Efficient and Enantioselective Rhodium(I)-Catalyzed Arylation of α-Ketoesters: Synthesis of (S)-Flutriafol

Article abstract of DOI:10.1002/adsc.201800575

An enantioselective addition of arylboronic acids and α-ketoesters promoted by a Rhodium(I)-chiral diene catalyst is reported. The transformation proceeds regioselectively in the presence of as low as 0.5 mol% of the catalyst generated in situ from a Rhod

Full text of DOI:10.1002/adsc.201800575

Title: Efficient and Enantioselective Rhodium(I)-Catalyzed Arylation of
α-Ketoesters: Synthesis of (<i>S</i>)-Flutriafol
Authors: Chiung-An Chang, Tsung-Ying Uang, Jia-Hong Jian, Meng-
Yi Zhou, Ming-Liang Chen, Ting-Shen Kuo, Ping-Yu Wu, and
Hsyueh-Liang Wu
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: Adv. Synth. Catal. 10.1002/adsc.201800575
Link to VoR: http://dx.doi.org/10.1002/adsc.201800575

10.1002/adsc.201800575
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Efficient and Enantioselective Rhodium(I)-Catalyzed Arylation
of -Ketoesters: Synthesis of (S)-Flutriafol
Chiung-An Chang,a Tsung-Ying Uang,a Jia-Hong Jian,a Meng-Yi Zhou,a Ming-Liang
Chen,a Ting-Shen Kuo,a Ping-Yu Wub and Hsyueh-Liang Wu a,*
a
Department of Chemistry, National Taiwan Normal University, No. 88, Section 4, Tingzhou Road, Taipei 11677,
Taiwan.
Fax: (+886)-2-77346142; email: hlw@ntnu.edu.tw
Oleader Technologies, Co., Ltd., 1F., No. 8, Aly. 29, Ln. 335, Chenggong Rd., Hukou Township 30345, Hsinchu,
b
Taiwan
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An enantioselective addition of arylboronic acids dinaphthyl substituents, to afford tertiary chiral -hydroxy
and -ketoesters promoted by a Rhodium(I)-chiral diene esters with high stereoselectivities (90–99% ee’s) and in
catalyst is reported. The transformation proceeds 50–>99% yields. The method provides an expeditious and
regioselectively in the presence of as low as 0.5 mol% of the enantioselective synthesis of (S)-flutriafol.
catalyst generated in situ from a Rhodium(I) salt and diene
L1, which is a bicyclo[2.2.1] ligand scaffold bearing 2,5-
Keywords: asymmetric catalysis; arylation; -ketoesters;
tertiary -hydroxy esters; rhodium
Introduction
The chiral tertiary -hydroxy ester moiety exists in a
significant number of natural products and
compounds of bio-logical interest. For example,
deoxyharringtonine is a potent anti-leukemia agent
isolated form Cephalotaxus;[1a] camptothecin, isolated
from Camptotheca acuminata, is a DNA
topoisomerase 1 (topo 1) inhibitor showing cytotoxi-
city;[1b] and a family of compounds containing a
chiral diarylhydroxyl ester moiety have been
identified as potential pharmaceutically active
ingredients as 2-adrenergic receptor agonists and
muscarinic receptor antagonists (Figure 1).[1c] In
addition, optically active tertiary -hydroxy esters are
frequently used as chiral building blocks in
asymmetric syntheses.[2a] As a consequence of the
prevalence of this moiety, there are clear benefits to
expanding the toolkit available to medicinal and
industrial chemists that allow for the access to tertiary
-hydroxy esters with high optical purities.[2–6] While
asymmetric hydroxylation of prochiral enolates
Figure 1. Examples of natural products and biologically
active com-pounds comprising a chiral tertiary -hydroxy
ester moiety.
diorganozincs impedes practical application on
manufacturing scales.[2f,4] Conversely, the Rh(I)-
catalyzed 1,2-arylation of -ketoesters, embodied by
the use of chiral spirophosphite ligands,[5a] chiral
allene-phosphine[5b] and olefin-sulfoxide[5c,d] hybrid
ligands, provides chiral tertiary -hydroxy esters with
high stereoselectivities.[5,6] This approach employs
arylboronic acids as aryl donors that are shelf-stable,
commercially available or readily synthesized, non-
pyrophoric and of low toxicity,[8a] and proceeds in the
proceeds in a highly stereoselective manner,[2b]
a
greater focus has been on the development of
transition metal-catalyzed enantioselective addition
methods. For instance, the Ti-,[4a,c] Al-[4e] and Zn-
catalyzed[4b, d, f-i] enantioselective addition of
diorganozinc reagents to -ketoesters[7] provides
straightforward access to chiral tertiary -hydroxy
esters. Unfortunately, the pyrophoric nature of
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800575
Advanced Synthesis & Catalysis
Results and Discussion
presence of Rh(I)-catalysts under mild reaction
conditions. While Xu et al.[5c] has already
demonstrated that a chiral diene ligand can be used in
this reaction giving a good yield of an α-hydroxy-α-
aryl ester, the ee was less than 10%. Similarly,
Johnson et al.[5e] has employed diene ligands, albeit in
the arylation of β-stereogenic α-ketoesters.
Exploration began with the asymmetric addition
reaction of 2.0 equiv of 4-tolylboronic acid (2a) with
methyl 2-oxo-2-phenylacetate (1a) (Table 1) in
toluene under reaction conditions previously
optimized for the asymmetric arylation of
nitroolefins.[10d] The active catalyst was generated in
situ from [RhCl(C2H4)2]2 and ligand L1, and KHF2
was used as the additive. This provided α-
hydroxyester 3aa in 36% yield with an 88% ee (entry
1). While the substitution of K2CO3 for KHF2
provided a slightly improved yield of 3aa (51%
yield), a significant amount of hydrolysis of 1a (35%)
occurred (entry 2). Increasing the steric bulk of the
aryl acceptor, by using t-butyl ester 1b in place of
methyl ester 1a, at 60 or 40 °C resulted in enhanced
asymmetric induction, while also mitigating ester
hydrolysis, giving 3ba in 40% yield with 94% ee or
45% yield with 95% ee (entries 3 and 4), respectively.
While the use of the basic additives KOH, CsOH or
NEt3 (entries 5–7) failed to induce both high ees and
reaction yields, the reaction carried out in the
presence of DABCO afforded 3ba in a pleasing 75%
yield with 97% ee (entry 8). Inferior results were
obtained when Et2O or DCM were tested as solvents
(entries 9 and 10).
More recently, chiral dienes have received
significant attention during the development of
asymmetric catalysis, particularly as ligands in Rh(I)-
catalyzed C−C bond formation.[8,9] In fact, recent
research in our laboratories has shown chiral 2,5-
disubstituted bicyclo[2.2.1]heptadienes L to be
effective ligands in a variety of Rh(I)-catalyzed
asymmetric reactions that are useful for the
preparation of synthetic precursors to natural
products and compounds of biological interest.[10,11]
Together with Rh(I) salts, the chiral diene ligands
form highly reactive Rh(I)-catalysts for asymmetric
1,4-addition reactions to a range of acceptors (TON
up to 2000)[10a] including 1,2-additions to aldimines
for the preparation of chiral amines.[11] Given the
importance of chiral tertiary -hydroxy esters as
synthetic building blocks and their prevalence in
natural products, we herein report the Rh(I)/chiral
diene-catalyzed enantioselective ary-lation of -
ketoesters with arylboronic acids using 0.5 mol% of a
Rh(I)-catalyst generated in situ from chiral diene L1
affording optically active tertiary -hydroxy esters
with up to >99.5% ee.
Table 1. Enantioselective addition of 4-tolyboronic acid (2a) to ketoesters: optimization of reaction conditions.[a]
Entry
1[e]
Additive
KHF2
K2CO3
K2CO3
K2CO3
KOH
CsOH
Et3N
DABCO
DABCO
DABCO
t (h)
3
3
2
3
2
3
2
3
Yield (%1)[b]
Yield (%3)[c]
36 (3aa)
51 (3aa)
40 (3ba)
45 (3ba)
46 (3ba)
81 (3ba)
27 (3ba)
75 (3ba)
35 (3ba)
18 (3ba)
ee (%)[d]
88
1
59
13f
58
49
52
16
67
20
10
10
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
2[e]
87
94
95
96
89
96
97
97
3[e]
4[g]
5[g]
6[g]
7[g]
8[g]
9[g,h]
10[g,i]
3
3
92
[a] Solution of 1 (0.2 mmol), 2a (0.4 mmol), [RhCl(C2H4)2]2 (1.5 mol%; 3.0 mol% of Rh), L1 (3.3 mol%) and additive (50
mol% based on 1a; 1.0 M in water) were stirred in toluene; reactions were worked up when TLC analysis indicated the
consumption of 2a. [b] Recovery based on the crude 1H NMR analysis using durene as an internal standard. [c] Isolated yield.
[d]
[e]
[f]
[g]
Determined by chiral HPLC analysis.
Conducted at 60 °C.
1a-hydrolyzed product was witnessed in 35%.
Conducted at 40 °C. [h] Conducted in Et2O. [i] Conducted in CH2Cl2.
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800575
Advanced Synthesis & Catalysis
Table 2. Enantioselective addition of 4-tolyboronic acid (2a) to ketoester 1b: Effects of ligands and catalyst loadings.[a]
entry
1
2
3
4
x
t (h)
23
48
20
24
3.5
3.5
3.5
3.5
5
yield (%)[b]
ee (%)[c]
64
L
2a
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.5
0.25
0.05
2.0
2.0
2.0
2.0
2.0
1.5
1.0
1.5
1.5
1.5
81
15
72
70
79
75
56
71
73
17
L2
L3
L4
L5
L6
L1
L1
L1
L1
L1
50
71
29
33
97
97
97
97
5
6
7
8[d]
9[e]
10[f]
30
98
[a] Solution of 1b (0.2 mmol), 2a (0.4 mmol), [RhCl(C2H4)2]2 (1.5 mol%; 3.0 mol% of Rh), L1 (3.3 mol%) and aq DABCO
[b]
(50 mol% based on 1a; 1.0 M) were stirred in toluene at 40 °C until TLC analysis indicated the consumption of 2a.
Isolated yield. [c] Determined by chiral HPLC analysis. [d] Conducted with 0.6 mmol of 1b. [e] Conducted with 1.2 mmol of
1b. [f] Conducted with 6.0 mmol of 1b.
Subsequent screening of an additional five bicy-
clo[2.2.1]heptadienes adorned with various aryl
substituents using the conditions specified in Table 1,
entry 8 failed to reveal ligands that could provide
better stereoselectivity (Table 2, entries 1–5) than the
1-naphthyl substituted ligand L1. While no erosion in
chemical yield or enantio-induction was observed
when the amount of 2a was reduced from 2.0 to 1.5
equiv (entry 6), the use of 1.0 equiv of 2a resulted in
a diminished chemical yield (entry 7). Next, the
catalyst loading was examined. Reducing the amount
of active catalyst from 3.0 mol% (entry 6) to 1.0
mol%, generated in situ from 0.5 mol% of
[RhCl(C2H4)2]2 and 1.1 mol% of diene ligand L1,
provided comparable degrees of catalytic activity and
enantioselectivity (entry 8). Notably, the reaction still
performed efficiently in the presence of 0.5 mol% of
the Rh(I)-L1 catalyst offering 3ba in 73% yield
without loss of ee (entry 9). In fact, high selectivity
was maintained even in the presence of 0.1 mol% of
the catalyst, although the conversion efficiency was
poor (17% after 30 h) (entry 10). The use of low
amounts of the metal catalyst in this transformation
would be particularly attractive to applications in the
pharmaceutical industry where regulations require
very low levels of residual Rh in active
pharmaceutical ingredients.[12]
were produced with high enantioselectivities (93–
98% ee) and in moderate to good chemical yields
(52–86%). While reaction with sterically encumbered
2-tolylboronic acid (2c) was low yielding (17% after
3 h) under the standard conditions, the addition of
extra catalyst, DABCO and 2c allowed for the
isolation of 52% of 3bc.[13] The absolute con-
figuration of 3bc was determined to be R by X-ray
single-crystal analysis.[14] Although arylboronic acids
with electron-withdrawing groups produced products
3bi–3bn with high ees, their comparably lower
reactivity resulted in inferior yields. As found for
sterically hindered substrate 2c, however, the addition
of extra reagents (see footnote b and c of Table 3)
allowed better yields to be obtained. The addition of
4-tolylboronic acid (2a) to i-propyl or ethyl ester sub-
strates 1c or 1d proceeded as efficiently as when
using t-butyl ester 1b. These reactions generated 3ca
or 3da in 73% yield with 94% ee or 77% yield with
92% ee, respectively, however, small decreases in
enantioselectivity were observed. Further exploration
of the substrate scope was conducted using ketoesters
bearing different aryl groups and phenylboronic acid
(2o) or 4-fluoro-phenylboronic acid (2i). The
corresponding α-hydroxyester products (ent-3ba, ent-
3bb, ent-3bj and 3ho–3ki) were obtained in moderate
to excellent yields (50–>99%) with good to excellent
selectivities (91–98% ee). Notably, higher
conversions were seen with electron-deficient esters
than for electron-rich esters. With the reaction
tolerating electron-rich and electron-deficient
reaction partners, either enantiomer of a given α-
hydroxyester product can be obtained by reversal of
As summarized in Table 3, the substrate scope was
explored using a variety of aryl acceptors 1 and
arylboronic acids 2 in the presence of 0.5 mol% of
the Rh(I)/L1 catalyst. When arylboronic acids
harboring alkyl, phenyl and alkoxy substituents (2a–
2h) were used, the corresponding products (3ba–3bh)
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800575
Advanced Synthesis & Catalysis
Table 3. Reaction Scope[a]
[a]
[b]
See text and Supporting Information for experimental details.
Obtained by adding three extra portions of
[c]
[RhCl(C2H4)2]2 (0.25 mol%), L1 (0.55 mol%), boronic acid (1.5 equiv) and DABCO (0.5 equiv).
The data in the
parenthesis was obtained by adding extra [RhCl(C2H4)2]2 (0.25 mol%), L1 (0.55 mol%), boronic acid (1.5 equiv) and
[d]
[e]
DABCO (0.5 equiv) after 16 hours. Determined by analyzing the corresponding diol. 1.5 equiv of boronic acid was
added after 10 hours.
Scheme 1. Synthesis of (S)-Flutriafol.
substrates while using the same homochiral Rh(I)-
diene catalyst. For example, both enantiomers of 3ba,
3bb and 3bj can be synthesized, respectively.
Furthermore, ester hydrolysis of compounds 3bi and
3io, compounds 3bm and 3jo yield either enantio-
enriched (R)- or (S)-hydroxy acids.
The stereochemistry of the product 3ba was
illustrated, shown in Figure 2, by carrying out the
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800575
Advanced Synthesis & Catalysis
DFT calculations of transition structures with the
coordination complex of substrate 1b and the Rh-L1-
tolyl species employing Gaussian 16 program[15]
using B3LYP functional[16,17] in conjunction with 6-
31G (d,p)[18] for the main group elements and
LAN2LDZ basis set[19] for the Rh atom. The steric
repulsion between the tert-butyl ester and benzene
ring of 1b and 2,5-dinaphthyl substituents of the
ligand backbone enables the addition reaction
proceeding favourably from the Re-face (complex A),
which is 2.77 kcal lower in energy than the
corresponding Si-faced-coordinated complex B,
giving rise to (R)-3ba.
66% ee (eq 1). While the asymmetric reaction of vari-
ous t-butyl arylketoesters proceeded with high
stereocontrol (Table 3, ent-3ba, ent-3bb, ent-3bj and
3ho), the corresponding addition to t-butyl pyruvate
(6b) was less stereoselective, resulting in the desired
α-hydroxyester 7bo being produced in 78% yield
with a modest 75% ee (eq 2). While less satisfying
than when using α-arylketoesters 1, we suspect that
the employment of other ligands and optimization of
the reaction conditions might yield higher ste-
reoselectivities.
Conclusion
In conclusion, tertiary chiral -hydroxy esters with
good to high enantioselectivities (91–>99.5% ee’s)
were obtained by the addition of arylboronic acids to
-ketoesters in the presence of as little as 0.5 mol%
of a Rh(I)-catalyst derived from [RhCl(C2H4)2]2 and
chiral diene ligand L1. A variety of arylboronic acids
and -ketoesters were applicable, supplying the
corresponding products with high yields (50–>99%)
in an industrially acceptable solvent, toluene, at 40 °C
in the presence of DABCO. The synthetic usefulness
of this asymmetric transformation was demonstrated
by supplying the chiral α-hydroxyester starting
material 3ki for the three-step-synthesis of (S)-
flutriafol. Further studies on other ostensibly more
challenging 1,2-dicarbonyl substrates are presently
under way in our laboratory.
tBuO2C
Ph
HO
A (0.0 kcal mol−1)
B (+2.77 kcal mol−1)
Figure 2. DFT-optimized transition structures for the
asymmetric addition reaction to 1b.
The utility of the method described above was
demonstrated by the synthesis of (S)-flutriafol from
3ki (Scheme 1). Flutriafol is a demethylation
inhibitor with excellent anti-fungal activity.[20] (S)-
Flutriafol was found to have better antimicrobial
activity than its (R)-configured counterpart toward
Alternaria solani and Alternaria mali.[21] Thus,
treatment of 3ki with LAH gave a 96% yield of diol 4
which, upon activation with TsCl, underwent
intramolecular ring-closure to give epoxide 5 in 73%
yield.[22] Reaction of epoxide 5 with 1H-1,2,4-triazole
in the presence of t-BuOK furnished the desired
product,[22] (S)-flutriafol, in a 64% overall yield
without loss of the high optical purity of the α-
hydroxyester 3ki.
Experimental Section
General Experimental.
All commercial chemicals and solvents were reagent grade
and were distilled before use. All reactions were carried
out under an atmosphere of argon or nitrogen gas.
Reactions were monitored by TLC using Merck 60 F 254
silica gel plates; zones were detected visually under
ultraviolet irradiation (254 nm) or by spraying with
KMnO4 solution followed by heating with a heat gun or on
a hot plate. Column chromatography was conducted over
silica gel. NMR spectra were recorded at room temperature
in deuterated solvents on Bruker spectrometers. Chemical
shifts δ were recorded in parts per million (ppm) and were
reported relative to the deuterated solvent signal for 13C
Scheme 2. Asymmetric addition to other 1,2-carbonyls.
1
1
NMR spectroscopy, the residual H-solvent signal for H
NMR spectroscopy. First order spin multiplicities are
abbreviated as s (singlet), d (doublet), t (triplet), q
(quartet), dd (doublet of doublets), sep (septet), and
multiplets are abbreviated as (m). High-resolution mass
spectra were obtained using EI and ESI ionization
methods. Optical rotations were measured on a Jasco P-
2000 polarimeter. Enantiomeric excess was determined by
HPLC analysis on a Chiralcel OD-H, OJ-H, Chiralpak AD-
H, AS-H, IA, IB columns (Daicel Chemical Industries,
Ltd). Substrates 1 were prepared according to the
literatures.[23]
Finally, the catalytic asymmetric addition reaction
described herein was extended to other 1,2-
dicarbonyl
substrates
(Scheme
2).
The
enantioselective addition of 4-tolylboronic acid (2a)
to 1,2-diphenylethane-1,2-dione (6a) in the presence
of 3 mol% of the Rh(I)/L1 catalyst afforded the
corresponding α-hydroxyketone 7aa in 25% yield and
General Procedure for Rhodium-Catalyzed 1,2-
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800575
Advanced Synthesis & Catalysis
13C NMR (100 MHz, CDCl3): δ 173.8, 141.9, 140.4, 138.2,
132.1, 128.3, 128.0, 127.9, 127.6, 127.0, 125.0, 83.9, 81.8,
27.7, 20.8. FT-IR (KBr neat): 3483, 2975, 1718, 1599,
1454, 1370, 1263, 1153, 1057, 753 cm−1. HRMS (ESI-
TOF): calcd for [C19H22O3Na]+ 321.1467, found 321.1466
[M+Na]+.
Addition.
Method A. To a stirred mixture of [RhCl(C2H4)2]2 (1.2 mg,
3.0 μmol, 0.5 mol% of Rh), chiral ligand L1 (2.6 mg, 6.6
μmol, 0.55 mol%) in toluene (1.0 mL) were added -
ketoester 1b (1.2 mmol, 1.0 equiv), 4-tolylboronic acid 2a
(1.8 mmol, 1.5 equiv), toluene (5.0 mL) and DABCO (1.0
M, 0.6 mL, 0.6 mmol, 50 mol%). The reaction vial was
heated to 40 °C, and the product mixture was concentrated
in vacuo when TLC indicated the consumption of 2a. The
residue was purified by column chromatography over silica
gel (hexanes / ethyl acetate, 50 / 1) to afford the desired
products 3ba as a colorless oil.
Method C. To a stirred mixture of [RhCl(C2H4)2]2 (1.2 mg,
3.0 μmol, 0.5 mol% of Rh), chiral ligand L1 (2.6 mg, 6.6
μmol, 0.55 mol%) in toluene (1.0 mL) were added -
ketoester
1b
(1.2
mmol,
1.0
equiv),
3-
methoxyphenylboronic acid 2h (1.8 mmol, 1.5 equiv),
toluene (5.0 mL) and DABCO (1.0 M, 0.6 mL, 0.6 mmol,
50 mol%). The reaction vial was heated to 40 °C, and
additional [RhCl(C2H4)2]2 (1.2 mg, 3.0 μmol, 0.5 mol% of
Rh), chiral ligand L1 (2.6 mg, 6.6 μmol, 0.55 mol%), 3-
methoxyphenylboronic acid 2h (1.8 mmol, 1.5 equiv), and
DABCO (1.0 M, 0.6 mL, 0.6 mmol, 50 mol%) were added
when TLC indicated the consumption of 2h. The product
mixture was then concentrated in vacuo and the residue
was purified by column chromatography over silica gel
(hexanes / ethyl acetate, 50 / 1) to afford the desired
products 3bh as a colorless solid.
(R)-tert-butyl 2-hydroxy-2-phenyl-2-(p-tolyl)acetate
(3ba)
5 h; isolated as a colorless oil: 260.9 mg, 73% yield. Rf
value = 0.7 (hexanes / ethyl acetate = 5 / 1). The ee was
determined on a Chiralpak AS-H column with hexanes : 2-
propanol = 95 : 5, flow = 1.0 mL/min, wavelength = 230
nm. Retention times: 5.52 min [(S)-enantiomer], 6.00 min
[(R)-enantiomer]; 97% ee. [α]2D5 = +2.3 (c 1.00, CHCl3). 1H
NMR (400 MHz, CDCl3): δ 7.44 (dd, J = 8.0, 1.6 Hz, 2H),
7.36–7.27 (m, 5H), 7.13 (d, J = 8.0 Hz, 2H), 4.30 (s, 1H),
2.35 (s, 3H), 1.45 (s, 9H). 13C NMR (100 MHz, CDCl3): δ
173.5, 142.6, 139.6, 137.4, 128.6, 127.9, 127.6, 127.4,
127.3, 83.8, 80.7, 27.8, 21.1. FT-IR (KBr neat): 3485,
2977, 2928, 1719, 1448, 1371, 1266, 1221, 1152, 1064
cm−1. HRMS (ESI-TOF): calcd for [C19H22O3Na]+
321.1467, found 321.1464 [M+Na]+.
(R)-tert-butyl
2-hydroxy-2-(3-methoxyphenyl)-2-
phenylacetate (3bh)
39 h; 243.2 mg, 64% yield. Additional catalyst and
reagents were added 16 h after the reaction started. Rf
value = 0.5 (hexanes / ethyl acetate = 5 / 1). The ee was
determined on a Chiralcel OD-H column with hexanes : 2-
propanol = 99 : 1, flow = 1.0 mL/min, wavelength = 230
nm. Retention times: 8.93 min [(S)-enantiomer], 9.71 min
[(R)-enantiomer]; 95% ee. [α]2D5 = +1.5 (c 1.00, CHCl3). 1H
NMR (400 MHz, CDCl3): δ 7.43 (dd, J = 8.0, 1.6 Hz, 2H),
7.35–7.27 (m, 3H), 7.27–7.20 (m, 1H), 7.03 (dd, J = 8.0,
1.6 Hz, 2H), 6.87–6.82 (m, 1H), 4.36 (s, 1H), 3.76 (s, 3H),
1.46 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 173.3, 159.3,
143.9, 142.3, 128.8, 127.9, 127.7, 127.4, 119.9, 113.3,
113.1, 84.0, 80.7, 55.2, 27.8. FT-IR (KBr neat): 3479,
2976, 2934, 2840, 1720, 1596, 1456, 1371, 1255 cm−1.
HRMS (ESI-TOF): calcd for [C19H22O4Na]+ 337.1416,
found 337.1417 [M+Na]+.
Method B. To a stirred mixture of [RhCl(C2H4)2]2 (1.2 mg,
3.0 μmol, 0.5 mol% of Rh), chiral ligand L1 (2.6 mg, 6.6
μmol, 0.55 mol%) in toluene (1.0 mL) were added -
ketoester 1b (1.2 mmol, 1.0 equiv), 4-tolylboronic acid 2c
(1.8 mmol, 1.5 equiv), toluene (5.0 mL) and DABCO (1.0
M, 0.6 mL, 0.6 mmol, 50 mol%). The reaction vial was
heated to 40 °C, and additional [RhCl(C2H4)2]2 (1.2 mg,
3.0 μmol, 0.5 mol% of Rh), chiral ligand L1 (2.6 mg, 6.6
μmol, 0.55 mol%), 4-tolylboronic acid 2c (1.8 mmol, 1.5
equiv), and DABCO (1.0 M, 0.6 mL, 0.6 mmol, 50 mol%)
were added when TLC indicated the consumption of 2c.
After repeating this sequence for three times (2.0 mol% of
Rh, 6.0 equiv. of 2c, and 2.0 equiv. of DABCO in total),
the product mixture was concentrated in vacuo and the
residue was purified by column chromatography over silica
gel (hexanes / ethyl acetate, 50 / 1) to afford the desired
products 3bc as a colorless solid.
Synthesis of 4[22]
To a suspension of LiAlH4 (259 mg, 6.82 mmol) in 3 mL
of dry THF was added a solution of 3ki (200 mg, 0.68
mmol) in 9 mL of dry THF at 0 °C. After being stirred at
refluxing temperature for 5 h, the reaction was cooled to
0 °C, quenched with 2 mL of water, 2 mL of 10% aq.
NaOH and 10 mL of water successively. After 5 minutes,
the mixture was stirred with additional 10 mL of ethyl
acetate. After being stirred for 30 minutes, the aqueous
layer was separated and was washed with ethyl acetate (30
mL x 2). The combined organic phase was dried over
anhydrous Na2SO4, filtered and the solvent were
concentrated in vacuo to give the crude product as a white
oil. The crude product was purified by column
chromatography on silica gel (hexanes / ethyl acetate = 5 /
1) to give compound 4 as a white solid.
(R)-tert-butyl
(3bc)
2-hydroxy-2-phenyl-2-(o-tolyl)acetate
24 h; 185.0 mg, 52% yield. Additional catalyst and
reagents were added 4 h, 16 h, 20 h, after the reaction
started. m.p. = 95.3–95.6 °C. Rf value = 0.7 (hexanes /
ethyl acetate, 5 / 1). The ee was determined on a Chiralpak
AS-H column with hexanes : 2-propanol = 98 : 2, flow =
1.0 mL/min, wavelength = 220 nm. Retention times: 11.04
min [(S)-enantiomer], 11.63 min [(R)-enantiomer]; 96% ee.
[α] 2D5 = +45.3 (c 1.00, CHCl3). H NMR (400 MHz,
1
CDCl3): δ 7.54 (d, J = 7.2 Hz, 2H), 7.38–7.28 (m, 3H),
7.23–7.13 (m, 2H), 7.06 (dd, J = 8.0, 8.0 Hz, 1H), 6.96 (d,
J = 8.0 Hz, 1H), 4.19 (s, 1H), 2.22 (s, 3H), 1.44 (s, 9H).
(S)-1-(2-fluorophenyl)-1-(4-fluorophenyl)ethane-1,2-
diol (4)
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800575
Advanced Synthesis & Catalysis
Isolated as a white solid: 164 mg, 96% yield; purified on
silica gel using hexanes / ethyl acetate, 5 / 1. m.p. = 92.9–
extracted with ethyl acetate (25 mL). The combined
organic layer was washed with brine (100 mL x 5), dried
over anhydrous Na2SO4, filtered and concentrated in vacuo.
The resulting crude residue was purified by column
chromatography on silica gel (hexanes / ethyl acetate = 1 /
1) to give (S)-Flutriafol as a colorless oil.
93.4 °C. Rf value = 0.2 (hexanes / ethyl acetate = 3 / 1). [α]
19
D
= –26.8 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ
7.72–7.71 (td, J = 8.0, 1.6 Hz, 1H), 7.36 (d, J = 8.4 Hz,
1H) 7.35 (d, J = 8.8 Hz, 1H), 7.34–7.27 (m, 1H), 7.21 (dd,
J = 7.6, 7.6 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.99 (d, J =
8.8 Hz, 1H), 7.04–6.96 (m, 1H), 4.27 (dd, J = 11.6, 7.2 Hz,
1H), 4.12 (dd, J = 11.6, 6.4 Hz, 1H), 3.41 (d, J = 4.8 Hz,
1H), 2.09 (dd, J = 6.4, 6.4 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 162.1 (d, J = 245.0 Hz), 160.1 (d, J = 244.0 Hz),
139.1, 130.5 (d, J = 11.0 Hz), 129.8 (d, J = 9.0 Hz), 128.8
(d, J = 4.0 Hz), 127.8 (d, J = 8.0 Hz), 124.3 (d, J = 3.0 Hz),
116.3 (d, J = 23.0 Hz), 115.1 (d, J = 21.0 Hz), 68.5 (d, J =
4.0 Hz). FT-IR (KBr neat): 3397, 3073, 2932, 1605, 1501,
1456, 1225, 1128, 1077 cm−1. HRMS (EI): calcd for
[C14H12O2F2]+ 250.0805, found 250.0805 [M]+.
(S)-Flutriafol
Isolated as a colorless oil: 104 mg, 91% yield; purified on
silica gel using hexanes / ethyl acetate, 1 / 1. Rf value = 0.3
(hexanes / ethyl acetate = 1 / 1). The ee was determined on
a Chiralpak AS-H column with hexanes : 2-propanol = 90 :
10, flow = 1.0 mL/min, wavelength = 220 nm. Retention
times: 16.11 min [(S)-enantiomer], 19.09 min [(R)-
enantiomer]; 98% ee. [α]2D9 = +20.0 (c 0.2, CHCl3). H
1
NMR (400 MHz, CDCl3): δ 7.96 (s, 1H), 7.73 (s, 1H), 7.63
(td, J = 8.0, 1.2 Hz, 1H), 7.43 (dd, J = 8.6, 5.6 Hz, 2H),
7.26–7.20 (m, 1H), 7.09 (dd, J = 7.6, 7.6 Hz, 1H), 7.05–
6.93 (m, 3H), 5.48 (s, 1H), 5.21 (d, J = 14.0 Hz, 1H), 4.79
(d, J = 14.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 162.3
(d, J = 246.0 Hz), 158.6 (d, J = 242.0 Hz), 151.6, 144.2,
138.0 (d, J = 3.0 Hz), 130.1 (d, J = 9.0 Hz), 129.5 (d, J =
12.0 Hz), 128.8 (d, J = 4.0 Hz), 127.8 (d, J = 8.0 Hz),
124.8 (d, J = 2.0 Hz), 115.9 (d, J = 24.0 Hz), 115.3 (d, J =
22.0 Hz), 76.8 (d, J = 3.0 Hz), 57.4 (d, J = 8.0 Hz). FT-IR
(KBr neat): 3204, 3140, 2929, 1605, 1507, 1452, 1275,
1224, 1132 cm−1. HRMS (ESI-TOF): calcd for
[C16H14N3OF2N]+ 302.1105, found 302.1108 [M+H]+.
Synthesis of 5[22]
To a solution of compound 4 (129 mg, 0.51 mmol) in
CH2Cl2 (5 mL) was added triethylamine (0.18 mL, 1.29
mmol) followed by 4-dimethylaminopyridine (10 mg, 0.08
mmol). The solution was cooled to 0 °C and p-
toluenesulfonyl chloride (115 mg, 0.60 mmol in 5 mL
CH2Cl2) was added, and the mixture was allowed to warm
to room temperature. After being stirred for 12 h, the
reaction mixture was diluted with CH2Cl2 (10 mL). The
organic layer was washed with water (20 mL), dried over
anhydrous Na2SO4, filtered and then concentrated. The
resulting crude residue was purified by column
chromatography on silica gel (hexanes / ethyl acetate = 10
/ 1) to give the compound 5 as a colorless oil.
Synthesis of 7aa
To a stirred mixture of [RhCl(C2H4)2]2 (1.2 mg, 3.0 μmol,
3.0 mol% of Rh), chiral ligand L1 (2.6 mg, 6.6 μmol, 3.6
mol%) in toluene (1.0 mL) were added -diketone 6a (0.2
mmol, 1.0 equiv), 4-tolylboronic acid 2a (0.4 mmol, 2.0
equiv) and DABCO (1.0 M, 0.1 mL, 0.1 mmol, 50 mol%).
The reaction vial was heated to 60 °C, and the product
mixture was concentrated in vacuo when TLC indicated
the consumption of 2a. The residue was purified by
column chromatography over silica gel (hexanes / ethyl
acetate, 20 / 1) to afford the desired products 7aa as a
colorless oil.
(S)-2-(2-fluorophenyl)-2-(4-fluorophenyl)oxirane (5)
Isolated as a colorless oil: 87 mg, 73% yield; purified on
silica gel using hexanes / ethyl acetate, 10 / 1. Rf value =
0.7 (hexanes / ethyl acetate = 5 / 1). [α]1D9 = –30.1 (c 1.00,
CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.48 (dd, J = 7.6,
7.2 Hz, 1H), 7.38–7.30 (m, 1H), 7.29–7.21 (m, 2H), 7.17
(dd, J = 7.6, 7.2 Hz, 1H), 7.08 (dd, J = 9.2, 8.8 Hz, 1H),
6.98 (dd, J = 8.8, 8.4 Hz, 2H), 3.30 (d, J = 5.4 Hz, 1H),
3.19 (d, J = 5.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
162.4 (d, J = 246.0 Hz), 160.3 (d, J = 247.0 Hz), 135.2 (d,
J = 3.0 Hz), 130.2 (d, J = 8.0 Hz), 129.8 (d, J = 3.0 Hz),
127.8 (d, J = 8.0 Hz), 126.6 (d, J = 14.0 Hz), 124.3 (d, J =
3.0 Hz), 115.6 (d, J = 21.0 Hz), 115.2 (d, J = 21.0 Hz),
57.7, 56.5. FT-IR (KBr neat): 2924, 2859, 1609, 1504,
1460, 1307, 1226, 1153, 1128, 1104 cm−1. HRMS (ESI-
TOF): calcd for [C14H11OF2]+ 233.0778, found 233.0779
[M+H]+.
(R)-2-hydroxy-1,2-diphenyl-2-(p-tolyl)ethanone (7aa)
24 h; isolated as a yellow oil: 15.1 mg, 25% yield. Rf value
= 0.3 (hexanes / ethyl acetate = 20/ 1). The ee was
determined on a Chiralpak OJ-H column with hexanes：2-
propanol = 96:4, flow = 1mL/min, wavelength = 220 nm.
Retention times: 35.73 min [(S)-enantiomer], 37.76 min
[(R)-enantiomer]; 66% ee. [α]2D5 = −15.9 (c 0.8, CHCl3). 1H
NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.0 Hz, 2H), 7.49–
7.41 (m, 3H), 7.39–7.25 (m, 7H), 7.17 (d, J = 8.0 Hz, 2H),
4.98 (s, 1H), 2.36 (s, 3H).13C NMR (100 MHz, CDCl3): δ
200.9, 142.0, 138.9, 137.9, 135.1, 132.8, 130.8, 129.0,
128.3, 128.24, 128.16, 128.0, 84.9, 21.0. FTIR (KBr neat):
3448, 3060, 2924, 2861, 1675, 1588, 1502, 1448, 1236,
1054 cm−1. HRMS (ESI): calcd for [C21H17O2]+ 301.1229,
found 301.1234 [M−H]+.
Synthesis of (S)-Flutriafol[22]
To a solution of 1H-1,2,4-triazole (29 mg, 0.42 mmol) in
DMF (10 mL) was added potassium tert-butoxide (46 mg,
0.41 mmol). The reaction mixture was heated to 70 °C for
15 min, and then cooled to room temperature. After adding
a solution of compound 5 (87 mg, 0.37 mmol in 5 mL
DMF), the reaction mixture was heated to 100 °C. After
being stirred for 12 h, the reaction mixture was cooled to
room temperature, and diluted with ethyl acetate (50 mL)
and water (50 mL). The aqueous layer was separated and
Synthesis of 7bo
To a stirred mixture of [RhCl(C2H4)2]2 (1.2 mg, 3.0 μmol,
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800575
Advanced Synthesis & Catalysis
3.0 mol% of Rh), chiral ligand L1 (2.6 mg, 6.6 μmol, 3.6
mol%) in toluene (1.0 mL) were added -ketoester 6b (0.2
mmol, 1.0 equiv), phenylboronic acid 2o (0.4 mmol, 2.0
equiv) and DABCO (1.0 M, 0.1 mL, 0.1 mmol, 50 mol%).
The reaction vial was heated to 60 °C, and the product
mixture was concentrated in vacuo when TLC indicated
the consumption of 2o. The residue was purified by
column chromatography over silica gel (hexanes / ethyl
acetate, 20 / 1) to afford the desired products 7aa as a
colorless oil.
Mashima, Angew. Chem. Int. Ed. 2011, 50, 6296–6300;
c) K. Aikawa, A. Kondo, K. Honda, K. Mikami, Chem.
Eur. J. 2015, 21, 17565–17569; d) D. W. Robbins, K.
A. Lee, D. L. Silverio, A. Volkov, S. Torker, A. H.
Hoveyda, Angew. Chem. Int. Ed. 2016, 55, 9610–9614.
[4] For representative examples of asymmetric addition of
diorganozincs to -ketoesters, see: a) E. F. DiMauro,
M. C. Kozlowski, J. Am. Chem. Soc. 2002, 124,
12668–12669; b) B. Jiang, Z. Chen, X. Tang, Org. Lett.
2002, 4, 3451–3453; c) E. F. DiMauro, M. C.
Kozlowski, Org. Lett. 2002, 4, 3781–3784; d) K.
Funabashi, M. Jachmann, M. Kanai, M. Shibasaki,
Angew. Chem. Int. Ed. 2003, 42, 5489–5492; e) L. C.
Wieland, H. Deng, M. L. Snapper, A. H. Hoveyda, J.
Am. Chem. Soc. 2005, 127, 15453–15456; f) G. Blay, I.
Fernández, A. Marco-Aleixandre, J. R. Pedro, Org. Lett.
2006, 8, 1287–1290; g) H.-L. Wu, P.-Y. Wu, Y.-Y.
Shen, B.-J. Uang, J. Org. Chem. 2008, 73, 6445–6447;
h) B. Zheng, S. Hou, Z. Li, H. Guo, J. Zhong, M. Wang,
Tetrahedron: Asymmetry 2009, 20, 2125–2129; i) R.
Infante, J. Nieto, C. Andrés, Chem. Eur. J. 2012, 18,
4375–4379.
Tert-butyl (R)-2-hydroxy-2-phenylpropanoate (7bo)
2 h; isolated as a yellow oil: 34.7 mg, 78% yield. Rf value
= 0.5 (hexanes / ethyl acetate = 10/ 1). The ee was
determined on a Chiralpak OJ-H column with hexanes：2-
propanol = 90:10, flow = 1mL/min, wavelength = 225 nm.
Retention times: 5.33 min [(S)-enantiomer], 7.66 min [(R)-
enantiomer]; 75% ee. [α]2D5 = −20.6 (c 1.0, CHCl3). H
1
NMR (400 MHz, CDCl3): δ 7.55 (d, J = 8.0 Hz, 2H), 7.37–
7.31 (m, 2H), 7.30–7.25 (m, 1H), 3.86 (s, 1H), 1.73 (s, 3H),
1.44 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 174.9, 143.3,
128.1, 127.5, 125.2, 83.0, 75.6, 27.8, 26.6. FTIR (KBr
neat): 3503, 2981, 1719, 1371, 1271, 1146, 845, 698 cm−1.
HRMS (ESI): calcd for [C13H18O3Na]+ 245.1154, found
245.1153 [M+Na]+.
[5] a) H.-F. Duan, J.-H. Xie, X.-C. Qiao, L.-X. Wang, Q.-L.
Zhou, Angew. Chem. Int. Ed. 2008, 47, 4351–4353; b)
F. Cai, X. Pu, X. Qi, V. Lynch, A. Radha, J. M. Ready,
J. Am. Chem. Soc. 2011, 133, 18066–18069; c) T.-S.
Zhu, S.-S. Jin, M.-H. Xu, Angew. Chem. Int. Ed. 2012,
51, 780–783; d) Y. Li, D.-X. Zhu, M.-H. Xu, Chem.
Commun. 2013, 49, 11659–11661; e) S. L. Bartlett, K.
M. Keiter, J. S. Johnson, J. Am. Chem. Soc. 2017, 139,
3911–3916. For Ru-catalyzed asymmetric addition of
arylboronic acids to -ketoesters, see: f) Y. Yamamoto,
T. Shirai, M. Watanabe, K. Kurihara, N. Miyaura,
Molecules 2011, 16, 5020–5034. For non-asymmetric
addition of arylboronic acids to -ketoesters, see: g) G.
R. Ganci, J. D. Chisholm, Tetrahedron Lett. 2007, 48,
8266–8269; h) S. Miyamura, T. Satoh, M. Miura, J.
Org. Chem. 2007, 72, 2255–2257.
Acknowledgements
We thank Dr. Julian P. Henschke for his input during the prep-
aration of this manuscript. Financial support from the Minis-try
of Science and Technology of Republic of China (102-2113-M-
003-006-MY2 and 104-2628-M-003-001-MY3) is greatly
acknowledged.
References
[1] a) H. Morita, M. Arisaka, N. Yoshida, J. Kobayashi,
Tetrahedron 2000, 56, 2929–2934; b) C.-J. Tang, M.
Babjak, R. J. Anderson, A. E. Greene, A. Kanazawa,
Org. Biomol. Chem. 2004, 4, 3757–3759; c) F. Rancati,
A. Rizzi, L. Carzaniga, I. Linney, C. Knight, Schmidt,
W. WO 2018/011090 A1.
[6] Selected examples on the addition to activated ketones
other than -ketoesters: for isatin substrates, see: a) R.
Shintani, M. Inoue, T. Hayashi, Angew. Chem. Int. Ed.
2006, 45, 3353–3356; b) P. Y. Toullec, R. B. C. Jagt, J.
G. de Vries, B. L. Feringa, A. Minnaard, J. Org. Lett.
2006, 8, 2715–2718; c) H. Lai, Z. Huang, Q. Wu, Y.
Qin, J. Org. Chem. 2009, 74, 283–288; d) Z. Liu, P. Gu,
M. Shi, P. McDowell, G. Li, Org. Lett. 2011, 13, 2314–
2317; e) J. Gui, G. Chen, P. Cao, J. Liao, Tetrahedron:
Asymmetry 2012, 23, 554–563. For trifluoromethyl
ketone substrates, see: f) S. L. X. Martina, R. B. C. Jagt,
J. G. de Vries, B. L. Feringa, A. Minnaard, J. Chem.
Commun. 2006, 4093–4095; g) V. R. Jumde, S.
Facchetti, A. Iuliano, Tetrahedron: Asymmetry 2010,
21, 2775–2781; h) R. Luo, K. Li, Y. Hu, W. Tang, Adv.
Synth. Catal. 2013, 355, 1297–1302. For simple ketone
substrates, see: i) Y.-X. Liao, C.-H. Xing, Q.-S. Hu,
Org. Lett. 2012, 14, 1544–1547; j) L. Huang, J. Zhu, G,
Jiao, Z. Wang, X. Yu, W.-P. Deng, W. Tang, Angew.
Chem. Int. Ed. 2016, 55, 4527–4531.
[2] a) Chiral alpha-Hydroxy Acids in Enantioselective
Synthesis. (Eds.: G. M. Coppola, H. F. Schuster),
Wiley-VCH: Weinheim, 1997; b) F. A. Davis, B.-C.
Chen, Chem. Rev. 1992, 92, 919–934; c) J. Christoffers,
A. Baro, T. Werner, Adv. Synth. Catal. 2004, 346,
143–151; d) B. Plietker, Tetrahedron: Asymmetry 2005,
16, 3453–3459; e) A. Ford, H. Miel, A. Ring, C. N.
Slattery, A. R. Maguire, M. A. McKervey, Chem. Rev.
2015, 115, 9981–10080; f) H.-L. Wu, C.-A. Chang, P.-
Y. Wu, B.-J. Uang, Tetrahedron Lett. 2017, 58, 706–
710; g) S. L. Barlett, J. S. Johnson, Acc. Chem. Res.
2017, 50, 2284–2296.
[3] For recent examples, see: a) J. Luo, H. Wang, X. Han,
L.-W. Xu, J. Kwiatkowski, K.-W. Huang, Y. Lu,
Angew. Chem. Int. Ed. 2011, 50, 1861–1864; b) T.
Ohshima, T. Kawabata, Y. Takeuchi, T. Kakinuma, T.
Iwasaki, T. Yonezawa, H. Murakami, H. Nishiyama, K.
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800575
Advanced Synthesis & Catalysis
[7] a) A. J. L. Cooper, J. Z. Ginos, A. Meister, Chem. Rev.
1983, 83, 321–358; b) B. Eftekhari-Sis, M. Zirak,
Chem. Rev. 2015, 115, 151–264.
Guideline for Elemental Impurities Q3D (Step 4, Dec.
2014).
[13] See the Supporting Information.
[8] a) D. Hall, Wiley-VCH: Weinheim, 2005; b) K. Fagnou,
M. Lautens, Chem. Rev. 2003, 103, 169–196; c) T.
Hayashi, K. Yamasaki, Chem. Rev. 2003, 103, 2829–
2844; d) T. Hayashi, Pure. Appl. Chem. 2004, 76, 465–
475; e) H. J. Edwards, J. D. Hargrave, S. D. Penrose, C.
G. Frost, Chem. Soc. Rev. 2010, 39, 2093–2105.
[14] CCDC 1835616 contains the supplementary data
crystallographic data for compound 3bc.
[15] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E.
Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani,
V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M.
Caricato, A. V. Marenich, J. Bloino, B. G. Janesko, R.
Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A.
F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F.
Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A.
Petrone, T. Henderson, D. Ranasinghe, V. G.
Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M.
Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
T. Vreven, K. Throssell, J. A. Montgomery, Jr., J. E.
Peralta, F. Ogliaro, M. J. Bearpark, J. J. Heyd, E. N.
Brothers, K. N. Kudin, V. N. Staroverov, T. A. Keith,
R. Kobayashi, J. Normand, K. Raghavachari, A. P.
Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M.
Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J.
W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J.
B. Foresman, and D. J. Fox, Gaussian, Inc.,
Wallingford CT, 2016.
[9] a) F. Glorius, Angew. Chem. Int. Ed. 2004, 43, 3364–
3366; b) J. B. Johnson, T. Rovis, Angew. Chem. Int. Ed.
2008, 47, 840–871; c) C. Defieber, H. Grützmacher, E.
M. Carreira, Angew. Chem. Int. Ed. 2008, 47, 4482–
4502; d) R. Shintani, T. Hayashi, Aldrichimica Acta
2009, 42, 31–38; e) C.-G. Feng, M.-H. Xu, G.-Q. Lin,
Synlett 2011, 1345–1356; f) P. Tian, H.-Q. Dong, G.-Q.
Lin, ACS Catal. 2012, 2, 95–119; g) X. Feng, H. Du,
Asian J. Org. Chem. 2012, 1, 204–213; h) D. Chen, M.-
H. Xu, Youji Huaxue 2017, 37, 1589−1612.
[10] For Rh(I)-catalyzed asymmetric 1,4-addition reaction,
see: a) W.-T. Wei, J.-Y. Yeh, T.-S. Kuo, H.-L. Wu,
Chem. Eur. J. 2011, 17, 11405–11409; b) C.-C. Liu, D.
Janmanchi, C.-C. Chen, H.-L. Wu, Eur. J. Org. Chem.
2012, 2503–2507; c) Y.-C. Chung, D. Janmanchi, H.-L.
Wu, Org. Lett. 2012, 14, 2766–2769; d) K.-C. Huang,
B. Gopula, T.-S. Kuo, C.-W. Chiang, P.-Y. Wu, J. P.
Henschke, H.-L. Wu, Org. Lett. 2013, 15, 5730–5733;
e) B. Gopula, Y.-F. Tsai, T.-S. Kuo, P.-Y. Wu, J. P.
Henschke, H.-L. Wu, Org. Lett. 2015, 17, 1142–1145;
f) B. Gopula, S.-H. Yang, T.-S. Kuo, J.-C. Hsieh, P.-Y.
Wu, J. P. Henschke, H.-L. Wu, Chem. Eur. J. 2015, 21,
11050–11055; g) J.-H. Fang, C.-A. Chang, B. Gopula,
T.-S. Kuo, P.-Y. Wu, J. P. Henschke, H.-L. Wu, Asian
J. Org. Chem. 2016, 5, 481–485; h) J.-H. Fang, J.-H.
Jian, H.-C. Chang, T.-S. Kuo, W.-Z. Lee, P.-Y. Wu, J.
P. Henschke, H.-L. Wu, Chem. Eur. J. 2017, 23, 1830–
1838. for a Rh(I)-catalyzed diastereoselective synthesis
of prostaglandins, see: i) J. F. Syu, Y.-T. Wang, K.-C.
Liu, P.-Y. Wu, J. P. Henschke, H.-L. Wu, J. Org. Chem.
2016, 81, 10832–10844.
[16] A. D. Becke, Phys. Rev. A 1998, 38, 3098–3100.
[17] C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1998, 37,
785–789.
[18] D. Andrae, U. Häussermann, M. Dolg, H, Stoll, H.
Preuss, Theor. Chim. Acta 1990, 77, 123–141.
[19] P. J. Hay, W. R. Wadt, J. Chem. Phys. 1985, 82, 299–
310.
[20] Y. Tao, F. Dong, J. Xu, X. Liu, Y. Cheng, N. Liu, Z.
Chen, Y. Zheng, J. Agric. Food Chem. 2014, 62,
11457–11464.
[21] F. M. Liu, D. Q. Wang, J. X. Ming, Y. Z. Zhao, Chin.
J. Pest. Sci. 2002, 4, 67–70.
[11] For Rh(I)-catalyzed asymmetric 1,2-addition to imines,
see: a) B. Gopula, C.-W. Chiang, W.-Z. Lee, T.-S. Kuo,
P.-Y. Wu, J. P. Henschke, H.-L. Wu, Org. Lett. 2014,
16, 632–635; b) C.-C. Chen, B. Gopula, J.-F. Syu, J.-H.
Pan, T.-S. Kuo, P.-Y. Wu, J. P. Henschke, H.-L. Wu, J.
Org. Chem. 2014, 79, 8077–8085; c) J.-F. Syu, H.-Y.
Lin, Y.-Y. Cheng, Y.-C. Tsai, Y.-C. Ting, T.-S. Kuo, D.
Janmanchi, P.-Y. Wu, J. P. Henschke, H.-L. Wu, Chem.
Eur. J. 2017, 23, 14515–14522.
[22] M. Chang, T. H. Kim, H.-D. Kim, Tetrahedron:
Asymmetry 2008, 19, 1504–1508.
[23] a) H.-L. Wu, P.-Y. Wu, Y.-Y. Shen, B.-J. Uang, J.
Org. Chem. 2008, 73, 6445–6447; b) J.-Q. Weng, Q.-M.
Deng, L. Wu, K. Xu, H. Wu, R.-R. Liu, J.-R. Gao, Y.-
X. Jia, Org. Lett. 2014, 16, 776–779.
[12] 100 μg per day for the oral PDE, or <10 μg/g in the
drug products; see: ICH Harmonised Guideline:
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800575
Advanced Synthesis & Catalysis
FULL PAPER
Efficient and Enantioselective Rhodium(I)-
Catalyzed Arylation of -Ketoesters: Synthesis of
(S)-Flutriafol
Adv. Synth. Catal. Year, Volume, Page – Page
Chiung-An Chang, Tsung-Ying Uang, Jia-Hong
Jian, Meng-Yi Zhou, Ming-Liang Chen, Ting-Shen
Kuo, Ping-Yu Wu, Hsyueh-Liang Wu*
10
This article is protected by copyright. All rights reserved.