Chiral Bicyclic Imidazole-Catalyzed Acylative Dynamic Kinetic Resolution for the Synthesis of Chiral Phthalidyl Esters

Article abstract of DOI:10.1002/anie.202012445

Utilizing a chiral bicyclic imidazole organocatalyst and adopting a continuous injection process, an alternative route has been developed for the efficient synthesis of chiral phthalidyl ester prodrugs via dynamic kinetic resolution of 3-hydroxyphthalides through enantioselective acylation (up to 99 % ee). The computational studies suggest a general base catalytic mechanism differing from the widely accepted nucleophilic catalytic mechanism. The structure analysis of the key transition states shows that the CH-π interactions and not the previously considered cation/π-π interactions between the catalyst and substrate is the dominant factor giving rise to the observed stereocontrol.

Full text of DOI:10.1002/anie.202012445

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Accepted Article
Title: Chiral Bicyclic Imidazole-Catalyzed Acylative Dynamic Kinetic
Resolution for the Synthesis of Chiral Phthalidyl Esters
Authors: Muxing Zhou, Tatiana Gridneva, Zhenfeng Zhang, Ende He,
Yangang Liu, and Wanbin Zhang
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Chiral Bicyclic Imidazole-Catalyzed Acylative Dynamic Kinetic
Resolution for the Synthesis of Chiral Phthalidyl Esters
Muxing Zhou,[a] Tatiana Gridneva,[b] Zhenfeng Zhang,[a] Ende He,[a] Yangang Liu,[a] and Wanbin
Zhang*[ab]
[a]
M. Zhou, Z. Zhang, E. He, Y. Liu, W. Zhang
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240, China
E-mail: wanbin@sjtu.edu.cn
[b]
T. Gridneva, W. Zhang
School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240, China
Supporting information for this article is given via a link at the end of the document.
Abstract: Utilizing a chiral bicyclic imidazole organocatalyst and
adopting a continuous injection process, an alternative route has been
developed for the efficient synthesis of chiral phthalidyl ester prodrugs
via dynamic kinetic resolution of 3-hydroxyphthalides by
enantioselective acylation (up to 99% ee). The computational studies
suggest a general base catalytic mechanism differing from the widely
accepted nucleophilic catalytic mechanism. The structure analysis of
the key transition states shows that the CH-π interactions and not the
previously considered cation/π-π interactions between the catalyst
and substrate is the dominant factor giving rise to the observed
stereocontrol.
resolution of 3-hydroxyphthalides as shown in Scheme 1) is
envisaged to overcome the above limitations and is therefore
worthy of further investigations.
Acylative dynamic kinetic resolution (DKR), combining alcohol
racemization and acylative kinetic resolution steps,[4] is one of the
most promising but less studied methods for the high-yielding
synthesis of chiral esters. In 2010, Qu and co-workers developed
an efficient DKR of meso-1,2-diol monodichloroacetates based on
a
DABCO-mediated racemization and modified histidine-
catalyzed enantioselective acylation.[5] Later in 2012, inspired by
enzyme-catalyzed transformation, Fu and coworkers introduced
a Ru-catalyzed racemization of secondary alcohols into the
DMAP-catalyzed enantioselective acylation and realized the non-
enzymatic DKR of secondary alcohols.[6] In addition to these two
developments, other examples utilize the spontaneous
equilibrium between aldehyde and hemiacetal/hemiaminal states
in the Lewis base-catalyzed acylative DKR for the synthesis of
tetrazole-, 5-fluorouracil-, and purine-derived prodrugs.[7]
However, in contrast to these successful acylative DKRs of
acyclic hemiaminals, the acylative DKR of cyclic hemiacetals
such as 3-hydroxyphthalides remains challenging.[8] To overcome
these deficiencies, a new and efficient catalytic system with
appropriate catalyst-substrate interactions is required.
Prodrugs, especially the carrier-linked type, provide possibilities
to overcome various barriers in pharmaceutical, pharmacokinetic,
and pharmacodynamic phases by changing the physicochemical
properties of the parent drugs. Among them, ester-based
prodrugs, which are generally formed by acylation of the initial
carboxylic acids or alcohols drugs and which can be easily
cleaved by enzymatic hydrolysis, have attracted extensive
attention (Figure 1).[1] However, due to deficiencies in concept
identification and technological developments, a strategy to
introduce chirality into the carriers has not gained the attention it
should, as it would greatly expand the chemical space and
biological activities of prodrugs. As a representative example, the
racemic phthalidyl carrier has already been applied in several
marketed prodrugs including Talosalate, Talniflumate, Talmetacin,
and Talampicilin (Figure 1).[2] It was only recently that Chi and co-
workers developed a reaction to access chiral phthalidyl ester
prodrugs via an intermolecular acetalization and NHC-catalyzed
intramolecular asymmetric acylation sequence (Scheme 1).[3]
However, poor regioselectivity using unsymmetrical dialdehydes
greatly limits structural diversity and thus further drug
development. In addition, the utilization of hard-to-get catalysts
and stoichiometric amounts of oxidants further diminishes the
practical applicability of this methodology. An alternative route via
an intramolecular acetalization and intermolecular asymmetric
acylation sequence (that is the acylative dynamic kinetic
In the last ten years, our group has developed a new type of easily
synthesized Lewis base organocatalysts derived from the bicyclic
imidazole skeleton.[9] Recently, carbamyloxy-substituted catalysts
were selected as the superior ones in enantioselective
phosphorylations for the synthesis of some important ProTide
drugs including Remdesivir.[9j] Futhermore, alkyloxy- and acyloxy-
substituted catalysts have been successfully applied in several
enantioselective C-acylation reactions, while the alkyl-substituted
catalysts show high catalytic activity and excellent
enantioselectivity in the O-acylative KR of secondary alcohols.[9c]
Considering that the corresponding acylation may proceed via a
similar catalytic mechanism and stereocontrol mode involving the
π-interactions, we applied the chiral bicyclic imidazole
organocatalysts to the acylative DKR of 3-hydroxyphthalides,
envisaging that excellent results would be obtained (Scheme 1).
1
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Figure 1. Representative Ester-Based Prodrugs.
Scheme 1. Asymmetric Synthesis of Chiral Phthalidyl Esters.
Initially, the alkyloxy- and acyloxy-substituted bicyclic imidazole
catalysts 3a-d were applied in the acylative DKR of 3-
hydroxyphthalide (1a) under general reaction conditions (Table 1,
entries 1-4). Catalysts with five-membered pyrrolidine (3c,d)
provided only slightly better results than that of catalysts bearing
a six-membered piperidine (3a,b), and catalysts with an OAc
substituent (3b,d) gave the desired product with better
enantioselectivities than that of catalysts with an OBn substituent
(3a,c). To our delight, the alkyl-substituted catalyst Cy-DPI (3e)
provided the best results to give the desired product 2a (R = Ac)
in 99% yield and with 69% ee (entry 5). Next, various bases and
solvents were screened using 3e as the catalyst. The sterically
bulky secondary amine tetramethylpiperidine (TMP) improved the
enantioselectivity to 76% and no better results could be obtained
compared with using toluene as the solvent (entry 6 and Table S1
in SI). The influence of different acylating reagents showed that
diphenyl acetyl chloride (DPACl) enabled the ee value of the
desired product 2a (R = DPA) to reach 84% (entry 7 and Table
S1 in SI). Further studies on the concentration and temperature
were conducted (entries 8-9 and Table S2 in SI). Reducing the
2
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reaction concentration from 0.1 M to 0.05 M increased the
enantioselectivity from 84% to 87%, while reducing the reaction
temperature from room temperature to -80 °C increased the
enantioselectivity from 87% to 92% (entries 8-9). Next, a batch
feeding mode was employed and the enantioselectivity was
surprisingly improved by 2% (entry 10). These results show that
the enantioselectivity of the reaction is not only controlled by the
asymmetric acylation process, but also by the rate of the substrate
racemization. Therefore, in order to improve the 1a/DPACl ratio
and ensure full racemization, a continuous feeding mode was
employed and the enantioselectivity was further improved by 2%
(entry 11). Increasing the injection rate from 0.2 to 0.3 mL/min did
not alter the results but the reaction time to reach completion
could be reduced from 15 h to 9 h (entry 12).
but not 6-position. 6-Br- and 5-Br-substituted substrates were
converted to the corresponding products 2n and 2o with 90% and
92% ee, respectively. Acylation of the substrates with CF3, OMe,
and OPh groups at the 5-position of the phenyl ring gave the
desired products 2p-r in about 90% yield and with 86-90% ee.
The performance on the 5-position-substituted substrates shows
that the electronic properties have little effect on the reaction
results. Substrates possessing naphthyl groups also provided
their corresponding products 2s-t with lower reactivity compared
with the above substrates (83% and 76% yield) and with distinctly
different enantioselectivities from each other (90% and 82% ee).
To our delight, the ee of product 2u bearing an alkenyl skeleton
instead of an arene was only slightly reduced to 91% from 96%.
Further changing the carbon-carbon double bond to a single bond
reduced the ee of product 2v to 59%. When 0.5 equivalents of
diphenyl acetyl chloride were applied, the enantioselectivity
increased to 71%, indicating that the dynamic equilibrium
between the two isomers of this substrate is not fast enough.
Table 1. Condition Optimization.
Entrya
Cat
3a
3b
3c
3d
3e
3e
3e
3e
3e
3e
3e
3e
Base
TEA
TEA
TEA
TEA
TEA
TMP
TMP
TMP
TMP
TMP
TMP
TMP
Tol/mL
R
T/°C
25
Yield/%b
86
ee/%c
30
1
2
2
2
2
2
2
2
2
4
4
4
4
4
Ac
Ac
25
88
41
3
Ac
25
93
33
4
Ac
25
93
42
5
Ac
25
99
69
6
Ac
25
99
76
7
DPA
DPA
DPA
DPA
DPA
DPA
25
90
84
8
25
87
87
9
-80
-80
-80
-80
84
92
10d
11e
12f
86
94
99
96
99
96
[a] Conditions: 1a (0.2 mmol), AcCl or DPACl (1.05 eq), 3 (10 mol %), TEA or
TMP (1.2 eq), toluene, 6 h, unless otherwise noted. [b] Yields were calculated
from 1H-NMR spectra. [c] ee values were determined by HPLC using chiral
columns. [d] 12 h, DPACl was added in two batches at 0 and 6 h. [e] 15 h,
DPACl in toluene (2 mL) was added via a continuous sampler at 0.2 mL/h. [f] 9
h, DPACl in toluene (2 mL) was added via a continuous sampler at 0.3 mL/h.
The substrate scope was then investigated using the optimized
reaction conditions as described in entry 12 of Table 1 (Scheme
2). Substrates bearing a methyl group at the 7-, 6-, 5- or 4-position
of the phenyl ring were acylated to the corresponding products
2b-e with 94%, 85%, 99% and 91% ee respectively. Substrates
bearing fluoro and chloro groups at different positions of the
phenyl ring were also tested and afforded the desired products 2f-
m with high yields and enantioselectivities. The highest ee was
obtained with substrates bearing a substituent at the 4-position
Scheme 2. Substrate Scope (the absolute configurations of 2a and 2i were
assigned to (S) by X-ray single crystal diffraction and others except 2u and 2v
are thought to be the same as 2a and 2i).
To investigate the generality of the reaction, the prodrugs of some
important carboxylic acid drugs were synthesized (Scheme 3).
Using our catalytic system and under the optimized reaction
conditions, Valproic acid, Indomethacin and (S)-Naproxen were
3
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converted to the corresponding chiral phthalidyl ester prodrugs
with excellent stereoselectivity. In particular, the target compound
6 was synthesized with >200:1 dr.
In order to elucidate the mechanism of stereoselection,
computational studies of two mechanisms wherein (S)-Cy-DPI
acts as a nucleophilic catalyst or a general base catalyst were
performed (Figures 2-3, and Figure S1 in SI). The nucleophilic
catalytic mechanism is considered to be favoured according to
previous research on similar asymmetric acylations.[4d,g,10] We
have computed numerous conformational modifications for both
possibilities, and selected the lowest energy pathway in each
case. In our hands both mechanisms were computed to be very
similar energetically. However, only the general base catalytic
mechanism coincides with the experimentally observed
handedness of the product, whereas nucleophilic catalytic
mechanism, forecasts formation of the product with an opposite
configuration (Figure S1 in SI).
The general base catalytic mechanism starts from the formation
of substrate-catalyst complexes 7R and 7S stabilized by H-bond
and CH-π interactions. The acylating reagent is introduced to
form the substrate-catalyst-reagent complexes 8R and 8S.
Through the corresponding transition states TSR and TSS with
energies of 7.8 and 9.3 kcal/mol, the catalytically assisted
acylation affords product-catalyst complexes 9R and 9S as the
HCl salt form. Elimination of HCl with TMP recovers the catalyst
and yields the product 2a (Figure 2).
Scheme 3. Practical Applications in the Synthesis of Prodrugs.
Figure 2. Free Energy Profile (ΔG298) of General Base Catalytic Mechanism Calculated at ωB97XD/6-31G(d,p) Level of Theory.
Optimized structures of TSR and TSS are shown in Figure 3. TSR
is 1.5 kcal/mol more stable than TSS, which is in good agreement
with the experimentally observed high enantioselectivity. Figure
3a shows that both are 4-membered transition states with
4
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[2]
a) Q. Dang, B. S. Brown, P. D. van Poelje, T. J. Colby, M. D. Erion, Bioorg.
Med. Chem. Lett. 1999, 9, 1505; b) R. G. Matheny, US20130122108,
2013; c) D. Camp, A. Garavelas, M. Campitelli, J. Nat. Prod. 2015, 78,
1370.
simultaneous movement of four atoms (O-C-Cl-H). Figure 3b
shows the most significant structural differences accounting for
the relative stability of TSR. In this transition state two different
protons of the catalyst form two CH-π interactions with the phenyl
rings of 1a and DPACl, thus maintaining the three-molecule
framework essential for the reaction to proceed. Two CH-π
interactions of the phenyl rings of 1a and DPACl are also possible
in the structure of TSS. However, to form the 4-membered
transition state, a significantly different conformation must be
stabilized. In this case, the CH-π interactions in TSS are notably
longer (especially that with the phenyl ring of 1a), resulting in the
greater stability of TSR.
[3]
[4]
Y. Liu, Q. Chen, C. Mou, L. Pan, X. Duan, X. Chen, H. Chen, Y. Zhao, Y.
Lu, Z. Jin, Y. R. Chi, Nat. Commun. 2019, 10, 1675.
Examples for kinetic resolution of alcohols: a) J. C. Ruble, H. A. Latham,
G. C. Fu, J. Am. Chem. Soc. 1997, 119, 1492; b) G. T. Copeland, S. J.
Miller, J. Am. Chem. Soc. 2001, 123, 6496; c) E. Vedejs, M. Jure, Angew.
Chem. Int. Ed. 2005, 44, 3974; Angew. Chem. 2005, 117, 4040; d) X. Li,
P. Liu, K. N. Houk, V. B. Birman, J. Am. Chem. Soc. 2008, 130, 13836;
e) B. Hu, M. Meng, Z. Wang, W. Du, J. S. Fossey, X. Hu, W.-P. Deng, J.
Am. Chem. Soc. 2010, 132, 17041; f) B. Hu, M. Meng, J. S. Fossey, W.
Mo, X. Hu, W.-P. Deng, Chem. Commun. 2011, 47, 10632; g) E. Larionov,
M. Mahesh, A. C. Spivey, Y. Wei, H. Zipse, J. Am. Chem. Soc. 2012, 134,
9390; h) G. Ma, J. Deng, M. P. Sibi, Angew. Chem. Int. Ed. 2014, 53,
11818; Angew. Chem. 2014, 126, 12012; i) T. Yamanaka, A. Kondoh, M.
Terada, J. Am. Chem. Soc. 2015, 137, 1048; j) N. Mittal, K. M. Lippert,
C. K. De, E. G. Klauber, T. J. Emge, P. R. Schreiner, D. Seidel, J. Am.
Chem. Soc. 2015, 137, 5748; k) M. D. Greenhalgh, S. M. Smith, D. M.
Walden, J. E. Taylor, Z. Brice, E. R. T. Robinson, C. Fallan, D. B. Cordes,
A. M. Z. Slawin, H. C. Richardson, M. A. Grove, P. H.-Y. Cheong, A. D.
Smith, Angew. Chem. Int. Ed. 2018, 57, 3200; Angew. Chem. 2018, 130,
3254; l) X. Dong, Y. Kita, M. Oestreich, Angew. Chem. Int. Ed. 2018, 57,
10728; Angew. Chem. 2018, 130, 10888.
[5]
[6]
J.-L. Cao, J. Qu, J. Org. Chem. 2010, 75, 3663.
a) S. Y. Lee, J. M. Murphy, A. Ukai, G. C. Fu, J. Am. Chem. Soc. 2012,
134, 15149; b) A. E. Díaz-Álvarez, L. Mesas-Sánchez, P. Dinér, Angew.
Chem. Int. Ed. 2013, 52, 502-504; Angew. Chem. 2013, 125, 522; c) S.
Agrawal, E. Martínez-Castro, R. Marcos, B. Martín-Matute, Org. Lett.
2014, 16, 2256.
Figure 3. Optimized Structures of TSR (up; 7.8 kcal/mol) and TSS (bottom; 9.3
kcal/mol). a) Interatomic distances (Å), light blue dashed lines and displacement
vectors (blue arrows) in the corresponding transition states. b) Complete
optimized structures of the transition states with the CH-π interactions shown
as green dashed lines and the distances (Å) between a proton and the center
of the corresponding phenyl ring as green numbers. Carbon: grey, hydrogen:
white, oxygen: red, nitrogen: blue, chlorine: green.
[7]
a) A. Ortiz, T. Benkovics, G. L. Beutner, Z. Shi, M. Bultman, J. Nye, C.
Sfouggatakis, D. R. Kronenthal, Angew. Chem. Int. Ed. 2015, 54, 7185;
Angew. Chem. 2015, 127, 7291; b) D. W. Piotrowski, A. S. Kamlet, A.-M.
R. Dechert-Schmitt, J. Yan, T. A. Brandt, J. Xiao, L. Wei, M. T. Barrila, J.
Am. Chem. Soc. 2016, 138, 4818; c) A. Kinens, M. Sejejs, A. S. Kamlet,
D. W. Piotrowski, E. Vedejs, E. Suna, J. Org. Chem. 2017, 82, 869; d)
M.-S. Xie, Y.-G. Chen, X.-X. Wu, G.-R. Qu, H.-M. Guo, Org. Lett. 2018,
20, 1212.
[8]
[9]
Low enantioselectivities were obtained by using chiral DMAP and
cinchonine organocatalysts: a) S. Yamada, K. Yamashita, Tetrahedron
Lett. 2008, 49, 32; b) D. Niedek, S. M. M. Schuler, C. Eschman, R. C.
Wende, A. Seitz, F. Keul, P. R. Schreiner, Synthesis 2017, 49, 371.
a) Z. Zhang, F. Xie, J. Jia, W. Zhang, J. Am. Chem. Soc. 2010, 132,
15939; b) S. Liu, Z. Zhang, F. Xie, N. A. Butt, L. Sun, W. Zhang,
Tetrahedron: Asymmetry 2012, 23, 329; c) Z. Zhang, M. Wang, F. Xie,
H. Sun, W. Zhang, Adv. Synth. Catal. 2014, 356, 3164; d) M. Wang, Z.
Zhang, S. Liu, F. Xie, W. Zhang, Chem. Commun. 2014, 50, 1227; e) M.
Wang, Z. Zhang, F. Xie, W. Zhang, Chem. Commun. 2014, 50, 3163; f)
M. Wang, X. Zhang, Z. Ling, Z. Zhang, W. Zhang, Chem. Commun. 2017,
53, 1381; g) L. Zhang, M. Wang, M. Zhou, Z. Zhang, M. Muraoka, W.
Zhang, Asian J. Org. Chem. 2019, 8, 1024; h) M. Zhou, E. He, L. Zhang,
J. Chen, Z. Zhang, Y. Liu, W. Zhang, Org. Chem. Front. 2019, 6, 3969; i)
M. Wang, M. Zhou, L. Zhang, Z. Zhang, W. Zhang, Chem. Sci. 2020, 11,
4801; j) M. Wang, L. Zhang, X. Huo, Z. Zhang, Q. Yuan, P. Li, J. Chen,
Y. Zou, Z. Wu, W. Zhang, Angew. Chem. Int. Ed. 2020, doi:
In conclusion, the acylative dynamic kinetic resolution of 3-
hydroxyphthalides has been efficiently implemented and
successfully applied in the synthesis of several chiral phthalidyl
ester prodrugs. Utilizing a chiral bicyclic imidazole organocatalyst
Cy-DPI and adopting a continuous injection process, a wide range
of phthalidyl esters were synthesized with high yields and
excellent enantioselectivities (up to 99% ee). Computational
studies suggest a general base catalytic mechanism and a CH-π
interaction-dominated stereocontrol mode.
Acknowledgements
This work was partially supported by National Natural Science
Foundation of China (Nos. 91856106, 21620102003 and
21991112) and National Key R&D Program of China (No.
2018YFE0126800). We thank the Instrumental Analysis Center of
Shanghai Jiao Tong University.
10.1002/anie.202011527;
Angew.
Chem.
2020,
doi:
10.1002/ange.202011527. Also utilized by other groups for the synthesis
of phosphonate prodrugs: k) D. A. DiRocco, Y. Ji, E. C. Sherer, A.
Klapars, M. Reibarkh, J. Dropinski, R. Mathew, P. Maligres, A. M. Hyde,
J. Limanto, A. Brunskill, R. T. Ruck, L.-C. Campeau, I. W. Davies,
Science 2017, 356, 426; l) D. A. Glazier, J. M. Schroeder, S. A. Blaszczyk,
W. Tang, Adv. Synth. Catal. 2019, 361, 3729.
Keywords: organocatalyst • bicyclic imidazole • dynamic kinetic
resolution • enantioselective acylation • phthalidyl ester prodrugs
[10] Q. Deng, F. Mu, Y. Qiao, D. Wei, Org. Biomol. Chem. 2020, 18, 6781.
[1]
V. Abet, F. Filace, J. Recio, J. Alvarez-Builla, C. Burgos, Eur. J. Med.
Chem. 2017, 127, 810.
5
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Entry for the Table of Contents
Utilizing a chiral bicyclic imidazole organocatalyst and adopting a continuous injection process, the acylative dynamic kinetic resolution
of 3-hydroxyphthalides has been implemented for the synthesis of a wide range of phthalidyl esters in high yields and with excellent
enantioselectivities (up to 99% ee). Computational studies suggest a general base catalytic mechanism and a CH-π interaction-
dominated stereocontrol mode.
6
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