Zhenhua Gu

Total Synthesis of Maoecrystal V: Early-Stage C–H Functionalization and Lactone Assembly by Radical Cyclization

A total synthesis of the unusual ent-kaurane maoecrystal V is described. The synthesis strategy features a counterintuitive early disconnection of the lactone subunit to a polycyclic enol ether intermediate in order to preserve the central tetrahydrofuran ring until the beginning stages of the synthesis. This strategy enables an application of C-H functionalization at the early phase of the synthesis during the construction of a dihydrobenzofuran intermediate.

Total Synthesis of Pinnatoxins A and G and Revision of the Mode of Action of Pinnatoxin A

Pinnatoxins belong to an emerging class of potent marine toxins of the cyclic imine group. Detailed studies of their biological effects have been impeded by unavailability of the complex natural product from natural sources. This work describes the development of a robust, scalable synthetic sequence relying on a convergent strategy that delivered a sufficient amount of the toxin for detailed biological studies and its commercialization for use by other research groups and regulatory agencies. A central transformation in the synthesis is the highly diastereoselective Ireland-Claisen rearrangement of a complex α,α-disubstituted allylic ester based on a unique mode for stereoselective enolization through a chirality match between the substrate and the lithium amide base. With synthetic pinnatoxin A, a detailed study has been performed that provides conclusive evidence for its mode of action as a potent inhibitor of nicotinic acetylcholine receptors selective for the human neuronal α7 subtype. The comprehensive electrophysiological, biochemical, and computational studies support the view that the spiroimine subunit of pinnatoxins is critical for blocking nicotinic acetylcholine receptor subtypes, as evidenced by analyzing the effect of a synthetic analogue of pinnatoxin A containing an open form of the imine ring. Our studies have paved the way for the production of certified standards to be used for mass-spectrometric determination of these toxins in marine matrices and for the development of tests to detect these toxins in contaminated shellfish.

Palladium-Catalyzed Intramolecular Asymmetric C–H Functionalization/Cyclization Reaction of Metallocenes: An Efficient Approach toward the Synthesis of Planar Chiral Metallocene Compounds

A palladium-catalyzed asymmetric synthesis of planar chiral metallocene compounds is reported. The reaction stereoselectively functionalized one of the ortho C-H bonds of Cp rings by intramolecular cyclization to form indenone derivatives in high yields with excellent enantioselectivity. The mild set of reaction conditions allowed a wide variety of chiral metallocene compounds to be synthesized with broad functional group tolerance. The influences of preinstalled chiralities on the other Cp-ring were also investigated.

Pd-Catalyzed Chemoselective Catellani Ortho-Arylation of Iodopyrroles: Rapid Total Synthesis of Rhazinal

A Pd-catalyzed chemoselective Catellani reaction of iodopyrroles was developed. The rare chemoselectivity between two different aryl halides was realized by optimizing the kinetics of the different steps of this multicomponent process. The new developed method led to the rapid synthesis of rhazinal in a highly efficient manner.

Concise Total Synthesis of Sintokamides A, B, and E by a Unified, Protecting‐Group‐Free Strategy

Considered rare and exotic only about 50 years ago, more than 4000 halogenated natural products have been isolated and characterized to date.[1] These compounds exhibit a wide range of biological activity, including antitumor,[2] anti-HIV,[3] and analgesic activity.[4] Chlorinated marine natural products containing dichloromethyl or trichloromethyl groups, such as barbamide,[5] dysithiazolamide,[6] and dysamide,[7] constitute an important subclass of compounds. In 2006, the Gerwick and Walsh groups uncovered a novel class of halogenating enzymes that catalyzed halogenation at unactivated aliphatic carbon atoms of amino acid residues linked to a peptide carrier protein.[8] However, chemical methods for stereoselective di- or trichloromethylation are still limited.[9] Recently, our research group described a practical and efficient method for the haloalkylation of titanium enolates with high diastereoselectivity.[10]

Total Synthesis of Rhazinilam: Axial to Point Chirality Transfer in an Enantiospecific Pd-Catalyzed Transannular Cyclization

A total synthesis of rhazinilam based on a transannular cyclization strategy is described. Using a Heck reaction, the axial chirality of a halogenated 13-membered lactam can be exploited to create the quaternary chiral stereogenic center in the target molecule with high enantiospecificity.

Pd-Catalyzed Heck-Type Cascade Reactions with N-Tosyl Hydrazones: An Efficient Way to Alkenes via in Situ Generated Alkylpalladium

A palladium-catalyzed Heck-type cascade reaction of aryl halides and N-tosyl hydrazones is reported. The neopentylpalladium species, generated from an intramolecular Heck-type insertion reaction of aryl halides, could efficiently react with carbenes to form highly functionalized alkenes. The synthesis of spiro compounds was also explored via a multiple Heck-type insertion reaction with N-tosyl hydrazone.

Studies toward the Synthesis of Maoecrystal V

An approach toward the synthesis of maoecrystal V is described. The synthetic strategy for this approach was designed to address unique challenges posed by the strained tetrahydrofuran ring at the center of the target structure.

Enantioselective Synthesis of (−)-Maoecrystal V by Enantiodetermining C–H Functionalization

The evolution of a program directed at the enantioselective total synthesis of maoecrystal V, a highly modified ent-kauranoid, is described. An early stage chiral auxiliary-directed asymmetric C–H functionalization for the construction of a key benzofuran intermediate enabled the first asymmetric synthesis of the natural enantiomer of maoecrystal V, confirming the assigned stereochemistry. A divergent course of the central intramolecular Diels–Alder reaction, which is dependent on the nature of the dienophile, initially led to the development of an unanticipated and previously unknown isomer of maoecrystal V, which we named maoecrystal ZG. In light of the reported selective and potent cytotoxic activity of maoecrystal V, the cytotoxic properties of maoecrystal ZG were also investigated.

Palladium‐Catalyzed Catellani ortho‐Acylation Reaction: An Efficient and Regiospecific Synthesis of Diaryl Ketones

A palladium-catalyzed, norbornene-mediated Catellani ortho-acylation reaction was developed by the use of either acyl chlorides or acid anhydrides as acylation reagents. The addition of more than a stoichiometric amount of H2 O is crucial for this transformation when acid chlorides are used, and kinetic studies indicate that the active acylation reagent is possibly an acid anhydride.