{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T22:51:26Z","timestamp":1783119086313,"version":"3.54.6"},"reference-count":34,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T00:00:00Z","timestamp":1687996800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NSF CHE CAREER","award":["#1848257"],"award-info":[{"award-number":["#1848257"]}]},{"name":"NSF CHE CAREER","award":["#0840390"],"award-info":[{"award-number":["#0840390"]}]},{"name":"NSF CHE CAREER","award":["#1449999"],"award-info":[{"award-number":["#1449999"]}]},{"name":"NSF MRI","award":["#1848257"],"award-info":[{"award-number":["#1848257"]}]},{"name":"NSF MRI","award":["#0840390"],"award-info":[{"award-number":["#0840390"]}]},{"name":"NSF MRI","award":["#1449999"],"award-info":[{"award-number":["#1449999"]}]},{"name":"NSF National Research Traineeship","award":["#1848257"],"award-info":[{"award-number":["#1848257"]}]},{"name":"NSF National Research Traineeship","award":["#0840390"],"award-info":[{"award-number":["#0840390"]}]},{"name":"NSF National Research Traineeship","award":["#1449999"],"award-info":[{"award-number":["#1449999"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>This paper describes the three-step synthesis of TBS-MAC, a masked acyl cyanide (MAC) and a versatile one-carbon oxidation state three synthon. We have developed a scalable and detailed synthesis that involves: (1) acetylation of malononitrile to form the sodium enolate, (2) protonation of the enolate to form acetylmalononitrile, and (3) epoxidation of the enol, rearrangement to an unstable alcohol, and TBS-protection to form the title compound. Both the sodium enolate and acetylmalononitrile are bench-stable precursors to the intermediate hydroxymalononitrile, which can be converted to other MAC reagents beyond TBS by varying the protecting group (Ac, MOM, EE, etc.).<\/jats:p>","DOI":"10.3390\/molecules28135087","type":"journal-article","created":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T01:14:12Z","timestamp":1688087652000},"page":"5087","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Scalable Preparation of the Masked Acyl Cyanide TBS-MAC"],"prefix":"10.3390","volume":"28","author":[{"given":"Haley","family":"Hinton","sequence":"first","affiliation":[{"name":"Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, MS 39406, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Patterson","sequence":"additional","affiliation":[{"name":"Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, MS 39406, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared","family":"Hume","sequence":"additional","affiliation":[{"name":"Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, MS 39406, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1232-3264","authenticated-orcid":false,"given":"Krunal","family":"Patel","sequence":"additional","affiliation":[{"name":"Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, MS 39406, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1289-5679","authenticated-orcid":false,"given":"Julie","family":"Pigza","sequence":"additional","affiliation":[{"name":"Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, MS 39406, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4515","DOI":"10.1021\/jo00302a008","article-title":"Development of a New Acyl Anion Equivalent for the Preparation of Masked Activated Esters and Their Use To Prepare a Dipeptide","volume":"55","author":"Nemoto","year":"1990","journal-title":"J. Org. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1039\/D1OB02411F","article-title":"A case study of the MAC (masked acyl cyanide) oxyhomologation of N,N-dibenzyl-Lphenylalaninal with anti diastereoselectivity: Preparation of (2S,3S)-allophenylnorstatin esters","volume":"20","author":"He","year":"2022","journal-title":"Org. Biomol. Chem."},{"key":"ref_3","unstructured":"Nemoto, H. (2007). e-EROS Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons, Ltd."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/anie.197902393","article-title":"Methods of Reactivity Umpolung","volume":"18","author":"Seebach","year":"1979","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_5","first-page":"73","article-title":"A Compilation of References on Formyl and Acyl Anion Synthons","volume":"14","author":"Hase","year":"1981","journal-title":"Aldrichimica Acta"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1021\/acs.orglett.6b00790","article-title":"One-Carbon Homologation of Primary Alcohols to Carboxylic Acids, Esters, and Amides via Mitsunobu Reactions with MAC Reagents","volume":"18","author":"Kagawa","year":"2016","journal-title":"Org. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1021\/acs.orglett.7b00449","article-title":"Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents","volume":"19","author":"Hethcox","year":"2017","journal-title":"Org. Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.1021\/ja00086a071","article-title":"Transition Metal Catalyzed Addition of Certain Nucleophiles to Imines","volume":"116","author":"Yamamoto","year":"1994","journal-title":"J. Am. Chem. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4245","DOI":"10.1021\/ol006816m","article-title":"A New One-Pot Method for the Synthesis of \u03b1-Siloxyamides from Aldehydes or Ketones and Its Application to the Synthesis of (-)-Bestatin","volume":"2","author":"Nemoto","year":"2000","journal-title":"Org. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"14546","DOI":"10.1021\/ja054010h","article-title":"A Highly Efficient Carbon-Carbon Bond Formation Reaction via Nucleophilic Addition to N-Alkylaldimines without Acids or Metallic Species","volume":"127","author":"Nemoto","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6038","DOI":"10.1021\/jo0607515","article-title":"Synthesis of \u03b1-Amino Acid Precursors Directly from Aldehydes Using Masked Acyl Cyanide Reagents and N,O-Dialkylated Hydroxylamines","volume":"71","author":"Nemoto","year":"2006","journal-title":"J. Org. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.tetasy.2007.01.032","article-title":"Highly diastereoselective nucleophilic addition reactions of masked acyl cyanide reagents to tert-butanesulfiminides","volume":"18","author":"Nemoto","year":"2007","journal-title":"Tetrahedron Asymm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"16148","DOI":"10.1021\/ja510135t","article-title":"Synthesis of \u03b1-Amino Acid Derivatives and Peptides via Enantioselective Addition of Masked Acyl Cyanides to Imines","volume":"136","author":"Yang","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1002\/adsc.202101114","article-title":"Enantiodivergent Reaction of Ketimines with Malononitriles Using Single Cinchona Alkaloid Sulfonamide Catalysts","volume":"364","author":"Nakamura","year":"2022","journal-title":"Adv. Syn. Catal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9850","DOI":"10.1021\/jo701859a","article-title":"Direct One-Pot Synthesis of \u03b1-Siloxy-Weinreb Amides from Aldehydes","volume":"72","author":"Nemoto","year":"2007","journal-title":"J. Org. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3819","DOI":"10.1055\/s-0028-1083219","article-title":"One-Pot Synthesis of \u03b1-Siloxy Esters Using a Silylated Masked Acyl Cyanide","volume":"23","author":"Nemoto","year":"2008","journal-title":"Synthesis"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1055\/s-0028-1088044","article-title":"One-Portion Synthesis of 2-Acetoxy Carbonyl Compounds from Aldehydes by Using an Acetylated Masked Acyl Cyanide","volume":"10","author":"Nemoto","year":"2009","journal-title":"Synthesis"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8387","DOI":"10.1002\/chem.201901093","article-title":"Synthesis of All Stereoisomers of Monomeric Spectomycin A1\/A2 and Evaluation of Their Protein SUMOylation-Inhibitory Activity","volume":"25","author":"Nomura","year":"2019","journal-title":"Chem. Eur. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2378","DOI":"10.1021\/acs.orglett.9b00664","article-title":"Reversal of Diastereoselectivity in a Masked Acyl Cyanide (MAC) Reaction: Synthesis of Protected erythro-\u03b2-Hydroxyaspartate Derivatives","volume":"21","author":"Esgulian","year":"2019","journal-title":"Org. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2529","DOI":"10.3762\/bjoc.14.229","article-title":"Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: Preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives","volume":"14","author":"Jentsch","year":"2018","journal-title":"Beilstein J. Org. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7195","DOI":"10.1021\/jo00026a003","article-title":"Synthesis of 1,4-Dicarbonyl Compounds via the Conjugate Addition of a Masked Activated Ester, ROCH(CN)2","volume":"56","author":"Kuboto","year":"1991","journal-title":"J. Org. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"16050","DOI":"10.1021\/ja409012q","article-title":"Squaramide-Catalyzed Enantioselective Michael Addition of Masked Acyl Cyanides to Substituted Enones","volume":"135","author":"Rawal","year":"2013","journal-title":"J. Am. Chem. Soc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1055\/s-0036-1590947","article-title":"Synthesis of Malononitrile-Substituted Diarylmethines via 1,6-Addition of Masked Acyl Cyanides to para-Quinone Methides","volume":"50","author":"Zhao","year":"2018","journal-title":"Synthesis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6840","DOI":"10.1002\/anie.200802005","article-title":"Total Synthesis of Cyclotheonamide C using a Tandem Backbone-Extension\u2013Coupling Methodology","volume":"47","author":"Roche","year":"2008","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1002\/anie.200804777","article-title":"A Synthesis of Tamiflu by Using a Barium-Catalyzed Asymmetric Diels\u2013Alder-Type Reaction","volume":"48","author":"Yamatsugu","year":"2009","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13683","DOI":"10.1021\/jacs.0c06641","article-title":"Total Synthesis of Tagetitoxin","volume":"142","author":"He","year":"2020","journal-title":"J. Am. Chem. Soc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1021\/acs.jmedchem.1c01583","article-title":"Elastase Inhibitor Cyclotheonellazole A: Total Synthesis and In Vivo Biological Evaluation for Acute Lung Injury","volume":"65","author":"Cui","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0040-4039(02)02483-8","article-title":"A three-step preparation of MAC reagents from malononitrile","volume":"44","author":"Nemoto","year":"2003","journal-title":"Tetrahedron Lett."},{"key":"ref_29","first-page":"216","article-title":"Acylation of cyanoacetic ester by acetic anhydride and potassium carbonate","volume":"56","author":"Hori","year":"1962","journal-title":"Sci. Papers Inst. Phys. Chem. Res."},{"key":"ref_30","unstructured":"Fleury, J.P., and Libis, B. (1964). Acyl-et sulfonylmalodinitriles et leurs sels de triethylamine. Bull. Soc. Chim. Fr., 413\u2013414."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1021\/acsmedchemlett.8b00269","article-title":"Synthesis and Evaluation of Aryl Quinolines as HIV-1 Integrase Multimerization Inhibitors","volume":"9","author":"Jentsch","year":"2018","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"100363","DOI":"10.1016\/j.jbc.2021.100363","article-title":"Optimized binding of substituted quinoline ALLINIs within the HIV-1 integrase oligomer","volume":"296","author":"Sun","year":"2021","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s40242-015-4495-6","article-title":"2-Hydroxymalonitrile\u2014A Useful Reagent for One-step Synthesis of \u03b1-Hydroxy Esters","volume":"31","author":"Yang","year":"2015","journal-title":"Chem. Res. Chin. Univ."},{"key":"ref_34","unstructured":"(2022, June 27). Organic Syntheses Instructions for Authors, Appendix 1. Available online: http:\/\/www.orgsyn.org\/instructions.aspx."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/13\/5087\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:03:29Z","timestamp":1760126609000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/13\/5087"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,29]]},"references-count":34,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["molecules28135087"],"URL":"https:\/\/doi.org\/10.3390\/molecules28135087","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,29]]}}}