Publications

Research from Toronto and Harvard

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  14- Niu, J.; Hili, R.; Liu, D. R. “Enzyme-Free Translation of DNA into Sequence-Defined Synthetic Polymers Structurally Unrelated to Nucleic Acids” Nature Chemistry, 2013, 5, 282–292.

  This work was featured in a News & Views article in Nature Chemistry 5, 252-253 (2013), in a Science and Technology Concentrate in C&E News91 [9], 45 (2013) and in a news story in Chemistry World (March 3, 2013), and in a News & Views article in Nature Biotechnology 31, 613 (2013).

   

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  The translation of DNA sequences into corresponding biopolymers enables the production, function and evolution of the macromolecules of life. In contrast, methods to generate sequence-defined synthetic polymers with similar levels of control have remained elusive. Here, we report the development of a DNA-templated translation system that enables the enzyme-free translation of DNA templates into sequence-defined synthetic polymers that have no necessary structural relationship with nucleic acids. We demonstrate the efficiency, sequence-specificity and generality of this translation system by oligomerizing building blocks including polyethylene glycol, α-(D)-peptides, and β-peptides in a DNA-programmed manner. Sequence-defined synthetic polymers with molecular weights of 26 kDa containing 16 consecutively coupled building blocks and 90 densely functionalized β-amino acid residues were translated from DNA templates using this strategy. We integrated the DNA-templated translation system developed here into a complete cycle of translation, coding sequence replication, template regeneration and re-translation suitable for the iterated in vitro selection of functional sequence-defined synthetic polymers unrelated in structure to nucleic acids. [READ ARTICLE]

  

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  13- Hili, R.; Niu, J.; Liu, D. R. “DNA Ligase-Mediated Translation of DNA Into Densely Functionalized Nucleic Acid Polymers” J. Am. Chem. Soc, 2013, 135, 98–101.

  This work was selected as a JACS Spotlight: J. Am. Chem. Soc., 2013, 135 (5), pp 1627–1628

   

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  We developed a method to translate DNA sequences into densely functionalized nucleic acids by using T4 DNA ligase to mediate the DNA-templated polymerization of 5′-phosphorylated trinucleotides containing a wide variety of appended functional groups. This polymerization proceeds sequence specifically along a DNA template and can generate polymers of at least 50 building blocks (150 nucleotides) in length with remarkable efficiency. The resulting single-stranded highly modified nucleic acid is a suitable template for primer extension using deep vent (exo-) DNA polymerase, thereby enabling the regeneration of template DNA. We integrated these capabilities to perform iterated cycles of in vitro translation, selection, and template regeneration on libraries of modified nucleic acid polymers. [READ ARTICLE]

  

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  12- Assem, N.; Hili, R.; He, Z.; Kasahara, T.; Inman, B.; Decker, S.; Yudin, A. K. “The Role of Reversible Dimerization in Reactions of Amphoteric Aziridine Aldehydes” J. Org. Chem., 2012, 77, 5613–5623.

   

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  Unprotected aziridine aldehydes belong to the amphoteric class of molecules by virtue of their dual nucleophilicity/electrophilicity. The dimeric nature of these molecules, brought together by a weak and reversible aminal “connection”, was found to be an important element of reactivity control. We present evidence that reversible dimer dissociation is instrumental in aziridine aldehyde transformations. We anticipate further developments that will unveil other synthetic consequences of remote control of selectivity through forging reversible covalent interactions. [READ ARTICLE]

  

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  11- Rotstein, B. H.; Rai, V.; Hili, R.; Yudin, A. K. “Synthesis of Peptide Macrocycles Using Unprotected Amino Aldehydes” Nature Protocols, 2010, 5, 1813–1822.

   

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  This protocol describes a method for synthesizing peptide macrocycles from linear peptide precursors, isocyanides and aziridine aldehydes. The effects of the reaction components on the efficiency of the process are discussed. Macrocyclization is exemplified by the preparation of a nine-membered ring peptide macrocycle. The product is further functionalized by nucleophilic opening of the aziridine ring with a fluorescent thiol. This transformation constitutes a useful late-stage functionalization of a macrocyclic peptide molecule. The experimental section describes the selection of the required starting materials, and the preparation of a representative aziridine-2-carboxaldehyde dimer. The synthesis and isolation of the peptide macrocycle can be accomplished in 6 h, and the ring-opening requires approximately 6–8 h. The aziridine-2-carboxaldehyde reagent is commercially available or can be synthesized from readily available starting materials in approximately 4 d. The strategy described is not limited to the specific peptide, isocyanide, aziridine aldehyde or nucleophile used in the representative synthesis. [READ ARTICLE]

  

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  10- Jebrail, M. J.; Ng, A. H. C.; Rai, V.; Hili, R.; Yudin, A. K.; Wheeler, A. “Synchronized Synthesis of Peptide-Based Macrocycles by Digital microfluidics“ Angew. Chem. Int. Ed. 2010, 49, 8625–8629. (Inside Cover issue)

   

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  Digital synthesis has been applied to the formation of peptide-based macrocycles and their analogues with side chains appended during late-stage aziridine ring-opening. Discrete nanoliter- to microliter-sized droplets of samples and reagents are controlled in parallel by applying a series of electrical potentials to an array of electrodes coated with a hydrophobic insulator. [READ ARTICLE] [COVER ART]

  

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  9- Hili, R.; Rai, V.; Yudin, A. K. “Macrocyclization of Linear Peptides Enabled by Amphoteric Molecules” J. Am. Chem. Soc. 2010, 132, 2889–2891.

  This work was highlighted in Science 2010, 327, 1430, and in Chem. Eng. News. 2010, 88, 34. It was also selected for Faculty 1000 Biology

   

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  There has been enormous interest in both naturally occurring and synthetic cyclic peptides as scaffolds that preorganize a given amino acid sequence into a rigid conformation. Such molecules have been employed as nanomaterials, imaging agents, and therapeutics. Unfortunately, the laboratory synthesis of cyclic peptides directly from linear precursors is afflicted by several thermodynamic and kinetic challenges, resulting in low chemical yields and poor chemo- and stereoselectivities. Here we report that amphoteric amino aldehydes can be used for efficient syntheses of cyclic peptides in high yields and selectivities starting from α-amino acids or linear peptides. The cyclizations effectively operate at unusually high molar concentrations (0.2 M), while side processes such as epimerization and cyclodimerization are not observed. The products are equipped with sites that allow for a highly specific, late-stage structural modification. The overall efficiency of the macrocyclization is due to the coexistence of nucleophilic and electrophilic reaction centers in amphoteric amino aldehydes. [READ ARTICLE]

   

  

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  8- Hili, R.; Yudin, A. K. “Amphoteric Amino Aldehydes Reroute the Aza-Michael Reaction” J. Am. Chem. Soc., 2009, 131, 16404–16406.

   

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  Amphoteric amino aldehydes, which exist as stable dimers, participate in an aza-Michael/aldol domino reaction with α,β-unsaturated aldehydes to afford stable 1,5-aminohydroxyaldehydes in high yields and diastereoselectivies. The reaction outcome hinges upon the dimeric nature of amphoteric amino aldehydes and the orthogonality between the NH aziridine and the two aldehyde functionalities during the reaction. Through the use of reaction conditions that disfavor dimer dissociation, the aza-Michael process has been directed toward a novel 8-(enolendo)-exo-trig cyclization. The results described herein further demonstrate the potential of amphoteric molecules in reaction discovery. [READ ARTICLE]

  

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  7- Baktharaman, S.; Hili, R.; Yudin, A. K. “Amino Carbonyl Compounds in Organic Synthesis’’ Aldrichimica Acta, 2008, 41, 109—119. +

   

  Amino aldehydes and amino ketones are versatile building blocks that are indispensable in the synthesis of natural products and pharmaceuticals. Their utility stems from the broad scope of synthetic transformations available to both the amino and carbonyl functional groups. However, the utility of amino aldehydes and ketones is not without shortcomings, as nitrogen- or carbon-protecting groups are usually needed in order to prevent undesired inter- and intramolecular selfcondensation reactions. While serving to prevent these undesired processes, nitrogen protection can also have a detrimental effect on subsequent transformations of the carbonyl group. This review focuses on recent advances in the field of amino carbonyl chemistry.

  [READ ARTICLE]

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  6- Hili, R.; Baktharaman, S.; Yudin, A. K. “Synthesis of Chiral Amines Using α-amino aldehydes” Eur. J. Org. Chem. 2008, 31, 5201—5213. (Cover Issue)

   

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  If one were to rank chemical reagents on the basis of their “synthetic content”, loosely defined as the density of functional groups per arbitrary unit of molecular space, the α-amino aldehydes will find themselves close to the very top of that list. The presence of synthetically ubiquitous amine and aldehyde functionalities predisposes α-amino aldehydes towards highly convergent bond-forming operations. Such juxtaposition does not come without a price: incompatibility of these functional groups calls for protecting groups. We discuss challenges and recently identified opportunities in this field. [READ ARTICLE] [COVER ART]

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  5- Hili, R.; Yudin, A. K. “Amphoteric Amino Aldehydes Enable Rapid Assembly of Unprotected Amino Alcohols” Angew. Chem. Int Ed.2008, 47, 4188—4191.

   

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  The term “amphoteric” is derived from the Greek “amphoteros”, which literally means “both of two”. Amphoteric amino aldehydes are counterintuitive molecules in that they contain both electrophilic and nucleophilic centers. These small but powerful reagents can be used for the streamlined construction of complex amino alcohol scaffolds (see scheme). Their premature self-destruction is prevented on kinetic grounds. [READ ARTICLE]

  

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  4- Yudin, A. K., Hili, R. “Overcoming the Demons of Protecting Groups with Amphoteric Molecules” Chem. Eur. J. 2007, 13, 6538—6542.

   

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  Synthetic organic chemists have long depended on protecting group manipulations when faced with the challenges of chemoselectivity and functional group incompatibility. Overcoming this dependence will improve the overall efficiency of chemical synthesis. By taking advantage of orthogonally reactive functional groups, amphoteric molecules can afford access not only to more efficient and strategic syntheses but also to the development of novel chemical transformations. [READ ARTICLE]

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  3- Hili, R.; Yudin, A. K. “Readily Available Unprotected Amino Aldehydes” J. Am. Chem. Soc. 2006, 128, 14772—14773.

   

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  We report a new class of bench-stable compounds that contain seemingly incompatible functional groups:  an aldehyde and an unprotected secondary amine. The thermodynamic driving force to undergo condensation between these two functionalities is offset by a high barrier imposed on this process by the aziridine ring strain. The resulting amino aldehydes exist as dimers and in the solid state. They are stable to epimerization and contain two orthogonal reaction centers, namely, an amine/aziridine and an aldehyde. Their ability to act as linchpins has been evaluated in complex heterocycle synthesis. For instance, pentacyclic frameworks can be made in one simple operation using N-benzyltryptamine as the reaction partner. Construction of other molecular skeletons with minimal use of protecting group manipulations should be feasible. [READ ARTICLE]

  

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  2- Hili, R., Yudin, A. K. “Making Carbon-Nitrogen Bonds in Biological and Chemical Synthesis” Nature Chem. Biol. 2006, 2, 284—287.

   

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  The function of many biologically active molecules requires the presence of carbon-nitrogen bonds in strategic positions. The biosynthetic pathways leading to such bonds can be bypassed through chemical synthesis to synthesize natural products more efficiently and also to generate the molecular diversity unavailable in nature. [READ ARTICLE]

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  1- Krasnova, L.B.; Hili, R.; Chernoloz, O.V.; Yudin, A.K. “Phenyliodine(III) Diacetate as a Mild Oxidant for Aziridination of Olefins and Imination of Sulfoxides with N-aminophthalimide” Arkivoc 2005, 4, 26—38.

   

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  Phenyliodine(III) diacetate (PIDA) was found to promote facile nitrene transfer to olefins and sulfoxides giving aziridines and sulfoximines, respectively, in high isolated yields and with high selectivities. The reactions are tolerant for a range of functional groups and proceed under mild conditions. The feasibility of scale-up has been demonstrated. [READ ARTICLE]