Indolizidine Derivatives Research Articles

Indolizidines from Actinomycetes: An Overview of Producers, Biosynthesis and Bioactivities.

Indolizidines have long been recognized for their valuable bioactivities, their common feature being a bicyclic structure connected via a nitrogen atom. Traditionally, plants have been identified as the primary producers. However, recent discoveries have revealed that certain bacterial strains belonging to the genus of actinomycetes also possess the ability to synthesize various indolizidine-based compounds. Among these strains, Streptomyces sp. HNA39, Saccharopolyspora sp. RL78, and Streptomyces NCIB 11649 have been identified as producers of cyclizidines, characterized by their distinctive cyclopropyl moiety. Additionally, Streptomyces griseus OS-3601 synthesizes a unique class of indolizidine derivatives known as iminimycins, distinguished by their rare imine-cation structure. Protoplast fusion of a Streptomyces griseus strain with Streptomyces tenjimariensis resulted in a new indolizidine named indolizomycin. This review aims to provide an overview of known bacterial indolizidine producers, summarize current knowledge regarding the biosynthesis of cyclizidines and iminimycins, and assess their respective bioactivities.

Catalyst‐Free [3+2] Cycloaddition of Isoquinolinium/Pyridinium Ylides and Electron‐Deficient Alkenes

AbstractThe development of simple‐to‐operate methods for the preparation of indolizidine derivatives are of great importance. A mild one‐pot protocol for the [3+2] cycloaddition of isoquinolinium/pyridinium ylides and electron‐deficient alkenes using NaBH3CN as reductant has been developed. The protocol has a broad substrate scope (more than 40 examples) and provides various novel hexahydroindolizidine derivatives in high yields and excellent diastereoselectivities (up to >20/1).

Synthesis of 1,5-Substituted Pyrrolidin-2-ones from Donor–Acceptor Cyclopropanes and Anilines/Benzylamines

We developed a straightforward synthetic route to pharmacologically important 1,5-substituted pyrrolidin-2-ones from donor-acceptor cyclopropanes bearing an ester group as one of the acceptor substituents. This method includes a Lewis acid-catalyzed opening of the donor-acceptor cyclopropane with primary amines (anilines, benzylamines, etc.) to γ-amino esters, followed by in situ lactamization and dealkoxycarbonylation. The reaction has a broad scope of applicability; a variety of substituted anilines, benzylamines, and other primary amines as well as a wide range of donor-acceptor cyclopropanes bearing (hetero)aromatic or alkenyl donor groups and various acceptor substituents can be involved in this transformation. In this process, donor-acceptor cyclopropanes react as 1,4-C,C-dielectrophiles, and amines react as 1,1-dinucleophiles. The resulting di- and trisubstituted pyrrolidin-2-ones can be also used in subsequent chemistry to obtain various nitrogen-containing polycyclic compounds of interest to medicinal chemistry and pharmacology, such as benz[g]indolizidine derivatives.

Lewis Acid Mediated Synthesis of Indolizidine Derivatives

Lewis Acid Mediated Synthesis of Indolizidine Derivatives

Superacid-promoted synthesis of indolizidine derivatives

A series of amido-acetals were reacted with the Brønsted superacid, CF3SO3H, to provides indolizidine derives by a cyclization cascade. A mechanism is proposed involving formation of a vinylogous enol which undergoes a 6π-electrocyclization reaction with an adjacent N-acyl iminium ion group. With aryl substituents, there is a strong tendency for the N-acyl iminium ion group to undergo Friedel-Crafts type cyclizations with the aryl group. The synthetic methodology was used to prepare the alkaloid natural product, ipalbidine.

Palladium-Catalyzed Aerobic Oxidative Cyclization of Aliphatic Alkenyl Amides for the Construction of Pyrrolizidine and Indolizidine Derivatives

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 N-heterocycles and the use of molecular oxygen (1 atm) as the green oxidant.

Sequential Nucleophilic C(sp3)‐Benzylation/C(sp2)–H Arylation for the Synthesis of Spiro[oxindole‐3,5′‐pyrrolo[2,1‐a]isoquinolines

An efficient strategy for the synthesis of spirocyclic indolizidine derivatives that have a 3,3′‐disubstituted oxindole framework has been described. By using sequential nucleophilic C(sp3)‐benzylation and palladium‐catalyzed C(sp2)–H arylation reactions of 3‐pyrrolyloxindoles and 2‐(bromomethyl)aryl bromides, a series of spiro[oxindole‐3,5′‐pyrrolo[2,1‐a]isoquinolines] were smoothly obtained in up to 92 % yield. A synthetic application of this method was also demonstrated by the transformation of 3u into functionalized compound 4. Moreover, the catalytic cycle of this cascade reaction was proposed on the basis of results of control experiments.

Synthesis of 3-substituted indolizidines from amino-ynones derivatives

Two types of indolizidine derivatives can be synthesized from amino-ynones. In the presence of methanesulfonic acid, Meyer–Schuster rearrangement furnished vinylogues of indolizidin-3-ones whereas treatment with zinc chloride gave stable 3-alkynyl-1,5,6,7,8,8a-hexahydroindolizine-zinc complexes that were reduced to 3-alkynylindolizidines.

Towards stereochemical control: A short formal enantioselective total synthesis of pumiliotoxins 251D and 237A.

A concise enantioselective synthesis of the advanced intermediate 5 for the synthesis of pumiliotoxins (Gallagher’s intermediate) is described. The synthesis started from the regio- and trans-diastereoselective (dr = 98:2) reductive 3-butenylation of (R)-3-(tert-butyldimethylsilyloxy)glutarimide 14. After O-desilylation and Dess–Martin oxidation, the resulting keto-lactam 10 was subjected to a highly trans-stereoselective addition of the methylmagnesium iodide to give carbinol 11 as sole diastereomer. An efficient ring closure procedure consisting of ozonolysis and reductive dehydroxylation provided the indolizidine derivative 5, which completed the formal enantioselective total synthesis of pumiliotoxins 251D and 237A.

Chiral Lewis Acid Catalyzed Asymmetric Cycloadditions of Carbonyl Ylides Generated from Diazoimide Derivatives and Their Synthetic Applications to Indolizidine Alkaloids

Highly enantioselective 1,3-dipolar cycloaddition reactions, catalyzed by chiral Lewis acids, between several 3-(2-alkenoyl)-2-oxazolidinones and carbonyl ylides that were generated from N-diazoacetyl lactams are described. Reactions of N-diazoacetyl lactams that possess 5-, 6-, and 7-membered rings were transformed to the corresponding epoxy-bridged indolizidines, quinolizidines, and 1-azabicyclo[5.4.0]undecanes with good to high enantioselectivities. Regio- and stereoselective ring-opening of the epoxy-bridged indolizidine cycloadduct gave the corresponding alcohol as a single diastereomer. The sequence of asymmetric cycloaddition followed by ring-opening was applied to the syntheses of several chiral indolizidine derivatives, including (+)-tashiromine.

New synthesis and reactions of indolizidine 167E and indolizidine derivatives

Two new methods of synthesizing indolizidines via ring-closing metathesis (RCM) have been developed. One method utilizes an alkene-isomerization, and the other method uses N-vinylation of an amide as the key step. Indolizidine 167E and many derivatives have also been synthesized.

An expeditious synthesis of an analogue of (−)-steviamine by way of the 1,3-dipolar cycloaddition of a nitrile oxide with a 1-C-allyl iminosugar

In our continuing effort to develop inhibitors of the mycobacterial galactan biosynthesis, we planned to synthesize original iminosugar-based analogues of UDP-galactofuranose by way of the 1,3-dipolar cycloaddition reaction between a 1-C-allyl iminosugar and a nitrile oxide, followed by the reductive cleavage of the resulting isooxazoline. In initial studies, it was found that this last step led in one pot to a new polyhydroxylated indolizidine derivative closely related to the recently isolated (−)-steviamine, in good yield, by way of a sequence involving at least five individual reactions. The activity of this new compound as a glycosidase inhibitor was evaluated against a panel of glycosidases and compared to (−)-steviamine.

Concise Synthesis of Pyrrolidine and Indolizidine Alkaloids by a Highly Convergent Three‐Component Reaction

The synthesis of pyrrolidine and indolizidine derivatives through radical carboazidation of alkenes with α-iodoketones, followed by reductive amination, is described. When properly substituted, further lactamization afforded pyrrolizidinones in good yield. This carboazidation/reductive amination sequence was efficiently applied to the total synthesis of three different simple alkaloids, including (±)-monomorine I.

ChemInform Abstract: Highly Diastereoselective Synthesis of Substituted Pyrrolidines Using a Sequence of Azomethine Ylide Cycloaddition and Nucleophilic Cyclization.

AbstractThis new method allows formation of a number of indolizidine derivatives with high diastereoselectivity.

Efficient and structurally controlled synthesis of novel polyhydroxylated indolizidine derivatives with an amino group

Novel polyhydroxylated indolizidine derivatives containing an amino group have been efficiently and divergently synthesized from azasugar aldehyde. The key steps of the strategy involved an effectively microwave assisted 1,3-dipolar cycloaddition of azasugar nitrone and methacrylate for installing a potential amino group and an ester group with a extended chain, and a structurally controlled intramolecular cyclo-amidation for constructing the indolizidine ring system via a key tricyclic indolizinone-containing intermediate.

Asymmetric Synthesis of 8-Aminoindolizidine from Chiral 2-Pyrroleimines

1-Allyl-2-pyrroleimines obtained from (S)-valinol and (S)-phenylglycinol underwent highly diastereoselective addition of allylmagnesium chloride, used in excess amounts, to give the corresponding secondary amines with concomitant allyl to (Z)-1-propenyl isomerization of the 1-pyrrole substituent. Transformation of the 2-amino alcohol moiety to an oxazolidinone, or its cleavage and subsequent N-protection, followed by ring-closing metathesis of the two alkene groups gave the unsaturated bicyclic compound. Full hydrogenation of the alkene function and the aromatic rings afforded the indolizidine derivative as a mixture of two or three diastereomers with a ratio which was dependent on the nature of both the N-substituent and the catalyst. The two prevalent diastereomers were isolated, and their configuration was determined by X-ray crystallographic analysis.

Synthesis of the Benzo-fused Indolizidine Alkaloid Mimics

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.

Efficient synthesis of 2,6,7,8-tetrahydroxyindolizidines (castanospermine analogues) via the dipolar cycloadditions of N-benzyl- C-(tetrofuranos-4-yl)nitrones to methyl acrylate

The dipolar cycloaddition of ( Z)- N-benzyl-(3- O-benzyl-1,2- O-isopropylidene-α- d-ribofuranos-5-ylidene)amine N-oxide to methyl acrylate gives a 53:16:26:5 diastereomeric mixture of isoxazolidine derivatives. The dipolar cycloaddition of the xylo analogue to methyl acrylate is more diastereoselective, producing a 44:13:43 mixture of only three diastereomers. The ribo-configured adducts have been converted (4 steps only) into the new (2 R,6 S,7 S,8 R,8a R)-, (2 S,6 S,7 S,8 R,8a R)-, (2 S,6 S,7 S,8 R,8a S)- and (2 R,6 S,7 S,8 R,8a S)-2,6,7,8-tetrahydroxyindolizidines. Similarly, the two xylo-configured major isoxazolidine derivatives were converted into the known derivatives (2 R,6 S,7 R,8 R,8a S)- and (2 S,6 S,7 R,8 R,8a R)-2,6,7,8-tetrahydroxyindolizidines. The six isomeric indolizidine derivatives obtained have been evaluated for their inhibiting activities towards 15 glycosidases. Only the (2 R,6 S,7 S,8 R,8a R)-configured isomer is a selective inhibitor of amyloglucosidases from Aspergillus niger (IC 50 = 350 μM) and from Rhizopus mold (IC 50 = 90 μM, K i = 195 μM, non-competitive), the other indolizidines show very little inhibitory activity at 1 mM concentration.

Intramolecular α-acylamino radical cyclizations with acylsilanes in the preparation of polyhydroxylated alkaloids: (+)-lentiginosine, (+)-1,8a-di- epi-lentiginosine, and (+)-1,2-di- epi-swainsonine

Acylsilanes with latent α-acylamino radical functionality were prepared from different chiral templates. Radical cyclizations of these acylsilanes efficiently constructed polyhydroxylated indolizidine derivatives with excellent stereoselectivity at the bridgehead position. These cyclization products were converted to (+)-lentiginosine, (+)-1,8a-di- epi-lentiginosine, and (+)-1,2-di- epi-swainsonine.

New alkaloid-like heterocycles via formal aza-[3+2] cycloaddition reaction of cyclic enaminones with cyclopropenones

The formal aza-[3+2] cycloaddition reactions of cyclopropenones and cyclic enaminones, including a chiral one, were employed for the first time in the direct formation of new pyrrolidine and indolizidine derivatives. The regiochemistry of cyclization is dependent of both ring size and steric factors of enaminones.