Asymmetric Total Synthesis of (−)‐Pironetin Employing the SAMP/RAMP Hydrazone Methodology

Enders, Dieter; Dhulut, Sylvie; Steinbusch, Daniel; Herrbach, Audrey

doi:10.1002/chem.200601672

Cited by 37 publications

(8 citation statements)

References 42 publications

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“…Intermediates 8 were then used to prepare the desired analogues 6 (Scheme ) . A SmI 2 ‐catalyzed anti ‐selective disproportionation between β‐hydroxy ketones 8 and acetaldehyde furnished the desired intermediate 15 . The relative configuration of intermediates 15 was assigned following hydrolysis of the acetate ester and conversion of the resulting diol into the acetonide .…”

Section: Resultsmentioning

confidence: 99%

“…[30] AS mI 2 -catalyzed anti-selective disproportionation between b-hydroxy ketones 8 and acetaldehyde furnished the desired intermediate 15. [30,33] The relative configuration of intermediates 15 was assigned following hydrolysis of the acetate ester and conversion of the resulting diol into the acetonide. [34,35] Intermediates 15 werer eadily converted into primary alcohols 17 by protection of the secondarya lcohol as the acetate andr emoval of the PMB protecting group.…”

Section: Synthesis Of Pironetin Analoguesmentioning

confidence: 99%

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Synthesis and Cytotoxicity Evaluation of C4‐ and C5‐Modified Analogues of the α,β‐Unsaturated Lactone of Pironetin

2017

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Pironetin is a natural product with potent antiproliferative activity that forms a covalent adduct with α‐tubulin via conjugate addition into the natural product's α,β‐unsaturated lactone. Although pironetin's α,β‐unsaturated lactone is involved in its binding to tubulin, the structure–activity relationship at different positions of the lactone have not been thoroughly evaluated. For a systematic evaluation of the structure–activity relationships at the C4 and C5 positions of the α,β‐unsaturated lactone of pironetin, twelve analogues of the natural product were prepared by total synthesis. Modifying the stereochemistry at the C4 and/or C5 positions of the α,β‐unsaturated lactone of pironetin resulted in loss of antiproliferative activity in OVCAR5 ovarian cancer cells. While changing the C4 ethyl substituent with groups such as methyl, propyl, cyclopropyl, and isobutyl were tolerated, groups with larger steric properties such as an isopropyl and benzyl groups were not.

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Section: Resultsmentioning

confidence: 99%

Section: Synthesis Of Pironetin Analoguesmentioning

confidence: 99%

Synthesis and Cytotoxicity Evaluation of C4‐ and C5‐Modified Analogues of the α,β‐Unsaturated Lactone of Pironetin

2017

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“…Small‐ring lactones are accessible through ring‐closing metathesis (RCM), but because of carbonyl coordination to the metal center, these processes are at times inefficient and demand elevated temperatures and relatively high catalyst loadings (e.g., 20 mol %) . In such instances a Lewis acidic additive can enhance efficiency but not always …”

Section: Methodsmentioning

confidence: 99%

Synthesis of Linear (Z)‐α,β‐Unsaturated Esters by Catalytic Cross‐Metathesis. The Influence of Acetonitrile

Johnson

Hoveyda

et al. 2016

Angewandte Chemie

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Kinetically-controlled catalytic cross-metathesis reactions that generate (Z)-α,β-unsaturated esters selectively are disclosed. A key finding is that the presence of acetonitrile obviates the need for using excess amounts of a more valuable terminal alkene substrates. On the basis of X-ray structure and spectroscopic investigations a rationale for the positive impact of acetonitrile is provided. Transformations leading to various E,Z-dienoates are highly Z-selective as well. Utility is highlighted by application to stereoselective synthesis of the C1-C12 fragment of biologically active natural product (−)-laulimalide. Keywordsalkenes; catalysis; enoates; cross-metathesis; dienoates; synthesis; molybdenum Conspicuously absent from the list of available kinetically-controlled stereoselective olefin metathesis reactions [1,2] are cross-metathesis (CM) processes that can deliver linear (Z)-α,β-unsaturated esters. [3,4,5] Such transformations would offer a valuable disconnection that may be complementary to Wittig-type [6] or alkyne partial hydrogenation reactions. [7] A case in point is a possible stereoselective route to the C1-C12 segment of (−)-laulimalide, a naturally occurring microtubule stabilizing agent (Scheme 1a). [8] Z-Enoate i could accordingly be synthesized through two Z-selective CM steps (ii→i and v→iv). Small-ring * amir.hoveyda@bc.edu. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript lactones are accessible through ring-closing metathesis (RCM), but because of carbonyl coordination to the metal center, these processes are at times inefficient and demand elevated temperatures and relatively high catalyst loadings (e.g., 20 mol %). [9] In such instances a Lewis acidic additive can enhance efficiency [10] but not always. [11] Development of a Z-selective enoate CM requires that the following problems are resolved (Scheme 1b): 1) The carbonyl unit of a carboxylic ester-substituted alkylidene might coordinate to the metal center to reduce reaction rates. 2) High efficiency might demand larger amounts of a structurally complex alkenyl compound. For example, excess of the more valuable α-alkenes ii or v might be required for high efficiency (Scheme 1a). 3) Electronic factors do not favor formation of productive metallacyclobutanes. Unlike macrocyclic RCM reactions, [12] where geometric constraints oppose the mismatched electronic factors (see I, Scheme 1b), in CM formation of electronically (and sterically) favored intermediates II-III would lead to nonproductive metallacyclobutanes (vs. IV-V, Scheme 1b). The active complex must therefore be sufficiently long living for productive CM that occurs subsequent to nonproductive cycles.We began by probing the ability of a number of complexes to promote CM between 1-decene (3.0 equiv.) and acrylate 1a (Table 1). With Ru-1 [13] formation of Z-2a was fully Zselective but inefficient (Table 1, entry 1) and with Ru-2 [5e] none of the expected product was formed (entry 2). Reaction with bis-alkoxide Mo-1 proceeded only ...

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“…The reaction with the Sn(II) enolate 34b should also be ''matched'' but was unselective for unknown reasons. Finally, Enders et al [119] assembled the carbon backbone of pironetin by reaction of 35 with 36 to obtain the desired adduct 37 in moderate yield. Although the major product is consistent with the biases expected of the (Z)-enolsilane (1,3-anti adducts; Scheme 6.7), aldehyde (1 , 3 -anti adducts; Scheme 6.9), and relative topicity (1,1 -syn adducts; Scheme 6.7; Tables 6.1 and 6.2), the poor selectivity observed presumably results because these stereocontrol elements are not highly biased (Section 6.2.2.3).…”

Section: -Methylalkyl Ethyl Ketones: 3-deoxy Polypropionate Equivalentsmentioning

confidence: 99%

Polypropionate Synthesis via Substrate‐Controlled Stereoselective Aldol Couplings of Chiral Fragments

Ward

2013

Modern Methods in Stereoselective Aldol Reactions

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Asymmetric Total Synthesis of (−)‐Pironetin Employing the SAMP/RAMP Hydrazone Methodology

Cited by 37 publications

References 42 publications

Synthesis and Cytotoxicity Evaluation of C4‐ and C5‐Modified Analogues of the α,β‐Unsaturated Lactone of Pironetin

Synthesis and Cytotoxicity Evaluation of C4‐ and C5‐Modified Analogues of the α,β‐Unsaturated Lactone of Pironetin

Synthesis of Linear (Z)‐α,β‐Unsaturated Esters by Catalytic Cross‐Metathesis. The Influence of Acetonitrile

Polypropionate Synthesis via Substrate‐Controlled Stereoselective Aldol Couplings of Chiral Fragments

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