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An efficient, one-pot, three-component [3+2] cycloaddition reaction of azomethine ylide obtained from α-dicarbonyl compounds (cyclic and acyclic diketone or keto ester) and amino acids with maleimides under catalyst-free conditions has been developed. This cascade protocol shows high efficiency and remarkable functional group tolerance, and the ubiquitous succinimide-fused pyrrolizidines with a highly compact and strained scaffold were obtained with high yield and excellent diastereoselectivity. Furthermore, this novel and atom-economical strategy could be performed on a gram scale with comparable reaction efficiency. [ABSTRACT FROM AUTHOR]

A general strategy for the facile construction of both the ABDE and ABCD cores of tronocarpine, chippiine and dippinine alkaloids through the retrosynthetic disconnection of the polycyclic motifs into an indole or tryptamine fragment and a suitably functionalized alkyl chain is presented. The approach is enabled by an efficient Ir(III)-catalyzed, photoredox-mediated radical addition of tetramethyl 1-bromopentane-1,1,3,5-tetracarboxylate and dimethyl 2-bromopentanedioate selectively at C-2 of the indole. Subsequent intramolecular cyclization events furnish the desired ABDE and ABCD polycyclic cores in good preparative yields. [ABSTRACT FROM AUTHOR]

The diterpenoid alkaloids serve as a rich source of synthetic targets for organic chemists, due to the intriguing structure of the overlapping ring systems, along with biological activities commonly associated with compounds of this group. Fifteen total syntheses and numerous synthetic studies towards construction of ring fragments have been reported since 2010. This review article gives a brief overview of diterpenoid alkaloids and summarizes the recent synthetic efforts. 1 Introduction 1.1 Structural Classification and Biosynthetic Origin 1.2 Structure Elucidation of the Aconitum Alkaloids 2 Total Syntheses 2.1 C18-Diterpenoid Alkaloids 2.2 C19-Diterpenoid Alkaloids 2.3 C20-Diterpenoid Alkaloids 3 Strategies To Synthesize Ring Systems 3.1 Radical-Based Cyclizations 3.2 Ruthenium-Mediated Enyne Cycloisomerization 3.3 Reductive Coupling 3.4 Diels–Alder Reactions 3.5 Oxidative Dearomatization/Diels–Alder Sequence 3.6 Transannular Aziridation 3.7 Intramolecular [5+2] Cycloaddition 3.8 Miscellaneous 4 Conclusion [ABSTRACT FROM AUTHOR]

A three-component reaction of β,γ-unsaturated α-keto esters, proline, and dialkyl maleates has been developed. This reaction provides pyrrolizidine derivatives containing three ester groups and a styrenyl group, as well as a quaternary center, in moderate to good yields and with good to excellent diastereoselectivities. [ABSTRACT FROM AUTHOR]

A simple and convenient method for the synthesis of bisfunctionalised pyrrolizidines starting from readily available N-Cbz-L-prolinal is described. This aldehyde was converted within two concise steps to the corresponding aminoepoxides, which were separately subjected to regioselective cyclisation induced by a reductive cleavage of the Cbz protecting group. The versatile and concise strategy holds great potential for practical application in the straightforward preparation of pyrrolizidine-based drugs and natural products. [ABSTRACT FROM AUTHOR]

This account describes an overview of the asymmetric syntheses of pyrrolizidines, indolizidines and quinolizidines via a common double reductive cyclisation protocol. The highly diastereoselective conjugate addition of an enantiopure lithium amide to an α,β-unsaturated ester incorporating a terminal C=C bond installed the nitrogenbearing stereogenic centre and was followed by enolate functionalisation to introduce the second olefinic functionality. Alternatively, conjugate addition to the corresponding α-alkenyl α,β-unsaturated ester followed by α-protonation of the intermediate enolate may also be used to access the cyclisation precursor. After oxidation of the two terminal olefinic units to give the corresponding dialdehyde, tandem hydrogenolysis/ hydrogenation was employed to efficiently construct the azabicyclic core of each target molecule. This double reductive cyclisation strategy was successfully utilised in the syntheses of 13 azabicyclic alkaloids or closely related analogues. 1 Introduction 2 Asymmetric Syntheses of (--)-Isoretronecanol and (--)-Trachelanthamidine 3 Asymmetric Syntheses of (+)-Trachelanthamidine [(+)-Laburnine], (+)-Tashiromine and (+)-epi-Lupinine 4 Asymmetric Syntheses of (--)-Hastanecine, (--)-Turneforcidine and (--)-Platynecine 5 Asymmetric Syntheses of (--)-Macronecine, (--)-Petasinecine, (--)-1-epi-Macronecine, (+)-1-epi-Petasinecine and (+)-2-epi-Rosmarinecine 6 Conclusion [ABSTRACT FROM AUTHOR]

A novel gold(I)/Brønsted acid sequential catalyzed/promoted procedure to synthesize 1-alkyl-3-(2-oxo-2-aryl/alkyl-ethyl)indolin-2-ones under mild reaction conditions is developed. This methodology is realized by relay actions of gold and a Brønsted acid in a one-pot multistep manner. The gold(I)-catalyzed chemoselective C(sp2)-H functionalization of enaminones and Brønsted acid promoted cleavage of the C=C bond are integrated effectively. Based on the results of control experiments and ESI-MS analysis, a possible reaction mechanism is proposed. [ABSTRACT FROM AUTHOR]

An efficient palladium-catalyzed aerobic oxidative cyclization has been developed to synthesize a variety of pyrrolizidine and indolizidine derivatives from simple aliphatic alkenyl amides in moderate to good yields. The reaction features the capability of accessing various Nheterocycles and the use of molecular oxygen (1 atm) as the green oxidant. [ABSTRACT FROM AUTHOR]

Herein we describe the synthesis of 1-hydroxymethyl pyrrolizidine and indolizidine alkaloids from epoxy-tethered pyrrole precursors. Two titanium-based methods are evaluated for the construction of the bicyclic scaffold: the Lewis acid mediated cyclization developed by Tanis and Raggon and the titanocene(III)-catalyzed reaction proceeding via radical intermediates. The former method, after hydrogenation of the pyrrole moiety, ultimately gives rise to enantiopure (-)-tashiromine, being the most concise and atom-economic procedure reported to date. [ABSTRACT FROM AUTHOR]

In this study, an efficient ring rearrangement of 2-[2-(1-pyrrolin-2-yl)alkyl]aziridines, prepared from 2-(bromomethyl)aziridines, toward novel trans- and cis-3-aminomethyl-substituted pyrrolizidines was developed. To that end, addition of In(OTf)3 as an appropriate Lewis acid catalyst resulted in the formation of intermediate pyrrolizidinium salts via regioselective aziridine ring opening, which were then trapped by a hydride or cyanide nucleophile. Column chromatographic purification allowed the isolation of the major trans-isomers, exclusively. [ABSTRACT FROM AUTHOR]

The selective functionalization of 2-formylpyrrole to provide diverse 1,2- and 1,2,5-substituted pyrroles is described. These compounds were used as versatile building blocks in a divergent synthesis of biologically valuable aza-bycyclic skeletons, such as pyrrolizine and pyrrolizidine derivatives. These bicycles were prepared following metal-free cascade synthetic approaches via regioselective intramolecular 1,3-dipolar cycloadditions and stereoselective Knoevenagel/Michael/ cyclization with dimethyl malonate. [ABSTRACT FROM AUTHOR]

An acid-mediated annulation reaction for the formation of 7a-substituted unnatural pyrrolizidines is described. To reach this goal, the pyrroline 3-(3,4-dihydro-2H-pyrrol-5-yl)propan-1-ol is reacted with a large variety of isonitriles directly resulting in the target compounds. The reaction is operationally simple and tolerates air and water, and the resulting pyrrolizidines can be further transformed to the corresponding oxidized and reduced derivatives. [ABSTRACT FROM AUTHOR]

α,α-Difluoro-α-phenylsulfanyl-α-trimethylsilylmethane (PhSCF2SiMe3) is a synthetically important fluorinating reagent. This account summarizes our work on the synthetic utility of α,α- difluoro-α-phenylsulfanyl-α-trimethylsilylmethane as a versatile gem-difluoromethylene building block for the preparation of a variety of gem-difluoromethylenated compounds. [ABSTRACT FROM AUTHOR]

A new approach to C5-hydroxymethyl-substituted pyrrolizidines involving 1,3-dipolar cycloaddition of a D-mannose-derived cyclic nitrone and the SN-reaction of a silyl ketene acetal is presented. The synthesis shows good stereoselectivity as a result of the presence of a dioxolane substituent at C5 of the nitrone, the bulkiness of the silyl ketene acetal, and the shape of the pyrrolizidinylium intermediate formed during intramolecular reductive amination. This approach provides access to pyrrolizidines with the same relative configuration as that found in hyacinthacines C2 and C3, and in (+)-pochonicine. [ABSTRACT FROM AUTHOR]

A diastereoselective Fráter-Seebach-type alkylation provides access to a highly functionalized pyrrolizidine, which could serve as a key building block for the total synthesis of Daphniphyllum alkaloids, such as oldhamine A. [ABSTRACT FROM AUTHOR]

Dimethyl 2-(aryloxy)fumarates and dimethyl 2-(alkylor arylthio)fumarates are shown to be efficient dipolarophiles in 1,3-dipolar cycloaddition reaction with azomethine ylides, which are generated by the reaction of isatin with the secondary amino acids proline or sarcosine. In these reactions, dimethyl 2-(alkyl- or arylthio)fumarates afforded spirooxindolopyrrolizidines or -pyrrolidines in high yields with excellent regioselectivities, while dimethyl 2-(aryloxy)fumarates produced mixtures of regioisomers. DFT calculations at the B3LYP/6-31G(d, p) level were consistent with the observed results. Tri- and tetracyclic compounds were obtained through regio- and stereoselective intramolecular cycloaddition of O-vinylic salicylaldehyde with secondary amino acids. [ABSTRACT FROM AUTHOR]

An efficient approach to the diastereoselective synthesis of benzylidene-, benzyl-pyrrolizidinones, and pyrrolizidines is described. The sequence is based on a highly stereoselective Heck reaction between a hydroxylated pyrrolizidinone, prepared from a Morita-Baylis-Hillman adduct, and a suitable aryl halide, using Nájera's oxime derived palladacycle as catalyst. [ABSTRACT FROM AUTHOR]

An efficient one-pot synthesis of a library of novel sugar-based spirooxindole-pyrrolidines or -pyrrolizidines has been accomplished by [3+2] cycloaddition. This method utilizes an azomethine ylide derived from isatin and sarcosine or L-proline with an α,β-unsaturated β-C-glycosidic ketone as the dipolarophile. All these sugar-based heterocyclics were characterized by NMR (¹H and 13C), HPLC, and elemental analysis [ABSTRACT FROM AUTHOR]

A convenient and efficient method has been used for the synthesis of ten new tetrahydroxylated pyrrolizidines 12a,b, 13a-c, 14a,b, and 15a-c starting from sugar-derived cyclic nitrones prepared from D-xylose, D-arabinose, D-ribose, and L-arabinose, through a five-step reaction sequence. Pyrrolizidine 12a is an enantiomer of 7-deoxycasuarine and pyrrolizidine 12b an enantiomer of the as yet unknown 7-deoxyuniflorine A. This method expands the scope of nitrone cycloadditions and is flexible enough for the synthesis of various stereoisomers of highly polyhydroxylated pyrrolizidines. [ABSTRACT FROM AUTHOR]

The stereoselective synthesis of a series of novel spiropyrrolidines and spiropyrrolizidines has been accomplished through an intermolecular 1,3-dipolar cycloaddition of an azomethine ylides with dipolarophiles derived from the Baylis-Hillman reaction of �isatins with N-methyl maleimide. [ABSTRACT FROM AUTHOR]

A facile and efficient entry into highly functionalized 3-spiropyrrolidine oxindoles and 3-spiropyrrolizidine oxindoles, as well as to 3-spiropyrrolidine acenaphthenones via one-pot four-component reactions of 3-cyanoacetylindoles, aldehydes, isatin/acenaphthylene-1,2-dione and amino acid has been developed. Particularly valuable features of this method include high yields of products, broad substrate scope and a straightforward procedure. [ABSTRACT FROM AUTHOR]

Easily accessible [(5,6-dihydro-4 H-1,2-oxazin-3-yl)methyl]malonates? 1 were converted into substituted 5-(3-hydroxypropyl)pyrrolidin-2-ones 2 and pyrrolizidinones 3, which are versatile products and intermediates for organic and bioorganic chemistry. The synthetic sequence suggested includes stereoselective two-step reduction of an oximino fragment, followed by intramolecular cyclization involving one of the CO 2Me groups and decarboxylation in the last stage. The efficiency of this strategy was demonstrated by the stereoselective synthesis of pyrrolizidinone RAC- 4, a highly efficient analogue of antidepressant Rolipram, from nitroethane. [ABSTRACT FROM AUTHOR]

A facile regio- and stereoselective synthesis of functionalized 3-spiropyrrolidines and 3-spiropyrrolizidines using the ?Baylis-Hillman adducts derived from nitroolefins via intermolecular [3+2] cycloaddition reaction is reported. [ABSTRACT FROM AUTHOR]

Primary cyclopropylamines bearing hydroxy side chains were obtained by Ti-mediated coupling of nitriles and homoallylic alcohols. Their usefulness as synthetic intermediates was demonstrated by the preparation of a constrained glutamic acid derivative and pyrrolizidine analogues. [ABSTRACT FROM AUTHOR]

An expedient Cope-House cyclization strategy is reported here for the synthesis of several polyhydroxy pyrrolizidine alkaloids starting from sugar-derived nitrones. [ABSTRACT FROM AUTHOR]

Nitrosoalkene 2 generated in situ from oxime 3 underwent smooth hetero Diels-Alder reaction with enol ethers 1 to afford 1,2-oxazine derivatives 4 bearing an exocyclic C=C bond. Methoxyallene 8 and 2 provided 6 H-1,2-oxazine 10 in good overall yield. The exocyclic double bond of this type of 1,2-oxazines can be employed for addition reactions as demonstrated by dihydroxylation of 4A with potassium permanganate, smoothly delivering 1,2-diol 11. A reductive cascade reaction involving ring cleavage at the N-O bond followed by cyclization steps furnished pyrrolizidinone derivatives 12 in good yields. In the case of 12B this transformation proceeded with excellent stereoselectivity. Finally, the lactam moiety of 12 could be reduced with borane to provide the corresponding pyrrolizidine derivatives 19 in good yield. [ABSTRACT FROM AUTHOR]