Stereoselective vinylogous Mannich reaction of 2-trimethylsilyloxyfuran with N-gulosyl nitrones

Article abstract of DOI:10.1039/c1ob06067h

Stereoselective vinylogous Mannich reaction of 2-trimethylsilyloxyfuran with l-gulose-derived chiral nitrones in the presence of a catalytic amount of trimethylsilyl trifluoromethanesulfonate was investigated. The selectivity was strongly influenced by the bulkiness of the C-substituent of the nitrone: for example, C-benzyloxymethyl nitrone afforded four stereoisomers, whereas bulky C-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]nitrone gave a single stereoisomer. The latter product was elaborated to afford key synthetic intermediates for polyoxin C and dysiherbaine.

Full text of DOI:10.1039/c1ob06067h

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PAPER
Stereoselective vinylogous Mannich reaction of 2-trimethylsilyloxyfuran with
N-gulosyl nitrones†
Osamu Tamura,*a Kodai Takeda,b Naka Mita,c Masanori Sakamoto,c Iwao Okamoto,a Nobuyoshi Moritaa and
Hiroyuki Ishibashib
Received 2nd July 2011, Accepted 5th August 2011
DOI: 10.1039/c1ob06067h
Stereoselective vinylogous Mannich reaction of 2-trimethylsilyloxyfuran with L-gulose-derived chiral
nitrones in the presence of a catalytic amount of trimethylsilyl trifluoromethanesulfonate was
investigated. The selectivity was strongly influenced by the bulkiness of the C-substituent of the nitrone:
for example, C-benzyloxymethyl nitrone afforded four stereoisomers, whereas bulky
C-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]nitrone gave a single stereoisomer. The latter product was
elaborated to afford key synthetic intermediates for polyoxin C and dysiherbaine.
Introduction
Nucleophilic addition reaction of dienolates 2 with imines or
iminium ions 1 leading to d-amino a,b-unsaturated carbonyl
compounds 3 is known as the vinylogous Mannich reaction,1 and
is useful in the synthesis of nitrogen-containing natural products
and related compounds (Scheme 1, equation 1).2 In this category,
addition reaction of 2-silyloxyfurans to a C–N double bond is very
attractive, allowing oxygen functionalities as well as C4-units to
be incorporated into nitrogen-containing carbon frameworks.3,4
Enantioselective addition reactions of 2-silyloxyfuran and re-
lated compounds have been addressed in recent years,4 and
recently diastereoselective addition reactions to C–N double
bond compounds bearing chiral auxiliaries have been reported.3g
Among C–N double bond compounds, nitrones 4 are known to
undergo Mannich reaction with 2-silyloxyfuran 5 in the presence
of a catalytic amount of TMSOTf to give bicyclic compounds
7 after TBAF treatment of the initial adducts 6 (equation 2).5,6
Previously, we described diastereoselective addition reaction of
2-trimethylsilyloxyfuran (5) to nitrone 8, which contains a hydrox-
ymethyl group equivalent and an L-gulose-derived chiral auxiliary
as an N-substituent; the resulting adduct was elaborated to afford
a synthetic intermediate of polyoxin C.7 Herein, we present a
Scheme 1 Vinylogous Mannich reactions.
full account of that work, including an additional application
of the reaction to synthesis of a key synthetic intermediate of
Results and discussion
1. Stereoselective nucleophilic addition of 2-trimethylsilyl-
dysiherbaine.
oxyfurane 5 to N-(2,3:5,6-O-isopropylidene-L-gulosyl)nitrones 8
For diastereofacially selective 1,3-dipolar cycloaddition or nu-
cleophilic addition of nitrones, protected glycosyl groups, such
as mannosyl8 and gulosyl groups,7,9,10 have been used as N-
chiral auxiliaries. These groups can be removed under mild acidic
conditions, whereas removal of benzyl-type auxiliaries, such as the
1-phenylethyl group, generally requires hydrogenolysis (Fig. 1).
Although both mannosyl and gulosyl groups often exhibit high
stereoselectivity, we have focused on the gulosyl auxiliary because
aShowa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
E-mail: tamura@ac.shoyaku.ac.jp; Fax: +81 (0)42 721 1579; Tel: +81
(0)42 721 1578
bDivision of Pharmaceutical Sciences, Graduate School of Natural Science
and Technology, Kanazawa University, Kanazawa 920-1192, Japan
cMeiji Pharmaceutical University, Kiyose, Tokyo 204-8588, Japan
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra. See DOI: 10.1039/c1ob06067h
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Fig. 1 Nitrones bearing chiral auxiliaries.
(i) both enantiomers are available and (ii) the stereochemistry of
the product can be predicted.7,10
Our investigation began with preparation of four types of
L-gulose-derived nitrone 8. Treatment of oxime 9, prepared
from 2,3:5,6-O-isopropylidene-L-gulonolactone in two steps, with
aldehydes 10a–d in the presence of MgSO4 in CHCl3 at room
temperature gave crystalline nitrones 8a–d (Scheme 2). Since these
nitrones were not very stable, they were used immediately for the
next step.
Scheme 3 Addition reaction of nitrones 8a–d with silyloxyfuran 5.
greater stereoselectivity (entry 3). Finally, nitrone 8d, bearing the
branched 2,2-dimethyldioxolane ring, exclusively afforded 11d.
The substituent effect on the stereoselectivity of the present
addition reaction of nitrones 8 may be explained in terms of the
effect of the bulkiness of the substituent R on the initially generated
siloxyiminium ion A. The stereochemistry of the products 11–
14 of the reaction of nitrone 8 with 2-trimethylsilyloxyfuran 5
should be determined at the step of the addition reaction of
furan 5 to siloxyiminium ion A, affording the initial adduct
B (Schemes 3 and 4). Three types of staggered approach of
silyloxyfuran 5 to siloxyiminium ion A can be considered (see
C–F in Scheme 4; for simplicity, only upper-face approaches of
silyloxyfuran to siloxyiminium ion A are illustrated). Among
the three approach routes C–F, approach C would be more
favorable than D or F because there is less interaction of the furan
ring of 5 with substituents of A. Approach C may be further
divided into two transition state models C1 and C2, which give
opposite relative stereochemistries. Since the 4-position of furan
is apparently bulkier than the 1-position is, the use of nitrone
having a sterically more demanding C-substituent makes model C2
more favorable than model C1. Transition state C2 should exhibit
high diastereofacial selectivity because of the closeness between
the 4-position and the chiral auxiliary, whereas both antipodal
transition states would be possible in the case of C1. Accordingly,
the use of bulky nitrones 8c and 8d causes addition reaction of
silyloxyfuran 5 to proceed preferentially by way of transition state
C2 to afford 11 with good diastereo- and diastereofacial selectivity.
It is known that addition reaction of the N-benzyl congener 8e
of 8d with silyloxyfuran 5 in the presence of TMSOTf gives four
stereoisomers of adducts with very low stereoselectivity.6c This fact
clearly indicates that the stereoselectivity of the present reaction
of 8d arises mainly from the effect of the gulose auxiliary.
Scheme 2 Synthesis of nitrones 8a–d.
When nitrones 8a–d were treated with 2-trimethylsilyloxyfuran
(5) (1.5 equiv) in the presence of TMSOTf (0.1 equiv) at low
temperature, smooth nucleophilic addition to siloxyiminium ion A
occurred to give butenolides B as the initial adducts, and these were
further treated with TBAF (0.1 equiv) to afford bicyclic products
11–14 (Scheme 3 and Table 1).
The results, summarized in Table 1, showed that all reactions
afforded the adducts 11 as the major products, and nitrones 8
having bulkier substituents exhibited greater stereoselectivity. C-
Benzyloxymethyl nitrone 8a gave a 76 : 13 : 8 : 3 mixture of four
isomers 11a–14a (entry 1). Nitrone 8b, having a triisopropylsi-
lyloxymethyl group as the substituent R, afforded a 74 : 21 : 5
mixture of three isomers (entry 2). Nitrone 8c carrying the
even bulkier tert-butyldiphenylsilyloxymethyl group showed still
Table 1 Addition reaction of nitrones 8a–d with silyloxyfuran 5
Entry
Nitrone 8 (R)
Yield (%)
Ratio 11 : (12 + 13 + 14)
1
2
3
4
8a (CH2OBn)
8b (CH2OTIPS)
8c (CH2OTBDPS)
84
80
80
72
76 : (13 + 8 + 3)
74 : (21 + 5)
86 : (8 + 6)
>97 : <3
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stereoselectively as described above. For the synthetic study of
polyoxin C, stereochemical correlation of adduct 11c with 11d
was first conducted (Scheme 5). Hydrolytic removal of the sugar
auxiliary of adduct 11c by acid treatment followed by N-protection
with a Boc group afforded 19. Similar treatment of adduct 11d
gave diol 20. Compound 19 was further treated with TBAF under
acidic conditions to provide alcohol 21, which was also obtained
by oxidative cleavage of diol 20, followed by reduction of the
resulting aldehyde with zinc borohydride.
Scheme 4 Approach of furan 5 to silylated nitrone.
2. Synthetic studies of polyoxin C from adducts 11c and 11d as
intermediates
Thymine and uracil polyoxin Cs (17a and 17b), which are hybrid
compounds of nucleosides and a-amino acids, are important as
the C-terminal amino acid components of polyoxin J (15) and
nikkomycin Bz (16), which exhibit anti-fungal activity (Fig. 2).
Therefore, stereoselective syntheses of the unique amino acids
17 have been intensively investigated.3e,11,12 An efficient method
for syntheses of polyoxin Cs would be elaboration of dihydroxy
lactone 18,12g and therefore we next examined the synthesis
of lactone 18 from adducts 11c and 11d, which we obtained
Scheme 5
Compound 21 was next elaborated to dihydroxylactone 18,12g
a key synthetic intermediate of polyoxin C (Scheme 6). Reductive
cleavage of the N–O bond of compound 21 by heating with
13
Mo(CO)6 in acetonitrile–water and subsequent treatment with
2,2-dimethoxypropane in the presence of PPTS provided N,O-
acetonide 22 in 54% yield. Mesylation of the secondary alcohol
of 22 induced b-elimination to yield butenolide 23 in 96% yield.
Finally, stereoselective dihydroxylation of butenolide 23 was
conducted as described in the literature to afford lactone 18.
Fig. 2 Structures of polyoxins, nikkomycin Bz, and intermediate 18.
Scheme 6 Synthesis of lactone 18.
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3. Synthetic studies of dysiherbaine from adduct 11d
Dysiherbaine (24), isolated from a Micronesian marine sponge
Dysydea herbacea, is a strong and selective agonist of non-NMDA
type glutamate receptors in the central nervous system (Fig. 3).14
Owing to this remarkable biological activity, considerable efforts
have been made to synthesize the natural product, and several
total syntheses of 24 have been reported to date.15,16 Among them,
Hatakeyama’s synthesis, in which tricyclic lactone 25 is used as
the key synthetic intermediate, seems to be one of the most
efficient.15c,f,16d Structural consideration of adduct 11d showed that
the stereochemistry of 11d is in accordance with that of lactone
25 (compare formula 25 with 11d¢). Thus, we next turned our
attention to the transformation of adduct 11d to lactone 25.
Scheme 7 Synthesis of lactone 30 via N-methylation.
Fig. 3 Stereochemical accordance of adduct 11d with lactone 25.
Elaboration to 25 began with monoprotection of diol 20,
prepared in the synthetic study of polyoxin C, with a TBDPS
group, affording 26, from which the Boc group was removed under
acidic conditions to give amino alcohol 27. The key N-methylation
was conducted by exposure of 27 to formaldehyde in ethanol,
followed by treatment of the resulting mixture of 28 and 29 with
triethylsilane and trifluoroacetic acid to provide compound 30
(Scheme 7).17
The next task was oxazolidinone formation and dihydropyran
construction. To this end, phenoxycarbonylation of the secondary
hydroxyl group of 30 was first conducted to provide carbonate 31
in 89% yield. When carbonate 31 was exposed to hydrogenolysis
conditions, reductive cleavage of the N–O bond and subsequent
ring closure of 32 occurred to give oxazolidinone 33 in 91% yield.
Chloromesylation of the secondary hydroxyl group of 33 induced
b-elimination to afford butenolide 34. Finally, dihydropyran
formation was accomplished by removal of the silyl protective
group of 34 under acidic conditions, followed by intramolecular
Michael addition of the primary hydroxyl group of 35 to afford
tricyclic lactone 25, which is a known key intermediate for
dysiherbaine (Scheme 8).
Conclusion
We have explored the stereoselective addition reaction of 2-
silyloxyfuran to N-gulosylnitrone and have found that the stereos-
electivity of the reaction can be controlled by the N-chiral auxiliary
of the nitrone. It was also found that nitrones with a bulkier C-
substituent afforded greater stereoselectivity. The products 11c
Scheme 8 Synthesis of lactone 25.
and 11d of the present reaction were successfully applied to the
synthesis of polyoxin C, and adduct 11d was transformed to a
synthetic intermediate of dysiherbaine.
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4.35 (1H, dd, J = 12.9, 4.4 Hz), 4.40 (1H, dd, J = 12.9, 4.4 Hz),
4.43 (1H, dd, J = 8.3, 4.4 Hz), 4.50 (2H, s), 4.74 (1H, dd, J = 6.0,
4.4 Hz), 5.12 (1H, d, J = 6.0 Hz), 5.31 (1H, s), 7.08 (1H, t, J =
4.4 Hz), 7.21–7.32 (5H, m); MS (EI) m/z: 408 (M++1). Following
the general procedure, a 76 : 13 : 8 : 3 mixture of bicyclic adducts
11a–14a (51 mg, 84%) was obtained from nitrone 8a (50 mg, 0.12
mmol), furan 5 (28 mg, 0.18 mmol), and TMSOTf (2.2 mL, 1.2
mmol). The ratio was estimated by HPLC [JASCO-Fine pack SIL-
5, AcOEt–hexane (3 : 2), 1.1 mL min-1, tR: 8.50 (13%), 9.40 (76%),
10.38 (3%), 12.00 (8%)]. The major isomer 11a was obtained by
column chromatography on silica gel with AcOEt–hexane (3 : 2).
11a: [a]1D7 +14.1 (c 0.83, CHCl3); IR (CHCl3) 1790 cm-1; 1H NMR
(300 MHz, CDCl3) d 1.22 (3H, s), 1.32 (3H, s), 1.35 (3H, s), 1.43
(3H, s), 2.61 (1H, dd, J = 18.7, 1.1 Hz), 2.70 (1H, dd, J = 18.7, 5.3
Hz), 3.52–3.58 (2H, m), 3.61 (1H, dd, J = 8.4, 7.0 Hz), 3.70 (1H, d,
J = 10.1 Hz), 3.95 (1H, dd, J = 8.3, 3.9 Hz), 4.13 (1H, dd, J = 8.4,
7.8 Hz), 4.28 (1H, br ddd, J = 8.3, 7.8, 7.0 Hz), 4.45 (1H, d, J =
12.1 Hz), 3.53 (1H, d, J = 12.1 Hz), 4.59 (1H, dd, J = 6.1, 3.9 Hz),
4.64 (1H, br ddd, J = 5.4, 4.4, 1.0 Hz), 4.67 (1H, s), 4.85 (1H, d, J =
6.1 Hz), 5.10 (1H, br d, J = 4.6 Hz), 7.23–7.31 (5H, m); 13C NMR
(75 MHz, CDCl3) d 24.9, 25.3, 26.1, 26.8, 34.5, 65.9, 68.6, 68.9,
73.5, 75.6, 77.0, 80.4, 83.7, 84.7, 89.0, 99.6, 109.7, 113.0, 127.7,
127.9, 128.5, 138.0, 174.5; HRMS (EI) m/z calcd for C25H33NO9
491.2153, found 491.2148.
Experimental
General
Melting points were determined with a Yanagimoto micro melting
point apparatus and are uncorrected. Optical rotations were
measured with a JASCO DIP-140 or Horiba SEPA-300 digital
polarimeter. Infrared spectra (IR) were recorded with a Shimadzu
1
FTIR-8100. H NMR spectra were recorded on a JEOL JNM-
EX270 (270 MHz), a JEOL JNM-AL300 (300 MHz), a JEOL
JNM-GSX400 (400 MHz) or a JEOL JNM-GSX500 (500 MHz)
spectrometer. The chemical shifts are expressed in ppm downfield
from tetramethylsilane (d = 0) as an internal standard (CDCl3
solution). 13C NMR spectra were recorded on a JEOL JNM-
EX270 (67.5 MHz), a JEOL JNM-AL300 (75 MHz), a JEOL
JNM-GSX400 (100 MHz) or a JEOL JNM-GSX500 (125 MHz)
spectrometer. The chemical shifts are reported in ppm, relative to
the central line of the triplet at 77.0 ppm for CDCl3. Measurements
of mass spectra (MS) and high-resolution MS (HRMS) were
performed with a JEOL JMS-SX102A or JEOL JMS-DX302
mass spectrometer. Column chromatography was carried out on
silica gel (silica gel 40–50 mm neutral, Kanto Chemical Co., Inc.).
Merck precoated thin layer chromatography (TLC) plates (silica
gel 60 F254, 0.25 mm, Art 5715) were used for the TLC analysis.
After extractive workup, organic layers were dried over anhydrous
sodium sulfate or anhydrous magnesium sulfate and the solvent
was removed by rotary evaporation under reduced pressure.
(3R,3aS,6aR)-N-(2¢,3¢:5¢,6¢-O-Diisopropylidene-a-L-gulofur-
anosyl)-3-(triisopropylsilyloxymethyl)tetrahydrofuro[2,3-
d]isoxazol-5-one (11b)
General procedure for the preparation of adducts 11 from oxime 9
and aldehydes 10
Following
the
general
procedure,
(Z)-N-(2,3:5,6-O-
A mixture of oxime 9 (1.0 equiv.), an aldehyde 10 (1.1 equiv.),
diisopropylidene-a-L-gulofuranosyl)-2-triisopropylsilyloxyethyl-
ideneamine N-oxide (8b) (139 mg, 63%) was prepared from
oxime 9 (129 mg, 0.47 mmol) and aldehyde 10b (110 mg, 0.52
mmol). This material was unstable, and was therefore used for
the next step without further purification. Following the general
procedure, a 74 : 21 : 5 mixture of bicyclic adducts (70 mg, 80%)
was obtained from nitrone 8b (74 mg, 0.16 mmol), furan 5
(37 mg, 0.24 mmol), and TMSOTf (2.8 mL, 1.6 mmol). The
and MgSO4 in CHCl3 was stirred overnight at room temperature.
R
The mixture was filtered through a pad of Celiteꢀ. The filtrate
was concentrated in vacuo, and the residue was passed through a
short column of silica gel to afford nitrone 8 as a colorless solid.
Nitrone 8 was used for the next step without further purification.
To a stirred solution of nitrone 8 (0.1 mmol) in CH2Cl2 (3 mL)
was added 2-trimethylsilyloxyfuran (5) (0.15 mmol) and TMSOTf
(0.01 mmol) at -78 ◦C. The mixture was stirred at the same
temperature for 15 min, then diluted with a saturated solution
of NaHCO3, and extracted with CH2Cl2. After drying (MgSO4),
the organic phase was concentrated in vacuo. The residue was
dissolved in CH2Cl2–THF (1 : 1, 5 mL). TBAF (0.01 mmol) was
1
ratio was estimated by H NMR (300 MHz). The major isomer
11b was obtained by column chromatography on silica gel with
AcOEt–hexane (1 : 2). 11b: [a]1D7 +3.3 (c 0.53, CHCl3); IR (CHCl3)
1786 cm-1; 1H NMR (400 MHz, CDCl3) d 1.06 (3H, s), 1.07 (18H,
s), 1.29 (3H, s), 1.38 (3H, s), 1.41 (3H, s), 1.44 (3H, s), 2.70 (1H,
d, J = 18.5 Hz), 2.78 (1H, dd, J = 18.5, 5.4 Hz), 3.64 (2H, m), 3.66
(1H, dd, J = 8.3, 6.4 Hz), 3.99 (1H, dd, J = 10.0, 8.3 Hz), 4.00
(1H, dd, J = 8.3, 3.9 Hz), 4.19 (1H, dd, J = 8.3, 6.6 Hz), 4.33 (1H,
br ddd, J = 8.3, 6.6, 6.4 Hz), 4.64 (1H, dd, J = 6.1, 3.9 Hz), 4.73
(1H, br dd, J = 5.4, 4.4 Hz), 4.74 (1H, s), 4.88 (1H, d, J = 6.1 Hz),
5.27 (1H, d, J = 4.4 Hz); 13C NMR (100 MHz, CDCl3) d 12.0,
18.1, 24.9, 25.5, 26.1, 26.8, 35.3, 62.3, 66.0, 70.1, 75.8, 77.0, 80.5,
83.7, 84.7, 89.1, 99.2, 109.5, 112.8, 173.9; HRMS (EI) m/z calcd
for C27H47NO9Si 557.3018, found 557.3022.
◦
added at 0 C, and the mixture was stirred for 10 min. Water (2
mL) was added, and the whole was extracted with CH2Cl2. The
R
extract was stirred with MgSO4 and Florisilꢀ. After filtration, the
filtrate was concentrated in vacuo. The residue was subjected to
column chromatography on silica gel to afford adducts 11–14.
(3R,3aS,6aR)-3-Benzyloxymethyl-N-(2¢,3¢:5¢,6¢-O-diisopropyli-
dene-a-L-gulofuranosyl)tetrahydrofuro[2,3-d]isoxazol-5-one (11a)
Following the general procedure, (Z)-2-benzyloxy-N-(2,3:5,6-
O-diisopropylidene-a-L-gulofuranosyl)ethylideneamine N-oxide
(8a) (176 mg, 72%) was prepared from oxime 9 (165 mg, 0.60
mmol) and aldehyde 10a (99.7 mg, 0.66 mmol). It was used for
the next step without further purification. 8a: IR (CHCl3) 3019,
1221, 1213 cm-1; 1H NMR (300 MHz, CDCl3) d 1.23 (3H, s), 1.32
(3H, s), 1.38 (3H, s), 1.40 (3H, s), 3.62 (1H, dd, J = 8.4, 7.2 Hz),
4.13 (1H, dd, J = 8.4, 6.6 Hz), 4.27 (1H, ddd, J = 8.3, 7.2, 6.6 Hz),
(3R,3aS,6aR)-3-tert-Butyldiphenylsilyloxymethyl-N-(2¢,3¢:5¢,6¢-
O-diisopropylidene-a-L-gulofuranosyl)tetrahydrofuro[2,3-
d]isoxazol-5-one (11c)
Following the general procedure, (Z)-2-tert-butyldiphenylsilyloxy-
N-(2,3:5,6-O-diisopropylidene-a-L-gulofuranosyl)ethylideneamine
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N-oxide (8c) (283 mg, 93%) was prepared from oxime 9 (151 mg,
0.55 mmol) and aldehyde 10c (181 mg, 0.61 mmol). It was used
for the next step without further purification. IR (CHCl3) 2994,
1219, 1210 cm-1; 1H NMR (300 MHz, CDCl3) d 1.04 (9H, s), 1.28
(3H, s), 1.38 (3H, s), 1.43 (3H, s), 1.45 (3H, s), 3.67 (1H, dd, J =
8.3, 6.2 Hz), 4.18 (1H, dd, J = 8.3, 6.2 Hz), 4.32 (1H, br dt, J =
8.8, 6.2 Hz), 4.43 (1H, dd, J = 8.8, 3.9 Hz), 4.61 (2H, br d, J = 3.9
Hz), 4.72 (1H, dd, J = 5.8, 3.9 Hz), 5.10 (1H, d, J = 5.8 Hz), 5.32
(1H, s), 7.14 (1H, t, J = 3.9 Hz), 7.32–7.43 (6H, m), 7.59–7.65
(4H, m); HRMS (EI) m/z calcd for C30H41NO7Si 555.2650,
found 555.2646. Following the general procedure, an 86 : 8 : 6
mixture of bicyclic adducts (91 mg, 80%) was obtained from
nitrone 8c (100 mg, 0.18 mmol), furan 5 (42 mg, 0.27 mmol), and
TMSOTf (3.2 mL, 1.8 mmol). The ratio was estimated by HPLC
[JASCO-Fine pack SIL-5, AcOEt–hexane (1 : 1), 1.0 mL min-1,
tR: 9.04 (86%), 9.40 (76%), 17.08 (6%)]. The major isomer 11c
was obtained by column chromatography on silica gel with
AcOEt–hexane (3 : 2). 11c: mp 166–167 ◦C (AcOEt–hexane);
18.8, 5.6 Hz), 3.56 (1H, dd, J = 4.6, 1.3 Hz), 3.68 (1H, dd, J =
8.5, 6.7 Hz), 3.79 (1 H, dd, J = 8.8, 5.9 Hz), 4.03 (1 H, dd, J =
8.3, 3.4 Hz), 4.16 (1H, dd, J = 8.8, 5.9 Hz), 4.19 (1 H, dd, J =
8.5, 6.7 Hz), 4.29 (1H, ddd, J = 6.8, 5.9, 4.6 Hz), 4.34 (1H, dt,
J = 8.3, 6.7 Hz), 4.65 (1H, s), 4.65 (1H, dd, J = 6.1 3.4 Hz), 4.73
(1H, ddd, J = 5.6, 4.6, 1.0 Hz), 4.90 (1H, d, J = 6.1 Hz), 5.27 (1H,
dd, J = 4.6, 1.3 Hz); 13C NMR (100 MHz, CDCl3) d 24.7, 25.1,
25.4, 26.2, 26.5, 26.9, 35.1, 66.0, 67.5, 71.9, 73.9, 75.5, 77.5, 80.4,
84.1, 84.7, 87.9, 100.1, 109.7, 109.9, 113.1, 173.6; HRMS (EI)
m/z calcd for C22H33NO10 471.2102, found 471.2101. Anal. Calcd
for C22H33NO10: C, 56.04; H, 7.05; N, 2.97. Found: C, 55.72; H,
6.95, N, 2.93.
(b) Following the general procedure, 11d (1.19 g, 87%) was
obtained as a sole product from nitrone 8d (1.19 g, 3.06 mmol),
furan 5 (717 mg, 4.59 mmol), and TMSOTf (68 mg, 0.306 mmol).
(3R,3aS,6aR)-3-(tert-Butyldiphenylsilyloxymethyl)-N-(tert-
butyloxycarbonyl)tetrahydrofuro[2,3-d]isoxazol-5-one (19)
1
[a]D21 +10.1 (c 0.99, CHCl3); IR (CHCl3) 1790 cm-1; H NMR
(300 MHz, CDCl3) d 1.00 (9H, s), 1.10 (3H, s), 1.22 (3H, s), 1.24
(3H, s), 1.36 (3H, s), 2.62 (1H, dd, J = 18.5, 1.5 Hz), 2.70 (1H,
dd, J = 18.5, 4.6 Hz), 3.50 (1H, dd, J = 8.3, 7.1 Hz), 3.58 (1H,
dd, J = 9.9, 6.4 Hz), 3.63 (1H, ddd, J = 6.4, 3.8, 1.1 Hz), 3.77
(1H, dd, J = 8.2, 4.0 Hz), 3.92 (1H, dd, J = 9.9, 3.8 Hz), 4.08
(1H, dd, J = 8.3, 6.6 Hz), 4.21 (1H, ddd, J = 8.2, 7.1, 6.6 Hz),
4.53 (1H, dd, J = 6.1, 4.0 Hz), 4.65 (1H, td, J = 4.6, 1.5 Hz),
4.67 (1H, s), 4.81 (1H, d, J = 6.1 Hz), 5.16 (1H, dd, J = 4.6, 1.1
Hz), 7.32–7.45 (6H, m), 7.62–7.66 (4H, m); 13C NMR (100 MHz,
CDCl3) d 19.4, 25.0, 25.5, 26.2, 26.4, 27.0, 35.0, 62.9, 65.9, 69.5,
75.7, 77.2, 80.5, 83.5, 84.5, 89.0, 99.2, 109.5, 112.9, 127.6, 127.7,
129.7, 129.8, 132.6, 132.9, 135.4, 135.5, 173.9; HRMS (EI) m/z
calcd for C34H45NO9Si 639.2861, found 639.2868. Anal. Calcd
for C34H45NO9Si: C, 68.83; H, 7.09; N, 2.19. Found: C, 63.55; H,
7.13; N, 2.16.
To a stirred solution of bicyclic adduct 11c (500 mg, 0.78 mmol)
in CH3CN (10 mL) was added a 0.96 M solution of HClO4
(1.6 mL, 1.5 mmol). The mixture was stirred at room temperature
for 5 h and neutralized with powdered NaHCO3. Then Boc2O
(853 mg, 3.9 mmol) was added, and the mixture was stirred
overnight, diluted with water, and extracted with CH2Cl2. The
organic solution was washed with brine, and dried over MgSO4.
After filtration, the filtrate was concentrated in vacuo. The residue
was purified by column chromatography on silica gel with AcOEt–
hexane (1 : 1) to afford 19 (246 mg, 64%) as a colorless oil. [a]D21
-18.8 (c 1.32, CHCl3); IR (CHCl3) 1794, 1734, 1429, 1371 cm-1;
1H NMR (300 MHz, CDCl3) d 1.01 (9H, s), 1.37 (9H, s), 2.68
(1H, dd, J = 19.2, 7.1 Hz), 2.91 (1H, d, J = 19.2 Hz), 3.56 (1H,
dd, J = 10.6, 7.7 Hz), 3.82 (1H, dd, J = 10.6, 5.3 Hz), 4.46 (1H,
dd, J = 7.7, 5.3 Hz), 4.72 (1H, br dd, J = 7.1, 5.3 Hz), 5.28 (1H,
d, J = 5.3 Hz), 7.29–7.41 (6H, m), 7.56–7.60 (4H, m); 13C NMR
(100 MHz, CDCl3) d 19.4, 27.1, 28.2, 35.2, 62.1, 67.6, 79.7, 83.9,
86.9, 128.4, 130.5, 130.6, 133.1, 133.2, 136.0, 136.1, 158.0, 173.9;
MS (EI) m/z 453 (M+-CO2), 424, 384, 340, 319. HRMS (EI) m/z
calcd for C26H35NO4Si–CO2 453.2333, found 453.2335.
[3R,3aS,6aR,(4S)]-N-(2¢,3¢:5¢,6¢-O-Diisopropylidene-a-L-
gulofuranosyl)-3-(2,2-dimethyl-[1,3]dioxolan-4-yl)tetrahydrofuro-
[2,3-d]isoxazol-5-one (11d)
(a) Following the general procedure, (4S)-(Z)-N-(2,3:5,6-O-
diisopropylidene-a-L-gulofuranosyl)(2,2-dimethyl-[1,3]dioxolan-
4-yl)methyleneamine N-oxide (8d) (175 mg, 63%) was prepared
from oxime 9 (200 mg, 0.72 mmol) and aldehyde 10d (103 mg, 0.79
mmol). It was used for the next step without further purification.
8d: IR (CHCl3) 2992, 1221, 1217 cm-1; 1H NMR (300 MHz,
CDCl3) d 1.29 (3H, s), 1.37 (6H, s), 1.41 (3H, s), 1.43 (3H, s), 1.46
(3H, s), 3.69 (1H, dd, J = 8.4, 7.2 Hz), 3.69 (1H, dd, J = 8.6, 5.7
Hz), 4.18 (1H, dd, J = 8.4, 6.6 Hz), 4.31 (1H, br ddd, J = 8.4, 7.2,
6.6 Hz), 4.33 (1H, t, J = 8.6 Hz), 4.54 (1H, dd, J = 8.4, 4.4 Hz),
4.83 (1H, dd, J = 5.9, 4.4 Hz), 5.09 (1H, br ddd, J = 8.6, 5.7, 5.0
Hz), 5.16 (1H, d, J = 5.9 Hz), 5.31 (1H, s), 7.09 (1H, d, J = 5.0 Hz);
HRMS (EI) m/z calcd for C18H29NO8 387.1891, found 387.1886.
Following the general procedure, bicyclic adduct 11d (55.7 mg,
72%) was obtained as a sole product from nitrone 8d (60 mg, 0.15
mmol), furan 5 (36 mg,◦0.23 mmol), and TMSOTf (2.8 mL, 1.5
mmol). 11d: mp 172–173 C (benzene–hexane); [a]2D1 +23.7 (c 0.90,
[3R,3aS,6aR,(2S)]-N-(tert-Butyloxycarbonyl)-3-(1,2-
dihydroxyethyl)tetrahydrofuro[2,3-d]isoxazol-5-one (20)
To a stirred solution of bicyclic adduct 11d (258 mg, 0.583
mmol) in CH3CN (10 mL) was added a 1 M solution of
HClO4 (1.17 mL, 1.17 mmol). The mixture was stirred at room
temperature for 15 min and neutralized with powdered NaHCO3.
Then Boc2O (636 mg, 2.91 mmol) was added, and the mixture
was stirred overnight, dried over MgSO4, and filtered. The filtrate
was concentrated in vacuo. The residue was purified by column
chromatography on silica gel with AcOEt–CH2Cl2 (5 : 1) to afford
20 (144 mg, 86%) as a colorless oil. [a]2D1 -16.1 (c 1.80, CHCl3);
1
IR (CHCl3) 3600, 1794, 1736, 1371 cm-1; H NMR (270 MHz,
CDCl3) d 1.49 (9H, s), 2.84 (1H, br s), 2.85 (1H, dd, J = 18.5, 6.9
Hz), 3.00 (1H, d, J = 18.5 Hz), 3.29 (1H, d, J = 7.3 Hz), 3.61 (1H,
ddt, J = 9.2, 7.3, 4.0 Hz), 3.77 (1H, dd, J = 15.5, 4.0 Hz), 3.85 (1H,
dd, J = 15.5, 4.0 Hz), 4.45 (1H, d, J = 9.2 Hz), 5.03 (1H, br dd,
J = 6.9, 5.3 Hz), 5.59 (1H, d, J = 5.3 Hz); 13C NMR (67.8 MHz,
1
CHCl3); IR (CHCl3) 1792 cm-1; H NMR (400 MHz, CDCl3) d
1.26 (3H, s), 1.32 (3H, s), 1.36 (3H, s), 1.39 (3H, s), 1.42 (3H, s),
1.44 (3H, s), 2.71 (1H, dd, J = 18.8, 1.0 Hz), 2.79 (1H, dd, J =
7416 | Org. Biomol. Chem., 2011, 9, 7411–7419
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CDCl3) d 28.0, 35.0, 63.2, 67.5, 69.1, 79.9, 84.3, 86.7, 157.9, 173.9;
MS (EI) m/z 230 (M+-tert-Bu), 216, 189, 128, 110, 57.
br t, J = 2.0 Hz); 13C NMR (67.8 MHz, CDCl3) d 24.2, 27.9, 28.4,
38.8, 54.5, 65.4, 67.3, 82.5, 82.9, 94.4, 154.1, 174.6; HRMS (EI)
m/z Calcd for C13H20NO6–CH3 286.1289, found 286.1287.
(3R,3aS,6aR)-3-(Hydroxymethyl)-N-(tert-butyloxycarbonyl)-
tetrahydrofuro[2,3-d]isoxazol-5-one (21)
(4R)-4-[(2S)-3,4-Dihydro-5-oxo-furan-2-yl]-2,2-
dimethyloxazolidine-3-carboxylic acid tert-butyl ester (23)
(a) Preparation of 21 from 19. A 1.0 M solution of TBAF (38 mL,
38 mmol) was adjusted to pH 4–5 by adding 80% AcOH. To the
mixture was added a solution of 19 (18.7 mg, 37.7 mmol) in THF
(2 mL) at 0 ◦C. The mixture was stirred at room temperature
for 3 h, diluted with water, and extracted with AcOEt. The
organic phase was dried over MgSO4, and filtered, and the filtrate
was concentrated in vacuo. The residue was purified by column
chromatography on silica gel with AcOEt–hexane (2 : 1) to give
21 (9.6 mg, 98%) as a colorless oil. [a]2D1 -23.1 (c 0.96, CHCl3);
IR (CHCl3) 1794, 1736, 1371 cm-1; 1H-NMR (300 MHz, CDCl3)
d 1.49 (9H, s), 2.12 (1H, br s), 2.81 (1H, dd, J = 19.2, 7.1 Hz),
3.03 (1H, dd, J = 19.2, 0.5 Hz), 3.78 (2H, m), 4.56 (1H, t, J = 5.7
Hz), 4.98 (1H, ddd, J = 7.1, 5.3, 0.5 Hz), 5.28 (1H, d, J = 5.3 Hz);
13C NMR (100 MHz, CDCl3) d 28.1, 34.9, 61.2, 67.9, 79.8, 84.0,
86.6, 157.5, 173.3; HRMS (EI) m/z calcd for C11H17NO6 259.1055,
found 259.1064.
To a stirred solution of 22 (12.9 mg, 42.8 mmol) in CH2Cl2 (1
mL) were added MsCl (13 mL, 171 mmol) and Et3N (47 mL, 342
mmol) at room temperature. The mixture was stirred for 2 h,
diluted with water, and extracted with Et2O. The Et2O solution
was washed with brine, and dried over MgSO4. After filtration,
the filtrate was concentrated in vacuo. The residue was purified
column chromatography on silica gel with AcOEt–hexane (1 : 1)
to give 23 (11.6 mg, 96%) as an oil. This compound was used
without further purification. IR (CHCl3) 3028, 1794, 1761, 1698,
1686 cm-1; 1H NMR (270 MHz, C6D6, 60 ◦C) d 1.32 (9H, s), 1.37
(3H, s), 1.53 (3H, s), 3.42 (1H, dd, J = 9.2, 5.3 Hz), 3.53 (1H, br
s), 3.70 (1H, d, J = 9.2 Hz), 4.60 (1H, br s), 5.60 (1H, dd, J = 5.7,
2.0 Hz), 6.81 (1H, dd, J = 5,7, 1.3 Hz).
(b) Preparation of 21 from 20. A mixture of diol 20 (31.8 mg,
0.11 mmol) and NaIO4 (35.3◦mg, 0.16 mmol) in MeOH–H2O
(10 : 1, 2 mL) was stirred at 0 C for 1 h. After evaporation, the
residue was partitioned between water and CH2Cl2. The aqueous
phase was further extracted with CH2Cl2. The combined organic
phase was washed with brine, dried over MgSO4, and filtered, and
the filtrate was concentrated in vacuo. The residue was dissolved
in Et2O (2 mL). To this solution was added a 0.1 M solution of
Zn(BH4)2 in Et2O (3.3 mL, 0.33 mmol) at 0 ◦C. After 1 h, 1 N HCl
(1 mL) was added, and the mixture was extracted with AcOEt. The
AcOEt solution was washed successively with a saturated solution
of NaHCO3 and brine, and dried over MgSO4. After filtration,
the filtrate was concentrated in vacuo. The residue was purified by
column chromatography on silica gel with CH2Cl2–MeOH (10 : 1)
to give 21 (16.0 mg, 56%) as a colorless oil. [a]2D1 -22.1 (c 0.81,
CHCl3). Spectral data of this sample were identical with those
obtained in (a).
(4R)-4-[(2R,3R,4R)-3,4-Dihydroxy-5-oxo-tetrahydrofuran-2-yl]-
2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (18)
Following Garner’s procedure, this material was obtained from 23
and Me3NO, and OsO4. [a]2D1 +31.0 (c 0.85, CHCl3), lit.12g [a]D
+31.8 (c 0.87, CHCl3); IR (CHCl3) 2984, 1786, 1695, 1678 cm-1;
1H NMR (400 MHz, C6D6, 60 ◦C) d 1.31 (9H, s), 1.33 (3H, s), 1.48
(3H, s), 2.49 (2H, br s), 3.41 (1H, dd, J = 9.4, 5.3 Hz), 3.48 (1H, dd,
J = 9.4, 5.3 Hz), 3.68 (1H, d, J = 9.4 Hz), 4.30 (1H, d, J = 9.4 Hz),
4.39 (1 H, br s); 13C NMR (100 MHz, C6D6, 60 ◦C) d 24.2, 27.9,
28.4, 57.9, 65.6, 69.2, 69.7, 81.1, 84.6, 94.8, 153.2, 174.1; HRMS
(EI) m/z calcd for C13H20NO7–CH3 302.1238, found 302.1239.
(3R,3aS,6aR)-3-[(S)-(2-tert-Butyldiphenylsilyloxy-1-
hydroxyethyl)]-2-(tert-butyloxycarbonyl)tetrahydrofuro[2,3-
d]isoxazol-5-one (26)
(4S)-4-[(2R,3R)3-Hydroxy-5-oxo-tetrahydro-furan-2-yl]-2,2-
dimethyloxazolidine-3-carboxylic acid tert-butyl ester (22)
To a stirred solution of diol 20 (2.23 g, 7.76 mmol) in DMF were
added imidazole (1,59 g, 23.3 mmol) and TBDPSCl (2.77 g, 10.1
mmol) at room temperature, and stirring was continued for 30 min.
The mixture was partitioned between water and Et2O, and the
organic layer was successively washed with water and brine, dried
(MgSO4), and concentrated under reduced pressure. The residue
was chromatographed on silica gel (hexane–EtOAc, 2 : 1) to give
26 (3.40 g, 83%) as a colorless oil. [a]2D3 -20.6 (c 0.30, CHCl3);
IR (CHCl3) 1792, 1734 cm-1; 1H NMR (270 MHz, CDCl3) d 1.09
(9H, s), 1.45 (9H, s), 2.69 (1H, d, J = 6.6 Hz), 2.79 (1H, dd, J =
19.3, 7.3 Hz), 3.05 (1H, d, J = 19.3 Hz), 3.58 (1H, m), 3.78 (1H,
dd, J = 10.6, 4.3 Hz), 3.86 (1H, dd, J = 10.6, 4.6 Hz), 4.58 (1H,
d, J = 8.5 Hz), 4.97 (1H, dd, J = 7.3, 5.2 Hz), 5.57 (1H, d, J =
5.2 Hz), 7.35–7.49 (6H, m, Ph), 7.64–7.69 (4H, m, Ph); 13C NMR
(67.5 MHz, CDCl3) d 19.2, 26.9, 28.0, 35.0, 63.9, 67.7, 68.9, 79.8,
83.9, 86.5, 127.9, 130.0, 132.5, 135.5, 157.8, 173.9; MS (EI) m/z
484 (2.5, -tBu), 370, 292. Anal. Calcd for C28H37NO7Si: C, 63.73;
H, 7.07; N, 2.65. Found: C, 63.56; H, 7.21; N, 2.63.
A solution of 21 (142 mg, 0.55 mmol) and Mo(CO)6 (289 mg,
1.1 mmol) in CH3CN–H2O (10 : 1, 15 mL) was heated at reflux
R
for 1.5 h. The mixture was filtered through a pad of Celiteꢀ, and
the filtrate was concentrated in vacuo. The residue was passed
through a pad of silica gel, and the filtrate was concentrated in
vacuo. The residue was dissolved in toluene (10 mL) containing
2,2-dimethoxypropane (338 mL, 2.75 mmol) and PPTS (13.8 mg,
55 mmol), and the solution was heated at reflux for 1.5 h. The
mixture was concentrated in vacuo, and the residue was purified
by column chromatography on silica gel with AcOEt–hexane (2 : 3)
to give 22 (89.5 mg, 54%). [a]2D1 +76.2 (c 0.79, CHCl3); IR (CHCl3)
3300, 1800, 1779, 1671, 1402 cm-1; 1H NMR (400 MHz, CDCl3)
d 1.51 (9H, s), 1.54 (3H, s), 1.57 (3H, s), 2.61 (1H, d, J = 17.3 Hz),
2.72 (1H, ddd, J = 17.3, 4.6, 2.0 Hz), 4.04 (1H, dd, J = 9.5, 5.1
Hz), 4.14 (1 H, dd, J = 10.2, 2.0 Hz), 4.24 (1H, d, J = 9.5 Hz), 4.30
(1H, dd, J = 10.2, 5.1 Hz), 4.34 (1H, dt, J = 4.6, 2.0 Hz), 5.71 (1H,
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(3R,3aS,6aR)-3-[(S)-2-tert-Butyldiphenylsilyloxy-1-
hydroxyethyl]-tetrahydrofuro[2,3-d]isoxazol-5-one (27)
dd, J = 18.8, 1.3 Hz), 2.72 (3H, s), 2.75 (1H, dd, J = 18.8, 5.3 Hz),
3.02 (1H, dd, J = 3.0, 2.6 Hz), 3.93 (1H, dd, J = 11.5, 5.5 Hz), 3.94
(1H, dd, J = 11.5, 6.2 Hz), 4.62 (1H, ddd, J = 5.3, 4.6, 1.3 Hz),
5.00 (1H, ddd, J = 6.2, 5.5, 2.6 Hz), 5.29 (1H, dd, J = 4.6, 3.0 Hz),
7.12–7.48 (11H, Ph), 7.68–7.73 (4H, Ph); 13C NMR (67.5 MHz,
CDCl3) d 19.2, 26.7, 33.8, 43.7, 63.1, 74.7, 76.2, 87.4, 126.2, 127.9,
129.5, 129.7, 130.0, 132.5, 135.6, 151.0, 153.0, 174.4. Anal. Calcd
for C28H35NO7Si: C, 66.29; H, 6.28; N, 2.49. Found: C, 66.18; H,
6.49; N, 2.42.
To a stirred solution of 24 (1.45 g, 2.75 mmol) in CH2Cl2
(75 ml) was added anhydrous TsOH (1.14 g, 6.60 mmol) at
0
◦C, and stirring was continued at room temperature for 7 h.
The mixture was poured into a saturated aqueous solution
of NaHCO3, and the whole was extracted with CHCl3, dried
(MgSO4), and concentrated under reduced pressure. The residue
was chromatographed on silica gel (hexane–EtOAc, 1.7 : 1) to give
25 (1.05 g, 90%) as a colorless oil. [a]2D0 +49.4 (c 0.22, CHCl3); IR
1
(CHCl3) 1786 cm-1; H NMR (270 MHz, CDCl3) d 1.08 (9H, s,
(4R,5S)-5-(tert-Butyldiphenylsilyloxymethyl)-3-methyl-4-
[(2R,3R)-tetrahydro-3-hydroxy-5-oxofuran-2-yl]oxazolidine-2-
one (33)
t-Bu), 2.64 (1H, d, J = 5.3 Hz), 2.68 (1H, dd, J = 19.1, 1.3 Hz),
2.84 (1H, dd, J = 19.1, 6.7 Hz), 3.53 (1H, m), 3.71 (1H, br), 3.84
(2H, d, J = 4.6 Hz), 4.77 (1H, ddd, J = 6.7, 6.3, 1.3 Hz), 5.51 (1H,
br), 5.83 (1H, dd, J = 6.3, 0.9 Hz), 7.37–7.48 (6H, m), 7.63–7.66
(4H, m); 13C NMR (67.5 MHz, CDCl3) d 19.3, 26.9, 34.6, 64.9,
67.9, 68.3, 87.8, 127.9, 130.1, 132.6, 135.5, 173.9. MS (EI) m/z
370, 293, 292. Anal. Calcd for C23H29NO5Si: C, 64.61; H, 6.84; N,
3.28. Found: C, 64.33; H, 7.00; N, 3.30.
A mixture of 31 (38.6 mg, 0.071 mmol) and 20% Pd(OH)2/C (38.6
mg) in MeOH–H2O (20 : 1, 1 mL) was stirred for 10 h under an
atmosphere of hydrogen. The catalyst was removed by filtration,
and the filtrate was concentrated under reduced pressure. The
residue was chromatographed on silica gel with (hexane–EtOAc,
1 : 1.5) to give 33 (30.1 mg, 91%) as a colorless oil. [a]1D8 +51.0 (c
0.48, CHCl3); IR (CHCl3) 1790, 1747 cm-1; 1H NMR (500 MHz,
CDCl3) d 1.04 (9H, s), 2.53 (1H, d, J = 17.4 Hz), 2.60 (1H, dd, J =
17.4, 4.6 Hz), 2.99 (3H, s), 3.45 (1H, br), 4.05 (1H, dd, J = 11.9,
2.7 Hz), 4.08 (1H, dd, J = 11.9, 2.7 Hz), 4.33 (1H, dt, J = 8.2, 2.7
Hz), 4.57 (1H, dd, J = 8.2, 3.6 Hz), 4.58 (1H, dt, J = 9.1, 4.6 Hz),
4.71 (1H, dd, J = 9.1, 3.6 Hz), 7.36–7.44 (6H, m), 7.63–7.65 (4H,
m); 13C NMR (125 MHz, CDCl3) d 19.1, 22.6, 26.7, 31.2, 31.6,
39.5, 56.4, 62.4, 68.3, 75.9, 80.8, 127.9, 130.1, 132.2, 132.8, 135.4,
135.6, 135.8, 159.1, 173.8. Anal. Calcd for C25H31NO6Si: C, 63.94;
H, 6.65; N, 2.98. Found: C, 64.01; H, 6.98; N, 2.97.
(3R,3aS,6aR)-3-[(S)-2-tert-Butyldiphenylsilyloxy-2-
hydroxyethyl]-2-methyl-tetrahydrofuro[2,3-d]isoxazole-5-one (30)
To a stirred solution of 27 (1.00 g, 2.35 mmol) in EtOH (5 mL)
was added a 35% aqueous solution of HCHO (1.66 mL, 20 mmol)
at room temperature, and the mixture was heated at 75 ◦C for 6 h.
After concentration, the residue was dissolved in CH3CN (50 mL).
Trifluoroacetic acid (1.78 mL, 23.5 mmol) and Et3SiH (2.81 mL,
17.6 mmol) were added at room temperature, and then the mixture
was heated at 60 ◦C for 1.5 h and poured into a saturated aqueous
solution of NaHCO3. The whole was extracted with CHCl3.
The organic extract was dried (MgSO4) and concentrated under
reduced pressure. The residue was chromatographed on silica gel
with (hexane–EtOAc, 1.5 : 1) to give 30 (880 mg, 85%) as colorless
Hatakeyama’s lactone 25
oil. [a]2D4 -0.3 (c 0.48, CHCl3); IR (CHCl3) 1786 cm-1; H NMR
1
Pyridine (30.8 mL, 0.383 mmol) and chloromethanesulfonyl chlo-
ride (17.1 mL, 0.192 mmol) were added to a stirred solution of
33 (30.0 mg, 0.064 mmol) in CH2Cl2 (0.4 mL) at 0 ◦C, and
stirring was continued at room temperature for 5 h. The reaction
was quenched by adding water, and the whole was extracted
with CHCl3. The organic layer was successively washed with
1 N HCl and a saturated aqueous solution of NaHCO3, then
dried (MgSO4), and concentrated under reduced pressure to
give crude 34. The crude 34 was dissolved in CH3CN. A 47%
aqueous solution of HF (0.5 mL) was added, and the mixture
was heated at 60 ◦C for 30 h, adjusted to pH 8 by adding
NaHCO3, further stirred at room temperature for 3 h, and then
partitioned between water and CHCl3. The organic layer was dried
(MgSO4) and concentrated under reduced pressure. The residue
was chromatographed on silica gel with (EtOAc–MeOH, 20 : 1)
to give 25 (9.6 mg, 71%) as colorless crystals. mp 191–192 ◦C
(500 MHz, CDCl3) d 1.08 (9H, s), 2.64 (1H, d, J = 19.2 Hz), 2.72
(3H, s), 2.73 (1H, dd, J = 19.2, 5.5 Hz), 2.95 (1H, dd, J = 4.0,
2.4 Hz), 3.78 (1H, m), 3.78 (2H, d, J = 4.9 Hz), 4.58 (1H, dd, J =
5.5, 4.9 Hz), 5.31 (1H, dd, J = 4.9, 2.4 Hz), 7.37–7.48 (6H, m,
Ph), 7.63–7.66 (4H, m, Ph); 13C NMR (67.5 MHz, CDCl3) d 19.2,
26.8, 34.2, 44.1, 64.9, 69.0, 75.8, 87.6, 127.9, 130.0, 132.7, 135.5,
174.6. MS (EI) m/z 441, 384, 307. Anal. Calcd for C28H35NO7Si:
C, 65.28; H, 7.08; N, 3.17. Found: C, 65.02; H, 7.47; N, 3.09.
(3R,3aS,6aR)-3-[(S)-2-tert-Butyldiphenylsilyloxyethyl-1-phenyl-
carbonyloxy]-2-methyl-tetrahydrofuro[2,3-d]isoxazole-5-one (31)
To a stirred solution of 30 (632 mg, 1.43 mmol) and DMAP
(350 mg, 2.86 mmol) in CH3CN (120 mL) was added phenyl
◦
chloroformate (336 mg, 2.15 mmol) at 60 C. After 2 h, further
phenyl chloroformate (224 mg, 1.43 mmol) and DMAP (175 mg,
1.43 mmol) were added, and stirring was continued for 2 h at
60 ◦C. The mixture was poured into a saturated aqueous solution
ofNaHCO3, and the whole was extracted with AcOEt. The organic
layer was dried (MgSO4) and concentrated under reduced pressure.
The residue was chromatographed on silica gel with (hexane–
AcOEt, 3 : 1) to give 31 (698 mg, 89%) as a colorless oil and starting
30 (44.8 mg, 7%). 31: [a]D24 +4.7 (c 0.38, CHCl3); IR (CHCl3) 1786,
1767 cm-1; 1H NMR (270 MHz, CDCl3) d 1.08 (9H, s), 2.65 (1H,
◦
(EtOAc); lit15c 199–201 C (EtOAc); lit16d 192–193 ◦C (EtOAc);
[a]D24 +128.2 (c 0.200, CH3OH); lit16d +131.8 (c 0.35, CH3OH); 1H
NMR (270 MHz, CD3OD) d 2.53 (1H, d, J = 17.2 Hz), 2.89 (1H,
dd, J = 17.2, 4.3 Hz), 2.90 (3H, s) 3.76 (1H, dd, J = 14.2, 2.0 Hz),
4.16 (1H, dd, J = 14.2, 1.3 Hz), 4.16 (1H, dd, J = 6.9, 5.9 Hz), 4.30
(1H, dd, J = 4.3, 2.3 Hz), 4.44 (1H, ddd, J = 6.9, 2.0, 1.3 Hz), 4.72
(1H, dd, J = 5.9, 2.3 Hz). These physical data are identical with
the reported values.15c,16d
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Chem., 1997, 62, 5385; (h) R. Fassler, D. E. Frantz, J. Oetiker and E. M.
Carreira, Angew. Chem., Int. Ed., 2002, 41, 3054; (i) S. K. Patel, S. Py,
S. U. Pandya, P. Y. Chavant and Y. Vallee, Tetrahedron: Asymmetry,
2003, 14, 525; (j) D. Topic, P. Aschwanden, R. Faessler and E. M.
Carreira, Org. Lett., 2005, 7, 5329; (k) U. Chiacchio, M. G. Saita, L.
Crispino, G. Gumina, S. Mangiafico, V. Pistara, G. Romeo, A. Piperno
and E. De Clercq, Tetrahedron, 2006, 62, 1171; Tetrahedron, 2007, 63,
4190.
Notes and references
1 For reviews on vinylogous Mannich reaction, see: (a) S. K. Bur and S. F.
Martin, Tetrahedron, 2001, 57, 3221; (b) G. Casiraghi, F. Zanardi, L.
Battistini and G. Rassu, Synlett, 2009, 1525; (c) L. Battistini, F. Zanardi,
C. Curti and G. Casiraghi, Chemtracts-Organic Chemistry, 2010, 23,
141. For leading references, see: (d) T. Liu, H. Cui, J. Long, B. Li, Y. Wu,
L. Ding and Y. Chen, J. Am. Chem. Soc., 2007, 129, 1878; (e) B. Niess
and K. A. Joergensen, Chem. Commun., 2007, 1620; (f) R. Villano,
M. R. Acocella, A. Massa, L. Palombi and A. Scettri, Tetrahedron,
2007, 63, 12317; (g) M. Sickert and C. Schneider, Angew. Chem., Int.
Ed., 2008, 47, 3631; (h) A. Yamaguchi, S. Matsunaga and M. Shibasaki,
Org. Lett., 2008, 10, 2319; (i) D. S. Giera, M. Sickert and C. Schneider,
Org. Lett., 2008, 10, 4259.
2 For vinylogous Mannich reactions in natural product syntheses, see:
(a) A. Deiters, K. Chen, C. T. Eary and S. F. Martin, J. Am. Chem.
Soc., 2003, 125, 4541; (b) D. M. Barnes, L. Bhagavatula, J. DeMattei,
A. Gupta, D. R. Hill, S. Manna, M. A. McLaughlin, P. Nichols, R.
Premchandran, M. W. Rasmussen, Z. Tian and S. J. Wittenberger,
Tetrahedron: Asymmetry, 2003, 14, 3541; (c) T. Nagata, M. Nakagawa
and A. Nishida, J. Am. Chem. Soc., 2003, 125, 7484; (d) R. Alibes, P.
Bayon, P. De March, M. Figueredo, J. Font, E. Garcia-Garcia and D.
Gonzalez-Galvez, Org. Lett., 2005, 7, 5107; (e) K. Tokumaru, S. Arai
and A. Nishida, Org. Lett., 2006, 8, 27; (f) G. G. Bardaji, M. Canto, R.
Alibes, P. Bayon, F. Busque, P. de March, M. Figueredo and J. Font,
J. Org. Chem., 2008, 73, 7657; (g) D. Gonza´lez-Ga´lvez, E. Garc´ı-Garc´ıa,
R. Alibe´s, P. Bayo´n, P. de March, M. Figueredo and J. Font, J. Org.
Chem., 2009, 74, 6199.
3 (a) M. V. Spanedda, M. Oure´vitch, B. Crousse, J. Be´gue´ and D. Bonnet-
Delpon, Tetrahedron Lett., 2004, 45, 5023; (b) L. D. Bari, S. Guillarme,
S. Hermitage, J. A. K. Howard, D. A. Jay, G. Pescitelli, A. Whiting and
D. S. Yufit, Synlett, 2004, 708; (c) J. M. Aurrecoechea and R. Suero,
Tetrahedron Lett., 2005, 46, 4945; (d) J. M. Aurrecoechea, R. Suero and
E. de Torres, J. Org. Chem., 2006, 71, 8767; (e) K. E. Hardinga and J. M.
Southard, Tetrahedron: Asymmetry, 2005, 16, 1845; (f) V. Liautard, V.
Desvergnes, K. Itoh, H. Liu and O. R. Martin, J. Org. Chem., 2008,
73, 3103; (g) J. Yu, Z. Miao and R. Chen, Org. Biomol. Chem., 2011, 9,
1756.
4 (a) E. L. Carswell, M. L. Snapper and A. H. Hoveyda, Angew. Chem.,
Int. Ed., 2006, 45, 7230; (b) H. Mandai, K. Mandai, M. L. Snapper and
A. H. Hoveyda, J. Am. Chem. Soc., 2008, 130, 17961; (c) L. C. Wieland,
E. M. Vieira, M. L. Snapper and A. H. Hoveyda, J. Am. Chem. Soc.,
2009, 131, 570; (d) Z.-L. Yuan, J.-J. Jiang and M. Shi, Tetrahedron,
2009, 65, 6001; (e) Q.-Y. Zhao, Z.-L. Yuan and M. Shi, Tetrahedron:
Asymmetry, 2010, 21, 943; (f) Q. Zhao, Z. Yuan and M. Shi, Adv. Synth.
Catal., 2011, 353, 637; (g) C. Curti, L. Battistini, B. Ranieri, G. Pelosi,
G. Rassu, G. Casiraghi and F. Zanardi, J. Org. Chem., 2011, 76, 2248;
(h) T. Akiyama, Y. Honma, J. Itoh and K. Fuchibe, Adv. Synth. Catal.,
2008, 350, 399.
9 (a) H. Iida, K. Kasahara and C. Kibayashi, J. Am. Chem. Soc., 1986,
108, 4647; (b) K. Kasahara, H. Iida and C. Kibayashi, J. Org. Chem.,
1989, 54, 2225; (c) A. Basha, R. Henry, M. A. McLaughlin, J. D.
Ratajczyk and S. J. Wittenberger, J. Org. Chem., 1994, 59, 6103.
10 (a) O. Tamura, N. Mita, N. Kusaka, H. Suzuki and M. Sakamoto,
Tetrahedron Lett., 1997, 38, 429; (b) O. Tamura, N. Iyama and H.
Ishibashi, J. Org. Chem., 2004, 69, 1475; (c) O. Tamura, A. Kanoh,
M. Yamashita and H. Ishibashi, Tetrahedron, 2004, 60, 9997; (d) T.
Shibue, T. Hirai, I. Okamoto, N. Morita and O. Tamura, Tetrahedron
Lett., 2009, 50, 3845; (e) T. Shibue, T. Hirai, I. Okamoto, N. Morita,
H. Masu, I. Azumaya and O. Tamura, Chem.–Eur. J., 2010, 16, 11678.
11 For a review, see: H. Akita, Heterocycles, 2009, 77, 67.
12 For synthesis of polyoxin Cs, see: (a) T. Naka, T. Hashizume and M.
Nishimura, Tetrahedron Lett., 1971, 12, 95; (b) N. P. Damodaran, G. H.
Jones and J. G. Moffatt, J. Am. Chem. Soc., 1971, 93, 3812; (c) H. Ohrui,
H. Kuzuhara and S. Emoto, Tetrahedron Lett., 1971, 12, 4267; (d) F.
Tabusa, T. Yamada, K. Suzuki and K. Mukaiyama, Chem. Lett., 1984,
405; (e) T. Mukaiyama, K. Suzuki, T. Yamada and Tabusa, Tetrahedron,
1990, 46, 265; (f) P. Garner and J. M Park, Tetrahedron Lett., 1989, 30,
5065; (g) P. Garner and J. M. Park, J. Org. Chem., 1990, 55, 3772;
(h) A. G. M. Barrett and S. A. Lebold, J. Org. Chem., 1990, 55, 3853;
(i) Y. Auberson and P. Vogel, Tetrahedron, 1990, 46, 7019; (j) A. Chen,
I. Savage, E. J. Thomas and P. D. Wilson, Tetrahedron Lett., 1993,
34, 6769; (k) N. Chida, K. Koizumi, K. Kitada, C. Yokoyama and S.
Ogawa, Chem. Commun., 1994, 111; (l) A. Dondoni, F. Junquera, F. L.
Merchan, P. Merino and T. Tejero, Tetrahedron Lett., 1994, 35, 9439;
(m) A. Dondoni, F. Junquera, F. L. Merchan, P. Merino and T. Tejero,
Chem. Commun., 1995, 2127; (n) B. M. Trost and Z. Shi, J. Am. Chem.
Soc., 1996, 118, 3037; (o) K. Kato, C. Y. Chen and H. Akita, Synthesis,
1998, 1527; (p) A. K. Ghosh and Y. Wang, J. Org. Chem., 1999, 64,
2789; (q) K. M. K. Kutterer and G. Just, Heterocycles, 1999, 51, 1409;
(r) A. Chen, E. J. Thomas and P. D. Wilson, J. Chem. Soc., Perkin Trans.
1, 1999, 3305; (s) K. Uchida, K. Kato, K. Yamaguchi and H. Akita,
Heterocycles, 2000, 53, 2253; (t) C. Dehoux, L. Gorrichon and M.
Baltas, Eur. J. Org. Chem., 2001, 1105; (u) J. D. More and N. S. Finney,
Synlett, 2003, 1307; (v) A. Plant, P. Thompson and D. M. Williams,
J. Org. Chem., 2008, 73, 3714; (w) T. Nishiyama, T. Kajimoto, S. S.
Mohile, N. Hayama, T. Otsuda, M. Ozeki and M. Node, Tetrahedron:
Asymmetry, 2009, 20, 230.
13 S. Cicchi, A. Goti, A. Brandi and A. Guarna, Tetrahedron Lett., 1990,
31, 3351.
5 For general reviews on nucleophilic additions to nitrones, see: (a) M.
Lombardo and C. Trombini, Synthesis, 2000, 759; (b) M. Lombardo
and C. Trombini, Curr. Org. Chem., 2002, 6, 695; (c) Y. Ukaji and K.
Inomata, Synlett, 2003, 1075; (d) P. Merino, Targets in Heterocyclic
Systems, 2003, 7, 140; (e) P. Merino, C. R. Chim., 2005, 8, 775; (f) Y.
Ukaji and K. Inomata, Chem. Rec., 2010, 10, 173.
6 For references on nucleophilic addition of 2-silyloxyfurans to nitrones,
see: (a) C. Camiletti, L. Poletti and C. Trombini, J. Org. Chem., 1994, 59,
6843; (b) C. Castellari, M. Lombardo, G. Pietropaolo and C. Trombini,
Tetrahedron: Asymmetry, 1996, 7, 1059; (c) F. Degiorgis, M. Lombardo
and C. Trombini, Tetrahedron, 1997, 53, 11721; (d) F. Degiorgis, M.
Lombardo and C. Trombini, Synthesis, 1997, 1243; (e) M. Lombardo
and C. Trombini, Tetrahedron, 2000, 56, 323.
14 R. Sakai, H. Kamiya, M. Murata and K. Shimamoto, J. Am. Chem.
Soc., 1997, 119, 4112.
15 For total synthesis of dysiherbaine, see: (a) B. B. Snider and N. A.
Hawryluk, Org. Lett., 2000, 2, 635; (b) M. Sasaki, T. Koike, R.
Sakai and K. Tachibana, Tetrahedron Lett., 2000, 41, 3923; (c) H.
Masaki, J. Maeyama, K. Kamada, T. Esumi, Y. Iwabuchi and S.
Hatakeyama, J. Am. Chem. Soc., 2000, 122, 5216; (d) D. Phillips and
A. R. Chamberlin, J. Org. Chem., 2002, 67, 3194; (e) M. Sasaki, N.
Akiyama, K. Tsubone, M. Shoji, M. Oikawa and R. Sakai, Tetrahedron
Lett., 2007, 48, 5697; (f) K. Takahashi, T. Matsumura, J. Ishihara
and S. Hatakeyama, Chem. Commun., 2007, 4158; (g) M. Sasaki, K.
Tsubone, K. Aoki, N. Akiyama, M. Shoji, M. Oikawa, R. Sakai and
K. Shimamoto, J. Org. Chem., 2008, 73, 264.
7 N. Mita, O. Tamura, H. Ishibashi and M. Sakamoto, Org. Lett., 2002,
4, 1111.
16 For formal synthesis and synthetic studies of dysiherbaine, see: (a) M.
Sasaki, T. Maruyama, R. Sakai and K. Tachibana, Tetrahedron Lett.,
1999, 40, 3195; (b) T. Naito, J. S. Nair, A. Nishiki, K. Yamashita and
T. Kiguchi, Heterocycles, 2000, 53, 2611; (c) J. Huang, K. Xu and T.
Loh, Synthesis, 2003, 755; (d) O. Miyata, R. Iba, J. Hashimoto and T.
Naito, Org. Biomol. Chem., 2003, 1, 772; (e) S. H. Kang and Y. M. Lee,
Synlett, 2003, 993; (f) J. L. Cohen and A. R. Chamberlin, Tetrahedron
Lett., 2007, 48, 2533; (g) R. Fernandez de la Pradilla, N. Lwoff and A.
Viso, Tetrahedron Lett., 2007, 48, 8141.
8 (a) A. Vasella and R. Voeffray, Helv. Chim. Acta, 1982, 65, 1953; (b) A.
Vasella, R. Voeffray, J. Pless and Huguenin, Helv. Chim. Acta, 1983, 66,
1241; (c) R. Huber and A. Vasella, Helv. Chim. Acta, 1987, 70, 1461;
(d) A. Basha, R. Henry, M. A. McLaughlin, J. D. Ratajczyk and S. J.
Wittenberger, J. Org. Chem., 1994, 59, 6103; (e) A. Abiko, Chem. Lett.,
1995, 357; (f) J. R. Flisak, I. Lantos, L. Liu, R. T. Matsuoka, W. L.
Mendelson, L. M. Tucker, A. J. Villani and W. Zhang, Tetrahedron
Lett., 1996, 37, 4639; (g) I. Lantos, J. Flisak, L. Liu, R. Matsuoka,
W. Mendelson, D. Stevenson, K. Tubman, L. Tucker, W. Zhang, J.
Adams, M. Sorenson, R. Garigipati, K. Erhardt and S. Ross, J. Org.
17 For N-methylation using the HCHO–Et3SiH/CF3CO2H sequence, see:
J. Auerbach, M. Zamore and S. M. Weinreb, J. Org. Chem., 1976, 41,
725.
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