Catalytic Asymmetric [8+2] Annulation Reactions Promoted by a Recyclable Immobilized Isothiourea

Abstract

Cyclic structures are ubiquitous in natural products and pharmaceutical compounds. Among the myriad strategies devised to construct such architectures, [1] cycloadditions constitute one of the most efficient approaches in terms of atom economy and overall reaction selectivity.[2] Indeed, the synthesis of rings having up to 6 members by either thermal or photochemical [2+2], [3] [3+2] [4] and [4+2] [5] processes is well established. On the other hand, the synthesis of medium and large rings through reactions involving more than six p electrons (the so called higher order cycloadditions [6] ) represents an interesting approach to build complex polycyclic compounds and bridge-containing carbocyclic products. However, this alternative [7] is often hampered by lack of periselectivity and other competing side reactions [8] which, along with the extra challenge of transferring chiral information across a number of bonds, can explain the lack of general methods to produce enantioenriched compounds via higher order cycloadditions.[9]Heptafulvenes [10] and their heteroanalogues (tropone, [11] tropothione [12] and the azaheptafulvenes [13] ), a subclass of the "non-benzenoid aromatic compounds" family, have been recognized as important synthons for higher order cycloadditions due to their conjugated cyclic polyolefin systems. Among all the possible reaction pathways that can be attained with heptafulvene derivatives, the [8+2] cycloaddition provides a direct approach to highly functionalized bicyclic [5.3.0] rings, which are core scaffolds in numerous natural products. [14] Since the first [8+2] cycloaddition introduced by Wiley et al. in 1960, [15] various methodologies to carry out this process have been described, [16] but enantioselective versions remain scarce: to the best of our knowledge, a metal-mediated cycloaddition reported by the Feng group [17] (Scheme 1a) and an organocatalytic cycloaddition described by the Jørgensen group [18] (Scheme 1b) are the only catalytic enantioselective [8+2] reactions found in the literature. Therefore, the development of a general and efficient approach for the peri-, regio-and stereoselective [8+2] cycloaddition reaction remains a highly attractive and challenging target.We envisioned that chiral ammonium enolates [19] (derived from activated carboxylic acids and isothioureas) could be suitable reaction partners to undergo catalytic [8+2] cycloadditions with azaheptafulvenes, which would play the role of 8p dipolarophiles. Herein, we present the implementation of this strategy, which leads to enantioenriched 7,5-fused heterocyclic compounds (Scheme 1c). The cycloheptatrienes generated can be either hydrogenated or derivatized in a Diels-Alder reaction that affords bridged polycyclic products in a highly regioselective manner. Based on our previous works on formal hetero-[4+2] cycloadditions promoted by an immobilized isothiourea of the benzotetramisole (BTM) type, [19e,19g] a model reaction of the azaheptafulvene 2a with phenylacetic acid 3a catalyzed by polystyre...

The Game of Electrons: Organocatalytic Higher‐Order Cycloadditions Involving Fulvene‐ and Tropone‐Derived Systems

“…In 2017 Pericàsa nd co-workersp resented ah ighly enantioselective approach to [8+ +2]-cycloaddition (Scheme 26). [35] In this protocol, rarely employed N-arylazaheptafulvenes 91 wereu tilized as hetero-tetraenes. Interestingly,c hiral ammonium enolates 95 weres elected as suitable tetraenophiles for this annulation.…”

Arylacetic Acids in Organic Synthesis

“…Similarly, treatment of arylacetic acids with pivaloyl chloride (PivCl) would lead to an electrophilic intermediate 44.1 , which then reacted with N, O, or Se‐nucleophiles (Eq. 44‐1).…”

“…As described by the Pericàs group, when 44.1 was subjected to the asymmetric [8+2]‐cycloaddition with azaheptafulvenes, cyclo heptatrienes 45.1 were obtained (Eq. 45‐1).…”

“…45‐1). These ring constructions utilized the polystyrene supported isothiourea (BTM) as recyclable catalyst (11 cycles, accumulated TON of 76.8). Besides, the Pericàs group also explored the utilization of BTM catalyst in the asymmetric [4+2]‐annulations via a Michael addition/cyclization process (Eq.…”

Recent Developments on Supported Hydrogen‐bond Organocatalysts

“…The immobilization of an isothiourea derived from benzotetramisole onto polystyrene led to a supported benzotetramisole catalyst, which has been successfully employed on enantioselective [8+2] annulation reactions between azaheptafulvalenes with phenylacetic acids . The catalyst reusability was studied by filtering it after completion of each catalytic cycle and reusing by addition of fresh reactants.…”