Modular Synthesis of Polycyclic Alkaloid Scaffolds via an Enantioselective Dearomative Cascade

Abstract

The polycyclic core of the akuammiline alkaloids can be synthesized from simple tryptamine and tryptophol derivatives via a Ag(I)-catalyzed enantioselective dearomative cyclization cascade sequence. The complex tetracyclic scaffolds are prepared via a rapid, versatile, three-step modular synthesis from simple commercially available indole derivatives in high yields and enantiomeric excess (up to 99% yield and >99% ee).C omplex polycyclic scaffolds are widely present in biologically important alkaloid natural products. The akuammiline alkaloids (see 1−5, Scheme 1A) are prominent examples, with various members of this diverse family of bioactive compounds based on a common tetracyclic core 6. 1 Accordingly, these alkaloids have attracted considerable attention from both synthetic and medicinal chemists; several innovative total syntheses have been accomplished, 2 although these methods often require multiple linear synthetic operations and are typically directed toward selected akuammiline synthetic targets. Alkaloids are unquestionably highly important in medicine, and strategies to access core alkaloid frameworks, via short and flexible synthetic sequences, are arguably of even greater value in medicinally oriented discovery, given their potential for the rapid assembly of diverse collections of complex, natural product-like scaffolds. 3 The dearomatization of indoles through reactions with tethered ynones is well established, 4 with many of these methods generating quaternary centers and forming multiple stereoisomers. However, partly due to the linear nature of the alkyne unit, controlling the enantioselectivity of such dearomatization reactions is challenging. This is illustrated by the limited number of enantioselective dearomatization reactions of alkyne-tethered indoles reported in the literature. 5 Furthermore, to the best of our knowledge, examples of highly enantioselective (>80% ee) indole dearomatization reactions employing ynone-tethered precursors have not yet been reported.In this manuscript, we report the successful realization of a Ag(I)-catalyzed enantioselective dearomatizing 6 cascade sequence for the rapid construction of the akuammiline alkaloid core scaffold 9 via ynone-tethered indoles 7 (Scheme 1B). Key to the success of this process was the selection of a chiral πacid catalyst able to perform three roles in the proposed cascade: (1) activation of the ynone moiety tethered to the C2-

Selectivity, Speciation, and Substrate Control in the Gold-Catalyzed Coupling of Indoles and Alkynes

“…In all cases the calculated transition states for carbon–carbon bond formation are located at low energy (<41 kJ mol –1 with respect to the reference state) and the C–C bond formation ( 1 → 2 ) step was calculated to be almost barrierless. These results, and others, − demonstrate the synthetic versatility of 1 as a framework to access a range of important structural motifs.…”

“… 5 , 35 Avoiding bis indolemethane formation is therefore a significant challenge, but one we were confident could be overcome by harnessing the unique reactivity of ynones. 3 , 5 , 8 , 9 , 11 , 13 In our previous work, we have shown that the electron-withdrawing carbonyl group of the ynone moiety can significantly enhance the reactivity of the alkyne when treated with a Au(I) catalyst. This enables ynones to be coupled with indoles under very mild conditions.…”

A Thiol-Mediated Three-Step Ring Expansion Cascade for the Conversion of Indoles into Functionalized Quinolines

“…This manuscript concerns a three-step cascade reaction sequence, starting from indole-tethered ynones 1 (Scheme ). In recent years, ynones of this type have emerged as valuable precursors for the preparation of a diverse array of molecular scaffolds. − For example, our groups and others have shown that the activation of the alkyne moiety of 1 promotes efficient dearomatizing spirocyclization , to form medicinally important spirocyclic indolenines 2 ; , this is most commonly done using π-acidic catalysts (especially Ag­(I) species), although Brønsted acids, palladium­(II) complexes, and electrophilic halogenation reagents can also be used ( 1 → 2 , Scheme a, step 1). ,, Our groups have also shown that dearomatization works well on 2-halogenated indoles (i.e., 1 where X = Cl, Br or I) and that the resulting indoleninyl halide products (i.e., 2 where X = Cl, Br or I) can be transformed further via reaction with nucleophiles, or via Pd-catalyzed cross-coupling, to substitute the halide for various other groups ( 2 → 3 , Scheme a, step 2) . Finally, our groups and others have demonstrated that spirocyclic indolenines of the form 3 will rearrange via a one-atom ring expansion reaction to form annulated quinolines, with both acidic and basic reagents able to promote this transformation ( 3 → 4 , Scheme a, step 3) …”

“…Quinolines are found in many marketed drugs, as well as in various other applications . On the basis of a growing understanding of each of the three individual processes discussed above, ,, we recognized that certain reagents may be able to promote all three steps and enable the transformation of 1 into 4 via a single-cascade process (Scheme b); such a reagent would need to act as an acid to promote step 1, a nucleophile in step 2, and a Brønsted acid to promote step 3. The successful realization of this strategy is reported herein, with thiols emerging as the optimum “multitasking” reagent class capable of promoting the envisaged cascade, under remarkably mild and operationally simple conditions.…”

Recent Advances in Synthetic Strategies for the C4a,C9a-Fused Tetracyclic Hydrocarbazole Core Structure of Minfiensine and Related Akuammiline Alkaloids

“…A similar type of activation of alkynes using Ag(I) for the construction of the tetracyclic hydrocarbazole skeleton was reported by Unsworth and co-workers (Scheme 5). 26,27 The 6-endo-dig cyclization of ynone 32 proceeded under similar conditions to those reported by Wang, and various tetracyclic hydrocarbazoles 35 were obtained in high yield with high enantioselectivity. The enantioselectivity of the products increased as the bulkiness of the R group was increased (35a-35c).…”