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Organic chemistry

Catalysis in tight spaces

Nature volume 483, pages 278279 (15 March 2012) | Download Citation

An acid has been found to catalyse the formation of a common chemical group, the spiroacetals, and to control which mirror-image isomer of the group is made. The key to success is the acid's bulky molecular structure. See Letter p.315

Opposites attract. When applied to the charges in organic molecules, this idea serves as a foundation for understanding how such molecules react. A large portion of organic chemistry can be explained by the concept that electron-rich molecules (or sites on molecules), which have negative character, seek to interact with, and potentially donate electrons to, electron-poor species that have positive character. On page 315 of this issue, Čorić and List1 describe a fresh use of this concept, with a report of a negatively charged, bulky catalyst that controls the reaction of a positively charged intermediate in the synthesis of potentially useful compounds known as spiroacetals.

Some of the most reactive, and therefore the most synthetically useful, species for organic transformations are those bearing a full negative or positive charge. Of these, oxocarbenium ions — oxygen-containing cations that form as reaction intermediates (Fig. 1a) — are particularly useful for making a variety of chemical linkages and groups. For example, they are used to make acetal groups, in which a carbon atom is connected to two oxygen atoms (Fig. 1b). Acetals are key linkages in numerous biomolecules, notably serving to bond sugar molecules together in long polymeric chains such as those found in amylose and amylopectin (the two components of starch), as well as in cellulose.

Figure 1: Acetals and an acetal precursor.
Figure 1

a, Oxocarbenium ions are reactive intermediates that can be used to make various chemical groups, including b, acetals and c, spiroacetals. The rings depicted in the spiroacetal structure represent rings of any size. d, One of the simplest spiroacetals is olean, the pheromone of the olive fruitfly.

The precise stereochemistry (the three-dimensional spatial arrangement) of acetals has profound implications. For example, both amylose and cellulose are made from the same glucose monomer, but have markedly different physical, chemical and biological properties. All that differentiates these two compounds is the stereochemistry at the acetal linker. Therefore, finding ways to control acetal stereochemistry — precisely what Čorić and List report1 in their reaction for constructing spiroacetals, a subclass of acetals formed when the acetal carbon joins two rings (Fig. 1c) — is a highly relevant challenge. The reaction that the authors report controls the chirality, or 'handedness', of the products that form.

Spiroacetals are found in a wide variety of naturally occurring, biologically active small molecules. For example, integramycin — a potent inhibitor of the integrase enzyme2 that allows HIV-1 to integrate its genetic material into the DNA of a host cell — contains a spiroacetal. Olean, the pheromone of the olive fruitfly, is one of the simplest spiroacetals (Fig. 1d), and provides another illustration of the importance of stereochemistry to a molecule's properties: the two mirror-image forms of olean selectively attract flies of a different sex3.

Čorić and List1 constructed the spiroacetals from a planar oxocarbenium ion that contained a pendant alcohol group (Fig. 2a). The stereochemical challenge was to control the addition of the alcohol group to just one face of the planar ion. One solution would be to use stereochemistry already present elsewhere in the molecule to direct the selectivity of the addition. But such internal control is, by definition, substrate-dependent and rarely allows both possible stereochemical outcomes of the reaction to be made selectively. A more recent and potentially more general approach is to control the stereochemistry using an external, negatively charged catalyst that interacts directly with the oxocarbenium ion through Coulombic attraction4,5. Ideally, the stereochemistry of the catalyst alone can determine which of the two isomers of acetal is generated.

Figure 2: A spiroacetal-forming reaction.
Figure 2

a, Čorić and List1 report a method for preparing chiral spiroacetals from a planar oxocarbenium ion. The ion is generated by treating its precursor with a Brønsted-acid catalyst, H–X. If the acid is not chiral, the alcohol group (OH) will attack the planar oxocarbenium ion from either face with equal likelihood, leading to a racemic (50:50) mixture of mirror-image isomers of a spiroacetal product (in this case, olean). b, With the chiral Brønsted acid developed by Čorić and List, the chiral anion X* generated after protonation (the asterisk denotes that the anion is chiral) can selectively block one face of the oxocarbenium ion, generating one mirror-image isomer selectively. The mirror-image isomer of the catalyst that is chosen determines which isomer of the product is produced. The anion formed from the acid catalyst is shown; the broken blue line indicates that the negative charge is delocalized across the atoms shown in blue.

The problem with this seemingly straightforward strategy is that a very specific spatial relationship between the reacting site and the chiral catalyst is required to obtain high stereoselectivity. Electrostatic attraction alone is not sufficient to impose the required level of order, because it is direction-independent. This problem could be overcome by incorporating other features into the catalyst, to allow it to orient the charged substrate through attractive, non-covalent interactions — a principle that is well established in enzymatic catalysis, and which has also been established in small-molecule catalysis6. An alternative approach is to create a rigid, highly restricted environment near the charged area on the catalyst that might allow the cationic substrate to interact with the catalyst only in a highly specific manner.

Čorić and List1 adopted the second of these strategies in their work. They used an exceptionally bulky Brønsted acid — a compound that can donate protons (H+) to other molecules — as a catalyst7 to construct a variety of small spiroacetals in a highly stereoselective manner. In the authors' system, the catalyst donates a proton to the substrate, which becomes an oxocarbenium ion. The deprotonated Brønsted acid (Fig. 2b) then acts as a counteranion for the oxocarbenium ion. A complementary approach8,9 for generating oxocarbenium ions is to use a catalyst that removes an anion from a suitably reactive substrate; by forming a negatively charged complex with the anion, the catalyst controls subsequent additions to the oxocarbenium ion.

A notable aspect of Čorić and List's work is that simple substrates can be used that lack the large or polar groups often required in Brønsted-acid-catalysed reactions to ensure effective catalyst–substrate interactions. The authors propose1 that this is because they used a particularly large Brønsted-acid catalyst, so the bulky anion that forms from the catalyst after the proton-transfer step can interact in a specific enough manner with the oxocarbenium ion to preferentially block one of the cation's faces. This prevents the alcohol from adding to that face and thereby directs addition selectively to the other face. Addition to either face can be selected for in a reaction simply by choosing the appropriate mirror-image form of the catalyst.

At present, Čorić and List's method seems to be limited to reactions that generate five- or six-membered spiroacetal rings. One remaining question is whether the success of the catalyst with simple substrates may be extended to more complex molecules. For example, the authors report1 that their Brønsted acid is unable to control and override the inherent selectivity of spiroacetal formation in a large steroidal molecule that contains many other chemical groups and rings of atoms. Many biologically active spiroacetals are similarly complex, and so a method for synthesizing them would be highly desirable.

A mechanistic investigation of Čorić and List's reactions will be needed to establish whether the proposed confined-space effect is in fact operative, and to discover precisely how the cation–anion pair formed during the reactions yields spiroacetals stereoselectively. But such effort seems worthwhile, given the potential of bulky Brønsted acids as catalysts for other valuable organic transformations.


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  1. Noah Z. Burns and Eric N. Jacobsen are in the Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

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Correspondence to Eric N. Jacobsen.

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