Catalytic asymmetric oxidative carbonylation-induced kinetic resolution of sterically hindered benzylamines to chiral isoindolinones

Article abstract of DOI:10.1039/d0cc07218d

A highly enantioselective kinetic resolution of sterically hindered benzylamines has been achieved for the first time through transition-metal-catalyzed oxidative carbonylation, in which the new KR strategy offered a new approach to afford chiral isoindolinones (er up to 97?:?3) and the origin of chemoselectivity and stereoselectivity was confirmed by density functional theory (DFT) calculations.

Full text of DOI:10.1039/d0cc07218d

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Catalytic asymmetric oxidative carbonylation-
induced kinetic resolution of sterically hindered
benzylamines to chiral isoindolinones†
Cite this: Chem. Commun., 2021,
57, 1778
Received 1st November 2020,
Accepted 11th January 2021
ad
Qiu-Qi Mu,‡abc Yi-Xue Nie,‡b Hang Li,‡b Xing-Feng Bai,*bc Xue-Wei Liu,
bc
Zheng Xub and Li-Wen Xu
*
DOI: 10.1039/d0cc07218d
rsc.li/chemcomm
A highly enantioselective kinetic resolution of sterically hindered was only suitable for the prochiral sulfonamides, which contain
benzylamines has been achieved for the first time through two prochiral C–H bonds, thus limiting the chiral isoindolinone
transition-metal-catalyzed oxidative carbonylation, in which the diversity. Therefore, exploring new methods for preparing chiral
new KR strategy offered a new approach to afford chiral isoindo- isoindolinone from readily available substrates is highly desirable.
linones (er up to 97 : 3) and the origin of chemoselectivity and
In recent years, kinetic resolution has emerged as an attrac-
stereoselectivity was confirmed by density functional theory (DFT) tive and efficient method to generate different types of chiral
calculations.
compounds from racemic starting substrates.4 In this context,
List demonstrated chiral phosphoric acid (STRIP) catalyzed
The chiral isoindolinone core serves as a privileged structure, enantioselective kinetic resolution of homoaldol acetals to
and is widely present in many medicine candidates.1 Typical obtain cyclic acetals via asymmetric transacetalization reaction
examples are the dopamine D4 receptor PD-172938,1a pagoclone in 2010.4a In 2015, Yu firstly reported the palladium-catalyzed
(an anxiolytic drug)1b and 9b-phenyl-2,3-dihydrothiazolo[2,3-a]- enantioselective C–H olefination of alfa-aminophenylacetic
isoindol-5(9bH)-one, which was used as an HIV-1 reverse tran- acids and alfa-hydroxy via kinetic resolution, which provided
scriptase inhibitor (Fig. 1).1c The chiral isoindolinone skeleton is a general protocol for the synthesis of olefinated mandelic
also an integral part of biologically significant natrual products acids and phenylglycines.4b The Oestreich group disclosed
such as the isoindolobenzazepine alkaloid (+)-lennoxamine Cu–H species catalyzed enantioselective silylation to give chiral
(Fig. 1).1d Thus, devising novel and facile methods to access tertiary propargylic alcohols for the first time in 2018.4c Subse-
the chiral isoindolinone motif is of great interest.1a,2 During our quently in 2019, Dong described Rh-catalyzed kinetic resolution
studies, we became interested in the synthesis of chiral isoindo- of cyclobutanones via a ‘‘cut-and sew’’ reaction to afford trans
linones based on the desymmetric amine carbonylation 5,6-fused bicycles and C2-substituted cyclobutanones with excellent
strategy.3 It should be noted that, our reported method for ee at room temperature.4d Recently, Zhang reported the kinetic
desymmetrization C–H bond activation/amine carbonylation resolution strategy to synthesized chiral piperidines and chiral
a Institute of Advanced Synthesis (IAS), Northwestern Polytechnical University
(NPU), Xi’an 710072, China, Yangtze River Delta Research Institute of NPU,
Taicang, Jiangsu, 215400, China
b Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of
Education, and Key Laboratory of Organosilicon Material Technology of Zhejiang
Province, Hangzhou Normal University, Hangzhou 311121, P. R. China.
E-mail: liwenxu@hznu.edu.cn
c State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research
Institute (SRI), Lanzhou Institute of Chemical Physics (LICP), University of the
Chinese Academy of Sciences (UCAS), Lanzhou 730000, P. R. China
d Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, 637371, Singapore
† Electronic supplementary information (ESI) available. CCDC 1971018. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
Fig. 1 Biological active compounds containing a chiral isoindolinone
d0cc07218d
motif.
‡ These authors contributed equally to this work.
1778 | Chem. Commun., 2021, 57, 1778ꢀ1781
This journal is The Royal Society of Chemistry 2021

View Article Online
Communication
ChemComm
Scheme 1 Kinetic resolution of racemic sterically hindered benzylamines.
1,4,5,6-tetrahydropyridines using racemic 1,4-dihydropyridines and
3,4-disubstituted 1,4,5,6-tetrahydropyridines through Rhodium-
catalyzed asymmetric hydrogenation.4e Although many kinetic
resolution strategis have been widely recognized and extensively
investigated in catalytic asymmetric reaction, catalytic asymmetric
carbonylation is still not easily accessible. To the best of our
knowledge, no reports on the construction of chiral isoindolinone
through the kinetic resolution strategy exist. Since racemic sterically
hindered benzylamines are readily accessible, kinetic resolution
can be an attractive alternative method for the preparation of chiral
isoindolinones based on a C–H activation/carbonylation strategy.
Herein, we firstly report an efficient protocol of kinetic resolution
for the synthesis of chiral isoindolinones through Pd/Cu-cocatalysis
C–H functionalization/amine carbonylation, which would fill a gap
in synthetic chemistry (Scheme 1).
Scheme 3 Substrate scope of catalytic asymmetric oxidative carbonylation-
induced kinetic resolution of sterically hindered benzylamines 1.
established catalyst system (ESI,† Table S1). Variation of the
N-protecting groups of rac-1 showed that different sulfinates,
such as methanesulfinate (Ms-), 4-methoxylbenzenesulfinate
(Ans-), 4-nitrobenzenesulfinate (Ns-), trifluoromethanesulfinate
(Tf-), and 4-methylbenzenesulfinate (Ts-), all worked well for
the reaction to give the corresponding chiral isoindolinones in
good conversion (33–55%) and good selectivity (S = 13.5–32.1).
Among them, 4-methoxylbenzenesulfinate (Ans-) was eventually
identified as the optimal N-protecting group of rac-1, achieving
high conversion (49%) and featuring the best selectivity
(S = 32.1). In analogy to the sulfinates, when using Boc- as
the protecting group, there was no reaction. To further explore
the effect of ligand structure on conversition and selectivity, a
wide range of chiral amino acid ligands was screened using
rac-1a as the model substrate (Scheme 2). After an extensive
survey of readily available Boc-N-protected amino acids, we
found that Boc-L-Leu-OH proved to be the optimal ligand for
this kinetic resolution protocol. In addition, when the acid
Considering our previous work on the C–H desymmetriza-
tion aminocarbonylation of prochiral sulfonamides by Pd/
Cu-cocatalysis,3 the study commenced with a survey of rac-1
with different N-protecting groups using our previously
Scheme 2 Catalytic asymmetric oxidative carbonylation-induced kinetic
resolution of racemic 1a. Enantiomeric excess (ee) was determined
by chiral HPLC analysis, where ee1 is the enantiomeric excess of the
recovered 1a0 and ee2 is the enantiomeric excess of 2a. S = selectivity
factor, and S = ln[(1-C)(1-ee)]/ln[(1-C)(1 + ee)], where ee = ee1/100 and
C = conversion/100.
Scheme 4 Enantioselective C–H activation/amine carbonylation of the
recovered starting material.
This journal is The Royal Society of Chemistry 2021
Chem. Commun., 2021, 57, 1778ꢀ1781 | 1779

View Article Online
ChemComm
Communication
(Scheme 3). In most cases, both isoindolinone 2 and benzylamines
1 were obtained with excellent enantioselectivity. For example, the
substrate bearing no substituent on the aromatic ring (rac-1a) was
resolved with high selectivity factors (S = 32.9) and 2a was obtained
in excellent optical purity (92 : 8 er). The nature of the aromatic
substituents did not exhibit a significant effect on the reaction, and
rac-1b-1f underwent superb kinetic resolutions, with selectivity
factors (S) up to 47.
Notably, high enantiomeric purity of the recovered starting
material (R)-1f0 and (R)-1k0, could be used to synthesize chiral
isoindolinones (R)-2f0 and (R)-2k0 in 94 : 6 er and 97 : 3 er using
a mono-N-protected amino acid ligand (Boc-D-Leu-OH) with the
opposite configuration, which demonstrated the feasibility of
affording both enantiomers of chiral isoindolinones through
Scheme 5 Potential application of the core segment.
moiety of the ligand was substituted with N-methoxyamide, no this approach (Scheme 4). Similarly, 2g and 2h were also
reaction was observed. Based on the previous studies, the N- produced in 90 : 10 er and 89 : 11 er, respectively, demonstrating
protecting group on the MPAA ligand exerts a significant influence that steric hindrance did not dramatically hamper the kinetic
on the enatioselectivity, and we then explored other protecting resolution. Gratifyingly, rac-1i and rac-1j proved to be excellent
groups on the amino group, such as Cbz-, Fmoc, and Ac-groups. substrates. Both 2i and 2j, the key intermediates for synthesis
Unfortunately, no significant improvement was observed with these of the bioactive compound derivatives ((S)-PD 172938, pazina-
ligands. Extensive experimentation using Boc-L-Leu-OH as the chiral clone and pagoclone) (Scheme 5),5 were obtained with 91 : 9 er
ligand revealed a series of critical reaction parameters (ESI,† and 96 : 4 er respectively. These results demonstrated that the
Tables S3–S6). In particular, no reaction occurred when PdCl2 current protocol could provide a versatile entry point for the
or Pd(TFA)2 was utilized as a palladium catalyst (Table S3, ESI†). asymmetric synthesis of bioactive isoindolinones.
And low levels of reactivity and selectivity were obtained using
The absolute configuration of 2h was confirmed by X-ray
Pd(CH3CN)2Cl2 instead of Pd(OAc)2. Other Cu salts could be crystallography analysis to be S, which prompted us to propose
used as the oxidant in this reaction, including Cu(OAc)2, a stereomodel to investigate the origin of the stereoselectivity.
Cu(TFA)2ꢁXH2O, and Cu(OTf)2, which could also reoxidized the
Inspired by previous reports on the reasonable transient state
Pd(0) species to active center Pd(II) with the aid of O2 to complete model for Pd-catalyzed and mono-N-protected amino acid pro-
the entire catalyzed cycle, albeit an inferior result was obtained moted asymmetric C(sp2)–H functionalization,6 we performed
(Tabel S4, ESI†). The use of other bases allowed for no improve- DFT calculations to elucidate the origin of the chemoselectivity
ment, and even led to no reaction (Table S5, ESI†). Attemps to and stereoselectivity (Fig. 2). Notably, both our group and Xia’s
further improve the reactivity and selectivity by investigating group have developed the Pd-catalyzed enantioselective C–H
various solvents were not fruitful (Table S6, ESI†).
activation/amine carbonylation by a desymmetrization strategy,
After establishing the optimized conditions, we began to explore and the DFT calculations have been conducted to clarify the
the substrate scope of the sterically hindered benzylamines possible reaction pathways.3,7 Based on the previous theoretical
Fig. 2 The free energy profiles for the Pd/Cu-cocatalyzed C–H functionalization/carbonylation. The free energies (in kcal molꢀ1) are calculated at the
B3lyp and BS (BS = 6-31g(d,p) for main group elements and LanL2DZ for Pd) level of theory.
1780 | Chem. Commun., 2021, 57, 1778ꢀ1781
This journal is The Royal Society of Chemistry 2021

View Article Online
Communication
ChemComm
Notes and references
1 (a) T. R. Belliotti, W. A. Brink, S. R. Kesten, J. R. Rubin, D. J. Wustrow,
K. T. Zoski, S. Z. Whetzel, A. E. Corbin, T. A. Pugsley, T. G. Heffner
and L. D. Wise, Bioorg. Med. Chem. Lett., 1998, 8, 1499; (b) T. L. Stuk,
B. K. Assink, R. C. Bates, D. T. Erdman, V. Fedij, S. M. Jennings,
J. A. Lassig, R. J. Smith and T. L. Smith, Org. Process Res. Dev., 2003,
7, 851; (c) A. Mertens, H. Zilch, B. Koing, W. Schafer, T. Poll,
W. Kampe, H. Seidel, U. Leser and H. Leinert, J. Med. Chem., 1993,
36, 2526; (d) A. Couture, E. Deniau, P. Grandclaudon and C. Hoarau,
Tetrahedron, 2000, 56, 1491; (e) J. N. Oak, J. Oldenhof and
H. H. M. Van Tol, Eur. J. Pharmacol., 2000, 405, 303; ( f ) K. Speck
and T. Magauer, Beilstein J. Org. Chem., 2003, 9, 2048;
(g) N. Kanamitsu, T. Osaki, Y. Itsuji, M. Yoshimura, H. Tsujimoto
and M. Soga, Chem. Pharm. Bull., 2007, 55, 1682; (h) J. J. Baldwin,
S. Cacatian, D. A. Claremon, L. W. Dillard, P. T. Flaherty,
A. V. Ishchenko, L. Jia, G. Mcgeehan, R. D. Simpson, S. B. Singh,
C. M. Tice, Z. Xu, J. Yuan, W. Zhao and L. Zhuang, Renin Inhibitors
WO2008156816A2, 2008.
Fig. 3 Optimized geometries of the transition states.
2 (a) V. Bisai, A. Suneja and V. K. Singh, Angew. Chem., 2014,
126, 10913; (b) J. Suc, I. Dokli and M. Gredicak, Chem. Commun.,
2016, 52, 2071; (c) R. Grigg, M. J. R. Dorrity, J. F. Malone,
T. Mongkolaussavaratana, W. D. J. A. Norbert and V. Sridharan,
Tetrahedron Lett., 1990, 31, 3075; (d) S. Adachi, M. Onozuka,
Y. Yoshida, M. Ide, Y. Saikawa and M. Nakata, Org. Lett., 2014,
16, 358; (e) M.-D. Chen, X. Zhou, M.-Z. He, Y.-P. Ruan and
P.-Q. Huang, Tetrahedron, 2004, 60, 1651; ( f ) D. L. Comins,
S. Schiling and Y. Zhang, Org. Lett., 2005, 7, 95; (g) A. Suneja,
V. Bisai and V. K. Singh, J. Org. Chem., 2016, 81, 4779–4788;
(h) S. K. Ray, M. M. Sadhu, R. G. Biswas, R. A. Unhale and
V. K. Singh, Org. Lett., 2019, 21, 417; (i) Y. Yoshinaga, T. Yamamoto
and M. Suginome, Angew. Chem., Int. Ed., 2020, 59, 7251;
( j) H. Mcalona, J. P. Murphy, M. Nieuwenhuyzen, K. Reynolds,
P. K. S. Sarma, P. J. Stevenson and N. Thompson, J. Chem. Soc.,
Perkin Trans. 1, 2002, 69.
studies, Pd(II)-amino acid salt was usually set to the relative zero
value. As shown in Fig. 2, four different transition states (TS1-S,
TS1-R, TS2-S, TS2-R of Fig. 3) were simulated from int3 to int4.
The lowest activation energy of the C(sp2)–H bond activation was
calculated to be 15.2 kcal molꢀ1 (TS1-S), while the C(sp3)–H bond
activation was calculated to be 18.4 kcal molꢀ1 (TS2-S), that is
3.2 kcal molꢀ1 higher than TS1-S, which was in agreement with
the experimental results of Scheme 3. In the transition state TS1-S
and TS1-R of C(sp2)–H bond activation, the higher energy state for
the R-enantiomer (TS1-R) was calculated to be 15.7 kcal molꢀ1
,
which is 0.5 kcal molꢀ1 higher than TS1-S. The energy difference
between TS1-S and TS1-R indicated that the S-configuration of
chiral isoindolinone 2a was formed preferentially.
3 X. F. Bai, Q.-C. Mu, Z. Xu, K.-F. Yang, L. Li, Z.-J. Zheng, C.-G. Xia and
L.-W. Xu, ACS Catal., 2019, 9, 1431.
4 (a) L. Coric, S. Muller and B. List, J. Am. Chem. Soc., 2010, 132, 17370;
(b) K.-J. Xiao, L. Chu and J.-Q. Yu, Angew. Chem., Int. Ed., 2016,
55, 2856; (c) J. Seliger, X. Dong and M. Oestreich, Angew. Chem., Int.
Ed., 2019, 58, 1970; (d) L. Deng, Y. Fu, S. Y. Lee, C. Wang, P. Liu and
G. Dong, J. Am. Chem. Soc., 2019, 141, 16260; (e) W. Li, H. Yang, R. Li,
H. Lv and X. Zhang, ACS Catal., 2020, 10, 2603; ( f ) S. Rajkumar, S. He
and X. Yang, Angew. Chem., Int. Ed., 2019, 58, 10315; (g) H. Yang and
W.-H. Zheng, Angew. Chem., Int. Ed., 2019, 58, 16177; (h) K.-J. Xiao,
L. Chu, G. Chen and J.-Q. Yu, J. Am. Chem. Soc., 2016, 138, 7796;
(i) S. Lu, S. B. Poh, W.-Y. Siau and Y. Zhao, Angew. Chem., 2013,
52, 1731.
5 (a) A. Di Moa, M. Tiffner, F. Scorzelli, L. Palombi, R. Filosa, P. De
Caprariis, M. Waser and A. Massa, Beilstein J. Org. Chem., 2015,
11, 2591; (b) C. Liu, Q. Zhang, H. Li, S. Guo, B. Xiao, W. Deng,
L. Liu and W. He, Chem. – Eur. J., 2016, 22, 6208.
6 (a) D. E. Hill, K. L. Bay, Y.-F. Yang, R. E. Plata, R. Takise, K. N. Houk
and J.-Q. Yu, J. Am. Chem. Soc., 2017, 139, 18500; (b) B. E. Haines,
J.-Q. Yu and D. G. Musaev, ACS Catal., 2017, 7, 4344; (c) G.-J. Cheng,
P. Chen, T.-Y. Sun, X.-H. Zhang, J.-Q. Yu and Y.-D. Wu, Chem. – Eur. J.,
2015, 21, 11180.
In conclusion, Pd/Cu-cocatalyzed enantioselective C–H activa-
tion/amine carbonylation of sterically hindered benzylamines by
kinetic resolution has been developed first, which will fill an
important gap in the synthesis of bioactive compounds containing
an isoindolinone motif. Elucidated by density functional theory
(DFT) calculations, the origin of the chemoselectivity and stereo-
selectivity could have implications for other kinetic resolution
reactions. The further development of the synthetic strategy is
ongoing in our laboratory.
We thank the National Natural Science Foundation of China
(NSFC 21702211, 21773051, 21703051, and 21801056), the
Natural Science Foundation of Jiangsu Province (BK20170421),
and Zhejiang Provincial Natural Science Foundation of China
(LZ18B020001).
7 (a) H. Han, T. Zhang, S.-D. Yang, Y. Lan and J.-B. Xia, Org. Lett., 2019,
21, 1749; (b) H. Han, S. D. Yang and J. B. Xia, J. Org. Chem., 2019,
84, 3357; (c) S. W. Yuan, H. Han, Y. L. Li, X. L. Wu, X. G. Bao, Z. Y. Gu
and J. B. Xia, Angew. Chem., Int. Ed., 2019, 58, 8887.
Conflicts of interest
There are no conflicts to declare.
This journal is The Royal Society of Chemistry 2021
Chem. Commun., 2021, 57, 1778ꢀ1781 | 1781