The enantioselective synthesis of spirocycles has long been pursued by organic chemists. Despite their unique 3D properties and presence in several natural products, the difficulty in their enantioselective synthesis makes them underrepresented in pharmaceutical libraries. Since the first pioneering reports of the enantioselective construction of spirosilanes by Tamao et al., significant effort has been devoted towards the development of new promising asymmetric methodologies. Remarkably, with the advent of organocatalysis, particularly over six years, the reported methodologies for the synthesis of spirocycles have increased exponentially. The aim of this review is to summarize the latest trends and developments in the enantioselective synthesis of spirocompounds during these last six years.

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New development in the enantioselective synthesis of spiro compounds

Synthesis of Spiroketals by Synergistic Gold and Scandium Catalysis.

Oxidative arylation of naphthoquinones has been developed through combination of o-iodoxybenzoic acid with arylhydrazines under mild conditions at open atmosphere. Arylated naphthoquinones with different electronic properties were obtained in moderate to good yields. The postulated radical mediated mechanism is supported by radical trapping experiments. Developed protocol for direct arylation of naphthoquinones has been extended toward short, high yielding, and an effective synthesis of antitumor–antibiotic precursor such as benzocarbazoledione.

Aryl-free radical-mediated oxidative arylation of naphthoquinones using o-iodoxybenzoic acid and phenylhydrazines and its application toward the synthesis of benzocarbazoledione.

Isolation, biological activity, biosynthesis and synthetic studies towards the rubromycin family of natural products

A one-pot hypoiodite catalysed oxidative cycloetherification approach to benzoxazoles.

Total synthesis of (±)-δ-rubromycin.

A tandem reaction consisting of a copper(I)-catalyzed cycloetherification and a hydrogen-bond-induced inverse-electron-demand oxa-Diels–Alder cycloaddition was performed from chiral propargyl alcohol, generating several kinds of optically pure [5, 6] spiroketals in excellent stereoselectivities and yields. The investigation on mechanism found that the cyclization prompted by a hydrogen bond not only improved the efficiency but also determined the diastereoselectivity.

Enantioselective syntheses of spiroketals via a tandem reaction of Cu(I)-catalyzed cycloetherification and hydrogen-bond-induced [4 + 2] cyclization.

A new core structure-motivated strategy for the intramolecular aromatic spiroketalization process was found and used for the enantioselective synthesis of bisbenzannulated spiroketals, the bioactive core of rubromycins, with high levels of enantioselectivity (up to 98% ee) via an organohalogenite-mediated asymmetric intramolecular aromatic spiroketalization. This is the first organocatalytic method for the construction of optically pure bisbenzannulated spiroketals.

Organohalogenite-Catalyzed Spiroketalization: Enantioselective Synthesis of Bisbenzannulated Spiroketal Cores

The first enantioselective total synthesis of (+)-coriandrone A and B, two bioactive natural products, has been achieved in 10 steps and 11 steps starting from commercially available methyl 2-hydroxy-4-methoxybenzoate. Key reactions include a Claison rearrangement, a Shi-type epoxidation–cyclization sequence and ortho-metallation of t-butylbenzamides with (S)-(−)-propylene oxide reaction.

The first asymmetric total synthesis of (+)-coriandrone A and B.

A novel multicomponent synthesis was found to be an efficient and elegant approach to 2,4-difunctionalized benzopyrans. This sequence includes ZnMe2-promoted alkynylation of salicylaldehyde and ZnCl2-mediated [4+2] cyclization proceeding in sequence of a one-pot process, providing a series of benzopyrans with good diastereoselectivities and moderate yields (dr 20:1 to 4:1). These products are potential precursors and bioactive core skeletons of natural products.

Tian Tian

Papers

Total synthesis of (±)-δ-rubromycin.

Enantioselective syntheses of spiroketals via a tandem reaction of Cu(I)-catalyzed cycloetherification and hydrogen-bond-induced [4 + 2] cyclization.

Organohalogenite-Catalyzed Spiroketalization: Enantioselective Synthesis of Bisbenzannulated Spiroketal Cores

The first asymmetric total synthesis of (+)-coriandrone A and B.

Multicomponent Syntheses to Alkene- and Alkyne-Functionalized Benzopyrans via Alkynylation and [4+2] Cyclization in One-Pot Process