Diastereoselective synthesis of tetrahydrofurans by Lewis acid catalyzed intermolecular carbenoid-carbonyl reaction-cycloaddition sequences: Unusual diastereoselectivity of Lewis acid catalyzed cycloadditions

Article abstract of DOI:10.1021/jo400858u

The effects of including metal salts for three-component reactions involving α-alkyl-α-diazo esters, aromatic aldehydes, and 3-(2-alkenoyl)-2-oxazolidinones are described, in terms of yields and diastereoselectivities. Metal tetrafluoroborates (10-30 mol

Full text of DOI:10.1021/jo400858u

Article
pubs.acs.org/joc
Diastereoselective Synthesis of Tetrahydrofurans by Lewis Acid
Catalyzed Intermolecular Carbenoid−Carbonyl Reaction−
Cycloaddition Sequences: Unusual Diastereoselectivity of Lewis Acid
Catalyzed Cycloadditions
Yuta Hashimoto,† Kennosuke Itoh,† Akikazu Kakehi,† Motoo Shiro,‡ and Hiroyuki Suga*,†
†Department of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, Wakasato, Nagano 380-8553, Japan
and
‡Rigaku Corporation, 3-9-12 Matsubaracho, Akishima, Tokyo 196-8666, Japan
S
* Supporting Information
ABSTRACT: The effects of including metal salts for three-
component reactions involving α-alkyl-α-diazo esters, aromatic
aldehydes, and 3-(2-alkenoyl)-2-oxazolidinones are described,
in terms of yields and diastereoselectivities. Metal tetrafluor-
oborates (10−30 mol %) such as Co(BF4)2·6H2O, Ni-
(BF4)2·6H2O, and AgBF4 were effective in delivering high
yields and diastereoselectivities (93:7 to 99:1) of the
corresponding tetrahydrofuran derivatives while suppressing
the competitive formation of 1,3-dioxolane. Using (S)-3-(2-
alkenoyl)-4-isopropyl-2-oxazolidinones as the dipolarophiles in
the three-component reactions, in the presence of Ni-
(BF4)2·6H2O or Co(ClO4)2·6H2O (10−30 mol %), optically active tetrahydrofurans that possess four successive asymmetric
centers were synthesized in high diastereoselectivities (99:1). On the basis of the configuration of the cycloadduct using the X-ray
analysis, the high diastereoselectivity could be explained by the unusual Re-face approach to the dipolarophile in the presence of
the Lewis acid, proceeding through the s-cis conformer of the 3-(2-alkenoyl)-2-oxazolidinone with the two carbonyls in opposing
directions (dipole−dipole interaction).
complexes was suppressed by employing dirhodium tetrapiva-
late (Rh2Piv4) as the catalyst at −78 °C. Furthermore, the
scope of the dipolarophiles was expanded to include reactive
olefinic and acetylenic dipolarophiles, albeit limited to terminal
olefins and acetylenes, cyclic olefins, and dipolarophiles
substituted with two electron-deficient groups. Consequently,
we decided to investigate the use of metal salts as the catalytic
Lewis acids for the purposes of (i) expanding the range of
usable olefinic dipolarophiles, especially for nonterminal olefins
of 2-alkenoic acid derivatives, (ii) eliminating the formation of
competing dioxolanes, and (iii) improving the stereoselectiv-
ities of the reactions. Herein, we report on the three-
component reactions of aromatic aldehydes, α-alkyl-α-diazo
esters, and 2-alkenoic acid derivatives in the presence of metal
salts Ni(BF4)2·6H2O and Co(BF4)2·6H2O, which not only
selectively promoted the cycloadditions with the olefinic
dipolarophiles but also effectively improved the diastereose-
lectivities. Surprisingly, for the three-component reactions
involving (S)-3-(2-alkenoyl)-4-isopropyl-2-oxazolidinones as
the dipolarophile in the synthesis of chiral tetrahydrofuran
derivatives, the use of these salts resulted in an unusual
INTRODUCTION
■
Recently we have reported that high levels of asymmetric
induction could be achieved by employing catalytic amounts of
chiral Lewis acids in the cycloaddition reactions of both
electron-deficient and -rich dipolarophiles with cyclic carbonyl
ylides that are generated from diazo carbonyl compounds via
intramolecular carbenoid−carbonyl cyclization reactions.1
Using this methodology, chiral epoxy-bridged bicyclic com-
pounds containing several asymmetric centers were effectively
constructed via a single cycloaddition step. Intramolecular
carbenoid−carbonyl cyclization reactions are regarded as one of
the most efficient scheme for the generation of carbonyl ylides,
favored in terms of entropy, and are applicable over a wide
range of dipolarophiles.2 In contrast, intermolecular carbe-
noid−carbonyl reactions are limited to dipolarophiles possess-
ing the same carbonyl components used for the carbonyl ylide
formation or highly reactive dipolarophiles.3 Although it is well-
known that precursor Rh carbenoid complexes undergo
undesirable β-hydride elimination,4 a recent breakthrough by
Fox describes the effective Rh-catalyzed three-component
reactions of aldehydes, α-alkyl-α-diazo esters, and dipolar-
ophiles to afford highly functionalized dihydro- and tetrahy-
drofuran products with high regio- and diastereoselectivities.5
The problematic β-hydride elimination of the Rh carbenoid
Received: April 21, 2013
Published: June 12, 2013
© 2013 American Chemical Society
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Scheme 1. Three-Component Reactions of Ethyl 2-Diazohydrocinnamate (1), Benzaldehyde (2), and Crotonoic Acid
Derivatives 3a−d
Table 1. Three-Component Reactions of Ethyl 2-Diazohydrocinnamate (1), Benzaldehyde (2), and Crotonoic Acid Derivatives
a
3a−d
b
c
entry
dipolarophile 3
Lewis acid
none
yield of 4 + 5 (%)
dr (4:5)
yield of 6 (%)
1
3a
3a
3b
3b
3c
3c
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
5 (4a + 5a)
9 (4a + 5a)
92:8
99:1
20
21
40
40
18
7
2
Co(ClO4)2·6H2O
none
3
3 (4b + 5b)
8 (4b + 5b)
52 (4c + 5c)
62 (4c + 5c)
79 (4d + 5d)
76 (4d + 5d)
69 (4d + 5d)
76 (4d + 5d)
74 (4d + 5d)
59 (4d + 5d)
81 (4d + 5d)
82 (4d + 5d)
89 (4d + 5d)
78 (4d + 5d)
61 (4d + 5d)
57 (4d + 5d)
67 (4d + 5d)
63 (4d + 5d)
44:56
95:5
4
Co(ClO4)2·6H2O
none
5
81:19
81:19
88:12
>99:1
>99:1
96:4
6
Co(ClO4)2·6H2O
none
7
4
8
Co(ClO4)2·6H2O
Fe(ClO4)2·6H2O
Ni(ClO4)2·6H2O
Zn(ClO4)2·6H2O
Cu(ClO4)2·6H2O
Co(BF4)2·6H2O
Ni(BF4)2·6H2O
AgBF4
2
9
4
10
11
12
13
14
15
16
17
18
19
20
5
99:1
7
99:1
10
2
>99:1
99:1
1
86:4
trace
9
Mg(OTf)2
74:26
99:1
Cu(OTf)2
5
Sc(OTf)3
>99:1
>99:1
>99:1
10
4
In(OTf)3
Gd(OTf)3
10
a
The reaction was carried out by adding a solution of ethyl 2-diazohydrocinnamate (1; 1.3 equiv) and benzaldehyde (2; 1.0 equiv) to a solution of
b
Rh2Piv4 (0.5 mol %), crotonoic acid derivatives 3a−d (1.1 equiv), and Lewis acids (10 mol %) in CH2Cl2 over a period of 1 h. Diastereomer ratio.
c
1
Determined by H NMR.
diastereoselective asymmetric induction that was not expected
for such Lewis acid catalyzed cycloadditions with bidentate-type
dipolarophiles.
tetrahydofurans were obtained in low yields (3−9%) in which
1,3-dioxolane 6 was the main product (yields of 20−40%),
either in the presence or absence of Co(ClO4)2·6H2O:
however, the diastereoselectivities of the tetrahydrofurans
were improved by addition of Co(ClO4)2·6H2O (entries 1−
4). The reactivities of 1-crotonoyl-3,5-dimethylpyrazole (3c)
(entries 5 and 6) were higher than those of 3a,b: moreover, the
addition of Co(ClO4)2·6H2O suppressed the formation of 1,3-
dioxolane 6, thus increasing the yield of the tetrahydrofuran to
62% while maintaining comparable diastereoselectivity (entry
6). In the case of 3-crotonoyl-2-oxazolidinone (3d), the
reaction readily afforded the product with a yield of 79%
(diastereoselectivity 88:12) without the aid of any Lewis acids
(entry 7). In the presence of Co(ClO4)2·6H2O, the
diastereoselectivity was improved to 99:16 (entry 8), albeit
without improved yields. To improve both yields and
RESULTS AND DISCUSSION
■
Initially, the three-component reactions of ethyl 2-diazohy-
drocinnamate (1), benzaldehyde (2), and the four crotonoic
acid derivatives 3a−d were carried out in CH2Cl2 at −78 °C in
the presence of Rh2Piv4 (0.5 mol %) and in the absence of a
Lewis acid. In general, a solution of 1 (1.3 equiv) and 2 (1.0
equiv) was added to a solution of olefins 3 (1.1 equiv) and
Rh2Piv4 over a period of 1 h (Scheme 1 and Table 1, entries 1,
3, 5, and 7). Reactions were also carried out under similar
conditions using Co(ClO4)2·6H2O (10 mol %) as the additive
(entries 2, 4, 6, and 8). In the cases of methyl crotonate (3a)
and 2-crotonoyl-3-pyrazolidinone (3b), the corresponding
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a
Table 2. Three-Component Reactions of Ethyl 2-Diazohydrocinnamate (1), Aldehydes, and 3-(2-Alkenoyl)-2-oxazolidinones
b
entry
aldehyde (Ar)
dipolarophile (R)
amt (mol %)
yield of THF (%)
dr
yield of Diox (%)
1
Ph
Me
Me
Et
none
10
79 (4d + 5d)
82 (4d + 5d)
53 (4e + 5e)
80 (4e + 5e)
58 (4f + 5f)
78 (4f + 5f)
16 (4g + 5g)
39 (4g + 5g)
64 (4h + 5h)
62 (4h + 5h)
59 (4i + 5i)
84 (4i + 5i)
60 (4j + 5j)
67 (4j + 5j)
63 (4k + 5k)
65 (4k + 5k)
57 (4l + 5l)
71 (4l + 5l)
88:12
99:1
4
1
2
Ph
3
Ph
none
10
86:14
99:1
4
4
Ph
Et
2
5
Ph
Pr
none
20
85:15
99:1
6
6
Ph
Pr
3
7
Ph
i-Pr
i-Pr
Ph
none
30
88:12
99:1
32
19
5
8
Ph
9
Ph
none
20
67:33
>99:1
81:19
99:1
10
11
12
13
14
15
16
17
18
Ph
Ph
4
p-MeC6H4
p-MeC6H4
p-ClC6H4
p-ClC6H4
p-NO2C6H4
p-NO2C6H4
2-naphthyl
2-naphthyl
Me
Me
Me
Me
Me
Me
Me
Me
none
20
6
3
none
10
88:12
99:1
6
3
none
10
74:26
93:7
8
6
none
83:17
99:1
6
c
10
1
a
The reaction was carried out by adding a solution of ethyl 2-diazohydrocinnamate (1; 1.3 equiv) and aldehyde (1.0 equiv) to a solution of Rh2Piv4
b
(0.5 mol %), 3-(2-alkenoyl)-2-oxazolidinone (1.1 equiv), and a Lewis acid (0−10 mol %) in CH2Cl2 over a period of 1 h. Diastereomer ratio of
THF derivatives determined by H NMR. Co(ClO4)2·6H2O was used.
c
1
Scheme 2. Three-Component Reactions of Ethyl 2-Diazohydrocinnamate (1), Benzaldehyde (2), and (S)-3-(2-Alkenoyl)-4-
isopropyl-2-oxazolidinones 7a−d
diastereoselectivities, several Lewis acids such as perchlorates,
tetrafluoroborates, and triflates were evaluated (entries 9−20).
The use of the tetrafluoroborates Co(BF4)2·6H2O, Ni-
(BF4)2·6H2O, and AgBF4 resulted in yields of 81−89% (entries
13−15). With the exceptions of AgBF4 and Mg(OTf)2, the
Lewis acids improved the diasteroselectivities (96:4−99:1). On
the basis of these results, the reaction conditions featuring
Ni(BF4)2·6H2O (entry 14) as the Lewis acid were chosen for
the next step of our investigations.
To investigate the scope of our methodology in terms of
aldehydes and olefinic dipolarophiles, the three-component
reactions were carried out using several aromatic aldehydes and
3-(2-alkenoyl)-2-oxazolidinones. The yields and diastereoselec-
tivities of the reactions, with or without Ni(BF4)2·6H2O, for 3-
(2-alkenoyl)-2-oxazolidinones having Et, Pr, i-Pr, or Ph as the R
substituent are given in Table 2 (entries 3−10). In most cases,
the addition of Ni(BF4)2·6H2O (10−30 mol %) improved both
the yields and diastereoselectivities of the corresponding
tetrahydrofuran cycloadducts (entries 4, 6, 8, and 10), with
the sole exception of the modest yield afforded by 3-(4-methyl-
2-pentenoyl)-2-oxazolidinone (entry 8). Of note, the addition
of Ni(BF4)2·6H2O dramatically improved the diastereoselectiv-
ity for the reaction of 3-cinnamoyl-2-oxazoridinone (from
67:33 to >99:1) (entry 9 vs 10). Next, the three-component
reaction was carried out, with or without Ni(BF4)2·6H2O, using
ethyl 2-diazohydrocinnamate (1), 3-crotonoyl-2-oxazolidinone
(3d), and several aromatic aldehydes that possess electron-
withdrawing or -releasing groups at the para position on the
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Table 3. Three-Component Reactions of Ethyl 2-Diazohydrocinnamate (1), Benzaldehyde (2), and (S)-3-(2-Alkenoyl)-4-
a
isopropyl-2-oxazolidinones 7a−d
b
c
entry
dipolarophile 7 (R)
Lewis acid (mol %)
none
yield of 8 + 9 (%)
dr (8:9)
yield of 6 (%)
1
2
7a (Me)
7a (Me)
7a (Me)
7a (Me)
7b (Et)
7b (Et)
7c (Pr)
7c (Pr)
7d (Ph)
7d (Ph)
58 (8a + 9a)
50 (8a + 9a)
51 (8a + 9a)
80 (8a + 9a)
32 (8b + 9b)
61 (8b + 9b)
27 (8c + 9c)
59 (8c + 9c)
39 (8d + 9d)
53 (8d + 9d)
65:35
>99:1
>99:1
99:1
20
20
11
3
Co(ClO4)2·6H2O (10)
Co(BF4)2·6H2O (10)
Ni(BF4)2·6H2O (10)
none
3
4
5
86:14
99:1
25
6
6
Ni(BF4)2·6H2O (30)
none
7
83:17
>99:1
67:33
>99:1
19
6
8
Ni(BF4)2·6H2O (30)
none
9
18
7
10
Ni(BF4)2·6H2O (30)
a
The reaction was carried out by adding a solution of ethyl 2-diazohydrocinnamate (1; 1.3 equiv) and benzaldehyde (2; 1.0 equiv) to a solution of
Rh2Piv4 (0.5 mol %), 3-(2-alkenoyl)-4-isopropyl-2-oxazolidinones 7a−d (1.1 equiv), and Lewis acids (0−30 mol %) in CH2Cl2 over a period of 1 h.
b
c
1
Diastereomer ratio. Determined by H NMR.
a
Table 4. Three-Component Reactions of α-Diazo Esters, Aldehydes, and (S)-3-Crotonoyl-4-isopropyl-2-oxazolidinone (7a)
b
entry
diazo ester (R1, R2)
aldehyde (Ar)
amt (mol %)
yield of THF (%)
dr
yield of Diox (%)
1
Bn, Et
Bn, Et
Et, Et
Ph
none
10
58 (8a + 9a)
80 (8a + 9a)
60 (8e + 9e)
75 (8e + 9e)
62 (8f + 9f)
82 (8f + 9f)
52 (8g + 9g)
79 (8g + 9g)
41 (8h + 9h)
70 (8h + 9h)
42 (8i + 9i)
67 (8i + 9i)
39 (8j + 9j)
68 (8j + 9j)
48 (8k + 9k)
71 (8k + 9k)
60 (8l + 9l)
78 (8l + 9l)
45 (8m + 9m)
73 (8m + 9m)
65:35
99:1
20
3
2
Ph
3
Ph
none
10
68:32
99:1
10
1
4
Et, Et
Ph
5
i-Bu, Et
i-Bu, Et
Ph
none
10
72:28
>99:1
69:31
>99:1
79:21
99:1
12
1
6
Ph
c
7
1-NAPCH2, Et
Ph
none
10
13
1
c
8
1-NAPCH2, Et
Ph
9
Bn, Et
Bn, Et
Bn, Et
Bn, Et
Bn, Et
Bn, Et
Bn, Et
Bn, Et
Bn, Me
Bn, Me
Bn, t-Bu
Bn, t-Bu
p-MeC6H4
p-MeC6H4
p-ClC6H4
p-ClC6H4
p-NO2C6H4
p-NO2C6H4
2-naphthyl
2-naphthyl
Ph
none
30
17
2
10
11
12
13
14
15
16
17
18
19
20
none
30
78:22
99:1
18
1
none
30
80:20
99:1
15
1
none
84:16
>99:1
63:27
99:1
6
d
20
2
none
10
15
2
Ph
Ph
none
10
>99:1
>99:1
24
9
Ph
a
The reaction was carried out by adding a solution of α-diazo ester (1.3 equiv) and aldehyde (1.0 equiv) to a solution of Rh2Piv4 (0.5 mol %), 3-
b
crotonoyl-2-oxazolidinone (1.1 equiv), and a Lewis acid (0−30 mol %) in CH2Cl2 over a period of 1 h. Diastereomer ratio of THF derivatives
determined by H NMR. 1-Naphthylmethyl. Co(ClO4)2·6H2O was used.
c
d
1
benzene ring (entries 11−18). Similarly, in all cases, the
addition of Ni(BF4)2·6H2O (10−20 mol %) resulted in higher
yields and diastereoselectivities ((93:7)−(99:1)) (entries 12,
14, 16, and 18).
Encouraged by the dramatic effects of the metal tetrafluor-
obarates on the three-component reactions, we next turned our
attention to the synthesis of optically active teterahydrofuran
derivatives using the diastereoselective synthesis starting with
chiral oxazolidinones. First, as shown in Scheme 2, a three-
component reaction involving ethyl 2-diazohydrocinnamate
(1), benzaldehyde (2), and (S)-3-crotonoyl-4-isopropyl-2-
oxazolidinone (7a) was carried out in the absence of a Lewis
acid (Table 3, entry 1), under conditions similar to those
previously described for 3-crotonoyl-2-oxazolidinone (3d).
Although there are eight possible diastereomers of the
corresponding tetrahydrofuran, the reaction afforded only two
diastereomers (with a ratio of 65:35 and a combined yield of
58%), along with 1,3-dioxolane 6 (20% yield). Next, the effect
of additives on this three-component reaction was investigated
using three metal salts (10 mol %). Again, the addition of
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Ni(BF4)2·6H2O was favorable, in terms of both diastereose-
lectivity (99:1) and yield (80%), by suppressing the formation
of 1,3-dioxolane 6 (3% yield) (entry 4). In contrast, the
addition of Co(ClO4)2·6H2O or Co(BF4)2·6H2O resulted in
lower yields, albeit with higher diastereoselectivities (>99:1)
(entries 2 and 3).
Scheme 3. Proposed Mechanism for High
Diastereoselectivity
Consequently, the reactions of (S)-3-(2-alkenoyl)-4-isoprop-
yl-2-oxazolidinones 7b−d (R = Et, Pr, Ph) were investigated
using Ni(BF4)2·6H2O as the catalyst (entries 5−10). Although
the reactions required a greater amount of Ni(BF4)2·6H2O (30
mol %) to afford moderate yields (53−61%), the presence of
the metal salt significantly improved the diastereoselectivities
((99:1)−(>99:1)) (entries 6, 8, and 10). It is important to note
that optically active tetrahydrofuran derivatives that possess
four successive asymmetric centers can be readily and
selectively prepared via this one-pot reaction.
We next investigated the applicability of our procedure to
aldehydes and diazo substrates that correspond to the Ar and
R1 substituents on the tetrahydrofuran ring (Table 4). Several
ethyl α-alkyl-α-diazo esters readily underwent the three-
component reaction involving benzaldehyde (2) and (S)-3-
crotonoyl-4-isopropyl-2-oxazolidinone (7a), in the presence of
Ni(BF4)2·6H2O (10 mol %), to give the products in good yields
(75−82%) and high diastereoselectivities ((99:1)−(>99:1))
(entries 4, 6, and 8). Several aromatic aldehydes were also
effective in affording high diastereoselectivities ((99:1)−
(>99:1)) for the reactions of 2-diazohydrocinnamate (1) and
(S)-3-crotonoyl-4-isopropyl-2-oxazolidinone (7a): the reac-
tions, however, required somewhat higher catalyst loadings
(20−30 mol %) of Ni(BF4)2·6H2O or Co(ClO4)2·6H2O to
afford moderate yields (67−71%) (entries 10, 12, 14, and 16).
For the 2-diazohydrocinnamates, our results indicate that large
R2 substituents such as t-Bu can afford high diastereoselectiv-
ities, even in the absence of Lewis acids (entry 19).
Nonetheless, the inclusion of Ni(BF4)2·6H2O (10 mol %)
was rather effective in affording a good yield (73%).
Lewis acid) was determined as having the 2R,3S,4S,5R
configuration using differential NOE spectra (Figure 2) of the
Figure 2. NOEs observed by differential NOE spectra.
In the case of the three-component reaction involving tert-
butyl 2-diazohydrocinnamate, benzaldehyde (2), and (S)-3-
crotonoyl-4-isopropyl-2-oxazolidinone (7a), the absolute ster-
eochemistry of the major diastereomer product (recystallized
from hexane) was determined using X-ray crystal analysis (see
the Supporting Information). As shown in Figure 1, cyclo-
corresponding isolable diol 11 that was obtained via LiAlH4
reduction (Scheme 4). This configuration suggests that the
addition of Ni(BF4)2·6H2O favors the formation of conformer
A between the two carbonyl ylide conformers proposed by
Fox5 (Scheme 5). To clarify the relative configuration of four
possible cycloadducts obtained from either conformer A or B
by endo or exo approaches, the expected transition states are
shown in Scheme 5. From the stereochemistry determined for
cycloadducts 8a and 9a, it is suggested that the continuous Re-
face selection of (S)-crotonoyl-4-isopropyl-2-oxazolidinone by
the endo approach exclusively occurred both with and without
Ni(BF4)2·6H2O after formation of the conformer A. Selective
formation of the conformer A and activation of the reaction by
Ni(BF4)2·6H2O seems to favor the reaction through TS-B in
the transition state (Scheme 3). Similar transition states were
proposed for N-metalated azomethine ylides in the diaster-
eoselective and enantioselective cycloaddition reactions with
electron-deficient olefinic dipolarophiles.8 Furthermore, re-
cently the similar highly diastereoselective Re-face selection of
the s-cis conformer for (S)-(2-alkenoyl)-4-phenyl-2-oxazolidi-
nones by dipole−dipole interactions in the cycloaddition
reactions of nitrile ylides in the absence of a Lewis acid were
reported by Sibi,9 although there have been only a few scattered
examples of moderate to good selectivity using the chiral
oxazolidinone auxiliaries without Lewis acids. Although 8a,m
Figure 1. Absolute configuration of cycloadduct 8m.
adduct 8m possesses a 2S,3S,4S,5R configuration on its
tetrahydrofuran ring. Similarly, the diol derivative of cyclo-
adduct 8a, which is the major product for the reaction involving
ethyl 2-diazohydrocinnamate (1), was also shown to possess
the same configuration (Scheme 6). Although the high
diastereoselectivities of these reactions are typically attributed
to the chelate complex of the s-cis conformer of 2-oxazolidinone
7a with Ni(BF4)2 allowing the Si-face approach of the carbonyl
ylide to the dipolarophile with endo orientation via strong
LUMO activation7 (Scheme 3, TS-A), the above absolute
configuration of the cycloadducts did not allow this
explanation. The stereochemistry of the tetrahydrofuran ring
of minor cycloadduct 9a (Table 4, entry 1; in the absence of
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Scheme 4. Reduction of Tetrahydrofurans with LiAlH4
Scheme 5. Proposed Transition States for Conformers A and B
Scheme 6. Selective Reduction of Chiral Tetrahydrofuran Derivatives
could be produced by Re-face selection of the s-trans
conformation of (S)-crotonoyl-4-isopropyl-2-oxazolidinone
chelated with Ni(BF4)2 as shown in TS-D (Scheme 3), it is
not likely to occur because of a steric interaction between the
olefin and the chiral substituent of the auxiliary. In the NMR
studies of (S)-crotonoyl-4-isopropyl-2-oxazolidinone in the
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are expressed in parts per million using the middle resonance of
CDCl3 (77.0 ppm) as an internal standard. Hydrogen multiplicity (C,
CH, CH2, CH3) information was obtained from carbon DEPT spectra.
For preparative column chromatography, Wakogel C-300HG was
employed. All reactions were carried out under an argon atmosphere
in dried glassware.
presence of Et2AlCl, chelated and nonchelated conformers both
having an s-cis conformation similar to TS-A and TS-B (Scheme
3), respectively, were observed, and the preferred conformer
depended on the amount of the Lewis acid.10 Therefore, the
configuration of 8a can be explained as the Re-face approach to
the dipolarophile, which proceeds through an s-cis conformer of
oxazolidinone 7a, with the two carbonyls in directions opposite
to each other (dipole−dipole interaction). Accordingly, the
high diastereoselectivity of the three-component reaction can
be attributed to the coordination of the Lewis acid to both the
ester carbonyl of the ylide and the carbonyl of an alkenoyl
group in the dipolarophile (Scheme 3, TS-B).
To expand the applicability of these chiral tetrahydrofurans
within organic syntheses, selective conversions of several
functional groups were undertaken (Scheme 6). Chiral
tetrahydrofuran 8a and its t-Bu ester analogue 8m were readily
converted to the monoalcohols by the selective reduction of the
oxazolidinone moiety using NaBH4 in THF−H2O in high
yields. Subsequent and successive reductions of the ester
moieties of the monoalcohols were achieved using LiAlH4 in
high yield to give the enantiomerically pure diol 10 (>99% ee,
confirmed using chiral HPLC analysis).
Materials. Methyl crotonate (3a) and aromatic aldehydes are
commercially available and were used without further purification. 3-
Crotonoyl-2-oxazolidinone (3b),11 1-crotonoyl-3,5-dimethylpyrazole
(3c),12 1-benzyl-2-crotonoyl-5,5-dimethyl-3-pyrazolidinone (3d),13 3-
[(E)-2-pentenoyl]-2-oxazolidinone,14 3-[(E)-2-hexenoyl]-2-oxazolidi-
none,11 3-[(E)-4-methyl-2-pentenoyl]-2-oxazolidinone,11 3-cinnamo-
yl-2-oxazolidinone,15 (S)-3-crotonoyl-4-isopropyl-2-oxazolidinone
(7a),16 (S)-4-isopropyl-3-[(E)-2-pentenoyl]-2-oxazolidinone (7b),17
and (S)-3-cinnamoyl-4-isopropyl-2-oxazolidinone (7d)16 were pre-
pared by the procedure reported in the literature. Dirhodium
tetrapivalate (Rh2Piv4) was prepared by the method reported in the
literature.18 Ethyl 2-diazohydrocinnamate (1), ethyl 2-diazopropa-
noate, ethyl 2-diazobutanoate, ethyl 2-diazo-4-methylpentanoate, and
ethyl 2-diazo-3-(1-naphthyl)propanoate were prepared from the
corresponding β-keto esters according to literature protocols.19,4a−d,5
Powdered 4 Å molecular sieves (MS 4 Å) are commercially available
(Aldrich) and were dried in vacuo at 200 °C for 12 h before use.
Ni(ClO4)2·6H2O, Ni(BF4)2·6H2O, Co(ClO4)2·6H2O, Co-
(BF4)2·6H2O and other metal salts are commercially available and
were used without further purification. CH2Cl2 was purified by
distillation first from CaCl2 and then CaH2 under argon before use.
General Procedure for the Ni(II)-Catalyzed Reaction
Exemplified by the Reaction of Ethyl 2-Diazohydrocinnamate
(1), Benzaldehyde (2), and 3-Crotonoyl-2-oxazolidinone (3d).
To a solution of 3-crotonoyl-2-oxazolidinone (68.3 mg, 0.44 mmol),
Rh2Piv4 (1.2 mg, 2.6 × 10−4 mmol), Ni(BF4)2·6H2O (13.6 mg, 0.040
mmol), and MS 4 Å (500 mg) in CH2Cl2 (4 mL) at −78 °C (dry ice/
acetone bath) was added a solution of ethyl 2-diazohydrocinnamate
(106.2 mg, 0.52 mmol) and benzaldehyde (41 μL, 0.40 mmol) in
CH2Cl2 (5 mL) over a period of 1 h using a syringe pump. The syringe
was washed with CH2Cl2 (1 mL), and then the stirring was continued
for 10 min at −78 °C. After the mixture was warmed to room
temperature, it was filtered through Celite (1 cm) and a plug of silica
gel (3 cm) with AcOEt/hexane (1/1, 80 mL) as an eluent. The solvent
was removed in vacuo, and the residue was purified by column
chromatography ((9/10)−(8/2), hexane/AcOEt) to provide 143.5 mg
(82%) of 4d and 5d along with 0.8 mg (1%) of 1,3-dioxolane 6. The
CONCLUSIONS
■
Our investigations of the three-component reactions of ethyl 2-
diazohydrocinnamate (1), aromatic aldehydes, and 3-(2-
alkenoyl)-2-oxazolidinones have demonstrated that the addi-
tion of metal tetrafluoroborates such as Co(BF4)2·6H2O,
Ni(BF4)2·6H2O, and AgBF4 was highly effective in improving
the yields of the desired tetrahydrofuran derivatives while
suppressing the competitive formation of 1,3-dioxolane.
Remarkably, the addition of Ni(BF4)2·6H2O resulted in high
diastereoselectivities ((93:7)−(>99:1)). For the three-compo-
nent reactions of α-alkyl-α-diazo esters, aromatic aldehydes,
and (S)-3-crotonoyl-4-isopropyl-2-oxazolidinone (7a) with
Ni(BF4)2·6H2O or Co(ClO4)2·6H2O as a catalyst, several
chiral terahydrofurans that possess four successive asymmetric
centers along with the corresponding chiral oxazolidinone
auxiliaries were successfully synthesized, with extremely high
diastereoselectivities ((99:1)−(>99:1)). For the three-compo-
nent reactions of tert-butyl 2-diazohydrocinnamate, benzalde-
hyde (2), and (S)-3-crotonoyl-4-isopropyl-2-oxazolidinone
(7a), X-ray crystal analysis of the product revealed unexpected
configurations, suggesting highly diastereoselective asymmetric
induction behavior of the metal salts. The mechanism for the
high diastereoselectivity can be attributed to the Re-face
approach to the dipolarophile proceeding through an s-cis
conformer of oxazolidinone 7a with the two carbonyls in
opposing directions (dipole−dipole interaction). Moreover, the
coordination of Ni(BF4)2 to both the ester carbonyl of the
carbonyl ylide and the carbonyl of an alkenoyl group in the
dipolarophile during the transition state (TS-B) would favor
the selective formation of a stable conformer of the carbonyl
ylide.
1
4d:5d ratio was determined to be 99:1 by H NMR analysis (400
MHz). Cycloadduct 4d (124.2 mg, 71%) could be separated from the
mixture of 4d and 5d by careful column chromatography (95/5,
hexane/AcOEt).
Cycloadducts 4e and 5e (144.5 mg, 80%, 4e:5e = 99:1) were
synthesized according to the general procedure. Cycloadduct 4e
(130.6 mg, 72%) could be separated from the mixture of 4e and 5e by
careful column chromatography.
Cycloadducts 4f and 5f (145.2 mg, 78%, 4f:5f = 99:1) were
synthesized according to the general procedure. Cycloadduct 4f (124.6
mg, 67%) could be separated from the mixture of 4f and 5f by careful
column chromatography.
Cycloadducts 4g and 5g (72.6 mg, 39%, 4g:5g = 99:1) were
synthesized according to the general procedure. Cycloadduct 4g (31.0
mg, 17%) could be separated from the mixture of 4g and 5g by careful
column chromatography.
Cycloadduct 4h (124.0 mg, 62%, 4h:5h = >99:1) was synthesized
according to the general procedure.
EXPERIMENTAL SECTION
General Methods. Melting points were determined on a melting
Cycloadducts 4i and 5i (151.6 mg, 84%, 4i:5i = 99:1) were
synthesized according to the general procedure. Cycloadduct 4i (142.6
mg, 79%) could be separated from the mixture of 4i and 5i by careful
column chromatography.
■
point apparatus and are uncorrected. IR spectra were taken with a FT/
1
IR spectrophotometer. H NMR spectra were recorded on 300, 400,
and 500 MHz spectrometers. Chemical shifts are expressed in parts
per million downfield from tetramethylsilane as an internal standard.
13C NMR spectra were recorded on 75, 100, and 125 MHz
spectrometers using broad-band proton decoupling. Chemical shifts
Cycloadducts 4j and 5j (126.6 mg, 67%, 4j:5j = 99:1) were
synthesized according to the general procedure. Cycloadduct 4j (110.5
mg, 58%) could be separated from the mixture of 4j and 5j by careful
column chromatography.
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Cycloadducts 4k and 5k (125.6 mg, 65%, 4k:5k = 93: 7) were
synthesized according to the general procedure. Cycloadduct 4k
(109.1 mg, 56%) could be separated from the mixture of 4k and 5k by
careful column chromatography.
Cycloadducts 4l and 5l (138.7 mg, 71%, 4l:5l = 99:1) were
synthesized according to the general procedure. Cycloadduct 4l (124.6
mg, 64%) could be separated from the mixture of 4l and 5l by careful
column chromatography.
4.57 (1H, t, J = 9.7 Hz), 5.63 (1H, d, J = 9.7 Hz), 7.13−7.31 (8H, m),
7.37−7.40 (2H, m); 13C NMR (100 MHz, CDCl3) δ 14.2 (CH3), 14.4
(CH3), 21.9 (CH2), 32.1 (CH2), 36.5 (CH2), 42.4 (CH2), 48.3 (CH),
55.3 (CH), 61.2 (CH2), 61.9 (CH2), 80.0 (CH), 88.4 (C), 126.3
(CH), 127.3 (CH), 127.7 (CH), 127.9 (CH), 128.1 (CH), 130.0
(CH), 135.7 (C), 138.0 (C), 153.0 (C), 170.3 (C), 171.8 (C); MS
(EI) m/z 465 (M+), 393, 374, 306, 287, 241, 213, 185, 157, 131, 105,
91, 77, 57, 43, 29, 15. Anal. Calcd for C27H31NO6: C, 69.66; H, 6.71;
N, 3.01. Found: C, 69.82; H, 6.83; N, 3.17.
(2R*,3S*,4S*,5R*)-Ethyl 2-benzyl-4-(2-oxo-3-oxazolidinylcarbon-
yl)-5-phenyl-3-propyltetrahydrofuran-2-carboxylate (5f): although
5f could not be separated by chromatography from a mixture with
major 4f and 3-(2-hexenoyl)-2-oxazolidinone, it could be characterized
by 1H NMR; 1H NMR (400 MHz, CDCl3) δ 0.95 (3H, t, J = 7.3 Hz),
1.30 (3H, t, J = 7.1 Hz), 1.51 (1H, m), 1.63 (1H, m), 1.70 (1H, m),
1.92 (1H, m), 2.84 (1H, ddd, J = 6.6, 9.8, 10.5 Hz), 3.11 (1H, dt, J =
5.1, 9.5 Hz), 3.29 (1H, d, J = 14.2 Hz), 3.46 (1H, d, J = 14.2 Hz), 3.61
(1H, ddd, J = 7.1, 9.5, 11.0 Hz), 3.81 (1H, m), 4.10−4.27 (3H, m),
4.50 (1H, t, J = 9.8 Hz), 5.83 (1H, d, J = 9.8 Hz), 7.00−7.02 (2H, m),
7.13−7.36 (8H, m).
(2S*,3S*,4S*,5R*)-Ethyl 2-benzyl-3-isopropyl-4-(2-oxo-3-oxazoli-
dinylcarbonyl)-5-phenyltetrahydrofuran-2-carboxylate (4g): color-
less needles; mp 155−158 °C (benzene); IR (KBr) 2964, 2922, 1774,
1733, 1700, 1390, 1217, 748, 700 cm−1; 1H NMR (500 MHz, CDCl3)
δ 0.91 (3H, d, J = 6.8 Hz), 1.09 (3H, d, J = 6.8 Hz), 1.28 (3H, t, J = 7.1
Hz), 2.10 (1H, m), 2.92 (1H, ddd, J = 6.9, 9.4, 10.9 Hz), 3.06 (1H, d, J
= 14.2 Hz), 3.28 (1H, dd, J = 8.4, 9.8 Hz), 3.40 (1H, d, J = 14.2 Hz),
3.67 (1H, ddd, J = 6.9, 9.4, 10.9 Hz), 3.87 (1H, dt, J = 6.9, 9.4 Hz),
4.10−4.28 (3H, m), 4.77 (1H, t, J = 9.8 Hz), 5.58 (1H, d, J = 9.8 Hz),
7.15 (1H, m), 7.19−7.32 (7H, m), 7.42−7.44 (2H, m); 13C NMR
(125 MHz, CDCl3) δ 14.0 (CH3), 22.36 (CH3), 22.41 (CH3), 36.0
(CH2), 36.0 (CH2), 42.5 (CH), 53.4 (CH), 55.6 (CH), 61.3 (CH2),
61.9 (CH2), 80.3 (CH), 88.5 (C), 126.4 (CH), 127.7 (CH), 127.9
(CH), 128.0 (CH), 128.3 (CH), 130.7 (CH), 136.2 (C), 138.5 (C),
153.3 (C), 171.1 (C), 172.6 (C); MS (EI) m/z 465 (M+), 392, 374,
306, 287, 241, 213, 185, 171, 157, 131, 115, 91, 77, 71, 43, 29, 15;
HRMS (EI) calcd for C27H31NO6: 465.2151, found 465.2148.
(2R*,3S*,4S*,5R*)-Ethyl 2-benzyl-3-isopropyl-4-(2-oxo-3-oxazoli-
dinylcarbonyl)-5-phenyltetrahydrofuran-2-carboxylate (5g):
although 5g could not be separated by chromatography from a
mixture with major 4g and 3-(4-methyl-2-pentenoyl)-2-oxazolidinone,
it could be characterized by 1H NMR; 1H NMR (500 MHz, CDCl3) δ
0.87 (3H, d, J = 7.0 Hz), 0.92 (3H, d, J = 7.0 Hz), 0.99 (3H, t, J = 7.1
Hz), 1.98 (1H, m), 2.99 (1H, ddd, J = 6.3, 9.4, 10.4 Hz), 3.10 (1H, dd,
J = 8.0, 11.0 Hz), 3.32 (1H, d, J = 13.9 Hz), 3.48 (1H, d, J = 13.9 Hz),
3.63 (1H, m), 3.79 (1H, m), 4.11−4.30 (3H, m), 4.68 (1H, dd, J = 9.8,
11.0 Hz), 5.68 (1H, d, J = 9.8 Hz), 6.97−7.02 (2H, m), 7.15−7.31
(8H, m).
(2S*,3S*,4S*,5R*)-Ethyl 2-benzyl-3,5-diphenyl-4-(2-oxo-3-
oxazolidinylcarbonyl)tetrahydrofuran-2-carboxylate (4h): colorless
needles; mp 168−170 °C (benzene); IR (KBr) 2981, 1778, 1745,
1698, 1388, 1197, 743, 701 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.20
(3H, t, J = 7.2 Hz), 2.81 (1H, d, J = 13.9 Hz), 2.96 (1H, ddd, J = 6.7,
9.3, 10.9 Hz), 3.10 (1H, d, J = 13.9 Hz), 3.58 (1H, ddd, J = 7.0, 9.3,
10.9 Hz), 3.87 (1H, m), 4.10−4.22 (3H, m), 4.52 (1H, d, J = 10.6 Hz),
5.36 (1H, dd, J = 9.8, 10.6 Hz), 5.91 (1H, d, J = 9.8 Hz), 7.10−7.17
(5H, m), 7.25−7.41 (8H, m), 7.49−7.51 (2H, m); 13C NMR (100
MHz, CDCl3) δ 14.2 (CH3), 38.2 (CH2), 42.2 (CH2), 54.3 (CH),
54.4 (CH), 61.2 (CH2), 62.1 (CH2), 79.9 (CH), 88.6 (C), 126.3
(CH), 127.1 (CH), 127.6 (CH), 127.8 (CH), 127.9 (CH), 128.2
(CH), 128.3 (CH), 129.3 (CH), 130.1 (CH), 135.2 (C), 135.5 (C),
138.2 (C), 153.0 (C), 169.0 (C), 171.1 (C); MS (EI) m/z 499 (M+),
426, 408, 339, 321, 293, 219, 192, 131, 105, 91, 77, 65, 43, 29, 15.
Anal. Calcd for C30H29NO6: C, 72.23; H, 5.85; N, 2.80. Found: C,
72.10; H, 5.79; N, 2.89.
(2S*,3S*,4S*,5R*)-Ethyl 2-benzyl-3-methyl-4-(2-oxo-3-oxazolidi-
nylcarbonyl)-5-phenyltetrahydrofuran-2-carboxylate (4d): colorless
needles; mp 129−131 °C (benzene); IR (KBr) 2980, 2917, 1774,
1
1725, 1703, 1387, 1280, 1218, 746, 704 cm−1; H NMR (400 MHz,
CDCl3) δ 1.24 (3H, t, J = 7.1 Hz), 1.29 (3H, d, J = 6.8 Hz), 2.97 (1H,
d, J = 13.9 Hz), 3.02 (1H, dq, J = 10.9, 6.8 Hz), 3.24−3.32 (2H, m),
3.70 (1H, ddd, J = 7.2, 9.4, 16.6 Hz), 3.94 (1H, dt, J = 7.2, 9.4 Hz),
4.14−4.25 (3H, m), 4.41 (1H, dd, J = 9.8, 10.9 Hz), 5.68 (1H, d, J =
9.8 Hz), 7.14−7.19 (1H, m), 7.21−7.29 (7H, m), 7.34−7.36 (2H, m);
13C NMR (100 MHz, CDCl3) δ 13.5 (CH3), 14.2 (CH3), 36.9 (CH2),
42.4 (CH2), 43.0 (CH), 56.6 (CH), 61.2 (CH2), 62.1 (CH2), 79.6
(CH), 88.3 (C), 126.4 (CH), 127.1 (CH), 127.8 (CH), 128.0 (CH),
128.2 (CH), 130.0 (CH), 135.6 (C), 138.6(C), 153.0 (C), 169.4 (C),
171.7 (C); MS (EI) m/z 437 (M+), 364, 346, 291, 273, 202, 184, 146,
131, 91, 77, 57, 43, 29; HRMS (EI) calcd for C25H27NO6 (M+)
437.1838, found 437.1811. Anal. Calcd for C25H27NO6: C, 68.63; H,
6.22; N, 3.20. Found: C, 68.91; H, 6.0; N, 3.09.
(2R*,3S*,4S*,5R*)-Ethyl 2-benzyl-3-methyl-4-(2-oxo-3-oxazolidi-
nylcarbonyl)-5-phenyltetrahydrofuran-2-carboxylate (5d): although
5d could not be separated by chromatography from a mixture with
major 4d and dipolarophile 3a, it could be characterized by 1H NMR;
1H NMR (400 MHz, CDCl3) δ 1.11 (3H, d, J = 6.8 Hz), 1.32 (3H, t, J
= 7.1 Hz), 2.90 (1H, dq, J = 6.8, 11.1 Hz), 3.25 (1H, d, J = 14.2 Hz),
3.42 (1H, d, J = 14.2 Hz), 3.04 (1H, m), 3.63 (1H, ddd, J = 7.2, 9.4,
10.8 Hz), 3.86 (1H, dt, J = 7.2, 9.0 Hz), 4.12−4.33 (3H, m), 4.32 (1H,
dd, J = 10.0, 11.1 Hz), 5.81 (1H, d, J = 10.0 Hz), 6.90−6.93 (2H, m),
7.13−7.37 (8H, m).
(2S*,3S*,4S*,5R*)-Ethyl 2-benzyl-3-ethyl-4-(2-oxo-3-oxazolidi-
nylcarbonyl)-5-phenyltetrahydrofuran-2-carboxylate (4e): colorless
needles; mp 155−157 °C (benzene); IR (KBr) 2972, 2933, 1767,
1726, 1703, 1387, 1274, 740, 703 cm−1; 1H NMR (400 MHz, CDCl3)
δ 0.92 (3H, t, J = 7.4 Hz), 1.24 (3H, t, J = 7.1 Hz), 1.55 (1H, m), 2.02
(1H, m), 2.95 (1H, ddd, J = 6.6, 9.8, 10.9 Hz), 3.02 (1H, d, J = 13.9
Hz), 3.23 (1H, m), 3.28 (1H, d, J = 13.9 Hz), 3.67 (1H, ddd, J = 7.0,
9.4, 10.9 Hz), 3.87 (1H, m), 4.11−4.25 (3H, m), 4.58 (1H, t, J = 9.8
Hz), 5.63 (1H, d, J = 9.8 Hz), 7.13−7.36 (8H, m), 7.38−7.51 (2H,
m); 13C NMR (100 MHz, CDCl3) δ 13.3 (CH3), 14.2 (CH3), 22.8
(CH2), 36.7 (CH2), 42.5 (CH2), 50.1 (CH), 55.0 (CH), 61.2 (CH2),
61.9 (CH2), 80.0 (CH), 88.4 (C), 126.3 (CH), 127.3 (CH), 127.7
(CH), 127.9 (CH), 128.1 (CH), 130.1 (CH), 135.8 (C), 138.1 (C),
153.0 (C), 170.3 (C), 171.9 (C); MS (EI) m/z 451 (M+), 379, 361,
291, 273, 264, 217, 199, 171, 131, 91, 77, 57, 43, 29, 15. Anal. Calcd
for C26H29NO6: C, 69.16; H, 6.47; N, 3.10. Found: C, 68.99; H, 6.37;
N, 3.39.
(2R*,3S*,4S*,5R*)-Ethyl 2-benzyl-3-ethyl-4-(2-oxo-3-oxazolidi-
nylcarbonyl)-5-phenyltetrahydrofuran-2-carboxylate (5e): although
5e could not be separated by chromatography from a mixture with
major 4e and 3-(2-pentenoyl)-2-oxazolidinone, it could be charac-
1
1
terized by H NMR; H NMR (400 MHz, CDCl3) δ 0.95 (3H, t, J =
7.3 Hz), 1.30 (3H, t, J = 7.1 Hz), 1.55 (1H, m), 1.74 (1H, m), 2.85
(1H, ddd, J = 6.4, 9.8, 10.5 Hz), 3.04 (1H, m), 3.30 (1H, d, J = 14.4
Hz), 3.47 (1H, d, J = 14.4 Hz), 3.61 (1H, m), 3.80 (1H, m), 4.07−4.27
(3H, m), 4.50 (1H, t, J = 9.8 Hz), 5.81 (1H, d, J = 9.8 Hz), 7.01−7.04
(2H, m), 7.13−7.31 (8H, m).
(2S*,3S*,4S*,5R*)-Ethyl 2-benzyl-4-(2-oxo-3-oxazolidinylcarbon-
yl)-5-phenyl-3-propyltetrahydrofuran-2-carboxylate (4f): colorless
needles; mp 162−164 °C (benzene); IR (KBr) 2929, 1771, 1721,
1702, 1384, 1219, 760, 702 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.95
(3H, t, J = 7.3 Hz, Me), 1.24 (3H, t, J = 7.1 Hz), 1.15−1.35 (2H, m),
1.50 (1H, m),1.92 (1H, m), 2.94 (1H, ddd, J = 6.7, 9.7, 10.9 Hz), 3.02
(1H, d, J = 14.0 Hz), 3.29 (1H, d, J = 14.0 Hz), 3.31 (1H, m), 3.67
(1H, ddd, J = 7.0, 9.3, 10.9 Hz), 3.86 (1H, m), 4.11−4.25 (3H, m),
(2R*,3S*,4S*,5R*)-Ethyl 2-benzyl-3,5-diphenyl-4-(2-oxo-3-
oxazolidinylcarbonyl)tetrahydrofuran-2-carboxylate (5h): although
5h could not be separated by chromatography from a mixture with
major 4h and trans-3-cinnamoyl-2-oxazolidinone, it could be
characterized by 1H NMR; 1H NMR (400 MHz, CDCl3) δ 1.02
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(3H, t, J = 7.2 Hz), 2.90 (1H, ddd, J = 6.4, 9.3, 10.0 Hz), 3.33 (1H, d, J
= 14.3 Hz), 3.46 (1H, d, J = 14.3 Hz), 3.54 (1H, ddd, J = 7.0, 9.3, 10.9
Hz), 3.74−3.84 (2H, m), 3.97−4.11 (2H, m), 4.28 (1H, d, J = 10.0
Hz), 5.26 (1H, t, J = 10.0 Hz), 6.14 (1H, d, J = 10.0 Hz), 7.15−7.18
(2H, m), 7.21−7.38 (13H, m).
(CH), 61.5 (CH2), 62.3 (CH2), 78.9 (CH), 88.8 (C), 123.1 (CH),
126.6 (CH), 127.9 (CH), 128.1 (CH), 130.0 (CH), 135.2 (C), 146.3
(C), 147.5 (C), 153.0 (C), 168.6 (C), 171.5 (C); MS (EI) m/z 482
(M+), 410, 391, 345, 304, 248, 232, 202, 174, 129, 115, 91, 56, 43, 29,
15. Anal. Calcd for C25H26N2O8: C, 62.23; H, 5.43; N, 5.81. Found: C,
62.06; H, 5.40; N, 6.02.
(2S*,3S*,4S*,5R*)-Ethyl 2-benzyl-3-methyl-4-(2-oxo-3-oxazolidi-
nylcarbonyl)-5-(p-tolyl)tetrahydrofuran-2-carboxylate (4i): colorless
needles; mp 150−153 °C (benzene); IR (KBr) 2975, 1770, 1724,
(2R*,3S*,4S*,5R*)-Ethyl 2-benzyl-3-methyl-5-(4-nitrophenyl)-4-
(2-oxo-3-oxazolidinylcarbonyl)tetrahydrofuran-2-carboxylate (5k):
although 5k could not be separated by chromatography from a mixture
1
1701, 1388, 1282, 1108, 706 cm−1; H NMR (400 MHz, CDCl3) δ
1
1.23 (3H, t, J = 7.1 Hz), 1.28 (3H, d, J = 6.8 Hz), 2.28 (3H, s), 2.96
(1H, d, J = 13.9 Hz), 3.08 (1H, ddd, J = 6.6, 9.3, 10.9 Hz), 3.26 (1H, d,
J = 13.9 Hz), 3.27 (1H, m), 3.73 (1H, ddd, J = 7.0, 9.3, 10.9 Hz), 3.99
(1H, m), 4.11−4.26 (3H, m), 4.34 (1H, dd, J = 9.9, 10.9 Hz), 5.66
(1H, d, J = 9.9 Hz), 7.06−7.08 (2H, m), 7.14−7.27 (7H, m); 13C
NMR (100 MHz, CDCl3) δ 13.5 (CH3), 14.2 (CH3), 21.2 (CH3),
36.9 (CH2), 42.4 (CH2), 42.9 (CH), 56.5 (CH), 61.1 (CH2), 62.1
(CH2), 79.5 (CH), 88.2 (C), 126.3 (CH), 126.9 (CH), 127.9 (CH),
128.4 (CH), 130.0 (CH), 135.6 (C), 135.7 (C), 137.7 (C), 152.9 (C),
169.5 (C), 171.8 (C); MS (EI) m/z 451 (M+), 379, 361, 291, 273,
217, 199, 171, 146, 131, 105, 91, 77, 57, 43, 29, 15. Anal. Calcd for
C26H29NO6: C, 69.16; H, 6.47; N, 3.10. Found: C, 69.03; H, 6.34; N,
3.37.
with major 4k and dipolarophile 3a, it could be characterized by H
1
NMR; H NMR (400 MHz, CDCl3) δ 1.11 (3H, d, J = 6.8 Hz), 1.34
(3H, t, J = 7.1 Hz), 3.05 (1H, m), 3.22 (1H, m), 3.27 (1H, d, J = 14.2
Hz), 3.41 (1H, d, J = 14.2 Hz), 3.70 (1H, ddd, J = 6.1, 9.3, 11.0 Hz),
4.06 (1H, dt, J = 6.4, 9.3 Hz), 4.16−4.37 (4H, m), 5.93 (1H, d, J =
10.0 Hz), 6.95−6.98 (2H, m), 7.18−7.31 (7H, m).
(2S*,3S*,4S*,5R*)-Ethyl 2-benzyl-3-methyl-5-(2-naphthyl)-4-(2-
oxo-3-oxazolidinylcarbonyl)tetrahydrofuran-2-carboxylate (4l): col-
orless needles; mp 161−163 °C (benzene); IR (KBr) 2972, 1778,
1727, 1696, 1387, 1289, 758, 701 cm−1; 1H NMR (400 MHz, CDCl3)
δ 1.28 (3H, t, J = 7.1 Hz), 1.31 (3H, d, J = 7.0 Hz), 2.79 (1H, m), 3.02
(1H, d, J = 14.0 Hz), 3.32 (1H, d, J = 14.0 Hz), 3.36 (1H, m), 3.55−
3.63 (2H, m), 4.07 (1H, m), 4.16−4.30 (2H, m), 4.50 (1H, (1H, dd, J
= 10.1, 10.9 Hz), 5.87 (1H, d, J = 10.1 Hz), 7.16−7.31 (5H, m), 7.42−
7.50 (3H, m), 7.74−7.83 (4H, m); 13C NMR (100 MHz, CDCl3) δ
13.6 (CH3), 14.6 (CH3), 37.0 (CH2), 42.3 (CH2), 43.2 (CH), 56.7
(CH), 61.3 (CH2), 62.1 (CH2), 79.8 (CH), 88.6 (C), 124.8 (CH),
125.99 (CH), 126.03 (CH), 126.2 (CH), 126.5 (CH), 127.5 (CH),
127.7 (CH), 127.9 (CH), 128.1 (CH), 130.1 (CH), 132.6 (C), 133.1
(C), 135.6 (C), 136.2 (C), 153.1 (C), 169.4 (C), 171.8 (C); MS (EI)
m/z 487 (M+), 415, 397, 332, 309, 283, 264, 235, 207, 182, 166, 141,
91, 65, 43, 29, 15. Anal. Calcd for C29H29NO6: C, 71.44; H, 6.00; N,
2.87. Found: C, 71.36; H, 6.07; N, 2.88.
(2R*,3S*,4S*,5R*)-Ethyl 2-benzyl-3-methyl-4-(2-oxo-3-oxazolidi-
nylcarbonyl)-5-(p-tolyl)tetrahydrofuran-2-carboxylate (5i): although
5i could not be separated by chromatography from a mixture with
1
major 4i and dipolarophile 3a, it could be characterized by H NMR;
1H NMR (400 MHz, CDCl3) δ 1.10 (3H, d, J = 6.8 Hz), 1.31 (3H, t, J
= 7.1 Hz), 2.27 (3H, s), 2.96 (1H, dq, J = 11.0, 6.8 Hz), 3.00 (1H, m),
3.23 (1H, d, J = 14.0 Hz), 3.41 (1H, d, J = 14.0 Hz), 3.63 (1H, ddd, J =
7.1, 9.4, 10.9 Hz), 3.88 (1H, m), 4.12−4.24 (3H, m) 4.32 (1H, dd, J =
9.8, 11.0 Hz), 5.76 (1H, d, J = 9.8 Hz), 6.93−6.96 (2H, m), 7.30−7.38
(7H, m).
(2S*,3S*,4S*,5R*)-Ethyl 2-benzyl-5-(4-chlorophenyl)-3-methyl-4-
(2-oxo-3-oxazolidinylcarbonyl)tetrahydrofuran-2-carboxylate (4j):
colorless needles; mp 162−165 °C (benzene); IR (KBr) 2974,
(2R*,3S*,4S*,5R*)-Ethyl 2-benzyl-3-methyl-5-(2-naphthyl)-4-(2-
oxo-3-oxazolidinylcarbonyl)tetrahydrofuran-2-carboxylate (5l):
although 5l could not be separated by chromatography from a
mixture with major 4l and dipolarophile 3a, it could be characterized
by 1H NMR; 1H NMR (400 MHz, CDCl3) δ 1.14 (3H, d, J = 6.9 Hz),
1.24 (3H, t, J = 7.1 Hz), 2.60 (1H, m), 3.12 (1H, dq, J = 6.9, 11.4 Hz),
3.44 (1H, d, J = 14.0 Hz), 3.45 (1H, m), 3.56 (1H, d, J = 14.0 Hz),
3.97 (1H, dt, J = 7.0, 9.2 Hz), 4.16−4.27 (3H, m), 4.39 (1H, dd, J =
10.3, 11.4 Hz), 5.98 (1H, d, J = 10.3 Hz), 6.89−6.96 (2H, m), 7.13−
7.52 (6H, m), 7.74−7.83 (2H, m), 7.94−8.01 (2H, m).
1
1766, 1722, 1697, 1390, 1230, 1108, 757, 705 cm−1; H NMR (400
MHz, CDCl3) δ 1.24 (3H, t, J = 7.1 Hz), 1.28 (3H, d, J = 6.8 Hz), 2.95
(1H, d, J = 14.0 Hz), 3.19 (1H, ddd, J = 7.0, 9.4, 11.0 Hz), 3.25 (1H,
m), 3.27 (1H, d, J = 13.9 Hz), 3.78 (1H, ddd, J = 6.7, 9.4, 11.0 Hz),
4.10 (1H, dt, J = 6.7, 9.2 Hz), 4.15−4.23 (2H, m), 4.28 (1H, dt, J =
7.0, 9.2 Hz), 4.39 (1H, dd, J = 9.8, 10.9 Hz), 5.68 (1H, d, J = 9.8 Hz),
7.14−7.26 (7H, m), 7.30−7.32 (2H, m); 13C NMR (100 MHz,
CDCl3) δ 13.5 (CH3), 14.2 (CH3), 21.2 (CH3), 36.9 (CH2), 42.4
(CH2), 42.9 (CH), 56.5 (CH), 61.1 (CH2), 62.1 (CH2), 79.5 (CH),
88.2 (C), 126.3 (CH), 126.9 (CH), 127.9 (CH), 128.4 (CH), 130.0
(CH), 135.6 (C), 135.7 (C), 137.7 (C), 152.9 (C), 169.5 (C), 171.8
(C); MS (EI) m/z 471 (M+), 399, 381, 312, 294, 248, 222, 192, 166,
129, 91, 65, 43, 29, 15. Anal. Calcd for C25H26ClNO6: C, 63.63; H,
5.55; N, 2.97. Found: C, 63.84; H, 5.41; N, 2.90.
General Procedure for the Ni(II)-Catalyzed Reaction
Exemplified by the Reaction of Ethyl 2-diazohydrocinnamate
(1), Benzaldehyde (2), and (S)-3-crotonoyl-4-isopropyl-2-
oxazolidinone (7a). To a solution of (S)-3-crotonoyl-4-isopropyl-
2-oxazolidinone (86.8 mg, 0.44 mmol), Rh2Piv4 (1.2 mg, 2.6 × 10−4
mmol), Ni(BF4)2·6H2O (13.6 mg, 0.040 mmol), and MS 4 Å (500
mg) in CH2Cl2 (4 mL) at −78 °C (dry ice/acetone bath) was added a
solution of ethyl 2-diazohydrocinnamate (120.8 mg, 0.52 mmol) and
benzaldehyde (41 μL, 0.40 mmol) in CH2Cl2 (5 mL) over a period of
1 h using a syringe pump. The syringe was washed with CH2Cl2 (1
mL), and then the stirring was continued for 10 min at −78 °C. After
the mixture was warmed to room temperature, it was filtered through
Celite (1 cm) and a plug of silica gel (3 cm) with AcOEt/hexane (1/1,
80 mL) as an eluent. The solvent was removed in vacuo, and the
residue was purified by column chromatography ((98/2)−(95/5),
hexane/AcOEt) to provide 153.5 mg (80%) of 8a and 9a along with
2.3 mg (3%) of 1,3-dioxolane 6. The 8a:9a ratio was determined to be
(2R*,3S*,4S*,5R*)-Ethyl 2-benzyl-5-(4-chlorophenyl)-3-methyl-4-
(2-oxo-3-oxazolidinylcarbonyl)tetrahydrofuran-2-carboxylate (5j):
although 5j could not be separated by chromatography from a
mixture with major 4j and dipolarophile 3a, it could be characterized
by 1H NMR; 1H NMR (400 MHz, CDCl3) δ 1.10 (3H, d, J = 6.8 Hz),
1.22 (3H, t, J = 7.1 Hz), 2.95 (1H, dq, J = 6.8, 10.0 Hz), 3.02 (1H,
ddd, J = 6.8, 9.2, 11.0 Hz), 3.39 (1H, d, J = 14.2 Hz), 3.45 (1H, d, J =
14.2 Hz), 3.67 (1H, ddd, J = 6.8, 9.2, 10.9 Hz), 3.97 (1H, dt, J = 7.0,
9.2 Hz), 4.15−4.38 (3H, m), 4.39 (1H, t, J = 10.0 Hz), 5.80 (1H, d, J =
10.0 Hz), 7.09−7.12 (2H, m), 7.25−7.38 (7H, m).
1
99:1 by H NMR analysis (400 MHz). Cycloadduct 8a (140.1 mg,
(2S*,3S*,4S*,5R*)-Ethyl 2-benzyl-3-methyl-5-(4-nitrophenyl)-4-
(2-oxo-3-oxazolidinylcarbonyl)tetrahydrofuran-2-carboxylate (4k):
colorless needles; mp 139−143 °C (benzene); IR (KBr) 2974, 1782,
73%) could be separated from the mixture of 8a and 9a by careful
column chromatography (98:2, hexane/AcOEt).
Cycloadducts 8b and 9b (120.5 mg, 61%, 8b:9b = 99:1) were
synthesized according to the general procedure. Cycloadduct 8b
(105.7 mg, 54%) could be separated from the mixture of 8b and 9b by
careful column chromatography.
Cycloadducts 8c and 9c (120.0 mg, 59%, 8c:9c = >99:1) were
synthesized according to the general procedure.
Cycloadducts 8d and 9d (114.9 mg, 53%, 8d:9d = >99:1) were
synthesized according to the general procedure.
1
1735, 1688, 1521, 1390, 1348, 743, 709 cm−1; H NMR (400 MHz,
CDCl3) δ 1.24 (3H, t, J = 7.1 Hz), 1.28 (3H, d, J = 6.8 Hz), 2.95 (1H,
d, J = 14.0 Hz), 3.19 (1H, ddd, J = 7.0, 9.4, 11.0 Hz), 3.25 (1H, m),
3.27 (1H, d, J = 14.0 Hz), 3.78 (1H, ddd, J = 6.7, 9.4, 11.0 Hz), 4.10
(1H, dt, J = 6.7, 9.2 Hz), 4.15−4.23 (2H, m), 4.28 (1H, dt, J = 7.0, 9.2
Hz), 4.39 (1H, dd, J = 9.8, 10.9 Hz), 5.68 (1H, d, J = 9.8 Hz), 7.14−
7.26 (7H, m), 7.30−7.32 (2H, m); 13C NMR (100 MHz, CDCl3) δ
13.2 (CH3), 14.3 (CH3), 37.3 (CH2), 42.4 (CH2), 43.3 (CH), 56.5
6190
dx.doi.org/10.1021/jo400858u | J. Org. Chem. 2013, 78, 6182−6195

The Journal of Organic Chemistry
Article
Cycloadducts 8e and 9e (125.4 mg, 75%, 8e:9e = 99:1) were
synthesized according to the general procedure. Cycloadduct 8e
(114.5 mg, 68%) could be separated from the mixture of 8e and 9e by
careful column chromatography.
128.3 (CH), 130.1 (CH), 135.8 (C), 138.0 (C), 153.8 (C), 170.4 (C),
172.0 (C); MS (EI) m/z 493(M+), 403, 291, 273, 217, 199, 171, 145,
130, 105, 91, 77, 57, 43, 29, 15. Anal. Calcd for C29H35NO6: C, 70.57;
H, 7.15; N, 2.84. Found: C, 70.78; H, 7.02; N, 2.75.
Cycloadducts 8f and 9f (146.1 mg, 82%, 8f:9f = >99:1) were
synthesized according to the general procedure.
Cycloadducts 8g and 9g (167.6 mg, 79%, 8g:9g = >99:1) were
(2R,3S,4S,5R)-Ethyl 2-benzyl-3-ethyl-4-[(S)-4-isopropyl-2-oxo-3-
oxazolidinylcarbonyl]-5-phenyltetrahydrofuran-2-carboxylate (9b):
although 9b could not be separated by chromatography from a mixture
1
with major 8b and dipolarophile 7b, it could be characterized by H
synthesized according to the general procedure.
1
NMR; H NMR (400 MHz, CDCl3) δ 0.72 (6H, d, J = 7.1 Hz), 0.96
Cycloadducts 8h and 9h (138.4 mg, 70%, 8h:9h = 99:1) were
synthesized according to the general procedure. Cycloadduct 8h
(129.7 mg, 67%) could be separated from the mixture of 8h and 9h by
careful column chromatography.
Cycloadducts 8i and 9i (137.9 mg, 67%, 8i:9i = 99:1) were
synthesized according to the general procedure. Cycloadduct 8i (125.9
mg, 61%) could be separated from the mixture of 8i and 9i by careful
column chromatography.
Cycloadducts 8j and 9j (142.6 mg, 68%, 8j:9j = 99:1) were
synthesized according to the general procedure. Cycloadduct 8j (134.7
mg, 64%) could be separated from the mixture of 8j and 9j by careful
column chromatography.
(3H, t, J = 7.3 Hz), 1.27 (3H, t, J = 7.1 Hz), 1.53 (1H, m), 1.77 (1H,
m), 2.04 (1H, m), 2.99 (1H, dq, J = 11.0, 7.1 Hz), 3.25 (1H, d, J =
14.2 Hz), 3.49−3.55 (2H, m), 3.85 (1H, m), 4.14−4.31 (3H, m), 4.55
(1H, dd, J = 9.8, 11.0 Hz), 5.79 (1H, d, J = 9.8 Hz), 6.99−7.02 (2H,
m), 7.15−7.37 (8H, m).
(2S,3S,4S,5R)-Ethyl 2-benzyl-4-[(S)-4-isopropyl-2-oxo-3-oxazolidi-
nylcarbonyl]-5-phenyl-3-propyltetrahydrofuran-2-carboxylate (8c):
25
colorless needles; mp 179−182 °C (benzene); [α]D = −26.5° (c
1.00, CHCl3); IR (KBr) 2963, 1775, 1731, 1702, 1388, 1211, 1091,
1
754, 700 cm−1; H NMR (400 MHz, CDCl3) δ 0.75 (6H, d, J = 7.0
Hz), 0.95 (3H, t, J = 7.3 Hz), 1.23 (3H, t, J = 7.1 Hz), 1.15−1.32 (2H,
m), 1.54 (1H, m), 1.92 (1H, m), 2.10 (1H, m), 3.02 (1H, d, J = 14.0
Hz), 3.29 (1H, d, J = 14.0 Hz), 3.33 (1H, m), 3.45 (1H, t, J = 8.2 Hz),
3.48 (1H, ddd, J = 1.7, 4.1, 8.2 Hz), 3.90 (1H, dd, J = 1.7, 8.2 Hz),
4.11−4.26 (2H, m,), 4.64 (1H, t, J = 9.8 Hz), 5.58 (1H, d, J = 9.8 Hz),
7.13−7.31 (8H, m), 7.38−7.40 (2H, m); 13C NMR (100 MHz,
CDCl3) δ 14.2 (CH3), 14.4 (CH3), 14.9 (CH3), 17.8 (CH3), 21.9
(CH2), 28.8 (CH), 32.1 (CH2), 36.4 (CH2), 48.7 (CH), 55.2 (CH),
58.7 (CH), 61.1 (CH2), 63.4 (CH2), 80.0 (CH), 88.4 (C), 126.3
(CH), 127.6 (CH), 127.7 (CH), 127.9 (CH), 128.2 (CH), 130.0
(CH), 135.8 (C), 137.9 (C), 153.7 (C), 170.3 (C), 171.8 (C); MS
(EI) m/z 507 (M+), 435, 418, 371, 343, 306, 289, 242, 213, 186, 158,
131, 115, 91, 77, 55, 29, 15. Anal. Calcd for C30H37NO6: C, 70.98; H,
7.45; N, 2.76. Found: C, 70.86; H, 7.30; N, 2.94.
Cycloadducts 8k and 9k (150.6 mg, 71%, 8k:9k = >99:1) were
synthesized according to the general procedure.
Cycloadducts 8l and 9l (145.1 mg, 78%, 8l:9l = 99:1) were
synthesized according to the general procedure. Cycloadduct 8l (135.8
mg, 73%) could be separated from the mixture of 8l and 9l by careful
column chromatography.
Cycloadducts 8m and 9m (148.4 mg, 73%, 8m:9m = >99:1) were
synthesized according to the general procedure.
(2S,3S,4S,5R)-Ethyl 2-benzyl-4-[(S)-4-isopropyl-2-oxo-3-oxazolidi-
nylcarbonyl]-3-methyl-5-phenyltetrahydrofuran-2-carboxylate
25
(8a): colorless needles; mp 125−127 °C (benzene); [α]D = −34.0°
(c 1.00, CHCl3); IR (KBr) 2981, 1775, 1725, 1702, 1495, 1380, 1276,
1218, 1105, 746, 704 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.77 (3H,
d, J = 6.9 Hz), 0.78 (3H, d, J = 6.9 Hz), 1.23 (3H, t, J = 7.1 Hz), 1.30
(3H, d, J = 6.8 Hz), 2.15 (1H, m), 2.98 (1H, d, J = 13.9 Hz), 3.26−
3.34 (3H, m), 3.49−3.56 (2H, m), 3.94 (1H, m), 4.11−4.25 (2H, m),
4.49 (1H, dd, J = 9.8, 10.8 Hz), 5.62 (1H, d, J = 9.8 Hz), 7.14−7.30
(8H, m), 7.34−7.37 (2H, m); 13C NMR (100 MHz, CDCl3) δ 13.6
(CH3), 14.2 (CH3), 14.9 (CH3), 17.9 (CH3), 28.9 (CH), 36.7 (CH2),
43.4 (CH), 56.7 (CH), 58.9 (CH), 61.1 (CH2), 63.5 (CH2), 79.5
(CH), 88.3 (C), 126.3 (CH), 127.3 (CH), 127.86 (CH), 127.94
(CH), 128.2 (CH), 130.0 (CH), 135.6 (C), 138.4 (C), 153.7 (C),
169.5 (C), 171.7 (C); MS (EI) m/z 479 (M+), 406, 389, 370, 342,
324, 299, 277, 260, 203, 185, 159, 143, 128, 103, 91, 86, 77, 65, 52, 43,
39, 30. Anal. Calcd for C28H33NO6: C, 70.13; H, 6.94; N, 2.92. Found:
C, 70.50; H, 6.91; N, 2.58.
(2R,3S,4S,5R)-Ethyl 2-benzyl-4-[(S)-4-isopropyl-2-oxo-3-oxazolidi-
nylcarbonyl]-5-phenyl-3-propyltetrahydrofuran-2-carboxylate (9c):
although 9c could not be separated by chromatography from a mixture
1
with major 8c and dipolarophile 7c, it could be characterized by H
1
NMR; H NMR (400 MHz, CDCl3) δ 0.72 (6H, d, J = 6.8 Hz), 0.98
(3H, t, J = 7.3 Hz), 1.31 (3H, t, J = 7.1 Hz), 1.56 (1H, m), 1.66−173
(2H, m), 2.03−2.09 (2H, m), 2.83 (1H, ddd, J = 6.8, 9.8, 10.5 Hz),
3.10 (1H, m), 3.35 (1H, d, J = 14.2 Hz), 3.47 (1H, d, J = 14.2 Hz),
3.51 (1H, m), 3.84 (1H, m), 4.13−4.25 (2H, m), 4.56 (1H, dd, J = 9.8,
10.0 Hz), 5.79 (1H, d, J = 9.8 Hz), 6.98−7.01 (2H, m), 7.11−7.34
(8H, m).
(2S,3S,4S,5R)-Ethyl 2-benzyl-3,5-diphenyl-4-[(S)-4-isopropyl-2-
oxo-3-oxazolidinylcarbonyl]-3-propyltetrahydrofuran-2-carboxy-
25
late (8d): colorless prisms; mp 213-215 °C (benzene); [α]D
=
(2R,3S,4S,5R)-Ethyl 2-benzyl-4-[(S)-4-isopropyl-2-oxo-3-oxazolidi-
nylcarbonyl]-3-methyl-5-phenyltetrahydrofuran-2-carboxylate
(9a): although 9a could not be separated by chromatography from a
mixture with major 8a and dipolarophile 7a, it could be characterized
by 1H NMR; 1H NMR (400 MHz, CDCl3) δ 0.72 (3H, d, J = 6.9 Hz),
0.73 (3H, d, J = 6.9 Hz), 1.13 (3H, d, J = 7.0 Hz), 1.36 (3H, t, J = 7.0
Hz), 2.09 (1H, m), 3.04 (1H, dq, J = 11.1, 7.0 Hz), 3.25 (1H, d, J =
14.2 Hz), 3.33−3.43 (2H, m), 3.86 (1H, dd, J = 1.8, 8.4 Hz), 4.11−
4.23 (3H, m), 4.38 (1H, dd, J = 10.2, 11.1 Hz), 5.75 (1H, d, J = 10.2
Hz), 6.88−6.90 (2H, m), 7.25−7.31 (8H, m).
−35.7° (c 1.00, CHCl3); IR (KBr) 2965, 1776, 1735, 1702, 1388,
1204, 1085, 755, 701 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.59 (3H,
d, J = 6.9 Hz), 0.64 (3H, d, J = 6.9 Hz), 1.21 (3H, t, J = 7.1 Hz), 1.98
(1H, m), 2.80 (1H, d, J = 14.0 Hz), 3.05 (1H, d, J = 14.0 Hz), 3.50−
3.51 (2H, m), 3.90 (1H, m), 4.11−4.23 (2H, m), 4.55 (1H, d, J = 10.3
Hz), 5.43 (1H, dd, J = 9.7, 10.3 Hz), 5.86 (1H, d, J = 9.7 Hz), 7.10−
7.19 (5H, m), 7.28−7.41 (8H, m), 7.51−7.53 (2H, m); 13C NMR
(100 MHz, CDCl3) δ 14.6 (CH3), 14.6 (CH3), 17.8 (CH3), 28.5
(CH), 38.4 (CH2), 54.3 (CH), 54.8 (CH), 58.9 (CH), 61.2 (CH2),
63.4 (CH2), 80.2 (CH), 88.7(C), 126.3 (CH), 127.4 (CH), 127.6
(CH), 127.8 (CH), 128.0 (CH), 128.3 (CH), 128.4 (CH), 129.1
(CH), 130.1 (CH), 135.4 (C), 135.6 (C), 138.2 (C), 153.8 (C), 169.3
(C), 171.3 (C); MS (EI) m/z 541 (M+), 469, 451, 405, 377, 340, 322,
294, 276, 248, 220, 192, 130, 115, 91, 65, 29, 15. Anal. Calcd for
C33H35NO6: C, 73.18; H, 6.51; N, 2.59. Found: C, 73.33; H, 6.57; N,
2.37.
(2R,3S,4S,5R)-Ethyl 2-benzyl-3,5-diphenyl-4-[(S)-4-isopropyl-2-
oxo-3-oxazolidinylcarbonyl]-3-propyltetrahydrofuran-2-carboxy-
late (9d): although 9d could not be separated by chromatography
from a mixture with major 8d and dipolarophile 7d, it could be
characterized by 1H NMR; 1H NMR (400 MHz, CDCl3) δ 0.56 (3H,
d, J = 6.8 Hz), 0.62 (3H, d, J = 6.8 Hz), 0.99 (3H, t, J = 7.1 Hz), 1.86
(1H, m), 3.28 (1H, d, J = 13.6 Hz), 3.41 (1H, d, J = 13.6 Hz), 3.51
(2S,3S,4S,5R)-Ethyl 2-benzyl-3-ethyl-4-[(S)-4-isopropyl-2-oxo-3-
oxazolidinylcarbonyl]-5-phenyltetrahydrofuran-2-carboxylate (8b):
25
colorless needles; mp 189−191 °C (benzene); [α]D = −31.2° (c
1.00, CHCl3); IR (KBr) 2964, 1776, 1725, 1770, 1387, 1264, 1206,
1088, 751, 700 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.76 (6H, d, J =
7.4 Hz), 0.91 (3H, t, J = 7.4 Hz), 1.23 (3H, t, J = 7.1 Hz), 1.56 (1H,
m), 1.99−2.15 (2H, m), 3.02 (1H, d, J = 14.1 Hz), 3.28 (1H, d, J =
14.1 Hz), 3.26 (1H, m), 3.45 (1H, t, J = 8.2 Hz), 3.49 (1H, ddd, J =
1.8, 4.0, 8.2 Hz), 3.90 (1H, dd, J = 1.8, 8.2 Hz), 4.10−4.62 (2H, m),
4.62 (1H, t, J = 9.8 Hz), 5.59 (1H, d, J = 9.8 Hz), 7.15−7.31 (8H, m),
7.38−7.40 (2H, m); 13C NMR (100 MHz, CDCl3) δ 13.2 (CH3), 14.1
(CH3), 14.9 (CH3), 17.8 (CH3), 22.8 (CH2), 28.8 (CH), 36.4 (CH2),
50.5 (CH), 54.9 (CH), 58.7 (CH), 61.2 (CH2), 63.4 (CH2), 80.0
(CH), 88.4 (C), 126.4 (CH), 127.7 (CH), 127.8 (CH), 128.0 (CH),
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(1H, m), 3.74 (1H, m), 3.82 (1H, dd, J = 1.7, 8.3 Hz), 3.90−3.99 (2H,
m), 4.26 (1H, d, J = 10.2 Hz), 5.34 (1H, dd, J = 9.5, 10.2 Hz), 6.10
(1H, d, J = 9.5 Hz), 7.18−7.24 (2H, m), 7.24−7.46 (13H, m).
(2S,3S,4S,5R)-Ethyl 2-ethyl-4-[(S)-4-isopropyl-2-oxo-3-oxazolidi-
nylcarbonyl]-3-methyl-5-phenyltetrahydrofuran-2-carboxylate
(CH), 88.3 (C), 123.9 (CH), 125.2 (CH), 125.4 (CH), 125.7 (CH),
127.35 (CH), 127.42 (CH), 128.0 (CH), 128.1 (CH), 128.4 (CH),
128.7 (CH), 132.2 (C), 132.8 (C), 133.9 (C), 138.9 (C), 154.0 (C),
169.8 (C), 172.6 (C); MS (EI) m/z 529 (M+), 388, 324, 259, 231,
213, 187, 157, 141, 130; HRMS (ESI-TOF) calcd for C32H36NO6 (M
+ H)+ 530.2537, found 530.2530.
25
(8e): colorless oil; [α]D = −34.7° (c 0.50, CHCl3); IR (neat) 2967,
1
1780, 1748, 1701, 1389, 1251, 1133, 741, 703 cm−1; H NMR (500
(2R,3S,4S,5R)-Ethyl 4-[(S)-4-isopropyl-2-oxo-3-oxazolidinylcar-
bonyl]-3-methyl-2-(1-naphthylmethyl)-5-phenyltetrahydrofuran-2-
carboxylate (9g): although 9g could not be separated by
chromatography from a mixture with major 8g and dipolarophile 7a,
it could be characterized by 1H NMR; 1H NMR (CDCl3, 500 MHz) δ
0.71 (3H, d, J = 6.9 Hz), 0.74 (3H, d, J = 6.9 Hz), 1.12 (3H, t, J = 7.1
Hz), 1.39 (3H, d, J = 6.9 Hz), 2.11 (1H, m), 3.24 (1H, dq, J = 11.1, 6.9
Hz), 3.30 (1H, d, J = 14.8 Hz), 3.45 (1H, d, J = 14.8 Hz), 3.58 (1H,
m), 3.90 (1H, m), 4.14−4.39 (3H, m), 4.52 (1H, dd, J = 9.8, 11.1 Hz),
5.75 (1H, d, J = 9.8 Hz), 6.98−7.05 (2H, m), 7.41−7.56 (6H, m),
7.64−7.79 (2H, m), 8.05−8.10 (1H, m), 8.12−8.18 (1H, m).
(2S,3S,4S,5R)-Ethyl 2-benzyl-4-[(S)-4-isopropyl-2-oxo-3-oxazolidi-
nylcarbonyl]-3-methyl-5-(p-tolyl)tetrahydrofuran-2-carboxylate
MHz, CDCl3) δ 0.76 (6H, d, J = 6.8 Hz), 0.97 (3H, t, J = 7.4 Hz), 1.15
(3H, d, J = 6.9 Hz), 1.36 (3H, t, J = 7.1 Hz), 1.70 (1H, dq, J = 14.2, 7.4
Hz), 2.01 (1H, dq, J = 14.2, 7.4 Hz), 2.13 (1H, m), 3.22 (1H, dq, J =
10.6, 6.8 Hz), 3.46−3.51 (2H, m), 3.91 (1H, m), 4.22−4.40 (3H, m),
5.36 (1H, d, J = 9.8, Hz), 7.25−7.37 (5H, m); 13C NMR (125 MHz,
CDCl3) δ 8.1 (CH3), 13.3 (CH3), 14.3 (CH3), 14.9 (CH3), 17.8
(CH3), 24.0 (CH2), 28.9 (CH), 42.8 (CH), 56.8 (CH), 59.0 (CH),
61.2 (CH2), 63.5 (CH2), 79.4 (CH), 88.5 (C), 127.5 (CH), 128.1
(CH), 128.4 (CH), 138.9 (C), 154.0 (C), 170.2 (C), 172.7 (C); MS
(EI) m/z 417 (M+), 344, 275, 215, 187, 159, 130, 105, 57; HRMS
(ESI-TOF) calcd for C23H32NO6 (M + H)+ 418.2224, found
418.2228.
25
(2R,3S,4S,5R)-Ethyl 2-ethyl-4-[(S)-4-isopropyl-2-oxo-3-oxazolidi-
nylcarbonyl]-3-methyl-5-phenyltetrahydrofuran-2-carboxylate
(9e): although 9e could not be separated by chromatography from a
mixture with major 8e and dipolarophile 7a, it could be characterized
by 1H NMR; 1H NMR (500 MHz, CDCl3) δ 0.71 (3H, d, J = 6.8 Hz),
0.80 (3H, d, J = 6.8 Hz), 1.02 (3H, t, J = 7.1 Hz), 1.16 (3H, d, J = 6.9
Hz), 1.36 (3H, t, J = 7.1 Hz), 1.67−1.75 (2H, m), 2.09 (1H, m), 3.06
(1H, dq, J = 11.0, 6.9 Hz), 3.47 (1H, m), 3.71 (1H, m), 3.86 (1H, dd, J
= 1.8, 8.6 Hz), 4.17−4.24 (2H, m), 4.37 (1H, dd, J = 10.0, 11.0 Hz),
5.42 (1H, d, J = 10.0, Hz), 7.19−7.30 (5H, m).
(8h): colorless needles; mp 138−140 °C (benzene); [α]D = −39.4°
(c 1.00, CHCl3); IR (KBr) 2976, 2881, 1779, 1724, 1697, 1387, 1209,
1084, 700 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.780 (3H, d, J = 6.8
Hz), 0.784 (3H, d, J = 6.8 Hz), 1.22 (3H, t, J = 7.1 Hz), 1.29 (3H, d, J
= 6.7 Hz), 2.14 (1H, m), 2.30 (3H, s), 2.97 (1H, d, J = 13.8 Hz), 3.27
(1H, d, J = 13.8 Hz), 3.28 (1H, m), 3.52−3.59 (2H, m), 3.95 (1H, t, J
= 6.5 Hz), 4.09−4.24 (2H, m), 4.47 (1H, dd, J = 10.0, 11.0 Hz), 5.59
(1H, d, J = 10.0 Hz), 7.06−7.08 (2H, m), 7.13−7.36 (7H, m); 13C
NMR (100 MHz, CDCl3) δ 13.6 (CH3), 14.2 (CH3), 15.0 (CH3),
17.9 (CH3), 21.3 (CH3), 28.9 (CH), 36.8 (CH2), 43.4 (CH), 56.7
(CH), 58.9 (CH), 61.1 (CH2), 63.6 (CH2), 79.4 (CH), 88.2 (C),
126.3 (CH), 127.2 (CH), 128.0 (CH), 128.5 (CH), 130.1 (CH),
135.5 (C), 135.7 (C), 137.8 (C), 153.7 (C), 169.6 (C), 171.8 (C); MS
(EI) m/z 493 (M+), 421, 402, 291, 273, 245, 201, 171, 145, 130, 105,
91, 77, 69, 57, 43, 29, 15. Anal. Calcd for C29H35NO6: C, 70.57; H,
7.15; N, 2.84. Found: C, 70.57; H, 7.16; N, 2.82.
(2S,3S,4S,5R)-Ethyl 2-isobutyl-4-[(S)-4-isopropyl-2-oxo-3-oxazoli-
dinylcarbonyl]-3-methyl-5-phenyltetrahydrofuran-2-carboxylate
25
(8f): colorless oil; [α]D = −28.7° (c 0.80, CHCl3); IR (neat) 2962,
1
1780, 1727, 1701, 1388, 1211, 1139, 762, 702 cm−1; H NMR (500
MHz, CDCl3) δ 0.75 (3H, d, J = 6.9 Hz), 0.76 (3H, d, J = 6.9 Hz),
0.89 (3H, d, J = 6.5 Hz), 1.02 (3H, d, J = 6.5 Hz), 1.13 (3H, d, J = 6.8
Hz), 1.36 (3H, t, J = 7.1 Hz), 1.63 (1H, dd, J = 5.0, 13.6 Hz), 1.80−
1.91 (2H, m), 2.12 (1H, m), 3.14 (1H, dq, J = 10.9, 6.8 Hz), 3.46−
3.50 (2H, m), 3.91 (1H, m), 4.23−4.35 (2H, m), 4.36 (1H, dd, J = 9.9,
10.9 Hz), 5.36 (1H, d, J = 9.9 Hz), 7.25−7.31 (3H, m), 7.35−7.37
(2H, m); 13C NMR (125 MHz, CDCl3) δ 13.1 (CH3), 14.2 (CH3),
14.9 (CH3), 17.8 (CH3), 23.0 (CH3), 24.2 (CH3), 24.5 (CH), 28.9
(CH), 38.8 (CH2), 44.0 (CH), 56.8 (CH), 59.0 (CH), 61.1 (CH2),
63.6 (CH2), 79.5 (CH), 87.4 (C), 127.6 (CH), 128.1 (CH), 128.4
(CH), 139.0 (C), 154.0 (C), 170.2 (C), 173.3 (C); MS (EI) m/z 445
(M+), 374, 324, 277, 245, 185, 130, 105, 77, 69; HRMS (ESI-TOF)
calcd for C25H36NO6 (M + H)+ 446.2537, found 446.2542.
(2R,3S,4S,5R)-Ethyl 2-benzyl-4-[(S)-4-isopropyl-2-oxo-3-oxazolidi-
nylcarbonyl]-3-methyl-5-(p-tolyl)tetrahydrofuran-2-carboxylate
(9h): although 9h could not be separated by chromatography from a
mixture with major 8h and dipolarophile 7a, it could be characterized
by 1H NMR; 1H NMR (400 MHz, CDCl3) δ 0.72 (3H, d, J = 6.9 Hz,),
0.73 (3H, d, J = 6.9 Hz), 1.13 (3H, d, J = 7.0 Hz), 1.35 (3H, t, J = 7.0
Hz), 2.09 (1H, m), 2.44 (3H, s), 3.04 (1H, dq, J = 11.1, 7.0 Hz), 3.23
(1H, d, J = 14.2 Hz), 3.34−3.46 (2H, m), 3.75 (1H, m), 3.84 (1H, dd,
J = 1.8, 8.4 Hz), 4.11−4.24 (2H, m), 4.35 (1H, dd, J = 9.6, 11.1 Hz),
5.75 (1H, d, J = 9.6 Hz), 7.04−7.11 (2H, m), 7.25−7.31 (7H, m).
(2S,3S,4S,5R)-Ethyl 2-benzyl-5-(4-chlorophenyl)-4-[(S)-4-isoprop-
(2R,3S,4S,5R)-Ethyl 2-isobutyl-4-[(S)-4-isopropyl-2-oxo-3-oxazoli-
dinylcarbonyl]-3-methyl-5-phenyltetrahydrofuran-2-carboxylate
(9f): although 9f could not be separated by chromatography from a
mixture with major 8f and dipolarophile 7a, it could be characterized
by 1H NMR; 1H NMR (500 MHz, CDCl3) δ 0.68 (3H, d, J = 6.8 Hz),
0.72 (3H, d, J = 6.8 Hz), 0.82 (3H, d, J = 6.6 Hz), 0.95 (3H, d, J = 6.6
Hz,), 1.17 (3H, d, J = 6.9 Hz), 1.34 (3H, t, J = 7.1 Hz), 1.71−1.84
(2H, m), 1.96−2.09 (2H, m), 3.06 (1H, dq, J = 11.0, 6.9 Hz), 3.44−
3.53 (2H, m), 3.81 (1H, m), 4.15−4.26 (2H, m), 4.30 (1H, dd, J = 9.6,
10.3 Hz), 5.42 (1H, d, J = 9.6 Hz), 7.07−7.32 (5H, m).
yl-2-oxo-3-oxazolidinylcarbonyl]-3-methyltetrahydrofuran-2-car-
25
boxylate (8i): colorless needles; mp 148−151 °C (benzene); [α]D
=
−35.7° (c 1.00, CHCl3); IR (KBr) 2976, 2881, 1779, 1728, 1699,
1388, 1206, 1086, 756, 701 cm−1; H NMR (400 MHz, CDCl3) δ
1
0.796 (3H, d, J = 6.9 Hz), 0.802 (3H, d, J = 6.8 Hz), 1.23 (3H, t, J =
7.1 Hz), 1.29 (3H, d, J = 6.8 Hz), 2.17 (1H, m), 2.95 (1H, d, J = 13.9
Hz), 3.28 (1H, d, J = 13.9 Hz), 3.26 (1H, m), 3.67−3.69 (2H, m), 4.02
(1H, m), 4.12−4.25 (2H, m), 4.47 (1H, dd, J = 9.8, 10.9 Hz), 5.62
(1H, d, J = 9.8 Hz), 7.15−7.32 (9H, m); 13C NMR (100 MHz,
CDCl3) δ 13.5 (CH3), 14.2 (CH3), 14.9 (CH3), 17.9 (CH3), 28.8
(CH), 36.8 (CH2), 43.4 (CH), 56.7 (CH), 58.7 (CH), 61.2 (CH2),
63.6 (CH2), 78.9 (CH), 88.4 (C), 126.4 (CH), 128.0 (CH), 128.0
(CH), 128.6 (CH), 130.0 (CH), 133.9 (C), 135.4 (C), 137.2 (C),
153.6 (C), 169.2 (C), 171.6 (C); MS (EI) m/z 513 (M+), 441, 423,
311, 298, 266, 247, 222, 191, 166, 130, 91, 65, 29, 15; HRMS (EI)
calcd for C23H32ClNO6 (M+) 513.1918, found 513.1913.
(2R,3S,4S,5R)-Ethyl 2-benzyl-5-(4-chlorophenyl)-4-[(S)-4-isoprop-
yl-2-oxo-3-oxazolidinylcarbonyl]-3-methyltetrahydrofuran-2-car-
boxylate (9i): although 9i could not be separated by chromatography
from a mixture with major 8i and dipolarophile 7a, it could be
characterized by 1H NMR; 1H NMR (400 MHz, CDCl3) δ 0.74 (3H,
d, J = 6.8 Hz), 0.75 (3H, d, J = 6.8 Hz), 1.12 (3H, d, J = 6.8 Hz), 1.33
(3H, t, J = 7.1 Hz), 2.10 (1H, m), 3.01 (1H, dq, J = 11.2, 6.8 Hz), 3.26
(1H, d, J = 14.2 Hz), 3.38 (1H, d, J = 14.2 Hz), 3.52 (1H, m), 3.93
(2S,3S,4S,5R)-Ethyl 4-[(S)-4-isopropyl-2-oxo-3-oxazolidinylcar-
bonyl]-3-methyl-2-(1-naphthylmethyl)-5-phenyltetrahydrofuran-2-
carboxylate (8g): colorless prisms; mp 132−134 °C (benzene);
25
[α]D = −30.5° (c 0.50, CHCl3); IR (KBr) 2966, 1777, 1720, 1700,
1457, 1206, 1076, 776, 701 cm−1; 1H NMR (CDCl3, 500 MHz) δ 0.79
(3H, d, J = 6.9 Hz), 0.81 (3H, d, J = 6.9 Hz), 1.07 (3H, t, J = 7.3 Hz),
1.45 (3H, d, J = 6.9 Hz), 2.18 (1H, m), 3.38 (1H, dq, J = 6.9, 11.0 Hz),
3.43 (1H, d, J = 14.8 Hz), 3.56 (1H, m), 3.61 (1H, t, J = 8.7 Hz), 3.85
(1H, d, J = 14.8 Hz), 3.98 (1H, dd, J = 2.2, 8.7 Hz), 4.06 (2H, dq, J =
1.1, 7.3 Hz), 4.65 (1H, dd, J = 9.8, 11.0 Hz), 5.68 (1H, d, J = 9.8 Hz),
7.23−7.27 (3H, m), 7.30−7.32 (2H, m), 7.34−7.37 (1H, m), 7.42−
7.45 (1H, m), 7.52−7.55 (2H, m), 7.69−7.70 (1H, m), 7.79−7.81
(1H, m), 8.14−8.15 (1H, m); 13C NMR (125 MHz, CDCl3) δ 13.7
(CH3), 14.1 (CH3), 14.9 (CH3), 17.8 (CH3), 28.9 (CH), 32.6 (CH2),
43.7 (CH), 56.8 (CH), 59.0 (CH), 61.2 (CH2), 63.6 (CH2), 79.9
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(1H, m), 4.14−4.29 (3H, m), 4.36 (1H, dd, J = 10.0, 11.2 Hz), 5.74
(1H, d, J = 10.0 Hz), 7.11−7.15 (2H, m), 7.20−7.37 (7H, m).
(2S,3S,4S,5R)-Ethyl 2-benzyl-4-[(S)-4-isopropyl-2-oxo-3-oxazolidi-
(CH3), 56.7 (CH), 59.0 (CH), 63.6 (CH2), 79.7 (CH), 88.7 (C),
126.7 (CH), 127.6 (CH), 128.2 (CH), 128.3 (CH), 128.5 (CH),
130.2 (CH), 135.8 (C), 138.6 (C), 154.0 (C), 169.9 (C), 172.6 (C);
MS (EI) m/z 465 (M+), 392, 374, 287, 227, 213, 185, 157, 143, 129,
103, 91, 86, 77, 65, 52, 43; HRMS (ESI-TOF) calcd for C27H32NO6
(M + H)+ 466.2224, found 466.2216.
(2R,3S,4S,5R)-Methyl 2-benzyl-4-[(S)-4-isopropyl-2-oxo-3-oxazoli-
dinylcarbonyl]-3-methyl-5-phenyltetrahydrofuran-2-carboxylate
(9l): although 9l could not be separated by chromatography from a
mixture with major 8l and dipolarophile 7a, it could be characterized
by 1H NMR; 1H NMR (300 MHz, CDCl3) δ 0.70 (3H, d, J = 6.8 Hz),
0.72 (3H, d, J = 6.8 Hz), 1.12 (3H, d, J = 7.0 Hz), 2.09 (1H, m), 3.04
(1H, dq, J = 11.0, 7.0 Hz), 3.27 (1H, d, J = 13.9 Hz), 3.33−3.43 (2H,
m), 3.72 (3H, s), 3.84 (1H, m), 4.19 (1H, m), 4.40 (1H, dd, J = 9.8,
11.0 Hz), 5.79 (1H, d, J = 9.8 Hz), 6.91−6.98 (2H, m), 7.22−7.34
(8H, m).
nylcarbonyl]-3-methyl-5-(4-nitrophenyl)tetrahydrofuran-2-carbox-
25
ylate (8j): colorless prisms; m.p 145−147 °C (benzene); [α]D
=
−49.6° (c 0.40, CHCl3); IR (KBr) 2968, 1778, 1733, 1700, 1523,
1388, 1202, 854, 741, 702 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.80
(6H, d, J = 6.9 Hz), 1.23 (3H, t, J = 7.1 Hz), 1.26 (3H, d, J = 7.1 Hz),
2.18 (1H, m), 2.96 (1H, d, J = 13.9 Hz), 3.26 (1H, dq, J = 11.4, 6.9
Hz), 3. 31 (1H, d, J = 13.9 Hz), 3.75 (1H, ddd, J = 3.0, 4.1, 9.0 Hz),
3.82 (1H, t, J = 9.0 Hz), 4.07 (1H, dd, J = 3.0, 9.0 Hz), 4.17−4.27 (2H,
m), 4.55 (1H, dd, J = 9.9, 11.4 Hz), 5.76 (1H, d, J = 9.9 Hz), 7.19−
7.26 (5H, m), 7.55−7.59 (2H, m), 8.12−8.16 (2H, m); 13C NMR
(125 MHz, CDCl3) δ 13.1 (CH3), 14.2 (CH3), 14.7 (CH3), 17.7
(CH3), 28.4 (CH), 37.2 (CH2), 43.8 (CH), 56.9 (CH), 58.6 (CH),
61.5 (CH2), 63.6 (CH2), 78.8 (CH), 88.9 (C), 123.3 (CH), 126.9
(CH), 128.2 (CH), 128.3 (CH), 130.2 (CH), 135.5 (C), 146.5 (C),
147.9 (C), 154.0 (C), 169.2 (C), 171.8 (C); MS (EI) m/z 524 (M+),
451, 433, 304, 232, 202, 130, 91; HRMS (ESI-TOF) calcd for
C28H33N2O8 (M + H)+ 525.2231, found 525.2226.
(2S,3S,4S,5R)-tert-Butyl 2-benzyl-4-[(S)-4-isopropyl-2-oxo-3-oxa-
zolidinylcarbonyl]-3-methyl-5-phenyltetrahydrofuran-2-carboxy-
25
late (8m): colorless prisms; mp 140−142 °C (hexane); [α]D
=
−38.3° (c 1.00, CHCl3); IR (KBr) 2979, 1776, 1720, 1702, 1386,
1290, 739, 703 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.77 (3H, d, J =
6.8 Hz), 0.78 (3H, d, J = 6.8 Hz), 1.27 (3H, d, J = 6.8 Hz), 1.43 (9H,
s), 2.15 (1H, m), 2.94 (1H, d, J = 14.0 Hz), 3.25 (1H, d, J = 14.0 Hz),
3.25 (1H, m), 3.50 (1H, m), 3.55 (1H, t, J = 8.4 Hz), 3.94 (1H, dd, J =
2.0, 8.4 Hz), 4.47 (1H, dd, J = 10.0, 11.0 Hz), 5.60 (1H, d, J = 10.0
Hz), 7.14−7.32 (8H, m), 7.37−7.39 (2H, m); 13C NMR (100 MHz,
CDCl3) δ 13.6 (CH3), 15.0 (CH3), 17.9 (CH3), 28.0 (CH3), 28.9
(CH), 36.3 (CH2), 43.5 (CH), 56.9 (CH), 58.9 (CH), 63.6 (CH2),
79.4 (CH), 81.6 (C), 88.2 (C), 126.2 (CH), 127.3 (CH), 127.8 (CH),
127.8 (CH), 128.1 (CH), 130.2 (CH), 136.0 (C), 138.8 (C), 153.7
(C), 169.6 (C), 170.6 (C); MS (EI) m/z 507 (M+), 407, 361, 277,
231, 213, 185, 160, 131, 91, 77, 57, 41, 15. Anal. Calcd for C30H37NO6:
C, 70.98; H, 7.35; N, 2.76. Found: C, 70.87; H, 7.36; N, 2.85.
Conversion of Cycloadduct 8a to (2S,3S,4S,5R)-Ethyl 2-
Benzyl-4-hydroxymethyl-3-methyl-5-phenyltetrahydrofuran-
2-carboxylate. To a solution of cycloadduct 8a (100.7 mg, 0.21
mmol) in THF (4 mL) and water (1 mL) was added NaBH4 (31.8 mg,
0.84 mmol) at room temperature. After the mixture was stirred for 20
h at room temperature, the mixture was quenched with 1 mol/L
hydrochloric acid (15 mL) and extracted with ethyl acetate (10 mL ×
3). The combined organic layers were dried over Na2SO4, and then the
solvent was removed in vacuo. The residue was purified by silica gel
column chromatography (9/1, hexane/AcOEt) to give 65.1 mg (81%)
of the corresponding alcohol. The enantiomeric excess (>99% ee) was
determined by HPLC analysis (Chiralpak AD-H, 2/8 iPrOH/hexane,
(2R,3S,4S,5R)-Ethyl 2-benzyl-4-[(S)-4-isopropyl-2-oxo-3-oxazolidi-
nylcarbonyl]-3-methyl-5-(4-nitrophenyl)tetrahydrofuran-2-carbox-
ylate (9j): although 9j could not be separated by chromatography from
a mixture with major 8j and dipolarophile 7a, it could be characterized
by 1H NMR; 1H NMR (400 MHz, CDCl3) δ 0.80 (6H, d, J = 6.8 Hz),
1.12 (3H, d, J = 6.8 Hz), 1.33 (3H, t, J = 7.1 Hz), 2.10 (1H, m), 3.01
(1H, dq, J = 11.2, 6.8 Hz), 3.26 (1H, d, J = 14.2 Hz), 3.38 (1H, d, J =
14.2 Hz), 3.52 (1H, m), 3.93 (1H, m), 4.14−4.29 (3H, m), 4.36 (1H,
dd, J = 10.0, 11.2 Hz), 5.74 (1H, d, J = 10.0 Hz), 7.11−7.15 (2H, m),
7.20−7.37 (7H, m).
(2S,3S,4S,5R)-Ethyl 2-benzyl-4-[(S)-4-isopropyl-2-oxo-3-oxazolidi-
nylcarbonyl]-3-methyl-5-(2-naphthalenyl)tetrahydrofuran-2-car-
25
boxylate (8k): colorless needles; mp 201−204 °C (benzene); [α]D
=
−30.7° (c 1.00, CHCl3); IR (KBr) 2978, 1777, 1720, 1695, 1387,
1280, 1218, 1105, 759, 701 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.67
(3H, d, J = 6.9 Hz), 0.73 (3H, d, J = 6.9 Hz), 1.27 (3H, t, J = 7.1 Hz),
1.33 (3H, d, J = 6.8 Hz), 2.05 (1H, m), 3.01 (1H, t, J = 9.0 Hz), 3.03
(1H, d, J = 13.9 Hz), 3.32 (1H, d, J = 13.9 Hz), 3.37 (1H, dq, J = 6.9,
11.0 Hz), 3.30 (1H, ddd, J = 2.4, 4.3, 9.0 Hz), 3.76 (1H, dd, J = 2.4, 9.0
Hz), 4.15−4.29 (2H, m), 4.56 (1H, dd, J = 10.0, 11.0 Hz), 5.81 (1H, d,
J = 10.0 Hz), 7.15−7.30 (5H, m), 7.45−7.51 (3H, m), 7.75−7.80 (4H,
m); 13C NMR (100 MHz, CDCl3) δ 13.6 (CH3), 14.3 (CH3), 15.0
(CH3), 17.83 (CH3), 28.9 (CH), 36.2 (CH2), 43.5 (CH), 56.8 (CH),
58.7 (CH), 61.2 (CH2), 63.5 (CH2), 79.7 (CH), 88.5 (C), 124.9
(CH), 126.0 (CH), 126.1 (CH), 126.2 (CH), 126.4 (CH), 127.5
(CH), 127.8 (CH), 127.8 (CH), 128.0 (CH), 130.1 (CH), 132.5 (C),
133.1 (C), 135.7 (C), 136.0 (C), 153.9 (C), 169.4 (C), 171.8 (C); MS
(EI) m/z 531 (M+), 439, 375, 328, 311, 292, 264, 236, 208, 166, 130,
93, 91, 65, 41, 29, 15. Anal. Calcd for C32H35NO6: C, 72.57; H, 6.66;
N, 2.64. Found: C, 72.21; H, 6.76; N, 2.90.
flow rate 0.5 mL/min, 35 °C) tR(minor) = 11.72 min, tR(major) =
25
13.44 min: colorless needles; mp 143−145 °C (Et2O); [α]D
=
−10.6° (c 0.40, CHCl3); IR (KBr) 3536, 2978, 1736, 1454, 1195,
1060, 739, 698 cm−1; H NMR (400 MHz, CDCl3) δ 0.83 (1H, bs),
1
1.24 (3H, t, J = 7.1 Hz), 1.30 (3H, d, J = 6.6 Hz), 2.41−2.56 (2H, m),
2.91 (1H, d, J = 13.9 Hz), 3.23 (1H, d, J = 13.9 Hz), 3.25 (1H, dd, J =
6.7, 11.6 Hz), 3.43 (1H, dd, J = 3.4, 11.6 Hz), 4.10−4.24 (2H, m), 5.41
(1H, d, J = 8.4 Hz), 7.14−7.35 (8H, m), 7.47−7.50 (2H, m); 13C
NMR (100 MHz, CDCl3) δ 13.5 (CH3), 14.3 (CH3), 37.9 (CH2),
42.7 (CH), 51.8 (CH), 61.0 (CH2), 61.2 (CH2), 81.5 (CH), 88.2 (C),
126.3 (CH), 126.7 (CH), 127.6 (CH), 127.9 (CH), 128.2 (CH),
130.2 (CH), 136.1 (C), 139.8 (C), 172.8 (C); MS (EI) m/z 354 (M+),
281, 263, 233, 171, 159, 145, 131, 117, 105, 91, 77, 43, 29, 15. Anal.
Calcd for C22H26O4: C, 74.55; H, 7.39. Found: C, 74.40; H, 7.37.
Conversion of Cycloadduct 8m to (2S,3S,4S,5R)-tert-Butyl 2-
Benzyl-4-hydroxymethyl-3-methyl-5-phenyltetrahydrofuran-
2-carboxylate. A procedure similar to that for NaBH4 reduction of
8a was employed. The enantiomeric excess (>99% ee) was determined
by HPLC analysis (Chiralpak IC, 1/9 iPrOH/hexane, flow rate 0.5
mL/min, 35 °C) tR(minor) = 10.92 min, tR(major) = 33.63 min:
(2R,3S,4S,5R)-Ethyl 2-benzyl-4-[(S)-4-isopropyl-2-oxo-3-oxazolidi-
nylcarbonyl]-3-methyl-5-(2-naphthalenyl)tetrahydrofuran-2-car-
boxylate (9k): although 9k could not be separated by chromatography
from a mixture with major 8k and dipolarophile 7a, it could be
1
characterized by H NMR; 1H NMR (400 MHz, CDCl3) δ 0.71 (3H,
d, J = 6.9 Hz), 0.72 (3H, d, J = 6.9 Hz), 1.15 (3H, d, J = 6.9 Hz), 1.37
(3H, t, J = 7.0 Hz), 2.11 (1H, m), 3.05 (1H, dq, J = 11.1, 6.9 Hz), 3.25
(1H, d, J = 14.2 Hz), 3.33−3.43 (2H, m), 3.88 (1H, dd, J = 1.8, 8.4
Hz), 4.10−4.25 (3H, m), 4.36 (1H, dd, J = 10.3, 11.1 Hz), 5.80 (1H, d,
J = 10.3 Hz), 6.90−7.42 (12H, m).
(2S,3S,4S,5R)-Methyl 2-benzyl-4-[(S)-4-isopropyl-2-oxo-3-oxazoli-
dinylcarbonyl]-3-methyl-5-phenyltetrahydrofuran-2-carboxylate
(8l): colorless needles; mp 131−133 °C (benzene); [α]D25 = −32.6° (c
0.40, CHCl3); IR (KBr) 2974, 1774, 1719, 1699, 1502, 1382, 1276,
1120, 743, 704 cm−1; 1H NMR (CDCl3, 300 MHz) δ 0.76 (3H, d, J =
6.9 Hz), 0.77 (3H, d, J = 6.9 Hz), 1.30 (3H, d, J = 6.8 Hz), 2.14 (1H,
m), 2.98 (1H, d, J = 13.9 Hz), 3.27 (1H, d, J = 13.9 Hz), 3.31 (1H, dq,
J = 10.9, 6.8 Hz), 3.46−3.52 (2H, m), 3.69 (3H, s), 3.92 (1H, m), 4.50
(1H, dd, J = 9.8, 10.9 Hz), 5.62 (1H, d, J = 9.8 Hz), 7.14−7.30 (8H,
m), 7.33−7.36 (2H, m); 13C NMR (125 MHz, CDCl3) δ 13.5 (CH3),
14.9 (CH3), 17.8 (CH3), 28.9 (CH), 36.8 (CH2), 43.4 (CH), 52.2
25
colorless prisms; mp 160−162 °C (Et2O); [α]D = −10.2° (c 0.5,
CHCl3); IR (KBr) 3482, 2975, 1718, 1496, 1368, 1155, 847 cm−1; 1H
NMR (500 MHz, CDCl3) δ 0.74 (1H, bs), 1.29 (3H, d, J = 6.8 Hz),
1.42 (9H, s), 2.40−2.53 (2H, m), 2.90 (1H, d, J = 13.9 Hz), 3.19 (1H,
d, J = 13.9 Hz), 3.29 (1H, m), 3.43 (1H, dd, J = 3.9, 11.7 Hz), 5.40
(1H, d, J = 8.5 Hz), 7.14−7.18 (1H, m), 7.21−7.60 (8H, m), 7.53−
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Article
7.55 (1H, m);13C NMR (125 MHz) δ 13.6 (CH3), 28.0 (CH3), 37.6
(CH2), 42.8 (CH), 52.1 (CH), 61.3 (CH2), 81.3 (CH), 81.6 (C), 88.1
(C), 126.4 (CH), 126.9 (CH), 127.8 (CH), 128.0 (CH), 128.4 (CH),
130.5 (CH), 136.7 (C), 140.2 (C), 172.2 (C); MS (EI) m/z 382 (M+),
281, 235, 217, 205, 171, 143, 91, 57; HRMS (ESI-TOF) calcd for
C24H30O4Na (M + Na)+ 405.2036, found 405.2038.
(2R,3S,4S,5R)-2-Benzyl-2,4-bis(hydroxymethyl)-3-methyl-5-phe-
25
nyltetrahydrofuran (11): colorless viscous oil; [α]D = −17.1° (c
0.40, CHCl3); IR (KBr) 3446, 2959, 1719, 1590, 1270, 1102, 1011,
1
755, 702 cm−1; H NMR (500 MHz, CDCl3) δ 0.67 (1H, bs), 0.93
(3H, d, J = 7.0 Hz), 2.09 (1H, dq, J = 10.3, 7.0 Hz), 2.11 (1H, bs), 2.48
(1H, m), 2.98 (1H, d, J = 13.8 Hz), 3.07 (1H, dd, J = 7.8, 11.4 Hz),
3.22 (1H, d, J = 13.8 Hz), 3.23 (1H, m), 3.49 (1H, d, J = 11.4 Hz),
3.76 (1H, d, J = 11.4 Hz), 5.16 (1H, d, J = 9.2 Hz), 6.98−7.00 (2H,
m), 7.22−7.35 (8H, m); 13C NMR (125 MHz, CDCl3) δ 12.6 (CH3),
40.15 (CH2), 40.19 (CH), 52.5 (CH), 62.3 (CH2), 62.9 (CH2), 80.2
(CH), 86.0 (C), 126.5 (CH), 127.0 (CH), 127.8 (CH), 128.1 (CH),
128.4 (CH), 131.2 (CH),136.7 (C), 139.6 (C); MS (EI) m/z 312
(M+), 310, 280, 267, 185, 183, 157, 155, 139, 104, 76, 49; HRMS (EI)
calcd for C20H24O3 (M+) 312.1725, found 312.1722.
Conversion of (2S,3S,4S,5R)-Ethyl 2-Benzyl-4-hydroxymeth-
yl-3-methyl-5-phenyltetrahydrofuran-2-carboxylate to
(2S,3S,4S,5R)-2-Benzyl-2,4-bis(hydroxymethyl)-3-methyl-5-
phenyltetrahydrofuran (10). To a solution of (2S,3S,4S,5R)-ethyl
2-benzyl-4-hydroxymethyl-3-methyl-5-phenyltetrahydrofuran-2-car-
boxylate (58.6 mg, 0.165 mmol) in diethyl ether (5 mL) was added
LiAlH4 (7.2 mg, 0.190 mmol), and then the mixture was stirred at
romm temperature for 2 h. The mixture was poured into a saturated
Na2SO4 solution (30 mL) and stirred for 20 min at room temperature.
The mixture was extracted with ethyl acetate (10 mL × 3). The
combined extracts were washed with saturated sodium chloride
solution, and the dried over Na2SO4. The residue was chromato-
graphed over silica gel (8/2 hexane/AcOEt) to give 50.0 mg (94%) of
the corresponding diol 10. The enantiomeric excess was determined
by HPLC analysis (Chiralpak IC, 2/8 iPrOH/hexane, flow rate 0.5
mL/min, 35 °C) tR(minor) = 10.50 min, tR(major) = 19.85 min:
Conversion of Cycloadducts 4d and 5d to (2S*,3S*,4S*,5R*)-
2-Benzyl-2,4-bis(hydroxymethyl)-3-methyl-5-phenyltetrahy-
drofuran (10) and (2R*,3S*,4S*,5R*)-2-Benzyl-2,4-bis-
(hydroxymethyl)-3-methyl-5-phenyltetrahydrofuran (11). To
a solution of cycloadducts 4d and 5d (4d:5d = 88:12, 136.5 mg,
0.312 mmol) in diethyl ether (20 mL) was added LiAlH4 (29.6 mg,
0.78 mmol), and then the mixture was heated under reflux for 30 min.
After the mixture was cooled to room temperature, it was poured into
a saturated Na2SO4 solution (30 mL) and stirred for 20 min at room
temperature. The mixture was extracted with ethyl acetate (10 mL ×
3). The combined extracts were washed with saturated sodium
chloride solution and then dried over Na2SO4. The residue was
chromatographed over silica gel (8/2 hexane/AcOEt) to give 68.0 mg
of diol 10 and 13.9 mg of diol 11 (total yield 84%, 10:11 = 83:17).
Preparation of (S)-4-Isopropyl-3-[(E)-2-hexenoyl]-2-oxazoli-
dinone (7c). 2-Oxazolidinone 7c was prepared according to the
procedure reported for the preparation of (S)-4-isopropyl-3-[(E)-2-
pentenoyl]-2-oxazolidinone (7b)15 in the literature: colorless oil;
25
colorless prism; mp 161−164 °C (Et2O); [α]D = −125.6° (c 0.60,
CHCl3); IR (KBr) 3290, 2932, 2874, 1485, 1455, 1067, 1031, 741, 699
cm−1; 1H NMR (400 MHz, CDCl3) δ 0.87 (1H, bs), 1.15 (3H, d, J =
6.5 Hz), 1.88 (1H, bs) 2.48−2.62 (2H, m), 2.59 (1H, d, J = 14.2 Hz),
2.97 (1H, d, J = 14.2 Hz), 3.31 (1H, dd, J = 7.6, 11.4 Hz), 3.45 (1H,
dd, J = 4.4, 11.4 Hz), 3.53 (1H, d, J = 11.8 Hz), 3.64 (1H, d, J = 11.8
Hz), 5.34 (1H, d, J = 8.6 Hz), 7.18−7.41 (10H, m); 13C NMR (100
MHz, CDCl3) δ 13.7 (CH3), 36.4 (CH2), 39.1 (CH), 52.1 (CH), 62.5
(CH2), 64.0 (CH2), 80.2 (CH), 86.0 (C), 126.1 (CH), 127.1 (CH),
127.8 (CH), 127.9 (CH), 128.3 (CH), 130.4 (CH), 136.9 (C), 139.8
(C); MS (EI) m/z 312 (M+), 310, 280, 267, 185, 183, 157, 155, 139,
104, 76, 49. Anal. Calcd for C20H24O3: C, 76.89; H, 7.74. Found: C,
76.62; H, 7.94.
25
[α]D = +89.7° (c 1.00, CHCl3); IR (neat) 2963, 1775, 1685, 1636,
1365, 1203, 714 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.89 (3H, d, J =
6.8 Hz), 0.93 (3H, d, J = 6.8 Hz), 0.96 (3H, t, J = 7.4 Hz), 1.53 (2H,
sext, J = 7.4 Hz), 2.26 (2H, q, J = 7.4 Hz), 2.41 (1H, m), 4.22 (1H, dd,
J = 3.0, 9.0 Hz), 4.28 (1H, t, J = 9.0 Hz), 4.49 (1H, m), 7.15 (1H, m),
7.27 (1H, m); 13C NMR (100 MHz, CDCl3) δ 13.7 (CH3), 14.7
(CH3), 18.0 (CH3), 21.4 (CH2), 28.5 (CH), 34.6 (CH2), 58.5 (CH),
63.3 (CH2), 120.5 (CH), 151.3 (CH), 154.1 (C), 165.1 (C); MS (EI)
m/z 225 (M+), 182, 130, 97, 71, 55; HRMS (ESI-TOF) calcd for
C12H19NO3Na (M + Na)+ 248.1257, found 248.1263.
Conversion of (2S,3S,4S,5R)-tert-Butyl 2-Benzyl-4-hydroxy-
methyl-3-methyl-5-phenyltetrahydrofuran-2-carboxylate to
(2S,3S,4S,5R)-2-Benzyl-2,4-bis(hydroxymethyl)-3-methyl-5-
phenyltetrahydrofuran (10). A similar procedure for LiAlH4
reduction of (2S,3S,4S,5R)-ethyl 2-benzyl-4-hydroxymethyl-3-methyl-
5-phenyltetrahydrofuran-2-carboxylate was employed.
Conversion of Cycloadduct 8a to (2S,3S,4S,5R)-2-Benzyl-2,4-
bis(hydroxymethyl)-3-methyl-5-phenyltetrahydrofuran (10).
To a solution of cycloadduct 8a (60.0 mg, 0.125 mmol) in diethyl
ether (10 mL) was added LiAlH4 (11.9 mg, 0.313 mmol), and then the
mixture was heated under reflux for 30 min. After the mixture was
cooled to room temperature, it was poured into a saturated Na2SO4
solution (30 mL) and stirred for 20 min at room temperature. The
mixture was extracted with ethyl acetate (20 mL × 3). The combined
extract was washed with saturated sodium chloride solution and then
dried over Na2SO4. The residue was chromatographed over silica gel
(8/2 hexane/AcOEt) to give 32.8 mg (84%) of the corresponding diol
10.
Conversion of Cycloadducts 8a and 9a to (2S,3S,4S,5R)-2-
benzyl-2,4-bis(hydroxymethyl)-3-methyl-5-phenyltetrahydro-
furan (10) and (2R,3S,4S,5R)-2-benzyl-2,4-bis(hydroxymethyl)-
3-methyl-5-phenyltetrahydrofuran (11). To a solution of cyclo-
adducts 8a and 9a (8a:9a = 65:35, 107.4 mg, 0.224 mmol) in diethyl
ether (20 mL) was added LiAlH4 (21.3 mg, 0.56 mmol), and then the
mixture was heated under reflux for 30 min. After the mixture was
cooled to room temperature, it was poured into a saturated Na2SO4
solution (30 mL) and stirred for 20 min at room temperature. The
mixture was extracted with ethyl acetate (20 mL × 3). The combined
extracts were washed with saturated sodium chloride solution and then
dried over Na2SO4. The residue was chromatographed over silica gel
(8/2 hexane/AcOEt) to give 38.4 mg of diol 10 and 19.0 mg of diol
11 (total yield 82%, 10:11 = 67:33). The enantiomeric excess of 11
was determined by HPLC analysis (Chiralpak IC, 2/8 iPrOH/hexane,
flow rate 0.5 mL/min, 35 °C) tR(major) = 13.35 min, tR(minor) =
14.48 min.
ASSOCIATED CONTENT
* Supporting Information
Text, tables, figures, and a CIF file giving X-ray crystallographic
data for 8m and 1H and 13C NMR spectra of cycloadducts. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*H.S.: tel, +81-26-269-5392; fax, +81-26-269-5424; e-mail,
sugahio@shinshu-u.ac.jp.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by a Grant-in-Aid for Scientific
Research (Nos. 20550094, 20200052, and 24550116) from the
Ministry of Education, Science and Culture of Japan.
REFERENCES
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1
LiAlH4 in comparison with H NMR spectra of (2S,3S,4S,5R)-10 and
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