Rapid Access to the Potential Intermediate for the Synthesis of Halenaquinol and Halenaquinone

Abstract

The short step access to the possible intermediate for the synthesis of halenaquinone and halenaquinol of the dihydrofuranfused tetracyclic ring core (7) using the intramolecular [4+2] cycloaddition reaction of the o-quinodimethane, generated from 6, as the key step is described.Halenaquinone (1) and halenaquinol (2) are pentacyclic polyketides isolated from tropical marine sponges, 1 and possess antibiotic, cardiotonic, and protein tyrosine kinase inhibitory activites. 2 The unique pentacyclic structure of these marine products as well as their intriguing biological activities has attracted much attention from synthetic chemists 3 ( Figure 1). Figure 1To date, adequate total syntheses 3b,d of the above marine natural products have been reported, however most of these have shortcoming due to multistep synthesis. In this paper, we plan to outline how to construct the furan-fused polycyclic ring system, using the o-quinodimethane chemistry, and wish to report a new and efficient strategy for the construction of this ring core, which would serve as a possible intermediate for the synthesis of 1 and 2. The elusive intermediate o-quinodimethane has a remarkable Diels-Alder reactivity 4 and we have used this chemistry for the second genaration of steroid synthesis. 5 The basic strategy we used to construct the polycyclic ring system is presented in Figure 2.Alkylation of benzocyclobutene 3 6 with bromide 5, which was prepared from known alcohol 4, 7 gave the alkylated product 6. The key thermal intramolecular [4+2] cycloaddition reaction was performed in refluxing o-dichlorobenzene to afford the cycloadduct 7 8 in excellent yield as the only cyclized product. To the best of our knowledge, there has been no previous example of an intramolecular DielsAlder type of [4+2] cycloaddition reaction of this type of o-quinodimethane with furan. The stereochemistry of 7 was determined to be cis form by X-ray diffraction analysis 9 (Scheme).

Strategies for the Synthesis of the Halenaquinol and Xestoquinol Families of Natural Products

“…In 2001, the Nemoto group described their strategy for accessing 79 (Scheme 12), the tetracyclic core of halenaquinol. [39,40] They planned to access a fused tetracycle resembling halenaquinol through an intramolecular o-quinodimethane Diels-Alder cycloaddition. Benzocyclobutene 76 was heated to reflux in o-dichlorobenzene to unveil the o-quinodimethane, which underwent facile intramolecular cycloaddition with the furan to Scheme afford endo product 77 exclusively.…”