Construction of C2‐C3 Contiguous Stereogenic Centers in Indoline Derivatives by 1,3‐Dipolar Cycloaddition

Abstract

We report a reduction‐condensation‐1,3‐dipolar cycloaddition sequence to create C2‐C3 contiguous stereogenic centers in indoline derivatives. This method includes a one‐pot procedure starting from easily obtainable nitroketones and can be applied to intrarmolecular cycloaddition to give highly functionalized isoxazolidines. Both a length of methylene tether and olefinic substituents strongly affect the cycloaddition mode (exo/endo approach) to give highly stereo‐controlled tri‐ and tetracyclic systems through a single operation. Intermolecular cycloaddition is also applicable to the construction of 3 stereocenters in range of 47‐87% yield.

Isatogenols as Precursors for the Synthesis of Fully Substituted Indolines through Regio- and Stereoselective [3 + 2] Cycloaddition Using Various Olefins

“…When the cycloaddition reaction was performed at 100 °C in toluene, the corresponding cycloadduct was obtained as a mixture of diastereomers in 55% yield, and the major isomer was assigned to be 3aa by X-ray crystallography (entry 1). This selectivity could be reasonably explained by an exo approach of 2a , which avoids the steric bulk of both the phenyl and ethyl groups in 1a . To improve the reaction efficacy, higher temperature conditions with/without microwaves (150 °C) were next investigated, and the latter conditions were found to be more suitable for this reaction: 3aa was obtained in 75% yield with higher selectivity in 8 h (entries 2 and 3).…”

“…1 Particularly, fully substituted indolines with a high density of tetra-substituted carbons and/or heteroatom functionalities often present serious difficulties in their quick and facile preparation, and new and efficient methods are still highly desired. 2 We also faced this problem in the course of synthetic studies on kopsia alkaloids and addressed the intramolecular cyclization reactions using well-designed substrates to construct contiguous stereocenters (Figure 1). 3 In general, the cycloaddition reaction is one of the most reliable and versatile synthetic methods for constructing complex ring systems, and new approaches and strategies are still strongly desired to enhance the synthetic efficiency and structural diversity of the substrates and products.…”

“…This selectivity could be reasonably explained by an exo approach of 2a, which avoids the steric bulk of both the phenyl and ethyl groups in 1a. 2 To improve the reaction efficacy, higher temperature conditions with/without microwaves (150 °C) were next investigated, and the latter conditions were found to be more suitable for this reaction: 3aa was obtained in 75% yield with higher selectivity in 8 h (entries 2 and 3). Subsequent solvent screening was also effective for optimizing the conditions, and we realized that acetonitrile was the best solvent and gave 3aa in 95% yield (entries 4−6).…”

“…Substituted indolines are one of the most important classes of heterocyclic synthons that are frequently observed in natural products, drug candidates, and the core structure of molecular catalysts, and the development of highly versatile synthetic methods that can accommodate various substitution patterns has been a major challenge in synthetic organic chemistry . Particularly, fully substituted indolines with a high density of tetra-substituted carbons and/or heteroatom functionalities often present serious difficulties in their quick and facile preparation, and new and efficient methods are still highly desired . We also faced this problem in the course of synthetic studies on kopsia alkaloids and addressed the intramolecular cyclization reactions using well-designed substrates to construct contiguous stereocenters (Figure ).…”