Ring-modified analogues and molecular dynamics studies to probe the requirements for fungicidal activities of malayamycin A and its N-nucleoside variants

The importance of functional group orientations and the integrity of the bicyclic perhydrofuran core of malayamycin A and two equally active N-nucleoside analogues as fungicides were investigated. Two analogues 10 and 11, representing a THP-truncated and a bicyclic aza-variant, were synthesized and found to be inactive. Molecular dynamics studies on malayamycin A and analogues were performed to highlight the importance of properly orientating the urea and methyl ether groups.     

Synthesis of constrained analogues of cholecystokinin/opioid chimeric peptides

In our ongoing research on the synthesis of constrained analogues of CCK/opioid chimeric peptides, a bicyclic dipeptide mimetic for Nle-Asp was designed and synthesized. Starting from β-allyl substituted aspartic acids, the terminal double bond was oxidized resulting in spontaneous cyclization to form racemic hemiaminals. Allylation of the hemiaminals afforded 5-allyl substituted proline analogues, which on oxidation, Horner-Emmons olefination, asymmetric hydrogenation, and bicyclization afforded bicyclic dipeptide mimetics for Nle-Asp. Constrained CCK/opioid peptide analogues containing bicyclic dipeptide mimetics for Nle-Gly, Nle-Asp, and homoPhe-Gly were then synthesized and analyzed at both the CCK and opioid receptors.     

Facile and highly stereoselective synthesis of the tetracyclic erythrinane core

A highly stereoselective synthesis of the tetracyclic core of the Erythrina alkaloids is reported through the application of a Meyers bicyclic lactam template.     

Enantioselective formal synthesis of uleine alkaloids from phenylglycinol-derived bicyclic lactams

A two-step route for the enantioselective construction of the tetracyclic ring system of uleine alkaloids, involving the stereoselective conjugate addition of an appropriate indole-containing nucleophile to a chiral bicyclic delta-lactam and the subsequent cyclization on the indole 3-position of the resulting 4,5-disubstituted 2-piperidone, has culminated in the formal total synthesis of several alkaloids of this group.     

Concise synthesis of bicyclic aminals and their evaluation as precursors to the sarain core

A number of bicyclic aminals have been prepared in a stereospecific manner as potential precursors to the core structure of the sarain alkaloids. Rearrangement of these aminals to new diazabicyclic and diazatricyclic systems has been observed under various conditions.     

A short and concise synthetic route to (−)-coniceine

(−)-Coniceine, the simplest framework of indolizidine alkaloids, has been successfully accessed using a route in which ruthenium-catalyzed ring-closing olefin metathesis (RCM) was the key reaction to establish the unsaturated bicyclic lactam system.     

A short route toward chiral, polyhydroxylated indolizidines and quinolizidines

In this paper, a rapid route toward functionalized bicyclic alkaloids is presented. In only three steps, an easily accessible carbohydrate derivative was converted into iodomethyl indolizidine 13, which can equilibrate to the corresponding iodoquinolizidine 15. We provide strong evidence that this equilibration proceeds via an aziridinium ion intermediate. Furthermore, nucleophilic substitution of the iodomethyl indolizidine as well as the aziridinium intermediate gives access to highly functionalized indolizidine and quinolizidine alkaloids.     

Analogues of a locked nucleic acid with three-carbon 2',4'-linkages: synthesis by ring-closing metathesis and influence on nucleic acid duplex stability and structure

Two bicyclic 2'-deoxynucleoside analogues containing a saturated and an unsaturated three-carbon 2',4'-linkage, respectively, have been synthesized using a ring-closing metathesis-based linear strategy starting from uridine. Both analogues have been incorporated into oligodeoxynucleotide sequences and increased the stability of DNA:RNA hybrid duplexes (DeltaT(m) approximately 2.5-5.0 degrees C per modification) and decreased the stability of dsDNA duplexes (DeltaT(m) approximately 2.5-1.0 degrees C per modification). CD spectroscopy revealed that the bicyclic nucleosides induced formation of A-type-like duplexes albeit to a lesser degree than found for locked nucleic acid (LNA) monomers. From the CD data and UV melting analysis, we propose that the 2'-oxygen atom of the bicyclic moiety is essential for the formation of stabilized A-type-like dsDNA but not for the formation of a stabilized A-type DNA:RNA hybrid.     

Asymmetric synthesis of (+)-isofebrifugine and (-)-sedacryptine from a common chiral nonracemic building block

The stereoselective syntheses of 2-substituted and 2,6-disubstituted 3-hydroxypiperidine alkaloids, (+)-isofebrifugine and (-)-sedacryptine, from a common, functionalized nonracemic bicyclic building block are achieved, demonstrating the flexibilty of the approach.     

Formal total syntheses of aspidosperma alkaloids via a novel and general synthetic pathway based on an intramolecular Heck cyclization

Cyclizations of bicyclic amides via an intramolecular Heck reaction followed by an oxidation reaction generate tricyclic spirocyclohexadienones. From these compounds, tetracyclic ketones can be synthesized to provide useful intermediates for the synthesis of indole alkaloids.     

Synthesis of bicyclic gamma-ylidenetetronates

The bicyclic gamma-ylidenetetronate motif found in several Stemona alkaloids was prepared in a stereoselective manner by addition of lithium methyl tetronate to an alkoxy oxonium ion formed from a lactone. The corresponding mixed alkyl ketal obtained was subjected to a Lewis acid-base-promoted dealkoxylation reaction to deliver the desired products.     

Antimicrobial activity of simplified mimics of celogentin C

Linear and bicyclic analogues of the peptide natural product, celogentin C, have been prepared in which the sidechain–sidechain crosslinks in celogentin are omitted or replaced with a mesitylenyl moiety. The simplified bicyclic peptides display moderate antibacterial activity, potentially through inhibition of bacterial protomicrotubule formation, while the linear analogs show higher antibacterial activity through a possible membrane disruption mechanism.     

Highly stereoselective synthesis of exo and endo indolotropanes

Highly stereoselective routes to exo and endo indolotropanes have been developed. This provides a facile route to these bicyclic analogues of the pharmaceutically active indolopiperidine motif.     

A striking difference between the stereochemical course of the photolysis of 5-hydroxy 6-oxo steroids and their bicyclic analogues

While 5α- and 5β-hydroxy 6-oxo steroids undergo stereospecific photoisomerization, their bicyclic analogues give identical product mixtures on photolysis. This is attributed to equilibration of the intermediate acyl alkyl diradicals in the bicyclic case, which does not occur in the steroid case because of slowing of rotation about the C-9 – C-10 bond.     

Synthesis from d-Altrose of (5R,6R,7R,8S)-5,7-Dihydroxy-8-hydroxymethylconidine and 2,4-Dideoxy-2,4-imino-d-glucitol, Azetidine Analogues of Swainsonine and 1,4-Dideoxy-1,4-imino-d-mannitol

Ring closure of a 3,5-di-O-triflate derived from d-altrose with benzylamine allowed the formation of both monocyclic and bicyclic azetidine analogues of swainsonine.     

Bicyclic proline analogues as organocatalysts for stereoselective aldol reactions: an in silico DFT study

Density functional theory has been employed in investigating the efficiency of a series of bicyclic analogues of proline as stereoselective organocatalysts for the aldol reaction. Three classes of conformationally restricted proline analogues, as part of either a [2.2.1] or [2.1.1] bicyclic framework, have been studied. Transition states for the stereoselective C-C bond formation between enamines derived from [2.2.1] and [2.1.1] bicyclic amino acids and p-nitrobenzaldehyde, leading to enantiomeric products, have been identified. Analysis of the transition state geometries revealed that the structural rigidity of catalysts, improved transition state organization as well as other weak interactions influence the relative stabilities of diastereomeric transition states and help contribute to the overall stereoselectivity in the aldol reaction. These bicyclic catalysts are predicted to be substantially more effective in improving the enantiomeric excess than the widely used organocatalyst proline. Enantiomeric excesses in the range 82-95% are predicted for these bicyclic catalysts when a sterically unbiased substrate such as p-nitrobenzaldehyde is employed for the asymmetric aldol reaction. More interestingly, introduction of substituents, as simple as a methyl group, at the ortho position of the aryl aldehyde bring about an increase in the enantiomeric excess to values greater than 98%. The reasons behind the vital energy separation between diastereomeric transition states has been rationalized with the help of a number of weak interactions such as intramolecular hydrogen bonding and Coulombic interactions operating on the transition states. These predictions could have wider implications for the rational design of improved organocatalysts for stereoselective carbon-carbon bond-forming reactions.     

Advances in the Chemical and Biological Characterization of Amaryllidaceae Alkaloids and Natural Analogues Isolated in the Last Decade

Amaryllidaceae are bulbous wild and cultivated plants well known for their beautiful flowers and pharmaceutical applications, essentially due to the alkaloids and flavonoids content. Hundreds of alkaloids have been isolated until now and several scientific publications reported their sources, chemical structures, and biological activities. During the last decade, some unstudied Amaryllidaceae plants were the object of in-depth investigations to isolate and chemically and biologically characterize new and already known alkaloids as well as some analogues. This review describes the isolation and chemical and biological characterization of the Amaryllidaceae alkaloids, and their analogues obtained in the last decade, focusing the discussion on the new ones.     

Studies towards the total synthesis of batzelladine A

Application of a diastereoselective three-component coupling to the bicyclic core of the batzelladine alkaloids is described. The synthesis features the elaboration of glutamic acid by use of Eschenmoser sulfide contraction. An earlier approach is also included, which shows some limitations of dithiane chemistry when applied to the particular compounds required for this target.     

Pyridine analogs of (−)-cytisine and varenicline: cholinergic receptor probes

A series of bicyclic pyridine containing alkaloids related to (−)-cytisine and varenicline are described. Synthetic access via regioisomeric metalation of alkoxy- and halo-pyridines gains entry to all four isomeric [3.3.1]-bicyclic targets. Regioselective and sequential oxidative cleavage of dicyclopentadiene generates a related [3.2.1]-bicyclic analog.     

Highly selective synthesis of bicyclic quinolizidine alkaloids and their analogues via double RCM reaction of N-alkynyl-N-(1,omega)-alkadienyl acrylamides

The double ring-closing metathesis reaction of N-alkynyl-N-(1,omega)-alkadienyl acrylamides 1 using first- or second-generation Grubbs' catalyst afforded, in a highly selectively manner, the fused bicyclic quinolizidine alkaloid derivatives and their analogues bearing a 1,3-diene moiety, which may further undergo a Diels-Alder reaction with a dienophile to afford N-containing polycyclic compounds. The excellent selectivity of fused/dumbbell-mode cyclization has been realized by the higher reactivity of the electron-rich C=C bond or carbon-carbon triple bond combined with the lower reactivity of the electron-deficient C=C bond toward metallocarbenes and the thermodynamically more stable nature of fused bicyclic compounds 3 vs dumbbell-type bicyclic compounds 4.