New Methods and Strategies in the Synthesis of Terpenoid Natural Products

Abstract

Indoloterpenoids of the paxilline type belong to a large family of secondary metabolites that exhibit unique molecular architectures and a diverse set of biological activities. More than 100 congeners identified to date share a common structural motif that contains an indole moiety fused to a rearranged diterpenoid fragment. The representative physiological and cellular effects attributed to this family of natural products include neurological and insecticidal activities, modulation of lipid balance, and inhibition of mitosis. The uniting polycyclic motif combined with the diversity of individual structural features of paxilline indoloterpenoids and the broad scope of their biological activities have fascinated organic chemists for the past four decades and have led to the development of numerous syntheses. In this Account, we describe our contributions to this field and how they in turn shape new directions that are developing in our laboratory.We begin with the discussion of our strategy for the synthesis of the shared indoloterpenoid core. To address stereochemical challenges encountered in earlier reports, we planned to leverage a suitably substituted cyclopentanone in a polycyclization to form the desired trans-decalin motif. This polycyclization relied on a radical-polar crossover cascade initiated by hydrogen atom transfer. The original process exhibited poor diastereoselectivity, but we discovered an efficient solution to this problem that took advantage of intramolecular tethering effects, culminating in short synthesis of emindole SB. During these studies, we also identified indium-mediated alkenylation of silyl enol ethers with alkynes as a suitable method for the synthesis of highly substituted β,γ-unsaturated ketones that was critical to achieving brevity of our route. We subsequently developed a catalytic version of this transformation that allowed for a formal bimolecular ene reaction that exhibited unusual and potentially useful selectivity in construction of quaternary centers.To test the scope and limitations of our approach to paxilline indoloterpenoids and identify potential improvements, we developed a synthesis of the more complex congener nodulisporic acid C. The convergent assembly of this natural product was enabled by identification of new elements of stereocontrol in the radical-polar crossover polycyclization en route to the polycyclic terpenoid motif and development of a highly diastereoselective enyne cycloisomerization to access the indenopyran motif and a ketone arylation protocol to unite the two complex fragments.In subsequent studies, we expanded the radical-polar crossover cascade underlying our approach to paxilline indoloterpenoids to a bimolecular setting, which allowed for annulation of two unsaturated carbonyl components to produce functionalized cyclohexanes. This transformation is particularly well suited for installation of fully substituted carbons and can be complementary to the venerable Diels-Alder reaction. The utility of the new annulation was tested in the synthesis of forskolin, allowing for rapid construction of the complex polycyclic motif in this densely functionalized labdane diterpenoid.Over the past five years, our initial forays into the synthesis of paxilline indoloterpenoids have grown into a program that incorporates development of new synthetic methods and pursues artificial assembly of terpenoid natural products from several different families. We are encouraged by the increasing diversity of structural motifs made accessible by application of this chemistry and continue to discover new aspects of the underlying reactivity.

Figure 1.

Examples of natural products (left) whose syntheses led to the development or were enabled by new chemical methods (right) in the Pronin laboratory (2015–2019; red dots highlight carbon atoms involved in key bond-forming events).

Scheme 1.

Representative Biosynthetic Pathways to Paxilline Indoloterpenoids That Highlight Structural Diversity of Congeners

Scheme 2.

Our Approach to the Common Terpenoid Motif

Scheme 3.

Synthesis of the Polycyclization Precursor and Discovery of the Tethering Effect

Scheme 4.

Synthesis of Emindole SB

Scheme 5.

Catalytic Bimolecular Alkenylation of Ketone-Derived Silyl Enol Ethers with Terminal Alkynes

Scheme 6.

Our Approach to Nodulisporic Acid C

Scheme 7.

Diastereocontrol in Radical-Polar Crossover Polycyclizations

Scheme 8.

Synthesis of the Dienoate Fragment of the Nodulisporic Acids

Scheme 9.

Synthesis of the Indenopyran Fragment of Nodulisporic Acid C

Scheme 10.

Synthesis of (−)-Nodulisporic Acid C

Scheme 11.

Development of Radical-Polar Crossover Annulation

Scheme 12.

Synthesis of Forskolin