Milbemycin Β3 Research Articles

Three new 16-membered macrolide compounds from a genetically engineered strain S. avermitilis MHJ1011

Three new 16-membered macrolide compounds, 13α-O-α-l-oleandrosyl milbemycin β3 (1), 13α-O-α-l-oleandrosyl-25-ethyl milbemycin β3 (2), 13α-O-α-l-oleandrosyl-25-isopropyl milbemycin β3 (3), were isolated from the genetically engineered strains Streptomyces avermitilis MHJ1011. Their structures were determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as ESI-MS and comparison with data from the literature. Both compounds 1–3 displayed impressive acaricidal activity against larval mites with the IC50 values of 0.0327, 0.0276 and 0.0235mg/L, respectively, which are higher than those of 13α-hydroxy milbemycin β3 and 13α-hydroxy-25-ethyl milbemycin β3.

Three new milbemycins from a genetically engineered strain S. avermitilis MHJ1011.

Three new β-class milbemycins, 13α-hydroxy-4-ethy1 milbemycin β3 (1), 13α-hydroxy-25-ethy1 milbemycin β3 (2), 13α-hydroxy milbemycin β3 (3), were isolated from the broth of the genetically engineered strains Streptomyces avermitilis MHJ1011, whose aveA1 gene was replaced by milA1 gene seamlessly. Their structures were determined on the basis of extensive spectroscopic analysis and comparison with data from the literature. These three compounds, especially compound 1, exhibited potent acaricidal activity.

Two New β-Class Milbemycins from Streptomyces bingchenggensis: Fermentation, Isolation, Structure Elucidation and Biological Properties

Two new beta-class milbemycins from Streptomyces bingchenggensis, named milbemycin beta(13) and beta(14), have been isolated and characterized. The producing organism has been deposited at the China General Microbiology Culture Collection Center (Accession No: CGMCC1734). On the basis of detailed spectroscopic analysis and comparison with reported data, their structures were determined to be the hydroxyl derivatives at C-27 of milbemycin beta(3) and 25-ethylmilbemycin beta(3), respectively. Milbemycins beta(13) and beta(14) possess potent acaricidal and nematocidal activity. The discovery of these two compounds plays an important role in understanding and perfecting the proposed pathways of milbemycins.

De Novo Asymmetric Synthesis of Milbemycin β3 via an Iterative Asymmetric Hydration Approach

The enantioselective synthesis of the spiroketal/macrolide natural product milbemycin beta3 has been achieved in 22 steps and 2.8% overall yield from an achiral dienoate. The spiroketal ring system was installed by three sequential asymmetric hydrations followed by sprioketalization. Both the absolute and relative stereochemistry of milbemycin beta3 was introduced by two Sharpless asymmetric dihydroxylations, two pi-allylpalladium-catalyzed reductions, and an iridium-catalyzed hydrogen migration/Claisen rearrangement to install the C-12 stereocenter.

Efficient synthesis of the left-hand subunit of milbemycin β3 using a suzuki coupling reaction

The efficient synthesis of the left-hand subunit of the antiparasitic agent milbemycin β3 using a Suzuki coupling is described. The unique role played by thallium carbonate in this palladium-catalysed reaction is discussed.

ChemInform Abstract: A Rapid Entry to Highly Functionalized p‐Methoxybenzoates: Synthesis of Aromatic Portion of Milbemycin β3.

Abstract A wide variety of easily accessible Hagemann's esters are converted to p-methoxybenzoates with iodine and methanol.

ChemInform Abstract: A Directed Aldol Approach to (+)‐Milbemycin β3.

ChemInformVolume 19, Issue 4 Natural Products ChemInform Abstract: A Directed Aldol Approach to (+)-Milbemycin β3. P. J. KOCIENSKI, P. J. KOCIENSKI Dep. Chem., Univ. Southampton, Southampton SO17 1BJ, UKSearch for more papers by this authorS. D. A. STREET, S. D. A. STREET Dep. Chem., Univ. Southampton, Southampton SO17 1BJ, UKSearch for more papers by this authorC. YEATES, C. YEATES Dep. Chem., Univ. Southampton, Southampton SO17 1BJ, UKSearch for more papers by this authorS. F. CAMPBELL, S. F. CAMPBELL Dep. Chem., Univ. Southampton, Southampton SO17 1BJ, UKSearch for more papers by this author P. J. KOCIENSKI, P. J. KOCIENSKI Dep. Chem., Univ. Southampton, Southampton SO17 1BJ, UKSearch for more papers by this authorS. D. A. STREET, S. D. A. STREET Dep. Chem., Univ. Southampton, Southampton SO17 1BJ, UKSearch for more papers by this authorC. YEATES, C. YEATES Dep. Chem., Univ. Southampton, Southampton SO17 1BJ, UKSearch for more papers by this authorS. F. CAMPBELL, S. F. CAMPBELL Dep. Chem., Univ. Southampton, Southampton SO17 1BJ, UKSearch for more papers by this author First published: January 26, 1988 https://doi.org/10.1002/chin.198804362Read 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 onFacebookTwitterLinked InRedditWechat Volume19, Issue4January 26, 1988 RelatedInformation

ChemInform Abstract: The 3,4‐Dihydro‐2H‐pyran Approach to (+)‐Milbemycin β3. Part 1. An Alternative Synthesis of (2S,4S,6R,8R,9S)‐2‐Formylmethyl‐4‐(dimethyl‐t‐butylsilyloxy)‐8,9‐dimethyl‐1,7‐dioxaspiro(5.5)undecane.

AbstractThe title compound (XVII) is an intermediate in the synthesis of the pesticide milbemycin β3.

ChemInform Abstract: Total Synthesis of (+)‐Milbemycin β3.

AbstractThe coupling of the iodide (+)‐(III) with the spiroacetal (+)‐(IV), whose synthesis has already been described in the preceding paper, represents the starting step in the synthesis of the synthon (+)‐(VIII).

Total synthesis of (+)-milbemycin (β3)

The total synthesis of (+)-milbemycin β3, has been achieved in two ways beginning from the appropriate spiroacetal moiety. In the first, coupling of a vinyl-lithium derivative (18) with the spiroacetal aldehyde (19), available from Swern oxidation of the corresponding alcohol generated the C(11)–C(25) segment of milbemycin β3. Removal of the allylic hydroxy group was achieved by tributyltin hydride reduction of the dithiocarbonate although a mixture of two double-bond isomers was obtained. In an alternative and superior approach the C(14)–C(15) trisubstituted double-bond of milbemycin β3, was established by reaction of a Wittig reagent with the spiroacetal aldehyde (19). The product of this reaction, after conversion into the iodide and enantiospecific alkylation to generate the 12-methyl group, was further elaborated to the same C(11)–C(25) segment prepared previously. The aromatic portion of milbemycin was incorporated by the Lythgoe-Kocienski modification of the Julia reaction involving reaction of a sulphone anion and an α,β-unsaturated aldehyde followed by reductive elimination to generate the C(8)–C(10) diene system. Final macrocyclisation followed essentially established procedures.

The 3,4-dihydro-2H-pyran approach to (+)-milbemycin β3. Part 1. An alternative synthesis of (2S,4S,6R,8R,9S)-2-formylmethyl-4-(dimethyl-t-butylsilyloxy)-8,9-dimethyl-1,7-dioxaspiro[5.5]undecane

A more efficient synthesis of the title compound (12), previously used in a total synthesis of (+)-milbemycin β3(2), is described. The key step in the sequence involves a nucleophilic cleavage of the oxirane (33) by the organocuprate (28) derived from metallation of (2R,3S)-2,3-dimethyl-3,4-dihydro-2H-pyran (26).

The 3,4-dihydro-2H-pyran approach to (+)-milbemycin β3. Part 2. An improved synthesis of (2R,4S,6S,8R,9S)-2-[(5R)-(2E)-3-methyl-5-formyl-hex-2-en-1-yl]-8,9-dimethyl-4-(dimethyl-t-butylsilyloxy)-1,7-dioxaspiro[5.5]undecane

A more efficient synthesis of the title compound (2), previously used in a total synthesis of (+)-milbemycin β3(1), is described. The key step in the sequence involves a nucleophilic cleavage of the oxirane (4) by the organocuprate derived from metallation of (2R,3S)-2,3-dimethyl-3,4-dihydro-2H-pyran (5).

Preparation of chiral lactone from laevoglucosan; a key intermediate for synthesis of the spiroacetal moieties of the avermectins and milbemycins

A synthesis of two diprotected (4S,6S)-4-hydroxy-6-hydroxymethyltetrahydropyran-2-ones has been developed from laevoglucosan. Reaction of these lactones with a substituted chiral lithium acetylide followed by hydrogenation and acid-catalysed cyclisation led to formation of the spiroacetal moiety of milbemycin β1 and β3. The acetylene was prepared by resolution of racemic material obtained from reaction of lithium acetylide and cis-butene epoxide. Alternatively a stereocontrolled synthesis was developed from (S)-methyl-3-hydroxy-2-methylpropionate which involved ‘chelation controlled’ addition of lithium dimethylcuprate to the corresponding tetrahydropyranyloxy aldehyde.

Structure of a milbemycin β3 intermediate

Structure of a milbemycin β3 intermediate

ChemInform Abstract: A Synthesis of (+)‐Milbemycin β3. The Directed Aldol Approach.

Chemischer InformationsdienstVolume 17, Issue 6 Natural Products ChemInform Abstract: A Synthesis of (+)-Milbemycin β3. The Directed Aldol Approach. S. D. A. STREET, S. D. A. STREETSearch for more papers by this authorC. YEATES, C. YEATESSearch for more papers by this authorP. KOCIENSKI, P. KOCIENSKISearch for more papers by this authorS. F. CAMPBELL, S. F. CAMPBELLSearch for more papers by this author S. D. A. STREET, S. D. A. STREETSearch for more papers by this authorC. YEATES, C. YEATESSearch for more papers by this authorP. KOCIENSKI, P. KOCIENSKISearch for more papers by this authorS. F. CAMPBELL, S. F. CAMPBELLSearch for more papers by this author First published: February 11, 1986 https://doi.org/10.1002/chin.198606322Read 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. Volume17, Issue6February 11, 1986 RelatedInformation

ChemInform Abstract: The Total Synthesis of (+)‐Milbemycin β3.

AbstractAuf dem im Formelschema skizzierten Weg erhält man die im Titel genannte Verbindung (VII).

Total synthesis of (+)-milbemycin β3

(+)-Milbemycin β3(1) was prepared by total synthesis from (6S,8R,9S)-methyl 8,9-dimethyl-4-oxo-1,7-dioxaspiro[5.5]undeco-2-ene-2-carboxylate (2), (4R,6R)-4-methyl-6-phenylsulphonyl-(E)-hept-2-en-1-ol (3a), and 2-ethyl-4-methoxy-5-methylbenzoic acid (4) using Julia–Lythgoe and benzylic anion chemistry to establish the carbon framework and a Mitsunobu reaction to close the lactone ring.

A formal synthesis of (+)milbemycin β 31: A Wittig approach

A new route has been established to generate the C 14–C 15 trisubstituted double bond of milbemycin β3 by reaction of a Wittig reagent with the appropriate spiroacetal aldehyde. The product of this reaction, after conversion to the iodide and enantiospecific alkylation to generate the C 12 methyl group, has been elaborated to an intermediate previously involved in a total synthesis of milbemycin β 3.

A synthesis of (+)-milbemycin β3. The 3,4-dihydro-2H-pyran approach

Nucleophilic scission of oxirane (8) by vinyl alanate (4) and oxirane (11) by metallated 3,4-dihydro-2H-pyran (15) were key steps in the synthesis of (+)-milbemycin β3(1).

The total synthesis of (+)-milbemycin β3

We report the total synthesis of (+)-milbemycin β3 from the optically pure precursors spiroacetal (3) and vinyl iodide (2), and the aromatic aldehyde (4).