Diastereoselection in the Formation of Spirocyclic Oxindoles by the Intramolecular Heck Reaction

Abstract

Diastereoselective double Heck cyclizations of cyclohexene diamides 1 and 3 form contiguous quaternary stereocenters, with diastereoselection being controlled by the trans-diol protecting group. In this, the first in a series of two papers, the origin of diastereoselection in the first ring-closure step of these reactions is examined. Nine simplified analogues of 1 and 3 were synthesized and cyclized to discern what structural features are required to realize high diastereoselection in the first intramolecular Heck reaction. These studies show that high stereoselection (>20:1) does not arise from a single structural feature: it is seen only in substrates that contain both a trans-acetonide and a tertiary amide substituent at C2. Two subtle factors appear to be involved: (1) Avoidance of eclipsing interactions between the forming C-C bond and the pseudoaxial hydrogen atom at C6 and between the pseudoequatorial hydrogen atom at C6 and the carbonyl carbon of the forming spirooxindole. (2) The vinylic amide substituent that is not involved in the insertion event preferentially adopts a perpendicular conformation, placing the sterically bulky NR(2) over the alkene pi bond. syn-Pentane-like interactions between this substituent and the C3 of the cyclohexene are avoided in the favored insertion topography. These two effects, when combined, produce a highly diastereoselective process.

Transition‐Metal‐Mediated Routes to 3,3‐Disubstituted Oxindoles through Anilide Cyclisation

“…The origin of the change in diastereoselectivity was further investigated by Overman and Watson in an in-depth study. [35] The trimeric member of the above family, idiospermuline, was also prepared by way of an oxindole-forming intramolecular Heck reaction onto a pre-existing dimeric subunit. [36] A further bis-oxindole-forming Heck reaction was also employed in the total syntheses of the tetrameric members, quadrigemine C (34) and psycholeine (35), by Overman and co-workers; in these particular cases the bis-cyclisation occurs at remote sites.…”

“…[35] The trimeric member of the above family, idiospermuline, was also prepared by way of an oxindole-forming intramolecular Heck reaction onto a pre-existing dimeric subunit. [36] A further bis-oxindole-forming Heck reaction was also employed in the total syntheses of the tetrameric members, quadrigemine C (34) and psycholeine (35), by Overman and co-workers; in these particular cases the bis-cyclisation occurs at remote sites. [37] The total synthesis of the highly complex alkaloid communesin F (36) via an oxindole intermediate generated through a Heck cyclisation was recently completed by Weinreb and co-workers.…”

Nucleophilic Aromatic Substitution

“…33 The use of a new bulky phosphoramidate ligand for the palladium catalyst has been reported in the debromohydrogenation reaction of (9), the chromium tricarbonyl complex of dibromonaphthalene; the product is formed in a highly enantiomerically enriched form. 34 Br Br Cr(CO) 3 (9) Diastereoselectivity has also been achieved in the intramolecular double-Heck cyclizations of some cyclohexene diamides to form spirocyclic oxindoles; the structural features responsible for imparting diastereoselection in the first 35 and second 36 ringclosure reactions have been examined. The results of studies of the Heck vinylation of aryl bromides with 2-substituted enol ethers using a tetraphosphine-palladium catalyst have been reported; the stereoselectivity of the reaction depends on both steric and electronic factors with the Z-isomers being favoured for electron-rich or sterically de congested aryl bromides.…”

Total Synthesis of Complex Cyclotryptamine Alkaloids: Stereocontrolled Construction of Quaternary Carbon Stereocenters

“…Cyclotryptamine Alkaloids Angewandte Chemie dimethylacetamide (DMA) proceeded with moderate stereoselectivity to provide pentacyclic dioxindole 52 bearing a cis relationship between its two spirooxindole groups (Scheme 13, top). [78,79] By changing the protecting groups on the trans vicinal diol precursor from silyl substituents to an acetonide, divergent stereoselectivity in the Heck cascade was observed under identical experimental conditions (Scheme 13, bottom). Remarkably, this latter reaction, in either the diiodide or ditriflate series, provided pentacyclic dioxindole 55 in nearly quantitative yield.…”