Targeting Structural and Stereochemical Complexity by Organocascade Catalysis: Construction of Spirocyclic Oxindoles Having Multiple Stereocenters

Abstract

Dedicated to Professor Alfredo Ricci on the occasion of his 70th birthdayThe structural complexity and well-defined three-dimensional architecture of natural molecules are generally correlated with specificity of action and potentially useful biological properties.[1] This complexity has inspired generations of synthetic chemists to design novel enantioselective strategies for assembling challenging target structures and reproducing the rich structural diversity inherent in natural molecules. This symbiotic correlation between natural compounds synthesis and the discovery of effective asymmetric-generally catalytic [2] -technologies lies at the heart of the synthetic chemistry innovation.[3] Despite the substantial advances made thus far, the construction of highly strained polycyclic structures (particularly those that contain spiro-stereocenters) and the generation of all-carbon quaternary stereocenters still remain daunting targets for synthesis. [4,5] The spirocyclic oxindole core is featured in a number of natural products [6] as well as medicinally relevant compounds [7] (Figure 1), but its stereocontrolled synthesis, particularly installing the challenging spiro-quaternary stereocenter, poses a great synthetic problem. Only a few venerable asymmetric transformations, such as cycloaddition processes [8] or the intramolecular Heck reaction, [9] have proven suitable for achieving this challenging goal.Herein we show that asymmetric organocascade catalysis, [10] which exploits the ability of chiral amines to efficiently combine two modes of catalyst activation of carbonyl compounds (iminium and enamine catalysis) into one mechanism, [11] allows the direct, one-step synthesis of complex spirooxindolic cyclohexane derivatives; these products have three or four stereogenic carbon atoms and are obtained with extraordinary levels of stereocontrol starting from simple precursors. Specifically, we developed complementary organocatalytic multicomponent domino reactions based on two distinct organocatalysts, A and B, which efficiently activate carbonyl compounds such as ketones and aldehydes, respectively, toward multiple asymmetric transformations in a welldefined cascade sequence. Both strategies provide straightforward access to natural product inspired compound collections, [12] which would be difficult to synthesize by other enantioselective methods.

Organocatalytic, Asymmetric [2+2+2] Annulation to Construct Six-Membered Spirocyclic Oxindoles with Six Continuous Stereogenic Centers

“…Thus, in the first step of this one-pot process, reaction of 3 with the lactol 2a affords the enamine A, which allows for si-face attack of the olefinic oxindole 1a, leading to formation of lactol B with (R,R)-configured stereocenters. This should be consistent with the observations of the earlier studies [33,38,40]. The key intermediate lactol B containing a lactol moiety is found as an equilibrium mixture with the corresponding hydroxyaldehyde C. Subsequently, the second Michael addition was conducted between the hydroxyaldehyde C and β-nitrostyrene 4g in the presence of TEA, which occurs from Si-face attack followed by the Henry reaction providing the desired product 5g as a single diastereoisomer, and obviously, the high stereoselectivity can be attributed to the directing effect of the primary chiral substituted groups in the structure.…”

“…The key intermediate lactol B containing a lactol moiety is found as an equilibrium mixture with the corresponding hydroxyaldehyde C. Subsequently, the second Michael addition was conducted between the hydroxyaldehyde C and β-nitrostyrene 4g in the presence of TEA, which occurs from Si-face attack followed by the Henry reaction providing the desired product 5g as a single diastereoisomer, and obviously, the high stereoselectivity can be attributed to the directing effect of the primary chiral substituted groups in the structure. Therefore, the structure and stereochemistry of 5g could be determined based on the relative configuration from the single-crystal X-ray analysis of racemate 5g and combined with several known activation modes in the reaction of olefinic oxindole 1a and aliphatic aldehydes driven by (S)-diphenylprolinol TMS ether 3 [33,38,40]. …”

“…As a result, great efforts have been devoted towards the development of practical methods for the production of these types of compounds with diverse substitution patterns [23][24][25][26][27]. However, concerning both the number of total stereoisomers and molecular complexity, it is challenging to stereoselectively install six continuous stereogenic centers on a six-membered ring, especially one containing spirocyclic oxindole structures which might have potential bioactivity [28][29][30][31][32][33][34][35][36][37]. Among the reported approaches, the organocatalyzed [2+2+2] tandem cycloaddition has emerged as a pivotal strategy to construct fully substituted six-membered carbocycles (Scheme 1) [38][39][40].…”

Direct asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes via dienamine catalysis

“…2), chiral primary amines easily derived from natural sources, as general and effective catalysts for a wide variety of asymmetric α and β functionalizations of ketones (35,36). We have further demonstrated the ability of catalyst A, derived from hydroquinine, to combine orthogonal aminocatalytic modes (iminium and enamine activations) into one mechanism, thus promoting cascade reactions with α,β-unsaturated ketones (37,38) and even with the challenging α,β-disubstituted enals (39).…”

Organocatalysis

“…9 The enantiomeric excess could be enhanced by a single recrystallization to afford essentially enantiomerically pure material. …”