A Concise Enantioselective Approach to Quassinoids

Abstract

A synthetic approach to quassinoids is described. The route to the tetracyclic core relies on an efficient and selective annulation between two unsaturated carbonyl components that is initiated by catalytic hydrogen atom transfer from an iron hydride to an alkene. Application of this strategy allows for enantioselective synthesis of quassin, which is prepared in 14 steps from commercially available starting material.

Quassinoids comprise a large group of terpenoid natural products isolated from plants of the Simaroubaceae family, which have been used in folk medicine to treat a variety of diseases.¹ These secondary metabolites exhibit a diverse set of biological activities that became a subject of frequent scientific inquiry in the latter half of the 20th century. Notable examples include potent cytotoxicity toward different cancer cell lines and antimalarial activity against drug-resistant strains of P. falciparum.^2,3 These effects have been commonly attributed to inhibition of protein synthesis in both mammalian and protozoan cells.^4,5 However, recent studies suggest a far more complex mechanism of action that accounts for the observed antineoplastic properties, including down-regulation of c-MYC oncoproteins and inhibition of NF-κB.^6,7 These findings spurred several subsequent investigations to further evaluate the therapeutic potential of quassinoids, driving a renewed interest in these natural products.^8,9

Biosynthetic assembly of the shared tricarbocyclic motif found in the structure of quassinoids involves oxidative degradation of a triterpenoid precursor.¹⁰ The resulting common core can be found in a variety of functionalization patterns in different congeners and often contains a fused δ-valerolactone moiety (e.g., 1, 2, and 3, Figure 1).¹¹ The combination of complex structural features and promising biological activities has prompted numerous investigations into the chemical synthesis of quassinoids over the past five decades.^12–17 These studies accumulated a wealth of knowledge in reactivity of complex polycyclic motifs, and the developed multistep sequences underscored the synthetic challenge associated with the target compounds, which continues to drive innovative research in the field of organic chemistry.¹⁸ Here, we demonstrate a new approach to quassinoids that provides rapid asymmetric access to the functionalized polycyclic core of these natural products. Application of our strategy has allowed for the synthesis of (+)-quassin (1) in 14 steps from commercially available material.

Figure 1.

Representative quassinoids and our approach to the common polycyclic motif.

In devising our route, we aimed to develop a concise approach to the tricarbocyclic motif of quassinoids. At the same time, we recognized that redox manipulations following assembly of the carbon framework had historically accounted for the bulk of transformations in prior campaigns, therefore judicious selection of the functionalization patterns would be requisite for a succinct synthesis. With these considerations in mind, we envisioned that annulation between two unsaturated carbonyl components would allow for convergent union of cyclic fragments found in the perhydrophenanthrene motif (Figure 1).¹⁹ The desired transformation was expected to take advantage of hydrogen atom transfer (HAT) from an iron hydride to the 1,1-disubstituted alkene followed by Giese addition of the resulting alkyl radical to the unsaturated ketone and ultimate cyclization onto the pendant aldehyde.^20,21 The functionalities formed at C7 and C14 would serve as handles for assembly of the fused lactone moiety, which is found in the majority of congeners. Although direct installation of the desired trans fusion at C8 and C9 during the annulation could be difficult to achieve, previous observations of facile proton exchange at C9 provided an outlet for possible solutions to the anticipated stereochemical challenge.²² Notably, the HAT-initiated annulation was expected to offer good tolerance of functional groups in the reaction partners, promising a considerable degree of flexibility during optimization of this crucial transformation.

After extensive experimentation with various annulation partners, we identified an optimal combination of unsaturated carbonyl components for construction of the desired tricarbocyclic motif. Synthesis of aldehyde 4 began with alkylation of a lithium enolate of unsaturated ketone 5, which could be prepared by IBX-mediated oxidation of (+)-3-methylcyclohexanone (Scheme 1).²³⁻²⁵ Direct treatment of the reaction mixture with hydrogen peroxide and DBU delivered epoxide 6. Wittig olefination of the ketone produced exocyclic alkene 7, which underwent reduction of the nitrile and allylic epoxide upon exposure to DIBAL-H. Protection of the resulting secondary alcohol secured access to the desired annulation partner 4 in five steps from commercially available material.

Scheme 1.

Synthesis of γ,δ-Unsaturated Aldehyde 4

Synthesis of unsaturated ketone 8 relied on regio- and diastereoselective epoxidation of tricyclic diene 9, which was prepared from 2,6-dimethylbenzoquinone in an enantioselective manner by taking advantage of oxazaborolidine catalysis (Scheme 2).²⁶ Thermal retro-Diels–Alder reaction accomplished efficient extrusion of cyclopentadiene and delivered annulation partner 8 in three steps from commercially available material.²⁷ Notably, this epoxyquinone derivative demonstrated superior performance in the HAT-initiated annulation reactions en route to the shared polycyclic motif of quassinoids when compared to diene 9, which was previously employed in our synthesis of forskolin.¹⁹

Scheme 2.

Synthesis of Epoxyquinone 8

Annulation of epoxyquinone 8 and aldehyde 4 resulted in highly selective formation of polycyclic intermediate 10 (Scheme 3).^28,29 To our surprise, the epoxide fragment exerted a substantial degree of stereocontrol during the construction of the new bond between C9 and C10.

Scheme 3.

Synthesis of (+)-Quassin (1)

This stereochemical relay is noteworthy and may prove valuable in the synthesis of other terpenoid scaffolds. In the annulation toward quassin, the resulting secondary alcohol was selectively produced with an undesired configuration at C7, but the observed conformational preferences of product 10 suggested a potential solution. Crystallographic studies with a TBS analog in the solid state revealed that the cyclohexanol motif adopts a twist boat conformation, which was also suggested for the solutions in deuterated chloroform by ¹H NMR analysis. We therefore speculated that the pseudoaxial orientation of the secondary hydroxy group could drive epimerization of the stereocenter at C7 upon a reversible retro-aldol reaction. Indeed, treatment of intermediate 10 with a strong base followed by addition of diethylphosphonoacetic acid and a coupling agent produced ester 11 with corrected configuration at C7. We empirically found that the application of toluene as a solvent in this transformation allowed us to selectively epimerize C7 without affecting the configuration of the stereocenter at C9, which was inverted under a variety of other conditions. This is noteworthy because epimerization of C9 was invariably accompanied by equilibration to the undesired configuration at C7 and therefore was necessary to avoid at this point in the sequence.

Initial attempts to affect the Horner–Wadsworth–Emmons reaction of phosphonate 11 were unsuccessful, likely due to unfavorable steric interactions associated with approach of the ester fragment from the concave face of the polycyclic system. We speculated that inversion of the C9 stereocenter would be beneficial at this stage, as it would likely lead to a less sterically encumbered transition state in the requisite addition to the ketone. We ultimately found that treatment with cesium fluoride in dimethyl sulfoxide induced epimerization of C9 and intramolecular olefination, delivering the desired tetracyclic core of the quassinoids. The resulting product mixtures contained varying amounts of deprotected secondary alcohol at C2, which we converged to the corresponding cyclohexanone 12 by oxidation with IBX in the presence of tosic acid hydrate.³⁰

With access to the complete polycyclic scaffold of quassinoids, we proceeded to explore its application in the synthesis of a representative congener, quassin (1). Conversion of the unsaturated epoxide to the corresponding ketone was accomplished upon isomerization of intermediate 12 with catalytic amounts of a palladium phosphine complex.^31,32 Direct addition of palladium on carbon and hydrogen to the reaction mixture allowed for chemoselective hydrogenation of the alkene to deliver lactone 13. Site-selective oxidation of related intermediates containing the saturated lactone moiety presented a significant challenge in previous studies and required protecting group manipulations to mitigate competing reactivity patterns.³³ After significant experimentation with precursors and conditions, we found that the desired functionalization of our system could be accomplished by allylic hydroxylation of silyl enol ether 14, which in turn was selectively prepared by soft enolization of cyclohexanone 13.³⁴ Subsequent oxidation of alcohol 15 delivered penultimate intermediate 16 containing the requisite polycarbonyl motif of the target natural product.³⁵ Ultimately, treatment of silyl enol ether 16 with a source of fluoride ions in the presence of methyl iodide resulted in direct production of (+)-quassin, completing the synthesis in 14 steps from a commercially available starting material.

In summary, we disclose a new synthetic approach to quassinoids that relies on a HAT-initiated annulation of two unsaturated carbonyl components for rapid access to the shared polycyclic motif. The judicious choice of annulation partners ensures efficient formation of the key structural bonds and provides pragmatic functional handles for subsequent elaborations. Application of this strategy to the synthesis of (+)-quassin allows for asymmetric assembly of the target natural product in 14 steps for commercially available material, which significantly reduces unproductive functional group manipulations and is notably shorter than the previous efforts in the field.³⁶ We expect our annulation-based approach to quassinoids to find application in the synthesis of other congeners, and corresponding studies are currently underway.