Shuangyi Wan

Total synthesis and biological evaluation of pederin, psymberin, and highly potent analogs.

The potent cytotoxins pederin and psymberin have been prepared through concise synthetic routes (10 and 14 steps in the longest linear sequences, respectively) that proceed via a late-stage multicomponent approach to construct the N-acyl aminal linkages. This route allowed for the facile preparation of a number of analogs that were designed to explore the importance of the alkoxy group in the N-acyl aminal and functional groups in the two major subunits on biological activity. These analogs, including a pederin/psymberin chimera, were analyzed for their growth inhibitory effects, revealing several new potent cytotoxins and leading to postulates regarding the molecular conformational and hydrogen bonding patterns that are required for biological activity. Second generation analogs have been prepared based on the results of the initial assays and a structure-based model for the binding of these compounds to the ribosome. The growth inhibitory properties of these compounds are reported. These studies show the profound role that organic chemistry in general and specifically late-stage multicomponent reactions can play in the development of unique and potent effectors for biological responses.

Total Synthesis of the Protein Phosphatase 2A Inhibitor Lactodehydrothyrsiferol

Red algae are a prolific source of squalene-derived poly-ethers[1] that show moderate to high levels of cytotoxicity[2] and very selective protein phosphatase 2A (PP2A) inhibition. [3] These unique structures (see Figure 1 for examples) have inspired total syntheses of the family members venus-atriol, [4] thyrsiferol and its esters, [4b,5] pseudodehydrothyrsiferol, [6] and dioxepanedehydrothyrsiferol, [7] in addition to subunit and analogue syntheses. [8] Our interest in this molecule class arose from our work[9] on the construction of cyclic ethers through epoxide-opening cascade reactions. [10] Lactodehydrothyrsiferol (1), isolated from the red seaweed Laurencia viridis found near the Canary Islands, [11] attracted our attention because of its unique butyrolactone group and the challenges associated with applying an epoxide-opening cascade to construct the tetrahydropyran subunits. Herein, we report the first total synthesis of 1. The sequence features an oxidatively initiated cascade reaction, a stereodivergent diene double epoxidation reaction, a diastereoselective fragment coupling through a Nozaki–Hiyama–Kishi reaction, and a selective monodeoxygenation of a triol.

Multicomponent Synthesis of α-Branched Amides

Alpha-branched amides are prepared by multicomponent reactions in which nitriles undergo hydrozirconation to form metalloimines that react with acyl chlorides. The resulting acylimines react with a variety of pi-nucleophiles in the presence of Lewis acids to form the desired amides.