Thiourea-Catalyzed Enantioselective Addition of Indoles to Pyrones: Alkaloid Cores with Quaternary Carbons

Abstract

We report the development of a catalytic method for the enantioselective addition of indoles to pyrone-derived electrophiles. Arylpyrrolidino-derived thioureas catalyze the addition with high stereoselectivity in the presence of catalytic quantities of an achiral Brønsted acid. The indole–pyrone adducts feature a quaternary stereocenter and represent an unusual class of indolines bearing structural resemblance to the hybrid natural product pleiocarpamine.

Complex indole alkaloids are important compounds that possess a wide range of bioactivities. For instance, pleiomaltinine is a hybrid natural product that features both indoline and γ-pyrone functionalities and exhibits an impressive ability to reverse multidrug resistance in vincristine-resistant cells.¹ Recently, we described a synthetic approach to pleiomaltinine through a Brønsted acid-promoted indole–pyrone annulation (Figure 1) involving a putative quinone methide-like intermediate.² Inspired by both the structural and biological uniqueness of pleiomaltinine and the relative scarcity of enantioselective catalytic transformations involving quinone methide intermediates,³ we sought to explore the development of a general asymmetric annulation of indoles and pyrones. The established ability of neutral hydrogen-bond donors to catalyze enantioselective transformations of cationic intermediates through anion-binding mechanisms⁴ led us to consider whether the cooperative action of a chiral thiourea and an achiral Brønsted acid⁵ could promote stereoselective additions of nucleophilic indoles to cationic pyrone-derived quinone methide-like intermediates. In such a transformation, the formation of a chiral ion pair could render the formal nucleophilic addition step enantioselective to afford a chiral indoline bearing a quaternary carbon stereocenter at C3 (Figure 1).^6,7 We describe here the successful development of this strategy.

Figure 1.

An indole–pyrone annulation approach to pleiomaltinine and a proposed enantioselective variant.

Using the benzoic acid-catalyzed reaction of pyrone precursor 1 and 1,2,3,4-tetrahydrocarbazole (2a) as a model,⁸ we evaluated several chiral urea and thiourea derivatives that have been utilized previously with success in Brønsted acid-cocatalyzed reactions.⁵ While promising levels of enantioselectivity and reactivity were obtained with different classes of neutral hydrogen-bond-donor catalysts (Table 1),⁹ particularly high ee’s were observed with thiourea derivatives bearing a t-leucine arylpyrrolidino amide component (7).¹⁰ Through a systematic investigation of such substituted arylpyrrolidino derivatives, we found that new catalysts bearing the m-terphenyl motif¹¹ promoted the indole–pyrone addition with >95% ee (7d and 7e). Thiourea 7e was ultimately selected for further evaluation in the addition of various indole nucleophiles to γ-pyrone precursor 1 (Table 2). Both electron-withdrawing (3b–f) and electron-donating (3g–j) substituents on the indole ring were well-tolerated, indicating that the nucleophilicity of the reactive 3-position of the indole is not critical for high enantioselectivity.¹² Variation of both the 2- and 3-substituents on the indole was also possible (3k–m), although substitution at the 3-position was necessary to avoid rearomatization to an achiral product. The absolute configuration of (R)-3a was established unambiguously by X-ray crystallography, and all of the derivatized adducts were assigned by analogy.

Table 1. Catalyst Structure Optimization Studies.

Conditions: [1] = 0.05 M, 3 days. All reactions were conducted on a 0.05 mmol scale. Isolated yields are reported. Enantioselectivities of the O-mesylated derivative of 3a were determined by HPLC analysis on commercial chiral columns. See the Supporting Information for details.

^aNo BzOH was added.

Table 2. Substrate Scope of Indole–Pyrone Additions.

Conditions: [1] = 0.05 M, 3 days. Products were derivatized to the corresponding O-mesylates (3 equiv of RSO₂Cl, 5 equiv of NEt₃, CH₂Cl₂, overnight) for isolation and ee determination. Products 3b and 3l were derivatized to O-tosylates. Isolated yields of the corresponding sulfonates are reported. All reactions were conducted on a 0.1 mmol scale. Enantioselectivities were determined by HPLC analysis on commercial chiral columns. See the Supporting Information for details.

^aThe reaction was conducted on a 0.05 mmol scale with 1.09 equiv of indole.

Several experiments were carried out with the goal of shedding light on the mechanism of catalysis and enantioinduction in this indole–pyrone addition reaction. Variation of the identity or the amount of the Brønsted acid cocatalyst had remarkably little effect on the reaction outcome (Figure 2), suggesting that the acid does not participate directly in the enantiodetermining step. In contrast, variation of the leaving group on the pyrone precursor was found to impact the enantioselectivity, as the chlorinated analogue 8 underwent the reaction to afford adduct 3a with 84% ee using catalyst 7b while the benzoyl derivative 9 proved unreactive (Figure 3). Finally, the N-methylated analogue of 2a reacted with 1 in the presence of chiral thiourea 7e to afford only racemic cycloaddition product, revealing a crucial role of the indole N–H in the catalytic mechanism. Taken together, these findings are most consistent with an enantiodetermining step involving specific interactions between the catalyst and both the pyrone leaving group and the indole N–H moiety. We propose that 1 undergoes desilylation in the presence of the Brønsted acid. A cationic quinone methide-like intermediate is then generated by anion abstraction by the thiourea catalyst, with general base activation of the indole in the stereodetermining addition step (Figure 4).¹³ Additional attractive interactions (e.g., π–π or C–H−π) between the cationic electrophile and the catalyst pyrrolidine substituent are suggested by the dependence of the reaction enantioselectivity on the nature of that aromatic group.¹¹ A mechanistic picture emerges that bears resemblance to that invoked previously in the ring-opening reaction of episulfonium ions with indole nucleophiles,^5b thereby suggesting a possible general principle for enantioselective additions of indoles to cationic electrophiles.

Figure 2.

Variation of the Brønsted acid cocatalyst. Conditions: [1] = 0.05 M, 3 days. ^aThe reaction was conducted at 0 °C. Isolated yields are reported. Enantioselectivities of the O-mesylated derivative of 3a were determined by HPLC analysis on commercial chiral columns. See the Supporting Information for details.

Figure 3.

Variation of the pyrone precursor. Conditions: [1] = 0.05 M, 3 days. Isolated yields are reported. Enantioselectivities of the O-mesylated derivative of 3a were determined by HPLC analysis on commercial chiral columns. See the Supporting Information for details.

Figure 4.

Proposed catalytic cycle.

In summary, we have uncovered a highly enantioselective method for the addition of 3-substituted indoles to γ-pyrone-derived electrophiles, providing a route to simplified pleiomaltinine analogues bearing a defined quaternary stereocenter. Investigation of the biological activity of these unusual structures is underway. In addition, identification of the m-terphenyl group as the optimal substituent in this class of chiral thiourea catalysts is new;¹⁰ we are currently exploring the specific transition-state interactions associated with this aromatic framework in an effort to elucidate the basis for the stereoinduction in this reaction.

Supporting Information Available

Complete experimental procedures, characterization data, additional discussion of catalyst optimization and substrate scope, and crystallographic information (CIF) for compound (R)-3a. This material is available free of charge via the Internet at http://pubs.acs.org.

Author Contributions

^§ C.S.Y. and R.E.Z. contributed equally.

The authors declare no competing financial interest.

Funding Statement

National Institutes of Health, United States