StereoPHIP: Stereoselective Parahydrogen-Induced Polarization

Abstract

Parahydrogen-induced polarization (PHIP) followed by polarization transfer to ¹³ C is a rapidly developing technique for the generation of ¹³ C-hyperpolarized substrates. Chirality plays an essential role in living systems and differential metabolism of enantiomeric pairs of metabolic substrates is well documented. Inspired by asymmetric hydrogenation, here we report stereoPHIP, which involves the addition of parahydrogen to a prochiral substrate with a chiral catalyst followed by polarization transfer to ¹³ C spins. We demonstrate that parahydrogen could be rapidly added to the prochiral precursor to both enantiomers of lactic acid (D and L), with both the (R,R) and (S,S) enantiomers of a chiral rhodium(I) catalyst to afford highly ¹³ C-hyperpolarized (over 20 %) L- and D-lactate ester derivatives, respectively, with excellent stereoselectivity. We also show that the hyperpolarized ¹ H signal decays obtained with the (R,R) and (S,S) catalysts were markedly different. StereoPHIP expands the scope of conventional PHIP to the production of ¹³ C hyperpolarized chiral substrates with high stereoselectivity.

Keywords: Lactate; NMR Spectroscopy; Parahydrogen-Induced Polarization; Pyruvate; Stereoselectivity.

Figure 1.

Hyperpolarized ¹H NMR spectra (45° flip angle, 5 s interscan delay, 1 T) of natural abundance O-acetyl enolpyruvate after PHIP with the achiral catalyst (3) (green), (R,R)-catalyst (4) (red), (S,S)-catalyst (5) (blue). The two HP-¹H spins originating from the parahydrogen appear as a quartet at around 4.9 ppm (attached to C2) and as a distorted doublet (attached to C3) at 1.3 ppm. The corresponding ¹H signal decay curves and T₁ values are shown in Figure S5.

Figure 2.

Hyperpolarized ¹³C NMR spectra (45° flip angle, 10 s interscan delay, 1 T) of natural abundance O-acetyl enolpyruvate after PHIP with MFC in the presence of the achiral catalyst (3) (green), (R,R)-catalyst (4) (red), (S,S)-catalyst (5) (blue). The downfield signal is the lactate carbonyl (170.6 ppm) while the upfield one is assigned to the acetate carbonyl (170.0 ppm).

Figure 3.

Chiral HPLC traces of O-acetyl ethyl DL-, D-, and L-lactate, the achiral catalyst product (green), (R,R)-catalyst product (red), and (S,S)-catalyst product (blue).

Figure 4.

¹H NMR spectra of DL-lactate, D-lactate, L-lactate, hydrolyzed achiral catalyst product (green), (R,R)-chiral catalyst product (red), and (S,S)-chiral catalyst product (blue) in the presence of YbDO3A-(L-alanylamide) at 9.4 T and pH 7.

Figure 5.

Hyperpolarized ¹³C NMR spectra (5° flip angle, 10 s interscan delay, 1 T) of O-acetyl ethyl L-[1-¹³C]lactate.

Scheme 1.

Catalytic addition of parahydrogen to O-acetyl ethyl enolpyruvate to form O-acetyl ethyl lactate and the catalysts used in this work.