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Milgram, Benjamin Charles

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Milgram

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Benjamin Charles

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Milgram, Benjamin Charles

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2011 - 20143

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Now showing 1 - 3 of 3
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    Progress Toward the Total Synthesis of Vinigrol and Hibarimicin B
    (2014-02-25) Milgram, Benjamin Charles; Shair, Matthew David; Myers, Andrew; Kishi, Yoshito
    Vinigrol is a structurally unique diterpenoid natural product featuring a tricyclo[4.4.4.0.4a,8a]tetradecene carbon skeleton containing eight contiguous stereocenters and a challenging oxygenation pattern. Vinigrol has been demonstrated to possess a wide array of biological activities including tumor necrosis factor (TNF) antagonism, antihypertensive activity, and platelet aggregation inhibitory activity. Our first-generation plan for the synthesis of vinigrol utilized a cascade reaction sequence involving: (1) diastereoselective alkylation of an α-alkenyl-β-ketoester, (2) retro-aldol-aldol equilibration (3) anion-accelerated oxy-Cope rearrangement, and (4) transannular Dieckmann condensation to afford the bicyclo[5.3.1]undecene ring system of vinigrol in a single operation. Discoveries concerning the limitations of this process are disclosed. Our second-generation approach to vinigrol employed a cis-decalin substrate in an alternative cascade reaction sequence, which was expected to deliver the complete tricyclo[4.4.4.0.4a,8a]tetradecene carbon skeleton of vinigrol in one step. An unexpected deviation from the envisioned reaction pathway instead afforded an alternative tricyclic enol silane.
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    Gram-Scale Synthesis of the A′B′-Subunit of Angelmicin B
    (American Chemical Society (ACS), 2011) Milgram, Benjamin Charles; Liau, Brian; Shair, Matthew
    A gram-scale enantiospecific synthesis of the A’B’-subunit of angelmicin B is reported. The synthesis involves a Lewis acid-catalyzed contrasteric Diels–Alder reaction and a tandem silyl zincate 1,6-addition/enolate oxidation sequence.
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    Total Syntheses of HMP-Y1, Hibarimicinone, and HMP-P1
    (American Chemical Society, 2012) Liau, Brian; Milgram, Benjamin Charles; Shair, Matthew
    Total syntheses of HMP-Y1, atrop-HMP-Y1, hibarimicinone, atrop-hibarimicinone, and HMP-P1 are described using a two-directional synthesis strategy. A novel benzyl fluoride Michael–Claisen reaction sequence was developed to construct the complete carbon skeleton of HMP-Y1 and atrop-HMP-Y1 via a symmetrical, two-directional, double annulation. Through efforts to convert HMP-Y1 derivatives to hibarimicinone and HMP-P1, a biomimetic mono-oxidation to desymmetrize protected HMP-Y1 was realized. A two-directional unsymmetrical double annulation and biomimetic etherification were developed to construct the polycyclic and highly-oxidized skeleton of hibarimicinone, atrop-hibarimicinone, and HMP-P1. The use of a racemic biaryl precursor allowed for the synthesis of both hibarimicinone atropisomers and provides the first confirmation of the structure of atrop-hibarimicinone. Additionally, this work documents the first reported full characterization of atrop-hibarimicinone, HMP-Y1, atrop-HMP-Y1, and HMP-P1. Lastly, a pH-dependent rotational barrier about the C2–C2' bond of hibarimicinone was discovered, which provides valuable information necessary to achieve syntheses of the glycosylated congeners of hibarimicinone.