Dynamic Kinetic Asymmetric Transformation of Racemic Diastereomers: Diastereo- and Enantioconvergent Michael–Henry Reactions to Afford Spirooxindoles Bearing Furan-Fused Rings

Article abstract of DOI:10.1002/anie.202108734

Dynamic kinetic asymmetric transformation (DYKAT) reactions of racemic diastereomer mixtures that afford the products as essentially single diastereomers with high enantioselectivities are described. We demonstrated the DYKAT in the diastereo- and enantio

Full text of DOI:10.1002/anie.202108734

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Accepted Article
Title: Dynamic Kinetic Asymmetric Transformation of Racemic
Diastereomers: Diastereo- and Enantioconvergent Michael-Henry
Reactions to Afford Spirooxindoles Bearing Furan-Fused Rings
Authors: Fujie Tanaka and Muhammad Sohail
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10.1002/anie.202108734
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Dynamic Kinetic Asymmetric Transformation of Racemic
Diastereomers: Diastereo- and Enantioconvergent Michael-Henry
Reactions to Afford Spirooxindoles Bearing Furan-Fused Rings
Muhammad Sohail[a] and Fujie Tanaka*[a]
[a]
Dr. M. Sohail, Prof. Dr. F. Tanaka
Chemistry and Chemical Bioengineering Unit
Okinawa Institute of Science and Technology Graduate University
1919-1 Tancha, Onna, Okinawa 904-0495 (Japan)
E-mail: ftanaka@oist.jp
Supporting information for this article is given via a link at the end of the document.
Abstract: Dynamic kinetic asymmetric transformation (DYKAT)
reactions of racemic diastereomer mixtures that afford the products
as essentially single diastereomers with high enantioselectivities are
described. We demonstrated the DYKAT in the diastereo- and
enantioselective synthesis of spirooxindoles bearing furan-fused
rings. The starting materials of the DYKAT, dihydrobenzofuranone
derivatives, were synthesized in racemic diastereomer mixtures, and
these were transformed to the spirooxindole derivatives in high
yields with high diastereo- and enantioselectivities through Michael-
Henry cascade reactions with nitrostyrenes under organocatalytic
conditions. In the reactions, regardless the stereochemistry of the
starting materials, all the four isomers were transformed to single
diastereomers with high enantioselectivities, and four new chiral
centers were created.
Scheme 1. Dynamic kinetic asymmetric transformation (DYKAT) for the
diastereo- and enantioconvergent synthesis of spirooxindoles bearing furan-
fused ring systems.
Dynamic kinetic resolution (DKR) and dynamic kinetic
asymmetric transformation (DYKAT) of racemic compounds
have been used for the synthesis of enantiomerically enriched
products.[1-3] Reported DKR and DYKAT of racemic starting
materials have mostly been performed on compounds with a
stereogenic center or axis.[1,2] There are only a few reports
regarding DYKAT reactions of racemic diastereomer mixtures
(i.e, compounds having more than one stereogenic center or
axis as starting materials) that give single diastereomer products
in high yields with high enantioselectivities.[3] Such reactions are
usually considered to be difficult.[3] When racemic diastereomers
having two stereogenic centers are used as starting materials of
DYKAT to afford enantiomerically enriched single diastereomer
products in high yields, isomerization at both the stereogenic
centers must occur during the transformation to generate an
actual reactant molecule used for the following selective reaction
step[3a] or all four stereoisomers of the racemic diastereomers
must be transformed to an achiral intermediate to be used for
the enantioselective reaction step.[3b] Here we report DYKAT of
racemic diastereomers with central and axial chiralities that
The development of methods for diastereo- and
enantioselective syntheses of various types of spirooxindoles is
of interest in drug discovery efforts and related research.[2a,4-6]
Furan-fused ring systems, in which at least two rings are fused
with the furan ring, are present in enzyme inhibitors and other
biofunctional natural products.[7] Therefore, we sought strategies
for the synthesis of spirooxindoles bearing furan-fused ring
systems. We designed a route starting from the reaction of
oxindole-derived enones 1 with 1,3-cyclohexanediones 2 to form
1,4-diketone derivatives 3 (Scheme 1). Products 3 were then
transformed into oxindole-functionalized dihydrobenzofuranones
4 by the reactions of the 1,4-diketone moieties. Michael-Henry
reactions of 4 with nitroolefins via DYKAT were designed to
afford spirooxindoles bearing furan-fused ring systems 5. It has
been reported that dihydrobenzofuranones linked to aryl
systems through a single bond are chiral.[8] We observed that 4
were diastereomers based on central chirality and axial chirality.
The axial chirality present in 4 was created by the restricted
rotation of the single bond between the dihydrobenzofuranones
and the oxindoles.[9] Thus, the DYKAT reactions of 4 to afford 5
as single diastereomers in high yields with high
enantioselectivities are distinct from the kinetic resolution
reactions we previously reported that afford spirooxindole
afford
essentially
single
diastereomers
with
high
enantioselectivities (Scheme 1). We demonstrated the DYKAT in
organocatalytic Michael-Henry cascade reactions that construct
four new chiral centers for the synthesis of enantiomerically
enriched spirooxindoles bearing furan-fused ring systems.
1
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10.1002/anie.202108734
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derivatives,5g which give the products in theoretically up to 50%
yield, and also differ from the DYKAT reactions of racemic
reactants that have only one chiral center or axis.1-3
catalyst C occurred through a DYKAT process.[1] Under the
optimized conditions but with catalyst D instead of catalyst C,
the opposite enantiomer of 5a was obtained with high
enantioselectivity as a single diastereomer (Table 2, entry 15).
First, conditions for the synthesis of oxindole-functionalized
dihydrobenzofuranones 4a from 1a and 2a were investigated. As
a result, we found that the reaction in the presence of DBU
followed by the reaction in the presence of TfOH in one pot led
to the formation of 4a from 1a and 2a (Scheme 2, see also
Supporting Information). Compound 1a has multiple electrophilic
reaction sites. For the formation of 4a, first selective formation of
3a was necessary. Treatment of 1a and 2a with acids alone did
not give 4a. Under the optimized conditions, 4a was obtained in
95% yield from 1a in one pot, as a mixture of diastereomers due
to central and axial chiralities.
Table 1. Formation of 4 from 1 and 2 in one pot.[a]
Scheme 2. Reaction of 1a and 2a to afford 4a in one pot.
Using the one pot reaction method, various oxindole
derivatives bearing dihydrobenzofuranones 4 were synthesized
from oxindole-derived enones 1 and 1,3-cyclohexanediones 2
(Table 1). Products 4 bearing various substituents were obtained
in high yields in most cases. Further, 5-substituted-1,3-
cyclohexanediones were successfully used for the formation of
4j and 4k. In all compounds 4 synthesized, diastereomers were
1
observed. Variable temperature H NMR analyses[10] of selected
compounds 4 in deuterated toluene showed that there was no
interconversion between the diastereomers at 25 °C (Supporting
Information), indicating that the rotation of the single bond
between the furan ring and the oxindole moiety was restricted.
For compound 4l, the rotation of the bond involving the axial
chirality was hindered even at 85 °C (Supporting Information).
For the formation of spirooxindoles bearing furan-fused ring
systems 5, catalyst systems and conditions were evaluated in
the Michael-Henry reaction of (±)-4l with nitrostyrene[11] to afford
5a in a high yield with high diastereo- and enantioselectivities
(Table 2). The reaction in the presence of catalyst C in toluene
at room temperature (25 °C) gave 5a as essentially a single
diastereomer (dr >97:3) with an enantiomer ratio (er) of 97:3
(Table 2, entry 11). Addition of 4 Å molecular sieves to the C-
catalyzed reaction led the formation of 5a with er 99:1, also as a
single diastereomer, in a full conversion (100% NMR yield,
Table 2, entry 14). In addition, during the formation of 5a, the dr
of unreacted 4l was the same as that of 4l used for the reaction
[a] See Supporting Information for conditions. [b] Reaction in the presence of
DBU. [c] Reaction in the presence of TfOH. [d] Data taken from Scheme 2. [e]
The dr value shown is for oxindole and furan-derived moieties.
(Supporting
Information).
Thus,
the
diastereo-
and
enantioselective formation of 5a from 4l in the presence of
2
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10.1002/anie.202108734
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Table 2. Evaluations of catalysts and conditions for the reaction of (±)-4l to
afford 5a.[a]
stereogenic centers, was also obtained with high
enantioselectivity.
Table 3. Scope of the reaction of (±)-4 to afford 5 in the presence of catalyst
C.[a]
entry
1
catalyst
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CHCl3
yield [%][b]
dr[b]
er[c]
DBU
10[d]
32
28
25
5
ND[e]
–
2
A
>97:3
>97:3
>97:3
ND[e]
–
3
quinine
88:12
28:72
85:15
90:10
94:6
88:12
93:7
70:30
97:3
97:3
71:29
99:1
4:96
4
quinidine
5
cinchonidine
6
hydroquinine
34
78
12
58
3
>97:3
>97:3
ND[e]
7
hydroquinine
8
hydroquinine
9[f]
10
11
12
13
14[g]
15[g,h]
hydroquinine
toluene
toluene
toluene
tBuC6H5
cyclohexane
toluene
toluene
>97:3
ND[e]
B
C
C
C
C
D
79
75
46
100
99
>97:3
>97:3
>97:3
>97:3
>95:5
[a] Conditions: (±)-4l (0.041 mmol, 1.0 equiv), nitrostyrene (1.5 equiv), and
catalyst (0.1 equiv) in solvent (1.0 mL for entries 1-6, 0.2 mL for entries 7-15)
at rt (25 °C) for 16 h. [b] Determined by 1H NMR analysis of the reaction
mixture. [c] Determined by HPLC analysis after purification. [d] Isolated yield.
[e] Not determined. [f] Reaction at 0 °C. [g] 4 Å molecular sieves (10 mg) were
added. [h] Reaction for 12 h instead of 16 h.
Using the optimal conditions for the formation of 5a (Table 2,
entry 14), various spirooxindole furan-fused tricycles 5 were
synthesized in high yields as single diastereomers with high
enantioselectivities in most cases (Tables 3 and 4). In these
reactions, all the four stereoisomers of 4 were transformed to 5
as single diastereomers with high enantioselectivities, and four
chiral carbon centers were created. Product 5l, which has five
[a] See Supporting Information for conditions. [b] Data after removal of
racemic precipitate. [c] The major product was isolated.
3
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Table 4. Scope of the reaction of (±)-4 to afford 5 in the presence of catalyst C.
mechanisms of the DYKAT step. The results will be reported in
due course.
Acknowledgements
We thank Dr. Michael Chandro Roy, Research Support Division,
Okinawa Institute of Science and Technology Graduate
University for mass analyses. This study was supported by the
Okinawa Institute of Science and Technology Graduate
University.
Keywords: asymmetric catalysis • dynamic kinetic asymmetric
transformation • Michael addition • organocatalysis • spiro
compounds
[1]
[2]
J. Steinreiber, K. Faber, H. Griengle, Chem. Eur. J. 2008, 14, 8060.
a) Z.-J. Zhang, Y.-H. Wen, J. Song, L.-Z. Gong, Angew. Chem. Int. Ed.
2021, 60, 3268; Angew. Chem. 2021, 60, 3268; b) H. Chu, J. Cheng, J.
Yang, Y.-L. Guo, J. Zhang, Angew. Chem. Int. Ed. 2020, 59, 21991;
Angew. Chem. 2020, 132, 22175; c) C.-X. Hu, L. Chen, Di. Hu, X. Song,
Z.-C. Chen, W. Du, Y.-C. Chen Org. Lett. 2020, 22, 8973; d) R. He, X.
Huo, L. Zhao, F. Wang, L. Jiang, J. Liao, W. Zhang, J. Am. Chem. Soc.
2020, 142, 8097; e) A. Matsumoto, K. Asano, S. Matsubara, Org. Lettt.
2019, 21, 2688; f) K.-Q. Chen, Z.-H. Gao, S. Ye, Angew. Chem. Int. Ed.
2019, 58, 1183; Angew. Chem. 2019, 131, 1195; g) P.-J. Yang, L. Qi, Z.
Liu, G. Yang, Z. Chai, J. Am. Chem. Soc. 2018, 140, 17211; h) G.
Zhang, S. Yang, X. Zhang, Q. Lin, D. K. Das, J. Liu, X. Fang, J. Am.
Chem. Soc. 2016, 138, 7932; i) C. G. Goodman, J. S. Johnson, J. Am.
Chem. Soc. 2015, 137, 14574; j) L. Yang, H. Zheng, L. Luo, J. Nan, J.
Liu, Y. Wang, X. Luan, J. Am. Chem. Soc. 2015, 137, 4876; k) M. T.
Corbett, J. S. Johnson, Angew. Chem. Int. Ed. 2014, 53, 255; Angew.
Chem. 2014, 126, 259; l) Y.-M. Wang, C. N. Kuzniewski, V. Rauniyar, C.
Hoong, F. D. Toste, J. Am. Chem. Soc. 2011, 133, 12972; m) B.-C.
Hong, N. S. Dange, C.-S. Hsu, J.-H. Liao, G.-H. Lee, Org. Lett. 2011,
13, 1338; n) B. M. Trost, M. Osipov, G. Dong, J. Am. Chem. Soc. 2010,
132, 15800; o) R. Millet, A. M. Träff, M. L. Patrus, J.-E. Bäckvall, J. Am.
Chem. Soc. 2010, 132, 15182; p) J. D. Jolliffe, R. J. Armstrong, M. D.
Smith, Nat. Chem. 2017, 9, 558.
The absolute and relative stereochemistries of the major
enantiomer of 5a obtained in the presence of catalyst C was
determined by X-ray crystal structural analysis; the absolute
configuration of 5a is shown in Table 3.[12]
To demonstrate the utility of the reaction, product 5a was
transformed to derivatives 6-9. During these reactions, the
enantiopurity of 5a was retained (Scheme 3).
[3]
[4]
a) C. Liu, J.-H. Xie, Y.-L. Li, J.-Q. Chen, Q.-L. Zhou, Angew. Chem. Int.
Ed. 2013, 52, 593; Angew. Chem. 2013, 125, 621; b) Z.-Q. Rong, Y.
Zhang, R. H. B. Chua, H.-J. Pan, Y. Zhao, J. Am. Chem. Soc. 2015,
137, 4944; c) M. Edin, J. Steinreiber, J.-E. Bäckvall, Proc. Natl. Acad.
Sci. 2004, 101, 5761; d) O. M. Beleh, E. Miller, F. D. Toste, S. J. Miller,
J. Am. Chem. Soc. 2020, 142, 16461.
a) G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112, 6104; b) N. Ye, H.
Chen, E. A. Wold, P.-Y. Shi, J. Zhou, ACS Infect. Dis. 2016, 2, 382; c)
N. R. Ball-Jones, J. J. Badillo, A. K. Franz, Org. Biomol. Chem. 2012,
10, 5165; d) D. Cheng, Y. Ishihara, B. Tan, C. F. Barbas, ACS Catal.
2014, 4, 743 and references cited therein; e) A. K. Franz, P. D.
Dreyfuss, S. L. Schreiber, J. Am. Chem. Soc. 2007, 129, 1020; f) B.
Han, X.-H. He, Y.-Q. Liu, G. He, C. Peng, J.-L. Li, Chem. Soc. Rev.
2021, 50, 1522.
[5]
a) C. Qian, P. Li, J. Sun, Angew. Chem. Int. Ed. 2021, 60, 5871; Angew.
Chem. 2021, 133, 5935; b) J. Wang, X.-Z. Zheng, J.-A. Xiao, K. Chen,
H.-Y. Xiang, X.-Q. Chen, H. Yang, Org. Lett. 2021, 23, 963; c) T. He, L.
Peng, S. Li, F. Hu, C. Xie, S. Huang, S. Jia, W. Qin, H. Yan, Org. Lett.
2020, 22, 6966; d) R.-J. Yan, B.-X. Liu, B.-X. Xiao, W. Du, Y.-C. Chen,
Org. Lett. 2020, 22, 4240; e) Q.-G. Tang, S.-L. Cai, C.-C. Wang, G.-Q.
Lin, X.-W. Sun, Org. Lett. 2020, 22, 3351; f) Z.-J. Zhang, L. Zhang, R.-L.
Geng, J. Song, X.-H. Chen, L.-Z. Gong, Angew. Chem. Int. Ed. 2019,
58, 12190; Angew. Chem. 2019, 131, 12318; g) J.-R. Huang, M. Sohail,
T. Taniguchi, K. Monde, F. Tanaka, Angew. Chem. Int. Ed. 2017, 56,
5853; Angew. Chem. 2017, 129, 5947; h) S. Jayakumar, K. Louven, C.
Strohmann, K. Kumar, Angew. Chem. Int. Ed. 2017, 56, 15945; Angew.
Scheme 3. Transformations of 5a.
In summary, we have developed the organocatalytic
DYKAT-based diastereo- and enantioconvergent Michael-Henry
reactions of racemic diastereomers that afford spirooxindoles
bearing furan-fused ring systems. In the DYKAT, all the four
stereoisomers originated by central and axial chiralities were
transformed to the single diastereomer product in high yields
with high enantioselectivities. We are investigating the detailed
4
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Chem. 2017, 129, 16161; i) K. Zhao, Y. Zhi, T. Shu, A. Valkonen, K.
Rissanen, D. Enders, Angew. Chem. Int. Ed. 2016, 55, 12104; Angew.
Chem. 2016, 128, 12283; j) Y.-L. Liu, X. Wang, Y.-L. Zhao, F. Zhu, X.-P.
Zeng, L. Chen, C.-H. Wang, X.-L. Zhao, J. Zhou, Angew. Chem. Int. Ed.
2013, 52, 13735; Angew. Chem. 2013, 125, 13980; k) X. Zeng, Q. Ni, G.
Raabe, D. Enders, Angew. Chem. Int. Ed. 2013, 52, 2977; Angew.
Chem. 2013, 125, 3050; l) L.-T. Shen, W.-Q. Jia, S. Ye, Angew. Chem.
Int. Ed. 2013, 52, 585; Angew. Chem. 2013, 125, 613; m) H.-L. Cui, F.
Tanaka, Chem. Eur. J. 2013, 19, 6213; n) J. Dugal-Tessier, E. A.
O’Brya, T. B. H. Schroeder, D. T. Cohen, K. A Scheidt, Angew. Chem.
Int. Ed. 2012, 51, 4963; Angew. Chem. 2012, 124, 5047; o) N. V.
Hanhan, N. R. Ball-Jones, N. T. Tran, A. K. Franz, Angew. Chem. Int.
Ed. 2012, 51, 989; Angew. Chem. 2012, 124, 1013; p) G. Bencivenni,
L.-Y. Wu, A. Mazzanti, B. Giannichi, F. Pesciaioli, M.-P. Song, G.
Bartoli, P. Melchiorre, Angew. Chem. Int. Ed. 2009, 48, 7200; Angew.
Chem. 2009, 121, 7336.
[6]
[7]
a) Z.-C. Chen, Z. Chen, Z.-H. Yang, L. Guo, W. Du, Y.-C. Chen, Angew.
Chem. Int. Ed. 2019, 58, 15021; Angew. Chem. 2019, 131, 15163; b) H.
Zheng, Y. Wang, C. Xu, Q. Xiong, L. Lin, X. Feng, Angew. Chem. Int.
Ed. 2019, 58, 5327; Angew. Chem. 2019, 131, 5381; c) T. Arai, H.
Ogawa, A. Awata, M. Sato, M. Watabe, M. Yamanaka, Angew. Chem.
Int. Ed. 2015, 54, 1595; Angew. Chem. 2015, 127, 1615.
a) Y. Ji, Z. Xin, H. He, S. Gao, J. Am. Chem. Soc. 2019, 141, 16208; b)
Y. Lu, H. Yuan, S. Zhou, T. Luo, Org. Lett. 2017, 19, 620; c) M. A.
Kienzler, S. Suseno, D. Trauner, J. Am. Chem. Soc. 2008, 130, 8604;
d) S. Goswami, K. Harada, M. F. El-Mansy, R. Lingampally, R. G.
Carter, Angew. Chem. Int. Ed. 2018, 57, 9117; Angew. Chem. 2018,
130, 9255; e) M. D. Bel, A. R. Abela, J. D. Ng, C. A. Guerrero, J. Am.
Chem. Soc. 2017, 139, 6819; f) E. Z. Oblak, M. D. VanHeyst, J. Li, A. J.
Wiemer, D. L. Wright. J. Am. Chem. Soc. 2014, 136, 4309.
[8]
[9]
V. S. Raut, M. Jean, N. Vanthuyne, C. Roussel, T. Constantieux, C.
Bressy, X. Bugaut, D. Bonne, J. Rodriguez, J. Am. Chem. Soc. 2017,
139, 2140.
Examples of hindered rotation of sp3-sp2 bonds: M. Oki, Angew. Chem.
Int. Ed. Engl. 1976, 15, 87.
[10] F. P. Gasparro, N. H. Kolodny, J. Chem. Educ. 1977, 54, 258.
[11] Reactions of nitrostyrenes to form cyclohexane rings: a) Y. Hayashi, T.
Okano, S. Aratake, D. Hazeland, Angew. Chem. Int. Ed. 2007, 46,
4922; Angew, Chem. 2007, 119, 5010; b) S. Varga, G. Jakab, L.
Drahos, T. Holczbauer, M. Czugler, T. Soos, Org Lett. 2011, 13, 5416.
[12] CCDC 2067701 for the major enantiomer of 5a obtained in the
presence of catalyst C. The data are provided free of charge by The
Cambridge Crystallographic Data Centre.
5
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Entry for the Table of Contents
Organocatalytic Michael-Henry cascade reactions that occur through dynamic kinetic asymmetric transformations of racemic
diastereomers having central and axial chiralities have been developed for the synthesis of spirooxindoles bearing furan-fused ring
systems. The products, with four new chiral carbon centers, were obtained as single diastereomers in high yields with high
enantioselectivities.
Institute and/or researcher Twitter usernames:
6
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