Asymmetric one-pot four-component coupling reaction: Synthesis of substituted tetrahydropyrans catalyzed by diphenylprolinol silyl ether

Article abstract of DOI:10.1002/anie.201005386

(Chemical Equation Presented) Domino effect: The title reaction uses an asymmetric Michael/Henry reaction/acetalization/Lewis acid mediated allylation reaction to provide highly substituted tetrahydropyrans with excellent enantioselectivity (see scheme; TMS=trimethylsilyl). All the carbon atoms in the tetrahydropyran ring are substituted with different groups, and the relative and absolute stereochemistry of the five contiguous carbon centers are completely controlled.

Full text of DOI:10.1002/anie.201005386

Communications
DOI: 10.1002/anie.201005386
Organocatalysis
Asymmetric One-Pot Four-Component Coupling Reaction: Synthesis
of Substituted Tetrahydropyrans Catalyzed by Diphenylprolinol Silyl
Ether
Hayato Ishikawa, Satoshi Sawano, Yusuke Yasui, Yusuke Shibata, and Yujiro Hayashi*
Multicomponent coupling reactions are one of the most
powerful methods for assembling a single molecule from
multiple starting materials and for forming several bonds in a
one-pot process.[1] This uninterrupted sequence of reactions in
a single flask eliminates several purifications, minimizes the
generation of chemical waste, and saves time. Many successful
examples of four-component reactions have been reported,
such as the Ugi reaction,[2] and the anion relay chemistry
reported by Smith et al.[3] The field of organocatalysis has
developed rapidly in recent years,[4] and some organocatalyst-
mediated four-component coupling reactions have been
established.[5]
Tetrahydropyran is a synthetically important structural
unit that is found in many natural products. Many methods
have been developed for the preparation of the chiral
tetrahydropyran structure,[6] including the hetero-Diels–
Alder reaction,[7] intramolecular epoxide opening,[8] Ferrier
rearrangement,[9] and the Prins reaction.[10]
the combination of the Michael reaction and a gold-catalyzed
acetalization.[16] Our group reported the domino Michael/
Henry reaction for the formation of chiral cyclohexane
derivatives,[17] and recently we reported the synthesis of
(ꢀ)-oseltamivir in two steps with a four-component coupling
reaction as a key step.[18] We hypothesized that tetrahydro-
pyran derivatives could be produced if the Michael adduct 2
[Eq. (2)] reacted with the aldehyde through the Henry
reaction to produce the alcohol 3, the hydroxy group of
which would readily react intramolecularly with the aldehyde
moiety to form the acetal, and thus generate the tetrahydro-
pyranol 4. Recently a similar reaction sequence was reported
for an asymmetric three-component reaction, in which the
conjugate addition of an aldehyde to a Michael acceptor was
catalyzed by diphenylprolinol silyl ether, with a subsequent
base-catalyzed addition/cyclization.[19] We thought that tetra-
hydropyranol 4 would react with a nucleophile to provide a
tetrahydropyran, in which all the carbon atoms on the pyran
ring are substituted with different groups. We report herein
the results of the experiments performed to demonstrate this
hypothesized process.
We have previously reported the asymmetric direct
Michael reaction of an aldehyde and a nitroalkene,[11]
catalyzed by diphenylprolinol silyl ether 1,[12] which was
independently developed by our group[11] and the group of
Jørgensen.[13] This synthetically important reaction[14] yields a
chiral g-nitroaldehyde with excellent enantioselectivity
[Eq. (1); TMS = trimethylsilyl]; such an aldehyde is a useful
intermediate that can be utilized in subsequent transforma-
tions. For instance, Enders and co-workers reported the
domino reaction[1d,e] for the synthesis of chiral cyclohexene-
carbaldehyde based on this reaction,[15] and Krause, Alexakis,
and co-workers developed a domino reaction that involved
Ethyl glyoxylate was chosen as an electrophilic aldehyde
because the anticipated 6-carboxy tetrahydropyran product is
a synthetically important building block. At the outset
propanal, nitrostyrene, and ethyl glyoxylate[20] were selected
as model substrates. Thus, the g-nitroaldehyde 2a (Table 1),
generated from the Michael addition of propanal to nitro-
styrene by our established method,[11] was treated with ethyl
glyoxylate in the presence of a base to produce a substituted
tetrahydropyranol derivative. The effect of the base (Table 1)
was studied using this one-pot reaction. The first Michael
reaction proceeded in the presence of 5 mol% of catalyst 1 in
toluene at room temperature for 7 hours. A small quantity of
[*] Dr. H. Ishikawa, S. Sawano, Y. Yasui, Y. Shibata, Prof. Dr. Y. Hayashi
Department of Industrial Chemistry, Faculty of Engineering
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
Fax : (+81)3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
Homepage: http://www.ci.kagu.tus.ac.jp/lab/org-chem1/
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005386.
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Angew. Chem. Int. Ed. 2011, 50, 3774 –3779

Table 1: The effect of base in the one-pot synthesis of tetrahydropyranol
produce the tetrahydropyran derivatives with good yield and
excellent enantioselectivity (Table 2, entries 2 and 3). In
addition to aromatic groups heteroaromatic groups including
pyridine and furan were also suitable (Table 2, entries 4 and
5). A tetrahydropyranol that contains two different ester
moieties can be successfully synthesized from tert-butyl 3-
nitropropenoate (Table 2, entry 6). The reaction can also be
applied to b-alkyl-substituted nitroethene, which produces
substituted tetrahydropyranols with excellent enantioselec-
tivity (Table 2, entries 7 and 8). With respect to the nucleo-
philic aldehyde, butanal, isovaleraldehyde, and 3-phenylpro-
panal were suitable aldehydes in addition to propanal, and the
tetrahydropyranol derivatives were obtained with excellent
enantioselectivity (Table 2, entries 9–11). A highly substi-
tuted tetrahydropyranol having an alkoxy and two ester
moieties was prepared with excellent enantioselectivity
(Table 2, entry 12).
derivatives.[a]
Entry Base Base
[equiv]
T [8C] t [h]
Yield
[%][b]
7
The kinetic product 6 has the nitro group in the axial
position, whereas the thermodynamic compound 7 has the
nitro moiety in the equatorial position. Therefore, the
isomerization of 6 into 7 was investigated. When 6 was
treated with DBU (1.0 equiv) at 08C for 1.5 hours, isomer-
ization into 7 occurred with a 95% yield [Eq. (3)]. This
6
8
1
2
3
4
5
DBU
DBU 0.1
Et3N
Et3N
2
23 17
23 10
<5
56
10
<5
<5
<5
<5
73
22[c]
24[c]
2
2
2
0
1
71 (98)[d]
ꢀ50 21
76 (>99)[d] 15[c]
K2CO3
23
1
76 (98)[d]
18[c]
[a] Reaction conditions: nitrostyrene (1.0 mmol), propanal (1.2 mmol),
catalyst 1 (0.05 mmol), ethyl glyoxylate (261 mL, 1.2 mmol; used in the
polymer form as a 47% toluene solution), toluene (1.0 mL). See the
Supporting Information for detail. [b] Yield of the isolated product.
[c] Isolated as an anomeric mixture. [d] Enantiomeric excess of 6 that was
determined by HPLC analysis on a chiral stationary phase. DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene.
indicates that good yields of both isomers 6 and 7 can be
obtained.
1
the reaction mixture was analyzed using H NMR spectros-
copy, which indicated that complete conversion had occurred
with a 10:1 diastereoselectivity. A toluene solution of the
polymeric form of ethyl glyoxylate and base was added to the
toluene solution of the first Michael adduct. When two
equivalents of DBU were used, the reaction produced a 56%
yield of tetrahydropyranol 7 and a 10% yield of dihydropyr-
anol 8 (Table 1, entry 1); the latter is formed by the
elimination of nitrous acid. When the quantity of the base
was decreased another isomer (6) having the nitro moiety in
the axial position was obtained (73% yield) along with a
mixture of other diastereomers (22% yield; Table 1, entry 2).
Compound 6 is the kinetic product obtained with excellent
enantioselectivity, whereas compound 7 is the thermody-
namic product (see below). Further investigation revealed
that compound 6 is the predominant product when Et3N and
K2CO3 are used as the base, and is obtained in good yield
(Table 1, entries 3–5). However, when all the reagents are
mixed together initially, instead of adding the ethyl glyoxylate
and base after the generation of the Michael product 2a, only
traces of the desired product were obtained.
Next we investigated the reaction using p-nitrobenzalde-
hyde as an electrophilic aldehyde. It was found that the one-
pot reaction also proceeded smoothly to produce good yields
of the 6-p-nitrophenyl-substituted tetrahydropyranols 9 and
10 with excellent enantioselectivity; in this reaction the
stereochemistry at the C6 position was completely controlled
[Eq. (4)]. The tetrahydropyranol 9 was successfully converted
quantitatively into the thermodynamically more stable 10 by
treatment with DBU in CH3CN. By adding DBU to the
reaction of a nitroalkane and an aldehyde, the Henry reaction
Having determined the best reaction conditions, the
general nature of the reaction could be investigated
(Table 2). In addition to nitrostyrene, b-aryl-substituted
nitroethenes were also found to be suitable substrates.
Phenyl groups that have electron-rich and electron-deficient
substituents at the para position were successfully used to
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Table 2: The general reaction of nitroalkene, aldehyde and ethyl glyoxylate in the one-pot synthesis of tetrahydropyranols.[a]
Entry
R1
R2
t1
[h]
T
[8C]
t2
[h]
Product
Yield
ee
[%][b,c]
[%][d]
1
2
3
Ph
Me
Me
Me
6
ꢀ50
21
55
9
76 (1:11)
75 (1:7)
>99
96
p-MeOC6H4
p-BrC6H4
10
8
ꢀ50
ꢀ50
67 (1:10)
49 (1:16)
74 (1:>20)
50 (1:6)
98
4
3-pyridyl
2-furyl
tBuO2C
PhCH2CH2
cyclohexyl
Ph
Me
Me
Me
Me
Me
Et
12
12
4
ꢀ50
12
9
98
5
ꢀ30
>99
98
6
ꢀ50
24
16
42
7
7
12
120
26
156
67
ꢀ30!ꢀ10
ꢀ20!0
ꢀ20
64 (1:1.4)
51 (1:3.5)
74 (1:9)
98
8
91
9
91
10
11
Ph
iPr
ꢀ20
8
81 (1:7)
99
Ph
PhCH2
ꢀ20
4
70 (1:7)
95
12
tBuO2C
Et2CHO
3
ꢀ50!ꢀ20
6
44 (1:2.9)
92
[a] Reaction conditions: nitroalkene (1.0 mmol), aldehyde (1.2 mmol), catalyst 1 (0.05 mmol), ethyl glyoxylate (261 mL, 1.2 mmol; used in the polymer
form as a 47% toluene solution), toluene (1.0 mL). See the Supporting Information for details. [b] Yield of the isolated product. [c] The figure in the
brackets is the diastereomeric ratio of a and b isomers. [d] Determined by HPLC analysis on a chiral stationary phase.
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Angew. Chem. Int. Ed. 2011, 50, 3774 –3779

Table 3: One-pot synthesis of tetrahydropyranols by an asymmetric Michael/Henry/acetalization/isomerization reaction sequence.[a]
Entry
R1
R2
R3
t1
[min]
t2
[h]
Product
Yield
ee
[%][b,c]
[%][d]
1[e,f]
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
CO2Et
15
15
15
15
15
38
5
79 (1:2.9)
79 (1:1)
99
99
94
99
95
2
Ph
3
1-naphthyl
2-naphthyl
p-BrC6H4
5
71 (1:1.3)
75 (1:4.7)
89 (1:1.6)
4
7
5[e]
21
6
Ph
Me
p-NO2C6H4
15
10
89 (1:13)
96
7
Ph
Ph
Ph
Ph
Me
Me
Me
Me
p-MeOC6H4
2-furyl
15
15
15
15
21
8
74 (1:1.3)
84 (1:2.2)
50 (1:1.5)
91 (1:2.1)
98
97
98
99
8[e]
9
styryl
7
10
3-pyridyl
3
11
12
13
Ph
iPr
Ph
Ph
Ph
1140
15
6
85 (1:2)
96
96
95
p-BrC6H4
p-MeOC6H4
Me
Me
5
86 (1:1.3)
78 (1:1.5)
15
23
[a] Reaction conditions: nitroalkene (1.0 mmol), nucleophilic aldehyde (1.2 mmol), electrophilic aldehyde (1.2 mmol), p-nitrophenol (0.05 mmol), and
catalyst 1 (0.05 mmol). Unless otherwise shown, the reaction was performed at room temperature. Toluene was employed in the Michael reaction and
CH3CN was used in the subsequent reaction. See the Supporting Information for details. [b] Yield of the isolated product. [c] The figure in the
parenthesis is the diastereomer ratio of a and b isomers. [d] Determined by HPLC analysis on a chiral stationary phase. [e] Toluene was employed in
the Henry/acetalization/isomerization reaction. [f] The reaction was performed at ꢀ208C.
Angew. Chem. Int. Ed. 2011, 50, 3774 –3779
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Communications
and acetalization, with subsequent isomerization proceeded
In summary, we have developed an asymmetric one-pot
synthesis of substituted tetrahydropyranols with excellent
diastereo- and enantioselectivity through the diphenylproli-
nol silyl ether mediated Michael reaction of aldehydes and
nitroalkenes, with subsequent Henry and acetalization reac-
tions. The one-pot four-component coupling reaction was also
realized by using an asymmetric Michael/Henry reaction/
acetalization/Lewis acid mediated allylation reaction to
provide highly substituted tetrahydropyran derivatives with
excellent diastereo- and enantioselectivity. All the carbon
atoms on the tetrahydropyran ring are substituted with
different groups, and the relative and absolute stereochem-
istry of the five contiguous carbon centers is completely
controlled. As the allyl moiety can be easily transformed into
other functional groups, the 2-allyl tetrahydropyran gener-
ated is a useful chiral building block.
in one pot to afford 10 in good yield (89%; Table 3, entry 5).
The scope of the selective synthesis of the thermodynami-
cally stable tetrahydropyranol, from the nitroalkene and two
different aldehydes, by a one-pot sequence involving the
asymmetric Michael/Henry/acetalization/isomerization reac-
tions was investigated (Table 3). As we found that the first
Michael reaction was accelerated by acid, this reaction was
performed in the presence of 5 mol% of p-nitrophenol, and
was completed within 15 minutes. Not only ethyl glyoxylate,
but also aromatic aldehydes, such as benzaldehyde, reacted
efficiently to afford the tetrahydropyranol in good yield and
with excellent diastereo- and enantioselectivities. Both elec-
tron-deficient aromatic aldehydes such as p-bromobenzalde-
hyde and p-nitrobenzaldehyde (Table 3, entries 5 and 6,
respectively) and electron-rich aromatic aldehydes such as
p-anisaldehyde (Table 3, entry 7) afforded the corresponding
tetrahydropyranols with excellent enantioselectivity. Hetero-
aromatic aldehydes such as furfural (Table 3, entry 8) were
also successfully employed.
The tetrahydropyranols had
Table 4: One-pot synthesis of tetrahydropyrans by the asymmetric Michael/Henry/acetalization/
been prepared in a highly diastereo-
and enantioselective manner. We
next investigated the four-compo-
nent coupling reaction to give
access to tetrahydropyranes, which
are synthetically useful chiral build-
ing blocks. The three-component
coupling product, which was gener-
ated above, was directly treated
with allyltrimethylsilane or triethyl-
silane in the presence of a Lewis
acid. After optimization of the
reaction conditions, TiCl4 was
found to be a suitable promoter to
afford the highly substituted tetra-
hydropyran with excellent enantio-
selectivity (Table 4). Not only benz-
aldehyde (Table 4, entry 1), but also
1- and 2-naphthalenecarbaldehyde,
and p-bromobenzaldehyde were
successfully employed as electro-
isomerization/nucleophilic addition reaction sequence.[a]
Entry
1
R
Nucleophile
t1
[h]
t2
[h]
Product
Yield
[%][b]
ee
[%][c]
=
Ph
CH2 CHCH2TMS
5
6
4
4
6
72
60
65
73
99
94
99
95
=
2
3
4
1-naphthyl
2-naphthyl
p-BrC6H4
CH2 CHCH2TMS
12
12
5
=
CH2 CHCH2TMS
philic
aldehydes
(Table 4,
entries 2–4). The heteroaromatic
aldehyde 3-pyridinecarbaldehyde
was also a suitable electrophilic
aldehyde (Table 4, entry 5). In all
cases, 2-allyltetrahydropyrans, in
which all the carbon atoms are
substituted with different substitu-
ents, were obtained with excellent
diastereo- and enantioselectivity.
When triethylsilane was used
instead of allyltrimethylsilane, the
reduction proceeded efficiently to
afford the tetrahydropyran in 75%
yield with 99% ee (Table 4,
entry 6). All these reactions were
performed in a single flask.
=
CH2 CHCH2TMS
=
5
6
3-pyridyl
Ph
CH2 CHCH2TMS
3
5
8
57
75
99
99
Et3SiH
10
[a] Reaction conditions: nitrostyrene (1.0 mmol), propanal (1.2 mmol), electrophilic aldehyde
(1.1 mmol), p-nitrophenol (0.05 mmol), catalyst 1 (0.05 mmol), and allylsilane (3.5 mmol) or Et3SiH
(3.5 mmol), and TiCl4 (3.5 mmol). See the Supporting Information for details. [b] Yield of the isolated
product. [c] For the determination of the enantiomeric excess, see the Supporting Information.
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Received: August 28, 2010
Published online: March 24, 2011
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Keywords: asymmetric synthesis · domino reactions ·
michael addition · multicomponent reactions · organocatalysis
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