A review of the total syntheses of triptolide

• Xiang Zhang,
• Zaozao Xiao and
• Hongtao Xu

Beilstein J. Org. Chem. 2019, 15, 1984–1995, doi:10.3762/bjoc.15.194

• and multiple promising biological activities. In this review, progress in the total syntheses of triptolide are systematically summarized. We hope to gain a better understanding of the field and provide constructive suggestions for future studies of triptolide. Keywords: total synthesis; Tripterygium

• development of total synthesis strategies. Structurally, it has nine chiral centers, three successive epoxides and a butenolide. Since the pioneering works of Berchtold, Tahara and their co-workers [45][63][64][65], several racemic and/or asymmetric total syntheses of triptolide and its relatives have been

• carried out in many research groups. The first racemic total synthesis of triptolide was reported 1980 by Berchtold and co-workers (Figure 2, route A, and Scheme 1) [66]. The key steps include: i) construction of the A-ring by aldol condensation, ii) construction of the butenolide (D-ring) by acid

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

• ,6S)-194a which appeared to be the enantiomer of natural microgrewiapine A although its structure was identical with the originally proposed. When the total synthesis started from the ester (2R,1'S)-5b and AD-mix-α was used the natural (+)-microgrewiapine A (2R,3S,6R)-194a was obtained. To synthesize

• (+)-deoxocassine ((2S,3S,6R)-190a) and (+)-spectaline ((2S,3S,6R)-190b) as already described. (+)-Microgrewiapine A ((2R,3S,6R)-194a) [107] and (+)-microcosamine A ((2R,3S,6R)-194b) [108] have recently been isolated and exhibited interesting biological activities, for example cytotoxicity [107]. The total

• synthesis of (−)-microgrewiapine A was initiated from the aziridine ketone 195 readily prepared from the ester (2S,1'R)-5b (Scheme 52) [109]. After chelation-controlled reduction of 195 with the NaBH4/ZnCl2 mixture and protection of a secondary alcohol the asymmetric dihydroxylation of the terminal C=C bond

Synthesis and biological evaluation of truncated derivatives of abyssomicin C as antibacterial agents

• Leticia Monjas,
• Peter Fodran,
• Johanna Kollback,
• Carlo Cassani,
• Thomas Olsson,
• Maja Genheden,
• D. G. Joakim Larsson and
• Carl-Johan Wallentin

Beilstein J. Org. Chem. 2019, 15, 1468–1474, doi:10.3762/bjoc.15.147

• benzyl group in the favorable subpocket position (Figure S1 in Supporting Information File 1). Synthesis The syntheses of 1 and 2 were inspired, in part, by previous strategies employed in the total synthesis of AbC [7][8][9][16][17]. Hence, the construction of the 11-membered ring was based on a

Efficiency Eff_syn of complex syntheses as multicomponent reactions, its algorithm and calculations based on concrete criteria

• Heiner Eckert

Beilstein J. Org. Chem. 2019, 15, 1425–1433, doi:10.3762/bjoc.15.142

• only show the synthesis path with the most spectacular molecules, such as the target molecule (TM), the total synthesis with all reactions is essential for production. The quantity of potential start molecule (STM) sets also rises strongly in complex syntheses. The example shows 5 STM sets (consisting

• (set-1) to which the parallel reactions are linked (set-2, set-3) is set up. The weighted arithmetical mean of the yields for each reaction set is formed at the connection forms. The overall yield yoa of the total synthesis is determined through the sequential operation of the main reaction sets. The

• values, together with the values from Π[Σ(Πyn)j]k, deliver the overall yield yoa of the total synthesis according to Equations 6–8. Parallel reactions set-2 to main reaction position (C), operation Σ(Πyn)j Parallel reactions set-3 to main reaction position (E), operation Σ(Πyn)j Sequential main reactions

Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids

• Herman O. Sintim,
• Hamad H. Al Mamari,
• Hasanain A. A. Almohseni,
• Younes Fegheh-Hassanpour and
• David M. Hodgson

Beilstein J. Org. Chem. 2019, 15, 1194–1202, doi:10.3762/bjoc.15.116

• corresponding 3° TBS ether) [14], and this strategy was subsequently also successfully applied in our most recent total synthesis of DDSQ (2) [13]. We now returned to study the Seebach alkylation chemistry in more detail. In 2008, Lipton and co-workers had observed that the cyclopentylidene derivative of

Novel (2-amino-4-arylimidazolyl)propanoic acids and pyrrolo[1,2-c]imidazoles via the domino reactions of 2-amino-4-arylimidazoles with carbonyl and methylene active compounds

• Victoria V. Lipson,
• Tetiana L. Pavlovska,
• Nataliya V. Svetlichnaya,
• Anna A. Poryvai,
• Nikolay Yu. Gorobets,
• Erik V. Van der Eycken,
• Irina S. Konovalova,
• Svetlana V. Shiskina,
• Alexander V. Borisov,
• Vladimir I. Musatov and
• Alexander V. Mazepa

Beilstein J. Org. Chem. 2019, 15, 1032–1045, doi:10.3762/bjoc.15.101

• the disruptors of microtubule dynamics, therefore are of great interest in cancer drug discovery [6]. Thereby, the stereocontrolled total synthesis of marine alkaloids such as axinellamines [16] and the search of new 2-aminoimidazole and pyrrole containing compounds with a core structure that mimics

New terpenoids from the fermentation broth of the edible mushroom Cyclocybe aegerita

• Frank Surup,
• Florian Hennicke,
• Nadine Sella,
• Maria Stroot,
• Steffen Bernecker,
• Sebastian Pfütze,
• Marc Stadler and
• Martin Rühl

Beilstein J. Org. Chem. 2019, 15, 1000–1007, doi:10.3762/bjoc.15.98

• -H3 and 1-Hb indicated methyl C-12 being on the opposite site of the molecular plane as 2-H and 9-H. This assignment was confirmed by the comparison of the 13C NMR shifts to pasteurestin A and B [6][7]. Since the absolute stereochemistry has been demonstrated for pasteurestins A and B by total

• synthesis, we tentatively conclude a 2S,3R,8S,9R absolute configuration for pasteurestin C (4). The systematic name for 4 is (4S,4aR,7aS,7bR)-4-hydroxy-6,6,7b-trimethyl-2,4,4a,5,6,7,7a,7b-octahydro-1H-cyclobuta[e]indene-3-carboxylic acid. Bovistol A (1) showed weak cytotoxic effects (IC50 for L929 = 15 µg

Heck- and Suzuki-coupling approaches to novel hydroquinone inhibitors of calcium ATPase

• Robert J. Kempton,
• Taylor A. Kidd-Kautz,
• Soizic Laurenceau and
• Stefan Paula

Beilstein J. Org. Chem. 2019, 15, 971–975, doi:10.3762/bjoc.15.94

• tissues are avoided. Compound 1b was found to be selectively toxic to PSA-producing prostate cancer cells as well as in animal studies at submicromolar concentrations [3]. Unfortunately, TG has been difficult to obtain: extraction yields from natural sources are low and the total synthesis of TG required

Stereochemical investigations on the biosynthesis of achiral (Z)-γ-bisabolene in Cryptosporangium arvum

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 789–794, doi:10.3762/bjoc.15.75

• and was reported from different sources such as the liverwort Dumortiera hirsuta [19]. Its (Z)-configured exocyclic double bond has also attracted the attention of synthetic chemistry for a diastereoselective total synthesis [20][21][22]. The wide occurrence of 5 is likely connected to the simple

Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

• Jan Hendrik Lang and
• Thomas Lindel

Beilstein J. Org. Chem. 2019, 15, 577–583, doi:10.3762/bjoc.15.53

• product 30 carrying an 8-OPMP group was obtained from PMP-protected polyketide 28. The endgame of a total synthesis of seragamide A (2) will have to address the macrocyclisation, desilylation of the threonine moiety, and O-demethylation of the D-iodotyrosine unit of 31. In orienting reactions on small

Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives

• Mikhail V. Makarov and
• Marie E. Migaud

Beilstein J. Org. Chem. 2019, 15, 401–430, doi:10.3762/bjoc.15.36

Synthesis of nonracemic hydroxyglutamic acids

• Dorota G. Piotrowska,
• Iwona E. Głowacka,
• Andrzej E. Wróblewski and
• Liwia Lubowiecka

Beilstein J. Org. Chem. 2019, 15, 236–255, doi:10.3762/bjoc.15.22

• was much lower (2.6:1 and 1:1, respectively). Acid hydrolysis of 64 gave (4S)-4-hydroxy-L-glutamic acid [(2S,4S)-3] as the hydrochloride, however, its enantiomeric purity was not checked. In connection with the total synthesis of thiopeptide antibiotic nosiheptide an orthogonally protected (4S)-4

• orthogonally protected (2S,4S)-4-hydroxyglutamic acid 85 as an intermediate in the total synthesis of antibiotic nosiheptide [83][84] employs the N-Boc derivative of natural (2S,4R)-4-hydroxyproline 82 as a starting material (Scheme 21) [84][85]. The inversion of configuration at C4 was carried out by

• precursor in the total synthesis of longicatenamycin A [25]. Syntheses of several modified cephems started from dimethyl (2S,4R)-N-Boc-4-hydroxyglutamate (81) [114]. Protected 4-hydroxyglutamic acids (2S,4S)-66 [75][76] and (2S,4S)-85a [84][85] after installation of the thiazole ring at the C1 terminus were

Synthesis of α-D-GalpN₃-(1-3)-D-GalpN₃: α- and 3-O-selectivity using 3,4-diol acceptors

• Emil Glibstrup and
• Christian Marcus Pedersen

Beilstein J. Org. Chem. 2018, 14, 2805–2811, doi:10.3762/bjoc.14.258

• pentasaccharide chain [5][6]. The pioneering work by Paulsen was later followed up by a total synthesis by the Ogawa group [7] and an oligosaccharide synthesis by the Magnusson group [8]. With the increasing understanding of glycobiology, the Forssman antigen has remained an interesting target for vaccine

Synthesis and biological evaluation of 1,2-disubstituted 4-quinolone analogues of Pseudonocardia sp. natural products

• Stephen M. Geddis,
• Teodora Coroama,
• Suzanne Forrest,
• James T. Hodgkinson,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2018, 14, 2680–2688, doi:10.3762/bjoc.14.245

• potent antibacterial activity against Helicobacter pylori and induce growth defects in Escherichia coli and Staphylococcus aureus. Taking inspiration from a methodology used in our total synthesis of natural products, we applied this methodology to access analogues possessing bulky N-substituents

• proposed that this development should be limited under certain conditions [7]. We wished to investigate the potential of 1–8 to modulate QS in P. aeruginosa, however, the compounds are available in only trace amounts from natural sources [3], and so we embarked on the total synthesis of the compounds. We

• flash column chromatography, which may account for the slightly lower yields in these cases (13ad and 13ae). With the compounds 13 now in hand, their cyclisation to the desired analogues 14 was explored. However, whilst the conditions which had proved successful in the total synthesis of natural

Synthesis of cis-hydrindan-2,4-diones bearing an all-carbon quaternary center by a Danheiser annulation

• Gisela V. Saborit,
• Carlos Cativiela,
• Ana I. Jiménez,
• Josep Bonjoch and
• Ben Bradshaw

Beilstein J. Org. Chem. 2018, 14, 2597–2601, doi:10.3762/bjoc.14.237

• application as advanced intermediates in the total synthesis of Lycopodium alkaloids [3][4][5][6], 3a-substituted 2,4-dicarbonyl compounds being particularly useful in this field. The synthetic approaches toward these versatile building blocks (i.e., compounds with the functionalization pattern A) are

Learning from B₁₂ enzymes: biomimetic and bioinspired catalysts for eco-friendly organic synthesis

• Keishiro Tahara,
• Ling Pan,
• Toshikazu Ono and
• Yoshio Hisaeda

Beilstein J. Org. Chem. 2018, 14, 2553–2567, doi:10.3762/bjoc.14.232

• (Figure 2b). We have been exploring the utility of hydrophobic B12 model complexes, such as heptamethyl cobyrinate perchlorate 1, that possess ester groups in place of the peripheral seven-amide moieties [28][29]. 1 was developed by Eschenmoser et al. as a model complex for the total synthesis of vitamin

Synthesis of a leopolic acid-inspired tetramic acid with antimicrobial activity against multidrug-resistant bacteria

• Luce Mattio,
• Loana Musso,
• Leonardo Scaglioni,
• Andrea Pinto,
• Piera Anna Martino and
• Sabrina Dallavalle

Beilstein J. Org. Chem. 2018, 14, 2482–2487, doi:10.3762/bjoc.14.224

• , as they possess biologically validated structures, which could become suitable leads in drug discovery [2]. Recently, our research group reported the first total synthesis of leopolic acid A (Figure 1), a fungal metabolite from a terrestrial-derived Streptomyces sp. isolated from the rhizosphere of

• -pyrrolidinedione nucleus are quite rare [8][9][10][11]. The lack of similar compounds may be due to the instability of the 2,3 pyrrolidinedione moiety [12]. Indeed, while developing the total synthesis of leopolic acid A, we encountered several difficulties in the construction of the ring, most of the

Synthesis of eunicellane-type bicycles embedding a 1,3-cyclohexadiene moiety

• Alex Frichert,
• Peter G. Jones and
• Thomas Lindel

Beilstein J. Org. Chem. 2018, 14, 2461–2467, doi:10.3762/bjoc.14.222

• carbinols afforded novel allene systems. Our study may be of help towards the total synthesis of solenopodin or klysimplexin derivatives. Keywords: conformational analysis; low valent titanium; marine natural products; pinacol coupling; ten-membered rings; Introduction Eunicellane-type diterpenoids share

Efficient catalytic alkyne metathesis with a fluoroalkoxy-supported ditungsten(III) complex

• Henrike Ehrhorn,
• Janin Schlösser,
• Dirk Bockfeld and
• Matthias Tamm

Beilstein J. Org. Chem. 2018, 14, 2425–2434, doi:10.3762/bjoc.14.220

• triphenylsiloxide ligands (type II) introduced by A. Fürstner and co–workers is frequently used in the total synthesis of natural products [23][24][25][26][27]. A unique catalytic reactivity towards conjugated diynes was observed for the tungsten benzylidyne complex with OSi(Ot-Bu)3 ligands (type III) [28][29][30

Stereoselective total synthesis and structural revision of the diacetylenic diol natural products strongylodiols H and I

• Pamarthi Gangadhar,
• Sayini Ramakrishna,
• Ponneri Venkateswarlu and
• Pabbaraja Srihari

Beilstein J. Org. Chem. 2018, 14, 2313–2320, doi:10.3762/bjoc.14.206

• 10.3762/bjoc.14.206 Abstract The stereoselective total synthesis of strongylodiol H and I has been accomplished. The synthetic procedure comprised the stereoselective reduction of a ketone functionality in an ene–yne–one employing CBS as a catalyst and a Cadiot–Chodkiewicz coupling reaction as the key

• concentrations [11]. There have been few contributions on the total synthesis of strongylodiols [12][13] employing alkynylation of an unsaturated aliphatic aldehyde catalyzed by Trost’s pro-phenol ligand [12][14], β-elimination of epoxy chloride [15], Noyori’s asymmetric reduction of ynones [16], diyne addition

• have accomplished the total synthesis of the diacetylenic polyol natural products petrosiols A, D, E (11,12,13) [22][23] and strongylodiols A–D (1–4) [24]. Herein we describe the total synthesis of strongylodiols H and I (9 and 10). Results and Discussion Retrosynthesis for strongylodiol H and

Studies towards the synthesis of hyperireflexolide A

• G. Hari Mangeswara Rao

Beilstein J. Org. Chem. 2018, 14, 2106–2111, doi:10.3762/bjoc.14.185

• cyclopentane 5, a functionalized key intermediate, is presented. Compound 5 is involved in hydrolysis, α-allylation at C-8 and α-methylation at C-10 stereoselectively from the convex face. Then it is subjected to cross metathesis to give α,β-unsaturated ketone 11 as precursor in the total synthesis of

D-Fructose-based spiro-fused PHOX ligands: synthesis and application in enantioselective allylic alkylation

• Michael R. Imrich,
• Jochen Kraft,
• Cäcilia Maichle-Mössmer and
• Thomas Ziegler

Beilstein J. Org. Chem. 2018, 14, 2082–2089, doi:10.3762/bjoc.14.182

• the desired biologic effect in living organisms, while the other enantiomer could be inactive, cause whole other biological responses or might even have the opposite effect. Hence, for the total synthesis of natural products or pharmaceuticals it is crucial to generate chirality with high

Assessing the possibilities of designing a unified multistep continuous flow synthesis platform

• Mrityunjay K. Sharma,
• Roopashri B. Acharya,
• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2018, 14, 1917–1936, doi:10.3762/bjoc.14.166

• integration of experimental conditions with smaller laboratory footprint. In addition to the most obvious purpose of having such a platform that will facilitate the synthesis of any molecule including several intermediate stages, it will help in terms of the following: End-to-end synthesis: Total synthesis of

Synthesis of spirocyclic scaffolds using hypervalent iodine reagents

• Fateh V. Singh,
• Priyanka B. Kole,
• Saeesh R. Mangaonkar and
• Samata E. Shetgaonkar

Beilstein J. Org. Chem. 2018, 14, 1778–1805, doi:10.3762/bjoc.14.152

• synthesis In 2005, Wipf and Spencer [79] reported the first total synthesis of the Stemona alkaloid (−)-tuberostemonine (40). In this report, PIDA (15) was used as an electrophile for the synthesis of spirolactone 16 in 35% yield by the cyclization of L-tyrosine 14 in nitromethane at room temperature for

• of ortho-spirocarbocyclic compounds which is broadly found to originate in most of bioactive natural products [111][112]. 4.3. Application of spirocarbocyclic compounds in natural product synthesis In 2003, Kita and co-workers [113][114] employed a iodine(III) reagent during the total synthesis of

• discorhabdin A (112). In 2006, Honda and co-workers [115] reported the total synthesis of spiro-isoquinoline alkaloid (±)-annosqualine (1). In this report, the substrate 113 was cyclized to form spirocyclic compound 114 via desilylation with TBAF in THF followed by reaction with n-BuLi in hexafluoroisopropanol

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• otherwise difficult to synthesize β-mannosides using the Mitsunobu procedure. This approach to 1,2-cis-mannosides is equally effective when cyclohexylidene protecting groups are used [28][47][62]. Mitsunobu glycosylation was also a successful method in total synthesis. In the course of a 17-step synthesis

•  15) [63]. Similar reaction conditions were applied by Nie et al. in the total synthesis of the nucleoside antibiotic A201A [64]. Notably, the n-Bu3P-ADDP reagent system led here to the formation of the pure α-glycoside. Likewise, a Mitsunobu glycosylation of complex phenols was successfully

• approach was recently adopted in a total synthesis of aurantoside G, involving the Mitsunobu ligation of a D-xylopyranose derivative 116 and N-nosylated methyl asparaginate 117 to give 118 (Scheme 22) [87]. Compared to N-sulfonylation, N-carbamoylation can also prove effective to enhance the acidity of a