Redox deracemization of α-substituted 1,3-dihydroisobenzofurans

Article abstract of DOI:10.1016/j.cclet.2021.02.021

Chiral α-substituted 1,3-dihydroisobenzofurans are key scaffolds in a number of bioactive natural products and synthetic pharmaceuticals. However, catalytic asymmetric approaches have been rarely developed. Here, a redox deracemization technology is adopted to address the catalytic asymmetric synthesis. A broad range of α-aryl substituted 1,3-dihydroisobenzofurans are effectively deracemized in high efficiency with excellent ee. α-Alkynyl substituted ethers were also compatible with the deracemization technology.

Full text of DOI:10.1016/j.cclet.2021.02.021

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Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Redox deracemization of α-substituted 1,3-dihydroisobenzofurans
Xiaohan Chena,b,1, Ran Zhaoa,1, Ziqiang Liua,e, Shutao Sunc, Yingang Maa,
a,c,d,
b,**
e,**
, Xia Sun , Lei Liu
*
Qingyun Liu
a
School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji’nan 250012, China
College of Chemical and Biological Engineering, State Key Laboratory of Mining Disaster Prevention and Control Co-founded by Shandong Province and the
b
Ministry of Science and Technology, Shandong University of Science and Technology, Qingdao, 266590, China
c
School of Chemistry and Chemical Engineering, Shandong University, Ji’nan 250100, China
Shenzhen Research Institute of Shandong University, Shenzhen 518057, China
Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Ji’nan 250012, China
d
e
A R T I C L E I N F O
A B S T R A C T
Article history:
Chiral α-substituted 1,3-dihydroisobenzofurans are key scaffolds in a number of bioactive natural
products and synthetic pharmaceuticals. However, catalytic asymmetric approaches have been rarely
developed. Here, a redox deracemization technology is adopted to address the catalytic asymmetric
synthesis. A broad range of α-aryl substituted 1,3-dihydroisobenzofurans are effectively deracemized in
high efficiency with excellent ee. α-Alkynyl substituted ethers were also compatible with the
deracemization technology.
Received 8 December 2020
Received in revised form 4 February 2021
Accepted 9 February 2021
Available online xxx
Keywords:
© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
1,3-Dihydroisobenzofuran
Asymmetric catalysis
Redox deracemization
Oxocarbenium ion
Synthetic method
Chiral α-substituted 1,3-dihydroisobenzofurans are key scaf-
folds in a number of bioactive natural products and synthetic
pharmaceuticals [1]. Although a variety of racemic routes have
been reported, there are surprisingly few catalytic enantioselective
approaches to this important class of chiral molecule [2–4].
Existing studies predominantly relied on asymmetric intramolec-
ular cyclization strategy involving C–O bond formation
(Scheme 1A) [2]. Despite excellent ee values, pre-installation of
reactive functional groups, such as alkenes and ethers, were
prerequisite. Subsequently, an elegant iridium(III)-catalyzed
enantioselective C–H alkylation of 1,3-dihydroisobenzofurans with
ethyl diazoacetate was disclosed, though 4.0 equiv. of the substrate
was required (Scheme 1B) [3]. Recently, our group developed a
kinetic resolution of racemic α-aryl and -alkynyl substituted 1,3-
dihydroisobenzofurans through asymmetric C–H oxidation with
excellent chiral recognition (Scheme 1C) [4]. However, the
theoretical yield of the recovered enantiopure phthalans can not
exceed a limit of 50%. Therefore, development of a strategically
different approach through C–H bond manipulation in high
efficiency would be a highly attractive project to pursue.
Deracemization, wherein a racemic target is directly and
completely converted to a single enantiomer of exactly the same
molecule in theoretically 100% yield, has emerged as an attractive
and straightforward alternative to conventional asymmetric
synthesis [5]. Despite conceptual simplicity and potential practical
benefits, catalytic non-enzymatic deracemization has remained
scarce [6], and existing methods typically focus on alcohol or
amine substrates through oxidation and reduction chemistry,
whose oxidized intermediates are stable and isolable ketones and
imines, respectively [7–9]. Redox deracemization of ethers
involving unstable oxidized oxocarbenium ion intermediates
remained rarely disclosed, and existing method always focuses
on six-membered cyclic benzylic ethers [10]. Herein, we report a
one-pot redox deracemization of α-substituted 1,3-dihydroiso-
benzofurans (Scheme 1D).
Initially, redox deracemication of 1,3-dihydroisobenzofuran
rac-1a was chosen for optimization employing Hantzsch ester 2
and chiral phosphoric acid (CPA) 3 as the asymmetric reduction
system (Table 1) [11]. The reaction was performed in a two-step,
one-pot manner to avoid direct quench of oxidant and reductant.
When 1 equiv. of DDQ was used as the oxidant, an incomplete
consumption of rac-1a was observed (entry 1, Table 1) [12]. Protic
additives proved to be crucial to complete oxidation and
* Corresponding author at: School of Pharmaceutical Sciences, Cheeloo College of
Medicine, Shandong University, Ji’nan, 250012, China.
** Corresponding authors.
E-mail addresses: qyliu@sdust.edu.cn (Q. Liu), sunxia@sdu.edu.cn (X. Sun),
leiliu@sdu.edu.cn (L. Liu).
1
These two authors contributed equally to this work.
https://doi.org/10.1016/j.cclet.2021.02.021
1001-8417/© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article as: X. Chen, R. Zhao, Z. Liu et al., Redox deracemization of α-substituted 1,3-dihydroisobenzofurans, Chin. Chem. Lett.,
https://doi.org/10.1016/j.cclet.2021.02.021

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enantioselectivity, and MeOH was identified to be optimal (entries
2-6). Reaction without 5 Å molecular sieve afforded an inferior
result (entry 7). A series of CPA catalysts were then evaluated,
revealing that C2-symmetric imidodiphosphoric acid 3e was the
best choice, which might be ascribed to the sterically highly
demanding and rigid chiral microenvironment around the active
site of 3e (entries 3 and 8-12). Solvent optimization suggested that
deracemization proceeded most efficiently in a mixed solvents of
CH2Cl2 and toluene (entry 13). Adding Hantzsch ester prior to the
oxidation was ineffective (entry 14).
With the optimized reaction conditions in hand, the scope of
redox deracemization of 1,3-dihydroisobenzofurans was explored
(Scheme 2). A range of electron-donating and -withdrawing
substituents on the benzylic ether arene skeleton were well
tolerated, as demonstrated by generation of enantiopure 1a-1e in
good yields (88%–95%) with excellent enantiocontrol (90%–96% ee)
(Scheme 2A). Modification of the geminal C1-disubstitution did not
impair the reactivity and selectivity for 1f-1j (Scheme 2B). Notably,
spirocyclic 1g-1j bearing diverse ring size and functionality pattern
were compatible with the deracemization process. The deracem-
ization of simple 1,3-dihydroisobenzofuran 1k without geminal C1
disubstitution was next explored. While a complete oxidation
could be achieved, a competitive oxidation at C1 position was also
observed. The geminal C1 disubstitution also proved to be crucial to
the enantioselectivity, and 1k was isolated in 30% yield with 6% ee.
The scope of α-substituent patterns was next investigated
(Scheme 3). A variety of electronically varied aryl moieties at α
Scheme 1. Overview of catalytic asymmetric synthesis of α-substituted 1,3-
dihydroisobenzofurans.
Table 1
Reaction condition optimization.a
Entry
Catalyst
Additive
Yield (%)b
ee (%)c
1
2
3
4
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
i.o.
50
75
70
47
85
60
30
65
70
83
75
93
n.o.
n.d.
35
58
45
30
20
50
20
68
20
85
53
95
0
H2O
MeOH
EtOH
5
iPrOH
6
CF3CH2OH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
7d
8
9
10
11
12
13e
14f
3e
3e
PMP = 4-Methoxyphenyl. i.o. = incomplete oxidation. n.o. = no oxidation. n.d. = not determined.
a
General conditions: a mixture of rac-1a (0.1 mmol), 5 Å molecular sieve (30 mg), additive (0.3 mmol), and DDQ (0.105 mmol) in CH2Cl2 (4.0 mL) at r.t. for 0.5 h, followed by
2 (0.14 mmol) and 3 (10 mol%) at -10 ꢀC for 24 h, unless otherwise specified.
b
Yield of isolated product.
Determined by chiral HPLC analysis.
Reaction without 5 Å molecular sieve.
CH2Cl2/toluene (v/v = 1:10) as solvent.
c
d
e
f
2 and 3e added before oxidation.
2

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Scheme 4. Redox deracemization of α-alkynyl substituted 1,3-dihydroisobenzo-
furans.
position participated in the redox deracemization smoothly,
providing respective 4a-4h in good yields with good to excellent
ee (83%-98%). Heteroaryl rac-4i was also a suitable component.
Besides diverse α-aryl substituents, α-alkynyl substituted 1,3-
dihydroisobenzofurans were also competent substrates, as dem-
onstrated by effective deracemization of rac-5 giving (S)-5 in 90%
yield with 80% ee (Scheme 4). Under the standard oxidation
conditions, α-alkyl substituted 1,3-dihydroisobenzofurans cannot
be completely oxidized (see Supporting information for details).
The additive MeOH proved to be beneficial for reaction
efficiency and enantioselectivity. Accordingly, the deracemization
process was performed stepwise to understand the role of MeOH.
Oxidation of rac-1a with DDQ and MeOH proceeded smoothly,
affording ketal 6 in high efficiency (Scheme 5A). Under the
standard deracemization conditions in the absence of oxidation
elements, ketal 6 was reduced to (S)-1a with comparable ee to that
observed in deracemization reaction (Scheme 5B). The observa-
tions suggested that a ketal intermediate might be involved in the
deracemization process. Based on the results in entries 2-6 in
Table 1, 1,3-dihydroisobenzofuran-based ketal bearing a methoxy
moiety might be the best intermediate for asymmetric transfer
hydrogenation with respective to the enantiocontrol, though the
origin of the observation remains unclear.
Scheme 2. The scope of 1,3-dihydroisobenzofuran skeleton.
Based on the above studies, a plausible mechanism for redox
deracemization of 1,3-dihydroisobenzofurans was suggested
(Scheme 5C). Ether rac-1a was oxidized by DDQ to generate
oxocarbenium intermediate 7, which was captured by MeOH
giving ketal 6. CPA 3e catalyzed the collapse of 6, furnishing a
Scheme 5. Control experiments and proposed mechanism for redox deracemiza-
Scheme 3. The scope of α-aryl substituents.
tion process.
3

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contact ion pair 8 for subsequent asymmetric reduction with
Hantzsch ester 2 to complete the redox deracemization process.
In summary, a one-pot redox deracemization of α-substituted
1,3-dihydroisobenzofurans has been disclosed. MeOH was found to
be crucial to the reaction efficiency and enantioselectivity by
forming a ketal intermediate. A range of α-aryl substituted five-
membered cyclic benzylic ethers were effectively deracemized. α-
Alkynyl substituted ethers were also compatible with the
deracemization technology.
(d) M. Rachwalski, N. Vermue, F.P.J.T. Rutjes, Chem. Soc. Rev. 42 (2013) 9268–
9282;
(e) R.C. Simon, N. Richter, E. Busto, W. Kroutil, ACS Catal. 4 (2014) 129–143.
[6] (a) A. Hölzl-Hobmeier, A. Bauer, A.V. Silva, et al., Nature 564 (2018) 240–243;
(b) A. Tröster, A. Bauer, C. Jandl, T. Bach, Angew. Chem. Int. Ed. 58 (2019) 3538–
3541;
(c) N.Y. Shin, J.M. Ryss, X. Zhang, et al., Science 366 (2019) 364–369.
[7] (a) C.V. Voss, C.C. Gruber, W. Kroutil, Angew. Chem. Int. Ed. 47 (2008) 741–745;
(b) C.V. Voss, C.C. Gruber, K. Faber, et al., J. Am. Chem. Soc. 130 (2008) 13969–
13972;
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
(c) C.J. Dunsmore, R. Carr, T. Fleming, et al., J. Am. Chem. Soc. 128 (2006) 2224–
2225;
(d) D. Ghislieri, A.P. Green, M. Pontini, et al., J. Am. Chem. Soc. 135 (2013)
10863–10869;
Acknowledgments
(e) K. Yasukawa, S. Nakano, Y. Asano, Angew. Chem. Int. Ed. 53 (2014) 4428–
4431.
This work was financial supported by the National Natural
Science Foundation of China (Nos. 21971148) and Shenzhen Special
Funds (No. JCYJ20190807093805572).
[8] (a) Y. Shimada, Y. Miyake, H. Matsuzawa, et al., Chem. Asian J. 2 (2007) 393–
396;
(b) G.R.A. Adair, J.M.J. Williams, Chem. Commun (2007) 2608–2609;
(c) P. Qu, M. Kuepfert, S. Jockusch, et al., ACS Catal. 9 (2019) 2701–2706;
Appendix A. Supplementary data
(d) A.D. Lackner, A.V. Samant, F.D. Toste, J. Am. Chem. Soc. 135 (2013) 14090–
14093;
Supplementarymaterialrelatedto thisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2021.02.021.
(e) Y. Ji, L. Shi, M.W. Chen, et al., J. Am. Chem. Soc. 137 (2015) 10496–10499;
References
(f) L. Zhang, R. Zhu, A. Feng, et al., Chem. Sci. 11 (2020) 4444–4449.
[9] (a) Y. Mao, Z. Wang, G. Wang, et al., ACS Catal. 10 (2020) 7785–7791;
[1] (a) V.J. Bauer, B.J. Duffy, D. Hoffman, et al., J. Med. Chem. 19 (1976) 1315–1324;
(b) Y. Ma, X. Liu, Y. Mao, et al., Org. Chem. Front. 7 (2020) 2526–2530.
[10] M. Wan, S. Sun, Y. Li, et al., Angew. Chem. Int. Ed. 56 (2017) 5116–5120.
[11] (a) T. Akiyama, Chem. Rev. 107 (2007) 5744–5758;
(b) E.G. Maestrup, C. Wiese, D. Schepmann, et al., Bioorg. Med. Chem. 19 (2011)
393–405.
ꢀ
ꢁ
[2] (a) I. Coric, J.H. Kim, T. Vlaar, et al., Angew. Chem. Int. Ed. 52 (2013) 3490–3493;
(b) B. Ravindra, B.G. Das, P. Ghorai, Org. Lett. 16 (2014) 5580–5583;
(c) D. Chen, S.R. Chemler, Org. Lett. 20 (2018) 6453–6456;
(b) M. Terada, Synthesis 42 (2010) 1929–1982;
(c) D. Parmar, E. Sugiono, S. Raja, et al., Chem. Rev. 114 (2014) 9047–9153;
ꢀ
ꢁ
(d) I. Coric, B. List, Nature 483 (2012) 315–319;
(d) D. Chen, I.A. Berhane, S.R. Chemler, Org. Lett. 22 (2020) 7409–7414.
[3] N.M. Weldy, A.G. Schafer, C.P. Owens, et al., Chem. Sci. 7 (2016) 3142–3146.
[4] (a) S. Sun, Y. Ma, Z. Liu, L. Liu, Angew. Chem. Int. Ed. 60 (2021) 176–180;
(e) C. Zheng, S.L. You, Chem. Soc. Rev. 41 (2012) 2498–2518;
(f) D. Wang, D. Astruc, Chem. Rev. 115 (2015) 6621–6686.
[12] (a) R. Zhao, G. Feng, X. Xin, et al., Chin. Chem. Lett. 30 (2019) 1432–1434;
P. Ye, X. Liu, G. Wang, L. Liu, Chin. Chem. Lett. (2020) DOI: 10.1016/j.cclet.
2020.08.034;.;
(b) S. Sun, Y. Yang, R. Zhao, D. Zhang, L. Liu, J. Am. Chem. Soc.142 (2020) 19346–
19353.
[5] (a) K. Faber, Chem. Eur. J. 7 (2001) 5004–5010;
(b) C.C. Gruber, I. Lavandera, K. Faber, W. Kroutil, Adv. Synth. Catal. 348 (2006)
1789–1805;
(b) Z. Wang, Y. Mao, H. Guan, et al., Chin. Chem. Lett. 30 (2019) 1241–1243;
(d) H. Guan, L. Chen, L. Liu, Acta Chim. Sinica 76 (2018) 440–444
(c) N.J. Turner, Curr. Opin. Chem. Biol. 14 (2010) 115–121;
4