A short route toward chiral, polyhydroxylated indolizidines and quinolizidines

In this paper, a rapid route toward functionalized bicyclic alkaloids is presented. In only three steps, an easily accessible carbohydrate derivative was converted into iodomethyl indolizidine 13, which can equilibrate to the corresponding iodoquinolizidine 15. We provide strong evidence that this equilibration proceeds via an aziridinium ion intermediate. Furthermore, nucleophilic substitution of the iodomethyl indolizidine as well as the aziridinium intermediate gives access to highly functionalized indolizidine and quinolizidine alkaloids.     

Concise syntheses of (±)-protoemetinol and related alkaloids using radical cyclisation

Both (±)-protoemetinol, its 3-epi-isomer and (±)-3-desmethyl protoemetinol have been prepared in five linear steps from a dihydroisoquinoline using a 6-exo-trig cyclisation of a vinyl radical in the key step. This novel and particularly short route has potential application in the synthesis of Alangium and Mitragyna alkaloids.     

Concise synthesis of quinazoline alkaloids, luotonins A and B, and rutaecarpine

The total synthesis of luotonin A was achieved in excellent yield by using a Pd-assisted biaryl coupling reaction of N-(bromoquinolinyl)methylquinazolinone with Cy₃P and KOAc. The successive treatment of luotonin A with NBS and aq. AgNO₃ gave luotonin B in good yield. Although the Pd-assisted coupling reaction of N-(2-bromoindolyl)ethylquinazolinone with Cy₃P and KOAc yielded rutaecarpine in poor yield, N-acetate under the same reaction conditions yielded the desired rutaecarpine directly in excellent yield.     

Synthetic approaches toward piperidine related structures: A review

Abstract

The current review covers explosive development of various synthetic approaches for piperidine scaffold and its analogues in the last few decades. The piperidine ring system is a key motif in many natural alkaloids and synthetic organic compounds. Further, piperidine moiety has gained significant consideration in drug discovery due to its wide range of therapeutic applications.     

Rh-catalyzed intramolecular cyclization of 1-sulfonyl-1,2,3-triazole and sulfinate. Concise preparation of sulfonylated unsaturated piperidines

When 4-[3-(methanesulfinyloxy)propyl]-1-(arenesulfonyl)-1,2,3-triazoles were treated with rhodium catalysts of the type Rh₂(RCO₂)₄, a new intramolecular cyclization took place to afford 2,3-didehydro-1-(arenesulfonyl)-3-(methanesulfonyl)piperidines in good yields. This reaction most likely proceeds via a new reorganization of bonds in the same molecule, consisting of the addition of the sulfur atom of sulfinate ester to the α-(sulfonylimino)carbene moiety generated from the sulfonyltriazole, followed by the counter attack of the sulfonylimino nitrogen to the carbon bearing the oxygen terminus of sulfinate ester.     

Chemistry of pyrrolizidine alkaloids revisited—semi-synthetic microwave and continuous-flow approaches toward Crotalaria-alkaloids

Efficient and rapid syntheses of various pyrrolizidine alkaloids via microwave synthetic protocols using monocrotaline from a natural source (Crotalaria spectabilis) are reported. Retronecine, hydroxydanaidal, and acetylated hydroxydanaidal (utilized in the chemical communication system of various insect species) were obtained. In addition, a continuous flow hydrogenolysis/hydrogenation approach to directly access platynecine, retronecanol, and desoxyretronecine was realized.     

Concise syntheses of 13-methylprotoberberine and 13-methyltetrahydroprotoberberine alkaloids

The concise syntheses of eight 13-methylprotoberberine (13-MePB) and eight enantioenriched 13-methyltetrahydroprotoberberine (13-MeTHPB) alkaloids have been achieved in a tactically modular fashion. This synthetic work features a one-pot metal-free Pictet-Spengler/Friedel-Crafts hydroxyalkylation/dehydration/oxidation sequence and a following highly enantioselective Ir-catalyzed hydrogenation. Given such brevity and modularity, our developed synthetic route would be greatly beneficial to the efficient syntheses of existing natural products and new fully synthetic variants of 13-MePB and 13-MeTHPB family.     

Preparation of some angularly substituted and highly functionalized quinolizidines as building blocks for the synthesis of various alkaloids and related scaffolds of medicinal interest

The epimeric forms of the angularly substituted quinolizidine 6, representing potentially useful building blocks for the synthesis of various alkaloids, have been prepared via a pathway involving two consecutive ring-closing metathesis reactions. Variously hydroxy-protected derivatives (21, 22, and 26-29) of these compounds have also been generated.     

A one-pot formal [4 + 2] cycloaddition approach to substituted piperidines, indolizidines, and quinolizidines. total synthesis of indolizidine (-)-209I

[reaction: see text] Heating a mixture of substituted N-benzyl gamma-chloropropylamines, conjugated alkynoates or alkynones, sodium carbonate, and a catalytic amount of sodium iodide in i-PrOH at 70-83 degrees C delivers substituted piperidines in good yields. This transformation goes through a cascade Michael addition/alkylation process and represents a facile one-pot formal [4 + 2] cycloaddition approach to piperidine ring. Using secondary cyclic gamma-chloropropylamines as substrates, this process produces substituted indolizidines or quinolizidines. On the basis of this approach, indolizidine (-)-209I is elaborated in 11 steps from methyl 2-hexenoate.     

New methodology toward chiral, non-racemic 2,5-cis-substituted piperidines via Suzuki cross-coupling

1,2,3,4-Tetrahydropyridines were halogenated upon treatment with iodine to obtain the desired cross-coupling precursors. Diastereoselective hydrogenation of Suzuki cross-coupling adducts allowed the facile asymmetric synthesis of 2,5-cis-substituted piperidines in five steps from readily available pyridine.     

Enantiospecific synthesis of pyridinones as versatile intermediates toward asymmetric piperidines

The enantiospecific syntheses of pyridinones from amino acids via a gold-catalyzed strategy are reported. Excellent stereocontrol was observed during the cyclization. This approach provides a straightforward tool for further synthetic applications toward piperidines.     

Cascade iminium ion reactions for the facile synthesis of quinolizidines. Concise syntheses of (+/-)-epilupinine and (-)-epimyrtine

Several novel cascade processes have been designed and developed that involve sequential reactions of imines and iminium ions to form substituted quinolizidine ring systems in a single step from simple and readily available starting materials. The utility and promise of these cascade reactions is evident from their application to extraordinarily concise syntheses of the representative quinolizidine alkaloids (+/-)-epilupinine and (-)-epimyrtine.     

A stereoselective route toward polyhydoxylated piperidines. A total synthesis of (+/-)-deoxymannojirimycin

[reaction: see text] A chemo- and stereoselective palladium-catalyzed amination of silylated butenediol dicarbonates has allowed for the introduction of a glycine moiety to obtain a desired functionalized epoxysilane. A stereoselective aldolization then delivered the piperidine ring which may be used as a precursor for the synthesis of a variety of polyhydroxylated azasugars. This efficient approach has been illustrated by the synthesis of 1-deoxymannojirimycin including a stereoselective reduction with LAH and a Tamao-Fleming oxidation of a C-SiMe(2)Ph bond.     

Asymmetric total synthesis of (+)-luciduline: toward a general approach to related Lycopodium alkaloids

As part of a research program directed toward the synthesis of Lycopodium alkaloids, a multigram scale asymmetric synthesis of intermediate 11 was achieved in 11 steps from pyridine (17). In addition to our alkene metathesis strategy, a key feature of this synthetic approach consists of a Fukuyama's Diels-Alder cycloaddition between 1,2-dihydropyridine and acrolein using MacMillan's catalyst (18) on a 50 g scale. This led to a 12-step catalytic asymmetric synthesis of (+)-luciduline (1). A broader subset of Lycopodium alkaloids could also be obtained, as demonstrated by the derivatization of 11 into advanced intermediates for the synthesis of some of these natural products.     

3,4'-Linked bis(piperidines) related to the haliclonacyclamine class of marine alkaloids: synthesis using crossed-aldol chemistry and preliminary biological evaluations

Compounds 2-5, incorporating various elements of the 3,4'-bis(piperidine) core associated with the sponge-derived alkaloid haliclonacyclamine A (HA, 1), have been prepared through, inter alia, aldol-type reactions of N-substituted piperidin-4-ones and certain derivatives. Screening of these compounds in various assays, including an ecological one, reveals that compound 5 exhibits allelochemical properties similar to those associated with HA itself.     

One-pot tandem route to fused indolizidines and quinolizidines: Application in the synthesis of alkaloids and bioactive compounds

Fused indolizidines and quinolizidines are important skeletons in a variety of natural products and pharmacologically important compounds. A one-pot tandem route from amide to fused indolizidines and quinolizidines is disclosed. This method is conducted in mild conditions and shows well tolerance of functional groups. It is also easy to be scaled up to gram scale and can be applied smoothly to the total synthesis of alkaloids such as (±)-crispine A, (±)-xylopinine, (±)-desbromoarborescidine A, (±)-harmicine and other bioactive substances.