Pericyclic Cascade with Chirality Transfer: Reaction Pathway and Origin of Enantioselectivity of the Hetero‐Claisen Approach to Oxindoles

Abstract

A new pericyclic cascade is proposed for the chiral auxiliary‐controlled synthesis of 3,3‐disubstituted oxindoles from nitrones and ketenes. The remarkable acyclic 1,6‐stereochemical induction, hitherto unexplained, is rationalized by a stereoselective 3+2 cycloaddition step, which installs the stereochemistry, and a chirality transfer step facilitated by a hetero‐[3,3]‐sigmatropic rearrangement (see picture; PG=protecting group).

An asymmetric pericyclic cascade approach to 3-alkyl-3-aryloxindoles: generality, applications and mechanistic investigations

“…25 Subsequent studies extended this methodology to the construction of asymmetric 3,3-spirocarbocyclic oxindoles, 26 and computational studies led to a revised mechanistic rationale for these processes. 27 The mechanistic pathway is consistent with a 3+2 cycloaddition across the ketene C=O bond, with preferential anti-addition with respect to the aryl portion of the ketene. Facial selectivity in this cycloaddition is controlled by the preferred arrangement of large and electronegative allylic groups, and 1,3-allylic strain 28 within the enantiopure nitrone chiral auxiliary 4, generating a stereodefined five-membered intermediate 5.…”

“…Each of these steps was established by computational studies of the reaction transition states. 27 Acidic hydrolysis and concomitant cyclization generates the oxindole 8 with excellent enantiocontrol and regenerates chiral aldehyde 9 (Fig 3). 29 The ability of this methodology to generate highly substituted quaternary stereocentres at the oxindole C(3)-position with excellent enantiocontrol (up to 90% ee), coupled with the inexpensive nature of the starting materials, warranted further development of this reaction manifold.…”

“…Using the optimised N-TIBPS nitrone 20, an extensive ketene screen showed that numerous alkylarylketenes were well tolerated in this process, yielding the respective oxindoles in good yields although varying ee (Fig 8). 37 β-Branching of the alkyl group of the ketene component was well tolerated (27) and reaction with halo-arylketenes yielded oxindoles 28, 29 and 30 in excellent ee. The transformation is also compatible with a C(3)-indolyl substituent, which is common to many natural products, 38 as oxindoles 31 and 32 were furnished in 88% and 84% ee, respectively.…”

“…27 These studies described a novel 1,3-dipolar cycloaddition and hetero-[3,3]-rearrangement cascade (Scheme 1, Pathway A) involving a chirality transfer between the highly asynchronous but concerted pericyclic steps. Here, we extend our calculations to the SCS-MP2/6-31G(d)//MP2/6-31G(d) level of theory ( Figure 12), which provided the best results in an equivalent key [3,3]-sigmatropic rearrangement step of the acid-promoted Fischer indole reaction, where B3LYP optimizations were shown to yield highly asynchronous and dissociative transition states.…”

“…The geometry and electronic features are in good agreement with the previously described 3+2 cycloaddition TS obtained using B3LYP. 27 This cycloaddition step sets the stereochemistry of the 5-membered ring in the cycloadduct involving an unsymmetrically substituted exocyclic alkylidene group. The cycloadduct int-1 is 6.9 kcal/mol more stable relative to the separated reactants, and smoothly undergoes an An analogous [3,3]-rearrangement transition structure, TS'-[3,3], in a previously proposed nucleophilic addition and hetero-Claisen rearrangement mechanism (Scheme 1, pathway B) led to dissociation rather than rearrangement (red inset, Fig 12).…”