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. 2019 Apr 10;141(14):6054-6059.
doi: 10.1021/jacs.9b01819. Epub 2019 Mar 29.

Stereoselective Synthesis of Molecular Square and Granny Knots

David A Leigh  1 , Lucian Pirvu  1 , Fredrik Schaufelberger  1
Affiliations

Stereoselective Synthesis of Molecular Square and Granny Knots

David A Leigh et al. J Am Chem Soc. .

Abstract

We report on the stereoselective synthesis of both molecular granny and square knots through the use of lanthanide-complexed overhand knots of specific handedness as three-crossing "entanglement synthons". The composite knots are assembled by combining two entanglement synthons (of the same chirality for a granny knot; of opposite handedness for a square knot) in three synthetic steps: first, a CuAAC reaction joins together one end of each overhand knot. Ring-closing olefin metathesis (RCM) then affords the closed-loop knot, locking the topology. This allows the lanthanide ions necessary for stabilizing the entangled conformation of the synthons to subsequently be removed. The composite knots were characterized by 1H and 13C NMR spectroscopy and mass spectrometry and the chirality of the knot stereoisomers compared by circular dichroism. The synthetic strategy of combining building blocks of defined stereochemistry (here overhand knots of Λ- or Δ-handed entanglement) is reminiscent of the chiron approach of using minimalist chiral synthons in the stereoselective synthesis of molecules with multiple asymmetric centers.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Parallels in the structural relationship between asymmetric centers in chiral molecules and strand crossings in knots. (a) Stereochemical consequences of combining two one-asymmetric-center synthons. (b) Topological consequences of combining two three-crossing entanglement synthons.
Figure 2
Figure 2
Lanthanide coordination induces folding and threading of L1/L2 to form entanglement synthons: alkene and alkyne- or azide-bearing overhand knots of single handedness (Λ or Δ). Reagents and conditions: (i) Lu(CF3SO3)3, MeCN, 80 °C, 16 h. Yields: 81% (Λ-L1•[Lu]), 82% (Δ-L1•[Lu]), 85% (Λ-L2•[Lu]), and 73% (Δ-L2•[Lu]).
Scheme 1
Scheme 1. Synthesis of Double Overhand Knot (Λ,Δ)-L3•[Lu]2 and Square Knot (Λ,Δ)-1
Reagents and conditions: (i) Cu(MeCN)4(CF3SO3), Tentagel-TBTA, MeCN/MeOH 1:1, RT, 16 h, 70%. (ii) Hoveyda-Grubbs second generation catalyst, MeNO2/CH2Cl2 1:1, 30%. (iii) Et4NF, MeCN, RT, 5 min, 95%.
Figure 3
Figure 3
(a) ESI-MS (positive mode) of square knot complex (Λ,Δ)-1•[Lu]2 (inset: isotopic distribution from HR-MS). (b) Partial 1H NMR spectra (600 MHz, MeCN-d3, 298 K) of (i) entanglement synthon Δ-L2•[Lu], (ii) entanglement synthon Λ-L1•[Lu], (iii) double overhand knot (Λ,Δ)-L3•[Lu]2, and (iv) square knot coordination complex (Λ,Δ)-1•[Lu]2. For full assignments, see the Supporting Information.
Figure 4
Figure 4
(a) Synthesis and HR-MS of granny knot complex (Λ,Λ)-1•[Lu]2. Conditions: (i) Cu(MeCN)4(CF3SO3), Tentagel-TBTA, MeCN/MeOH 1:1, RT, 16 h, 79%. (ii) Hoveyda-Grubbs 2nd generation catalyst, MeNO2/CH2Cl2 1:1, 33%. (b) Synthesis and HR-MS of granny knot complex (Δ,Δ)-1•[Lu]2. Conditions: (iii) Cu(MeCN)4(CF3SO3), Tentagel-TBTA, MeCN/MeOH 1:1, RT, 16 h, 52%. (iv) Hoveyda-Grubbs 2nd Gen, MeNO2/CH2Cl2 1:1, 31%. For each of the ion isotopic distributions, the experimentally observed spectrum is shown above the theoretically calculated spectrum.
Figure 5
Figure 5
Circular dichroism spectra (1.0 × 10–4 M, MeCN, 298 K) of granny knots (Λ,Λ)-1•[Lu]2 (blue) and (Δ,Δ)-1•[Lu]2 (red) and square knot (Λ,Δ)-1•[Lu]2 (green). Normalized for absorbance.
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