{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T15:27:04Z","timestamp":1787412424510,"version":"build-2736575974"},"reference-count":21,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K20571"],"award-info":[{"award-number":["22K20571"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24H01766"],"award-info":[{"award-number":["24H01766"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K01636"],"award-info":[{"award-number":["24K01636"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hemiketal D2 (HKD2) is a recently identified eicosanoid produced from arachidonic acid via a crossover pathway involving 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2), and has been shown to stimulate angiogenesis by inducing endothelial cell tubulogenesis. However, its limited availability by enzymatic reactions has hindered detailed biological investigation. Herein, we report the first total synthesis of HKD2 through a convergent coupling of three segments bearing all required stereogenic centers. Key transformations include addition of dithiane anion to a lactone segment to construct the hemiacetal moiety and a late-stage cross metathesis with carboxylic acid segment to complete the synthesis.<\/jats:p>","DOI":"10.1021\/acs.joc.6c01433","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T15:02:38Z","timestamp":1786201358000},"page":"11587-11590","source":"Crossref","is-referenced-by-count":0,"title":["Total Synthesis of Hemiketal\nD2 via a Convergent\nCoupling Strategy"],"prefix":"10.1021","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3143-4576","authenticated-orcid":true,"given":"Tadachika","family":"Miyasaka","sequence":"first","affiliation":[{"name":"Nagoya University , , Furo-cho , Chikusa-ku, ,","place":["Nagoya, Japan, 464-8601"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotoha","family":"Osuna","sequence":"additional","affiliation":[{"name":"Nagoya University , , Furo-cho , Chikusa-ku, ,","place":["Nagoya, Japan, 464-8601"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumie","family":"Nakashima","sequence":"additional","affiliation":[{"name":"Nagoya University , , Furo-cho , Chikusa-ku, ,","place":["Nagoya, Japan, 464-8601"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3194-607X","authenticated-orcid":true,"given":"Takahiro","family":"Shibata","sequence":"additional","affiliation":[{"name":"Nagoya University , , Furo-cho , Chikusa-ku, ,","place":["Nagoya, Japan, 464-8601"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1955-6618","authenticated-orcid":true,"given":"Toshio","family":"Nishikawa","sequence":"additional","affiliation":[{"name":"Nagoya University , , Furo-cho , Chikusa-ku, ,","place":["Nagoya, Japan, 464-8601"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,8]]},"reference":[{"key":"2026082211144668900_cit1","doi-asserted-by":"publisher","first-page":"1871","DOI":"10.1126\/science.294.5548.1871","article-title":"Prostaglandins\nand Leukotrienes: Advances in Eicosanoid Biology","volume":"294","author":"Funk","year":"2001","journal-title":"Science"},{"key":"2026082211144668900_cit2","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1042\/BJ20070289","article-title":"Biosynthesis and\nMetabolism of Leukotrienes","volume":"405","author":"Murphy","year":"2007","journal-title":"Biochem. J."},{"issue":"Suppl","key":"2026082211144668900_cit3","doi-asserted-by":"publisher","first-page":"S29","DOI":"10.1194\/jlr.R800042-JLR200","article-title":"Cyclooxygenases: Structural and Functional Insights","volume":"50","author":"Rouzer","year":"2009","journal-title":"J. Lipid Res."},{"key":"2026082211144668900_cit4","doi-asserted-by":"publisher","first-page":"6945","DOI":"10.1073\/pnas.1019473108","article-title":"Biosynthesis\nof Hemiketal Eicosanoids\nby Cross-Over of the 5-Lipoxygenase and Cyclooxygenase-2 Pathways","volume":"108","author":"Griesser","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026082211144668900_cit5","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1021\/ja056517y","article-title":"Convergent\nOxygenation of Arachidonic Acid by 5-Lipoxygenase and Cyclooxygenase-2","volume":"128","author":"Schneider","year":"2006","journal-title":"J. Am. Chem. Soc."},{"key":"2026082211144668900_cit6","doi-asserted-by":"publisher","first-page":"103050","DOI":"10.1016\/j.jbc.2023.103050","article-title":"The 5-Lipoxygenase\/Cyclooxygenase-2\nCross-Over Metabolite, Hemiketal E2, Enhances VEGFR2 Activation\nand Promotes Angiogenesis","volume":"299","author":"Nakashima","year":"2023","journal-title":"J. Biol. Chem."},{"key":"2026082211144668900_cit7","doi-asserted-by":"publisher","first-page":"4020","DOI":"10.1021\/acs.orglett.8b01578","article-title":"Total Synthesis and Biological Activity\nof the Arachidonic\nAcid Metabolite Hemiketal E2","volume":"20","author":"Boer","year":"2018","journal-title":"Org.\nLett."},{"key":"2026082211144668900_cit8","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1021\/jo051916x","article-title":"Total Synthesis of\n8,12-iso-iPF3r-VI, an EPA-Derived Isoprostane: Stereoselective Introduction\nof the Fifth Asymmetric Center","volume":"71","author":"Jacobo","year":"2006","journal-title":"J. Org. Chem."},{"key":"2026082211144668900_cit9","doi-asserted-by":"publisher","first-page":"11921","DOI":"10.1039\/D2CC04574E","article-title":"Asymmetric Total Synthesis of (+)-Dihydroitomanallene\nB and Formal Synthesis of (\u2212)-Kumausallene","volume":"58","author":"Fernandes","year":"2022","journal-title":"Chem. Commun."},{"key":"2026082211144668900_cit11","doi-asserted-by":"publisher","first-page":"2267","DOI":"10.1016\/S0040-4039(03)00282-X","article-title":"An Efficient\nMethod for Para-Methoxybenzyl Ether Formation with Lanthanum\nTriflate","volume":"44","author":"Rai","year":"2003","journal-title":"Tetrahedron Lett."},{"key":"2026082211144668900_cit12","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.1021\/jo00870a052","article-title":"Organoselenium\nChemistry. A Facile\nOne-Step Synthesis of Alkyl Aryl Selenides from Alcohols","volume":"41","author":"Grieco","year":"1976","journal-title":"J. Org. Chem."},{"key":"2026082211144668900_cit13","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.3987\/R-1983-08-1541","article-title":"Influence of Heteroaromatic Amines\nto Knoevenagel Condensation","volume":"20","author":"Yamanaka","year":"1983","journal-title":"Heterocycles"},{"key":"2026082211144668900_cit17","doi-asserted-by":"publisher","first-page":"2491","DOI":"10.1246\/bcsj.72.2491","article-title":"Room-Temperature\nMetallation of 2-Substituted 1,3-Dithiane\nDerivatives and Subsequent Coupling with 2,3-Disubstituted Oxiranes","volume":"72","author":"Ide","year":"1999","journal-title":"Bull. Chem. Soc. Jpn."},{"key":"2026082211144668900_cit18","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1002\/anie.200502485","article-title":"Soluble Lanthanide Salts (LnCl3\u00b72LiCl) for the Improved Addition of OrganomagnesiumReagents\nto Carbonyl Compounds","volume":"45","author":"Krasovskiy","year":"2006","journal-title":"Angew. Chem., Int. 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Commun."},{"key":"2026082211144668900_cit21","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/S0040-4039(00)95181-5","article-title":"Simple Method of\nDethioacetalization","volume":"30","author":"Stork","year":"1989","journal-title":"Tetrahedron Lett."},{"key":"2026082211144668900_cit22","first-page":"109","article-title":"3-Alkylated and\n3-Acylated Indoles from a Common Precursor:\n3-Benzylidole and 3-Benzoylindole","volume":"6","author":"Stu\u0308tz","year":"1988","journal-title":"Org. Synth.,\nCollect"},{"key":"2026082211144668900_cit23","doi-asserted-by":"publisher","first-page":"4037","DOI":"10.1016\/S0040-4039(02)00740-2","article-title":"An Efficient Method\nfor the Cleavage of p-Methoxybenzylidene (PMP), Tetrahydropyranyl\n(THP) and 1,3-Dithiane\nProtecting Groups by Selectfluor","volume":"43","author":"Liu","year":"2002","journal-title":"Tetrahedron\nLett."},{"key":"2026082211144668900_cit24","doi-asserted-by":"publisher","first-page":"3553","DOI":"10.1021\/jo00822a019","article-title":"Oxidative Hydrolysis\nof 1,3-Dithiane Derivatives to\nCarbonyl Compounds using N-Halosuccinimide Reagents","volume":"36","author":"Corey","year":"1971","journal-title":"J. Org. Chem."},{"key":"2026082211144668900_cit25","doi-asserted-by":"publisher","first-page":"2123","DOI":"10.1039\/c001794a","article-title":"Structure\nElucidation of Hypocreolide A by Enantioselective Total Synthesis","volume":"8","author":"Go\u0308tz","year":"2010","journal-title":"Org. Biomol. Chem."}],"container-title":["The Journal of Organic Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.joc.6c01433","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/joceah\/article-pdf\/91\/33\/11587\/66464532\/acs.joc.6c01433.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/joceah\/article-pdf\/91\/33\/11587\/66464532\/acs.joc.6c01433.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T15:15:34Z","timestamp":1787411734000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/joceah\/article\/91\/33\/11587\/5250671\/Total-Synthesis-of-Hemiketal-D2-via-a-Convergent"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,8]]},"references-count":21,"journal-issue":{"issue":"33","published-online":{"date-parts":[[2026,8,8]]},"published-print":{"date-parts":[[2026,8,21]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.joc.6c01433","relation":{},"ISSN":["0022-3263","1520-6904"],"issn-type":[{"value":"0022-3263","type":"print"},{"value":"1520-6904","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,8]]}}}