Highly chemo- and diastereoselective synthesis of substituted tetrahydropyran-4-ones via organocatalytic oxa-Diels-Alder reactions of acyclic α,β-unsaturated ketones with aldehydes

Article abstract of DOI:10.1016/j.tetlet.2008.01.025

The first organocatalytic oxa-Diels-Alder reaction of acyclic α,β-unsaturated ketones with aldehydes is described. This reaction represents a highly chemo- and diastereoselective synthesis of substituted tetrahydropyran-4-ones in good yields with dr up to

Full text of DOI:10.1016/j.tetlet.2008.01.025

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1631–1635
Highly chemo- and diastereoselective synthesis of
substituted tetrahydropyran-4-ones via organocatalytic
oxa-Diels–Alder reactions of acyclic a,b-unsaturated
ketones with aldehydes
Liang-Qiu Lu a, Xiao-Ning Xing a, Xu-Fan Wang a, Zhi-Hui Ming a, Hong-Mei Wang a,b
Wen-Jing Xiao a,*
,
a Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan,
Hubei 430079, PR China
b Beijing Institute of Pharmaceutical Chemistry, Beijing 102205, China
Received 22 November 2007; revised 28 December 2007; accepted 8 January 2008
Available online 11 January 2008
Abstract
The first organocatalytic oxa-Diels–Alder reaction of acyclic a,b–unsaturated ketones with aldehydes is described. This reaction
represents a highly chemo- and diastereoselective synthesis of substituted tetrahydropyran-4-ones in good yields with dr up to >95:5.
Ó 2008 Elsevier Ltd. All rights reserved.
Substituted di- and tetrahydropyran rings are frequently
occurring structural motifs in biologically active natural
products.1 The oxa-Diels–Alder (ODA) reaction is a valu-
able method for the construction of six-membered oxygen-
containing ring systems.2 Many Lewis acid catalysts have
been well established for this particular transformation,3
while Brønsted acid, for instance, hydrogen bonding has
been also developed as a mode of activation for the ODA
reaction.4 However, only a few active dienes, such as Dani-
shefsky’s diene5 and Brassard’s diene,6 are used as the sub-
strates in most cases. Recently, Barbas and co-workers7a
reported amine catalyzed self-cycloaddition7b of a,b-unsat-
urated ketones, their direct Diels–Alder reaction with nitro
olefins,7c and Knoevenagel–Diels–Alder reaction.7d–f Criti-
cal to the success of this strategy involved in situ generation
of 2-amino-1,3-butadienes with amine catalyst provid-
ing for the synthesis of cyclohexanone derivatives. Utiliz-
ing the similar benign fashion, Yamamoto et al.8a,b and
8c
´
Cordova have also developed the organocatalytic asym-
metric hetero-Diels–Alder (HDA) reactions using cyclic
a,b-unsaturated ketones with nitroso compounds and imi-
nes as dienophiles, respectively. However, to the best of our
knowledge, there is no organocatalytic HDA reaction yet
involving acyclic a,b-unsaturated ketones probably due
to the favored formation of the trans acyclic dienes, which
is disadvantageous for the progress of the HDA reaction.
Accordingly, the exploration of such reaction between
acyclic a,b-unsaturated ketones with aldehydes should pro-
vide new protocol toward selective synthesis of biologically
important tetrahydropyran rings.
Recently, we have reported that chiral secondary amine
catalysts can react with ketones or aldehydes forming
enamines intermediate, which can be exploited as nucleo-
philes in aldol9a–d and Michael reactions,9e,f or imines
intermediates to realize inter- and intramolecular Friedel–
Crafts reactions.9g,h Based on the mechanism of amine
catalysis, we envisioned that enamines generated from
a,b-unsaturated ketones and amine would act as dienes
*
Corresponding author. Tel./fax: +86 27 67862041.
E-mail address: wxiao@mail.ccnu.edu.cn (W.-J. Xiao).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.025

1632
L.-Q. Lu et al. / Tetrahedron Letters 49 (2008) 1631–1635
and undergo ODA reactions with aldehydes. Herein, we
demonstrate the first organocatalytic ODA reaction of
acylic a,b-unsaturated ketones with aldehydes for the con-
struction of six-membered oxa-heterocycles.
Considering the possible side reactions between a,b-
unsaturated ketones with aldehydes catalyzed by amine,
for example, aldol reaction, self-DA reaction of a,b-unsat-
urated ketones, and Baylis–Hillman reaction (Scheme 1),
we initially studied a variety of parameters for the reaction
of a,b-unsaturated ketones with aldehydes to provide tetra-
hydropyran derivatives by the ODA approach. Some
selected results are shown in Table 1.
Application of pyrrolidine and HOAc as the ODA reac-
tion catalytic system (Table 1) was firstly studied by mixing
1a (2.5 mmol) with 2a (0.5 mmol) and pyrrolidine
(0.15 mmol), HOAc (0.15 mmol) in dichloromethane
(0.5 mL) at room temperature. Fortunately, the syn ODA
product 3a (Scheme 2) was obtained in 65% isolated yield
after 24 h when the full conversion of 2a was observed by
1H NMR (Table 1, entry 1), with dr (syn/anti) = 90:10
and ODA/aldol product = 87:13. However, when other
amines, such as dibenzylamine, morpholine, and piperidine
were used as the catalyst, the reaction proceeded much
more slowly with decreased diastereoselectivities or
chemo-selectivities (Table 1, entries 2–4). Variation in co-
catalysts,9,10 Brønsted acid, of pyrrolidine catalyst was next
investigated and we found that this changing had a very
pronounced effect on the reaction (Table 1, entries 1, 6–8).
As can be seen from Table 1, weak acid, such as HOAc,
PhCO2H can effectively promote the ODA reaction, while
stronger acid, NCCH2CO2H, showed somewhat poorer
results. No reaction happened when very strong acid HCl
was used. Notably, without any acid, a slight decrease in
the chemo- and diastereoselectivities was observed though
with comparable conversion (Table 1, entries 1 vs 5). Pre-
sumably, the tautomerization of enamine and imine inter-
mediates may be sensitive to the nature of acid that are
crucial to the ODA reaction. When strong acid was
employed as the co-catalyst, the conjugated imine inter-
mediate might be dominant,9g which was detrimental to both
ODA and aldol reactions. After further examination of the
solvents, dichloromethane was the best of choice in terms
O
O
O
O
O
OH
R'
OH
R
O
O
amine catalyst
+
+
+
+
R'
R
R
H
R'
R
R'
R
R
O
1
2
ODA product
Aldol product
Self-DA product B-H product
3-C 3-D
3-A
3-B
Scheme 1. Envisaged oxa-Diels–Alder reactions and possible side reactions of a,b-unsaturated ketones with aldehydes.
Table 1
Optimization of the reaction conditionsa
O
O
30 mol % catalyst
30 mol % co-catalyst
CHO
Aldol adduct
+
+
Ph
O
solvent (1.0 M)
rt
O2N
Ph
NO2
1a
2a
3a
4a
Entry
Catalyst
Co-catalyst
Solvent
Conv.b
3a/4ab
dr (syn/anti)b
1
2
3
4
5
6
7
8
9
10
11
12
13
a
Pyrrolidine
Bn2NH
HOAc
HOAc
HOAc
HOAc
No acid
PhCO2H
NCCH2CO2H
HCl
HOAc
HOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
>99
<5
31
40
97
99
44
<5
84
98
92
99
99
87:13
NDc
90:10
NDc
Morpholine
Piperidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
79:21
90:10
85:15
71:29
70:30
NDc
69:13
62:38
76:24
71:29
77:23
81:19
73:27
84:16
90:10
75:25
NDc
68:32
81:29
83:17
83:17
82:18
i-BuOH
CHCl3
THF
HOAc
HOAc
HOAc
Toluene
All reactions were carried out using 1 equiv of 2a, 5 equiv of 1a in the presence of 30 mol % of catalyst and 30 mol % of co-catalyst in 0.5 mL of solvent
at room temperature, 24 h.
b
Determined by 1H NMR.
Not determined.
c

L.-Q. Lu et al. / Tetrahedron Letters 49 (2008) 1631–1635
1633
Scheme 2. The related configuration of product 3a determined by X-ray.11
of selectivity and reaction efficiency. So, we chose the follo-
wing parameters for the highly chemo- and diastereoselec-
tive ODA reaction of a,b-unsaturated ketones with
aldehydes: pyrrolidine as catalyst, HOAc as co-catalyst
and dichloromethane as reaction medium.
Based on the above observation and related litera-
tures,7,8a–c a possible mechanism was proposed to account
for the chemoselectivity of the reaction (Scheme 3). The
pyrrolidine catalyst reacts first with a,b-unsaturated ketone
1 to form diene A, which then is attacked by 2 affording
activated iminium salt B. The oxygen anion of the iminium
salt B undergoes the subsequent cyclization to furnish the
corresponding six-membered oxygen-containing ring C,
while competitive aldol reaction proceeds if the oxygen
anion captures a proton before it attacks the b-position
of conjugated iminium salt B. The ODA adduct is obtained
after hydrolysis and the pyrrolidine is released for the next
catalytic cycle. The high syn-selectivity was ascribed to the
lower energy of transition state when both subsititutes are
in e-position.
Under the optimal reaction conditions, the scope of the
ODA reaction was examined with a number of a,b-unsat-
urated ketones and aromatic aldehydes. As presented in
Table 2, pyrrolidine and HOAc catalyzed the reactions
between 1 and 2 efficiently to provide the substituted tetra-
hydropyran-4-ones derivatives 3. All reactions shown in
Table 2 gave the desired ODA products as the major prod-
ucts with high chemo- and diastereoselectivities. Signifi-
cantly, the ODA adducts and Aldol adducts can be easily
separated by column chromatography. However, this strat-
egy was limited to activated aromatic aldehydes, such as
p-nitrobenzaldehyde, o-nitrobenzaldehyde, m-nitrobenzalde-
hyde, and p-cyanobenzaldehyde (Table 1, entries 1–4).12
For the a,b-unsaturated ketones, both aromatic and ali-
phatic ketones with electronic and steric variations are well
tolerated in this reaction.
Finally, an attempt to carry out the organocatalytic
asymmetric version of this reaction has also been tried.
The bifunctional organocatalyst 5, originally developed
for enantioselective Aldol reactions of ketones,9a–d was
employed in the reaction of 1a and 2a (Scheme 4). The
reaction gave promising results with 45% yield, 77:23 dr,
Table 2
Organocatalytic oxa-Diels–Alder reaction of a,b-unsaturated ketones and aldehydesa
O
O
30 mol % pyrrolidine
30 mol % HOAc
R2CHO
+
+
Aldol adduct
CH2Cl2 (1.0 M), rt
R1
R1
O
3
R2
1
2
4
Entry
R1
R2
Time (h)
3/4b
87:13
93:7
>95:5
>95:5
85:15
91:9
Yieldc (%)
dr (syn/anti)b
1
2
3
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
p–NO2–Ph (1b)
p-Cl–Ph (1c)
p-Br–Ph (1d)
m-Br–Ph (1e)
p-MeO–Ph (1f)
C6H11 (1g)
p-NO2–Ph (2a)
o-NO2–Ph (2b)
m-NO2–Ph (2c)
p-NC–Ph (2d)
p-NO2–Ph (2a)
p-NO2–Ph (2a)
p-NO2–Ph (2a)
p-NO2–Ph (2a)
p-NO2–Ph (2a)
p-NO2-Ph (2a)
24
24
24
96
24
21
24
24
21
21
65 (3a)
62 (3b)
67 (3c)
78 (3d)
66 (3e)
55 (3f)
65 (3g)
69 (3h)
80 (3i)
56 (3j)
90:10
95:5
92:8
94:6
92:8
93:7
93:7
92:8
>95:5
95:5
4
5d
6
7
8
9
94:6
>95:5
>95:5
95:5
10
a
All reactions were carried out using 1 equiv of aldehyde, 5 equiv of a,b-unsaturated ketone in the presence of pyrrolidine (30 mol %) and HOAc
(30 mol %) in 0.5 mL of CH2Cl2 at room temperature.
b
Determined by 1H NMR.
Isolated yield.
c
d
Reaction was carried out in THF.

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L.-Q. Lu et al. / Tetrahedron Letters 49 (2008) 1631–1635
O
H2O
1
R
N
O
N
H
R
A
R'CHO
R
O
3
R'
2
N
R
H2O
O
R'
H2O
TS
N
N
N
H3O
N
OH
H
O
OH
R'
R'
R
O
R'
R
O
B
R'
R
R
4
C
D
Scheme 3. Proposed mechanism for the pyrrolidine catalyzed oxa-Diels–Alder reaction.
O
O
O
CHO
20 mol % Cat. 5
20 mol % HOAc
+
Ph
Ph
O2N
THF (1.0 M), rt, 72 h
NO2
1a
2a
3a
45% yield,
77/23 dr, 40% ee
O
O
NH HN
NH
Cat. 5
Scheme 4. Asymmetric catalytic oxa-Diels–Alder reaction of 1a and 2a.
and 40% ee of the cis isomer. Attempts to carry out this
asymmetric ODA reaction with L-proline as the catalyst
were unsuccessful.
In summary, we have demonstrated for the first time
organocatalyzed ODA reaction of acyclic a,b-unsaturated
ketones with aldehydes to generate substituted tetrahydro-
pyran rings. High chemo- and diastereoselectivities were
obtained by the use of pyrrolidine and HOAc as the organ-
ocatalysts.13 Further studies on the chiral amine catalyzed
asymmetric ODA reactions are underway in our laboratory.
References and notes
1. Ruijter, E.; Schultingkemper, H.; Wessjohann, L. A. J. Org. Chem.
2005, 70, 2820.
2. (a) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder Methodology in
Organic Synthesis; Academic Press: San Diego, 1987; (b) Boger, D. L.
In Comprehensive Organic Synthesis; Pergamon: New York, 1991;
Vol. 5, p 451.
3. (a) Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007; (b) Jørgensen,
K. A. Angew. Chem., Int. Ed. 2000, 39, 3558; (c) Kumar, A.
Chem. Rev. 2001, 101, 1; (d) Jørgensen, K. A. Eur. J. Org. Chem.
2004, 2093; (e) Gouverneur, V.; Reiter, M. Chem. Eur. J. 2005, 11,
5806.
Acknowledgments
4. (a) Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662; (b)
Domingo, L. R.; Andres, J. J. Org. Chem. 2003, 68, 8662; (c) Huang,
Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146;
(d) Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am.
Chem. Soc. 2005, 127, 1336; (e) Rojaram, S.; Sigman, M. S. Org. Lett.
2005, 7, 5473; (f) Polo, V.; Domingo, L. R.; Adres, J. J. Phys. Chem.
A 2005, 109, 10438; (g) Tonoi, T.; Mikami, K. Tetrahedron Lett. 2005,
46, 6355.
5. Danishefsky, S.; Kerwin, J. F. J. J. Org. Chem. 1982, 47, 3183.
6. Savard, J.; Brassard, P. Tetrahedron Lett. 1979, 20, 4911.
7. (a) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004,
37, 580; (b) Thayumanowan, R.; Dhevalapally, B.; Sakthivel, K.;
Tanaka, F.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 3817; (c)
Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Tetrahedron
Lett. 2002, 43, 6743; (d) Ramachary, D. B.; Chowdari, N. S.; Barbas,
C. F., III. Angew. Chem., Int. Ed. 2003, 42, 4233; (e) Ramachary, D.
We are grateful to the National Science Foundation of
China (20472021 and 20672040), the Program for New
Century Excellent Talents in University (NCET-05-0672),
and the Cultivation Fund of the Key Scientific and Techni-
cal Innovation Project (Ministry of Education of China,
No. 705039) for support of this research.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.01.025.

L.-Q. Lu et al. / Tetrahedron Letters 49 (2008) 1631–1635
1635
B., ; Chowdari, N. S.; Barbas, C. F., III. Synlett 2003, 1910; (f)
Ramachary, D. B.; Anebouselvy, K.; Chowdari, N. S.; Barbas, C. F.,
III. J. Org. Chem. 2004, 69, 5838.
Yoda, H., ; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem.
Soc. 2006, 128, 734.
11. Single crystal X-ray diffraction data for 3a at 292 K on a Bruker
Smart Apex Area CCD equipped with Mo Ka radiation (k =
8. (a) Yamamoto, Y.; Momiyama, N.; Yamamoto, H. J. Am. Chem.
Soc. 2004, 126, 5962; (b) Momiyama, N.; Yamamoto, Y.; Yamamoto,
H. J. Am. Chem. Soc. 2007, 129, 1190; (c) Sundn, H.; Ibrahem, I.;
˚
0.71073 A). Crystallographic data (excluding structure factors) for
the structures in this Letter have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication No.
CCDC 638439. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: +44 1223 336033 or email: deposit@ccdc.cam.ac.uk).
´
Eriksson, L.; Cordova, A. Angew. Chem., Int. Ed. 2005, 44, 4877.
More recently, for alternate organocatalytic approaches to activated
dienes in situ, Rueping’s group and Gong’s group independently
reported the Brønsted acid catalyzed asymmetric Azo-Diels–Alder
reactions between cyclohexenone and imines, where acid induced the
formation of diene: (d) Rueping, M.; Azap, C. Angew. Chem., Int. Ed.
2006, 45, 7832; (e) Liu, H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong,
L.-Z. Org. Lett. 2006, 8, 6023.
12. When active aliphatic aldehydes, such as 2,2,2-trichloro-acetaldehyde
and ethyl glycoxylic acid were used, only aldol adducts were isolated
as the main products.
13. Representative procedure: a,b-unsaturated ketone 1a (2.5 mmol),
pyrrolidine (0.15 mmol), and HOAc (0.15 mmol) were stirred in
0.5 mL dichloromethane for 30 min at room temperature. Aldehyde
2a (0.5 mmol) was added and the mixture was then stirred until the
completion of the reaction (monitored by TLC). The crude mixture
was purified to give oxa-Diels–Alder adduct 3a through flash column
chromatography on silica gel (hexane/ ethyl acetate = 6:1). 3a: pale
yellow solid. 1H NMR d 8.25 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz,
1H), 7.48–7.36 (m, 5H), 4.98 (dd, J1 = 12 Hz, J2 = 2.4 Hz, 1H), 4.88
(dd, J1 = 10.4 Hz, J2 = 4.4 Hz, 1H), 2.80–2.60 (m, 4H); 13C NMR d
204.7, 147.6, 147.4, 140.0, 128.7, 128.3, 126.3, 125.5, 123.8, 78.9, 77.6,
49.3, 49.1. MS: m/z = 297.1. Anal. Calcd for C17H15NO4: C, 68.59; H,
5.07; N, 4.75. Found: C, 68.68; H, 5.09; N, 4.71. The enantiomeric
excess was determined by HPLC (Chiralpak OD column, hexane/
i-PrOH 80:20, flow rate 1 mL/min; tminor = 31.8 min; tmajor = 41.3 min,
k = 254 nm).
9. (a) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.; Xiao,
W.-J. Org. Lett. 2005, 7, 4543; (b) Chen, J.-R.; Li, X.-Y.; Xing,
X.-N.; Xiao, W.-J. J. Org. Chem. 2006, 71, 8198; (c) Huang, W.-P.;
Chen, J.-R.; Li, X.-Y.; Cao, Y.-J.; Xiao, W.-J. Can. J. Chem. 2007,
85, 208; (d) Chen, J.-R.; Liu, X.-P.; Zhu, X.-Y.; Li, L.; Qiao, Y.-F.;
Zhang, J.-M.; Xiao, W.-J. Tetrahedron 2007, 63, 10437; (e) Cao,
Y.-J.; Lu, H.-H.; Lai, Y.-Y.; Lu, L.-Q.; Xiao, W.-J. Synthesis 2006,
22, 3795; (f) Cao, Y.-J.; Lai, Y.-Y.; Wang, X.; Li, Y.-J.; Xiao, W.-J.
Tetrahedron Lett. 2007, 48, 21; (g) Li, D.-P.; Guo, Y.-C.; Ding, Y.;
Xiao, W.-J. Chem. Commun. 2006, 799; (h) Li, C.-F.; Liu, H.; Liao,
J.; Cao, Y.-J.; Liu, X.-P.; Xiao, W.-J. Org. Lett. 2007, 9,
1847.
10. For some examples about co-catalyst effects on chemoselectivity and
stereoselectivity, see: (a) Peelen, T. J.; Chi, Y.; Gellman, S. H. J. Am.
Chem. Soc. 2005, 127, 11598; (b) Mase, N.; Nakai, Y.; Ohara, N.;