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oai:figshare.com:article/34018396 2026-09-28T20:10:10Z category_1 category_4 category_7 category_21 category_24 category_873 category_39 category_45 category_62 category_69 category_132 category_133 portal_63 item_type_6 month_year_09_2026

Resolving Structural Ambiguity through Total Synthesis: Evolution of a Synthetic Strategy for Secalosides A and B Yunchan Nam (17708891) Anthony T. Tam (14373174) Diego N. Rojas (22908516) Troy E. Reynolds (2319940) Jonathan A. Brekan (2310949) Sneha Sil (22908519) Karl A. Scheidt (493484) Biophysics Biochemistry Medicine Biotechnology Evolutionary Biology Chemical Sciences not elsewhere classified Ecology Sociology Marine Biology Inorganic Chemistry Infectious Diseases Plant Biology standing ambiguity regarding spectral data comparison intramolecular heck cyclization inefficient redox manipulations highly strained ten definitive structural elucidation configurationally correct stereotriad >- heterocyclic carbene resolving structural ambiguity induced divergent reactivity first total synthesis complex total syntheses embedded indane core total synthesis indane core undesired reactivity thereby resolving successful syntheses ultimately enabled true structures tactical exploitation successful late stage ring routes suffer revised route proposed structures poor selectivity n </ membered bis macrocyclic character initial efforts house methodologies full account ene reaction cyclopentane bearing concomitant formation asymmetric carbonyl acyclic variant Herein, we report a full account of the evolution of a strategy that ultimately enabled the first total synthesis and definitive structural elucidation of secalosides A and B. The unambiguous structural assignment required the complex total syntheses of two proposed diastereomeric structures. Initial efforts were based on the use of our in-house methodologies to access the indane core of secalosides. These featured an asymmetric carbonyl-ene reaction, an intramolecular Heck cyclization, and <i>N</i>-heterocyclic carbene (NHC) chemistry. However, these routes suffer from inefficient redox manipulations, poor selectivity, and undesired reactivity, hindering the preparation of the embedded indane core. The key to our revised route was a successful late-stage ring-contraction strategy that allowed for the concomitant formation of the highly strained ten-membered bis-lactone and the cyclopentane bearing the configurationally correct stereotriad. This transformation was achieved by tactical exploitation of macrocyclic character, which induced divergent reactivity from its acyclic variant, enabling an unusual transannular oxidative enolate coupling. This strategy led to successful syntheses of both proposed structures and allowed for spectral data comparison with those of the natural secalosides, thereby resolving the long-standing ambiguity regarding the true structures of secalosides A and B. 2026-09-28T00:00:00Z Text Journal contribution 10.1021/jacs.6c10893.s001 https://figshare.com/articles/journal_contribution/Resolving_Structural_Ambiguity_through_Total_Synthesis_Evolution_of_a_Synthetic_Strategy_for_Secalosides_A_and_B/34018396 CC BY-NC 4.0