An N‐Heterocyclic Carbene/Lewis Acid Strategy for the Stereoselective Synthesis of Spirooxindole Lactones

Abstract

A cooperative catalysis approach for the enantioselective formal [3+2] addition of α,β-unsaturated aldehydes to isatins has been developed. The N-heterocyclic carbene (NHC)-catalyzed homoenolate annulations of β-aryl enals require the addition of lithium chloride for high levels of enantioselectivity. This NHC-catalyzed annulation provides efficient access to the 3-hydroxy indole skeleton and has been applied to the first eantioselective total synthesis of maremycin B. Keywordscatalysis; asymmetric synthesis; N-heterocyclic carbene; homoenolate; Lewis acid; total synthesis The development of efficient strategies for the stereoselective construction of privileged heterocyclic systems is an ongoing objective in chemical synthesis. Over the last decade, the development of powerful NHC-catalyzed homoenolate equivalents has allowed access to a wide range of hetero-and carbocyclic structural motifs. [1] Despite significant advancements in this NHC-homoenolate field with additions to activated C=X systems by Glorius, Bode, Nair, our group, and others, [2] the combination of these interesting and unconventional nucleophilic species with less active electrophiles, such as ketones, remains challenging. [3] In addition, rendering these carbonyl addition processes enantioselective remains an important goal since these annulation reactions provide an efficient method for accessing bioactive γ-butyrolactones. We have been investigating cooperative carbene catalysis [7] However, the use of alkali metal salts in NHC reactions is underexplored and represents a new combination given that these salts play critical roles in a variety of carbon-carbon bond forming reactions. [8] The impact of alkali metal salt effects on carbene catalyzed reactions has been observed by us, [9a] Lupton, [9b] and You, [9c] and we sought to explore for the first time the potential of these metal salts in the context of NHC-homoenolate additions to ketones. We report herein the highly enantioselective, NHC-catalyzed addition of αβ-unsaturated aldehydes to isatins activated by lithium cations (Figure 1). In this formal [3+2] annulation, the alkali salt significantly enhances the level of enantioselectivity in the resultant spirooxindole products.In 2006, Nair reported an interesting NHC-catalyzed annulation of 1,2-diketones with enals to generate racemic spirocyclic lactone products as a 1:1 mixture of diastereomers. [3b, 10] Recently, You reported a related enantioselective annulation which relies on a hydrogenbonding NHC catalyst. [11] Our group has been interested in the preparation of spirooxindoles [12] due to the prevalence of this structural motif in a number of architecturally complex and biologically relevant natural products ( Figure 1). [13] Given our strong interest in the synthesis of these compounds and carbene catalysis, we became interested in developing an NHC-catalyzed method for accessing these privileged structures in a diastereo-and enantioselective manner.We began our studies by combining N-methyl isatin (1) with ...

Kooperative Katalyse mit N‐heterocyclischen Carbenen

“…[14] Zuvor hatte unsere Gruppe über eine NHC-katalysierte intramolekulare Michael-Reaktion berichtet, die mit hoher Enantioselektivitätz uR ingsystemen führt (Schema 5b). [18] Bei Kontrollreaktionen zeigte sich, dass der Austausch von Lithium gegen verschiedene Lewis-Säuren (Na + oder K + )o der die Sequestrierung mit Kronenether zu einer geringeren Enantioselektivitätführte. [16] Stark chelatisierende Substrate waren ein vorrangiges Ziel fürd ie kooperative NHC/Lewis-Säure-Katalyse.…”

A Cooperative N‐Heterocyclic Carbene/Chiral Phosphate Catalysis System for Allenolate Annulations

“…Notably, the use of NHC/Lewis acid or Brønsted acid cooperative catalysis for enhancing selectivity and incorporating previously inactive reaction partners has seen significant success. [7],[8] Despite the demonstrated utility of chiral Brønsted acids (CBAs) for a variety of asymmetric transformations, [9],[10],[11] the combination of NHCs and chiral Brønsted acids represents new opportunity for small molecule activation. Herein we report a general cooperative NHC/chiral Brønsted acid strategy to achieve a highly enantioselective addition of alkynals to α-ketoesters (Figure 1).…”

“…of lithium chloride (entry 3). [7f] Even though the reaction yield was poor, this result indicated that lithium cations may be activating methyl benzoylformate toward addition. The introduction of chiral Brønsted acid F ( 20 mol %) with achiral NHC from B produced a significant increase in yield (54%), but the annulation product was effectively racemic (entry 4).…”

“…Considering the p K a values of the azolium and Brønsted acids, [15],[16] it is likely under these conditions that phosphoric acid F would be deprotonated initial, and the NHC might not be generated in high enough concentrations from the azolium salt precatalyst. A second aspect is whether the lithium cation is involved in organizing the transition state [7f],[17] or if lithium tert -butoxide was simply acting as a base. To probe this possibility, sodium tert -butoxide or magnesium di- tert -butoxide was employed as the base, no product was obtained, suggesting the involvement of lithium cation in the reaction mechanism (entries 17 and 18).…”

Highly Enantioselective Intermolecular Stetter Reaction of Simple Acrylates: Synthesis of α‐Chiral γ‐Ketoesters

“…[7] Encouraged by this result, an extensive screening of the reaction parameters, such as solvent, base, and temperature, was conducted, but the conversion could not be increased above 20 %. [11] When the benzhydrylpyrrolidine moiety was replaced with the common benzylpyrrolidine system, a significant reduction of ee (91 to 82 %) was observed. A crystal structure of 5 b is shown in Figure 1.…”