RESUMO
A short and economical synthesis of various 2-methylaminopyidine amides (MAPA) from 2-bromopyridine has been developed using the catalytic Goldberg reaction. The effective catalyst was formed in situ by the reaction of CuI and 1,10-phenanthroline in a 1/1 ratio with a final loading of 0.5-3 mol%. The process affords high yields and can accommodate multigram-scale reactions. A modification of this method provides a new preparation of 2-N-substituted aminopyridines from various secondary N-alkyl(aryl)formamides and 2-bromopyridine. The intermediate aminopyridine formamide is cleaved in situ through methanolysis or hydrolysis to give 2-alkyl(aryl)aminopyridines in high yields.
Assuntos
Amidas , Aminopiridinas , Catálise , Hidrólise , Indicadores e ReagentesRESUMO
The syntheses of seven novel amido nicotine derivatives 12-18 from (S)-nicotine are presented. (S)-Nicotine and (S)-6-chloronicotine derivatives were cross-coupled with the corresponding amides 6-10 at the C-4 position of the pyridine ring via copper(I)-mediated reactions. Derivatives 16-18 were also obtained via copper(II)-mediated reactions from (S)-nicotine containing a C-4 boronic acid pinacol ester group. The optimization of reaction conditions for both routes provided a useful method for preparing C-4 amide-containing nicotine analogs.
Assuntos
Amidas/química , Cobre/química , Nicotina/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Catálise , Espectrometria de Massas , Nicotina/química , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Herein is described an original approach to access a tricyclic framework of the lepadiformine-type alkaloids. A Grignard/N-acylpyridinium salt reaction of a 4-methoxytetrahydroquinoline is the key carbon-carbon bond-forming step that was used to establish the desired absolute stereochemistry at the C2 position of the target alkaloid. The synthesis features an allylation reaction with an N-acyliminium ion to set the C10 quaternary stereocenter, a mild dissolving-metal cleavage of hindered phenyl carbamates, and an aminoiodocyclization to form the pyrrolidine ring. While this route does not provide the correct C10 stereochemistry, it showcases an efficient method to build analogues with the ring system of this class of alkaloids in 11 steps overall.
Assuntos
Alcaloides/síntese química , Alcaloides/química , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Ciclização , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Estereoisomerismo , Urocordados/químicaRESUMO
Concise and highly stereocontrolled total syntheses of racemic and enantiopure frog alkaloid 205B (1) were accomplished in 11 steps from 4-methoxypyridines 6 and 7 in overall yields of 8 and 8%, respectively. The assembly of the core of the natural product relies on a stereoselective Tsuji-Trost allylic amination reaction and a ring-closing metathesis. The synthesis features the use of an N-acylpyridinium salt reaction to introduce the first stereocenter and an unprecedented trifluoroacetic anhydride-mediated addition of an allylstannane to a vinylogous amide with complete facial selectivity. Deoxygenation of the C4 ketone proved difficult but was accomplished via a modified Barton-McCombie reaction in the presence of a catalytic amount of diphenyl diselenide.
Assuntos
Alcaloides/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Piridinas/síntese química , Alcaloides/química , Catálise , Compostos Heterocíclicos com 3 Anéis/química , Estrutura Molecular , Piridinas/química , EstereoisomerismoRESUMO
The role of twist-boat conformers of cyclohexanones in hydride reductions was explored. The hydride reductions of a cis-2,6-disubstituted N-acylpiperidone, an N-acyltropinone, and tert-butylcyclohexanone by lithium aluminum hydride and by a bulky borohydride reagent were investigated computationally and compared to experiment. Our results indicate that in certain cases, factors such as substrate conformation, nucleophile bulkiness, and remote steric features can affect stereoselectivity in ways that are difficult to predict by the general Felkin-Anh model. In particular, we have calculated that a twist-boat conformation is relevant to the reactivity and facial selectivity of hydride reduction of cis-2,6-disubstituted N-acylpiperidones with a small hydride reagent (LiAlH4) but not with a bulky hydride (lithium triisopropylborohydride).
Assuntos
Cicloexanonas/química , Cetonas/química , Piperidonas/química , Tropanos/química , Boroidretos/química , Catálise , Compostos de Lítio/química , Conformação Molecular , Estrutura Molecular , EstereoisomerismoRESUMO
A strategy for the synthesis of the lycopodium alkaloid dihydrolycolucine (1) has been investigated. Synthetic routes were developed based on N-acylpyridinium salt chemistry to prepare target fragments 3 and 4 that could ultimately converge to the natural product. Key reactions include IMDA cycloadditions and retro-Mannich ring-openings to form both the AB and the EF ring fragments. The ring C precursor was prepared using pyridine substitution and directed lithiation chemistry. A Suzuki cross-coupling of rings C and EF led to the CEF ring fragment. Initial attempts at closure of the seven-membered D ring were unsuccessful.
Assuntos
Alcaloides/síntese química , Lycopodium/química , Quinolinas/síntese química , Alcaloides/química , Estrutura Molecular , Compostos de Piridínio/química , Quinolinas/química , EstereoisomerismoRESUMO
The analysis of N-linked glycans by mass spectrometry (MS) has been characterized by low signal-to-noise ratios and high limits of detection due to their hydrophilicity and lack of basic sites able to be protonated. As a result, every step in glycan sample preparation must be thoroughly optimized in order to minimize sample loss, contamination, and analytical variability. Importantly, properties of glycans and their derivatized counterparts must be thoroughly studied in order to exploit certain characteristics for enhancing MS analysis. Herein, the effectiveness of the incorporation of a permanent charge is studied and determined to hamper glycan analysis. Also, a procedure for glycan hydrazone formation is optimized and outlined where a large number of variables were simultaneously analyzed using a fractional factorial design (FFD) in order to determine which conditions affected the reaction efficiency of the hydrazone formation reaction. Finally, the hydrophobic tagging of glycans is shown to be a viable opportunity to further increase the ion abundance of glycans in MS.
RESUMO
During the course of a study aimed at constructing azaspirocycles from 2,3-dihydro-4-pyridones, an unexpected product was obtained in the SET ring-opening reaction of photocycloadduct 1. Differences in reactivity between homologues 1 and 2 were observed in the presence of SmI(2). Tricyclic ketone 2 afforded azaspiro[5.5]undecane 15 when treated with SmI(2); however, when ketone 1 was submitted to similar reaction conditions a double ring-opening/reduction sequence gave cis-piperidinol 10.
Assuntos
Piridonas/síntese química , Ciclização , Estrutura Molecular , Fotoquímica , Piridonas/química , EstereoisomerismoRESUMO
The synthesis of novel fused-ring bicyclic (4-6) and tricyclic (7-10) nicotine derivatives from natural (S)-nicotine are described. Enantiopure bicyclic dioxino, dihydrofuro, and dihydropyranol nicotine derivatives as well as tricylic benzofuro and benzopyran derivatives were synthesized from simple alkoxy or halonicotine intermediates. Attempts to synthesize furonicotines (11, 12) resulted in formation of the furonicotine dimers 42 and 49.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Dioxinas/síntese química , Nicotina/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Ciclização , Dioxinas/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Nicotina/química , EstereoisomerismoRESUMO
The asymmetric synthesis of all four of the known natural phlegmarines and one synthetic derivative has been accomplished in 19-22 steps from 4-methoxy-3-(triisopropylsilyl)pyridine. Chiral N-acylpyridinium salt chemistry was used twice to set the stereocenters at the C-9 and C-2' positions of the phlegmarine skeleton. Key reactions include the use of a mixed Grignard reagent for the second N-acylpyridinium salt addition, zinc/acetic acid reduction of a complex dihydropyridone, and a von Braun cyanogen bromide N-demethylation of a late intermediate. These syntheses confirmed the absolute stereochemistry of all of the known phlegmarines.
Assuntos
Alcaloides/síntese química , Alcaloides/química , Indicadores e Reagentes/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , EstereoisomerismoRESUMO
Hydrophobic tagging of biomolecules has been reported by our group and others to increase their ionization efficiency during electrospray ionization and facilitate their detection by mass spectrometry. As such, hydrophobic tagging should provide a viable method for augmenting MS-based quantification of low abundance proteins by decreasing their detection limits. Herein we have evaluated two commercial alkylation reagents and several newly synthesized hydrophobic alkylation reagents for their utility in quantifying B-type Natriuretic Peptide, a low abundance cardiac biomarker, by protein cleavage isotope dilution mass spectrometry. For the cysteine containing tryptic peptide evaluated, a approximately 3.5-fold decrease in the detection limit was observed for the best performing hydrophobic reagent, 2-iodo-N-octylacetamide, relative to the commonly used alkylation reagent, iodoacetamide. Additionally, we have evaluated the use of nonpolar surface areas as a metric for assessing the effectiveness of the alkylation reagents in improving ESI response.
Assuntos
Peptídeo Natriurético Encefálico/análise , Espectrometria de Massas por Ionização por Electrospray/métodos , Alquilantes/química , Interações Hidrofóbicas e Hidrofílicas , Iodoacetamida/química , Marcação por Isótopo , Limite de Detecção , Tripsina/metabolismoRESUMO
A new route to C2-symmetric diamines via an asymmetric reductive dimerization of 1-acylpyridinium salts and their benzo derivatives is described. This method is practical as the starting heterocycles and chiral auxiliaries are readily available. The titanium reducing agent is inexpensive and easy to prepare. Several novel enantiopure C2-symmetric diamine derivatives were synthesized using this method.
Assuntos
Diaminas/síntese química , Compostos de Piridínio/química , Catálise , Diaminas/química , Dimerização , Estrutura Molecular , Sais/química , EstereoisomerismoRESUMO
Multisubstituted piperidines containing a phenyl group at C-2 can be opened regio- and stereoselectively with cyanogen bromide. The ring-opened products contain useful cyanamide and benzylic bromide functional groups. This methodology is useful for the stereoselective synthesis of uniquely substituted alkylamine derivatives containing multiple chiral centers and various functionality.
Assuntos
Amino Álcoois/síntese química , Piperidinas/química , Compostos de Benzil/química , Cianamida/química , Brometo de Cianogênio/química , Ciclização , EstereoisomerismoRESUMO
Various multisubstituted piperidines containing a phenyl group at C-2 can be opened regio- and stereoselectively with cyanogen bromide. The ring-opened products contain useful cyanamide and benzylic bromide functional groups. The benzyl bromide can be cleanly reduced, or substituted with various nucleophiles via an S(N)2 process to add additional heteroatoms stereoselectively. This methodology is useful for the stereoselective synthesis of uniquely substituted alkylamine derivatives containing multiple chiral centers and various functionality. Diastereomerically pure amino alcohols containing three to five contiguous stereocenters were prepared using this strategy.
Assuntos
Amino Álcoois/química , Amino Álcoois/síntese química , Catálise , Brometo de Cianogênio/química , Hidrogenação , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Conformação Molecular , Piperidinas/química , Espectrofotometria Infravermelho , EstereoisomerismoRESUMO
A one-carbon homologation of terminal alkenes has been developed utilizing an olefin cross-metathesis followed by a palladium-mediated allylic carbonate reduction; various substrates were used to demonstrate the scope of the reaction, with yields ranging from 65 to 86%.
Assuntos
Alcenos/química , Carbonatos/química , Reagentes de Ligações Cruzadas/química , Microscopia Eletrônica de Transmissão , Estrutura Molecular , Oxirredução , Análise Espectral , TitulometriaRESUMO
A general synthesis of various benzo-fused indolizidine alkaloid mimics has been developed. The indolizidine derivatives 8 were prepared via heteroaryl Grignard addition to N-acylpyridinium salts followed by an intramolecular Heck cyclization. Further substitution reactions were developed to demonstrate that heterocycles 8 are good scaffolds for chemical library preparation.
RESUMO
[reaction: see text] A six-step synthesis of (S)-brevicolline from (S)-nicotine is reported. Regioselective trisubstitution of the pyridine ring of nicotine, followed by successive Suzuki cross-coupling and Buchwald amination reactions, afforded the enantiopure beta-carboline alkaloid, brevicolline.
Assuntos
Alcaloides/síntese química , Carbolinas/síntese química , Nicotina/química , Alcaloides/química , Alcaloides/isolamento & purificação , Carbolinas/química , Carbolinas/isolamento & purificação , Carex (Planta)/química , Indóis/química , Indóis/isolamento & purificação , Estrutura Molecular , EstereoisomerismoRESUMO
[reaction: see text] A variety of novel nicotine derivatives were prepared via reductive disilylation of (S)-nicotine. Treatment of nicotine with lithium powder and chlorotrimethylsilane afforded 1,4-bis(trimethylsilyl)-1,4-dihydronicotine in high yield. Addition of various carbonyl electrophiles and a catalytic amount of TBAF provided either C-5 substituted nicotines or 1,4-dihydronicotine derivatives.
Assuntos
Lítio/química , Nicotina , Catálise , Estrutura Molecular , Nicotina/análogos & derivados , Nicotina/síntese química , Nicotina/química , Oxirredução , Silanos/química , EstereoisomerismoRESUMO
[reaction: see text] The ladybird alkaloid, (+)-hyperaspine, has been synthesized in a concise and highly stereoselective manner. The total synthesis was accomplished in six steps and 21% overall yield.