Asymmetric organocatalytic Michael-hemiacetalization reaction: Access to chiral spiro cis-δ-lactones by in situ oxidation of spiro δ-lactols

Article abstract of DOI:10.1016/j.tetlet.2013.03.039

Asymmetric tandem Michael-hemiacetalization reaction between 1-nitromethylcycloalkanol and α,β-unsaturated aldehydes was investigated, which provided an efficient and facile synthesis for spiro cis-δ-lactones by in situ oxidation of spiro δ-lactols in goo

Full text of DOI:10.1016/j.tetlet.2013.03.039

Tetrahedron Letters 54 (2013) 2546–2548
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric organocatalytic Michael–hemiacetalization reaction: access
to chiral spiro cis-d-lactones by in situ oxidation of spiro d-lactols
Mo-Hui Wei a, Yi-Rong Zhou a, Liang-Hu Gu a, Fan Luo a, , Fang-Lin Zhang a,b,
⇑
⇑
a School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, China
b School of Chemical Engineering, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430074, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric tandem Michael–hemiacetalization reaction between 1-nitromethylcycloalkanol and
Received 19 January 2013
Revised 24 February 2013
Accepted 8 March 2013
Available online 20 March 2013
a
,b-unsaturated aldehydes was investigated, which provided an efficient and facile synthesis for spiro
cis-d-lactones by in situ oxidation of spiro d-lactols in good overall yields with high to excellent
enantioselectivities and diastereoselectivities.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Asymmetric catalysis
Cascade reaction
Spirolactone
Natural products containing a spirolactone unit are usually
found to exhibit a wide range of biological activities. For examples,
drospirenone is a component of certain birth control formulations;1
gaertneroside is an inhibitor for the activation of the classical path-
way of the complement system;2 and abyssomicin C is a potent
antibacterial agent against Gram-positive bacteria.3 Besides, spiro-
lactones as useful building blocks have already been applied to the
total synthesis of bioactive natural products and pharmaceuticals,
including variecolin,4 mevinolin,5 biyouyanagin A,6 and (À)-b-
molecules,12 including substituted d-lactones, b-amino alcohols,
and -amino acid derivatives. Just recently, we reported
Michael–hemiacetalization reaction of b-substituted b-nitroetha-
nols with ,b-unsaturated aldehydes to afford d-lactol derivatives
a
a
a
bearing N-substituted quaternary carbons with excellent enanti-
oselectivities.13a Encouraged by our previous work,13 we become
interested in Michael addition of
a-substituted b-nitroethanols
to ,b-unsaturated aldehydes, especially, 1-nitromethylcycloalka-
a
nols which could provide a facile way for the construction of a
spiro carbon after subsequent hemiacetalization (Scheme 1). Here,
we describe an efficient Michael–hemiacetalization reaction of
vetivone.7 To date,
a variety of synthetic routes have been
developed for constructing the spirolactone frameworks,8 such as
dearomatization of phenol to quinine,9a,b reductive cross-coupling
1-nitromethylcycloalkanols 1 and
a,b-unsaturated aldehydes 2
of ketones with
a
,b-unsaturated esters,9c radical-based approa-
to access spiro d-lactols 3, and by in situ oxidation, spiro cis-
d-lactones 4 were isolated with high to excellent enantioselectiv-
ities and diastereoselectivities, as well as in good overall yields.
The tandem reaction of 1-nitromethylcyclohexanol (1a) and
cinnamaldehyde (2a) was first investigated by using 20 mol % of
ches,9d and furanyl dienolate-based cyclization.9e However, few
enantioselective approaches to spirolactones have been reporte-
d.9a,b It is crucial to develop efficient and facile approaches to access
highly functionalized spirolactones with high enantioselectivities.
The catalytic asymmetric Michael addition is one of the
fundamental bond-forming reactions in organic synthesis. In the
past few years, the field of organocatalytic Michael addition has
received widespread attention.10 Among these reactions, the
secondary amine-catalyzed asymmetric Michael addition of nitro-
(S)-a,a-diphenylprolinol trimethylsilyl ether as a catalyst in the
presence of 20 mol % of benzoic acid in CH2Cl2 (Table 1, entry 2).
The reaction had completed within 24 h and 3a was obtained al-
most quantitatively. After oxidization in situ by pyridinium chloro-
chromate (PCC), cis-spirolactone 4a was isolated in good overall
yield. The diastereo- and enantioselectivities of the reaction were
respectively determined by 1H NMR and by chiral HPLC after 3a
was oxidized to 4a. Solvent effects on the above reaction were then
examined. Among the solvents listed in Table 1, toluene was the
most appropriate one, in which 4a was obtained with high diaste-
reomeric ratio and enantioselectivity (95:5 dr; 95% ee; Table 1,
entry 1). Either dr or ee values of 4a were decreased to some
ethanols to
a,b-unsaturated aldehydes provides an attractive ap-
proach to substituted tetrahydropyran,11 which could be a useful
synthetic intermediate for the synthesis of nitrogen-containing
⇑
Corresponding authors. Tel.: +86 027 8754 3232; fax: +86 027 8754 3632 (F.L.);
tel.: +86 027 8785 0919; fax: +86 027 8785 0919 (F.L.Z.).
E-mail addresses: luofan05@163.com (F. Luo), hyvzfl@gmail.com (F.-L. Zhang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.039

M.-H. Wei et al. / Tetrahedron Letters 54 (2013) 2546–2548
2547
Ph
R
O
R
O
NO2
R
O
Ph
OTMS
NO2
NO2
OH
N
H
PCC
+
HO
O
n
n
n
1
2
3
cis-4
Scheme 1. Synthesis of spiro d-lactones 4 by Michael–hemiacetalization reaction and in situ oxidation.
Table 1
Optimization of catalytic tandem reaction of 1-nitromethylcyclohexanol with cinnamaldehydea
Ph
Ph
Ph
Ph
NO2
OTMS
N
H
NO2
NO2
OH
(20 mol%)
PCC
Ph
+
O
HO
O
O
O
CH2Cl2
Additive (20 mol%)
solvent
1a
2a
cis-4a
3a
Entry
Solvent
Additive
t (h)
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
PhCH3
CH2Cl2
CHCl3
CH3CN
CH3OH
Et2O
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
—
CH3COOH
4-NO2PhCOOH
Imidazole
DMAP
DABCO
NMM
TEA
DBU
Imidazole
24
24
24
24
24
24
24
36
24
24
14
20
20
20
20
12
48
82
80
80
76
78
78
79
80
75
78
85
82
80
81
75
82
85
95:5
91:9
89:11
91:9
90:10
91:9
95:5
97:3
95:5
94:6
98:2
93:7
97:3
97:3
91:9
80:20
98:2
95
91
90
88
90
94
92
94
94
94
94
95
93
94
81
0
THF
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
9
10
11
12
13
14
15
16
17e
96
a
Reactions performed with 1a (1 mmol), 2a (0.5 mmol), (S)-a,a-diphenylprolinol trimethylsilyl ether (0.1 mmol), and additive
(0.1 mmol) in indicated solvents (1 mL) at room temperature.
b
Isolated yield of cis-4a.
c
cis:trans determined by 1H NMR spectroscopy of crude 4a.
d
The ee value of cis-4a, which was determined by chiral HPLC analysis.
Reaction carried out at 4 °C.
e
extent, when the reaction was performed in other solvents (Table
1, entries 2–7).
this reaction could be elevated to 96% when reaction temperature
was lowered to 4 °C, albeit a prolonged reaction time (48 h) was
needed (Table 1, entry 17).
Subsequently, the effect of additives was taken into consider-
ation. Some typical acids and bases were tested, and the data are
summarized in Table 1 (entries 8–16). When no additive was used,
the reaction was accomplished within 36 h and gave 80% yield of
cis-4a with 94% ee. Meanwhile, the dr value was improved to
97:3 which was higher than that obtained in the reaction in the
presence of benzoic acid (Table 1, entry 8). This result indicated
that acid additive could accelerate the reaction but lower the dia-
stereoselectivity. With slight decline of dr values in the presence of
acid additives, however, ee values of the reaction almost kept
unchanged. Further evidence was obtained when p-nitro benzoic
acid was used as a stronger acid additive (Table 1, entry 10).
Besides, base additives were also estimated. When imidazole
served as the additive, the reaction proceeded much faster and
was completed within 14 h; the resulting product cis-4a was
formed in 85% yield with ameliorated diastereomeric ratio (98:2)
(Table 1, entry 11). Similar ee and relatively lower dr values were
obtained when the reaction was carried out with bases DMAP,
DABCO, and NMM (Table 1, entries 12–14). However, in the pres-
ence of a strong organic base DBU, both dr and ee values of the
reaction declined (Table 1, entry 16). In addition, the ee value of
Under the above optimized conditions, the scope of the tandem
Michael–hemiacetalization reaction was explored in the presence
of 20 mol % of (S)-a,a-diphenylprolinol trimethylsilyl ether and
20 mol % of imidazole in toluene at 4 °C. As shown in Table 2, both
electron-withdrawing and electron-donating groups on phenyl
group were tolerated in the catalytic system (Table 2, entries
1–8). In each case, cis-4 was formed with high to excellent enanti-
oselectivities and diastereoselectivities. However, 3-(furan-2-
yl)acrylaldehyde just gave a moderate dr value even at À20 °C
(Table 2, entry 9), which might be derived from the different steric
hindrance of the different aryl groups. In contrast to our recent re-
sults,13a the reaction of crotonaldehyde proceeded smoothly and
achieved completion within 48 h, although the product cis-4k
was formed with moderate diastereoselectivity and enantioselec-
tivity owning to the less bulky methyl group (Table 2, entry 10).
Hex-2-enal was also tolerated in this reaction, furnishing a good
yield of cis-4l with moderate enantioselectivity (Table 2, entry
11). In addition, good yield and high enantioselectivity were ob-
tained for the reaction between 1-nitromethylcyclopentanol (1b)
and p-chlorocinnamaldehyde with 91:9 dr value (Table 2, entry

2548
M.-H. Wei et al. / Tetrahedron Letters 54 (2013) 2546–2548
Table 2
Scope of the reaction between 1-nitromethylcyclohexanols 1 and 2a
Ph
Ph
OTMS
R
R
O
NO2
R
N
H
NO2
NO2
OH
PCC
(20 mol%)
+
HO
O
O
CH2Cl2
n
O
imidazole (20 mol%)
PhCH3
n
n
1
2
3
cis-4
1a: n=2
1b: n=1
Entry
1
R
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
2-ClC6H4
3-ClC6H4
4-ClC6H4
2,4-diClC6H3
2-FC6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
2-Furanyl
Me
73(4b)
75(4c)
81(4d)
74(4e)
71(4f)
78(4g)
73(4h)
67(4i)
65(4j)
67(4k)
63(4l)
80(4m)
95:5
96:4
95:5
91:9
91:9
98:2
96:4
98:2
79:21
86:14
76:24
91:9
98
96
>99
93
98
90
92
92
93e
59
72
93
9
10
11
12
n-Pr
4-ClC6H4
a
Reactions performed with 1 (1 mmol), 2 (0.5 mmol), (S)-a,a-diphenylprolinol trimethylsilyl ether (0.1 mmol), and imidazole
(0.1 mmol) in PhCH3 (1 mL) at 4 °C for 48 h.
b
Isolated yield of cis-4.
c
cis:trans determined by 1H NMR spectroscopy of crude 4.
d
The ee value of cis-4, which was determined by chiral HPLC analysis.
À20 °C for 96 h.
e
12).The absolute configuration of the spiro cis-d-lactone was deter-
mined to be 4S,5R by single-crystal X-ray analysis of the compound
cis-4b.14 Furthermore, we have studied the relationship between
the enantiomeric excess of spiro cis-d-lactone cis-4a and the
enantiomeric purity of the organocatalyst.15 Similar results were
observed compared to our previous work, which clearly showed
a modest negative non-linear effect.13a
References and notes
1. Elger, W.; Beier, S.; Pollow, K.; Garfield, R.; Shi, S. Q.; Hillisch, A. Steroids 2003,
68, 891–905.
2. Cimanga, K.; Hermans, N.; Apers, S.; Van Miert, S.; Van den Heuvel, H.; Claeys,
M.; Pieters, L.; Vlietinck, A. J. Nat. Prod. 2003, 66, 97–102.
3. (a) Bister, B.; Bischoff, D.; Strobele, M.; Riedlinger, J.; Reicke, A.; Wolter, F.; Bull,
A. T.; Zahner, H.; Fiedler, H. P.; Süssmuth, R. D. Angew. Chem., Int. Ed. 2004, 43,
2574–2576; (b) Riedlinger, J.; Reicke, A.; Zahner, H.; Krismer, B.; Bull, A. T.;
Maldonado, L. A.; Ward, A. C.; Goodfellow, M.; Bister, B.; Bischoff, D.; Süssmuth,
R. D.; Fiedler, H. P. J. Antibiot. 2004, 57, 271–279.
In summary, we have developed an efficient tandem Michael–
hemiacetalization reaction between 1-nitromethylcyclohexanol
4. Molander, G. A.; Quirmbach, M. S.; Silva, L. F.; Spencer, K. C., Jr.; Balsells, J. Org.
Lett. 2001, 3, 2257–2260.
and
a,b-unsaturated aldehydes for the construction of chiral
spiro cis-d-lactones by in situ oxidation of spiro d-lactols, which
are potential intermediates for the total synthesis of natural
products and pharmaceuticals. The resulting functionalized spiro
cis-d-lactones were formed in good overall yields with high to
excellent enantioselectivities. Moreover, aliphatic unsaturated
aldehydes can also be applied to this tandem reaction providing
corresponding products with moderate stereoselectivities.
5. Wovkulich, P. M.; Tang, P. C.; Chadha, N. K.; Batcho, A. D.; Barrish, J. C.;
Uskokovic´, M. R. J. Am. Chem. Soc. 1989, 111, 2596–2599.
6. Tanaka, N.; Okasaka, M.; Ishimaru, Y.; Takaishi, Y.; Sato, M.; Okamoto, M.;
Oshikawa, T.; Ahmed, S. U.; Consentino, L. M.; Lee, K. H. Org. Lett. 2005, 7, 2997–
2999.
7. Posner, G. H.; Hamill, T. G. J. Org. Chem. 1988, 53, 6031–6035.
8. For reviews on synthesis of spirolactones, see: (a) Bartoli, A.; Rodier, F.;
Commeiras, L.; Parrain, J. L.; Chouraqui, G. Nat. Prod. Rep. 2011, 28, 763–782; (b)
Rodriguez, S.; Wipy, P. Synthesis 2004, 17, 2767–2783.
9. For selected publications on synthesis of spirolactones: (a) Dohi, T.; Maruyama,
A.; Takenaga, N.; Senami, K.; Minamitsuji, Y.; Fujioka, H.; Caemmerer, S. B.;
Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 3787–3790; (b) Uyanik, M.; Yasui, T.;
Ishihara, K. Angew. Chem., Int. Ed. 2010, 49, 2175–2177; (c) Merlic, C. A.; Walsh,
J. C. J. Org. Chem. 2001, 66, 2265–2274; (d) Zhang, W.; Pugh, G. Tetrahedron Lett.
2001, 42, 5617–5620; (e) Maulide, N.; Markó, I. E. Org. Lett. 2006, 8, 3705–3707.
10. For reviews, see: (a) Enders, D.; Wang, C.; Liebich, J. X. Chem. Eur. J. 2009, 15,
11058–11076; (b) Sarah, S. M.; Alexandre, A. Chem. Commun. 2007, 3123–
3135; (c) Almasi, D.; Alonso, D. A.; Nájera, C. Tetrahedron: Asymmetry 2007, 18,
299–365; (d) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–1716.
11. Gotoh, H.; Okamura, D.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2009, 11, 4056–
4059.
Acknowledgments
This work was supported by the National Natural Science Foun-
dation of China (20902030) and The Central Colleges and Universi-
ties Basic Scientific Research Foundation of China (0117013919).
The Analysis and Testing Centre of Huazhong University of Science
and Technology is acknowledged for characterization of new
compounds.
12. Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105,
933–971.
13. (a) Zhang, F. L.; Wei, M. H.; Dong, J. F.; Zhou, Y. R.; Lu, D. F.; Gong, Y. F.; Yang, X.
L. Adv. Synth. Catal. 2010, 352, 2875–2880; (b) Xiong, G.; Wei, M. H.; Zhou, Y. R.;
Li, Y. G.; Zhang, F. L.; Gong, Y. F. Synthesis 2011, 21, 3439–3446; (c) Zhou, Y. R.;
Dong, J. F.; Zhang, F. L.; Gong, Y. F. J. Org. Chem. 2011, 76, 588–600.
14. The X-ray crystal structure of cis-4b is presented in Supplementary data.
15. The relationship between cis-4a ee and organocatalyst ee values is given in
Supplementary data.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.03.
039.