Asymmetric Autocatalysis: Triggered by Chiral Isotopomer Arising from Oxygen Isotope Substitution

Abstract

The substitution of the atoms in the enantiotopic moiety of an achiral molecule by their isotopes makes the present molecule chiral. [1, 2] Isotopically labeled compounds [3] have been used to elucidate structural information, [3b] mechanisms of organic reactions, [3c-e] and drug kinetics, [3f] however, asymmetric synthesis using the chirality generated by isotope substitution alone is difficult because of the very low enantiomeric excess (ee) displayed when using deuterated chiral compounds as a source of chirality. [4] Amplification effects of the helicity in the polyisocianates [5a] and supramolecular polymers [5b] that results from hydrogen isotopes (D/H) have been reported. And discrimination of hydrogen isotope chirality using spectroscopic methods [6] and HPLC analyses with a chiral stationary phase [7] have been reported.Recently, we have reported asymmetric autocatalysis with amplification of ee values [8][9][10][11] that was triggered by chiral compounds resulting from hydrogen (D/H) [12] and carbon isotope ( 13 C/ 12 C) [13] substitutions. Meanwhile, the syntheses of chiral compounds resulting from oxygen isotope substitutions [14] and oxygen kinetic isotope effects (KIEs) [15] have been reported. However, to the best of our knowledge, there have been no reports of asymmetric synthesis or induction utilizing chiral compounds resulting from oxygen isotope substitution. Therefore, asymmetric autocatalysis initiated by chiral compounds arising from 18 O/ 16 O substitution is challenging.We selected a meso compound as the oxygen isotope enantiomer (Scheme 1). Achiral meso hydrobenzoin forms chiral oxygen isotopomers 1 after 18 O labeling of the hydroxy group in an enantioselective manner. These diols should be chiral only as a result of the oxygen isotope ( 18 O/ 16 O) substitution. The enantiomer whose 18 O atom is bound to the S-configured carbon center is described as [ 18 O](S)-1, while the opposite is described as [ 18 O](R)-1.Herein we report the first asymmetric induction by chiral compounds arising from oxygen isotope substitution in conjunction with asymmetric autocatalysis (Scheme 1). The chiral compound created by oxygen isotope substitution serves as the chiral trigger of asymmetric autocatalysis to afford alkanol 3 with high ee values. The relationship between the absolute configurations of the chiral 18 O-labeled hydrobenzoin ([ 18 O]1) and the product alkanol 3 is reproducible.The enantiomers of [ 18 O]1 were synthesized from chiral trans-stilbene oxide (4), which was obtained by resolution of its racemate by HPLC methods using a chiral stationary phase. The enantiomers of oxide 4 had ee values greater than 99.5 % and were submitted to the epoxide-opening reaction using [ 18 O]H 2 O under basic reaction conditions (Figure 1 A). By using 2-methoxyethanol as a cosolvent, the hydrolysis of the epoxide by [ 18 O]H 2 O proceeded stereoselectively to form the chiral [ 18 O]1 predominantly. The enantioenrichment of the synthesized compound 1 was confirmed by 13 C NMR spectroscopic analysis...

Mechanisms of Autocatalysis

“…Early studies varied the alkylating agent,165, 168 and other substrates have been studied, including ferrocene derivatives,169, 170 quinolyl alcohols,171–173 chiral diols,174, 175 pyridine carbaldehydes,165 and nicotinamides 176. 177…”

Mechanismen der Autokatalyse

“…[166] In den meisten Studien wurden 2-Alkinyl-5-pyrimidylalkohole in der Alkylierung mit Diisopropylzink eingesetzt, da sich zeigte, dass diese Substrate sehr empfindlich auf ¾nderungen der Reaktionsbedingungen reagierten. [167] In früheren Studien wurde das Alkylierungsmittel variiert, [165,168] außerdem wurden andere Substrate untersucht, darunter Ferrocenderivate, [169,170] Chinolylalkohole, [171][172][173] chirale Diole, [174,175] Pyridincarbaldehyde [165] und Nicotinamide. [167] In früheren Studien wurde das Alkylierungsmittel variiert, [165,168] außerdem wurden andere Substrate untersucht, darunter Ferrocenderivate, [169,170] Chinolylalkohole, [171][172][173] chirale Diole, [174,175] Pyridincarbaldehyde [165] und Nicotinamide.…”

“…H/D-Substitution, [180,181] 12 C/ 13 C-Substitution, [182] 16 O/ 18 O-Substitution [175] und teildeuterierte Methylgruppen [183] kçnnen eine reproduzierbare Enantioselektivität der Reaktion induzieren. H/D-Substitution, [180,181] 12 C/ 13 C-Substitution, [182] 16 O/ 18 O-Substitution [175] und teildeuterierte Methylgruppen [183] kçnnen eine reproduzierbare Enantioselektivität der Reaktion induzieren.…”

“…Das Verfahren wurde im Laufe der Zeit weiterentwickelt, von manuellen Runden aus Reaktion und Aufreinigung [166] hin zu einem Ein-Topf-Verfahren ohne Produktaufreinigung zwischen den Reaktionen. [167] In früheren Studien wurde das Alkylierungsmittel variiert, [165,168] außerdem wurden andere Substrate untersucht, darunter Ferrocenderivate, [169,170] Chinolylalkohole, [171][172][173] chirale Diole, [174,175] Pyridincarbaldehyde [165] und Nicotinamide. [176,177] Die Reaktion reagiert sehr empfindlich auf winzige Chiralitätsquellen, und selbst sehr kleine ee-Werte im Produkt kçnnen bis zur optischen Reinheit verstärkt werden (Schema 66).…”

“…Die Reaktion hängt sehr empfindlich von einer aus der Isotopensubstitution hervorgehenden Chiralität ab (Schema 68). H/D-Substitution, [180,181] 12 C/ 13 C-Substitution, [182] 16 O/ 18 O-Substitution [175] und teildeuterierte Methylgruppen [183] kçnnen eine reproduzierbare Enantioselektivität der Reaktion induzieren.…”