Total synthesis: an enabling science

• Bastien Nay

Beilstein J. Org. Chem. 2023, 19, 474–476, doi:10.3762/bjoc.19.36

• syntheses ever published in the Beilstein Journal of Organic Chemistry, such as those of frog indolizidine alkaloids [5][6]. However, no thematic issue specifically related to total synthesis has been published before, and we thought it would be time to fill this gap. Although innovative developments are

Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

• Robin Klintworth,
• Garreth L. Morgans,
• Stefania M. Scalzullo,
• Charles B. de Koning,
• Willem A. L. van Otterlo and
• Joseph P. Michael

Beilstein J. Org. Chem. 2021, 17, 2543–2552, doi:10.3762/bjoc.17.170

• ] and procuramine (10) [13], have also attracted attention recently. Our continuing efforts to exploit enaminones as building blocks for the synthesis of alkaloids and other nitrogen-containing heterocycles have largely concentrated on targets containing indolizidine and quinolizidine backbones [14

• ]. The pyrrolizidine motif has up to now eluded us other than when it forms part of the tricyclic 2,3-dihydro-1H-pyrrolo[1,2-a]indole system [15], as in our route to aziridinomitosenes [16][17]. In the course of our attempts at the syntheses of aryl-bearing indolizidine alkaloids via N-phenacyl

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

Synthesis of legonmycins A and B, C(7a)-hydroxylated bacterial pyrrolizidines

• Wilfred J. M. Lewis,
• David M. Shaw and
• Jeremy Robertson

Beilstein J. Org. Chem. 2021, 17, 334–342, doi:10.3762/bjoc.17.31

• was established with, in this case, PxaB achieving the oxidative steps from indolizidine intermediates 5–8 produced by PxaA. An important aspect of this work was the finding that at least 90 different bacterial strains, spanning 23 species, contain gene sequences encoding proteins related to PxaB

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

New syntheses of (±)-tashiromine and (±)-epitashiromine via enaminone intermediates

• Darren L. Riley,
• Joseph P. Michael and
• Charles B. de Koning

Beilstein J. Org. Chem. 2016, 12, 2609–2613, doi:10.3762/bjoc.12.256

• of the naturally occurring indolizidine alkaloid (±)-tashiromine and its unnatural epimer (±)-epitashiromine are demonstrated through the use of enaminone chemistry. The impact of various electron-withdrawing substituents at the C-8 position of the indolizidine core on the preparation of the bicyclic

• system is described. Keywords: alkaloid; enaminone; epitashiromine; indolizidine; tashiromine; Introduction Tashiromine (1) is a monosubstituted indolizidine alkaloid originally isolated from the Asian deciduous shrub Maackia tashiroi [1] and subsequently from the genera Poecilanthe [2] and Crotalaria

• [3] (Figure 1). To date this natural product and its unnatural epimer 2 have been the targets of numerous enantioselective and racemic syntheses [4][5][6][7][8][9]. Typical approaches to accessing the alkaloid’s indolizidine skeleton have included a key cyclisation onto the nitrogen atom of either a

Enantioselective additions of copper acetylides to cyclic iminium and oxocarbenium ions

• Jixin Liu,
• Srimoyee Dasgupta and
• Mary P. Watson

Beilstein J. Org. Chem. 2015, 11, 2696–2706, doi:10.3762/bjoc.11.290

• –77%), but poor enantioselectivities (1–11% ee). However, the use of activated acetylenes provides a functional group handle for elaboration, which the authors demonstrate in the preparation of indolizidine 223AB. Building on their initial discovery of a non-asymmetric, copper-catalyzed, three

Recent applications of ring-rearrangement metathesis in organic synthesis

• Sambasivarao Kotha,
• Milind Meshram,
• Priti Khedkar,
• Shaibal Banerjee and
• Deepak Deodhar

Beilstein J. Org. Chem. 2015, 11, 1833–1864, doi:10.3762/bjoc.11.199

• (Scheme 49). Homologous starting material 242 underwent a RRM with catalyst 2 in the presence of ethylene (24) at 80 °C to produce indolizidine-based compound 243 in 63% yield. Under similar reaction conditions, the azabicyclic system 244 generated pyrrolo[1,2-a]azepine derivative 245. When the RRM

Novel stereocontrolled syntheses of tashiromine and epitashiromine

• Loránd Kiss,
• Enikő Forró and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2015, 11, 596–603, doi:10.3762/bjoc.11.66

• reactions of the cis- or trans-cyclooctene β-amino acids. Keywords: alkaloids; amino acids; ring closure; ring opening; stereocontrolled synthesis; Introduction Indolizidine alkaloids are an important class of naturally occurring compounds which have received considerable attention as a result of their

• valuable physiological properties. A number of representatives of this class exhibit glycosidase inhibitory activity or antimetastatic, anticancer, antitumour or anti-HIV properties [1][2][3]. A large number of natural products contain an indolizidine framework, among them (−)-δ-coniceine, (−)-swainsonine

• , indolizidine 167B [4][5][6][7][8][9][10], (+)-lentiginosine [11][12][13][14][15], (+)-slaframine [16], (−)-elaeokanine C [17], (+)-cyclizidine [18], lepadiformine [19], the highly oxygenated (+)-castanospermine [20][21], or pumiliotoxin [22]. Figure 1 illustrates the structures of several such compounds

Enantioselective synthesis of polyhydroxyindolizidinone and quinolizidinone derivatives from a common precursor

• Nemai Saha and
• Shital K. Chattopadhyay

Beilstein J. Org. Chem. 2014, 10, 3104–3110, doi:10.3762/bjoc.10.327

• from a common intermediate which featured a highly selective dihydroxylation reaction and a RCM reaction as key steps. Keywords: chiral pool; dihydroxylation; indolizidines; quinolizidine; ring-closing metathesis; Introduction Polyhydroxylated indolizidine derivatives have attracted continued

• other reasons, several novel methodologies have been developed towards the synthesis of polyhydroxylated indolizidine and quinolizidine derivatives as analogues of natural products which involved RCM [21][22][23][24], dipolar cycloaddition [25][26], nucleophilic substitution [27][28], diazo insertion

• [29], ring expansion–transannular cyclization [30], Cope–House cyclization [31], etc. as key steps. Although great advances have been made, creation of diverse entities from a single source remains important. Herein, we report a synthetic entry to some polyhydroxylated indolizidine and quinolizidine

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

• Jie Zhang,
• Hong-Kui Zhang and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2013, 9, 2358–2366, doi:10.3762/bjoc.9.271

• consisting of ozonolysis and reductive dehydroxylation provided the indolizidine derivative 5, which completed the formal enantioselective total synthesis of pumiliotoxins 251D and 237A. Keywords: enantioselective synthesis; Grignard reagent; pumiliotoxin 237A; pumiliotoxin 251D; reductive dehydroxylation

• ; ring closure; trans-methylation; Introduction Pumiliotoxins (PTXs, 1, Figure 1) such as pumiliotoxin 251D (2) are a subclass of indolizidine alkaloids isolated from the skin secretion of neotropical frogs. A total of 19 members have been isolated and partially characterized [1]. Pumiliotoxins are

Some aspects of radical chemistry in the assembly of complex molecular architectures

• Béatrice Quiclet-Sire and
• Samir Z. Zard

Beilstein J. Org. Chem. 2013, 9, 557–576, doi:10.3762/bjoc.9.61

• allow the second cyclisation to proceed in a 5-exo fashion by starting with an un-chlorinated substrate. The total synthesis of fortucine (15), also hinges on the sequential fashioning of an indolizidine-type skeleton, with the second cyclisation taking place on an aromatic ring (Scheme 3) [14][15]. The

Inter- and intramolecular enantioselective carbolithiation reactions

• Asier Gómez-SanJuan,
• Nuria Sotomayor and
• Esther Lete

Beilstein J. Org. Chem. 2013, 9, 313–322, doi:10.3762/bjoc.9.36

• further extended to 4-functionalized 6-phenyl-hex-5-enylcarbamates [41]. Following a similar approach, deprotonation of racemic (carbamoyloxy)methyl-N-cinnamylpiperidine 30 with s-butyllithium/(−)-sparteine (L1), and subsequent anionic 5-exo-trig cyclization, leads to indolizidine 31 with high

Two-directional synthesis as a tool for diversity-oriented synthesis: Synthesis of alkaloid scaffolds

• Kieron M. G. O’Connell,
• Monica Díaz-Gavilán,
• Warren R. J. D. Galloway and
• David R. Spring

Beilstein J. Org. Chem. 2012, 8, 850–860, doi:10.3762/bjoc.8.95

• , respectively. The corresponding reaction of phenyl-substituted analogue 4 also gave a mixture of two diastereomers; the major diastereomer was 4,10-trans-7,10-cis isomer (trans-6), which was formed in 50% yield, and a 17% yield of the 4,7,10-cis-isomer (cis-6) was also obtained. Indolizidine 7 was produced in

• effected the desired double reductive amination to give 17 in 30% yield. It is likely that the scope of this sequence could be extended to include indolizidine and quinolizidine scaffolds, and so provide an alternative route to these frameworks, instead of the double Michael addition strategy. The three

Gold-catalyzed heterocyclizations in alkynyl- and allenyl-β-lactams

• Benito Alcaide and
• Pedro Almendros

Beilstein J. Org. Chem. 2011, 7, 622–630, doi:10.3762/bjoc.7.73

• starting materials were mostly unreacted in the case of cyclohexene substrates and partly decomposed in the case of cyclopentene substrates. This method allows an expedient formal synthesis of indolizidine 167B. Oxycyclizations Transition metal-assisted intramolecular addition of oxygen nucleophiles across

Rh-Catalyzed rearrangement of vinylcyclopropane to 1,3-diene units attached to N-heterocycles

• Franca M. Cordero,
• Carolina Vurchio,
• Stefano Cicchi,
• Armin de Meijere and
• Alberto Brandi

Beilstein J. Org. Chem. 2011, 7, 298–303, doi:10.3762/bjoc.7.39

• Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany 10.3762/bjoc.7.39 Abstract Dienes embedded in quinolizidine and indolizidine structures can be prepared in four steps from cyclic nitrones and bicyclopropylidene. The key intermediates α-spirocyclopropanated N-heterocyclic ketones, generated via a

Total synthesis of the indolizidine alkaloid tashiromine

• Stephen P. Marsden and
• Alison D. McElhinney

Beilstein J. Org. Chem. 2008, 4, No. 8, doi:10.1186/1860-5397-4-8

• Stephen P. Marsden Alison D. McElhinney School of Chemistry, University of Leeds, Leeds LS2 9JT, UK 10.1186/1860-5397-4-8 Abstract Background Tashiromine (1) is a naturally occurring indolizidine alkaloid. It has been the subject of thirteen successful total syntheses to date. Our own approach

• centres on the stereoselective construction of the indolizidine core by capture of an electrophilic acyliminium species by a pendant allylsilane. The key cyclisation precursor is constructed using olefin cross-metathesis chemistry, which has the potential to facilitate both racemic and asymmetric

• desired bicyclic indolizidine skeleton as a 96:4 mixture of diastereomers. Simple functional group interconversions allowed the completion of the total synthesis of racemic tashiromine in six steps (19% overall yield). Three chiral α-alkoxyallylsilanes (12, 14 and 15) were prepared in enantioenriched form

Facile synthesis of two diastereomeric indolizidines corresponding to the postulated structure of alkaloid 5,9E- 259B from a Bufonid toad (Melanophryniscus)

• Angela Nelson,
• H. Martin Garraffo,
• Thomas F. Spande,
• John W. Daly and
• Paul J. Stevenson

Beilstein J. Org. Chem. 2008, 4, No. 6, doi:10.1186/1860-5397-4-6

• Institutes of Health, Bethesda, MD 20892-0820, USA 10.1186/1860-5397-4-6 Abstract A short synthesis of the postulated structure for indolizidine alkaloid 259B with the hydrogens at C5 and C9 entgegen has been achieved with complete control of stereochemistry at C5. Both diastereoisomers at C8 were obtained

• times of the two synthetic compounds were markedly longer than that of the natural 5,9E-259B. Background Indolizidines are common in nature [1] and to date over eighty 5,8-disubstituted indolizidine alkaloids have been isolated from the skins of frogs [2]. Due to the scarcity of such indolizidine

• alkaloids from the natural sources, for the most part the biological properties of these materials have not been fully evaluated. However, synthetic 5,8-disubstituted indolizidine 5,9Z-235B' (Figure 1), has recently been shown to be a potent and selective non-competitive inhibitor of nicotinic acetylcholine

Analogues of amphibian alkaloids: total synthesis of (5R,8S,8aS)-(−)-8-methyl- 5-pentyloctahydroindolizine (8-epi-indolizidine 209B) and [(1S,4R,9aS)-(−)-4-pentyloctahydro- 2H-quinolizin- 1-yl]methanol

• Joseph P. Michael,
• Claudia Accone,
• Charles B. de Koning and
• Christiaan W. van der Westhuyzen

Beilstein J. Org. Chem. 2008, 4, No. 5, doi:10.1186/1860-5397-4-5

• development of enaminones as versatile intermediates for the synthesis of alkaloids and other nitrogen-containing heterocycles. In this paper we describe the enantioselective synthesis of indolizidine and quinolizidine analogues of bicyclic amphibian alkaloids via pyrrolidinylidene- and piperidinylidene

• -containing enaminones. Results Our previously reported synthesis of racemic 8-epi-indolizidine 209B has been extended to the laevorotatory enantiomer, (−)-9. Attempts to adapt the synthetic route in order to obtain quinolizidine analogues revealed that a key piperidinylidene-containing enaminone intermediate

• indolizidine (1-azabicyclo[4.3.0]nonane), quinolizidine (1-azabicyclo[4.4.0]decane) and lehmizidine (1-azabicyclo[5.3.0]decane) classes [1][2]. The first of these classes is by far the most populous, and has commanded enormous attention from organic chemists stimulated by the challenges of designing novel

Knorr- Rabe partial reduction of pyrroles: Application to the synthesis of indolizidine alkaloids

• Brendon S. Gourlay,
• John H. Ryan and
• Jason A. Smith

Beilstein J. Org. Chem. 2008, 4, No. 3, doi:10.1186/1860-5397-4-3

• -alkylindolizidines and the stereoselectivity obtained is opposite to that of catalytic hydrogenation. Conclusion An efficient stereoselective synthesis of indolizidine alkaloids has been developed from α-ketopyrrole intermediates using a modified version of Knorr and Rabe's pyrrole reduction. Background The Birch

• electron density of the heterocycle such that reasonable yields of the 3-pyrrolines are obtained [3]. This method was recently exploited for the elegant synthesis of the pyrrolidine alkaloid (±)-1-epiaustraline (3) (Scheme 1) [4]. During our studies towards the synthesis of indolizidine alkaloids we

• ] and has also been exploited for the synthesis of numerous indolizidine alkaloids [16][17]. The presence of a substituent at C-5 directs the hydrogenation at C-8a from the opposite, least hindered face, to give the cis derivative (Scheme 6). We were interested in the stereochemical outcome for C-8a

Synthesis of (–)-Indolizidine 167B based on domino hydroformylation/cyclization reactions

• Giuditta Guazzelli,
• Raffaello Lazzaroni and
• Roberta Settambolo

Beilstein J. Org. Chem. 2008, 4, No. 2, doi:10.1186/1860-5397-4-2

• Chimica e Chimica Industriale, Università di Pisa, Via Risorgimento 35, 56126 Pisa, Italy 10.1186/1860-5397-4-2 Abstract The synthesis of (–)-Indolizidine 167B has been achieved from optically active (R)-3-(pyrrol-1-yl)hex-1-ene. The key step is a highly regioselective hydroformylation reaction and a one

• -pot intramolecular cyclization providing a general approach to the indolizine nucleus. Background Indolizidine alkaloids are widely diffused in nature and have attracted considerable attention because of their varied range of pharmaceutical application. Indolizidine 167B (Figure 1), one of the

• simplest amphibian indolizidine alkaloids, was originally identified as (5R,9R)-octahydroindolizine from the skin secretions of a frog belonging to the genus Dendrobates [1][2], which acts as noncompetitive blocker of neuromuscular transmission. Although the structure has been questioned [3], this alkaloid

Synthesis of crispine A analogues via an intramolecular Schmidt reaction

• Ajoy Kapat,
• Ponminor Senthil Kumar and
• Sundarababu Baskaran

Beilstein J. Org. Chem. 2007, 3, No. 49, doi:10.1186/1860-5397-3-49

• key intermediate is described. Background The indolizidine skeleton is one of the most important structural subunits present in numerous biologically active molecules. [1][2][3][4] The polyhydroxylated indolizidines are potent inhibitors of carbohydrate processing enzymes and hence they are

• considered to be lead drug molecules in the treatment of metabolic diseases such as diabetes, cancer and HIV infection. [5][6][7] The alkyl indolizidine alkaloids, also called gephyrotoxins, are well-known for their ability to function as non-competitive blockers of neuromuscular transmission [2] by

• interacting with nAChRs. In addition, the indolizidine skeleton is also present in anticancer molecules such as lepadiformine,[8] antofine,[9] and tylophorine [9] as well as a immunosuppressive agent, FR901483.[10] The wide range of biological activities associated with the indolizidine alkaloids has elicited

Desymmetrization of 7-azabicycloalkenes by tandem olefin metathesis for the preparation of natural product scaffolds

• Wolfgang Maison,
• Marina Büchert and
• Nina Deppermann

Beilstein J. Org. Chem. 2007, 3, No. 48, doi:10.1186/1860-5397-3-48

• . Background Azabicyclo [x.y.0]alkane scaffolds are ubiquitous structural elements in pharmaceutically important peptide mimetics [1][2][3] and several important classes of natural products such as indolizidine and quinolizidine alkaloids and azasugars. [4][5][6] In consequence, a number of groups have

Synthesis of densely functionalized enantiopure indolizidines by ring- closing metathesis (RCM) of hydroxylamines from carbohydrate- derived nitrones

• Marco Bonanni,
• Marco Marradi,
• Francesca Cardona,
• Stefano Cicchi and
• Andrea Goti

Beilstein J. Org. Chem. 2007, 3, No. 44, doi:10.1186/1860-5397-3-44

• (Firenze), Italy 10.1186/1860-5397-3-44 Abstract Background Indolizidine alkaloids widely occur in nature and display interesting biological activity. This is the reason for which their total synthesis as well as the synthesis of non-natural analogues still attracts the attention of many research groups

• yields from enantiopure hydroxylamines obtained straightforwardly from carbohydrate-derived nitrones. Background Indolizidine alkaloids have widespread occurrence in nature. They can be found in widely different organisms such as bacteria, fungi, higher plants, invertebrates and vertebrates.[1] For

• . [5][6][7][8][9][10][11][12][13][14][15][16][17][18] We accomplished the total syntheses of some indolizidine alkaloids and of several non-natural analogues employing chiral nitrones as key intermediates, either as dipolarophiles in 1,3-dipolar cycloaddition chemistry [19][20] or as electrophiles in

Synthesis of the Benzo- fused Indolizidine Alkaloid Mimics

• Daniel L. Comins and
• Kazuhiro Higuchi

Beilstein J. Org. Chem. 2007, 3, No. 42, doi:10.1186/1860-5397-3-42

• 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. Background As part of a program directed at studying the synthesis and synthetic utility of N-acyldihydropyridones, the heterocycles 1 were developed as useful building blocks for alkaloid synthesis (Figure 1). [1][2] Biologically active indolizidine alkaloids [3] such as

• (+)-allopumiliotoxin 267A (2) [4], (±)-indolizidine 209B (3) [5], (+)-indolizidine 209D (4) [6], and (±)-tylophorine (5) [7] were prepared in racemic or enantiopure form using these dihydropyridone intermediates. Herein we demonstrate the utility of this chemistry for preparing diverse benzo-fused indolizidine