Enantioselective Synthesis of a Furan Lignan (+)-Sylvone

Article abstract of DOI:10.1021/acs.joc.5b01677

A synthesis of natural tetrahydrofuran lignan (+)-sylvone is achieved starting from methyl allenoate in 5 steps. The synthesis begins from an enantioselective aldol reaction of methyl allenoate with 3,4-dimethoxybenzaldehyde to afford α-addition aldol add

Full text of DOI:10.1021/acs.joc.5b01677

Note
pubs.acs.org/joc
Enantioselective Synthesis of a Furan Lignan (+)-Sylvone
Eunhye Lee, Jiyun Bang, Jisook Kwon, and Chan-Mo Yu*
Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea
S
* Supporting Information
ABSTRACT: A synthesis of natural tetrahydrofuran lignan
(+)-sylvone is achieved starting from methyl allenoate in 5 steps.
The synthesis begins from an enantioselective aldol reaction of
methyl allenoate with 3,4-dimethoxybenzaldehyde to afford α-
addition aldol adduct. Key steps for the synthesis of sylvone include
an oxacyclization of the α-hydroxy allenyl adduct followed by a
Michael addition of a 1,3-dithiane derivative to establish a sylvone
skeleton with suitable stereoselections.
evelopment of new synthetic protocols for achieving
stereoselectivity in the construction of a highly
D
substituted tetrahydrofuran system is a valuable objective
owing to the presence of this core unit in many natural
products including lignans possessing a diverse array of
biological activities.1 We report herein an efficient enantiose-
lective route to (+)-sylvone, a naturally occurring lignan
containing a highly functionalized tetrahydrofuran core.
The lignans are a large family of secondary metabolites
widely distributed in plants, representing a vast and rather
structurally diverse group of phenylpropane derivatives
biochemically produced by oxidative dimerization of two
phenylpropanoid units.2 Within this large family of lignans, a
class of tetrahydrofuran derivatives has long been recognized as
important natural products in terms of chemistry, biology,
nutrition, and medicine.3 In particular, 2,3,4-trisubstituted
tetrahydrofuran lignans are a group of natural products that
exhibit a wide range of interesting biological activities which has
resulted in them receiving considerable attention over the years.
As a consequence, stereoselective construction of these
structures, representing a core structure of the furan lignan
class, has been an important synthetic target.4
Sylvone (1) is a class of 2,3,4-trisubstituted tetrahydrofuran
lignans isolated from the petrol extracts of seeds derived from
piper sylvaticum5 and powdered fruits of piper logum,6 which
have been widely used as traditional medicine in Asia.
Structurally, sylvone (1) contains three contiguous stereogenic
centers having a unique substituent arrangement with the 2,3-
cis stereochemistry, whereas the majority of furan lignans have
the substituents arranged with the 2,3-trans relationship as
shown in Figure 1. The relative stereochemistry of 1 was
established by a series of NMR study including NOE
experiments5 and X-ray crystallography.6 In addition, Rovis
and Nasveschuk confirmed the structure of sylvone through
synthesis, although its absolute configuration is still not
Figure 1. Sylvone (1) and related bioactive lignans.
confirmed.7 Although the biological activity of 1 has not been
reported, its 3-epimer (−)-hernone displayed in vitro cytotoxic
activity against several cell lines.8
In our continuous efforts to utilize allenyl functionality,9 we
have demonstrated a highly efficient α-addition of methyl
allenoate with aldehydes to furnish the aldol adduct 2 with high
levels of enantioselectivity.10 From a synthetic viewpoint, it was
envisaged that aldol adduct 2 would serve as a starting material
for a sylvone skeleton (type A). As illustrated in the synthetic
strategy (Scheme 1), our synthesis of a sylvone skeleton type A
involves three major transformations: an enantioselective
Received: July 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01677
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
formation of 3 in 83% yield as a sole product when the allenyl
alcohol 2 was treated with AgNO3 (20 mol %) in acetone at 40
°C for 12 h.14
Scheme 1. Synthetic Strategy for the Synthesis of Lignans
Having achieved a reliable synthesis of the dihydrofuran
intermediate 3 through a two-step sequence from methyl
allenoate, we proceeded to use this compound for the
construction of a 2,3,4-substituted furan framework of sylvone
skeleton 4 via a Michael addition (Scheme 3).15 Although there
Scheme 3. Conjugate Addition of 8 to 3 To Afford 4
synthesis of 2, an oxacyclization of 2 to afford dihydrofuran 3,
and a Michael addition of a 1,3-dithiane derivative to 3 to afford
a crucial intermediate 4. Moreover, synthetic applications of
this protocol can be foreseen to extend to structurally related
bioactive lignans such as types B, C, and D from a synthetic
intermediate 5 as illustrated in Scheme 1 and Figure 1.11
With this issue in mind, our investigations began with methyl
allenoate for the synthesis of 2 based on methods previously
developed in our laboratory (Scheme 2).10 To a solution of
have been many examples of Michael addition reactions of
furan-2(5H)-one derivatives by a 2-aryl-1,3-dithiane with a base
in the literature,15c cyclic olefins connected to an external ester
functionality as a Michael acceptor are not known. Initial
attempts for addition of the lithiodithiane Li-8, prepared from 8
with n-BuLi in THF,15 to 3 indicated that the conversion to the
Michael adduct 4 could not be realized presumably due to a
lack of reactivity of Li-8 (Table 1, entry 1). We subsequently
speculated that an activation of the intermediate Li-8 might
require an additive to enhance nucleophilic addition to the α,β-
unsaturated ester 3.16
Scheme 2. Synthesis of 3 from Methyl Allenoate
a
Table 1. Additive Effect for the Addition of 8 to 3
b
entry
additive
equivalent
t, h
yield, %
c
1
2
3
4
5
6
none
−
5
2
NR
HMPA
HMPA
NMP
1
23
63
34
18
<5
5
0.5
0.5
0.5
1
10
10
3
DMF
TMEDA
a
After lithiation of 8 with n-BuLi at −78 °C in THF, additive was
b
added at −78 °C and then reaction was performed. Refer to isolated
and purified yield of 4. No addition products.
c
freshly prepared 6 was added a mixture of methyl allenoate and
i-Pr2NEt (2 equiv) in CH2Cl2 at −78 °C. After 20 min, the
resulting mixture was treated with 3,4-dimethoxybenzaldehyde
at −78 °C for 2 h in CH2Cl2. Neutral aqueous workup using a
buffer solution (pH = 7) afforded 2 in 64% yield with 93% ee.
Initial attempts of an oxacyclization of 2 to 3 using Au(I) or
Au(III) catalysts12 under various conditions turned out to be
unproductive, always producing undesired 7 as a major
component along with 3 mainly due to a strong electron-
donating factor of a 3,4-dimethoxyphenyl moiety.13a After
screening numerous reaction conditions with Ag(I) and Cu(II)
catalysts, we were delighted to find optimal conditions for the
After screening various reaction conditions with coordinating
reagents such as HMPA, NMP, DMF, and TMEDA, we found
that HMPA was a useful additive in this Michael addition
(Table 1). This additive was generally superior to others and
was chosen for systematic studies. Initial experiments on the
addition of 3 to a solution of Li-8 and HMPA (5 equiv) at −78
°C in THF for 1 h afforded encouraging but marginal results.
Although the Michael adduct 4 was produced during the
reaction along with other decomposed impuries, the problem of
a low chemical yield (23%) still required resolution (Table 1,
entry 2). This low chemical yield was attributed to an instability
of a reaction intermediate B. Finally, we observed that the
B
DOI: 10.1021/acs.joc.5b01677
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The Journal of Organic Chemistry
Note
reaction time was a crucial factor for optimal results (Table 1,
entry 3). Using the optimized conditions, the reaction was
conducted by dropwise addition of 3 (1 equiv) to Li-8 (1.5
equiv) and HMPA (5 equiv) at −78 °C in THF. After 30 min
at −78 °C, the reaction was quenched by the addition of
precooled aqueous EtOH via a cannula needle. A neutral
aqueous workup procedure gave the Michael adduct 4 as a
major component along with another unidentified minor
EXPERIMENTAL SECTION
■
General Methods. Unless otherwise stated, reactions were run in
flame-dried glassware under an atmosphere of nitrogen or argon.
Solvents were dried by passage through an activated alumina column
under argon. And also, dichloromethane was distilled from P2O5 prior
to use. All liquid reagents purchased from commercial sources were
distilled properly prior to use, unless otherwise indicated. Diisopropyl-
ethylamine was distilled from CaH2 prior to use. Hexamethyl-
phosphoramide (HMPA), N-methyl-2-pyrrolidone (NMP), dimethyl-
formamide (DMF), and tetramethylethylenediamine (TMEDA) were
distilled from CaH2 prior to use. Purification was conducted by flash
column chromatography on silica gel (230−400 mesh), eluting with a
mixture of hexanes and ethyl acetate, unless otherwise stated. The
reported yields refer to chromatographically purified and isolated
products. All reactions were monitored by thin layer chromatography
carried out on a silica gel plate (F254) using UV light as a visualizing
agent and ethanolic anisaldehyde solution and heat as a developing
agent. The reported yields are for chromatographically pure isolated
1
diasteromer in a ratio of 93:7 as judged by the H NMR of
crude products. Finally, column chromatography on silica gel
afforded 4 as a pure form in 63% isolated yield.
From a mechanistic perspective, two major functions for the
stereoselectivity in the course of 1,4-addition are immediately
discernible: π-facial stereoselectivity and protonation of the
enoate B in Scheme 3. Stereochemical model A in Scheme 3
could illustrate a possible stereochemical route for the π-facial
facial selectivity of Li-8 to 3. After the conjugate addition, the
resulting enolate B requires a stereoselective protonation by the
addition of aqueous EtOH to give the more sterically favored 4
to establish the 2,3-cis relatioship.
With the 2,3,4-trisubstituted furan 4 in hand, all that
remained for sylvone 1 was a reduction of the ester
functionality and conversion of the thioacetal to a carbonyl
group (Scheme 4). Thus, reduction of 4 with LiAlH4 in ether
1
products. H NMR spectra were recorded in CDCl3 as a solvent with
TMS or residual chloroform as the internal standard (δ 7.26 ppm). 13C
NMR spectra were measured in CDCl3 as a solvent and are reportedly
related to CHCl3 (δ 77.16 ppm). Optical rotations were measured at
ambient temperature (Na line). Elemental Analysis was performed by
the Analytical Laboratories. All reported values are within 0.5% of the
calculated value. Enantiomeric excesses were determined by HPLC
analysis using a chiral column (Chiracel OD-H) in comparison with
the sample obtained from (S,S)-6.
(−)-(S)-Methyl 2-{(3,4-Dimethoxyphenyl)(hydroxy)methyl}-
buta-2,3-dienoate (2). A flame-dried 20 mL Schlenk flask containing
(+)-(1R,2R)-1,2-diphenyl-1,2-bis-p-toluenesulfonylamide (0.50 g, 0.96
mmol) was charged with dry CH2Cl2 (7 mL) under a nitrogen
atmosphere. The resulting mixture was cooled to 0 °C and treated
with BBr3 (freshly prepared 1 M solution in CH2Cl2, 1.0 mL, 1.0
mmol). The solution was stirred at 0 °C for 30 min, warmed to 25 °C
followed by sitting for an additional 2 h, and then concentrated under
vacuum (1 mmHg) through a side neck of the flask connected with a
three way regulating valve. Dryness of the vacuum line was maintained
with a drying tube containing anhydrous CaSO4 and two traps (NaOH
pellets and cold trap at −78 °C). Freshly distilled CH2Cl2 (5 mL) was
added and evaporated under vauum as mentioned above. Freshly
distilled CH2Cl2 (3 mL) was added, and the homogeneous solution of
(R,R)-6 was cooled to −78 °C and treated dropwise with a mixture of
methyl allenoate (0.1 g, 1.02 mmol) and i-Pr2NEt (0.35 mL, 0.26 g,
2.01 mmol) in CH2Cl2 (1 mL). The reaction mixture was allowed to
proceed at −78 °C. After stirring for 20 min at −78 °C, precooled 2,3-
dimethoxybenzaldehyde (0.167 g, 1.0 mmol) in CH2Cl2 (1 mL) was
added via a cannular needle along the wall of the flask while keeping
the temperature below −78 °C. The reaction was allowed to proceed
for 2 h at −78 °C and then was quenched by addition of an aqueous
buffer solution (pH 7, 7 mL) followed by CH2Cl2 (ca. 10 mL) to
dissolve the white precipitate (bis-sulfonamide). The aqueous layer
was extracted with CH2Cl2 (ca. 10 mL × 2). The combined organic
extracts were washed with brine (1×), dried over anhydrous Na2SO4,
filtered, evaporated, and taken up in ether (ca. 20 mL). The solution
was cooled to 0 °C for 20 min to complete precipitation of
(+)-(1R,2R)-1,2-diphenyl-1,2-bis-p-toluenesulfonylamide by filtration
through a sintered glass funnel; the filtrate was concentrated under
reduced pressure to give the crude product in fairly pure form. Final
purification was effected by flash chromatography on SiO2 (Hexanes/
EtOAc = 85:15) to afford 2 (0.16 g, 0.61 mmol, 64%) as a colorless
Scheme 4. Synthesis of (+)-Sylvone (1)
gave 5 in 88% yield. Finally, treatment of 5 with HgCl2 and
HgO in CH3CN and H2O (4:1) furnished (+)-sylvone (1) in
75% yield.17 All physical data including optical rotation for 1 to
prove the absolute configuration were consistent with literature
values (observed, [α]D +9.76°; Lit.5 +9.6°).5,7
20
In summary, this paper describes a facile enantioselective
synthesis of sylvone (1) from methyl allenoate involving the
use of several key transformations to construct a 2,3,4-
trisubstituted sylvone skeleton with the appropriate three
contiguous stereogenic centers: α-addition of an aldehyde of an
allenoate, oxacyclization of 2 to 3, and diastereoselective
conjugate addition of a 1,3-dithiane derivative to 3. This
synthetic route may prove to be a general and efficient method
for synthesis of related furan lignan natural products and their
analogues.
20
oil: [α]D −7.84 (c 1.1, CHCl3); IR (neat) 3496, 3061, 2952, 2836,
1
1963, 1721, 1594, 1518, 1271, 1026, 859, 735 cm−1; H NMR (300
MHz, CDCl3) δ 3.36 (d, J = 5.4 Hz, 1H), 3.75 (s, 3H), 3.86 (s, 3H),
3.87 (s, 3H), 5.20 (d, J = 1.8 Hz, 2H), 5.52−5.54 (m, 1H), 6.80−6.89
(m, 2H), 6.96−6.97 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 52.4,
55.8, 71.4, 81.2, 103.8, 109.7, 110.7, 118.6, 118.6, 134.0, 148.5, 148.8,
167.1, 213.0; MS (ESI) m/z 265.2 (M+1). Anal. Calcd for C14H16O5:
C, 63.63; H, 6.10. Found: C, 63.37; H, 6.33; 93% ee. The enantiomeric
purity was determined by HPLC analysis (Daicel Chiralcel OD-H,
C
DOI: 10.1021/acs.joc.5b01677
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Hexane/i-PrOH = 9/1, flow rate = 1.2 mL/min, retention time: 7.2
min (major) and 9.0 min (minor)).
1H), 4.96 (d, J = 8.4 Hz, 1H), 6.76−6.77 (m, 3H), 7.25−7.26 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 24.9, 27.4, 27.5, 51.6, 52.4, 55.6,
55.8, 55.9, 56.3, 60.9, 61.5, 68.8, 83.6, 106.3, 109.5, 110.4, 119.0, 130.2,
136.2, 137.1, 148.4, 148.5, 153.2, 172.5; MS (ESI) m/z 551.1 (M+1).
Anal. Calcd for C27H34O8S2: C, 58.89; H, 6.22. Found: C, 59.07; H,
6.28.
(+)-(R)-Methyl 2-(3,4-Dimethoxyphenyl)-2,5-dihydrofuran-3-
carboxylate (3). A 20 mL flask containing AgNO3 (24 mg, 0.14
mmol) was charged with acetone (5 mL). The reaction flask was
wrapped with aluminum foil as protection from light. To this solution
allenylcarbinol 2 (0.185 g, 0.7 mmol) in acetone (1 mL) was added at
20 °C. The reaction mixture was allowed to warm to 40 °C. The
reaction progress was monitored by TLC. After 12 h at 40 °C, the
reaction mixture was cooled to room temperature and the solvent was
evaporated under reduced pressure. Purification of the residue by
column chromatography (Hexanes/EtOAc = 90:10) afforded 3 (0.154
g, 0.58 mmol, 83%) as a clear liquid: [α]D20 +96.26 (c 1.0, CHCl3); IR
(neat) 3058, 2956, 2839, 1721, 1640, 1593, 1515, 1261, 1026, 734
cm−1; 1H NMR (300 MHz, CDCl3) δ 3.65 (s, 3H), 3.85 (s, 3H), 3.87
(s, 3H), 4.83 (ddd, J = 1.8, 3.8, 14.4 Hz, 1H), 4.98 (ddd, J = 1.8, 6.1,
14.4 Hz, 1H), 5.86−5.90 (m, 1H), 6.81−6.88 (m, 3H), 6.99−7.05 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 51.8, 55.9, 55.9, 75.1, 86.8, 110.3,
111.0, 119.6, 133.3, 135.5, 138.6, 149.0, 149.1, 162.9; MS (ESI) m/z
265.1 (M+1). Anal. Calcd for C14H16O5: C, 63.63; H, 6.10. Found: C,
63.77; H, 6.21.
(+)-(2R,3R,4S)-2-(3,4-Dimethoxyphenyl)-4-{2-(3,4,5-
trimethoxyphenyl)-1,3-dithian-2-yl)tetrahydrofuran-3-yl}-
methanol (5). To a stirred suspension of lithium aluminum hydride
(30 mg, 2.09 mmol) in dry ether (4 mL) at 0 °C was added a solution
of 4 (0.15 g, 0.27 mmol) in ether (1 mL) over a period of 5 min. After
stirring for an additional 3 h at 0 °C, the reaction mixture was
sequentially treated with water (0.3 mL) and aqueous NaOH solution
(15%, 0.5 mL). Stirring was continued vigorously for another 30 min,
while the resulting mixture was allowed to warm to room temperature.
The resulting suspension was carefully triturated with ether and then
dried over Na2SO4. The filtrate was concentrated in vacuo to give a
crude product in fairly pure form. The crude mixture was purified by
flash chromatography (silica gel, EtOAc/hexanes = 85:15) to give the
20
product 5 (124 mg, 0.24 mmol, 88%) as a pale yellow oil: [α]D
+19.47 (c 0.7, CHCl3); IR (neat) 3531, 3056, 2936, 2833, 1584, 1516,
1
1318, 1267, 1234, 736 cm−1; H NMR (300 MHz, CDCl3) δ 1.89−
2-(3,4,5-Trimethoxyphenyl)-1,3-dithiane (8). An oven-dried 50
mL round-bottom flask was flushed with nitrogen and charged with
CH2Cl2 (20 mL) and 3,4,5-trimethoxybenzaldehyde (1.0 g, 5.1 mmol).
To this solution propane-1,3-dithiol (0.56 mL, 0.57 g, 5.6 mmol) was
added at 20 °C. The reaction mixture was allowed to cool to 0 °C
using an ice bath, and BF3·OEt2 (0.7 mL, 0.78 g, 5.6 mmol) in CH2Cl2
(2 mL) was added over 15 min via syringe with the temperature
maintained at 0 °C. The reaction mixture was warmed to 20 °C. After
12 h at 20 °C, the organic layer was washed sequentially with 2.0 M
aqueous NaOH (3 × 50 mL) and with brine (1 × 25 mL) and then
dried over anhydrous MgSO4. Volatile organics were evaporated under
reduced pressure to give a white solid. Final purification was effected
by recrystallization from EtOAc to give 8 (0.64 g, 2.23 mmol, 44%) as
colorless needles:14 Mp 87−88 °C; IR (film) 3019, 2967, 1591, 1507,
1.98 (m, 2H), 2.68−2.82 (m, 5H), 2.88−2.91 (m, 1H), 3.11−3.16 (m,
2H), 3.21−3.23 (m, 1H), 3.86−3.89 (m, 16H), 3.92−4.03 (m, 1H),
4.79 (d, J = 6.3 Hz, 1H), 6.84 (s, 3H), 7.33 (s, 2H); 13C NMR (75
MHz, CDCl3) δ 25.1, 27.5, 47.9, 54.9, 56.0, 56.1, 56.5, 56.5, 61.0, 62.9,
63.6, 68.1, 82.7, 106.7, 108.8, 111.3, 117.9, 130.6, 136.3, 137.3, 148.4,
149.2, 153.4; MS (ESI) m/z 523.3 (M+1). Anal. Calcd for
C26H34O7S2: C, 59.75; H, 6.56. Found: C, 59.66; H, 6.71.
(+)-Sylvone (1). To a solution of 5 (0.107 g, 0.20 mmol) in
CH3CN (2 mL) and H2O (0.5 mL) were added HgO (48 mg, 0.22
mmol) and HgCl2 (120 mg, 0.44 mmol) at 20 °C. The suspension was
allowed to proceed for an additional 2 h at 20 °C. The reaction
mixture was filtered through a sintered glass funnel with Celite and
extracted with ethyl acetate. The organic layers were washed with brine
(1×), dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (hexane/
ethyl acetate = 4:1) to afford sylvone 1 (65 mg, 0.15 mol, 75%) as a
pale yellow solid:5,7 Mp 138−139 °C (recrystallized from EtOAc);
[α]D20 +9.76 (c 0.7, CHCl3); IR (film) 3462, 3054, 2986, 2939, 2838,
1
1459, 1418, 1335, 1238, 1125, 1006, 761, 673 cm−1; H NMR (500
MHz, CDCl3) δ 1.93 (dtt, J = 13.3, 13.3, 3.0 Hz, 1H), 2.18 (dtt, J =
13.3, 3,0, 2.5 Hz, 1H), 2.92 (ddd, J = 13.3, 3.0, 2.5 Hz, 2H), 3.06 (ddd,
J = 13.5, 13.5, 2.5, Hz, 2H), 3.83 (s, 3H), 3.87 (s, 6H), 5.10 (s, 1H),
6.70 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 25.1, 32.3, 52.0, 56.1,
60.8, 104.7, 134.7, 137.9, 153.4.
1
1672, 1586, 1416, 1265, 1129 cm−1; H NMR (300 MHz, CDCl3) δ
1.40 (br s, −OH), 2.88−2.90 (m, 1H), 3.42 (d, J = 6.3 Hz, 2H), 3.87−
3.92 (m, 15H), 4.23−4.31 (m, 2H), 4.42 (t, J = 7.5 Hz, 1H), 5.04 (d, J
= 6 Hz, 1H), 6.86 (s, 3H), 7.41 (s, 2H); 13C NMR (75 MHz, CDCl3)
δ 48.9, 49.8, 56.0, 56.0, 56.4, 61.0, 62.1, 69.2, 81.5, 106.3, 108.8, 111.2,
117.8, 130.5, 131.4, 142.9, 148.3, 149.0, 153.2, 198.6; MS (ESI) m/z
433.2 (M+1).
(+)-(2R,3S,4S)-Methyl-2-(3,4-dimethoxyphenyl)-4-{2-(3,4,5-
trimethoxyphenyl)-1,3-dithian-2-yl}tetrahydrofuran-3-carbox-
ylate (4). A flame-dried 20 mL round-bottom flask with a Teflon-
coated magnetic stir bar was capped with a septa, flushed with nitrogen
and charged with THF (5 mL) and 1,3-dithiane 8 (0.21 g, 0.73 mmol,
1.5 equiv) at 20 °C. The reaction mixture was cooled to −78 °C. To
this solution n-BuLi (2.5 M in hexane, 0.3 mL, 0.75 mol, good quality
required) was added dropwise, and the reaction proceeded for 1 h at
−78 °C. After HMPA (0.64 mL, 0.66 g, 3.65 mmol) in THF (0.5 mL)
was added to the reaction vessel, stirring was continued for another 10
min. Compound 3 (0.13 g, 0.49 mmol) in THF (0.5 mL) was added
to the resulting reaction mixture. The reaction was allowed to proceed
for 30 min at −78 °C. Precooled aqueous EtOH (2 mL) was added via
a cannular needle to quench the reaction. Stirring was continued for
another 10 min, while the reaction mixture was allowed to warm to
room temperature. The product was extracted with EtOAc (3 × 20
mL). The combined extracts were washed with water (3×) and brine
(1×) and dried over anhydrous Na2SO4. After solid materials were
filtered through a sintered glass funnel, the filtrate was concentrated
under reduced pressure to give the crude products. The
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01677.
1
Copies of HPLC chromatogram of 2, H and 13C NMR
spectra for all products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cmyu@skku.edu.
1
Notes
diastereoselectivity (dr = 93:7) was determined by H NMR analysis
of the crude products at δ 4.94 ppm (major, d, J = 8.9 Hz) and 4.63
ppm (minor, d, J = 9.0 Hz). Final purification was effected by SiO2
chromatography (Hexanes/EtOAc = 90:10) to afford 4 (0.17 g, 0.31
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
20
■
mmol, 63%) as a yellowish oil: [α]D +15.48 (c 0.7, CHCl3); IR
We are grateful to the National Research Foundation of Korea
(NRF) funded by the Ministry of Education
(2012R1A1A2006930) for generous financial support of this
research.
(neat) 3055, 2938, 2909, 2835, 1731, 1584, 1517, 1408, 1266, 1235,
1129, 1027, 703 cm−1; 1H NMR (300 MHz, CDCl3) δ 2.85−2.00 (m,
2H), 2.66−2.80 (m, 4H), 3.05 (s, 3H), 3.35−3.41 (m, 1H), 3.71−3.74
(m, 1H), 3.80−3.85 (m, 15H), 3.90−3.98 (m, 1H), 4.01−4.06 (m,
D
DOI: 10.1021/acs.joc.5b01677
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The Journal of Organic Chemistry
Note
5550−5555. (c) Alcaide, B.; Almendros, P.; Rodríguez-Acebes, R. J.
Org. Chem. 2006, 71, 2346−2351.
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■
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DOI: 10.1021/acs.joc.5b01677
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