Synthesis of Spiroligomer-Containing Macrocycles

We demonstrate the synthesis and characterization of the solution conformations of a collection of functionalized spiroligomer-based macrocycles. These macrocycles contain 14 independently controllable stereocenters and four independently controllable functional groups on a highly preorganized scaffold. These molecules are being developed to display complex, preorganized surfaces for binding proteins and to create enzyme-like active sites. In this work, we demonstrate the convergent synthetic approach to this new class of macrocycles and demonstrate that the conformational properties of these molecules can be changed by altering the configuration stereocenters within the backbone

One-Pot Synthesis of Chiral, Spirocyclic 4‑Hydantoin-Proline Derivatives for Incorporation into Spiroligomer-Based Macromolecules

Derivatives of 4-hydantoin-proline have been synthesized via a direct two-step alkylation method. This method is valuable in the development of applications of <i>N</i>,<i>N</i>′-disubstituted hydantoin bearing α-amino acids by improving yields, reducing the time and number of steps required to synthesize these substituted molecules, and enabling late stage functionalization of spiroligomer termini. Over 20 unique electrophiles have been tested, highlighting the inherent versatility of this chemistry

Development of Spiroligomer–Peptoid Hybrids

Creating functional macromolecules that possess the diversity and functionality of proteins poses an enormous challenge, as this requires large, preorganized macromolecules to facilitate interactions. Peptoids have been shown to interact with proteins, and combinatorial libraries of peptoids have been useful in discovering new ligands for protein binding. We have created spiroligomer–peptoid hybrids that have a spirocyclic core that preorganizes functional groups in three-dimensional space. By utilizing spiroligomers, we can reduce the number of rotatable bonds between functional groups while increasing the stereochemical diversity of the molecules. We have synthesized 15 new spiroligomer monomer amines that contain two stereocenters and three functional groups (67–84% yields from a common hydantoin starting material) as well as a spiroligomer trimer <b>25</b> with six stereocenters and five functional groups. These 16 amines were used to synthesize five first-generation spiroligomer–peptoids hybrids

Architectural Spiroligomers Designed for Binuclear Metal Complex Templating

The first structurally, spectroscopically, and electronically characterized metal-spiroligomer complexes are reported. The binuclear [M₂L₂]⁴⁺ ions (M = Mn, Zn) are macrocyclic “squares” and are characterized by X-ray diffraction, ¹H and ¹³C NMR, electronic absorption, emission, and mass spectroscopies. The manganese complex contains two spin-independent Mn^II ions and is additionally characterized using EPR and CD spectroscopies and CV

Architectural Spiroligomers Designed for Binuclear Metal Complex Templating

The first structurally, spectroscopically, and electronically characterized metal-spiroligomer complexes are reported. The binuclear [M₂L₂]⁴⁺ ions (M = Mn, Zn) are macrocyclic “squares” and are characterized by X-ray diffraction, ¹H and ¹³C NMR, electronic absorption, emission, and mass spectroscopies. The manganese complex contains two spin-independent Mn^II ions and is additionally characterized using EPR and CD spectroscopies and CV

Hydrophobic Substituent Effects on Proline Catalysis of Aldol Reactions in Water

Derivatives of 4-hydroxyproline with a series of hydrophobic groups in well-defined orientations have been tested as catalysts for the aldol reactions. All of the modified proline catalysts carry out the intermolecular aldol reaction in water and provide high diastereoselectivity and enantioselectivity. Modified prolines with aromatic groups <i>syn</i> to the carboxylic acid are better catalysts than those with small hydrophobic groups (<b>1a</b> is 43.5 times faster than <b>1f</b>). Quantum mechanical calculations provide transition structures, TS-<b>1a</b>_water and TS-<b>1f</b>_water, that support the hypothesis that a stabilizing hydrophobic interaction occurs with <b>1a</b>

Acceleration of an Aromatic Claisen Rearrangement via a Designed Spiroligozyme Catalyst that Mimics the Ketosteroid Isomerase Catalytic Dyad

A series of hydrogen-bonding catalysts have been designed for the aromatic Claisen rearrangement of a 1,1-dimethylallyl coumarin. These catalysts were designed as mimics of the two-point hydrogen-bonding interaction present in ketosteroid isomerase that has been proposed to stabilize a developing negative charge on the ether oxygen in the migration of the double bond. Two hydrogen bond donating groups, a phenol alcohol and a carboxylic acid, were grafted onto a conformationally restrained spirocyclic scaffold, and together they enhance the rate of the Claisen rearrangement by a factor of 58 over the background reaction. Theoretical calculations correctly predict the most active catalyst and suggest that both preorganization and favorable interactions with the transition state of the reaction are responsible for the observed rate enhancement

Acceleration of an Aromatic Claisen Rearrangement via a Designed Spiroligozyme Catalyst that Mimics the Ketosteroid Isomerase Catalytic Dyad

A series of hydrogen-bonding catalysts have been designed for the aromatic Claisen rearrangement of a 1,1-dimethylallyl coumarin. These catalysts were designed as mimics of the two-point hydrogen-bonding interaction present in ketosteroid isomerase that has been proposed to stabilize a developing negative charge on the ether oxygen in the migration of the double bond. Two hydrogen bond donating groups, a phenol alcohol and a carboxylic acid, were grafted onto a conformationally restrained spirocyclic scaffold, and together they enhance the rate of the Claisen rearrangement by a factor of 58 over the background reaction. Theoretical calculations correctly predict the most active catalyst and suggest that both preorganization and favorable interactions with the transition state of the reaction are responsible for the observed rate enhancement

Spiroligozymes for Transesterifications: Design and Relationship of Structure to Activity

Transesterification catalysts based on stereochemically defined, modular, functionalized ladder-molecules (named spiroligozymes) were designed, using the “inside-out” design strategy, and mutated synthetically to improve catalysis. A series of stereochemically and regiochemically diverse bifunctional spiroligozymes were first synthesized to identify the best arrangement of a pyridine as a general base catalyst and an alcohol nucleophile to accelerate attack on vinyl trifluoroacetate as an electrophile. The best bifunctional spiroligozyme reacted with vinyl trifluoroacetate to form an acyl-spiroligozyme conjugate 2.7 × 10³-fold faster than the background reaction with a benzyl alcohol. Two trifunctional spiroligozymes were then synthesized that combined a urea with the pyridine and alcohol to act as an oxyanion hole and activate the bound acyl-spiroligozyme intermediate to enable acyl-transfer to methanol. The best trifunctional spiroligozyme carries out multiple turnovers and acts as a transesterification catalyst with <i>k</i>₁/<i>k</i>_uncat of 2.2 × 10³ and <i>k</i>₂/<i>k</i>_uncat of 1.3 × 10². Quantum mechanical calculations identified the four transition states of the catalytic cycle and provided a detailed view of every stage of the transesterification reaction

A Spiroligomer α-Helix Mimic That Binds HDM2, Penetrates Human Cells and Stabilizes HDM2 in Cell Culture

<div><p>We demonstrate functionalized spiroligomers that mimic the HDM2-bound conformation of the p53 activation domain. Spiroligomers are stereochemically defined, functionalized, spirocyclic monomers coupled through pairs of amide bonds to create spiro-ladder oligomers <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0045948#pone.0045948-Schafmeister1">[1]</a>. Two series of spiroligomers were synthesized, one of structural analogs and one of stereochemical analogs, from which we identified compound <b>1</b>, that binds HDM2 with a Kd value of 400 nM. The spiroligomer <b>1</b> penetrates human liver cancer cells through passive diffusion and in a dose-dependent and time-dependent manner <em>increases</em> the levels of HDM2 more than 30-fold in Huh7 cells in which the p53/HDM2 negative feed-back loop is inoperative. This is a biological effect that is not seen with the HDM2 ligand nutlin-3a. We propose that compound <b>1</b> modulates the levels of HDM2 by stabilizing it to proteolysis, allowing it to accumulate in the absence of a p53/HDM2 feedback loop.</p> </div