Chapter 1: Asymmetric Autocatalysis: The Soai Reaction, an Overview
Published:28 Oct 2022
K. Soai, T. Kawasaki, and A. Matsumoto, in Asymmetric Autocatalysis: The Soai Reaction, ed. K. Soai, T. Kawasaki, and A. Matsumoto, The Royal Society of Chemistry, 2022, ch. 1, pp. 1-32.
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Asymmetric autocatalysis of 5-pyrimidyl alkanol, 3-quinolyl alkanol, and 5-carbamoylpyridyl alkanol is described in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, quinoline-3-carbaldehyde, and 5-carbamoylpyridine-3-carbaldehyde, respectively. Significant amplification of enantiomeric excess from extremely low (ca. 0.00005%) ee to near enantiopure >99.5% ee is observed along with the formation of the product. Asymmetric autocatalysis with amplification of ee has been invoked in several theories of the origins of homochirality. Circularly polarized light, chiral inorganic crystals such as quartz, chiral organic crystals composed of achiral compounds such as glycine, spontaneous absolute asymmetric synthesis without the intervention of any chiral factor, and chiral hydrogen (D/H), carbon (13C/12C), nitrogen (15N/14N), and oxygen (18O/16O) isotopomers were found to act as chiral triggers, i.e., the origin of chirality, in asymmetric autocatalysis to afford highly enantioenriched compounds.
1.1.1 Characteristic Features of Life
126.96.36.199 Self-replication of Organic Molecules
One of the characteristic features of life is self-replication at both cellular and individual levels. Although individuals are mortal, species exist in the long-term because parents produce children. Thus, self-replication provides a mechanism through which a species can exist for longer periods. Self-replication of organic molecules has attracted much attention and has become one of the topics of systems chemistry. Chemical self-replication of nucleotide by forming templates was reported by von Kiedrowski.1a Rebek et al. reported self-replication of organic compounds.1b Gadhiri et al. devised self-replicating peptides.1c These processes do not produce new stereogenic centers.
188.8.131.52 Overwhelming One Handedness, i.e., Homochirality, of Biomolecules
Another characteristic feature of life is the homochirality of biomolecules such as l-amino acids and d-sugars. Why is homochirality essential for life? Let's think about the situation of shaking hands: when both persons use right hands, it is normal shaking hands. When one uses right hand and the other uses left hand, the situation of shaking hands is very different from the normal one. Similarly, dipeptides of l-alanyl-l-alanine and d-alanyl-l-alanine are diastereomers and have different melting points. If d-amino acids are incorporated irregularly in proteins, conformations of proteins change and enzymatic functions do not operate. If l-deoxyribose is incorporated irregularly in DNA, the formation of the helix is disrupted and genetic information cannot be transferred. Eschenmoser et al. examined oligomerization of tetranucleotide cyclophosphates of d-pyronosyl-RNA.2 They found that the incorporation of l-enantiomer instead of d-enantiomer in tetranucleotides results in the efficiency of assembling of tetramers dropping by a magnitude in the order of two. As described, the homochirality of biomolecules is essential for life.
1.1.2 Origin of Homochirality and Amplification of Enantiomeric Excess
Ever since Pasteur discovered the molecular dissymmetry of sodium ammonium tartrate in 1848, the origins of biological homochirality have attracted considerable attention from many scientists.3a Indeed, Pasteur himself stated in his lecture notes that he tried to induce chirality using a magnet or by inversed movement of sunlight.3b Thus, research on the origin of chirality of organic compounds has been a historically venerable theme. Although theories for the origins of homochirality such as circularly polarized light and quartz have been proposed,2,4 the enantiomeric excesses induced by these conditions have usually been very low. An amplification process of ee is required to observe the resulting highly enantioenriched organic compounds.5
Considering two of the characteristic features of lie, i.e., self-replication and homochirality, it is natural for chemists to conceive the chiral molecule which is capable of self-replicating. In this context, we distinguish the following two concepts: asymmetric autoinduction and asymmetric autocatalysis.
Asymmetric autoinduction is a reaction in which the chiral product has effects on the stereochemical course of the reaction. Alberts and Wynberg reported enantioselective alkylation of benzaldehyde using chiral metal alkoxide of which the chiral ligand and the chiral product have the same structure.6a Danda et al. reported asymmetric hydrocyanation catalyzed by chiral 2,5-diketopiperadine.6b The chiral product increased the enantioselectivity of the catalyst. Soai et al. reported asymmetric autoinductive reduction of amino ketone to 1,2-amino alcohol using lithium aluminum hydride modified with the same chiral beta-amino alcohol as the chiral ligand.6c In these asymmetric autoinductions, the chiral catalyst and product have different structures and the amounts of the initial catalysts do not increase.
In this chapter, we describe the trajectory of discovery of asymmetric autocatalysis, state of the art of asymmetric autocatalysis, and research on the origin of homochirality of organic compounds by using asymmetric autocatalysis with amplification of ee.7
1.2 Asymmetric Autocatalysis
1.2.1 Principle of Asymmetric Autocatalysis
Asymmetric autocatalysis is a reaction in which a chiral product acts as a chiral catalyst for its own production (see Scheme 1.1). The reaction involves the process of automultiplication, i.e., self-replication, of a chiral compound. Asymmetric autocatalysis has superiority over conventional asymmetric catalysis in four regards. (1) The process involves automultiplication with high efficiency. (2) During the reaction, the amount of catalyst, i.e., the product, increases. In ideal cases, the catalytic activity does not decrease as the amount of catalyst increases during the reaction. On the other hand, in usual asymmetric catalysis, loss of catalyst through imperfect recovery and deterioration of asymmetric catalyst due to the action of heat, acid, base, mechanical damage, etc., is often observed. (3) The process of separation of the product from the catalyst is not necessary because the structure of the catalyst and the product is the same. (4) From the standpoint of green chemistry, three chemical compounds are required in asymmetric autocatalysis: A, B, and P*, whereas four compounds are usually required for asymmetric catalysis: A, B, C*, and D.
1.2.2 Discovery of Asymmetric Autocatalysis of 5-Pyrimidyl, 3-Quinolyl, and 5-Carbamoyl-3-pyridyl Alkanols with Amplification of Enantiomeric Excess: The Soai Reaction
In 1953, Frank proposed a mathematical scheme of asymmetric autocatalysis without referring to any chemical structure.5c However, no real asymmetric autocatalysis had been reported until our first report in 1990 on the asymmetric autocatalysis of 3-pyridyl alkanol in the enantioselective addition of dialkylzincs to pyridine-3-carbaldehyde.8a In 1995, we found asymmetric autocatalysis of pyrimidyl alkanol 1 with amplification of enantiomeric excess (ee) in the reaction between pyrimidine-5-carbaldehyde 2 and diisopropylzinc (see Scheme 1.2).9a,b
Moreover, we found that quinolyl alkanol 410a,b,c and 5-carbamoylpyridyl alkanol 511a,b act as asymmetric autocatalysts for amplification of ee in the reactions between quinoline-3-carbaldehyde and 5-carbamoylpyridine-3-carbaldehyde, respectively, with diisopropylzinc (see Scheme 1.3).
Asymmetric autocatalysis with amplification of ee provides an efficient process through which homochirality can be achieved.
1.2.3 Trajectory Leading to the Discovery of Asymmetric Autocatalysis
Enantioselective addition of organometallic reagents to aldehydes using chiral ligands affords enantioenriched sec-alcohols. In 1979, Mukaiyama and Soai (one of the present authors) et al. reported highly enantioselective addition of alkyllithium and dialkylmagnesium to aldehydes using a chiral β-diaminoalkanol derived from (S)-proline as a chiral ligand.12a We also observed that diethylzinc adds to benzaldehyde in the presence of diaminoalcohol to afford 1-phenylpropanol in 76% yield.12a Given that the reactivity of dialkylzinc to aldehydes is usually low, this result showed amino alcohol accelerates the nucleophilicity of dialkylzinc enough to add to aldehydes. Enantioselective addition of diethylzinc to benzaldehyde using a β-aminoalcohol as a chiral catalyst was reported by Oguni and Omi,12b and then by Noyori et al.12c
(S)-N-Methyldiphenylprolinol (DPMPM) catalyzes the addition of Et2Zn to benzaldehyde 6 to afford (S)-1-phenylpropanol 7 with 97% ee (see Scheme 1.4). We observed that the catalyst (S,S)-threo-N-methylphenylprolinol (PMPM) affords (S)-alkanol 7, while (S,R)-erythro-PMPM affords (R)-alkanol 7. These results show that the sense of enantioselectivity is controlled by the absolute configuration of the stereogenic center of the alcohol moiety of the catalysts.
We also observed, in 1989, that the reaction of pyridine-3-carbaldehyde 8, a nitrogen-containing aldehyde, and dialkylzinc catalyzed by (1S,2R)-DBNE completed within 1 h to afford (S)-3-pyridyl alkanol 9,10i while the reaction of benzaldehyde 6 needed 16 h to reach completion to afford (S)-alkanol 7 (see Scheme 1.5).10f,g We considered that the isopropylzinc alkoxide of pyridyl alkanol, i.e., the product in situ, catalyzes the addition of diisopropylzinc to pyridine-3-carbaldehyde 8.
Based on these observations, we got an idea that a nitrogen-containing chiral alkanol with a suitable structure would act as an asymmetric autocatalyst in the enantioselective addition of dialkylzinc to a nitrogen-containing aldehyde with a suitable structure. In his stimulating essay, Wynberg challenged “red-blooded” chemists to realize asymmetric autocatalysis.13
1.2.4 The First Asymmetric Autocatalysis of 3-Pyridyl Alkanol
In 1990, we found chiral 3-pyridyl alkanols act as asymmetric autocatalysts in the addition of dialkylzincs to pyridine-3-carbaldehyde (see Scheme 1.6).8a Although the ee values of products were lower than those of the asymmetric autocatalysts, this stands as the first demonstration of asymmetric autocatalysis.
1.2.5 Highly Enantioselective Asymmetric Autocatalysis
We continued to search for asymmetric autocatalytic systems with studies on chiral alkanol systems.8b,c In 1995, we identified the highly enantioselective asymmetric autocatalysis of pyrimidyl alkanol.9a,b Pyrimidyl alkanol acts as a highly enantioselective asymmetric autocatalyst in the enantioselective addition of diisopropylzinc (i-Pr2Zn) to pyrimidine-5-carbaldehyde. (S)-Pyrimidyl alkanols9a,b with 93–95% ee catalyzed the addition of i-Pr2Zn to pyrimidine-5-carbaldehyde to afford (S)-pyrimidyl alkanols9a,b with the same structure and absolute configuration with 91–95% ee (see Scheme 1.7).9b
After examining the effect of substituents at the 2-position, we found that (S)-2-alkynylpyrimidyl alkanol 1c, with >99.5% ee, was a practically perfect asymmetric autocatalyst to afford itself (S)-1c with >99.5% ee in >99% yield (see Scheme 1.7).9c (S)-Pyrimidyl alkanol 1c obtained in one asymmetric autocatalysis was used as an asymmetric autocatalyst for the next run. Even after 10 rounds of consecutive asymmetric autocatalysis, the yield of (S)-1c was >99% and the ee was >99.5%. No deterioration of catalytic activity or enantioselectivity was observed. Thus, 2-alkynyl-5-pyrimidyl alkanol 1c is a practically perfect asymmetric autocatalyst for the addition of i-Pr2Zn to 2-alkynylpyrimidine-5-carbaldehyde 2c.9c
1.2.6 Discovery of Asymmetric Autocatalysis with Amplification of Enantiomeric Excess. The Soai Reaction
Moreover in 1995, we found a highly enantioselective asymmetric autocatalysis of pyrimidyl alkanol 1 with amplification of ee in the enantioselective addition of i-Pr2Zn to pyrimidine-5-carbaldehyde 2a (see Scheme 1.8).9a Consecutive asymmetric autocatalysis of pyrimidyl alkanol (S)-1a with 2% ee in the enantioselective addition of diisopropylzinc (i-Pr2Zn) to pyrimidine-5-carbaldehyde 2a enabled amplification of ee to 88%.9a In the reaction, pyrimidyl alkanol 1a with 2% ee acts as an asymmetric autocatalyst to afford more of itself with the same absolute configuration and with an amplified 10% ee as a mixture of the newly formed and the initial alkanol. Alkanol 1a with 10% ee was used as the next round of asymmetric autocatalysis and the ee was amplified to 57%. Subsequent consecutive asymmetric autocatalysis enabled ee amplification from 57% to 81% ee, then to 88% ee.9a It should be emphasized that the origin of amplification of ee was the initial slight enantiomeric imbalance (2% ee) of asymmetric autocatalyst 1a itself and that, unlike non-autocatalytic systems, no other chiral factor was necessary.
In non-autocatalytic amplification in asymmetric catalysis, the structures of chiral catalysts and products are different.5a Therefore, the ee of the product cannot be amplified further.
Soai et al. found that the asymmetric autocatalysis of (S)-2-alkynylpyrimidyl alkanol9c,d exhibits significant amplification of ee (see Scheme 1.9).9d Thus, asymmetric autocatalysis of (S)-2-alkynylpyrimidyl alkanol 1c with an extremely low ee of ca. 0.00005% (i.e., enantiomeric ratio of ca. 50.000025 : 49.999975) afforded (S)-alkanol 1c with significantly amplified 57% ee. Subsequent consecutive asymmetric autocatalysis using (S)-alkanol 1c with 57% ee amplified the ee to 99% ee, and then the third asymmetric autocatalysis increased the ee to >99.5%. During these three consecutive asymmetric autocatalysis runs, the amount of the initial slightly major (S)-alkanol 1c automultiplied by a factor of ca. 630 000 times, while the minor (R)-alkanol 1c only ca. 950 times.9d
It was also found that 2-alkenylpyrimidyl alkanol 1e,9e 3-quinolyl alkanol 4,10b,c and 5-carbamoylpyridyl alkanol 5 with one nitrogen atom in the aromatic ring11b are highly enantioselective asymmetric autocatalysts with amplification of ee (see Schemes 1.2 and 1.3). Moreover, asymmetric autocatalysis of multiply functionalized pyrimidyl alkanol 3 was achieved.9f Ultra-remote intramolecular asymmetric autocatalysis was also observed.9g
The most characteristic feature of the present amplification of ee by asymmetric autocatalysis is that the amplification of ee is made possible without the intervention of any chiral factor other than the initial enantiomeric imbalances of the asymmetric autocatalysts themselves. The results proved that there is a real chemical reaction in which very slight enantiomeric excess can be amplified to near enantiopure levels (> 99.5%ee)by asymmetric autocatalysis.
1.2.7 Investigation of the Mechanism of Asymmetric Autocatalysis
Asymmetric autocatalysis described in the preceding sections is unique and leads to significant amplification of ee. Thus, mechanistic aspects of asymmetric autocatalysis have attracted great attention. Several groups showed interest in the reaction, and both theoretical and experimental studies of the reaction have been performed using a range of techniques. These are described in other chapters of this book. For non-autocatalytic nonlinear effects in asymmetric catalysis, the dimer mechanism was proposed by Noyori et al.14a and the MLn mechanism was put forward by Kagan et al.14b
We reported the relationship between the reaction time and yield of the product in asymmetric autocatalysis using an enantiopure pyrimidyl alkanol 1c,15a for which a sigmoidal curve of product formation was observed. We also reported kinetic analysis of the relationship between the time and the yield, including ee of the product of asymmetric autocatalysis based on chiral HPLC analysis,15b which suggested that dimeric or more highly aggregated catalytic species were involved.
Measurement of heat flow with a microcalorimeter by Blackmond and Brown et al. revealed the reaction rate to be a function of the progress of the reaction, which suggested the dimeric catalyst model.15c NMR experiments with direct observation of the reaction solution led to the presence of dimeric and tetrameric species being proposed.15d,e Structures of catalyst aggregates have also been proposed based on DFT calculations by the groups of Ercolani15f,g and Gridnev.15h,i Reaction models based on spontaneous mirror-symmetry breaking have also been presented. These approaches led to the proposal of mechanistic frameworks for asymmetric autocatalysis of pyrimidyl alkanol 1c.15j–q Denmark et al. employed NMR and react-IR for the study of the reaction using 6-alkynylpyrimidyl alkanol as the substrate.15r Trapp et al. reported an acetal intermediate based on the in situ mass spectrometry study of the reaction.15s
Based on X-ray diffraction analysis, we clarified that the crystal structures of asymmetric autocatalysts, i.e., isopropylzinc alkoxide of 1c, are either tetrameric or oligomeric (see Figure 1.1).15t,u The tetrameric crystal structure is formed in the presence of an excess molar amount of i-Pr2Zn (Figure 1.1a,b) whereas higher-order aggregates are formed in the presence of equimolar or a slight excess of i-Pr2Zn. It should be noted that Zn2O2 square has a coordinatively unsaturated Zn atom to which the oxygen atom of aldehyde is considered to coordinate (Figure 1.1c). It should also be noted that 6 molecules of activated i-Pr2Zn are involved in the enantiopure crystal structure by coordination with nitrogen atoms of the pyrimidine ring (Figure 1.1a).
Recent reaction modeling also supports the suggestion that the tetramer or higher-order aggregates are significant species in asymmetric autocatalysis.15v Circular dichroism (CD) spectroscopy by Matsumoto et al. of the catalyst in solution revealed the equilibrium of tetramer and dimer.15w Clarification of the overall reaction pathway of asymmetric autocatalysis awaits further investigation.
More detailed description of the theoretical and experimental studies on the mechanisms of asymmetric autocatalysis are described in other chapters of this book.
1.3 Studies on the Origins of Homochirality by Using Asymmetric Autocatalysis
With regard to the origins of homochirality, several theories such as circularly polarized light and chiral inorganic quartz have been proposed. However, the ee values induced by the processes proposed in these theories have usually been very low. We thought that the low ee induced by the origin of homochirality could be enhanced to the highly enantioenriched compound through asymmetric autocatalysis with amplification of ee.
1.3.1 Circularly Polarized Light
Left (l) and right (r) circularly polarized light (CPL) has been proposed as the origin of chirality of organic compounds.4c The generation of relatively strong CPL has been observed in some star-forming regions.16a Asymmetric photodecomposition of racemic leucine by CPL leaves leucine with ca. 2% ee.4c Asymmetric photosynthesis of helicene with low ee by CPL has also been reported.16b By using leucine16c and helicene with low ee as chiral triggers of asymmetric autocatalysis, enantioenriched pyrimidyl alkanols 1b,c with the corresponding absolute configurations to those of the chiral triggers were obtained. Thus, for the first time, the chirality of CPL has been correlated to the very high ee of the generated organic compound by using asymmetric autocatalysis.16c
The direct irradiation with l-CPL of racemic (rac) asymmetric autocatalyst, i.e., pyrimidyl alkanol 1c, and subsequent asymmetric autocatalysis with amplification of ee afforded (S)-alkanol 1c with >99.5% ee (see Scheme 1.10).16d In sharp contrast, irradiation with r-CPL afforded (R)-1c with >99.5% ee. The correlation between the handedness of l- and r-CPL and (S)-1c and (R)-1c is explained as follows: in their circular dichroism (CD) spectra at 313 nm, (R)-1 and (S)-1c exhibited positive and negative Cotton effects, respectively. Therefore, irradiation with l-CPL of rac-1c would induce the asymmetric photoreaction of (R)-1c due to its preferential absorbance of l-CPL. The less reactive (S)-1c would then become enriched as the remaining enantiomer over (R)-1c. Subsequent asymmetric autocatalysis increases the ee of (S)-1c to >99.5% ee.16d The asymmetric photoequilibrium of rac-olefin 11 under irradiation with CPL, and the subsequent asymmetric autocatalysis afforded pyrimidyl alkanol 1c with absolute configuration correlated to CPL.16e Thus, the first direct correlation was accomplished between the handedness of CPL and that of an organic compound with very high ee.
Recently, under CPL irradiation, Viedma-type racemization–crystallization of an amino acid derivative was reported.16f
1.3.2 Chiral Inorganic Crystals of Quartz, Cinnabar, Sodium Chlorate, Retgersite, and the Enantiotopic Face of Achiral Crystals of Gypsum
Quartz exhibits enantiomorphism and optical activity was found with this mineral. Chiral minerals such as quartz have been proposed as the origin of homochirality.4g Several results were reported on attempts to use quartz to induce chirality in organic compounds; however, most of the earlier reports were later disproved.17a Only low enantioenrichment was reported for an enantiomer-selective adsorption of racemic amino acid detected by radioactivity.17b
We anticipated that d- and l-quartz could act as a chiral trigger in the reaction between pyrimidine-5-carbaldehyde and diisopropylzinc. The initially formed isopropylzinc alkoxide of pyrimidyl alkanol would be enantioenriched with the absolute configuration corresponding to that of the chiral initiator. Subsequent asymmetric autocatalysis would then amplify significantly the ee of the product pyrimidyl alkanol.17c Indeed, asymmetric autocatalysis using pyrimidine-5-carbaldehyde 2c and i-Pr2Zn in the presence of d-quartz gave (S)-1c with 97% ee in a yield of 95% (see Scheme 1.11).17c In contrast, l-quartz afforded (R)-1c with 97% ee. These results clearly show that d- and l-quartz act as chiral initiators of asymmetric autocatalysis. Thus, the chirality of d- and l-quartz was correlated for the first time to the chirality of a near enantiopure organic compound.
Sodium chlorate (NaClO3) and sodium bromate (NaBrO3) are chiral inorganic ionic crystals.18a,b It was found that d-NaClO3 can also trigger asymmetric autocatalysis to afford (S)-1c with high ee. In contrast, l-NaClO3 triggers the formation of (R)-1c.18c Moreover, d-NaBrO3 and l-NaBrO3 trigger the formation of (R)- and (S)-1c, respectively.18d It should be noted that d-NaClO3 and l-NaBrO3 of the opposite signs of optical rotation have the same type of enantiomorph.
Enantiomorphic P- and M-crystals of cinnabar, mercury(ii) sulfide (HgS), are constructed with –S–Hg–S–Hg spiral chains. We found that P-HgS induces asymmetric autocatalysis to afford (R)-1c with high ee and that M-HgS induces the formation of (S)-1c.18e
Asymmetric autocatalysis triggered by retgersite (NiSO4·6H2O) of [CD(+)390Nujol] afforded (S)-1c with high ee, whereas retgersite of the opposite [CD(−)390Nujol] afforded (R)-1c with high ee.18f As described, chiral minerals such as quartz, cinnabar, sodium chlorate, and retgersite act as origins of chirality to afford, in conjunction with asymmetric autocatalysis, highly enantioenriched organic compounds.
Gypsum (CaSO4·2H2O; calcium sulfate dihydrate) has been widely used for plaster boards in buildings and for sculptures. Although gypsum has an achiral crystal structure, it exhibits two-dimensional enantiotopic cleavage (010) and (01̄0) faces. Pyrimidine-5-carbaldehyde 2c was grasped on the enantiotopic (010) face and was exposed to the vapor of i-Pr2Zn. Asymmetric autocatalysis on the enantiotopic (010) face afforded (R)-pyrimidyl alkanol 1c.19 In contrast, asymmetric autocatalysis on the opposite enantiotopic (01̄0) face afforded (S)-alkanol 1c. Thus, the enantiotopic face of achiral gypsum acts as an origin of chirality.
As described, by using asymmetric autocatalysis, chiral inorganic crystals were shown to act as the origin of chirality to afford highly enantioenriched organic compounds with correlated absolute configurations.
1.3.3 Organic Crystals
184.108.40.206 Chiral Organic Crystals Composed of Achiral Compounds
There are certain classes of achiral organic compounds that form chiral crystals.20a Some of the chiral crystals composed of achiral organic compounds have been used as reactants in stereospecific reactions.4d However, chiral organic crystals formed from achiral organic compounds have rarely been used as chiral inducers. We found that chiral crystals composed of achiral organic compounds can act as the origin of chirality and trigger asymmetric autocatalysis (see Schemes 1.12 and 1.13).
It is known that glycine is the only achiral amino acid among proteinogenic amino acids and that the crystal structure of γ-glycine polymorph is chiral; nevertheless, it took years to determine the correlation between the optical rotation and the absolute crystal structure of the γ-glycine polymorph. Asahi et al., including the present authors (Kawasaki and Soai), determined the relation between the absolute crystal structure of the γ-glycine polymorph and the optical rotatory dispersion.20b Guillemin reported that γ-glycine exhibits circular dichroism (CD) spectra,20c and we then clarified the correlation between the absolute crystal structure of γ-glycine and CD spectra: left-handed crystal (P32) of γ-glycine exhibits CD(−)at 215 nm observed using a KBr disk, whereas right-handed crystal (P31) exhibits CD(+).20d
We examined asymmetric autocatalysis in the presence of γ-glycine crystal as a chiral trigger. In the presence of a P32 crystal (left-handed) of γ-glycine, (S)-pyrimidyl alkanol 1c was formed with up to >99.5% ee (see Scheme 1.12).20d In contrast, in the presence of a P31 crystal, (R)-alkanol 1c was obtained with up to >99.5% ee. Thus, achiral glycine acts as the origin of homochirality by forming a chiral γ-polymorph, then triggering the asymmetric autocatalysis with amplification of ee.
Cytosine is an achiral nucleobase. Chiral cytosine crystals formed by crystallization from methanol trigger asymmetric autocatalysis. When a chiral [CD(+)310Nujol]-cytosine crystal was used as a chiral trigger of the reaction between pyrimidine-5-aldehyde 2c and i-Pr2Zn, asymmetric autocatalysis with amplification of ee afforded (R)-pyrimidyl alkanol 1c (see Scheme 1.13).20e In contrast, a [CD(−)310Nujol]-cytosine crystal afforded (S)-1c. Thus, the chiral cytosine crystal composed of achiral cytosine is capable of acting as the origin of chirality in conjunction with asymmetric autocatalysis.
Crystallization of cytosine from water generates achiral cytosine monohydrate crystals. It was found that a chiral dehydrated cytosine crystal is formed by elimination of crystal water by heating one of the enantiotopic faces of the achiral crystal.20f Surprisingly, the chirality of the formed dehydrated cytosine crystal is correlated to the enantiotopic face of the achiral cytosine monohydrate from which heating is applied. It should be noted that dehydration of crystal water of cytosine monohydrate under reduced pressure conditions from one of the enantiotopic faces at room temperature gave the chiral cytosine dehydrated crystal,20g but surprisingly again, the formed crystal chirality is opposite to that formed by dehydration upon heating. It should also be noted that the sign of the Cotton effects (CD spectra) of the chiral cytosine crystal are opposite to those observed when using a KBr disk and Nujol mull; that is, CD(+)310KBr (CD plus at 310 nm with KBr disk) and CD(−)310Nujol (CD minus at 310 nm with Nujol mull) arise from the same chirality of cytosine crystal. These results are the first example of the formation of chiral crystals with controlled chirality by dehydration from an achiral crystal monohydrate.
Adenine is another achiral nucleobase that we investigated; a chiral crystal of adenine dinitrate was found to act as a chiral trigger of asymmetric autocatalysis, and highly enantioenriched pyrimidyl alkanols were formed with the absolute configurations corresponding to those of chiral adenine dinitrate (see Scheme 1.13).20h These results show that achiral nucleobases, i.e., cytosine and adenine, can act as the origin of chirality in their chiral crystalline form in conjunction with asymmetric autocatalysis with amplification of ee.
Moreover, enantiomorphous crystals composed of achiral N-benzoylglycine (hippuric acid),20i triglycine sulfate (TGS),20j 2-thenoylglycine,20k tetraphenylethylene,20l certain chiral cocrystals consisting of two achiral compounds,20m aromatic trimester,20n 2,6-di-tert-butyl-p-cresol (BHT),20o benzil,20p and ethylenediammonium sulfate20q are all capable of inducing asymmetric autocatalysis as chiral triggers. It is interesting to note that a chiral crystal composed of a racemic serine can also act as a chiral trigger of asymmetric autocatalysis. Thus, M-crystals of dl-diserinium sulfate hydrate induce asymmetric autocatalysis to give (R)-pyrimidyl alkanol 1c, while P-crystals afford (S)-alkanol 1c.20r
220.127.116.11 Enantiotopic Face of the Achiral Organic Crystal of Achiral Organic Compounds
Some achiral organic compounds are known to form achiral crystals with enantiotopic faces. Achiral 2-(tert-butyldimethylsilylethynyl)pyrimidine-5-carbaldehyde 2f forms an achiral crystal (P1̄) that has enantiotopic faces. When one of the enantiotopic faces, i.e., Re-face of the aldehyde, was exposed to the vapor of i-Pr2Zn in a solvent, (R)-pyrimidyl alkanol 1f was formed (see Scheme 1.14).21 In contrast, exposure of i-Pr2Zn vapor on the Si-face of the aldehyde gave (S)-alkanol 1f. The ee values of the formed pyrimidyl alkanol 1f were amplified to >99.5% ee by subsequent asymmetric autocatalysis. Thus, it was shown that the enantiotopic faces of an achiral crystal composed of an achiral compound can act as the origin of homochirality in conjunction with asymmetric autocatalysis.
1.4 Absolute Asymmetric Synthesis
The term “absolute asymmetric synthesis” has often been used for the asymmetric synthesis “without using any chiral chemical substance.” However, Mislow proposed a new definition of absolute asymmetric synthesis as the formation of an enantioenriched compound “without the intervention of any chiral factor.”4a
It is known that, when achiral reactants form a chiral product without the intervention of any chiral factor, the chiral product always becomes a racemate. For example, the reaction of benzaldehyde with methylmagnesium bromide always affords racemic 1-phenylethanol. Although the ee is far below the level of detection, the numbers of enantiomers almost always have statistical fluctuations.4a By comparison, in the case of flipping a coin 100 times, the probability of flipping 50 heads and 50 tails is only 8%; in the other 92% of cases, some statistical bias exists between the number of heads and tails.
1.4.1 Realization of Absolute Asymmetric Synthesis
As described in the preceding section, asymmetric autocatalysis of pyrimidyl alkanol is capable of amplifying extremely low (ca. 0.00005%) ee to near enantiopure (>99.5%)ee.9d What will happen if the reaction between pyrimidine-5-carbaldehyde 2 and i-Pr2Zn is run without the intervention of any chiral factor? We envisaged that the reaction of achiral reactants of pyrimidine-5-carbaldehyde 2 and i-Pr2Zn affords enantioenriched product, i.e., zinc alkoxide of pyrimidyl alkanol, as a result of statistical fluctuation, and that the initial ee would be amplified by the subsequent asymmetric autocatalysis (see Scheme 1.15).
Indeed, enantioenriched pyrimidyl alkanol of either S or R absolute configuration is formed through spontaneous absolute asymmetric synthesis in the reaction between pyrimidine-5-carbaldehyde 2 with i-Pr2Zn without the addition of any chiral substance. We first applied for a patent for this absolute asymmetric synthesis in 1996.22a Enantioenriched (S)-pyrimidyl alkanol 1a,b or (R)-pyrimidyl alkanol 1a,b are formed in the reaction without adding any chiral substance.22a When i-Pr2Zn was reacted with aldehyde 2c in a mixed solvent of ether and toluene without adding any chiral substance, (S)-pyrimidyl alkanol 1c was formed 19 times and (R)-1c 18 times in a total of 37 reactions (see Figure 1.2(a)).22b The formation of S and R enantiomers of 1c produced showed a stochastic distribution. The initially formed enantioenriched zinc alkoxide of pyrimidyl alkanol 1c produced in situ is considered to be enantioenriched by statistical fluctuation, and the subsequent amplification of ee by asymmetric autocatalysis gave (S)- or (R)-1 with detectable ee values.22b Moreover, in the presence of achiral amorphous silica gel, which is used as the stationary phase for column chromatography, the reaction of aldehyde 2c and i-Pr2Zn afforded (S)- or (R)-alkanol 1c with stochastic distribution.22c Soai et al. reported that achiral diamines promote the addition reaction of dialkylzincs to aldehydes.22d In the presence of achiral amines, the reaction between aldehyde 2c and i-Pr2Zn afforded (S)- or (R)-alkanol 1c with stochastic distribution.22e The stochastic distribution of the product (S)- or (R)-1b has also been reported between pyrimidine-5-carbaldehyde 2b and i-Pr2Zn.22f These results show that the reaction between pyrimidine-5-carbaldehydes and i-Pr2Zn allows spontaneous absolute asymmetric synthesis.22g–j
1.4.2 Absolute Asymmetric Synthesis under Solid–Vapor Conditions
In the preceding paragraph, we describe absolute asymmetric synthesis in solution. We here describe absolute asymmetric synthesis under heterogeneous conditions of solid aldehyde–vapor phase i-Pr2Zn (see Scheme 1.16).22k In a desiccator, powders of pyrimidine-5-carbaldehyde 2c in vials were exposed to the vapor of i-Pr2Zn and toluene. (R)-Pyrimidyl alkanol 1c was formed 61 times, and (S)-alkanol 1c 58 times in a total of 129 reactions (1c was formed with <0.5% ee 10 times and was regarded as below the detection level) (see Figure 1.2(b)). These results show that the distribution of (S)- and (R)-alkanol 1c is stochastic. The observed various ee values could be amplified to >99.5% ee by subsequent asymmetric autocatalysis. Thus, spontaneous absolute asymmetric synthesis is achieved under solid–vapor phase conditions.
1.5 Chiral Hydrogen, Carbon, Oxygen, and Nitrogen Isotopomers Act as the Origin of Homochirality in Conjunction with Asymmetric Autocatalysis
Isotopes are defined as atoms of the same atomic number (number of positrons) but with different numbers of neutrons. The number of electrons is the same and the chemical character is very similar. There are a few examples of the use of chiral isotopomers as chiral auxiliaries for low levels of asymmetric induction by using chiral hydrogen (D/H) isotopomers.23a,b Although the difference in atomic weight between H and D is 100%, the difference in atomic weight between 12C and 13C is only 8%; indeed, asymmetric induction by chiral 13C/12C, 15N/14N, and 18O/16O isotopomers is unprecedented.
Many apparent achiral organic compounds become chiral by substituting carbon (12C), nitrogen (14N), or oxygen (16O) for their isotopes of 13C, 15N, and 18O, respectively. Given that it has two identical methyl groups, 1-methyl-1-phenylethanol 12 is achiral; however, when one of the carbon atoms of the methyl groups is labeled with 13C, the alkanol becomes either chiral (R)-1-methyl-1-phenylethanol 12(13C) or (S)-alkanol 12(13C) (see Scheme 1.17). Because the mass difference of carbon (13C/12C) isotopes is so small, asymmetric induction using chiral carbon (13C/12C) isotopomers was unprecedented.
The reaction between pyrimidine-5-carbaldehyde 2c and i-Pr2Zn was examined in the presence of a chiral carbon (13C/12C) isotopomer, namely (R)- or (S)-1-methyl-1-phenylethanol 12(13C), as a chiral trigger. Pyrimidyl alkanol 1c was formed with very high ee with an absolute configuration corresponding to that of the carbon isotopomer (see Scheme 1.17). (S)-Pyrimidyl alkanol 1c with high ee was formed in the presence of (R)-carbon isotopomer 12(13C). In contrast, (R)-pyrimidyl alkanol 1c was formed in the presence of (S)-carbon isotopomer 12(13C).23c It was also found that asymmetric autocatalysis is triggered by the chiral nitrogen (15N/14N) isotopomer, [15N](S), and [15N](R)-diamine 13(15N).23d Moreover, pyrimidyl alkanol 1c with high ee with the corresponding absolute configurations with those of oxygen (18O/16O) isotopomers; that is, [18O](R) and [18O](S)-diol 14(18O), were formed as the result of asymmetric autocatalysis triggered by oxygen isotopomers 14.23e,f Thus, carbon, nitrogen, and oxygen isotopomers were proved to act as the origin of homochirality in conjunction with asymmetric autocatalysis with amplification of ee.
It was also found that chiral isotopomers labeled with deuterium act as chiral triggers of asymmetric autocatalysis.23g,h Achiral glycine 15 becomes chiral by labeling one of the hydrogen atoms of the methylene group with deuterium (D). Chiral (S)-glycine-α-d 15(D) acts as chiral trigger for asymmetric autocatalysis to afford (S)-pyrimidyl alkanol 1c with high ee with the corresponding absolute configurations of the chiral trigger.23i Blackmond et al. reported mechanistic investigation on asymmetric autocatalysis triggered by a hydrogen (H/D) isotopomer.23j
1.6 Various Chiral Materials Including Cryptochiral Compounds as Triggers for Asymmetric Autocatalysis
Asymmetric autocatalysis can also be applied as a chiral sensor of compounds with low ee. Amino acids with low ee are generated from the respective racemate upon CPL irradiation and are often found in meteorites. Asymmetric autocatalysis has been used to correlate the chirality of amino acids with low (ca. 0.1%) ee to chiral organic compound with high (see Scheme 1.18).16c,24a
Thus, l-alanine (ca. 0.1% ee), l-methionine (ca. 0.1% ee), and l-valine (ca. 0.1% ee) act as chiral triggers for asymmetric autocatalysis in the reaction between 2-(2-t-butylethynyl)pyrimidine-5-carbaldehyde 2 and i-Pr2Zn to afford (S)-2-(2-t-butylethynyl)-5-pyrimidyl alkanol 1c with enhanced ee (91–92%). However, l-histidine with ca. 0.1% ee as a chiral trigger exhibited the opposite sense of enantioselectivity. Thus, (R)-pyrimidyl alkanol 1c was formed with 97% ee. In contrast, d-alanine, d-methionine, and d-valine with low ca. 0.1% ee act as chiral triggers to give (R)-pyrimidyl alkanol 1c with an enhanced ee of 72–90%. d-Histidine with ca. 0.1% ee as a chiral trigger afforded (S)-pyrimidyl alkanol 1c with 92% ee. Thus, the chirality of amino acids with low ee can be determined by application of asymmetric autocatalysis.24a
Helicene 17,24b tetrathiahelicene 18,24c and 2-azahelicene 1924d trigger asymmetric autocatalysis to afford pyrimidyl alkanol 1c with the corresponding absolute configuration of the chiral triggers (see Scheme 1.19). A cryptochiral saturated quaternary hydrocarbon, (n-butyl)ethyl(n-hexyl)(n-propyl)methane, i.e., 5-ethyl-5-propylundecane 20, does not exhibit any detectable value of optical rotation because the differences in the structures of four substituents are so small.24e
Asymmetric autocatalysis was found to discriminate the isomers of cryptochiral 5-ethyl-5-propylundecane 2024f and cryptochiral isotactic polystyrene 21.24g The chiralities of artificially designed inorganic helical silica 2224h and mesoporous helical silica 2324i were also discriminated by asymmetric autocatalysis (see Scheme 1.19). In addition, asymmetric autocatalysis discriminates a single-wall carbon nanotube molecule with helical chirality 24,24j and chiral [2.2]paracyclophanes 25,24k chiral metal complexes due to the topology of the coordination of achiral ligands 26,24l ruthenium complex,24m 2724n and 1,3-disubstituted hydrocarbon allene 28.24o
1.7 Unusual Phenomena of the Reversal of the Sense of Enantioselectivities Detected by Asymmetric Autocatalysis
Asymmetric autocatalysis revealed unusual inversion of enantioselectivity (see Scheme 1.20). (1R,2S)-N,N-Dimethylnorephedrine (DMNE) alone triggers the reaction of aldehyde 2c and i-Pr2Zn to afford (R)-pyrimidyl alkanol 1c. On the other hand, achiral N,N-dibutylaminoethanol (DBAE) is considered to promote the formation of racemate. Thus, it is natural to anticipate that the mixture of R-affording (1R,2S)-DMNE and racemate-affording achiral DBNE triggers the reaction to afford (R)-alkanol. However, a counterintuitive inversion of the sense of enantioselectivity was observed when the reaction was triggered by a mixture of (1R,2S)-DMNE and achiral DBAE, that is, the opposite (S)-alkanol 1c instead of anticipated (R)-alkanol was formed!25a,b The formation of aggregation of chiral DMNE and achiral DBAE is the origin of the inversion of the sense of enantioselectivity. Moreover, the mixture of two R-affording chiral catalysts, i.e., (1R,2S)-DMNE and (R)-2-[(1-phenylethyl)amino]ethanol, reverses the sense of enantioselectivity to afford the opposite (S)-alkanol 1c.25c In asymmetric autocatalysis using chiral aromatic alcohols and amines as chiral triggers, changing the temperature induced the inversion of the sense of enantioselectivity.25d
1.8 Application of Asymmetric Autocatalysis for the Synthesis of Various Chiral Compounds
Asymmetric autocatalysis with amplification of ee was successfully applied in asymmetric synthesis of chiral sec-alcohols26a and asymmetric amplification of alkynyl alkanols.26b Carreira et al. reported asymmetric synthesis of efavirenz, a chiral drug for the treatment of HIV, by asymmetric autocatalytic alkynylation of ketone.27
Pyrimidyl alkanols, 5-carbamoyl pyridyl alkanol, and 3-quinolyl alkanols act as asymmetric autocatalysts with amplification of ee in the enantioselective addition of i-Pr2Zn to pyrimidine-5-carbaldehydes, 5-carbamoylpyridine, and quinoline-3-carbaldehydes, respectively. Typically, the ee of (S)-2-alkynylpyrimidyl alkanol 1 with very low (ca. 0.00005%) ee was enhanced to >99.5% ee during three consecutive asymmetric autocatalysis runs. The amplification of ee by asymmetric autocatalysis is unique in that no chiral factor other than the asymmetric autocatalyst itself, i.e., pyrimidyl alkanol 1, is necessary. Mislow referred to the asymmetric autocatalysis as the Soai reaction.4a
The origins of homochirality were examined by using asymmetric autocatalysis with amplification of ee. Asymmetric autocatalysis with amplification of ee enhanced the initially low ee induced by the origin of chirality. Irradiation with CPL of racemic pyrimidyl alkanol followed by asymmetric autocatalysis correlated for the first time the chirality of CPL and chiral organic compound with very high ee. Chiral inorganic crystals such as quartz and cinnabar also act as chiral triggers of asymmetric autocatalysis. Thus, quartz as the origin of chirality was correlated for the first time to a chiral organic compound with very high ee. Chiral organic crystals composed of achiral compounds such as glycine, cytosine, and adenine also act as chiral initiators of asymmetric autocatalysis to afford highly enantioenriched pyrimidyl alkanol with the corresponding absolute configurations that correlate to those of the chiral initiators. Moreover, absolute asymmetric synthesis, namely, the formation of enantioenriched compound without the intervention of any chiral factor, was achieved for the first time in the reaction between pyrimidine-5-carbaldehdye and i-Pr2Zn followed by asymmetric autocatalysis with amplification of ee. Stochastic distributions of absolute configurations of the products were also observed. Carbon (13C/12C), nitrogen (15N/14N), oxygen (16O/18O), and hydrogen (H/D) isotopomers act as the origin of chirality in asymmetric autocatalysis to afford highly enantioenriched pyrimidyl alkanol with the absolute configurations corresponding to those of the chiral isotopomers.
As described, asymmetric autocatalysis, i.e., the Soai reaction, is the catalytic self-replication of a chiral compound with amplification of ee. Extremely low ee is amplified to very high >99.5% ee by consecutive asymmetric autocatalysis. The reaction is capable of discriminating the chirality of various materials even with low ee. The origin of chirality can thus be examined by using asymmetric autocatalysis. Spontaneous absolute asymmetric synthesis was also achieved by asymmetric autocatalysis. Chiral carbon, nitrogen, and oxygen isotopomers work as the origin of chirality in conjunction with asymmetric autocatalysis. Further aspects of reaction mechanisms will be elucidated through ongoing research by several groups, and it is anticipated that the reaction may be applied to examine the physical origins of chirality in a wide range of systems.
Financial support by JSPS KAKENHI (Grant number 15H03781,18H04518, 19K05482 and 19K22190) is gratefully acknowledged. The authors gratefully acknowledge the collaborators whose names appear in the cited literature.