Total Synthesis of the EF Fragment of Spongistatin 1 en Route to a Spongistatin 1 Analog

A major goal of the Leighton group is the synthesis of biologically relevant polyketide natural products. Among the most potent and chemically intriguing member of this class is spongistatin 1. This molecule has interested biologists and chemists for more than two decades. In this thesis, we report a highly practical and efficient synthesis of the EF fragment of spongistatin 1. This relied on the rapid introduction of a complex stereochemical array using double cross-metathesis/Sharpless asymmetric dihydroxylation reactions to quickly build the F-ring of spongistatin. The six contiguous stereocenters of the F-ring were established in just five steps. A new one-pot asymmetric strained-silane mediated allylation was developed that was greatly improved over previous methods in regards to practicality and substrate scope. This methodology was used to introduce the sensitive chlorodiene side chain. Finally, completion of the EF fragment led to the synthesis of a spongistatin 1 analog, using our previously developed redesigned ABCD fragment

Shattered Legs, Softened Hearts:

What does it look like to cooperate with God’s grace, and what does it look like to hide from it? In 1521, Ignatius of Loyola, an ambitious and promising young soldier in the Spanish army, is shot in the leg and suffers a career-ending injury that sparks his eventual conversion to Christianity. It would appear, looking back on this event, that grace came for Ignatius in a form that could only be recognized at the time as tragedy and senseless suffering. Four hundred thirty four years later, Flannery O’Connor, a young novelist from Georgia, writes the short story of a woman named Hulga who, after losing a leg in a shooting accident as a young girl, recedes into isolation and naked contempt for all those closest to her until one day a mysterious visitor knocks at the door of her family home. For Hulga too, grace may be out to find her in the place she might least expect. This paper will hold up the figures of St. Ignatius and Hulga as a comparative case study in which to examine the working out of God’s grace in the economy of a human life. Ignatius, through his humility and loyalty to Christ in the wake of his injury, is an icon of God’s grace and the conversion to which it calls him. Hulga, in her obstinate scorn and self-proclaimed superiority over all those who seek relationship with her, is the epitome of the one who resists the love of the Other. Even still, there may be hope for Hulga yet by the story’s end.</jats:p

Maine Milestones piece on Parker Small, 72, of Wells, who, in 1938, was awarde

Maine Milestones piece on Parker Small, 72, of Wells, who, in 1938, was awarded the George H. Vinall Trophy for being the top player-sportsman in the Western Maine basketball championship

Shattered Legs, Softened Hearts:

What does it look like to cooperate with God’s grace, and what does it look like to hide from it? In 1521, Ignatius of Loyola, an ambitious and promising young soldier in the Spanish army, is shot in the leg and suffers a career-ending injury that sparks his eventual conversion to Christianity. It would appear, looking back on this event, that grace came for Ignatius in a form that could only be recognized at the time as tragedy and senseless suffering. Four hundred thirty four years later, Flannery O’Connor, a young novelist from Georgia, writes the short story of a woman named Hulga who, after losing a leg in a shooting accident as a young girl, recedes into isolation and naked contempt for all those closest to her until one day a mysterious visitor knocks at the door of her family home. For Hulga too, grace may be out to find her in the place she might least expect. This paper will hold up the figures of St. Ignatius and Hulga as a comparative case study in which to examine the working out of God’s grace in the economy of a human life. Ignatius, through his humility and loyalty to Christ in the wake of his injury, is an icon of God’s grace and the conversion to which it calls him. Hulga, in her obstinate scorn and self-proclaimed superiority over all those who seek relationship with her, is the epitome of the one who resists the love of the Other. Even still, there may be hope for Hulga yet by the story’s end

Exploiting Pseudo <i>C</i>₂‑Symmetry for an Efficient Synthesis of the F‑Ring of the Spongistatins

A concise and efficient synthesis of the F-ring fragment of the potent antimitotic marine macrolide spongistatin 1 has been developed. The key sequence involves double cross-metathesis/Sharpless asymmetric dihydroxylation reactions to establish four stereocenters in a pseudo <i>C</i>₂-symmetric array, followed by a selective protection reaction that breaks the pseudosymmetry, establishes a fifth stereocenter, and effectively differentiates the ester termini. Overall, the six contiguous stereocenters in the C(37)–C(45) F-ring fragment are established in just seven steps

Exploiting Pseudo <i>C</i>₂‑Symmetry for an Efficient Synthesis of the F‑Ring of the Spongistatins

A concise and efficient synthesis of the F-ring fragment of the potent antimitotic marine macrolide spongistatin 1 has been developed. The key sequence involves double cross-metathesis/Sharpless asymmetric dihydroxylation reactions to establish four stereocenters in a pseudo <i>C</i>₂-symmetric array, followed by a selective protection reaction that breaks the pseudosymmetry, establishes a fifth stereocenter, and effectively differentiates the ester termini. Overall, the six contiguous stereocenters in the C(37)–C(45) F-ring fragment are established in just seven steps

Design, 22-step synthesis, and evaluation of highly potent D-ring modified and linker-equipped analogs of spongistatin 1

With an average GI50 value against the NCI panel of 60 human cancer cell lines of 0.12 nM, spongistatin 1 is among the most potent anti-proliferative agents ever discovered rendering it an attractive candidate for development as a payload for antibody-drug conjugates and other targeted delivery approaches. It is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive, however, and its development requires more efficient and step-economical synthetic access. Using novel and uniquely enabling direct complex fragment coupling alkallyl- and crotylsilylation reactions, we have developed a 22-step synthesis of a rationally designed D-ring modified analog of spongistatin 1 that is equipotent with the natural product, and have used that synthesis to establish that the C(15) acetate may be replaced with a linker functional group-bearing ester with only minimal reductions in potency.</div

Design, 22-step synthesis, and evaluation of highly potent D-ring modified and linker-equipped analogs of spongistatin 1

With an average GI50 value against the NCI panel of 60 human cancer cell lines of 0.12 nM, spongistatin 1 is among the most potent anti-proliferative agents ever discovered rendering it an attractive candidate for development as a payload for antibody-drug conjugates and other targeted delivery approaches. It is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive, however, and its development requires more efficient and step-economical synthetic access. Using novel and uniquely enabling direct complex fragment coupling alkallyl- and crotylsilylation reactions, we have developed a 22-step synthesis of a rationally designed D-ring modified analog of spongistatin 1 that is equipotent with the natural product, and have used that synthesis to establish that the C(15) acetate may be replaced with a linker functional group-bearing ester with only minimal reductions in potency.&lt;br&gt;&lt;div&gt;&lt;br&gt;&lt;/div&gt;</jats:p

Design, 22-step synthesis, and evaluation of highly potent D-ring modified and linker-equipped analogs of spongistatin 1

With an average GI50 value against the NCI panel of 60 human cancer cell lines of 0.12 nM, spongistatin 1 is among the most potent anti-proliferative agents ever discovered rendering it an attractive candidate for development as a payload for antibody-drug conjugates and other targeted delivery approaches. It is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive, however, and its development requires more efficient and step-economical synthetic access. Using novel and uniquely enabling direct complex fragment coupling alkallyl- and crotylsilylation reactions, we have developed a 22-step synthesis of a rationally designed D-ring modified analog of spongistatin 1 that is equipotent with the natural product, and have used that synthesis to establish that the C(15) acetate may be replaced with a linker functional group-bearing ester with only minimal reductions in potency.<br><div><br></div