Polyhydroxylated indolizidine alkaloids—an efficient synthesis of 1-deoxy-8,8a-di-epi-castanospermine

A new and efficient enantioselective total synthesis of the title deoxycastanospermine derivative has been developed, based on amino acid and β-ketophosphonate chemistry, as well as employment of internal asymmetric induction for the creation of the new chiral centers proved successful. With proper choice of reaction conditions, the approach can also be applied in selective preparation of several isomers of deoxycastanospermine. The length (9 steps) and overall yield of the title compound trihydroxyindolidine 1, 7.3%, compares well with the literature syntheses of similar compounds.     

Daphniphyllum alkaloids—III

The structures of yuzurimine and yuzurimines-A and B are presented. The structure of yuzurimine, established by X-ray analysis, is in full agreement with its chemical and spectral data. The structures of yuzurimines-A and B were deduced by comparison of the NMR, IR and mass spectra with those of yuzurimine. The structure of the latter was confirmed by chemical transformation from yuzurimine to yuzurimine-B mesylate. Finally, chemical transformation of yuzurimine to a biogenetically plausible compound (XXXI or XXXII) was carried out.     

A new indolizidine synthesis

The intramolecular 1,6 Michael type addition of a primary amine to an electrophilic diene occurs under very mild conditions; it is the key step for a new preparation of indolizidines.     

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.     

Straightforward synthesis of indolizidine alkaloid 167B

The synthetic access to indolizidines, substituted in C-5 position, was reported with good diastereoselectivity. The strategy developed was based on a key step of Michael addition associated with a Clauson-Kaas condensation.     

Solid-phase synthesis of indolizidine and quinolizidine derivatives

An efficient method for the construction of simple indolizidine and quinolizidine derivatives on solid support has been developed. An intramolecular tandem Michael reaction initiated by the nucleophilic attack of a suitably placed amino group on the tethered Wittig condensation products between 4- or 5-aminoaldehydes attached to a trityl chloride resin and 4-[(4-methylphenyl)sulfonyl]-1-(triphenylphosphoranylidene)-2-b utanon e is the key step.     

Enantioselective synthesis of indolizidine alkaloid trans-209D

(S)-N-Boc-baikiain, readily accessible from enantiomerically enriched 2,3-epoxy-5-hexen-1-ol 4 (prepared by Sharpless asymmetric epoxidation), was used as the starting material in the synthesis of indolizidine alkaloid trans-209D , which was obtained in 13 steps and 14% yield from 1 (5% from 4).     

Enantiospecific synthesis of an indolizidine alkaloid, (+)-ipalbidine

Enantiospecific total synthesis of an indolizidine alkaloid, ipalbidine, was achieved starting from (−)-pyroglutamic acid by employing an intramolecular McMurry coupling reaction with a low-valent titanium, as a key step.     

A facile synthesis of simple alkaloids—synthesis of 2,3-polymethylene-4(3H)-quinazolinones and related alkaloids

An efficient procedure for preparation of the simple alkaloids, 2,3-polymethylene-4(3H)-quinazolinones, luotonin A, tryptanthrin, and rutaecarpine has been established by the reaction of lactam-HCl salts with POCl₃ followed by cyclization with methyl anthranilate.     

Highly diastereoselective synthesis and NMR characterization of natural indolizidine alkaloids

A diastereoselective, general and versatile access to disubstituted indolizidines is described. The nmr conformational analysis permits us to establish preferred conformations.     

Nonstabilized N-unsubstituted azomethine ylides: a synthesis of indolizidine 239CD

[formula: see text] Treatment of a (2-azaallyl)stannane with HF.pyridine generated a nonstabilized N-unsubstituted azomethine ylide, which was found to undergo an efficient and stereoselective dipolar cycloaddition with phenyl vinyl sulfone to produce a trans-2,5-dialkylpyrrolidine that was further transformed into the dendrobatid alkaloid indolizidine 239CD.     

Concise synthesis of two advanced intermediates for the asymmetric synthesis of polyhydroxylated indolizidine alkaloids

A concise five-step approach to indolizidinones 10 and 11, two advanced intermediates for the asymmetric synthesis of polyhydroxylated indolizidine alkaloids, has been developed by using N-Cbz pyrrolidin-2-yl pyridin-2-yl sulfide 13 as the chiral building block. The method features a SmI₂-mediated coupling of sulfide 13 with functionalized aldehyde 14 and a tandem N-deprotection-lactamization, which constitutes a stepwise “2 + 4” annulation method for the construction of the indolizidinone ring system of 12a.     

Annulation of pyrrole: application to the synthesis of indolizidine alkaloids

The nucleophilicity of pyrrole has been exploited to rapidly assemble the bicyclic skeleton of the indolizidine alkaloids. The key sequence is the annulation of a second ring onto pyrrole from a γ-lactone and has been exploited in the synthesis of the natural products (±)-monomorine and (±)-indolizidine 209D.     

Enantioselective synthesis of indolizidine and quinolizidine derivatives from chiral non-racemic bicyclic lactams

Chiral non-racemic bicyclic lactams 2b,c, derived from (R)- and (S)-phenylglycinol, were used in the enantioselective synthesis of (−)-lupinine and 5-epitashiromine, respectively. The efficiency of the synthesis relied on the high diastereoselectivities of formation and reduction of compounds 2b,c.     

Concise enantioselective synthesis of 3,5-dialkyl-substituted indolizidine alkaloids via sequential cross-metathesis-double-reductive cyclization

An efficient stereoselective synthesis of two 3,5-dialkyl-substituted indolizidine alkaloids is reported. The convergent syntheses are based on a novel sequence of a cross-metathesis (CM) reaction of an alpha,beta-unsaturated ketone and a chiral homoallylic amine followed by a domino reaction involving hydrogenation, N-deprotection, and two diastereoselective reductive aminations. Our concept presents one of a few examples of a highly selective CM reaction in the synthesis of a natural product.     

A practical method for the synthesis of pyrrolizidine, indolizidine and pyrroloazepinolizidine nucleus

The alkylation of α,ω-dibromoalkanes, with the sodium salt of succinimide, followed by the reduction with sodium borohydride gives the respective N-ω-bromoalkyl-5-hydroxy-2-pyrrolidinones. These substrates are precursors of N-acyliminium ions under acidic conditions. The condensation of these intermediates with ethyl malonate in the presence of TiCl₄ and diisopropylethylamine following the intramolecular cyclization provides a convenient route to substituted pyrrolizidinone, indolizidinone and pyrroloazepinolizidinone nucleus in a good yield.     

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.     

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.