Total synthesis: an enabling science

• Bastien Nay

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

• " (edited by D. Chen and D. Ma) [1] or "Natural products in synthesis and biosynthesis" (edited twice by J. Dickschat) [2][3]. Previously, the early thematic issue "Indolizidines and quinolizidines: natural products and beyond" (edited by J. P. Michael) from 2007 [4] displayed some of the very first total

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

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

• Mikhail K. Klychnikov,
• Radek Pohl,
• Ivana Císařová and
• Ullrich Jahn

Beilstein J. Org. Chem. 2021, 17, 688–704, doi:10.3762/bjoc.17.58

• ; electron transfer; γ-lactams; tandem reactions; Introduction Nitrogen-containing heterocycles are widely distributed in biologically active compounds [1][2][3][4]. Saturated nitrogen heterocycles such as pyrrolidines [5][6][7][8][9], piperidines, pyrrolizidines or indolizidines [10][11][12][13][14][15][16

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

Synthesis of 1,4-imino-L-lyxitols modified at C-5 and their evaluation as inhibitors of GH38 α-mannosidases

• Maroš Bella,
• Sergej Šesták,
• Ján Moncoľ,
• Miroslav Koóš and
• Monika Poláková

Beilstein J. Org. Chem. 2018, 14, 2156–2162, doi:10.3762/bjoc.14.189

• , indolizidines etc. which exhibited remarkable biological activities and are highly interesting as pharmaceutical agents [15][16][17][18][19]. In addition, iminosugars exhibited a powerful inhibitory activity against a wide range of glycoside hydrolases [20][21][22]. One naturally occurring iminosugar, alkaloid

Exploring endoperoxides as a new entry for the synthesis of branched azasugars

• Svenja Domeyer,
• Mark Bjerregaard,
• Henrik Johansson and
• Daniel Sejer Pedersen

Beilstein J. Org. Chem. 2017, 13, 644–647, doi:10.3762/bjoc.13.63

• hydrolysis transition states as well as having many other interesting properties. They are found in nature as pyrrolidines, piperidines, indolizidines, pyrrolizidines or nortropane alkaloids with a variety of ring substituents, typically hydroxy groups, carboxylic acids and amides [1]. The ability of

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

• electrophilic substituents are attached to the nitrogen, alkylating or acylating cyclisation onto the enamine carbon site leads to the formation of bicyclic systems with nitrogen located at the bridgehead. Our approach to the synthesis of indolizidines is thus unusual in that it entails the formation of the C-7

• /C-8 bond. In this article we describe further extensions to our route to substituted indolizidines, and an application to the synthesis of racemic tashiromine (1) and epitashiromine (2). Results and Discussion One of the most versatile methods for preparing the enaminones of interest is the

• indolizidine skeleton. To this end we chose to investigate the reaction of 3-(2-thioxo-1-pyrrolidinyl)propyl acetate (3), which we had previously used as a precursor to enaminones and indolizidines [28], with three different reaction partners, namely, α-bromoacetone, ethyl α-bromoacetate and α

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

• , antimetastatic, immunoregulating, antitumor, and anticancer activities [6][7][8][9]. Although naturally occurring polyhydroxylated quinolizidines are less documented, several synthetic derivatives have been prepared in the quest for analogues of the more abundant indolizidines [10][11][12][13][14][15]. Ring-size

• variation and/or stereochemical manipulation of the hydroxy groups have been adequately practiced for such purpose [16][17]. Indolizidines and quinolizidines with fewer hydroxy groups such as lentiginosine (3) [18][19] and lupinine (4) [20] also display a useful level of biological activities. For this, and

Total synthesis of (−)-epimyrtine by a gold-catalyzed hydroamination approach

• Thi Thanh Huyen Trinh,
• Khanh Hung Nguyen,
• Patricia de Aguiar Amaral and
• Nicolas Gouault

Beilstein J. Org. Chem. 2013, 9, 2042–2047, doi:10.3762/bjoc.9.242

• in this work that this natural product is easily accessible from D-alanine by a gold-mediated intramolecular hydroamination in a unique 6-endo-dig process. The approach provides a straightforward tool for synthetic applications toward quinolizidines and indolizidines. Experimental All reagents of

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

• extra equivalent of tributylstannane ensures its in situ reductive removal. This domino radical cyclisation represents, in fact, a general strategy for the construction of indolizidines and pyrrolizidines, which constitute the core structure of numerous alkaloids. For pyrrolizidines, one needs simply to

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

• formation of six-membered rings, though the slow cyclization rate results in racemization. The use of a phenylthio-substituted alkene favors the cyclization, and the faster reaction rate results in an improved optical purity of the indolizidines 35 and 36, though with moderate diastereo- and

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

• this methodology it was possible to access five bicyclic and tricyclic scaffolds covering a range of 3D shapes, including pyrrolizidines, indolizidines and quinolizidines, along with 6-6-6 and 5-6-6 azatricyclic species in a single transformation from a small collection of structurally simple linear

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

• regioselective in the case of indolizidines 15 and 17, showing that the Wilkinson Rh(I) catalyst is also capable of inducing the VCP rearrangement in the presence of strongly nucleophilic azaheterocycles. Accordingly, new functionalised heterocyclic compounds can be produced by the straightforward methodology

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

• 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

• receptors [3]. Earlier work had reported that indolizidines 5,9Z-203A and 5,9Z-235B' (Figure 1), and other 5,8-disubstituted indolizidines were non-competitive blockers of the ganglionic subtype of nicotinic receptors [4]. For most of the 5,8-disubstituted indolizidines the structures have been assigned by

• a combination of GC-mass spectrometry and GC-FTIR spectroscopy [2] and such structures must be considered tentative until NMR studies on isolated pure compounds can be obtained or until synthetic material is available for comparison. In the EI-mass spectrum of 5,8-disubstituted indolizidines loss of

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

• cis-5,8-disubstituted indolizidines and cis-1,4-disubstituted quinolizidines, as well as the naturally occurring trans-disubstituted alkaloids. Background The astonishingly diverse range of alkaloids isolated from the skins of amphibians includes numerous 1-azabicyclic systems belonging to the

• -containing heterocycles [10], we previously reported total syntheses of (−)-indolizidine 167B 7 [11][12], the 5,8-disubstituted indolizidine (−)-209B 8 and its racemic diastereomer (±)-9 [13], and the 5,6,8-trisubstituted indolizidines (+)-10 and (+)-11 [14], among other similar compounds (Figure 2). While

• in boiling ethanol gave ambiguous results no matter how we modified the reaction conditions. Conclusion Few approaches to 1,4-cis-disubstituted quinolizidines and 5,8-cis-disubstituted indolizidines of amphibian origin have been reported in the literature. Because the route we have devised proceeds

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

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

• -azabicycloalkenes by intra- and intermolecular tandem metathesis sequences with ruthenium based catalysts. Conclusion Desymmetrization of 7-azabicycloalkenes by olefin metathesis is an efficient process for the preparation of common natural product scaffolds such as pyrrolidines, indolizidines and isoindoles

• intramolecular RORCM or intermolecular ROCM sequences to give a range of common natural product scaffolds such as pyrrolidines, indolizidines and isoindoles. The protocols use readily available starting materials, are simple and give densely functionalized metathesis products ready for further manipulations

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

• hydroxy groups gave novel highly functionalized indolizidines. The synthesis of a pyrroloazepine analogue is also described. Conclusion We have developed a new straightforward methodology for the synthesis of densely functionalized indolizidines and pyrroloazepine analogues in 6 steps and 30–60% overall

• instance, the plant-derived polyhydroxylated indolizidines are well known as potent glycosidases inhibitors, and for this reason they are potential therapeutic agents. [2][3][4] A great deal of research is still devoted to the structural elucidation of these alkaloids as well as to their total syntheses

• second addition in the stepwise process, giving rise to two diastereoisomers, opens the way to the synthesis of diastereomeric indolizidines. The RCM reaction has been successfully employed for the synthesis of polyfunctional indolizidines. [25][26][27][28][29] In order to accomplish successfully the key

A divergent asymmetric approach to aza-spiropyran derivative and (1S,8aR)-1-hydroxyindolizidine

• Jian-Feng Zheng,
• Wen Chen,
• Su-Yu Huang,
• Jian-Liang Ye and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2007, 3, No. 41, doi:10.1186/1860-5397-3-41

• variable optical density, and photomechanical biomaterials etc. And (1R,8aS)-1-hydroxyindolizidine (3) has been postulated to be a biosynthetic precursor of hydroxylated indolizidines such as (+)-lentiginosine 1, (−)-2-epilentiginosine 2 and (−)-swainsonine, which are potentially useful antimetastasis

• ,[11] and photomechanical biomaterials etc.[12] On the other hand, hydroxylated indolizidines [13][14][15][16][17][18][19][20] such as castanospermine, (−)-swainsonine, (+)-lentiginosine (1) [21][22][23] and (−)-2-epilentiginosine (2) [21][22][23][24][25][26] constitute a class of azasugars showing

• compounds. The observed NOE correlations (in part) and the region expanded NOESY spectrum of compound 7. The skeletons of useful aza-spiroketals and some naturally occurring hydroxylated indolizidines. Synthetic strategy based on N,O-dibenzylmalimide (4). Stereoselectivity synthesis of aza-spiropyran 7

The enantiospecific synthesis of (+)-monomorine I using a 5-endo- trig cyclisation strategy

• Malcolm B. Berry,
• Donald Craig,
• Philip S. Jones and
• Gareth J. Rowlands

Beilstein J. Org. Chem. 2007, 3, No. 39, doi:10.1186/1860-5397-3-39

• -Hydride® to give the free amines 23 and 15c, which were subjected to mercury-mediated hydroamination (Scheme 6 and Scheme 7). [20] Cyclisation of 23 proceeded in good yield to give a 9:4 mixture of two indolizidines, epimeric at the C-5 methyl group 24-anti and 24-syn (Scheme 6). Cyclisation of the

• isopropyl analogue 15 proceeded with improved stereoselectivity to give a 5:1 mixture of epimeric indolizidines 26-anti and 26-syn (Scheme 7). Presumably, the increased steric bulk of the isopropyl group is responsible for the higher anti-selectivity. Assignment of the relative stereochemistry of the

An asymmetric synthesis of all stereoisomers of piclavines A1-4 using an iterative asymmetric dihydroxylation

• Yukako Saito,
• Naoki Okamoto and
• Hiroki Takahata

Beilstein J. Org. Chem. 2007, 3, No. 37, doi:10.1186/1860-5397-3-37

• -4 with high enantiomeric purity (amplification) for the major diastereomer via iterative AD reaction of terminal olefins. [8] Results Actually we developed a general access to 5-substituted indolizidines 10 (all four stereoisomers of indolizidine 209D) with high enantio-enhancement (92–98% ee) via a

• monocyclic compounds (pyrrolidines) to bicyclic derivatives (indolizidines) provides rigid conformation and causes close proximity (a change from 1,5- to 1,3-relationship) between the two asymmetric centers. With indolizidine (5R, 8aR)-18 in hand, we examined partial-reduction of their triple bonds. First

A convenient allylsilane- N-acyliminium route toward indolizidine and quinolizidine alkaloids

• Roland Remuson

Beilstein J. Org. Chem. 2007, 3, No. 32, doi:10.1186/1860-5397-3-32

• of an allylsilane on an N-acyliminium ion. In this paper, we describe the synthesis of racemic indolizidine 167B and chiral indolizidines: (-)-indolizidines 167B, 195B, 223AB, (+)-monomorine, (-)-(3R,5S,8aS)-3-butyl-5-propylindolizidine and (-)-dendroprimine. Next, we relate the synthesis that we

• have developed in the quinolizidines field: (±)-myrtine and epimyrtine, (±)-lasubines I and II and chiral quinolizidines: (+)-myrtine, (-)-epimyrtine, (-)-lasubines I and II and (+)-subcosine II. Background Bicyclic indolizidines and quinolizidines are commonly occurring structural skeleta found in

• natural alkaloids. Such compounds have been isolated from animals: poison frogs of the family Dendrobatidae have provided a rich source of novel pharmacologically active alkaloids, including a variety of bicyclic nitrogen heterocyclic compounds such as indolizidines. [1][2] Several quinolizidine alkaloids

Flexible synthesis of poison- frog alkaloids of the 5,8-disubstituted indolizidine- class. II: Synthesis of (-)-209B, (-)-231C, (-)-233D, (-)-235B", (-)-221I, and an epimer of 193E and pharmacological effects at neuronal nicotinic acetylcholine receptors

• Soushi Kobayashi,
• Naoki Toyooka,
• Dejun Zhou,
• Hiroshi Tsuneki,
• Tsutomu Wada,
• Toshiyasu Sasaoka,
• Hideki Sakai,
• Hideo Nemoto,
• H. Martin Garraffo,
• Thomas F. Spande and
• John W. Daly

Beilstein J. Org. Chem. 2007, 3, No. 30, doi:10.1186/1860-5397-3-30

• Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA 10.1186/1860-5397-3-30 Abstract Background The 5,8-disubstituted indolizidines constitute the largest class of poison-frog alkaloids. Some alkaloids have been

• shown to act as noncompetitive blockers at nicotinic acetylcholine receptors but the proposed structures and the biological activities of most of the 5,8-disubstituted indolizidines have not been determined because of limited supplies of the natural products. We have therefore conducted experiments to

• configuration of natural 193E should be revised. The selectivity for α4β2 and α7 nicotinic receptors differed markedly for the 5,8-disubstituted indolizidines tested, and thus it appears that the nature of the side chains in these indolizidines is crucial with regard to subtype-selectivity. Introduction In the

Flexible synthetic routes to poison- frog alkaloids of the 5,8-disubstituted indolizidine- class I: synthesis of common lactam chiral building blocks and application to the synthesis of (-)-203A, (-)-205A, and (-)-219F

• Naoki Toyooka,
• Dejun Zhou,
• Hideo Nemoto,
• H. Martin Garraffo,
• Thomas F. Spande and
• John W. Daly

Beilstein J. Org. Chem. 2007, 3, No. 29, doi:10.1186/1860-5397-3-29

• Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA 10.1186/1860-5397-3-29 Abstract Background The 5,8-disubstituted indolizidines are the largest class of poison-frog alkaloids found in anuran skin, and are of considerable interest because of their inhibitory effects on the neuronal

• , plant, and animal sources, and many natural products containing this ring system show interesting biological activities. [1] The skin extracts of poison-frogs are a rich source of indolizidines. [2] There are about 20 examples of 3,5-disubstituted indolizidines and about 80 of the 5,8-disubstituted

• indolizidines. Furthermore, many of such poison-frog alkaloids show significant activities, for example with nicotinic acetylcholine receptors (nAChRs) of the central nervous system. [3] Our syntheses and then biological evaluations of poison-frog alkaloids, [4][5][6][7][8][9][10] revealed that the 5,8

Indolizidines and quinolizidines: natural products and beyond

• Joseph P. Michael

Beilstein J. Org. Chem. 2007, 3, No. 27, doi:10.1186/1860-5397-3-27

• 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

• 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][3][4] and the alkylindolizidines

• flow of publications in prominent journals. [7] Several general reviews on these alkaloids have also appeared in recent years. [8][9][10][11] The interest in indolizidines and quinolizidines, although inspired by alkaloids, nowadays extends far beyond natural product chemistry. Considerable effort is