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

• thioester 64 on the ACP domain. Subsequent carbon chain extension and macrolactonization catalyzed by two PKS modules, TylGIV and TylGV, are pivotal enzymatic transformations for the chemo-enzymatic total synthesis of 4. TylGIV catalyzes the carbon chain extension reaction using a methylmalonyl-CoA and the

• ACP domain and regioselective macrolactonization to furnish the 16-membered tylactone (4). The research group led by Sherman accomplished the efficient chemo-enzymatic total synthesis of tylactone (4) and a series of M-4365 (juvenimicin) by merging consecutive enzymatic transformations by JuvEIV and

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

• type B streptogramin variants [41], including pristinamycin IE (8), which belongs to the class of depsipeptide antibiotics. Similarly, the linear peptide-SNAC was prepared through the SPPS method on 2-chlorotrityl resin, and macrolactonization was catalyzed by SnbDE TE, a thioesterase from

• macrolactonization, leading to the formation of tylactone (39) in 69% yield. Furthermore, the Streptomyces strain S. venezuelae DHS316 [76] performed an in vivo glycosylation resulting in M-4365 G1 (50) in 15 linear steps and 4.6% overall yield from commercial resources. With regio- and stereoselective C–H

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

• . An o-phenolic coupling between two units of tyrosine furnishes the intermediate Int-1, which by deamination, selective reduction of one of the carboxylate groups, macrolactonization, and subsequent structural modifications would lead to the aforementioned combretastatins D (Scheme 1). The second

• would give compounds 12 and 13. A coupling reaction would give the corresponding diaryl ether Int-2, in a similar way to that suggested by Pettit, which could be selectively reduced to afford the corresponding seco-acid (intermediates Int-3 and Int-4). Subsequent macrolactonization would give the

• for synthesis. In general, the synthesis of these macrocyclic compounds can be accomplished by using two distinct disconnections (Scheme 3): one concerns the formation of the macrocycle through macrolactonization reaction from the former seco-acid formed from the Ar–O–Ar coupling from the aryl donor

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

• dimerization/macrolactonization reaction for the synthesis of cyanolide A. Hoye and Hu’s synthesis of (−)-dactyloide by intramolecular Sakurai cyclization. Minehan and co-workers’ strategy for the synthesis of THPs 157. Yu and co-workers’ allylic transfer strategy for the construction of tetrahydropyran 161

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

• complexity, by essentially using a Ru-catalyzed alkene–alkyne (Ru-AA) coupling reaction and a macrolactonization step (Scheme 8). In this carefully designed total synthesis, after applying a Marshall coupling reaction aimed at installing a propargyl group into the initial acetylene component, an enyne

Recyclable hypervalent-iodine-mediated solid-phase peptide synthesis and cyclic peptide synthesis

• Dan Liu,
• Ya-Li Guo,
• Jin Qu and
• Chi Zhang

Beilstein J. Org. Chem. 2018, 14, 1112–1119, doi:10.3762/bjoc.14.97

• mediated by hypervalent iodine(III) reagents in recent years. In 2012, for the first time, we reported that the hypervalent iodine(III) reagent iodosodilactone (Figure 1) can serve as a condensing reagent to promote esterification, macrolactonization, amidation and peptide coupling reactions in the

Recent developments in the asymmetric Reformatsky-type reaction

• Hélène Pellissier

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

• previously reported syntheses by the fact that it included for the first time as key step a totally diastereoselective chromium-mediated macrolactonization. The same year, Schulze et al. reported the synthesis of chiral β-hydroxy-α-methyl-δ-trichloromethyl-δ-valerolactone (39) through a diastereoselective Sm

Intramolecular glycosylation

• Xiao G. Jia and
• Alexei V. Demchenko

Beilstein J. Org. Chem. 2017, 13, 2028–2048, doi:10.3762/bjoc.13.201

• efficiency of macrocyclization. The macrolactonization using the phthaloyl group clamp was accomplished using DCC and DMAP in refluxing 1,2-dichloroethane. A fairly high dilution (0.04 M) allowed to achieve the formation of the cyclic ester in 79% yield. This impressive yield was explained by the ability of

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

• principal approaches have been used to establish the 12-membered macrolactone ring, namely (1) ring-closure by macrolactonization, the approach followed by Kishi, Negishi and Aggarwal, or (2) ring-closing olefin metathesis (RCM) to form the C8–C9 double bond, which is part of Burkart’s and Altmann’s

• mycolactone core structure is depicted in Scheme 1. It relied on two consecutive Negishi cross-coupling reactions [124] to construct the linear C1–C20 fragment, which was to be cyclized by macrolactonization [39]. Vinyl iodide 19, corresponding to the C14–C20 part of the core extension, was synthesized from

• secondary TES and the primary TBS ether protecting groups was followed by selective oxidation of the ensuing primary alcohol to deliver seco acid 27. The crucial macrolactonization was performed under Yamaguchi conditions [135] in 70% yield and subsequent cleavage of the secondary TBS ether under mildly

A new member of the fusaricidin family – structure elucidation and synthesis of fusaricidin E

• Marcel Reimann,
• Louis P. Sandjo,
• Luis Antelo,
• Eckhard Thines,
• Isabella Siepe and
• Till Opatz

Beilstein J. Org. Chem. 2017, 13, 1430–1438, doi:10.3762/bjoc.13.140

• natural fusaricidin by the Jolliffe group employed a ring closure via a lactonization in solution and subsequent attachment of the side chain to the cyclized depsipeptide [10]. Since the macrolactonization approach suffered from diastereoselectivity issues and low yield, it was decided to perform an on

• macrolactonization suggested that a partial loss of stereochemical integrity had taken place during either cyclization or esterification [11]. The site of epimerization could not be determined with certainty, but most likely, the D-Ala residue was affected. As the assumed diastereomers could not be observed or

An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydrate-derived building blocks

• Sushil K. Maurya and
• Rohit Rana

Beilstein J. Org. Chem. 2017, 13, 1106–1118, doi:10.3762/bjoc.13.110

• the synthesis. The cyclization of the linear precursor is usually achieved by utilizing various ring-closing reactions such as Diels–Alder reactions, [15] aldol reactions, [16] copper-catalyzed azide–alkyne cycloaddition, [17][18] macrolactonization, macrolactamizations, Staudinger ligation or

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

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

• positions in the polyketide chains. Building of the polyketide core is typically terminated by a thioesterase (TE) domain situated at the end of the final PKS multienzyme, which releases the product by hydrolysis or more usually macrolactonization, using an internal hydroxy nucleophile. This PKS-free

A carbohydrate approach for the formal total synthesis of (−)-aspergillide C

• Pabbaraja Srihari,
• Namballa Hari Krishna,
• Ydhyam Sridhar and
• Ahmed Kamal

Beilstein J. Org. Chem. 2014, 10, 3122–3126, doi:10.3762/bjoc.10.329

• nitrile functionality was hydrolysed with 8 N NaOH in ethanol to yield the seco acid 4. The seco acid 4 was already utilized for the total synthesis of (−)-aspergillide C through macrolactonization and TBS deprotection as reported earlier by Kuwahara (Table 1) [23]. Thus, by synthesizing 4, we have

Sacrolide A, a new antimicrobial and cytotoxic oxylipin macrolide from the edible cyanobacterium Aphanothece sacrum

• Naoya Oku,
• Miyako Matsumoto,
• Kohsuke Yonejima,
• Keijiroh Tansei and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2014, 10, 1808–1816, doi:10.3762/bjoc.10.190

• should be routed through α-linolenic acid-derived allene oxide (Scheme 3) [16]. The addition of H2O to this intermediate gives α,β-unsaturated-γ-ketol, which accepts further oxidation at the α'-position, and macrolactonization of the resulting α',γ-ketodiol would yield 1. Similar, but rather simpler

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

Bidirectional cross metathesis and ring-closing metathesis/ring opening of a C₂-symmetric building block: a strategy for the synthesis of decanolide natural products

• Bernd Schmidt and
• Oliver Kunz

Beilstein J. Org. Chem. 2013, 9, 2544–2555, doi:10.3762/bjoc.9.289

• carboxylic acid and (iii) a Ru–lipase-catalyzed dynamic kinetic resolution to establish the desired configuration at C9. Ring closure was accomplished by macrolactonization. Curvulide A was synthesized from stagonolide E through Sharpless epoxidation. Keywords: dienes; enzyme catalysis; lactones; metathesis

• planned to use a macrolactonization of precursor 7 as the cyclization step. For the synthesis of 7, a cross metathesis of 1 (or a protected derivative) with methyl vinyl ketone (8) was envisaged as the first step, followed by an esterification of the more distant OH group with vinylacetic acid (9). This

• RCM/base-induced ring-opening sequence. Unfortunately, the expected macrolactonization precursor 19 was not obtained, but an inseparable mixture of products. To access the intended substrate for the resolution, secondary alcohol 19, we investigated an inverted sequence of steps: ketone 14 was first

A macrolactonization approach to the total synthesis of the antimicrobial cyclic depsipeptide LI-F04a and diastereoisomeric analogues

• James R. Cochrane,
• Dong Hee Yoon,
• Christopher S. P. McErlean and
• Katrina A. Jolliffe

Beilstein J. Org. Chem. 2012, 8, 1344–1351, doi:10.3762/bjoc.8.154

• -F04a was synthesised by using a modified Yamaguchi macrolactonization approach. Alternative methods of macrolactonization (e.g., Corey–Nicolaou) resulted in significant epimerization of the C-terminal amino acid during the cyclization reaction. The D-stereochemistry of the alanine residue in the

• naturally occurring cyclic peptide may be required for the antifungal activity of this natural product. Keywords: antifungal; cyclic depsipeptide; epimerization; lipopeptide; macrolactonization; peptides; Introduction The LI-F or fusaricidin class of cyclic depsipeptides are produced by a number of

• epimers (Scheme 1). While macrocyclization to give the core 2 could be performed at any of the amide or ester bonds [10], we chose to use a macrolactonization approach to enable ready access to analogues of the LI-F04a core through straightforward Fmoc solid-phase peptide synthesis of the linear