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]...

Kinetic Evidence of an Apparent Negative Activation Enthalpy in an Organocatalytic Process

“…The bond indices were calculated from canonical molecular orbitals in the atomic orbital basis and can be used to analyze the covalent bonding between atoms. The computed bond orders of 0.057 and 0.032 for these α-C-H···O bonding interactions are more significant with reference from our recent DFT studies with different derivatives of thiourea for catalytic organic transformation4546. The N-H···O hydrogen bonding interactions showed similar to prominently higher bond orders of 0.040, 0.098, and 0.155.…”

New Developments of the Principle of Vinylogy as Applied to π-Extended Enolate-Type Donor Systems

“…In 2013 Jiang and co-workers, inspired by previous work of Shibasaki, 239 − 241 where acyclic allyl cyanides were used as donors in direct asymmetric vinylogous aldol reactions, developed the first example of application of allyl ketones in catalytic asymmetric reactions. 242 The enantioselective direct vinylogous aldol reaction between allyl ketones 251 and isatins 252 ( Scheme 69 ) was catalyzed by the l -valine-derived bifunctional tertiary amine/thiourea catalyst ( C6 ), that is supposed to first deprotonate the allyl ketone at the α position and then bring the resulting enolate and the isatin electrophile together to form the hydrogen-bonded complex for the C–C bond formation. The reaction is highly enantio- and E -selective, and the best reaction outcome was achieved with unprotected isatins.…”

Asymmetric Synthesis of Tetrahydroisoquinoline Derivatives through 1,3-Dipolar Cycloaddition of C,N-Cyclic Azomethine Imines with Allyl Alkyl Ketones

“…The 1,3-dipoles of 1 [ 43 ], 2 [ 44 ], 3 [ 45 ] and 4 [ 46 , 47 , 48 , 49 , 50 , 51 ] were synthesized according to the literature methods. The substrates 5a−h were prepared according to the literature procedures [ 36 , 52 , 53 , 54 , 55 , 56 , 57 ]. Catalyst C1 was commercially available.…”