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Covering: up to 2014In this review we investigate the use of complex ester fragment couplings within natural product total synthesis campaigns. We first outline the different biosynthetic and chemical strategies for performing complex ester couplings and on this mechanistic background we then present and discuss a collection of successful examples...
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... mentioned in the introduction, many classes of metabolites contain ester functionalities. These range from the volatile ester odorants of the teaching laboratories, important neurotrans- mitters such as acetylcholine, lipids of all kinds, to complex terpenoids (taxol), polyketides (erythromycin) and cyclo- depsipeptides (FK228 and rapamycin, Fig. 1). In this section we will outline the enzymatic mechanisms employed during the biosyntheses of ester-containing metabolites and discuss the different activation strategies that nature has developed. The focus will remain on the complex secondary metabolites. This section will also include a short introduction to the logic of ...
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... amide bond formation. Several modications can then occur to the amino acid unit, giving rise to an enormous structural diversity from the shuffling of rela- tively few different types of enzymes ordered in a specic assembly line. Many natural product macrocyclic lactones are synthesized by PKS-NRPS hybrid assembly lines (e.g. rapamy- cin, Fig. 1). Throughout the biosynthesis a thioester bond links the growing linear molecule to the assembly line until the last unit releases the chain (Scheme ...
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... MA026. MA026 is a lipocyclodepsipeptide isolated from the fermentation broth of Pseudomonas sp. RtIB026 found in the digestive tract of the rainbow trout (Fig. 10). 142 It exhibits anti-hepatitis C virus (HCV) activity by means of suppressing HCV infection in host hepatocytes by inhibiting the entry process, with an IC 50 value of 4.68 mM. 143 The structure of MA026 was established in 2002 and was found to comprise a 25-membered cyclodepsipeptidic core, a chain peptide composed of six amino acid ...
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... is a lipodepsipeptide anti- biotic that belongs to the non-ribosomal peptide family and was isolated from the bacteria Streptomyces roseosporus, obtained from a soil sample from Mount Ararat in Turkey (Fig. 11). 144 The chemical structure of daptomycin was established in 1986 by Debono et al., 145 and was found to contain a 10-amino acid ring, a 3-amino acid side chain and a decanoyl lipid side chain at the ...
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... FK228. FK228, formerly known as FR-901228, (Fig. 12) is a bicyclic depsipeptide isolated in 1994 from the fermenta- tion broth of Chromobacterium violaceum. 147 The structural complexity of FK228 and its remarkable antitumor activity against a range of solid tumor cells immediately established it as a "hot target" for total synthesis. FK228 showed potent inhibitory activity against ...
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... in patients with neuroendocrine tumors. 148,149 The rst total synthesis and structural conrmation of this cyclodepsipeptide was disclosed in 1996 by Simon and co-workers. 150 Towards the rst total synthesis of FK228 Simon and co-workers employed the Mitsunobu macrolactonization conditions to construct the depsipeptidic ester bond, giving rise Fig. 11 The chemical structure of ...
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... 20 Ester bond formation conditions towards the synthesis of daptomycin. Fig. 12 The chemical structure of ...
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... (+)-Migrastatin. (+)-Migrastatin (Fig. 13) is a 14-membered ring macrolide isolated from two different strains of Streptomyces, sp. MK929-43F1 157 and NRRL 18993. 158 Migrastatin was found to inhibit anchorage-independent growth and migration of human tumor cells in vitro. 146,159 The absolute stereochemistry of this macrolide was deter- mined in 2002 160 and the rst total ...
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... (À)-Laulimalide. (À)-Laulimalide (Fig. 14) is a 20- membered marine macrolide isolated from two different marine sponges, the Indonesian Hyattella sp. 163 and the Caco- spongia mycojiensis 164 collected from Vanuatu. Initially, lauli- malide was found to exhibit potent cytotoxicity against a panel of drug-sensitive cancer cell lines 163,165 in the low nanomolar range. However, ...
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... Leucascandrolide A. Leucascandrolide A (Fig. 15) is an 18-membered marine macrolide isolated in 1996 from the sponge Leucascandra caveolata. 174 The natural product possesses a unique structure comprising two trisubstituted tetrahydropyran rings, with one of them having an appending oxazole-containing side chain. Leucascandrolide A exhibits antifungal activity and potent cytotoxicity ...
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... the Mitsunobu esterication method, resulting in inversion of the stereochemistry of the ester to the desired axial position. This coupling proceeded without any difficul- ties, using an excess of DEAD and PPh 3 , to afford ester 43 in excellent yield (90%). Scheme 25 Ester bond formation conditions towards the synthesis of (À)-laulimalide. Fig. 15 The chemical structure of leucascandrolide A. 624 | Nat. Prod. Rep., 2015, 32, 605-632 This journal is © The Royal Society of Chemistry 2015 4.5.2 Pochonin C. Pochonin C (Fig. 16) belongs to a family of closely-related resorcyclic macrolides, pochonins A-F, iso- lated in 2003 from the fermentation of Pochonia chlamydo- sporia. 177 From ...
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... ties, using an excess of DEAD and PPh 3 , to afford ester 43 in excellent yield (90%). Scheme 25 Ester bond formation conditions towards the synthesis of (À)-laulimalide. Fig. 15 The chemical structure of leucascandrolide A. 624 | Nat. Prod. Rep., 2015, 32, 605-632 This journal is © The Royal Society of Chemistry 2015 4.5.2 Pochonin C. Pochonin C (Fig. 16) belongs to a family of closely-related resorcyclic macrolides, pochonins A-F, iso- lated in 2003 from the fermentation of Pochonia chlamydo- sporia. 177 From these natural products, pochonin C stood out by exhibiting potent inhibitory activity in a cellular replica- tion assay against the herpes simplex virus (HSV). Pochonin C is also ...
Citations
... Moreover, tosyl groups are known to preferentially target and interact with the non-binding, crystallizable (Fc) domain of antibodies. [23] Therefore, we installed a tosyl leaving group available by linker 3 to the end of the PEGylated MagSiGlow analogs through esterification with EDC using a saturated solution of linker 3. [24] Esterification was monitored by zeta potential studies ( Figure S9) and we observed equally efficient coupling using anhydrous acetonitrile or aqueous buffers. This four-step synthesis resulted in a high recovery rate (~85 %) due to the strong retention of magnetic properties even in aqueous media (see Figure 3, G). ...
Multiplexed bead assays for solution‐phase biosensing often encounter cross‐over reactions during signal amplification steps, leading to unwanted false positive and high background signals. Current solutions involve complex custom‐designed and costly equipment, limiting their application in simple laboratory setup. In this study, we introduce a straightforward protocol to adapt a multiplexed single‐bead assay to standard fluorescence imaging plates, enabling the simultaneous analysis of thousands of reactions per plate. This approach focuses on the design and synthesis of bright fluorescent and magnetic microspheres (MagSiGlow) with multiple fluorescent wavelengths serving as unique detection markers. The imaging‐based, single‐bead assay, combined with a scripted algorithm, allows the detection, segmentation, and co‐localization on average of 7500 microspheres per field of view across five imaging channels in less than one second. We demonstrate the effectiveness of this method with remarkable sensitivity at low protein detection limits (100 pg/mL). This technique showed over 85 % reduction in signal cross‐over to the solution‐based method after the concurrent detection of tumor‐associated protein biomarkers. This approach holds the promise of substantially enhancing high throughput biosensing for multiple targets, seamlessly integrating with rapid image analysis algorithms.
... The intermediate can then couple with Rhod B to produce a fluorescent PCE-marker molecule by using ethylenediamine (EDA) as a linker molecule. The synthesis is carried out like shown in Figure 2 out in two steps, Rhod B (1) has a carboxyl group that can be activated with EDC and NHS to form a reactive NHS ester with Rhod B (2). 20 Analogously, the respective PCE (3) can be activated in parallel with EDC and NHS in order to be able to covalently bind with a primary amine of the EDA molecule (4) while still in the solution. The product (5) of this reaction step is a molecule in which the PCE is connected to the EDA by an amide bond. ...
Global efforts to minimise carbon dioxide emissions are also leading to attempts to use calcined clays (CC) as a partial substitute for cement in concrete. While the hydration mechanism of such CC blended cements is now well understood, the range of effective admixtures like polycarboxylate ethers (PCE) is limited. There are PCE types that promise relatively high effectiveness, but the mechanisms of action are not yet sufficiently understood. For a detailed understanding of the adsorption of such PCEs, spatially resolved studies of the binder were performed using a combination of fluorescence and scanning electron microscopy. In a comparison of two superplasticisers, the investigations have shown different sites of preferred adsorption in a CC blended system and the results can be correlated with flow tests and setting behaviour. The investigations have shown that a certain PCE type has a higher adsorption on CC and other components of a blended system in comparison to other types.
... The proposed synthetic approach is shown in Scheme 2. In brief, we propose the reaction of PEG 1 with S-Mmt mercapto acids 6 by the Steglich esterification method. This requires the use of N,N′-diisoproplylcarbodiimide (DΙC) and 4-(dimethylamino)pyridine (DMAP) as the carboxylic acid activating system (Scheme 2) [37,38] to initially afford the S-Mmt-mercaptoacylated poly(ethylene glycol)s 12 (abbreviated as di-S-Mmt-PEGdithiols hereafter). In this approach, the use of S-Mmt-protecting group during the esterification reaction has a double role, which is to (a) prevent oxidation of the thiol For the synthesis of α,ω-bis-mercaptoacyl poly(alkyl oxide)s, we considered the synthesis of two S-Mmt-mercaptoacids: (a) S-Mmt-2-mercaptopropionic acid (6a; R ′ = CH 3 ; r = 1) and (b) S-Mmt-3-mercaptopropionic acid (6b; R ′ = H; r = 2). ...
... The proposed synthetic approach is shown in Scheme 2. In brief, we propose the reaction of PEG 1 with S-Mmt mercapto acids 6 by the Steglich esterification method. This requires the use of N,N ′ -diisoproplylcarbodiimide (DIC) and 4-(dimethylamino)pyridine (DMAP) as the carboxylic acid activating system (Scheme 2) [37,38] to initially afford the S-Mmt-mercaptoacylated poly(ethylene glycol)s 12 (abbreviated as di-S-Mmt-PEG-dithiols hereafter). In this approach, the use of S-Mmt-protecting group during the esterification reaction has a double role, which is to (a) prevent oxidation of the thiol groups of mercapto acids to the corresponding disulfides and (b) prevent the formation of thioesters and/or thiolactones (which would be formed due to inter-molecular, and/or intra-molecular nucleophilic attack of the free thiol groups to the activated carboxylic acid groups) and/or polymerization processes (due to the formation of active thioester/thiolactone intermediates, along with the presence of free thiol groups) [39][40][41]. ...
With the aim to develop novel scaffolds for the sustained release of drugs, we initially developed an easy approach for the synthesis of α,ω-homobifunctional mercaptoacyl poly(alkyl oxide)s. This was based on the esterification of the terminal hydroxyl groups of poly(alkyl oxide)s with suitably S-4-methoxytrityl (Mmt)-protected mercapto acids, followed by the removal of the acid labile S-Mmt group. This method allowed for the efficient synthesis of the title compounds in high yield and purity, which were further used in the development of a thioether cross-linked liposome scaffold, by thia–Michael reaction of the terminal thiol groups with pre-formed nano-sized liposomes bearing maleimide groups on their surface. The reaction process was followed by 1H-NMR, using a Carr–Purcell–Meiboom–Gill (CPMG) relaxation dispersion NMR experiment (1H-NMR CPMG), which allowed for real-time monitoring and optimization of the reaction process. The thioether cross-linked liposomal scaffold that was synthesized was proven to preserve the nano-sized characteristics of the initial liposomes and allowed for the sustained release of calcein (which was used as a hydrophilic dye and a hydrophilic drug model), providing evidence for the efficient synthesis of a novel drug release scaffold consisting of nanoliposome building blocks.
... However, regarding the synthesis of imatinib, we were uncertain whether using a poorly nucleophilic aromatic amine would be equally successful, considering that competitive esterication reactions can be facilitated by common coupling reagents. [9][10][11][12][13][14][15] While numerous mechanochemical amide coupling protocols have been reported, 6,16-25 limited attention has been given to studying the chemoselectivity issues in these transformations. In particular, the amide bond formation in the presence of a free hydroxyl group in starting materials has not Scheme 1 Outline of the work. ...
... Initially, we expected that free hydroxyl of 1 could act as a competitive nucleophile, [9][10][11][12][13][14][15] thereby leading to the formation of ester by-products. However, we observed a variety of side processes, the prevalence of which was inuenced by the specic coupling conditions employed. ...
Despite considerable advancements in mechanochemical amide couplings, there is a paucity of studies addressing chemoselective issues in these transformations, such as the tolerance of unmasked hydroxyl groups. In view of the high practical significance of amide coupling reactions in the synthesis of active pharmaceutical ingredients (APIs), we aimed to investigate the tolerance of unprotected hydroxyls in carboxylic acids towards various reported mechanochemical amide coupling conditions. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) in combination with ethyl acetate as a liquid-assisted grinding (LAG) additive was revealed as the most selective amide coupling system that delivers 76–94% yields of amides from a range of hydroxycarboxylic acids, including N-Boc-protected amino acids serine and tyrosine. The EDC-mediated amide coupling protocol was employed in the synthesis of imatinib, an anticancer drug included in the World Health Organization's List of Essential Medicines. The target API was synthesized in an overall 86% yield and 99% HPLC purity through a two-step mechanochemical C–N bond assembling reaction sequence starting from 4-(hydroxymethyl)benzoic acid.
... So far, many methods have been developed for the synthesis of esters from carboxylic acids employing various chemical reagents, catalysts and reaction media, and methods [10,11]. ...
... Acid halides constitute useful intermediates in ester synthesis due to their full conversion and high yields [10,13]. Nonetheless, the procedure involves two distinct reaction steps: the formation of the chloride and its subsequent reaction with alcohol in a basic medium. ...
Ester compounds, widely found in pharmaceutical and natural products, play a crucial role in organic synthesis, prompting the development of numerous methods for their synthesis. An important chemical approach in synthesizing esters from carboxylic acids involves the activation of the carboxyl function, requiring the conversion of the hydroxyl group into a suitable leaving group. This paper presents the findings of our investigations into an efficient method for producing esters from carboxylic acids and alcohols, using the Lewis acid titanium tetrachloride. Titanium tetrachloride has proven highly effective as a coupling reagent for the one-pot formation of esters from carboxylic acids and alcohols operating under mild and neutral conditions. Notably, the reaction eliminates the need for bases, yielding carboxylic esters in high purity and yields. The method is efficient, even with long-chain carboxylic acids, and operates well with primary alcohols in dichloromethane. Steric hindrance, potentially present in carboxylic acids, has a moderate effect on the reaction. Alcohol substrates that easily form stable carbocations require, instead, the use of non-polar solvents like hexane for the reaction.
... DMAP acts as an active reagent to transfer the acyl group. Without DMAP or active reagents for acyl transfer, irreversible reactions occur generating side products i.e., N-acyl urea or possible anhydrides leading towards poor or diminished yields of desired products (Scheme 2) [12]. ...
The exploitation of natural products and their analogues in the field of pharmacology has been regarded as of great importance. It can be attributed to the fact that these scaffolds exhibit diverse chemical properties, distinct biological activities and zenith specificity in their biochemical processes, enabling them to act as favorable structures for lead compounds. The synthesis of natural products has been a crafty and hard-to-achieve task. Steglich esterification reaction has played a significant role in that area. It is a mild and efficient technique for constructing ester linkages. This technique involves the establishment of ester moiety via a carbodiimide-based condensation of a carboxylic acid with an alcohol, thiol or an amine catalyzed by dimethyl aminopyridine (DMAP). Specifically, labile reagents with multiple reactive sites are esterified efficiently with the classical and modified Steglich esterification conditions, which accounts for their synthetic utility. This review encloses the performance of the Steglich esterification reaction in forging the ester linkage for executing the total synthesis of natural products and their derivatives since 2018.
... To get methoxybezamide−NHS ester (MBA−NHS), methoxybenzoic acid was activated using N-hydroxysuccinimide (NHS) and dicyclohexylcarbodiimide (DCC). 51,52 Finally, the PLG− MBA was synthesized by reacting the amino group of PLG with activated MBA−NHS. The confirmation of PLG−MBA conjugation was done through 1 H NMR analysis, where a characteristic peak at 7.73 ppm was due to the formation of an amide bond between MBA−NHS and PLG (Figure 1b,c). ...
... Countless methods can be found in the literature to generate the macrolactone framework. [13][14][15][16][17][18][19][20][21] To cite but a few examples , macrocyclizations involving ring-closing metathesis , intramolecular cross-coupling reactions, and olefinations have been devised. In this short review, we will focus on the advances made to forge the lactone motif for macrolactones and macrodiolides over the past twenty years. ...
The study of macrolactonization processes has been a steady endeavor for synthetic chemists to access macrocycles that are fundamental in the development of numerous high-added-value compounds, notably drugs and fragrances. This field of research is essential as macrolactonizations usually take place at the end of manifold syntheses and chemists need reliable, efficient, and versatile tools to avoid unpredictable results that would lead them to completely redesign their synthetic plan. Here, we highlight the recent methods reported to achieve macrolactonizations towards the formation of both macrolactones and macrodiolides, which feature either Lewis acids, transition metals or organic molecules as activating agents.
1 Introduction
2 Stoichiometric Carboxylic Acid Activation
3 Lewis Acid Catalyzed Reaction
4 C–H Activation
5 Ring-Expansion Strategy
6 Chemoenzymatic Synthesis
7 Other Macrolactonization Variants
8 Conclusion and Outlook
... Furthermore, these spacers possess carboxyl groups that can be coupled to the PVA hydroxyl groups, resulting in an ester bond and leading to self-particle formation. This can occur during the coupling reaction between the modified PVA and both MMC and MNPs using 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) as a crosslinking agent [22]. ...
... The carboxyl groups of the GQDs were selectively modified with PXZ-OH via well-established estercoupling chemistry. [23] The formation of PXZ-GQD, in which the PXZ tether and GQD backbone were ester-linked, was confirmed by FT-IR spectroscopy ( Figure S22, Supporting Information). In the PXZ-GQD, the characteristic signals for the ester group appeared at 1656 cm −1 (C≐O), 1255 cm −1 (C−C−O), and 1093 cm −1 (O−C−C), along with peaks of the C−N−C unit of the PXZ ring at 1437 cm −1 and 1383 cm −1 . ...
In the quest for materials sustainability for grid‐scale applications, graphene quantum dot (GQD), prepared via eco‐efficient processes, is one of the promising graphitic‐organic matters that have the potential to provide greener solutions for replacing metal‐based battery electrodes. However, the utilization of GQDs as electroactive materials has been limited; their redox behaviors associated with the electronic bandgap property from the sp² carbon subdomains, surrounded by functional groups, are yet to be understood. Here, the experimental realization of a subdomained GQD‐based anode with stable cyclability over 1000 cycles, combined with theoretical calculations, enables a better understanding of the decisive impact of controlled redox site distributions on battery performance. The GQDs are further employed in cathode as a platform for full utilization of inherent electrochemical activity of bio‐inspired redox‐active organic motifs, phenoxazine. Using the GQD‐derived anode and cathode, an all‐GQD battery achieves a high energy density of 290 Wh kgcathode⁻¹ (160 Wh kgcathode+anode⁻¹), demonstrating an effective way to improve reaction reversibility and energy density of sustainable, metal‐free batteries.
