Kinetic Resolution Driven Diastereo- and Enantioselective Synthesis of cis-β-Heteroaryl Amino Cycloalkanols by Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation

Article abstract of DOI:10.1021/acs.orglett.6b03334

The utility of tethered Ru-TsDPEN catalyst has been demonstrated for the asymmetric transfer hydrogenation of rac-α-heteroaryl amino cycloalkanones to construct biologically important cis-β-heteroaryl amino cycloalkanols with two contiguous chiral centers

Full text of DOI:10.1021/acs.orglett.6b03334

Letter
pubs.acs.org/OrgLett
Kinetic Resolution Driven Diastereo- and Enantioselective Synthesis
of cis-β-Heteroaryl Amino Cycloalkanols by Ruthenium-Catalyzed
Asymmetric Transfer Hydrogenation
Vijyesh K. Vyas and Bhalchandra M. Bhanage*
Department of Chemistry, Institute of Chemical Technology, Mumbai 400019, India
S
* Supporting Information
ABSTRACT: The utility of tethered Ru-TsDPEN catalyst has
been demonstrated for the asymmetric transfer hydrogenation
of rac-α-heteroaryl amino cycloalkanones to construct bio-
logically important cis-β-heteroaryl amino cycloalkanols with
two contiguous chiral centers via dynamic kinetic resolution.
The stated (R,R)-Teth-TsDPEN-Ru-catalyzed transformation
is carried out under mild conditions using formic acid/triethylamine as a hydrogen source with excellent diastereo- and
enantioselectivities. Further, this methodology has been applied for the synthesis of an antileishmanial agent and chiral ionic
liquid.
Scheme 1. Asymmetric Hydrogenation/Transfer
Hydrogenation of α-Amino Cycloalkanones
ynamic kinetic resolution (DKR) effected by asymmetric
1
Dhydrogenation (AH) as well as by asymmetric transfer
hydrogenation (ATH)2 has sparked extensive interest and has
found endless application in the field of academics as well as in
the pharmaceutical industry. Recently, DKR-ATH of rac-α-
substituted ketones was extensively studied to produce optically
active β-substituted alcohols. In particular, the synthesis of
chiral β-amino alcohol with two contiguous chiral centers has
attracted considerable interest as a building block in
pharmaceutical drug synthesis and as a ligand in asymmetric
synthesis.3
Enantiopure vicinal β-amino cycloalkanols along with triazole
and the imidazole nucleus at the β-position have emerged as
important structural motifs in pharmaceutical and carbohydrate
chemistry.4 In addition, these β-heteroaryl amino cycloalkanols
with an imidazole ring at the β-position show excellent chiral
ionic liquid properties.5 In general, efforts have been made to
synthesize optically active β-amino cycloalkanols via AH-DKR
by Zhou et al.3b,c (Scheme 1Aa) and more recently by Zhang et
al.3g (Scheme 1Ab). However, to the best of our knowledge,
there is no report for the catalytic asymmetric hydrogenation or
asymmetric transfer hydrogenation to produce optically active
β-heteroaryl amino cycloalkanols. Previously, these scaffolds
were synthesized by ring opening of meso epoxides, which
produces the trans isomer.6 Therefore, there is an urgent need
for the development of an efficient route that can be applied for
the synthesis of cis-β-heteroaryl amino cycloalkanols. Herein,
we report an efficient protocol for the synthesis of cis-β-
heteroaryl amino cycloalkanols by ruthenium-catalyzed DKR-
ATH of rac-α-heteroaryl amino cycloalkanones. Additionally,
the substrate scope was extended by altering heteroaryl nucleus
at α-position. Triazole, imidazole, and pyrazole as heterocycles
were successfully investigated. This protocol provides access to
cis-β-heteroaryl amino cycloalkanols with up to 99.9%
enantiomeric excess (ee) and a diastereomer ratio (dr) up to
99/1.
We began our optimization study with rac-2-(4-phenyl-1H-
1,2,3-triazol-1-yl)-3,4-dihydronaphthalen-1(2H)-one (1a) as a
model substrate. First, a unique and well-documented chiral
ligand in ATH N-sulfonylated 1,2-diamines7 with various
ruthenium complexes was examined for hydrogenation of the
model substrate (Table 1). A high ee was observed with catalyst
Received: November 7, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03334
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Catalyst and Solvent Screening
Table 2. Catalyst Loading, Temperature, and Time
Screening
a
catalyst loading
(mol %)
temp
(°C)
time
(h)
conv (%) (cis/
ee (%)
b
b
entry
trans)
(cis)
1
2
27
27
27
40
60
27
27
27
27
27
48
48
48
48
48
24
12
06
03
01
99/1
99/1
58/1
99/1
99/1
99/1
99/1
99/1
87/1
50/1
94
>99
>99
94
2
1
3
0.5
1
4
b
b
entry catalyst
solvent
CH2Cl2
conv (%) (cis/trans)
ee (%) (cis)
5
1
93
1
2
3
4
5
6
7
8
9
10
A
15/05
18/02
28/02
99/01
80/20
82/18
78/22
96/04
94/06
98/02
85/15
50/04
99/01
93
95
97
94
91
92
90
92
90
91
88
92
94
6
1
>99
>99
>99
>99
99
B
CH2Cl2
CH2Cl2
CH2Cl2
CH3OH
C2H5OH
(CH3)2CHOH
toluene
CH3CN
THF
7
1
C
D
D
D
D
D
D
D
D
D
D
8
1
9
1
10
1
a
Conditions: 0.5 mmol of 1a, respective mol % of (R,R)-D, and 0.5
mL of FA/TEA (5:2) were added into DCM (3.0 mL), and the
mixture was stirred at the respective time and temperature.
b
Conversions and ee were calculated from chiral HPLC.
a
11
DMF
Scheme 2. Substrate Scope
c
12
CH2Cl2
CH2Cl2
d
13
a
Conditions: 0.5 mmol of 1a, 2 mol % of catalyst, and 0.5 mL of FA/
TEA (5:2) were added to the solvent (3.0 mL), and the mixture was
b
stirred at 27 °C for 48 h. Conversions and ee were calculated from
c
d
chiral HPLC. FA/TEA (0.2:1) was used. FA/TEA (5:2) was added
in portions over 2 h.
(R,R)-A, (R,R)-B, and (R,R)-C in DCM, but conversion was on
the lower side (Table 1, entries 1−3). The complete conversion
was obtained by using tethered Ru−TsDPEN catalyst (R,R)-D
developed by Wills and co-workers8 with excellent diastereo-
and enantioselectivity (Table 1, entry 4). A solvent study was
carried out using tethered complex (R,R)-D (Table 1, entries
4−11). It was found that polar protic solvents were able to give
high % ee, but the dr ratio was low (Table 1, entries 5−7).
However, aprotic solvents were able to furnish high % ee and dr
(Table 1, entries 4, 8−11). We observed that DCM gave the
highest % ee and dr (Table 1 entry 4). Thus, DCM was
selected as the optimized solvent for further studies. Next, the
ratio of FA/TEA was altered to check its effect on % ee. When
the ratio of FA/TEA was taken as 0.2/1, a lower conversion
was observed with no effect on % ee (Table 1, entry 12).
Prolonged addition of hydrogen source did not show any
improvement in % ee and dr (Table 1, entry 13).
In order to increase enantioselectivity of cis-isomer, the effect
of catalyst loading was examined (Table 2, entries 1−3).
Delightfully, a catalyst loading of 1 mol % is sufficient enough
to produce the highest % ee with no loss in conversion (Table
2, entry 2). Decreasing the catalyst loading to 0.5 mol %
resulted in a lower conversion (Table 2, entry 3). An increase in
temperature leads to a decrease in diasteroselectivity as well as
enantioselectivity (Table 2, entries 4 and 5). A detailed time
study revealed that 6 h is enough to achieve maximum diastero-
and enantioselectivity (Table 2, entries 6−10).
a
Conditions: 0.5 mmol of 1a, 1 mol % of (R,R)-D, and 0.5 mL of FA/
With the optimized reactions conditions in hand, a range of
different substrates were hydrogenated in the presence of
tethered Ru−TsDPEN catalyst by using FA/TEA as the
hydrogen source (Scheme 2). For a better understanding, the
TEA (5:2) were added into CH2Cl2 (3.0 mL), and the mixture was
stirred at 27 °C for 6 h. The yields were for the mixture of cis/trans-
isomers isolated by preparative chromatography. The dr and ee values
were determined by chiral HPLC.
B
DOI: 10.1021/acs.orglett.6b03334
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substrates were divided in different groups depending on the
substitution pattern. In group 1, the substrates 1a, 1b, and 1c
having phenyl and substituted phenyl groups on the triazole
nucleus, gave 2a, 2b, and 2c in excellent % ee and dr. In group
2, we studied the effect of substitution on the triazole nucleus
by replacing the phenyl group with alkyl chains and alicyclic
counterparts. This resulted in a marginal decrease in % ee in the
case of 2d and 2e, whereas 2f was obtained with 87.6% ee.
However, no effect on dr was observed in group 2. To extend
the substrates scope and considering the pharmacological
importance of imidazole and the pyrazole nucleus at the β-
position of cycloalkanols, we further included the benzotriazole
(1g), imidazole (1h), and pyrazole (1i) nucleus at the α-
position of the substrates. The corresponding cycloalkanols 2g,
2h, and 2i were obtained in 88.3%, 99.5%, and 91.8% ee,
respectively, with uniform dr of 99/1 in group 3. In group 4, the
tetralone functionality was replaced by cyclohexanone
functionality. Substrates 1j, 1k and 1l were efficiently reduced
by a marginal decrease in % ee and dr. In group 5, we combined
the cyclohexanone functionality with different heterocyclic
nuclei. As compared to group 3, we observed a decrease in %
ee, especially in the case of 2n and 2o. We observed that
varying the cycloalkanone ring size in group F results in 95.5%
ee in the case of cycloheptanone (2p) and 91.5% ee in the case
of indanone (2r). However, the cyclopentanone (2q)
functionality brings down the % ee to 25.2.
presence of sodium hydride in DMF. The product 1-((1R,2S)-
2-((3-chlorobenzyl)oxy)cyclohexyl)-1H-imidazole was isolated
with 52% yield (SI).
In continuation, considering the ability of chiral ionic liquid
in inducing chirality in organic transformations, substrate 2h
was n-alkylated with n-butyl bromide to afford chiral ionic
liquid 5 in 65% yield (Scheme 4 and SI).
Scheme 4. Synthesis of Chiral Ionic Liquid
To determine the stereochemistry of the stereogenic centers,
the compound with anomalous scatterer [5-bromo-2-(4-
phenyl-1H-1,2,3-triazol-1-yl)-2,3-dihydro-1H-inden-1-one]
(1s) was synthesized. DKR-ATH of 1s with optimized reaction
conditions afforded 2s in 78% yield with 99% ee (99/1 dr).
Recrystallization from n-hexane/DCM and subsequent X-ray
crystallographic analysis revealed that the absolute config-
uration at the vicinal carbon atoms was determined to be 1S,2R
(Figure 2) (see the SI).
The ruthenium-catalyzed-transfer hydrogenation proceeds
through the well-known catalytic cycle for the hydrogenation of
ketones.2j,8g,9 The proposed catalytic cycle in this case is shown
in the Supporting Information. The plausible transition states
for this DKR-ATH catalyzed by the tethered Ru−TsDPEN
complex (R,R)-D with 1h is shown in Figure 1. The transition
Figure 2. X-ray structure of 2s (CCDC 15122464).
Figure 1. Plausible transition states ([Ts-S] and [Ts-R]) for the DKR-
ATH of 1h with (R,R)-D.
In conclusion, tethered Ru−TsDPEN complex catalyzed
synthesis of cis-β-heteroaryl amino cycloalkanols by DKR-ATH
was developed for the first time. Through this protocol, a range
of cis-β-heteroaryl amino cycloalkanols with two contiguous
chiral centers could be synthesized with excellent diastereo- and
enantioselectivities. The established methodology was applied
for the synthesis of an antileishmanial agent and a chiral ionic
liquid. The absolute configuration of the vicinal chiral centers
was determined by single-crystal X-ray analysis and was found
to be 1S,2R.
state [Ts-S] of (R,R)-D with S-1h is unfavored because of steric
hindrance, whereas [Ts-R] is favored due to lack of steric
hindrance, thereby producing the 2h with cis-selectivity
((1S,2R)-isomer).
The synthetic utility of this methodology was demonstrated
by carrying out the synthesis of the antileishmanial agent 4
(Scheme 3). This was carried out by preparing (1R,2S)-2-(1H-
imidazol-1-yl)cyclohexanol (3) followed by the alkylation of the
hydroxyl group in 3 using 3-chlorobenzyl bromide in the
ASSOCIATED CONTENT
■
S
* Supporting Information
Scheme 3. Synthesis of Antileishmanial Drug
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03334.
Synthetic details for substrates; typical procedures for
asymmetric transfer hydrogenation reactions; NMR
spectra; HPLC data (PDF)
Crystallographic data for compound 2s (CIF)
C
DOI: 10.1021/acs.orglett.6b03334
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Montejo-Bernardo, J.; García-Granda, S.; Gotor, V.; Luis, S.; García-
AUTHOR INFORMATION
■
Verdugo, E.; Gotor-Fernan
́
dez, V. ChemCatChem 2011, 3, 1921−1928.
Corresponding Author
*E-mail: bm.bhanage@gmail.com.
ORCID
(d) Paul, C.; Gotor-Fernan
́
dez, V.; Lavandera, I.; Montejo-Bernardo,
J.; García-Granda, S.; Gotor, V. RSC Adv. 2012, 2, 6455−6463.
(e) Porcar, R.; Ríos-Lombardía, N.; Busto, E.; Gotor-Fernandez, V.;
́
Gotor, V.; Garcia-Verdugo, E.; Burguete, M.; Luis, S. Catal. Sci.
Technol. 2013, 3, 2596−2601. (f) Vasiloiu, M.; Gaertner, P.; Zirbs, R.;
Bica, K. Eur. J. Org. Chem. 2015, 2015, 2374−2381.
Bhalchandra M. Bhanage: 0000-0001-9538-3339
Notes
(6) (a) Kotsuki, H.; Hayashida, K.; Shimanouchi, T.; Nishizawa, H. J.
Org. Chem. 1996, 61, 984−990. (b) Torregrosa, R.; Pastor, I.; Yus, M.
Tetrahedron 2007, 63, 469−473. (c) Bhanushali, M.; Nandurkar, N.;
Bhor, M.; Bhanage, B. Tetrahedron Lett. 2008, 49, 3672−3676. (d) Lu,
H.-F.; Sun, L.-L.; Le, W.-J.; Yang, F.-F.; Zhou, J.-T.; Gao, Y.-H.
Tetrahedron Lett. 2012, 53, 4267−4272. (e) Shinde, S. S.; Said, M. S.;
Surwase, T. B.; Kumar, P. Tetrahedron Lett. 2015, 56, 5916−5919.
(7) (a) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226−236.
(b) Ikariya, T.; Blacker, A. Acc. Chem. Res. 2007, 40, 1300−1308.
(c) Wang, C.; Wu, X.; Xiao, J. Chem. - Asian J. 2008, 3, 1750−1770.
(d) Morris, R. H. Chem. Soc. Rev. 2009, 38, 2282−2291. (e) Chen, F.;
Wang, T. L.; He, Y. M.; Ding, Z. Y.; Li, Z. W.; Fan, Q. H. Chem. - Eur.
J. 2011, 17, 1109. (f) Ding, Z. Y.; Chen, F.; Qin, J.; He, Y. M.; Fan, Q.
H. Angew. Chem., Int. Ed. 2012, 51, 5706. (g) Li, Y.-Y.; Yu, S.-L.; Shen,
W.-Y.; Gao, J.-X. Acc. Chem. Res. 2015, 48, 2587−2598. (h) Liu, R.;
Zhou, G.; Hall, T.; Clarkson, G.; Wills, M.; Chen, W. Adv. Synth. Catal.
2015, 357, 3453−3457. (i) Vyas, V. K.; Bhanage, B. M. Org. Chem.
Front. 2016, 3, 614−619.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
V.K.V. is thankful to the Department of Science and
Technology (DST), New Delhi, India, for providing a Senior
Research Fellowship (SRF).
REFERENCES
■
(1) Representative papers and reviews for DKR-AH: (a) Bai, W.; Xie,
J.; Li, Y.; Liu, S.; Zhou, Q. Adv. Synth. Catal. 2010, 352, 81−84.
(b) Perez, M.; Echeverria, P.; Martinez-Arripe, E.; Zoubir, M.; Touati,
R.; Zhang, Z.; Genet, J.; Phansavath, P.; Ayad, T.; Ratovelomanana-
Vidal, V. Eur. J. Org. Chem. 2015, 2015, 5949−5958. (c) Echeverria, P.-
G.; Ayad, T.; Phansavath, P.; Ratovelomanana-Vidal, V. Synthesis 2016,
48, 2523−2539. (d) Horiguchi, K.; Yamamoto, E.; Saito, K.;
Yamanaka, M.; Akiyama, T. Chem. - Eur. J. 2016, 22, 8078−8083.
(2) Representative papers and reviews for DKR-ATH (a) Mohar, B.;
Valleix, A.; Desmurs, J.-R.; Felemez, M.; Wagner, A.; Mioskowski, C.
Chem. Commun. 2001, 0, 2572−2573. (b) Alcock, N.; Mann, I.; Peach,
P.; Wills, M. Tetrahedron: Asymmetry 2002, 13, 2485−2490. (c) Ding,
Z.; Yang, J.; Wang, T.; Shen, Z.; Zhang, Y. Chem. Commun. 2009, 0,
(8) Representative paper for Ru-tethered catalysts: (a) Hannedouche,
J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2004, 126, 986−987.
(b) Cheung, F. K.; Hayes, A. M.; Hannedouche, J.; Yim, A. S. Y.; Wills,
M. J. Org. Chem. 2005, 70, 3188−3197. (c) Hayes, A. M.; Morris, D. J.;
Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2005, 127, 7318−7319.
(d) Morris, D. J.; Hayes, A. M.; Wills, M. J. Org. Chem. 2006, 71,
571−573. (d) Cartigny, D.; Puntener, K.; Ayad, T.; Scalone, M.;
̈
Ratovelomanana-Vidal, V. Org. Lett. 2010, 12, 3788−3791. (e) Stew-
ard, K.; Corbett, M.; Goodman, C.; Johnson, J. J. Am. Chem. Soc. 2012,
134, 20197−201206. (f) Son, S.-M.; Lee, H.-K. J. Org. Chem. 2013, 78,
8396−8404. (g) Corbett, M.; Johnson, J. J. Am. Chem. Soc. 2013, 135,
594−597. (h) Son, S.-M.; Lee, H.-K. J. J. Org. Chem. 2014, 79, 2666−
2681. (i) Monnereau, L.; Cartigny, D.; Scalone, M.; Ayad, T.;
Ratovelomanana-Vidal, V. Chem. - Eur. J. 2015, 21, 11799−11806.
(j) Cheng, T.; Ye, Q.; Zhao, Q.; Liu, G. Org. Lett. 2015, 17, 4972−
4975. (k) Wang, D.; Astruc, D. Chem. Rev. 2015, 115, 6621−6686.
(3) Representative paper for DKR of amino ketones: (a) Ros, A.;
́
7035−7044. (e) Cheung, F. K.; Lin, C.; Minissi, F.; Criville, A. L.;
Graham, M. A.; Fox, D. J.; Wills, M. Org. Lett. 2007, 9, 4659−4662.
(f) Martins, J. E. D.; Morris, D. J.; Tripathi, B.; Wills, M. J. Organomet.
Chem. 2008, 693, 3527−3532. (g) Soni, R.; Collinson, J.-M.; Clarkson,
G. C.; Wills, M. Org. Lett. 2011, 13, 4304−4307. (h) Jolley, K. E.;
Hancock, A. Z.-G. F.; Dyke, A.; Grainger, D. M.; Medlock, J. A.;
Nedden, H. G.; Paih, J. J. M. L.; Roseblade, S. J.; Seger, A.; Sivakumar,
V.; Morris, D. J.; Wills, M. Adv. Synth. Catal. 2012, 354, 2545−2555.
(9) (a) Wu, X.; Li, X.; Hems, W.; King, F.; Xiao, J. Org. Biomol. Chem.
2004, 2, 1818−1821. (b) Wu, X.; Li, X.; King, F.; Xiao, J. Angew.
Chem. 2005, 117, 3473−3477. (c) Peach, P.; Cross, D. J.; Kenny, J. A.;
Mann, I.; Houson, I.; Campbell, L.; Walsgrove, T.; Wills, M.
Tetrahedron 2006, 62, 1864−1876.
́
Magriz, A.; Dietrich, H.; Fernandez, R.; Alvarez, E.; Lassaletta, J. Org.
Lett. 2006, 8, 127−30. (b) Liu, S.; Xie, J.; Wang, L.; Zhou, Q. Angew.
Chem., Int. Ed. 2007, 46, 7506−7508. (c) Liu, S.; Xie, J.-H.; Li, W.;
Kong, W.-L.; Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2009, 11, 4994−
4997. (d) Xie, J.-H.; Liu, S.; Kong, W.-L.; Bai, W.-J.; Wang, X.-C.;
Wang, L.-X.; Zhou, Q.-L. J. Am. Chem. Soc. 2009, 131, 4222−4223.
(e) Seashore-Ludlow, B.; Villo, P.; Hacker, C.; Somfai, P. Org. Lett.
̈
2010, 12, 5274−5277. (f) Limanto, J.; Krska, S.; Dorner, B.; Vazquez,
E.; Yoshikawa, N.; Tan, L. Org. Lett. 2010, 12, 512−515. (g) Hu, Q.;
Chen, J.; Zhang, Z.; Liu, Y.; Zhang, W. Org. Lett. 2016, 18, 1290−
1293.
(4) (a) Marrapu, V.; Srinivas, N.; Mittal, M.; Shakya, N.; Gupta, S.;
Bhandari, K. Bioorg. Med. Chem. Lett. 2011, 21, 1407−1410.
(b) Yousuf, S.; Majeed, R.; Ahmad, M.; Sangwan, P.; Purnima, B.;
Saxsena, A. K.; Suri, K. A.; Mukherjee, D.; Taneja, S. Steroids 2011, 76,
1213−1222. (c) Feher
́
, K.; Balogh, J.; Csok
Skoda-Foldes, R. Steroids 2012, 77, 738−44. (d) Anastasopoulou, P.;
́
, Z.; Keg
́
l, T.; Kollar
́
, L.;
̈
Kythreoti, G.; Cosmidis, T.; Pyrkotis, C.; Nahmias, V.; Vourloumis, D.
Bioorg. Med. Chem. Lett. 2014, 24, 1122−1126. (e) Saikia, P.; Kaishap,
P.; Goswami, J.; Singh, A.; Boruah, H.; Gogoi, S.; Boruah, R. Steroids
2014, 84, 36−45.
(5) (a) Busto, E.; Gotor-Fernan
Verdugo, E.; Alfonso, I.; García-Granda, S.; Menen
Burguete, M.; Luis, S.; Gotor, V. Tetrahedron Lett. 2007, 48, 5251−
5254. (b) Ríos-Lombardía, N.; Busto, E.; Gotor-Fernandez, V.; Gotor,
V.; Porcar, R.; García-Verdugo, E.; Luis, S. V.; Alfonso, I.; García-
Granda, S.; Menendez-Velazquez, A. Chem. - Eur. J. 2010, 16, 836−
847. (c) Ríos-Lombardía, N.; Porcar, R.; Busto, E.; Alfonso, I.;
́
dez, V.; Ríos-Lombardía, N.; García-
́
dez-Velazquez, A.;
́
́
́
́
D
DOI: 10.1021/acs.orglett.6b03334
Org. Lett. XXXX, XXX, XXX−XXX