Enantiopure Tetrahydro-β-carbolines via Pictet−Spengler Reactions with <i>N</i>-Sulfinyl Tryptamines

Gremmen, Christiaan; Willemse, Bianca; Wanner, Martin J.; Koomen, Gerrit‐Jan

doi:10.1021/ol006034t

Cited by 79 publications

(34 citation statements)

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“…To prove the absolute configuration of the obtained product 3 d , two independent asymmetric syntheses of optically enriched material according to reported procedures were repeated to have material to identify the elution order of the enantiomers. Both methods, namely using a chiral Brønsted acid4a or a chiral auxiliary,22 are reported to give the ( S )‐enantiomer. Comparison of the elution order of the enantiomers clearly proved that the four enzymes investigated led to the formation of the R ‐configured ( R )‐ 3 d (see Figure S20) 23…”

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confidence: 99%

Asymmetric Synthesis of (R)‐1‐Alkyl‐Substituted Tetrahydro‐ß‐carbolines Catalyzed by Strictosidine Synthases

et al. 2018

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Stereoselective methods for the synthesis of tetrahydro‐ß‐carbolines are of significant interest due to the broad spectrum of biological activity of the target molecules. In the plant kingdom, strictosidine synthases catalyze the C−C coupling through a Pictet–Spengler reaction of tryptamine and secologanin to exclusively form the (S)‐configured tetrahydro‐ß‐carboline (S)‐strictosidine. Investigating the biocatalytic Pictet–Spengler reaction of tryptamine with small‐molecular‐weight aliphatic aldehydes revealed that the strictosidine synthases give unexpectedly access to the (R)‐configured product. Developing an efficient expression method for the enzyme allowed the preparative transformation of various aldehydes, giving the products with up to >98 % ee. With this tool in hand, a chemoenzymatic two‐step synthesis of (R)‐harmicine was achieved, giving (R)‐harmicine in 67 % overall yield in optically pure form.

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confidence: 99%

Asymmetric Synthesis of (R)‐1‐Alkyl‐Substituted Tetrahydro‐ß‐carbolines Catalyzed by Strictosidine Synthases

et al. 2018

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“…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%

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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“…It should be noted that camphorsulfonic acid was used as the acid catalyst. However, it did not influence stereochemistry, because either racemic or pure (+)-isomer gave the same diastereomeric ratio of the N-sulfinyl-β-carboline (Scheme 14) [58]. The first attempt dates back to 1994 and used Nb-α-methylbenzyl substituted 5,6-dimethoxytryptamine, which provided a 60:40 dr [55].…”

Section: Chiral Auxiliariesmentioning

confidence: 99%

“…It should be noted that camphorsulfonic acid was used as the acid catalyst. However, it did not influence stereochemistry, because either racemic or pure (+)-isomer gave the same diastereomeric ratio of the N-sulfinyl-β-carboline (Scheme 14) [58]. (S)-Tetrahydro-β-carbolines were also obtained from Pictet-Spengler reaction using a chiral carbamate of tryptamine (Scheme 15).…”

Section: Chiral Auxiliariesmentioning

confidence: 99%

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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Enantiopure Tetrahydro-β-carbolines via Pictet−Spengler Reactions with N-Sulfinyl Tryptamines

Abstract: The influence of N-sulfinyl chiral auxiliaries on the stereochemistry of the Pictet-Spengler reaction has been investigated. From enantiopure (R)-N-p-toluenesulfinyltryptamine a new and efficient route to enantiopure tetrahydro-beta-carbolines has been established.

Cited by 79 publications

References 24 publications

Asymmetric Synthesis of (R)‐1‐Alkyl‐Substituted Tetrahydro‐ß‐carbolines Catalyzed by Strictosidine Synthases

Asymmetric Synthesis of (R)‐1‐Alkyl‐Substituted Tetrahydro‐ß‐carbolines Catalyzed by Strictosidine Synthases

Catalytic Asymmetric Pictet–Spengler Reactions via Sulfenyliminium Ions

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

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