RESUMO
Daphniphyllum is an evergreen species known since 1826. After initial systematic investigations, more than 320 members of this family have been isolated, which comprise complex and fascinating structures. Unique azapolycyclic architectures containing one or more quaternary stereocenters render these alkaloids synthetically challenging. This review covers efforts toward the synthesis of Daphniphyllum alkaloids spanning the period from 2005 to the beginning of 2016, including reported biological activities as well as the isolation of new members of this genus.
Assuntos
Alcaloides/química , Saxifragaceae/químicaRESUMO
Herein we describe synthetic efforts toward the total synthesis of calyciphylline B-type alkaloids. In the process, we disclose a detailed DFT study of equilibrium geometries and transition states that explains the stereochemical outcome during the formation of critical intermediates. X-ray crystallographic analysis reveals interesting conformational features in the naturally occurring deoxycalyciphylline B and its synthetic congeners.
Assuntos
Alcaloides/síntese química , Compostos Policíclicos/síntese química , Alcaloides/química , Biologia Computacional , Cristalografia por Raios X , Compostos Heterocíclicos de 4 ou mais Anéis , Indicadores e Reagentes , Modelos Moleculares , Compostos Policíclicos/química , EstereoisomerismoRESUMO
Herein, we report the enantioselective synthesis of a functionalized aza-octahydropentalene and its elaboration to a model tetracyclic core structure of calyciphylline B-type alkaloids.
Assuntos
Alcaloides/síntese química , Compostos Aza/química , Ciclopentanos/química , Compostos Policíclicos/síntese química , Alcaloides/química , Estrutura Molecular , Compostos Policíclicos/química , EstereoisomerismoRESUMO
Herein we describe the first synthetic efforts toward the total synthesis of isodaphlongamineâ H, a calyciphyllineâ B-type alkaloid. The strategy employs a chemoenzymatic process for the preparation of a functionalized cyclopentanol with a quaternary center. This molecule is elaborated to form an enantiopure 1-aza-perhydrocyclopentalene core, representing ringsâ A andâ E of all calyciphyllineâ B-type alkaloids. Further transformations involve the formation of a cyclic enaminone, 1,4-conjugate addition with a cyclopentenyl subunit, and intramolecular aldol cyclization to achieve a pentacyclic intermediate, ultimately forming isodaphlongamineâ H in a total of 24 steps from the commercially available compound 2-carbethoxycyclopentanone. Isodaphlongamineâ H exhibits promising inhibitory activity against a panel of human cancer cell lines.
Assuntos
Alcaloides/química , Alcaloides/síntese química , Alcaloides/farmacologia , Modelos MolecularesRESUMO
Cyclic enaminones are versatile intermediates to construct a variety of azacyclic frameworks and have been widely used in alkaloid synthesis. Here, we summarize three approaches for stereoselective syntheses of cyclic enaminones and their functionalized derivatives. These include chiral substrates (chirons) as starting materials, syntheses employing non-catalytic (stoichiometric) reagents, and catalytic asymmetric methods.
RESUMO
Among many other strategies, the enaminone approach is an important strategy to construct and diversify the azacyclic core in various alkaloids syntheses. In this brief review we discuss the application of cyclic enaminones as building blocks, as well as potential intermediates in the total synthesis of selected alkaloids.
RESUMO
A one-pot, mild, two-component iminium ion-enamine cascade reaction to construct structurally diverse azacyclic frameworks from l-proline and l-pipecolic acid, and its application to indolizidine and quinolizidine alkaloids and azasteroids, is reported.
Assuntos
Aminas/química , Compostos Aza/síntese química , Produtos Biológicos/síntese química , Compostos Bicíclicos com Pontes/síntese química , Iminas/química , Compostos Aza/química , Produtos Biológicos/química , Compostos Bicíclicos com Pontes/química , Ciclização , Íons/química , Estrutura MolecularRESUMO
Although the [2,3]-Wittig and Wittig-Still rearrangements have long been known, their application in the generation of quaternary carbon centers in carbocyclic ring systems is sparse. Model studies utilizing this strategy and possible mechanisms are discussed herein. Unprecedented examples of an α-elimination pathway from stannylmethyl allyl ethers as a major undesired product in some Wittig-Still rearrangements are reported.
RESUMO
Biosynthetically and chemically derived analogs of the antibiotic pactamycin and de-6-methylsalicylyl (MSA)-pactamycin have attracted recent interest as potential antiprotozoal and antitumor drugs. Here, we report a 3.1-Å crystal structure of de-6-MSA-pactamycin bound to its target site on the Thermus thermophilus 30S ribosomal subunit. Although de-6-MSA-pactamycin lacks the MSA moiety, it shares the same binding site as pactamycin and induces a displacement of nucleic acid template bound at the E-site of the 30S. The structure highlights unique interactions between this pactamycin analog and the ribosome, which paves the way for therapeutic development of related compounds.
Assuntos
Pactamicina/química , Pactamicina/metabolismo , Subunidades Ribossômicas Menores de Bactérias/química , Subunidades Ribossômicas Menores de Bactérias/metabolismo , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Cristalografia por Raios X , Modelos Moleculares , Conformação Molecular , Pactamicina/análogos & derivados , Ligação Proteica , RNA Ribossômico 16S/química , RNA Ribossômico 16S/metabolismo , Thermus thermophilus/metabolismoRESUMO
A total of eight new analogs of pactamycin were prepared and tested alongside pactamycin and three of its natural congeners for antibacterial, anticancer, and antiprotozoal activities. The present study highlights the effects of changing the urea and aniline groups especially with regard to anticancer and antiprotozoal activities.
Assuntos
Antibacterianos/química , Antineoplásicos/química , Antiprotozoários/química , Pactamicina/análogos & derivados , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Malária Falciparum/tratamento farmacológico , Neoplasias/tratamento farmacológico , Pactamicina/farmacologia , Plasmodium falciparum/efeitos dos fármacosRESUMO
A convergent total synthesis of the cytotoxic natural product cruentaren B is completed in 26 steps (longest linear sequence) with an overall yield of 7.1%. For the construction of the C1-C11 benzolactone fragment of the molecule, the key steps used were O-methylation, using a Mitsunobu reaction, a Stille coupling method to construct the C7-C8 bond, and a Brown's asymmetric crotylboration reaction for the direct enantioselective installation of the two chiral centers present in this fragment. For diastereoselective installation of the chiral centers in the C12-C20 polyketide fragment, an Evans syn aldol reaction on a chiral aldehyde, derived from methyl (R)-3-hydroxyl-2-methylpropionate, and subsequently a Mukaiyama aldol reaction were employed. For the construction of the C21-C28 tail, a "non-Evans" syn aldol reaction was used. The three fragments were coupled by an SN2 reaction and a Wittig olefination reaction followed by standard functional group manipulations to furnish the target molecule.