Asymmetric induction by retgersite, nickel sulfate hexahydrate, in conjunction with asymmetric autocatalysis

The origin of biological homochirality is of great interest to the scientific community and several possible origins of homochirality have been proposed.[1] Chiral inorganic crystals are considered to be one possible origin of homochirality because the inorganic minerals are considered to have existed widely on Earth before the emergence of life.[2, 3] Metal sulfates are one of the most abundant minerals on Earth, and the sulfate and metal ions are symmetric achiral ions.

Retgersite, nickel sulfate hexahydrate, is a naturally occurring mineral and exhibits enantiomorphism. Nickel sulfate forms various hydrate salts such as hexahydrate and heptahydrate depending on the crystallization conditions. The relatively stable $\alpha$-form of hexahydrate has a chiral structure. The hexahydrate crystal 1, crystallized at 31.5–53.3 °C,[4] has a bright blue-green colour and has absorption bands in the visible light region; the optical properties of the crystal have been studied, including the chiral optical properties such as ORD and CD.[5] The absolute structure, analyzed by X-ray and ORD spectra, of 1 was first reported in 1987 and the detailed chiral optical properties of the crystal were studied recently by Asahi et al.[6] The chiral optical properties of the chiral crystal of achiral nickel sulfate have thus attracted broad interest. However, to the best of our knowledge, usage of the chirality of $\mathrm{NiSO}_{4}\cdot6\mathrm{H}_{2}\mathrm{O}$ in chemical reactions has not been realized. In this paper, we report asymmetric induction using chiral crystals of nickel sulfate hexahydrate in conjunction with asymmetric autocatalysis (Figure 1).

Asymmetric autocatalysis is the reaction in which the product acts as an asymmetric catalyst for the reaction to form a product with the same structure and absolute configuration. We have been studying the asymmetric autocatalytic reaction of the pyrimidyl alkanols with amplification of enantiomeric excess.[7, 8] By using asymmetric autocatalysts, we have reported that various inorganic[10] and organic[11] crystals act as chiral triggers for the asymmetric autocatalysis. Herein, we report that the chiral nickel sulfate hexahydrate crystal triggers asymmetric autocatalysis.

The chiral single crystal of nickel sulfate hexahydrate was obtained by recrystallization. $\mathrm{NiSO}_{4}\cdot6\mathrm{H}_{2}\mathrm{O}$ 1 (25 g) was dissolved in distilled water (33 mL) at 70 °C and was kept for 12 h and water was allowed to evaporate for 2–3 d at above 31.5 °C in a Petri dish to give a crystal of $\mathrm{NiSO}_{4}\cdot6\mathrm{H}_{2}\mathrm{O}$ 1 of ca. 2 cm size (Figure 1). The solid state CD spectrum was measured with the powdered crystal of 1 in Nujol. Although the base line of the obtained CD spectrum was not flat due to the anisotropy of the crystal powders, a distinguishable signal was observed around the 390 nm region (Figure 1). The chirality of the crystal was determined by the CD spectrum in the 390 nm region and confirmed by the X-ray single crystal diffraction analysis using the Flack parameter (Figure 1).[12, 13] The $P4_{1}2_{1}2$ crystal exhibits the negative Cotton effect at 390 nm, and the $P4_{3}2_{1}2$ crystal exhibits the opposite positive Cotton effect at 390 nm.[5, 6]

Using these chiral crystals of $\mathrm{NiSO}_{4}\cdot6\mathrm{H}_{2}\mathrm{O}$ 1 as chiral initiators, asymmetric autocatalysis of diisopropylzinc (i-Pr$_2$Zn) and

pyrimidine-5-carbaldehyde 2 was performed.[14] Thus, the chiral crystal of NiSO$_4$·6H$_2$O 1 was ground with agate and mortar, then it was mixed immediately with pyrimidine-5-carbaldehyde 2 and used in the reaction before the progress of the dehydration of the crystal. By adding i-Pr$_2$Zn slowly, addition reaction was performed in combination with asymmetric autocatalysis with amplification of enantiomeric excess (ee). After purification, the enantiomeric excess of the formed pyrimidyl alkanol 3 was determined by HPLC using a chiral column.

The results are summarized in Table 1. As shown in entry 1, ($S$)-pyrimidyl alkanol 3 was obtained in the presence of a chiral crystal of NiSO$_4$·6H$_2$O with the positive Cotton effect at 390 nm [CD(+)$_{390\mathrm{Nujol}}$]. On the other hand, ($R$)-3 was obtained in the presence of a chiral crystal of NiSO$_4$·6H$_2$O with the negative Cotton effect [CD(−)$_{390\mathrm{Nujol}}$] (entry 2). Although the yields and ees were not so high probably due to the heterogeneous conditions with the existence of crystallization water, the sense of enantioselectivity exhibits good reproducibility for the several different crystal samples. It should be noted that the ee of the formed alkanol 3 was amplified to be nearly enantiomerically pure (>99.5% ee) during the subsequent asymmetric autocatalysis (entries 1 and 2).

Entry	Crystal 1 CD390 mNujol	Pyrimidyl alkanol 3 Yield (%)	Pyrimidyl alkanol 3 ee$^{d}$ (%)	Amplification of ee by asymmetric autocatalysis Yield (%)	Amplification of ee by asymmetric autocatalysis ee$^{d}$ (%)	Configuration
1$^{a}$	(+)	27	3	77	50 (>$99.5) | $S$
2$^{a}$	(−)	28	3	72	37 (>$99.5) | $R$
3$^{a}$	(+)	81	9	72	28	$S$
4$^{a}$	(+)	27	2	78	76	$S$
5$^{a}$	(+)	27	5	74	95	$S$
6$^{a}$	(−)	37	6	80	91	$R$
7$^{b}$	(+)	14	4	85	53	$S$
8$^{b}$	(−)	30	4	73	68	$R$

We have demonstrated, by using asymmetric autocatalysis of pyrimidyl alkanols, that the chiral natural mineral of retgersite NiSO$_4$·6H$_2$O induces the chirality of the chiral organic compound with high ee. These results suggest that common inorganic sulfate minerals on Earth may be considered to be the origin of chirality of the chiral organic compounds.

Acknowledgements

This work has been financially supported by the Grant-in-Aid for Scientific Research from the Promotion of Science (JSPS KAKENHI grant numbers 26810026 & 15H03781) and the MEXT-Supported Program for the Strategic Research Foundation at Private Universities, 2012–2016.

Notes and references

1 (a) I. Weissbuch, L. Addadi, Z. Berkovitch-Yellin, E. Gati, M. Lahav and L. Leiserowitz, Nature, 1984, 310, 161; (b) M. Bolli, R. Micura and A. Eschenmoser, Chem. Biol., 1997, 4, 309; (c) B. L. Feringa and R. A. van Delden,