Highly diastereo- and enantioselective NHC-catalyzed [3+2] annulation of enals and isatins

Abstract

The chiral N-heterocyclic carbene bearing a proximal hydroxy group derived from L-pyroglutamic acid was found to be an efficient catalyst for the [3+2] annulation of enals and isatins to give the corresponding spirocyclic oxindolo-γ-butyrolactones in good yield with good diastereo- and enantioselectivities.

N‐Heterocyclic Carbene Catalyzed [4+3] Annulation of Enals and o‐Quinone Methides: Highly Enantioselective Synthesis of Benzo‐ε‐Lactones

“…and 94 % ee) when B3, having a bulky N-2-isopropylphenyl group, was utilized (entry 5). As reported, [8] the bulky substituent of B3 could circumvent the possible C1 addition of the generated Breslow intermediate, and thus facilitate the C3 addition. Solvent screening revealed that reaction went smoothly in various solvents with a slightly better diastereoselectivity observed in diethyl ether or 1,4-dioxane (entries 6- With the optimized reaction conditions in hand, the scope with respect to the o-quinone methides and enals was examined (Scheme 2).…”

“…[7] In 2004, Bode et al and Glorius et al independently reported the pioneering NHC-catalyzed [3+2] annulation of enals with aldehydes to give g-butyrolactones (Scheme 1 a). [8] Then, g-lactams were synthesized by reaction with imines.…”

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

“…Employing chiral azolium catalysts B-E resulted in a wide range of diastereo-and enantioselectivities, with the 2,6-diethylphenyl substituted triazolium precatalyst B being the catalyst of choice (entry 12-15). We discovered that with only 5 mol % catalyst B similar levels of conversion and selectivity were obtained (entry 16).With the optimized reaction conditions, we surveyed isatins with varying nitrogen protecting groups and substitution around the aromatic ring (Table 2, [3][4][5][6][7][8][9][10][11][12][13][14]. Electron withdrawing and donating substituents on the aromatic ring were well accommodated, providing the lactone products in 1.6-3.0:1 dr and 77-99% ee.…”

“…With the optimized reaction conditions, we surveyed isatins with varying nitrogen protecting groups and substitution around the aromatic ring ( Table 2, [3][4][5][6][7][8][9][10][11][12][13][14]. Electron withdrawing and donating substituents on the aromatic ring were well accommodated, providing the lactone products in 1.6-3.0:1 dr and 77-99% ee.…”

“…[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.…”