Recent Research Developments

Index of Recent Research News
March 16th, 2005
Ring Around the Nitrogen

    The 1,2,4-dithiazolidine-3,5-dione heterocycle 3 [alternatively, a dithiasuccinoyl (Dts)-amine] was first described in the German patent literature. The realization in 1977 that heterocycle 3 constituted an orthogonal amino protecting group, readily removable by thiols and other reducing agents was followed by extensive mechanistic work, as well as the development of applications to the syntheses of peptides, amino-sugars in glycopeptides, and peptide nucleic acids (PNA). The Dts heterocycle has also proved useful as a masked isocyanate and (inversely) as a sulfurization reagent for trivalent phosphorus, particularly for synthesis of phosphorothioate DNA.

    Methods described to date for transformation of amines to Dts-amines involve multiple operations, with concomitant reductions in overall yield and increases in formation of byproducts. It seemed plausible that bis(chlorocarbonyl)disulfane (1), the two-sulfur analogue of succinyl chloride, might be used in facile single-step elaborations of Dts-heterocycles 3 from primary amines. This seemingly straightforward approach failed, for a variety of reasons that have been studied thoroughly. Inspired by precedents from organosilicon chemistry, reactions of 1 with bis(trimethylsilyl)amines 2 instead of primary amines have been investigated. Now, Michael J. Barany, Robert P. Hammer, R.B. Merrifield, and George Barany have published [J. Amer. Chem. Soc. 127, 508-509 (2005)] on the development of a high-yield, direct synthesis of Dts-amines based on this plan (Scheme 1).

Scheme 1. Bis(silyl)amine route to Dts-amines

    The cited paper can be consulted for the experimental documentation and mechanistic reasoning behind the work (Scheme 1), which has demonstrated that Dts-amines can indeed be synthesized directly in a simple and robust reaction that uses the trimethylsilyl group as a “large proton” to circumvent extant synthetic problems. This simplification and improvement in the synthesis of 1,2,4-dithiazolidine-3,5-diones promises to open up new avenues for the application of Dts‑based protection strategies to meet a wide spectrum of goals in synthetic organic and biological chemistry research.

    Besides its intrinsic scientific interest, the cited paper is noteworthy as a cross-generational tour-de-force. At the time if was published, the respective ages of the authors were 17 (MJB), 42 (RPH), 49 (GB), and 83 (RBM). R.B. Merrifield, 1984 Nobel laureate in Chemistry, was GB’s Ph.D. mentor at The Rockefeller University in New York. Bob Hammer, now a full Professor at LSU, received his Ph.D. at Minnesota with GB in 1990. Michael J. Barany was chosen as a national finalist in the 2005 Intel Science Talent Search for this project. Click on this link for more information about the research accomplishments of the Barany laboratory.

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