Side by side by synthesis

10 Nov 2009

Nitrogen atom-directed ortho-lithiation aids preparation of anti-HIV drug

Fig. 1: Efficient synthesis of a range of heterocycles has been realized using an ortho-lithiation strategy.

Fig. 1: Efficient synthesis of a range of heterocycles has been realized using an ortho-lithiation strategy.

Redrawn from Ref. 1 © 2009 The American Chemical Society

Nitrogen heterocycles—chemical compounds formed from a ring of carbon atoms into which nitrogen atoms have been incorporated—are one of the most important classes of organic molecules, and are ubiquitous in both natural and man-made molecules.

From the caffeine in our morning coffee and many of the vitamins that fortify the food we eat, to the pigments that brighten our world, and a wide range of natural and synthetic drugs—nitrogen heterocycles touch virtually every aspect of our existence. Indeed the very origins of life itself are inextricably linked to nitrogen heterocycles, as they form one of the three key components of the hereditary messenger, DNA. Unsurprisingly therefore, chemists are always looking for new and more efficient ways to make ever more complex and interesting nitrogen heterocycles.

Now, a team from the Chemical Synthesis Laboratory at the A*STAR Biopolis and the Scripps Research Institute in La Jolla, California have developed a new, flexible method for the synthesis of several important members of the nitrogen heterocycle family. Their discovery, reported recently in the Journal of the American Chemical Society, makes use of the propensity of N-protected anilines—a class of nitrogen-containing organic molecules—to undergo a process known as ortho-lithiation, by which the nitrogen atom directs the selective formation of a bond between the carbon atom two places in the ring away from itself, and an atom of the reactive metal lithium.

The researchers found that the resulting ‘organolithium’ compound could be treated with the chloride salt of a rare-earth metal, either cerium or lanthanum, to generate an intermediate organo-lanthanide complex. This species reacts smoothly and efficiently with a class of compounds described as aminoketones, which incorporate another atom of nitrogen.

The alcohol products afforded by these reactions can be elaborated into a more complex class of compounds called nitrogen spiroheterocycles either spontaneously or by treatment with a strong alkali. These nitrogen spiroheterocycles, as well as being important molecules in their own right, can then be converted into other useful nitrogen heterocycles, such as dihydropyrroles and tryptamines, simply by treatment with an acid (Fig. 1).

The A*STAR–Scripps team have further demonstrated the practical uses of their new methodology by employing it to synthesize a non-nucleoside reverse transcriptase inhibitor (NNRTI) called efavirenz, the active ingredient in the anti-HIV-1 drug, Sustiva. With the new technology they were able to prepare efavirenz in only three steps and with 68% overall efficiency—a very considerable improvement on the previous best route.

The new A*STAR–Scripps protocol is expected to expand the uses of anilines as versatile feedstock for chemical synthesis and offer rapid access to a range of biologically and pharmaceutically relevant molecules.

The A*STAR-affiliated authors in this highlight are from the Chemical Synthesis Laboratory.

Want to stay up-to-date with A*STAR’s breakthroughs? Follow us on Twitter and LinkedIn!


Nicolaou, K.C., Krasovskiy, A., Majumder, U., Trépanier, V.E. & Chen, D.Y.-K. New synthetic technologies for the construction of heterocycles and tryptamines. Journal of the American Chemical Society 131, 3690–3699 (2009). | article

This article was made for A*STAR Research by Nature Research Custom Media, part of Springer Nature