Development of a C2-Symmetric Chiral aza Spirocyclic Diol

Article abstract of DOI:10.1021/acs.orglett.0c00858

A C₂-symmetric chiral spirocyclic diol aza-SPINOL containing a spirooxindole scaffold has been designed, synthesized, and optically resolved. The product could be synthesized on gram scale in an overall yield of 22%. Moreover, elaborations of aza-SPINOL to other chiral ligands as well as the preliminary investigation of the related bisphosphine ligand in the desymmetrization of bisallylic amide were reported.

Full text of DOI:10.1021/acs.orglett.0c00858

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Development of a C2‑Symmetric Chiral aza Spirocyclic Diol
Weicong Guo, Qinzhe Liu, Jijun Jiang, and Jun Wang*
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ABSTRACT: A C2-symmetric chiral spirocyclic diol aza-SPINOL
containing a spirooxindole scaffold has been designed, synthesized,
and optically resolved. The product could be synthesized on gram
scale in an overall yield of 22%. Moreover, elaborations of aza-
SPINOL to other chiral ligands as well as the preliminary
investigation of the related bisphosphine ligand in the desymmet-
rization of bisallylic amide were reported.
xially chiral 1,1′-spirobiindane-7,7′-diol (SPINOL) was
A
first synthesized and optically resolved by Birman in
1999.1 Thanks to Zhou’s pioneering2 and subsequent
extensive3 contributions to the development and application
of SPINOL-derived ligands and catalysts, chiral 1,1′-
spirobiindane has now become one of the most privileged
chiral scaffolds in asymmetric catalysis. In order to tune steric
and electronic effects of ligands or catalysts, some SPINOL
analogues or derivatives have been designed and synthesized,
including CHEXDBSPINOL by Venugopal,4 SBIFOL by
Zhou,5 SBITOL by Zhou,6 and HMSIOL by Lin.7 While
optically pure SPINOL and its analogues were conventionally
obtained by optical resolution, remarkably, their asymmetric
syntheses have been recently realized by Ding,8 Tan,9 and
Dou.10 Moreover, besides an all-carbon spiro framework, chiral
oxa-SPINOLs have also been developed, including SBIXOL11
and O-SPINOL12 by Zhang, and SPIROL by Nagorny.13
However, aza-SPINOLs are still unknown. Herein, we report
the first example of aza-SPINOL, providing a new chiral
skeleton for the development of chiral spirocyclic ligands and
catalysts (Figure 1).
It is well-known that the ketone I is the key intermediate for
the synthesis of SPINOL, which can undergo a twofold
Friedel−Crafts reaction to give the chiral spirocyclic
intermediate II under acidic conditions (Scheme 1a).1 We
proposed that the spirocyclic compound IV might be
successfully constructed if the 2-oxomalonamide III could
also undergo the acid-promoted spirocyclization. Further
elaborations of IV would provide a class of potentially useful
C2-symmetric chiral aza-SPINOLs (Scheme 1b). With this
proposal in mind, we launched this research and finally
succeeded in preparing aza-SPINOL 8. It should be noted that
literature surveys indicated while aza-SPINOL is still
unknown, the spirooxindole skeleton is known. In 2012, Du,
Figure 1. Chiral spirocyclic diols.
Received: March 6, 2020
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© XXXX American Chemical Society
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Scheme 1. Design the Synthesis of aza-SPINOL
Scheme 2. Synthetic Route for aza-SPINOL
Zhao and co-workers synthesized several C2-symmetric or
unsymmetric spirooxindoles via a phenyliodine bis-
(trifluoroacetate) (PIFA)-mediated cascade oxidation of
N1,N3-diphenylmalonamides.14 Later, this reaction was
achieved highly enantioselectively with a chiral organoiodine
catalyst by Gong and co-workers.15 In addition, recently Cai
and co-workers developed a copper(I)-catalyzed intramolecu-
lar asymmetric double C-arylation for the synthesis of diverse
enantioenriched spirooxindoles.16
As outlined in Scheme 2, our synthesis starts from
commercially available 7-hydroxy-3,4-dihydroquinolin-2(1H)-
one 1. The secondary amine 2 was prepared by reduction of 1
with LiAlH4. After tosylation, the tosylate 3 was obtained in
92% yield, which was further treated with malonyl chloride in
the presence of triethylamine to afford the malonamide 4 in
48% yield. To oxidize the malonamide 4 to the key 2-
oxomalonamide intermediate 6, a two-step procedure was
applied. Specifically, the malonamide 4 was first treated with p-
tosyl azide (TsN3) to produce the diazo compound 5
quantitatively, which was then oxidized with t-BuOCl to give
the 2-oxomalonamide 6 in 64% yield.17 To our delight,
promoted by a catalytic amount of trifluoromethanesulfonic
acid (TfOH), the successive dual Friedel−Crafts reactions
proceeded well to deliver the desired spirocyclic compound 7
in 94% yield. Notably, this reaction could be performed on
gram scale without any difficulties. Attempting to directly
convert the malonamide 4 into the spirocyclic product 7 by
PIFA-mediated tandem oxidation14 proved unsuccessful.
Finally, removal of the tosyl group with KOH afforded the
targeted racemic 9,9′-dihydroxy-1,1′-spirooxindole 8 in 90%
yield. Furthermore, optical resolution of racemate 8 was
efficiently achieved via its bis-L-menthoxycarboxylate as the
two diastereomers could be separated by silica gel chromatog-
raphy. The structure and the absolute configuration of the
diastereomer 9′ with the lower Rf value were identified by
single-crystal X-ray diffraction. Upon saponification, both of
the optically pure enantiomers of aza-SPINOL 8 were
obtained facilely.
counterparts of some classic chiral ligands were selectively
prepared (Scheme 3). First, synthesis of 8,8′-disubstituted
spirooxindoles was explored. Gladly, 8,8′-diiodination of aza-
SPINOL (S)-8 proved successful with NIS and TsOH,
providing the product (S)-10 in 85% yield. After the Pd/C
catalyzed Suzuki coupling9 with phenylboronic acid, the 8,8′-
diphenyl spirooxindole (S)-11 was obtained in 34% yield
(Scheme 3a). Second, synthesis of bisphosphine ligand was
studied. Treatment of aza-SPINOL (R)-8 with trifluoro-
methanesulfonic anhydride produced the triflate (R)-12 in
92% yield. Then, coupling (R)-12 with diphenylphosphine in
the presence of Pd(OAc)2/dppb gave the corresponding
bisphosphine (R)-13 in 44% yield (Scheme 3b).18 Third, the
aza-SPINOL (S)-14 bearing a spiroindoline scaffold was
successfully prepared by reduction of (S)-8 with borane.
Moreover, it could be further converted to the corresponding
phosphoramidite (S)-15 in 85% yield by refluxing with
hexamethylphosphorous triamide in toluene (Scheme 3c).19
To show potential application of spirooxindole catalyst in
the asymmetric catalysis, the asymmetric catalytic desymmet-
rization of bisallylic amide 16 with NBS was studied, which
was previously reported by Hamashima et al.20 It was found
that, in the presence of 10 mol % of (R)-13, the oxazoline
product 17 was obtained in 55% yield with 72% ee (Scheme
4).
In order to investigate the potential use of this newly
developed aza-SPINOL in the synthesis of chiral ligands, the
B
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Scheme 3. Elaborations of aza-SPINOL 8 to Chiral Ligands
AUTHOR INFORMATION
Corresponding Author
■
Jun Wang − Key Laboratory of Bioinorganic and Synthetic
Chemistry of Ministry of Education, School of Chemistry, Sun
Yat-Sen University, Guangzhou 510275, P. R. China;
orcid.org/0000-0002-4035-2786; Email: wangjun23@
mail.sysu.edu.cn
Authors
Weicong Guo − Key Laboratory of Bioinorganic and Synthetic
Chemistry of Ministry of Education, School of Chemistry, Sun
Yat-Sen University, Guangzhou 510275, P. R. China
Qinzhe Liu − Key Laboratory of Bioinorganic and Synthetic
Chemistry of Ministry of Education, School of Chemistry, Sun
Yat-Sen University, Guangzhou 510275, P. R. China
Jijun Jiang − Key Laboratory of Bioinorganic and Synthetic
Chemistry of Ministry of Education, School of Chemistry, Sun
Yat-Sen University, Guangzhou 510275, P. R. China;
orcid.org/0000-0001-9483-6033
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00858
Notes
The authors declare no competing financial interest.
Scheme 4. Application of Chiral Phosphine Ligand in the
Desymmetrization of Bisallylic Amide
a
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21971263).
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In conclusion, we describe the design, synthesis, and optical
resolution of a new class of C2-symmetric chiral spirocyclic
diol, namely, aza-SPINOL. It could be prepared on gram scale
in an overall yield of 22%. In addition, its elaborations to some
representative chiral ligands and preliminary application in
asymmetric catalysis were explored.
ASSOCIATED CONTENT
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* Supporting Information
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data for this paper. These data can be obtained free of charge
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data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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