Kinetic Analysis of a Cysteine-Derived Thiyl-Catalyzed Asymmetric Vinylcyclopropane Cycloaddition Reflects Numerous Attractive Noncovalent Interactions

Abstract

Kinetic studies of a vinylcyclopropane (VCP) cycloaddition, catalyzed by peptide-based thiyl radicals, are described. Reactions were analyzed by using reaction progress kinetic analysis, revealing that ring-opening of the VCP is both rate- and enantio-determining. These conclusions are further corroborated by studies involving racemic and enantiopure VCP starting material. Noncovalent interactions play key roles throughout: both the peptide catalyst and VCP exhibit unproductive self-aggregation, which appears to be disrupted by binding between the catalyst and VCP. This in turn explains the requirement for the key catalyst feature, a substituent at the 4-position of the proline residue, which is required for both turnover/rate and selectivity.

Figure 1.

In all graphs, duplicate data are simultaneously plotted and analyzed. (a) Different-excess experiment, [VCP]₀ = 0.05 M, [1]_T = 2.5 mM. (b) Different-excess experiment, [TBVE]₀ = 0.1 M, [1]_T = 2.5 mM. (c) Alternative Michaelis–Menten fit to experiment with [VCP]₀ = 0.05 M, [TBVE]₀ = 0.1 M, [1]_T = 2.5 mM. (d) Determination of catalyst order in lower [1]_T regime; overlay is attained when the x-axis is normalized assuming 0.5-order dependence on [1]_T. (e) Determination of catalyst order in higher [1]_T regime; overlay is attained when the x-axis is normalized assuming 0.2-order dependence on [1]_T. (f) Same-excess experiment, [1]_T = 2.5 mM. Experiment A = 0.05 M VCP, 0.1 M TBVE; Experiment B = 0.035 M VCP, 0.085 M TBVE; Experiment C = 0.035 M VCP, 0.085 M TBVE, 0.015 M P; truncated and time-adjusted to exclude induction period.

Figure 2.

Comparison of (±)-VCP, (S)-VCP, and (R)-VCP. In all graphs, duplicate data are simultaneously plotted and analyzed. (a) Relative rates and product enantiomeric excess. The ee values shown are the averages of multiple runs, and the standard deviation in these values is also shown. Ar = 4-CF₃Ph. (b) Concentration profiles for enantiopure and racemic VCP. (c) Same-excess experiment with (R)-VCP, [1]_T = 2.5 mM, truncated and time-adjusted to exclude induction period.

Figure 3.

(a) Computational analysis of different configurations of the intramolecular H-bond. (b) Models for binding of (R)- and (S)-VCP to peptide catalyst. (c) Computational analysis of heterochiral and homochiral dimers. For all calculations, initial conformational searches were performed with metadynamics using CREST at the GFN2-xTB/ALPB(THF) level. Geometries were optimized at the B3LYP-D3BJ/6-31+G(d,p)/PCM(THF) level, followed by single-point energy calculations at the DLPNO-CCSD(T)/def2-TZVPP level, with M05-2X/6-31G(d)/SMD(THF) solvation free energies. Electronic energies are reported in parentheses.

Figure 4.

Comparison of catalysts 1 and 2. In all graphs, duplicate data are simultaneously plotted and analyzed. (a) Relative rates and product enantiomeric excess. Ar = 4-CF₃Ph. Values in parenthesis indicate the relative rate when compared with the 1-catalyzed reaction. (b) Concen-tration profiles. (c) Different-excess experiment, [VCP]₀ = 0.05 M, [2]_T = 2.5 mM. (d) Same-excess experiment, [2]_T = 2.5 mM, truncated and time-adjusted to exclude induction period. (e) Comparison of (±)-VCP and enantiopure VCP using 2.

Figure 5.

Computed lowest-energy geometries of the post-ring-opening adducts I_S and I_R. Initial conformational searches were performed with metadynamics using CREST at the GFN2-xTB/ALPB(THF) level. DFT calculations were carried out at the B3LYP-D3BJ/6-31G(d)/PCM(THF) // B3LYP-D3BJ/6-311+G(d,p)/PCM(THF) level. Electronic energies are reported in parentheses.

Scheme 1.

Enantioselective cysteine radical-mediated VCP cycloaddition.

Scheme 2.

Stereochemical hypotheses

Scheme 3.

Updated catalytic cycle.