Organocatalysis offers a number of opportunities in polymer synthesis and was among the earliest methods of catalyzing the synthesis of polyesters. In the following Perspective we attempt to highlight the opportunities and challenges in the use of organic molecules as catalysts or initiators for polymerization reactions. The ring-opening polymerization of cyclic monomers is used as a representative polymerization process to illustrate some of the features of organic catalysts and initiators and to compare them to metal-based approaches. The convergence of convenience, functional group tolerance, fast rates, and selectivities will continue to drive innovations in polymerization catalysis, and it is our perspective that organocatalysis will continue to play an important role in these developments.

The bicyclic guanidine 1,5,7- triazabicyclo[4.4.0]dec-5-ene (TBD) is an effective organocatalyst for the formation of amides from esters and primary amines. Mechanistic and kinetic investigations support a nucleophilic mechanism where TBD reacts reversibly with esters to generate an acyl-TBD intermediate that acylates amines to generate the amides. Comparative investigations of the analogous bicyclic guanidine 1,4,6-triazabicyclo[3.3.0]oct-4-ene (TBO) reveal it to be a much less active acylation catalyst than TBD. Theoretical and mechanistic studies imply that the higher reactivity of TBD is a consequence of both its higher basicity and nucleophilicity than TBO as well as the high reactivity of the acyl-TBD intermediate, which is sterically prevented from adopting a planar amide structure.

The polyanionic nature of oligonucleotides and their enzymatic degradation present challenges for the use of siRNA in research and therapy; among the most notable of these is clinically relevant delivery into cells. To address this problem, we designed and synthesized the first members of a new class of guanidinium-rich amphipathic oligocarbonates that noncovalently complex, deliver, and release siRNA in cells, resulting in robust knockdown of target protein synthesis in vitro as determined using a dual-reporter system. The organocatalytic oligomerization used to synthesize these co-oligomers is step-economical and broadly tunable, affording an exceptionally quick strategy to explore chemical space for optimal siRNA delivery in varied applications. The speed and versatility of this approach and the biodegradability of the designed agents make this an attractive strategy for biological tool development, imaging, diagnostics, and therapeutic applications.amphipathic co-oligomers | nanoparticles | oligonucleotide delivery | biodegradable oligomers | organocatalysis R NA interference (RNAi) is an emerging technology that is revolutionizing many strategic approaches to biochemical pathway analysis, drug discovery, and therapy (1-6). As part of the RNAi pathway, small interfering RNAs (siRNAs) induce post-transcriptional, sequence-specific gene silencing utilizing endogenous intracellular machinery to selectively suppress gene expression and, thereby, reduce target protein synthesis (7). The net effect is equivalent to protein inhibition without the use of small molecule inhibitors. The specificity of RNAi also allows one to make inhibitors against previously undruggable targets. Both the ubiquity of the RNAi pathway within the body and the ease with which siRNA can be used to suppress a specific target of interest have made siRNAs a promising class of molecules for the treatment of cancer, viral infections, ocular disorders, and genetic diseases (5). In 2004, the first siRNA-based therapy entered Phase 1 clinical trials (4). Since then, several other RNAi-based therapies have reached clinical evaluation for a number of indications including cancer, viral infections, and genetic skin disorders (5,8,9). Notwithstanding this progress, formidable challenges remain for the application of RNAi technology in basic research and therapy, the most fundamental of which is delivery of siRNA across biological barriers.The siRNAs are double-stranded RNA molecules typically consisting of a 19-23 base-paired region with two 3′ overhanging nucleotides. It is polyanionic, polar, and large (ca. 13 kDa), compared to small molecule therapeutics. These physical properties suppress or prevent its unassisted passage through nonpolar membranes and, thus, its access to the intracellular RNA-induced silencing complex (RISC) components required for target protein knockdown (6). This problem is further exacerbated by siRNA's susceptibility to enzymatic degradation (i.e., RNases) (3). To address these problems, two strategies have been pursued: d...

A new family of guanidinium-rich molecular transporters featuring a novel oligocarbonate backbone with 1,7-sidechain spacing is described. Conjugates can be rapidly assembled irrespective of length in a one step oligomerization strategy that can proceed with concomitant introduction of probes (or by analogy drugs). The new transporters exhibit excellent cellular entry as determined by flow cytometry and fluorescence microscopy, and the functionality of their drug delivery capabilities was confirmed by the delivery of the bioluminescent small molecule probe luciferin and turnover by its intracellular target enzyme.New strategies, devices and agents that enable or enhance the passage of drugs or probes across biological barriers are required to address a range of major challenges in chemotherapy, imaging, diagnostics, and mechanistic chemical biology. 1 In 2000, we reported that the cellular uptake of the Tat 49-57 peptide could be mimicked by homooligomers of arginine. 2 Uptake was shown to be a function of the number and array of guanidinium groups, observations that led to the design and synthesis of the first guanidinium-rich (GR) peptoids, 2 GR-spaced peptides, 3 GR-oligocarbamates 4 and GR-dendrimeric molecular transporters (MoTrs). 5 Noteworthy subsequent studies from several groups showed that a variety of other scaffolds, including betapeptides, carbohydrates, heterocycles, and peptide nucleic acids, upon perguanidinylation, exhibit cell-penetrating activity. 6 GR MoTrs have been shown to carry a variety of cargos into cells, including small molecules, probes, metals, peptides, proteins, siRNA, morpholinoRNAs, and DNA plasmids. 7 Activatable MoTrs have been reported for targeted therapy and imaging, 8 a releasable octaarginine-drug conjugate has been shown to overcome Pgp-mediated resistance in animal models of cancer, 9 and a drug-heptaarginine conjugate has been advanced to phase II human clinical trials. 10Correspondence to: James L. Hedrick; Robert M. Waymouth; Paul A. Wender, wenderp@stanford.edu. Supporting Information Available: Experimental procedures, flow cytometry and concentration dependent uptake data, NMR data and fluorescence microscopy images. This material is available free of charge via the internet at http://pubs.acs.org. While octaarginine MoTrs have been made on scale under GMP conditions and a step-saving segment doubling approach has been introduced, 11 the length and associated costs of these syntheses preclude some anticipated applications. A solid phase synthesis of octaarginine requires ≥16 steps, while the segment doubling approach involves 9 steps. 11 We report herein a new family of oligocarbonate GR MoTrs that can be flexibly and efficiently assembled in a one-step organocatalytic ring opening oligomerization process that also allows for concomitant probe (or drug) attachment and control over transporter length. NIH Public AccessWe have previously shown that a metal-free, organocatalytic ring-opening polymerization (ROP) 12 of cyclic carbonates 13 initiated by a var...

A new class of H-bond donating ureas was developed for the ring-opening polymerization (ROP) of lactone monomers, and they exhibit dramatic rate acceleration versus previous H-bond mediated polymerization catalysts. The most active of these new catalysts, a tris-urea H-bond donor, is among the most active organocatalysts known for ROP, yet it retains the high selectivity of H-bond mediated organocatalysts. The urea cocatalyst, along with an H-bond accepting base, exhibits the characteristics of a "living" ROP, is highly active, in one case, accelerating a reaction from days to minutes, and remains active at low catalyst loadings. The rate acceleration exhibited by this H-bond donor occurs for all base cocatalysts examined. A mechanism of action is proposed, and the new catalysts are shown to accelerate small molecule transesterifications versus currently known monothiourea catalysts. It is no longer necessary to choose between a highly active or highly selective organocatalyst for ROP.

A new biradical polarizing agent, bTbtk-py, for dynamic nuclear polarization (DNP) experiments in aqueous media is reported. The synthesis is discussed in light of the requirements of the optimum, theoretical, biradical system. To date, the DNP NMR signal enhancement resulting from bTbtk-py is the largest of any biradical in the ideal glycerol/water solvent matrix, ε = 230. EPR and X-ray crystallography are used to characterize the molecule and suggest approaches for further optimizing the biradical distance and relative orientation.

Thiourea (TU)/amine base cocatalysts are commonly employed for well-controlled, highly active “living” organocatalytic ring-opening polymerizations (ROPs) of cyclic esters and carbonates. In this work, several of the most active cocatalyst pairs are shown by 1H NMR binding studies to be highly associated in solution, dominating all other known noncovalent catalyst/reagent interactions during ROP. One strongly binding catalyst pair behaves kinetically as a unimolecular catalyst species. The high selectivity and activity exhibited by these ROP organocatalysts are attributed to the strong binding between the two cocatalysts, and the predictive utility of these binding parameters is applied for the discovery of a new, highly active cocatalyst pair.

Organocatalysts typically used for the ring-opening polymerization (ROP) of cyclic ester monomers are applied to a thiolactone, ε-thiocaprolactone (tCL). In the absence of an H-bond donor, a nucleophilic polymerization mechanism is proposed. Despite the decreased ability of thioesters and thiols (versus esters and alcohols) to H-bond, H-bonding organocatalysts—a thiourea in combination with an H-bond accepting base—are also effective for the ROP of tCL. The increased nucleophilicity of thiols (versus alcohols) is implicated in the increased Mw/Mn of the poly(thiocaprolactone) versus poly(caprolactone), but deleterious transesterification is suppressed in the presence of a thiourea. The thioester monomer, tCL, is shown to be thermodynamically similar to ε-caprolactam but kinetically similar to ε-caprolactone.