Direct Asymmetric Vinylogous Aldol Reaction of Allyl Ketones with Isatins: Divergent Synthesis of 3‐Hydroxy‐2‐Oxindole Derivatives

Abstract

Hydroxy-2-oxindole derivatives, which contain a quaternary stereogenic center at the 3-position, are a family of structurally diverse natural or nonnatural products with interesting biological activities. [1] The asymmetric synthesis of 3-hydroxy-2-oxindole derivatives, such as donaxaridine (1), [1b-c] (R)chimonamidine (2), [1d] CPC-1 (3), [1e] and (À)-flustraminol B (4) [1f] (Scheme 1, series I), has recently been intensely pursued, as these compounds exhibit a broad spectrum of biological activities and are promising potential drugs. Previously established methods [2] for the preparation of these derivatives mainly focused on the asymmetric hydroxylation of 3-substituted 2-oxindoles [3] and the nucleophilic addition to isatins, [4] employing compound A as a viable synthon (Scheme 1). The synthesis of related 3-hydroxy-2oxindole derivatives (5-7) of series II has attracted considerable interest for a long time because of their fascinating architectures and potential biological activities. For example, spirolactone 5 has shown potential cytotoxic activity. [1g-i] Spiroether 6 was reported to be a CB2 agonist and is thus a potential drug candidate for reducing neuropathic and bone pains, and for treating a host of diseases, including osteoarthritis, atherosclerosis, osteoporosis, and cancers. [1g] Hexahydrozaepino[2,3-b]indole 7, which bears a unique 5,7bicyclic framework, can be used as a tranquilizer for mammals and birds. [1h-i] However, to the best of our knowledge, no asymmetric protocol that affords this class of compounds has been presented to date.Compared with the traditional "single target" approach, the design of a common intermediate is the key in the total synthesis of different products through a divergent synthesis strategy, which has enabled the formation of a variety of target molecules without compromising efficiency. [5] As part of our ongoing research efforts toward the development and utilization of synthetic tools for the formation of quaternary stereogenic centers, [3b, 6] we were interested in designing a novel organocatalytic asymmetric reaction to achieve the divergent synthesis of 3-hydroxy-2-oxindole derivatives, including those in series I and II.Retrosynthetic analyses suggested that the synthetic route to intermediates A and B was reasonable. We deduced that compound C could be assembled as the common intermediate for the divergent synthesis of 3-hydroxy-2-oxindole derivatives of series I and II. We therefore focused on the asymmetric vinylogous aldol reaction of the carbonyl-activated allyl nucleophile D with isatin (Scheme 1).The Mukaiyama-type aldol reaction of silyl dienol ethers is the favored protocol to furnish vinylogous aldol adducts, but can suffer from low atom economy and efficiency. [7] In this context, a direct asymmetric approach for these reactions would be highly valuable. In recent years, cyclic 2-furanone derivatives have been used as versatile nucleophiles in direct vinylogous aldol reactions, as shown by the research groups of Zhang, [8a] Terada, [8b...

Catalytic Enantioselective Ynamide Additions to Isatins: Concise Access to Oxindole Alkaloids

“…To the best of our knowledge, this is the first example of a natural product synthesis utilizing a terminal ynamide in a catalytic enantioselective nucleophilic addition reaction. This approach to oxindole alkaloids is very efficient and it compares favorably with previous reports on asymmetric chimonamidine synthesis ,,. The reductive tosyl deprotection was also successfully applied in the synthesis of the chimonamidine derivative 24 , which demonstrates that the ynamide chemistry is well suited for the production of a variety of medicinally interesting alkaloids.…”

“…This is particularly the case for the family of 3‐substituted 3‐hydroxyindolin‐2‐ones, which share an important structural motif commonly found in alkaloids such as chimonamidine and various emerging drug candidates . To this end, we noticed that a few reports on the asymmetric synthesis of chimonamidine I , all suffering from low overall yields, have appeared in the literature ,,. Retrosynthetic analysis pointed toward an unprecedented 3‐(aminoethynyl)‐3‐hydroxyindolin‐2‐one scaffold II that could be generated through catalytic enantioselective addition of terminal ynamides to isatins III of which a wide variety is commercially available (Figure ).…”

Chitosan Aerogel Catalyzed Asymmetric Aldol Reaction in Water: Highly Enantioselective Construction of 3-Substituted-3-hydroxy-2-oxindoles

“…Consequently, the 3-substituted-3-hydroxy-2-oxindole framework has been an intensively investigatedsynthetic target. To construct 3-substituted-3-hydroxy-2-oxindoles, asymmetric aldol reaction has been considered one of the most powerful and efficient measures for the formation of carbon-carbon bond at C-3 position [16][17][18][19][20][21]. In this context, the asymmetric aldol reaction between isatin and carbonyl compounds has attracted much attention.…”

Organocatalytic γ-oxidation of α,β-unsaturated aldehydes

“…A chiral catalyst not only forms dienamine but also differentiates between the two faces of the double bond providing an enantioselective process. The γ-nucleophilic character of dienamine was exploited in the vinylogous aldol, [10][11][12] and Michael 13,14 reactions. For example, the reaction of allyl ketones with isatins catalyzed by Lvaline-derived bifunctional tertiary amine/thiourea catalyst gave E-configured vinylogous aldol adducts in high yield and ee up to 99%.…”

“…This mode of activation was also applied in the elegant synthesis of tocopherol 10 and chromenes. 12 The organocatalytic formal [4+2] cycloaddition reaction of α,β-unsaturated aldehydes was applied in the synthesis of (+)-palitantin.…”