Organocatalytic asymmetric formal [3+3] cycloaddition reactions of α,β-unsaturated aldehydes with nazarov reagents

Article abstract of DOI:10.1002/adsc.200800174

An organocatalytic asymmetric formal [3+3] cycloaddition reaction of α,β-unsaturated aldehydes with Nazarov reagents promoted by prolinol derivatives afforded, after oxidation, 3,4-dihydropyranones in good yields with high enantioselectivities of up to 97

Full text of DOI:10.1002/adsc.200800174

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DOI: 10.1002/adsc.200800174
Organocatalytic Asymmetric Formal [3+3]Cycloaddition
Reactions of a,b-Unsaturated Aldehydes with Nazarov Reagents
Ming-Kui Zhu,a,c Qiang Wei,b and Liu-Zhu Gonga,b,*
a
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, Peopleꢀs Republic of China
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science
b
and Technology of China, Hefei 230026, Peopleꢀs Republic of China
Fax : (+86)-551-360-6266; e-mail: gonglz@ustc.edu.cn
Graduate School of Chinese Academy of Sciences, Beijing, Peopleꢀs Republic of China
c
Received: March 5, 2008; Published online: May 19, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An organocatalytic asymmetric formal
[3+3]cycloaddition reaction of a,b-unsaturated al-
dehydes with Nazarov reagents promoted by proli-
nol derivatives afforded, after oxidation, 3,4-dihy-
dropyranones in good yields with high enantioselec-
tivities of up to 97% ee.
derivatives[10,11] which, after a subsequent oxidation,
leads to the formation of 6-vinyl-3,4-dihydropyra-
nones 3 with excellent enantioselectivities (97% ee).
Keywords: asymmetric catalysis; formal [3+3]cy-
cloaddition; Nazarov reagents; organocatalysis;
prolinol derivatives; unsaturated aldehydes
Tetrahydropyran and dihydropyran derivatives are
structural subunits that commonly appear in numer-
ous natural products and biologically active com-
pounds;[1,2] they also serve as versatile and important
building blocks that have widespread applications in
organic synthesis.[2,3] Synthetic methods that yield
chiral tetrahydropyran and dihydropyran derivatives
have thus received much research interest. The focus
of studies on this synthetic methodology has been the
Very recently, an elegant study by Jørgensen and
development of asymmetric hetero-Diels–Alder co-workers revealed that a,b-unsaturated aldehydes 4
(HDA) reactions that provide an efficient pathway to underwent a tandem Michael/Morita–Baylis–Hillman
access 2,3-dihydropyran derivatives.[4] A number of reaction (MBH) with Nazarov reagent 5 in the pres-
excellent asymmetric HDA procedures catalyzed ence of prolinol derivatives 6, leading to the forma-
either by chiral Lewis acids[5] or by organic mole- tion of cyclohexenone derivatives with high levels of
cules[6,7] have readily afforded 3,4-dihydropyran deriv- stereoselectivity [Eq. (1)].[12]
atives 1 and 2 in high optical purity. Compared with 1
However, we observed that Nazarov reagent 9a,
and 2, the presence of a C=C bond conjugated to an which differs from 5 by the presence of a phenyl sub-
enol in 3 definitely increases the possibility for the stituent at C-5, did not undergo the tandem Michael/
structural modulation and thereby enhances the syn- Morita–Baylis–Hillman reaction under the promotion
thetic utility. However, no efficient synthetic method of 6a using para-nitrobenzoic acid as an additive, but
is yet available to access chiral vinyl-3,4-dihydropyran underwent rather a formal [3+3]cycloaddition reac-
architectures like 3. In this communication, we de- tion which, after oxidation using PCC, furnished a
scribe an organocatalytic asymmetric formal oxa-[3+ chiral pyranone in 86% yield with 88% ee (Table 1,
3]cycloaddition reaction[8] of a,b-unsaturated alde- entry 1). This interesting result, together with the im-
hydes with Nazarov reagents[9] catalyzed by prolinol portance of pyranones in organic synthesis, triggered
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Ming-Kui Zhu et al.
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Table 1. Catalyst screening and optimization of reaction con- the protected diarylprolinol derivatives showed good
ditions.[a]
catalytic activity and some of them provided high
yields when the reactions were conducted for 12 h.
The enantioselectivity varied depending highly on the
aryl substituent and 6a was identified as the optimal
catalyst (entry 1). Unprotected prolinol 6j showed no
stereoselectivity (entry 10). Lowering the reaction
temperature from room temperature to 08C enabled
the enantioselectivity to be improved to 95% ee when
either 6a or 6b was used as the catalyst while not
compromising the yields (entries 11 and 12). A survey
of solvents revealed that THF and toluene are not
suitable for the reaction, in which much lower enan-
tioselectivities were obtained (entries 14 and 15).
Other polar solvents such as chloroform, acetonitrile,
and ethanol all provided lower enantioselectivity than
dichloromethane (entries 13, 16, and 17). The best re-
sults were attained by conducting the reaction in di-
chloromethane (entry 11).
The optimized procedure was then extended to
formal [3+3]cycloaddition reactions between various
a,b-unsaturated aldehydes and Nazarov reagents
(Table 2). The scope of a,b-unsaturated aldehydes
was first investigated by their reaction with 9a. Cinna-
maldehydes with different substituents could be toler-
ated and underwent smooth cyclization reactions,
after oxidation with PCC, furnishing 11a–j in varying
yields and enantioselectivities that both depended
highly on the electronic features of the substituent in
the aldehydes. Accordingly, the electron-withdrawing
group facilitates the formation of the desired cyclic
products with excellent enantioselectivities ranging
from 91% to 96% ee (entries 1–6). However, cinna-
maldehyde and its analogues substituted with either a
methyl or a halogen provided comparably lower
enantioselectivities although the products were at-
tained in good yields (entries 7–11). Despite this, the
enantiopurity of 11h–j could be enhanced to over
99% ee by a single recrystallization to compensate the
disadvantage associated with the unsatisfactory ee
Entry
Catalyst
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
THF
86
86
73
66
54
71
70
67
65
44
88
82
63
71
68
83
81
88
86
82
79
68
83
68
84
70
0
95
95
90
78
82
90
93
9
10
11[d]
12[d]
13
14
15
16
17
6j
6a
6b
6a
6a
6a
6a
6a
PhCH3
CH3CN
EtOH
[a]
The reaction of 4a (0.24 mmol) with 9a (0.20 mmol) in
the presence of an organocatalyst 6 (0.02 mmol) and 4-ni-
trobenzoic acid (0.02 mmol) was performed in CH2Cl2
(1.0 mL) at 258C.
Isolated yield of 10a.
Determined by HPLC.
[b]
[c]
[d]
The reaction was performed at 08C.
us to optimize the reactions parameters. Various proli- (entries 9–11). Alkyl-substituted a,b-unsaturated alde-
nol derivatives were then screened for the model re- hydes show a poor reactivity. However, an acryl alde-
action between 4a and 9a. As shown in Table 1, all hyde with an ester substituent at the b-position pro-
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Table 2. Scope and limitations of the unsaturated aldehydes and Nazarov reagents.[a]
Entry
R1
R2
R3
11
Time [h]
Yield [%][b]
ee [%][c]
1
4-NO2C6H4 (4a)
3-NO2C6H4 (4b)
3-NO2C6H4 (4b)
2-NO2C6H4 (4c)
4-CF3C6H4 (4d)
4-CNC6H4 (4e)
Ph (4f)
4-CH3C6H4 (4g)
4-BrC6H4 (4h)
4-ClC6H4 (4i)
2,3-Cl2C6H3 (4j)
COOEt (4k)
4-NO2C6H4 (4a)
COOEt (4k)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
11a
11b
11b
11c
11d
11e
11f
11g
11h
11i
12
30
36
36
18
24
36
36
36
36
36
10
36
6
18
18
24
10
6
18
20
24
36
20
30
77
78
71
58
41
47
54
41
58
44
45
63
43
57
51
56
48
45
78
58
72
57
51
56
51
95
92
94
91
96
95
84
2
3[d]
4
5
6
7[d]
8
83
9
84 (>99[e])
10
11[f]
12
13
14
15
16
17
18
19
20
21
22
23
24[f]
25[f]
90 (>99[e])
11j
11k
11l
79 (>99[e])
97
96
96
94
94
92
97
96
91
93
92
81
93
92
t-Bu
CH2CH=CH2
CH2CH=CH2
CH2CH=CH2
Bn
Bn
Et
Et
Et
Et
Et
Et
Et
11m
11n
11o
11p
11q
11r
11s
11t
11u
11v
11w
11x
4-NO2C6H4 (4a)
3-NO2C6H4 (4b)
4-NO2C6H4 (4a)
COOEt (4k)
Ph
Ph
COOEt (4k)
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-NO2C6H4
4-CH3C6H4
4-OCH3C6H4
2-OCH3C6H4
3-NO2C6H4 (4b)
4-NO2C6H4 (4a)
4-NO2C6H4 (4a)
4-NO2C6H4 (4a)
3-NO2C6H4 (4b)
4-NO2C6H4 (4a)
[a]
The reaction mixture of 4 (0.24 mmol) with 9 (0.20 mmol), 6a (0.02 mmol), and 4-nitrobenzoic acid (0.02 mmol) was
stirred in CH2Cl2 (1.0 mL) at 08C.
Isolated yield of 11.
Measured by chiral HPLC.
The reaction was performed at À108C.
After a single recystallization.
Yield of the products of cyclization.
[b]
[c]
[d]
[e]
[f]
vided the desired product in 63% yield with 97% ee ture (Figure 1, for crystallographic data, see Support-
(entry 12). Evaluation of the effect of R3 group in the ing Information).
Nazarov reagents on the reaction indicated that the
The 3,4-dihydropyranol 10a has been readily re-
stereoselectivity is quite independent on the size of duced to tetrahydropyran 12a in moderate yield with
R3. However, the yield seemingly suffered with more an almost maintained enantiopurity by exposure to
bulky substituent (entries 13–18). The general toler- triethylsilane and Amberlyst resin in dichloromethane
ance of the substituent at C-5 of the Nazarov reagents under mild conditions [Eq. (2)].
was demonstrated by reactions with unsaturated alde-
According to these experimental results, we pro-
hydes 4a, 4b, and 4k (entries 19–25). Both the elec- posed a mechanism to account for the formal [3+
tron-rich and electron-poor aryl substitents at C-5 of 3]cycloaddition (Scheme 1). The unsaturated alde-
the Nazarov reagent could be tolerated and high hydes 4 first condensed with the chiral pyrrolidine 6
enantioselectivities of over 90% ee were realized, to generate iminium salts I.[11] Enantioselective Mi-
with the exception of the reaction with a Nazarov re- chael addition of Nazarov reagents 9 to the active
agent bearing a p-tolyl group at C-5 (entry 23). The iminium salts I afforded intermediates II.[12] Numer-
absolute configuration of the stereogenic center of 11j ous reports on the Morita–Baylis–Hillman reaction
was assigned to be S on the basis of the X-ray struc- have demonstrated that acyclic electron-deficient al-
Adv. Synth. Catal. 2008, 350, 1281 – 1285
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Ming-Kui Zhu et al.
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Figure 1. X-ray structure of 11j; thermal ellipsoids at 50% probability.
densation step releases the products 10 and the orga-
nocatalyst 6.
In conclusion, we have disclosed a formal [3+3]cy-
cloaddition reaction of a,b-unsaturated aldehydes
with Nazarov reagents bearing an aryl group at C-5
which, after oxidation, affords 3,4-dihydropyranones
in good yields with high enantioselectivities of up to
97% ee. In addition, chiral tetrahydropyrans could be
accessed in high enantiopurity by diastereoselective
reduction of the pyranols obtained directly from the
[3+3]cycloaddition reaction.
kenes with a substituent at the a-position are seem-
ingly not reactive components of the Baylis–Hillman
reaction.[13] Thus, the intermediates II have difficultly
to undergo the Morita–Baylis–Hillman reaction after
being isomerized to IV under the influence of pyrroli-
dine 6. Alternatively, the intermediates II can be iso-
merized to III that occur from an intramolecular oxo-
addition to form intermediates V. The hydrolysis of
intermediates V with water generated from the con-
Experimental Section
General Procedure for the Organocatalytic Asym-
metric Formal [3+3]Cycloaddition of a,b-Unsatur-
ated Aldehydes with Nazarov Reagents and Oxida-
tion to the Corresponding 6-Vinyl-3,4-dihydropyran-
ones
The catalyst 6 (0.02 mmol, 10 mol%), 4-nitrobenzoic acid
(0.02 mmol, 10 mol%) and the a,b-unsaturated aldehydes 4
Scheme 1. Proposed mechanism for the formal [3+3]cycloaddition of a,b-unsaturated aldehydes with Narzarov reagents.
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Organocatalytic Asymmetric Formal [3+3]Cycloaddition Reactions
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(0.24 mmol, 1.2 equiv.) were stirred at ambient temperature
in CH2Cl2 (1.0 mL) for 30 min, then stirred at 08C for
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15 min before the addition of Nazarov reagents
9
(0.2 mmol). The reaction mixture was stirred for 6–36 h. The
solvent was removed under reduced pressure and the resi-
due was purified through column chromatography on silica
gel. The products were stirred at ambient temperature in
CH2Cl2 (3 mL) for 10 min, then oxidized using PCC
(1.0 mmol, 5 equiv.) for 4 h. The solvent was removed under
the reduced pressure and the residue was purified through
column chromatography on silica gel.
Acknowledgements
We are grateful for financial support from National Science
Foundation of China (20732006 and 20325211) and the Chi-
nese Academy of Sciences.
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organocatalysis, see: b) Y. Hoashi, T. Yabuta, Y. Take-
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