{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:43:36Z","timestamp":1784249016793,"version":"3.55.0"},"reference-count":191,"publisher":"Wiley","issue":"29","license":[{"start":{"date-parts":[[2015,6,10]],"date-time":"2015-06-10T00:00:00Z","timestamp":1433894400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Chemistry A European J"],"published-print":{"date-parts":[[2015,7,13]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mandelalide\u2005A and three congeners had recently been isolated as the supposedly highly cytotoxic principles of an ascidian collected off the South African coastline. Since these compounds are hardly available from the natural source, a concise synthesis route was developed, targeting structure <jats:bold>1<\/jats:bold> as the purported representation of mandelalide\u2005A. The sequence involves an iridium\u2010catalyzed two\u2010directional Krische allylation and a cobalt\u2010catalyzed carbonylative epoxide opening as entry points for the preparation of the major building blocks. The final stages feature the first implementation of terminal acetylene metathesis into natural product total synthesis, which is remarkable in that this class of substrates had been beyond the reach of alkyne metathesis for decades. Synthetic <jats:bold>1<\/jats:bold>, however, proved not to be identical with the natural product. In an attempt to clarify this issue, NMR spectra were simulated for 20 conceivable diastereomers by using DFT followed by DP4 analysis; however, this did not provide a reliable assignment either. The puzzle was ultimately solved by the preparation of three diastereomers, of which compound <jats:bold>6<\/jats:bold> proved identical with mandelalide\u2005A in all analytical and spectroscopic regards. As the entire \u201cnorthern sector\u201d about the tetrahydrofuran ring in <jats:bold>6<\/jats:bold> shows the opposite configuration of what had originally been assigned, it is highly likely that the stereostructures of the sister compounds mandelalides\u2005B\u2013D must be corrected analogously; we propose that these natural products are accurately represented by structures <jats:bold>68<\/jats:bold>\u2013<jats:bold>70<\/jats:bold>. In an attempt to prove this reassignment, an entry into mandelalides\u2005C and D was sought by subjecting an advanced intermediate of the synthesis of <jats:bold>6<\/jats:bold> to a largely unprecedented intramolecular Morita\u2013Baylis\u2013Hillman reaction, which furnished the \u03b3\u2010lactone derivative <jats:bold>74<\/jats:bold> as a mixture of diastereomers. Whereas (24<jats:italic>R<\/jats:italic>)\u2010<jats:bold>74<\/jats:bold> was amenable to a hydroxyl\u2010directed dihydroxylation by using OsO<jats:sub>4<\/jats:sub>\/TMEDA as the reagent, the sister compound (24<jats:italic>S<\/jats:italic>)\u2010<jats:bold>74<\/jats:bold> did not follow a directed path but simply obeyed Kishi\u2019s rule; only this unexpected escape precluded the preparation of mandelalides\u2005C and D by this route. A combined spectroscopic and computational (DFT) study showed that the reasons for this strikingly different behavior of the two diastereomers of <jats:bold>74<\/jats:bold> are rooted in their conformational peculiarities. This aspect apart, our results show that the OsO<jats:sub>4<\/jats:sub>\/TMEDA complex reacts preferentially with electron deficient double bonds even if other alkenes are present that are more electron rich and less encumbered. Finally, in a brief biological survey authentic mandelalide\u2005A (<jats:bold>6<\/jats:bold>) was found to exhibit appreciable cytotoxicity only against one out of three tested human cancer cell lines and all synthetic congeners were hardly active. No significant fungicidal properties were observed.<\/jats:p>","DOI":"10.1002\/chem.201501491","type":"journal-article","created":{"date-parts":[[2015,6,19]],"date-time":"2015-06-19T10:29:55Z","timestamp":1434709795000},"page":"10416-10430","source":"Crossref","is-referenced-by-count":97,"title":["Total Synthesis, Stereochemical Revision, and Biological Reassessment of Mandelalide\u2005A: Chemical Mimicry of Intrafamily Relationships"],"prefix":"10.1002","volume":"21","author":[{"given":"Jens","family":"Willwacher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berit","family":"Heggen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conny","family":"Wirtz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Thiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alois","family":"F\u00fcrstner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,6,10]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo3008622"},{"key":"e_1_2_6_2_2","unstructured":"P.\u2005L. 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the successful engagement of the terminal alkyne in the RCAM\u2010based macrocyclization is therefore not only advantageous in terms of step count but also from a practical perspective."},{"key":"e_1_2_6_102_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja110332r"},{"key":"e_1_2_6_103_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)97884-5"},{"key":"e_1_2_6_104_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(01)98365-0"},{"key":"e_1_2_6_105_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2318(08)60150-X"},{"key":"e_1_2_6_106_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr990101j"},{"key":"e_1_2_6_107_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr300129n"},{"key":"e_1_2_6_108_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.197805221"},{"key":"e_1_2_6_108_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.19780900718"},{"key":"e_1_2_6_109_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200601859"},{"key":"e_1_2_6_109_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.200601859"},{"key":"e_1_2_6_110_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(01)01843-3"},{"key":"e_1_2_6_111_2","unstructured":"Trace amounts ofZ\u201060were removed by flash chromatography at this point."},{"key":"e_1_2_6_112_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201200621"},{"key":"e_1_2_6_113_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja104800w"},{"key":"e_1_2_6_114_2","unstructured":"For the most advanced applications see:"},{"key":"e_1_2_6_115_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201103270"},{"key":"e_1_2_6_115_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201103270"},{"key":"e_1_2_6_116_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201301700"},{"key":"e_1_2_6_116_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201301700"},{"key":"e_1_2_6_117_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201106117"},{"key":"e_1_2_6_117_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201106117"},{"key":"e_1_2_6_118_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201402550"},{"key":"e_1_2_6_118_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201402550"},{"key":"e_1_2_6_119_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201304580"},{"key":"e_1_2_6_120_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201404873"},{"key":"e_1_2_6_121_2","unstructured":"Propyne and even more so acetylene are effective catalyst poisons that need to be removed to ensure productive metathesis see ref.\u2005[23]; the currently most effective way uses the sieving effect of MS 4\/5\u2005\u00c5 which are able to trap small alkynes as originally disclosed in ref.\u2005[69]."},{"key":"e_1_2_6_122_2","doi-asserted-by":"publisher","DOI":"10.1002\/hlca.19870700415"},{"key":"e_1_2_6_123_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6215(02)00443-3"},{"key":"e_1_2_6_124_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja105035r"},{"key":"e_1_2_6_125_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201007719"},{"key":"e_1_2_6_125_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201007719"},{"key":"e_1_2_6_126_2","unstructured":"Scheme showing the entire routes are contained in the Supporting Information."},{"key":"e_1_2_6_127_2","unstructured":"This follows from the fact that the configurations at C2 and C3 are correlated by strong ROESY contacts with those of the neighboring chiral centers."},{"key":"e_1_2_6_128_2","doi-asserted-by":"publisher","DOI":"10.1016\/0040-4020(82)85023-0"},{"key":"e_1_2_6_129_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol1023008"},{"key":"e_1_2_6_130_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja973846k"},{"key":"e_1_2_6_131_2","unstructured":"Studies with model systems suggested that small nucleophilic phosphines can promote such challenging transformations; for details see the Supporting Information."},{"key":"e_1_2_6_132_2","unstructured":"A strong NOE between the protons H4 and H24 is indicative; the assignment is consistent with the significant downfield shift of H3 which suggests that this proton experiences the anisotropy of the ester carbonyl."},{"key":"e_1_2_6_133_2","unstructured":"\u00a0"},{"key":"e_1_2_6_134_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(97)01061-7"},{"key":"e_1_2_6_135_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(99)01371-4"},{"key":"e_1_2_6_136_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo026161y"},{"key":"e_1_2_6_137_2","unstructured":"\u00a0"},{"key":"e_1_2_6_138_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo01072a030"},{"key":"e_1_2_6_139_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00254a067"},{"key":"e_1_2_6_140_2","unstructured":"In the spectrum of the crude mixture the enoate proton is easily discerned by its characteristic downfield shift."},{"key":"e_1_2_6_141_2","unstructured":"We are only aware of examples in which an electron\u2010deficient alkene could be selectively dihydroxylated in the presence of a more electron\u2010rich alkene if the latter is sterically shielded see:"},{"key":"e_1_2_6_142_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2006.03.072"},{"key":"e_1_2_6_143_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2009.04.022"},{"key":"e_1_2_6_144_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.199421871"},{"key":"e_1_2_6_144_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.19941062128"},{"key":"e_1_2_6_145_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol025766d"},{"key":"e_1_2_6_146_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2003.09.209"},{"key":"e_1_2_6_147_2","first-page":"1183","author":"Hassfeld J.","year":"2005","journal-title":"Synthesis"},{"key":"e_1_2_6_148_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(98)00103-3"},{"key":"e_1_2_6_149_2","unstructured":"\u00a0"},{"key":"e_1_2_6_150_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)88231-3"},{"key":"e_1_2_6_151_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)88232-5"},{"key":"e_1_2_6_152_2","doi-asserted-by":"publisher","DOI":"10.1016\/0040-4020(84)80008-3"},{"key":"e_1_2_6_153_2","unstructured":"The reported spectra of deacyl\u2010mandelalide D are of rather poor quality whereas those of mandelalide\u2005C are better resolved and therefore constitute a more accurate calibration point."},{"key":"e_1_2_6_154_2","unstructured":"Even in the second\u2010lowest conformer which is approximately 4\u2005kcal\u2009mol\u22121higher in energy the C.24\uf8ffOH group seems fairly inaccessible."},{"key":"e_1_2_6_155_2","volume-title":"Drugs from the Sea","year":"2000"},{"key":"e_1_2_6_156_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol501917g"},{"key":"e_1_2_6_157_2","unstructured":"For total syntheses from our laboratory designed to provide significant amounts of bioactive natural products for testing see ref.\u2005[14b] [16b] and the following:"},{"key":"e_1_2_6_158_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201100178"},{"key":"e_1_2_6_159_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201411618"},{"key":"e_1_2_6_159_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201411618"},{"key":"e_1_2_6_160_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201405790"},{"key":"e_1_2_6_161_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201501608"},{"key":"e_1_2_6_161_3","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201501608"},{"key":"e_1_2_6_162_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.200601136"}],"container-title":["Chemistry \u2013 A European Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fchem.201501491","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/chem.201501491","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T20:03:29Z","timestamp":1760299409000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/chem.201501491"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,6,10]]},"references-count":191,"journal-issue":{"issue":"29","published-print":{"date-parts":[[2015,7,13]]}},"alternative-id":["10.1002\/chem.201501491"],"URL":"https:\/\/doi.org\/10.1002\/chem.201501491","archive":["Portico"],"relation":{},"ISSN":["0947-6539","1521-3765"],"issn-type":[{"value":"0947-6539","type":"print"},{"value":"1521-3765","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,6,10]]}}}