Catalytic Asymmetric Darzens-Type Epoxidation of Diazoesters: Highly Enantioselective Synthesis of Trisubstituted Epoxides

Article abstract of DOI:10.1002/anie.202108454

Highly enantioselective Darzens-type epoxidation of diazoesters with glyoxal derivatives was accomplished using a chiral boron–Lewis acid catalyst, which facilitated asymmetric synthesis of trisubstituted α,β-epoxy esters. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction proceeded in high yield (up to 99 %) with excellent enantio- and diastereoselectivity (up to >99 % ee and >20:1 dr, respectively). The synthetic potential of this method was illustrated by conversion of the products to various compounds such as epoxy γ-butyrolactone, tertiary β-hydroxy ketone and epoxy diester.

Full text of DOI:10.1002/anie.202108454

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: Catalytic Asymmetric Darzens-type Epoxidation of Diazoesters:
Highly Enantioselective Synthesis of Trisubstituted Epoxides
Authors: Do Hyun Ryu, Dong Guk Nam, Su Yong Shim, and Hye-Min
Jeong
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202108454
Link to VoR: https://doi.org/10.1002/anie.202108454

Angewandte Chemie International Edition
10.1002/anie.202108454
COMMUNICATION
Catalytic Asymmetric Darzens-Type Epoxidation of Diazoesters:
Highly Enantioselective Synthesis of Trisubstituted Epoxides
[+]
[+]
Dong Guk Nam , Su Yong Shim , Hye-Min Jeong, and Do Hyun Ryu*
[*]
D. G. Nam,[+] Dr. S. Y. Shim, [+] H.-M. Jeong, Dr. D. H. Ryu
Department of Chemistry, Sungkyunkwan University
300 Cheoncheon-dong, Jangan-gu, Suwon, 16419, Korea
E-mail: dhryu@skku.edu
Dr. S. Y. Shim [+]
Present address: Department of Chemistry, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, California 92037, United States
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract: Highly enantioselective Darzens-type epoxidation of
diazoesters with glyoxal derivatives was accomplished using a chiral
boron-Lewis acid catalyst, which facilitated asymmetric synthesis of
construction of optically active β-keto ester and the all-carbon
quaternary aldehyde, respectively (Scheme 1B). However,
epoxide products were observed as side products in the case of
o-fluorobenzaldehyde.[12a] Based on our observations and reports
in the literature,[1a] we envisioned that the reaction of electron-
trisubstituted α,β-epoxy esters. In the presence of
a chiral
oxazaborolidinium ion catalyst, the reaction proceeded in high yield
(up to 99%) with excellent enantio- and diastereoselectivity (up to >99% withdrawing group-substituted aldehyde such as glyoxal with
ee and >20:1 dr, respectively). The synthetic potential of this method
was illustrated by conversion of the products to various compounds
such as epoxy γ-butyrolactone, tertiary β-hydroxy ketone and epoxy
diester.
diazo compound would generate the epoxide through direct ring-
closure of oxygen atom (path c). Efficient enantioselective
reactions of glyoxal derivatives with α-substituted diazo
compounds could provide a valuable method for asymmetric
synthesis of optically active trisubstituted α,β-epoxy carbonyl
compounds (Scheme 1B). Herein, we describe the first highly
asymmetric catalytic method for synthesis of trisubstituted α,β-
epoxy carbonyl compounds in Darzens-type reaction.
Optically active α,β-epoxy carbonyl compounds are versatile
building blocks for the synthesis of biologically active molecules
and powerful key intermediates in a broad array of applications
for asymmetric synthesis.[1-3] Accordingly, numerous efforts have
been dedicated to efficient preparation of these compounds.[4,5]
Among the various synthetic methods, asymmetric Darzens
condensation[6,7] and Corey-Chaykovsky reaction[8,9] using a
sulfur ylide are a particularly powerful approaches in terms of
direct asymmetric conversion of carbonyl compounds into
epoxides.[2a-b] However, except for a few examples of catalytic
methods, synthetic application of these reactions depends on
A. Enantioselective Darzens epoxidation with diazoacetamide
N2
O
H
N
Chiral L.A
H
N
O
R2
R1
R2
H
R1
H
or
O
O
Zn or Ti complex
R2 = n-Bu or Ph
B. This work : Enantioselective epoxidation for producing trisubstituted epoxide
O
[6-
path a
chiral auxiliary methods or chiral reagent-mediated approaches.
CO2R
R3
9
]
R4
O
A
carbonyl addition-initiated ring-closure of carbonyl
cat
c
N2
O
R3
compounds using diazo compounds is complementary to these
variants.[1b] Since Gong reported pioneering studies on catalytic
enantioselective versions with diazoacetamide to afford α,β-Z-
epoxy amide compounds, there have been a few reports using
diazoacetamide as the ylide to give disubstituted α,β-epoxy
amides (Scheme 1A).[10] However, no study has been successful
in synthesizing trisubstituted epoxides, which remain the most
challenging class of oxirane despite having been documented in
a Darzens-type aziridination.[6c],[11]
H
cat.
O
path b
CO R
R4
2
H
H
H
a
CO R
R4 R3
CO2R
R4
R3
2
b
N2
R4
tetrahedral
intermediates
O
path c
This work
R3
2
CO R
R3 = COAr
·
·
Highly functionalized trisubstituted epoxide
Excellent stereoselectivity (>20:1 dr, up to 99% ee)
Recently, our group reported highly enantioselective catalytic
tandem reactions of diazo compounds with the chiral
oxazaborolidinium ion (COBI)[12,13] as a Lewis acid catalyst. After
forming tetrahedral intermediate through nucleophilic addition of
diazo compounds into aldehyde, H-migration[12a-12d] (Roskamp
reaction, path a) and C-migration (path b)[12e] led to the
Scheme 1. Enantioselective synthesis of epoxide with diazo compounds.
1
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202108454
COMMUNICATION
Table 1. Optimization of conditions for enantioselective synthesis of
trisubstituted α,β-epoxy ester.[a,b]
13
2k
2-Furyl
8
99
99
O
H
O
Ph
O
N2
Cat. 1 (20 mol %)
[a] The reaction of α-phenyldiazoester (0.2 mmol) with aromatic glyoxal (0.3
mmol) was performed in the presence of 1e (20 mol %) and powdered 3 Å
molecular sieves (100 mg) in 1.8 ml of toluene at –78 °C. [b] Isolated yield of 2.
[c] ee was determined by chiral HPLC. [d] Performed on a 1.0 mmol scale. [e]
H
Ph
Ph
Ph
Ph
CO2t-Bu
toluene
-78 °C, 8 h
Ph
CO2t-Bu
O
O
OHC CO2t-Bu
2
a
3a
1
0 mol % of catalyst 1e was used. [f] 3e and 3h were produced in 41% and 32%
Ar1
1a, Ar1 = Phenyl, Ar2 = Phenyl
b, Ar1 = 3,5-Dimethylphenyl, Ar2 = Phenyl
1c, Ar1 = 3,5-Dimethylphenyl, Ar2 = 4-Methoxyphenyl
Ar1
yield, respectively.
1
N
O
B
Table 3. Enantioselective formation of trisubstituted α,β-epoxy ester with
various aromatic diazoesters.[a]
Tf2N
H
d, Ar1 = 3,5-Dimethylphenyl, Ar2 = 4-(trifluoromethyl)phenyl
e, Ar1 = 2,3-Dimethylphenyl, Ar2 = 4-(trifluoromethyl)phenyl
1
1
Ar2
catalyst
O
Ar2
H
O
N2
Cat. 1e (20 mol %)
H
Ar1
Ar2
2
CO R
toluene
3Å MS
Ar1
Entry
1
Cat. 1
1a
Z/E
Yield (%)[c]
ee (%)[d]
90
CO R
2
O
O
-78 °C, 8 h
2
10:1
29
56
63
59
80
85
54
d.r. >20:1
2
1b
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
99
Entry
2
Ar1
Ar2
R
Yield
%)[b]
ee
3
1c
76
[c]
(
(%)
4
1d
99
1
2
3
4
5
6
7
8
9
1
2l
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-FC
4-ClC
4-BrC
6
H
4
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
76
83
81
70
>99
>99
99
5
1e
99
2m
2n
2o
2p
2q
2r
6 4
H
6[e]
7[e,f]
1e
99
6
H
4
1e
95
4-IC
6
H
4
>99
>99
99
[
a] The reaction of phenyl glyoxal (0.6 mmol) with α-phenyldiazoester (0.2 mmol)
was performed in the presence of catalyst 1 (20 mol %) in 2.0 ml of toluene at
78 °C for 8 hours. [b] The diastereomeric ratio was determined by 1H NMR
3
4-CF C
6
H
4
75
–
41[d],[e]
6 4
4-MeC H
analysis of the crude reaction mixture. [c] lsolated yield of 2a. [d] The ee of 2a
was determined by chiral HPLC. [e] The reaction was carried out with powdered
3-BrC
2-BrC
6
H
4
4
80
99
98
69
78
98
66
72
60
86
>99
>99
99
3
Å molecular sieves (100 mg) and phenyl glyoxal (0.3 mmol). [f] The catalyst
was activated by triflic acid instead of triflimide.
2s
2t
6
H
2-FC
6
H
4
Table 2. Enantioselective formation of trisubstituted α,β-epoxy ester with
various aromatic glyoxal.[a]
0
2u
2v
2w
2x
2y
2z
2-MeC
6
H
4
>99
99
O
H
O
Ph
CO t-Bu
N2
Cat. 1e (20 mol %)
11
12
4-BrC
6
H
4
4-BrC
4-BrC
Ph
6
H
H
4
4
H
Ar
Ph
CO2t-Bu
toluene
3 Å MS
Ar
2
4-MeOC
Ph
6
H
4
6
99
O
O
-
78 °C, 8 h
2
13
14
15
16
>99
>99
>99
>99
d.r. >20:1
Ph
Ph
Et
Entry
2
Ar
Time (h)
Yield (%)[b]
ee (%)[c]
Ph
Ph
i-Pr
Bn
1
2a
2a
2a
2b
2c
2d
2e
2f
Ph
Ph
Ph
8
85
83
80
74
90
86
50[f]
73
85
58[f]
68
99
99
99
99
98
98
>99
96
98
98
93
99
94
2aa
Ph
Ph
2[d]
3[e]
4
9
[
a] The reaction of α-aromatic diazoester (0.2 mmol) with aromatic glyoxal (0.3
14
24
24
8
mmol) was performed in the presence of 1e (20 mol %) and powdered 3 Å
molecular sieves (100 mg) in 5.0 ml of toluene at –78 °C for 8 h. [b] Isolated
yield of 2. [c] ee was determined by chiral HPLC. [d] Isolated by deactivated
silica gel column chromatography at -78 ℃. [e] β-keto aldehyde 3q was
produced in 58%.
4-MeC
6 4
H
5
4-MeOC
6
H
4
6
4-BrC
2-BrC
6
H
H
4
4
Initially, enantioselective formation of trisubstituted α,β-epoxy
ester from reaction of phenyl glyoxal and t-butyl α-phenyl
diazoester was examined in the presence of 20 mol % COBI
catalyst activated by bis(trifluoromethane)sulfonimide (Table 1).
When the reaction was carried out at –78 °C in toluene with
catalyst 1a, α,β-epoxy γ-keto ester 2a was formed in 29% yield
with 90% ee and high Z selectivity (Table 1, entry 1). At the same
time, a 60% yield of β-keto aldehyde 3a was isolated via Lewis
acid-mediated rearrangement.[2a],[14] Since partial rearrangement
of the epoxide was observed during purification on a silica gel
7
6
8
8
3-ClC
4-CNC
4-NO
2-Naph
2-Thienyl
6
H
4
8
9
2g
2h
2i
6
H
4
6
10
11
12
2
C
6
H
4
5
8
2j
8
2
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202108454
COMMUNICATION
column, product 2a was purified by deactivated silica gel column
chromatography.[15] Changing the catalyst diaryl substituent (Ar1)
to sterically bulky 3,5-dimethylphenyl group led to dramatically
improved yield and enantioselectivity (Table 1, entry 2). After
screening various catalyst structures, we found that the electron-
deficient catalyst 1e, which has a 4-(trifluoromethyl) phenyl Ar2
rationalized on the basis of the transition-state model shown in
Figure 2. The coordination mode of the phenyl glyoxal to catalyst
1e and the enantioselective carbonyl addition of phenyl
diazoester are the same as have been observed for the
asymmetric Roskamp reaction.[12b-12e] In the pre-transition-state
assembly 4, shown in Figure 2. the glyoxal is activated through
coordination to the boron in a monodentate fashion[19] and placed
above the 2,3 dimethylphenylgroup of COBI catalyst 1e. This
group effectively block the re face (back) from attack by the phenyl
diazoester. Because of the dipole-dipole interaction between the
aldehyde of glyoxal and ester of phenyl diazoester, the diazoester
approaches for nucleophilic addition with its ester group situated
away from the aldehyde group of glyoxal. Meanwhile, π-π
interaction hold together the benzoyl group of glyoxal and phenyl
group of diazoester.[20],[12d] Thus, nucleophilic addition of the
phenyl diazoester from the si face (front) of the aryl diazoester
leads to intermediate 5, which then cyclizes with loss of nitrogen
to form trisubstituted α,β-Z-(2R,3S)-epoxy ester 2a as the major
enantiomer.
1
substituent and 2,3-dimethylphenyl Ar substituent, activated by
triflimide, gave the best result of 80% yield and 99% ee (Table 1,
entries 2-5). Significantly, this reaction exhibited excellent
1
diastereoselectivity and no E-diastereomer was detected by H
NMR analysis of the crude mixture. Interestingly, adding 3 Å
molecular sieves led to an improved yield of 85%, and the amount
of aryl glyoxal was decreased to 1.5 equivalents (Table 1, entry
6
). When the COBI catalyst activated by triflic acid was used,
product 2a was obtained with reduced yield and enantioselectivity
Table 1, entry 7). To the best of our knowledge, catalytic
(
enantioselective formation of a trisubstituted α,β-epoxy γ-keto
ester is without precedent.
Having optimized the reaction conditions, we examined the
scope of this reaction with a range of substituted aromatic
glyoxals (Table 2).[16] 10 mol % of catalyst loading was
successfully applied giving epoxide in 80% yield with 99% ee
(
Table 2, entry 3). Regardless of the electronic properties of
substituents on the phenyl glyoxal, highly enantioenriched
H
O
Ph
trisubstituted α,β-epoxy esters 2 were obtained (Table 2, entries
Ph
CO2t-Bu
4
-10). Phenyl glyoxals with electron-donating groups such as 4-
O
methyl or 4-methoxy group showed lower reactivities, but high
yields with excellent enantioselectivities (Table 2, entries 4, 5).
Notably the strongly electron-withdrawing 4-nitrophenyl-glyoxal
and 2-bromophenyl-glyoxal gave the products in reduced yields
due to formation of β-keto aldehydes 3 (Table 2, entries 7, 10).
The condensed-ring glyoxal (2-naphthylglyoxal) reacted with α-
phenyl diazoester, giving the desired product with 99% ee (entry
2
a
Figure 1. X-ray structure of 2a.
1
1). This catalytic system was successfully applied to reactions of
various heteroaromatic glyoxals such as thienyl, and furyl (Table
, entries 12, 13). In particular, furyl-substituted glyoxal gave the
F3C
F3C
2
desired epoxide 2k in excellent yield with excellent
enantioselectivity (99% yield, 99% ee; entry 13).
Encouraged by the good results exhibited in Table 2, we applied
this catalytic methodology to Darzens-type epoxidation of various
substituted aromatic diazoester (Table 3).[17] Various aromatic
diazoesters with halogen and electron-withdrawing groups
successfully reacted to give the corresponding epoxides in high
O
N
O
N
N2
B
B
H
H
H
H
O
O
Tf2N
N2
Tf2N
CO2t-Bu
CO2t-Bu
Ph
O
O
Ph
Ph
Ph
4
5
to
excellent
yields
with
excellent
diastereo-
and
enantioselectivities (Table 3, entries 1-5, 7-9). Use of p-tolyl
diazoester diminished the yield due to the undesired formation of
β-keto aldehyde 3q as side product, but high diastereo- and
enantiocontrol were achieved for major epoxide 2q (99% ee, dr
F3C
H
O
Ph
>
20:1; Table 3, entry 6). The reaction of substituted phenyl glyoxal
Ph
(
4-methoxy-, 4-bromo-) with 4-bromophenyl diazoester were
CO2t-Bu
O
O
N
successful, resulting high to excellent yield with excellent
enantioselectivities (Table 3, entries 11-12). Asymmetric
formation of α,β-epoxy esters with various ester groups of the
diazoester proceeded with complete control of enantio- and
diastereoselectivities (Table 3, entries 13-16). The absolute
configurations of trisubstituted α,β-epoxy ester 2a was
unambiguously established by X-ray crystallographic analysis
B
O
HPh
2a
H
N2
2
Tf N
t-BuO2C
O
Ph
Figure 2. Transition-state model for enantioselective formation of trisubstituted
α,β-Z-epoxy ester 2a catalyzed by COBI 1e.
(
Figure 1), and the configurations for all other products 2b-2aa
are based on this assignment by analogy.[18]
The observed stereochemistry for enantioselective formation of
trisubstituted α,β-Z-epoxy ester with COBI catalyst 1e can be
3
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202108454
COMMUNICATION
H
O
Ph
O
O
[1]
Reviews on the syntheses, properties and reactivities of epoxide
derivatives; a) J. Aube in Comprehensive Organic Synthesis Vol. 1 (Eds.:
B. M. Trost, I. Fleming), Pergamon Press, Oxford, 1991, pp. 819-842; b)
H. Pellissier, A. Lattanzi, R. Dalpozzo, Asymmetric Epoxidation in
Asymmetric Synthesis of Three-Membered Rings, Wiley-VCH, 2017, pp.
TFA, EtOH
reflux, 8 h
H
Ph
O
X
Ph
CO t-Bu
2
OH
Ph
X
6
6
a X = H, 95%, 99% ee
b X = 2-thienyl, 96%, 99% ee
7a X = H, 90%, 99% ee
7b X = 2-thienyl, 90%, 99% ee
379-514; c) C. Wang, L. Luo, H. Yamamoto, Acc. Chem. Res. 2016, 49,
NaBH , EtOH
rt, 10 min
or
193-204; d) B. S. Lane, K. Burgess, Chem. Rev. 2003, 103, 2457-2473.
For a review, see; a) C. Lauret, Tetrahedron Asymmetry 2001, 12, 2359-
4
Zn, NH Cl
O HO CO t-Bu
[2]
4
2
2383; b) M. J. Porter, J. Skidmore, Chem. Commun. 2000, 1215-1225;
2-thienylMgBr
Ph
Ph
EtOH, reflux, 4 h
c) D. Díez, M. G. Núñez, A. B. Antón, P. García, R.F. Moro, N.M. Garrido,
I. S. Marcos, P. Basabe, J. G. Urones, Curr. Org. Synth. 2005, 5, 186-
216.
THF, -40 °C
8
95%, 99% ee
H
O
Ph
[
3]
4]
a) J.-L. Giner, W. V. Ferris, J. J. Mullins, J. Org. Chem. 2002, 67, 4856-
4859; b) G. Righi, G. Rumboldt, J. Org. Chem. 1996, 61, 3557-3560.
a) T. Ooi, D. Ohara, M. Tamura, K. Maruoka, J. Am. Chem. Soc. 2004,
126, 6844-6845; b) H. Kakei, R. Tsuji, T. Ohshima, M. Shibasaki, J. Am.
Chem. Soc. 2005, 127, 8962-8963; c) C. M. Reisinger, X. Wang, B. List,
Angew. Chem. Int. Ed. 2008, 47, 8112-8115; d) A. Lee, C. M. Reisinger,
B. List, Adv. Synth. Catal. 2012, 354, 1701-1706.
H
O
Ph
Ph
CO t-Bu
mCPBA, CH Cl2
2
2
O
[
PhO
CO t-Bu
reflux, 16 h
2
2a, 99% ee
O
9
7
0%, 99% ee
Scheme 2. Derivatizations of trisubstituted α,β-epoxy esters.
[5]
a) O. Lifchits, C. M. Reisinger, B. List, J. Am. Chem. Soc. 2010, 132,
10227-10229; b) Y. Nishikawa, H. Yamamoto, J. Am. Chem. Soc. 2011,
133, 8432-8435; c) H. Kawai, S. Okusu, Z. Yuan, E. Tokunaga, A.
To demonstrate the synthetic utility of these products, further
chemical transformations of the resulting optically active α,β-
epoxy ester 2a were conducted and illustrated in Scheme 2.
Yamano, M. Shiro, N. Chibata, Angew. Chem. Int. Ed. 2013, 52, 2221-
2225; d) H. Zhang, Q. Yao, L. Lin, C. Xu, X. Liu, X. Feng, Adv. Synth.
Catal. 2017, 359, 3454-3459; e) C. De Fusco, C. Tedesco, A. Lattanzi,
J. Org. Chem. 2011, 76, 676-679; f) L. Luo, H. Yamamoto, Eur. J. Org.
Chem. 2014, 7803-7805.
4
Chelation-controlled reduction with NaBH proceeded effectively
to afford a single diastereomeric epoxy alcohol 6a in 95% yield
without loss of enantiopurity.[21] Subsequent cyclization of alcohol
[
6]
a) M. S. Newman, B. J. Magerlein, The Darzens Glycidic Ester
Condensation in Organic Reactions, Wiley, New York, 2011, pp. 413-440;
b) Z. Wang, Darzens condensation in Comprehensive Organic Name
Reactions and Reagents, Wiley, 2009, pp. 841-845; c) J. M. de los
Santos, A. M. Ochoa de Retana, E. Martínez de Marigorta, J. Vicario, F.
Palacios, ChemCatChem 2018, 10, 5092−5114; d) V. K. Aggarwal, D. M.
Badine, V. A. Moorthie, Asymmetric Synthesis of Epoxides and
Aziridines from Aldehydes and Imines In Aziridines and Epoxides in
Organic Synthesis (Eds.: A. K. Yudin), Wiley-VCH, Weinheim, 2006, pp.
6
a with trifluoroacetic acid gave optically active α,β-epoxy-γ-
butyrolactone 7a.[22],[23] Grignard addition with 2-thienyl
magnesium bromide also successfully produced single
a
diastereomeric epoxy tert-alcohol 6b in 96% yield and acid
mediated cyclization gave 4-disubstituted epoxy-γ-butyrolactone
7
b in 90% yield with 99% ee. This intriguing structure is found in
numerous naturally occurring biologically active compounds, such
as Clavilactones,[24] Coralloidolides,[25] and Briaranolides.[26]
1
-35.
a) V. K. Aggarwal, G. Hynd, W. Picoul, J.-L. Vasse, J. Am. Chem. Soc.
002, 124, 9964-9965; b) Y. Liu, B. A. Provencher, K. J. Bartelson, L.
[7]
[8]
[9]
4
Additionally, reduction of the epoxide with Zn and, NH Cl led to
2
the highly enantioenriched tertiary β-hydroxy ketone 8 in 95%
yield. [27] Baeyer-Viliger oxidation of the epoxide successfully
provided epoxide 9 bearing two different ester groups.
Deng, Chem. Sci. 2011, 2, 1301-1304; c) V. Ashokkumar, A. Siva, R. R.
Chidambaram, Chem. Commun. 2017, 53, 10926-10929; d) S. Arai, Y.
Shirai, T. Ishida, T. Shioiri, Tetrahedron 1991, 55, 6375-6386; e) D. P.
Hahajan, H. M. Godbole, G. P. Shngh, G. G. Shenoy, J. Chem. Sci. 2019,
In summary, the first case of highly enantiocontrolled catalytic
Darzens-type epoxidation with a diazoester was successfully
developed. This highly enantio- and diastereocontrolled synthetic
method provides optically active trisubstituted α,β-epoxy esters in
high yields. The resulting densely functionalized esters can be
easily converted to optically active α,β-epoxy-γ-butyrolactone and
tertiary β-hydroxy ketone without loss of optical purity. The
absolute configuration of the product was predicted by the
transition state model in Figure 2. We believe that the resulting
trisubstituted α,β-Z-epoxy esters could be highly valuable and
versatile intermediates for further transformations.
131, 22.
a) J.-F. Briere, P. Metzner, T. Toru, C. Bolm, Synthesis and Use of Chiral
Sulfur Ylides in Organosulfur Chemistry in Asymmetric; Wiley-VCH, 2008,
pp. 179– 208; b) M. M. Heravi, S. Asadi, N. Nazari, M. Lashkariani, Curr.
Org. Synth. 2016, 13, 308-333; c) E. M. McGarrigle, E. L. Myers, O. Illa,
M. A. Shaw, S. L. Riches, V. K. Aggarwal, Chem. Rev. 2007, 107, 5841-
5883; d) V. K. Aggarwal, C. L. Winn, Acc. Chem. Res. 2004, 37, 611-620;
e) A.-H. Li, L.-X. Dai, Chem. Rev. 1997, 97, 2341-2372.
a) V. K. Aggarwal, I. Bae, H.-Y. Lee, J. Richardson, D. T. Willians, Angew.
Chem. Int. Ed. 2003, 42, 3274-3278; b) Y. Arroyo, M. A. Sanz-Tejedor,
J. L. G. Ruano, Org. Lett. 2008, 10, 11, 2151-2154; c) O, Illa. M. Arshad,
A. Ros, E. M. McGarrigle, V. K. Aggarwal, J. Am. Chem. Soc. 2010, 132,
1828-1830; d) O. Illa, M. Namutebi, C. Saha, M. Ostovar, C. C. Chen, M.
F. Haddow, S. Nocquet-Thibault, M. Lusi, E. M. McGarrigle, V. K.
Aggarwal, J. Am. Chem. Soc. 2013, 135, 11951-119661; e) T. Sone, A.
Yamaguchi, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2008, 130,
Acknowledgements
10078-10079; f) V. K. Aggarwal, J. Richardson, Chem. Commun. 2003,
2
644-2651.
This work was supported by National Research Foundation of
Korea (NRF) grants funded by the Korean government (MSIP)
[
10] a) A. K. Gupta, X. Yin, M. Mukherjee, A. A. Desai, A. Mohammadlou, K.
Jurewicz, W. D. Wulff, Angew. Chem. Int. Ed. 2019, 58, 3361-3367; b) L.
He, W.-J. Liu, L. Ren, T. Lei, L.-Z. Gong, Adv. Synth. Catal. 2010, 352,
(
NRF-2019R1A4A2001440 and No. 2019R1A2C2087018).
1123-1127; c) W.-J. Liu, B.-D. Lv, L.-Z. Gong, Angew. Chem. Int. Ed.
2009, 48, 6503-6506; d) G.-L. Chal, J.-W. Han, H. N. C. Wong, Synthesis
Keywords: enantioselectivity • trisubstituted epoxide • Lewis
2016, 48, A-G; e) G. Liu, D. Zhang, J. Li, G. Xu, J. Sun, Org. Biomol.
Chem. 2013, 11, 900-904.
acid • diazoester • Darzens reaction
4
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202108454
COMMUNICATION
[11] a) L. Huang, W. D. Wulff, J. Am. Chem. Soc. 2011, 133, 8892-8895; b)
T. Hashimoto, H. Nakatsu, K. Yamamoto, K. Maruoka, J. Am. Chem. Soc.
2011, 133, 9730-9733.
[12] a) S. Y. Shim, D. H. Ryu, Acc. Chem. Res. 2019, 52, 2349-2360; b) L.
Gao, B. C. Kang, G.-S. Hwang, D. H. Ryu, Angew. Chem. Int. Ed. 2012,
51, 8322-8325; c) S. H. Shin, E. H. Baek, G.-S. Hwang, D. H. Ryu, Org.
Lett. 2015, 17, 4736-4749; d) B. C. Kang, D. G. Nam, G.-S. Hwang, D.
H. Ryu, Org. Lett. 2015, 17, 4810-4813; e) J. Y. Kim, B. C. Kang, D. H.
Ryu, Org. Lett. 2017, 19, 5936-5939; f) L. Gao, B. C. Kang, D. H. Ryu, J.
Am. Chem. Soc. 2013, 135, 14556-14559.
[13] Selected recent examples for asymmetric reactions with COBI catalysts;
a) J. Y. Kim, Y. S. Lee, Y. Choi, D. H. Ryu, ACS Catal. 2020, 10,
10585−10591; b) T. Kim, H.-M. Jeong, A. Venkateswarlu, D. H. Ryu, Org.
Lett. 2020, 22, 5198−5201; c) K.-T. Kang, S. H. Park, D. H. Ryu, Org.
Lett. 2019, 21, 6679−6683; d) R. P. Pandit, S. T. Kim, D. H. Ryu, Angew.
Chem. Int. Ed. 2019, 58, 13427–13432; e) K.-T. Kang, S. T. Kim, G.-S.
Hwang, D. H. Ryu, Angew. Chem. Int. Ed. 2017, 56, 3977-3981; f) S. Y.
Shim, Y. Choi, D. H. Ryu, J. Am. Chem. Soc. 2018, 140, 11184−11188;
g) S. Y. Shim, S. M. Cho, A. Venkateswarlu, D. H. Ryu, Angew. Chem.
Int. Ed. 2017, 56, 8663–8666; h) S. Y. Shim, J. Y. Kim, M. Nam, G.-S.
Hwang, D. H. Ryu, Org. Lett. 2016, 18, 160−163.
[14] a) J. M. Domagala, R. D. Bach, J. Am. Chem. Soc. 1978, 100, 1605-
1
606; b) R. D. Bach, J. M. Domagala, J. Org. Chem. 1984, 49, 4181-
188; c) R. D. Bach, R. C. Klix, Tetrahedron Lett. 1985, 26, 985-988.
4
[
15] W. J. Jang, S. M. Song, Y. Park, J. Yun, J. Org. Chem. 2019, 84, 4429-
434.
4
[
16] The alkyl glyoxal gave less than 20 % isolated yield of epoxide 2,
producing the rearrangement product β-keto aldehyde 3 as the major
product in ~50 % yield.
[
17] As an example of alkyl diazoester, the reaction of benzyl diazo t-butyl
ester gave epoxide 2 in 24% yield with 90 % ee along with the β-keto
aldehyde 3 in 60 % yield.
[
18] CCDC 2071928 contains the supplementary crystallographic data for this
paper. These data are provided free of charge by The Cambridge
Crystallographic Data Centre.
[19] For NMR analysis of pretransition-state assembly 4, see Supporting
Information.
[
20] For selected reviews on π-π interaction, see; a) L. M. Salonen, M.
Ellermann, F. Diederich, Angew. Chem. Int. Ed. 2011, 50, 4808-4842.
For selected paper on π-π interaction b) A. Jain, C. S. Purohit, S. Verma,
R. Sankararamakrishnan, J. Phys. Chem. B, 2007, 111, 30, 8680-8683.
21] M. Taniguchi, H. Fujii, K. Oshima, K. Utimoto, Tetrahedron 1995, 51, 3,
[
[
6
79-686.
22] K. Liu, Y. Li, W. Liu, X. Zheng, Z. Zong, Z. Li, Chem. Asian. J. 2013, 8,
59-363.
3
[23] Diastereomeric side products were not detected.
[
24] a) L. Larrosa, M. I. Da Silva, P. M. Gómez, P. Hannen, E. Ko, S. R.
Lenger, S. R. Linke, A. J. P. White, D. Wilton, A. G. M. Barrett, J. Am.
Chem. Soc. 2006, 128, 14042-14043; b) L. Lv, B. Shen, Z. Li, Angew.
Chem. Int. Ed. 2014, 53, 4164-4167; c) L. Lv, B. B. Snider, Z. Li, J. Org.
Chem. 2017, 82, 5487-5497; d) K.-I. Takao, R. Nemoto, K. Mori, A.
Namba, K. Yoshida, A. Ogura, Chem. Eur. J. 2017, 23, 3828-3831.
25] a) I. di Chimica, D. Fabbri, A. Guerriero, F. Pietra, Helv. Chim. Acta. 1987,
[
70, 63-70; b) T. J. Kimbrough, P. A. Roethle, P. Mayer, D. Trauner,
Angew. Chem. Int. Ed. 2010, 49, 2619-2621.
[26] A. Hoshino, H. Mitome, S. Tamai, H. Takiyama, H. Miyaoka, J. Nat. Prod.
2
005, 68, 1328-1335.
27] Z. Yao, D. Ye, H. Liu, K. Chen, H. Jiang, Synth. Commun. 2007, 37, 149-
56.
[
1
5
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202108454
COMMUNICATION
Entry for the Table of Contents
Chiral trisubstituted epoxides were synthesized by boron-Lewis acid catalyzed Darzens-
type epoxidation of diazoesters in high yields with excellent enantio- and
diastereoselectivity. The developed reaction provides an efficient synthetic route to
various chiral compounds such as epoxy γ-butyrolactone, tertiary β-hydroxy ketone, and
epoxy diester.
6
This article is protected by copyright. All rights reserved.