Cooperative catalysis of N-heterocyclic carbene and Brønsted acid for a highly enantioselective route to unprotected spiro-indoline-pyrans

Abstract

A chiral cooperative catalysis of NHC and Brønsted acid for a formal [4+2] reaction of unprotected isatins and enals was developed for the direct synthesis of unprotected spiro[indoline-3,2'-pyran]-2,6'(3'H)-diones in good to excellent yields (up to 95%) with high enantioselectivities (up to >93% ee).

A Cooperative Ternary Catalysis System for Asymmetric Lactonizations of α‐Ketoesters

“…[1] Homoenolate annulations with carbonyl compounds give rise to enantioenriched γ-butyrolactones, which are prevalent structural motifs in natural and bioactive products, [2] as well as direct precursors to substituted tetrahydrofurans, [3] furans, [4] and nucleoside analogues. [5] While isatins, [6] acyl phosphonates, [7] and trifluoromethyl-substituted aryl ketones [8] are selective carbonyl electrophiles with NHC-homoenolate annulations, aryl aldehyde electrophiles [9] afford only moderate annulation yields and enantioselectivities, and simple alkyl ketones are not currently productive substrates (Figure 1A). [1d] The use of α-ketoesters as electrophiles for homoenolate annulations has had only limited success to date.…”

“…[1d] The use of α-ketoesters as electrophiles for homoenolate annulations has had only limited success to date. [10] Successful examples of homoenolate additions to carbonyl groups, particularly isatins, [6a-c] have employed an additive or co-catalyst (e.g., Lewis acid (LA), Brønsted acid (BA), or hydrogen bond donor (HBD)) to enhance the enantioselectivity and yield of the reaction (Figure 1A). Cooperative NHC catalysis with compatible Lewis acid or HBD catalysts [11] to activate electrophiles for Umpolung transformations has recently emerged as a powerful strategy to access complex molecular frameworks with high selectivity.…”

“…Cooperative NHC catalysis with compatible Lewis acid or HBD catalysts [11] to activate electrophiles for Umpolung transformations has recently emerged as a powerful strategy to access complex molecular frameworks with high selectivity. [6b, 9, 12] Despite these advances, the use of co-catalysts has not been explored for NHC-catalyzed homoenolate additions to α-ketoesters. We envisioned that under this new type of activation, a co-catalyst could potentially preorganize the α-ketoesters in a fixed geometry, generating a stereodefined ensemble in the enantiodetermining bond formation step (Figure 1B).…”

“…Inspired by previous cooperatively-catalyzed NHC annulations, conditions using lithium chloride, [3e, 6b] titanium isopropoxide, [9c] scandium triflate, [12e] zinc triflate, magnesium di-tert-butoxide, [12a, 12e] and HBDs as co-catalysts were screened with no improvement to the enantioselectivity (see SI). A variety of magnesium and calcium alkoxides and HBDs were screened as co-catalysts with azolium A , which led to moderate enantioselectivities (32–45% ee, entries 2–3 and SI).…”

“…Aromatic ortho-, meta-, and para-substituted enals ( 3e–3k ) effectively formed lactones with moderate to high levels of %ee (75–99). While alkyl enals expectedly afforded lower yields (35% of 3l , 57% of 3m ), [6b, 9b, 16] they provided lactone products with good %ee’s (up to 87%). Ortho-substituted aromatic α-ketoesters did not react, as reported previously, [10c, 10e] but other aromatic α-ketoesters ( 3o–3q ) gave lactones with moderate to high enantioselectivities (89–98% ee).…”