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Addition of ethanol aided an early termination of the cascade by scavenging the THP group after the halofunctionalization stage, furnishing monobromospiroketals. Alternatively, exclusion of ethanol from the reaction mixture biased the transient oxocarbenium towards \u03b1\u2010deprotonation that precedes a second bromofunctionalization event thus, furnishing dibrominated spiroketals. The regio\u2010 and stereoselectivity exploited in the current methodology provides a novel and rapid access to the dibrominated spiroketal motifs exhibited by several natural products.<\/jats:p>","DOI":"10.1002\/anie.202115173","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T06:00:43Z","timestamp":1639029643000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Mechanistically Inspired Halenium Ion Initiated Spiroketalization: Entry to Mono\u2010 and Dibromospiroketals"],"prefix":"10.1002","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8264-6558","authenticated-orcid":false,"given":"Kumar Dilip","family":"Ashtekar","sequence":"first","affiliation":[{"name":"Cancer Biology Institute Yale School of Medicine  West Haven Connecticut 06516 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USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,1,11]]},"reference":[{"key":"e_1_2_3_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr00097a015"},{"key":"e_1_2_3_2_1","unstructured":"\u00a0"},{"key":"e_1_2_3_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00156a031"},{"key":"e_1_2_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)94309-0"},{"key":"e_1_2_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)98454-5"},{"key":"e_1_2_3_6_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00225a031"},{"key":"e_1_2_3_7_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr050559n"},{"key":"e_1_2_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10932"},{"key":"e_1_2_3_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja302704m"},{"key":"e_1_2_3_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201203847"},{"key":"e_1_2_3_10_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201203847"},{"key":"e_1_2_3_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol500853q"},{"key":"e_1_2_3_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.1c02271"},{"key":"e_1_2_3_13_1","unstructured":"\u00a0"},{"key":"e_1_2_3_14_2","doi-asserted-by":"publisher","DOI":"10.1080\/00397919408011735"},{"key":"e_1_2_3_15_2","doi-asserted-by":"publisher","DOI":"10.1039\/b200215a"},{"key":"e_1_2_3_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol070488"},{"key":"e_1_2_3_17_2","doi-asserted-by":"publisher","DOI":"10.1039\/c2ob25100k"},{"key":"e_1_2_3_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol500741a"},{"key":"e_1_2_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41929-020-00530-9"},{"key":"e_1_2_3_20_1","unstructured":"\u00a0"},{"key":"e_1_2_3_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja4072145"},{"key":"e_1_2_3_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja506889c"},{"key":"e_1_2_3_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b02877"},{"key":"e_1_2_3_24_1","unstructured":"\u00a0"},{"key":"e_1_2_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(01)86430-3"},{"key":"e_1_2_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)88283-0"},{"key":"e_1_2_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2005.08.008"},{"key":"e_1_2_3_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo00022a003"},{"key":"e_1_2_3_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr00054a001"},{"key":"e_1_2_3_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5b12528"},{"key":"e_1_2_3_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b02856"},{"key":"e_1_2_3_32_1","unstructured":"\u00a0"},{"key":"e_1_2_3_33_2","doi-asserted-by":"publisher","DOI":"10.1039\/c39860000855"},{"key":"e_1_2_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)95911-2"},{"key":"e_1_2_3_35_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00274a061"},{"key":"e_1_2_3_36_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol0266875"},{"key":"e_1_2_3_37_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol202483u"},{"key":"e_1_2_3_38_1","doi-asserted-by":"publisher","DOI":"10.1039\/c3cc43950j"},{"key":"e_1_2_3_39_1","unstructured":"In accord to the Boltzmann distributions observed in our computational analysis (HalA) we surmise as follows: the conformational constrains in the cyclic \u2212OTHP ether of7\u2009aallows for a more pronounced anomeric effect (towards stability of the oxacarbenium intermediate) in comparison to the conformationally pliable \u2212OMOM ether. Similarly the conformational flexibility (and the sterics associated with the rotation along ArCH2\u2013O bond) in thep-methoxybenzyl protection in7\u2009a-PMB limits the extent of \u03c3\u2192\u03c3* donation required for templating the oxacarbenium intermediate. In contrast the steric bulk alone of the silyl ethers in7\u2009a(-TBS and -TES) restrict the proximity of \u2013OSiR3to ketone carbonyl required for the templation (see TS-4 in Scheme\u20053b). Hence the observed mass balance (after extended reaction times) accounted for undesired oxidation and elimination products."},{"key":"e_1_2_3_40_1","unstructured":"HalA values are thermodyamic state functions. Although the predicted HalA(Br) for the formation of12\u2009ais lower by about 5\u2005kcal\u2009mol\u22121(in comparison to11\u2009a\u2019\u21928\u2009a) the corresponding hemiketal11\u2009ais energetically more favored due to its trans-decalin arrangement orienting the more nucleophilic ether moiety for olefin bromofunctionalization. This case demonstrates the drawback resulting from kinetic bias caused by pre-existing mixture of hemiketals undergoing spiroketalization (Curtin\u2013Hammett principle). Hence the present approach using protected alcohol circumvents this bias recoursing the reaction pathway under thermodynamic control. See Supporting Information for further discussion."},{"key":"e_1_2_3_41_1","unstructured":"\u00a0"},{"key":"e_1_2_3_42_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo9716688"},{"key":"e_1_2_3_43_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja005892h"},{"key":"e_1_2_3_44_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol701768n"},{"key":"e_1_2_3_45_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol2011117"},{"key":"e_1_2_3_46_1","unstructured":"Owing to the intramolecular dominance of the templating group hemiketal adducts of ethanol and7\u2009awere not observed by1H NMR analysis (see Supporting Information for details) consequently the inter-molecular halofunctionalized products arising from the putative ethanol adducts were not obtained."},{"key":"e_1_2_3_47_1","unstructured":"Deposition Numbers 2124151 (for macrocyclic bromoether-12a) 124153 (for monobromospiroketal-8c) 2124154 (for 6 5-spiroketal-15) and 2124152 (for dibromospiroketal-9c)contain the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures servicewww.ccdc.cam.ac.uk\/structures."},{"key":"e_1_2_3_48_1","unstructured":"\u00a0"},{"key":"e_1_2_3_49_2","doi-asserted-by":"publisher","DOI":"10.1080\/00397919208021632"},{"key":"e_1_2_3_50_2","doi-asserted-by":"publisher","DOI":"10.1002\/1099-0690(200208)2002:15<2640::AID-EJOC2640>3.0.CO;2-9"},{"key":"e_1_2_3_51_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo0513966"},{"key":"e_1_2_3_52_2","doi-asserted-by":"publisher","DOI":"10.1039\/c2cy20403g"},{"key":"e_1_2_3_53_1","unstructured":"\u00a0"},{"key":"e_1_2_3_54_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1005296107"},{"key":"e_1_2_3_55_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja100173w"},{"key":"e_1_2_3_56_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol1028805"},{"key":"e_1_2_3_57_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol203033k"},{"key":"e_1_2_3_58_2","doi-asserted-by":"publisher","DOI":"10.1039\/c2cc31148h"},{"key":"e_1_2_3_59_2","doi-asserted-by":"publisher","DOI":"10.1002\/chir.22259"},{"key":"e_1_2_3_60_2","doi-asserted-by":"publisher","DOI":"10.1071\/CH20184"},{"key":"e_1_2_3_61_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol102201z"},{"key":"e_1_2_3_62_1","unstructured":"\u00a0"},{"key":"e_1_2_3_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/0031-9422(81)85190-4"},{"key":"e_1_2_3_64_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00229a029"},{"key":"e_1_2_3_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(01)89125-0"},{"key":"e_1_2_3_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/0031-9422(90)80183-H"},{"key":"e_1_2_3_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/0031-9422(91)84132-C"},{"key":"e_1_2_3_68_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00061a025"},{"key":"e_1_2_3_69_2","first-page":"5927","volume":"16","author":"Demirel Z.","year":"2011","journal-title":"Rom. 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