Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Enantioselective Protonation of Enol Esters with Bifunctional Phosphonium/Thiourea Catalysts Eiji Yamamoto,* Kodai Wakafuji, Yusuke Mori, Gaku Teshima, Yuki Hidani, and Makoto Tokunaga* Department of Chemistry, Graduate School of Science, Kyushu University, Fukuoka, 819-0395, Japan
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S Supporting Information *
ABSTRACT: Bifunctional phosphonium/thioureas derived from tert-leucine behaved as highly selective catalysts for enantioselective protonation of enol esters, providing α-chiral ketones in yields of up to 99% with high enantioselectivities (up to 98.5:1.5 er). Control experiments clarified that a bulky tertbutyl group and phosphonium and thiourea moieties were necessary to achieve such high stereoselectivity. In addition, mechanistic investigations indicated the catalyst was converted to the corresponding betaine species, which served as a monomolecular catalyst.
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Scheme 1. (a) Hydrolytic Enantioselective Protonation of Enol Esters Catalyzed by PTC 1; (b) Hypothesized Reaction Mechanism with Chiral Phosphonium/Thiourea Bifunctional Phase-Transfer Catalysts
nantioselective protonation (EP) is a straightforward and fundamental reaction to construct chiral tertiary carbon centers, which are found in numerous biologically active molecules.1 However, controlling the enantioselectivity of EP is difficult because a proton is the smallest electrophile in organic synthesis and rapid proton exchange decreases the optical purity of the products. Much effort has been devoted to developing the catalytic EP of enolates such as silyl enol ethers (alkenyloxysilanes)2 and 1,3-dicarbonyl compounds.3 In particular, enol esters (alkenyl esters) are useful enolate equivalents for EP because of their good synthetic accessibility and stability.4 However, there have been few investigations of EP of enol esters to date. In addition, the substrate scope of the reactions also could be expanded.5 Chiral phase-transfer catalysis is one of the major catalytic principles with ionic reagents in asymmetric synthesis.6 Previously, we reported EP of chloroacetyl enolates via base hydrolysis using chiral ammonium salt catalysts derived from cinchona alkaloids (Scheme 1a).5a,c,7 Our experimental and theoretical mechanistic studies suggested that the 9-OH group in the catalyst functioned as a chiral proton source in the EP of the ammonium enolate ion pair. Based on these mechanistic insights, we then focused on the use of quaternary phosphonium/thiourea catalysts because this motif includes various accessible unique structures and the acidic hydrogen bond donor would be the proton source in the enantioselective step (Scheme 1b). In addition, the thiourea group would form a hydrogen bond with hydroxide, protecting the relatively fragile phosphonium moiety from decomposition via βelimination by the strong hydroxide base. Considering the modularity and synthetic accessibility of the catalysts, we used phosphonium/thiourea catalysts derived from amino acids, which were first developed by Zhao’s group.8 Herein, we © XXXX American Chemical Society
report phosphonium/thiourea bifunctional phase-transfer catalysts (PTCs) derived from tert-leucine as highly selective catalysts for EP of enol esters. This system achieves good to high yields and enantioselectivities using enol ester substrates having a five- to eight-membered ring. The mechanism of this catalytic system was investigated by control experiments, revealing the importance of the bulky t-Bu group and phosphonium and thiourea moieties. In addition, investigations Received: April 6, 2019
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DOI: 10.1021/acs.orglett.9b01216 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters of the nonlinear effects and analyses of the reaction mixtures using 31P NMR and MS indicate the phosphonium/thiourea catalyst is converted to the corresponding betaine species, which catalyzes the EP of the enol esters as a monomolecular catalyst. We first determined the optimum reaction conditions with enol ester 2a using 5 M NaOH (aq) and 2-methoxyethanol (5) as an additive in CHCl3/mesitylene solvent, which provided the corresponding chiral ketone in 92% yield with a 95.5:4.5 enantiomer ratio (er) after screening of the reaction conditions with PTC 4a (Table 1, entry 1). In this catalytic system,
Scheme 2. Enantioselective Protonation of Enol Esters: Catalyst Screeninga
Table 1. Enantioselective Protonation of Enol Esters: Optimization of Reaction Conditionsa
entry
deviation from standard conditions
Yieldb (%)
erc
1 2 3 4 5 6 7
standard conditions without MeOCH2CH2OH (5) 2 equiv of MeOCH2CH2OH (5) without PTC 4a solvent: CHCl3 solvent: mesitylene reaction temperature: −10 °C
92 18 47 47 65 79 99
95.5:4.5 86:14 96:4 50:50 94.5:5.5 79.5:20.5 93.5:6.5
a Standard reaction conditions: Enol ester 2a (0.1 mmol) was added to a mixture of PTC 4a (10 mol %), MeOCH2CH2OH (5) (3 equiv), and 5 M NaOH aq (100 μL) in CHCl3/mesitylene (v/v = 1:1, 400 μL) at −20 °C and then stirred for 20 h at 800 rpm. bGC yield. cEr was determined using chiral GC analysis.
a
Standard reaction conditions in Table 1 are employed.
to achieve high stereoselectivity. Next, we investigated the substituent effects of the bifunctional phosphonium/thiourea catalysts. The use of PTC 4b with a phenyl group on the thiourea moiety lowered the enantioselectivity. In addition, substitution of the sulfur atom with an oxygen atom resulted in a low er. These results suggest that the high acidity of the thiourea moiety is essential to obtain the high selectivity. Catalysts 4d−4f derived from different amino acids were also examined. The smaller the substituent, the lower the stereoselectivity of the reaction. The bulky tert-butyl group would fix the acyclic conformation of the catalyst, which would lead to the high stereoselectivity. Finally, we examined the catalysts 4g−4i having different substituents on the benzyl group on the phosphorus atom, and catalyst 4g bearing 1naphthylmethyl group showed the highest stereoselectivity (98%, 97.5:2.5 er). In addition, the 1 mmol scale reaction with the catalyst 4g successfully proceeded without significant loss of the stereoselectivity (75%, 97:3 er). We next set out to explore the substrate scope for the reaction (Scheme 3). Reactions of substrates with aliphatic groups gave the corresponding α-chiral ketones in good yields with good to high enantioselectivities (3b: 70%, 89.5:10.5 er; 3c: 79%, 94:6 er; 3d, 76%, 93.5:6.5 er; 3e: 94%, 98.5.1.5 er). It is worth noting that product 3d is the useful synthetic intermediate for ent-10-methyl-6-undecanolide.5a The sub-
addition of 2-methoxyethanol (5) (3 equiv) is important to raise both the reactivity and enantioselectivity (entries 2−4). The reaction in the absence of 5 provided the product in low yield and er (18% yield, 86:14 er, entry 2). In addition, 5 promoted the degradation of the substrate even in the absence of PTC 4a (entry 4). Furthermore, additives such as sterically hindered alcohols or aprotic polar compounds significantly lowered the yields based on the preliminary screening of the additives (see Supporting Information (SI), for details). These results suggest that the alcoholic additives serve as a nucleophile instead of hydroxide. As for the solvent, the stereoselectivity decreased when the reactions were performed in CHCl3 or mesitylene alone (entries 5 and 6) instead of a mixture of these solvents. Raising the temperature lowered the enantioselectivity (entry 7). With the optimized reaction conditions in hand, we then screened chiral PTCs with different scaffolds and investigated the substituent effects of the phosphonium/thiourea catalysts (Scheme 2). PTC 1 derived from Cinchona alkaloids, which showed the highest enantioselectivity in our previous work,5a gave the corresponding ketone 3a in 98% yield with 15.5:84.5 er. Other quaternary ammonium salts such as TaDiAS9 or the Maruoka catalyst10 were also examined under the reaction conditions, but provided the racemic product. These results indicated that the hydrogen-bond donor group was important B
DOI: 10.1021/acs.orglett.9b01216 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Substrate Scopea
five-, seven-, and eight-membered ring, dienyl ester 2t, or enol ester 2u having a bromopropyl group reacted to provide the corresponding ketones in moderate to good yields with good to high stereoselectivities (3q: 92%, 92.5:7.5 er; 3r: 88%, 92:8 er; 3s: 44%, 95:5 er; 3t: 89%, 91.5:8.5 er, 3u: 98%, 88.5:11.5 er). To investigate the roles of the thiourea and phosphonium groups in the stereodetermining step, reactions with Nmethylated catalyst PTC 4j and thiourea-phosphine catalyst PTC 4k were performed (Scheme 4). PTC 4j provided the Scheme 4. Control Experiments To Investigate the Substituent Effects of the Bifunctional PTC 4j and 4k
racemic product under the standard reaction conditions. In addition, the lack of quaternarization of the phosphorus atom retarded the selectivity (Scheme 4, 60:40 er). These results suggested that the hydrogen bonding donor and ionic interaction of the catalyst both played important roles in the stereodetermining step. The effort was next directed toward elucidating the roles of the alcohol additives. To improve the stereoselectivity of the reaction using additives, we hypothesized that 2-methoxyethanol would serve as a nucleophile instead of hydroxide and suppress the formation of the chloroacetic acid, which would be a potential achiral proton source, close to the enolate anion species. To probe this hypothesis, we investigated the formation of 2-methoxyethyl chloroacetate under the standard reaction conditions, and observed a small amount of the compound by GC analysis. In addition, methoxyethyl chloroacetate was found to readily decompose under the reaction conditions. Furthermore, additives such as sterically hindered alcohols or aprotic polar compounds significantly lowered the yields based on the preliminary screening of the additives. These results support the above hypothesis (see SI, for details). We then further investigated the reaction mechanism by focusing on PTC 4g under the standard reaction conditions (Scheme 5). 31P NMR analysis of the chloroform extracts of the reaction mixtures under standard conditions suggested that new compounds derived from 4g formed after 1 h, although the conversion of the substrate was low (Catalyst Recovery: 25%, Substrate Conv: 17%). In addition, Atmospheric Pressure Solid Analysis Probe MS (ASAP-MS) analysis of the organic phase of the reaction mixture revealed a signal at m/z = 737.2 corresponding to a deprotonated hydrated sodium salt of PTC 4g. These results suggested that PTC 4g was initially deprotonated to form betaine 8, which also catalyzed the alcoholytic or hydrolytic EP.
a
Reactions were carried out on 0.25 mmol scale under the reaction conditions described in Table 1. Isolated yields are presented, and er’s were determined by HPLC or GC on a chiral stationary phase. bNMR yield.
strate derived from α-benzyl cyclohexanone also showed good stereoselectivity (3f: 86%, 93.5:6.5 er). Methyl substitution of the o-, m-, and p-positions of the benzyl (Bn) group had little effect on the yield and stereoselectivity (3g: 80%, 94:6 er; 3h: 80%, 95:5 er, 3i: 93%, 94:6 er). The reaction of a sterically hindered substrate also gave the product in high yield with good selectivity (3j: 94%, 93:7 er). As for the electronic effects, a substrate with an electron-deficient Bn group resulted in a lower er, whereas an enol ester bearing an electron-rich Bn group showed good stereoselectivity (3k: 84%, 89.5:10.5 er; 3l: 93%, 94:6 er). Bn groups substituted with synthetically useful halogen functionalities were also tolerated (3m: 75%, 92:8 er; 3n: 81%, 95:5 er; 3o: 94%, 92.5:7.5 er), whereas a substrate with a thiomethyl (SMe) group resulted in low stereoselectivity (3p: 93%, 89.5:10.5 er). Enol esters bearing a C
DOI: 10.1021/acs.orglett.9b01216 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
In conclusion, we developed an enantioselective protonation reaction of enol esters using phosphonium/thiourea bifunctional catalysts. This catalytic system delivered enantioenriched α-chiral ketones with good to high er values. In addition, experimental mechanistic investigations suggested the roles of the alcohol additive and the phosphonium and thiourea moieties in the catalysts, which were necessary to achieve the high stereoselectivity. Further application of this catalytic system and theoretical investigations are underway by our group.
Scheme 5. ASAP-MS Analysis of the Reaction Mixture under the Standard Reaction Conditions
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01216.
To gain further mechanistic insight into the enantioselective process, the relationship between the enantiomeric excess (ee) value of the PTC 4 and the product 3a was explored. Potentially, PTC 4 and the corresponding betaine species could work cooperatively because of the difference between the acidity of the corresponding N−H protons. However, a clear linear proportionality was observed, indicating that the monomeric catalytic active species is involved in the stereodetermining step (see SI, for details). The putative main reaction mechanism is presented in Scheme 6. Initially, catalyst 4 is deprotonated by the base to
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Experimental procedures, characterization data, and additional experimental data supporting the proposed reaction mechanism (PDF) 1 H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Scheme 6. Proposed Reaction Mechanism
Eiji Yamamoto: 0000-0001-5968-8186 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant Nos. 16H07042 and 15K05431); a Grant-in-Aid for Scientific Research on Innovative Areas “Advanced Molecular Transformations by Organocatalysts” from The Ministry of Education, Culture, Sports, Science and Technology, Japan (No. 26105744); and the Research Program for Next Generation Young Scientists of “Five-star Alliance” in “NJRC Mater. & Dev.” We appreciate the reviewers for the fruitful suggestions in the peer review process.
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REFERENCES
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DOI: 10.1021/acs.orglett.9b01216 Org. Lett. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.orglett.9b01216 Org. Lett. XXXX, XXX, XXX−XXX
