Total synthesis of chromanol 293B and cromakalim via stereoselective amination of chiral benzylic ethers

Article abstract of DOI:10.1016/j.tetlet.2019.151431

Stereoselective benzylic amination reaction is important for their further application as pharmaceuticals and agrochemicals, and other chemical entities. Herein, we describe the diastereoselective amination of 1,2-anti-dialkoxychromane on chromane framewo

Full text of DOI:10.1016/j.tetlet.2019.151431

Journal Pre-proofs
Total Synthesis of Chromanol 293B and Cromakalim via Stereoselective Ami-
nation of Chiral Benzylic Ethers
Sang-Ho Ma, Yeon Su Kim, Jun Min Jung, Pulla Reddy Boggu, Seung Chan
Kim, In Su Kim, Young Hoon Jung
PII:
S0040-4039(19)31222-5
DOI:
https://doi.org/10.1016/j.tetlet.2019.151431
TETL 151431
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
17 October 2019
18 November 2019
20 November 2019
Please cite this article as: Ma, S-H., Su Kim, Y., Min Jung, J., Reddy Boggu, P., Chan Kim, S., Su Kim, I., Hoon
Jung, Y., Total Synthesis of Chromanol 293B and Cromakalim via Stereoselective Amination of Chiral Benzylic
Ethers, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151431
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Total Synthesis of Chromanol 293B and
Cromakalim via Stereoselective Amination
of Chiral Benzylic Ethers
Leave this area blank for abstract info.
Sang-Ho Ma, Yeon Su Kim, Jun Min Jung, Pulla Reddy Boggu, Seung Chan Kim, In Su Kim and Young Hoon
Jung*
O
Me
S
O
Me
NHCO Me
N
2
OMe
O
NC
NC
OMe
NC
OH
NC
OMe
Me
CSI
4 steps
Me
Me
Me
Me
O
O
Me
9
0%, dr = 98:2 dr
Chromanol 293B
NHCO Me
2
O
N
OMe
O
OMe
NC
OMe
Me
CSI
NC
OH
4
steps
Me
Me
O
Me
Me
Cromakalim
O
Me
8
8%, dr = 96:4 dr

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Total Synthesis of Chromanol 293B and Cromakalim via Stereoselective
Amination of Chiral Benzylic Ethers
Sang-Ho Ma, Yeon Su Kim, Jun Min Jung, Pulla Reddy Boggu, Seung Chan Kim, In Su Kim, and Young
Hoon Jung*
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Stereoselective benzylic amination reaction is important for their further application as
pharmaceuticals and agrochemicals, and other chemical entities. Herein, we describe the
diastereoselective amination of 1,2-anti-dialkoxychromane on chromane framework using
chlorosulfonyl isocyanate. Notably, the utility of this protocol is highlighted by the total
synthesis of chromanol 293B and cromakalim.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Amination
Chromanol
Cromakalim
Chlorosulfonyl isocyanate
Total synthesis
1
. Introduction
chromanol 293B (Scheme 1). Initially, (2H)-chromene 1 was
smoothly reacted with m-CPBA in the presence of (R,R)-
Jacobsen catalyst and N-methylmorpholine-N-oxide (NMO) to
Bicyclic molecules with amine functionality at the benzylic
position are attractive from the perspectives of medicinal
chemistry and drug discovery due to their remarkable therapeutic
potential. In particular, 4-amino-3-chromanols are privileged
heterocyclic units that are found in a number of pharmaceuticals
for the treatment of arrhythmia, hypertension, migraine, and
cystic fibrosis (Figure 1). Conventional route for 4-amino-3-
5
afford the chiral epoxide 2 in 99% yield. Regioselective
i
hydrolysis of chiral epoxide 3 was subjected with Ti(O Pr)
4
and
1
2
H O to give 1,2-anti-diol adduct 3, which was coupled with BnBr
or MeI, furnishing 1,2-anti-dibenzyloxychromane 4 and 1,2-anti-
dimethoxychromane 5, respectively.
2
chromanol scaffold is the asymmetric epoxidation of chromenes
followed by regioselective ring-opening reaction using various
O
2
a
Me
S
Me
O
amine nucleophiles. For example, chromanol 293B as a
N
O
N
O
2
b
+
selective IKs-channel blocker and cromakalim as a selective K -
channel opener were synthesized by the stereoselective amination
of chiral expoxides for the formation of anti-amino alcohol
moiety. Recently, our group has developed the regioselective and
stereoselective amination of allylic and benzylic ethers using
NC
OH
NC
OH
F
Cl
Me
Me
Me
Me
O
Chromanol 293B
(IKs-channel blocker
for arrhythmia)
Cromakalim
+
(K -channel opener
for hypertension)
O
O
NH
O
3
chlorosulfonyl isocyanate (CSI). Notably, this method provided
OH
Me
Me
a facile route for the total synthesis of carbocyclic bioactive
4
a
4b
molecules such as (+)-sertraline, (+)-indatraline, and (+)-
HN
Me
H
4
c
neplanocin A. In connection with our previous works on the
stereoselective amination of chiral benzylic ethers using CSI, we
herein report the stereoselective amination of 1,2-anti-
dialkoxychromane on chromane framework and its application to
the total synthesis of chromanol 293B and cromakalim.
N
OH
Me
Tonabersat
(
gab junction modulator
O
for migraine)
MeO
O
O N
2
Me
NIP-142
(multi ionchannel blocker for
cystic fibrosis)
2
. Results and discussion
Figure 1. Structure of bioactive 4-amino-3-chromanol compounds.
Our study started from the efficient construction of chiral 1,2-
Subsequently, the diastereoselectivity of the reaction of 4 with
anti-dialkoxychromane as key precursors for the synthesis of
CSI was evaluated under various reaction conditions, and
_
_______
*
Corresponding author. Tel.: +82-31-290-7711; fax: +82-31-292-8800; e-mail: yhjung@skku.edu

2
Tetrahedron
selected results are summarized in Table 1. The reaction of
,2-anti-dibenzyloxychromane 4 with CSI in CH Cl solvent at 0
C afforded benzyl carbamate 6 in 60% yield with 80:20 of
diastereomeric ratio (Table 1, entry 1). Next, screening of
solvents revealed that toluene is more effective than CH Cl , and
n-hexane, but both chemical yield and diastereoselectivity still
displayed unsatisfactory results (Table 1, entries 2–4). Thus, we
further screened the reactivity and diastereoselectivity of the
reaction of 1,2-anti-dimethoxychromane 5. To our delight, a high
yield (90%) and an excellent diastereoselectivity (98:2) on
product 7 were observed in toluene solvent at –20 °C under
otherwise identical reaction conditions (Table 1, entry 9). These
results suggested that the methyl group is very crucial for the
diastereoselectivity as well as yield. The observed
stereochemistry can be rationalized by the competition between
remove a carbamate group of 7 to provide free-(NH
2
)-amine 8 in
6
1
°
2
2
a high yield (82%), as shown in entry 3.
To complete the synthesis of chromanol 293B, compound 8
was reacted with EtSO Cl to afford sulfonamide 9, which was
further methylated with MeI, generating 10 in 96% yield
Scheme 2). Finally, demethylation of 10 with BBr gave
2
2
2
(
3
chromanol 293B in 87% yield. The spectroscopic data and
specific rotation value of synthesized chromanol 293B were in
full agreement with the reported literatures.
2
a
Table 2. Deprotection of carbamate groupa
NHCO2Me
NH2
NC
OMe
NC
OMe
Me
reagent, solvent
reflux, 4 h
the S
the S
N
i mechanism leading to retention of stereochemistry and
1 mechanism inducing racemization through carbocation
Me
O
O
N
Me
Reagent
Me
4
a
intermediate. Notably, a toluene solvent at low temperature
might mainly affect the S i mechanism through tight ion pair
intermediate in a four-centered transition state. It has been
reported that the reaction proceeds in the same S i manner in the
7
8
b
N
Entry
Solvent
1,4-dioxane/H
EtOH/H
THF
Yield (%)
1
2
3
LiOH·H
2
2
O
O
2
O (3:1)
12
5
N
LiOH·H
2
O (95:5)
case of the benzylic alkoxy compound without homobenzylic
alkoxy group under the above reaction conditions.4a
TBAF
82
a
Reaction conditions: reagent (5 equiv.), solvent (0.48 M) at reflux for 4 h.
O
i
NC
(R,R)-Jacobsen cat. NC
NMO, m-CPBA
Ti(O Pr)4
THF/H2O
b
Isolated yield by column chromatography.
Me
Me
Me
Me
2, 99%, ee = 90%
O
CH Cl , 0 oC to rt, 1 h
O
0 oC to rt, 4 h
2
2
O
1
S
O
Me
NH2
O
HN
OH
OR
NC
OMe
Me
NC
OMe
EtSO2Cl, Et3N
CH2Cl2, rt, 2 h
NaH, MeI
NC
OH
NC
OR
Me
NaH, BnBr or MeI
THF, rt, 12 h
Me
Me
THF, rt, 2 h
Me
O
Me
Me
O
O
Me
8
9
, 90%
4
5
, 78% (R = Bn)
, 82% (R = Me)
3
, 99%
O
O
Me
S
Me
Me
S
Me
Scheme 1. Synthesis of chiral 1,2-anti-dibenzyl ethers.
N
N
O
O
OH
NC
OMe
BBr3, CH2Cl2
-78 oC, 6 h
NC
Me
Me
Me
Me
chromanol 293B, 87%
O
O
Table 1. Optimization for the reaction of 4 and 5 with CSIa
1
0, 96%
Scheme 2. Total synthesis of chromanol 293B
OR
NHCO2R
OR
NC
OR
Me
i) CSI, Na CO , solvent
NC
2
3
(
S,S)-Jacobsen cat.
NMO, m-CPBA
O
HClO4
NC
NC
ii) sat. Na2SO3
Me
Me
O
O
THF/H2O
Me
Me
Me
CH2Cl2, 0 oC to rt, 4 h
Me
Me
O
O
rt, 0.5 h
4
or 5
6 (R = Bn), 7 (R = Me)
b
drc
1
11, 94%, ee=91%
Entry
Ethers
Solvent
CH Cl
Temp (°C)
Yield (%)
OH
OMe
1
2
3
4
5
6
7
8
9
4
4
4
4
4
5
5
5
5
5
2
2
0
0
60
20
68
65
53
85
83
88
90
50
80:20
67:33
80:20
83:17
83:17
94:6
i) CSI, Na2CO3, toluene
NC
OH
Me
NC
OMe
Me
o
NaH, MeI
-20 C, 72 h
n-hexane
toluene
toluene
toluene
THF, rt, 12 h
2 3
ii) sat. Na SO , rt, 12 h
O
O
Me
Me
rt
1
2, 85%
13, 92%
0
NHCO2Me
OMe
NH2
–20
0
4-chlorobutanoyl
chloride
NC
NC
OMe
TBAF, THF
2 2
CH Cl
Me
Me
Me
Me
reflux, 4 h
Et3N, CH2Cl2, rt, 0.5 h
O
O
toluene
toluene
toluene
toluene
rt
92:8
1
4, 88% (dr = 96:4)
15, 72%
0
96:4
Cl
O
–20
–78
98:2
O
N
HN
KI, K2CO3
NC
OMe
Me
NC
OMe
1
0
93:7
acetone, reflux, 24 h
Me
Me
a
Reaction conditions: i) Chlorosulfonyl isocyanate (20 equiv.), Na
2
CO
3
(20
O
O
Me
equiv.), solvent (0.15 M) at indicated temperature for 72 h; ii) saturated
16, 90%
17, 89%
2 3
Na SO solution at rt for 12 h.
O
N
BBr3, CH2Cl2
78 oC, 6 h
b
NC
OH
Isolated yield by column chromatography.
-
Me
Me
c
Diastereomeric ratio was determined by 1H NMR analysis of a crude
O
reaction mixture.
cromakalim, 91%
Scheme 3. Total synthesis of cromakalim.
Next, the deprotection of a carbamate group of 7 was
performed, as shown in Table 2. Basic hydrolysis conditions
were found to be unsuccessful in this transformation (Table 2,
entries 1 and 2). Surprisingly, TBAF could be readily used to
Inspired by the above results, we further examined the total
synthesis of cromakalim as an enantiomeric analogue of
chromanol 293B (Scheme 3). Compound 1 was readily converted

3
into 1,2-anti-dialkoxychromane 13 in good yields through
2. (a) Gerlach, U.; Brendel, J.; Lang, H.-J.; Paulus, E. F.;
7
asymmetric epoxidation, HClO
4
-mediated hydrolysis, and O-
Weidmann, K.; Brüggemann, A.; Busch, A. E.; Suessbrich, H.;
Bleich, M.; Greger, R. J. Med. Chem. 2001, 44, 3831–3837. (b)
Sebille, S.; Gall, D.; de Tullio, P.; Florence, X.; Lebrun, P.;
Pirotte, B. J. Med. Chem. 2006, 49, 4690–4697. (c) Kim, Y.;
Griffin, J. M.; Nor, M. N. M.; Zhang, J.; Freestone, P. S.; Danesh-
Meyer, H. V.; Rupenthal, I. D.; Acosta, M.; Nicholson, L. F. B.;
O’Carroll, S. J.; Green, C. R. Neurotherapeutics 2017, 14, 1148–
1165. (d) Nagasawa, H.; Fujiki, A.; Fujikura, N.; Matsuda, T.;
Yamashita, T.; Inoue, H. Circ. J. 2002, 66, 185–191.
methylation. The reaction of 13 with CSI under the optimized
reaction conditions afforded 1,2-anti-amino alcohol adduct 14 in
8
8% yield with a diastereoselectivity of 96:4. Exchange of amido
group was performed with a treatment of TBAF and subsequent
-chlorobutanoyl chloride to furnish 16, which underwent
4
intramolecular cyclization to give 17 in 89% yield. Finally,
cromakalim was formed in 91% by demethylation reaction using
BBr .
3
3
.
(a) Lee, S. H.; Kim, I. S.; Li, Q. R.; Dong, G. R.; Jung, Y. H.
Tetrahedron Lett. 2011, 52, 1901–1904. (b) Kim, S. J.; Jeon, T.
H.; Min, I. S.; Kim, I. S.; Jung, Y. H. Tetrahedron Lett. 2012, 53,
3
. Conclusion
In conclusion, we have described the diastereoselective
amination of 1,2-anti-dialkoxychromane on chromane framework
3
680–3682.
using chlorosulfonyl isocyanate. Notably, the reaction of 1,2-
Total Synthesis of Chromanol 293B and
Cromakalim via Stereoselective Amination
of Chiral Benzylic Ethers
Leave this area blank for abstract info.
Sang-Ho Ma, Yeon Su Kim, Jun Min Jung, Pulla Reddy Boggu, Seung Chan Kim, In Su Kim and Young Hoon
Jung*
O
Me
S
O
Me
NHCO Me
N
2
OMe
O
NC
NC
OMe
NC
OH
NC
OMe
Me
CSI
4 steps
Me
Me
Me
Me
O
O
Me
9
0%, dr = 98:2 dr
Chromanol 293B
NHCO Me
2
O
N
OMe
O
OMe
NC
OMe
Me
CSI
NC
OH
4
steps
Me
Me
O
Me
Me
Cromakalim
O
Me
8
8%, dr = 96:4 dr
anti-dialkoxychromane with chlorosulfonyl isocyanate in toluene
solvent afforded exclusively the anti-1,2-amino alcohols in high
yield with excellent level of diastereoselectivities. These
4. (a) Lee, S. H.; Kim, I. S.; Li, Q. R.; Dong, G. R.; Jeong, L. S.;
Jung, Y. H. J. Org. Chem. 2011, 76, 10011–10019. (b) Lee, S. H.;
Park, S. J.; Kim, I. S.; Jung, Y. H. Tetrahedron 2013, 69, 1877–
1880. (c) Jung, Y. H.; Kim, S. I.; Hong, Y. J.; Park, S. J.; Kang, K.
T.; Kim, S. Y.; Kim, I. S. Tetrahedron 2015, 71, 1068–1073.
N
observations can be explained by S i mechanism leading to
retention of stereochemistry of methyl ethers at the benzylic
position. Therefore, we believe that this synthetic strategy can be
readily applied to the preparation of heterocyclic molecules with
amine functionality at the benzylic position.
5
.
(a) Wang, D.; Wang, W.; Wang, X.; Chen, Y.; Gao, A.; Sun, L. J.
Catal. 2006, 237, 248–254. (b) Wang, Q.; She, X.; Ren, X.; Ma,
J.; Pan, X. Tetrahedron: Asymmetry 2004, 15, 29–34.
Acknowledgements
6
7
.
.
Jacquemard, U.; Bénéteau, V.; Lefoix, M.; Routier, S.; Mérour, J.-
This work was supported by the National Research Foundation
of Korea (NRF) funded by the Korea government (MSIP) (No.
Y.; Coudert, G. Tetrahedron 2004, 60, 10039–10047.
Patel, R. N.; Banerjee, A.; Davis, B.; Howell, J.; MaNamee, C.;
Brzozowaski, D.; North, J.; Kronenthal, D.; Szarka, L. Bioorg.
Med. Chem. 1994, 2, 535–542.
2
016R1D1A1B03932216).
Appendix A. Supplementary data
Supplementary data (experimental and spectroscopic data for
all compounds) associated with this article can be found in the
online version, at http://
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Appendix A. Supplementary data
Supplementary data (experimental and spectroscopic data for all
compounds) associated with this article can be found in the
online version, at http://
References and notes
1
.
(a) Radesca, L.; Bowen, W. D.; Paolo, L. D.; De Costa, B. R. J.
Med. Chem. 1991, 34, 3058–3065. (b) Roxburgh, C. J. Synthesis
1
996, 307–320. (c) Horarth, J.; Lloyd, D. G. J. Antimicrob.
Chemother. 2000, 46, 625–628.

4
Tetrahedron
8
.
Highlights



Total synthesis of chromanol 293B and
cromakalim
Stereoselective amination of chiral benzylic
ethers using chlorosulfonyl isocyanate
SNi mechanism leading to retention of
stereochemistry
9
.