Calcium-catalyzed Pictet-Spengler reactions

Pictet-Spengler reactions of m-tyramine and aldehydes produced tetrahydroisoquinolines in the presence of a catalytic amount of Ca[OCH(CF3)2]2. This reaction occurs with a variety of aryl, heteroaryl, and alkyl aldehydes, producing tetrahydroisoquinolines in high yield and with high regioselectivity. This calcium-promoted Pictet-Spengler reaction provides a mild alternative to the traditional Br?nsted acids typically employed in these reactions.     

Regioselectivity of Pictet-Spengler cyclization reactions to construct the pentacyclic frameworks of the ecteinascidin-saframycin class of tetrahydroisoquinoline antitumor antibiotics

The regiochemical outcome of Pictet-Spengler cyclization reactions directed toward the preparation of the pentacyclic core of the ecteinascidin class of antitumor antibiotics has been investigated on two different phenolic substrates. In one substrate, the assistance of an incipient benzylamine group at C-4 is postulated to direct the cyclization in favor of the pentacyclic framework of ET-743, which bears a hydroxyl group at C-18. Conversely, cyclization of an alternative substrate lacking a heteroatom at C-4 favors the opposite regiochemical outcome, primarily affording an unnatural pentacyclic core bearing a hydroxyl group at C-16.     

Chemistry of dicationic electrophiles: superacid-catalyzed reactions of amino acetals

Amino acetals are shown to form highly electrophilic systems in Bronsted superacids. It is proposed that amino acetals give dicationic electrophiles, and this proposal is supported by the direct observation of a dication by low-temperature (13)C NMR. When reacted with C(6)H(6) and superacidic CF(3)SO(3)H, amino acetals are shown to provide 1-(3,3-diphenylpropyl)amines and 1-(2,2-diphenylethyl)amines as condensation products in good yields (50-99%).     

Calcium-promoted Pictet-Spengler reactions of ketones and aldehydes

Calcium bis-1,1,1,3,3,3-hexafluoroisopropoxide is shown to be an effective catalyst for Pictet-Spengler reactions of 3-hydroxyphenethylamine and 3-hydroxy-4-methoxyphenethylamine with various aldehydes and ketones. Previous Lewis acid catalyzed Pictet-Spengler reactions of unactivated ketones typically require two separate reactions (imine formation, cyclization) to obtain the same results. The reactions described within directly provide 1,1'-disubstituted tetrahydroisoquinolines from the corresponding amine and ketone. These rare examples of Pictet-Spengler reactions of unactivated ketones demonstrate the unique nature of calcium as a Lewis acid catalyst.     

Stereoselectivity and regioselectivity in the segment-coupling Prins cyclization

The scope of the segment-coupling Prins cyclization has been investigated. The method is outlined in Scheme 1 and involves esterification of a homoallylic alcohol (1), reductive acetylation to give the alpha-acetoxy ether (3), and cyclization on treatment with a Lewis acid to produce a tetrahydropyran (4). Alkene geometries dictate the product configurations, with E-alkenes leading to equatorial substituents and Z-alkenes leading to axial substituents (Table 1). Not unexpectedly, applying the method to allylic alcohols leads to fragmentation rather than a disfavored 5-endo-trig cyclization. Dienols in which one alkene is allylic and the other alkene is homoallylic cyclize efficiently and produce the tetrahydropyrans 49-54, Table 3. Dienols with two homoallylic alkenes cyclize with modest to high regioselectively, generating tetrahydropyrans 40-45, Table 2. The relative rates for cyclization decrease in the order of vinyl > Z-alkene > E-alkene > alkyne. The configurations of the products are consistent with cyclization via a chair conformation, Figure 1. The 2-oxonia Cope rearrangement may be a factor in the regioselectivity of diene cyclizations and in the erosion of stereoselectivity with Z-alkenes. This investigation establishes the stereoselectivity and regioselectivity for a number of synthetically useful segment-coupling Prins cyclizations.     

Enantioselective BINOL-phosphoric acid catalyzed Pictet-Spengler reactions of N-benzyltryptamine

Optically active tetrahydro-beta-carbolines were synthesized via an ( R)-BINOL-phosphoric acid-catalyzed asymmetric Pictet-Spengler reaction of N-benzyltryptamine with a series of aromatic and aliphatic aldehydes. The tetrahydro-beta-carbolines were obtained in yields ranging from 77% to 97% and with ee values up to 87%. The triphenylsilyl-substituted BINOL-phosphoric acid proved to be the catalyst of choice for the reaction with aromatic aldehydes. For the aliphatic aldehydes, 3,5-bistrifluoromethylphenyl-substituted BINOL-phosphoric acid was identified as the best catalyst.     

Solid-phase parallel synthesis of natural product-like diaza-bridged heterocycles through Pictet-Spengler intramolecular cyclization

A multistep, practical solid-phase strategy for the synthesis of natural product-like diaza-bridged heterocycles was developed. A key step in the library synthesis is tandem acidolytic cleavage with subsequent in situ iminium formation followed by the Pictet-Spengler intramolecular cyclization. The Pictet-Spengler-type intramolecular cyclization step was regioselective and diastereoselective to give final products as single diastereomers in exceptional yields and purities, which was confirmed by NMR structural study and LC/MS analysis. This approach is exemplified by the preparation of a 384-member library of 3,9-diazabicyclo[3.3.1]non-6-en-2-one skeletons, fused with indole and dihydroxybenzene and diversified at two bridging nitrogen atoms, using the solid-phase parallel synthetic methodology without further purification. In this pilot library, two diastereomerically enriched diaza-bridged core skeletons were modified by amide and urea bond formation on bridging nitrogen atoms, and this scheme exhibits the potential for expansion to obtain further diversification.     

Stereoselectivity in 6-halopenicillanate grignard reactions

Structural modifications of 6-halopenicillanate Grignards result in increased “aldol” stereoselectivity. The intermediacy of tetrahedral penicillin carbanions in THF and β-lactam enolates in CH₂Cl₂/toluene is proposed.     

Stereoselectivity in micellar and vesicular reactions

The diastereoselectivity of esterolytic cleavage of certain dipeptide and tripeptide activated esters is lower in thiol-functionalized vesicles than in comparable micelles. This is thought to be a mechanism-specific effect related to the greater molecular ordering in vesicular systems.     

Thiophenol-mediated improvement of the Pictet-Spengler cyclization of N-tosyl-β-phenethylamines with aldehydes

The Lewis acid-catalyzed Pictet-Spengler condensation of N-tosyl-β-phenethylamines with aldehydes is improved by the addition of thiophenol, furnishing better yields of 1-substituted tetrahydroisoquinolines at a given time.     

Organomediated Morita-Baylis-Hillman cyclization reactions

We have developed the Morita-Baylis-Hillman reaction to include, for the first time in a completely organomediated process, intramolecular examples bearing allylic leaving groups as the electrophilic partner providing a facile, high yielding, straightforward synthesis of densely functionalized cyclic molecules.     

Short synthesis of piperizinohydroisoquinoline ring by selective Pictet-Spengler cyclization and evaluation of antitumor activity

A rapid access to the piperizinohydroisoquinoline motif, which has feature of the saframycins and related pentacyclic antitumor alkaloids is described. The key features of the synthetic strategy include (1) a controlled mono-Pictet-Spengler cyclization of the symmetrical 3,6-bis-[(2,5-dimethoxy-phenyl)methyl]piperizine-2,5-dione (1), with aldehydes to give 2, under a critically controlled ratio of acetic acid and trifluoroacetic acid as solvent and (2) reduction of the activated amide to the hemiaminal, which then undergoes an unexpected dehydrogenation reaction to remove the steric hindrance for the second Pictet-Spengler cyclization to form the pentacyclic piperizinohydroisoquinoline 6. The in vitro antitumor activity of these compounds was tested against five human cancer cell lines (A549 lung, HeLa cervical, SAS oral, SKHep1 hepatoma and PC-3 prostate carcinoma). The pentacyclic saframycin analogues 6, 7 and 9 showed only weak activities. Interestingly, compound 6, having a closer relation to cribrostatin IV, is selective towards oral cancer.     

Stereoselectivity in reactions of atropisomeric lactams and imides

A range of reactions of cyclic lactam systems is described in which an atropisomeric C-N axis controls the stereochemical outcome of ring substitution or addition. In the case of enantiopure menthol adducts, substitution via N-acyliminium intermediates occurred with essentially complete control. However, the range of nucleophiles that participate in the reaction is very limited and at present the removal of the N-aryl substituent is problematic. A six-membered enamide is of moderate configurational stability and the axis exerts synthetically useful levels of control over enolate alkylations of the system. A novel Lewis acid mediated enamide arylation process was identified.     

Stereoselectivity in the diels-alder reactions of tropylium ion

New Diels-Alder reactions of tropylium ion are studied, and the observed stereo-selectivities suggest that solvent effects determine the steric course of these reactions.     

Solid-phase intramolecular N-acyliminium Pictet-Spengler reactions as crossroads to scaffold diversity

A novel solid-phase intramolecular Pictet-Spengler reaction is presented. The approach utilizes masked aldehyde building blocks protected as their N-Boc-1,3-oxazinanes for the clean generation of solid-supported aldehydes. When exposed to simple acidic treatment, the aldehyde functionality is rapidly released and becomes susceptible to nucleophilic attack from an amide nitrogen of the peptide backbone, which results in the formation of a highly reactive cyclic N-acyliminium ion. Subsequently, a quantitative and highly stereoselective Pictet-Spengler reaction takes place by attack of the indole from a neighboring tryptophan, thus appending two new N-fused rings to the indole moiety. Extension of this intramolecular reaction to substituted indoles, and other reactive heterocycles, such as furane and thiophenes, provides a convenient and rapid access to a range of pharmacologically interesting tri- and tetracyclic scaffolds. Finally, the reaction products may conveniently be released from the solid support (PEGA) by cleavage of the base-labile linker (HMBA).     

Reactive dications: the superacid-catalyzed reactions of alkynes bearing adjacent N-heterocycles or amine groups

A variety of aminoalkynes and related heterocycles are reacted in the Bronsted superacid CF(3)SO(3)H (triflic acid), and products are obtained in generally good yields (69-99%) from Friedel-Crafts-type reactions. The reactions are consistent with the formation of novel dicationic intermediates having a vinyl cationic site and an adjacent protonated N-heterocycle or ammonium cation.     

Pictet-Spengler reactions of Tryptamine and tryptophan with cycloalkanones and ketonicMannich bases

APictet-Spengler reaction of Tryptamine (1) with cyclopentanone under physiological conditions gave 3-(cyclopentylideneaminoethyl)indole (3), which was cyclized to the 1-spirocyclic 1,2,3,4-tetrahydro-2-carboline (4). Treatment of (±)-tryptophan with cyclopentanone and cyclohexanone in acidic medium afforded the spirocyclic systems5 and6, respectively. ThePictet-Spengler reaction was extended further using ketonic bis-Mannich bases, to give compounds7 and8. The possibility of using other types of ketonic bases was investigated.

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DiePictet-Spengler-Reaktion von Tryptamin and Tryptophan mit Cycloalkanonen und Keto-Mannich-Basen

Zusammenfassung DiePictet-Spengler-Reaktion von Tryptamin (1) mit Cyclopentanonen ergab unter physiologischen Bedingungen 30(Cyclopentylidenaminoethyl)indole (3), die zu den spirocyclischen Tetrahydro-2-carbolinen4 cyclisiert wurden. Die Behandlung von (±)-Tryptophan mit Cyclopentanon oder Cyclohexanon in saurem Milieu ergab die spirocyclischen Systeme5 oder6. DiePictet-Spengler-Reaktion wurde auch auf Keto-Bis-Mannich-Basen zur Synthese der Verbindungstypen7 und8 ausgeweitet. Die Möglichkeiten zur Nutzung anderer Keto-Basen wurde untersucht.

     

Highly efficient Lewis acid-catalysed Pictet-Spengler reactions discovered by parallel screening

High yielding Lewis acid-catalysed one-pot Pictet-Spengler reactions of tryptophan methyl ester and tryptamine with aliphatic and aromatic aldehydes were achieved in short reaction times with the aid of microwave irradiation.     

Racemization in Prins cyclization reactions

Isotopic labeling experiments were performed to elucidate a new mechanism for racemization in Prins cyclization reactions. The loss in optical activity for these reactions was shown to occur by 2-oxonia-Cope rearrangements by way of a (Z)-oxocarbenium ion intermediate. Reaction conditions such as solvent, temperature, and the nucleophile employed played a critical role in whether an erosion in enantiomeric excess was observed. Additionally, certain structural features of Prins cyclization precursors were also shown to be important for preserving optical purity in these reactions.