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Proceedings of the Japan Academy. Series B, Physical and Biological Sciences logoLink to Proceedings of the Japan Academy. Series B, Physical and Biological Sciences
. 2023 Sep 6;99(8):328–333. doi: 10.2183/pjab.99.022

Highly enantioselective hydroxymethylation of unmodified α-substituted aryl ketones in water

Taku KITANOSONO *1,†, Tomoya KAWASE *1, Yasuhiro YAMASHITA *1, Shū KOBAYASHI *1,†
PMCID: PMC10749394  PMID: 37673660

Abstract

Catalytic asymmetric direct-type aldol reactions of ketones with aldehydes are a perennial puzzle for organic chemists. Notwithstanding the emergence of a myriad of chiral catalysts to address the inherent reversibility of the aldol products, a general method to access acyclic α-chiral ketones from prochiral aryl ketones has remained an unmet synthetic challenge. The approach outlined herein is fundamentally different to that used in conventional catalysis, which typically commences with an α-proton abstraction by a Brønsted base. The use of a chiral 2,2′-bipyridine scandium complex enabled the hydroxymethylation of propiophenone to be run under base-free conditions, which avails effectual suppression of hydrolytic deactivation of the Lewis acid catalyst. Intriguingly, the use of water as a reaction medium had an overriding effect on the progress of the reaction. The sagacious selection of sodium dodecyl sulfate and lithium dodecyl sulfate as surfactants allowed a variety of propiophenone derivatives to react in a highly enantioselective manner.

Keywords: direct aldol reaction, enantioselective synthesis, scandium, hydroxymethylation, water, micelle

1. Introduction

The construction of carbon–carbon bonds in a highly enantioselective manner is of prominent importance for organic synthesis. However, the development of highly enantioselective direct-type aldol reactions of ketones with aldehydes, wherein the enolate is catalytically generated in situ, represents a formidable challenge. Nevertheless, the highly atom-economical nature of this approach has driven continual efforts since the seminal works1–5) and led to the rapid evolution of metal catalysts and organocatalysts. Cyclic ketones, aliphatic ketones, acetophenone, 2-hydroxy acetophenone, activated carbonyls, enones, and ynones serve as applicable donor ketones,6–8) whereas stereoselective processes that are amenable to prochiral, acyclic α-substituted ketones without a chiral auxiliary or a directing group have rarely been reported, with the exception of our previous work9,10) with aryl ketones such as propiophenone. These methods are of paramount importance in forging chirality at the α-carbon of carbonyl groups in complex small-molecule synthesis. The practical synthesis of enantiomerically enriched β-hydroxyketone using unmodified propiophenone dates back to the seminal report using a stoichiometric amount of chiral source.11) Organocatalytic methods12) for converting propiophenone may be stymied by facile reversibility of the product by a retro-aldol reaction, which is corroborated by a lack of success in this area.13,14) On the other hand, advances made in metal-based catalysis include aldol-Tishchenko reactions, which involve the corresponding metallated aldolates. The stereochemistry of Tishchenko products is not a result of the reversible aldol process, but rather, stem from the bond reorganization of irreversible cyclic Evans’ intermediate (Scheme 1a).15–17) As such, the protonation of the metal aldolates, furnishing racemic aldols with no diastereoselectivity,15,16) was hardly expected to enable highly enantioselective catalysis without Tishchenko reduction.18) Although the Mannich reaction approach serves as an alternative strategy to bestow α-chirality along with a newly fashioned carbon–carbon bond using aldehyde equivalents, it suffered from low enantioselectivity (Scheme 1b).19,20)

Scheme 1.

Scheme 1.

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Enantioselective processes involving enolates derived from α-substituted aryl ketones without a directing group.

Although the adoption of base-free conditions to sidestep the reversibility issue enabled catalytic enantioselective reactions of active methylene compounds,21) propiophenones were not accessible. Notwithstanding its reluctance to undergo enolization, propiophenone was found to react in water in the presence of chiral N,N′-dioxide scandium complexes combined with surfactant and pyridine, albeit with low yield.9,10) In sharp contrast to innumerable advances of techniques in organic solvents, asymmetric synthesis in aqueous environments has proved to be a formidable challenge,22) and is perceived to be an idiosyncratic approach.23) Fundamentally, the major difficulty of Lewis acid catalysis lies in the relentless hydration that puts chiral environments on the verge of collapse. On the other hand, the role of inner-sphere water molecules to facilitate the proton transfer and desilylation has been discussed in the Mukaiyama aldol reactions,24) which is supposed to be in part applicable to direct-type aldol reactions. A straightforward approach to limit the hydration number is the adoption of multidentate chiral ligands such as N,N′-dioxide along with a micellar system to protect the central metal ion from the intrusion of water molecules; however, this concurrently entails a heightened risk of decreased performance due to the decreased Lewis acidity and the deterioration of water effect. In this reaction, a longer reaction time was found to retard the reaction rate conspicuously (Scheme 1c), which is ascribable to the hydrolytic decomposition of an active scandium complex. Nevertheless, the use of a basic additive was of prominent importance for improving both the yield and enantioselectivity of the reaction. With the reversibility issue being solved, our attention turned to hydrolytic deactivation. Bypassing both the reversibility and hydrolysis issues, we herein describe a base-free protocol to realize a highly enantioselective direct-type aldol reaction in water.

2. Results and discussion

We set our sights on a chiral 2,2′-bipyridine L1, bearing 6,6′-dicarbinol substituents (Table 1).25,26) Given that alcohol units are known to stabilize complexation with metal cations through hydrogen bonding with the counteranion,27,28) more stable chiral environments can be anticipated even in aqueous environments. It appeared that L1 had a privileged position in catalysis exerted in water.22) An initial attempt to render the direct-type aldol reaction of propiophenone revealed that, despite using a challenging electrophile,29) a small amount of the desired hydroxymethylated product was produced with 59% ee when Sc(DS)3, a typical Lewis acid-surfactant–combined catalyst, was used in the presence of L1, in the absence of exogenous base (entry 1). The inclusion of mixed micelles formed with sodium dodecyl sulfate (SDS) improved the performance of the reaction with respect to yield and enantioselectivity (entry 2). Encouraged by this promising result, an extensive range of scandium salts were screened, and it was concluded that scandium tris(dodecyl sulfate) (Sc(DS)3) was the optimal scandium source (entries 2–6). A surfactant screen demonstrated that non-ionic surfactants imparted poorer reactivity than anionic surfactants, along with comparable enantioselectivity, and that C10H21SO4Na and lithium dodecyl sulfate (LiDS) showed the best performance (entries 7–13). The latter was superior, albeit with a longer reaction time (entries 14, 15), perhaps due to the higher stability of the micelle. The alcohol groups of the ligands played an important role in determining the reaction efficiency, with L1 proving optimal (entries 16, 17). An equimolar amount of paraformaldehyde provided a comparable yield (entry 18). Significantly, the failure of the reaction in methanol underpins the indispensability of water in the reaction (entry 19).

Table 1.

Asymmetric hydroxymethylation of propiophenone in waterInline graphic

Entry Sc salt Surfactant Yield (%) Ee (%)
1 Sc(DS)3 — 6 59
2 Sc(DS)3 SDS 15 90
3 Sc(OSO2C12H25)3 SDS 19 74
4 Sc(OTf)3 SDS 17 85
5 Sc(OPf)3 SDS 21 71
6 Sc(NTf2)3 SDS 3 81
7 Sc(DS)3 Triton X-705 or 114 1 82
8 Sc(DS)3 Sodium laureth sulfate 13 85
9 Sc(DS)3 Sodium 2-ethylhexyl sulfate 8 81
10 Sc(DS)3 DHEA sulfate 3 70
11 Sc(DS)3 C14H29SO4Na 6 87
12 Sc(DS)3 C10H21SO4Na 26 89
13 Sc(DS)3 LiDS 25 88
14a Sc(DS)3 C10H21SO4Na 50 88
15a Sc(DS)3 LiDS 70 88
16b Sc(DS)3 C10H21SO4Na 4 —
17c Sc(DS)3 C10H21SO4Na 16 65
18d Sc(DS)3 C10H21SO4Na 23 90
19e Sc(DS)3 LiDS NR —
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a Reaction run for 168 h. b 2,2′-Bipyridyl (24 mol%) was used instead of L1. c L2 (12 mol%) was used instead of L1. d An equivalent of (CH2O)n was used. e Reaction run in MeOH.graphic file with name pjab-99-328-t001.jpg

A variety of propiophenone derivatives (R = Me or Et) that are difficult to react due to high pKa value30) were studied under the optimized reaction conditions as depicted in Fig. 1, with direct comparison for representative examples 1–4 to the Mukaiyama aldol variant using the corresponding silicon enolates. Aside from onerous enolate isolation, the demonstrated Mukaiyama aldol reactions showed heavy dependence of catalytic performance on the structure of propiophenones while retaining the absolute configuration of the product 1–4. Above all, the Mukaiyama aldol reaction of butyrophenone and 4′-methoxypropiophenone suffered from lower enantioselectivity. Notably in this work, SDS was found to be a complementary additive of LiDS to explore the scope of propiophenones. The use of SDS instead of LiDS enhanced the reactivity of propiophenones bearing electron-donating substituents on the aromatic ring, albeit at the expense of somewhat lower enantioselectivity. Almost no reaction occurred with electron-deficient propiophenones 4 and 6 when SDS was employed as a surfactant, whereas the use of LiDS significantly enhanced the reactivity. The method was compatible with 2-propionylthiophene to give 7, and highly hydrophobic naphthyl ketone could be converted stereoselectively into the corresponding product 8, albeit with low conversion. On the whole, the use of LiDS gave products with higher enantioselection than using SDS.

Figure 1.

Figure 1.

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Asymmetric hydroxymethylation of propiophenones in water.

Unlike propiophenone, several catalytic systems have been documented since 2001 for the asymmetric aldol reaction of 2-hydroxy acetophenone, wherein a bidentate binding of its enolate with multinuclear metal complexes was likely to play a pivotal role in governing the stereoselectivity.31,32) In this work, the adoption of concentrated reaction conditions to leverage the high solubility of 2-hydroxy acetophenone in water enabled α,β-dihydroxypropiophenone 9 to be formed with satisfactory yield and enantioselectivity (Fig. 2). This underlines the power of the Sc-L1 complex for the synthesis of 9; previously reported N,N′-dioxides did not deliver any enantioselectivity, probably because of their inherent basicity. Moreover, this synthesis is not viable in the Mukaiyama aldol variant because the silicon enolate is not formed from 2-hydroxy acetophenone.

Figure 2.

Figure 2.

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Asymmetric hydroxymethylation of 2-hydroxyacetophenone in water.

Aging propiophenone in deuterium oxide together with Sc(DS)3, L1, and either SDS or LiDS resulted in low levels of incorporation of deuterium atom (ca. 5% for SDS and ca. 2.5% for LiDS) even after 72 h, indicating a low population of the enol tautomer under the optimized reaction conditions. In addition, no solvent kinetic isotope effect was observed, and no deuterium incorporation in the product was found when the reaction was run in deuterium oxide. The amount of deuterium in the unreacted propiophenone was on par with that observed in the above experiment. It was reported that the stereochemistry of lanthanide enolates derived from propiophenone was mainly the E-isomer, and that a subsequent aldol reaction with aldehydes tended to proceed with anti-selectivity.33) To elucidate the critical role of scandium ion, 3-phenylpropanal was substituted with paraformaldehyde (Fig. 3). The reaction, albeit unoptimized, proved to be syn-selective, negating the involvement of a scandium enolate formed in situ. The reaction also proved to be irreversible. Additional surfactants, SDS or LiDS, may contribute to increase the nucleophilicity of the enol form of propiophenone,34) which, together with the intrinsic surfactant properties,35) may provide a felicitous environment for asymmetric aldol reactions.

Figure 3.

Figure 3.

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Attempted reaction with 3-phenylpropanal.

3. Conclusion

In summary, the use of scandium-based micellar catalysis comprising chiral 2,2′-bipyridine L1 enabled enantioselective hydroxymethylation of propiophenones in water. Although aldol reactions are one of the most oft-employed methods for C–C bond formation, the catalytic asymmetric aldol reaction has posed a challenge to organic synthesis. Metal catalysis has entailed the use of a Brønsted base for deprotonation of the α-carbon to initiate the catalytic cycle, rendering this reaction characteristically reversible, as observed for the enamine-based organocatalysis. Especially, α-substituted aryl ketones have not been amenable to catalytic aldol reactions in high yield and high enantioselectivity. The conditions developed in this work do not include a base additive, which has allowed both the notorious reversibility issue and the hydrolytic decomposition of a metal catalyst to be overcome. Notably, this enantioselective process could be uniquely enabled in water. The mixed micelle with either SDS or LiDS was found to be effective for accommodating a variety of propiophenone derivatives.

Supplementary Material

Supplementary materials (1.2MB, pdf)

Supplementary materials are available at https://doi.org/10.2183/pjab.99.022.

DOI: 10.2183/pjab.99.022

Acknowledgments

This work was supported by a Grant-in-Aid for Science Research (JP22H04972 to TK, YY, and SK) from the Japan Society for the Promotion of Science.

Non-standard abbreviation list

DS

dodecyl sulfate (OSO3C12H25)

SDS

sodium dodecyl sulfate

Tf

trifluoromethanesulfonyl (SO2CF3)

OPf

perfluorooctane-1-sulfonate (OSO2C8F17)

DHEA

dehydroepiandrosterone

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Supplementary Materials

Supplementary materials (1.2MB, pdf)

Supplementary materials are available at https://doi.org/10.2183/pjab.99.022.

DOI: 10.2183/pjab.99.022

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