Asymmetric N-Hydroxyalkylation of Indoles with Ethyl Glyoxalates Catalyzed by a Chiral Phosphoric Acid: Highly Enantioselective Synthesis of Chiral N,O-Aminal Indole Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b00757

A method of SPINOL-derived chiral phosphoric acid catalyzed asymmetric intermolecular N-hydroxyalkylation of multisubstituted indoles with ethyl glyoxalates is described in this report. This protocol provides an alternative, convenient, and direct strategy for efficient access to structurally unique α-chiral indole N,O-acyclic aminals with a broad substrate scope and good to excellent enantioselectivities. The synthetic utility of this methodology is illustrated by a gram-scale experiment and the subsequent efficient synthesis of more complex chiral N,O-aminal indole derivatives.

Full text of DOI:10.1021/acs.orglett.9b00757

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Asymmetric N‑Hydroxyalkylation of Indoles with Ethyl Glyoxalates
Catalyzed by a Chiral Phosphoric Acid: Highly Enantioselective
Synthesis of Chiral N,O-Aminal Indole Derivatives
†
,‡
†
†,‡
†
†
†
,†
Le Wang, Jia Zhou, Tong-Mei Ding, Zhi-Qiang Yan, Si-Hua Hou, Guo-Dong Zhu,*
,
and Shu-Yu Zhang*
†Shanghai Jiao Tong University Affiliated Sixth People’s Hospital South Campus & Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs & School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, 200240,
P. R. China
‡
School of Chemistry & Environmental Engineering, International Healthcare Innovation Institute, Wuyi University, Jiangmen,
5
29020, P. R. China
*
S Supporting Information
ABSTRACT: A method of SPINOL-derived chiral phos-
phoric acid catalyzed asymmetric intermolecular N-hydrox-
yalkylation of multisubstituted indoles with ethyl glyoxalates is
described in this report. This protocol provides an alternative,
convenient, and direct strategy for efficient access to
structurally unique α-chiral indole N,O-acyclic aminals with
a broad substrate scope and good to excellent enantioselectiv-
ities. The synthetic utility of this methodology is illustrated by a gram-scale experiment and the subsequent efficient synthesis of
more complex chiral N,O-aminal indole derivatives.
he framework for the asymmetric synthesis of chiral
T
indoles is important and of interest because of their
1
prevalence in bioactive natural products and pharmaceuticals.
Consequently, extensive efforts have been undertaken to
explore the catalytic asymmetric reactions of indoles. In the
past decades, significant advances have been made in the
enantioselective functionalization of indoles at the C3- or C2-
2
positions. However, enantioselective functionalization of
indole N−H was still a challenge due to the weak
3
nucleophilicity. In recent years, some successful examples of
catalytic asymmetric N-alkylations of indoles were established,
4
a,b
such as aza-Michael additions (Bandini and Umani-Ronchi,
4
c
4d
4e
4f
4g
Wang, You, Trost, Lu, Shi ), N-allylic alkylation
Xiao ), and hydro-
amination of alkenes (Hartwig), alkynes (Dong), and
5
a
5b
5c
5d,e
5f
(
Trost, Chen, Hartwig, You,
6a
6b
6
c
7a
allenes (Breit). More recently, Peters and Fu demonstrated
asymmetric copper-catalyzed N−H functionalization of indoles
7b
Figure 1. Important molecules containing chiral indole N,O-aminals
skeletons.
induced by visible light. The Sun reported a novel N-
alkylation of indoles via 1,6-conjugate addition of aza-para-
quinone methides. Despite these advances, the development of
more efficient and novel chiral indole N-functionalization
formation methods continues to be extensively investigated in
synthetic chemistry.
11
improving the global cerebral blood flow; Elbasvir, an
inhibitor of the HCV (hepatitis C virus) NS5A protein, has
been clinically studied as a highly effition compound in the
treatment of the HCV infection. In addition, compared to the
Chiral N,O-aminals of indoles, molecules bearing an N,O-
substituted α-chiral carbon center on the N1-position of
indoles, have been recognized as important structural motifs
and are often critical to the biological activity in natural
1
2
corresponding imines, N,O-aminals often display trans-
13
formations in organic syntheses. Therefore, the design and
8
,9
products and pharmaceutical drugs (Figure 1). For example,
Received: February 28, 2019
1
0
vincamine has cerebroprotective activity and functions in
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00757
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
development of an efficient method for the direct catalytic
enantioselective synthesis of chiral N,O-aminals of indoles is
highly desirable. Over the past decades, the asymmetric
Table 1. Optimization of Asymmetric N-
a f
,
Hydroxyalkylaltion
14
15
construction of N,N-aminals and N,O-aminals has drawn
considerable attention from synthetic chemists. In 2008, the
seminal work of enantioselective synthetic N,O-aminals via
addition of alcohols to imines catalyzed by a chiral phosphoric
15a
acid was reported by Antilla (Scheme 1A). In 2009, direct
Scheme 1. Asymmetric Catalytic Works for Forming N,O-
Aminals
b
c
entry
cat.
solvent
t (°C)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
I
II
Toluene (Tol)
−30
−30
−30
−30
−30
−30
−30
−20
−10
0
85
90
76
86
43
56
49
80
95
97
95
93
5
7
Tol
Tol
Tol
Tol
Tol
III
IV
V
VI
VI
VI
VI
VI
VI
VI
35
39
68
82
90
91
92
84
93
85
Tol/Et O (1:1)
2
Tol/Et O (1:1)
2
Tol/Et O (1:1)
2
1
1
1
0
1
2
Tol/Et O (1:1)
2
d
d
Tol/Et O (4:1)
−10
−10
2
,
e
Tol/Et O (4:1)
2
a
Reaction conditions: 2,3-dimethylindole (0.1 mmol, 1.0 equiv), ethyl
glyoxalate (3.0 equiv), and catalyst (10 mol %) in solvent (0.5 mL) at
b
c
the indicated temperature for 48 h. Isolated yield. ee was
determined by HPLC analysis. Performed for 60 h. 5 mol %
catalyst loading. Chiral metal-phosphates catalyzed addition data
d
e
f
were shown in the Supportting Information.
produced the desired product 1 in 85−90% yield with a low
level (5−7%) of ee (entries 1−2). Interestingly, when the
SPINOL-derived chiral phosphoric acids III−V served as
catalysts in our reaction system, we found that the conversion
was controlled efficiently and the enantioselectivity of the
desired product was notably improved to 35−68% ee (entries
asymmetric N,O-acetalization of aldehydes catalyzed by a chiral
15b
Brønsted acid was reported by List (Scheme 1B). However,
to date, only a few examples of the asymmetric formation of
N,O-aminals of indoles by the metal-catalyzed N-alkylaltion
were reported; for example, the seminal work of Chen and
Xiao reported a Cu-catalyzed highly enantioselective Friedel−
Crafts C-2 alkylation/intramolecular N-hemiacetalization
tandem reaction to efficiently construct 2,3-dihydro-1H-
3−5). Significantly, the use of the hindered Ph Si-substituted
3
20
SPINOL-derived chiral phosphoric acid VI in the reaction
system gave the best result, generating 82% ee with a 56%
isolated yield (entry 6). Encouraged by this impressive result,
we further extensively screened various solvents and temper-
15c
pyrrolo[1,2-α]indoles in 2013 (Scheme 1C).
It is noted
atures; finally, the toluene/Et O (4:1) mixture stood out as the
2
that the direct asymmetric organocatalytic N-functionalization
of indoles to form chiral N,O-aminals has not been reported.
Through our continuing interest and efforts to develop
efficient and selective amination reactions with potential
applications in the synthesis of natural products, we
developed and described in this report a novel methodology
for the highly regioselective and enantioselective construction
of N,O-aminal indoles catalyzed by chiral phosphoric acid. This
protocol provides access to the structurally unique α-chiral
N,O-acyclic aminals of indoles starting from commercially
available materials.
best-performing solvent at −10 °C, producing the best isolated
yield of 95% with 93% ee (entry 11). Additionally, reducing
the catalyst loading from 10 to 5 mol % resulted in a slight
decrease of the ee value (85%) (Table 1, entry 12).
1
6
With the optimized conditions, we next examined the
substrate scope and limitations of this asymmetric N-
hydroxyalkylation reaction. As shown in Scheme 2, a broad
range of indoles were well tolerated in the reaction and
smoothly provided the corresponding N,O-aminal products.
For the C2- and C3-position substituted indoles (2−11), the
results indicated that a variety of substituted functional groups
such as alkyl, aryl, and halogens were well tolerated under the
optimal reaction conditions and produced the N,O-acyclic
aminal indoles in good to excellent yield with up to 99% ee.
Interestingly, the N,O-aminal products substituted by methoxy-
carbonylmethyl (7), cyanomethyl (10), and bromine (11)
could provide a convenient and potential method for the
further synthesis of a variety of indole derivatives. Sub-
Inspired by work by Terada in chiral phosphoric acid catalyis
in which glyoxalates were successfully employed as electro-
1
7
philes, our investigation started with the reaction of 2,3-
dimethylindole and ethyl glyoxalate in the presence of various
18,19
chiral phosphoric acid catalyzed systems
−6). As shown in Table 1, the BINOL-derived chiral
phosphoric acids promoted this reaction smoothly and
(Table 1, entries
1
B
DOI: 10.1021/acs.orglett.9b00757
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
, ,
a b c
Scheme 2. Substrate Scope
98% ee. The dibenzocarbazole produced 29 in 63% yield with
98% ee. In addition, the absolute stereochemistry of product
2
3 was unambiguously determined to be (R) by X-ray
crystallographic analysis, and those of other products were
assigned by analogy.
To investigate and enhance the scalability and application of
our strategy in enantioselective N-hydroxyalkylaltion chemistry
for the synthesis of bioactive molecules, we applied our process
to the late-stage modification of the L-tryptophan derivative 30
21
and the tadalafil intermediate 32 (Scheme 3). The desired N-
Scheme 3. Synthetic Applicability
hydroxyalkylation products 31 (92% yield, dr >20:1) and 33
(
67% yield, dr >20:1) were obtained with good functional
group tolerance, demonstrating the value of this asymmetric
transformation in synthetic chemistry. Furthermore, applica-
tions of the chiral N,O-aminals of indoles in the synthesis of
natural indole alkaloids are currently under investigation. In
addition, the proposed transition state for the enantioselective
N-hydroxyalkylation is shown in Scheme 4. The indole and the
Scheme 4. Proposed Transition State
a
Reaction conditions: indole derivative (0.1 mmol, 1.0 equiv), ethyl
glyoxalate (3.0 equiv), and VI (10 mol %) in solvent (0.5 mL) at −10
b
c
°
C for 48 h. Isolated yield. Ee was determined by HPLC analysis.
d
e f
Performed at −30 °C. Performed for 60 h. Performed for 24 h.
sequently, the C4- to C7-substituted indole substrates were
used to examine the effects of steric hindrance and electrons on
the benzene ring of the indoles (12−21). The results clearly
indicate that the lower steric hindrance of the C4- (18), C5-
ethyl glyoxalate are both activated by the phosphoric acid;
then, the indole attacks the ethyl glyoxalate from the Re-face
preferentially, affording the (R)-isomer of the product with
high enantioselectivity and good to excellent yield.
(12), and C6 (13)-substituted substrates produced excellent
yields with 90−93% ee. The steric hindrance of the C7-
position slowly depresses the reaction activity which gave a
5
5% yield with 76% ee (14). Moreover, the effects of both the
In conclusion, we have successfully developed a method for
the SPINOL-derived chiral phosphoric acid catalyzed asym-
metric N-hydroxyalkylation of indoles. This protocol provides
an alternative, convenient, and direct strategy to efficiently
access the structurally unique α-chiral N,O-acyclic hemiaminals
of indoles, and this method uses a broad substrate scope and
has excellent functional group compatibility. Further, this
reaction proceeds with high efficiency (up to >95% yield, 99%
ee) and starts from commercially available materials. The
applications of this N−H hydroxyalkylation methodology for
indoles in the synthesis of complex, natural alkaloids
containing various α-chiral N,O-acyclic hemiaminals, such as
vincamine, are currently under investigation.
electron-withdrawing and -donating groups on the benzene
ring of the indoles were found to be well-accommodated (15−
1
7), affording satisfactory product yields and high levels of
stereocontrol. Furthermore, multisubstituted indoles also
reacted efficiently to produce N-hydroxyalkylation with high
enantioselectivity and good to excellent yield (18−21).
Encouraged by these results, we turned our attention to
complicated polyheterocyclic indole analogies. As expected, a
series of polyheterocyclic indoles reacted predictably under the
optimal reaction conditions (22−29). For instance, carbazole
and 4-methoxycarbazole generated the desired N,O-aminal
products 26 in 94% yield with 97% ee and 27 in 92% yield with
C
DOI: 10.1021/acs.orglett.9b00757
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
5) (a) Trost, B. M.; Krische, M. J.; Berl, V.; Grenzer, E. M. Org.
ASSOCIATED CONTENT
Supporting Information
■
Lett. 2002, 4, 2005. (b) Cui, H.-L.; Feng, X.; Peng, J.; Lei, J.; Jiang, K.;
Chen, Y.-C. Angew. Chem., Int. Ed. 2009, 48, 5737. (c) Stanley, L. M.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2009, 48, 7841. (d) Liu, W.-B.;
Zhang, X.; Dai, L.-X.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51,
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00757.
5
183. (e) Zhao, Q.; Zhuo, C.-X.; You, S.-L. RSC Adv. 2014, 4, 10875.
f) Chen, L.-Y.; Yu, X.-Y.; Chen, J.-R.; Feng, B.; Zhang, H.; Qi, Y.-H.;
Xiao, W.-J. Org. Lett. 2015, 17, 1381.
6) (a) Sevov, C. S.; Zhou, J.; Hartwig, J. F. J. Am. Chem. Soc. 2014,
(
Experimental procedures, NMR spectra, and X-ray and
analytical data for all new compounds (PDF)
(
1
2
36, 3200. (b) Chen, Q.-A.; Chen, Z.; Dong, V. M. J. Am. Chem. Soc.
015, 137, 8392. (c) Xu, K.; Gilles, T.; Breit, B. Nat. Commun. 2015,
Accession Codes
CCDC 1892289 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
6, 7616.
(7) (a) Kainz, Q. M.; Matier, C. D.; Bartoszewicz, A.; Zultanski, S.
L.; Peters, J. C.; Fu, G. C. Science 2016, 35, 6274. (b) Chen, M.; Sun,
J. Angew. Chem., Int. Ed. 2017, 56, 4583.
(8) (a) Warriner, S. In Science of Synthesis; Bellus, D., Ed.; Thieme:
Stuttgart, 2007; Vol. 30, p 7. (b) Zhang, L.; Dong, J.-H.; Xu, X.-X.;
Liu, Q. Chem. Rev. 2016, 116, 287.
(
9) (a) Link, J. T.; Raghavan, S.; Danishefsky, S. J. J. Am. Chem. Soc.
AUTHOR INFORMATION
Corresponding Author
■
*
1995, 117, 552. (b) Link, J. T.; Raghavan, S.; Gallant, M.; Chou, T.
C.; Ballas, L. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 2825.
(
c) Chen, H.; Bai, J.; Fang, Z. F.; Yu, S. S.; Ma, S. G.; Xu, S.; Li, Y.;
Qu, J.; Ren, J. H.; Li, L.; Si, Y. K.; Chen, X. G. J. Nat. Prod. 2011, 74,
438.
10) (a) Lounasmaa, M.; Toluaen, A. The Alkaloids; Acedemic Press:
E-mail: zhangsy16@sjtu.edu.cn.
ORCID
2
(
Shu-Yu Zhang: 0000-0002-1811-4159
Notes
New York, 1992; Vol. 42, pp 1−116. (b) Schlittler, E.; Furlenmeier, A.
Helv. Chim. Acta 1953, 36, 2017. (c) Atta-ur-Rahman; Sultana, M.
Heterocycles 1984, 22, 841. (d) Nge, C.-E.; Chong, K.-W.; Thomas, N.
F.; Lim, S.-H.; Low, Y.-Y.; Kam, T.-S. J. Nat. Prod. 2016, 79, 1388.
The authors declare no competing financial interest.
(
11) (a) Coburn, C. A.; Meinke, P. T.; Chang, W.; Fandozzi, C. M.;
ACKNOWLEDGMENTS
We thank the “Thousand Youth Talents Plan”, the NSFC
■
Graham, D. J.; Hu, B.; Huang, Q.; Kargman, S.; Kozlowski, J.; Liu, R.;
McCauley, J. A.; Nomeir, A. A.; Soll, R. M.; Vacca, J. P.; Wang, D.;
Wu, H.; Zhong, B.; Olsen, D. B.; Ludmerer, S. W. ChemMedChem
2013, 8, 1930. (b) Li, H.; Belyk, K. M.; Yin, J.; Chen, Q.; Hyde, A.; Ji,
Y.; Oliver, S.; Tudge, M. T.; Campeau, L.; Campos, K. R. J. Am. Chem.
Soc. 2015, 137, 13728.
(
(
21672145, 21602131, and 51733007), the Shuguang Program
16SG10) from the Shanghai Education Development
Foundation and Shanghai Municipal Education Commission,
and the Science and Technology Commission of Shanghai
Municipality (17JC1403700) and the Drug Innovation Major
Project of the Ministry of Science and Technology of China
(
12) (a) Xie, Y.; Zhao, Y.; Qian, B.; Yang, L.; Xia, C.; Huang, H.
Angew. Chem., Int. Ed. 2011, 50, 5682. (b) Shi, Y.-C.; Wang, S.-G.;
Yin, Q.; You, S.-L. Org. Chem. Front. 2014, 1, 39. (c) Trost, B. M.;
Gnanamani, E.; Hung, C.-I. Angew. Chem., Int. Ed. 2017, 56, 10451.
d) Cai, Y.; Gu, Q.; You, S.-L. Org. Biomol. Chem. 2018, 16, 6146.
e) Zhang, L.; Wu, B.; Chen, Z.; Hu, J.; Zeng, X.; Zhong, G. Chem.
(
2018ZX09711001-005-002). We gratefully thank Prof. Yong-
Qiang Tu (Shanghai Jiao Tong University) and Prof.
Changkun Li (Shanghai Jiao Tong University) for helpful
suggestions and comments on this manuscript.
(
(
Commun. 2018, 54, 9230.
13) (a) March, J. Advanced Organic Chemistry Reactions, Mechanisms
and structure, 3rd ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 1985.
b) For recent selected reviews, see: Huang, Y.-Y.; Cai, C.; Yang, X.;
Lv, Z.-C.; Schneider, U. ACS Catal. 2016, 6, 5747.
14) (a) Rowland, G. B.; Zhang, H.; Rowland, E. B.;
Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc.
005, 127, 15696. (b) Cheng, X.; Vellalath, S.; Goddard, R.; List, B. J.
(
REFERENCES
■
(
(
1) For selected reviews, see: (a) Scholz, U.; Winterfeldt, E. Nat.
Prod. Rep. 2000, 17, 349. (b) Humphrey, G.-R.; Kuethe, J.-T. Chem.
Rev. 2006, 106, 2875. (c) Bandini, M.; Eichholzer, A. Angew. Chem.,
Int. Ed. 2009, 48, 9608. (d) Kochanowska-karamyan, A.-J.; Hamann,
M.-T. Chem. Rev. 2010, 110, 4489. (e) Ishikura, M.; Yamada, K.; Abe,
T. Nat. Prod. Rep. 2010, 27, 1630. (f) Ishikura, M.; Abe, T.; Choshi,
T.; Hibino, S. Nat. Prod. Rep. 2013, 30, 694.
(
2
Am. Chem. Soc. 2008, 130, 15786. (c) Rueping, M.; Antonchick, A. P.;
Sugiono, E.; Grenader, K. Angew. Chem., Int. Ed. 2009, 48, 908.
(15) (a) Li, G.; Fronczek, F. R.; Antilla, J. C. J. Am. Chem. Soc. 2008,
(
2) For selected reviews, see: (a) Bandini, M.; Eichholzer, A. Angew.
Chem., Int. Ed. 2009, 48, 9608. (b) Lancianesi, S.; Palmieri, A.; Petrini,
̌
130, 12216. (b) Vellalath, S.; Coric, I.; List, B. Angew. Chem., Int. Ed.
́
M. Chem. Rev. 2014, 114, 7108. (c) Dalpozzo, R. Chem. Soc. Rev.
2010, 49, 9749. (c) Cheng, H.-G.; Lu, L.-Q.; Wang, T.; Yang, Q.-Q.;
Liu, X.-P.; Li, Y.; Deng, Q.-H.; Chen, J.-R.; Xiao, W.-J. Angew. Chem.,
Int. Ed. 2013, 52, 3250. (d) Arai, T.; Tsuchiya, K.; Matsumura, E. Org.
Lett. 2015, 17, 2416. (e) Jiang, F.; Zhao, D.; Yang, X.; Yuan, F.-R.;
Mei, G.-J.; Shi, F. ACS Catal. 2017, 7, 6984.
(16) (a) Bai, H.-Y.; Ma, Z.-G.; Yi, M.; Lin, J.-B.; Zhang, S.-Y. ACS
Catal. 2017, 7, 2042. (b) Zhang, T.-Y.; Liu, C.; Chen, C.; Liu, J.-X.;
Xiang, H.-Y.; Jiang, W.; Ding, T.-M.; Zhang, S.-Y. Org. Lett. 2018, 20,
220. (c) Dong, J.-W.; Ding, T.; Zhang, S.-Y.; Chen, Z.-M.; Tu, Y.-Q.
Angew. Chem., Int. Ed. 2018, 57, 13192.
2
(
015, 44, 742.
3) (a) Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont, R.;
Boubaker, T.; Ofial, A. R.; Mayr, H. J. Org. Chem. 2006, 71, 9088.
b) Otero, N.; Mandado, M.; Mosquera, R. A. J. Phys. Chem. A 2007,
11, 5557.
4) (a) Bandini, M.; Eichholzer, A.; Tragni, M.; Umani-Ronchi, A.
(
1
(
Angew. Chem., Int. Ed. 2008, 47, 3238. (b) Bandini, M.; Bottoni, A.;
Eichholzer, A.; Miscione, G. P.; Stenta, M. Chem. - Eur. J. 2010, 16,
1
2462. (c) Hong, L.; Sun, W.; Liu, C.; Wang, L.; Wang, R. Chem. -
Eur. J. 2010, 16, 440. (d) Cai, Q.; Zheng, C.; You, S.-L. Angew. Chem.,
Int. Ed. 2010, 49, 8666. (e) Trost, B. M.; Osipov, M.; Dong, G. J. Am.
Chem. Soc. 2010, 132, 15800. (f) Dou, X.; Yao, W.; Jiang, C.; Lu, Y.
Chem. Commun. 2014, 50, 11354. (g) Ma, C.; Zhang, T.; Zhou, J.-Y.;
Mei, G.-J.; Shi, F. Chem. Commun. 2017, 53, 12124.
(17) (a) Terada, M.; Soga, K.; Momiyama, N. Angew. Chem., Int. Ed.
2008, 47, 4122−4125. (b) Momiyama, N.; Tabuse, H.; Terada, M. J.
Am. Chem. Soc. 2009, 131, 12882−12883.
(18) Seminal reports on chiral phosphoric acid catalysis:
(a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int.
D
DOI: 10.1021/acs.orglett.9b00757
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc.
2
004, 126, 5356.
19) The selected reviews on chiral phosphoric acid catalysis:
a) Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) Terada, M. Synthesis
(
(
2010, 2010, 1929. (c) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M.
Chem. Rev. 2014, 114, 9047. (d) James, T.; van Gemmeren, M.; List,
B. Chem. Rev. 2015, 115, 9388.
(
20) Catalyst VI was first reported by Hu and co-workers: (a) Xing,
C.-H.; Liao, Y.-X.; Sabarova, D.; Bassous, M.; Hu, Q.-S. Eur. J. Org.
Chem. 2012, 2012, 1115. For selected reviews on ligands with
spirocyclic skeletons, see: (b) Xie, J.-H.; Zhou, Q.-L. Acc. Chem. Res.
2
2
2
1
008, 41, 581. (c) Chung, Y. K.; Fu, G. C. Angew. Chem., Int. Ed.
009, 48, 2225. (d) Ding, K.; Han, Z.; Wang, Z. Chem. - Asian J.
009, 4, 32. (e) Zhu, S.-F.; Zhou, Q.-L. Acc. Chem. Res. 2012, 45,
365. (f) Xie, J.-H.; Zhou, Q.-L. Huaxue Xuebao 2014, 72, 778.
(
21) Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville,
A. C.; Coste, H.; Kirilovsky, J.; Hyafil, F.; Labaudiniere, R. J. Med.
Chem. 2003, 46, 4525.
̀
E
DOI: 10.1021/acs.orglett.9b00757
Org. Lett. XXXX, XXX, XXX−XXX