A Diversity‐Oriented Approach to Spiroindolines: Post‐Ugi Gold‐Catalyzed Diastereoselective Domino Cyclization

Abstract

Gold-catalyzed carbocyclization and heteroannulation strategies have recently attracted much attention owing to the selective and efficient activation of the CC bond towards a wide range of nucleophiles that these methods provide.[1] Domino approaches involving gold-catalysis lead to complex heterocyclic compounds under exceedingly mild reaction conditions.[2] Although gold-catalyzed approaches are rising to prominence, they suffer in terms of diversity and procedural length. Multistep sequences are usually required for assembling the starting material for cyclization. We have recently reported a concise route to indoloazocines by a sequential Ugi/gold-catalyzed intramolecular hydroarylation approach.[3] Inspired by these findings and as a result of our continued synthetic interest in the indole core, [4] multicomponent reactions [5] and transition metal-catalysis, [6] we have developed a post-Ugi gold-catalyzed domino cyclization method to generate spiroindolines.The Ugi four-component reaction (4-CR) [7] of indole-3-carboxaldehyde (1 a) with p-methoxybenzyl amine (2 a), 2-butynoic acid (3 a) and tert-butyl isonitrile (4 a) in methanol at 50 8C gave Ugi-adduct 5 a in 71 % yield. When this was treated with 5 mol % of Au[PPh 3 ]OTf (OTf = trifluoromethanesulfonate) in CDCl 3 at RT, the expected outcome of the reaction was indoloazepinone 6 a' through an endo-dig cyclization [1m,n, 3] followed by rearrangement (Scheme 1). Surprisingly, an exo-dig cyclization followed by intramolecular trapping of the spiro intermediate occurred instead, resulting in the diastereoselective formation of tetracyclic spiroindoline 6 a in 61 % yield (Scheme 1).This observation was remarkable, as the attack on the a-position of an alkyne conjugated with an amide is rare, and trapping of the spiro intermediate by a sterically hindered tert-butyl amide is rather unexpected, as was the diastereoselectivity observed. Spiroindolines [8] are prominent molecular motifs that are frequently encountered among the large family of alkaloids; for example, it is present in communesines [8,9] and perophoramidines [8,10] (Figure 1), which display distinct pharmacological properties. [8][9][10] These fused polycyclic systems, which feature quaternary stereocenters, present a nontrivial challenge for organic chemists to develop synthetic approaches.

Metal-mediated post-Ugi transformations for the construction of diverse heterocyclic scaffolds

“…33,34 The developed post-Ugi, Au(I)-catalyzed diastereoselective domino cyclization process involved a ''branched-handed'' pre-cyclization architecture resulting from the chiral center present in the Ugi adduct 81. The expected outcome of the reaction was an indoloazepinone through an endo-dig cyclization and rearrangement sequence.…”

“…[32][33][34] To access such alkaloids in a one pot cascade fashion and securing diversity is highly desirable from the viewpoint of sustainable chemistry. The first one-pot multicomponent attempt towards such complex alkaloids was reported by El Kaïm and co-workers 32 whereby spirocyclization was achieved using a stoichiometric amount of Cu(II) salt in refluxing DBU-THF system.…”

Regioselective Synthesis of Elusive 4,9-Dihydro-1H-Carbazoles by Gold-Catalyzed Cycloisomerization of 3-Allenylmethylindoles

“…In this regard, goldcatalyzed reactions of alkyne-functionalized indoles allow the construction of a wide range of heteropolycyclic frameworks. [23][24][25][26][27][28][29][30][31][32][33] However, related cycloisomerizations of indoles with a tethered allene have been less studied. [34][35][36] In particular, a gold-catalyzed hydroarylation of N-allenylmethylindoles that furnishes dihydro-pyrido[1,2-a]-1H-indoles has been described (Scheme 1a).…”

Diastereoselective synthesis and biological evaluation of enantiomerically pure tricyclic indolines

“…20 It was hypothesized that a chiral precursor would induce a change in the transition state of the cyclization, ultimately favouring one stereochemical outcome over the others. Computation studies also suggest the stereochemical outcome for these reactions is often under kinetic control.…”