Asymmetric Control in the Pictet–Spengler Reaction by Means of <i>N</i>‐Protected Amino Acids as Chiral Auxiliary Groups

Schmidt, G.; Waldmann, Herbert; Henke, Henning; Burkard, Michael

doi:10.1002/chem.19960021215

Cited by 35 publications

(13 citation statements)

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“…This salt was collected by filtration and then neutralized to provide pure 1 a in 87 % yield and with 84 % ee ( Table 2). Comparison of the sign of the specific rotation of the product with literature data [3] indicated that (S)-1 a was formed as the major enantiomer when (R)-9 d was used as the catalyst.…”

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confidence: 94%

“…It is possible to start with an enantiomerically pure chiral tryptamine, such as a tryptophan derivative, or aldehyde; alternatively, the use of a chiral auxiliary attached to the nitrogen atom has been successful. Two remarkable examples are the cyclization of the N-acyliminium ion 2, in which an a-N,Nphthaloylamino acid is used as a chiral auxiliary, [3] and the cyclization of the N-sulfinyliminium ion 3, with the use of menthyl p-toluenesulfinate as a chiral reagent.[4] The former procedure proceeds with very high diastereoselectivity, but the chiral auxiliary can be removed only under relatively harsh reductive conditions. Lower selectivity is observed with the second method, but the diastereomers are readily separable, and the sulfinyl auxiliary can be cleaved easily by mild hydrolysis.…”

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confidence: 99%

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Catalytic Asymmetric Pictet–Spengler Reactions via Sulfenyliminium Ions

et al. 2007

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The Pictet-Spengler condensation of tryptamine (or a substituted analogue) with an aldehyde, usually in the presence of an excess of a Brønsted acid, [1] is the reaction of choice for the preparation of tetrahydro-b-carbolines (for example, 1), a structural moiety present in many alkaloids and related biologically active molecules. [2] Several strategies have been applied to the synthesis of tetrahydro-b-carbolines in enantiomerically pure form. It is possible to start with an enantiomerically pure chiral tryptamine, such as a tryptophan derivative, or aldehyde; alternatively, the use of a chiral auxiliary attached to the nitrogen atom has been successful. Two remarkable examples are the cyclization of the N-acyliminium ion 2, in which an a-N,Nphthaloylamino acid is used as a chiral auxiliary, [3] and the cyclization of the N-sulfinyliminium ion 3, with the use of menthyl p-toluenesulfinate as a chiral reagent.[4] The former procedure proceeds with very high diastereoselectivity, but the chiral auxiliary can be removed only under relatively harsh reductive conditions. Lower selectivity is observed with the second method, but the diastereomers are readily separable, and the sulfinyl auxiliary can be cleaved easily by mild hydrolysis.The first example of a reagent-controlled enantioselective Pictet-Spengler-type cyclization was reported by Nakagawa and co-workers.[5] They described the ring closure of nitrone 4 with up to 90 % ee under the influence of a chiral borane (ca. 2 equiv) as a Lewis acid. Two examples of catalytic asymmetric Pictet-Spengler reactions have been reported recently: Taylor and Jacobsen described the cyclization of the N-acyliminium ion 5 with up to 95 % ee under the catalysis of an enantiomerically pure thiourea, [6a] and List and co-workers disclosed the cyclization of the iminium diester 6 with up to 96 % ee under the catalysis of an enantiomerically pure phosphoric acid derived from binaphthol.[6b] Although both methods are impressive examples of the power of asymmetric organocatalysis, the former has the disadvantage that the Nacetyl group is difficult to remove, and the latter is clearly limited in scope by the requirement of two ester functionalities.Within our research program on the development of asymmetric reactions of iminium ions catalyzed by chiral Brønsted acids, we considered the use of N-sulfenyliminium ions as intermediates in the Pictet-Spengler condensation. [7] The sulfenyl substituent was expected to stabilize the intermediate iminium ion and thus favor Pictet-Spengler cyclization over undesired enamine formation.[8] Another advantage of the sulfenyl group is that its ready removal after the cyclization is ensured. Herein, we demonstrate the powerful combination of chiral phosphoric acids and Nsulfenyl tryptamines as a useful method for catalytic asymmetric Pictet-Spengler reactions.The use of phosphoric acids derived from binaphthol as chiral catalysts in asymmetric synthesis was shown recently by two Japanese research groups to be highly successful for the addition of...

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Catalytic Asymmetric Pictet–Spengler Reactions via Sulfenyliminium Ions

et al. 2007

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“…The reaction conditions were suitable for both aliphatic and aromatic aldehydes. However, removal of the auxiliary was obtained with LiAlH4 in only 66% yield (Scheme 16) [60]. The obtained carboline was R-configured that is enantiomeric with that obtained in the previous examples.…”

Section: Chiral Auxiliariesmentioning

confidence: 82%

The Chiral Pool in the Pictet–Spengler Reaction for the Synthesis of β-Carbolines

Dalpozzo

2016

Molecules

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Abstract:The Pictet-Spengler reaction (PSR) is the reaction of a β-arylethylamine with an aldehyde or ketone, followed by ring closure to give an aza-heterocycle. When the β-arylethylamine is tryptamine, the product is a β-carboline, a widespread skeleton in natural alkaloids. In the natural occurrence, these compounds are generally enantiopure, thus the asymmetric synthesis of these compounds have been attracting the interest of organic chemists. This review aims to give an overview of the asymmetric PSR, in which the chirality arises from optically pure amines or carbonyl compounds both from natural sources and from asymmetric syntheses to assemble the reaction partners.

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“…The stereoselectivity was influenced by condensation with chiral carbonyl derivatives [6] or by the use of internal [7] or external devices [8]. 4.…”

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The Pictet-Spengler Reaction Updates Its Habits

et al. 2020

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The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores such as tetrahydro-isoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), and polyheterocyclic frameworks. In the lustro (five-year period) following its centenary birthday, the P-S reaction did not exit the stage but it came up again on limelight with new features. This review focuses on the interesting results achieved in this period (2011–2015), analyzing the versatility of this reaction. Classic P-S was reported in the total synthesis of complex alkaloids, in combination with chiral catalysts as well as for the generation of libraries of compounds in medicinal chemistry. The P-S has been used also in tandem reactions, with the sequences including ring closing metathesis, isomerization, Michael addition, and Gold- or Brønsted acid-catalyzed N-acyliminium cyclization. Moreover, the combination of P-S reaction with Ugi multicomponent reaction has been exploited for the construction of highly complex polycyclic architectures in few steps and high yields. The P-S reaction has also been successfully employed in solid-phase synthesis, affording products with different structures, including peptidomimetics, synthetic heterocycles, and natural compounds. Finally, the enzymatic version of P-S has been reported for biosynthesis, biotransformations, and bioconjugations.

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Asymmetric Control in the Pictet–Spengler Reaction by Means of N‐Protected Amino Acids as Chiral Auxiliary Groups

Cited by 35 publications

References 22 publications

Catalytic Asymmetric Pictet–Spengler Reactions via Sulfenyliminium Ions

Catalytic Asymmetric Pictet–Spengler Reactions via Sulfenyliminium Ions

The Chiral Pool in the Pictet–Spengler Reaction for the Synthesis of β-Carbolines

The Pictet-Spengler Reaction Updates Its Habits

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