Diels–Alder cyclization for the synthesis of carbazolespirooxindoles.
Source: Modified from Ren et al. [32].
In 2015, Jørgensen and coworkers reported an elegant catalytic methodology for the synthesis of biologically relevant complex spirocyclobutaneoxindole derivatives 236 (Scheme 3.22) [34]. The chemistry is based on the organocatalytic enamine‐based activation of cyclopropanes 237, forming a reactive donor–acceptor cyclopropane intermediate that in the presence of 3‐alkylidene oxindoles 238 promotes the formal [2+2] cycloaddition reaction to construct the spiranic products 236 in good yields, high diastereomeric ratios, and excellent enantiomeric excesses (15 examples, 3.2 : 1–>25 : 1 dr,70–97% ee). In fact, the reaction outcome is surprising since the traditional Lewis acid activation of donor–acceptor cyclopropanes typically promotes the [3+2]‐cycloaddition pathway. After mechanistic studies, the authors propose two possible reaction mechanisms for the spirocyclobutaneoxindole formation. The first plausible mechanism involves the organocatalytic activation of the cyclopropyl functionality leading to the formation of the iminium‐ion intermediate 239 by ring opening. From this intermediate, the dienamine 240 can be formed by deprotonation. Then, this dienamine intermediate reacts in a formal [2+2]‐cycloaddition with the 3‐olefinic oxindole 238 to form the spirocyclobutaneoxindole product 236. An alternative mechanistic possibility considers an initial [3+2]‐cycloaddition between the 3‐alkylidene oxindole and the organocatalytically activated cyclopropane, followed by a ring‐contracting rearrangement. However, the lack of a rational driving force for this rearrangement makes the latter reaction pathway more unlike.
Scheme 3.21 NHC‐catalyzed [4+3] annulation of oxotryptamines with enals to access enantioenriched spiro‐ϵ‐lactam oxindoles.
Source: Modified from Liu et al. [33].
Scheme 3.22 Organocatalytic enamine‐activation of cyclopropanes for highly stereoselective formation of spiranic cyclobutanes.
Source: Modified from Halskov et al. [34].
The development of switchable intermolecular reactions that afford divergent reaction pathways is an attractive and powerful strategy to build up structural and stereogenic diversity in drug discovery. In this context, Ouyang, Chen, and coworkers reported an aminocatalytic divergent cycloaddition toward the formation of two different types of spirocompounds 249 and 250 using the same set of substrates (Scheme 3.23) [35]. By simply changing the cocatalyst, the reaction pathway is switched from trienamine to dienamine activation mode. On the one hand, the in situ‐generated 4‐aminofulvenes act as 6π partners in the γ,β´‐regioselective [6+2] cycloaddition with activated 2π alkenes under the catalysis of 252 or 253 and salicylic acid 254. On the other hand, the α,γ‐regioselective [4+2] cycloaddition reaction is promoted with the catalytic system 255/2‐mercaptobenzoic acid 256. In the latter case, the β′‐regioselective sulfur addition of thiol 256 to 251 gives access to the enone 257 that after condensation with the chiral amine forms the 4π dienamine component in the reaction with activated alkenes. The [6+2] cycloaddition reaction mode provides fused bicycles linked to a pyrrolidinone ring 250 with five contiguous stereogenic centers (28 examples) while the [4+2] pathway affords spiro‐bridged cyclic scaffold 249 (22 examples).
Scheme 3.23 Chiral primary amine‐catalyzed regiodivergent asymmetric cycloadditions.
Source: Modified from Zhou et al. [35].
3.3.4 Organocatalytic Miscellaneous Strategies to Construct Spiro Compounds
The group of Tu reported the enantioselective synthesis of spiro[4.4]nonane‐1,6‐diones 266, which represents the first direct example for the asymmetric synthesis of cyclopentanones using a Nazarov cyclization/semipinacol‐rearrangement sequence (Scheme 3.24) [36]. Substrate design revealed key for the successful development of the present strategy, where a cyclobutanol motif is connected to the α‐position of the cyclization precursor to induce the 1,2‐rearrangement. This tandem process is promoted by means of a chiral N‐triflylphosphoramide catalyst 268 to construct complex spirocompounds with four consecutive stereocenters in excellent stereocontrol (15 examples, 93 : 7–>99 : 1 dr, 84–97% ee). Computational calculations were performed to understand the reaction mechanism as well as the stereochemical outcome. The reaction begins with the formation of a hydrogen‐bond complex between the substrate and the catalyst. Then, the substrate is protonated by the catalyst and can be regarded as a pentadienyl cation, which then undergoes 4π‐conrotatory electrocyclization via TS1. The Nazarov reaction step is irreversible, since the transition state TS2 following the ring expansion event is much lower in energy. Then, the intermediate 269 undergoes a [1, 2] migration via TS2 to generate the intermediate 270 that is finally protonated to afford the spiranic product 266.
In other example of Bronsted acid catalysis, Tan and coworkers developed an enantioselective strategy for the construction of axially chiral compounds 277 (Scheme 3.25) [37]. This important class of spirocompounds is widely found in materials, organocatalysts, and ligands. The enantioselective intramolecular cyclization of ketals 278 to afford the SPINOL derivatives 277 is successfully catalyzed by the chiral phosphoric acid 279. Various ketals with different substitution patterns, including electron‐donating and electron‐withdrawing groups at the aryl ring, performed smoothly, affording the corresponding products 281–284 in high enantioselectivities and good to excellent yields (90−96% ee, 62−95% yield, conditions a). In the case of ketals bearing aromatic groups at the ortho position, the catalyst 280 (conditions b) was necessary to obtain the corresponding products. Remarkably, the catalytic system can be used at gram‐scale and the catalyst loading can be decreased as little as 0.1 mol%, despite higher temperature and prolonged reaction time are necessary.
Scheme 3.24 Organocatalytic asymmetric tandem Nazarov cyclization/semipinacol rearrangement.
Source: Modified from Yang et al. [36].
On
