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 Society1, 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.
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.
*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
3690–3699 (2009). | article
Posted November 10th, 2009
