Total Synthesis of Virgatolide B via Exploitation of Intramolecular Hydrogen Bonding

Abstract

A full account of the enantioselective total synthesis of virgatolide B is reported. Key features of the synthesis include an sp(3)-sp(2) Suzuki-Miyaura cross-coupling of a β-trifluoroboratoamide with an aryl bromide, regioselective intramolecular carboalkoxylation, and a 1,3-anti-selective Mukaiyama aldol reaction. Intramolecular hydrogen bonding governed the regioselectivity of the key spiroketalization step, affording the natural product as a single regioisomer.

Ag/Brønsted Acid Co-Catalyzed Spiroketalization of β-Alkynyl Ketones toward Spiro[chromane-2,1′-isochromene] Derivatives

“…Compounds incorporating a spiroketal core structure have been found to exhibit a wide spectrum of biological activities . Among the family of spiroketals, the 6,6-benzannulated spiroketals behave as a key pharmacophore in many bioactive natural products, such as cynandione B, chaetoquadrin B, and virgatolide B (Figure ). In particular, cynandione B displays significant in vitro cytotoxic activity against both T-24 cell lines and PLC/PRF/5 cell lines and anti-inflammatory activity .…”

“…Consequently, much effort has been made toward identifying general methods for the synthesis of these 6,6-benzannulated spiroketals. Generally, strategies for 6,6-benzannulated spiroketal syntheses include acid-promoted cyclization of protected diol with ketone precursors or dehydration-cyclization of dihydroxy ketones, intramolecular Michael reaction, Ti-mediated spirocyclization, and oxidative cyclization, hetero Diels–Alder reaction, reductive cyclization reaction, and Me 3 SiI-promoted spiroketalization of salicylic aldehydes . In spite of all these significant achievements, Ag/Brønsted acid co-catalysis toward 6,6-benzannulated spiroketals via bicyclization cascade of β-alkynyl ketones, to the best of our knowledge, is virtually unexplored so far.…”

De Novo Synthesis of Tricyclic 5,5-Benzannulated Spiroketals

“…Spiroketals are ubiquitous structural units present in several natural products comprising structurally simple to complex frameworks. , A few tricyclic spiroketals containing natural products were also recently isolated, and benzannulated spiroketal-based natural products such as purpuromycin, rubromycins, etc., are known to exhibit anticancer activity (Figure ). General synthetic methods of spiroketal synthesis include the ketalization of suitably substituted ketones tethered with hydroxyl groups, the 4+2 cycloaddition of o -quinone, Me 3 SiI-promoted spirocyclization, oxidative cyclizations, metal-catalyzed hydroalkoxylation of alkynes, etc . Despite an array of available methods, a general method for the synthesis of tricyclic benzannulated spiroketals is still needed.…”

Synthesis of Benzannulated [6,6]-Spiroketals by a One-Pot Carbonylative Sonogashira Coupling/Double Annulation Reaction

“…Among the family of spiroketals, the benzannulated [6,6]-spiroketal is a key skeleton that exists in many bioactive natural products and chiral ligands (Figure ). Key examples include the chaetoquadrin and virgatolide families, which have demonstrated compelling bioactivities; ( S , S , S )-SKP is a type of privileged chiral ligands with excellent performance in catalytic enantioselective transformations . In view of the critical roles of benzannulated [6,6]-spiroketal moiety, a range of novel spirocyclization methodologies have been developed in recent years.…”