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Organic chemistry

A tuxedo for iodine atoms

Nature volume 445, pages 826827 (22 February 2007) | Download Citation

  • A Correction to this article was published on 07 March 2007

Iodine atoms can be fitted with a chemical jacket to control the conversion of simple carbon chains into complex iodine-containing molecules. Previously, such reactions were only possible with enzymes.

The biosynthesis of hopene molecules showcases a spectacular enzyme-catalysed reaction. In one fell swoop, a simple floppy chain of carbon atoms is transformed by a cyclase enzyme into a complex system containing molecular rings, arranged in a well-defined, three-dimensional shape1,2. This cyclization process creates five carbon–carbon bonds and nine stereogenic centres — asymmetric carbon atoms that are especially difficult to prepare in a controlled way. Furthermore, the reaction is enantioselective, meaning that only one of two possible mirror-image (chiral) forms of the molecule is produced. Chemists can only envy this exquisite level of molecular manipulation.

Amazingly, this type of reaction is not unique. It is just one of hundreds of similar naturally occurring transformations used to create the molecules of life. A common thread in these reactions is that a hydrogen atom is transferred from an enzyme to a specific location in the product (Fig. 1a). But other atoms may also be introduced enzymatically at this position, such as oxygen and, more exotically, halogens — chlorine, bromine or iodine. Although chemists have successfully emulated certain aspects of these cyclization reactions, the incorporation of halogen atoms has been a long-standing challenge. The first bromine-induced cyclization was observed more than 40 years ago3, but only as a side reaction and without any enantioselectivity. On page 900 of this issue, Ishihara and colleagues4 report a tremendous advance: the first non-enzymatic, high-yielding, enantioselective cyclization induced by a halogen atom.

Figure 1: Enzymatic and synthetic cyclization reactions.
Figure 1

a, Squalene undergoes a cyclization reaction to form hopene in bacteria, using an enzymatic equivalent of a chiral hydrogen ion (H+). b, Ishihara and colleagues4 prepared a chiral source of iodine ions (I+) that induces a similar halocyclization reaction, so achieving a long-standing goal in organic chemistry. Only one of two possible mirror-image products is made in the reaction.

In recent years, chemists have edged closer to recreating the power of enzymes in these reactions. Indeed, the challenge of cyclizing substrates using the equivalent of a chiral hydrogen ion (H+) — so mimicking the hopene biosynthesis — has already been met by Ishihara and Yamamoto's group5, yielding products with a moderate excess of one chiral form over the other. They designed an artificial cyclase that delivers H+ to the substrate from one side only. The imitation enzyme was a sort of chemical tuxedo for H+ — a molecule that surrounds the ion, simulating the chiral environment found in natural cyclase. The whole assembly was activated by the addition of a Lewis acid (a molecule that accepts electron pairs from other molecules) to dramatically increase the acidity and reactivity of the H+ ion.

So far, so good, but one objective still remained: to accomplish a so-called halocyclization. This is the same type of reaction as described above, but using a halogen atom rather than H+. Thousands of exotic halogenated compounds have been isolated from natural sources, many of which show promise as medicinal leads for the treatment of various diseases. Several of these compounds have structures that probably arise from enzymatic reactions resembling the remarkable hopene cyclization, but initiated with a halogen atom6. For this reason, synthetic halocyclizations are highly desirable. But there are many inherent problems that must be solved to perform this reaction in the laboratory, which makes the present accomplishment by Ishihara and co-workers4 all the more impressive.

The authors required a highly reactive reagent that acts as a halogen source and that gives only one chiral product in a halocyclization reaction (Fig. 1b). They chose to work with iodine, and designed a reagent that is conceptually similar to the chiral H+ complex described above. The new reagent comprises a chemical tuxedo that fits around an iodine atom, creating a chiral environment for, and enhancing the reactivity of, that atom. Instead of using a Lewis acid to activate the assembly, the authors used a Lewis base (an electron-pair donor). The resulting 'halocyclase' is capable of converting simple hydrocarbons into iodinated architectures containing carbon rings, with near-enzyme-like control of the enantioselectivity. To explain this phenomenal selectivity, the authors suggest that the starting material and the iodine atom must square up to each other in just one optimal alignment before the reaction can proceed, in much the same way that two people must face each other before they can shake hands.

As with any breakthrough, there is still more work to be done. Although this halocyclization can also be initiated with bromine, the reaction is only enantioselective if iodine is used. The authors get around this problem by demonstrating that iodine atoms in the product can be transformed into other halogens without affecting the all-important chiral form of the product. Another limitation is that the reaction requires one molar equivalent of the chiral promoter — this is inefficient, as, in principle, a smaller quantity of the promoter should suffice. However, the authors have shown that other simple promoters can be used catalytically, if not enantioselectively, thus opening the door for future advances in this area. Finally, more 'halocyclases' are necessary, as many of the halocyclizations reported in this work terminate after the first ring is formed, thereby requiring a second acid-catalysed step to forge the remaining rings.

Before this work, there were no halocyclization methods that approached the exquisite enantioselectivity of enzymes — it seemed that such fine control could only be achieved with a complex biological catalyst. What is so striking about Ishihara and colleagues' method is that it uses relatively simple reagents. With a chiral jacket for iodine in the closet, the foundation is in place for catalytic versions of this reaction, and for the synthesis of halogenated, naturally occurring compounds.


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  1. Phil S. Baran and Thomas J. Maimone are in the Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

    • Phil S. Baran
    •  & Thomas J. Maimone


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