Terry P. Lebold

Intramolecular annulations of donor–acceptor cyclopropanes

The intramolecular reaction of donor–acceptor cyclopropanes with various dipoles and dipolar equivalents allows access to a variety of bicyclic adducts with good stereocontrol. The linkers can often be cleaved to provide stereodefined products.

Zn(II)-Catalyzed synthesis of piperidines from propargyl amines and cyclopropanes.

The reaction of benzyl-protected propargyl amines and 1,1-cyclopropane diesters in the presence of catalytic Zn(NTf(2))(2) allows access to highly functionalized piperidines in excellent yields. The process proceeds via a tandem cyclopropane ring-opening/Conia-ene cyclization.

Tandem cyclopropane ring-opening/Conia-ene reactions of 2-alkynyl indoles: a [3 + 3] annulative route to tetrahydrocarbazoles.

A Zn(NTf(2))(2) catalyzed tandem reaction consisting of a nucelophilic ring opening of 1,1-cyclopropanediesters by 2-alkynyl indoles followed by a Conia-ene ring closure results in the efficient one-step synthesis of tetrahydrocarbazoles. The adducts may be further elaborated to carbazoles.

Synthesis of tetrahydropyrans from propargyl alcohols and 1,1-cyclopropanediesters: a one-pot ring-opening/Conia-ene protocol.

Lewis acid catalyzed ring opening of 1,1-cyclopropanediesters by the hydroxyl group of a propargyl alcohol sets up a subsequent Conia-ene cyclization to afford substituted tetrahydropyrans in a one-pot, high-yielding procedure.

Stereodivergent Synthesis of Fused Bicyclopyrazolidines: Access to Pyrazolines and Pyrrolidines

The reaction of hydrazinoethyl 1,1-cyclopropanediesters with aldehydes in the presence of catalytic Yb(OTf)(3) allows access to structurally complex fused bicyclo pyrazolidines. Either 2,5-cis or 2,5-trans adducts can be obtained in good to excellent yields in most cases by simply controlling the order of addition of the catalyst and aldehyde.

Network Analysis Guided Synthesis of Weisaconitine D and Liljestrandinine

General strategies for the chemical synthesis of organic compounds, especially of architecturally complex natural products, are not easily identified. Here we present a method to establish a strategy for such syntheses, which uses network analysis. This approach has led to the identification of a versatile synthetic intermediate that facilitated syntheses of the diterpenoid alkaloids weisaconitine D and liljestrandinine, and the core of gomandonine. We also developed a web-based graphing program that allows network analysis to be easily performed on molecules with complex frameworks. The diterpenoid alkaloids comprise some of the most architecturally complex and functional-group-dense secondary metabolites isolated. Consequently, they present a substantial challenge for chemical synthesis. The synthesis approach described here is a notable departure from other single-target-focused strategies adopted for the syntheses of related structures. Specifically, it affords not only the targeted natural products, but also intermediates and derivatives in the three subfamilies of diterpenoid alkaloids (C-18, C-19 and C-20), and so provides a unified synthetic strategy for these natural products. This work validates the utility of network analysis as a starting point for identifying strategies for the syntheses of architecturally complex secondary metabolites.

A divergent approach to the synthesis of the yohimbinoid alkaloids venenatine and alstovenine

The yohimbinoid alkaloids continue to receive considerable attention from the synthetic community because of their interesting chemical structures and varied biological activity. Although there are several elegant syntheses of certain members of this group of alkaloids, a truly unified approach has yet to be developed. In short, general approaches to this compound class are hampered by a lack of complete control in setting the C(3) stereocentre at a late stage. Herein, we report that a functionalized hydrindanone enables a divergent strategy that builds on existing precedent to address this long-standing challenge. Utilizing an aminonitrile intermediate, the stereochemistry at C(3) of the yohimbinoid skeleton can be controlled effectively in a Pictet–Spengler reaction. We applied this approach to the first total syntheses of the C(3) epimeric natural products venenatine and alstovenine. A hydrindanone-based approach to yohimbinoid natural products has been developed. A judicious choice of reaction conditions — inspired by prior work by the Stork group — allows effective control of the stereochemistry at C3 of the yohimbinoid skeleton. This approach has resulted in the first total syntheses of the C3 epimeric natural products venenatine and alstovenine.

Total Syntheses of Clausamines A−C and Clausevatine D

The first total syntheses of clausamines A-C and clausevatine D are reported. The key step involves a Diels-Alder reaction between an imine quinone and cyclic diene, allowing for the subsequent construction of the carbazole core in a regiospecific manner. Stereochemistry of the natural products is also discussed.

Syntheses of Denudatine Diterpenoid Alkaloids: Cochlearenine, N-Ethyl-1α-hydroxy-17-veratroyldictyzine, and Paniculamine

The denudatine-type diterpenoid alkaloids cochlearenine, N-ethyl-1α-hydroxy-17-veratroyldictyzine, and paniculamine have been synthesized for the first time (25, 26, and 26 steps from 16, respectively). These syntheses take advantage of a common intermediate (8) that we have previously employed in preparing aconitine-type natural products. The syntheses reported herein complete the realization of a unified strategy for the preparation of C20, C19, and C18 diterpenoid alkaloids.

Synthesis of the bridging framework of phragmalin-type limonoids.

An efficient synthesis of the octahydro-1H-2,4-methanoindene core of phragmalin-type limonoids, such as xyloccensins O and P, is reported. The success of the synthetic route is predicated on the use of network analysis in the retrosynthetic analysis and a Diels-Alder reaction for the synthesis of a key hydrindanone derivative.