Enantioselective Synthesis of 1-Substituted 1,2,3,4-Tetrahydroisoquinolines through 1,3-Dipolar Cycloaddition by a Chiral Phosphoric Acid

Article abstract of DOI:10.1055/s-0039-1690108

A new approach is described for the asymmetric synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinolines that is based on the enantioselective 1,3-dipolar cycloaddition reaction of a nitrone and a vinyl ether in the presence of a chiral phosphoric acid that gives the chiral tetrahydroisoquinolines in high yields and with high enantioselectivities. ¹ H and ³¹ P NMR analyses of the mixture of nitrone and chiral phosphoric acid suggest the formation of a 1:1 complex.

Full text of DOI:10.1055/s-0039-1690108

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
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A
en
Y. Jin et al.
Letter
Synlett
Enantioselective Synthesis of 1-Substituted 1,2,3,4-Tetrahydro-
isoquinolines through 1,3-Dipolar Cycloaddition by a Chiral
Phosphoric Acid
Yuan Jin
Cy
Yasuhiro Honma
Cy
R
Hisashi Morita
N
O
Masamichi Miyagawa
0
0
0
0-0
0
0
2-0
8
7
4-
6
7
2
6
Cy
O
Takahiko Akiyama*
0
0
0
0-0
0
0
3-4
7
0
9-
4
1
0
7
Chiral Phosphoric Acid
O
O
t-Bu
R
+
P
O-t-Bu
O
N
OH
Cy
O
Department of Chemistry, Faculty of Science, Gakushuin Uni-
versity, Mejiro, Toshima-ku, Tokyo 171-8588, Japan
takahiko.akiyama@gakushuin.ac.jp
exo-selective
up to 87% ee
Cy
Cy
Enantioselective 1,3-Dipolar Cycloaddition Reaction
Chiral Phosphoric Acid
Received: 20.05.2019
Accepted after revision: 18.06.2019
Published online: 27.06.2019
The organocatalyzed enantioselective 1,3-dipolar cyclo-
addition reactions of nitrones and alkenes are known to af-
ford chiral isoxazolidine derivatives. Yamamoto’s group re-
ported a 1,3-dipolar cycloaddition reaction that uses a chi-
ral phosphoramide to generate an endo product selectively
with excellent enantioselectivity.5 Although chiral isoxazo-
lidines can be obtained efficiently by using organocatalysts,
reports of enantioselective syntheses of the tetrahydroiso-
quinolines are limited to the use of chiral transition-metal
catalysts.6,7 There is only one work that uses a chiral or-
ganocatalyst, but its enantioselectivity was inadequate.8
Chiral Brønsted acids are known to catalyze the forma-
tion of a hydrogen bond with a heteroatom to produce a
chiral intermediate.9 Motivated by these circumstances, we
turned our attention to the development of a catalytic
asymmetric 1,3-dipolar cycloaddition reaction in the pres-
ence of a chiral phosphoric acid for the enantioselective
construction of a chiral exo-1-substituted 1,2,3,4-tetrahy-
droisoquinoline skeleton. Here we report a highly enanti-
oselective synthesis of a chiral 1,2,3,4-tetrahydroisoquino-
line skeleton based on asymmetric ring-closing methodolo-
gy (Scheme 1).
This research commenced with the asymmetric 1,3-di-
polar cycloaddition reaction of nitrone 2a and vinyl ether
3a (2.5 equiv) in the presence of chiral phosphoric acid 1 in
mesitylene (Table 1).10,11 Several phosphoric acids with var-
ious substituents at the 3,3′-positions of the binaphthyl
scaffold were tested.12 All the chiral phosphoric acids gave
the desired exo-product 4aa in good to high yields. Catalyst
1a catalyzed the reaction smoothly (74% yield), but gave
4aa with low enantioselectivity (27% ee) (Table 1, entry 1).
The product was obtained with 70% ee when chiral phos-
phoric acid 1b was used (entry 2). This result indicated that
the 2,4,6-trisubstituted phenyl group might be suitable for
this reaction. Therefore, catalysts 1c and 1d were examined.
Catalyst 1c did not give beneficial results (entry 3). We
DOI: 10.1055/s-0039-1690108; Art ID: st-2019-u0278-l
Abstract A new approach is described for the asymmetric synthesis of
1-substituted 1,2,3,4-tetrahydroisoquinolines that is based on the en-
antioselective 1,3-dipolar cycloaddition reaction of a nitrone and a vinyl
ether in the presence of a chiral phosphoric acid that gives the chiral
tetrahydroisoquinolines in high yields and with high enantioselectivi-
ties. 1H and 31P NMR analyses of the mixture of nitrone and chiral phos-
phoric acid suggest the formation of a 1:1 complex.
Key words phosphoric acids, asymmetric synthesis, 1,3-dipolar cyclo-
addition, nitrones, vinyl ethers, tetrahydroisoquinolines
The isoquinoline skeleton is a fundamental structural
motif found in numerous natural products and compounds
with biological activity.1 The asymmetric synthesis of chiral
1-substituted 1,2,3,4-tetrahydroisoquinolines has attracted
much attention, as these compounds are extremely useful
for the synthesis of biologically active alkaloids and have
been extensively studied in recent years.2 Although a num-
ber of approaches to the synthesis of tetrahydroisoquino-
lines have been reported, including the formation of nitro-
gen-containing heterocyclic rings and the introduction of
substituents at the 1-position of the isoquinoline, the sub-
stituents must be introduced onto the nitrogen atom of the
tetrahydroisoquinoline at an early stage of the synthesis. In
research on the synthesis of biologically active compounds,
it is necessary to introduce substituents onto the nitrogen
atom at a late stage. A 1,3-dipolar cycloaddition reaction of
nitrones and vinyl ethers would be a valuable synthetic
method for the generation of the tetrahydroisoquinoline
skeleton, because the corresponding products could be con-
verted into N-unprotected 1-substituted 1,2,3,4-tetrahydro-
isoquinolines by cleavage of the N–O bond.3,4
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y. Jin et al.
Letter
Synlett
Next, we investigated the effects of substituent on the
vinyl ether on the reaction rate and the enantioselectivity
(Table 2). Vinyl ethers bearing tert-butyl (3a), isopropyl
(3b), ethyl (3c), or butyl groups were examined in the pres-
ence of catalyst 1d. The reaction rate and enantioselectivity
decreased dramatically with decreasing size of the alkyl
group on the vinyl ether (Table 2, entries 1–4). The substit-
uent on the vinyl ether had a significant effect on the reac-
tion rate, the exo/endo ratio, and the enantioselectivity; vinyl
ether 3a gave the best result.
A) Enantioselective organocatalytic 1,3-dipolar cycloaddition reaction
X1
O
R1
R1
O
O
(S)-CPA
OEt
O
N
N
P
+
OEt
O
NHTf
R2
R2
H
X1
endo
>99% yield
X1 = 4-Ad-2,6-(i-Pr)2C6H2
(S)-CPA
up to 93% ee
B) Enantioselective synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinoline
using a transition-metal catalyst
R
transition-metal catalyst
N
+
R = OEt, CHO
N
O
R
O
C) This work
Enantioselective synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinoline
using an organocatalyst
X2
O
Table 2 Effect of Substituents on the Vinyl Ethera
O
P
N
O
OH
(R)-CPA
t-Bu
+
O
O
N
(S)
1d (10 mol%)
O
N
N
X2
+
+
O
O
OR
(S)
N
O-t-Bu
O
mesitylene (0.45 M)
X2 = 2,4,6-(Cy)3C6H2
(R)-CPA
r.t.
time
OR
OR
2a
3 (2.5 equiv)
4 exo-product
5 endo-product
Scheme 1 Reported 1,3-dipolar cycloaddition reactions for the prepa-
R = t-Bu, i-Pr, Et, Bu
ration of chiral 1-substituted 1,2,3,4-tetrahydroisoquinoline derivatives
Entry
R
Time (h)
Yield (%)
exo/endob eec
were delighted to find that the product was obtained with
77% ee and 96% yield when phosphoric acid 1d was used
(entry 4). The absolute stereochemistry of product 4aa was
unambiguously confirmed from the symbol of its optical
rotation in comparison with the reported value.4 From the
results, the best catalyst is chiral phosphoric acid 1d.
1
2
3
4
t-Bu (3a)
i-Pr (3b)
Et (3c)
20
40
40
40
96
89
88
94
95/5
77
66/34
62/38
66/34
57
26
29
Bu (3d)
a Reaction conditions: 2a (0.15 mmol), 1d (10 mol%), 3 (2.5 equiv), mesity-
lene (0.33 mL).
b Determined by 1H NMR spectroscopy.
c Enantiomeric excess of exo product determined by chiral HPLC analysis.
Detailed conditions are described in the Supporting Information.
Table 1 Effect of Substituents at 3,3′-Positions of the Chiral Phosphoric
Acida
Ar
The effect of the reaction temperature was then investi-
gated (Table 3).13 Compared with the reaction at room tem-
perature, the reaction conducted at 50 °C resulted in a slight
decrease in enantioselectivity and required a short reaction
time (Table 3, entry 1). In view of the fact that a lower tem-
perature leads to a lower reaction rate but a higher enanti-
oselectivity, the reactions were performed at a low tem-
perature. Further, to remove trace water from the reaction
system, 4Å molecular sieve was added. A slight increase in
the ee (81%) was obtained when the reaction was run at
0 °C, but the reaction time was longer (entry 3). To our de-
light, further decreasing the temperature to –10 °C afforded
a product in 94% yield with 84% ee, and the ee decreased in
the absence of 4Å molecular sieves (entries 4 and 5). How-
ever, the enantioselectivity was not improved by a further
decrease in the temperature, and at the same time, a dra-
matic decrease in the reaction rate was observed (entry 6).
At –10 °C, an 84% ee was obtained as the best result, and
these reaction conditions were chosen as the optimal reac-
tion conditions.
O
O
P
O
OH
Ar
N
N
1 (10 mol%)
O
O
O
O
+
+
N
O
mesitylene (0.45 M)
O
r.t.
20 h
2a
3a (2.5 equiv)
4aa exo-product
5aa endo-product
Entry
Ar
Yield (%)
exo/endob
eec
1
2
3
4
1a
1b
1c
1d
74
87
64:36
92:8
91:9
95:5
27
70
46
77
89
96
1a
1b
1c
1d
Ar =
a Reaction conditions: 2a (0.15 mmol), 1 (10 mol%), 3a (2.5 equiv), mesi-
tylene (0.33 mL).
b Determined by 1H NMR spectroscopy.
Having successfully achieved the catalytic enantioselec-
tive 1,3-dipolar cycloaddition reaction, we investigated the
reactions of a range of substituted cyclic nitrones 2 under
the standard reaction conditions (Figure 1). In the case of
nitrones bearing electron-withdrawing groups at the 5- or
c Enantiomeric excess of exo product as determined by chiral HPLC analy-
sis. Detailed conditions are described in the Supporting Information.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

C
Y. Jin et al.
Letter
Synlett
Table 3 Effect of the Reaction Temperaturea
Ar
N
O
O
O
O
O
P
N
OH
O
N
N
1d (10 mol%)
2a
O
O
O
O
+
+
Ar
4aa
N
O
mesitylene (0.75 M)
O
1d: Ar = 2,4,6-Cy3C6H2
temp.
time
2a
3a (2.5 equiv)
4aa exo-product
5aa endo-product
Entry
Temp (°C)
Time
Yield (%)
exo/endob
eec
O
O
H
P
*
N
O
O
O
O
O
1
50
6 h
20 h
2 d
3 d
3 d
3 d
86
99
94
94
90
55
93:7
97:3
96:4
97:3
97:3
97:3
70
77
81
84
80
83
P
*
N
O
O
O
O
H
2
r.t.
0
intermediate E
intermediate F
3d
4d
5
–10
–10
–20
O
3a
6d
Figure 2 Plausible reaction mechanism for the enantioselective 1,3-di-
a Reaction conditions: 2a (0.15 mmol), 1d (10 mol%), 3a (3.0 equiv), mesi-
tylene (0.2 mL).
polar cycloaddition
b Determined by 1H NMR spectroscopy.
c Enantiomeric excess of exo product determined by chiral HPLC analysis.
c 4Å MS (68 wt%). Detailed conditions are described in the Supporting In-
formation.
Interestingly, the stereoselectivity of the 1,3-dipolar cy-
cloaddition reaction using a chiral Brønsted acid in our
work differed from that in the work of Yamamoto’s group.5
This difference was ascribed to the structure of the nitrone,
because our group and Yamamoto’s group used E- and Z-ni-
trones, respectively, as starting materials. The Z-nitrone in
Yamamoto’s work had a steric repulsion between the
ethoxy and R2 groups in the transition state for the exo-
product (Scheme 2). On the other hand, in the reaction of
the E-nitrones, the starting materials of this work, favored
the transition state for the exo product compared with the
endo product, resulting in a different exo/endo selectivity.
7-position of isoquinoline, moderate yields (46–75%), excel-
lent exo/endo ratios (up to 100:0), and moderate to good en-
antioselectivities (75–87% ee) were achieved. In contrast,
the reaction of nitrones with electron-donating groups and
vinyl ethers under the standard reaction conditions did not
proceed at all.
1d (10 mol%)
MS 4Å (68 wt%)
R
R
N
N
O
O
O
O
R
+
+
N
O
mesitylene (0.75 M)
O
–10 °C
3 d
3a
5
2
4
Yamamoto’s work
2.5 equiv
exo-product
endo-product
EtO
H
H
Br
F
EtO
R2
R2
O
O
N
H
N
H
N
N
O
N
R1
exo
disfavored
Br
O
O
O
R1
endo
favored
O
O
4ca
4ba
53% yield
4da
46% yield
This work
75% yield
t-BuO
H
exo/endo = 88:12
exo/endo = 97:3
exo/endo = 100:0
H
t-BuO
75% ee (exo-product)
87% ee (exo-product)
76% ee (exo-product)
H
H
O
O
N
N
Cl
MeO
MeO
exo
favored
endo
disfavored
N
N
O
N
F
O
O
O
:Brønsted acid
O
O
4ga
4ea
4fa
Scheme 2 Transition states for the 1,3-dipolar cycloaddition of the
63% yield
63% yield
exo/endo = 98:2
N.R
nitrone and vinyl ether
exo/endo = 100:0
86% ee (exo-product)
85% ee (exo-product)
Figure 1 Substrate scope
To check the validity of our hypothesis, we performed
1H NMR experiments in toluene-d8. The 1H NMR spectra of
chiral phosphoric acid 1d and starting material 2a are
shown in Figure 3a. Upon comparing the 1H NMR spectrum
of the 1:1 mixture (chiral intermediate E) with those of 1d
and 2a (signals for the starting material 2a are indicated by
circles), clear signal shifts for both the starting material 2a
and the chiral phosphoric acid 1d were observed (Figure
3a). Furthermore, one equivalent of 3a was added to chiral
A plausible mechanism for the catalytic enantioselective
1,3-dipolar cycloaddition reaction is shown in Figure 2.
First, catalyst 1d interacts with cyclic nitrone 2a to form
chiral intermediate E, which undergoes a [3+2]-cycloaddi-
tion reaction with vinyl ether 3a to furnish intermediate F.
Then, F releases cycloaddition product 4aa to regenerate
catalyst 1d.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

D
Y. Jin et al.
Letter
Synlett
intermediate E, and after 30 hours at room temperature, the
desired product 4aa was obtained in 43% yield with 81% ee
(Figure 3b). We assumed that the low yield might be due to
decomposition of 3a in the presence of one equivalent of 1d
and that the high exo/endo ratio and the ee were due to the
high loading of 1d.14 In addition, a 31P NMR measurement
was also conducted (Figure 3c). By using PPh3 as an internal
standard in a sealed capillary, a clear shift in the phospho-
rus signal could be observed. On the basis of the above lines
of evidence, we can say with confidence that chiral inter-
mediate E exists and is crucial to the enantioselective 1,3-
dipolar cycloaddition reaction.
efficiency, high yield, high exo/endo ratio, and high enantio-
selectivity. By using cyclic nitrones as starting materials,
products were obtained with exo-form selectively.
Funding Information
Grant-in-Aid for Scientific Research on Innovative Areas ‘Advanced
Transformation Organocatalysis’ from MEXT, Japan, and JSPS KAKEN-
HI Grant number 17H03060.
M
i
n
i
stryof
E
d
u
c
ati
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,
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T
e
c
h
n
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o
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y
(1
7
H
0
3
0
6
0)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690108.
S
u
p
p
orit
n
gInformati
o
n
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References and Notes
(1) (a) Herbert, R. B. In The Chemistry and Biology of Isoquinoline
Alkaloids; Philipson, J. D.; Roberts, M. F.; Zenk, M. H., Ed.;
Springer: Berlin, 1985, 213. (b) Bentley, K. W. Nat. Prod. Rep.
1998, 341.
(2) For reviews of asymmetric syntheses of 1,2,3,4-tetrahydroiso-
quinolines, see: (a) Liu, W.; Liu, S.; Jin, R.; Guo, H.; Zhao, J. Org.
Chem. Front. 2015, 2, 288. (b) Gualandi, A.; Mengozzi, L.;
Manoni, E.; Cozzi, P. G. Catal. Lett. 2015, 145, 398.
(c) Chrzanowska, M.; Grajewska, A.; Rozwadowska, M. D. Chem.
Rev. 2016, 116, 12369.
(3) Jensen, K. B.; Roberson, M.; Jørgensen, K. A. J. Org. Chem. 2000,
65, 9080.
(4) For selected examples of the reaction of vinyl ethers catalyzed
by chiral Brønsted acid, see: (a) Akiyama, T.; Morita, H.;
Fuchibe, K. J. Am. Chem. Soc. 2006, 128, 13070. (b) Mosey, R. A.;
Fisk, J. S.; Friebe, T. L.; Tepe, J. J. Org. Lett. 2008, 10, 825.
(c) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc. 2009,
131, 3430. (d) Lu, C.; Su, X.; Floreancig, P. E. J. Org. Chem. 2013,
78, 9366.
(5) Jiao, P.; Nakashima, D.; Yamamoto, H. Angew. Chem. Int. Ed.
2008, 47, 2411.
(6) For selected examples of enantioselective 1,3-dipolar cycloaddi-
tion reactions of nitrones and alkenes with organocatalysts,
see: (a) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 9874. (b) Karlsson, S.; Högberg, H.-E. Eur. J.
Org. Chem. 2003, 2782. (c) Chow, S. S.; Nevalainen, M.; Evans, C.
A.; Johannes, C. W. Tetrahedron Lett. 2007, 48, 277. (d) Du, W.;
Liu, Y.-K.; Yue, L.; Chen, Y.-C. Synlett 2008, 2997. (e) Weselinski,
L.; Slyk, E.; Jurczak, J. Tetrahedron Lett. 2011, 52, 381.
(f) Weseliński, L.; Kalinowska, E.; Jurczak, J. Tetrahedron: Asym-
metry 2012, 23, 264. (g) Selim, K. B.; Beauchard, A.; Lhoste, J.;
Martel, A.; Laurent, M. Y.; Dujardin, G. Tetrahedron: Asymmetry
2012, 23, 1670. (h) Poulsen, P. H.; Vergura, S.; Monleón, A.;
Jørgensen, D. K. B.; Jørgensen, K. A. J. Am. Chem. Soc. 2016, 138,
6412.
(7) For selected examples of enantioselective syntheses of chiral 1-
substituted 1,2,3,4-tetrahydroisoquinolines by 1,3-dipolar cyc-
loaddition reaction, see: (a) Viton, F.; Benardinelli, G.; Kündig, E.
P. J. Am. Chem. Soc. 2002, 124, 4968. (b) Carmona, D.; Lamata, M.
P.; Viguri, F.; Rodríguez, R.; Oro, L. A.; Lahoz, F. J.; Balana, A. I.;
Tejero, T.; Merino, P. J. Am. Chem. Soc. 2005, 127, 13386.
Figure 3 (a) 1H NMR spectra of 1d, 2a, and a 1:1 (mol/mol) mixture of
1d and 2a in toluene-d8. (b) Reaction of chiral intermediate E and 3a.
(c) 31P NMR spectra of 1d and a mixture of 1d and 2a (1:1 mol/mol) in
toluene-d8 with an internal standard.
In summary, we have developed enantioselective syn-
thesis of 1-substituted 1,2,3,4-tetrahydroisoquinoline de-
rivatives in the presence of a chiral phosphoric acid catalyst.
NMR studies suggested that interaction occurs between the
chiral phosphoric acid and the nitrone. The reaction is a
metal-free approach that is characterized by high catalytic
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

E
Y. Jin et al.
Letter
Synlett
(c) Carmona, D.; Lamata, M. P.; Viguri, F.; Rodríguez, R.; Fischer,
T.; Lahoz, F. J.; Dobrinovitch, I. T.; Oro, L. A. Adv. Synth. Catal.
2007, 349, 1751.
quenched with sat. aq NaHCO3. The resulting mixture was
extracted with EtOAc (×3) and the combined organic layer was
washed with brine, dried (Na2SO4), and concentrated in vacuo.
The residue was purified by preparative TLC [hexane–EtOAc–
Et3N (100:25:3)] to give a colorless oil; yield: 35 mg [94%,
exo/endo = 97:3; 84% ee (exo)]; []D24 +88.8 (c 1.1, CHCl3).HPLC:
(8) Seerden, J.-P. G.; Boeren, M. M. M.; Scheeren, H. W. Tetrahedron
1997, 53, 11843.
(9) For seminal papers on chiral phosphoric acid catalysis, see:
(a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int.
Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc.
2004, 126, 5356For selected reviews, see:. (c) Akiyama, T. Chem.
Rev. 2007, 107, 5744. (d) Terada, M. Synthesis 2010, 1929.
(e) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev.
2014, 114, 9047. (f) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M.
Chem. Rev. 2017, 117, 10608. (g) Merad, J.; Lalli, G.; Bernadat, G.;
Maur, J.; Masson, G. Chem. Eur. J. 2018, 24, 3925.
Daicel Chiralpak IB column (4.6
× 250 mm), hexane–i-
PrOH (100:1), 0.75 mL/min,  = 244 nm; tmajor = 12.00 min,
tminor = 9.9 min. 1H NMR (400 MHz, CDCl3):  = 7.08–7.20 (m, 4
H), 5.57 (dd, J = 1.2, 5.6 Hz, 1 H), 4.76 (dd, J = 8.0, 8.4 Hz, 1 H),
3.28 (ddd, J = 4.8, 5.6, 10.4 Hz, 1 H), 3.14 (ddd, J = 5.2, 7.6, 12.8
Hz, 1 H), 2.81–2.99 (m, 2 H), 2.53 (ddd, J = 1.6, 6.8, 12.8 Hz, 1 H),
2.43 (ddd, J = 5.6, 8.8, 12.8 Hz, 1 H), 1.28 (s, 9 H). 13C NMR (100
MHz, CDCl3):  = 135.9, 133.8, 128.2, 127.5, 126.4 (2 peaks),
96.9, 74.6, 60.4, 49.5, 44.1, 29.0, 27.1.
(10) (2S,10bS)-2-tert-Butoxy-1,5,6,10b-tetrahydro-2H-isoxaz-
olo[3,2-a]isoquinoline (4aa); Typical Procedure
(11) Details of solvent screening are summarized in the Supporting
Information.
Under a N2 atmosphere, a mixture of nitrone 2a (0.15 mmol),
MS 4Å (68 wt%, activated), and chiral phosphoric acid 1d (0.015
mmol, 10 mol%) in mesitylene (0.2 mL) was stirred at r.t. for
5 min. The mixture was then cooled to –10 °C and vinyl ether
3a (0.38 mmol, 2.5 equiv) was added. The mixture was stirred
at –10 °C for 3 d. When the reaction was complete (TLC), it was
(12) Chiral phosphoric acids with electron-deficient substituents
were also tested; see Supporting Information for details.
(13) For the variations of the concentration and the addition of
molecular sieves, see Supporting Information for details.
(14) See Supporting Information for details.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E