Oxidative C-H Activation: Convergent Fragment-Coupling approaches to Spiroacetals and the Total Synthesis of Clavosolide A

Two one-pot oxidative cyclization strategies to spiroacetals are described herein. The first approach utilizes a Lewis acid-mediated Ferrier reaction for the initial fragment coupling followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-initiated oxidative carbon–hydrogen bond cleavage and cyclization. The second approach relies on a Heck cross coupling for fragment assembly followed by a DDQ-mediated dehydrogenation of enol ethers into enones and subsequent acid-induced cyclization. These methods provide mild convergent protocols to spiroketal subunits, which are ubiquitous in natural products, medicinal drugs, and chemical libraries. Cyclopropane-substituted allylic ethers undergo carbon–hydrogen bond cleavage to form stable oxocarbenium ions upon reaction with DDQ. Significantly, in the presence of an appending nucleophile, facile ring closure occurs to yield highly functionalized tetrahydropyrans with no accompanied cyclopropane scission. This methodology was showcased during the total synthesis of the sponge-derived macrodiolide clavosolide A

Cyclopropane Compatibility with Oxidative Carbocation Formation: Total Synthesis of Clavosolide A

Cyclopropane-substituted allylic ethers react with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to form oxocarbenium ions with no competitive ring cleavage. This reaction can be used for the preparation of cyclopropane-substituted tetrahydropyrans. The protocol was used as a key step in the total synthesis of the sponge-derived macrolide clavosolide A

Convergent One-Pot Oxidative [<i>n</i> + 1] Approaches to Spiroacetal Synthesis

Two one-pot oxidative annulative approaches to spiroacetal synthesis are described. One approach uses a Lewis acid mediated Ferrier reaction in the fragment-coupling stage followed by DDQ-promoted oxidative carbon–hydrogen bond cleavage and cyclization. An alternative approach employs a Heck reaction for fragment coupling followed by DDQ-mediated enone formation and cyclization. These strategies provide convergent routes to common subunits in natural products, medicinal agents, and chemical libraries under mild reaction conditions

A Spirobicyclo[3.1.0] Terpene from the Investigation of Sesquiter-pene Synthases from Lactarius deliciosus

Milk cap mushrooms in the genus Lactarius are known to produce a wide variety of terpene natural products. However, their repertoire of terpene biosynthetic enzymes has not been fully explored. In this study, several candidate sesquiterpene synthases were identified from the genome of the saffron milk cap mushroom L. deliciosus, and expressed in a sesquiterpene-overproducing Escherichia coli strain. In addition to enzymes that produce several known terpenes, we identified an enzyme belonging to a previously unknown clade of sesquiterpene synthases that produces a terpene with a unique spirotricyclic scaffold. These findings further add to the rich diversity of terpene scaffolds and mushroom terpene synthases and are valuable for biotechnological applications in producing these terpenoids

A Spirobicyclo[3.1.0]Terpene from the Investigation of Sesquiterpene Synthases from <i>Lactarius deliciosus</i>

Milk cap mushrooms in the genus Lactarius are known to produce a wide variety of terpene natural products. However, their repertoire of terpene biosynthetic enzymes has not been fully explored. In this study, several candidate sesquiterpene synthases were identified from the genome of the saffron milk cap mushroom L. deliciosus and expressed in a sesquiterpene-overproducing Escherichia coli strain. In addition to enzymes that produce several known terpenes, we identified an enzyme belonging to a previously unknown clade of sesquiterpene synthases that produces a terpene with a unique spiro-tricyclic scaffold. These findings add to the rich diversity of terpene scaffolds and mushroom terpene synthases and are valuable for biotechnological applications in producing these terpenoids

Site-selective Chlorination of Pyrrolic Heterocycles by Flavin Dependent Enzyme PrnC

Halogenation of pyrrole requires strong electrophilic reagents and often leads to undesired polyhalogenated products. Biocatalytic halogenation is a highly attractive approach given its chemoselectivity and benign reaction conditions. Whilst there are several reports of enzymatic phenol and indole halogenation in organic synthesis, corresponding reports on enzymatic pyrrole halogenation has been lacking. Here we describe the first in vitro functional and structural characterization of PrnC, a flavin-dependent halogenase that can act on free-standing pyrroles. Computational modelling and site mutagenesis studies identified three key residues in the catalytic pocket. Moderate resolution map using single-particle cryogenic electron microscopy (CryoEM) reveals PrnC to be a dimer. This native PrnC can halogenate a library of structurally diverse pyrrolic heterocycles in a site-selective manner and was applied in the chemoenzymatic synthesis of a chlorinated analog of the agrochemical fungicide, Fludioxonil