Enantioselective Protonation of Enol Esters with Bifunctional Phosphonium/Thiourea Catalysts

Article abstract of DOI:10.1021/acs.orglett.9b01216

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 tert-butyl 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.

Full text of DOI:10.1021/acs.orglett.9b01216

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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
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 tert-
butyl 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 mono-
molecular catalyst.
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
Efundamental 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 β-
elimination 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
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
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01216
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Letter
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.
Scheme 2. Enantioselective Protonation of Enol Esters:
Catalyst Screening
a
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,
Table 1. Enantioselective Protonation of Enol Esters:
a
Optimization of Reaction Conditions
b
c
entry
deviation from standard conditions
Yield (%)
er
1
2
3
4
5
6
7
standard conditions
92
18
47
47
65
79
99
95.5:4.5
86:14
96:4
without MeOCH2CH2OH (5)
2 equiv of MeOCH2CH2OH (5)
without PTC 4a
solvent: CHCl3
solvent: mesitylene
50:50
94.5:5.5
79.5:20.5
93.5:6.5
reaction temperature: −10 °C
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
b
c
μL) at −20 °C and then stirred for 20 h at 800 rpm. GC yield. Er
a
Standard reaction conditions in Table 1 are employed.
was determined using chiral GC analysis.
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
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 1-
naphthylmethyl 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-
B
DOI: 10.1021/acs.orglett.9b01216
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Letter
a
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).
Scheme 3. Substrate Scope
To investigate the roles of the thiourea and phosphonium
groups in the stereodetermining step, reactions with N-
methylated 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-methoxyetha-
nol 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. NMR
yield.
b
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
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Organic Letters
Letter
In conclusion, we developed an enantioselective protonation
reaction of enol esters using phosphonium/thiourea bifunc-
tional 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
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.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).
Experimental procedures, characterization data, and
additional experimental data supporting the proposed
reaction mechanism (PDF)
1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
The putative main reaction mechanism is presented in
Scheme 6. Initially, catalyst 4 is deprotonated by the base to
*E-mail: eiyam@chem.kyushu-univ.jp.
*E-mail: mtok@chem.kyushu-univ.jp.
ORCID
Scheme 6. Proposed Reaction Mechanism
Eiji Yamamoto: 0000-0001-5968-8186
Notes
The authors declare no competing financial interest.
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 Trans-
formations 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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