Enantioselective Total Synthesis of (-)-Artatrovirenol A.

We report herein an enantioselective total synthesis of (-)-artatrovirenol A, a structurally unprecedented cage-like sesquiterpenoid. The synthesis features the following key steps: (a) cationic chiral oxazaborolidinium-catalyzed Diels-Alder reaction between isoprene and ethyl (E)-5-((tert-butyldimethylsilyl)oxy)-4-oxopent-2-enoate for the rapid synthesis of an enantioenriched 10-carbon bicyclic lactone; (b) union of two enantioenriched fragments by a diastereoselective Mukaiyama-Michael addition for the convergent assembly of an intermediate with all 15 carbons of the natural product; (c) intramolecular de Mayo [2 + 2] cycloaddition/retro-aldol sequence transforming a bicyclic compound to a tetracyclic one with concomitant generation of a five- and a seven-membered ring; (d) Lewis acid-triggered intramolecular ring opening of epoxide generating the norbornane substructure; and (e) Chugaev elimination converting the norbornane to the more strained norbornene.

Terminal Alkynes as One-Carbon Donors in [5+1] Heteroannulation: Synthesis of Pyridines via Ynimine Intermediates and Application in the Total Synthesis of Anibamine B.

Transition-metal-catalyzed [4+2] heteroannulation of α,ß-unsaturated oximes and their derivatives with alkynes has been developed into a powerful strategy for the synthesis of pyridines. It nevertheless lacks regioselectivity when unsymmetrically substituted alkynes are used. We report herein the unprecedented synthesis of polysubstituted pyridines by a formal [5+1] heteroannulation of two readily accessible building blocks. A copper-catalyzed aza-Sonogashira cross-coupling between ß,γ-unsaturated oxime esters and terminal alkynes affords ynimines, which, without isolation, undergo an acid-catalyzed domino reaction involving ketenimine formation, 6π-electrocyclization and aromatization to afford pyridines. Terminal alkynes served as a one-carbon donor to the pyridine core in this transformation. Di- through pentasubstituted pyridines are accessible with complete regioselectivity and excellent functional-group compatibility. The first total synthesis of anibamine B, an indolizinium alkaloid with potent antiplasmodial activity, was accomplished featuring this reaction as a key step.

Copper-Catalyzed Aza-Sonogashira Cross-Coupling To Form Ynimines: Development and Application to the Synthesis of Heterocycles.

Nitrogen-substituted alkynes, such as ynamines and ynamides, are versatile synthetic building blocks. Ynimines bearing additional nucleophilic and electrophilic centers relative to ynamines and ynamides are expected to have high synthetic potential. However, their chemical reactivity remains unexplored owing mainly to the lack of synthetic accessibility. We report herein a versatile copper-catalyzed synthesis of ynimines from readily available O-acetyl ketoximes and terminal alkynes. A wide range of O-acetyl ketoximes derived from diaryl ketones, aryl alkyl ketones and dialkyl ketones underwent cross-coupling with a diverse set of terminal alkynes to afford the ynimines in good to excellent yields. An unprecedented [5+1] heteroannulation reaction exploiting the reactivity of the ynimine generated in situ was subsequently developed for the synthesis of medicinally important heterocycles, including isoquinolines, azaindoles, azabenzofurans, azabenzothiophenes and carbolines.

Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Acyclic α-N-Pyrrolyl/Indolyl Ketones.

The synthesis of fully substituted α-N-pyrrolyl and indolyl ketones via enantioselective palladium-catalyzed allylic alkylation is described. The acyclic ketones are alkylated in high yields with high enantioselectivities through the use of an electron-deficient phosphinooxazoline ligand, furnishing a highly congested and synthetically challenging stereocenter. The obtained alkylation products contain multiple reactive sites poised for additional functionalizations and diversification.

Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Protected Benzoin-Derived Enol Carbonates.

The enantioselective palladium-catalyzed decarboxylative allylic alkylation of fully substituted α-hydroxy acyclic enol carbonates providing tetrasubstituted benzoin derivatives is reported. Investigation into the transformation revealed that preparation of the starting material as a single enolate isomer is crucial for optimal enantioselectivity. The obtained alkylation products contain multiple reactive sites that can be utilized toward the synthesis of stereochemically rich derivatives. COMMUNICATION.