Organocatalytic, Asymmetric Eliminative [4+2] Cycloaddition of Allylidene Malononitriles with Enals: Rapid Entry to Cyclohexadiene‐Embedding Linear and Angular Polycycles

Abstract

A direct aminocatalytic synthesis has been developed for the chemo-, regio-, diastereo-, and enantioselective construction of densely substituted polycyclic carbaldehydes containing fused cyclohexadiene rings. The chemistry utilizes, for the first time, remotely enolizable π-extended allylidenemalononitriles as electron-rich 1,3-diene precursors in a direct eliminative [4+2] cycloaddition with both aromatic and aliphatic α,β-unsaturated aldehydes. The generality of the process is demonstrated by approaching 6,6-, 5,6-, 7,6-, 6,6,6-, and 6,5,6-fused ring systems, as well as biorelevant steroid-like 6,6,6,6,5- and 6,6,6,5,6-rings. A stepwise reaction mechanism for the key [4+2] addition is proposed as a domino bis-vinylogous Michael/Michael/retro-Michael reaction cascade. The utility of the malononitrile moiety as traceless activating group of the dicyano nucleophilic substrates is demonstrated.

Exploiting the Distal Reactivity of Indolyl Methylenemalononitriles: An Asymmetric Organocatalyzed [4+2] Cycloaddition with Enals Enables the Assembly of Elusive Dihydrocarbazoles

“…At the outset, we easily prepared N ‐Boc‐protected 2‐methylindolyl‐methylenemalononitrile 1 a from commercially available 2‐methylindole‐3‐carboxaldehyde by N‐protection and a high‐yielding Knoevenagel condensation with malononitrile (see the Supporting Information for details). To test the feasibility of the transformation described in Scheme C, the reaction between 1 a and cinnamaldehyde ( 2 a ) was first carried out in CH 2 Cl 2 at room temperature in the presence of 20 mol % ( S )‐configured TMS‐prolinol [( S )‐ C1 ] and 20 mol % Et 3 N, using the previously established catalytic conditions . We were pleased to find that under these conditions, 1 a underwent the desired eliminative cycloaddition with 2 a giving dihydrocarbazole 3 aa with an exceptional enantioselectivity (99 % ee ), albeit in only moderate yield (Table , entry 1).…”

“…The chiral environment in the resulting donor/acceptor complex AB allows the subsequent bis‐vinylogous Michael attack to proceed stereoselectively, forming the chiral enamine C . Next, this intermediate undergoes an intramolecular Michael ring closure to form substituted tetrahydrocarbazole D which, upon hydrolysis and release of both the catalyst and the malononitrile handle, finally furnishes the ( R )‐configured dihydrocarbazole 3 aa…”

“…In particular, it is reasonable to assume that initial formation of the indole o-quinodimethane A and iminium ion B from the respective malononitrile 1a and aldehyde 2a takes place under the assistance of the binaryp rolinol/(iPr) 2 NEt catalytic system. The chirale nvironment in the resultingd onor/acceptor complex AB allows the subsequent bis-vinylogousM ichael attack [12] to proceed stereoselectively,f orming the chiral enamine C.N ext, this intermediate undergoes an intramolecular Michael ring closure to form substituted tetrahydrocarbazole D which,u pon hydrolysis andr elease of both the catalysta nd the malononitrile handle, [5,13] finally furnishes the (R)-configured dihydrocarbazole 3aa.…”

“…To test the feasibility of the transformation described in Scheme 1C,t he reaction between 1a and cinnamaldehyde (2a)w as first carriedo ut in CH 2 Cl 2 at room temperature in the presence of 20 mol %( S)-configured TMS-prolinol [(S)-C1]a nd 20 mol %E t 3 N, using the previously established catalytic conditions. [5] We were pleasedt of ind that under these conditions, 1a underwent the desired eliminative cycloaddition with 2a giving dihydrocarbazole 3aa with an exceptional enantioselectivity (99 % ee), albeit in only moderate yield (Table 1, entry 1). With this promisingr esult in hand, we proceeded to optimize the reaction, aiming to increase the efficiency,a nd at the same time, maintain the almostp erfect enantiocontrolo ft he lead conditions.…”

“…With this promisingr esult in hand, we proceeded to optimize the reaction, aiming to increase the efficiency,a nd at the same time, maintain the almostp erfect enantiocontrolo ft he lead conditions. Variation of solvents indicatedt hat, except for toluene,o ther solvents such as THF, acetonitrile, and ethanolf urnished very low yields, if any,o f 3aa (entries [2][3][4][5]. No substantial improvement in yield was observed under increased or decreased reactionc oncentration (entries 6a nd 7), whereas the yield dropped to about 20 % when the catalystl oadingw as reduced to 10 mol %( entry 8).…”