Heterogeneous Heterobimetallic Catalysis Enabling Expeditious Access to CF3-Containing vic-Amino Alcohols

Article abstract of DOI:10.1021/acs.orglett.7b03767

A highly anti-selective catalytic asymmetric nitroaldol reaction of trifluoromethyl ketones based on Nd/Na and Pr/Na heterobimetallic catalysts was developed. These catalysts function as heterogeneous catalysts to engage nitroethane and a range of trifluoromethyl ketones in a stereoselective assembly to afford CF₃-appended vic-nitroalkanols that could be readily converted to enantioenriched vic-amino alcohols, which are privileged structural motifs in medicinal chemistry.

Full text of DOI:10.1021/acs.orglett.7b03767

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Heterogeneous Heterobimetallic Catalysis Enabling Expeditious
Access to CF3‑Containing vic-Amino Alcohols
Tomoya Karasawa, Naoya Kumagai,* and Masakatsu Shibasaki*
Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
S
* Supporting Information
ABSTRACT: A highly anti-selective catalytic asymmetric
nitroaldol reaction of trifluoromethyl ketones based on Nd/
Na and Pr/Na heterobimetallic catalysts was developed. These
catalysts function as heterogeneous catalysts to engage nitro-
ethane and a range of trifluoromethyl ketones in a stereo-
selective assembly to afford CF3-appended vic-nitroalkanols that
could be readily converted to enantioenriched vic-amino
alcohols, which are privileged structural motifs in medicinal
chemistry.
he catalytic asymmetric nitroaldol (Henry) reaction has
trifluoromethyl ketones via La(III) catalysis,8 furnishing
Testablished its unwavering position as a high-fidelity enantioenriched vic-nitroalkanols possessing an α-CF3 tertiary
alcohol unit. The tertiary alcohol substructure contains a
tetrasubstituted stereogenic center9 that is not accessible via
the well-established hydrogenation methodology. Although
strategic use of the nitroaldol reaction to access this class of
chiral building blocks is noteworthy, the need for a 25 mol %
loading of La(III) complex (and a 3-fold excess of a chiral
ligand relative to La(III)) with a 25 mol % loading of proton
sponge as a base and a long reaction time poses limitations,
leaving much room for improvement toward a more practical
synthesis of CF3-appended vic-amino alcohols. A couple of
organocatalysts10 and metal-based catalysts11 were developed
for the nitroaldol arsenal to engage nitromethane in an
enantioselective addition to trifluoromethyl ketones, but the
implementation of higher nitroalkanes is less well explored.
Xu and Wolf11a reported the only example utilizing
nitroethane with a 10 mol % loading of a Cu(II)/
bisoxazolidine complex and 20 mol % Bu3N, displaying four
different examples ranging from 77−89% de and 78−91% ee.
Herein we report a general anti-selective nitroaldol reaction
using nitroethane and nitropropane with high enantio- and
diastereoselectivity (Scheme 1c). Heterogeneous catalysts
comprising an amide-based ligand and Nd/Na or Pr/Na
bimetallic salts were competent to promote the reaction with
catalyst loadings of 3−9 mol %.
carbon−carbon bond-forming reaction with a high level of
stereochemical control.1,2 The requisite nitroalkane pronu-
cleophiles are readily available and reactive under mild
conditions, allowing for atom-economical reaction settings in
which a simple proton transfer drives the catalysis. Because
the nitroaldol adducts (vic-nitroalkanols) are direct precursors
of vic-amino alcohols, which are privileged structural motifs in
medicinal chemistry, considerable effort has been devoted to
this specific transformation (Scheme 1a).3−5
Scheme 1. Access to CF3-Containing vic-Amino Alcohols
via Nitroaldol Reaction
We planned a stereoselective assembly of 2,2,2-trifluor-
oacetophenone (2a) and nitroethane (3a) as a representative
trifluoromethyl ketone and nitroalkane, respectively, which
were submitted to a reaction with the heterogeneous Nd/Na
heterobimetallic catalyst identified by our group (Table 1).12
The characteristic features of this heterobimetallic complex
are (1) the spontaneous formation of an insoluble catalyst
As the methodology enabling the incorporation of fluorine
atoms into active pharmaceutical ingredients (APIs) has
attracted growing attention,6 several approaches have been
developed to apply the nitroaldol reaction manifold to
produce enantioenriched fluorine-containing vic-amino alco-
hols (Scheme 1b).7 Saa and co-workers were the first to
Received: December 4, 2017
́
report an enantioselective addition of nitromethane to
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03767
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Anti-Selective Catalytic Asymmetric Nitroaldol Reaction of Nitroethane (3a) with 1,1,1-Trifluoroacetophenone
a
(2a)
e
f
g
entry
RE
method
solvent
THF
THF
THF
THF
T (°C)
yield (%)
anti/syn
ee (anti) (%)
1
2
3
4
5
6
7
8
Nd
Nd
Nd
Nd
Nd
Nd
Nd
Nd
La
Pr
Pr
Sm
Gd
Dy
Er
A
A
A
B
B
B
B
B
A
A
B
A
A
A
A
A
−40
−60
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
−78
99
92
90
95
84
trace
62
70
trace
92
91
12
trace
trace
trace
trace
90/10
93/7
96/4
95/5
84/16

76
85
93
92
90

82
84

95
94
56



Et2O
DME
CPME
2-Me-THF
THF
THF
THF
THF
THF
THF
THF
92/8
92/8

h
9
10
11
12
13
14
97/3
96/4

h
h

h

h
15
16

h
Yb
THF


a
b
c
2 (0.12 mmol), 3a (1.2 mmol). Isolated yields are shown. RE denotes rare-earth metal. For Pr, Dy, Er, and Yb, RE(OiPr)3 was used. NdCl3·
d
e
6H2O or PrCl3·7H2O. Based on RE salts used for catalyst preparation. Determined by 1H NMR analysis of the crude mixtures with mesitylene as
f
g
h
1
an internal standard. Determined by H NMR analysis. Determined by HPLC analysis. The catalyst mixture did not form a heterogeneous
complex, and the resulting homogeneous mixture was used as catalyst.
from amide-based ligand 1, NdO1/5(OiPr)13/5, and NaHMDS
via self-assembly (method A)13 and (2) the competence of
the thus-formed solid material as a heterogeneous catalyst in
ethereal solvents to promote the nitroaldol reaction with
aldehydes in an anti- and enantioselective manner. Given the
unparalleled efficiency of the 1/Nd/Na complex toward the
deprotonative activation of nitroalkanes and stereochemical
control of the nitronate addition, we reasoned that this
heterogeneous catalysis would be proficient in the addition to
trifluoromethyl ketones 2. The heterogeneous catalyst
isolated by centrifugation was used for the reaction.
Gratifyingly, suitable catalytic conditions quickly emerged
by slight modification of the previously identified conditions
to give the anti-configured product 4aa with high stereo-
selectivity. Little or no retro reaction was observed, and the
stereoselectivity, which was kinetically determined, displayed
the ordinary dependence on the reaction temperature (entries
1−3). Because of the limited availability and high cost of
NdO1/5(OiPr)13/5/NaHMDS (method A), catalyst prepara-
tion using NdCl3·6H2O/NaOtBu (method B) was more
favorable and exhibited almost identical catalytic performance
(entries 3 and 4). The reaction settings were more sensitive
to the solvent than the reactions with aldehydes, and THF
was an indispensable solvent among ethereal solvents (entries
4−8). Screening of rare-earth metal (RE) alkoxides revealed
that the Pr/Na bimetallic system was also competent in the
present reaction, while other RE/Na systems failed in the
reaction (entries 4, 9, 10, and 12−16). The stereochemical
outcomes were highly dependent on the reaction temper-
ature, and the reaction reached completion with the highest
stereoselectivity at −78 °C. For the Pr/Na catalytic system,
catalyst preparation using inexpensive PrCl3·7H2O instead of
Pr(OiPr)3 was valid and provided similar reaction outcomes
(entries 10 and 11). On the basis of their similar ionic radii,
coordination characteristics, and Lewis acidity, the Nd/Na
and Pr/Na heterobimetallic complexes likely shared a similar
three-dimensional architecture responsible for both the
catalytic activity and stereoselectivity.14
The scope of the nitroaldol reaction using a range of
trifluoromethyl ketones 2 with the catalyst prepared via
method B is displayed in Scheme 2. The reaction was
scalable to obtain 1.2 g of anti-configured vic-nitroalkanol 4aa
bearing an α-CF3 tertiary alcohol unit. Despite the fact that
the o-substituted trifluoromethyl ketone exhibited significantly
diminished reactivity, the m,p-substitution was accommodated
even with a t-Bu group (4ba−da), and the Pr/Na catalyst
exhibited similar catalytic performance. Other nonfunctional-
ized and p-halo-substituted ketones produced the desired
adducts with high stereoselectivity (4ea−ha). While the
electron-donating m-OMe-substituted ketone had a slightly
eroded yield and stereoselectivity with the Nd/Na catalyst,
the Pr/Na catalyst provided a superior reaction outcome,
B
DOI: 10.1021/acs.orglett.7b03767
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
anti-4aa (93% ee) was submitted to hydrogenation over
Pd(OH)2/C to give vic-amino alcohol 5 in an excellent yield
without compromising the stereochemical integrity. Reductive
amination with formalin and NaB(CN)H3 afforded 6, sharing
the overall architecture of ephedrine except having an
appended CF3 group on the tertiary alcohol moiety.
Scheme 2. Anti-Selective Catalytic Asymmetric Nitroaldol
Reaction of Nitroethane (3a) with Trifluoromethyl
Ketones 2
a
Scheme 4. Enantioselective Synthesis of CF3-Appended
Ephedrine 6
In conclusion, we have developed an anti-selective catalytic
asymmetric nitroaldol reaction of trifluoromethyl ketones and
nitroethane. The Nd/Na or Pr/Na heterobimetallic catalyst
ligated with a chiral diamide promoted the reaction with high
stereoselectivity, allowing for expeditious access to enantioen-
riched vic-nitroalkanols with an α-CF3 tertiary alcohol unit.
The facile reduction to the corresponding vic-amino alcohol
as well as the enantioselective synthesis of CF3-appended
ephedrine highlight the potential utility of the reaction in
medicinal chemistry.
a
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03767.
2 (0.12 mmol), 3a (1.2 mmol). Isolated yields of anti diastereomers
■
b
S
are shown. RE denotes rare-earth metal. NdCl3·6H2O or PrCl3·
7H2O. Based on RECl3 hydrate used for catalyst preparation. 2a
(5.74 mmol, 1.0 g), 3a (57.4 mmol). Isolated yield of the anti
diastereomer.
c
d
e
Experimental procedures, spectroscopic data for new
compounds, and NMR spectra (PDF)
presumably because the small deviation in the structural
parameters of the catalyst was beneficial for higher stereo-
selectivity as well as for catalytic efficiency (4ia). Notably,
trifluoromethyl ynone served as a suitable substrate to give
desired adduct 4ja bearing a propargylic tertiary alcohol unit
that could be used as a convenient chiral building block for
further elaboration.15 Intriguingly, difluoromethyl ketone 2k
could be transformed to the desired nitroaldol adduct 4ka
with the Nd/Na catalyst with high stereoselectivity, although
a catalyst loading of 9 mol % (method B) and extended
reaction times were essential because of the low electro-
philicity (Scheme 3a). An attempt to use nitropropane (3b)
as the pronucleophile produced 4ab in a highly anti-selective
manner, albeit with eroded enantioselectivity (Scheme 3b).16
The utility of the present catalytic asymmetric protocol was
demonstrated by the enantioselective synthesis of CF3-
decorated ephedrine 6 (Scheme 4).17 The nitroaldol adduct
Accession Codes
CCDC 1587722 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 e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*nkumagai@bikaken.or.jp
*mshibasa@bikaken.or.jp
ORCID
Naoya Kumagai: 0000-0003-1843-2592
Masakatsu Shibasaki: 0000-0001-8862-582X
Notes
Scheme 3. Extended Scope: Reaction with Difluoromethyl
Ketone 2k or Nitropropane (3b)
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by ACT-C
(JPMJCR12YO) from JST and by KAKENHI (17H03025
and JP16H01043 in Precisely Designed Catalysts with
Customized Scaffolding) from JSPS and MEXT. Dr. Ryuichi
Sawa, Ms. Yumiko Kubota, and Dr. Kiyoko Iijima at the
Institute of Microbial Chemistry are gratefully acknowledged
for their assistance with the spectroscopic analysis. We thank
C
DOI: 10.1021/acs.orglett.7b03767
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
VCH: Weinheim, Germany, 2005. (c) Trost, B. M.; Jiang, C.
Synthesis 2006, 369. (d) Riant, O.; Hannedouche, J. Org. Biomol.
Chem. 2007, 5, 873. (e) Shibasaki, M.; Kanai, M. Chem. Rev. 2008,
108, 2853. (f) Kumagai, N.; Shibasaki, M. Bull. Chem. Soc. Jpn.
2015, 88, 503.
(10) (a) Bandini, M.; Sinisi, R.; Umani-Ronchi, A. Chem. Commun.
2008, 4360. (b) Palacio, C.; Connon, S. J. Org. Lett. 2011, 13, 1298.
(11) (a) Xu, H.; Wolf, C. Chem. Commun. 2010, 46, 8026.
(b) Das, A.; Choudhary, M. K.; Kureshy, R. I.; Jana, K.; Verma, S.;
Khan, N. H.; Abdi, S. H. R.; Bajaj, H. C.; Ganguly, B. Tetrahedron
2015, 71, 5229.
Dr. Tomoyuki Kimura at the Institute of Microbial Chemistry
for assistance with X-ray crystallography.
REFERENCES
■
(1) Henry, L. C. R. Hebd. Seances Acad. Sci. 1895, 120, 1265.
(2) For reviews of asymmetric nitroaldol reactions, see: (a) Boruwa,
J.; Gogoi, N.; Saikia, P. P.; Barua, N. C. Tetrahedron: Asymmetry
2006, 17, 3315. (b) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org.
́
Chem. 2007, 2007, 2561. (c) Blay, G.; Hernandez-Olmos, V.; Pedro,
J. R. Synlett 2011, 2011, 1195.
(3) For selected examples of syn-selective catalytic asymmetric
nitroaldol reactions, see: (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.;
Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418. (b) Sasai, H.;
Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J.
Org. Chem. 1995, 60, 7388. (c) Sohtome, Y.; Hashimoto, Y.;
Nagasawa, K. Eur. J. Org. Chem. 2006, 2006, 2894. (d) Arai, T.;
Watanabe, M.; Yanagisawa, A. Org. Lett. 2007, 9, 3595. (e) Sohtome,
Y.; Takemura, N.; Takada, K.; Takagi, R.; Iguchi, T.; Nagasawa, K.
Chem. - Asian J. 2007, 2, 1150. (f) Arai, T.; Takashita, R.; Endo, Y.;
Watanabe, M.; Yanagisawa, A. J. Org. Chem. 2008, 73, 4903.
(g) Kim, H. Y.; Oh, K. Org. Lett. 2009, 11, 5682. (h) Jin, W.; Li, X.;
Wan, B. J. Org. Chem. 2011, 76, 484. (i) White, J. D.; Shaw, S. Org.
Lett. 2012, 14, 6270. (j) Qin, D. D.; Yu, W.; Zhou, J. D.; Zhang, Y.
C.; Ruan, Y. P.; Zhou, Z. H.; Chen, H. B. Chem. - Eur. J. 2013, 19,
16541. (k) Kaldun, J.; Prause, F.; Scharnagel, D.; Freitag, F.;
Breuning, M. ChemCatChem 2016, 8, 1846.
(4) For selected examples of anti-selective catalytic asymmetric
nitroaldol reactions, see: (a) Uraguchi, D.; Sakaki, S.; Ooi, T. J. Am.
Chem. Soc. 2007, 129, 12392. (b) Handa, S.; Nagawa, K.; Sohtome,
Y.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2008, 47,
3230. (c) Sohtome, Y.; Kato, Y.; Handa, S.; Aoyama, N.; Nagawa,
K.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2008, 10, 2231.
(d) Uraguchi, D.; Nakamura, S.; Ooi, T. Angew. Chem., Int. Ed.
2010, 49, 7562. (e) Lang, K.; Park, J.; Hong, S. Angew. Chem., Int.
Ed. 2012, 51, 1620. (f) Xu, K.; Lai, G.; Zha, Z.; Pan, S.; Chen, H.;
Wang, Z. Chem. - Eur. J. 2012, 18, 12357. (g) Li, Y.; Deng, P.;
Zeng, Y.; Xiong, Y.; Zhou, H. Org. Lett. 2016, 18, 1578.
(12) (a) Nitabaru, T.; Kumagai, N.; Shibasaki, M. Tetrahedron Lett.
2008, 49, 272. (b) Nitabaru, T.; Nojiri, A.; Kobayashi, M.; Kumagai,
N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 13860. (c) Nitabaru,
T.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2012, 51,
1644. (d) Ogawa, T.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int.
Ed. 2013, 52, 6196. (e) Sureshkumar, D.; Hashimoto, K.; Kumagai,
N.; Shibasaki, M. J. Org. Chem. 2013, 78, 11494. (f) Hashimoto, K.;
Kumagai, N.; Shibasaki, M. Org. Lett. 2014, 16, 3496. (g) Nonoyama,
A.; Hashimoto, K.; Saito, A.; Kumagai, N.; Shibasaki, M.
Tetrahedron Lett. 2016, 57, 1815.
(13) Nitroethane was also used for complexation and may be an
indispensable component of the solid catalyst, as evidenced by
HRMS analysis. See ref 12b for details.
(14) The catalyst without Nd or Pr (ligand 1/NaOtBu = 1/6) led
to no reaction, indicating that the heterobimetallic complex was of
prime importance for reaction progress as well as stereoselectivity.
(15) Trost, B. M.; Li, C.-J. Modern Alkyne Chemistry: Catalytic and
Atom-Economic Transformations; Wiley: Hoboken, NJ, 2014.
(16) Although 3a was used for catalyst preparation and was likely
included in the thus-formed heterogeneous catalyst after centrifuga-
tion, the amount of added 3b in the reaction mixture was
significantly higher, and no product derived from 3a was observed.
(17) Abourashed, E. A.; El-Alfy, A. T.; Khan, I. A.; Walker, L.
Phytother. Res. 2003, 17, 703.
(5) For selected examples of anti-selective catalytic asymmetric
nitroaldol reactions with moderate stereoselectivity, see: (a) Blay,
G.; Domingo, L. R.; Hernandez-Olmos, V.; Pedro, J. R. Chem. - Eur.
J. 2008, 14, 4725. (b) Ube, H.; Terada, M. Bioorg. Med. Chem. Lett.
́
2009, 19, 3895. (c) Blay, G.; Hernandez-Olmos, V.; Pedro, J. R.
Org. Lett. 2010, 12, 3058. (d) Noole, A.; Lippur, K.; Metsala, A.;
Lopp, M.; Kanger, T. J. Org. Chem. 2010, 75, 1313. (e) Qiong ji, Y.;
Qi, G.; Judeh, Z. M. A. Eur. J. Org. Chem. 2011, 2011, 4892.
(f) Boobalan, R.; Lee, G.-H.; Chen, C. Adv. Synth. Catal. 2012, 354,
2511. (g) Yao, L.; Wei, Y.; Wang, P.; He, W.; Zhang, S. Tetrahedron
2012, 68, 9119. (h) Arai, T.; Joko, A.; Sato, K. Synlett 2015, 26,
209.
(6) For reviews, see: (a) Muller, K.; Faeh, C.; Diederich, F. Science
̈
2007, 317, 1881. (b) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (c) Kirsch, P. Modern
Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, 2nd ed.;
Wiley-VCH: Weinheim, Germany, 2013. (d) Wang, J.; Sanchez-
Rosello, M.; Acena, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero,
S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432.
(e) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.;
Meanwell, N. A. J. Med. Chem. 2015, 58, 8315. (f) Zhou, Y.; Wang,
J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.; Soloshonok, V. A.;
Izawa, K.; Liu, H. Chem. Rev. 2016, 116, 422.
́
(7) (a) Mloston, G.; Obijalska, E.; Heimgartner, H. J. Fluorine
́
Chem. 2010, 131, 829. (b) Tur, F.; Mansilla, J.; Lillo, V. J.; Saa, J.
M. Synthesis 2010, 2010, 1909.
́
́
(8) (a) Tur, F.; Saa, J. M. Org. Lett. 2007, 9, 5079. (b) Saa, J. M.;
Tur, F.; Gonzalez, J. Chirality 2009, 21, 836.
(9) For reviews of the construction of tetrasubstituted stereogenic
centers, see: (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int.
Ed. 1998, 37, 388. (b) Christoffers, J.; Baro, A. Quaternary
Stereocenters: Challenges and Solutions for Organic Synthesis; Wiley-
D
DOI: 10.1021/acs.orglett.7b03767
Org. Lett. XXXX, XXX, XXX−XXX