Discovery of an Organic Trefoil Knot

1. Nandhini Ponnuswamy¹, 
2. Fabien B. L. Cougnon¹, 
3. Jessica M. Clough¹, 
4. G. Dan Pantoş²,
5. Jeremy K. M. Sanders¹,*

+Author Affiliations

1. ¹Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
2. ²Department of Chemistry, University of Bath, Bath BA2 7AY, UK.

1. ↵*To whom correspondence should be addressed. E-mail: jkms@cam.ac.uk

ABSTRACT

Molecular knots remain difficult to produce using the current synthetic methods of chemistry because of their topological complexity. We report here the near-quantitative self-assembly of a trefoil knot from a naphthalenediimide-based aqueous disulfide dynamic combinatorial library. The formation of the knot appears to be driven by the hydrophobic effect and leads to a structure in which the aromatic components are buried while the hydrophilic carboxylate groups remain exposed to the solvent. Moreover, the building block chirality constrains the topological conformation of the knot and results in its stereoselective synthesis. This work demonstrates that the hydrophobic effect provides a powerful strategy to direct the synthesis of entwined architectures.

Related Resources

In Science Magazine

• PERSPECTIVECHEMISTRYDriving the Formation of Molecular Knots

  • Jay S. Siegel

  Science 9 November 2012: 752-753.

Molecular knots first observed in DNA (1) and then in proteins (2) have been associated with increased thermal and mechanical robustness. The protein knots are highly conserved throughout evolution and appear to protect active regions by providing resistance against degradation, but the mechanisms involved in the spontaneous threading of a polypeptide chain through a loop to form a knot are not well understood (3).

Chemists are well acquainted with this problem: The synthesis of molecular knots is particularly difficult because it requires precisely defined pathways and transition states that are entropically much more demanding than topologically simpler macrocyclization or catenation processes. Over the past two decades, the only strategy that has provided the necessary well-defined geometry relies on metal coordination (4–10). Only two examples of knot syntheses based on weaker interactions, such as hydrogen bonding (11, 12), have been reported: These knots were formed unexpectedly and in low yields during the process of macrocyclization, and the forces underlying the knotting process remain difficult to rationalize, which limits the scope of the discovery. Trefoil knots are inherently chiral structures, and the previously published syntheses produce, with two notable exceptions (10, 12), only racemic mixtures.

We now report the stereoselective synthesis of a purely organic molecular trefoil knot in water. The knot was assembled almost quantitatively from a readily accessible amino acid–derived dithiol building block, following a dynamic combinatorial approach (13). The knot appears to be the smallest structure that minimizes the solvent-exposed hydrophobic surface. Hydrophobicity has been suggested to be involved in the formation of certain knotted proteins (14), and we propose that our system may offer a simple model of the relation between the chemical structure of an oligomer and its potential to fold into a knot.

The building block is composed of three hydrophobic electron-deficient π-systems (1,4,5,8-naphthalenediimide, NDI) connected by flexible hydrophilic amino acids (L-β-amino-alanine). It is terminated at both ends by L-cysteine, which provides a thiol for disulfide exchange and additional carboxylate anions for water solubility. The building block was readily synthesized in five steps with a 62% overall yield.