Organometallic chemistry

• Bernd F. Straub,
• Rolf Gleiter,
• Claudia Meier and
• Lutz H. Gade

Beilstein J. Org. Chem. 2016, 12, 2216–2221, doi:10.3762/bjoc.12.213

• investigation of more active and more selective homogeneous catalysts, catalytic transformations in the total synthesis of natural products, the theoretical and kinetic unravelling of reaction mechanisms, and the verification of rare coordination modes. These various facets underline the importance of

Evidence for an iterative module in chain elongation on the azalomycin polyketide synthase

• Hui Hong,
• Yuhui Sun,
• Yongjun Zhou,
• Emily Stephens,
• Markiyan Samborskyy and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2016, 12, 2164–2172, doi:10.3762/bjoc.12.206

• in a cis-AT PKS is well-precedented [45][46][47]. The bioinformatic prediction of the configuration at each of the seven asymmetric centres was also in accord with the configuration of authentic ebelactone confirmed by total synthesis [48] (Scheme 1). The essentially complete congruence between

The direct oxidative diene cyclization and related reactions in natural product synthesis

• Juliane Adrian,
• Leona J. Gross and
• Christian B. W. Stark

Beilstein J. Org. Chem. 2016, 12, 2104–2123, doi:10.3762/bjoc.12.200

• stereochemical aspects, this review article provides a summary on applications in natural product synthesis. Moreover, current limitations and future directions in this area of chemistry are discussed. Keywords: asymmetric synthesis; natural products; oxidation catalysis; tetrahydrofurans; total synthesis

• isolated from the mould fungus Fusarium solani as a phytotoxin against barnyardgrass and duckweed in 1996 [30]. The Donohoe group presented a total synthesis in 2003 using an Os(VIII)-catalyzed oxidative cyclization as the key step [31] (Scheme 4). Several other total syntheses of that natural product did

• obtained, which was subsequently cyclized. The reaction yielded the desired THF diol 10a in 61% as a single diastereoisomer together with over-oxidized 10b as side product. The total synthesis was finally achieved from 10a via some protecting group operations and an oxidation of the primary alcohol to the

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• -nitrosopyridine (206) are collected in Table 7. This method was subsequently applied to the first total synthesis of enantiomerically pure (+)-trans-dihydronarciclasine [3] and, with a number of cyclic dienes, 205 gave ee values of 81–95% for hetero-Diels–Alder products 210, some of which are shown in Scheme 40

• de values of more than 95% in both cases [65]. Kibayashi prepared a set of optically active acylnitroso arylmenthol derivatives 142 (Scheme 27) that were subsequently reacted with 1,3-cyclohexadiene (120) to give the hetero-Diels–Alder products 143, serving as intermediates for an asymmetric total

• synthesis of (−)-epibatidine [5][124]. The stereoselectivity of the reaction was affected by the substituent on the menthol group. The introduction of a phenyl and a 4-methoxyphenyl substituent gave the products with de values of >85%, but this could be improved to up to 91% for the 2-napthyl, 4-bromophenyl

From supramolecular chemistry to the nucleosome: studies in biomolecular recognition

• Marcey L. Waters

Beilstein J. Org. Chem. 2016, 12, 1863–1869, doi:10.3762/bjoc.12.175

• organometallic methodology, asymmetric catalysis, total synthesis, and mechanistic studies. I opted for the latter and spent my Ph.D. studying the mechanism of the Wulff–Dötz reaction [1], while at the same time gaining a broad background in methodology and synthesis (Figure 2). I had a fantastic time in

Synthesis of the C8’-epimeric thymine pyranosyl amino acid core of amipurimycin

• Pramod R. Markad,
• Navanath Kumbhar and
• Dilip D. Dhavale

Beilstein J. Org. Chem. 2016, 12, 1765–1771, doi:10.3762/bjoc.12.165

• configurations at the C6’, C2” and C3” of the cis-pentacin are still undefined. Thus, the partially unresolved structure, a potent antifungal activity, the unexplored mode of action and the limited synthetic study make amipurimycin (1) an attractive target for futher investigation. As of now, a total synthesis

Rearrangements of organic peroxides and related processes

• Ivan A. Yaremenko,
• Vera A. Vil’,
• Dmitry V. Demchuk and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2016, 12, 1647–1748, doi:10.3762/bjoc.12.162

Total synthesis of leopolic acid A, a natural 2,3-pyrrolidinedione with antimicrobial activity

• Atul A. Dhavan,
• Rahul D. Kaduskar,
• Loana Musso,
• Leonardo Scaglioni,
• Piera Anna Martino and
• Sabrina Dallavalle

Beilstein J. Org. Chem. 2016, 12, 1624–1628, doi:10.3762/bjoc.12.159

• Veterinary Medicine - Microbiology and Immunology, Università degli Studi di Milano, via Celoria 10, I-20133 Milano, Italy 10.3762/bjoc.12.159 Abstract The first total synthesis of leopolic acid A, a fungal metabolite with a rare 2,3-pyrrolidinedione nucleus linked to an ureido dipeptide, was designed and

• suggests that they could be considered as promising candidates for future developments. Keywords: antimicrobial; heterocyclic compounds; natural products; pyrrolidinedione; total synthesis; Introduction Great concern has recently been expressed about the diminishing efficacy of current antibiotic

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• is followed by allylic oxidation at the 9a-position in 78 and cyclisation [13]. This reaction was exploited in the chemoenzymatic total synthesis of (+)-aureothin (79) [67][68]. The molecule also contains a pyran-4-one. Reminiscent of type II and type III-PKS, this results from elimination

Selective bromochlorination of a homoallylic alcohol for the total synthesis of (−)-anverene

• Frederick J. Seidl and
• Noah Z. Burns

Beilstein J. Org. Chem. 2016, 12, 1361–1365, doi:10.3762/bjoc.12.129

• homoallylic alcohol. Critical factors for optimization of this reaction are highlighted. The utility of the product bromochloride is demonstrated by the first total synthesis of an antibacterial polyhalogenated monoterpene, (−)-anverene. Keywords: enantioselective catalysis; halogenation; natural products

• ; total synthesis; Introduction The directed enantioselective functionalization of olefins is an extremely powerful tool in synthesis. A preeminent example is the Sharpless asymmetric epoxidation (SAE), which has been featured in countless syntheses of enantioenriched small molecules [1][2]. While the

• regio- and enantioselectivity. Disclosed herein, this discovery has enabled the first total synthesis of (−)-anverene (1) (Scheme 1, bottom), a secondary metabolite from the algae Plocamium cartilagineum with selective antibiotic activity against vancomycin-resistant Enterococcus faecium (VREF) [10

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• further improvement in enantioselectivity was observed (Scheme 33b). For example, for R = Me an 86% yield and 96.5:3.5 er was obtained [61]. The Shibasaki group went on to apply their conjugate addition–enantioselective protonation of α,β-unsaturated thioesters to the total synthesis of epothilones A and

• acroleins. Luo and Cheng’s proposed mechanism and transition state. Shibasaki’s enantioselective addition of 4-tert-butyl(thiophenol) to α,β-unsaturated thioesters. Shibasaki’s application of chiral (S)-SmNa3tris(binaphthoxide) catalyst 144 to the total synthesis of epothilones A and B. Shibasaki’s

Modular synthesis of the pyrimidine core of the manzacidins by divergent Tsuji–Trost coupling

• Sebastian Bretzke,
• Stephan Scheeff,
• Felicitas Vollmeyer,
• Friederike Eberhagen,
• Frank Rominger and
• Dirk Menche

Beilstein J. Org. Chem. 2016, 12, 1111–1121, doi:10.3762/bjoc.12.107

• revised by a total synthesis [6] which adds to the importance of a flexible route to such substructures. Herein we report in full detail the design, development and application of an innovative strategy for the high-yielding synthesis of 1,3-syn- and anti-configured tetrahydropyrimidinones, based on an

Towards the total synthesis of keramaphidin B

• Pavol Jakubec,
• Alistair J. M. Farley and
• Darren J. Dixon

Beilstein J. Org. Chem. 2016, 12, 1096–1100, doi:10.3762/bjoc.12.104

Cationic Pd(II)-catalyzed C–H activation/cross-coupling reactions at room temperature: synthetic and mechanistic studies

• Takashi Nishikata,
• Alexander R. Abela,
• Shenlin Huang and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2016, 12, 1040–1064, doi:10.3762/bjoc.12.99

• ), while acrylamides having simple amine or amino acid moieties also participated in cross-coupling reactions with the arylurea to produce the corresponding amide derivatives in moderate to good yields (5s, 5t). Total synthesis of boscalid® via C–H activation The rationale behind the attention recently

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• last decades. Additionally, 3-hydroxyoxindoles as versatile precursors have also been used in the total synthesis of natural products and for constructing structurally novel scaffolds. In this review, we aim to provide an overview about the catalytic asymmetric synthesis of biologically important 3

• to the total synthesis of natural TMC-95A. In 2015, Yang and co-workers reported α-amino acid sulfonamide (cat. 7)-catalyzed aldol reactions of ketones with isatins under neat conditions (Scheme 20) [36]. Interestingly, the reactions proceeded smoothly, giving the desired products in high yields (up

• also been studied for the total synthesis of natural products and accessing biologically important scaffolds. In 2012, Bisai et al. reported the Lewis acid-catalyzed Friedel–Crafts alkylation of 3-hydroxy-2-oxindoles with electron-rich phenols (Scheme 46) [63]. They found that various Lewis acids (e.g

The synthesis of functionalized bridged polycycles via C–H bond insertion

• Jiun-Le Shih,
• Po-An Chen and
• Jeremy A. May

Beilstein J. Org. Chem. 2016, 12, 985–999, doi:10.3762/bjoc.12.97

• this intermediate was not advanced in a total synthesis of the natural product, it demonstrates the potential of the strategy. Additionally, the reaction was described to proceed through the lowest energy conformation of the carbene intermediate 16, but an extensive study of conformational effects was

• led to a formal total synthesis of garryine, which is closely related to atisine. The initial lactam 26 that was formed by methyl C–H insertion was quite unstable, and so it was quickly converted to the acetamide 27. Advancing that intermediate intercepted a route to garryine completed by Pelletier

• synthesis of phomoidride B (Scheme 16) [76]. While this strategy was ultimately not productive for the total synthesis of the natural product, it did synthesize the key synthetic intermediate 62 very rapidly by taking advantage of insertion into the ether-activated C–H bond of 61. A carbene cascade reaction

Enantioselective carbenoid insertion into C(sp³)–H bonds

• J. V. Santiago and
• A. H. L. Machado

Beilstein J. Org. Chem. 2016, 12, 882–902, doi:10.3762/bjoc.12.87

• activation; chiral catalysis; diazo compounds; total synthesis; Introduction One of the major challenges met in organic synthesis is the formation of carbon–carbon bonds, in particular in a stereoselective way. Nucleophilic substitution reactions, radical reactions, cross-coupling reactions and the Heck

• new C–O bond (Scheme 20) [62]. A wide range of benzyl silyl ethers and diazo compounds were tested providing the desired 2,3-dihydrobenzofuran in good yields and excellent diastereo- and enantioselectivity. Later, this strategy was further used by Davies, Zakarian and coworkers to access the total

• synthesis of (−)-maoecrystal V [63]. During this study, the authors observed an unexpected result when ortho–halosubstituted diazo compounds were used. Here the formation of a β-lactone by the carbenoid insertion into the C(sp3)–H bond of the alkyl substituent of the alkoxy moiety of the ester (Scheme 21

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• , aldehyde 30, amine 31 and the urea dipeptide building block 27. A two-step global deprotection then gave the desired muraymycin D2 and its epimer which could be separated by HPLC [96][97]. In 2012, Kurosu et al. also reported the synthesis of potential key intermediates for the total synthesis of

Unconventional application of the Mitsunobu reaction: Selective flavonolignan dehydration yielding hydnocarpins

• Guozheng Huang,
• Simon Schramm,
• Jörg Heilmann,
• David Biedermann,
• Vladimír Křen and
• Michael Decker

Beilstein J. Org. Chem. 2016, 12, 662–669, doi:10.3762/bjoc.12.66

• silymarin complex for protection of liver damage, and for preventing skin tumor promotion, these compounds have attracted efforts on their total synthesis (e.g., isosilybin) [6] and structural modification [5][7][8][9] to improve their water-solubility, bioavailability and biological activities. Recently

Studies on the synthesis of peptides containing dehydrovaline and dehydroisoleucine based on copper-mediated enamide formation

• Franziska Gille and
• Andreas Kirschning

Beilstein J. Org. Chem. 2016, 12, 564–570, doi:10.3762/bjoc.12.55

• the conditions using copper(I) iodide, cesium carbonate and N,N-dimethylglycine in 1,4-dioxane. Recently, Inoue applied this cross-coupling protocol to the synthesis of peptides (Scheme 2) [11][12] as demonstrated in the total synthesis of Yaku'amide A [13]. As part of our study on the total synthesis

• total synthesis when the guanidine group has either to be liberated by the removal of the protecting groups or used for the introduction to the corresponding ornithine residue. These results demonstrate that the copper-mediated cross-coupling reaction depends on the functional groups present in the

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• proceeded in good to excellent yield and excellent enantioselectivity for almost all of the substrates that were tested. This methodology was further extended in the total synthesis of (−)-mesembrine. This natural product contains a sterically hindered and arylated quaternary carbon center, which was

Cupreines and cupreidines: an established class of bifunctional cinchona organocatalysts

• Laura A. Bryant,
• Rossana Fanelli and
• Alexander J. A. Cobb

Beilstein J. Org. Chem. 2016, 12, 429–443, doi:10.3762/bjoc.12.46

• racemic synthesis severely deteriorated this, preventing completion of the total synthesis [70][71]. Conclusion Cupreine and cupreidine and their derivatives have been demonstrated to be suited to a wide range of reaction processes, often with very good enantioinduction. In most cases these catalysts are

• ) Dixon’s 6’-OH cinchona alkaloid catalyzed oxidative coupling. (b) An asymmetric oxidative coupling en route to the attempted total synthesis of some amaryllidaceae alkaloids. Acknowledgements The University of Reading (to RF) and GW Pharmaceuticals, along with the BBSRC (BB/L015714/1 to LAB) are

• oxidative coupling – initially between 3-methoxycatechol (100) and tert-butyl 1-oxoindan-2-carboxylate (101) using an adamantane derivative of cupreidine CPD-102 to give the corresponding adduct 103 in 84% yield and 81% ee (Scheme 24a) [69]. An attempt to develop this methodology towards an asymmetric total

Diastereoselective synthesis of new O-alkylated and C-branched inositols and their corresponding fluoro analogues

• Charlotte Collet,
• Françoise Chrétien,
• Yves Chapleur and
• Sandrine Lamandé-Langle

Beilstein J. Org. Chem. 2016, 12, 353–361, doi:10.3762/bjoc.12.39

• biological evaluations but also as useful diastereoisomeric intermediates to anchor various groups such as carbohydrates, for example, opening up new avenues for the total synthesis of new inositol derivatives. The synthesized inositol derivatives with fluorinated arms could be more specifically interesting

Study on the synthesis of the cyclopenta[f]indole core of raputindole A

• Nils Marsch,
• Mario Kock and
• Thomas Lindel

Beilstein J. Org. Chem. 2016, 12, 334–342, doi:10.3762/bjoc.12.36

• and coworkers for benzyl ether cleavage in the presence of Boc-protected amines when studying the late stages of the total synthesis of the trisindole alkaloid yatakemycin [44]. As an alternative, the 3,4-dimethoxybenzyl (DMB) protecting group was installed (13). We favored the DMB over the related

• become useful in a future total synthesis of raputindole A (1) as a reduction–elimination sequence of the benzylic ketone could be used to introduce the olefinic double bond. Since neither from 22 nor from 24 the indole-5-OH group could be liberated, we turned back to the originally dismissed idea of

• of cyclopentene anellation by cyclization of aryl-substituted allyl cations. High yields were reported by Alvarez-Manzaneda et al. in the course of their total synthesis of taiwaniaquinone H. They induced the cyclization by treatment of arylvinylcarbinols with the mild Lewis acid SnCl4, which were

A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

• Steven C. Zimmerman

Beilstein J. Org. Chem. 2016, 12, 125–138, doi:10.3762/bjoc.12.14

• postdoctoral fellowship, I spent just under two years with Sir Alan Battersby at the University of Cambridge where we completed the total synthesis of sirohydrochlorin, an intermediate in the biosynthesis of vitamin B12. Then in July 1985, it was off to the University of Illinois at Urbana-Champaign. Molecular