Aminocatalytic asymmetric exo-Diels-Alder reaction with methiodide salts of Mannich bases and 2,4-dienals to construct chiral spirocycles

Article abstract of DOI:10.1021/ol4002015

An asymmetric exo-Diels-Alder reaction of α-methylene carbonyl compounds, generated in situ from stable methiodide salts of Mannich bases, with 2,4-dienals, has been developed through trienamine activation of a chiral secondary amine. A spectrum of spirocyclanes with high molecular complexity was efficiently constructed in moderate to excellent diastereo- and enantioselectivity.

Full text of DOI:10.1021/ol4002015

ORGANIC
LETTERS
2013
Vol. 15, No. 4
968–971
Aminocatalytic Asymmetric
exo-DielsꢀAlder Reaction with Methiodide
Salts of Mannich Bases and 2,4-Dienals to
Construct Chiral Spirocycles
Shan-Jun Zhang,† Jun Zhang,† Qing-Qing Zhou,† Lin Dong,† and Ying-Chun Chen*,†,‡
Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of
Education, West China School of Pharmacy, and State Key Laboratory of Biotherapy,
West China Hospital, Sichuan University, Chengdu 610041, China, and College of
Pharmacy, Third Military Medical University, Chongqing 400038, China
ycchenhuaxi@yahoo.com.cn
Received January 23, 2013
ABSTRACT
An asymmetric exo-DielsꢀAlder reaction of R-methylene carbonyl compounds, generated in situ from stable methiodide salts of Mannich bases,
with 2,4-dienals, has been developed through trienamine activation of a chiral secondary amine. A spectrum of spirocyclanes with high molecular
complexity was efficiently constructed in moderate to excellent diastereo- and enantioselectivity.
Spirocycles, having two rings connected by a single
atom, were first created by von Baeyer in 1900.1 The spiro-
cyclic motifs are ubiquitous in a large number of natural
products or synthetic materials, such as spirolides, spiro-
bacillene A, β-vetivone, etc., exhibiting a broad spectrum
of biological activities.2 Moreover, spirocycles possess
unique structural features with central chirality or even
axial chirality (Figure 1), allowing for the development
of an array of “privileged” chiral ligands and catalysts
over the past decades.3 As a result, studies on spirocycles
provoke continuing interest in organic chemistry, and
several synthetic strategies involving alkylation, rearrange-
ment, radical cyclization, cleavage of bridged systems, etc.,
have been developed.4
Recently, enantioselective construction of spirocycles
has made great progress. An abundance of highly asym-
metric metal- or organocatalytic reactions have been de-
veloped to access chiral spirocyclic compounds5 but still
suffer from limited structural diversity. Among them, we
and other groups presented stereoselective DielsꢀAlder
cycloadditions with 3-olefinic oxindoles and various trien-
amine intermediates in situ generated from 2,4-dienals or
even 2,4-dienones and a chiral amine catalyst, providing
efficient protocols to construct chiral spirocyclic oxindoles
incorporating a six-membered ring system.6 Nevertheless,
such a straightforward [4 þ 2] cycloaddition strategy
has been much less applied for the synthesis of chiral
† Sichuan University.
‡ Third Milirary Medical University.
(1) Von Baeyer, A. Ber. Dtsch. Chem. Ges 1900, 33, 3771.
(2) (a) Kong, K.; Moussa, Z.; Lee, C.; Romo, D. J. Am. Chem. Soc.
2011, 133, 19844. (b) Kelly, T. R.; Ohashi, N.; Armstrong-Chong, R. J.;
Bell, S. H. J. Am. Chem. Soc. 1986, 108, 7100. (c) Kita, Y.; Higuchi, K.;
Yoshida, Y.; Iio, K.; Kitagaki, S.; Akai, S.; Fujioka, H. Angew. Chem.,
Int. Ed. 1999, 38, 683. (d) White, J. D.; Ruppert, J. F.; Avery, M. A.;
Torii, S.; Nokami, J. J. Am. Chem. Soc. 1981, 103, 1813. (e) Park, H. B.;
Kim, Y.-J.; Lee, J. K.; Lee, K. R.; Kwon, H. C. Org. Lett. 2012, 14, 5002.
(f) Liu, Y.; Kubo, M.; Fukuyama, Y. J. Nat. Prod. 2012, 75, 1353. (g)
Watanabe, N.; Ikeno, A.; Minato, H.; Nakagawa, H.; Kohayakawa, C.;
Tsuji, J.-i. J. Med. Chem. 2003, 46, 3961.
(4) For reviews on spirocyclic compounds, see: (a) Kotha, S.; Deb,
A. C.; Lahiri, K.; Manivannan, E. Synthesis 2009, 165. (b) Pradhan, R.;
Patra, M.; Behera, A. K.; Mishra, B. K.; Behera, R. K. Tetrahedron
2006, 62, 779. (c) Sannigrahi, M. Tetrahedron 1999, 55, 9007.
(3) (a) Xie, J.-H.; Zhou, Q.-L. Acc. Chem. Res. 2008, 41, 581. (b)
Ding, K.; Han, Z.-B.; Wang, Z. Chem. Asian J. 2009, 4, 32.
(5) For a review, see: Rios, R. Chem. Soc. Rev. 2012, 41, 1060.
r
10.1021/ol4002015
Published on Web 02/07/2013
2013 American Chemical Society

Scheme 1. Asymmetric DielsꢀAlder Cycloaddition with
Methiodide Salts of Mannich Bases and Trienamine Inter-
mediates
Figure 1. Natural products or chiral ligands containing spiro-
cyclic motifs.
spirocycles with other ring architectures, probably because
of the lower electrophilicity of the corresponding dieno-
philes and suitable catalytic systems.7
catalysis should be well compatible with the presence of
byproduct trimethylamine or its salt.
Consequently, we initially investigated the reaction with
readily available methiodide salt12 2a from 1-tetralone and
2,4-dienal 3a in the presence of amine catalyst 1a and
excess PhCO2Na.13 Pleasingly, the desired cycloaddition
occurred in chloroform at 60 °C, and product 4a was
isolated in a fair yield after 72 h but with high diastereo-
(>19:1) and enantioselectivity (94% ee) (Table 1, entry 1).
Subsequently, a number of reaction parameters were ex-
plored. A few solvents were tested (entries 2ꢀ6), and better
results were obtained in 1,2-dimethoxylethane (DME,
entry 6). Using less amounts of PhCO2Na significantly
decreased the yield (entry 7). Other bases, such as
o-FPhCO2Na or AcONa, also gave lower yields but without
effects on stereoselectivity (entries 8 and 9). While inferior
data was obtained with chiral amine 1b (entry 10),
excellent enantioselectivity with higher yield was achieved
by the catalysis of a bulky amine 1c (entry 11).14 Never-
theless, both yield and enantiocontrol were decreased
when the reaction was conducted at elevated temperature
(entry 12). On the other hand, we also investigated the
cycloadditions with other ammonium salts under the
optimized conditions, but worse results (2b, entry 13) or
even very poor conversion (2c, entry 14) were observed.
Consequently, an array of methiodide salts of various
Mannich bases derived from cyclic ketones and 2,4-dienals
were explored in DME in the presence of chiral amine 1c
(20 mol %) and PhCO2Na (2 equiv) at 60 °C. The results
are summarized in Scheme 2. In comparison with 2a, a
methiodide salt derived from 4-chromanone exhibited
higher reactivity in the reaction with 2,4-dienal 3a, giving
spirocyclic product 4b in a slightly better yield and with
excellent stereoselectivity. In addition, cycloadducts 4cꢀ4f
bearing either electron-withdrawing or -donating substitu-
tions were produced with the similar good results. Never-
theless, much poor diastereoselectivity was observed for a
R-Methylene cyclic carbonyl compounds generally show
good reactivity in DielsꢀAlder reactions7 or other cyclo-
additions8 to construct spirocyclic compounds; however,
they are labile and may dimerize even stored in a
refrigerator.9 It has been reported that such a type of
compound could be in situ generated from Mannich bases
but usually under harsh conditions.10 Fortunately, the
formation of the methiodide salts of Mannich bases could
significantly facilitate elimination to form the correspond-
ing dienophilesinthe presenceof base.11 Weenvisaged that
an aminocatalytic asymmetric DielsꢀAlder cycloaddition
withstableand easilyhandledmethiodide salts of Mannich
bases and 2,4-dienals could be developed via trienamine
activation as outlined in Scheme 1, since the amine
(6) (a) Jia, Z.-J.; Jiang, H.; Li, J.-L.; Gschwend, B.; Li, Q.-Z.; Yin, X.;
Grouleff, J.; Chen, Y.-C.; Jørgensen, K. A. J. Am. Chem. Soc. 2011, 133,
5053. (b) Liu, Y.; Nappi, M.; Arceo, E.; Vera, S.; Melchiorre, P. J. Am.
Chem. Soc. 2011, 133, 15212. (c) Halskov, K. S.; Johansen, T. K.; Davis,
R. L.; Steurer, M.; Jensen, F.; Jørgensen, K. A. J. Am. Chem. Soc. 2012,
134, 12943. (d) Xiong, X.-F.; Zhou, Q.; Gu, J.; Dong, L.; Liu, T.-Y.;
Chen, Y.-C. Angew. Chem., Int. Ed. 2012, 51, 4401. For other
DielsꢀAlder reactions via trienamine activation, see: (e) Jia, Z.-J.; Zhou,
Q.; Zhou, Q.-Q.; Chen, P.-Q.; Chen, Y.-C. Angew. Chem., Int. Ed. 2011,
50, 8638. (f) Jiang, H.; Gschwend, B.; Albrecht, Ł.; Hansen, S. G.;
Jørgensen, K. A. Chem.ꢀEur. J. 2011, 17, 9032. (g) Albrecht, Ł.; Acosta,
F. C.; Fraile, A.; Albrecht, A.; Christensen, J.; Jørgensen, K. A. Angew.
ꢀ
Chem., Int. Ed. 2012, 51, 9088. (h) Liu, Y.; Nappi, M.; Escudero-Adan,
E. C.; Melchiorre, P. Org. Lett. 2012, 14, 1310. (i) Ma, C.; Jia, Z.-J.; Liu,
J.-X.; Zhou, Q.-Q.; Dong, L.; Chen, Y.-C. Angew. Chem., Int. Ed. 2013,
52, 948. (j) Dieckmann, A.; Breugst, M.; Houk, K. N. J. Am. Chem. Soc.
201310.1021/ja312043g. For reviews, see: (k) Li, J.-L.; Liu, T.-Y.; Chen,
Y.-C. Acc. Chem. Res. 2012, 45, 1491. (l) Arceo, E.; Melchiorre, P.
Angew. Chem., Int. Ed. 2012, 51, 5290.
(7) For selected examples in a racemic form, see: (a) Grigg, R.; Liu, A.;
Shaw, D.; Suganthan, S.; Washington, M. L.; Woodall, D. E.; Yoganathan,
G. Tetrahedron Lett. 2000, 41, 7129. (b) Shanmugasundaram, M.;
Raghunathan, R. Tetrahedron 2000, 56, 5241. (c) Nakamura, H.;
Yamamoto, H. Chem. Commun. 2002, 1648. (d) Goldring, W. P. D.;
Bouazzaoui, S.; Malone, J. F. Tetrahedron Lett. 2011, 52, 960. (e)
Butt, N. A.; Moody, C. J. Org. Lett. 2011, 13, 2224. (f) Xu, S.; Chen,
R.; Qin, Z.; Wu, G.; He, Z. Org. Lett. 2012, 14, 996.
(8) Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 10988.
(9) Karmakar, R.; Mal, D. Tetrahedron Lett. 2011, 52, 6098.
(12) Tramontini, M. Synthesis 1973, 703.
(13) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, Ł.; Jørgensen,
K. A. Acc. Chem. Res. 2012, 45, 248.
(14) Liu, Y.-K.; Ma, C.; Jiang, K.; Liu, T.-Y.; Chen, Y.-C. Org. Lett.
2009, 11, 2848.
€
ꢀ
(10) Kraft, P.; Frech, D.; Muller, U.; Frater, G. Synthesis 2006, 2215.
(11) (a) Coop, A.; Grivas, K.; Husbands, S.; Lewis, J. W.; Porter, J.
Tetrahedron Lett. 1995, 36, 1689. (b) Angcloni, A. S.; Angiolini, L.; De
Mario, P.; Fini, A. J. Chem. Soc. C 1968, 2295.
Org. Lett., Vol. 15, No. 4, 2013
969

Table 1. Screening of Conditions for DielsꢀAlder Reaction with
Methiodide Salts 2 and 2,4-Dienal 3aa
Scheme 2. Substrate Scope of DielsꢀAlder Reactions with
Methiodide Salts from Cyclic Aryl Ketonesa
entry
1
solvent
base
yieldb (%)
42
eec (%)
94
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1c
1c
1c
CHCl3
Toluene
CH3CN
Dioxane
THF
PhCO2Na
PhCO2Na
PhCO2Na
PhCO2Na
PhCO2Na
PhCO2Na
PhCO2Na
o-FPhCO2Na
AcONa
2
3
4
52
48
90
96
96
95
96
96
93
98
92
90
/
5
6
DME
55
7d
8
DME
40
DME
42
9
DME
36
10
11
12e
13f
14g
DME
PhCO2Na
PhCO2Na
PhCO2Na
PhCO2Na
PhCO2Na
49
DME
DME
61
58
a Conditions: Unless noted otherwise, reactions were performed with
0.2 mmol of salt 2, 0.1 mmol of dienal 3, 20 mol % of 1c and 0.2 mmol of
PhCO2Na in 0.5 mL of DME at 60 °C for 72 h; isolated yields of pure
exo-isomers; ee was determined by chiral HPLC analysis after conver-
sion, see the SI; dr was determined by 1H NMR analysis of crude
products. b At 40 °C. c 0.4 mmol of salt was used. d Combined yield of
diastereomers.
DME
59
DME
<10
a Unless noted otherwise, reactions were performed with 0.2 mmol of
2a, 0.1 mmol of 3a, 20 mol % of 1 and 0.2 mmol of base in 0.5 mL solvent
at 60 °C for 72 h. b Isolated yield. c By chiral HPLC analysis; dr >19:1 by
1H NMR analysis. d Base (0.02 mmol) was used. e At 70 °C. f With salt 2b.
g With salt 2c.
efficiently constructed with modest yields and high stereo-
selectivity from methiodide salts 5 bearing various β-aryl
groups, even with less reactive 2,4-hexadienal (6f). It
should be noted that salts 5 with β-alkyl groups could
not participate in such cycloadditions under the current
catalytic conditions due to reduced reactivity. Moreover,
we gratifyingly found that methiodide salts 7 derived from
3-aryl or 3-phenylethynyl cyclic enones could be success-
fully applied, delivering multifunctional spirocyclic prod-
ucts 8aꢀ8c in good stereocontrol, though the isolated
yields were not satisfactory.
In addition, it was possible to introduce more sub-
stitutions into the spirocycles with β-substituted enone
substrates. As illustrated in Scheme 4, although R-benzyl-
ideneindanone 9a was inert in the reaction with 2,4-
dienals, using enone 9b bearing a β-ethoxycarbonyl group
smoothly produced the densely substituted spirocyclic
products 10a and 10b in excellent enantioselectivity
and modest diastereoselectivity. The absolute confi-
guration of 10a was ambiguously determined by X-ray
crystallographic analysis, which shows anomalous exo-
selectivity.7,16
methiodide salt from 1-indanone, while the enantioselec-
tivity was high for both diastereomers (4g). In addition,
methiodide salts with a seven-membered ring showed
lower reactivity, but the corresponding cycloadducts 4h
and 4i were produced in good diastereoselectivity and with
noteworthy ee values. On the other hand, several 2,4-
dienals with diverse substitution patterns were tested,
and spirocyclic products 4jꢀ4n were generally obtained
in high stereoselectivity, while the isolated yields were fair
to moderate. However, simple 2,4-hexadienal showed
much lower reactivity, and very poor conversion was
observed.
In order to introduce more structural diversity into
spirocyclic architectures, methiodide salts of other cyclic
ketones were further explored. While methiodide salts
from simple cyclohexanone or cyclopentanone failed to
afford the desired [4 þ 2] cycloadducts,11 it was pleasing
that the reactivity could be enhanced by introducing an
R-alkylidene moiety into cyclic aliphatic ketones, and com-
plete regioselective cycloaddition occurred at less hindered
R-methylene motif. Moreover, much better conversion
could be attained by adding a catalytic amount of (S,S)-
TADDOL, which is thought to activate the dienophiles
via hydrogen bonding interaction.15 As summarized in
Scheme 3, a number of spirocyclic products 6aꢀ6g were
The spirocycles with multifunctional groups enable
further synthetic transformations to produce more com-
plex molecules. As outlined in Scheme 5, double reductive
(16) CCDC-920336 (10a) contains the supplementary crystallo-
graphic 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.
(15) (a) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature
2003, 424, 146. (b) Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal,
V. H. J. Am. Chem. Soc. 2005, 127, 1336.
970
Org. Lett., Vol. 15, No. 4, 2013

aldol reaction sequence catalyzed by a chiral thiourea-
tertiaryamine 12,17 deliveringa framework13containing a
polyhydromethanobenzo[7]annulen-10-one motif, a ubi-
quitous bridged substructure in many tetracyclic diter-
penes and other natural products.18
Scheme 3. Substrate Scope of DielsꢀAlder Reactions with
Methiodide Salts from Functional Cyclic Enonesa
Scheme 5. Transformations of Spirocyclic Products
In conclusion, we have presented an asymmetric exo-
DielsꢀAlder reaction with bench-stable methiodide salts
of Mannich bases and 2,4-dienals, which relies on the in
situ generation of labile R-methylene carbonyl dienophiles
and subsequent cycloaddition with HOMO-activated tri-
enamine intermediates. A spectrum of multifunctional
spirocyclic frameworks has been efficiently constructed
with moderate to excellent diastereo- and enantioselectiv-
ity. Moreover, the products could be smoothly trans-
formed into polycyclic compounds with high molecular
complexity. We believe that such easily handled methio-
dide salts of Mannich bases would find more applications
in asymmetric catalysis, and the results will be reported in
due course.
a Unless noted otherwise, reactions were performed with 0.2 mmol of
salt 5 or 7, 0.1 mmol of 2,4-dienal 3, 20 mol % of 1c and TADDOL,
0.2 mmol of PhCO2Na in 0.5 mL of DME at 60 °C for 72 h; isolated yields
of pure exo-isomers; ee was determined by chiral HPLC analysis; dr was
determined by 1H NMR analysis of crude products. b With catalyst 1a.
Scheme 4. Synthesis of Highly Substituted Spirocycles
Acknowledgment. We are grateful for the financial
support from the NSFC (21125206 and 21021001), and
the National Basic Research Program of China (973
Program, 2010CB833300).
Supporting Information Available. Experimental pro-
cedures, structural proofs, NMR spectra and HPLC
chromatograms of the products, cif file of enantiopure
10a. This material is available free of charge via the
Internet at http://pubs.acs.org.
amination reactions with spirocycle 4a and BnNH2 pro-
ceeded efficiently in the presence of NaBH(OAc)3, producing
a highly fused piperidine derivative 11 with exclusive diastereo-
control. Moreover, spirocycle 6b was used in a domino
diastereoselective sulfur-Michael additionꢀintramolecular
(18) For selected examples, see: (a) Bell, R.; Ireland, R. E.; Partyka,
R. A. J. Org. Chem. 1962, 27, 3741. (b) Kametani, T.; Suzuki, K.;
Nemoto, H.; Fukumoto, K. J. Org. Chem. 1979, 44, 1036. (c) Shi, Y.-P.;
Rodrıguez, I. I.; Rodrıguez, A. D. Tetrahedron Lett. 2003, 44, 3249.
(17) (a) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y.
Synlett 2005, 603. (b) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem.
Soc. 2003, 125, 12672.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
971