Catalytic asymmetric tamura cycloadditions

Article abstract of DOI:10.1002/anie.201309297

In the presence of a novel, tert-butyl-substituted squaramide-based catalyst, enolizable anhydrides react with alkylidene oxindoles to generate spirooxindole products of significant synthetic interest with excellent enantio- and diastereocontrol. The methodology is of wide scope and encompasses both homophthalic and glutaconic anhydride derivatives, which lead to structurally diverse products. Glutaconic acid-derived anhydrides undergo a clean post-cyclization decarboxylation process which is not a feature of reactions involving homophthalic acid-derived anhydrides. The unusual influence of reaction temperature on diastereocontrol has been probed, with reactions occurring at 30 °C and -30 °C delivering products epimeric at one stereocenter only, in near optical purity. Squared away: The first strategy for bringing about enantioselective Tamura reactions is reported. In the presence of a squaramide-based catalyst, enolizable anhydrides react with alkylidene oxindoles to generate spirooxindole products with excellent enantio- and diastereocontrol. The methodology is of wide scope and leads to structurally diverse products.

Full text of DOI:10.1002/anie.201309297

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Angewandte
Communications
DOI: 10.1002/anie.201309297
Organocatalysis
Catalytic Asymmetric Tamura Cycloadditions**
Francesco Manoni and Stephen J. Connon*
Abstract: In the presence of a novel, tert-butyl-substituted
squaramide-based catalyst, enolizable anhydrides react with
alkylidene oxindoles to generate spirooxindole products of
significant synthetic interest with excellent enantio- and
diastereocontrol. The methodology is of wide scope and
encompasses both homophthalic and glutaconic anhydride
derivatives, which lead to structurally diverse products. Gluta-
conic acid-derived anhydrides undergo a clean post-cyclization
decarboxylation process which is not a feature of reactions
involving homophthalic acid-derived anhydrides. The unusual
influence of reaction temperature on diastereocontrol has been
probed, with reactions occurring at 308C and ꢀ308C deliver-
ing products epimeric at one stereocenter only, in near optical
purity.
reaction with homophthalic anhydride (1) without aromati-
zation to give racemic 7 (Figure 1C).
We have recently[10] shown that the bifunctional organo-
catalyst 9 can promote the formal cycloaddition of benzalde-
hyde (8) to 1 to afford the substituted dihydroisocoumarin
I
n 1981 Tamura et al. first reported the reaction of homo-
phthalic anhydride (1) with activated alkynes and alkenes at
high temperatures (Figure 1A).[1] These C C bond-forming
ꢀ
processes leading to 2 and 4 have been postulated to proceed
by an initial Diels–Alder reaction (via enol 2a) and sub-
sequent loss of CO2 from 2b, although an alternative pathway
involving initial Michael-type addition (via enol 2c) and
subsequent ring closure has not been ruled out.[1–3] In the case
of alkene substrates, aromatization most likely results by
hydride transfer to excess 3.[2,4] Later it was found that clean
deprotonation of the anhydride with stoichiometric strong
base allowed the reaction to occur under milder reaction
conditions.[5,6] It is noteworthy that these reactions required
dienophiles equipped with activating groups at both termini,[7]
and a predilection for enol(ate) attack at the most electro-
philic dienophile carbon atom was observed.
These reactions have been exploited in the syntheses of
medicinally relevant polycyclic aromatic natural products,[8]
of which dynemycin A[9] (5, Figure 1B) is a particularly
elegant example.
The propensity of the Tamura cycloaddition for stereo-
center-ablating aromatization, and the absence of promoters
for this reaction have thus far precluded any utility in catalytic
asymmetric synthesis. While simple Michael acceptors such as
methyl acrylate and acrylonitrile are unreactive substrates, we
were intrigued by a report that the enedione 6 underwent
Figure 1. The Tamura cycloaddition reaction. Bz=benzoyl, DMAD=
dimethyl acetylenedicarboxylate, MTBE=methyl tert-butyl ether,
THF=tetrahydrofuran, TMS=trimethylsilyl, Boc=tert-butoxycarbonyl.
lactone 10 with excellent yield, and enantio- and diastereo-
control (Figure 1D).[11] We had posited that 9 both catalyzes
the tautomeric equilibrium between 1 and 2c and organizes
the encounter between 2c and the squaramide-bound 8 by
general acid-base catalysis. This offers the possibility of an
extension to conjugated electrophiles, and the first enantio-
selective Tamura cycloaddition reactions. While this manu-
script was being prepared, Ye et al.[12] reported the mecha-
nistically distinct TMS-quinidine-catalyzed enantioselective
cycloaddition of 11 with b-aryl[13] crotyl chlorides (12) at
[*] F. Manoni, Prof. S. J. Connon
Trinity Biomedical Sciences Institute, School of Chemistry
The University of Dublin
Trinity College, Dublin 2 (Ireland)
E-mail: connons@tcd.ie
[**] Financial support from the European Research Council and Science
Foundation Ireland is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309297.
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Table 1: Catalyst evaluation and optimization.
Table 2: Substrate scope: Enolizable anhydrides.
Entry
1
Anhydride
Product
t
[h]
Yield
[%][a]
ee
[%][b]
19
20
21
92
95
96
95
92
2
3
Entry
Cat.
T
[8C]
t
[h]
Conv. [%][a]
d.r. [%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
9
30
30
30
30
30
30
30
0
19
16
19
13
16
19
19
17
>98
97
97
96:3:1
97.5:2:0.5
98.5:1:0.5
98:1:1
98.5:1:0.5
96:3:1
93
83
88
88
90
88
95
85
19
20
21
22
23
24
24
>99
97
>98
>98
>98
95
94.5:4:1.5
40:59:1
4
5
6
7
22
19
21
26
95
94
95
82
95
99
[a] Determined by 1H NMR spectroscopy. [b] Determined by CSP-HPLC.
Boc=tert-butoxycarbonyl.
ꢀ788C in the presence of excess NEt3 (2.0 equiv, Figure 1D)
to generate the spirooxindoles 13.
Herein we report catalytic asymmetric Tamura cyclo-
addition reactions between alkylidene oxindoles 14 and
a variety of stable, enolizable anhydrides 15 to afford one-
step, base-free access to more densely functionalized 3,3-
spirooxindoles (16, found in a wide range of bioactive natural
products and molecules of medicinal interest),[14] with the
formation of two new C C bonds and three new contiguous
stereocenters, all of which are completely carbogenic and one
of which is quaternary (Figure 1E).
In preliminary experiments, the N-Boc oxindole 17 was
reacted with the stable and the readily handled homophthalic
anhydride (1) in the presence of squaramide 9 (the previously
identified optimum catalyst for the cycloaddition of aldehydes
with 1[10]) in MTBE at 308C (entry 1, Table 1).[15a] Under these
reaction conditions, the Tamura cycloaddition proceeded to
full conversion, thus producing the tetracyclic spiroadduct 18
with excellent diastereo- and enantiocontrol. The use of the
corresponding squaramide 19, which is devoid of the C2’
phenyl moiety, led to improved diastereoselectivity, however
product ee value decreased significantly (entry 2). The thio-
urea-based alkaloid 20[15b–f] proved superior from a diastereo-
control standpoint (entry 3), however enantiocontrol was less
efficient than in the reaction catalyzed by 9. Since neither the
corresponding urea 21 nor its C2’-arylated analogue (22,
entries 4 and 5) were capable of a more enantioselective
catalysis than 9, we returned to catalysts containing the
squaramide unit.
>98
>99
ꢀ
[a] Yield of product isolated after chromatography. [b] Determined by
CSP-HPLC.
rial 23 was inferior to 9 (entry 6, Table 1), the analogue
lacking this substituent 24 could catalyze the formation of 18
with excellent diastereocontrol and in 95% ee (entry 7).
Intriguingly, a repeat of this reaction at reduced temperature
led to a drastic reduction in diastereocontrol and significantly
diminished enantioselectivity (entry 8).
With a satisfactory catalyst and protocol identified,
attention next turned to the question of substrate scope.
The Michael acceptor 17 was reacted with a range of
enolizable anhydrides 1 and 25–30 in the presence of 24 at
308C (Table 2). The tetracyclic diastereomer 18 could be
isolated in greater than 90% yield and 95% ee under these
conditions (entry 1). The brominated analogue 31 was formed
with comparable efficacy and stereocontrol (entry 2). The
cycloaddition of the fused heterocyclic anhydrides 26 and 27
with 17 afforded the corresponding thiophene- 32 and
pyrrole-substituted 33 tetracyclic ketones with excellent
The novel tert-butyl squaramide catalysts 23 and 24
exhibited interesting behavior: while the C2’-arylated mate-
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Table 3: Organocatalytic cycloadditions involving 39.
enantioselectivity (entries 3 and 4). Gratifyingly, the scope of
the methodology is not confined to homophthalic anhydride
derivatives: the phenyl glutaconic anhydride (28), and its
methyl variant 29, underwent smooth cycloaddition to afford
the highly substituted cyclohexenones 34 and 35, respectively
in excellent yields and with near optical purity (entries 5 and
6). These reactions represent the first examples of the
expansion of enantioselective cycloadditions involving eno-
lizable anhydrides beyond either homophthalic-[10] or a-aryl
succinic[11] analogues. To demonstrate the potential of this
protocol for the rapid, efficient, and enantioselective syn-
thesis of complex products, the tricyclic anhydride 30 was
reacted with 17 under the influence of 24 to generate 36 in
high yield and 99% ee (entry 7).
Entry
1
Anhydride
Product
Yield
[%][a]
ee
[%][b]
96
98
65
89
89
It is noteworthy that 34–36 were isolated as cyclohex-
enones, which are devoid of methyl ester moieties (see the
crystal structures of 31 and 34; Scheme 1A,B). This trans-
formation, which deletes a stereocenter but renders the
product a Michael acceptor primed for further structural
elaboration, is most likely the result of a vinylogous ketode-
carboxylation and subsequent in situ alkene isomerization,
which is reminiscent of the known decarboxylation of
Hagemannꢀs ester (itself the parent structure of a family of
highly useful synthetic building blocks for natural product
synthesis,[16] that is, 37!38, Scheme 1C) upon hydrolysis. We
would suggest that this does not occur in the case of
homophthalic anhydride substrates as it would require
disturbance of the aromatic system (Scheme 1D).
2
3
>99
[a] Yield of product isolated after chromatography. [b] Determined by
CSP-HPLC.
strate 17. In both cases 1H NMR spectroscopic analysis of the
crude reaction mixture indicated that the products formed
with outstanding diastereocontrol. Conversely, the reaction of
39 with the glutaconic anhydride 29 led to the isolation of 42
in reduced yield but with outstanding enantioselectivity
(> 99%, entry 3).
Finally, we investigated the curious effect of the reaction
temperature on both the enantio- and diastereocontrol
observed in our preliminary experiments (i.e. entries 7 and
8, Table 1). Upon lowering the reaction temperature (Table 4)
from 30 to 208C a significant increase in the levels of the
kinetic product diastereomer 43 (epimeric at the stereocenter
incorporating the ethyl ester) was detected [along with trace
levels of another diastereomer 44 of indeterminate config-
uration], with a concurrent decrease in the ee value of 18
Table 4: The effect of temperature on enantio- and diastereocontrol.
Scheme 1. The crystal structures of 31 (A) and 34 (B), Hagemann’s
ester (C), and a rationale for the resistance of a homophthalic-
anhydride-derived substrate to decarboxylation (D). Gray C, white H,
red O, blue N, yellow Br.
Given that previous reports involving the uncatalyzed
(racemic) Tamura reaction involve alkenes incorporating
activating groups at both termini exclusively, we were
interested in evaluating the performance of the less electro-
philic benzylidene derivative 39 as a substrate (Table 3). This
was found to participate in cycloadditions with the homo-
phthalic anhydrides 1 and 25 to furnish 40 and 41, respectively
in excellent yield (entries 1 and 2). Enantiocontrol, though
high (89% ee), was marginally diminished relative to the
corresponding reactions involving the ester-substituted sub-
Entry
T
[8C]
t
[h]
Conv.
[%][a]
d.r.
18
43
(18/43/44)[b]
ee [%][b]
ee [%][b]
1[c]
2
30
20
0
19
19
17
44
18d
15d
>98
96
95
>98
85
91
94.5:4:1.5
90:9.5:0.5
40:59:1
34:65:1
16:82:2
95
93
85
95
43
94
n.d.
n.d.
n.d.
96
>99
99
3[c]
4
ꢀ15
ꢀ50
ꢀ50
5
6[d]
17:82:1
[a] Determined by 1H NMR spectroscopy. [b] Determined by CSP-HPLC.
[c] Data reproduced from Table 1. [d] Using 20 mol% catalyst loading.
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(entries 1 and 2). As the temperature was reduced further,
this trend continued. As seen previously, at 08C, 43 is formed
as the major diastereomer (entry 3), while reactions con-
ducted at progressively lower temperatures favored the
formation of 43 in greater amounts and with higher enantio-
control (at the expense of the ee value of 18 and the reaction
time; entries 4 and 5). Using a 20 mol% catalyst loading at
ꢀ508C, the cycloaddition proceeded to form 43 as the
dominant diastereomer in greater than 99% ee at 91%
conversion (entry 6). Thus selective access to either 18 or 43 is
possible simply by changing the reaction temperature. By way
of demonstration, the diastereomer 43 can be isolated in 74%
yield and 98% ee from the reaction of 1 with 17 catalyzed by
24 at ꢀ308C (Scheme 2). This form of highly enantioselective
kinetic control significantly augments the potential utility of
the methodology in target-oriented synthesis. We observed
a similar phenomenon using oxindole 39, however, in this case
the effect was less pronounced.
squaramide-based catalyst 24 promotes the highly enantiose-
lective formal cycloaddition of enolizable anhydrides to
alkylidene oxindoles to form densely functionalized 3,3-
spirooxindole products in excellent yield and stereocontrol.
Substitution of the ester functionality on the Michael acceptor
for a phenyl ring is well tolerated by the catalyst, and a highly
unusual dependence on temperature in relation to diastereo-
control was observed: at higher temperatures the diastereo-
mer 18 could be generated from 1 and 17 with excellent
control over the stereochemistry, while at lower temperatures
the epimeric diastereomer 43 could be isolated in high yield
and in near optical purity. This phenomenon potentially offers
the practitioner more precise control over the stereochemical
outcome of these reactions than is usually observed in
organocatalytic reactions involving alkylidene oxindoles.
Received: October 24, 2013
Published online: February 7, 2014
Keywords: asymmetric catalysis · cycloaddition ·
.
organocatalysis · spirocompounds · synthetic methods
[1] Y. Tamura, A. Wada, M. Sasho, Y. Kita, Tetrahedron Lett. 1981,
22, 4283.
[2] Y. Tamura, A. Wada, M. Sasho, Y. Kita, Chem. Pharm. Bull.
1983, 31, 2691.
Scheme 2. Enantioselective synthesis of the syn diastereomer of 43 at
low temperature.
[3] For
a review of formal cycloaddition reactions involving
enolizable anhydrides, see: M. Gonzꢁlez-Lꢂpez, J. T. Shaw,
Chem. Rev. 2009, 109, 164.
[4] Y. Tamura, A. Wada, M. Sasho, K. Fukunaga, H. Maeda, Y. Kita,
J. Org. Chem. 1982, 47, 4376.
The stereochemical relationship between 18 and 43 (i.e.
epimeric at the ethyl-ester-containing stereocenter only)
deserves comment. It is difficult to rationalize this outcome
in terms of catalyst–substrate face-selective binding interac-
tions alone, and we were unable to bring about the efficient
epimerization of 43 to 18 with amine bases such as diisopro-
pylethylamine. We therefore suggest that 17 may undergo
reversible E to Z isomerization under the reaction conditions.
[5] a) Y. Tamura, M. Sasho, K. Nakagawa, T. Tsugoshi, Y. Kita, J.
Org. Chem. 1984, 49, 473; b) Y. Kita, S.-I. Mohri, T. Tsugoshi, H.
Maeda, Y. Tamura, Chem. Pharm. Bull. 1985, 33, 4723; c) For an
example of the reaction of homophthalic anhydrides with an
alkyne in the presence of catalytic NEt3, see: F. T. Smith, R. V.
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[6] This methodology has also been used to bring about intra-
molecular Tamura cycloadditions: a) Y. Kita, R. Okunaka, M.
Sasho, M. Taniguchi, T. Honda, Y. Tamura, Tetrahedron Lett.
1988, 29, 5943; b) Y. Kita, R. Okunaka, T. Honda, M. Shindo, M.
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[7] a,b-Unsaturated imines are an exception. A second activating
group is not required, see: a) A. Georgieva, E. Stanoeva, S.
Spassov, M. Haimova, N. De Kimpe, M. Boeleus, M. Keppens,
A. Kemme, A. Mishnev, Tetrahedron 1995, 51, 6099; b) A.
Georgieva, S. Spassov, E. Stanoeva, I. Topalova, C. Tchanev, J.
Chem. Res. Synop. 1997, 148.
1
While we could not observe this isomerization by H NMR
spectroscopic analysis, we did find that during the synthesis of
substrate 39, that DMAP-mediated Boc protection of either
pure (E)- or (Z)-45 provided (E)-39 exclusively at ambient
temperature (Scheme 3). Thus, while a definitive conclusion
on this point awaits a full mechanistic study, the involvement
of nucleophile-catalyzed isomerization of the alkylidene
oxindole starting materials is certainly not impossible.[17,18]
In summary, 32 years after the first report concerning the
Tamura cycloaddition reaction, the first catalytic asymmetric
variants have been developed. The novel, ad-hoc designed
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Kishimoto, J. Sekihachi, Y. Kita, Chem. Pharm. Bull. 1987, 35,
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Scheme 3. Amine-mediated isomerization of an alkylidene oxindole.
DMAP=4-(N,N-dimethylamino)pyridine.
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[13] The aromatic ring is absolutely necessary in this process.
Replacement with an isopropyl moiety led to reduced product
ee value of 65%.
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[17] It is acknowledged that the alkaloid quinuclidine moiety is less
nucleophilic, however this does not preclude isomerization.
[18] When the alkylidene moiety is substituted at the b-position with
ꢀ
a group incorporating C H bonds (e.g. CH3) isomerization has
been recently reported to proceed by deprotonation, however
this is a different situation not involving interconversion of E/Z
isomers: C. Curti, G. Rassu, V. Zambrano, L. Pinna, G. Pelosi, A.
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