Russell C. Smith

Enantioselective synthesis of a hydroxymethyl-cis-1,3-cyclopentenediol building block.

A brief, enantioselective synthesis of a hydroxymethyl-cis-1,3-cyclopentenediol building block is presented. This scaffold allows access to the cis-1,3-cyclopentanediol fragments found in a variety of biologically active natural and non-natural products. This rapid and efficient synthesis is highlighted by the utilization of the palladium-catalyzed enantioselective allylic alkylation of dioxanone substrates to prepare tertiary alcohols.

Model Studies To Access the [6,7,5,5]-Core of Ineleganolide Using Tandem Translactonization–Cope or Cyclopropanation–Cope Rearrangements as Key Steps

Recently, we reported a convergent cyclopropanation-Cope approach to the core of ineleganolide, which was the first disclosed synthesis of the core of the norditerpene natural product ineleganolide. In this complementary work, a model system for the core of ineleganolide has been prepared through a series of tandem cyclopropanation-Cope and translactonization-Cope rearrangements. Work with this model system has enriched our understanding of the cyclopropanation-Cope rearrangement sequence. Additionally, research into this model system has driven the development of tandem translactonization-Cope rearrangements.

Preparation of 1,5-Dioxaspiro[5.5]undecan-3-one

A. 3-Amino-3-(hydroxymethyl)-1,5-dioxaspiro[5.5]undecane. A 1-L single-necked, round-bottomed flask is equipped with an egg-shaped, Teflon®-coated magnetic stirring bar (3.5 cm x 1.5 cm), capped with a rubber septum, flame-dried under vacuum, and cooled under an argon atmosphere (Note 1). After cooling to ambient temperature (21-23 °C), to the flask is added anhydrous N,N-dimethylformamide (DMF, 365 mL, 0.78 M) via cannula. Subsequently, tris(hydroxymethyl)aminomethane hydrochloride (45.0 g, 286 mmol, 1.00 equiv) (Note 2 and 3) is added in a single portion as white crystalline solid. The reaction vessel is immediately resealed with a rubber septum under inert atmosphere and stirring is commenced (Figure 1). To this white suspension is added 1,1-dimethoxycyclohexane (50.0 mL, 47.4 g, 329 mmol, 1.15 equiv) via syringe in one portion (Note 4). Lastly, to the off-white slurry is added para-toluenesulfonic acid monohydrate (p-TsOH•H2O, 1.63 g, 8.57 mmol, 0.03 equiv) as a solid in one portion quickly, immediately replacing the rubber septum to maintain an inert atmosphere.

Development of a Unified Enantioselective, Convergent Synthetic Approach Toward the Furanobutenolide-Derived Polycyclic Norcembranoid Diterpenes: Asymmetric Formation of the Polycyclic Norditerpenoid Carbocyclic Core by Tandem Annulation Cascade

An enantioselective and diastereoselective approach toward the synthesis of the tetracyclic scaffold of the furanobutenolide-derived polycyclic norditerpenoids is described. Focusing on synthetic efforts toward ineleganolide, the synthetic approach utilizes a palladium-catalyzed enantioselective allylic alkylation for the construction of the requisite chiral tertiary ether. A diastereoselective cyclopropanation-Cope rearrangement cascade enabled the convergent assembly of the ineleganolide [6,7,5,5]-tetracyclic scaffold. Investigation of substrates for this critical tandem annulation process is discussed along with synthetic manipulations of the [6,7,5,5]-tetracyclic scaffold and the attempted interconversion of the [6,7,5,5]-tetracyclic scaffold of ineleganolide to the isomeric [7,6,5,5]-core of scabrolide A and its naturally occurring isomers. Computational evaluation of ground-state energies of late-stage synthetic intermediates was used to guide synthetic development and aid in the investigation of the conformational rigidity of these highly constrained and compact polycyclic structures.

CCDC 1061009: Experimental Crystal Structure Determination

Related Article: Robert A. Craig, II, Jennifer L. Roizen, Russell C. Smith, Amanda C. Jones, Scott C. Virgil, Brian M. Stoltz|2017|Chemical Science|8|507|doi:10.1039/C6SC03347D