Enantioselective Protonation of Cyclic Carbonyl Ylides by Chiral Lewis Acid Assisted Alcohols

Article abstract of DOI:10.1002/chem.202101491

Chiral Lewis acid-catalyzed asymmetric alcohol addition reactions to cyclic carbonyl ylides generated from N-(α-diazocarbonyl)-2-oxazolidinones featuring a dual catalytic system are reported. Construction of a chiral quaternary heteroatom-substituted carb

Full text of DOI:10.1002/chem.202101491

Accepted Article
Accepted Article
Title: Enantioselective Protonation of Cyclic Carbonyl Ylides by Chiral
Lewis Acid Assisted Alcohols
Authors: Yasunori Toda, Takayuki Yoshida, Kaoru Arisue, Kazuaki
Fukushima, Hiroyoshi Esaki, Ayaka Kikuchi, and Hiroyuki
Suga
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To be cited as: Chem. Eur. J. 10.1002/chem.202101491
Link to VoR: https://doi.org/10.1002/chem.202101491
01/2020

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Enantioselective Protonation of Cyclic Carbonyl Ylides by Chiral
Lewis Acid Assisted Alcohols
Yasunori Toda,[a] Takayuki Yoshida,[a] Kaoru Arisue,[a] Kazuaki Fukushima,[b] Hiroyoshi Esaki,[b] Ayaka
Kikuchi,[a] and Hiroyuki Suga*[a]
Abstract: Chiral Lewis acid-catalyzed asymmetric alcohol addition
reactions to cyclic carbonyl ylides generated from N-(-
diazocarbonyl)-2-oxazolidinones featuring a dual catalytic system
are reported. Construction of a chiral quaternary heteroatom-
substituted carbon center was accomplished in which the unique
heterobicycles were obtained in good yields with high
stereoselection. The alcohol adducts were successfully converted to
optically active oxazolidine-2,4-diones by hydrolysis. Mechanistic
studies by DFT calculations revealed that alcohols could be
activated by Lewis acids, enabling enantioselective protonation of
the carbonyl ylides.
cyclization reactions of diazo carbonyl compounds are realized
as one of the most efficient methods for the generation of cyclic
carbonyl ylides.[4,5] We have demonstrated that a dual catalytic
system including a chiral Lewis acid was effective in performing
enantioselective 1,3-dipolar cycloadditions.[6] In order to expand
this attractive 1,3-dipolar system, we sought to explore the
enantioselective protonation of carbonyl ylides. This would be
accomplished by electrophilic activation of an alcohol by a chiral
Lewis acid catalyst as if the alcohol behaved like the
dipolarophile in a 1,3-dipolar system. Although a few examples
of alcohol addition reactions to cyclic carbonyl ylides have been
reported,[7,8] there are a number of issues to be overcome for the
chiral Lewis acid-catalyzed enantioselective reaction as follows:
(1) efficient activation of alcohols by Lewis acids; (2) asymmetric
induction by chiral Lewis acids; and (3) undesired -elimination
Asymmetric protonation of enolates represents one of the most
straightforward approaches for the construction of chiral tertiary
carbon centers, which are found in a large number of optically
active and biologically relevant organic compounds.[1] The
development of catalytic asymmetric protonation has long been
considered arduous owing to the nature of the proton. Its empty
when -alkyl diazo carbonyl substrates possessing
a -
hydrogen are utilized as the cyclic carbonyl ylide precursors.[9] In
this communication, we demonstrate the first example of an
enantioselective protonation of cyclic carbonyl ylides generated
1s orbital makes the construction of
a highly-controlled
asymmetric environment challenging. Additionally, the smallest
element in the Periodic Table can cause fast proton exchanges,
which lead to non-enantioselective processes. It is also
necessary to prevent racemization of the stereocenter and to
control the enolate E/Z geometry. To-date, several strategies
have been employed for enantioselective protonation, including
(a) protonation of enol ethers and enol esters by chiral proton
donors, (b) protonation of enolates generated by chiral Brønsted
base catalysts, and (c) protonation of Pd enolates by achiral
Brønsted acids (Scheme 1).[1g,k,l] In the cases involving chiral
proton catalysis, pre-preparation of the enolate equivalents is
typically required for activation of the carbonyl compounds. In
contrast to these strategies, we envisioned
a
novel
enantioselective protonation of in situ-generated transient
enolate equivalents. For this purpose, we focused on cyclic
carbonyl ylides derived from diazo compounds. Until now, there
have been no examples of enantioselective protonation of 1,3-
dipole type ylide species by chiral Lewis acid catalysis.[2,3]
Rh(II)-catalyzed
intramolecular
carbenoid-carbonyl
[a]
[b]
Dr. Y. Toda, T. Yoshida, K. Arisue, A. Kikuchi, and Prof. Dr. H. Suga
Department of Materials Chemistry
Faculty of Engineering
Shinshu University
4-17-1 Wakasato, Nagano 380-8553 (Japan)
E-mail: sugahio@shinshu-u.ac.jp (H.S.)
Prof. Dr. K. Fukushima, Dr. H. Esaki
Department of Chemistry
Scheme 1. Strategies for enantioselective protonation of
Hyogo College of Medicine
enolate derivatives.
1-1 Mukogawa-Cho, Nishinomiya, Hyogo 663-8501 (Japan)
Supporting Information for this article is given via a link at the end of
the document.
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from -alkyl diazo carbonyl compounds using a dual catalytic
system that consists of a Rh(II) complex and chiral Lewis acids.
Computational studies to gain insight into the addition
mechanism are also described.
Initially, the reaction of 3-(3-phenyl-2-diazo-1-propanoyl)-2-
oxazolidinone (1a) with benzyl alcohol (1.5 equiv) was carried
out in the absence of a Lewis acid using a dirhodium complex (2
mol%) as the sole catalyst. We selected dirhodium tetrapivaloate
(Rh2Piv4) to avoid undesired -elimination from the
corresponding carbenoid.[9] As a result, desired alcohol adduct
2a was obtained in 27% NMR yield with high diastereoselectivity
(dr = 99:1) (Table 1, entry 1). The -elimination product, (Z)-3-
cinnamoyl-2-oxazolidinone (3), was also detected in 8% NMR
yield along with 61% NMR yield[10] of starting diazo substrate 1a.
In contrast, the addition of 10 mol% of Lewis acids was effective
in accelerating the addition of the alcohol to give 2a in 71–95%
NMR yields (entries 2–9). By-product 3 was also reduced to less
than 2% NMR yield[10] in most cases. Although product 2a was
partly decomposed by column chromatography due to its
instability, it could be isolated in a relatively good yield (Table 1,
entry 6). The reactions of diazo compound 1b, bearing dimethyl
groups at the 5-position, with ethanol, p-methoxybenzyl alcohol,
and p-bromobenzyl alcohol using Zn(BF4)2•xH2O afforded stable
alcohol adducts 2b–2d, respectively, in high to good yields with
high diastereoselectivities, and the products could be isolated by
column chromatography (Scheme 2). The unique structure and
relative configuration of 2d were unambiguously confirmed by X-
ray structure analysis, revealing that syn-addition of the alcohol
to the carbonyl ylides occurred.[11]
Scheme 2. Alcohol addition reactions to a cyclic carbonyl
ylide generated from diazo compound 1b.
with Gaussian09 D.01 and Gaussian16 C.01.[12] Geometries
were optimized using the M06-2X/6-311+G(d,p) (H,C,N,O,Cl) +
SDD (Zn) level of theory in the gas phase. The intrinsic reaction
coordinate (IRC) approach was used to search for reactants and
products.[13] The energies were then refined by M06-2X/def2-
TZVPP single-point energy calculations in solution (CH2Cl2)
using the SMD solvation model.[14] The refined energies were
converted to zero-point energy-corrected free energies at 298.15
K and 1 atm with use of the M06-2X/6-311+G(d,p) (H,C,N,O,Cl)
+ SDD (Zn) harmonic frequencies. Our goal in this study was to
elucidate whether the activation of alcohols by Lewis acids was
possible. We considered three types of coordination of Zn(ClO4)2
as shown in Figure 1: (1) to an unshared electron pair of MeOH
(Model I); (2) to each one of the two unshared electron pairs on
the carbonyl group of the carbonyl ylide (Models II and III).[15]
Two transition states (TS1a and TS1b) are obtained in the case
of Model I, suggesting a stepwise mechanism consisting of
protonation of the carbonyl ylide followed by addition of MeOH.
The first protonation step is rate-limiting since the energy of
TS1a is higher than that of TS1b (Figure 2). In contrast, Model II
The role of the Lewis acid in the alcohol addition to cyclic
carbonyl ylides was studied by density functional theory (DFT).
To simplify the calculations, MeOH and the carbonyl ylide in
Figure 1 were used as models. All calculations were performed
Table 1. Screening of achiral Lewis acids in the reaction
of 1a with BnOH[a]
affords
a concerted-type mechanism, wherein C-H bond
formation (protonation) and C-O bond formation (MeOH
addition) occur simultaneously. On the other hand, Model III
corresponds to another stepwise mechanism derived from the
Lewis acid activation of the carbonyl ylide. In this mechanism,
the carbonyl ylide undergoes MeOH addition before protonation.
Although R2 (G = 0.0 kcal mol-1) is energetically more stable
than R1 (G = 1.9 kcal mol-1), the stepwise protonation/addition
mechanism would be the most favored pathway in terms of
relative Gibbs energies of each transition state in the whole
Entry
Lewis acid
None
2a / Yield[b] (%)
1
2
3
4
5
6
7
8
9
27
83
Fe(ClO4)2•6H2O
Co(ClO4)2•6H2O
Ni(ClO4)2•6H2O
Cu(ClO4)2•6H2O
Zn(ClO4)2•6H2O
AgClO4•6H2O
Zn(BF4)2•xH2O[d]
Zn(OTf)2
83
71
95
86 (71)[c]
85
81
75
[a] The Reaction was carried out using diazo compound 1a,
benzyl alcohol (1.5 equiv), Rh2pPiv4 (2 mol%), and a Lewis acid
(10 mol%) in CH2Cl2 (0.05 M) at –78 °C for 24 h. [b] Determined
1
by H NMR analysis using (CH2Cl)2 as an internal standard. [c]
Isolated yield. [d] Hexa- or heptahydrate.
-
Figure 1. Possible types of coordination (L = ClO4 ).
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-
Figure 2. Energy profiles of the Lewis acid-catalyzed reaction between the carbonyl ylide and MeOH (L = ClO4 ). The
relative energies based on R2 are shown. Energy deference from each reactant (R1 or R3) is shown in parenthesis. All
energies in kcal mol−1.
energy profiles. It is hence concluded that this transformation
can be extended to enantioselective protonation because the
protonation step is not only a rate-determining step but also a
stereo-determining step.
Encouraged by these computational studies, we attempted
the enantioselective protonation of the cyclic carbonyl ylide by
chiral Lewis acids (Table 2). The chiral Lewis acids were first
prepared by mixing Zn salts with (R)-N,N’-(2-quinolylmethylene)-
2,2’-binaphthyldiamine[16] ((R)-BINIM-2QN) in CH2Cl2 at room
temperature for 6 h, and then the reaction was carried out at –
78 °C for 72 h after successively adding Rh2Piv4 (2 mol%),
benzyl alcohol (1.5 equiv), and diazo compound 1b. An initial
investigation using Zn(BF4)2•xH2O in dry CH2Cl2 showed
promising enantioselectivity (68% ee) with good yield of 2e
(entry 1). It is interesting to note that improved enantioselectivity
(83% ee) was observed when the reaction was performed in wet
CH2Cl2 (entry 2).[17] By the investigation of counter anions for
–
zinc salts, BF4 was revealed to exhibit slightly better
–
enantioselectivity than ClO4 and OTf– (entries 2–4). To further
explore the effect of wet CH2Cl2, we tested the reaction in dry
Table 2. Chiral Lewis acid-catalyzed enantioselective protonation of a cyclic carbonyl ylide[a]
Entry
Zn salt
BnOH (equiv)
Solvent
dry CH2Cl2
Yield[b] (%) Dr (trans:cis)
ee[c] (%)
68
1
2
3
4
5
6
7
8
9
Zn(BF4)2•xH2O
Zn(BF4)2•xH2O
Zn(ClO4)2•6H2O
Zn(OTf)2
1.5
1.5
1.5
1.5
1.5
3.5
5.5
7.5
9.5
86
86
87
59
85
88
89
87
87
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
> 99:1
wet CH2Cl2
wet CH2Cl2
wet CH2Cl2
dry CH2Cl2 + H2O[d]
dry CH2Cl2
83
82
81
Zn(BF4)2•xH2O
Zn(BF4)2•xH2O
Zn(BF4)2•xH2O
Zn(BF4)2•xH2O
Zn(BF4)2•xH2O
81
72
dry CH2Cl2
84
dry CH2Cl2
85
dry CH2Cl2
85
[a] The reactions were carried out using 1b, benzyl alcohol, Rh2Piv4 (2 mol%), Zn salt (10 mol%), and (R)-BINIM-2QN (11
mol%) in CH2Cl2 (0.05 M) at –78 °C for 72 h. [b] Isolated yield. [c] Determined by HPLC analysis. [d] 2.0 equiv based on 1b.
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toluenesulfonic acid in a THF/H2O mixed solvent, providing
oxazolidine-2,4-dione 4 in quantitative yield without loss of
enantiopurity (Scheme 3b). Enantiomerically pure (S)-4 (>99%
ee) was obtained by recrystallization from CH2Cl2/hexane, which
was then used for X-ray crystallographic analysis to determine
the absolute configuration.[11]
In summary, we have demonstrated an enantioselective
protonation of cyclic carbonyl ylides generated from -alkyl
diazo carbonyl compounds. The reactions were effectively
catalyzed by a chiral Lewis acid in the presence of alcohols. The
unique heterobicyclic products having a quaternary heteroatom-
substituted carbon center were obtained with high diastereo-
and enantioselectivities. DFT calculations indicated that
coordination of the Lewis acid to alcohols in a stepwise manner
was favored. Current investigations are directed towards the
development of other types of enantioselective transformations
of cyclic carbonyl ylides.
Acknowledgements
This work was partially supported by the Japan Society for the
Promotion of Science (JSPS) through Grants-in-Aid for Scientific
Research (C) (Grant Nos. JP15K05497, JP17KT0096, and
JP19K05454).
Keywords: asymmetric protonation • enantioselective reaction •
chiral Lewis acid • carbonyl ylide • diazo compound
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Scheme 3. Substrate scope and derivatization.
CH2Cl2 in the presence of 2.0 equiv of H2O (entry 5). Notably,
the addition of H2O was effective in achieving good
enantioselection (entry 5, 81% ee), as high as that obtained in
wet CH2Cl2 (entry 2, 83% ee). Thus, we examined the influence
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improved the enantioselectivity up to 85% ee (entries 8 and 9).
With the optimal conditions in hand, we investigated the
scope of substrates (Scheme 3a). Diazo substrates bearing an
[2]
[3]
[4]
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Alcohol adduct 2h was easily hydrolyzed by treatment with p-
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as an internal standard.
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[17] After vigorously stirring dry CH2Cl2 with water for overnight, the organic
layer was simply used as wet CH2Cl2.
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Entry for the Table of Contents
Enantioselective protonation of cyclic carbonyl ylides by chiral Lewis acid-assisted alcohol addition
reactions featuring a dual catalytic system is reported. The unique heterobicyclic products bearing a
quaternary heteroatom-substituted carbon center were obtained with high diastereo- and
enantioselectivities. The alcohol adducts were successfully converted to optically active oxazolidine-
2,4-diones by hydrolysis. Computational mechanistic studies indicated that a stepwise syn-addition of
alcohols under the influence of a Lewis acid was favored.
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