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This is the first report on an intramolecular C-N bond formation of an amide-tethered benzylic/allylic system using DDQ under neutral conditions which has been successfully applied to the total synthesis of naturally occurring pyrolidine alkaloids. The key steps for the synthesis of corresponding precursors involve Julia-Kociensky olefination/cross-metathesis and dihydroxylation reactions, and this methodology is also extended to the ω-unsaturated N-sulfanilamide to furnish piperidines. [ABSTRACT FROM AUTHOR]

Inexpensive and air stable triphenylcarbenium tetrafluoroborate efficiently promoted the carbofluorination of N-arylpropargylpyrrolidines bearing a tertiary allylic alcohol tether at the 2-position of the pyrrolidine ring to provide 1-isobutenyl-2-(fluoro(phenyl)methylenylhexahydro-1H-pyrrolizidines in a stereoselective fashion. When subjected to bis(trifluoromethane)sulfonamide, the same substrates underwent cycloisomerization reaction within minutes to generate 1-isobutenyl-2-benzoylhexahydro-1H-pyrrolizidines with excellent stereoselectivity. [ABSTRACT FROM AUTHOR]

A versatile and efficient protocol for the synthesis of highly substituted benzopyrrolizidines (tetrahydro-3H-pyrrolo[2,1-a]isoindol-3-ones) is reported. The strategy consisted of an Ugi four-component reaction/elimination methodology to afford dehydroalanines containing trans-cinnamic acid derivatives and different substituted 2-bromobenzylamines, followed by a palladium-catalyzed 5-exo-trig/5-exo-trig cascade carbocyclization process. Gratifyingly, benzopyrrolizidines were obtained in moderate to good yields (42-77%) with a Z geometry due to the structural requirements for syn-β-hydride elimination. The prepared heterocyclic scaffolds are decorated with several substituents and incorporate a benzopyrrolizidine-fused system, along with an embedded cinnamic acid derivative, two privileged medicinal chemistry scaffolds. Additionally, since some of the compounds are derived from the well-known antioxidants ferulic and sinapinic acids, they were tested for their in vitro antioxidant capacity. The data suggested that compounds having a p-hydroxyl group showed moderate 2,2-diphenyl-1-picrylhydrazyl-radical-scavenging activity and were effective antioxidants in preventing lipoperoxidation in a thiobarbituric acid reactive substances assay. [ABSTRACT FROM AUTHOR]

A series of original spiropyrrolizidine derivatives has been prepared by a one-pot three-component [3 + 2] cycloaddition reaction of (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-diones, l-proline, and the cyclic ketones 1H-indole-2,3-dione (isatin), indenoquinoxaline-11-one and acenaphthenequinone. We disclose an unprecedented isomerization of some spiroadducts leading to a new family of spirooxindolepyrrolizidines. Furthermore, these cycloadducts underwent retro-1,3-dipolar cycloaddition yielding unexpected regioisomers. Upon treatment of the dipolarophiles with in situ generated azomethine ylides from l-proline or acenaphthenequinone, formation of spiroadducts and unusual polycyclic fused piperazines through a stepwise [3 + 3] cycloaddition pathway is observed. The stereochemistry of these N-heterocycles has been confirmed by several X-ray diffraction studies. Some of these compounds exhibit extensive hydrogen bonding in the crystalline state. To enlighten the observed regio- and stereoselectivity of the [3 + 2] cycloaddition, calculations using the DFT approach at the B3LYP/6-31G(d,p) level were carried out. It was found that this reaction is under kinetic control. [ABSTRACT FROM AUTHOR]

The loline alkaloids present a compact polycyclic pyrrolizidine skeleton and contain a strained five-membered ethereal bridge, structural features that have proven challenging for synthetic chemists to incorporate since the discovery of this natural product family more than 100 years ago. These alkaloids are produced by mutualistic fungal symbionts (endophytes) living on certain species of pasture grasses and protect the host plant from insect herbivory. The asymmetric total synthesis of loline alkaloids is reported and extends our first-generation (racemic) synthesis of this alkaloid family. Key to the synthesis is a diastereoselective tethered aminohydroxylation of a homoallylic carbamate function and a Petasis Borono-Mannich addition. [ABSTRACT FROM AUTHOR]

A practical one-pot synthesis of bi- and triantennated australine analogues from a pivotal sp²-iminosugar-type reducing castanospermine precursor is reported. The transformation involves a gem-diamine intermediate that undergoes the indolizidine → pyrrolizidine Amadori-type rearrangement and proceeds under strict control of the generalized anomeric effect to afford a single diastereomer. The final compounds behave as selective competitive inhibitors of β-glucosidase and are promising candidates as pharmacological chaperones for Gaucher disease. [ABSTRACT FROM AUTHOR]

Allylating agents were explored for the asymmetric synthesis of α-allyl-α-aryl α-amino acids by tandem N-alkylation/π-allylation. Cross-metathesis of the tandem product was developed to provide allylic diversity not afforded in the parent reaction; the synthesis of homotyrosine and homoglutamate analogues was completed. Cyclic α-amino acid derivatives could be accessed by ring-closing metathesis presenting a viable strategy to higher ring homologue of enantioenriched α-substituted proline. The eight-membered proline analogue was successfully converted to the pyrrolizidine natural product backbone. [ABSTRACT FROM AUTHOR]

An asymmetric synthesis of gem-difluoromethylenated dihydroxypyrrolizidines and indolizidines is described. The fluoride-catalyzed nucleophilic addition of PhSCF2SiMe3 (1) to chiral imides was achieved in satisfactory yields to provide mixtures of syn- and anti-isomers 6-9 with moderate to good diastereoselectivities. Reductive cleavage of the phenylsulfanyl group followed by intramolecular radical cyclization of the syn-isomers 6-9 occurred under refluxing conditions to afford the corresponding gem-difluoromethylenated 1-azabicyclic compounds 10-13 in moderate yields as a separable mixture of cis- and trans-isomers. The cis-isomers of compounds 10 and 12 and trans-13 were readily transformed to gem-difluoromethylenated dihydroxypyrrolizidines 20 and 27 and indolizidine 28, respectively, by reductive cleavage of the hydroxyl group and organometallic addition followed by hydrogenolysis. [ABSTRACT FROM AUTHOR]

The total synthesis of enantiopure 4-epi-(+)-codonopsinine was achieved in 10 steps starting from d-ribose as a chiral building block. The key step involved a highly stereoselective nucleophilic addition of a Grignard reagent to a protected ribosylamine. Synthesis of the N-desmethyl derivative and its p-tolyl analogue was also accomplished, and the compounds were assayed against a-fucosidase. [ABSTRACT FROM AUTHOR]

New syntheses of (-)-deoxoprosophyllinc. (+)-2-epi- dcoxoprosopininc. and (2 R.3 R)- and (2R.3S)-3-hydroxy- pipecolic acids are reported. Utilization of the chiral functionalitics of Perlin aldehvdes. derived Irons 3.4.6- tri-O-benzyl glycals. has been done along with cherno- selective saturation of olefins and reductive animations as key steps. [ABSTRACT FROM AUTHOR]

A flexible method for the diastereoselective total synthesis of the pyrrolizidine alkaloids uniflorine A, casuarine, australine, and 3-epi-australine and the unnatural epimer 3,7-di-epi-australine from a common chiral 2,5-dihydropyrrole precursor is described. [ABSTRACT FROM AUTHOR]

The reaction of α,β-unsaturated carbonyl compounds with aminoacetonitrile hydrochloride furnishes 3,5-disubstituted 3,4-dihydro-2H-pyrrole-2-carbonitriles in a one-pot reaction sequence. While these products can serve as starting materials for the preparation of polysubstituted pyrrolizidines, they are kinetically stable against the base-induced elimination of HCN. In contrast, their 2-substituted analogues obtained from re-substituted α-aminonitrites can be readily converted to the corresponding 2,3,5-trisubstituted pyrroles under microwave irradiation. The key step presumably involves the thermal electrocyclization of a stabilized 2-azapentadienyl anion formed by condensation of the reactants and subsequent deprotonation. [ABSTRACT FROM AUTHOR]

A reaction sequence, involving the addition of (substituted) propargylsilanes to lactam-derived N-acyliminium ions followed by gold-catalyzed cyclization of the resulting α-allenyl amide, is applied in expedient syntheses of pyrrolizidine alkaloids heliotridine and ent-retronecine in five steps from (S)-malic acid. [ABSTRACT FROM AUTHOR]

1,3-Dipolar cycloaddition reaction of nitrone 7 and chemo-enzymatically obtained alkenediols 12 and 13 has been used in the synthesis of pentahydroxylated pyrrolizidines (8 and 10) and indolizidines (9 and H). The pyrrolizidinic and indolizidinic skeletons were built after internal n-alkylation of the suitably functionalized pyrroloisoxazolidine intermediates obtained by the necessary protecting group manipulations. This method expands the scope of cycloaddition reactions in the synthesis of new and highly polyhydroxylated sugar-like alkaloids. [ABSTRACT FROM AUTHOR]

PhSCF2SiMe3 (1) was found, for the first time, to undergo fluoride-catalyzed nucleophilic difluoro(phenylsulfanyl)methylation reaction to cyclic imides 2, affording the corresponding adducts 3 in moderate to good yields. Reductive cleavage of the phenylsulfanyl group of N-alkylated adducts 3 with Bu3SnH/AIBN yielded gem-difluoromethylated products 4. Under the same reduction conditions, N-alkenylated and N-alkynylated adducts 3 afforded the corresponding gem-difluoromethylenated 1-azabicyclic compounds 5 and 6 with trans stereoselectivity. These compounds were employed as precursors for preparing substituted gem-difluoromethylenated pyrrolizidinones and indolizidinones 7 and 8 by treatment with Et3SiH/BF3·OEt2, and compounds 9 and 10 by nucleophilic displacement of the hydroxyl group, using organosilanes in the presence of BF3·OEt2. The synthesis of highly substituted gem-difluoromethylenated pyrrolizidines 13 and 14 was also demonstrated. [ABSTRACT FROM AUTHOR]

Simple N-substituted azetidines were heated with diazocarbonyl compounds in the presence of catatlytic Cu(acac)2 to furnish substituted pyrrolidines via Stevens [1,2]-shift. In all but two examples, complete selectivity was seen for ring expansion rather than migration of the other exocyclic group on the azetidinium nitrogen. The two exceptions, observed with ylides substituted with two carbonyl groups and lacking a stabilizing group at the 2-position of the azetidine, underwent exocyclic benzyl migration in preference to ring expansion. [ABSTRACT FROM AUTHOR]

New scaffolds for the stereoselective synthesis of diversely functionalized chiral enantiopure indolizidines and pyrrolizidines were synthesized from the cross and ring-closing metathesis reactions of appropriate intermediates, readily available from L-pyroglutamic acid. The versatility of this strategy was demonstrated by the synthesis of an indolizidine-based azasugar analogue and of the natural alkaloid (+)-monomorine. [ABSTRACT FROM AUTHOR]

A new approach to the synthesis of indolizidine and pyrrolizidine skeletons is reported. (-)-Lentiginosine and (1R,2R,7aR)-dihydroxypyrrolizidine have both been synthesized in 13 steps from di-O-isopropylidene- D-mannitol. The common key intermediate is (-)-dihydroxyproline benzyl ester 10. [ABSTRACT FROM AUTHOR]

Nitrogen-containing sugar analogues, known as azasugars or iminosugars, such as polyhydroxylated piperdines, pyrrolidines, pyrrolizidines, and indolizidines, have the potential to become important therapeutic agents due to their ability to inhibit glycosidases. Synthetic pathways that are able to systematically produce a variety of these azasugars are eagerly sought after, since even minute structural or stereochemical changes often significantly alter the degree of inhibition. The synthesis of tetra-hydroxylated pyrrolizidines 40 and 41 starting from methyl α-D-glucopyranoside is described and will be used as a template to develop syntheses of all the stereoisomers of polyhydroxylated pyrrolizidine 9 as well as other analogous bicyclic polyhydroxylated iminosugars. The key steps in this synthesis involve a one-pot conversion of a halopyranoside to a divinylamine by employing a simultaneous Zn reduction and reductive amination of the resulting aldehyde. After protection of the amine, a ring-closing metathesis results in a multifunctional eight-membered ring that then undergoes an internal SN2 cyclization to form an alkene-containing pyrrolizidine 33. Dihydroxylation of the alkene followed by hydrogenolysis of the benzyl protecting groups results in tetrahydroxylated pyrrolizidines 40 and 41. [ABSTRACT FROM AUTHOR]

A new straightforward and inexpensive one-pot procedure is described for the preparation of enantiopure five-membered cyclic nitrones starting from the corresponding lactols. Its efficiency relies on the condensation of unprotected hydroxylamine with readily available lactols and on the chemoselectivity of the subsequent esterification with methanesulfonyl chloride. The targeted enantiomerically pure pyrroline N-oxides are versatile synthetic intermediates: one of the nitrones so-obtained has been converted into new polyhydroxypyrrolizidines, analogues of the alkaloids rosmarinecine and crotanecine, which were assayed for their inhibitory activities toward 22 commercially available glycosidase enzymes. One of them ((-)-7a-epi-crotanecine) is a potent and selective inhibitor of α-mannosidases from jack beans and almonds. [ABSTRACT FROM AUTHOR]

Three natural pyrrolizidines, (+)-amphorogynines A and D and (+)-retronecine, have been prepared from a common lactam intermediate. This central compound, in turn, was synthesized in diastereomerically enriched form through a highly selective [2 + 2]-cycloaddition of dichloroketene with a chiral enol ether, followed by Beckmann ring expansion and reduction. Subsequent stereocenters were then cleanly introduced through internal induction. [ABSTRACT FROM AUTHOR]

The radical cascade cyclizations of N-alkenyl-2-aziridinylmethyl radicals to pyrrolizidines and indolizidines were examined using density functional theory (DFT) calculations. A large preference for cyclization to pyrrolizidines was found. These predictions corroborated very well with experimental results, leading to an efficient synthesis of pyrrolizidines. No radical cascade cyclization to indolizidines could be performed in practice as only ring opening of N-alkenyl-2-aziridinylmethyl radicals to N-allyl-N-alkenylamines occurred. [ABSTRACT FROM AUTHOR]

A concise total synthesis of (+)-hyacinthacine A2, a polyhydroxylated pyrrolizidine alkaloid, is described using our recently discovered inversion of the C-N bond polarity in nitrones. In the key step, the diastereoselective reductive coupling of a L-xylose-derived cyclic nitrone with ethyl acrylate allowed the assembly of the bicyclic core of the target molecule, by way of a tandem formation of the C-C and C-N bonds. The method opens a novel, short, and general route for the synthesis of other pyrrolizidine alkaloids. [ABSTRACT FROM AUTHOR]

This paper describes the palladium-catalyzed arylation of 1-substituted 3-aminopyrrolidines or piperidines. Palladium(O) (1-2 mol %) in conjunction with "Buchwald's ligand" [2-(dimethylamino)2'-(dicyclohexylphosphine)biphenyl] was shown to be the catalyst of choice for the coupling with aryl bromides or chlorides. When bromobenzene was used, a strong temperature effect was noticed. Whereas no reaction occurred at 100 °C, yields higher than 85% were obtained at 130 °C for each substrate. Such an effect was not observed when diphosphines were used. Whereas Xantphos and, to a lesser extent BINAP, were moderately efficient in the coupling of all diamines, the palladiummediated arylation in the presence of monophosphines was strongly dependent on the substrate. The results suggest the participation of both nitrogens of the aminoheterocycle in the reactive intermediate. This participation could also account for the highly selective arylation of the endocyclic nitrogen of unsubstituted 3-aminopyrrolidine or piperidine. Optimal conditions were found for the arylation using 2- or 4-substituted electron-poor or enriched aryl halides. [ABSTRACT FROM AUTHOR]

A survey of routes for aminal cleavage of N-sulfinylimidazolidines has been carried out, and selective conditions to cleave the aminal moiety while preserving the sulfinamide group unaltered have been found. Thus, the treatment of enantiopure N-sulfinylimidazolidines with aqueous H3PO4 in THF affords enantiopure N-sulfinyldiamino esters in excellent yields, while the presence of MeOH as cosolvent allows for the simultaneous removal of the sulfinamide group and aminal cleavage. The behavior of these substrates in a variety of chemical transformations has been explored. [ABSTRACT FROM AUTHOR]

Enantiopure (3S,5R,8S)-3-[N-(Boc)amino]-1-azabicyclo[3.3.0]octan-2-one 8-carboxylic acid (1) was synthesized in nine steps and 16% overall yield from aspartate β-aldehyde 7. Carbene-catalyzed acyloin condensation of 7, followed by acetylation and samarium iodide reduction, gave linear precursor (2S,7S)-α,ω-diamino-4-oxosuberate 11, which was converted to N-(Boc)aminopyrrolizidin2-one carboxylic acid 1 by a reductive amination/lactam cyclization sequence. X-ray analysis of (3S,5R,8S)-methyl N-(Boc)aminopyrrolizidin-2-one carboxylate 21 showed that its internal backbone dihedral angles (ψ = -149°, phi; = -49°) were in good agreement with the ideal values for a type II' β-turn. Proton NMR experiments on N'-methyl-N-(Boc)aminopyrrolizidin-2-one carboxamide 23 demonstrated significantly different NH chemical displacements and temperature coefficients suggestive of solvent shielded and exposed hydrogens indicative of a turn conformation. Because pyrrolizidinone amino acids can serve as conformationally rigid dipeptide surrogates, this synthesis should facilitate their application in the exploration of conformation-activity relationships of various biologically active peptides. [ABSTRACT FROM AUTHOR]

Examines the synthesis of a constrained tricyclic pyrrolizidinone carboxylic acids. Reactions involved in the intramolecular cyclopropanation; Introduction of various substituents; Antibacterial activity of ceftazidine.

Describes the enantioselective synthesis of the naturally occurring pyrrolizidine alkaloid (+)-latifoline. Biological properties of bifunctional pyrrolizidine alkaloids; Description of latifoline; Double esterification of retronecine.

Examines the synthesis of fused 2-pyrrolines via thermolysis of 6-substituted-3,5-hexadienyl azidoformates. Production of a cis and trans mixture; Formation of acyl nitrene; Generation of the C-C bond of a vinylazomethine ylide;

Examines the preparation of polyfunctionalized pyrrolizidine systems by rapid and stereocontrolled synthesis. Variation of targets in natural products such as azasugars and alkaloids; Use of standard methodology in preparing 4-oxoazetidine-2carbaldehydes; Stereochemistry of tricyclic compounds.

Describes the synthesis of polyhydroxylated pyrrolizidine alkaloids of the alexine family by tandem ring-closing metathesis (RCM)-transannular cyclization. Designing a synthesis for the olefin metathesis precursor; Facial selectivity in epoxidation of the azacyclooctene; Inability of RCM to accommodate two allylic oxygen substituents in the diene substrate.

Describes the synthesis of tetrahydroxylated pyrrolizidines using a chemoenzymatic method utilizing a stereospecific aldol reaction coupled with selective bis-reductive amination. Potential of the method to access other stereosomers and analogues related to the hydroxylated pyrrolizidine class of alkaloids; Improved epoxidation of divinyl carbinol.

Examines three methods for the total synthesis of 3-(hydromethyl)pyrrolizidines. Intramolecular cycloaddition of azide with 1,3-diene bearing alkoxymethyl substituents; Azide cycloaddition with pure-S-t-Bu-substituted diene; Transformation of L-xylose into azido epoxy tosylate using Wittig reactions and epoxidation.

Describes the synthesis of (-)-7-epiaustraline and (-)-1-epicastranospermine. Difference of the cycloaddition process used in the synthesis with other applications; Regio- and stereoselective cycloaddition of nitronate with siloxymethyl (Z)-beta-silylvinyl ketone; Selective reduction of the resulting ketone with L-Selectride; Use of X-ray crystallography.

Describes the first synthesis of positive-casuarine, a pentahydroxy pyrrolizidine alkaloid of alexine/australine subclass. Nitroalkene cycloaddition of nitrobenzoate, chiral vinyl ether, and vinyl silane; Dependence of hydride reduction of chiral ketones on its reactive conformation; Factors influencing the successful implementation of the nitroalkene cycloaddition.

Demonstrates a concise enantiospecific synthesis of nemorensic acid, a necic acid component of the macropyrrolizidine alkaloid nemorensine isolated from Senecio nemorensis. Formation of a fragmentation product where a carbon-carbon bond cleavage reaction occurred between the gamma and delta positions of the carbonyl group; Deprotection of the silyl group.

Demonstrates the synthesis of benzopyrrolizidines and macrocyclic lactones via decarboxylative photocyclization. Decarboxylative photocyclization of potassium salts in aqueous acetone; Diastereoselectivity of the radical coupling step; Transformation of the benzopyrrolizidines cis/trans mixture; Structure of the macrolide.

Explores the catalytic and chemical reduction of various chiral pyrrolidine tetrasubstituted beta-enamino esters from (S)-alpha-methylbenzylamine. Enantioselective synthesis of pyrrolizidine and inolizidine alkaloids; Synthesis of (+)-laburnine, (+)-tashiromine and (-)-isoretronecanol.

Demonstrates a short and efficient route for the synthesis of enantiomerically pure 3,5-diarylpyrrolizidines. Synthesis based on a double nucleophilic displacement occurring in chiral 1,7-diaryl-4-((N-benzyl)amino)heptane-1,7-diols; Cyclization reactions involved in the four-step synthesis; Removal of the N-protection by alkaline hydrolysis.

Describes the convergent synthesis of dolastatin, a cytostatic depsipeptide isolated from the Indian Ocean sea hare. Condensation of peptide and pyrrolidone fragments; Use of hexafluorophospate as a coupling agent; Synthesis of model dipeptides and tripeptides.

Provides information on a study which developed a new approach to the pyrrolizidine and indolizidine skeletons, essentially based upon the intramolecular cycloaddition of nitrones derived from 1-allyl-2-pyrrolecarbaldehyde. Experimental procedures; Results from the synthesis of enantiopure compounds; Conclusions.

Presents a study which was conducted to determine the stereochemical influence of substitutens on the pyrrolidine ring in carbocyclization reaction. Discussion of the stereochemistry of tetrasubstituted pyrrolidines; Method used to conduct study; Outcome of study.

Examines the synthesis of glycosidase-inhibitory hydroxymethyl-substituted polyhydroxylated indolizidines. Potential therapeutic use of alexin and australine; Preparation of ring-expanded analogs of the pyrrolizidine alkaloids; Investigation of alternative route involving stereoselective epoxidation of the nine-membered lactones.

Reports on the preparation of four stereoisomers of dihydroxypyrrolizidine compounds. Stereochemistry; Use of unsaturated substituted lactams; Multi-gram scale preparation of two epimeric enantiopairs.

Reports on the enantioselective synthesis of a methylene acetal derivative of the necic acid. Oxidation and silylation yielding silyl ether; Stereoselective dihydroxylation; Protection of the vicinal diol; Synthesis of the chiral pyranone.

Simple three-step asymmetric and racemic syntheses of GlaxoSmithKline's highly potent PDE IVb inhibitor 1 were developed. The suggested approach is based on reductive domino transformations of 3-β-carbomethox-yethyl-substituted six-membered cyclic nitronates, which are easily accessed by a stereoselective [4 + 2] cydoaddition of an appropriate nitroalkene to vinyl ethers. In vitro studies of PDE IVb inhibition by enantiomeric pyrrolizidinones (+)-1 and (-)-1 were performed. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the synthesis of hyacinthacine A1. It describes the key steps taken in achieving the synthesis. It starts from L-(+)-DET with the use of the azido group introduction with retention of configuration while opening epoxide and the domino-pyrrolizidone construction in one stroke. It concludes that the appropriate choice of Sharpless asymmetric epoxidation and chiral synthon and epoxide opening will provide various stereo analogs.

Dscusses the synthesis of (-)-croalbinecine, an enantiomer of the polyhydroxylated pyrrolizidine. Use of ester-imine condensation and ring-closing metathesis.

Investigates the samarium diiodide-promoted cyclization on N-(omega-iodoalkyl)imides to polyhydroxylated indolizidinones and pyrrolizidinones. Synthesis of (+)-lentiginosine; Synthetic approach for diverse nitrogen-fused bicyclic alkaloids and their analogues.

Part XII. Examines the flexibility of nitroalkene tandem cycloaddition chemistry for the assymmetric synthesis of polyhydroxylated pyrrolizidine alkaloids, through the synthesis of (-)-platenecine. Steps of formation; Reaction scheme; Experimental procedure.