A Tunable and Enantioselective Hetero-Diels–Alder Reaction Provides Access to Distinct Piperidinoyl Spirooxindoles

Article abstract of DOI:10.1002/anie.201708355

The active complexes of chiral N,N′-dioxide ligands with dysprosium and magnesium salts catalyze the hetero-Diels–Alder reaction between 2-aza-3-silyloxy-butadienes and alkylidene oxindoles to selectively form 3,3′- and 3,4′-piperidinoyl spirooxindoles, respectively, in very high yields and with excellent enantioselectivities. The exo-selective asymmetric cycloaddition successfully regaled the construction of sp³-rich and highly substituted natural-product-based spirooxindoles supporting many chiral centers, including contiguous all-carbon quaternary centers.

Full text of DOI:10.1002/anie.201708355

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Accepted Article
Title: A Tunable and Enantioselective Hetero-Diels-Alder Reaction
Provides Access to Distinct Piperidinoyl Spirooxindoles
Authors: Kamal Kumar, Samydurai Jayakumar, Kathrin Louven, and
Carsten Strohmann
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708355
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10.1002/anie.201708355
Angewandte Chemie International Edition
DOI: 10.1002/anie.201…………
Asymmetric HDA Reaction
A Tunable and Enantioselective Hetero-Diels-Alder Reaction Provides
Access to Distinct Piperidinoyl Spirooxindoles*
Samydurai Jayakumar, Kathrin Louven, Carsten Strohmann and Kamal Kumar*
Dedicated to Prof. Dr. Herbert Waldmann on the occasion of his 60th birthday
Abstract: The active complexes of chiral N,N-oxide ligand with
dysprosium and magnesium salts catalyze the hetero-Diels-Alder
reaction between 2-aza-3-silyloxy-butadienes and alkylidene
oxindoles to selectively form 3,3´- and 3,4´-piperidinoyl
spirooxindoles respectively in very high yields and with excellent
enantioselectivities. The exo-selective asymmetric cycloaddition
successfully regaled the construction of sp3 rich and highly
substituted natural product based spirooxindoles supporting many
chiral centers including consecutive all-carbon-quaternary centers.
with up to four consecutive chiral centers (Scheme 1).[7]
I
n the quest for gaining asymmetric synthetic access to heterocyclic
scaffolds existing in natural product structures as well as synthetic
bioactive molecules, the hetero-Diels-Alder (HDA) reaction is
undoubtedly amongst the most efficient tools in a chemist´s
toolbox.[1] Ghosez and coworkers introduced the HDA reaction of 2-
aza-3-silyloxy-1,3-butadienes (2-ASBs, I, Scheme 1) with carbonyl
compounds as well as electron-poor olefins in 90´s.[2] Strangely,
since its inception and in more than 30 years, only one asymmetric
HDA reaction of 2-ASBs with olefinic dienophiles was reported in
1999 by the Ghosez lab using conjugated imides.[3] Our interest in
developing asymmetric annulation and cycloaddition reactions[4]
affording natural product based scaffolds that are rich in stereogenic
centers inspired us to explore this intriguing and potentially useful
chemical transformation.[5] We envisioned that a chiral metal
complex as Lewis acid could catalyze the HDA reaction of 2-ASBs
with isatin-derived olefins (II) in asymmetric fashion and that might
be tuned to selectively afford enantiomerically enriched 3,3´- or
3,4´-piperidinoyl-spirooxindoles III and IV respectively. Notably,
the piperidinoyl-spirooxindole cores represent vital elements of
biologically intriguing natural products[6] that are often decorated
Scheme 1. Biologically active piperidinoyl spirooxindoles and the strategy to
make them via HDA reaction.
Initially, the racemic HDA reaction of trimethylsilyl (TMS)-
azadiene 1a with cyano substituted alkylidene N-Boc-oxindole 3a
was performed by heating the mixture in toluene at 110 °C for 4 h.
The racemic cycloadduct 4a was obtained in quantitative yield and
with >10:1 diastereomeric ratio. Towards asymmetric cycloaddition
reaction between 1a and 3a, unfortunately the reported catalytic
system of copper triflate complexed with C2-symmetric bis-
oxazoline ligand A[3] did not provide any enantioselectivity,
although the adduct 4a was obtained in 64% yield. Therefore, a
number of transition metal salts of silver, copper and magnesium in
combination with various chiral ligands were attempted in the
reaction of 1a with olefin 3a. Although the reactions yielded the
desired adduct in moderate to high yields, no enantioselectivity was
observed (see Supporting information, Table S1).
We suspected that the nucleophilic azadiene 1a might have
poisoned the Lewis acid metal complex and thereby facilitated the
non-catalytic racemic synthesis of 4a. We reasoned that a bulkier
silyl group might sterically prevent such an interaction of imine
nitrogen with metal complex, favours dienophile-catalyst interaction
and facilitates the stereoselective cycloaddition reaction (Supporting
information, Scheme S1). The reaction of 2a supporting a bulky
TBS group with 3a in the presence of copper triflate and bis-
oxazoline (A) as catalytic complex yielded the desired adduct 4a in
high yield (84%) and good diastereoselectivity. However the
enantioselectivity still remained elusive in this reaction (Table 1,
entry 1). Nevertheless, further reaction condition optimization was
performed using more stable diene 2a with olefin 3a (Table 1).
Different chiral Lewis acid complexes of indium, zinc,
magnesium, rhodium and titanium did support the HDA reaction[8]
and provided very high diastereoselectivities (Table 1, entries 2-6),
yet only racemic adduct 4a was obtained. The first ray of hope in
[]
Dr. S. Jayakumar, Dr. K. Kumar
Max-Planck-Institut für Molekulare Physiologie, Abteilung
Chemische Biologie, Otto-Hahn-Straße 11, 44227 Dortmund,
Germany.
M. Sc. K. Louven, Prof. Dr. C. Strohmann.
Fakultät Chemie und Chemische Biologie, Technische Universität
Dortmund, Otto-Hahn Str. 6, 44227-Dortmund, Germany.
Fax: (+) 49-231-133-2499
E-mail: kamal.kumar@mpi-dortmund.mpg.de
Web: http://www.mpi-dortmund.mpg.de/research-groups/kumar
[]
Acknowledgements. Authors are grateful to Max Planck Society for
the financial support.
1
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10.1002/anie.201708355
Angewandte Chemie International Edition
this optimization appeared when magnesium perchlorate in complex
with N,N-oxide ligand G afforded 4a in excellent yield and with
78% ee (Table 1, entry 7). Feng group had successfully used this
class of ligands in a number of diverse asymmetric cycloaddition
and cyclization reactions,[9] including HDA reaction of Brassard-
type and Danishefsky´s dienes.[10] Nickel triflate with G catalyzed
the reaction to give 4a in high yield and slightly improved ee (Table
1, entry 8). However, copper triflate with G could hardly provide
any enantioselectivity in the reaction (Table 1, entry 9). Zinc triflate
did not make improvement over magenisum perchlorate (Table 1,
entry 10).
between 2a and 3a (see supporting Table S2-3). Notably, trivalent
and divalent metal complexes with ligand G delivered opposite
enantiomers of adduct 4a (cf. entries 7-10 vs 12-16, Table 1) and
thus offer construction of both enantiomers of piperidinoyl-
spirooxindole with the help of just one chiral ligand.
Table 2. Scope of the asymmetric HDA reaction of 2-ASBs to yield 3,3´-
piperidinoyl-spirooxindoles.[a]
Table 1. Optimization of enantioselective HDA reaction of 2-ASBs.[a]
No.
R1
R2
R3
Yield 4 (%)b
drc
eed,e
(%)
98
96
96
96
94
99
96
40
94
97
94
81
96
98
66
38
1
2
3
4
5
6
7
8
9
10
H
5-F
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
nPr
tBu
Me
Me
4a (94)
4b (93)
4c (85)
4d (86)
4e (93)
4f (93)
4g (94)
4h (97)
4i (85)
4j (86)
4k (85)
4l (87)
4m (99)
4n (98)
4o (93)
4p (97)
>20:1
14:1
5-Cl
5-Br
5-I
Ph
>20:1
>20:1
>20:1
>20:1
>20:1
6.2:1
Ph
Ph
7-F
Ph
7-Br
5-NO2
5-Me
5-OMe
Ph
Ph
Ph
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
Ph
11 5-OCF3
Ph
12
13
14
15
16
5,7-Me2
Ph
H
H
H
H
Ph
Ph
4-F-C6H4
2-Furan
No.
Catalystb
Ligand Solvent
Yield (%)c
drd
4a
eee,f
(%)
0
0
0
0
0
0
(+)78
(+)81
(+)06
(+)76
(-)48
(-)98
(-)34g
(-)90
(-)78
(-)74
[a] At the scale of 0.05 mmol of 3a at 0.033 M concentration; [b] isolated yields; [c]
determined by 1H NMR; [d] determined by chiral HPLC; [e] for major diastereomer.
1
2
3
4
5
6
7
8
Cu(OTf)2
InI3
ZnEt2
A
B
C
DCM
DCM
Et2O
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
84
96
98
98
93
96
99
94
99
99
87
94
52
98
99
99
16:1
17:1
15:1
---- D -----
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
9.5:1
>20:1
>20:1
>20:1
Mg(OtBu)2
E
Further scope of the reaction to form substituted 3,3´-
piperidinoyl-spirooxindoles was investigated using substituted
isatine-derived E-olefins 3 as well as differently substituted 2-ASBs
2 (Table 2). The absolute configuration of adducts 4a-p was
established on the basis of x-ray diffraction analysis of 4k (see
Supporting information).
----- F -----
Mg(ClO4)2
G
G
G
G
G
G
G
G
G
G
Ni(OTf)2
Cu(OTf)2
Zn(OTf)2
Yb(OTf)3
Dy(OTf)3
Dy(OTf)3
LaOTf)3
9
10
11
12
13
14
15
16
2-ASB 2a reacted smoothly with a number of alkylidene
oxindoles decorated with electron withdrawing groups and afforded
spirooxindole 4b-g in high yields and with excellent ee´s (Table 2,
entries 2-7). A drastic reduction in enantio- and diastereoselectivity
was observed in 4h and could be attributed to the competitive
coordination of 5-NO2 group with catalyst (Table 2, entry 8).
Electron-rich alkylidene oxindoles were also well tolerated under
optimized reaction conditions providing methyl, methoxy,
trifluoromethoxy as well as 5,7-di-methyl substitution on to the core
scaffold and without compromising efficiency or enantioselectivity
(4i-l, Table 2, entries 9-12). We also tested some variations on the
azadiene itself. Interestingly, different alkyl groups on the diene
including bulky tert-butyl group were well tolerated affording
spirooxindoles 4m-n in excellent yields and with excellent enantio-
and diastereoselectivities (Table 2, entries 13-14). However, when
1-aryl-4-alkyl azadienes were used, moderate to low
enantioselectivity was observed, although the cycloadducts 4o-p
were obtained in very high yields (Table 2, entries 15-16). Overall,
dysprosium triflate in combination with N,N-oxide ligand G
catalyzed a highly regio- and enantioselective HDA reaction
between 2-ASB´s 2 and isatin-derived olefins 3 to provide 3,3´-
piperdinoyl- spirooxindoles as exo-adducts in excellent yields. No
trace of endo-adduct was observed.[11]
Nd(OTf)3
Eu(OTf)3
[a] At the scale of 0.05 mmol of 3a and 0.075 mmol of 2a at 0.033 M conc.; [b]
based on 3a; [c] isolated yields; [d] determined by 1H NMR; [e] determined by
chiral HPLC for major diastereomer; [f] (+) and (-) refers to the clock- and
anticlockwise direction respectively of the measured specific optical rotation of
the adduct; [g]0.075 mmol of 1a was used instead of 2a.
When resorted to chiral lanthanide metal complexes as Lewis acid
catalysts for the HDA reaction, ytterbium triflate with G led to a
moderate enantioselectivity (Table 1, entry 11). To our delight,
dysprosium triflate in combination with ligand G steered the HDA
reaction efficiently and providing exo-cycloadduct 4a with excellent
enantiomeric excess of 98% (entry 12, Table 1). Under the same
reaction condition, TMS azadiene 1a failed to provide acceptable
yield and enantioselectivity, plausibly owing to its nucleophilic
character (entry 13, Table 1, see Supporting Scheme S1). Some
other lanthanides were also tested for the HDA reaction of 2a with
3a, however none of them appeared better than dysprosium (Table 1,
entries 14-16). Further reaction screening using 10 mol % of
Dy(OTf)3 and a series of chiral N,N-oxide ligands in different
solvents revealed that ligand G (11 mol %) in dichloromethane
offered the best reaction conditions for an asymmetric HDA reaction
Many natural products, for instance, Surugatoxin also embodies
3,4´-piperidinoyl-spirooxindole scaffold.[7b, 7c] We wondered if the
2
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10.1002/anie.201708355
Angewandte Chemie International Edition
HDA reaction can be tuned to selectively form this core framework.
As we did not find a trace of this regioisomer formed in above HDA
reaction, we hypothesized that modulating the direction of
electrophilicity in the olefin might result into selective formation of
3,4´-piperidinoyl-spirooxindole. To this end, dicyano alkylidene
oxindole 3a´ was explored with 2-ASB 2a under the above
optimized reaction conditions. To our surprise, this very fast
asymmetric HDA reaction delivered the desired adduct 5a as minor
product and 3,3´-piperidinoyl-spirooxindole 4a´ was obtained as the
major product. Unfortunately, all our attempts to resolve 4a´ using
different chiral stationary phases failed and the enantiomeric excess
could not be ascertained. Very intriguingly, the non-catalyzed
reaction of 3a´ and 2a yielded the desired racemic adduct 5a as the
sole product (Scheme 2 and Supporting Table S4). Resorting to
azadiene 2a´ lacking a substitution on the silyl enol, the reaction
afforded the desired spirooxindole 6a as the major product (dr >
20:1) along with minor regioisomer 6a´ (Scheme 2). However, no
enantioselectivity was observed in this reaction.
The scope of newly optimized reaction condition to form
substituted 3,4´-piperidinoyl-spirooxindoles was evaluated by
employing differently substituted dicyano-alkylidene oxindoles 3´ in
reaction with 2-ASB 2´ (Scheme 3). Electron-withdrawing as well
as donating substitutions on the oxindole aryl ring were nicely
tolerated to afford corresponding spirooxindoles 6a-h in excellent
yields and in most cases with excellent enantioselectivities (Scheme
3). In the reaction of 5,7-dimethyl alkylidene oxindole, a detrimental
reduction in enantioselectivity to form adduct 6i was observed,
probably owing to the steric reasons. Varying aryl substitutions on
the azadiene part successfully afforded the corresponding adducts 6j
and 6k with excellent and moderate enantioselectivity respectively
(Scheme 3). Absolute stereochemistry of the adducts was
established on the basis of x-ray crystal structure of a derivative of
adduct 6b (Scheme 3).
The optimized HDA reactions of 2-ASBs and alkylidene
oxindoles address one of the most daunting challenges in
asymmetric organic syntheses, i.e. formation of a number of
consecutive stereogenic centers.[12] In this regard, we targeted highly
complex piperidinoyl spirooxindoles bearing four consecutive
stereogenic centers including two vicinal all-carbon-quaternary
centers.[13] To this end, (E)- and (Z)-alkylidene oxindoles 7
supporting an ester and cyano function on olefin were employed in
the HDA reaction with 2-ASBs. To our delight, the reaction of E-7
olefin with mono-substituted 2-ASB 2a´ afforded the 3,3´-
piperidinoyl-spirooxindole 8a as the major product in excellent yield
and with excellent enantioselectivity (Scheme 4). Formation of 8a as
the major product further supports our earlier observation that steric
factors favored the formation of 3,3´-piperidinoyl-spirooxindole
scaffold over 3,4´-piperidinoyl spirooxindoles. The E-7 olefin could
also smoothly react with 1,4-disubstituted 2-ASB 2a-b, giving
spirooxindoles 8b-c supporting four consecutive chiral centers
including two consecutive all-carbon-quaternary centers, in good
yields and with excellent enantioselectivities (Scheme 4). Using Z-7
as dienophile with 2a afforded the expected adduct 8a´ as the major
adduct with moderate regioselectivity. However, the catalytic
system developed could maintain the excellent enantioselectivity in
this case too (Scheme 4).
Scheme 2. Reaction of dicyano alkylidene oxindole 3a´ with 2-ASB 2a.
Scheme 3. Scope of enantioselective HDA reaction of monosusbtituted 2-ASBs
to form 3,4´-piperidinoyl-spirooxindoles.
Scheme 4. Enantioselective HDA reaction of diverse oxindole dienophiles with
2-ASBs.
A further exploration of tri- and divalent metal complexes with
ligand G unravelled magnesium(II) bis(trifluoromethanesulfonyl)-
imide as the best Lewis acid to catalyze asymmetric HDA reaction
between oxindole 3a´and 2-ASB 2a to afford the desired adduct 6a
in excellent yield and enantiomeric excess (see Supporting Table
S5-6).
Further utility of asymmetric HDA reaction to deliver 3,3´-
piepridinoyl spirooxindole scaffold decorated with important
functional groups was demonstrated with the reactions of differently
substituted alkylidene oxindoles. Thus, a reaction of oxindole E-9
supporting an ester function on olefin with 2a afforded the 3,3´-
3
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10.1002/anie.201708355
Angewandte Chemie International Edition
spirooxindole 10 in excellent yield and with 81% ee (Scheme 4).
Importantly, the ester function offers a synthetic handle that can be
easily manipulated in compound collection synthesis.
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Having biaryl groups in syn-configuration at 2´- and 4´-position
on the 3,3´-piperidinoyl spirooxindole bequeaths anticancer activity
to the molecules (Scheme 1).[7e] No enantioselective synthesis to this
class of scaffold is yet known. Using magnesium salt with ligand G,
the reaction of oxindole E-11 bearing a phenyl substituted olefin and
2-ASB 2a, afforded diphenyl substituted 3,3´-piperidinoyl
spirooxindole 12 in very high yield and with excellent
enantioselectivity and thus demonstrated the broader synthetic
utility of the asymmetric HDA reaction (Scheme 4).
Mechanistically, ligand G acts as a tetradentate ligand to
trivalent Dy(III) and along with alkylidene oxindole forms a
distorted octahedral complex. N,N-oxides as well as the amide
carbonyls of G stabilize the highly congested exo-transition state
that strictly permits 2-ASB to approach only the si-face of cyano-
olefin and form the exo-adduct 4 exclusively (Scheme 5a). However,
the transition state of a relatively puckered divalent magnesium
complex with ligand G and dicyano-alkylidene oxindole 3´ gets the
si-face of olefin completely blocked and therefore azadiene
approaches it from the re-face.[14] In this situation, 2-ASBs lacking
4-alkyl group (R = H) successfully form the 3,4´-piepidinoyl
spirooxindole 6a. However, 1,4-disubstituted 2-ASBs (e.g. R = Me)
face steric hindrance from aryl groups of amide functions in ligand
G and thus prefer to form 3,3´-piperidinoyl-spirooxindole 4a´ and
exo-8 (in case of disubstituted olefin (E)-7) via a flipped azadiene
approach where we assume that the - interaction of aryl groups of
diene and dienophile stabilize the complex (Scheme 5b-c).
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Scheme 5. a) A transition state for exo-selective HDA reaction of mono-cyano
alkylidene oxindoles 3 with 2-ASBs; b) a transition state for enantioselective
HDA reaction of 2-ASBs (2´) with dicyano- (3´) and c) cyano, ester substituted
alkylidene oxindoles (7).
In summary, we have developed highly enantioselective and
easily tunable hetero-Diels-Alder reactions of 2-aza-silyloxy-1,3-
butadienes with alkylidene oxindoles. In this rarely explored class of
cycloaddition reactions, chiral N,N-dioxide ligand G in complex
with dysprosium or magnesium metal salts regaled a facile and
selective construction of 3,3´- and 3,4´-piperidinoyl-spirooxindoles
respectively that represent scaffolds of biologically intriguing
synthetic and natural small molecules. The disclosed asymmetric
cycloaddition reaction can create molecular scaffolds beholding a
number of consecutive chiral centers including all-carbon-
quaternary centers in a very efficient manner and therefore can offer
various applications in asymmetric organic synthesis of complex
small molecules.
[14] a) X. H. Liu, L. L. Lin, X. M. Feng, Org. Chem. Front. 2014, 1, 298-
302; b) K. Zheng, C. K. Yin, X. H. Liu, L. L. Lin, X. M. Feng, Angew.
Chem. Int. Ed. 2011, 50, 2573-2577; c) W. Li, X. H. Liu, X. Y. Hao,
Y. F. Cai, L. Lin, X. M. Feng, Angew. Chem. Int. Ed. 2012, 51, 8644-
8647.
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Published online on ((will be filled in by the editorial staff))
Keywords: hetero-Diels-Alder reaction • piperidones • azadienes •
spirooxindoles • asymmetric synthesis
4
This article is protected by copyright. All rights reserved.

10.1002/anie.201708355
Angewandte Chemie International Edition
Asymmetric HDA Reaction
Tune to Ring! Dy(III)- and Mg(II) salts
with N,N-dioxide ligand catalyse
S. Jayakumar, K. Louven, C. Strohmann,
K. Kumar* __________ Page – Page
enantioselective hetero-Diels-Alder
reaction of silyloxy-2-azadienes with
alkylidene oxindoles to selectively form
3,3´- and 3,4´-piperidinoyl- spiro-
oxindoles respectively in excellent yields
and with excellent enantiomeric ratios!
A Tunable and Enantioselective Hetero-
Diels-Alder Reaction Provides Access to
Distinct Piperidinoyl Spirooxindoles
5
This article is protected by copyright. All rights reserved.