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

Abstract

The first enantioselective Pictet–Spengler reaction of acyclic α-ketoesters with tryptamines has been developed. Excellent yields and enantioselectivity were obtained for the reaction using chiral imidazoline-phosphoric acid catalysts. Density functional theory calculations suggested possible transition states that explain the origin of chiral induction. This process provides an efficient route for the synthesis of tetrahydro-β-carboline derivatives.

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

“…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) [12] . It is important to note that 1,1‐disubstituted tetrahydro‐β‐carbolines have been found in a number of bioactive natural products such as ecteinascidins, [13] peganumine, [14] arborisidine, [15] subincanadine alkaloids [16] and is a much sought‐after skeleton in medicinal chemistry [17] .…”

“…[5b] Very recently, Nakamura reported a CPA-catalyzed enantioselective PSR involving α-ketoesters as electrophiles (Scheme 1e). [12] It is important to note that 1,1-disubstituted tetrahydro-β-carbolines have been found in a number of bioactive natural products such as ecteinascidins, [13] peganumine, [14] arborisidine, [15] subincanadine alkaloids [16] and is a much sought-after skeleton in medicinal chemistry. [17] The development of a catalytic enantioselective PSR with ketones is therefore a challenging yet important endeavor.…”

Enantioselective Reaction of N-Unprotected Activated Ketimines with Phosphine Oxides Catalyzed by Chiral Imidazoline-Phosphoric Acids

“…The reaction using commercially available chiral phosphoric acid catalysts 4a – c proceeded to give desired product 3aa in moderate yield with low enantioselectivity (Table , entries 1–3). To improve the enantioselectivity, the reaction was conducted using bis­(imidazoline)-phosphoric acid catalysts 4d – f and imidazoline-phosphoric acid catalysts 4g , 4h (Table , entries 4–8) . The bis­(imidazoline)-phosphoric acid catalyst 4d was an efficient catalyst for this reaction giving high yields and enantioselectivities (Table , entry 4).…”