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Organic chemistry

How to beat an alcohol problem

Nature volume 456, pages 711712 (11 December 2008) | Download Citation

Some alcohols can't be made in a way that controls the crucial arrangement of chemical groups in the molecule. A reaction that uses common laboratory reagents offers a practical route to these compounds.

Since the discovery that many organic molecules have mirror-image forms1, chemists have sought to control which of these 'enantiomers' is synthesized in reactions. Several strategies have been developed, such as the use of catalysts2 or enzymes3 to direct reactions towards making a particular chiral form. Alternatively, desired enantiomers can be separated from mixtures using chromatography4 or other 'resolution' techniques5. Certain classes of compounds can now be easily prepared as pure enantiomers, but others — in particular those with many chemical groups attached to a single carbon atom — remain a challenge.

Reporting on page 778 of this issue, Aggarwal and colleagues6 describe a striking reaction in which an alkyl (hydrocarbon) group is attached to a chiral carbon atom so that the enantiomeric purity of the reactant is retained in the product. Because a compound's enantiomers often have different biological activities, this could be particularly useful for drug discovery and development.

So what is the molecular basis of chirality in molecules? When four different chemical groups (or atoms) are attached to a carbon atom, two geometrically distinct arrangements of the groups around the carbon are possible (Fig. 1a). The two resulting molecules are mirror images, and can't be superimposed on each other. These molecules behave identically in chemical reactions unless they interact with other chiral molecules — in the same way that a left hand is, to all intents and purposes, the same as a right hand until you try to insert it into a right-handed glove.

Figure 1: Preparing single enantiomers of tertiary alcohols.
Figure 1

a, Organic compounds that contain carbon atoms to which four different groups are attached can form as two possible enantiomers — mirror images of each other, as shown for this secondary alcohol (Me is a methyl group). Secondary alcohols can be easily synthesized as single enantiomers. b, Tertiary alcohols are structurally similar to secondary alcohols, but contain an extra hydrocarbon group (in this case, hydrocarbon R1 replaces the hydrogen atoms shown in red in a). Single enantiomers of tertiary alcohols cannot be made using methods analogous to those used for secondary alcohols. Aggarwal and colleagues6 report a method that solves this problem (ce). c, Carbamates (readily made from secondary alcohols) can be treated with a base to generate an anion. d, If the anion is reacted with a boronate ester (R1B(OR2)2, where R2 is any hydrocarbon group) and then with hydrogen peroxide, a single enantiomer of a tertiary alcohol is produced, which retains the arrangement of groups in the carbamate. e, If a borane (R1BR22) is used instead of a boronate ester, the opposite enantiomer is made.

Because almost all of the components in cells — proteins, nucleic acids and so on — are chiral, two enantiomers of the same molecule will almost always interact with those components in different ways. An everyday example of this is a molecule called carvone7: one enantiomer smells of caraway, whereas the other smells of spearmint, because of the way each isomer interacts with olfactory receptors.

In the case of chiral medicines, the consequences of such isomerism can be grave. One enantiomer of a drug might bind to its intended target protein much more strongly than the other. Even worse, the 'wrong' form might interact with a completely different receptor. The most drastic and oft-cited case of this is thalidomide8: one enantiomer is a sedative, the other causes severe birth defects. Drugs for human use were often sold as one-to-one mixtures of enantiomers, because such mixtures are easier to prepare than the single isomers. But since the thalidomide tragedy, drug-regulatory agencies strongly prefer chiral molecules to be prepared and marketed as pure enantiomers9.

Chemists have risen to this synthetic challenge magnificently. It is now possible to prepare many kinds of compound routinely in enantiomerically pure form, including a structural class known as secondary alcohols. Secondary alcohols are useful as chiral building blocks for more complex, biologically active molecules, and often have interesting biological activities in their own right. They consist of a hydrogen atom, a hydroxyl (OH) group and two alkyl groups attached to a central carbon atom (Fig. 1a). One of the most successful ways to prepare single enantiomers of secondary alcohols is to add hydrogen to carbonyl compounds (which contain carbon–oxygen double bonds) in the presence of a chiral catalyst.

But alcohols of another class are much more difficult to make as pure enantiomers. Tertiary alcohols contain carbon atoms to which a hydroxyl group and three alkyl groups are attached (Fig. 1b), and are just as useful as secondary alcohols. In principle, they could be prepared by adding an alkyl group to a carbonyl compound in the presence of a chiral catalyst. Unfortunately, although chemists have developed many powerful catalysts that allow pure enantiomers of secondary alcohols to be made by adding hydrogen to carbonyls, there are far fewer general methods that control the addition of alkyl groups to carbonyls to make single enantiomers of tertiary alcohols10.

Aggarwal and colleagues6 have therefore taken a different approach. They have devised a way to transform chiral molecules known as carbamates — which can be prepared easily from secondary alcohols — into tertiary alcohols (Fig. 1c–e). The method involves plucking a hydrogen atom from the carbamate using a base, thus forming an intermediate anion. The anion is then reacted with a boron-containing reagent, which acts as a source of alkyl groups. Finally, an oxidizing agent (hydrogen peroxide) is added. This acts as a source of hydroxyl groups and its addition results in the formation of the desired tertiary alcohol.

There are several interesting and useful aspects of this work. First, the chiral 'information' in the starting material is transferred efficiently to the product — that is, an enantiomerically pure reactant is converted into essentially a single enantiomer of product. Often, the anions of chiral compounds quickly convert back and forth between enantiomers, so that the chiral information from the reactant is lost and the product forms as a mixture of isomers. But Aggarwal and colleagues form their anion intermediates under conditions in which this interconversion is slow, thus preventing the formation of a mixture.

Another impressive feature of the method is that it allows many different tertiary alcohols to be prepared from a single carbamate. A wide array of boron reagents is commercially available (or can be easily prepared) that can act as sources of different alkyl groups. This means that a diverse set of products can be made conveniently from a common starting material.

The most remarkable aspect of this process, however, is that the exact enantiomer of the product prepared in the reaction is governed by the nature of the boron reagent selected. The authors observed that the use of a boronate ester (which contains two boron–oxygen bonds and one boron–carbon bond, Fig. 1d) results in the groups around the chiral carbon atoms retaining the same arrangement in the product as in the carbamate. But when they used a borane (which contains three boron–carbon bonds and no boron–oxygen bonds, Fig. 1e), the groups 'flip' into the mirror-image arrangement. Thus, either enantiomer of the product can be prepared from a single chiral precursor — a rare feature that is not only practically useful, but also interesting in terms of fundamental reactivity.

Aggarwal and colleagues' findings6 are likely to inspire others to explore the chemistry of stable chiral anions in organic molecules, opening up new areas of research. Moreover, by replacing hydrogen peroxide in the final step of the procedure with other reagents, it might be possible to make other chiral molecules that have been difficult to prepare as single enantiomers. But what is particularly exciting is how rapidly this work can be put into practice by others in the field: many of the required reagents and substrates are common items in the stockrooms of organic chemistry labs around the world.

References

  1. 1.

    & Stereochemistry of Organic Compounds (Wiley, 1994).

  2. 2.

    & Fundamentals of Asymmetric Catalysis (Univ. Sci. Books, 2008).

  3. 3.

    Biocatalysis (Nature Insight) Nature 409, 225–268 (2001).

  4. 4.

    (ed.) Preparative Enantioselective Chromatography (Blackwell, 2005).

  5. 5.

    , & Enantiomers, Racemates and Resolutions (Wiley, 1981).

  6. 6.

    , , & Nature 456, 778–782 (2008).

  7. 7.

    , , , & J. Agric. Food Chem. 19, 785–787 (1971).

  8. 8.

    Chem. Eng. News 83 (25), 122–123 (2005).

  9. 9.

  10. 10.

    & Org. Biomol. Chem. 5, 873–888 (2007).

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  1. Karl B. Hansen is in the Department of Small Molecule Process and Product Development, Amgen, One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, USA.  karl@amgen.com

    • Karl B. Hansen

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