Use of a Sonogashira−Acetylide Coupling Strategy for the Synthesis of the Aromatic Spiroketal Skeleton of γ-Rubromycin

Abstract

[reaction: see text] The synthesis of the fused aromatic spiroketal core of gamma-rubromycin is described via addition of an aryl acetylide fragment to an aryl acetaldehyde fragment. In turn, the aryl acetylene precursor was readily prepared with use of a Sonogashira reaction.

An Efficient Formal Synthesis of the Human Telomerase Inhibitor (±)‐γ‐Rubromycin

“…[6] Thus, 56 years since the isolation of 1, the rubromycins still attract considerable synthetic efforts because of their unprecedented structures and intriguing pharmacological profile. [5] Numerous syntheses of the naph-thalene [9][10][11] and isocoumarin [12] fragments together with model doubly benzannelated [13][14][15][16] and naphthyl-benzannelated [11,15] spiroketal systems have been reported. However, only two successful total syntheses have been achieved to date, namely, the aglycon of (AE )-5 by Danishefsky and coworkers, [17] in which spiroketalization of a hemiketal occurred under Mitsunobu conditions, and (AE )-1 by Kita et al [18] who used a double aromatic Pummerer-type reaction to install the spiroketal.…”

“…Elimination of the electron-withdrawing mesomeric effect on the eastern fragment of the advanced spiroketal precursor 7 was expected to increase the nucleophilicity of the phenol, thus encouraging the key acidmediated cyclization to form the D ring (see the insert in Scheme 2). Alkynol 8 was synthesized by the Sonogashira acetylide coupling strategy [14] that we developed to construct simpler aryl spiroketals, and was envisaged to be a flexible building block from which several members of the rubromycin family of antibiotics could be accessed.…”

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.…”

An Efficient Formal Synthesis of the Human Telomerase Inhibitor (±)‐γ‐Rubromycin

“…Elimination of the electron‐withdrawing mesomeric effect on the eastern fragment of the advanced spiroketal precursor 7 was expected to increase the nucleophilicity of the phenol, thus encouraging the key acid‐mediated cyclization to form the D ring (see the insert in Scheme ). Alkynol 8 was synthesized by the Sonogashira acetylide coupling strategy14 that we developed to construct simpler aryl spiroketals, and was envisaged to be a flexible building block from which several members of the rubromycin family of antibiotics could be accessed.…”