Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• Ericaceae plants, comprising more than 160 natural products. Most of them exhibit interesting biological activities, often representative of Ericaceae use in traditional medicine. Over the last 50 years, various strategies were described for the total synthesis of these diterpenoids. In this review, we

• of each strategy, as well as the challenges remaining to be tackled. Keywords: enantioselectivity; grayananes; oxidation; 1,2-shift; total synthesis; Introduction The Ericaceae are a large plant family, with over 4250 known species all around the world [1]. While Ericaceae’s toxicity has been known

• extraction yields have prompted various research groups to undertake the total synthesis of grayanane natural products. In this work, we will survey the literature for synthetic routes to grayanane diterpenoids, including uncompleted approaches. The review is chronologically organized, starting from the

Rhodium-catalyzed intramolecular reductive aldol-type cyclization: Application for the synthesis of a chiral necic acid lactone

• Motoyuki Isoda,
• Kazuyuki Sato,
• Kenta Kameda,
• Kana Wakabayashi,
• Ryota Sato,
• Hideki Minami,
• Yukiko Karuo,
• Atsushi Tarui,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2022, 18, 1642–1648, doi:10.3762/bjoc.18.176

• . Therefore, various types of intramolecular aldol-type reactions have been developed and widely applied to the total synthesis of diverse natural products [9][10][11][12][13][14][15][16][17][18]. The reductive aldol-type reaction is another important variation that has been reported using metal catalysts

Synthetic study toward the diterpenoid aberrarone

• Liang Shi,
• Zhiyu Gao,
• Yiqing Li,
• Yuanhao Dai,
• Yu Liu,
• Lili Shi and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2022, 18, 1625–1628, doi:10.3762/bjoc.18.173

• the 6-5-5 tricyclic skeleton includes the mediation of Nagata reagent for constructing the C1 all-carbon quaternary centers and gold-catalyzed cyclopentenone synthesis through C–H insertion. Keywords: aberrarone; C–H insertion; gold; Pauson–Khand; total synthesis; Introduction Marine natural

• were reported [30][31] and more recently, Carreira and co-workers reported [32] the first total synthesis of aberrarone through an impressive cascade reaction including a gold-catalyzed Nazarov cyclization, a cyclopropanation followed by intramolecular aldol reaction to forge the A, B and D rings

• . Impressed by the structural features and biological profiles, our group embarked a project on the total synthesis of this natural product. Herein, we report our stereoselective synthesis of its 6-5-5 tricyclic skeleton. Our retrosynthetic analysis is shown in Scheme 1. For the formation of the D ring with

Formal total synthesis of macarpine via a Au(I)-catalyzed 6-endo-dig cycloisomerization strategy

• Jiayue Fu,
• Bingbing Li,
• Zefang Zhou,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2022, 18, 1589–1595, doi:10.3762/bjoc.18.169

• 110016, P. R. China Institute of Drug Research in Medicine Capital of China, Benxi 117000, P. R. China 10.3762/bjoc.18.169 Abstract The formal total synthesis of macarpine was accomplished by the construction of a naphthol intermediate in Ishikawa’s synthetic route with two different synthetic routes

• . The convergent synthetic strategies feature the utilization of Au(I)-catalyzed cycloisomerizations of a 1,5-enyne and alkynyl ketone substrates, which were prepared by Sonogashira coupling reactions. Keywords: benzo[c]phenanthridine alkaloids; 1,5-enyne; formal total synthesis; gold catalysis

• developed the total synthesis of macarpine by Hofmann elimination from protoberberine by introducing rings B and C (Scheme 2a) [11]. In 1995, Ishikawa and co-workers accomplished the total synthesis via a Reformatsky reaction and aromatic nitrosation through the building of rings B and C (Scheme 2b) [12

Solid-phase total synthesis and structural confirmation of antimicrobial longicatenamide A

• Takumi Matsumoto,
• Takefumi Kuranaga,
• Yuto Taniguchi,
• Weicheng Wang and
• Hideaki Kakeya

Beilstein J. Org. Chem. 2022, 18, 1560–1566, doi:10.3762/bjoc.18.166

• communication in the microbial world. Herein, we report the solid-phase total synthesis and structural confirmation of longicatenamide A. First, commercially unavailable building blocks were chemically synthesized with stereocontrol. Second, the peptide chain was elongated via Fmoc-based solid-phase peptide

• longicatenamide A was confirmed. The developed solid-phase synthesis is expected to facilitate the rapid synthesis of diverse synthetic analogues. Keywords: antimicrobial; longicatenamides; peptidic natural product; solid-phase synthesis; total synthesis; Introduction Naturally occurring bioactive compounds can

• microbial world. To elucidate the role of compounds 1–4 in the microbial world, developing a strategy to synthesize compounds 1–4, including future derivatization to produce probe molecules, is required. Herein, we report the total synthesis of peptide 1 by Fmoc-based solid-phase peptide synthesis [9] and

Preparation of an advanced intermediate for the synthesis of leustroducsins and phoslactomycins by heterocycloaddition

• Anaïs Rousseau,
• Guillaume Vincent and
• Cyrille Kouklovsky

Beilstein J. Org. Chem. 2022, 18, 1385–1395, doi:10.3762/bjoc.18.143

• fragment was accomplished in a stereoselective fashion through a vinyllithium intermediate. An advanced synthetic intermediate was then obtained after functional group transformation. Keywords: cycloaddition; organolithium; stereoselective; total synthesis; Introduction Leustroducsins 1a–c and

• stereoselectivity of the coupling reaction. This validates the overall strategy for the synthesis of leustroducsins or phoslactomycins by the synthesis of a central cyclic core and its coupling with the other fragments. Conclusion We have synthesized an advanced intermediate for the total synthesis of

• completion of the total synthesis via the preparation and coupling of the fragment 5 is under study in our laboratory. Experimental Unless otherwise stated, all reactions were conducted in oven-dried glassware under an atmosphere of dry argon. Tetrahydrofuran was distilled over sodium/benzophenone ketyl

On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

• human pharmacology. Moreover, preparing fully artificial β-lactam analogues is also an active research field since, for instance aztreonam (61), is produced by total synthesis [304][305]. Amongst other issues, the main concern in this domain remains the design of compounds capable of resisting the

Enantioselective total synthesis of putative dihydrorosefuran, a monoterpene with an unique 2,5-dihydrofuran structure

• Irene Torres-García,
• Josefa L. López-Martínez,
• Rocío López-Domene,
• Manuel Muñoz-Dorado,
• Ignacio Rodríguez-García and
• Miriam Álvarez-Corral

Beilstein J. Org. Chem. 2022, 18, 1264–1269, doi:10.3762/bjoc.18.132

• decided to perform its total synthesis. Results and Discussion Our synthetic strategy is based on two metal-mediated steps (Scheme 1). In this way, we thought that the 2,5-dihydrofuran structural motif that is found in the target molecule 1 could be prepared through a Ag(I)-induced intramolecular addition

• rosiridol (Table 1), a substance that has been isolated from other natural sources [18][19], whose structure was also confirmed by total synthesis some years ago [20]. Comparison of NMR data (Table 1) confirmed the initial suspicion. We are still intrigued about the real structure of the natural product

• cyclization is a simple and efficient strategy for the preparation of the 2,5-dihydrofuran moiety present in many natural products. In fact, we have achieved the total synthesis of the 2,5-dihydrofuran structure 1. After systematic data analysis of our prepared compound and those in the literature, it can be

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• intermediates in the total synthesis of natural products utilizing their electrophilic keto group as reactive site. Suitable key reactions are, e.g., aldol additions, carbonyl ene reactions, Mannich reactions, and additions of organometallic reagents. The vicinal arrangement of carbonyl groups allows the

• stabilization of reactive conformations by chelation or dipole control. Keywords: aldol addition; ketoesters; natural products; total synthesis; Introduction Vicinal ketoesters contain a carbonyl group adjacent to an ester group. One keto group results in α-ketoesters 1 and two vicinal keto groups lead to α,β

• as key intermediates for the total synthesis of natural products [1]. Thus, the high electrophilicity of the central carbonyl group in α,β-diketoesters 2 allows the formation of stable hydrates 5. In case of an enolizable position enolization (2→6) is facilitated. The chemistry of vicinal

Synthesis of protected precursors of chitin oligosaccharides by electrochemical polyglycosylation of thioglycosides

• Md Azadur Rahman,
• Kana Kuroda,
• Hirofumi Endo,
• Norihiko Sasaki,
• Tomoaki Hamada,
• Hiraku Sakai and
• Toshiki Nokami

Beilstein J. Org. Chem. 2022, 18, 1133–1139, doi:10.3762/bjoc.18.117

• blocks can reduce the number of steps in the total synthesis. However, it requires manipulation of the anomeric leaving groups and deprotection of the protected hydroxy group at the 4-position prior to glycosylation. Although automated electrochemical assembly, which is a one-pot iterative synthesis of

Structural basis for endoperoxide-forming oxygenases

• Takahiro Mori and
• Ikuro Abe

Beilstein J. Org. Chem. 2022, 18, 707–721, doi:10.3762/bjoc.18.71

• dynamics of the active site during the enzyme reaction. Conclusion Endoperoxide compounds have recently attracted keen attention as a source of new drug leads, due to their unique structures and remarkable biological activities. To date, the total synthesis of endoperoxide-containing natural products and

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• stereochemistry in the Ir-catalyzed allylic substitution reactions. In 2016, Billingsley and co-workers disclosed the total synthesis of (−)-indolactam V (6), a nanomolar agonist of protein kinase C (Scheme 3) [12]. The authors applied an intramolecular SEAr reaction of 4-substituted indole derivative to

• construct a 3,4-fused tricyclic indole in a late stage of their total synthesis. Specifically, Michael-type addition of compound 4 took place regio- and diastereoselectively at the indole C3 position, furnishing tricyclic compound 5 (77%) which was then elaborated into the target natural product 6 in two

• or annulation of: (A) substituted arenes/heteroarenes and (B) 3,5-unsubstituted, 4-substituted indoles. Indole C3 regioselective intramolecular alkylation of indolyl allyl carbonates. Indole C3 regioselective Michael-type cyclization in the total synthesis of (−)-indolactam V. Synthesis of azepino

Iridium-catalyzed hydroacylation reactions of C1-substituted oxabenzonorbornadienes with salicylaldehyde: an experimental and computational study

• Angel Ho,
• Austin Pounder,
• Krish Valluru,
• Leanne D. Chen and
• William Tam

Beilstein J. Org. Chem. 2022, 18, 251–261, doi:10.3762/bjoc.18.30

• intermediates have found use in the total synthesis of (+)-norchelidonine (an isoquinoline alkaloid) [55], sertraline (an antidepressant) [56], and arnottin I (an anti-inflammatory) [57]. Although OBD 1 has been shown to undergo many different modes of reactivity in both a stereo- and enantioselective manner

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• . Supporting Information Supporting Information File 16: Detailed synthetic procedures, characterization of all molecules and copies of NMR spectra. Acknowledgements This article is part of the PhD thesis of Phil Servatius “Total synthesis of natural HDAC inhibitors and derivatives thereof”, Saarland

The enzyme mechanism of patchoulol synthase

• Houchao Xu,
• Bernd Goldfuss,
• Gregor Schnakenburg and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 13–24, doi:10.3762/bjoc.18.2

• (ca. 40%) [1][2]. Pure patchoulol is a crystalline material that has first been described by Gal in 1869 [3]. Its planar structure was initially described as that of compound 1 (Figure 1) by Treibs [4], and later reassigned to structure 2 based on a total synthesis from camphor by Büchi [5]. Because

• CAS number 21698-41-9 is even assigned the opposite absolute configuration as expected from these biosynthetic considerations. After a recent correction [22] of its initially reported relative configuration [23] that was shown to be erroneous by total synthesis [24], we now address the problem of the

First total synthesis of hoshinoamide A

• Haipin Zhou,
• Zihan Rui,
• Yiming Yang,
• Shengtao Xu,
• Yutian Shao and
• Long Liu

Beilstein J. Org. Chem. 2021, 17, 2924–2931, doi:10.3762/bjoc.17.201

• -sensitive Plasmodium falciparum. Herein, we describe the first total synthesis of hoshinoamide A by the combination of liquid-phase and solid-phase peptide synthesis. Liquid-phase synthesis is to improve the coupling yield of ʟ-Val3 and N-Me-ᴅ-Phe2. Connecting other amino acids efficiency and convergence is

• achieved by solid-state synthesis. Our synthetic strategy could synthesize the target peptide in high yield with good purity Keywords: antimalarial; highly methylated polypeptides; hoshinoamides; total synthesis; Introduction Malaria is an insect-borne infectious disease caused by parasites of the genus

• cytotoxicity compared to hoshinoamide B. Herein, we report the initial progress on the total synthesis of hoshinomaide A. The key challenges for the total synthesis of hoshinoamide A are the coupling of highly methylated amino acids and the purification of hydrophobic peptides. Results and Discussion As shown

Total synthesis of the O-antigen repeating unit of Providencia stuartii O49 serotype through linear and one-pot assemblies

• Tanmoy Halder and
• Somnath Yadav

Beilstein J. Org. Chem. 2021, 17, 2915–2921, doi:10.3762/bjoc.17.199

• , we herein report the total synthesis of a trisaccharide repeating unit of the O-antigen polysaccharide of the P. stuartii O49 serotype containing the →6)-β-ᴅ-Galp-(1→3)-β-ᴅ-GalpNAc(1→4)-α-ᴅ-Galp(1→ linkage. The synthesis of the trisaccharide repeating unit was carried out first by a linear strategy

• synthesis of the O-antigens, that of Providencia rustigianii O34 was reported by Mukhopadhyay et al. in 2013 [34]. Chheda and co-worker, in 2015, reported the total synthesis of the pentasaccharide repeating unit of the O-specific polysaccharide of Providencia alcalifaciens O28 [35]. In 2017, Kulkarni and

• co-worker accomplished the total synthesis of a O-polysaccharide of Providencia alcalifaciens O22 via a one pot assembly of the oligosaccharide unit [36]. Recently in 2020 Werz and co-workers completed the total synthesis of a tri-, hexa-, and heptasaccharide of the O-polysaccharide of Providencia

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• , the reactivity and applicability outperformed the racemic variant. Application of this methodology was applied towards the total synthesis of maraviroc, an anti-HIV drug, which was synthesized in 5 steps starting from styrene (115a) and CBr4 (20a). Carboamination In 2017, the Bao group investigated

Highly stereocontrolled total synthesis of racemic codonopsinol B through isoxazolidine-4,5-diol vinylation

• Lukáš Ďurina,
• Anna Ďurinová,
• František Trejtnar,
• Ľuboš Janotka,
• Lucia Messingerová,
• Jana Doháňošová,
• Ján Moncol and
• Róbert Fischer

Beilstein J. Org. Chem. 2021, 17, 2781–2786, doi:10.3762/bjoc.17.188

• were inactive towards the examined α-glucosidases. The enantiomer of 2 was the only one that still exhibited inhibitory activity against yeast α-glucosidase [2]. To our knowledge, the sole total synthesis of (−)-codonopsinol B and similar hydroxylated pyrrolidines to date was reported in the above

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• considerable attention in recent years due to their wide application in the total synthesis of axially chiral natural products, functional materials, bioactive compounds, privileged chiral ligands, and have further potential applications in asymmetric catalysis and drug discovery. Accordingly, considerable

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

• Marco Keller,
• Karl Sauvageot-Witzku,
• Franz Geisslinger,
• Nicole Urban,
• Michael Schaefer,
• Karin Bartel and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2716–2725, doi:10.3762/bjoc.17.183

• relationships in this chemotype. Keywords: acyl Pictet–Spengler reaction; alkaloids; antiproliferative activity; benzyltetrahydroisoquinolines; ion channels; protective group; total synthesis; Introduction The benzylisoquinoline alkaloids are a large and diverse class of plant secondary metabolites including

• by lithium alanate reduction [18][19]. In a novel total synthesis of the racemic alkaloid N-methylcoclaurine (1) performed in this course we also used the ethoxycarbonyl group successfully for protection of two phenolic groups at two different rings during the N-acyl-Pictet–Spengler reaction [15

Synthesis of highly substituted fluorenones via metal-free TBHP-promoted oxidative cyclization of 2-(aminomethyl)biphenyls. Application to the total synthesis of nobilone

• Ilya A. P. Jourjine,
• Lukas Zeisel,
• Jürgen Krauß and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2668–2679, doi:10.3762/bjoc.17.181

• groups for phenols) and was further utilized in the first total synthesis of the natural product nobilone. Keywords: cross-dehydrogenative coupling; cyclization; fluorenones; nobilone; total synthesis; Introduction Fluorenones are an important class of aromatic natural products, and since the

• activated derivatives (intramolecular Friedel–Crafts acylation) [29][30][31] found wide application here. In a different approach, a total synthesis of dengibsin (1a) was accomplished by Wang and Snieckus in 15 steps by means of a directed remote metalation [32], using a benzamide residue as the directing

• -radical reagents [62]. An extremely poor yield was further obtained with methylenedioxy substrate 15p. Our application of this new protocol to the first total synthesis of the natural product nobilone (1d) is depicted in Scheme 7. The commercially available phenol 16 was TBS-protected to give compound 17

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• tertiary amine-thiourea catalyst (cat. 82). This cascade reaction afforded aza-Michael adducts in 77–92% yields with high ee (up to 90%) (Table 19) [55]. Du et al. developed an enantioselective catalytic tandem aminolysis/aza-Michael addition for the asymmetric total synthesis of two natural Apocynaceae

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• , tandem reactions, and the total synthesis and biosynthesis of natural products. This review explores the use of α-ketol rearrangements in these contexts over the past two decades. Keywords: acyloin rearrangement; asymmetric synthesis; iminol rearrangement; ketol rearrangement; tandem reactions

• reactions through mid-2002 have been thoroughly discussed in a past review by Paquette [1]. The current review expands on that work by providing an updated account from mid-2002 through early 2021, including the following recently developed applications: asymmetric synthesis, total synthesis, tandem

• 1,4-dioxane with a single drop of water. α-Ketol rearrangements implemented in total syntheses Although rare, α-ketol rearrangements have been included in the total syntheses of some natural products with high success. In the first total synthesis of periconianone A (31), an α-ketol rearrangement was

Strategies for the synthesis of brevipolides

• Yudhi D. Kurniawan and
• A'liyatur Rosyidah

Beilstein J. Org. Chem. 2021, 17, 2399–2416, doi:10.3762/bjoc.17.157

• brevipolide H (8) Two years after the successful synthesis of ent-brevipolide H (ent-8), in 2016, Hou and co-workers reported the first total synthesis of natural brevipolide H (8) [15]. The retrosynthesis was initiated by disconnection of the cinnamate ester bond to give intermediate 79. The 5,6-dihydro-α

• (13) Sabitha and Raju demonstrated the first total synthesis of brevipolide M (13) in 2017 [17]. In the retrosynthesis, compound 93 is hypothesized from the Mitsunobu inversion at the C6’ stereocenter with (E)-p-methoxycinnamic acid (17) and ring-closing metathesis of tetrahydrofuran 93 (Scheme 11

• , Sabitha and Raju reported another approach to synthesize brevipolide M (13) which was shorter and more efficient than the former strategy [18]. Furthermore, this improved strategy was applied to achieve the first total synthesis of brevipolide N (14) by utilizing a different acid counterpart in the late