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1.
Org Biomol Chem ; 12(9): 1518-24, 2014 Mar 07.
Article in English | MEDLINE | ID: mdl-24448828

ABSTRACT

A short synthesis of N-substituted 3,4-diarylpyrroles by condensation of a phenacyl halide with a primary amine and a phenylacetaldehyde is reported. The key step is an intramolecular cyclization of an in situ generated enamine onto a ketone. Using differently substituted aromatic reactants and N-(3-aminopropyl)azatricyclodecane as the amine component, the preparation of analogs of the cytotoxic marine alkaloid halitulin could be achieved. The cytotoxicity of some of the compounds obtained by this method was studied, and one of them proved to be a very potent derivative, acting at a nanomolar concentration, in a caspase-independent cell death mechanism.


Subject(s)
Antineoplastic Agents/pharmacology , Pyrroles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Death/drug effects , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HCT116 Cells , Humans , K562 Cells , Molecular Structure , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity Relationship
3.
Org Lett ; 12(21): 4760-3, 2010 Nov 05.
Article in English | MEDLINE | ID: mdl-20882970

ABSTRACT

Addition of 5-alkylaminopenta-2,4-dienals onto N-acyliminium ions, generated in situ from α-hydroxycarbamates derived from pyrrolidine or piperidine, in the presence of zinc triflate, followed by dehydrative cyclization, allowed the formation of pyridinium salts substituted at their 3-position by a five- or six-membered nitrogen heterocycle. Subsequent N-dealkylation of the pyridinium moiety and deprotection of the secondary amine or reduction of the carbamate function led to (±)-nicotine and analogs.


Subject(s)
Acrylates/chemistry , Amines/chemistry , Imines/chemistry , Nicotine/chemical synthesis , Piperidines/chemistry , Pyridinium Compounds/chemistry , Pyrrolidines/chemistry , Alkylation , Ions/chemistry , Molecular Structure , Nicotine/analogs & derivatives
4.
J Org Chem ; 75(12): 4311-4, 2010 Jun 18.
Article in English | MEDLINE | ID: mdl-20499884

ABSTRACT

N-Acylation of furfurylamines provided 1, which on double deprotonation with LDA led to the formation of N-acyl-5-aminopenta-2,4-dienals 2 via an isomerization involving opening of the furan ring. The scope and limitations of the procedure were examined by considering the influence of substituents on the carbonyl group and also on the heterocycle moiety. The efficacy of the reaction was shown to be very dependent on the nature of these groups.


Subject(s)
Aldehydes/chemistry , Furans/chemistry , Nitrogen/chemistry , Acylation , Aldehydes/chemical synthesis , Molecular Structure
6.
J Org Chem ; 74(24): 9413-21, 2009 Dec 18.
Article in English | MEDLINE | ID: mdl-19924881

ABSTRACT

Aminopentadienals resulting from the condensation of tryptamine or homoveratrylamine with glutaconaldehydes were treated with trifluoroacetic anhydride, allowing the formation of tetrahydro-beta-carbolines and tetrahydroisoquinolines bearing an enal function. In this N-acyl Pictet-Spengler reaction the electrophilicity of the aminopentadienals was dramatically increased by O,N-bistrifluoroacetylation. Recovery of the nitrogen nucleophilicity was achieved using a reductive process, and the heterocyclic amines were converted into aminonitriles by a Strecker reaction in the presence of butanal. Cyclization, by intramolecular Michael addition of the in situ generated enamines onto the enal moiety, was achieved in the presence of zinc triflate and involved cyanide ion trapping. In this manner, compounds related to protoemetine and dihydrocorynantheal were obtained, and a reduction step led to a short synthesis of (+/-)-protoemetinol.


Subject(s)
Aldehydes/chemistry , Alkadienes/chemistry , Alkaloids/chemical synthesis , Carbolines/chemical synthesis , Fluoroacetates , Tetrahydroisoquinolines/chemical synthesis , Acetic Anhydrides , Acetylation , Alkaloids/chemistry , Amination , Carbolines/chemistry , Cyanides/chemistry , Cyclization , Hydrocarbons, Aromatic/chemistry , Indoles/chemistry , Ions , Magnetic Resonance Spectroscopy , Mesylates/chemistry , Nitriles/chemistry , Tetrahydroisoquinolines/chemistry , Trifluoroacetic Acid/chemistry , Tryptamines/chemistry
8.
J Org Chem ; 73(3): 1169-72, 2008 Feb 01.
Article in English | MEDLINE | ID: mdl-18184007

ABSTRACT

N-tert-Butylimino derivatives of aldehydes were deprotonated with LDA and reacted with vinamidinium chloride to give 2-alkylaminopentadienimine derivatives, which were isolated as their corresponding hydrochloride in 68-81% yield. Reaction of these derivatives with ammonium acetate or salts of primary amines, in n-butanol at 80 degrees C, afforded the corresponding 3-alkylpyridines or 3-alkylpyridinium salts in high yield. Alkaline hydrolysis of 2-alkylaminopentadieneimine derivatives allowed a practical accesss to potassium salts of 2-alkylglutaconaldehyde.


Subject(s)
Aldehydes/chemistry , Imines/chemistry , Pyridines/chemistry , Vinblastine/analogs & derivatives , Alkalies , Alkylation , Amination , Animals , Anions/chemistry , Cyclization , Hydrogen-Ion Concentration , Hydrolysis , Porifera/chemistry , Vinblastine/chemistry
9.
J Org Chem ; 72(15): 5916-9, 2007 Jul 20.
Article in English | MEDLINE | ID: mdl-17590050

ABSTRACT

The reaction of Zincke salts with primary amines to give pyridinium salts generally requires rather elevated temperature to go to completion (50-100 degrees C). It is shown that the addition of 1 equiv of a secondary amine allows formation, at ambient temperature, of intermediate aminopentadiene imine salts which can be isolated and were found to cyclize in acidic medium to give pyridinium salts at temperatures which do not exceed 50 degrees C. If this process has a tendency to give lower yields of pyridinium salt than the standard Zincke procedure, it can be advantageous in some cases, as illustrated by the synthesis of pyridinium salts from amino acids, a challenging reaction which does not work starting from Zincke salt in the absence of diethylamine. More generally, the reaction can be extended to primary amines featuring polar functions, as exemplified by a pyridinium salt synthesis (75 degrees C) in 55% yield from l-carnosine.


Subject(s)
Amino Acids/chemistry , Imines/chemistry , Pyridines/chemistry , Salts/chemistry , Magnetic Resonance Spectroscopy , Pyridines/chemical synthesis , Spectrometry, Mass, Electrospray Ionization
10.
Org Lett ; 9(2): 287-9, 2007 Jan 18.
Article in English | MEDLINE | ID: mdl-17217286

ABSTRACT

Conditions were found for the successful Effenberger alpha,alpha'-annulation of 3,3-dimethyl-2,4,6-triprenyl cyclohexanone silyl enol ethers with malonyl chloride to give the corresponding bicyclo[3.3.1]nonane-trione in 35% yield, this result allowing a short synthesis of (+/-)-clusianone. An isomeric rearranged bicyclo[3.3.1]nonane-trione was also isolated in 25% yield, and changing the Lewis acid resulted in formation of a lavandulyl-substituted phloroglucinol derivative in 38% yield. The mechanism of formation of these two last products mimics the biogenetic pathway to PPAPs. [reaction: see text].


Subject(s)
Biomimetic Materials/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Cyclohexanones/chemical synthesis , Hydrocarbons, Chlorinated/chemistry , Benzophenones , Benzoquinones , Biomimetic Materials/chemistry , Bridged Bicyclo Compounds/chemistry , Cyclohexanones/chemistry , Molecular Structure , Stereoisomerism
11.
J Nat Prod ; 69(5): 774-7, 2006 May.
Article in English | MEDLINE | ID: mdl-16724839

ABSTRACT

Oblongifolins A-D (2-5), four new polyprenylated 3,4-dihydroxybenzoylphloroglucinol compounds, were isolated from the bark of Garcinia oblongifolia collected in Vietnam. The bark was also found to contain the known compounds camboginol and guttiferone B. Extraction of the leaves gave 2 and camboginol. Details of the structure elucidation of 2-5 and stereochemical comparisons with known natural derivatives of general formula 1a,b are presented. The biological activity of these compounds concerning interactions with tubulin was investigated.


Subject(s)
Garcinia/chemistry , Phloroglucinol , Plants, Medicinal/chemistry , Molecular Structure , Phloroglucinol/analogs & derivatives , Phloroglucinol/chemistry , Phloroglucinol/isolation & purification , Phloroglucinol/pharmacology , Plant Bark/chemistry , Plant Leaves/chemistry , Terpenes/isolation & purification , Tubulin/drug effects , Vietnam
12.
J Org Chem ; 70(19): 7780-3, 2005 Sep 16.
Article in English | MEDLINE | ID: mdl-16149815

ABSTRACT

[reaction: see text] 3-Alkyl-1,4-dihydropyridines dimerize in acidic medium, at low temperature, to give polycyclic imminium salts derivatives that were reduced to afford new polycyclic diamine scaffolds. The reaction can be extended to enantiopure series starting from R-(+)- or S-(-)-1-phenylethylamine. Long exposure of the polycyclic imminium salt intermediates to air moisture at 20 degrees C resulted in formation of new amide derivatives. This is probably due to the addition of water followed by an intramolecular oxido-reduction process.

13.
Org Lett ; 7(12): 2437-40, 2005 Jun 09.
Article in English | MEDLINE | ID: mdl-15932217

ABSTRACT

[reaction: see text] A short synthesis of intermediates possessing the tricyclic core of natural madangamines, bioactive alkaloids found in marine sponges, is described. The key reaction entails the condensation of the sodium salt of diethylacetonedicarboxylate with a dihydropyridinium salt derivative. This new approach is modeled on a biogenetic proposal linking madangamines to ircinals, related alkaloids occurring in sponges of the same order.


Subject(s)
Alkaloids/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Animals , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Porifera/chemistry
14.
J Org Chem ; 69(8): 2737-40, 2004 Apr 16.
Article in English | MEDLINE | ID: mdl-15074921

ABSTRACT

Potassium ferricyanide oxidation of salt 1 gave isoquinolinone 7 whose treatment with Grignard reagents resulted in a high-yield formation of substituted isoquinolinium salts 5. The selectivity of the reduction of these salts to give derivatives 6 has been studied. Particularly good selectivities (82-84%) were observed when R is a benzylic group. On the basis of these results, a practical and enantioselective synthesis of the natural alkaloid (-)-argemonine is presented.

15.
J Org Chem ; 68(23): 8883-9, 2003 Nov 14.
Article in English | MEDLINE | ID: mdl-14604358

ABSTRACT

First results of an evaluation of the synthetic sequence depicted in Scheme 4 are reported. This sequence is based upon biosynthetic considerations concerning the manzamine family of sponge alkaloids. Stable equivalents 21 and 31 of the tetraaldehyde 7 have thus been obtained by using the chemistry of malondialdehyde previously reported by Tietze. These compounds afforded pyridinium salts 23 and 33 when treated with a primary amine in acidic medium. Further reductive amination and cyclization yielded bicyclic derivatives 25 and 35, thus demonstrating the feasibility of this synthetic approach for the preparation of halicyclamine derivatives 13. Products resulting from cycloaddition reactions leading to 9 were not observed.


Subject(s)
Aldehydes/chemistry , Amines/chemistry , Bridged Bicyclo Compounds/chemistry , Piperidines/chemistry , Animals , Magnetic Resonance Spectroscopy , Mass Spectrometry , Porifera , Spectrophotometry, Infrared
16.
J Org Chem ; 67(18): 6474-8, 2002 Sep 06.
Article in English | MEDLINE | ID: mdl-12201769

ABSTRACT

A new convergent and unified synthesis of the marine natural alkaloid haliclamine A is described. The synthesis of 3-alkylpyridine monomers 8 and 9 was first achieved from a common thiophene intermediate 5. These syntheses make use of thiophene chemistry and the ability of cyclopropylcarbinols 20 and 21 to rearrange to the homoallylic bromides 22 and 23, respectively. The Zincke procedure for the synthesis of pyridinium salts was then applied to the corresponding amino derivatives 8 and 9 to give efficiently unsymmetrical bis-pyridinium macrocycle 1, whose reduction afforded haliclamine A.


Subject(s)
Alkaloids/chemical synthesis , Chemistry, Organic/methods , Porifera/chemistry , Pyridines/chemistry , Pyridines/chemical synthesis , Animals , Catalysis , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Thiophenes/chemistry
17.
J Org Chem ; 67(6): 1890-7, 2002 Mar 22.
Article in English | MEDLINE | ID: mdl-11895407

ABSTRACT

On the basis of a biogenetic proposal for explaining the biogenesis of manzamine A, the cycloaddition of dihydropyridinium salt 26 with diene derivative 5 leads to adducts 27. These adducts, as well as their related and previously described analogues 9, are now shown to be precursors of diene derivatives such as 10, 13, and 28. Treatment of diene 32 with sodium azide resulted in a one-step formation of the tricyclic imino derivative 34. This key intermediate was further transformed into tricyclic derivative 40, which possesses the essential features of the ABC ring of manzamine A.


Subject(s)
Indoles/chemistry , Indoles/chemical synthesis , Pyrroles/chemistry , Pyrroles/chemical synthesis , Animals , Biotransformation , Carbazoles , Catalysis , Chromatography, Thin Layer , Cyclization , Mass Spectrometry , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Porifera/chemistry , Structure-Activity Relationship
18.
J Org Chem ; 64(10): 3778-3782, 1999 May 14.
Article in English | MEDLINE | ID: mdl-11674518
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