CATALYSIS

Triumph of a chemical underdogGorka Peris and Scott J. Miller

In the fable of the tortoise and the hare, the reptilian slowcoach beats its fleet-footed rival in a race. A zinc catalyst recreates this story by giving a less reactive chemical group a turn of speed over a rival group.

Ranking the inherent reactivity of chemi-cal groups was crucial for propelling organic chemistry into the realms of rational science. This groundwork was achieved over the course of many decades, and a basic knowledge of which groups react faster than others is still essential today. But can the reactivity of chemi-cal groups be tinkered with, so that, in a mol-ecule containing several groups, the less-active ones react before the more reactive? Report-ing in the Journal of the American Chemical Society, Ohshima et al.1 report a remarkable catalyst that can reorder the reactivity of two common chemical groups — a revelation that is certain to inspire chemists everywhere.

Catalysts come in many forms (enzymes, metal complexes, polymers, small organic molecules and so on), each with an armoury of features that chemists exploit in different situations. The most powerful catalysts enable otherwise inert groups to take part in all sorts of useful reactions. But one of the toughest chal-lenges for a catalyst is to distinguish between many reactive sites within a single, complex mol-ecule, especially when the same chemical group occurs several times. Furthermore, in organic synthesis, it isn’t always desirable to work with the most reactive chemical groups first, so cata-lysts that allow reactions to occur selectively at less reactive sites are highly desirable.

Enzymes are the acknowledged masters at reversing the reactivity of chemical groups in molecules2, but non-enzymatic catalysts may on occasion compete for the accolade. For example, transition-metal complexes have been discovered that reverse the order in which car-bon–carbon double bonds (C=C) tend to react in oxidation reactions of geraniol3, a molecule commonly used in studies of chemical synthesis and biosynthesis. In some reactions, antibodies can be generated that control the conformation of a substrate in a transition state, redirecting the course of the reaction so that the less reac-tive of two otherwise similar bonds is broken4. In our own laboratory5, we have found that small, peptide-based catalysts can reorder the reactivity of several hydroxyl (OH) groups within the antibiotic erythromycin A.

But changing the order in which two differ-ent chemical groups react is another matter

entirely, especially if one of those groups ordi-narily reacts much faster than the other. A good example from classical chemistry uses copper catalysts to make organomagnesium reagents react at C=C bonds, rather than at adjacent, more polarized carbonyl (C=O) bonds6 that would normally react first.

Perhaps more dramatic is reversing the order of reactivity of hydroxyl groups and amino groups (nitrogen-containing groups found in organic bases known as amines). These two chemical groups are nucleophilic — they attack other molecules, called electrophiles, that contain areas of positive charge. But amino groups are generally far more nucleo-philic than hydroxyls, so that when an amine and an alcohol (a compound that contains a hydroxyl group) are mixed together with a limited amount of a common electrophile, the electrophile reacts almost exclusively with the amine7. Similarly, for compounds that contain both an amino group and a hydroxyl group, an electrophile will typically react at the amine part of the molecule. Reaction at the hydroxyl is often not possible unless the amino group is first modified in a separate step using a ‘protecting group’ to make it less reactive.

But Ohshima et al.1 have successfully reversed the reactivity of hydroxyl and amino groups by using a zinc catalyst (Fig. 1). When they mixed equal molar quantities of an amine and an alcohol together with an electrophile, in the presence of the catalyst, the alcohol reacted far more rapidly to form an ester prod-uct (instead of the amine reacting to form an amide). Likewise, when the authors mixed a compound containing both amino and hydroxyl groups with the same electrophile and catalyst, the hydroxyl group reacted much faster to produce an ester (Fig. 1b). The reac-tions are remarkable not only for their selec-tivity, but also for their speed and high yields: uncatalysed versions of these reactions are staggeringly slow under similar conditions.

The net result of these reactions is known as an ‘ester interchange’, because the elec-trophile, like the product, contains an ester group (an oxygen adjacent to a C=O bond). Catalytic ester-interchange reactions have been described before8, as have the analogous

Figure 1 | Selective reactions with a zinc catalyst. Ohshima et al.1 have made a zinc catalyst that reverses the intrinsic reactivity of alcohols (which contain OH groups) and amines (which often contain NH2 groups). Zn is zinc, F is fluorine. a, When a 1:1 mixture of an alcohol (red) and an amine (blue) is reacted with an ‘electrophile’ (such as benzoyl chloride) in the presence of a base, only the amine will react. b, In the presence of Ohshima and colleagues’ catalyst, the alcohol reacts preferentially. Here, the electrophile is methyl benzoate, a less reactive analogue of benzoyl chloride. c, When a molecule containing both an OH group and an NH2 group reacts with methyl benzoate in the presence of the catalyst, the OH group reacts preferentially.

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NEWS & VIEWS

— and chemically more demanding — catalytic amide-interchange reactions9. But Ohshima and colleagues’ reaction1 is truly striking because it overrides the order of reactivity that would be expected in the absence of catalysts.

It has long been known that catalysts not only speed up chemical transformations, but can also make reactions occur in ways that would otherwise be impossible. Similarly, the ability to manipulate reactions to obtain just one product when many others are likely to form is a long-standing goal of synthetic chemists. Ohshima and colleagues’ work1 thus represents a real advance in nucleophilic reac-tions. But it also reminds chemists to challenge their assumptions about the relative reactivity of the chemical groups in organic molecules. Such assumptions may be the biggest barrier

to the discovery of exciting new reactions. ■

Gorka Peris and Scott J. Miller are in the Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107, USA.e-mail: scott.miller@yale.edu

1. Ohshima, T., Iwasaki, T., Maegawa, Y., Yoshiyama, A. & Mashima, K. J. Am. Chem. Soc. 130, 2944–2945 (2008).

2. Gardossi, L., Bianchi, D. & Klibanov, A. M. J. Am. Chem. Soc. 113, 6328–6329 (1991).

3. Sharpless, K. B. & Michaelson, R. C. J. Am. Chem. Soc. 95, 6136–6137 (1973).

4. Janda, K. D. et al. Science 259, 490–493 (1993).5. Lewis, C. A. & Miller, S. J. Angew. Chem. Int. Edn 45,

5616–5619 (2006).6. Kharasch, M. S. & Tawney, P. O. J. Am. Chem. Soc. 63,

2308–2316 (1941).7. Sontag, N. O. Chem. Rev. 52, 237–416 (1952).8. Stanton, M. G. & Gagne, M. R. J. Am. Chem. Soc. 119,

5075–5076 (1997).9. Hoerter, J. M. et al. J. Am. Chem. Soc. 128, 5177–5183 (2006).

CIRCADIAN RHYTHMS

Stem cells traffic in time David T. Scadden

Circadian activity in the brain regulates the movement of blood stem cells into and out of the bone marrow. Perhaps this process is testing the suitability of these cell ‘tenants’ for their new home — the remodelling bone.

All tissue-specific stem cells move around dur-ing embryonic development. But mammalian haematopoietic stem cells (HSCs), which are precursors to all blood cell types, continue to migrate via the bloodstream throughout adulthood. Many of the molecules that locally mediate HSC movement between the bone marrow and the bloodstream have been iden-tified, perhaps the most prominent example being CXCL12. This protein is essential for the movement of HSCs to the bone marrow during development and their retention there in adult-hood. By contrast, the mechanisms underlying the trafficking of stem cells in adulthood, and their physiological significance, have remained relatively obscure. On page 442 of this issue, Frenette and colleagues (Méndez-Ferrer et al.)1 show that HSC circulation and CXCL12 expression are coupled to the homeostatic oscil-latory processes that regulate broad aspects of an organism’s function — circadian rhythms.

Virtually all life-forms, from unicellu-lar organisms to humans, experience cyclic increases and decreases in the levels of cellular molecules as a consequence of self-inhibitory regulatory networks. So, were it not for the hier-archical organization of pacemaker regulation, the complexity of the switches involved and the networks of interacting regulators would together result in the molecular equivalent of a cacophony. The more advanced pacemakers are often influenced by external cues, such as the light–dark cycle, resulting in circadian (daily) and circannual (yearly) physiological rhythms.

In mammals, certain circadian events are

intrinsic to a specific tissue or cell type, but they are largely subservient to the master pacemaker in the central nervous system, the suprachias-matic nucleus located in the hypothalamus. The phased activity of this brain structure in response to the light–dark cycle leads to a pro-found array of fluctuations, including changes in metabolic rate, cognitive function and immune-system reactivity. The effect of the suprachiasmatic nucleus is largely mediated by noradrenaline, an adrenergic neurotransmit-ter that is secreted by the sympathetic nervous system. Méndez-Ferrer and colleagues’ work1 directly links circadian control of the sympa-thetic nervous system to HSC function.

The stem-cell repertoire of adult tissues generally consists of a small number of self-replenishing cells that turn over very slowly — for primate HSCs, turnover occurs over months to years2. In culture, these cells are rela-tively unaffected by immune mediators such as inflammatory cytokines. But when in their niche (microenvironment) in the body, they respond to stressors that may be occurring at the organismal level, for example infection or cancer chemotherapy. How signals at the organismal level are integrated into activity in the stem-cell niche remains an underexplored area of research. The Frenette laboratory1 is a leader in this area, having been the first to show3 that, by means of their niche, HSCs respond to the ultimate integrating system in the body, the nervous system, or, specifically, to the adrener-gic signals originating from it.

The authors now show that, during a day,

CXCL12 levels in the bone marrow oscillate with periods of light and dark in counterpoint to the concentration of HSCs in the blood; dur-ing times when it is light — the rest period for mice — HSC levels are about 2.5-fold higher than those during times of darkness, and this is mirrored in the opposite direction for CXCL12 levels in the bone marrow. These cycling events do not seem to be mediated by the clock genes within either HSCs or the bone-marrow stro-mal support cells; rather, the authors find that oscillations in both circulating HSC levels and CXCL12 expression are regulated by adrener-gic stimulation.

The function of adrenergic signals from the suprachiasmatic nucleus varies depending on the receptor subtype to which they bind on their target cells. Méndez-Ferrer et al. find that, in the bone marrow, noradrenaline activates β3-adrenergic receptors. As bone-forming cells called osteoblasts have β2, but not β3, receptors,

Figure 1 | Pacemaker activity and cooperativity between bone and bone-marrow cells. Circadian activity is regulated by a central neural pacemaker, the suprachiasmatic nucleus, which activates distant sites by stimulating the secretion of adrenergic hormones by the sympathetic nervous system. These hormones are known to bind to β2-adrenergic receptors on osteoblasts, activating a signalling cascade that alters cell proliferation (not shown) and ends in bone remodelling. Méndez-Ferrer et al.1 find that adrenergic hormones also activate β3 receptors on the surface of bone-marrow stromal cells. This results in the degradation of the Sp1 transcription factor and decreased levels of the anchoring protein CXCL12. The result is that haematopoietic stem cells (HSCs) are free to leave the bone marrow and transiently enter the bloodstream. The movement of HSCs into and out of non-osteoblast stromal niches is probably synchronized with circadian growth and remodelling of their ‘home’ — osteoblast-generated bones.

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