Bifunctional organocatalytic strategy for inverse-electron-demand diels-alder reactions: Highly efficient in-situ substrate generation and activation to construct azaspirocyclic skeletons

Article abstract of DOI:10.1002/anie.201107716

Skeletons in the flask: The first highly enantioselective organocatalytic version of the title reaction using an in-situ substrate generation/activation catalytic mode is described (see scheme). The reaction provides an efficient enantioselective construction of functionalized azaspirocyclic skeletons. The in-situ generation of the enolate provides a new way in which to use this important nucleophile in organic synthesis. Copyright

Full text of DOI:10.1002/anie.201107716

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DOI: 10.1002/anie.201107716
Asymmetric Synthesis
Bifunctional Organocatalytic Strategy for Inverse-Electron-Demand
Diels–Alder Reactions: Highly Efficient In Situ Substrate Generation
and Activation to Construct Azaspirocyclic Skeletons**
Xianxing Jiang, Xiaomei Shi, Shoulei Wang, Tao Sun, Yiming Cao, and Rui Wang*
The catalytic asymmetric Diels–Alder reaction (DAR)[1] is
among the most powerful protocols for the stereoselective
construction of six-membered functionalized cyclic frame-
works. Its versatility in the synthesis of diverse natural
products provides organic chemists with a prodigious starting
point to discover new reaction modes for this cycloaddition.
In the wake of the emergence of the first metal complexes for
the Lewis acid catalyzed asymmetric inverse-electron-
demand Diels–Alder reactions (IEDDAR) through the
LUMO-lowering strategy reported by the group of Kobaya-
shi,[2] several remarkable studies have been presented involv-
ing the activation of dienes through lowering of the LUMO
energy by Lewis acidic metal complexes[3] or organic mole-
cules[4] [Eq. (1), Scheme 1]. Recently, amine organocatalysis
has been attracting considerable interest since the develop-
Scheme 1. Different activation strategies for the IEDDAR. LA=Lewis
ment of the highly enantioselective organocatalytic DAR by
MacMillan and co-workers.[5] Alternatively, Jørgensen and
co-workers[6] reported the first organocatalytic asymmetric
IEDDAR with dienophiles whose HOMO energy has been
raised by an enamine activation [Eq. (2)], and considerable
advances in this field have recently been achieved by the
Chen group.[7] Bifunctional organocatalysis has emerged as
a potentially powerful tool in catalytic asymmetric synthesis.[8]
This concept aims to efficiently achieve asymmetric trans-
formations that cannot be approached by using either a Lewis
acid or base catalyst alone. To the best of our knowledge,
there is no report to date of an asymmetric IEDDAR that is
controlled with a single reactive catalyst through a bifunc-
tional activation strategy; that is simultaneous activation of
the HOMO of the dienophile and the LUMO of the diene
[Eq. (3)]. There is a report on the use of a combination of an
enamine with metal Lewis acid activation that proved to have
potential for this transformation.[9] Herein, we introduce
a bifunctional catalyst for an in situ substrate generation/
activation strategy as a new platform for the design of
acid, LB=Lewis base.
organocatalytic intermolecular cycoaddition processes. In this
context, we document the first highly enantioselective bifunc-
tional catalytic IEDDAR that involves dual control of the
HOMOdienophiles and LUMOdienes energies of the substrates.
The spirocyclic core is a privileged structural element that
is featured in a large number of naturally occurring bioactive
alkaloids. Although the significant bioactivity and prepara-
tion methods of such motifs attract the interest of chemists, as
reported in some elegant works including intramolecular
alkylation, metal-based cyclization, intermolecular cycload-
dition, rearrangements, and other reactions,[10] the enantiose-
lective catalytic approach to access chiral spiro architectures
containing all-carbon quaternary stereocenters still remains
challenging. As an important skeleton in the larger spirocycle
family, the spirolactam scaffold not only often shows inter-
esting biological activities, but it can also act as an inter-
mediate in the synthesis of more sophisticated spirocyclic
frameworks (Figure 1).[11] However, it is worth noting that the
enantioselective catalytic synthesis of this kind of skeleton has
not yet been established. Given the demand for new catalytic
asymmetric methodology for the construction of spirocyclic
scaffolds, we present a highly efficient in situ generation/
activation catalytic system that allows rapid construction of
highly functionalized chiral spirocyclic skeletons with all-
carbon quaternary stereocenters using the above-mentioned
bifunctional strategy for catalytic asymmetric IEDDAR of
cyclic keto/enolate salts.
[*] Dr. X. Jiang, X. Shi, S. Wang, T. Sun, Dr. Y. Cao, Prof. Dr. R. Wang
Key Laboratory of Preclinical Study for New Drugs of Gansu
Province; Institute of Biochemistry and Molecular Biology
School of Basic Medical Sciences, Lanzhou University
Lanzhou 730000 (China)
E-mail: wangrui@lzu.edu.cn
[**] We are grateful for the grants from the National Natural Science
Foundation of China (nos. 20932003 and 90813012) and the Key
National S&T Program “Major New Drug Development” of the
Ministry of Science and Technology of China (2012ZX09504-001-
003).
We postulated that cyclic keto/enolates could serve as the
perfect dienophiles because of their high reactivity as well as
unique structural characteristics for the construction of
spirocycles. However, enolates require harsh conditions and
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107716.
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To explore the possibility of the proposed cyclization
process, a model reaction of cyclopentyl keto/enolate sodium
salt (2a) with N-tosyl-2-methylenebut-3-enoate (3a) was
performed at room temperature (Table 1). The rosin-derived
bifunctional primary amine/thiourea 1a (10 mol%) in combi-
nation with different acids (20 mol%) smoothly catalyzed the
reactions to give the desired product with excellent yields and
diastereoselectivity (95–99% yields, d.r. > 99:1, entries 1–3).
The compound 4a having a 75% ee was obtained in the
presence of 20 mol% of acetic acid (entry 2). A survey of the
solvents indicated that a substantial change in the solvent has
a significant effect on the enantioselective outcome (entries 2
and 4–7); the biphasic solvent mixture of toluene and water is
the most suitable reaction media. Notably, although 1b–
Figure 1. Natural products and bioactive compounds containing spiro-
lactams scaffolds.
Table 1: Optimization of IEDDAR parameters.[a]
their purification and storage are rather troublesome. There-
fore, in this study, we established an efficient in situ gen-
eration/activation catalysis, wherein a salt was directly used as
a reactant in the asymmetric catalysis. Subsequently, an
attempt was made in the asymmetric process to obtain the
enolates from easily available and more stable enolate salts by
employing an in situ generation/activation strategy. The
generation of a ketiminium ion by the interaction between
primary amine salts as iminium catalysts and ketones has been
explored recently.[12] Herein, we found that the activation of
cyclic keto/enolates through the formation of a ketimine
cation would be more feasible. The N-tosyl-2-methylenebut-
3-enoates, activated by lowering of the LUMOdienes through
the Lewis acid, would be expected undergo nucleophilic
attack by the cyclic keto/enolates, which are activated by
raising of the HOMOdienophiles energy through the Lewis base,
to lead to the generation of spirohemiaminals, which can then
be oxidized into the spirolactams in a single transformation
(Scheme 2). We recently embarked upon the development of
a bifunctional strategy for organocatalytic processes based
upon design features of a rosin-derived bifunctional amine/
thiourea catalysts.[13] We surmised that this kind of primary
amine/thiourea would be suitable for catalyzing the asym-
metric IEDDAR through in situ generation/activation. In
addition, this in situ enolate generation strategy using a salt
opened up a promising way for the wide application of an
enolate as an important nucleophile in organic synthesis.
Entry
Cat.
Acid
Solvent[b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1 f
BzOH
AcOH
TFA
toluene/H2O
toluene/H2O
toluene/H2O
CH2Cl2/H2O
CHCl3/H2O
Et2O/H2O
98
99
95
99
90
93
89
96
92
83
90
86
99
99
58
99
71
75
58
55
31
22
18
À55
29
25
61
3
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
THF/H2O
toluene/H2O
toluene/H2O
toluene/H2O
toluene/H2O
toluene/H2O
toluene/H2O
toluene/H2O
toluene/H2O
toluene/H2O
9
10
11
12
13[e]
14[f]
15[g]
16[f,h]
1a
1a
1a
1a
83
90
80
56
[a] The reaction was performed on 0.1 mmol scale with 2a (2.0 equiv),
3a (1.0 equiv), and acid (20 mol%). [b] Organic solvent/H2O (1.0 mL,
1:1). [c] Yield of isolated product. [d] Determined by HPLC analysis on
a chiral stationary phase, and products were observed with d.r.>20:1
(1H NMR spectroscopic analysis). [e] The reaction was performed at
08C. [f] At À138C. [g] At À408C. [h] Using 2b. THF=tetrahydrofuran,
TFA=trifluoroacetic acid, Ts=4-toluenesulfonyl.
Scheme 2. Bifunctional catalyst for the asymmetric IEDDAR.
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e could provide excellent product yields and diastereoselec-
tivities, poor enantioselectivities were observed in all reac-
tions (entries 8–11). To gain a better understanding of this
catalytic system, the tertiary amine/thiourea 1 f was also
tested under the same reaction conditions. The result showed
that 1 f afforded an almost racemic product (entry 12), and
the asymmetric reaction was indeed promoted by the acetic
acid salt of the bifunctional primary amine/thiourea. Gratify-
ingly, the more favorable outcome of 90% ee was observed
without a decrease in yield when the reaction was performed
at À138C (entry 14). In addition, the keto/enolate potassium
salt 2b was tested, and a 99% yield was still obtained, but with
a low ee value of 56% (entry 16).
Having established optimal reaction conditions, the new
method for the synthesis of chiral spirohemiaminals was
explored with a variety of substituted N-tosyl-2-methylene-
but-3-enoates and cyclic keto/enolate salts. As summarized in
Scheme 3, various substituted N-tosyl-2-methylenebut-3-
enoates including those bearing electron-withdrawing and
electron-donating substituents at different positions on the
aromatic ring, as well as heterocyclic groups could be
tolerated, and gave the corresponding compounds 4a–l in
excellent yield (95–99%), diastereoselectivity (> 20:1 d.r.),
and high to excellent enantioselectivity (88– > 99% ee).
Gratifyingly, the diversely structured spirohemiaminals 4m–
q were obtained in high to excellent yield (84–96%),
enantioselectivity (88– > 99% ee), and excellent diastereose-
lectivity (> 20:1 d.r.). Additionally, as expected, the catalytic
system also proved to be efficient for aromatic dienophiles,
again leading to 4r with 90% yield, 93% ee, and a greater
than 20:1 d.r. The configurations of the products were
determined by X-ray crystal structure analysis of 4k and 4j.
On the basis of our experimental results and recent
studies,[8h,14] we have proposed a possible model to explain the
stereochemistry of the IEDDAR employing a bifunctional
in situ generation/activation strategy (Figure 2). The N-tosyl-
2-methylenebut-3-enoate is fixed activated (lowering of the
LUMO energy) by the two thiourea hydrogen atoms through
weak hydrogen bonds, while the cyclic keto/enolate salt is
activated (raising of the HOMO energy) by the simultaneous
formation of ketiminium cation and protonation (the
Brønsted acid not only involves in the formation of ketimi-
nium intermediates, but also promotes the protonation of
enolate salt). In recent studies,[15] we also tried to investigate
the role of the structural features of the rosin-derived
thiourea catalysts in obtaining high enantioselectivity by
carrying out reactions with catalysts bearing different config-
urations of the chiral scaffold moiety as well as in comparison
with other thiourea catalysts. As a result of the main
stereochemical control from the 1,2-diaminocyclohexane
moiety and steric hindrance from the dehydroabietic amine
moiety of the thiourea, high Re face and endo selectivity
would be enforced to give the desired chiral product, which is
consistent with the experimental results.
Scheme 3. The reaction time required for each substrate is given. The
reported yields are of the isolated products. The ee and d.r. values
were determined by HPLC analysis.
without any loss of enantioselectivity, by reduction with
Et3SiH/BF3·Et2O at À788C. Furthermore, because of the
significant bioactivity of spirolactams and the versatility in
organic synthesis, the transformation into this scaffold was
also performed. Upon oxidation with PCC, the spirolactam
5a resulted in 82% yield and 94% ee. Compound 5a was first
subjected to DIBAL reduction and subsequent oxidation
using DMP to give 6a in 68% yield in two steps. Exposure of
6a to vinyl magnesium bromide afforded allylic alcohol 7a as
a single isomer in 55% yield (we found that 7a exhibited the
significant antiproliferative activity, see the Supporting Infor-
With the successful construction of chiral azaspirocyclic
skeletons as described above, the transformation of the spiro-
cycloaddition product to a number of valuable compounds
was performed. As an illustration in Scheme 4, 4b could be
converted smoothly into the spiropyridine 5b, in 61% yield
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Scheme 4. Synthetic transformations of the chiral azaspirocyclic
ketone 4b. Reagents and conditions: a) Et3SiH, BF3·Et2O, CH2Cl2,
À788C, 5 h; b) PCC, CH2Cl2, 368C, 7 h; c) DIBAL, CH2Cl2, À788C, 5 h;
d) DMP, NaHCO3, CH2Cl2, RT, 2 h; e) vinylmagnesium bromide, THF,
À40–À108C. DIBAL=diisobutylaluminum hydride, DMP=Dess–
Martin periodinate, PCC=pyridinium chlorochromate.
mation). This representative example demonstrates the
inherent synthetic potential of this kind of azaspirocycles.
In summary, we have disclosed a highly efficient in situ
generation/activation strategy that has enabled the develop-
ment of the first highly enantioselective inverse-electron-
demand Diels–Alder reaction using a bifunctional organo-
catalyst. Furthermore, this process provides a promising
method for the enantioselective construction of densely
functionalized azaspirocyclic skeletons (up to 99% yield,
> 20:1 d.r., and > 99% ee).
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Received: November 2, 2011
Published online: January 23, 2012
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Keywords: asymmetric synthesis · cycloadditions ·
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heterocycles · organocatalysis · synthetic methods
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