Facile Synthesis of Naphthoquinone Spiroketals by Diastereoselective Oxidative [3 + 2] Cycloaddition

Abstract

A highly selective oxidative [3 + 2] cycloaddition of chiral enol ethers and hydroxynaphthoquinone is described. This convergent strategy is amenable to an enantioselective synthesis of β-rubromycin and related naphthoquinone spiroketals. Several compounds were found to inhibit DNA-polymerase and telomerase in a manner resembling α-rubromycin and β-rubromycin.(+)-β-Rubromycin belongs to a unique family of optically active spiroketal natural products with a rich and emerging history ( Figure 1). 1 Brockmann first isolated α-rubromycin (1), β-rubromycin (2a), and γ-rubromycin (3) in 1966 from strains of Streptomyces collinus bacteria. 2 However, Zeeck later revisited the structure in 2000 and assigned it as the p-quinone (2b). 3 With assistance from Bringmann, an S-configuration was assigned to the unique spiroketal in 2b using circular dichroism. 4 β-Rubromycin (2b) and γ-rubromycin (3) inhibited telomerase with an IC 50 of less than 3 µM. 1 On the other hand, α-rubromycin (1) proved inactive (IC 50 > 200 µM), exhibiting efficacy well outside the window of the assay. 1 Because of this discrepancy between 1 and 2 and 3, Hayashi proposed that the spiroketal moiety found in the structure of the inhibitors was responsible for their efficacy and as a privileged structural component offered a good starting point for synthetic chemists.From a synthetic perspective, rubromycins (2 and 3) pose several interesting questions. 1 These molecules are presumably biosynthesized as single enantiomers. However, each contains a single spiroketal stereocenter. Therefore, these compounds do not appear to be biosynthesized by a conventional thermodynamic ketalization. Nevertheless, the universal strategy has been to anneal two components together about a centralized carbonyl moiety. 5 Researchers synthesized lower oxidation surrogates of the naphthoquinone moiety, such as naphthazarin and benzyloxy derivatives. Most have reported methods to anneal these fragments together. 6 Despite several extraordinary efforts, only Danishefsky and co-workers reported synthesizing a naphthoquinone-isocoumarin spiroketal, albeit the aglycone of heliquinomycin. 7 However, their nontraditional spiroketalization method is not easily adapted to the synthesis of 2 and 3. 8 We therefore thought thermodynamic spiroketalization of compounds 2 and 3 was an unsound strategy.We imagined instead that a p-naphthoquinone spiroketal could be produced in a single kinetic step amenable to diastereoselective control whereupon the stereochemistry that directed the formation of the spiroketal stereocenter could be erased (Figure 2). The [3 + 2] oxidative cycloaddition initially observed by Roy and Mandal could be used to test our plan. 9 pettus@chem.ucsb.edu. Supporting Information Available: Experimental procedures and key spectral data for all new isolable compounds 5, 7-9, and 14-16. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe...

New strategies for natural products containing chroman spiroketals

“…We also demonstrated that this reaction was susceptible to diastereocontrol by incorporating a directing group into the enol ether, 73 . This guided the hydroxynapthoquinone, 74 , to approach from one face of the enol ether during the cycloaddition reaction and furnished chroman spiroketal 75 as single diastereomer [19]. …”

Advanced Routes in Synthesis and Reactions of Lawsone Molecules (2‐Hydroxynaphthalene‐1,4‐dione)

“…Refluxing in H 2 O mixture of 1 , malononitrile, and isatin in the presence of p‐ TSA for 7 h produced 2‐aminospiro[benzo[g]chromen‐4,3″‐indoline]‐2″,5,10‐trione derivatives 294 . Stirring at r.t. lawsone 1 with (6aS,7S,10R,10aS)‐6‐methyl‐6a,7,10,10a‐tetrahydro‐6H‐7,10‐methanobenzo[c]chromene in THF in the presence of CAN gave spiro[naphtho[2,3‐b]furan‐2,6″‐methanobenzo[c]chromen]‐4,9‐dione 295 (Scheme ).…”

“…Finally, stirring lawsone 1 with chroman‐2‐one or 2,2‐dimethyl‐3a,9b‐dihydro‐4H‐[1,3]dioxolo[4,5‐c]chromen‐4‐one in THF in the presence of CAN at r.t. gave 3″H‐spiro[chroman‐2,2″‐naphtho[2,3‐b]furan]‐4″,9″‐dione ( 296 ) or 2″,2″‐dimethyl‐3a″,9b″‐dihydro‐3H‐spiro[naphtho[2,3‐b]furan‐2,4″‐[1,3]dioxolo[4,5‐c]chromen]‐4,9‐dione ( 297 ) . Stirring under reflux lawsone 1 with 1 H ‐pyrazole‐4‐amines and isatin or acenaphthylene‐1,2‐dione afforded spiro compounds 298 or 299 , respectively (Scheme ).…”

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

“…Based on the [3+2]-cycloaddition of an enol ether with a β-diketone-derived zwitterion [167], early studies on simple substrates afforded the 5,6-spiroacetal in moderate yield [168,169].…”