Stereo-Differentiating Asymmetric Rh(I)-Catalyzed Pauson-Khand Reaction: A DFT-Informed Approach to Thapsigargin Stereoisomers

Abstract

We report a stereo-differentiating dynamic kinetic asymmetric Rh(I)-catalyzed Pauson-Khand reaction, which provides access to an array of thapsigargin stereoisomers. Using catalyst-control, a consistent stereochemical outcome is achieved at C2─for both matched and mismatched cases─regardless of the allene-yne C8 stereochemistry. The stereochemical configuration for all stereoisomers was assigned by comparing experimental vibrational circular dichroism (VCD) and ¹³C NMR to DFT-computed spectra. DFT calculations of the transition-state structures corroborate experimentally observed stereoselectivity and identify key stabilizing and destabilizing interactions between the chiral ligand and allene-yne PKR substrates. The robust nature of our catalyst-ligand system places the total synthesis of thapsigargin and its stereoisomeric analogues within reach.

Figure 1

(A) Stereodifferentiation using substrate control; (B) DFT-informed asymmetric PKR; (C) thapsigargin and analogues, highlighting key stereochemical sites; (D) stereodifferentiation using catalyst control; (E) this work: stereodifferentiation in a DyKAT-based asymmetric PKR and access to stereoisomeric analogues of thapsigargin.

Scheme 1. Synthesis of Aldol Adducts 18a–18e

Figure 2

DFT-calculated (green) and experimental (blue) VCD and IR spectra of ketone (R)-17.

Scheme 2. Synthesis of Allene-yne Precursors 13a–13f

Figure 3

Computed reaction energy profiles for the oxidative cyclization of (R)- and (S)-13d with a (S)-MonoPhos-alkene (4)-supported Rh catalyst. DFT calculations were performed at the ωB97X-D/def2-TZVP/SMD(DCE)//B3LYP-D3/LANL2DZ-6-31G(d) level of theory.

Figure 4

Lowest energy oxidative cyclization transition-state isomers with (R)-13d (matched pairs). All energies are in kcal/mol with respect to 20. See Supporting Information for computational details, including distortion and through-space interaction energy calculations.

Figure 5

Lowest energy oxidative cyclization transition-state isomers with (S)-13d (mismatched pairs). All energies are in kcal/mol with respect to 20. See Supporting Information for computational details, including distortion and through-space interaction energy calculations.

Figure 6

Absence of kinetic resolution in PKR of allene-yne 13a.

Figure 7

DFT-calculated (green) and experimental (blue) VCD and IR spectra of (A) (2R,8R)-14g; and (B) (2S,8R)-14g.