two Aromatic Pummerer‐Type Reactions

“…Typical examples include heliquinomycin (4), [4] an inhibitor of DNA helicase, [5] and purpuromycin (5), [6] a potential topical agent for vaginal infections (Scheme 1). [7] Much effort has been devoted to the synthesis of these compounds, [8][9][10][11][12][13][14][15][16] and special attention has been focused on the preparation of the vital bisbenzannelated spiroketal core structure I. [8][9][10][11][12][13] The reported methods are based on the acidcatalyzed spiroketalization of ketones [10][11][12] or a hemiketal, [9b] the haloetherification of a benzofuran, [9a] or the oxidative [3+2] cycloaddition of an enol ether with a b-diketone.…”

“…[7] Much effort has been devoted to the synthesis of these compounds, [8][9][10][11][12][13][14][15][16] and special attention has been focused on the preparation of the vital bisbenzannelated spiroketal core structure I. [8][9][10][11][12][13] The reported methods are based on the acidcatalyzed spiroketalization of ketones [10][11][12] or a hemiketal, [9b] the haloetherification of a benzofuran, [9a] or the oxidative [3+2] cycloaddition of an enol ether with a b-diketone. [13] However, multiple steps were required to build up the ketals I from smaller fragments, and the applicability of these methods to a wide range of analogues has not been demonstrated.…”

Synthesis of 5,6- and 6,6-Spirocyclic Compounds

“…The synthesis of members of rubromycin family of bis(benzannulated) spiroacetals under acid-catalyzed conditions have been hampered by the complex Scheme 16 Kozlowski et al's dehydrative spirocyclization studies toward purpuromycin [62] stereoelectronic properties of naphthalene and/or isocoumarin precursors [58][59][60]. In their formal synthesis of γ-rubromycin 58, Brimble et al [61] successfully balanced these factors to access the bis(benzannulated) core via dehydrative spirocyclization of a dihydroxyketone 59 (Scheme 15).…”