Electronic control of helical chirality

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Electronic control of helical chirality James W. Canary and Steffen Zahn Chiral phenomena are common in living systems. Despite the fact that development of materials has often been inspired by chemistry from the biological world, materials that take advantage of inherent chirality have found relatively few applications. It is therefore probable that much remains to be gained from novel applications of molecular, macromolecular and supramolecular chirality. Among the most intriguing recent advances in studies of chiral materials is the development of mechanisms to control the shape and properties of chiral molecules. Photo-induced helical chirality inversions have been studied for several years and significant achievements have been reported. Recently, electronically triggered systems have drawn significant attention. These technologies offer the potential for development of novel materials that take advantage of photonic or electronic modulation of molecular recognition, optical or mechanical properties.

Chirality permeates biology and properties of biological compounds are affected by chiral phenomena. Amino acids, nucleic acids, carbohydrates, metabolic intermediates, lipids and many other biomolecules are chiral. Indeed, it is difficult to find molecules of physiological significance that do not possess at least one chiral center. Nearly all medicinal agents are chiral, with one enantiomer effecting the biological response and the other giving either no response or one that is completely unrelated and possibly undesirable. Homochirality of biomolecules is a widely recognized phenomenon with potentially significant implications for the origins of life and the search for extraterrestrial life1. Chiral materials

James W. Canary* Steffen Zahn Dept of Chemistry, New York University, New York, NY 10003, USA. *e-mail: James.Canary@ nyu.edu

In materials science, chirality has been ignored or avoided in the development of new materials. In fact, only a few materials utilize chiral molecules in a manner in which the chirality is central to the properties of the substance. One example is chiral stationary phases for gas or liquid chromatography, needed for the assay and/or purification of chiral medicinal agents. A second example is cholesteric liquid crystals, which are used in optical displays for their special properties. Even-order nonlinear optical materials also require a certain level of asymmetry and the use of chiral compounds has been a popular strategy for satisfying the symmetry requirements. Such compounds are being used as frequency doublers for lasers and other applications. Considering the large variety of materials produced commercially, this list is short and suggests that modern technology might not be utilizing properties of materials related to their chirality to the fullest possible extent. Further research and development should be exerted into chiral phenomena.

Recent work on the development of chiral materials has led to systems with strong chiroptical (e.g. circular dichroic or polarimetric) properties that can be modulated by various means. Among the triggering mechanisms, photo-inversion of chirality has been the most widely studied and recently electronic control of helical chirality has been demonstrated. Photo-inversion of helical chirality

Photochemical conversion of alkenes between cis and trans forms can invert helical chirality if the isomerized alkene is part of a chiral center resulting from hindered rotation. Feringa et al.2 identified several requirements for photochemical molecular switches as follows: (1) the material should undergo ‘read’ and ‘write’ events without degradation; (2) temperature changes should not erase the information; (3) ‘on’ and ‘off’ forms should be readily detectable; and (4) the detection method should not erase the written information. There are two broad classes of molecules that exhibit photo-invertable chirality. The first class includes molecules in which a photon induces a change in conformation resulting in the formation of a pseudo-enantiomer; that is, the helical ‘sense’ of the new molecule has reversed even though technically it does not contain any inverted chiral centers. This was illustrated in the interconversions of thioxanthenes 1 and 2, as shown in Fig. 1 (Ref. 3). The compounds are not enantiomers but diastereomers, and the interconversion of 1 to 2 can be effected with light of significantly different wavelength than the interconversion of 2 to 1. This property allows the state of the molecule to be controlled. The other approach to chiroptical photoswitches is employment of truly enantiomeric molecules that are addressed by circularly polarized light. Irradiation of compounds such as 3 and 4 (Fig. 1; Ref. 3), which are enantiomers, will obviously result in an equal population of the two. However, irradiation with circularly polarized light can result in preferential formation of one or the other. The problem with this approach is that only small preferences for one enantiomer have been observed in any of the several systems that have been studied, as a result of the relatively low preference for absorption of light of a given polarization by known molecules. Although some investigators are searching for molecules with greater response to circularly polarized light, other ingenious tactics have been developed. For example, one strategy takes advantage of the fact that polymer

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Fig 1. Examples of photoswitches. Irradiation with light (hν) of various wavelengths interconverts diastereomeric compounds 1 and 2. Irradiation with polarized light induces a preponderance of a single enantiomer (3,4). Phototriggered compounds 5 and 6 modulated the pitch of cholesteric liquid crystals as a function of the wavelength of irradiation.

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systems can take on a single form of helical chirality in the presence of a small chiral bias4. Linking a photoresolvable ketone to a polymer with dynamically interconverting left and right helical configurations produced a material that could be induced to change to a singly helical form on irradiation with circularly polarized light. Another intriguing approach employs an electric field to orient enantiomeric photolabile compounds5. That is, molecules capable of photoracemization are irradiated in a film; application of the electric field induces a particular configuration because the two enantiomers give opposite molecular dipoles. Turning off the light removes the configurational lability. The major problem that has been discussed with photolabile systems is ‘destructive readout’ – reading the position of the switch might also erase it. A possible solution to this problem might be to use optical rotatory dispersion to retrieve written information because light of significantly different wavelength can be used in the readout. Another approach was illustrated by the study of a photochromic fulgide 5 (Fig. 1) dissolved in a photochemically inert cholesteric liquid crystal that is bistable and ‘switchable’ by repetitive application of ultraviolet and visible light6. The pitch of a cholesteric liquid crystal was shown to be controlled photochemically by the fulgide dopant. The pitch changes were measurable at reasonable fulgide concentrations and both states of the liquid crystal and fulgide mixture were thermally stable under the http://tibtech.trends.com

conditions tested. The change of the pitch was bidirectional and reversible and was controlled by light of suitable wavelength. Recently, the groups of Feringa and Harada reported a system that undergoes sequential photochemical and thermal isomerizations enabling a 360° rotation in a single direction7. This is a particularly exciting development because it suggests that the system could be adapted to a molecular machine application that enables it to do useful work. For example, it might be possible to use this approach to develop molecular motors that could propel particles through a solution powered by light.

Advantages of redox-triggered optical switches include the fact that reading and writing events are independent phenomena, eliminating issues such as destructive readout. Technology is already in place for electrically powered devices. Furthermore, redox systems are less likely to suffer from interference from thermal processes than photolabile systems are. Thus, two of the four criteria cited for photoswitches are inherently less problematic when redox systems are used. However, bistability of redox systems in air might become an issue. Although resistance to oxidation by air might not be a firm requirement, such stability would simplify device fabrication. Among the many redox systems that have been reported, catenanes and rotaxanes that function as ‘molecular mechano’ have been described8. The assembly 7 (Fig. 2) consists of a tetracationic bis-pyridinium cyclophane that moves back and forth like a shuttle between two dialkoxybenzenes that are situated symmetrically on a polyether, which is terminated at the ends by large groups that act as stoppers. Reduction of the viologen (N,N′-dialkyl-4, 4′bipyridinium) moieties in this and similar molecules results in the relocation of the viologen macrocycle from a dialkoxybenzene to the crown ether region. Recent work on device fabrication yielded an electronically configurable logic gate9. Electrochemically triggered switching and shuttling in [2]-catenate copper complexes 8 (Fig. 2) was reported10. One ring contained two binding sites, bi- and tridentate, whereas the second ring featured only one bidentate coordination site. Thus, the interlocked rings presented one tetradentate and one pentadentate ligation site. Introducing copper ions (Cu2+) into the system led to the formation of the pentacoordinate complex, whereas Cu+ induced the sliding of one ring through the other enabling it to occupy the tetracoordinate site. Another Cu+/Cu2+based conformational redox switch was reported, which involved a cyclotriveratrylene scaffold11. The system is chiral, although studies of enantiopure materials were not reported. Several other interesting approaches to redox switches have been undertaken, including systems that display on/off switching of luminescence12,13.

Review

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The first redox-triggered chiroptical switch involved translocation of a metal ion between two possible binding sites on redox change. Coordination complexes featuring iron ions (Fe2+ or Fe3+) embedded in the triple stranded ligand 9 (Fig. 2) were interconverted by chemical means14. The Fe2+ ion bound to a tris(hydroxamate) site in the molecule (10, Figure 2), whereas Fe3+ was observed to preferentially bind to a tris(bipyridyl) site (11, Figure 2). Primarily, the process was monitored using UV spectroscopy, but different amplitudes for the circular dichroism (CD) spectra of the two metal complexes was also noted. The system did not show reversible behavior; indeed, the oxidation reaction required heating to 50°C. Several systems have been studied in which organic molecules undergo redox changes to produce species with pronounced changes in CD properties15. In cases such as bispyrene compound 12 (Fig. 2), one of the redox partners (the bis-radical anion) is a species observed only under the conditions of the electrochemical experiment and is not isolated or otherwise characterized16. In these cases, the change in chiroptical spectral properties arise as a result of http://tibtech.trends.com

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Fig. 2. Redox-switched molecules. Pioneering work with compounds such as 7 and 8 established that molecules could be shuttled between different states using redox chemistry. The first redox-triggered chiroptical switch, 9, involved translocation of an iron atom on oxidation or reduction (10 and 11). Recent spectroelectrochemical studies of 12 yielded transient species with strong circular dichroism spectra on oneelectron reduction of the two pyrene moieties.

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Fig. 3. An on–off redox switch. Compounds 13 and 14 are stable in both redox states. (a) Compound 13 displays a strong circular dichroism (CD) spectrum originating from three pairwise interactions between chromophores, each pair giving rise to exciton coupling, and consequently yielding exceptionally strong CD spectra. In contrast, complex 14 has only one pair of chromophores and that one less strongly coupled owing to the presence of less twist in the propeller conformation. (b) Circular dichroism (top) and absorption (bottom) spectra of complexes 13 and 14.

changes in electronic structure of the compounds on oxidation-state change. A complementary approach is to use redox chemistry to induce a change in conformation in a molecule that, in turn, drives a change in chiroptical spectral signal. Complex 13 (Fig. 3) affords highly intense CD spectra whereas reduction of the metal ion to the Cu+ state gives weak spectra17. Solution studies using chemical oxidants and/or reductants, as well as electrochemical measurements, indicated remarkably reversible interconversion. Both complexes were prepared in pure form and shown to be relatively air-stable in the solid state. The Cu+ complex 14 (Fig. 3) oxidized to the Cu2+ form in solution in the presence of oxygen. Scrutiny of the mechanism yielded the conclusion that, in the Cu2+

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Fig. 4. Electron-mediated inversion of helical chirality. (a) Cu2+ prefers coordination of carboxylate in 15 whereas Cu+ prefers sulfide (16). (b) Cartoon showing the gearing between ligand exchange and orientation of quinolines that form part of the propeller (17 and 18). Abbreviations: MOX, oxidated methionine; MRED, reduced methionine.

Acknowledgements We thank the National Institutes of Health, the donors of the Petroleum Research Fund, administered by the American Chemical Society and the National Science Foundation for support of our research.

complex, all three heterocycle arms are coordinated to the metal ion, whereas in the Cu+ complex, one arm de-coordinates. Given that the mechanism giving rise to the CD spectrum involves pairwise, additive interactions between proximal quinoline chromophores, the Cu2+ complex with three pairs of interactions is much more intense than that of the Cu+ complex with only one pair of quinoline arms proximal at any given time. Recently, it was shown that the copper complexes can be dissolved in an achiral nematic liquid crystalline phase to induce chirality, similar to observations made for photoswitched molecules18. Replacement of one quinoline arm in this system with methionine led to the development of a +/− chiroptical switch19. Because Cu2+ coordinates carboxylate and Cu+ binds softer ligands, such as sulfur, derivatives of methionine, as shown in Fig. 4, exchange carboxylate for sulfide ligands on redox change. Subsequently, the orientation of the chromophores inverts as a result of the fact that the chiral arm originating from the methionine is geared with the two achiral arms. A pivot about the bond between the chiral carbon atom of the amino acid and the nitrogen atom of the ligand ratchets the propeller twist of the molecule in the opposite directional sense, affording an effective inversion of the chirality of the propeller. Essentially, one electron oxidation or reduction of the complex inverts the helical chirality of the molecule, creating a diastereomeric ligand conformation. The CD spectra shown in Fig. 5 give the appearance of mirror-image complexes, even though the redox pair http://tibtech.trends.com

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Fig. 5. Exciton-coupled circular dichroism spectra showing similar UV–vis spectra for Cu2+ (15) and Cu+ (16) complexes but nearly mirror image circular dichroism spectra.

is not even truly diastereomeric because the metal ions have different charges. Potential applications

These new materials might find applications in current areas of chirotechnology or they might open up new opportunities. For example, perhaps it will be possible to develop a chiral chromatographic support that can be electrically switched to invert the order of elution of enantiomers. The electrochiral materials demonstrate similar properties to cholesteric liquid crystals; some compounds dissolve in nematic phases to induce chirality. However, the development of films or monolayers that show electrochiroptical modulation would be even more desirable. Certainly, the realm of molecular electronics offers many opportunities for application of the compounds in optical data-processing devices such as light valves, modulators, shutters, light deflectors, optical filtration, logic elements and storage devices20. Finally, the conformational changes that occur when redox states are changed suggest application in nanotechnological phenomena, such as molecular electromechanical tranducers21. In this context, photonic or electronic control of molecular motions might permit the design of molecular motors similar to those found in the cell.

Review

References 1 Palyi, G. et al. (1999) Advances in BioChirality, Elsevier 2 Feringa, B.L. et al. (2000) Chiroptical molecular switches. Chem. Rev. 100, 1789–1816 3 Huck, N.P.M. et al. (1996) Dynamic control and amplification of molecular chirality by circular polarized light. Science 273, 1686–1687 4 Li, J. et al. (2000) Switching a helical polymer between mirror images using circularly polarized light. J. Am. Chem. Soc. 122, 2603–2612 5 Hutchison, K.A. et al. (2000) Chiropticenes: molecular chiroptical dipole switches for optical data storage. Proc. SPIE-Int. Soc. Opt. Eng. 3937, 64–72 6 Janicki, S.Z. and Schuster, G.B. (1995) A liquid-crystal opto-optical switch – nondestructive information-retrieval based on a photochromic fulgide as trigger. J. Am. Chem. Soc. 117, 8524–8527 7 Koumura, N. et al. (1999) Light-driven monodirectional molecular rotor. Nature 401, 152–155

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8 Stoddart, J.F. et al. (1992) Molecular meccano. 1. [2]Rotaxanes and a [2]catanane made to order. J. Am. Chem. Soc. 114, 193–218 9 Collier, C.P. et al. (1999) Electronically configurable molecular-based logic gates. Science 285, 391–394 10 Armaroli, N. et al. (1999) Rotaxanes incorporating two different coordinating units in their thread: synthesis and electrochemically and photochemically induced molecular motions. J. Am. Chem. Soc. 121, 4397–4408 11 Wytko, J.A. et al. (1996) Copper(II/I) Complexes of a hexakis(bipyridyl)cyclotriveratrylene ligand: a redox-induced conformational switch. Inorg. Chem. 35, 4469–4477 12 Goulle, V. et al. (1993) An electrophotoswitch: redox switching of the luminescence of a bipyridine metal complex. J. Chem. Soc. Chem. Commun. 1034–1036 13 Fabbrizzi, L. and Poggi, A. (1995) Sensors and switches from supramolecular chemistry. Chem. Soc. Rev., 197–202 14 Zelikovich, L. et al. (1995) Molecular redox switches based on chemical triggering of iron translocation in triple-stranded helical complexes. Nature 374, 790–792

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15 Beer, G. et al. (2000) Redox switches with chiroptical signal expression based on binaphthyl boron dipyrromethene conjugates. Angew. Chem. Int. Ed. 39, 3252–3255 16 Westermeier, C. et al. (1999) Bispyrene based chiroptical molecular redox switch. Chem. Commun., 2427–2428 17 Zahn, S. and Canary, J.W. (1998) Redox-switched exciton-coupled circular dichroism: a novel strategy for binary molecular switching. Angew. Chem. Int. Ed. Eng. 37, 305–307 18 Zahn, S. et al. (2001) Supramolecular detection of metal ion binding: ligand conformational control of cholesteric induction in nematic liquid crystalline phases. Chem. Eur. J. 7, 88–93 19 Zahn, S. and Canary, J.W. (2000) Electroninduced inversion of helical chirality in copper complexes of N,N-dialkylmethionines. Science 288, 1404–1407 20 Schadt, M. (1997) Liquid crystal materials and liquid crystal displays. Annu. Rev. Mater. Sci. 27, 305–379 21 Mao, C. et al. (1999) A nanomechanical device based on the B–Z transition of DNA. Nature 397, 144–146

Delivering on the promise of bone morphogenetic proteins Rebecca H. Li and John M. Wozney The advent of bone growth factors has been widely anticipated since their successful production using recombinant DNA technology. Bone morphogenetic proteins (BMPs) are an important class of bone growth factors and will be the focus of this article. In the near future these therapeutics might revolutionize how clinicians treat such diverse orthopedic applications as the healing of broken bones, increasing bone density lost through aging, and strengthening the spine. These potent proteins require application directly at the site of repair via a delivery system. The choice of delivery system has a profound effect on the clinical outcome. In the past decade, researchers have focused on developing efficient delivery systems and advancing these factors from the bench to the clinic.

Rebecca H. Li* John M. Wozney Genetics Institute, 1 Burtt Road, Andover, MA 01810, USA. *e-mail: [email protected]

Every bone in the human skeleton contains a reservoir of bone-building cells (osteoblasts) of which the function is to continually deposit rigid extracellular matrix (ECM), which is subsequently converted into mineralized hard tissue. The skeleton also includes bone-resorbing cells (osteoclasts), of which the sole function is to break down the hard tissue. This delicate balance of bone building and destroying is tipped only in special circumstances, such as trauma or aging. In trauma, a bone is fractured and the healing defense stimulates osteoblast activity; bone formation outpaces bone resorption, and the tissue is repaired. The balance is tipped in the other direction – in favor of the

osteoclasts – when we age; bone is destroyed faster than it is replaced, and the skeleton becomes weaker and less dense. The challenge of how to stimulate osteoblasts to respond faster, and in greater numbers to accelerate fracture healing, repair large defects the body cannot ordinarily rebuild, strengthen the spine, or even to turn back the clock on bone density lost with aging, has engaged scientists for decades. However, it appears that we are on the brink of tremendous advances in the use of bone growth factors as therapeutics, which will revolutionize how clinicians treat such problems. Bone contains a cocktail of growth factors including transforming growth factor beta (TGF-β), plateletderived growth factor (PDGF), bone morphogenetic proteins (BMPs), insulin-like growth factors I and II (IGF-I and IGF-II) and fibroblast growth factors (FGFs). BMPs differ from other growth factors in that they are OSTEOINDUCTIVE (see Glossary). Currently, local application of these potent growth factors is being investigated for several bone regeneration applications. For a clinically beneficial outcome, these growth factors require a delivery system to guide tissue regeneration and prevent rapid dispersal of the factors from the site. This article provides a perspective on how bone

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