Remarkable Switch of Regioselectivity in Diels–Alder Reaction: Divergent Total Synthesis of Borreverine, Caulindoles, and Flinderoles

Switchable reaction patterns of dimerization of indole substituted butadienes via a Lewis acid and thermal activation are reported. While under acidic conditions dimerization occurred around the internal double bond of the dienophile, a complete switch of regioselectivity was observed under thermal conditions, where dimerization occurred around the terminal double bond of the dienophile. This switch of regioselectivity was further exploited for the divergent total synthesis of structurally diverse indole alkaloid natural products

Remarkable Switch of Regioselectivity in Diels–Alder Reaction: Divergent Total Synthesis of Borreverine, Caulindoles, and Flinderoles

Switchable reaction patterns of dimerization of indole substituted butadienes via a Lewis acid and thermal activation are reported. While under acidic conditions dimerization occurred around the internal double bond of the dienophile, a complete switch of regioselectivity was observed under thermal conditions, where dimerization occurred around the terminal double bond of the dienophile. This switch of regioselectivity was further exploited for the divergent total synthesis of structurally diverse indole alkaloid natural products

Remarkable Switch of Regioselectivity in Diels–Alder Reaction: Divergent Total Synthesis of Borreverine, Caulindoles, and Flinderoles

Switchable reaction patterns of dimerization of indole substituted butadienes via a Lewis acid and thermal activation are reported. While under acidic conditions dimerization occurred around the internal double bond of the dienophile, a complete switch of regioselectivity was observed under thermal conditions, where dimerization occurred around the terminal double bond of the dienophile. This switch of regioselectivity was further exploited for the divergent total synthesis of structurally diverse indole alkaloid natural products

Improved Total Synthesis of Tubulysins and Design, Synthesis, and Biological Evaluation of New Tubulysins with Highly Potent Cytotoxicities against Cancer Cells as Potential Payloads for Antibody–Drug Conjugates

Improved, streamlined total syntheses of natural tubulysins such as V (<b>Tb45</b>) and U (<b>Tb46</b>) and pretubulysin D (<b>PTb-D43</b>), and their application to the synthesis of designed tubulysin analogues (<b>Tb44</b>, <b>PTb-D42</b>, <b>PTb-D47</b>–<b>PTb-D49</b>, and <b>Tb50</b>–<b>Tb120</b>), are described. Cytotoxicity evaluation of the synthesized compounds against certain cancer cell lines revealed a number of novel analogues with exceptional potencies [e.g., <b>Tb111</b>: IC₅₀ = 40 pM against MES SA (uterine sarcoma) cell line; IC₅₀ = 6 pM against HEK 293T (human embryonic kidney cancer) cell line; and IC₅₀ = 1.54 nM against MES SA DX (MES SA with marked multidrug resistance) cell line]. These studies led to a set of valuable structure–activity relationships that provide guidance to further molecular design, synthesis, and biological evaluation studies. The extremely potent cytotoxic compounds discovered in these investigations are highly desirable as potential payloads for antibody–drug conjugates and other drug delivery systems for personalized targeted cancer chemotherapies

Streamlined Total Synthesis of Trioxa­carcins and Its Application to the Design, Synthesis, and Biological Evaluation of Analogues Thereof. Discovery of Simpler Designed and Potent Trioxa­carcin Analogues

A streamlined total synthesis of the naturally occurring antitumor agents trioxa­carcins is described, along with its application to the construction of a series of designed analogues of these complex natural products. Biological evaluation of the synthesized compounds revealed a number of highly potent, and yet structurally simpler, compounds that are effective against certain cancer cell lines, including a drug-resistant line. A novel one-step synthesis of anthra­quinones and chloro anthra­quinones from simple ketone precursors and phenyl­selenyl chloride is also described. The reported work, featuring novel chemistry and cascade reactions, has potential applications in cancer therapy, including targeted approaches as in antibody–drug conjugates