Enantioselective Total Synthesis of (−)-Laurenditerpenol

A highly convergent total synthesis of (−)-laurenditerpenol has been accomplished through an organolithium to aldehyde nucleophilic addition. Preparation of the prerequisite key intermediates in optically pure form was based on an improved, short, and efficient synthesis of “<i>wine lactone</i>” from (<i>S</i>)-limonene and Corey’s catalytic enantioselective Diels–Alder reaction of 2,5-dimethyl furan with diethyl fumarate

Enantioselective Total Synthesis of (−)-Laurenditerpenol

A highly convergent total synthesis of (−)-laurenditerpenol has been accomplished through an organolithium to aldehyde nucleophilic addition. Preparation of the prerequisite key intermediates in optically pure form was based on an improved, short, and efficient synthesis of “<i>wine lactone</i>” from (<i>S</i>)-limonene and Corey’s catalytic enantioselective Diels–Alder reaction of 2,5-dimethyl furan with diethyl fumarate

Total Synthesis and Full Structural Assignment of Namenamicin

Namenamicin is a rare natural product possessing potent cytotoxic properties that may prove useful as a lead compound for payloads of antibody–drug conjugates (ADCs). Its scarcity, coupled with the uncertainty of its full absolute configuration, elevates it to an attractive synthetic target. Herein we describe the total synthesis of the two C7′-epimers of namena­micin and assign its complete structure, opening the way for further chemical and biological studies toward the discovery of potent payloads for ADCs directed toward targeted cancer therapies

A Fast Entry to Furanoditerpenoid-Based Hedgehog Signaling Inhibitors: Identifying Essential Structural Features

New, small molecule Hedgehog (Hh) pathway inhibitors, such as the furanoditerpenoid taepeenin D, are of high medicinal importance. To establish key structure–activity relationships (SARs) for this lead, a synthetic sequence has been developed for the expedient preparation of several derivatives and their evaluation as Hh inhibitors exploiting its structural similarity to abietic acid. While C(14) substitution is not essential for biological activity, the presence of a hydrogen bond acceptor at C(6) and an intact benzofuran moiety are

Streamlined Total Synthesis of Uncialamycin and Its Application to the Synthesis of Designed Analogues for Biological Investigations

From the enediyne class of antitumor antibiotics, uncialamycin is among the rarest and most potent, yet one of the structurally simpler, making it attractive for chemical synthesis and potential applications in biology and medicine. In this article we describe a streamlined and practical enantioselective total synthesis of uncialamycin that is amenable to the synthesis of novel analogues and renders the natural product readily available for biological and drug development studies. Starting from hydroxy- or methoxyisatin, the synthesis features a Noyori enantioselective reduction, a Yamaguchi acetylide-pyridinium coupling, a stereoselective acetylide-aldehyde cyclization, and a newly developed annulation reaction that allows efficient coupling of a cyanophthalide and a <i>p</i>-methoxy semiquinone aminal to forge the anthraquinone moiety of the molecule. Overall, the developed streamlined synthesis proceeds in 22 linear steps (14 chromatographic separations) and 11% overall yield. The developed synthetic strategies and technologies were applied to the synthesis of a series of designed uncialamycin analogues equipped with suitable functional groups for conjugation to antibodies and other delivery systems. Biological evaluation of a select number of these analogues led to the identification of compounds with low picomolar potencies against certain cancer cell lines. These compounds and others like them may serve as powerful payloads for the development of antibody drug conjugates (ADCs) intended for personalized targeted cancer therapy