Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• macrolactonization catalyzed by two massive PKS modules exemplifies a refined and innovative method in chemo-enzymatic synthesis. Tylactone (4), a 16-membered macrolactone, was isolated from a Streptomyces fradiae mutant and characterized as the aglycone of the macrolide antibiotic tylosin (Scheme 7) [69]. Since the

Methodology for awakening the potential secondary metabolic capacity in actinomycetes

• Shun Saito and
• Midori A. Arai

Beilstein J. Org. Chem. 2024, 20, 753–766, doi:10.3762/bjoc.20.69

• -acyltransferase polyketide synthase biosynthetic gene cluster sdl (80 kb) from Streptomyces sp. B59 was cloned and transferred into a heterologous host, Streptomyces albus J1074, resulting in the production of a class of polycyclic macrolide shuangdaolides A (1), B, and D and dumulmycin (2) [29]. Furthermore

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• biocatalytic cyclization, a crucial feature for the chemoenzymatic synthesis of macrolides and PKS/NRPS hybrids. The pikromycins Methymycin (20) and pikromycin (21) are 12- and 14-membered macrolide antibiotics both isolated from Streptomyces venezuelae ATCC15439. The Kang lab reported the total synthesis of

• contrast to Kang’s chemical synthesis route, this biotransformation provided a more efficient and productive strategy for the desoaminylation of macrolide aglycones. Combining in vitro and in vivo enzymatic reactions together, this chemoenzymatic platform exhibits the potential to access a broader range of

• unnatural macrolides with similar skeletons. The juevnimicins Juvenimicins belong to a family of broad-spectrum macrolide antibiotics [73], playing an essential role in veterinary medicine, isolated from Micromonospora chalcea and Micromonospora capillata. They contain a 16-membered macrolide aglycone

Isolation and structure determination of a new analog of polycavernosides from marine Okeania sp. cyanobacterium

• Kairi Umeda,
• Naoaki Kurisawa,
• Ghulam Jeelani,
• Tomoyoshi Nozaki,
• Kiyotake Suenaga and
• Arihiro Iwasaki

Beilstein J. Org. Chem. 2024, 20, 645–652, doi:10.3762/bjoc.20.57

• polycavernosides. Keywords: macrolide glycoside; marine cyanobacterium; marine natural products; polycavernosides; terminal alkyne; Introduction In 1991, an outbreak of food poisoning caused by a species of red algae known as ‘Polycavernosa tsudai’ occurred in Guam, which resulted in killing of three people. Two

• novel macrolide glycosides, polycavernosides A (2) and B (3), were reported as the causative compounds for the illness [1]. After that, the second fatal food poisoning incidents occurred in the Philippines caused by the ingestion of polycavernoside A (2)-contaminated red algae [2]. Subsequently

• ). We then focused on the macrolide structure of 1. Six HMBC, δH 0.94 (H-30)/δC 82.0 (C-3), δH 0.94 (H-30)/δC 38.3 (C-4), δH 0.94 (H-30)/δC 85.3 (C-5), δH 0.90 (H-31)/δC 82.0 (C-3), δH 0.90 (H-31)/δC 38.3 (C-4), and δH 0.90 (H-31)/δC 85.3 (C-5), along with COSY correlations shown in Figure 2, revealed a

Secondary metabolites of Diaporthe cameroonensis, isolated from the Cameroonian medicinal plant Trema guineensis

• Bel Youssouf G. Mountessou,
• Élodie Gisèle M. Anoumedem,
• Blondelle M. Kemkuignou,
• Yasmina Marin-Felix,
• Frank Surup,
• Marc Stadler and
• Simeon F. Kouam

Beilstein J. Org. Chem. 2023, 19, 1555–1561, doi:10.3762/bjoc.19.112

• elucidation of a new polyketide 1 and a new acetylated alternariol derivative 2 as well as fifteen known compounds including three alternariol derivatives 3–5, one chromone 6, one biphenyl 7, seven cytochalasins 8–14, two cytosporones 15 and 16, and one macrolide 17 from the endophytic fungus, Diaporthe

Combretastatins D series and analogues: from isolation, synthetic challenges and biological activities

• Jorge de Lima Neto and
• Paulo Henrique Menezes

Beilstein J. Org. Chem. 2023, 19, 399–427, doi:10.3762/bjoc.19.31

• alternative experimental strategies to achieve the target molecule, as will be discussed further in this review. 2.3 Synthesis of combretastatins D series Boger and co-workers were the first to report the total synthesis of compound 2 using both routes A and B to obtain the desired macrolide [27]. Initially

• under different conditions [30] did not lead to the desired macrolide 2, but only the formation of the diolide was observed (Scheme 4). Once the first synthetic pathway did not furnish the desired compound, the authors carried out the formation of the macrocycle using an intramolecular Ullmann-type

• 97% yield. Subsequent intramolecular Ullmann-type reaction using CuMe under high dilution conditions [31] gave macrolide 28 in low yield. Finally, demethylation using boron triiodide [32] led to the formation of combretastatin D-2 (2, Scheme 5). Using this strategy, Boger succeeded to synthesize

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• heating and the residence time was only 12 minutes. The Macrolide® 89 was obtained in 14% together with the aliphatic macrocyclic 90, the latter can be oxidatively converted into the corresponding ketone, which is of practical importance in the fragrance industry. It is clear that this process could not

Unsaturated fatty acids and a prenylated tryptophan derivative from a rare actinomycete of the genus Couchioplanes

• Shun Saito,
• Kanji Indo,
• Naoya Oku,
• Hisayuki Komaki,
• Masashi Kawasaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2021, 17, 2939–2949, doi:10.3762/bjoc.17.203

• calicheamicin γ1I [16], and Clostridium difficile-specific macrolide fidaxomicin [17]. At present, only 5 out of 29 valid genera in this family [18] – Actinoplanes, Dactylosporangium, Micromonospora, Salinispora, and Verrucosispora – have mainly been investigated [11] and the remaining 24 are still untouched or

• Micromonosporaceae first isolated in 1994 from a sandy soil in Japan [23], was set to be the next target. While the anti-SMASH-assisted genome mining [24] in C. caeruleus DSM 43634 revealed approximately 20 secondary metabolite biosynthetic gene clusters, only one compound, heptaene macrolide 67-121C, is known to

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

•  13 [40]. This approach was further extended to the synthesis of the macrolide lecasacandrolide A [41]. BF3·OEt2 in combination with 2,6-di-tert-butylpyridine (DTBP) was a suitable combination for the synthesis of the THP unit of leucasacandrolide A, while TiBr4 [42] was found suitable in conjunction

• (−)-blepharocalyxin D29 [45] and the macrolide leucascandrolide A [46]. In another type, the triflic acid-catalyzed Prins cyclization was used for the synthesis of 2,4,5,6-tetrasubstituted tetrahydropyran with complete control of stereochemistry, which is an important core of a variety of natural products, such as

Automated high-content imaging for cellular uptake, from the Schmuck cation to the latest cyclic oligochalcogenides

• Rémi Martinent,
• Javier López-Andarias,
• Dimitri Moreau,
• Yangyang Cheng,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2020, 16, 2007–2016, doi:10.3762/bjoc.16.167

• an endosomal pathway. The low pKa value of the four GCP moieties could result in an improved buffering capacity, which could facilitate endosomal escape by the proton-sponge effect [28]. Significant inhibition of DNA transfection by bafilomycin (a macrolide antibiotic that can block the endosomal

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

• , thereby affording the triene intermediate in a substantial yield. Additional transformations using conventional methods efficiently provided (−)-amphidinolide E (3). Amphidinolide K, another important bioactive macrolide endowed with specific cytotoxic activity against L1210 and KB cancer cells, was also

Current understanding and biotechnological application of the bacterial diterpene synthase CotB2

• Ronja Driller,
• Daniel Garbe,
• Norbert Mehlmer,
• Monika Fuchs,
• Keren Raz,
• Dan Thomas Major,
• Thomas Brück and
• Bernhard Loll

Beilstein J. Org. Chem. 2019, 15, 2355–2368, doi:10.3762/bjoc.15.228

• -dolabellatriene (12) possesses a mainly weak antibiotic activity against different types of Staphylococcus aureus strains (two epidemic MRSA strains, a macrolide-resistant variant and two multidrug-resistant efluxing strains) [72]. By contrast, 3,7,18-dolabellatriene (12, Scheme 3), only altered at C14 with a

• hydroxy group, showed a significant increase in potency (compound 14). Here the MIC values were as low as 4 µg mL−1 for a macrolide-resistant and one multidrug-resistant effluxing variant, as well as 2 µg mL−1 for two epidemic MRSA and another multidrug-resistant effluxing strain. The first bioactive

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• pathways, was studied in a clinical trial (Figure 6) [74]. The macrolide antibiotic of natural origin, which does not resemble the structures of signal molecules, was shown to reduce the presence of quorum sensing molecules in vitro and in vivo. It prevented the selection of QS-mutants (lasR) that rapidly

Semi-synthesis and insecticidal activity of spinetoram J and its D-forosamine replacement analogues

• Kai Zhang,
• Jiarong Li,
• Honglin Liu,
• Haiyou Wang and
• Lamusi A

Beilstein J. Org. Chem. 2018, 14, 2321–2330, doi:10.3762/bjoc.14.207

• as the glycosylation donor of C9–OH, but also the protecting group of C17–OH, greatly reducing the synthetic steps and costs. Macrolide compounds are a new kind of insecticides and fungicides which have also been widely applied in medicine [14][15]. Currently, research on structural modification of

• macrolide compounds, such as modification of the macrolide and the branched chain glycosyl residue, and replacement of the sugar group, are in the limelight [16][17]. The unique macrolide structure of spinosyns and the efficient appearance of resistance in some insect pests have prompted further exploration

Lanyamycin, a macrolide antibiotic from Sorangium cellulosum, strain Soce 481 (Myxobacteria)

• Lucky S. Mulwa,
• Rolf Jansen,
• Dimas F. Praditya,
• Kathrin I. Mohr,
• Patrick W. Okanya,
• Joachim Wink,
• Eike Steinmann and
• Marc Stadler

Beilstein J. Org. Chem. 2018, 14, 1554–1562, doi:10.3762/bjoc.14.132

• and the human nasopharyngeal cell line KB3 with IC50 values of 3.1 and 1.5 μM, respectively, and also suppressed the growth of the Gram-positive bacterium Micrococcus luteus. Keywords: antimicrobial; HCV; lanyamycin; macrolide; Sorangium cellulosum; Introduction Viral hepatitis (HCV) has recently

• seem to be bending closer to the centre of the open chain as shown by the NOE correlation pairs of H-36/42, 3/42, 31/43, 35/43, 35/24. These NOEs are not present in the case of 2. Aside from their related macrolide rings lanyamycin (1/2) and bafilomycins, including hygrolidins, micromonospolides and

• other bafilomycin type antibiotics, show very little similarity in their structures. The typical α-methyl-β-hydroxy part of the bafilomycin side chain is absent in 1/2, which features a unique α-methylene group. However, both share a carbonyl function in δ-position to the macrolide, which often is

Recent developments in the asymmetric Reformatsky-type reaction

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 325–344, doi:10.3762/bjoc.14.21

• in the presence of LiI. A subsequently deprotection of this product by treatment with TFA led to the expected naturally occurring cytotoxic macrolide epothilone D. It must be noted that this novel highly convergent and stereocontrolled total synthesis of epothilone D clearly differed from other

A semisynthesis of 3'-O-ethyl-5,6-dihydrospinosyn J based on the spinosyn A aglycone

• Kai Zhang,
• Shenglan Liu,
• Anjun Liu,
• Hongxin Chai,
• Jiarong Li and
• Lamusi A

Beilstein J. Org. Chem. 2017, 13, 2603–2609, doi:10.3762/bjoc.13.257

• and deprotection steps. Then, with 10% Pd/C as catalyst, the 5,6-double bond of the macrolide was selectively reduced to afford 3'-O-ethyl-5,6-dihydrospinosyn J. In addition, the 3-O-ethyl-2,4-di-O-methylrhamnose is synthesized from rhamnose which is available commercially, while the D-forosamine and

• . Furthermore, this synthesis provides a chemical method to synthesize spinosyn analogues containing different substituents at C9-position and C17-position of the macrolide. Also, we developed an efficient synthesis of 3-O-ethyl-2,4-di-O-methylrhamnose from rhamnose in 4 steps, and this method can also be used

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

• origin and its chemical structure, this compound was named mycolactone. It is worth noting that mycolactone represented the first polyketide macrolide isolated from a mycobacterial species and was also the first example of a polyketide acting as the virulence factor of a human pathogen [34]. The purified

Total syntheses of the archazolids: an emerging class of novel anticancer drugs

• Stephan Scheeff and
• Dirk Menche

Beilstein J. Org. Chem. 2017, 13, 1085–1098, doi:10.3762/bjoc.13.108

• macrolide natural products, presumably due to conformational factors. In contrast, the Z,Z,E-triene system at northern part of the target molecule (i.e., C9 to C14) was stable, also in an acyclic state, presumably due to distortion of the conjugated system due to constraints exerted by the methyl groups at

• unambiguously confirming the stereochemistry of this macrolide [59]. Menche’s total synthesis of archazolid B One the methodological incentives of the synthetic campaign of the Menche group directed towards the archazolids were the further development and application of the Heck reaction in complex target

• by an intermolecular HWE reaction of 36 with 37 using the procedure evaluated above. Final stereoselective CBS reduction and global deprotection liberated archazolid B in 41% yield over 3 steps [42]. This accomplishment presented the second total synthesis of this macrolide while the first total

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

Beilstein J. Org. Chem. 2017, 13, 348–371, doi:10.3762/bjoc.13.39

• labeling at C-2, C-4, and C-10 of the macrolide ring. This result was consistent with incorporation of (2S)-methylmalonyl-CoA during the second, fifth, and sixth chain extension cycles, with inversion of configuration at the C-2 center as found for fatty acid biosynthesis (vide infra) [24]. However

• stage. This modification results in an experimentally tractable δ-lactone 9 instead of the 14-membered macrolide, 6-deoxyerythronolide B. Notably, the two methyl centers in the lactone have opposite configurations (for clarity, that at C-2 will be referred to as D-configured, and that at C-4 as L), and

Identification, synthesis and mass spectrometry of a macrolide from the African reed frog Hyperolius cinnamomeoventris

• Markus Menke,
• Pardha Saradhi Peram,
• Iris Starnberger,
• Walter Hödl,
• Gregory F.M. Jongsma,
• David C. Blackburn,
• Mark-Oliver Rödel,
• Miguel Vences and
• Stefan Schulz

Beilstein J. Org. Chem. 2016, 12, 2731–2738, doi:10.3762/bjoc.12.269

• , Institute of Zoology, 38106 Braunschweig, Germany 10.3762/bjoc.12.269 Abstract The contents of the gular glands of the male African reed frog Hyperolius cinnamomeoventris consist of a mixture of aliphatic macrolides and sesquiterpenes. While the known macrolide gephyromantolide A was readily identified

• in femoral glands of male mantellid frogs such as Spinomantis aglavei. The mass spectra of the synthesized macrolides as well as their rearranged isomers obtained during ring-closing metathesis showed that it is possible to assign the location of the double bond in an unsaturated macrolide on the

• Hyperolius cinnamomeoventris showed the presence of several unknown compounds, sesquiterpenes and macrolides (Figure 2). Gephyromantolide A (5), known from the mantellid frog Gephyromantis boulengeri [4], was readily identified. A second macrolide (A in Figure 2) showed a mass spectrum similar to that

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

• PKS module to make an alternative product is rare, the best-characterised example being the production of both the 12-membered macrolide methymycin and the 14-membered macrolide pikromycin from the same PKS [19], the smaller ring arising from use of an alternative start codon leading to a

Organic chemistry meets polymers, nanoscience, therapeutics and diagnostics

• Vincent M. Rotello

Beilstein J. Org. Chem. 2016, 12, 1638–1646, doi:10.3762/bjoc.12.161

• ". I kept my eye on the literature, however, and when Dave Williams published the "Central America" fragment of the related macrolide FK-506, I urged Harry to see if he could get some intermediate that I could use to demonstrate our methodology for tricarbonyl synthesis. Dave generously obliged by

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

• isoprenoid biosynthesis. The designated branching modules of lactone and glutarimide-producing PKS show similar designs: a branching domain (B or X), which is flanked by a KS and an ACP domain (Scheme 20b and c). In vitro reconstitution experiments with the branching module of the macrolide rhizoxin (130

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

• reported for aminoglycoside-modifying proteins [13], and alteration of the drug target, as can be found in macrolide-resistant bacteria that contain mutations in the bacterial ribosome [14]. Further mechanisms are an increased efflux [15] and a change in permeability of the cell wall [16][17]. Due to the