Catalytic enantioselective amide allylation of isatins and its application in the synthesis of 2-oxindole derivatives spiro-fused to the α-methylene-γ-butyrolactone functionality

Article abstract of DOI:10.1002/chem.201403357

This article is a full account of the work exploring the potential utility of catalytic enantioselective amide allylation of various isatins using indium-based chiral catalysts. A survey of various isatin substrates and NH-containing stannylated reagents revealed that the reaction has a remarkably wide scope to result in extremely high yields and enantioselectivities (up to >99 %, 99 % ee) of variously substituted homoallylic alcohols. Several mechanistic investigations demonstrated that the substrate-reagent hydrogen-bond interaction plays a critical role in the formation of the key transition states to result in enhanced catalytic reaction. The success of this approach allowed convenient access to chiral 2-oxindoles spiro-fused to the α-methylene- γ-butyrolactone functionality and their halogenated derivatives in almost enantiopure forms, thus highlighting the general utility of this synthetic method to deliver a large variety of antineoplastic drug candidates and pharmaceutically meaningful compounds.

Full text of DOI:10.1002/chem.201403357

DOI: 10.1002/chem.201403357
Full Paper
&
Asymmetric Catalysis
Catalytic Enantioselective Amide Allylation of Isatins and Its
Application in the Synthesis of 2-Oxindole Derivatives Spiro-
Fused to the a-Methylene-g-Butyrolactone Functionality
Masaki Takahashi,[a] Yusuke Murata,[b] Fumitoshi Yagishita,[c] Masami Sakamoto,[c]
Tetsuya Sengoku,[a] and Hidemi Yoda*[a, b]
Abstract: This article is a full account of the work exploring
the potential utility of catalytic enantioselective amide allyla-
tion of various isatins using indium-based chiral catalysts. A
survey of various isatin substrates and NH-containing stan-
nylated reagents revealed that the reaction has a remarkably
wide scope to result in extremely high yields and enantiose-
lectivities (up to >99%, 99% ee) of variously substituted ho-
moallylic alcohols. Several mechanistic investigations dem-
onstrated that the substrate–reagent hydrogen-bond inter-
action plays a critical role in the formation of the key transi-
tion states to result in enhanced catalytic reaction. The suc-
cess of this approach allowed convenient access to chiral
2-oxindoles spiro-fused to the a-methylene-g-butyrolactone
functionality and their halogenated derivatives in almost
enantiopure forms, thus highlighting the general utility of
this synthetic method to deliver a large variety of antineo-
plastic drug candidates and pharmaceutically meaningful
compounds.
Introduction
The enantioselective allylation of carbonyl compounds using
b-carbonyl allylstannanes is a reaction of fundamental signifi-
cance in the synthesis of key homoallylic alcohol intermediates
to deliver a large variety of biologically attractive com-
pounds.[1–3] Among several examples of such entities,[4] chiral
a-methylene-g-butyrolactones, accessible by means of a two-
step reaction sequence that involves amide allylation followed
by acid-promoted lactonization (Scheme 1a), have proven par-
ticularly appealing owing to their profound impact on the de-
velopment of new potential drugs and chemotherapeutic
agents for the treatment of a wide range of human diseases
including bacterial infections and various cancers.[5,6] The great-
er importance of this application has been exemplified by our
recent work[7] on the synthesis of antineoplastic 2-oxindole
Scheme 1. Examples of enantioselective allylation.
derivatives spiro-fused to the a-methylene-g-butyrolactone
functionality,[8–10] which was achieved with perfect enantiose-
lectivity (>99%, 99% ee) by means of indium-catalyzed amide
allylation of N-methyl isatin (1a; Scheme 1b).
[a] Dr. M. Takahashi, Dr. T. Sengoku, Prof. Dr. H. Yoda
Department of Applied Chemistry
Despite the inherent benefits of this protocol, which offers
efficient short-step syntheses of the cytotoxic antineoplastic
drug candidates in almost enantiopure forms, our current suc-
cess with these molecular systems has been limited to just one
particular isatin substrate and the mechanistic foundation for
the extremely high enantioselectivity remained poorly under-
stood. Accordingly, the principal objective of the present work
is to extend the scope and potential application of the enan-
tioselective amide allylation of various isatins and stannylated
reagents, and to provide a detailed mechanistic picture of this
transformation. Herein, we report a full account of our efforts
in exploring the potential utility of our synthetic methodology
Graduate School of Engineering, Shizuoka University
3-5-1 Johoku, Naka-ku, Hamamatsu 432-8561 (Japan)
Fax: (+81)53-478-1150
E-mail: tchyoda@ipc.shizuoka.ac.jp
[b] Y. Murata, Prof. Dr. H. Yoda
Graduate School of Science and Technology
Shizuoka University, 3-5-1 Johoku, Naka-ku
Hamamatsu 432-8561 (Japan)
[c] Dr. F. Yagishita, Prof. Dr. M. Sakamoto
Department of Applied Chemistry and Biotechnology
Graduate School of Engineering, Chiba University
1-33 Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403357.
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to access a variety of enantiomerically enriched 2-oxindole de-
rivatives, in addition to understanding the origin of the stereo-
control induced by the local molecular environment of the
transition states for the indium-mediated nucleophilic proc-
esses.
shortened dramatically to around 3 h. This phenomenon was
also observed for (S)-1,1’-bi(2-naphthol) L2 and (S,S)-phenylpy-
box L3, whereas sterically more congested (S,R)-indapybox L4
was less effective but still substantial in accelerating the reac-
tion (Table 1, entries 4–6). The above kinetic effects of the
chiral ligands to favor the amide allylation is therefore indica-
tive of the possible involvement of these species, which inter-
act considerably with the reacting components, in the transi-
tion states required to accomplish the highly efficient process-
es. Thus, these reaction systems were suggested to achieve
significant levels of asymmetric induction on the stereochemi-
cal courses of the nucleophilic additions under steric influences
of the chiral ligands, as has been shown in a series of the pre-
ceding reports by Franz and co-workers on enantioselective re-
actions onto isatins.[12–14] This expectation could be observed
experimentally by chiral HPLC analyses of the isolated products
on a Chiralpak IC chiral stationary phase; high levels of enan-
tioselectivity (84–97% ee) were obtained in each case
with the series of the pybox ligands, but failed in the
one with L2 (7% ee; Table 1, entries 3–6).
Results and Discussion
As in our earlier studies of the amide allylation of N-methyl
isatin (1a) with N-phenyl-b-amido allyltributylstannane (2a),
indium(III) triflate (In(OTf)3) has been demonstrated to be the
best-performing catalyst among the Lewis acids examined, in-
cluding scandium(III) triflate, samarium(III) triflate, and indium-
(III) chloride.[7] At the same time, we noticed that the use of
Lewis acids is essential to drive the reaction smoothly, in view
of the fact that only a sluggish and incomplete reaction took
place in the absence of any catalyst source (Table 1, entry 1).
Table 1. Reactivity of amide allylation.[a]
Given that L3 proved to be the most effective by
providing up to 99% yield and 97% ee, as shown in
Table 1, further investigations on the model reaction
of converting 1a to 3a are being pursued intensively
with the [In(L3)(OTf)3] catalyst system based on stoi-
chiometric mixtures of components 1a and 2a. Once
the proper catalyst was selected, a systematic screen-
ing of different parameters was undertaken to find
the optimal conditions for producing the most prom-
inent enhancement in either reactivity or enantiose-
Entry
Catalyst
[mol%]
Chiral ligand
t
[h]
Yield[b]
[%]
ee[c]
[%]
lectivity. Beginning with a search for the optimum
amount of catalyst loading, practically identical re-
sults were obtained in cases at catalyst loadings
ranging from 5 to 20 mol% (Table 2, entries 1–3),
whereas a catalyst loading as low as 1 mol% was
found ineffective for promoting the reaction (Table 2,
entry 4). Thus, the results would suggest that
10 mol% catalyst loading is needed to ensure a quali-
ty product. In continuing the efforts to improve the
level of reaction efficiency and asymmetric induction,
we turned to the use of different solvents for com-
parison. On replacing the solvent by 1,2-dichloro-
1
2
3
4
5
6
0
–
–
L1
L2
L3
L4
139
24
3
47[d]
63
97
90
99
99
0
0
84
7
97
88
10
10
10
10
10
1
3
18
[a] The absolute configuration of the major enantiomer was assigned on the basis of
further X-ray diffraction works (discussed later). [b] Isolated yields. [c] The ee values
were determined by HPLC analysis with a Daicel Chiralpak IC. [d] A large amount of
the starting material was recovered intact.
For these reasons, a series of experiments were designed to
operate with indium(III) triflate to further test the efficiency of
Table 2. Optimization for amide allylation of 1a with 2a.
the amide allylation process. Initially, we attempted the reac-
tion of 1a with 1.2 equiv of 2a in the presence of 10 mol% of
In(OTf)3 and activated 4 ꢁ molecular sieves (MS4ꢁ) in dichloro-
methane (CH2Cl2) at RT. Under these conditions, the reaction
proceeded up to its completion after a period of 24 h, and rac-
emic allylated adduct 3a was obtained in 63% isolated yield
as the predominant product (Table 1, entry 2). For this transfor-
mation, a catalytic amount of 2,6-bis[4’-(S)-isopropyloxazolin-2-
yl]pyridine ((S,S)-isopropylpybox; L1)[11] can markedly increase
the reaction rate and enable a high yield of the desired prod-
uct (Table 1, entry 3). Indeed, the addition of this chiral ligand
resulted in reduction of the entire reaction period, which was
Entry
[In(L3)(OTf)3]
[mol%]
Solvent
t
[h]
Yield[a]
[%]
ee[b]
[%]
[c]
1
2
3
4
5
6
7
10
20
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3
2
4
99
99
98
67
99
97
97
96
41
97
92
98
[c]
[c]
[c]
1
44
3
19
3
10
10
10
DCE[c]
toluene[c]
MeCN[d]
89
100
[a] Isolated yields. [b] The ee values were determined by HPLC analysis
with a Daicel Chiralpak IC. [c] Reactions performed with MS4ꢁ. [d] Reac-
tions performed with MS3ꢁ.
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ethane (DCE), there was no dramatic change in the reaction
outcome (Table 2, entry 5). In a nonpolar solvent, toluene, the
reaction proceeded sluggishly to completion in 19 h and gave
89% yield of the product with a slight diminution in enantiose-
lectivity (Table 2, entry 6). In contrast, the use of MeCN as sol-
vent, together with activated MS3ꢁ as a substitute for MS4ꢁ,
produced a further substantial improvement with regard to re-
action time in addition to excellent isolated yield and enantio-
selectivity (100%, 98% ee; Table 2, entry 7). Consequently, we
could identify the optimal conditions for the most efficient
protocol, which involve the use of 10 mol% of [In(L3)(OTf)3] in
MeCN.
thus indicating that the constituent molecules crystallizes in
the monoclinic P21 space group and adopts a twisted confor-
mation (see Figure S1 in the Supporting Information), with the
S absolute configuration in the new stereogenic carbon atom
as assigned on the basis of further X-ray diffraction work that
will be discussed later. The behavior of N-methyl-N-phenyl-b-
amido-functionalized allylstannane 2g that lacks the NÀH hy-
drogen atom, in contrast, is fundamentally different from those
stated above. The amide allylation with this stannylated re-
agent proceeded at an impractically slow rate to result in in-
complete consumption of the starting material even after 72 h,
and rather poor enantioselectivity was observed with the reac-
tion product 3g (Table 3, entry 7). This is most likely due to the
difference of the mechanism that operated in the transition
state, despite the close steric similarity of this reagent to the
others.
With the optimal conditions in hand, the scope of the cata-
lytic amide allylation was next explored to demonstrate the
general utility of this protocol, and the results are compiled in
Tables 3 and 4. By applying the conditions used for 2a
On the basis of the above observation that highlights the
importance of the secondary amide functionality in the stanny-
lated reagent, we sought to encompass a broader substrate
scope to ensure reliability of this catalytic system, with the use
of the most promising reagent 2e as a representative selec-
tion. To this end, a variety of N-substituted isatin analogues—
1b–e, nonsubstituted isatin 1 f, and C5-halogenated N-methyl
derivatives 1g–i—were subjected to the amide allylation con-
ditions. The results are summarized in Table 4. It can be noted
Table 3. Scope of amide allylation of 1a.[a]
Entry
Reagent
R
t
Product
Yield[b]
[%]
ee[c]
[%]
[h]
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2 f
NHPh
NHC5H11
NH(tBu)
NH(1-naph)
NH(p-tolyl)
NH(p-tBuPh) 17
NMePh 72
3
4
8
4
3
3a
3b
3c
3d
3e
3 f
100
88
91
95
99
98
95
90
98
99
94
66
Table 4. Scope of amide allylation with 2e.[a]
92
37[d]
2g
3g
[a] The absolute configurations of major enantiomers were assigned on
the basis of further X-ray diffraction works (discussed later). [b] Isolated
yields. [c] The ee values were determined by HPLC analysis with Daicel
Chiralpaks IC (for 3a, 3b, 3c, 3e, and 3 f), IE (for 3g), and IF (for 3d).
[d] A large amount of the starting material was recovered intact after pro-
longed reaction times.
Entry
Substrate
R
X
t
[h]
Product
Yield[b]
[%]
ee[c]
[%]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Me
nBu
iBu
Bn
Ph
H
Me
Me
Me
H
H
H
H
H
H
I
3
3e
4b
4c
4d
4e
4 f
4g
4h
4i
99
95
99
100
97
99
99
99
99
99
2
3
3
2
2
2
2
2
99
98
98
98
96
97
97
98
(Table 3, entry 1), all the new stannylated reagents that bore
NÀH groups, 2b–f, allowed for good to excellent yields (88–
99%) and enantioselectivities (90–99% ee) of the correspond-
ing products 3b–f, respectively, upon reaction of 1a (Table 3,
entries 2–6), although negligible reactivity attenuation was ob-
served for sterically more demanding analogues such as 2c
and 2 f (Table 3, entries 3 and 6). Thus, one can see that the
electronic and steric properties of aryl rings and alkyl chains in
the stannylated reagents have little influence on the mecha-
nism of the reaction, and that the protocol is characterized by
broad functional-group tolerance with respect to the secon-
dary amides. Among the results obtained, we placed particular
emphasis on the case of using 2e since the enantioselectivity
reached up to the highest value of 99% ee with a quantitative
isolated yield (Table 3, entry 5). This example allowed us to
confirm the geometric structure of the allylated adduct 3e un-
ambiguously from single-crystal X-ray diffraction analysis,[15]
Br
Cl
[a] The absolute configurations of major enantiomers were assigned on
the basis of further X-ray diffraction works (discussed later). [b] Isolated
yields. [c] The ee values were determined by HPLC analysis with Daicel
Chiralpaks IC (for 3e, 4b, 4c, 4d, and 4g–i) and IF (for 4e and 4 f).
that all of these compounds underwent an analogous reaction,
regardless of any functionalization on the nitrogen atom,
thereby allowing for smooth conversion to the desired prod-
ucts 4b–i with extremely high isolated yields (95–100%) and
enantioselectivities (96–99% ee; Table 4, entries 2–9), compara-
ble to those found in 3e (Table 4, entry 1).
During the course of our investigation on the scope of the
enantioselective amide allylation of isatins, we realized that the
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use of stannylated reagents functionalized with secondary
amide moieties should be the key requirement for the success
of the reaction. To confirm this hypothesis, nonsubstituted al-
lyltributylstannane 2h was used as a nucleophilic species.
When this reagent was subjected to the typical amide allyla-
tion conditions (10 mol% of [In(L3)(OTf)3], MS3ꢁ, MeCN, RT)
with 1a, the corresponding allylated adduct 3h was smoothly
produced in 99% isolated yield within 1 h. The composition
analysis of 3h by the chiral HPLC method on the Chiralpak IC
showed that the reaction is much less enantioselective than
those with the NH-containing ones to give an unsatisfactory ee
value of 25% (Table 5, entry 1).[16] With identical purpose, we
to result in exclusive formation of 3i with an isolated yield of
45% as a virtually racemic product (5% ee; Table 5, entry 6).
The main features of the results presented above can be sum-
marized as follows: 1) the non-NH-functionalized types of stan-
nylated reagents such as 2g, 2h, and 2i lose their propensity
to interact with chiral ligand/indium/substrate complexes and
hence fail to facilitate highly efficient and fully stereocontrolled
processes; 2) the NH moieties are therefore critically important
elements to direct the stannylated reagents toward the catalyt-
ically active centers; and 3) the homoallylic alcohol 3i is acid-
labile and very likely to cyclize to 5a under the conditions em-
ployed.[3,10b]
In a series of pioneering con-
tributions, Franz and co-workers
Table 5. Allylation with non-NH-functionalized stannylated reagents.[a]
have established an important
method for highly stereoselec-
tive catalytic allylation of isatins,
wherein allylsilanes act as an effi-
cient nucleophile and allow for
asymmetric [3+2] annulation to
access enantiomerically enriched
spirocyclic 2-oxindoles.[4c,13] The
Entry
Reagent
Lewis
acid
Chiral
ligand
Solvent
t
[h]
Yield of 3[b]
Yield of 5a[b]
[%] (ee[c] [%])
[%] (ee[c] [%])
success of the work prompted
us to examine whether structur-
ally related allylsilanes could be
used for the present system, and
the results are summarized in
Table 6. Despite repeated efforts
in this direction, our results
clearly show that two typical
sets of silyl reagents 2j and 2k
fail to initiate the reaction even
in the presence of trimethylsilyl
1
2
3
4
5
6
2h
2i
2i
2i
2i
2i
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
InCl3
L3
L3
L1
L2
L1
L2
MeCN[d]
MeCN[d]
1
72
44
45
72
64
99 (25)
0 (–)
0 (–)
40 (10)
0 (–)
45 (5)
0 (–)
46 (83)
52 (38)
37 (10)
0 (–)
[e]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
[e]
[e]
[e]
InCl3
0 (–)
[a] The absolute configuration of major enantiomer for 3h was assigned by comparison with the reported
value of optical rotation (see Ref. [13b]), and that of 3i was assigned on the basis of further X-ray diffraction
works (discussed later). [b] Isolated yields. [c] The ee values were determined by HPLC analysis with Daicel Chir-
alpaks IC (for 3h and 3i) and IB (for 5a). [d] Reactions performed with MS3ꢁ. [e] Reactions performed with
MS4ꢁ.
next examined whether b-methoxycarbonyl allylstannane 2i
can conduct reactions with high levels of stereocontrol. Under
Table 6. Allylation with allylsilanes.[a]
the same conditions, substrate 1a was treated with this re-
agent much more slowly to give incomplete conversion even
after 72 h with exclusive formation of spirocyclic lactone 5a,
instead of the expected product 3i, in only low isolated yield
(46%) and moderate enantioselectivity (83% ee) (Table 5,
Entry
Reagent
Chiral catalyst
Additive
Solvent
t [h]
entry 2). This set of results was reproduced using analogous
conditions that involved the use of the chiral ligand L1 and
CH2Cl2 solvent. In this case, the reaction appeared relatively
fast and afforded exclusively a comparable isolated yield (52%)
of 5a after a reaction time of 44 h, albeit with only modest
enantioselectivity (38% ee; Table 5, entry 3). A further modifica-
tion, replacement of the chiral ligand with L2, led to a consider-
able change in the reaction outcome, thus giving a certain
amount (40% isolated yield) of 3i together with a nearly equal
amount (37% isolated yield) of 5a over a long period of time
(45 h), but obtained in almost racemic (10% ee) forms (Table 5,
entry 4). When the catalyst of choice was [In(L1)Cl3], no reac-
tion was observed, even after a prolonged reaction time (>
72 h) (Table 5, entry 5). By using the chiral catalyst [In(L2)Cl3],
only a sluggish and incomplete reaction took place over 64 h
[b]
1
2
3
4
2j
2k
2k
2k
[In(L1)(OTf)3]
[In(L1)(OTf)3]
[In(L3)(OTf)3]
[In(L3)(OTf)3]
–
–
–
CH2Cl2
CH2Cl2
91
121
72
[b]
MeCN[c]
MeCN[c]
TMSCl[d]
72
[a] NR (no reaction). [b] Reactions performed with MS4ꢁ. [c] Reactions
performed with MS3ꢁ. [d] A stoichiometric amount (1.2 equiv) was added
to the reaction mixture.
chloride (TMSCl), which would serve as a Lewis acid promot-
er,[13,17] to result in complete recovery of unchanged starting
isatin 1a in all cases (Table 6, entries 1–4). Thus, the silyl re-
agents prove to be totally ineffective in our catalytic systems,
even though they include the NÀH group in their structures.
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With the objective of determining the mechanistic origins of
the asymmetric induction during the catalytic amide allylation,
a further discussion should be given of the structural require-
ments for substrates to be used. To address this issue, we
tested the utility of propiophenone substrate S1 as a monoke-
tone analogue of isatin. Subjection of this material to the most
favorable conditions that involve the use of 10 mol% of
[In(L3)(OTf)3] in MeCN ultimately resulted in no reaction over
a period of 72 h upon treatment with the stannylated reagent
2e (Scheme 2a). In contrast, N-phenyl benzoylformamide S2,
Figure 1. Proposed transition-state models.
from the sterically allowed spaces. It is of interest to note that
our current rationale for the Re-face attack enables proper pre-
diction of the stereochemical courses that lead to predominant
formation of the S enantiomers, which is in good agreement
with further evidence for the absolute stereochemistry assign-
ments on the basis of X-ray analyses that will be described
later.
Within the framework of the proposed model, one may
design a modified method for enantioselective catalysis of the
amide allylation with the stannylated reagent 2g (Figure 1b).
This reaction has met with unsatisfactory outcomes (37%,
66% ee) in the foregoing experiments (Table 3, entry 7), and
one might see whether this synthetic operation could be
aided by the addition of the chemically inert but equally effec-
tive hydrogen-bond donor, allylsilane 2k, to reflect any real
change in product-forming behavior. To examine effects of the
modification and validity of our proposed mechanistic model,
we attempted to treat a reaction mixture that contained 1a (c:
0.5m), 2k (1.2 equiv), and [In(L3)(OTf)3] (10 mol%) with 2g
(1.2 equiv) in MeCN. It is remarkable that this reaction took
place at an appreciably increased rate relative to the per-
formance under the original conditions and led to preferential
formation of the desired product 3g with much improved iso-
lated yield (98%) and enantioselectivity (90% ee) after a period
of 12 h for reaction completion (Scheme 2b). Furthermore, sim-
ilar but much more distinct behavior was observed in another
attempt made with the use of N-phenyl methacrylamide 2l,
which represents a structurally simplified alternative to 2k. In
this case, the catalyst was found to be much more active and
accelerated the reaction with approximately sixfold rate en-
hancement to result in a clean and full conversion in 2 h to 3g
with quantitative isolated yield and comparably high ee value
of 90%. Besides, N-phenyl acetamide (2m), N-phenyl benza-
mide (2n), and even ethyl N-phenylcarbamate (2o) still afford-
ed enhanced isolated yields and enantioselectivities (93%,
93% ee; 98%, 93% ee; and 98%, 91% ee, respectively) in short
reaction times of 5, 2, and 2 h, respectively, thereby suggesting
that the conjugated C=C double bonds have little involvement
in the rate- and stereochemistry-determining steps.[19] These
dramatically enhanced effects of the chemically inert additives
on the catalytic activity strongly support our conclusion that
the mechanistic origin of the highly efficient and enantioselec-
tive amide allylation lies in the precise control over the spatial
Scheme 2. Mechanistic studies.
an acyclic ketoamide derivative, was shown to achieve a con-
siderable degree of asymmetric induction to afford the corre-
sponding homoallylic alcohol P2 with an ee value of 67%, al-
though the reaction ended with incomplete conversion and
a moderate isolated yield of 72% (Scheme 2a).[18] The observed
differences in both the reactivity and enantioselectivity empha-
size the importance of functional-group compatibility of the
substrates with the chiral catalyst–reagent association. There-
fore, it is reasonable to assume that the ketoamide structural
motif of isatins is responsible for the precise control over enan-
tiotopic differentiation of two faces of the carbonyl moieties
through the N-C=O···H-N-C=O hydrogen-bond interactions be-
tween the catalyst-bound substrates 1 and reagents 2.
This situation likely arises when the related elements assem-
ble around the six-coordinate indium(III) ion, thus connecting
to three nitrogen atoms of L3, two oxygen atoms of 1, and
one oxygen atom of 2 into a highly ordered structure with
a well-defined chiral environment. In view of this structural de-
scription, a mechanistic possibility of engaging another re-
agent molecule in the transition state must be taken into con-
sideration as illustrated in Figure 1a, because the substrate–re-
agent complexes adopt a conformation with the nucleophilic
residues away from the keto carbonyl carbon atoms, which is
clearly unfavorable for facilitating the nucleophilic processes
between these two reacting centers. In fact, this transition-
state model provides mechanistically reasonable reaction path-
ways that avoid the Si-face attack of nucleophiles owing to the
steric repulsion from the phenyl group of the chiral ligand L3
and rather assist the strong preference for the Re-face attack
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arrangement and orientation of the molecular constituents im-
parted by the catalyst system. The O=C-NH-containing species
play a key role in activating the chiral transition states through
the hydrogen-bond interactions with the substrates.[20]
siderably long times necessary to complete the processes
(Table 7, entries 3 and 4). In continuation of our efforts, it was
noted that an approach with the use of PTSA offered the most
effective and rapid access to a diverse set of spirocyclic lac-
tones, 5a–f, 6a, 7a, and 8a, of the highest quality (Ree =100%)
in sufficiently high isolated yields (91–100%) for all ten sub-
strates investigated (Table 7, entries 5–14).
Having successfully established a reasonably efficient proto-
col for the production of nearly enantiopure forms of the ho-
moallylic alcohols with a full understanding of the mechanistic
course, we directed our attention to the application of these
compounds to the synthesis of spiro-fused bicyclic a-methyl-
ene-g-butyrolactones, which are of great pharmaceutical inter-
est.[8,10] As the first step towards this goal, we explored an ap-
proach upon acidic treatment to cyclize the substrates to the
spirocyclic lactones, as indicated by previous results.[2,3] Our
major concern was to identify optimal conditions that would
satisfy a primary requirement to maintain the original level of
the stereochemical integrity. The results listed in Table 7 imply
A particularly noteworthy feature of this approach is the per-
fectly controlled formation of 5a as the essentially enantiopure
form with up to 99% ee, starting from 3e (Table 7, entry 6).
Thus we obtained single crystals of this compound from
a chloroform/hexane mixture and determined its structure by
means of X-ray analysis (see Figure S2 in the Supporting Infor-
mation).[21] The structure was solved in the orthorhombic chiral
space group P212121, attributable to the chirality of the molec-
ular constituents, and thus provided the most conclusive evi-
dence for the successful con-
struction of the rigid spirocyclic
Table 7. Lactonization of homoallylic alcohols.[a]
framework with complete reten-
tion of the configuration. It is in-
teresting to remark that despite
unsatisfactory Flack parameter
value of 0.1 (3),[22] the configura-
tional assignment of this struc-
ture composed entirely of light
[c,d]
Entry
Substrate
R1
R2
X
Reagent
Solvent
t
[h]
Product
Yield[b]
[%]
Ree
atomic elements was found to
be valid, in good accord with
the results unambiguously se-
cured by more reliable X-ray dif-
fraction studies conducted on its
halogenated derivatives, thereby
assuring the S configurations as
reported in our earlier work.[7]
Given that the straightforward
cyclization is guaranteed to
work, we envisaged that the ab-
solute configurations of 3a–d,
3 f, and 3g could be established
by distinct correlations with the
chiral HPLC analyses of the cor-
responding cyclization products
with that of the authentic
sample of (S)-5a. Upon subjec-
tion of each to the lactonization
conditions, smooth conversion
[%]
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3e
4b
4c
4d
4e
4 f
4g
4h
4i
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
nBu
iBu
Bn
Ph
H
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
I
TfOH
BF3·OEt2
HCl (concd)
TFA
CH2Cl2
CH2Cl2
1,4-dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
123
97
139
44
11
11
9
5a
5a
5a
5a
5a
5a
5b
5c
5d
5e
5 f
62
94
88
98
98
96
91
97
99
96
95
99
99
100
22
87
100
100
100
100
100
100
100
100
100
100
100
100
Ph
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA[e]
PTSA[e]
PTSA[e]
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
7
9
9
10
11
12
13
14
10
24
61
24
63
6a
7a
8a
Br
Cl
[a] The absolute configurations of major enantiomers were assigned on the basis of further X-ray diffraction
works (discussed later). [b] Isolated yields. [c] Retention of enantiomeric purities (Ree =100À{ee [%] (substra-
te)Àee [%] (product)}). [d] The product enantioselectivities were determined by HPLC analysis with Daicel Chir-
alpaks IB (for 5a, 5d, 5e, 6a, 7a, and 8a), IE (for 5 f), and IF (for 5b and 5c). [e] 2.0 equiv of the reagent was
employed.
that solutions of triflic acid (TfOH) and BF3·OEt2 in CH2Cl2 are
synthetically useless in causing serious and significant decreas-
es in the ee values, respectively, possibly due to comparatively
fast racemization of the substrate taking place at RT in the
acid-promoted processes (Table 7, entries 1 and 2). The milder
Brønsted acids, such as concentrated HCl (solution in 1,4-diox-
ane), trifluoroacetic acid (TFA), and p-toluenesulfonic acid
(PTSA; solution in CH2Cl2), can likely be utilized to address the
above issues. Indeed, the use of the former two acids was
found to promote the formation of the desired product with
no detectable degradation of enantiomeric purity under analo-
gous reaction conditions, but to be impractical owing to con-
was observed, and similar yields of 5a could be obtained with
enantiomeric excesses exactly identical to those of their pre-
cursors. All these isolated products exhibited HPLC profiles, in
qualitative agreement with the result obtained for the enantio-
merically pure (S)-5a, thus leading to a conclusion that all the
absolute configurations of 3a–d, 3 f, and 3g should be as-
signed as S.
Concerning the biological impact of the spirocyclic lactones
as potential drug candidates, an early report by Heindel indi-
cated that C5-iodinated N-methyl 2-oxindole of the spirocyclic
lactone is more attractive than the nonsubstituted one owing
to the potent antineoplastic activity against cells derived from
Chem. Eur. J. 2014, 20, 11091 – 11100
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human carcinoma of the nasopharynx (KB).[8] The pharmaceuti-
cal importance of the C5-halogenated analogue, along with
the additional advantage of making it possible to determine
the absolute stereochemistry of the spirocyclic systems, stimu-
lated our continuing interest in exploring an efficient approach
to install halogen atoms at the C5 positions of the parent spi-
rocyclic lactones 5.[23]
In the beginning, we treated a mixture of 5a and TFA
(1.0 equiv) in MeCN with N-iodosuccinimide (NIS; 2.0 equiv) at
RT to attempt a straightforward derivatization by using a proce-
dure reported by Colobert and co-workers.[24] Fortunately, the
acid-promoted substitution of the aromatic protons took place
smoothly at the desired C5 position over a period of 15 h at
RT to afford the iodinated derivative 6a in 98% isolated yield
as an exclusive product (Table 8, entry 1). Initially, the relatively
1
Figure 2. The aromatic regions of H NMR spectra (300 MHz, CDCl3) of 5e
(top) and 6e (bottom).
give simple patterns of downfield- and upfield-shift-
ed signals for the C4, C6, and C7 aromatic protons,
respectively, as the reaction progressed, whereas the
other aromatic resonances remained almost un-
changed, as demonstrated by a clear example from
entry 5 of Table 8 (Figure 2).
Table 8. Halogenation of spirocyclic lactones.[a]
With such success in obtaining several examples of
the iodinated products, we applied this approach to
reagent-guided chemical functionalization to prepare
Entry
Substrate
R
Reagent
t
[h]
Product
X
Yield[b]
[%]
ee[c] [%]
(Ree [%])
the other halogenated derivatives, such as brominat-
ed and chlorinated spirocyclic lactones. This is exem-
plified by the reactions of 5a, which were performed
under analogous conditions using N-bromosuccini-
mide (NBS) and N-chlorosuccinimide (NCS) as the
electrophilic halogen sources. Our attempts to effect
the individual transformations also met with equally
satisfactory outcomes, thereby affording excellent
yields (>98%) of the brominated and chlorinated de-
rivatives 7a and 8a, respectively, with complete re-
tention of the enantiopurities (Table 8, entries 7 and
8). Thus, the above method was demonstrated to
have appreciable tolerance for variations in the sub-
strates and reagents, thereby offering convenient
access to a large diversity of the C5-halogenated 2-
[d]
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5 f
5a
5a
Me
NIS
NIS
NIS
NIS
NIS
NIS
NBS
NCS
15
15
16
19
19
25
14
10
6a
6b
6c
6d
6e
6 f
I
I
I
I
I
I
Br
Cl
98
93
90
94
91
99
98
99
99 (100)
99 (100)
98 (100)
98 (100)
98 (100)
96 (100)
99 (100)
99 (100)
nBu
iBu
Bn
Ph
H
Me
Me
7a
8a
[a] The absolute configurations were assigned on the basis of further X-ray diffraction
works (discussed later). [b] Isolated yields. [c] The product enantioselectivities were de-
termined by HPLC analysis with Daicel Chiralpaks IB (for 6a, 6e, 7a, and 8a), IC (for
6 f), IE (for 6d), and IF (for 6b and 6c). [d] Retention of enantiomeric purities (Ree
100À{ee [%] (substrate)Àee [%] (product)}).
=
harsh conditions required for this operation led to some con-
cern with regard to potential detrimental effects on the stereo-
chemical outcome. However, the very high level of the enan-
tiomeric purity was completely retained in the product with
the ee value of 99% as confirmed by chiral HPLC analysis. This
transformation could be effected on all the other spirocyclic
lactones 5b–f, which underwent clean reactions only at the
relevant C5 positions to result in very high isolated yields (>
90%) of the corresponding iodinated analogues 6b–f with
complete retention of the stereochemistry, respectively
(Table 8, entries 2–6). Of particular interest is the fact that the
cases of entries 4 and 5 of Table 8, in which R contains an aryl
(benzyl and phenyl) group, maintain structural integrity of the
aromatic substituents during the course of the reaction. In this
oxindoles in high yields without degradation of the pre-exist-
ing labile a-methylene-g-butyrolactone moieties.
At the final stage of our research, we undertook comprehen-
sive X-ray studies to reveal the unspecified absolute stereoche-
mistries of the halogenated compounds.[25–31] The selected
crystallographic data obtained from the X-ray results are
shown in Table 9. Accordingly, all the structures were solved in
the chiral space groups commonly attributed to one-handed-
ness, established in crystallization of the enantiopure mole-
cules and thoroughly refined to allow for high accuracy, with
the final R1 and wR2 values being less than 0.0716 and 0.1939,
respectively. As seen in the case of 5a, the given structures
show the rigid conformations owing to geometric constraints
imposed by the cross-linked bicyclic systems (see Figures S3–
10 in the Supporting Information). It deserves to be mentioned
here that all the absolute configurations in the C3-stereogenic
centers are assigned as S with satisfactory Flack parameter
1
regard, H NMR spectroscopy allowed us to follow the reaction
trajectories of the individual molecules; the characteristic reso-
nances assignable to the C5 aromatic protons disappeared to
Chem. Eur. J. 2014, 20, 11091 – 11100
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11097
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Experimental Section
Table 9. Selected crystallographic data.
General procedure for asymmetric amide allyla-
tions
Compound Empirical
formula
Crystal
system
Space Absolute
group configuration parameter
Flack
R1
wR2
6a[a]
6b
6c
6d
6e
6 f
C13H10INO3 monoclinic
C2
S
S
S
S
S
S
S
S
0.098(16) 0.0716 0.1939
0.020(12) 0.0301 0.0706
À0.028(18) 0.0307 0.0636
0.049(6) 0.0311 0.0740
All the experiments for the asymmetric amide allyla-
tions were carried out as described in the following
typical procedure. For example, the reaction of isatin
1a with stannylated reagent 2c to generate homoal-
lylic alcohol 3c (entry 3 in Table 3) was exemplified
as follows.
C16H16INO3 orthorhombic P212121
C16H16INO3 orthorhombic P212121
C19H14INO3 orthorhombic P212121
C18H12INO3 orthorhombic P212121
À0.02(2)
0.0469 0.1052
0.0387 0.1031
C12H8INO3
hexagonal
P63
P21
P21
0.09(2)
7a
8a
C13H10BrNO3 monoclinic
C13H10ClNO3 monoclinic
0.064(8) 0.0216 0.0563
0.065(5) 0.0412 0.1076
Synthesis of homoallylic alcohol 3c
[a] See Ref. [7].
Under
a
nitrogen atmosphere, (S,S)-Ph-pybox
(9.4 mg, 0.025 mmol) was added at RT to the suspen-
sion of In(OTf)3 (10.5 mg, 0.0187 mmol) and MS3ꢁ
values less than 0.098, which would be attributed to the possi-
ble heavy atom effects of the halogen atoms.[22] From an as-
sessment of the stereochemical correlations, these results
allow us to unambiguously assign the S absolute configura-
tions to all the related chiral intermediates 3–5.[32] The ob-
served general preference for the S enantiomers appears to be
in agreement with our predictions on the basis of the afore-
mentioned transition state model for the stereochemical
course of the catalytic amide allylation with the NH-containing
stannylated reagents, thus yielding definitive proof of the suit-
ability of the foregoing mechanistic interpretation.
(93.5 mg, 0.5 gmmolÀ1) in anhydrous MeCN (0.37 mL), which was
degassed by at least three freeze/pump/thaw cycles. After stirring
for 1 h, compound 1a (30.1 mg, 0.187 mmol) was added, and the
resulting mixture was stirred for 0.5 h. Compound 2c (96.6 mg,
0.224 mmol) was added at the same temperature to this mixture,
and the resulting mixture was stirred for 8 h. The reaction was
then quenched by the addition of saturated aqueous NaHCO3
(5.0 mL), extracted with ethyl acetate (30 mL), washed with 3%
w/w aqueous HCl (10 mL) and brine (10 mL), dried over Na2SO4, fil-
tered, and concentrated under vacuum to provide a crude residue.
Purification of the residue by column chromatography on 10% w/
w anhydrous K2CO3/silica gel[33] (eluent: hexane/AcOEt 1:1) gave 3c
(51.6 mg, 91%, 90% ee) as a white solid.
CCDC-976630 (3e), CCDC-976631 (5a), CCDC-976632 (7a), CCDC-
976633 (8a), CCDC-976951 (6b), CCDC-976952 (6c), CCDC-976954
(6e), CCDC-976956 (6 f), and CCDC-977774 (6d) contain the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Conclusion
We have demonstrated that the indium-catalyzed amide allyla-
tion presented here represents an attractive and powerful
means to achieve extremely high levels of enantioselectivity
and exhibits a remarkably wide scope in a variety of isatins
and NH-containing stannylated reagents to provide the homo-
allylic alcohols in almost enantiopure forms. Also worthy of
note is that the successful synthesis of these chiral compounds
allows the straightforward and rapid construction of a diverse
set of the spirocyclic lactones and their halogenated deriva-
tives under the perfect stereocontrol, with an operational con-
venience that would make this method adaptable to large-
scale synthesis. Several mechanistic investigations have shown
that the substrate–reagent hydrogen-bond interaction plays
a critical role in the formation of the key transition states that
give rise to emergence of the high catalytic activity and enan-
tioselectivity. This finding further inspired the employment of
the hydrogen-bond donors, which led to a striking discovery
that the externally added O=CÀNH-containing species can be
effective as a catalyst activator to achieve high levels of enan-
tiocontrol in the amide allylation processes. Therefore, the re-
sults of our studies can offer not only potential synthetic ad-
vantages to deliver a large variety of antineoplastic drug candi-
dates and pharmaceutically meaningful compounds, but also
many attractive opportunities to design and create new cata-
lytic systems.
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan. The authors are grateful to Mr. Ta-
kashi Yamada for assistance with NMR spectroscopic measure-
ments and Prof. Vadim A. Soloshonok (University of the Basque
Country) for his valuable suggestions and comments on a pos-
sibility of self-disproportionation of enantiomers (SDE).
Keywords: allylation
·
antitumor agents
·
asymmetric
catalysis · lactones · spiro compounds
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[15] Crystal data for 3e (recrystallized from solution in methanol): monoclin-
ic, space group P21 (no. 4), a=8.54669(13) ꢁ, b=4.98993(8) ꢁ, c=
20.4302(3) ꢁ, a=g=908, b=92.9900(7)8, V=870.11(2) ꢁ3, Z=2, 1=
1.284 MgmÀ3, m(CuKa)=0.705 cmÀ1, T=173 K. In the final least-squares
refinement cycles on F2, the model converged at R1 =0.0386 (I>2s(I)),
wR2 =0.1116, GoF=1.228, and Flack absolute structure parameter=
0.10(6) for 2582 reflections and 222 parameters.
[16] For the absolute stereochemistry of 3h, the R configuration was as-
signed to the newly created stereogenic center by comparison of the
optical rotation with that reported in the literature (see Ref. [13b]). The
opposite stereochemical preference in addition to the observed very
low enantioselectivity (25% ee) can be interpreted in terms of ineffi-
cient chirality transfer from the chiral environment at the catalytic
center.
[17] a) S. E. Denmark, J. Fu, Chem. Rev. 2003, 103, 2763–2794; b) C.-T. Chen,
S.-D. Chao, J. Org. Chem. 1999, 64, 1090–1091; c) J. Beignet, L. R. Cox,
Org. Lett. 2003, 5, 4231–4234; d) J. Lu, S.-J. Ji, Y.-C. Teo, T.-P. Loh, Org.
Lett. 2005, 7, 159–161.
[18] The lower efficiency of the reaction than with the isatin substrates is
probably responsible for intrinsic low reactivity of the acyclic ketoamide
system, which would be attributed to the greater conformational flexi-
bility. The ee value of P2 was determined by HPLC analysis with the
Daicel Chiralpak IF.
[25] Crystal data for 6b (recrystallized from solution in chloroform/hexane):
orthorhombic, space group P212121 (no. 19), a=5.1110(5) ꢁ, b=
16.8944(17) ꢁ, c=18.6050(18) ꢁ, a=b=g=908, V=1606.5(3) ꢁ3, Z=4,
1=1.642 MgmÀ3, m(MoKa)=2.002 cmÀ1, T=173 K. In the final least-
squares refinement cycles on F2, the model converged at R1 =0.0301
(I>2s(I)), wR2 =0.0706, GoF=1.062, and Flack absolute structure pa-
rameter=0.020(12) for 3675 reflections and 191 parameters.
[26] Crystal data for 6c (recrystallized from solution in chloroform/hexane):
orthorhombic, space group P212121 (no. 19), a=5.1577(5) ꢁ, b=
17.4431(17) ꢁ, c=18.1558(17) ꢁ, a=b=g=908, V=1633.4(3) ꢁ3, Z=4,
1=1.615 MgmÀ3, m(MoKa)=1.969 cmÀ1, T=173 K. In the final least-
squares refinement cycles on F2, the model converged at R1 =0.0307
(I>2s(I)), wR2 =0.0636, GoF=1.027, and Flack absolute structure pa-
rameter=À0.028(18) for 3715 reflections and 192 parameters.
[27] Crystal data for 6d (recrystallized from solution in chloroform/hexane):
orthorhombic, space group P212121 (no. 19), a=5.3720(2) ꢁ, b=
16.4015(5) ꢁ, c=18.8857(6) ꢁ, a=b=g=908, V=1664.00(10) ꢁ3, Z=4,
1=1.721 MgmÀ3, m(CuKa)=15.265 cmÀ1, T=173 K. In the final least-
squares refinement cycles on F2, the model converged at R1 =0.0311
(I>2s(I)), wR2 =0.0740, GoF=1.031, and Flack absolute structure pa-
rameter=0.049(6) for 2909 reflections and 217 parameters.
[28] Crystal data for 6e (recrystallized from solution in chloroform/hexane):
orthorhombic, space group P212121 (no. 19), a=5.5595(6) ꢁ, b=
13.5457(14) ꢁ, c=20.892(2) ꢁ, a=b=g=908, V=1573.3(3) ꢁ3, Z=4,
1=1.761 MgmÀ3, m(MoKa)=2.050 cmÀ1, T=173 K. In the final least-
squares refinement cycles on F2, the model converged at R1 =0.0469
(I>2s(I)), wR2 =0.1052, GoF=1.005, and Flack absolute structure pa-
rameter=À0.02(2) for 3532 reflections and 208 parameters.
[29] Crystal data for 6 f (recrystallized from solution in chloroform/hexane):
hexagonal, space group P63 (no. 173), a=18.1986(15) ꢁ, b=
18.1986(15) ꢁ, c=6.8251(7) ꢁ, a=b=908, g=1208, V=1957.6(4) ꢁ3, Z=
6, 1=1.939 MgmÀ3, m(MoKa)=2.658 cmÀ1, T=173 K. In the final least-
squares refinement cycles on F2, the model converged at R1 =0.0387
(I>2s(I)), wR2 =0.1031, GoF=1.108, and Flack absolute structure pa-
rameter=0.09(2) for 2988 reflections and 166 parameters.
[30] Crystal data for 7a (recrystallized from solution in chloroform/hexane):
monoclinic, space group P21 (no. 4), a=5.9706(3) ꢁ, b=12.0484(6) ꢁ,
c=8.7734(4) ꢁ, a=g=908, b=103.9550(15)8, V=612.50(5) ꢁ3, Z=2,
1=1.671 MgmÀ3 m(CuKa)=4.591 cmÀ1
, , T=173 K. In the final least-
squares refinement cycles on F2, the model converged at R1 =0.0216
(I>2s(I)), wR2 =0.0563, GoF=1.039, and Flack absolute structure pa-
rameter=0.064(8) for 1717 reflections and 164 parameters.
[31] Crystal data for 8a (recrystallized from solution in chloroform/hexane):
monoclinic, space group P21 (no. 4), a=5.9100(2) ꢁ, b=12.3070(5) ꢁ,
c=8.5206(3) ꢁ, a=g=908, b=103.2334(13)8, V=603.28(4) ꢁ3, Z=2,
1=1.452 MgmÀ3 m(CuKa)=2.818 cmÀ1
, , T=173 K. In the final least-
[19] In the mechanistic studies with the hydrogen-containing additives, it
was found that use of imidazole (1.2 equiv) had a detrimental effect on
both the reactivity and enantioselectivity of the amide allylation to 3g.
squares refinement cycles on F2, the model converged at R1 =0.0412
(I>2s(I)), wR2 =0.1076, GoF=1.081, and Flack absolute structure pa-
rameter=0.065(5) for 2109 reflections and 164 parameters.
Chem. Eur. J. 2014, 20, 11091 – 11100
www.chemeurj.org
11099
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[32] On the basis of these results, the absolute configurations of 4g–i,
which were left unassigned, could be determined to be S by distinct
correlations with the chiral HPLC analyses of the corresponding cycliza-
tion products with those of the authentic samples of (S)-6a–8a, respec-
tively.
[33] D. C. Harrowven, D. P. Curran, S. L. Kostiuk, I. L. Wallis-Guy, S. Whiting,
K. J. Stenning, B. Tang, E. Packard, L. Nanson, Chem. Commun. 2010, 46,
6335–6337.
Received: May 28, 2014
Published online on July 22, 2014
Chem. Eur. J. 2014, 20, 11091 – 11100
www.chemeurj.org
11100
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim