Attempted synthesis of central furopyran core of Diocollettines A via a Gold-Catalyzed cascade 1,6-Diyne cycloisomerization process

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Highlights

Abstract

Herein, we describe an Au-catalyzed cascade diyne cycloisomerization process that was projected to construct the central furopyran bicyclic core of Diocollettines A. Our intended strategy for the annulation of the third thf ring is based on epoxidation and subsequent intramolecular acetalization. However, the initial alkynol cyclization occurred in an undesired 5-exo-dig mode, ultimately leading to an undesired furopyran.

Introduction

The accomplishment of the total synthesis of any natural product has its own significance in terms of the strategy, which has paved the path and choice/compatibility of functional/protecting groups and chemical transformations that contribute to this success [1]. However, in many cases, there are bottlenecks and roadblocks resulting from the incompatibility between the components, which result in the undesired reactivity/selectivity at an advanced stage [2]. As has been described by Nicolaou, each successful total synthesis was a result of learning from many unsuccessful efforts [3]. In this manuscript, we describe an unsuccessful effort towards the synthesis of the recently isolated natural product Diocollettines A (1), due to an undesired regioselectivity in the key skeletal construction event.

In 2017, Gao and co-workers reported the isolation of Diocollettines A (1) from the rhizomes of the plant D. collettii (belonging to the genus Dioscorea). Diocollettines A is a novel diaryl heptanoid possessing an unprecedented [6–5–5] fused tricyclic skeleton comprising of one tetrahydropyran ring and two tetrahydrofuran rings with five stereogenic centres [4]. The preliminary biological evaluation of Diocollettines A (1) against the lung cancer cell line NCL-H460 revealed promising cytotoxity (IC50 = 20.15 μM). Very recently, streptoglycerides A − D, having a similar unique [6–5–5] tricyclic core of Diocollettines A, were isolated from the Streptomyces strain and found to have anti-neuroinflammatory activity [5]. After the report on the isolation of Diocollettines A appeared, we started a program of synthesizing the natural product by following a modular strategy that employs an alcohol initiated yne-yne cyclization cascade process. Recently, the Ito and Kuwahara groups reported the enantioselective total syntheses of Diocollettines A, featuring stereoselective aldol reaction as one of the key steps [6].

Section snippets

Results and discussion

As shown in Scheme 1, our applied key skeletal construct was inspired from the work of Yang's group on gold catalyzed tandem cyclisation of 1,6-/1,7-diynes for the synthesis of natural products like oxygenated C-15 sesquiterpeniods and Cladiellins [7], [8]. We intended to employ a gold-catalyzed cascade cyclisation of the 1,6-diyne system (a dipropargyl ether) with an ether linkage, which had not been explored earlier [9]. A regioselective 6-endo/5-exo dig mode of cascade cyclisation of

Conclusion

An approach comprising of gold-catalyzed cascade cyclization of a 1,6-diyne followed by epoxidation and intramolecular ketalization has been proposed for the construction of the central tricyclic core/total synthesis of Diocollettines A (1) and attempted. The key gold-catalyzed cascade cyclization resulted in undesired selectivity that has been realized after the failure during the cyclization step of the penultimate epoxides. Currently, work in the direction of tuning the regioselectivity and

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We thank CSIR, New Delhi for funding and UGC, New Delhi for the award of a Research Fellowship to V.M.

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