{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:38:26Z","timestamp":1790753906855,"version":"4.1.0"},"reference-count":70,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2015,12,7]],"date-time":"2015-12-07T00:00:00Z","timestamp":1449446400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003006","name":"ETH Z\u00fcrich","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003006","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Chemistry A European J"],"published-print":{"date-parts":[[2016,1,22]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A new convergent total synthesis of the marine macrolide mandelalide\u2005A (<jats:bold>1<\/jats:bold>) has been developed that is based on macrocyclic ring closure by a Shiina\u2010type macrolactonization and the construction of the requisite precursor seco acid by a highly efficient Sonogashira cross\u2010coupling reaction between two fragments of comparable complexity. Key steps in the elaboration of the acid building block were the enantioselective, catalytic addition of a protected acetylene to crotonaldehyde and the construction of the tetrahydropyran unit that is embedded in the macrocycle by means of an acid\u2010catalyzed Prins reaction. The synthesis of the alcohol fragment features the formation of the trisubstituted tetrahydrofuran ring through an acetal cleavage\/epoxide opening cascade reaction and a rarely used radical alkynylation of a primary alkyl iodide. Intriguingly, the dihydroxylation of a terminal double bond as part of the synthesis of this building block gave the same major product for both the \u03b1\u2010 and \u03b2\u2010AD\u2010mix reagents, albeit with moderate or low selectivity. Synthetic mandelalide\u2005A (<jats:bold>1<\/jats:bold>) was a potent proliferation inhibitor of A549, HT460, and H1299 human lung cancer cells in vitro, but not of SK\u2010<jats:italic>N<\/jats:italic>\u2010SH neuroblastoma cells. However, in no case did we observe complete cell kill even at the highest compound concentration tested (5\u2005\u03bc<jats:sc>m<\/jats:sc>).<\/jats:p>","DOI":"10.1002\/chem.201504230","type":"journal-article","created":{"date-parts":[[2015,12,8]],"date-time":"2015-12-08T12:44:31Z","timestamp":1449578671000},"page":"1292-1300","source":"Crossref","is-referenced-by-count":28,"title":["Total Synthesis and Biological Assessment of Mandelalide\u2005A"],"prefix":"10.1002","volume":"22","author":[{"given":"Tobias Michael","family":"Br\u00fctsch","sequence":"first","affiliation":[{"name":"Swiss Federal Institute of Technology (ETH) Z\u00fcrich Department of Chemistry and Applied Biosciences Institute of Pharmaceutical Sciences, HCI H405  Vladimir-Prelog-Weg 4 8093 Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Bucher","sequence":"additional","affiliation":[{"name":"Swiss Federal Institute of Technology (ETH) Z\u00fcrich Department of Chemistry and Applied Biosciences Institute of Pharmaceutical Sciences, HCI H405  Vladimir-Prelog-Weg 4 8093 Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0747-9734","authenticated-orcid":false,"given":"Karl\u2010Heinz","family":"Altmann","sequence":"additional","affiliation":[{"name":"Swiss Federal Institute of Technology (ETH) Z\u00fcrich Department of Chemistry and Applied Biosciences Institute of Pharmaceutical Sciences, HCI H405  Vladimir-Prelog-Weg 4 8093 Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,12,7]]},"reference":[{"key":"e_1_2_6_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo3008622"},{"key":"e_1_2_6_2_1","unstructured":"The structure shown here for mandelalide\u2005B (2) is not the one proposed by McPhail and co-workers but the more likely one proposed by F\u00fcrstner for which the absolute configuration of the northern part of the structure corresponds with the (revised)configuration of mandelalide\u2005A (1) (see ref.\u2005[16])."},{"key":"e_1_2_6_3_1","unstructured":"For recent reviews see for example:"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/9781118391815.ch13"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/np200906s"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/np50067a001"},{"key":"e_1_2_6_7_1","unstructured":"See for example:"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1201\/b16662-48"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/md12010255"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1039\/C4NP00064A"},{"key":"e_1_2_6_11_1","unstructured":"\u00a0"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.4155\/fmc.11.118"},{"key":"e_1_2_6_13_2","first-page":"1","volume-title":"Bioactive Compounds from Marine Foods: Plant and Animal Sources","author":"Vaske Y. M.","year":"2014"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1039\/b808331m"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-386009-5.00013-8"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-0488"},{"key":"e_1_2_6_17_1","unstructured":"\u00a0"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1039\/b501014b"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1116364"},{"key":"e_1_2_6_20_1","unstructured":"For reviews see:"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2011.06.011"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1039\/b809658a"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.3390\/md7030314"},{"key":"e_1_2_6_24_1","unstructured":"For selected recent examples see:"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201501252"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201402129"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201301796"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201300576"},{"key":"e_1_2_6_28_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201300576"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201202553"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201400605"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201400605"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201403542"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201403542"},{"key":"e_1_2_6_32_1","unstructured":"It is not possible for us to determine with certainty which group was the first to publicly disclose a total synthesis of1. The results reported in ref.\u2005[16] below on the total synthesis and stereochemical reassignment of mandelalide\u2005A were first presented at theSymposium for Cooperative Effects M\u00fcnster Germany on May\u20059 2014 (https:\/\/www.uni-muenster.de\/imperia\/md\/content\/organisch_chemisches_institut\/sfb858\/wwu_muenster_sfb_858_mscec_2014_boa_short.pdf) while ref.\u2005[14] was first published online on May 20 2014. On the other hand according to one of the reviewers of our manuscript the first total synthesis of the revised structure of mandelalide\u2005A (1) was presented by Ye's group at the Gordon Research Conference on Marine Natural Products held from March 2\u20137 2014 in Ventura CA. Unfortunately we cannot verify this information. The program published for this meeting on the website of the Gordon Research Conferences organization does not include a lecture on the synthesis of mandelalide\u2005A (https:\/\/www.grc.org\/programs.aspx?id=11553). However the website does not offer access to poster abstracts."},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201501491"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol500875e"},{"key":"e_1_2_6_35_1","unstructured":"Our supposition that1may be the true structure of mandelalide\u2005A even before the publication of Xu and Ye's total synthesis shortly after F\u00fcrstner's first disclosure in ref.\u2005[13] was based on the fact that the configurations of the stereocenters in the tetrahydrofuran moiety in madeirolides [19]which are marine natural products structurally related to the mandelalides are opposite to those originally proposed (and found to be wrong) for mandelalide\u2005A (1). The same considerations led F\u00fcrstner to pursue the synthesis of1as the possible structure of mandelalide\u2005A. (For a discussion see ref.\u2005[16])."},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol400280b"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr0301402"},{"key":"e_1_2_6_38_1","unstructured":"\u00a0"},{"key":"e_1_2_6_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)91094-3"},{"key":"e_1_2_6_39_3","doi-asserted-by":"publisher","DOI":"10.1039\/C4RA02529F"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00071a074"},{"key":"e_1_2_6_41_1","first-page":"1630","author":"Oh K.","year":"2005","journal-title":"Synlett"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr00032a009"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/0040-4020(95)00875-9"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)85909-2"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00538a077"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200904486"},{"key":"e_1_2_6_46_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.200904486"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/1615-4169(20010330)343:3<264::AID-ADSC264>3.0.CO;2-T"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol402081p"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.201201557"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo2011494"},{"key":"e_1_2_6_51_1","unstructured":"While it would have been conceivable to protect the C7 hydroxy group at the stage of ester16and then perform the Sonogashira coupling prior to ester cleavage the corresponding protecting group would have been required to be selectively removable in the presence of the TBS groups on C21\/C24 and also to be stable under the conditions for ester cleavage. This would have excluded a base-labile acetate ester for the protection of the C7 hydroxy group. Attempts to perform the macrolactonization with a free hydroxy group were unsuccessful."},{"key":"e_1_2_6_52_1","unstructured":"Without recrystallization the selectivity of the reaction was only 4:1. The recrystallized material can be stored in a drybox without loss of quality. If the olefination reaction was conducted with NaH (in the absence of the crown ether) theZ\/Eproduct ratio was only 3:1."},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo970509l"},{"key":"e_1_2_6_54_1","unstructured":"For example treatment of TMS-acetylene with LDA at \u221278\u2009\u00b0C followed by the addition of alkyl iodide21gave 15\u2009% of an impure product which according to1H\u2005NMR and MS data appeared to be the result of the intramolecular attack of the C23 hydroxy group (mandelalide numbering) on the iodide carbon atom. Performing the same reaction after prior TMS protection of21gave a complex mixture of products from which no identifiable compound could be isolated."},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(98)01924-8"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja061559n"},{"key":"e_1_2_6_57_1","unstructured":"Unfortunately we were unable to convert24\/ent-24into the corresponding Mosher esters for the direct analysis of the C23 configuration."},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja037096s"},{"key":"e_1_2_6_59_1","first-page":"289","volume":"45","author":"Kumar P.","year":"2012","journal-title":"Acc. Chem. 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