2-azadiene derivatives. Therefore, the development of
ketone-involved Povarov reactions, especially the catalytic
asymmetrictransformations, hasbecomeanurgent need in
the organic community.
We recently described a number of chiral phosphoric
acid7 catalyzed multicomponent reactions for the synthesis
of enantioenriched heterocycles with biological relevance.3m,8
Inspired by the above success and the fact that there has
not been a report on an enantioselective ketone-involved
Povarov reaction for the synthesis of important spiro-
[indolin-3,20-quinoline] scaffolds, we considered utiliz-
ing isatin in the asymmetric Povarov reaction, wherein the
isatin-derived ketimine should be activated by the chiral
phosphoric acid. In this work, we present the first enantio-
selective ketone-involved Povarov reaction, which directly
assembles isatins, anilines, and styrenes into biologically
important spiro[indolin-3,20-quinolines] with two quaternary
stereogenic centers in high yields and excellent stereoselectiv-
ities (all >99:1 dr’s, up to 97% ee).
Our study commenced with a three-component reaction
of 1-benzylisatin 1a, 4-methoxyaniline 2a, and R-methyl
o-hydroxystyrene 3a in the presence of 10 mol % of chiral
phosphoric acids 5 in toluene at 50 °C (Table 1). All the
chiral phosphoric acids 5 enabled the reaction to proceed
smoothly to afford a single diastereomer of spiro[indolin-
3,20-quinoline] 4aaa in high yields but with various levels
of enantioselectivity (entries 1ꢀ6). The results revealed
that 2,4,6-triisopropylphenyl-substituted phosphoric acid
(Trip-PA) 5f was far more superior toother analogues with
regard to enantioselectivity (entry 6 vs 1ꢀ5). The subse-
quent screening of the solvents at 25 °C disclosed that
toluene was the most suitable reaction media, affording the
desired product in 92% yield and 81% ee (entry 7 vs 8ꢀ10).
Lowering the reaction temperature from 25 to ꢀ20 °C led
to a substantial increase in the enantioselectivity with
maintained reactivity (entries 7, 11ꢀ12), but lowering the
temperature further to ꢀ30 °C resulted in a moderate yield
albeit with an excellent enantiomeric excess (entry 13).
Finally, increasing the stoichiometry of 3a rendered
the reaction to proceed at ꢀ20 °C in a quantitative yield
of 99% with a maintained enantioselectivity of 94% ee
(entry 14 vs 12).
With the optimal conditions in hand, we then carried out
the investigation on the substrate scope of isatins 1 (Table 2).
At first, isatins bearing different types of N-substituents
were utilized as substrates (entries 1ꢀ5), which demon-
strated that this approach was applicable to various isatins
with N-benzyl, alkyl, or phenyl substituents, affording
spiro[indolin-3,20-quinolines] in excellent diastereoselec-
tivities (all >99:1 drs) and witha high level of enantiomeric
excesses (up to 97% ee). Generally speaking, isatins with
N-benzyl groups were superior to those with N-alkyl or
N-phenyl groups in terms of yield and enantioselectivity
(entries 1ꢀ3 vs 4ꢀ5). As for N-benzyl substituted isatins,
changing the substituents on the benzyl group had some
delicate effect on the enantioselectivity (entries 1ꢀ3).
Notably, the perfluorinated N-benzylisatin 1c exhibited
the highest capability of affording the corresponding prod-
uct in 99% yield and 97% ee (entry 3). Basically, the
reactivity of N-alkyl and N-phenyl substituted isatins was
lower than that of N-benzylisatins; therefore the reac-
tion temperature was increased to 50 °C to render a cleaner
reaction (entries 4ꢀ5). Moreover, the use of CCl4 as
Figure 1. Bioactive spiro-tetrahydroquinolines.
More importantly, the asymmetric Povarov reaction
with ketones, in particular with unsymmetrical cyclic
ketones, would directly furnish enantioenriched spiro-
tetrahydroquinolines with a new quaternary stereogenic
center (eq 2), which defines the characteristic structural
core of a large family of heterocycles with pronounced and
diverse bioactivities (Figure 1).4b,5 Of particular concern is
that isatins, a type of unsymmetrical cyclic ketones with
high activity, have emerged as privileged building blocks in
the synthesis of spiro-fused heterocycles withpotential bio-
activities.6 In this context, the asymmetric Povarov reac-
tion of isatin-derived 2-azadiene with electron-rich olefins
would allow for the construction of an optically pure
spiro[indolin-3,20-quinoline] scaffold, which constitutes
the core structural element of antitumoral molecules4b
(in Figure 1) and hence holds great synthetic importance.
(5) (a) Dorey, G.; Lockhart, B.; Lestage, P.; Casara, P. Bioorg. Med.
Chem. Lett. 2000, 10, 935. (b) Ramesh, E.; Manian, R. D. R. S.;
Raghunathan, R.; Sainath, S.; Raghunathan, M. Bioorg. Med. Chem.
2009, 17, 660. (c) Kouznetsov, V. V.; Leonor, Y.; Acevedo, A. M. Lett.
Drug Des. Discovery 2010, 7, 710. (d) Brown, D. W.; Mahon, M. F.;
Ninan, A.; Sainsbury, M. J. Chem. Soc., Perkin Trans. 1 1997, 16, 2329.
(6) For a recent review: Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012,
112, 6104.
(7) For early examples: (a) Akiyama, T.; Itoh, J.; Yokota, K.;
Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.;
Terada, M. J. Am. Chem. Soc. 2004, 126, 5356. For reviews:
(c) Akiyama, T. Chem. Rev. 2007, 107, 5744. (d) Terada, M. Chem.
Commun. 2008, 4097. (f) Terada, M. Synthesis 2010, 1929.
(8) (a) Shi, F.; Luo, S.-W.; Tao, Z.-L.; He, L.; Yu, J.; Tu, S.-J.; Gong,
L.-Z. Org. Lett. 2011, 13, 4680. (b) Shi, F.; Tao, Z.-L.; Luo, S.-W.; Tu,
S.-J.; Gong, L.-Z. Chem.;Eur. J. 2012, 18, 6885. (c) Yu, J.; Shi, F.;
Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156. (d) Shi, F.; Gong, L.-Z.
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Org. Lett., Vol. 15, No. 1, 2013
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