An organocatalytic [3+2] cyclisation strategy for the highly enantioselective synthesis of spirooxindoles

Article abstract of DOI:10.1002/chem.201001791

Power of P: Phosphine-promoted [3+2] annulation reactions between electron-poor allenes and 3-arylidene indolin-2-ones afford a new organocatalytic strategy for the synthesis of the spirocyclic core of oxindolic cyclopentanes (see scheme). Asymmetric vari

Full text of DOI:10.1002/chem.201001791

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DOI: 10.1002/chem.201001791
An Organocatalytic [3+2] Cyclisation Strategy for the Highly
Enantioselective Synthesis of Spirooxindoles
Arnaud Voituriez, Nathalie Pinto, Mathilde Neel, Pascal Retailleau, and
Angela Marinetti*[a]
Spirooxindole cores are featured in a number of natural
and unnatural biologically active compounds, as well as in
drug candidates. Among them, pyrrolidin-3,3’-oxindole units
are the most widespread,[1] however, spirocyclic oxindoles
with carbocyclic five- or six-membered rings are not uncom-
mon either. Specifically, 3-spirocyclopentane-2-oxindole
scaffolds are embodied in natural alkaloid derivatives such
as marcfortines,[2] citrinadins[3] cyclopiamines,[4] notoamides
and versicolamides.[5] They also find applications in the area
of medicinal chemistry.[6]
rolidin-3,3’-oxindole units.[7] However, efficient methodolo-
gies for the enantioselective synthesis of oxindoles with car-
bocyclic spiranic rings have been barely disclosed. Catalytic
enantioselective approaches include three palladium-pro-
moted processes, namely, the intramolecular Heck reaction,
introduced by Overman et al.,[8] the [3+2] cycloaddition of
trimethylenemethane on 3-alkylideneindolin-2-ones report-
ed by Trost et al.,[9] as well as the cyclisation of 3-(4-pentyn-
yl)-2-silyloxy indoles recently reported by Toste and
Corkey.[10] Alternatively, aminocatalysis has been envisioned
by Melchiorre, Gong and Chen who carried out cascade cyc-
lisation reactions between 3-alkylideneindolin-2-ones and
either suitable enones[11] or aldehydes[12]
.
Herein, we report on the first enantioselective approach
for the construction of spirocyclic oxindolic cyclopentanes
based on a phosphine-mediated organocatalytic process.
The [3 +2] annulations between activated allenes and
electron-poor olefins are among the seminal reactions in the
field of phosphine organocatalysis.[13] When applied to 3-al-
kylideneindolin-2-ones, they would afford a straightforward
approach to spirocyclic oxindolic cyclopentanes, through the
formal reaction pathway shown in Scheme 1.[14] This strategy
In this context, the development of efficient synthetic
methods for the construction of spirocyclic oxindole scaf-
folds is of considerable importance. The challenging point is
that biologically relevant spirooxindoles often display a ste-
reogenic all-carbon quaternary centre at the C3-position,
the stereochemistry of which must be controlled through ap-
propriate synthetic strategies. This point has been quite
commonly addressed for spirocyclic cores composed of pyr-
Scheme 1. Targeted approach to enantiomerically enriched oxindolic cy-
clopentanes. EWG=electron-withdrawing group.
[a] Dr. A. Voituriez, N. Pinto, M. Neel, P. Retailleau, Dr. A. Marinetti
CNRS, UPR 2301, Institut de Chimie des Substances Naturelles
Centre de Recherche de Gif, 1, av. de la Terrasse, 91198 Gif-sur-
Yvette (France)
might also allow the stereocontrolled construction of the
two contiguous stereocentres, since enantioselective variants
of the [3+2] annulations are known to take place when
using suitable chiral phosphorus catalysts.[15,16]
Fax : (+33)169077247
E-mail: angela.marinetti@icsn.cnrs-gif.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001791.
Chem. Eur. J. 2010, 16, 12541 – 12544
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12541

In our work, this synthetic approach has been established
at first through [3+2] cyclisation experiments[17] between
ethyl 2,3-butadienoate (3) and (E)-3-benzylideneindolin-2-
ones 4a (R1 =CO2Et) or 4b (R1 =Ac) in the presence of
PPh3 (entries 1 and 2 in Table 1). The expected reaction
took place in mild conditions and afforded the desired spi-
rooxindoles as 9:1 mixtures of the two regioisomers 5 and 6,
with the so-called “g-adduct” 5 being the major isomer.
(PMB; 4d) and Me (4e) groups as the N substituents have
been subjected to the same cyclisation reactions (Table 1,
entries 5–7). Screening revealed that all of these are suitable
substrates, giving the expected products with good regiose-
lectivity and moderate to high levels of enantioselectivity.
Although 1 afforded a satisfying enantiomeric excess in
these initial cyclisation experiments (eemax =96%; Table 1,
entry 4), a systematic screening of chiral phosphines was un-
dertaken. Compound 4b was used as the model substrate
(entries 8–12 in Table 1). These additional tests demonstrat-
ed that (R,R)-Me-DuPHOS, (R,R)-Et-FerroTANE and (R)-
BINAP give only moderate ee values (39–55% ee; entries 8–
10 in Table 1). On the other hand, (S)-PHANEPHOS gave
a significant 85% ee (Table 1, entry 11), the reaction dis-
plays, however, an unsatisfying regioselectivity, with a 62:38
ratio of the regioisomeric products 5b and 6b. Finally, (S)-
tBu-Binepine (2) was highlighted as an excellent organoca-
talyst for these annulations, giving quantitative yield and
almost perfect enantioselectivity (Table 1, entry 12)[18]
Subsequently, the scope of the [3+2] cyclisation method-
ology was investigated with (S)-2 as the catalyst, as summar-
ised in Table 2 and Scheme 2. The reactions gave the desired
spirocyclic indanones 5 with very high enantiomeric excesses
from substrates with naphthyl groups (entries 2 and 3 in
Table 2), substituted aryl groups (Table 2, entries 4–9) and
heterocyclic moieties (Table 2, entries 10 and 11) on the exo-
cyclic double bond.
Table 1. Phosphine-promoted [3+2] annulation reactions of ethyl 2,3-bu-
tadienoate with (E)-3-benzylideneindolin-2-ones (4).
[a]
Entry R1 PR3
Yield [%]
5/6
5 ee [%][b]
1
2
3
4
5
6
7
8
4a PPh3
4b PPh3
81
89
71
98
63
82
99
90[d]
85:15
90:10
85:15
>95:5
95:5
>95:5
>95:5[c]
79:21
53:47
88:12
62:38
>95:5
–
–
80
96
73
88
90
55
51
4a
4b
4c
4d
4e
4b
4b
1
1
1
1
1
A
9
(R,R)-Et-FerroTANE 18[d]
10
11
12
4b (R)-BINAP
4b (S)-PHANEPHOS
28[d]
51[d]
95
39
85
>99
Table 2. Phosphine-promoted [3+2] annulations on 3-alkylidene-oxin-
4b
2
doles: variations of the olefin substituents R2.[a]
[a] (R,R)-Me-DuPHOS=(À)-1„2-bis
benzene, (R,R)-Et-FerroTANE=(+)-1,1’-bis
phenato)ferrocene, (R)-BINAP=(R)-(+)-2,2’-bis(diphenylphosphino)-
ACHTUNGTRENNUNG
Entry Substrate
R2
PR3 Yield
[%]
5/6
5
AHCTUNGTRENNUNG
ee [%]
1,1’-binaphthalene, (S)-PHANEPHOS=(S)-(+)-4,12-bis(diphenlyphos-
phino)-[2,2]-paracycloheptane. [b] Enantiomeric excess (ee) values were
determined by chiral HPLC. [c] The X-ray crystal structure of 5e is given
in the Supporting Information (CCDC-777517). [d] Conversion rates
1
2
3
4
5
6
7
8
Ph (4b)
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
95
98
92
20
62
63
80
82
99
25
75
38
61
80
56
>95:5
>95:5
>95:5
90:10
85:15
90:10 >99
92:8
85:15 >99
88:12 >99
76:24
90:10
74:26
92:8
77:23
80:20
>99
>99[b]
99
99
99
1-naphthyl (4 f)
2-naphthyl (4g)
4-Ph-C6H4 (4h)
4-CF3-C6H4 (4i)
1
were determined by H NMR spectroscopy.
4-Br-C6H
(4j)
4-Cl-C6H4 (4k)
3-Br-C6H4 (4l)
4-Me-C6H4 (4m)
2-furyl (4n)
>99
9
10
11
12
13
14
15
97
97
97
92
90
86
2-quinolyl (4o)
À ꢀ
C CC5H11 (4p)
4-Ph-C6H4 (4h)
2-furyl (4n)
À ꢀ
C CC5H11 (4p)
Based on these preliminary results, we next considered
the use of chiral phosphorus catalysts and especially that of
(S,S)-FerroPHANE (1), a new chiral phosphine from our
group, the efficiency of which as an organocatalyst in [3+2]
annulation reactions has already been demonstrated.[15f–h]
The annulation reactions were performed in toluene at
room temperature with a catalyst loading of 10 mol%
(Table 1, entries 3 and 4). Gratifyingly, the expected prod-
ucts were obtained in good yields, high regioselectivity and
high stereochemical control, with ee values of 80 and 96%
for 5a and 5b, respectively.
[a] All reactions were performed under argon on a 0.15 mmol scale at a
concentration of 0.3m in toluene (0.5 mL); 3/4 ratio=2:1. The 5/6 isomer-
ic ratios were evaluated by NMR spectroscopy on the crude mixture; ee
values were determined by chiral HPLC. Racemic samples of 4b–p have
been obtained by using PPh3 as the catalyst. [b] According to X-ray data,
compound 5 f has 1S,5R configuration.
Yields were usually good with the exception of reactions
involving the biphenyl-, 2-furyl- and 1-heptynyl-substituted
substrates 4h, 4n and 4p. In such cases, the use of Ferro-
PHANE 1 as the catalyst under the same reaction condi-
tions allowed higher yields to be attained (61, 80 and 56%,
Then, in additional experiments, 3-benzylideneindolin-2-
ones with tert-butyloxycarbonyl (Boc; 4c), p-methoxybenzyl
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Chem. Eur. J. 2010, 16, 12541 – 12544

Enantioselective Synthesis of Spirooxindoles
COMMUNICATION
respectively), while retaining good levels of enantioselectivi-
ty (86–92% ee; Table 2, entries 13–15).
The reaction in entry 2 (Table 2) afforded 5 f as a crystal-
line compound, which was recrystallised twice from CH2Cl2/
heptane to obtain crystals of enantiopure 5 f suitable for X-
ray diffraction studies.[19] X-ray data confirmed the structural
assignment and demonstrated that the stereochemistry of
the annulation product reflects the E geometry of the
double bond of the starting indolinone. The absolute config-
uration of 5 f was also assigned as 1S,5R (Figure 1, see also
the Supporting Information).[20]
Scheme 3. Synthesis of the enantiomerically enriched tricyclic spirooxin-
dole 8 under catalysis by 2.
Finally, application of this methodology to the stereoselec-
tive synthesis of spirooxindoles with a phosphonate function
has been envisioned, due to the extraordinary richness of or-
ganophosphorus compounds as reagents, ligands and biolog-
ically active derivatives.[22] Thus, the organocatalytic [3+2]
cyclisation between allenylphosphonate 9 and 4 f has been
investigated by using both
1 and 2 as the catalysts
(Scheme 4). Catalyst 2 afforded a low conversion rate,
mainly because of the relative inertness of allene 9 com-
pared with allenoate 3.[15h,23] Catalyst 1 led, however, to the
desired spiranic phosphonate 10 in good yield through a
highly regio- and stereoselective cyclisation reaction. Com-
pound 10 was obtained as the major regioisomer (85:15
ratio) in 92% ee despite the harsh reaction conditions re-
quired for this reaction to take place.
Figure 1. X-ray crystal structure of the spirocyclic oxindole (1S,5R)-5 f.
The (S)-2 promoted cyclisation reactions could be extend-
ed then to benzylidene indolinones with substituents on the
5’- and 6’-positions of the fused benzo rings.[21] The corre-
sponding spirocyclic oxindoles 5q–t were obtained in good
yields (69–77%) and regioselectivity (>9:1 regioisomers
ratios), with almost total enantioselectivity (Scheme 2).
Scheme 4. Stereoselective synthesis of the a-phosphorylated spirooxin-
dole 10 under catalysis by 1.
In summary, the challenging goal of building the spirocy-
clic core of oxindolic cyclopentanes has been achieved
through a new, highly stereoselective approach based on
phosphine organocatalysis. The [3+2] cyclisation strategy
allows the easy conversion of simple starting materials into
the desired functionalised spirocyclic compounds, with
almost perfect stereochemical control of two contiguous ste-
reogenic centres, including the quaternary stereogenic
centre joining the two rings. It constitutes an appropriate, ef-
ficient and synthetically useful method to access a valuable
class of spirocyclic compounds.
Scheme 2. Spirocyclic indolinones from (S)-2-promoted annulation reac-
tions on oxindoles with substituted aryl units.
Acknowledgements
Furthermore, the reaction has been applied to the tricyclic
indolinone 7[21] to produce the unusual spirocyclic alkaloid
scaffold 8 in acceptable isolated yield (59%) and 94% ee,
after 3 days at room temperature (Scheme 3). The spirocy-
clic moiety of 8 constitutes the core unit of known natural
products such as Cyclopiamine B.[4]
We are grateful to ICSN and to the Agence Nationale de la Recherche
(ANR) for financial support. This work has been done within the PhoSci-
Net COST action.
Chem. Eur. J. 2010, 16, 12541 – 12544
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12543

A. Marinetti et al.
[14] Other, non-enantioselective approaches to spirooxindoles based on
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Pyne, A. T. Ung, B. W. Skelton, A. H. White, P. Turner, Tetrahedron
2005, 61, 8120–8129; b) K. Selvakumar, V. Vaithiyanathan, P. Shan-
mugam, Chem. Commun. 2010, 46, 2826–2828.
Keywords: cyclization
phosphanes · spiro compounds
·
organocatalysis
·
oxindoles
·
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Received: June 24, 2010
Published online: September 17, 2010
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