Polyhydroxylated Indolizidines Research Articles

Synthetic strategy for polyhydroxylated indolizidine iminosugar from sugar-derived HWE precursor

The diversity of polyhydroxylated indolizidine (PI) iminosugars is ever-expanding due to the wide range of methods developed and substrate choice during synthesis. This study used an HWE precursor derived from d-glucose to extend the chain length at the C1 position. A double reductive amination and dihydroxylation of the resulting olefin, followed by intramolecular cyclization, enabled the successful synthesis of a new PI. In addition, the precursor intermediate for Mitsunobu reaction was utilized in synthesis of a new iminononulol.

Biosynthesis of the α-D-Mannosidase Inhibitor (-)-Swainsonine.

(-)-Swainsonine is a polyhydroxylated indolizidine alkaloid with potent inhibitory activity against α-D-mannosidases. In this work, we successfully reconstituted swainsonine biosynthetic pathway both in vivo and in vitro. Our study unveiled a surprising epimerization mechanism involving an imine reductase (SwnN) and two non-heme iron and α-ketoglutarate-dependent oxygenases (SwnH2 and SwnH1). SwnH2 is a multifunctional enzyme responsible for both C2-hydroxylation and amine desaturation, while SwnN completes the oxidation-reduction sequence to achieve the net redox neutral epimerization. Notably, SwnN exhibits substrate-dependent stereospecificity and the stereochemical outcome of SwnN-catalyzed iminium reduction is determined by SwnH1-catalyzed C8-hydroxylation. We also discovered that an O -acetyl ester can serve as a detachable protecting/directing group, altering the site-selectivity of SwnH2-catalyzed hydroxylation while maintaining the stereoselectivity. Insights gained from the biochemical characterization of these tailoring enzymes enabled biocatalytic synthesis of a new polyhydroxylated indolizidine alkaloid, opening doors to the biosynthesis of diverse natural product-based glycosidase inhibitors.

Recent Developments in the Synthesis of Polyhydroxylated Indolizidines

AbstractSince their discovery, polyhydroxylated indolizidines have been the focus of attention for both biologists and synthetic chemists. They are classified as iminosugar alkaloids: nitrogen‐based carbohydrate mimetics that are potent inhibitors of glycosidases. Many discovered glycosidase inhibitors were found to possess biological activity, and they are therefore considered to be potential therapeutics in the treatment of various diseases such as viral infections, diabetes, or cancer. Not surprisingly, the interest in the preparation of these substances has been enormous. This review presents the latest developments in the synthesis of naturally occurring polyhydroxylated indolizidines and their synthetic enantiomers. In addition, the synthesis of several novel polyhydroxylated indolizidines, which were discovered to have inhibitory activity, is reported.

Divergent Synthesis of Amino‐Substituted Indolizidine Alkaloids, Decahydropyrazino[2,1,6‐cd]pyrrolizine Triols, and (–)‐Pochonicine Stereoisomers

A reagent‐directed divergent synthesis of three skeletally distinct compounds, namely, amino‐substituted indolizidine alkaloids, decahydropyrazino[2,1,6‐cd]‐pyrrolizine triols and (–)‐pochonicine stereoisomers have been accomplished from a single precursor. Tri‐O‐benzyl‐d‐glucal was converted into a diastereomeric mixture of homoallylic alcohols through a seven‐step sequence developed earlier in our lab. Intramolecular iodo‐amination of the homoallylic alcohols proceeded through a 5‐exo‐tet ring opening of initially formed iodonium ion to give the iodo‐substituted pyrrolizidine {[5,5‐]‐fused} derivatives. Upon exposure to AgOAc, these iodo‐pyrrolizidines underwent a ring enlargement under the reaction condition and delivered polyhydroxylated indolizidine {[5,6]‐fused} derivatives as the main products. On the other hand, when the iodo‐pyrrolizidines were treated with NaH, a smooth intramolecular substitution reaction took place resulting in the formation of novel decahydropyrazino[2,1,6‐cd]pyrrolizine triols in good yields. Diversely, epoxidation of the homoallyic alcohols followed by intramolecular ring opening and subsequent synthetic transformations delivered stereoisomers of (–)‐pochonicine. The structure and stereochemistry of the final compounds were established through detailed 2D‐NMR analysis.

Contribution to the synthesis of polyhydroxylated indolizidines starting from sugar isothiocyanates

A straightforward stereoselective route towards castanospermine analogues starting from the corresponding d-gluco- and l-ido-hexofuranose isothiocyanates (5S)-2 and (5R)-2 is described. The key transformations of this approach rely on ring-closing metathesis and reductive amination to form the final polyhydroxylated indolizidines 10–13 in good overall yields.

Hydroxymethyl-Branched Polyhydroxylated Indolizidines: Novel Selective α-Glucosidase Inhibitors.

α,α-Disubstituted piperidines and conformationally constrained polyhydroxylated indolizidines bearing a hydroxymethyl substituent in position 8a were synthesized from a readily available l-sorbose-derived ketonitrone. Diastereoselective vinylation under two sets of complementary conditions allowed access to both configurations of the newly formed quaternary stereocenter. Subsequent N-allylation and ring-closing metathesis afforded 8a-branched indolizidines in high yield. The newly prepared iminosugars demonstrated highly potent inhibition of α-glucosidases. Most interestingly, compound 9b exhibits very high selectivity toward this class of enzymes, with an unusual mode of binding.

ChemInform Abstract: Synthesis of Polyhydroxylated Indolizidines and Piperidines from Garner′s Aldehyde: Total Synthesis of (‐)‐Swainsonine, (+)‐1,2‐Di‐epi‐swainsonine, (+)‐8,8a‐Di‐epi‐castanospermine, Pentahydroxy Indolizidines, (‐)‐1‐Deoxynojirimycin, (‐)‐1‐Deoxy‐altro‐nojirimycin, and Related Diversity.

AbstractDiastereoselective and diverse syntheses of polyhydroxylated indolizidines and piperidines are described, where the common chiral intermediate 2‐(hydroxymethyl) piperidine‐3‐ol is converted into 1‐deoxy‐altro‐nojirimycin derivatives (I), 1‐deoxynojirimycin (II), 1,2‐di‐epi‐swainsonine (III), swainsonine (IV), 8,8a‐di‐epi‐castanospermine (V), and isomeric pentahydroxy indolizidines (VI) and (VII).

ChemInform Abstract: Ruthenium—NHC‐Catalyzed Asymmetric Hydrogenation of Indolizines: Access to Indolizidine Alkaloids.

Indolizidine alkaloids constitute a very important class of natural products. These metabolites derived from lysine can be isolated from diverse sources, like fungi, bacteria, higher plants, invertebrates, and vertebrates. Their core structure is characterized by fused sixand five-membered rings, with a bridgehead nitrogen atom, and is found in 25–30% of all naturally occurring alkaloids. The most important types of indolizidines are plant-derived polyhydroxylated indolizidines, like swainsonine and castanospermine, which are glycosidase inhibitors with activity against HIV, as well as alkylindolizidines, like monomorine (3), which is isolated from ants (Monomorium pharaonis) and from the skin of amphibians (Melanophryniscus stelzneri), and is believed to serve in their defense against predators (Scheme 1).

Synthesis of polyhydroxylated indolizidines and piperidines from Garner's aldehyde: total synthesis of (−)-swainsonine, (+)-1,2-di-epi-swainsonine, (+)-8,8a-di-epi-castanospermine, pentahydroxy indolizidines, (−)-1-deoxynojirimycin, (−)-1-deoxy-altro-nojirimycin, and related diversity

Diastereoselective and diverse synthesis of polyhydroxylated indolizidines and piperidines have been described, where a common chiral intermediate 2-(hydroxymethyl) piperidine-3-ol is converted into (−)-swainsonine, (+)-1,2-di-epi-swainsonine, (+)-8,8a-di-epi-castanospermine, pentahydroxy indolizidines, (−)-1-deoxynojirimycin, (−)-1-deoxy-altro-nojirimycin, and related diversity. The key steps were hydroxy directed intramolecular aminomercuration, Mitsunobu cyclization, and diastereoselective dihydroxylation.

A Diastereoselective Cyclic Imine Cycloaddition Strategy To Access Polyhydroxylated Indolizidine Skeleton: Concise Syntheses of (+)-/(−)-Lentiginosines and (−)-2-epi-Steviamine

We describe in this paper the development of a novel diastereoselective cyclic imine cycloaddition strategy to access the polyhydroxylated indolizidine skeleton and its application in the concise syntheses of (+)-/(-)-lentiginosines and (-)-2-epi-steviamine.

Chemoenzymatic synthesis, structural study and biological activity of novel indolizidine and quinolizidine iminocyclitols

The synthesis, conformational study and inhibitory properties of diverse indolizidine and quinolizidine iminocyclitols are described. The compounds were chemo-enzymatically synthesized by two-step aldol addition and reductive amination reactions. The aldol addition of dihydroxyacetone phosphate (DHAP) to N-Cbz-piperidine carbaldehyde derivatives catalyzed by L-rhamnulose 1-phosphate aldolase from Escherichia coli provides the key intermediates. The stereochemical outcome of both aldol addition and reductive amination depended upon the structure of the starting material and intermediates. The combination of both reactions furnished five indolizidine and six quinolizidine type iminocyclitols. A structural analysis by NMR and in silico density functional theory (DFT) calculations allowed us to determine the population of stereoisomers with the trans or cis ring fusion, as a consequence of the inversion of configuration of the bridgehead nitrogen. The trans fusion was by far the most stable, but for certain stereochemical configurations of the 3-hydroxymethyl and hydroxyl substituents both trans and cis fusion stereoisomers coexisted in different proportions. Some of the polyhydroxylated indolizidines and quinolizidines were shown to be moderate to good inhibitors against α-L-rhamnosidase from Penicillium decumbens. Indolizidines were found to be moderate inhibitors of the rat intestinal sucrase and of the exoglucosidase amyloglucosidase from Aspergillus niger. In spite of their activity against α-L-rhamnosidase, all the compounds were ineffective to inhibit the growth of the Mycobacterium tuberculosis, the causative agent of tuberculosis.

Optimization of different process variables for the production of an indolizidine alkaloid, swainsonine from Metarhizium anisopliae

Swainsonine is a polyhydroxylated indolizidine alkaloid having anticancer, antimetastatic, antiproliferative and immunomodulatory activities and also potential therapeutic applications against AIDS. In the present study, ten isolates of M. anisopliae were screened and enzyme assayed for the production of swainsonine in different media (Complex oatmeal, Czapekdox media with and without lysine (8% w/v) and Sabouraud dextrose broth (SDB)). Among these strains, ARSEF 1724 (UM8) was found to produce highest amount of swainsonine (1.34 μg/l) after 72 h of incubation under shake flask conditions at 180 rpm and 28 °C in complex oatmeal media. In order to maximize the yield of swainsonine the media composition including macro and micronutrients were optimized. The process variables including the chemical factors like carbon sources, nitrogen sources of both organic and inorganic nature and pH with constant inoculum size (1 × 10(8) spores/ml) were screened using classical one-factor-at-a-time (OFAT) approach to find their optimum levels. The present study shows that the nutrient requirement is specific for each strain of Metarhizium. Oatmeal extract (6%) was found to be the best supporting media along with nitrogen source, glucose (2%) as best carbon source and pH (~5) as the best for swainsonine production.

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 two advanced intermediates for the asymmetric synthesis of polyhydroxylated indolizidine alkaloids

National Natural Science Foundation of China [20832005]; National Basic Research Program (973 Program) of China [2010CB833200]

Stereocontrolled Cyclic Nitrone Cycloaddition Strategy for the Synthesis of Pyrrolizidine and Indolizidine Alkaloids

The synthesis of polyhydroxylated indolizidines and pyrrolizidines belonging to the class of iminosugars, endowed with a vast and assorted biological activity, can be achieved in a straightforward manner by a general strategy consisting of a highly stereoselective 1,3-dipolar cycloaddition of polyhydroxylated pyrroline-N-oxides followed by simple transformations of the isoxazolidine adducts. The strategy allows the complete control of the relative and absolute stereochemistry of the numerous stereogenic centers decorating these compounds.

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.

Synthesis and Glycosidase Inhibitory Study of New Polyhydroxylated Indolizidines

AbstractThe synthesis of two polyhydroxylated indolizidines as potenticial glycosidase inhibitors is reported. The piperidine ring was formed by an intramolecular Mannich‐type reaction between ethyl trans‐4‐oxo‐2‐butenoate and the two β‐amino ketones (–)‐1‐(2‐methyl‐1,3‐dioxan‐2‐yl)propan‐2‐amine and(+)‐1‐(benzyloxymethyl)‐2‐(2‐methyl‐1,3‐dioxan‐2‐yl)ethylamine. The synthesis of this amine was performed in eight steps from L‐aspartic acid. The key steps of the formation of the framework involved dihydroxylation, nucleophilic substitution, and reduction. The last hydroxy group was introduced by hydrolysis of the acetal moiety followed by reduction of the resulting ketone. The inhibitory properties of the two synthesized indolizidines were evaluated against a variety of commercial glycosidases. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Concise and divergent total synthesis of swainsonine, 7-alkyl swainsonines, and 2,8a-diepilentiginosine via a chiral heterocyclic enaminoester intermediate

Abstract The concise and divergent total syntheses of (−)-swainsonine, (−)-7-alkyl swainsonines, and (−)-2,8a-diepilentiginosine from a common chiral heterocyclic enaminoester intermediate in five-step sequences are presented. The highly efficient annulation reaction of the chiral heterocyclic enaminoester with various α,β-unsaturated carboxylates, and a straightforward carboxy inversion constituted the key features of the synthetic pathway. This work provides an example for divergent synthesis of different natural and unnatural polyhydroxylated indolizidines from a readily available platform.

Synthesis of 1-Deoxy-1-hydroxymethyl- and 1-Deoxy-1-epi-hydroxymethyl Castanospermine as New Potential Immunomodulating Agents

Two new C-1 epimeric hydroxymethyl castanospermine congeners 2a and 2b, synthesized by stereocontrolled intramolecular double reductive amination of D-glucose derived beta-keto ester as a key step, showed impressive immuno-potentiating property. The bioactivity was mediated through up-regulation of T(H1)/T(H2) cytokine ratio. The finding suggested that immunmodulatory activity of polyhydroxylated indolizidine alkaloids can be tuned by minor structural/stereochemical alterations.

Indolizidines and quinolizidines: natural products and beyond

Alkaloids occur in such astonishing profusion in nature that one tends to forget that they are assembled from a relatively small number of structural motifs. Among the motifs that are most frequently encountered are bicyclic systems containing bridgehead nitrogen, especially 1-azabicyclo[4.3.0]nonanes and 1-azabicyclo[4.4.0]decanes or their unsaturated analogues – the indolizidines and quinolizidines to which this Thematic Series is devoted. These two azabicyclic systems may occur in the natural products either in isolation (the so-called 'simple izidine' alkaloids) or, more commonly, embedded within fused polycyclic arrays. Just how widespread they are was pointed out over two decades ago in a review in which it was estimated that between 25% and 30% of all alkaloids possess structures incorporating one or other of these motifs. [1] As might be expected of systems that are so pervasive, their natural sources are extremely diverse: they occur in organisms as widely different as bacteria, fungi, higher plants, invertebrates and vertebrates; and both terrestrial and marine sources are represented. For example, two of the best-known and most widely investigated groups of 'simple izidine' alkaloids are the plant-derived polyhydroxylated indolizidines that function as potent glycosidase inhibitors, [2-4] and the alkylindolizidines and analogues sequestered from dietary sources in the skins of amphibians. [5,6] It is thus hardly surprising that both the structural elucidation and the total synthesis of these and related alkaloids continue to attract the attention of eminent chemists, as borne out by the seemingly inexhaustible flow of publications in prominent journals. [7] Several general reviews on these alkaloids have also appeared in recent years. [8-11] The interest in indolizidines and quinolizidines, although inspired by alkaloids, nowadays extends far beyond natural product chemistry. Considerable effort is being invested in the development of innovative methods for preparing the parent bicyclic systems and, more especially, for the stereocontrolled attachment of substituents. Studies on the biological activity of compounds containing azabicyclic building blocks (for example, rigid bicyclic peptidomimetics) are gaining momentum. Structural, spectroscopic and computational studies on both natural and synthetic indolizidines and quinolizidines are also reported regularly. In this Thematic Series, there are representative articles covering several of these aspects. A number of authors have contributed reviews in which their own contributions to the development of indolizidine and quinolizidine chemistry are highlighted. There are articles on the total synthesis of relevant natural products, as well as articles describing novel methodological approaches to the systems of interest. That what may appear to be a marginal, passe or recondite outpost of chemistry still attracts a healthy measure of international attention bears testimony to the durability of a topic that is sure to retain its fascination for the foreseeable future. Jo Michael Guest Editor