Organocatalytic enantioselective conjugate addition of 2-nitrocyclohexanone to acrylaldehyde: A concise two-step synthesis of chiral building block 1-azaspiro[4.5]decan-6-one

Article abstract of DOI:10.1016/j.tetlet.2013.01.114

A gram-scale organocatalytic enantioselective Michael addition of a-nitrocyclohexanone to acrolein has been developed, and it was successfully applied to a concise two-step synthesis of (1S)-azaspiro[4.5] decan-6-one, a useful chiral building block for th

Full text of DOI:10.1016/j.tetlet.2013.01.114

Tetrahedron Letters 54 (2013) 1956–1959
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalytic enantioselective conjugate addition of 2-nitrocyclohexanone
to acrylaldehyde: a concise two-step synthesis of chiral building block
1-azaspiro[4.5]decan-6-one
⇑
Xiao-Hua Ding , Wei-Chen Cui , Xiang Li, Xuan Ju, Dan Liu, Shaozhong Wang, Zhu-Jun Yao
State Key Laboratory of Coordination, Nanjing National Laboratory for Microstructures, School of Chemistry and Chemical Engineering, Nanjing University, 22 Hankou Road, Nanjing,
Jiangsu 210093, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A gram-scale organocatalytic enantioselective Michael addition of a-nitrocyclohexanone to acrolein has
Received 22 December 2012
Revised 17 January 2013
Accepted 28 January 2013
Available online 4 February 2013
been developed, and it was successfully applied to a concise two-step synthesis of (1S)-azaspiro[4.5]
decan-6-one, a useful chiral building block for the synthesis of a variety of natural alkaloids.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
1-Azaspiro[4.5]decan-6-one
Enantioselective synthesis
Building block
Michael addition
Organocatalysis
1-Azaspiro ring systems uniquely incorporate a carbo- and a
heterocycle by an aza-quaternary center, whose nitrogen atom is
adjacent to the junction. Among them, the 1-azasipro[4.5]decane
motif can be frequently observed in many natural alkaloids includ-
ing cylindricine A,1 lepadiformine A,2 TAN1251A,3 and FR9014834
(Fig. 1). A considerable number of synthetic efforts have been re-
ported to establish the peculiar structure, including closing the
two rings in separate steps or achieving the spirocycle in a single
step.5 Furthermore, in the aforementioned natural products, the
quaternary carbon bearing nitrogen atom is usually stereogenic,
and necessary stereochemical control is thus required in its forma-
tion. Development of efficient enantioselective construction of the
aza-quaternary carbon is always the crucial task in the synthesis.
For example, stereoselective 1,3-dipolar cycloaddition,6a catalytic
asymmetric Michael reaction, and tandem cyclization6b were ap-
plied in the synthesis of cylindricines6 by Bochet and Shibasaki
and co-workers. Since Kibayashi’s revision of originally assigned
configuration of lepadiformine7a utilizing N-acyliminium-initiated
olefin azacyclization (to elaborate the azaspirocyclic core), several
other elegant syntheses have also been reported.7 Rychnovsky’s
group recently reported a new construction of the spirocyclic ring
of (ꢀ)-lepadiformine using a trianion synthon derived from N-Boc
FR9014839 involved initial formation of 1-azaspiro[4.5]decane fol-
lowed by ring-closure to establish the tricyclic system. Undoubt-
edly, more efficient and direct approaches to elaborate the chiral
1-azaspiro[4.5]decane ring system are of extreme value in the syn-
thesis of these biologically interesting alkaloids. Herein, we wish to
report a catalytic enantioselective synthesis of the chiral 1-azaspi-
ro[4.5]decane motif, using a newly developed organocatalyzed
Me
O
O
Me
Me
N
H
∗
N
O
∗
N
H
C6H13
O
Cl
O
Cylindricine A
TAN1251A
∗
OMe
N
O
∗
HO
N
N
NHMe
C6H13
∗
a
-amino nitrile.7g,h Most synthetic approaches to TAN1251A8 and
H
OH
O
P
HO
O
Lepadiformine A
FR901483
⇑
Corresponding author. Tel./fax: +86 25 83593732.
E-mail address: yaoz@nju.edu.cn (Z.-J. Yao).
These authors contributed equally to this work.
OH
Figure 1. Several alkaloids containing 1-azaspiro[4.5]decane motif.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.114

X.-H. Ding et al. / Tetrahedron Letters 54 (2013) 1956–1959
1957
used as Michael donor/acceptor in asymmetric synthesis in the last
two decades,11 few applications of
-nitroketones and -nitrocy-
Reduction
HN
a
a
O
H
O
O
cloketones12–14 have been explored in organocatalytic reactions
for their higher acidity (pKa ꢁ 4.0) and considerable difficulty to
be handled in such reactions. Therefore, exploration of the above
mentioned transformation not only will help to establish a new
concise synthesis of the required chiral building block, but also will
provide new addition to current literatures on organocatalytic con-
jugate additions.
NO2
NO2
∗
∗
+
H
O
O
1-azaspiro[4.5]decan-6-one
Organocatalytic
Conjugate Addtion
Figure 2. Asymmetric formation of 1-azaspiro[4.5]decane ring system.
As mentioned, an organocatalytic Michael addition of
cyclohexanone to acrolein was considered as the crucial step to
establish the aza-quaternary carbon (Fig. 2). Our study began with
a-nitro-
Michael addition of a-nitrocycloketone to acrolein followed by C–
N cyclization with reductive amination (Fig. 2).
Though organocatalytic conjugate additions10 have been inten-
sely explored and nitroalkanes and nitroalkenes have been widely
the screening for
a
proper organocatalyst. Usually, Michael
Table 1
Screening of conditions for the conjugate addition reaction
OH
OH
N
OMe
N
N
O
N
O
N
OH
N
N
N
Cl
I
II
III
OMe
N
CF3
CF3
N
O
O
S
NH
N
H
N
H
CF3
N
N
CF3
S
NH
H
H
N
N
VI
IV
V
F3C
CF3
O
O
O
CHO
O
O
O
O
O
10 mol% catalyst
solvent, temp
NO2
5 mol% pTsOH
NO2
NO2
H
+
rt, 12 h
90%
1
2
3
4
Entrya
Cat.
Solvent
T (°C)
Time (h)
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
I
DCM
DCM
DCM
DCM
DCM
DCM
Toluene
Dioxane
2-MeTHF
Et2O
CHCl3
1,2-DCE
Acetone
DMF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
0.1
0.3
0.3
0.2
0.5
0.3
1
5
3
7
1
1
4.5
5
5
6
6.5
9
12
9
9
81
79
85
83
89
75
87
73
76
86
83
72
92
79
76
90
90
89
76
91
93
17
27
21
43
64
4
II
III
IV
V
VI
V
V
V
V
V
V
V
V
V
V
V
V
V
V
V
68
73
68
53
44
37
37
20
31
68
80
82
82
87
80
MeOH
Dioxane/toluene (1:2)
Dioxane/toluene (1:2)
Dioxane/toluene (1:2)
Dioxane/toluene (1:2)
Dioxane/toluene (1:3)
Dioxane/toluene (1:4)
ꢀ10
ꢀ20
ꢀ30
ꢀ20
ꢀ20
a
Unless otherwise noted, the reaction was carried out with 1 (0.125 mmol), 2 (0.15 mmol), and catalyst (0.0125 mmol) in solvent (1.25 mL).
ee value of 4 was determined by chiral HPLC.
b

1958
X.-H. Ding et al. / Tetrahedron Letters 54 (2013) 1956–1959
Table 2
Application of derivatives of Takemoto’s catalyst in the conjugate addition
CF3
CF3
CF3
S
S
S
N
H
N
H
CF3
N
H
N
H
CF3
N
H
N
H
CF3
N
N
N
VII
VIII
V
CF3
CF3
S
S
N
H
N
H
CF3
N
H
N
H
CF3
N
O
N
X
IX
O
O
O
CHO
O
O
O
O
O
10 mol% catalyst
NO2
5 mol% pTsOH
NO2
NO2
H
+
dioxane/toluene (1:3)
-20 oC
rt, 12 h
90%
1
2
3
4
Entrya
Cat.
Time (h)
Yield (%)
eeb (%)
1
2
3
4
5
V
9
10
10
10
10
81
80
84
86
82
87
73
88
89
83
VII
VIII
IX
X
a
Unless otherwise noted, the reaction was carried out with 1 (0.125 mmol), 2 (0.15 mmol), and catalyst (0.0125 mmol) in solvent (1.25 mL).
ee value of 4 was determined by chiral HPLC.
b
CHO
CF3
O
O
O
10 mol% IX
NO2
H
NO2
+
S
dioxane/toluene (1:3)
-20 oC, 76%
CHO
F3C
H
O
N
unfavourable
O
N
H
3
1
2
(84% ee)
EtO2C
(5 gram)
Zn/HOAc
N
NO2
H
H
H
O
O
N
N
HN
ClCO2Et, Et3N
rt
O
R-configuration
0
oC-rt
70%
85%
O
6
O
CF3
5
CHO
O
S
Scheme 1. Scale-up of the reaction and determination of the absolute
configuration.
F3C
H
favourable
N
O
N
NO2
O
H
N
N
H
H
H
reaction of
a
-nitroketones and
a
,b-unsaturated aldehydes could be
O
O
S-configuration
conventionally carried out in organic solvents using DBU, Ph3P, and
nBu4N+Fꢀ as catalysts,15 or in water without adding catalysts.16 To
achieve a satisfactory control of stereochemistry, the bifunctional
organocatalysts equipped with a tertiary-amine moiety and a
hydrogen-bond donor were considered to bind both substrates
with correct configurations in the transition state. Initial applica-
tion of natural quinine (I) showed a very weak influence on the
enantioselectivity (Table 1, entry 1). Modified catalysts II and
III17 by replacing the 60-methoxyquinoline moiety of quinine with
60-hydroxyquinoline and masking the C-9 alcohol slightly in-
creased the enantiomeric excess of product 4 (Table 1, entries 2
and 3). To our delight, utilization of thiourea moiety as the
hydrogen-bond donor in the catalysts IV and V,18,19 instead of
the hydroxyl group in quinine derivatives, remarkably improved
Scheme 2. Proposed reaction mechanism.
the enantioselectivity (Table 1, entries 4 and 5). However, the
catalyst VI with squaramide moiety20 turned out to be invalid
(Table 1, entry 6).
Based on the above observation, effects of solvent and temper-
ature were then examined in the reactions with Takemoto’s thio-
urea-tertiary amine V (Table 1, entries 7–19). Reaction in toluene
gave a similar result as that in dichloromethane (Table 1, entries
5
and 7). The reactions afforded the Michael product with

X.-H. Ding et al. / Tetrahedron Letters 54 (2013) 1956–1959
1959
2. (a) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.; Vercauteren, J.; Weber, J. F.;
Boukef, K. Tetrahedron Lett. 1994, 35, 2691–2694; (b) Weinreb, S. M. Acc. Chem.
Res. 2003, 36, 59–65.
3. Shirafuji, H.; Tuboya, S.; Ishimaru, T.; Harada, S. Jpn. Kokai Tokkyo Koho 94-
501916.
4. Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.; Shigematsu, N.;
Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49, 37–44.
5. For reviews on the synthesis of azaspiro[4,5]decane and related natural
products, see: (a) Dake, G. Tetrahedron 2006, 62, 3467–3492; (b) Weinreb, S.
M. Chem. Rev. 2006, 106, 2531–2549.
6. For the asymmetric synthesis of cylindricines, see: (a) Oppolzer, W.; Bochet, C.
G. Tetrahedron: Asymmetry 2000, 11, 4761–4770; (b) Abe, H.; Aoyagi, S.;
Kibayashi, C. J. Am. Chem. Soc. 2005, 127, 1473–1480; (c) Shibuguchi, T.; Mihara,
H.; Kuramochi, A.; Sakuraba, S.; Ohshima, T.; Shibasaki, M. Angew. Chem., Int.
Ed. 2006, 45, 4635–4637; (d) Swidorski, J. J.; Wang, J.; Hsung, R. P. Org. Lett.
2006, 8, 777–780; (e) Mihara, H.; Shibuguchi, T.; Kuramochi, A.; Ohshima, T.;
Shibasaki, M. Heterocycles 2007, 72, 421–438; (f) Zhang, X. M.; Wang, M.; Tu, Y.
Q.; Fan, C. A.; Jiang, Y. J.; Zhang, S. Y.; Zhang, F. M. Synlett 2008, 2831–2835.
7. For the asymmetric synthesis of lepadiformines, see: (a) Abe, H.; Aoyagi, S.;
Kibayashi, C. Angew. Chem., Int. Ed. 2002, 41, 3017–3020; (b) Sun, P.; Sun, C.;
Weinreb, S. M. J. Org. Chem. 2002, 67, 4337–4345; (c) Liu, J.; Hsung, R. P.; Peters,
S. D. Org. Lett. 2004, 6, 3989–3992; (d) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am.
Chem. Soc. 2005, 127, 1473–1480; (e) Lygo, B.; Kirton, H. M. E.; Lumley, C. Org.
Biomol. Chem. 2008, 6, 3085–3090; (f) Mei, S. L.; Zhao, G. Eur. J. Org. Chem. 2010,
1660–1668; (g) Perry, M. A.; Morin, M. D.; Slafer, B. W.; Wolckenhauer, S. A.;
Rychnovsky, S. D. J. Am. Chem. Soc. 2010, 132, 9591–9593; (h) Perry, M. A.;
Morin, M. D.; Slafer, B. W.; Rychnovsky, S. D. J. Org. Chem. 2012, 77, 3390–3400.
8. For the asymmetric synthesis of TAN1251A, see: (a) Snider, B. B.; Lin, H. Org.
Lett. 2000, 2, 643–646; (b) Wardrop, D. J.; Basak, A. Org. Lett. 2001, 3, 1053–
1056; (c) Mizutani, H.; Takayama, J.; Soeda, Y.; Honda, T. Tetrahedron Lett. 2002,
43, 2411–2414; (d) Nagumo, S.; Matoba, A.; Ishii, Y.; Yamaguchi, S.; Akutsu, N.;
Nishijima, H.; Nishida, A.; Kawahara, N. Tetrahedron 2002, 58, 9871–9877; (e)
Auty, J.; Churcher, I.; Hayes, C. J. Synlett 2004, 8, 1443–1445; (f) Mizutani, H.;
Takayama, J.; Soeda, Y.; Honda, T. Heterocycles 2004, 62, 343–355.
moderate enantiomeric excesses in ether solvents 1,4-dioxane, 2-
methyltetrahydrofuran, and diethyl ether (Table 1, entries 8–10).
Chloroform and 1,2-dichloroethane and more polar solvents, such
as acetone, DMF, and methanol were detrimental to the enantiose-
lectivity (Table 1, entries 11–15). Occasionally, a mixed solvent of
1,4-dioxane and toluene (v/v = 1/2) was found to give 68% ee of the
product at 0 °C (Table 1, entry 16). Thus, it was chosen as the media
for further temperature screening (Table 1, entries 17–19). These
experiments revealed that the best results with regard to chemical
yield and enantioselectivity were obtained at ꢀ20 °C (Table 1,
entry 18). Further decrease in temperature did not show any signif-
icant improvement on the selectivity (Table 1, entry 19). Finally,
the volume ratio of the solvents (1,4-dioxane and toluene) was
adjusted to 1:3, affording product 4 in 87% ee (Table 1, entry 20).
Under the above optimized conditions, we decided to further
modify the tertiary amine functionality of the catalyst (Table 2).
The diethylamine-substituted catalyst VII showed a negative influ-
ence on the selectivity (Table 2, entry 2), while pyrrolidine-thio-
urea catalyst VIII provided a slightly improved enantioselectivity
(Table 2, entry 3). With piperidine-thiourea catalyst IX, the enan-
tiomeric excess of the product 4 was proven to be the best, up to
89% (Table 2, entry 4). Whereas, a similar morpholine-thiourea
catalyst X resulted in a slight decrease of the enantioselectivity.
For provision of adequate materials for the total synthesis of
natural products, we then examined the scale-up capability of tar-
get transformation under the optimal reaction conditions. A five
9. For the asymmetric synthesis of FR901483, see: (a) Snider, B. B.; Lin, H. J. Am.
Chem. Soc. 1999, 121, 7778–7786; (b) Scheffler, G.; Seike, H.; Sorensen, E. J.
Angew. Chem., Int. Ed. 2000, 39, 4593–4595; (c) Ousmer, M.; Braun, N. A.;
Ciufolini, M. A. Org. Lett. 2001, 3, 765–767; (d) Ousmer, M.; Braun, N. A.;
Bavoux, C.; Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123, 7534–7538;
(e) Kan, T.; Fujimoto, T.; Ieda, S.; Asoh, Y.; Kitaoka, H.; Fukuyama, T. Org. Lett.
2004, 6, 2729–2731; (f) Brummond, K. M.; Hong, S. P. J. Org. Chem. 2005, 70,
907–916; (g) Kaden, S.; Reissig, H. U. Org. Lett. 2006, 8, 4763–4766; (h) Gotchev,
D. B.; Comins, D. L. J. Org. Chem. 2006, 71, 9393–9402; (i) Asari, A.; Angelov, P.;
Auty, J. M.; Hayes, C. J. Tetrahedron Lett. 2007, 48, 2631–2634; (j) Simila, S. T.
M.; Martin, S. F. J. Org. Chem. 2007, 72, 5342–5349; (k) Carson, C. A.; Kerr, M. A.
Org. Lett. 2009, 11, 777–779; (l) Ieda, S.; Kan, T.; Fukuyama, T. Tetrahedron Lett.
2010, 51, 4027–4029; (m) Ma, A. J.; Tu, Y. Q.; Peng, J. B.; Dou, Q. Y.; Hou, S. H.;
Zhang, F. M.; Wang, S. H. Org. Lett. 2012, 14, 3604–3607; (n) Huo, H.-H.; Zhang,
H.-K.; Xia, X.-E.; Huang, P.-Q. Org. Lett. 2012, 14, 4834–4837.
10. For reviews on the organocatalytic asymmetric conjugate additions, see: (a)
Reyes, E.; Fernandez, M.; Uria, U.; Vicario, J. L.; Badia, D.; Carrillo, L. Curr. Org.
Chem. 2012, 16, 521–546; (b) Zhang, Y.; Wang, W. Catal. Sci. Technol. 2012, 2,
42–53; (c) Enders, D.; Wang, C.; Liebich, J. X. Chem. Eur. J. 2009, 15, 11058–
11076; (d) Li, N.; Xi, G. H.; Wu, Q. H.; Liu, W. H.; Ma, J. J.; Wang, C. Chin. J. Org.
Chem. 2009, 29, 1018–1038; (e) Vicario, J. L.; Badia, D.; Carrillo, L. Synth. Stuttg.
2007, 14, 2065–2092.
gram-scale reaction between
1 and 2 was attempted with
10 mol % loading of the catalyst IX. To our delight, the conjugated
addition product was obtained in 76% yield and 84% ee (Scheme 1).
Afterward, the nitro group of 3 was reduced to amine with zinc
dust in HOAc,21 which spontaneously underwent an intramolecu-
lar reductive amination with 20-aldehyde to give the spiro-pyrrol-
idine ring. Therefore, we completed a concise catalytic asymmetric
synthesis of 1-azaspiro[4.5]decan-6-one, a potential useful chiral
building block in various total syntheses, in two steps from the
simple starting materials. In order to determine the absolute con-
figuration, product 5 was converted into the known derivative 6,22
whose N-acyl derivatives were reported as potent opioid receptor
ligands.23 Accordingly, the aza-quaternary center of the 1-azaspi-
ro[4.5]decane ring system was determined to be of S configuration.
According to the absolute configuration of the product, mecha-
nism of the bifunctional catalysis was proposed as Scheme 2. The
enantioselectivity might be caused by the steric hindrance
between the aryl moiety of the catalyst and the cyclohexanone.
In conclusion, we have developed a gram-scale enantioselective
11. For
a review on the organocatalytic reactions involving nitroalkanes and
nitroalkenes, see: Roca-Lopez, D.; Sababa, D.; Delso, I.; Herrera, R. P.; Tejero, T.;
Merino, P. Tetrahedron: Asymmetry 2010, 21, 2561–2601.
12. (a) Latvala, A.; Stanchev, S.; Linden, A.; Hesse, M. Tetrahedron: Asymmetry 1993,
4, 173–176; (b) Lu, R. J.; Yan, Y. Y.; Wang, J. J.; Du, Q. S.; Nie, S. Z.; Yan, M. J. Org.
Chem. 2011, 76, 6230–6239.
13. Gao, Y.; Ren, Q.; Siau, W. Y.; Wang, J. Chem. Commun. 2011, 47, 5819–5821.
14. Jorres, M.; Schiffers, I.; Atodiresei, I.; Bolm, C. Org. Lett. 2012, 14, 4518–4521.
15. (a) Lorenziriatsch, A.; Nakashita, Y.; Hesse, M. Helv. Chim. Acta 1984, 67, 249–
253; (b) Giorgi, G.; Miranda, S.; Ruiz, M.; Lopez-Alvarado, P.; Menendez, J. C.;
Rodriguez, J. Eur. J. Org. Chem. 2011, 11, 2101–2110.
organocatalytic Michael addition of a-nitrocyclohexanone to acro-
lein, with 84% ee.24 This protocol offers a concise two-step chiral
synthesis of 1-azaspiro[4.5]decan-6-one, a potential useful chiral
building block in the synthesis of a variety of natural alkaloids.
Acknowledgements
16. Miranda, S.; Lopez-Alvarado, P.; Giorgi, G.; Rodriguez, J.; Avendano, C.;
Menendez, J. C. Synlett 2003, 14, 2159–2162.
17. Wu, F.; Hong, R.; Khan, J.; Liu, X.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 4301–
4305.
18. Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967–1969.
19. Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672–12673.
20. Qian, Y.; Ma, G.; Lv, A.; Zhu, H.-L.; Zhao, J.; Rawal, V. H. Chem. Commun. 2010,
46, 3004–3006.
Financial supports from MOST 973 project (2010CB833200),
NSFC grant (21032002), and National Science Fund for Talent
Training in Basic Science (No. J1103310) are greatly appreciated.
Supplementary data
21. Zou, W.; Wu, A.-T.; Bhasin, M.; Sandbhor, M.; Wu, S.-H. J. Org. Chem. 2007, 72,
2686–2689.
22. Sawamura, M.; Nakayama, Y.; Tang, W.-M.; Ito, Y. J. Org. Chem. 1996, 61, 9090–
9096.
23. Fujimoto, R. A.; Boxer, J.; Jackson, R. H.; Simke, J. P.; Neale, R. F.; Snowhill, E. W.;
Barbaz, B. J.; Williams, M.; Sills, M. A. J. Med. Chem. 1989, 32, 1259–1265.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.01.
114.
24. Generality of the reaction between a-nitrocyclohexanone and a variety of a,b-
References and notes
unsaturated aldehydes was also explored. Unfortunately, the yields of the
Michael adducts dropped dramatically under the optimized conditions. It is
speculated that additional substituents of acrylaldehyde might unfavorably
interact with the catalyst and make the transition state unstable.
1. Blackman, A. J.; Li, C.; Hockless, D. C. R.; Skelton, B. W.; White, A. H. Tetrahedron
1993, 49, 8645–8656.