Synthesis of chiral isoindolinones via asymmetric propargylation/lactamization cascade

Article abstract of DOI:10.1016/j.tetlet.2018.03.024

A Zn-mediated propargylation/lactamization cascade reaction with chiral 2-formylbenzoate derived N-tert-butanesulfinyl imines was realized, which provided a practical and efficient method for the synthesis of chiral isoindolinones. High diastereoselectivities (up to 97:3 dr) and good reaction yields were observed for most examined cases.

Full text of DOI:10.1016/j.tetlet.2018.03.024

Accepted Manuscript
Synthesis of Chiral Isoindolinones via Asymmetric Propargylation/Lactamiza-
tion Cascade
Jiao-Long Meng, Tang-Qian Jiao, Ya-Heng Chen, Rui Fu, Shu-Sheng Zhang,
Qian Zhao, Chen-Guo Feng, Guo-Qiang Lin
PII:
S0040-4039(18)30321-6
https://doi.org/10.1016/j.tetlet.2018.03.024
TETL 49793
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 January 2018
6 March 2018
9 March 2018
Please cite this article as: Meng, J-L., Jiao, T-Q., Chen, Y-H., Fu, R., Zhang, S-S., Zhao, Q., Feng, C-G., Lin, G-
Q., Synthesis of Chiral Isoindolinones via Asymmetric Propargylation/Lactamization Cascade, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.03.024
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Tetrahedron Letters
Synthesis of Chiral Isoindolinones via Asymmetric Propargylation/Lactamization
Cascade
Jiao-Long Menga,†, Tang-Qian Jiaoa,†, Ya-Heng Chenb, Rui Fua, Shu-Sheng Zhangb, Qian Zhaoa,, Chen-
Guo Fengb,, and Guo-Qiang Linb
a
Jiangsu Key Laboratory of Chiral Drug Development, Jiangsu Aosaikang Pharmaceutical CO., LTD., Nanjing, Jiangsu 211112, PR China
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, PR
b
China
† These authors equally contributed to this work.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A Zn-mediated propargylation/lactamization cascade reaction with chiral 2-formylbenzoate
derived N-tert-butanesulfinyl imines was realized, which provided a practical and efficient
method for the synthesis of chiral isoindolinones. High diastereoselectivities (up to 97:3 dr) and
good reaction yields were observed for most examined cases.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Propargylation
Isoindolinone
N-Tert-butansulfinyl Imine
Asymmetric Synthesis
Cascade Reaction
Chiral isoindolinones are important core structures found in
many biologically active compounds (Fig 1).1 As a result,
significant effort has been devoted to their asymmetric synthesis.2
Despite the rapid advancement in catalytic approaches,3-5
methods relying on the utilization of chiral auxiliaries continued
to be an attractive strategy due to a myriad of advantages, like the
reliability in stereoselectivity control, the easy accessibility of the
auxiliary reagents and the possibility of obtaining optical pure
products through simple silicon chromatography purification.
Several chiral auxiliaries have been used for the
diastereoselective synthesis of isoindolinones, including chiral 1-
amino-2-methoxymethylpyrrolidines,6 chiral amino alcohol
derivatives,7 chiral amines and alcohols,8 and chiral N-tert-
butansulfinamide.9
previous In-mediated one-pot synthesis of
isoindolinone derivatives.9
chiral 3-allyl
Since the seminal work by Ellman and co-workers, chiral N-
tert-butansulfinamide auxiliary went through
a
quick
development and proved to be one of the most reliable chiral
controller for asymmetric transformation.10 The addition to chiral
2-formylbenzoate derived N-tert-butansulfinyi imines followed
by lactamization can serve as a convenient way to generate 3-
Fig 1. Selected bio-active chiral isoindolinones
s—ub—stit—uted isoindolinones, which has been exampled by the
 Corresponding author.
E-mail address: zhaoqian@ask-pharm.com (Q. Zhao)
E-mail address: fengcg@ sioc.ac.cn (C.-G. Feng)

2
Tetrahedron Letters
Inspired by recent progresses in Zn-mediated
Table 2
propargylation of N-tert-butansulfinyl imines,11 we envision a
Substrate scope of asymmetric propargylation/lactamization
cascade
propargylation/lactamization
cascade
with
chiral
2-
formylbenzoate derived N-tert-butansulfinyi imines could take
place and lead to the easy synthesis of chiral 3-propargyl
isoindolinone derivatives, which could also be used as
intermediate for the synthesis of more chiral isoindolinone
compounds due to the rich transformations associated with
propargyl group.12
Initially,
we
tested
the
proposed
propargylation/lactamization cascade with 3-bromopropyne
under the reaction conditions developed by Xu and co-workers.11a
The reaction system was rather complicated and only a small
amount of the desired isoindolinone 2 was generated, which may
ascribe to the existence of an acidic terminal hydrogen and an
active alkyne moiety in 3-bromopropyne (Scheme 1).
Scheme 1. Initial attempt with 3-bromopropyne
Therefore, silyl-protected 3-bromopropyne was used in the
next examination (Table 1). To our delight, with 3-(trimethylsilyl)
propargyl bromide, the desired product 3a was produced in 94%
yield and 94:6 dr under the reaction conditions reported
previously (entry 1).11b However, effort to further improve the
reaction by solvent screening or adding various Lewis base and
acid , a successful tactics in similar allylation reactions,13 proved
fruitless(entries 2-6). Switching the TMS (trimethylsilyl)
protecting group to more sterically hindered TBS (tert-
butyldimethylsilyl) group gave a similar reaction result (entry 7).
a Reactions performed using imine 1 (0.5 mmol), Zn powder (1.0 mmol), and
3-Bromo-1-(trimethylsilyl)-1-propyne (1.0 mml) in THF (2 mL) at room
temperature for 16 h.
b Yield refers to the isolated major isomer.
c
Diaterstreoselectivity ratio was determined by 1H NMR analysis of the
Table 1
crdued product.
Optimization of reaction conditions for propargylation/
lactamization cascade with silyl-protected 3-bromopropyne
Having established optimal reaction conditions, we began to
explore the substrate generality. A variety of 2-formylbenzoate
derived N-tert-butansulfinyi imines bearing different substituents
on the phenyl ring were examined (Table 2). Imines containing
either electron-donating or electron-withdrawing groups at C-4 or
C-5 position gave excellent reaction yields and high
diastereoselectivities (3c-j). Introduction of a methyl group to
the C-3 or C-6 position resulted in decreased reaction yields and
diastereoselectivities (3b and 3k), probably due to the steric
interaction of between imine (or ester) moiety and the
neighboring methyl group. Multi-MeO substituted imines were
also suitable substrates, which would be interesting molecules as
a mimic of some natural products (3l-n). Replacing the phenyl
ring by a naphthyl group also proceed well albeit in reduced
diastereoselectivity(3o).
Entrya
PG
Solvent
THF
Additive
none
Yield (%)b
94
dr c
1
2
3
4
5
6
TMS
TMS
TMS
TMS
TMS
TMS
TBS
94:6
DMF
MeCN
THF
none
trace
trace
63
-
none
-
0.1 mL HMPA
0.3 eq In(OTf)3
0.3 eq Mg(OTf)2
none
92:8
THF
trace
trace
91
-
THF
-
7
THF
92:8
a
Reactions performed using imine 1a (0.5 mmol), Zn powder (1.0 mmol),
and 3-bromo-1-(trimethylsilyl)-1-propyne (1.0 mml) in solvent (2 mL) at
room temperature for 16 h.
b Yield refers to the isolated major isomer.
c
Diaterstreoselectivity ratio was determined by 1H NMR analysis of the
crdued product.
Scheme 2. Absolute configuration of 3a and proposed favored
transition state

3. For selected examples with organocatalysts: (a) Yu, X.; Wang, Y.;
Wu, G.; Song, H.; Zhou, Z.; Tang, C., Eur. J. Org. Chem. 2011,
3060. (b) Luo, J.; Wang, H.; Zhong, F.; Kwiatkowski, J.; Xu, L.-
W.; Lu, Y., Chem. Commun. 2012, 48, 4707. (c) Tiso, S.; Palombi,
L.; Vignes, C.; Di Mola, A.; Massa, A., RSC Adv. 2013, 3, 19380.
(d) Bisai, V.; Unhale, R. A.; Suneja, A.; Dhanasekaran, S.; Singh,
V. K., Org. Lett. 2015, 17, 2102. (e) Suneja, A.; Unhale, R. A.;
Singh, V. K., Org. Lett. 2017, 19, 476.
By X-ray crystallography analysis of 3a, the newly generated C3-
stereogenic center was unambiguously determined to be R,14 which
may be explained by a six-membered transition-state as depicted in
Scheme 2, a similar model proposed previously by Fandrick.15
Assuming an analogous reaction mechanism, the stereochemistry of
other products was tentatively assigned as the same.
As demonstrated in Scheme 3, the N-tert-butansulfinyl group in
3a could be easily cleaved to afford isoindolinone 5 in almost
quantitative yield and excellent ee. Deprotection of TMS group by
treatment with K2CO3 in MeOH gave isoindolinone 6 in excellent
yield, but accompanied by a slight racemization. As a versatile
intermediate, isoindolinone 6 can undergo a variety of organic
transformations, such as click reaction or Sonogashira coupling, to
afford new chiral isoindolinone derivatives.
4. For selected examples with chiral phase transfer catalysts:, see: (a)
Sallio, R.; Lebrun, S.; Schifano-Faux, N.; Goossens, J.-F.;
Agbossou-Niedercorn, F.; Deniau, E.; Michon, C., Synlett 2013,
24, 1785. (b) Di Mola, A.; Tiffner, M.; Scorzelli, F.; Palombi, L.;
Filosa, R.; De Caprariis, P.; Waser, M.; Massa, A., Beilstein J.
Org. Chem. 2015, 11, 2591. (c) Lebrun, S.; Sallio, R.; Dubois, M.;
Agbossou-Niedercorn, F.; Deniau, E.; Michon, C., Eur. J. Org.
Chem. 2015, 1995. (d) Scorzelli, F.; Di Mola, A.; De Piano, F.;
Tedesco, C.; Palombi, L.; Filosa, R.; Waser, M.; Massa, A.,
Tetrahedron 2017, 73, 819.
5. For selected examples with chiral transition-metal catalysts: (a)
Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q., J. Am. Chem.
Soc. 2007, 129, 5336. (b) Guo, S.; Xie, Y.; Hu, X.; Xia, C.; Huang,
H., Angew. Chem., Int. Ed. 2010, 49, 2728. (c) Yang, G.; Shen, C.;
Zhang, W., Angew. Chem., Int. Ed. 2012, 51, 9141. (d) Bisai, V.;
Suneja, A.; Singh, V. K., Angew. Chem., Int. Ed. 2014, 53, 10737.
(e) Karmakar, R.; Suneja, A.; Bisai, V.; Singh, V. K., Org. Lett.
2015, 17, 5650. (f) Suneja, A.; Bisai, V.; Singh, V. K., J. Org.
Chem. 2016, 81, 4779.
6. (a) Grigg, R.; Dorrity, M. J. R.; Malone, J. F.;
Mongkolaussavaratana, T.; Norbert, W. D. J. A.; Sridharan, V.,
Tetrahedron Lett. 1990, 31, 3075. (b) Enders, D.; Braig, V.; Raabe,
G., Can. J. Chem. 2001, 79, 1528. (c) Deniau, E.; Enders, D.;
Couture, A.; Grandclaudon, P., Tetrahedron-Asymmetry 2005, 16,
875.
7. (a) Pérard-Viret, J.; Prangé, T.; Tomas, A.; Royer, J., Tetrahedron
2002, 58, 5103. (b) Bahajaj, A. A.; Vernon, J. M.; Wilson, G. D.,
Tetrahedron 2004, 60, 1247. (c) Chen, M.-D.; Zhou, X.; He, M.-
Z.; Ruan, Y.-P.; Huang, P.-Q., Tetrahedron 2004, 60, 1651.
8. (a) McAlonan, H.; Murphy, J. P.; Nieuwenhuyzen, M.; Reynolds,
K.; Sarma, P. K. S.; Stevenson, P. J.; Thompson, N., J. Chem. Soc.,
Perkin Trans. 1 2002, 69. (b) Comins, D. L.; Schilling, S.; Zhang,
Y., Org. Lett. 2005, 7, 95. (c) Comins, D. L.; Hiebel, A.-C.,
Tetrahedron Lett. 2005, 46, 5639.
Scheme 3. Transformation of the obtained product 3a
In summary, a propargylation/lactamization cascade with
chiral 2-formylbenzoate derived N-tert-butansulfinyi imines was
realized for the easy preparation of a variety of chiral
isoindolinones. The reaction was run under mild reaction
conditions, and high diastereoselectivities and good reaction
yields were observed for most cases. Further applications of these
resulting chiral isoindolinone structures in the synthesis of
bioactive molecules are currently underway.
9. Sun, X.-W.; Liu, M.; Xu, M.-H.; Lin, G.-Q., Org. Lett. 2008, 10,
1259.
10. For reviews on N-tert-butanesulfinyl imine chemistry, see: (a)
Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han, Z.;
Gallou, I., Aldrichimica Acta 2005, 38, 93. (b) Lin, G.-Q.; Xu, M.-
H.; Zhong, Y.-W.; Sun, X.-W., Acc. Chem. Res. 2008, 41, 831. (c)
Ferreira, F.; Botuha, C.; Chemla, F.; Pérez-Luna, A., Chem. Soc.
Rev. 2009, 38, 1162. (d) Robak, M. T.; Herbage, M. A.; Ellman, J.
A., Chem. Rev. 2010, 110, 3600. (e) Dong, H.-Q.; Xu, M.-H.;
Feng, C.-G.; Sun, X.-W.; Lin, G.-Q., Org. Chem. Front. 2015, 2,
73.
Acknowledgments
Financial support from the National Natural Science
Foundation of China (21472212, 21572253) and the Strategic
Priority Research Program of the Chinese Academy of Sciences
(XDB 20020100) is acknowledged.
11. (a) Chen, D.; Xu, M.-H., Chem. Commun. 2013, 49, 1327. (b)
Guo, T.; Song, R.; Yuan, B.-H.; Chen, X.-Y.; Sun, X.-W.; Lin, G.-
Q., Chem. Commun. 2013, 49, 5402.
12. For review: Ding, C.-H.; Hou, X.-L., Chem. Rev. 2011, 111, 1914.
13. Sun, X.-W.; Xu, M.-H.; Lin, G.-Q., Org. Lett. 2006, 8, 4979.
14. CCDC 1813069 (3a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
References and notes
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
1. (a) Kondo, T.; Yoshida, K.; Yamamoto, M.; Tanayama, S.,
Arzneim. Forsch. 1996, 46, 11. (b) Baldwin, J. J.; Cacatian, S.;
Claremon, D. A.; Dillard, L. W.; Flaherty, P. T.; Ishchenko, A. V.;
Jia, L.; Mcgeehan, G.; Simpson, R. D.; Singh, S. B.; Tice, C. M.;
Xu, Z.; Yuan, J.; Zhao, W.; Zhuang, L., WO2008156816A2, 2008.
(c) Wacker, D. A.; Zhao, G.; Kwon, C.; Varnes, J. G.; Stein, P. D.,
US20050080074A1, 2005. (d) Mertens, A.; Zilch, H.; König, B.;
Schäfer, W.; Poll, T.; Kampe, W.; Seidel, H.; Leser, U.; Leinert,
H., J. Med. Chem. 1993, 36, 2526. (e) Belliotti, T. R.; Brink, W.
A.; Kesten, S. R.; Rubin, J. R.; Wustrow, D. J.; Zoski, K. T.;
Whetzel, S. Z.; Corbin, A. E.; Pugsley, T. A.; Heffner, T. G.; Wise,
L. D., Bioorg. Med. Chem. Lett. 1998, 8, 1499. (f) Björe, A.;
Boström, J.; Davidsson, Ö.; Emtenäs, H.; Garn, U.; Kajanus, J.;
Olsson, R.; Sandberg, L.; Strandlund, G.; Sundell, J.; Yuan, Z.-Q.,
WO2008008022A1, 2008.
15. Fandrick, D. R.; Johnson, C. S.; Fandrick, K. R.; Reeves, J. T.;
Tan, Z.; Lee, H.; Song, J. H. J.; Yee, N. K.; Senanayake, C. H.,
Org. Lett. 2010, 12, 748.
Supplementary Data
Supplementary data associated with this article can be found
in the online version, at.
2. For reviews, see: (a) Di Mola, A.; Palombi, L.; Massa, A., Curr.
Org. Chem. 2012, 16, 2302. (b) Speck, K.; Magauer, T., Beilstein
J. Org. Chem. 2013, 9, 2048.

4
Tetrahedron Letters
Click here to remove instruction text...
Graphical Abstract
Synthesis of Chiral Isoindolinones via
Asymmetric Propargylation/Lactamization
Cascade
Leave this area blank for abstract info.
Jiao-Long Menga,†, Tang-Qian Jiaoa,†, Ya-Heng Chenb, Rui Fua, Shu-Sheng Zhangb, Qian Zhaoa,, Chen-Guo
Fengb,, and Guo-Qiang Linb

3
Highlights for this paper:
 Easy operation, benign reaction conditions and
high diastereoselectivity
 A practical and efficient method for the
synthesis of chiral isoindolinones
 Versatile transformations associated with the
resulting products