Synthesis of aza-quaternary centers via Pictet–Spengler reactions of ketonitrones

Abstract

Despite the array of advances that have been made in Pictet–Spengler chemistry, particularly as it relates to the synthesis of β-carboline derivatives of both natural and designed origin, the ability...

Screening for Generality in Asymmetric Catalysis

“…3A) is a venerable reaction with crucially important applications in laboratory and biological synthesis (27,28). The reaction has inspired intensive research efforts in search of asymmetric catalytic variants, and so far over a dozen distinct catalytic systems have been described (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Each study relied on optimization of catalyst and conditions around very limited numbers of model substrates, and resulted in the identification of highly enantioselective reactions.…”

“…Pictet-Spengler reactions can proceed via N-acyl-, N-protio-, and N-alkyl-iminium ion intermediates, and enantioselective catalytic variants have been identified for each of these manifolds (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). We selected reactions between N-benzyl tryptamines and aldehydes as a particularly convenient platform to survey the substrate/catalyst landscape.…”

Catalytic Enantioselective Pictet–Spengler Reaction of α‐Ketoamides Catalyzed by a Single H‐Bond Donor Organocatalyst

“…Leighton developed the first examples of chiral Lewis acidic chlorosilane ( 2 , 1.5 equiv) promoted enantioselective PSR of tryptamines with linear α‐ketoamides (Scheme 1b) [10] . Snyder and co‐workers reported recently a thiourea ( 1 b )‐catalyzed reaction of N ‐hydroxyl tryptamines with ketones involving a nitrone intermediate (Scheme 1c) [11] . In connection with the total synthesis of arborisidine, our group reported a squaramide ( 3 )‐catalyzed PSR between tryptamine and pentane‐2,3‐dione (Scheme 1d) [5b] .…”

“…[10] Snyder and co-workers reported recently a thiourea (1 b)catalyzed reaction of N-hydroxyl tryptamines with ketones involving a nitrone intermediate (Scheme 1c). [11] In connection with the total synthesis of arborisidine, our group reported a squaramide (3)-catalyzed PSR between tryptamine and pentane-2,3-dione (Scheme 1d). [5b] Very recently, Nakamura reported a CPA-catalyzed enantioselective PSR involving α-ketoesters as electrophiles (Scheme 1e).…”

Enantioselective Pictet–Spengler Reaction of Acyclic α-Ketoesters Using Chiral Imidazoline-Phosphoric Acid Catalysts

“…Recently, one example of the enantioselective Pictet–Spengler reaction of tryptamine with 2,3-pentanedione as an acyclic ketone using a chiral squaramide catalyst was reported by Zhu and co-workers (≤88% ee) . Snyder and co-workers reported an excellent result for the stepwise Pictet–Spengler type reaction of ketonitrones prepared from N -hydroxy tryptamines with ketones using chiral thiourea catalysts (≤84% ee). , However, to the best of our knowledge, there have been no reports on the catalytic enantioselective Pictet–Spengler reaction of acyclic α-ketoesters with tryptamines. On the contrary, we recently reported enantioselective Friedel–Crafts reactions and various enantioselective reactions with ketimines .…”