The widespread use of controlled molecular-level motion in key natural processes suggests that great rewards could come from bridging the gap between the present generation of synthetic molecular systems, which by and large rely upon electronic and chemical effects to carry out their functions, and the machines of the macroscopic world, which utilize the synchronized movements of smaller parts to perform specific tasks. This is a scientific area of great contemporary interest and extraordinary recent growth, yet the notion of molecular-level machines dates back to a time when the ideas surrounding the statistical nature of matter and the laws of thermodynamics were first being formulated. Here we outline the exciting successes in taming molecular-level movement thus far, the underlying principles that all experimental designs must follow, and the early progress made towards utilizing synthetic molecular structures to perform tasks using mechanical motion. We also highlight some of the issues and challenges that still need to be overcome.

Synthetic molecular motors and mechanical machines.

Nature relies on large molecules to carry out sophisticated chemical operations, such as catalysis, tight and specific binding, directed flow of electrons, or controlled crystallization of inorganic phases. The polymers entrusted with these crucial tasks, mostly proteins but sometimes RNA, are unique relative to other biological and synthetic polymers in that they adopt specific compact conformations that are thermodynamically and kinetically stable. These folding patterns generate “active sites” via precise three-dimensional arrangement of functional groups. In terms of covalent connectivity, the groups that comprise the active site are often widely spaced along the polymer backbone. The remarkable range of chemical capabilities that evolution has elicited from proteins suggests that it might be possible to design analogous capabilities into unnatural polymers that fold into compact and specific conformations. Since biological evolution has operated under many constraints, the functional properties of proteins and RNA should be viewed as merely exemplifying the potential of compactly folded polymers. The chemist’s domain includes all possible combinations of the elements, and the biological realm, vast and complex though it may be, is only a small part of that domain. Therefore, realization of the potential of folding polymers may be limited more by the human imagination than by physical barriers. I use the term “foldamer” to describe any polymer with a strong tendency to adopt a specific compact conformation. Among proteins, the term “compact” is associated with tertiary structure, and there is as yet no synthetic polymer that displays a specific tertiary structure. Protein tertiary structure arises from the assembly of elements of regular secondary structure (helices, sheets, and turns). The first step in foldamer design must therefore be to identify new backbones with well-defined secondary structural preferences. “Well-defined” in this case means that the conformational preference should be displayed in solution by oligomers of modest length, and I will designate as a foldamer any oligomer that meets this criterion. Within the past decade, a handful of research groups have described unnatural oligomers with interesting conformational propensities. The motivations behind such efforts are varied, but these studies suggest a collective, emerging realization that control over oligomer and polymer folding could lead to new types of molecules with useful properties. The purpose of this “manifesto” is to introduce a large audience to the broad research horizons offered by the concept of synthetic foldamers. The path to creating useful foldamers involves several daunting steps. (i) One must identify new polymeric backbones with suitable folding propensities. This goal includes developing a predictively useful understanding of the relationship between the repetitive features of monomer structure and conformational properties at the polymer level. (ii) One must endow the resulting foldamers with interesting chemical functions, by design, by randomization and screening (“evolution”), or by some combination of these two approaches. (iii) For technological utility, one must be able to produce a foldamer efficiently, which will generally include preparation of the constituent monomers in stereochemically pure form and optimization of heteropolymer synthesis. Each of these steps involves fascinating chemical challenges; the first step is the focus of this Account.

Foldamers: A Manifesto

The miniaturization of components used in the construction of working devices is being pursued currently by the large-downward (top-down) fabrication. This approach, however, which obliges solid-state physicists and electronic engineers to manipulate progressively smaller and smaller pieces of matter, has its intrinsic limitations. An alternative approach is a small-upward (bottom-up) one, starting from the smallest compositions of matter that have distinct shapes and unique properties-namely molecules. In the context of this particular challenge, chemists have been extending the concept of a macroscopic machine to the molecular level. A molecular-level machine can be defined as an assembly of a distinct number of molecular components that are designed to perform machinelike movements (output) as a result of an appropriate external stimulation (input). In common with their macroscopic counterparts, a molecular machine is characterized by 1) the kind of energy input supplied to make it work, 2) the nature of the movements of its component parts, 3) the way in which its operation can be monitored and controlled, 4) the ability to make it repeat its operation in a cyclic fashion, 5) the timescale needed to complete a full cycle of movements, and 6) the purpose of its operation. Undoubtedly, the best energy inputs to make molecular machines work are photons or electrons. Indeed, with appropriately chosen photochemically and electrochemically driven reactions, it is possible to design and synthesize molecular machines that do work. Moreover, the dramatic increase in our fundamental understanding of self-assembly and self-organizational processes in chemical synthesis has aided and abetted the construction of artificial molecular machines through the development of new methods of noncovalent synthesis and the emergence of supramolecular assistance to covalent synthesis as a uniquely powerful synthetic tool. The aim of this review is to present a unified view of the field of molecular machines by focusing on past achievements, present limitations, and future perspectives. After analyzing a few important examples of natural molecular machines, the most significant developments in the field of artificial molecular machines are highlighted. The systems reviewed include 1) chemical rotors, 2) photochemically and electrochemically induced molecular (conformational) rearrangements, and 3) chemically, photochemically, and electrochemically controllable (co-conformational) motions in interlocked molecules (catenanes and rotaxanes), as well as in coordination and supramolecular complexes, including pseudorotaxanes. Artificial molecular machines based on biomolecules and interfacing artificial molecular machines with surfaces and solid supports are amongst some of the cutting-edge topics featured in this review. The extension of the concept of a machine to the molecular level is of interest not only for the sake of basic research, but also for the growth of nanoscience and the subsequent development of nanotechnology.

Artificial Molecular Machines.

III. Foldamer Research 3910 A. Overview 3910 B. Motivation 3910 C. Methods 3910 D. General Scope 3912 IV. Peptidomimetic Foldamers 3912 A. The R-Peptide Family 3913 1. Peptoids 3913 2. N,N-Linked Oligoureas 3914 3. Oligopyrrolinones 3915 4. Oxazolidin-2-ones 3916 5. Azatides and Azapeptides 3916 B. The â-Peptide Family 3917 1. â-Peptide Foldamers 3917 2. R-Aminoxy Acids 3937 3. Sulfur-Containing â-Peptide Analogues 3937 4. Hydrazino Peptides 3938 C. The γ-Peptide Family 3938 1. γ-Peptide Foldamers 3938 2. Other Members of the γ-Peptide Family 3941 D. The δ-Peptide Family 3941 1. Alkene-Based δ-Amino Acids 3941 2. Carbopeptoids 3941 V. Single-Stranded Abiotic Foldamers 3944 A. Overview 3944 B. Backbones Utilizing Bipyridine Segments 3944 1. Pyridine−Pyrimidines 3944 2. Pyridine−Pyrimidines with Hydrazal Linkers 3945

A field guide to foldamers.

beta-Peptides: from structure to function.

Highly isotactic PMMAs with narrow molecular weight distribution (Mw/Mn<1.2) have been prepared by the polymerization of MMA in toluene at −78°C initiated by t-C4H9MgBr prepared in diethyl ether. The polymerization proceeded in a “living” manner, in which the initiation reaction was fast and quantitative whereas the propagation was slow. The ether solution of t-C4H9MgBr used as the initiator contained almost equal amounts of MgBr2 produced by an Wurtz type coupling during the preparation. It has been found from 1H NMR analyses that the excess amount of MgBr2 contributes to form the initiating species of homogeneous activity and stereospecificity. Polymerizations of MMA by n-, iso-, and s-C4H9MgBr were also investigated in toluene at −78°C. With an increase in the bulkiness of the alkyl group the isotacticity of the polymer increased and the molecular weight distribution became narrower. The addition of MgBr2 also increased the isotacticity of the polymer. The results of block copolymerizations of MMA and MMA-d8 or ethyl methacrylate are also described.

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Living and Highly Isotactic Polymerization of Methyl Methacrylate by t-C4H9MgBr in Toluene

Cellulose was bonded chemically to 3-aminopropyl silica gel with diisocyanates and then allowed to react with a large excess of 3,5-dimethylphenyl- or 3,5-dichlorophenylisocyanate. Optical resolving power of these chiral stationary phases was compared with that of the cellulose triphenylcarbamate derivatives coated on silica gel. ∗Chromatographic Resolution XV, for part XIV, see Y. Okamoto, R. Aburatani, and K. Hatada, J. Chromatogr., in press.

Chiral Stationary Phases for HPLC: Cellulose Tris(3,5-dimethylphenylcarbamate) and Tris(3,5-dichlorophenylcarbamate) Chemically Bonded to Silica Gel∗

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Preparation of Highly Isotactic Poly(methyl methacrylate) of Low Polydispersity

Optical resolution of dihydropyridine enantiomers by high-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase

Triphenylmethyl methacrylate (TrMA) was polymerized with two types of asymmetric anionic catalyst, lithium (R)-N-(1-phenylethyl)anilide (LiAn) and (-)-sparteine–butyllithium complex (Sp–BuLi), at −78°C. Both catalysts yielded optically active polymers. The polymers obtained with LiAn in toluene and tetrahydrofuran (THF) showed specific rotations [α] of from −50° to −90° (in THF). The [α] of the polymer obtained with Sp–BuLi in toluene was positive and increased with polymer yield reaching above +300°s, whereas the polymer obtained in THF showed a low [α] (ca. +7°). Gel permeation chromatograms of both polymers obtained with LiAn and Sp–BuLi in THF exhibited rather narrow molecular weight distributions, whereas those obtained in toluene showed at least two or three components with markedly different molecular weights. The circular dichroism (CD) spectrum of the polymer obtained with Sp–BuLi showed strong positive peaks at 208 and 232 nm and a weak band at 250–280 nm; the polymer produced with LiAn showed a similar spectrum with opposite sign. The poly(methyl methacrylate)s derived from these poly(TrMA)s were highly isotactic but showed negligible rotations ([α] ± 2° in toluene). The polymer of high molecular weight showed clear polarization under a polarizing microscope and the low polymer obtained with LiAn appeared to show flow birefringence in chloroform at room temperature.

Yoshio Okamoto

Papers

Living and Highly Isotactic Polymerization of Methyl Methacrylate by t-C4H9MgBr in Toluene

Chiral Stationary Phases for HPLC: Cellulose Tris(3,5-dimethylphenylcarbamate) and Tris(3,5-dichlorophenylcarbamate) Chemically Bonded to Silica Gel∗

Preparation of Highly Isotactic Poly(methyl methacrylate) of Low Polydispersity

Optical resolution of dihydropyridine enantiomers by high-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase

Asymmetric polymerization of triphenylmethyl methacrylate by optically active anionic catalysts