Macrolactonization Reaction Research Articles

Synthesis of the Phormidolide A Macrocycle Supports the Proposed Configurational Reassignment.

We describe the successful synthesis of the phormidolide A macrocycle as a crucial step toward its total synthesis and configurational assignment. Exhaustive exploration of macrocyclization strategies revealed the detrimental effects of a bulky protecting group on the C17 hydroxyl function, leading to the successful use of a C17 p-methoxybenzyloxymethyl (PMBM) ether in the macrolactonization reaction. Further elaboration of the macrocycle with a truncated C18-C23 side chain afforded an advanced C1-C23 fragment of phormidolide A. Detailed comparison of spectroscopic data with those of phormidolide A supports the proposed configurational reassignment.

Macrolactonization Reactions Driven by a Pentafluorobenzoyl Group*.

Macrolactones constitute a privileged class of natural and synthetic products with a broad range of applications in the fine chemicals and pharmaceutical industry. Despite all the progress made towards their synthesis, notably from seco-acids, a macrolactonization promoter system that is effective, selective, flexible, readily available, and, insofar as possible, compatible with manifold functional groups is still lacking. Herein, we describe a strategy that relies on the formation of a mixed anhydride incorporating a pentafluorophenyl group which, due to its high electronic activation enables a convenient access to macrolactones, macrodiolides and esters with a broad versatility. Kinetic studies and DFT computations were performed to rationalize the reactivity of the pentafluorophenyl group in macrolactonization reactions.

Macrolactonization Reactions Driven by a Pentafluorobenzoyl Group**

AbstractMacrolactones constitute a privileged class of natural and synthetic products with a broad range of applications in the fine chemicals and pharmaceutical industry. Despite all the progress made towards their synthesis, notably from seco‐acids, a macrolactonization promoter system that is effective, selective, flexible, readily available, and, insofar as possible, compatible with manifold functional groups is still lacking. Herein, we describe a strategy that relies on the formation of a mixed anhydride incorporating a pentafluorophenyl group which, due to its high electronic activation enables a convenient access to macrolactones, macrodiolides and esters with a broad versatility. Kinetic studies and DFT computations were performed to rationalize the reactivity of the pentafluorophenyl group in macrolactonization reactions.

Asymmetric total syntheses of naturally occurring α,β-enone-containing RALs, L-783290 and L-783277 through intramolecular base-mediated macrolactonization reaction.

Asymmetric total synthesis of two naturally occurring α,β-enone containing RALs, L-783290 and L-783277 is described in this article. An E-selective Horner-Wadsworth-Emmons (HWE) olefination was used as a key reaction to construct the C7'-C8' olefinic unsaturation in L-783290. An enantiopure alkyne addition to the aldehyde followed by Z-selective partial reduction was employed to construct the C7'-C8' olefinic unsaturation in L-783277. Biomimetic lactonization reaction was used to construct the macrolactone core in both the target molecules.

Sequence-Controlled Polymers Through Entropy-Driven Ring-Opening Metathesis Polymerization: Theory, Molecular Weight Control, and Monomer Design.

The bulk properties of a copolymer are directly affected by monomer sequence, yet efficient, scalable, and controllable syntheses of sequenced copolymers remain a defining challenge in polymer science. We have previously demonstrated, using polymers prepared by a step-growth synthesis, that hydrolytic degradation of poly(lactic- co-glycolic acid)s is dramatically affected by sequence. While much was learned, the step-growth mechanism gave no molecular weight control, unpredictable yields, and meager scalability. Herein, we describe the synthesis of closely related sequenced polyesters prepared by entropy-driven ring-opening metathesis polymerization (ED-ROMP) of strainless macromonomers with imbedded monomer sequences of lactic, glycolic, 6-hydroxy hexanoic, and syringic acids. The incorporation of ethylene glycol and metathesis linkers facilitated synthesis and provided the olefin functionality needed for ED-ROMP. Ring-closing to prepare the cyclic macromonomers was demonstrated using both ring-closing metathesis and macrolactonization reactions. Polymerization produced macromolecules with controlled molecular weights on a multigram scale. To further enhance molecular weight control, the macromonomers were prepared with cis-olefins in the metathesis-active segment. Under these selectivity-enhanced (SEED-ROMP) conditions, first-order kinetics and narrow dispersities were observed and the effect of catalyst initiation rate on the polymerization was investigated. Enhanced living character was further demonstrated through the preparation of block copolymers. Computational analysis suggested that the enhanced polymerization kinetics were due to the cis-macrocyclic olefin being less flexible and having a larger population of metathesis-reactive conformers. Although used for polyesters in this investigation, SEED-ROMP represents a general method for incorporation of sequenced segments into molecular weight-controlled polymers.

Total Synthesis of (−)-Marinisporolide C

The first total synthesis of (-)-marinisporolide C is described, which establishes unequivocally the relative and absolute configuration of this oxopolyene macrolide. Key features of this synthesis include a series of highly stereoselective aldol reactions followed by directed reductions to build the polyol domain, a Stille cross-coupling reaction to assemble the polyene, and an intramolecular Horner-Wadsworth-Emmons olefination to forge the macrocyclic ring. Despite the initial approach to marinisporolide A using a Yamaguchi macrolactonization reaction that was unsuccessful due to steric hindrance of the oxygen at the C33 position, we were able to prepare a known derivative of marinisporolide A and consequently confirm its stereochemical assignment.

Regio- and Stereoselective Homologation of 1,2-Bis(Boronic Esters): Stereocontrolled Synthesis of 1,3-Diols and Sch 725674.

1,2‐Bis(boronic esters), derived from the enantioselective diboration of terminal alkenes, can be selectively homologated at the primary boronic ester by using enantioenriched primary/secondary lithiated carbamates or benzoates to give 1,3‐bis(boronic esters), which can be subsequently oxidized to the corresponding secondary‐secondary and secondary‐tertiary 1,3‐diols with full stereocontrol. The transformation was applied to a concise total synthesis of the 14‐membered macrolactone, Sch 725674. The nine‐step synthetic route also features a novel desymmetrizing enantioselective diboration of a divinyl carbinol derivative and high‐yielding late‐stage cross‐metathesis and Yamaguchi macrolactonization reactions.

Regio‐ and Stereoselective Homologation of 1,2‐Bis(Boronic Esters): Stereocontrolled Synthesis of 1,3‐Diols and Sch 725674

Abstract1,2‐Bis(boronic esters), derived from the enantioselective diboration of terminal alkenes, can be selectively homologated at the primary boronic ester by using enantioenriched primary/secondary lithiated carbamates or benzoates to give 1,3‐bis(boronic esters), which can be subsequently oxidized to the corresponding secondary‐secondary and secondary‐tertiary 1,3‐diols with full stereocontrol. The transformation was applied to a concise total synthesis of the 14‐membered macrolactone, Sch 725674. The nine‐step synthetic route also features a novel desymmetrizing enantioselective diboration of a divinyl carbinol derivative and high‐yielding late‐stage cross‐metathesis and Yamaguchi macrolactonization reactions.

A Lanthanide(III) Triflate Mediated Macrolactonization/Solid-Phase Synthesis Approach for Depsipeptide Synthesis.

The effect of dysprosium(III) triflate on macrolactonization reactions to form depsipeptides using MNBA (Shiina's reagent) is reported. Improved yields were obtained for the formation of 16-membered depsipeptides using lanthanide triflate additives. The use of a macrocyclization strategy permits the use of a semiautomated solid-phase synthesis approach for the rapid synthesis of analogues of the antibacterial A54556 acyldepsipeptides in only two physical operations, requiring only final product purification after cyclization.

ChemInform Abstract: Stereoselective Total Synthesis of Marine Cyclodepsipeptide Calcaripeptides A—C.

ChemInformVolume 46, Issue 15 Natural Products ChemInform Abstract: Stereoselective Total Synthesis of Marine Cyclodepsipeptide Calcaripeptides A—C. Sayantan Das, Sayantan Das Dep. Org. Chem., Indian Assoc. Cultiv. Sci., Kolkata 700 032, IndiaSearch for more papers by this authorRajib Kumar Goswami, Rajib Kumar Goswami Dep. Org. Chem., Indian Assoc. Cultiv. Sci., Kolkata 700 032, IndiaSearch for more papers by this author Sayantan Das, Sayantan Das Dep. Org. Chem., Indian Assoc. Cultiv. Sci., Kolkata 700 032, IndiaSearch for more papers by this authorRajib Kumar Goswami, Rajib Kumar Goswami Dep. Org. Chem., Indian Assoc. Cultiv. Sci., Kolkata 700 032, IndiaSearch for more papers by this author First published: 26 March 2015 https://doi.org/10.1002/chin.201515272Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume46, Issue15April, 2015 RelatedInformation

Stereoselective total synthesis of marine cyclodepsipeptide calcaripeptides A-C.

The first stereoselective total syntheses of marine cyclodepsipeptides, calcaripeptides A-C, have been accomplished. Emphasis was given particularly in identification of an efficient strategy for the macrocyclization. The notable features of our synthesis include Evans alkylation, Crimmins syn-aldol, Crimmins acetate aldol, Wittig olefination, and Shiina macrolactonization reactions. An anomaly in the (1)H NMR of the proposed calcaripeptide B has been amended during this synthetic study.

ChemInform Abstract: Asymmetric Synthesis of Naturally Occurring Nonenolide Xyolide Through Cross Metathesis and Macrolactonization Reaction.

AbstractThe asymmetric synthesis of xyolide (VI) from nonanal with an overall yield of 5% is reported.

Asymmetric synthesis of naturally occurring (−)-seimatopolides A and B

Asymmetric total synthesis of polyhydroxylated naturally occurring nonenolide seimatopolide A (3S,6S,7S,9R) and seimatopolide B (3S,6R,9R) is described in this article. An E-selective cross metathesis (CM) reaction between two suitable fragments followed by macrolactonization reaction is the main highlight of our synthesis for the two natural products. The fragment containing 6S,7S,9R stereocenters for seimatopolide A has been synthesized from l-tartaric acid as a chiral pool starting material, by employing (R)-CBS-mediated stereoselective keto reduction reaction. Another fragment, which is common for both the molecules, containing the 3S stereocenter was prepared by ME-DKR (metal enzyme combined dynamic kinetic resolution) method. The fragment having 6R,9R stereocenters for seimatopolide B has been prepared from n-decanal by adopting (R)-CBS-mediated keto reduction and Brown asymmetric allylation reaction.

Asymmetric synthesis of naturally occurring nonenolide xyolide through cross metathesis and macrolactonization reaction

Asymmetric total synthesis of xyolide, a small ring macrolide is presented in this article. The synthesis is achieved through an ‘E’ selective cross metathesis (CM) reaction between two appropriate fragments followed by lactonization by Shiina method. One of the fragments containing 7S,8S,9R stereocenters of xyolide is accessed from n-nonanal by adopting an organocatalytic asymmetric α-aminooxylation, Z-selective Ando olefination, and substrate directed dihydroxylation reaction. The other fragments containing 4S stereocenter was prepared by ME-DKR (metal enzyme combined dynamic kinetic resolution) method.

Asymmetric total synthesis of paecilomycin E, 10'-epi-paecilomycin E and 6'-epi-cochliomycin C.

The asymmetric total syntheses of naturally occurring resorcylic acid lactone paecilomycin E and two of its structural congeners have been reported in this article. The major highlight of the synthetic venture is the application of the late stage Mitsunobu macrolactonization method (as it is difficult to achieve the desired products through the standard carboxyl activation method) of a properly functionalized seco-acid. The macrolactonization precursor was synthesized by applying an "E"-selective Julia-Kocienski olefination of a highly functionalized aromatic aldehyde and a sulphone, which constitutes all the stereocenters (C4', C5', C6' and C10'; 3S,7R,8R,9S) in the target molecule.

Cytochrome P450-mediated hydroxylation is required for polyketide macrolactonization in stambomycin biosynthesis

Many polyketide antibiotics contain macrolactones that arise from polyketide synthase chain release via thioesterase (TE) domain-catalyzed macrolactonization. The hydroxyl groups utilized in such macrolactonization reactions typically derive from reduction of β-ketothioester intermediates in polyketide chain assembly. The stambomycins are a group of novel macrolide antibiotics with promising anticancer activity that we recently discovered via rational activation of a silent polyketide biosynthetic gene cluster in Streptomyces ambofaciens. Here we report that the hydroxyl group utilized for formation of the macrolactone in the stambomycins is derived from cytochrome P450-catalyzed hydroxylation of the polyketide chain rather than keto reduction during chain assembly. This is a novel mechanism for macrolactone formation in polyketide antibiotic biosynthesis.

Asymmetric total synthesis of 5′-epi-cochliomycin C

Asymmetric total synthesis of one of the stereoisomers of naturally occurring chlorine containing 14-membered ring macrolide cochliomycin-F (5′-epi) has been described in this article. The main highlight of the presented synthetic strategy involves a highly regioselective chlorination and Julia–Kocienski olefination with a highly substituted aromatic chloro-aldehyde to create the required E-olefinic unsaturation in the target molecule. Mitsunobu macrolactonization reaction at the late stage enables us to synthesize the target molecule.

Total synthesis of (29S,37S)-isomer of malevamide E, a potent ion-channel inhibitor

The first total synthesis of (29S,37S)-malevamide E (1), a potent ion channel inhibitor, has been achieved in a convergent fashion involving Julia-Kocienski olefination, Urpi acetal aldol and Shiina macrolactonization reactions as the key steps. The strategy developed herein is amenable for the synthesis of the other possible isomers in search for the correct stereoisomer of the naturally occurring molecule.

Study Toward the Total Synthesis of Pyrenophorin

Macrodiolides are macrocyclic compounds containing two ester groups in a cyclic chain. Of this class of compounds, Pyrenophorin ( 1 ) shows antifungal activity, and is produced from the pathogenic fungus Pyrenophora avenae. As this substance, derived from nature, is isolated in small quantities, an asymmetric synthesis using a simple and efficient methodology would be of great interest. The proposed synthetic route starts with the protection of propargyl alcohol 3 using DHP and feldspar as catalyst. Compound 5 obtained in this reaction was then subjected to acid-base reaction between the acetylenic proton and 1 eq. n-BuLi, leading to formation of the acetylide 5A . The 1,2- addition reaction between 5A and g -valerolactone ( 6 ) leads to the formation of alkinone 7 in 67% yield. Subsequently, compound 7 was subjected to a ketalization reaction using the same feldspar catalyst. Ketal 8 was formed under concomitant removal of the THP group. The product of this reaction ( 8 ) was then submitted to a reduction reaction of the triple bond to form olefin 9 with E configuration. Currently, the conditions for obtaining 10 by oxidation using Jones reagent, are being optimized. Compound 10 , obtained as described, is being subjected to a macrolactonization reaction. Various conditions including the use of enzymes are being studied. In addition, a study involving the enantioselective synthesis of (R,R)-(-)-pyrenophorin, using enzymatic kinetic resolution of the racemic mixture of compound 8 , is in progress in the group

Synthesis of myxobacteria metabolites

Myxobacteria are an excellent source of novel secondary metabolites with a range of biological activities. This review details the synthesis of several examples of these natural products. The total synthesis of all the members of the crocacin family is presented where the stereochemistry of the stereotetrad was set via a tin-mediated syn-aldol reaction followed by selective anti-reduction. The other key step in the route to crocacins A, B, and D was the introduction of the enamide functionality by acylation of an enecarbamate. A formal synthesis of apicularen A is also discussed, which involved a base-induced macrolactonization reaction and a transannular oxy-Michael cyclization to secure the tetrahydropyran ring. Finally, the total synthesis of deshydroxyajudazol B is summarized. This route details a modified approach to the 2,4-disubstituted oxazole, and a Diels–Alder reaction followed by aromatization was utilized to form the isochromanone moiety. A highly efficient Sonogashira coupling followed by partial reduction then gave deshydroxyajudazol B.