A rapid formal synthesis of the macrolide (−)-A26771B

(−)-A26771B, a novel 16-membered macrolide with antibiotic activity, has been formally synthesized. In the synthesis ruthenium catalyzed ring-closing olefin metathesis (RCM) was used as a key reaction to construct the lactone ring.     

Total synthesis of 10-deoxymethynolide and narbonolide

A flexible and convenient approach was developed for the synthesis of 10-deoxymethynolide (1) and narbonolide (2), which are aglycones of the methymycin and the pikromycin families of macrolide antibiotics. These lactones are produced by pikromycin polyketide synthase from Streptomyces venezuelae. Polyketide lactones, 10-deoxymethynolide and narbonolide, which contain 12- and 14-membered rings, respectively, were synthesized efficiently. These target lactones were retrosynthetically divided into three parts and assembled by using an asymmetric aldol reaction, the Yamaguchi esterification, and ring-closing metathesis. The ring-closing metathesis reaction catalyzed by the second-generation Grubbs catalyst is particularly efficient in preparing these macrocyclic polyketide lactones.     

Asymmetric total synthesis of 5′-epi-paecilomycin-F

The asymmetric total synthesis of one of the stereoisomers of the naturally occurring 14-membered ring macrolide paecilomycin-F (5′-epi) has been reported in this article. The main highlight of the synthetic strategy involves the successful application of a ring closing metathesis (RCM) reaction at a late stage. Asymmetric Keck allylation, Sharpless asymmetric dihydroxylation, and Mitsunobu esterification have also been used successfully for the total synthesis of 5′-epi-paecilomycin-F.     

Total synthesis of amphidinolide Y by formation of trisubstituted (E)-double bond via ring-closing metathesis of densely functionalized alkenes

Amphidinolide Y, a 17-membered cytotoxic macrolide isolated from marine dinoflagellates, has been synthesized via ring-closing metathesis to assemble the congested trisubstituted (E)-double bond. The seco precursor was prepared from readily available chiral synthons with the tetrahydrofuran ring formed via 5-endo epoxide ring-opening cyclization. It was found that the C6-keto seco substrate showed higher reactivity toward Grubbs' second generation catalyst while Schrock's Mo catalyst was completely inactive for formation of the macrocycle.     

Biosynthesis of the 17-membered carbocyclic ring of lankacidin antibiotics

A mechanism involving contraction of an 18-membered polyketide ring was proposed for the biosynthesis of the 17-membered carbocyclic ring of lankacidin antibiotics based on the feeding experiments of deuterated glycine and ²H-NMR spectroscopy.     

Total synthesis of neomethymycin and novamethymycin

Total synthesis of neomethymycin and novamethymycin has been achieved. These two macrolides contains 12-membered macrolactones as aglycones and belong to the methymycin family of antibiotics, which appears in the pikromycin biosynthetic pathway. The segments in the 12-membered macrolactone that are responsible for causing structural difference in neomethymycin and novamethymycin were synthesized by starting with methyl d-(+)-lactate and d-glucose, for neomethynolide, and for novamethynolide, respectively. The key steps in synthesis of neomethynolide and novamethynolide, which are aglycones for neomethymycin and novamethymycin, respectively, were asymmetric aldol reactions, Yamaguchi esterification, and ring-closing metathesis using Grubbs’ second generation catalyst. Finally, the coupling of agylcones with the corresponding trichloroacetimidates, followed by deprotection, completed the total synthesis of these two macrolide antibiotics.     

Structure-activity studies of irumamycin type macrolides from Streptomyces sp. INA-Ac-5812

Three natural glycosylated macrolide compounds, known irumamycin 1 and X-14952B 2, as well as new isoirumamycin 3, were isolated from ethyl acetate mycelium extract of Streptomyces sp. INA-Ac-5812. Structures of the compounds were elucidated using 1D and 2D NMR. Isoirumamycin 3 was found to be an isomer of irumamycin with an 18-membered macrolactone ring instead of 20-membered macrolide in irumamycin. A previously unknown stereo configuration of irumamycin epoxide (C23, C24) and hemiketal (C3, C7) fragments was deduced from NMR data (ROESY/NOESY and HSQMBC). Cytotoxic, antifungal and antibacterial activities were studied for all isolated compounds. Comparison of the collected data showed crucial importance of 20-membered macrolactone ring for antimicrobial properties of this antibiotic family.     

Ring Closing Metathesis Using Chiral Template Consisting of Hard and Soft Parts

Summary: Macrocyclic compounds having 18-, 19-, 22-, and 23-membered rings were prepared quantitatively by ring closing metathesis of diene substrates consisting of a rigid o- or m-phthalate group and flexible but geometrically regulated 2,4-pentanediol tethers. From the p-phthalate analogues, the ring closing metathesis and the cyclic dimmer formation were observed to give 24-membered ring (70% yield) and 40-membered ring (65% yield) respectively.     

Total synthesis of natural (−)- and unnatural (+)-Melearoride A

This communication details the first total synthesis of the 13-membered macrolide, (?)-Melearoride A, as well as unnatural (+)-Melearoride A. The synthesis features a concise 13 step synthesis (11 steps longest linear sequence) that offers flexible stereo-control and multiple opportunities for unnatural analog synthesis to delve into antifungal SAR. The route features a cuprate addition, an Evans asymmetric alkylation, and a ring-closing metathesis (RCM) to close the 13-membered macrocyclic core.     

Synthesis of gamma,delta-unsaturated-beta-keto lactones via sequential cross metathesis-lactonization: a facile entry to macrolide antibiotic (-)-A26771B

A simple access to gamma,delta-unsaturated-beta-keto lactones is presented, allowing a rapid total synthesis of the naturally occurring 16-membered macrolide antibiotic (-)-A26771B via cross metathesis, asymmetric dihydroxylation, and lactonization as the key steps.     

Synthesis of 16-membered ring macrolide antibiotics I. Stereoselective construction of the ‘right wing” of the carbomycins and leucomycins from D-glucose

$\text{D}$-Glucose was converted to a backbone chain containing the appropriate functionalities and correct stereochemistry for the construction of the C1–C9 fragment of the 16-membered ring macrolide antibiotics carbomycin A and B and leucomycin A₃.     

Synthesis and structure of novel cyclonucleoside analogues of uridine

Novel cyclonucleoside analogues of uridine having pentylene and hexylene linker between the 5′-O and 3-N positions (thereby generating a 13- and 14-membered ring, respectively) were synthesized from uridine via ring-closing metathesis. An example of cyclic dinucleosides having two butylene linkers between the 5′-O and 3-N positions (24-membered ring) was synthesized from uridine via tandem cross-metathesis and ring-closing metathesis.     

Total synthesis of (+)-lasonolide A

[structure: see text]. An enantiocontrolled total synthesis of (+)-lasonolide A has been accomplished by using the sequential cross metathesis and macrolactonization for the key assembly of the 20-membered polyene macrolide core of the natural product.     

Mononuclear copper(II) complexes of the macrolide antibiotics tylosin and tilmicosin

Transition Metal Chemistry - The 16-membered macrolide antibiotics tylosin (HTyl) and tilmicosin (HTilm) react with Cu(II) to form isostructural mononuclear complexes of composition [CuL2]...     

Ring closing enyne metathesis: control over mode selectivity and stereoselectivity

Ring closing enyne metathesis to form 10-15-membered rings was achieved by using a tartrate-derived linker to attach ene and yne subunits. The exo/endo selectivity of the ring closure reaction of these substrates was found to be a function of ring size, whereby larger rings (12-15) give endo-products selectively, while smaller rings (5-11) give exo-products. The E/Z selectivity of the resultant macrocyclic 1,3-dienes was not predictable except for 10- and 11-membered rings. However, both the exo/endo-mode selectivity of the ring closure and the E/Z selectivity of the 1,3-dienes were improved by performing these reactions under ethylene atmosphere. The presence of ethylene induces a selective cross metathesis between the alkyne moiety and ethylene to generate an acyclic 1,3-diene which can undergo ring closing diene metathesis between the isolated olefin and the distal monosubstituted double bond of the 1,3-diene to generate exclusively the endo-product with high E-selectivity.     

A convergent synthesis of the macrolide core of migrastatin

We describe an efficient synthesis of the 14-membered macrolide core 2 of migrastatin via key intermediate 3 employing a diastereoselective aldol condensation, Lewis acid mediated diastereoselective addition and an exclusive (Z)-olefination sequence. Yamaguchi esterification of the key intermediate 3 followed by ring-closing metathesis (RCM) produced macrolide 2 with high selectivity and good yield.     

Total synthesis of aigialomycin D

[reaction: see text] The first total synthesis of resorcinylic macrolide aigialomycin D was described. The resorcinylic moiety was constructed by a highly efficient Diels-Alder reaction using a disiloxydiene and a 14-membered "ynolide" as the dienophile synthesized by ring-forming olefin metathesis.     

Synthesis of 2′-O,3′-O bicyclic adenosine analogues using ring closing metathesis

The synthesis of 2′-O,3′-O bicyclic adenosine derivatives is presented as the first examples of a new family of 13-membered ring bicyclic nucleoside analogues. Cyclisation was achieved through ring closing metathesis (RCM) on a diene intermediate using Grubbs’ catalyst. The Z and E isomers were purified and characterised.     

A novel intramolecular reversible reaction between the hydroxyl group and isobutenylene chain in a cyclophane-type macrocycle

A novel Hg²⁺ ion induced reversible ring contraction was achieved employing the intramolecular reaction of isobutylene with an aromatic hydroxyl group of cyclophane; reversibility of the reaction was facilitated by excess addition of NaBH₄ which also resulted in complexation. The ring contraction and expansion was monitored by UV-VIS absorption, and by fluorescence and ¹H NMR spectra. Switchable fluorescence behavior (on—off—on) was observed when the ring-size was tuned from a 19-membered ring to an 18-membered and vice versa. This fine tuning has the potential to be applied in the construction of new supramolecular devices.     

Sanctolide A, a 14-membered PK-NRP hybrid macrolide from the cultured cyanobacterium Oscillatoria sancta (SAG 74.79)

Sanctolide A (1), a 14-membered polyketide-nonribosomal peptide (PK-NRP) hybrid macrolide, was isolated from the cultured cyanobacterium Oscillatoria sancta (SAG 74.79). The planar structure was determined using various spectroscopic techniques including HRESIMS, and 1D and 2D NMR analyses. The relative configuration was assigned by J-based configurational analysis in combination with NOE correlations. The absolute configuration was determined by Mosher ester and enantioselective HPLC analyses. The structure of sanctolide A (1) features a rare N-methyl enamide and a 2-hydroxyisovaleric acid, which are incorporated to form a 14-membered macrolide ring structure, comprising a new type of cyanobacterial macrolides derived from a PKS-NRPS hybrid biosynthetic pathway.