Carbene-Catalyzed Dynamic Kinetic Resolution and Asymmetric Acylation of Hydroxyphthalides and Related Natural Products

Article abstract of DOI:10.1002/anie.201912926

A catalytic dynamic kinetic resolution and asymmetric acylation reaction of hydroxyphthalides is developed. The reaction involves formation of a carbene catalyst derived chiral acyl azolium intermediate that effectively differentiates the two enantiomers of racemic hydroxyphthalides. The method allows quick access to enantiomerically enriched phthalidyl esters with proven applications in medicine. It also enables asymmetric modification of natural products and other functional molecules that contain acetal/ketal groups, such as corollosporine and fimbricalyxlactone C.

Full text of DOI:10.1002/anie.201912926

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Carbene-Catalyzed Dynamic Kinetic Resolution and Asymmetric
Acylation of Hydroxyphthalides and Related Natural Products
Authors: Yingguo Liu, Pankaj Kumar Majhi, Runjiang Song, Chengli
Mou, Lin Hao, Huifang Chai, Zhichao Jin, and Yonggui Robin
Chi
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912926
Angew. Chem. 10.1002/ange.201912926
Link to VoR: http://dx.doi.org/10.1002/anie.201912926
http://dx.doi.org/10.1002/ange.201912926

10.1002/anie.201912926
Angewandte Chemie International Edition
COMMUNICATION
Carbene-Catalyzed Dynamic Kinetic Resolution and Asymmetric
Acylation of Hydroxyphthalides and Related Natural Products
Yingguo Liu†, Pankaj Kumar Majhi†, Runjiang Song†, Chengli Mou, Lin Hao, Huifang Chai*, Zhichao
Jin, Yonggui Robin Chi*
Abstract: A catalytic dynamic kinetic resolution and asymmetric
acylation reaction of hydroxyphthalides is developed. The reaction
involves formation of a carbene catalyst-derived chiral acyl azolium
intermediate that effectively differentiates the two enantiomers of
racemic hydroxyphthalides. Our method allows for quick access to
enantiomerically enriched phthalidyl esters with proven applications in
medicines. It also enables asymmetric modification of natural
products and other functional molecules that contain acetal/ketal
groups, such as Corollosporine and Fimbricalyxlactone C.
spiroacetalization was developed in high yield and excellent e.r. value.
In the area of N-heterocyclic carbene (NHC) organic catalysis, studies
by Wang and co-workers showed 6-hydroxypyranones could be
esterified asymmetrically with enals or alkynals through dynamic
[13]
kinetic resolution pattern to form chiral acetal units.
Tang and
coworkers reported the dynamic kinetic diastereoselective acylation
of lactols through chiral isothiourea catalytic reactions.[14] We recently
disclosed
a carbene-catalyzed enantioselective modification of
carboxylic acids for asymmetric access to optically enriched acetal
products (Figure 1b).[15]
Phthalides are core structures of diverse natural products found
in plants and fungal genera. [1] Many of these phthalide-containing
molecules exhibit a broad spectrum of biological activities[2] with
proven applications such as for the treatments of circulatory and heart
diseases. [3] Hydroxyphthalides, with a hydroxyl group attached to the
anomeric carbon to form a ketal/acetal moiety, are a subgroup of
phthalides with wide natural occurrence and significant utilities (Figure
1a). [4] For example, talosalate was marked to treat inflammation and
pain. [5] Luteorosin was found in chromodoris luteorosa and exhibit
ichthyotoxic activities. [6] Corollosporine is an antibacterial metabolite
of marine fungus corollospora maritima. [7] Fimbricalyxlactone B & C
were isolated from Strophioblachia fimbricalyx which is used as folk
medicine to treat migraine, fever, and cancer.[4b] Acylated
hydroxyphthalides (such as talniflumate[8], talampicillin[9] and
talmetacin[10]) have also been used as prodrugs of carboxylic acids.
The acetal/ketal moiety in hydroxyphthalides and their derivatives
contains a labile chiral center. Therefore, it remains difficult to prepare
hydroxyphthalide-containing molecules in enantiomerically pure
forms. Indeed, enantioselective access to acetals/ketals is a general
challenge in organic synthesis.[11] List showed that with confined chiral
phosphoric acids based on a C2-symmetric imidodiphosphoric acid
motif as organic catalysts[12], an enantioselective approach for
[*]
Dr. C. Mou, Prof. H. Chai
School of Pharmacy, Guizhou University of Traditional Chinese
Medicine, Huaxi District, Guiyang, Guizhou, 550025, China
Email: hfchai@126.com
Dr. Y, Liu†, P. K. Majhi†, R. Song†, Dr. L. Hao, Prof. Y. R. Chi
Nanyang Technological University, Division of Chemistry &
Biological Chemistry, School of Physical & Mathematical Sciences,
Singapore 637371, Singapore
Figure 1. Hydroxyphthalides and their enantioselective acylation via carbene-
catalyzed dynamic kinetic resolution
Here we disclose a new approach for enantiomeric access to
acylated hydroxyphthalides via a carbene-catalyzed dynamic
kinetic resolution (DKR) process (Figure 1b). The o-acetylbenzoic
(or formylbenzoic) acid substrate (1) undergoes an equilibirum
with the corresponding racemic hydrophthalide (predominant in
most solvents).[16] The aldehyde substrate (2) reacts with an NHC
catalyst in the presence of an oxidant to form a chiral acyl azolium
intermediate (I). [17] Similar acyl azolium intermediates can also be
Prof. Z. Jin, Prof. Y. R. Chi.
Key Laboratory of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, Guizhou University, Huaxi District, Guiyang
550025, China
Email: robinchi@ntu.edu.sg
[†] Y. Liu, P. K. Majhi, and R. Song contributed equally to this work.
Supporting information and the ORCID identification number(s) for
this article is available on the WWW under
http://www.angewandte.org.
This article is protected by copyright. All rights reserved.

10.1002/anie.201912926
Angewandte Chemie International Edition
COMMUNICATION
formed using enals as the aldehyde substrates without the need
of oxidants. Selective acylation of hydroxyphthalide by acyl
azolium intermediate I via a dynamic kinetic resolution process
led to chiral acylal (3) with high e.r. values. Our method works well
for diverse substrates and allows for enantioselective access to
commercially used pharmaceuticals such as talosalate with 1:99
e.r. value. We have also shown that with our method
in loweryields, although the e.r.of the product was not affected
(entries 7-8).
Table 2 Examples of the aldehyde substrates[a]
hydroxyphthalide-containing
natural
products
such
as
corollosporine[7] and fimbricalyxlactone C[4b] can be kinetically
resolved and acylated to form optically enriched ester products.
Table 1. Condition optimization[a]
Entry
NHC
Base
Solvent
Yield (%)
e.r.
1
2
3
4
5
6
7
8
A
B
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DIEA
THF
THF
48
24
59
80
81
96
87
76
52:48
32:68
6:94
95:5
98:2
98:2
98:2
99:1
C
THF
D
THF
D
THF
D
DIEA
EtOAc
EtOAc
EtOAc
D[b]
D[c]
DIEA
DIEA
[a] Reaction condition: 1a (0.12 mmol.), 2a (0.1 mmol), NHC pre-cat. (0.02
mmol), Base (0.1 mmol.), DQ (0.12 mmol) 3,3',5,5'-tetra-tert-
=
butyldiphenoquinone, solvent (2 mL). DIEA = N, N-Diisopropylethylamine.
EtOAc = ethyl acetate. Yields were determined by isolation. The e.r. was
determined via chiral-phase HPLC analysis. [b] 10 mol% D was used. [c] 5 mol%
D was used.
We started by using o-carboxybenzaldehyde (1a) and methyl
4-formylbenzoate (2a) as the model substrates to search for
suitable catalysts and conditions. Key results from condition
optimizations (see the Supporting Information) are shown in Table
1. The reaction was first performed in THF as a solvent with
triazolium salt A[18] as a NHC pre-catalyst in presence of Cs2CO3
as a base. Product 3a was obtained in a moderate yield but a very
low e.r. value (entry 1, 51% yield, 52:48). When we replaced NHC
[a] Reaction condition: 1a (0.12 mmol), RCHO (0.1 mmol.), NHC D (0.02 mmol),
DQ (0.12 mmol) = 3,3',5,5'-tetra-tert-butyldiphenoquinone, DIEA (0.1 mmol),
EtOAc (2 mL), 12 h. [b] carried out using C as the NHC pre-catalyst. Yields were
determined by isolation. The e.r. was determined via chiral-phase HPLC
analysis. DQ
= 3,3',5,5'-tetra-tert-butyldiphenoquinone, DIEA = N, N-
Diisopropylethylamine, EtOAc = ethyl acetate. e.r. = enantiomeric ratio. X-ray
crystal information of 3o is available under CCDC number 1914214.
precursor A with chiral morpholine-derived NHC pre-catalyst B[19]
,
With a few acceptable conditions in hand, we moved to
explore the substrate scope (Table 2) with both aryl aldehydes
and aliphatic aldehydes as the formal acylating agents.
Benzaldehyde derivatives containing various substituents [such
as halogen, nitro (-NO2), methylcarbonyl (-COOCH3) and acetoxyl
(-OAc) groups] were all tolerated to give the desired products with
excellent yields and e.r. values (3a-l). In most of the cases, the
substitution patterns on the benzene ring have little influence on
the reaction enantioselectivities and yields (3a-j). When iodine or
acetoxyl group were installed at the ortho-position of the benzene,
relatively lower yields and e.r. values were obtained under the
encouraging e.r. value was obtained but the yield was frustrating
(entry 2, 24% yield, 32:68). Replacing it with aminoindanol-
derived pre-catalyst C[20], D[21] led to the satisfactory yield and e.r.
values. Between them, the electron-rich pre-catalyst D could
produce 3a with the best yield and e.r. (entry 5). Additional studies
on the effect of bases and solvents (entries 4-6) eventually
revealed that DIEA was an optimal base with ethyl acetate as an
excellent solvent (entry 6). Decreasing the catalyt loading resulted
This article is protected by copyright. All rights reserved.

10.1002/anie.201912926
Angewandte Chemie International Edition
COMMUNICATION
standard condition (with NHC precursor D, 3k, 26% 93:7 e.r.; 3l,
22%, 86:14 e.r.). We then found that when D was replaced by C
as the NHC pre-catalyst, much-improved yields and e.r. values
were obtained for 3k (53%, 6:94 e.r.) and 3l (54% yield, 1:99 e.r.).
It’s worth to note that talosalate (3l) is a drug marketed in the
racemic form. With our method, talosalate could be prepared in
essentially an optically pure form (1:99 e.r.). Replacing the phenyl
unit of the aryl aldehyde substrate with a bromonaphthalene
substituent was also tolerated (3m). A diverse set of heteroaryl
aldehydes (such as those containing pyridine, furan, or
thiofurans) also reacted effectively to afford the products (3n-q)
with good to excellent yields and excellent e.r. values. The
absolute configuration of 3o was confirmed via single crystal X-
ray analysis. Using aliphatic aldehydes as the substrates, the high
e.r. values of the products remained, while the reaction yields
dropped significantly (3s-t) under the standard and a few other
through an internal redox process enals can be converted to acyl
azolium intermediate for efficient and enantioselective acylation
reactions (7a-c).
Table 4. Use of enals as acylation reagents without the need of external oxidants
[a]
.
conditions (see the Supporting Information).
[a] Reaction condition: 1a (0.1 mmol.), 6a-c (0.15 mmol.), NHC D (0.02 mmol),
DIEA (0.1 mmol), EtOAc (2 mL), 12 h. Yields were determined by isolation. The
Table 3. Example of the acetylbenzoic and formylbenzoic acid substrates [a]
e.r. was determined via chiral-phase HPLC analysis. DIEA
= N,N-
Diisopropylethylamine, EtOAc = ethyl acetate. e.r. = enantiomeric ratio.
At last, we applied our method for asymmetric acylation of
two natural products (Corollosporine and Fimbricalyxlactone C)
containing a hydroxyphthalide moiety (Scheme 2). Corollosporine,
prepared in one step using reported protocols[23](see the
Supporting Information), could be asymmetrically acylated under
our standard condition to form product 8 with 75% yield and 83:17
e.r. We then developed
fimbricalyxlactone C by starting from 1,6-dimethoxynaphthalene
(Scheme 2b). The synthesis took steps to afford
fimbricalyxlactone C in 44% overall yield(see the Supporting
Information). Treatment of fimbricalyxlactone under our
a route for total synthesis of
8
C
standard catalytic reaction condition could afford acylated product
10 with 80% yield and 82:18 e.r.
[a] Reaction condition: 4a-g (0.12 mmol), RCHO (0.1 mmol), 2a or 2c (0.12 mmol),
NHC precursor
D
(0.02 mmol), DQ (0.12 mmol)
=
3,3',5,5'-tetra-tert-
butyldiphenoquinone, DIEA (0.1 mmol), EtOAc (2 mL), 12 h. [b] carried out by NHC
D. Yields were determined by isolation. The e.r. was determined via chiral-phase HPLC
analysis. DQ
=
3,3',5,5'-tetra-tert-butyldiphenoquinone, DIEA
=
N, N-
Diisopropylethylamine, EtOAc = ethyl acetate. e.r. = enantiomeric ratio.
We next examined the scope of the acetylbenzoic and
formylbenzoic acid substrates(Table 3). Placing substituents to
the benzene ring of the formylbenzoic acid substrates led to a
slight loss on product e.r. values under current conditions (5a-b).
We were then delighted to find that when the aldehyde moiety in
the benzoic acid was replaced with a ketone group, our dynamic
kinetic resolution process still worked effectively to deliver the
acylated hydroxyphthalide products with excellent yields (5c-g).
The e.r. values of these products (5c-g) varied from 28:72 to 2:98
depending on both the benzoic acid and the aryl aldehyde
substrates. It appears the steric hindrance introduced by the
ketone moiety has an influence on the selective acylation step of
the reaction.
Scheme 2. Modification of natural products
In summary, we have developed a carbene-catalyzed
dynamic kinetic resolution and asymmetric acylation reaction of
3-hydroxyphthalide for quick access to optically enriched
phthalidyl esters. Our reaction also offers a convenient approach
for asymmetric modification of natural products and other
functional molecules bearing labile acetal moieties that are
difficult to be fixed stereo-selectively. We also expect our method
to find unique application for saccharide molecules containing
many hydroxyl groups with minute reactivity differences.
The NHC catalyst-derived acyl azolium intermediate for the
acylation reaction could also be prepared by using enals as the
substrates[22] (Table 4). Without the need of external oxidants,
This article is protected by copyright. All rights reserved.

10.1002/anie.201912926
Angewandte Chemie International Edition
COMMUNICATION
[5]
[6]
J. Castaer, J. Prous, Drugs Fut. 1986, 11. 394.
Acknowledgements
G. Cimino, A. Crispino, M. Gavagnin, G. Sodano, J. Nat. Prod. 1990, 53.
102.
We thank Dr. Yongxin Li (NTU) and Dr. Rakesh Ganguly for
assistance with X-ray structure analysis. We acknowledge
financial support by the Singapore National Research Foundation
(NRF-NRFI2016-06), the Ministry of Education of Singapore
(MOE2016-T2-1-032, MOE2018-T3-1-003, RG108/16, RG1/18),
A*STAR Individual Research Grant (A1783c0008, A1783c0010),
GSK-EDB Trust Fund, Nanyang Research Award Grant,
Nanyang Technological University; the Guizhou Province First-
Class Disciplines Project (Yiliu Xueke Jianshe Xiangmu)-
GNYL(2017)008, Guizhou University of Traditional Chinese
Medicine (China), the National Natural Science Foundation of
China (No. 21772029, 21472028, No. 21801051, No. 21961006,
No. 21807019), the 10 Talent Plan (Shicengci) of Guizhou
Province ([2016]5649), and Guizhou University. National Key
Technologies R&D Program (No. 2014BAD23B01), the Natural
Science Foundation of Guizhou Province(GNU[2018]2802,
GZU[2017]35), the Opening Foundation of the Key Laboratory of
Green Pesticide and Agricultural Bioengineering, Ministry of
Education, Guizhou University (2018GDGP0101).
[7]
[8]
[9]
K. Liberra, R. Jansen, U. Lindequist, Pharmazie 1998, 53. 578.
D. Knight, Curr. Opin. Investig. Drugs 2004, 5. 557.
J. P. Clayton, M. Cole, S. W. Elson, H. Ferres, J. C. Hanson, L. W. Mizen,
R. Sutherland, J. Med. Chem. 1976, 19. 1385.
[10] H. Torriani, Drugs Fut. 1982, 7. 825.
[11] Selected chiral acetal/ketal synthesis: a) I. Čorić, S. Vellalath, S. Müller,
X. Cheng, B. List, in Inventing Reactions, Springer Berlin Heidelberg,
Berlin, Heidelberg, 2013, pp. 165; b) J. Y. Hamilton, S. L. Rossler, E. M.
Carreira, J. Am. Chem. Soc. 2017, 139. 8082; c) B. Ye, J. Zhao, K. Zhao,
J. M. McKenna, F. D. Toste, J. Am. Chem. Soc. 2018, 140. 8350; d) B.
M. Paz, L. Klier, L. Naesborg, V. H. Lauridsen, F. Jensen, K. A.
Jorgensen, Chemistry 2016, 22. 16810; e) J. H. Kim, I. Coric, S. Vellalath,
B. List, Angew. Chem. Int. Ed. 2013, 52. 4474; f) J. H. Kim, I. Čorić, C.
Palumbo, B. List, J. Am. Chem. Soc. 2015, 137. 1778.
[12] I. Coric, B. List, Nature 2012, 483. 315.
[13] C. Zhao, F. Li, J. Wang, Angew. Chem. 2016, 128. 1852;Angew. Chem.
Int. Ed. 2016, 55. 1820.
[14] a) H.-Y. Wang, K. Yang, D. Yin, C. Liu, D. A. Glazier, W. Tang, Org. Lett.
2015, 17, 5272; b) H.-Y. Wang, C. J. Simmons, Y. Zhang, A. M. Smits,
P. G. Balzer, S. Wang, W. Tang, Org. Lett. 2017, 19, 508.
[15] 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.
[16] D. D. Wheeler, D. C. Young, D. S. Erley, J. Org. Chem. 1957, 22. 547.
[17] Selected acyl azolium formation: a) H. U. Vora, P. Wheeler, T. Rovis,
Adv. Synth. Cata. 2012, 354. 1617. b) C. Zhang, J. F. Hooper, D. W.
Lupton, ACS Catal. 2017, 7. 2583; c) S. De Sarkar, S. Grimme, A. Studer,
J. Am. Chem. Soc. 2010, 132. 1190; d) Z. Huang, X. Huang, B. Li, C.
Mou, S. Yang, B. A. Song, Y. R. Chi, J. Am. Chem. Soc. 2016, 138. 7524;
e) R. M. Gillard, J. E. M. Fernando, D. W. Lupton, Angew. Chem. Int. Ed.
2018, 57. 4712; Angew. Chem. 2018, 130. 4802; f) K.-Q. Chen, Z.-H.
Gao, S. Ye, Angew. Chem. Int. Ed. 2019, 58. 1183; Angew. Chem. 2019,
131. 1195.
Keywords: Dynamic kinetic resolution • Phthalidyl esters• N-
heterocyclic carbene • Natural product synthesis • Chiral prodrug
synthesis.
[1]
[2]
R. Karmakar, P. Pahari, D. Mal, Chem. Rev. 2014, 114. 6213.
a) G. Lin, S. S.-K. Chan, H.-S. Chung, S.-L. Li, in Stud. Nat. Prod. Chem.,
Vol. 32, Elsevier, 2005, pp. 611; b) M. Antonia Di, P. Laura, M. Antonio,
Curr. Org. Chem. 2012, 16. 2302; c) J. J. Beck, S.-C. Chou, J. Nat. Prod.
2007, 70. 891; d) L.-B. Zhang, J.-L. Lv, J.-W. Liu, J. Nat. Prod. 2016, 79.
1857; e) K. Tianpanich, S. Prachya, S. Wiyakrutta, C. Mahidol, S.
Ruchirawat, P. Kittakoop, J. Nat. Prod. 2011, 74. 79; f) E. L. Mullady, W.
P. Millett, H.-D. Yoo, A. S. Weiskopf, J. Chen, D. DiTullio, V. Knight-
Connoni, D. E. Hughes, W. E. Pierceall, J. Nat. Prod. 2004, 67. 2086.
a) X. Diao, X. Pang, C. Xie, Z. Guo, D. Zhong, X. Chen, Drug Metab.
Dispos. 2014. dmd.113.056218; b) X. Mo Jun, L. Zhong Hui, Curr. Org.
Chem. 2007, 11. 833.
[18] P.-C. Chiang, M. Rommel, J. W. Bode, J. Am. Chem. Soc. 2009, 131.
8714.
[19] N. E. Wurz, C. G. Daniliuc, F. Glorius, Chem-Eur. J. 2012, 18. 16297.
[20] J. Yan, R. Sun, K. Shi, K. Li, L. Yang, G. Zhong, J. Org. Chem. 2018, 83.
7547.
[3]
[4]
[21] M. He, J. R. Struble, J. W. Bode, J. Am. Chem. Soc. 2006, 128. 8418.
[22] a) A. Chan, K. A. Scheidt, Org. Lett. 2005, 7. 905; b) S. S. Sohn, J. W.
Bode, Org. Lett. 2005, 7. 3873.
a) M. Alam, R. H. Thomson, Handbook of Natural Products from Marine
Invertebrates, CRC Press, 1998; b) P. Seephonkai, S. G. Pyne, A. C.
Willis, W. Lie, J. Nat. Prod. 2013, 76. 1358.
[23] T. Ohzeki, K. Mori, Biosci. Biotech. Bioch. 2001, 65. 172.
This article is protected by copyright. All rights reserved.

10.1002/anie.201912926
Angewandte Chemie International Edition
COMMUNICATION
Layout 2:
COMMUNICATION
Yingguo Liu†, Pankaj Kumar Majhi†,
Runjiang Song†, Chengli Mou, Lin Hao,
Huifang Chai*, Zhichao Jin, Yonggui
Robin Chi*
Page No. – Page No.
Dynamic kinetic process: a carbene-catalyzed dynamic kinetic resolution process
is developed for asymmetric acylation and modification of medicines and natural
products that bear hydroxyphthalide and acetal/ketal moieties.
Carbene-Catalyzed Dynamic Kinetic
Resolution and Asymmetric Acylation
of Hydroxyphthalides and Related
Natural Products
This article is protected by copyright. All rights reserved.