Asymmetric synthesis of α-alkylidene-β-hydroxy-γ- butyrolactones via enantioselective tandem michael-aldol reaction

Article abstract of DOI:10.1021/jo302369q

A simple and efficient method for the asymmetric synthesis of α-alkylidene-β-hydroxy-γ-butyrolactones and related natural products was developed on the basis of the catalytic asymmetric tandem Michael-aldol reaction and simple transformations. The synthetic utility of this method was illustrated by the facile synthesis of trisubstituted γ-butyrolactone natural products.

Full text of DOI:10.1021/jo302369q

Note
pubs.acs.org/joc
Asymmetric Synthesis of α‑Alkylidene-β-hydroxy-γ-butyrolactones
via Enantioselective Tandem Michael−Aldol Reaction
Sung Il Lee,† Jin Hee Jang,† Geum-Sook Hwang,*,‡ and Do Hyun Ryu*,†
†Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea
‡Korea Basic Science Institute, Seoul 136-713, Korea
S
* Supporting Information
ABSTRACT: A simple and efficient method for the
asymmetric synthesis of α-alkylidene-β-hydroxy-γ-butyrolac-
tones and related natural products was developed on the basis
of the catalytic asymmetric tandem Michael−aldol reaction and
simple transformations. The synthetic utility of this method
was illustrated by the facile synthesis of trisubstituted γ-
butyrolactone natural products.
α-Alkylidene-γ-butyrolactones have a rich history across the
fields of natural product chemistry, biology, pharmacology, and
synthetic organic chemistry. (Z)-α-Alkylidene-β-hydroxy-γ-
butyrolactone represents an important core structure in many
biologically active natural products (Figure 1).1 Because of its
Scheme 1. Oxazaborolidinium Ion Catalyzed Asymmetric
Synthesis of (Z)-β-Iodo Morita−Baylis−Hillman (MBH)
Ester
olactones via a highly enantioselective tandem Michael−aldol
reaction and its applications to total synthesis of naturally
occurring γ-butyrolactones (Scheme 2).
Figure 1. (Z)-α-Alkylidene-β-hydroxy-γ-butyrolactones in natural
products.
Methacrolein 4a was selected for the initial optimization.
Surprisingly, tandem Michael−aldol reactions of α,β-unsatu-
rated aldehyde with oxazaborolidinium catalyst 3a and 3e
(Figure 2), which successfully catalyzed aromatic and aliphatic
aldehydes, afforded only a trace amount of β-iodo MBH ester
(Table 1, entry 1 and 2). Replacement of the R group by a
smaller methyl group (3b) under similar conditions produced
the desired product with poor yield and enantioselectivity
(Table 1, entry 3). Oxazaborolidinium catalyst has a more
sterically demanding 9-phenanthrenyl group (3c) and did not
activate the aldehyde (Table 1, entry 4). During our
investigation, oxazaborolidinium catalyst 3d3d,e was the most
suitable for tandem Michael−aldol reaction of methacrolein
(Table 1, entry 5). This catalyst furnished (R)-β-iodo MBH
ester in moderate yield and with excellent enantioselectivity. To
improve the yield further, we changed focus to the workup
procedure. Unlike the reaction with aromatic aldehydes,
interesting biological activities, such as antitumor and antibiotic
properties, synthetic methods for chiral (Z)-α-alkylidene-β-
hydroxy-γ-butyrolactones have received considerable attention
during the past few decades.2 Among them, catalytic
enantioselective methods using Sharpless dihydroxylation2c
and Corey−Bakshi−Shibata reduction2d have been developed.
We recently reported a highly enantioselective and (Z)-
stereocontrolled Michael−aldol tandem reaction of α,β-
acetylenic esters, aldehydes, and trimethylsilyl iodide (TMSI)
using chiral cationic oxazaborolidinium catalysts.3 The reaction
provides optically active (Z)-β-iodo Morita−Baylis−Hillman
(MBH) esters with good to excellent yield and enantiose-
lectivity in a straightforward manner (Scheme 1).4
We anticipated that the optically active (Z)-β-iodo MBH
esters would be suitable precursors for producing various chiral
(Z)-α-alkylidene-β-hydroxy-γ-butyrolactones through simple
transformations. Herein, we introduce a general procedure for
producing optically pure (Z)-α-alkylidene-β-hydroxy-γ-butyr-
Received: October 29, 2012
Published: December 19, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
in all cases regardless of steric congestion at the α-position
(Table 2).
Scheme 2. Retrosynthetic Analysis of Various (Z)-α-
Alkylidene-β-hydroxy-γ-butyrolactones via β-Iodo MBH
Ester
Table 2. Result of Asymmetric (Z)-Selective Michael−Aldol
Tandem Reaction with α-Substituted Acroleins
a
b
entry
R1
Me
time (h) yield (%) ee (%)
Z/E
1
2
3
4
5
a
b
c
24
48
48
48
48
94
84
82
87
72
94
90
95
95
85
>99/1
>99/1
98/2
Et
c
i-Pr
c-Hex
d
e
>99/1
>99/1
n-C5H11
a
b
Isolated yield. The ee was determined by chiral GC or HPLC
c
analysis. Determined by isolation.
For the synthesis of (Z)-α-alkylidene-β-hydroxy-γ-butyrolac-
tones, oxidative cleavage of (Z)-β-iodo MBH ester 5 was
carried out with ozone furnished by hydroxy ketone 6.
Unfortunately, silica gel chromatographic separation of the
resulting mixture induced partial alcohol racemization. To
prevent loss of enantiopurity, crude ketone 6 was used for
stereoselective reduction.
To control the relative stereochemistry of diol 7, several
kinds of reducing agent and solvent were tested. We anticipated
that high anti stereoselectivity would be achieved by strong
metal chelation between ketone and alcohol. Initial attemps
with LiBH4 and DIBAl-H were unfruitful (Table 3, entry 1 and
2). Under ethereal solvents, Zn(BH4)2 yielded vicinal diol with
Figure 2. Structure of oxazaborolidinium ion.
Table 1. Oxazaborolidinium Catalyst Screening for
Asymmetric (Z)-Selective Michael−Aldol Tandem Reaction
With Methacrolein
a
b
c
entry
catalyst
yield (%)
ee (%)
Z/E
1
2
3
4
5
3a
3e
3b
3c
3d
3d
<10
0
93
5
Table 3. Optimization of the Anti-Selective Reduction of
Ketone (6a)
29
0
>99/1
63
81
94
94
94
94
>99/1
>99/1
d
6
e
7
3d
>99/1
a
b
c
Isolated yield. The ee was determined by chiral GC analysis. Only
d
(Z)-isomer was observed. Reaction was quenched with 2 M aq HCl/
EtOAc (1:1) and stirred for 20 min at rt. Reaction was quenched with
e
2 M aq HCl/EtOAc (1:1) and stirred for 35 min at 0 °C.
tandem Michael−aldol reactions with α,β-unsaturated aldehyde
afforded a mixture of alcohol 5a and corresponding
trimethylsilyl (TMS) ether. Acidic workup with 2 M HCl at
room temperature successfully removed the TMS group and
gave the desired product with improved yield (81%) and
without loss of enantiopurity (Table 1, entry 6). Careful
deprotection at 0 °C furnished (R)-(Z)-β-iodo MBH ester with
excellent yield and enantioselectivity (Table 1, entry 7).
After optimizing reaction conditions for the asymmetric (Z)-
selective Michael−aldol tandem reaction, the reaction’s scope
was investigated using α-substituted acrolein. Excellent yields,
enantiomeric excess values, and Z/E selectivities were obtained
a
b
c
entry
conditions
yield (%)
anti-7a/syn-7a
1
2
3
4
5
6
LiBH4, THF, −78 °C
0
55
50
68
46
72
DIBAl-H, THF, −78 °C
Zn(BH4)2, Et2O, −78 °C
Zn(BH4)2, Et2O, −30 °C
Zn(BH4)2, THF, −78 °C
Zn(BH4)2, THF, −30 °C
6/1
9/1
12/1
2/1
20/1
a
The reaction was performed using 1.0 equiv of reducing agent.
b
c
Isolated yield. The anti/syn ratio was determined by 1H NMR
analysis.
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Note
high anti selectivity (Table 3, entry 4 and 6).5 Surprisingly,
higher anti selectivity was obtained at a higher temperature
(−30 °C) rather than at −78 °C (Table 3, entry 3 and 5).
Diol anti-7a was then converted to (Z)-α-iodomethylene-β-
hydroxy-γ-lactone 8a by a trifluoroacetic acid catalyzed
intramolecular cyclization with 96% yield. (Z)-β-iodo MBH
esters 5b and 5c subjected to a similar oxidation−reduction−
cyclization process gave (Z)-α-alkylidene-β-hydroxy-γ-butyro-
lactones with excellent overall yields and selectivity. Optically
pure and fully functionalized γ-butyrolactones were obtained
after one recrystallization (Scheme 3).
manner, the cross-coupling of ent-8a from (S)-β-iodo MBH
ester10 with suitable Grignard reagent produced (Z)-α-
alkylidene butyrolactones 10, 11, and (+)-dihydromahubeno-
lide (2)7 in excellent yields of 97%, 85%, and 83%, respectively
(Scheme 4).
Enantiomerically pure α-alkylidene-β-hydroxy-γ-butyrolac-
tones are particularly useful as synthetic building blocks for
trisubstituted γ-butyrolactones. Catalytic hydrogenation of 10
and 11 was achieved to give (+)-blastmycinolactol (12) and
(+)-NFX-2 (13) in 96% yields with complete diastereoselec-
tivity. Under the reported reaction conditions, alcohol acylation
using isovaleryl chloride and DMAP furnished the desired
natural product (+)-blastmycinone (14)2b,11,12 and (+)-anti-
mycinone (15)2b,11,13 in 91% and 87% yields, respectively
(Scheme 5). The spectral data are identical to those reported in
the literature.
Scheme 3. Synthesis of (Z)-α-Iodomethylene-β-hydroxy-γ-
lactone
Scheme 5. Synthesis of (+)-Blastmycinone and
(+)-Antimycinone
We demonstrated that the iodine atom of β-iodo MBH ester
easily converted to alkyl, aryl, and alkynyl groups through
transition-metal-catalyzed cross-coupling reactions.4,6 Thus,
enantiopure α-iodomethylene-β-hydroxy-γ-lactone was chosen
as a key precursor for (Z)-α-alkylidene-β-hydroxy-γ-butyrolac-
tones.
The cross-coupling of 8a with undec-10-enylmagnesium
bromide in the catalytic presence of LiCuBr2 produced
(−)-litsenolide A1 (1)2b,7,8 in 56% yield while coupling with
n-tridecanylmagnesium bromide afforded (−)-litsenolide C1
(9)2b,7−9 in 78% yield without changing olefinic geometry
(Scheme 4). The spectroscopic data and specific rotation of the
synthetic samples of 1 and 9 (1H, 13C NMR) were in full
agreement with those reported in the literature. In the same
In conclusion, we suggest a simple and efficient general
procedure for synthesizing optically pure (Z)-α-alkylidene-β-
hydroxy-γ-butyrolactones and related natural products. By
using (Z)-α-alkylidene-β-hydroxy-γ-butyrolactone as the key
intermediate, we synthesized trisubstituted γ-butyrolactone
natural products in short steps and with high overall yield.
EXPERIMENTAL SECTION
■
1H and 13C NMR were measured at 300 and 75 MHz in CDCl3,
respectively. HRMS were obtained on a double-focusing magnetic
sector mass spectrometer
General Procedure for (R)-β-Iodo MBH Ester 5. A freshly
prepared solution of trifluoromethanesulfonimide in CH2Cl2 (0.20 M
solution, 1.25 mL, 0.25 mmol) was added dropwise to an (S)-
oxazaborolidine (0.3 mmol) in 6 mL of CH2Cl2 at −40 °C under
nitrogen. After the mixture was stirred for 15−20 min, a pale yellow
homogeneous solution of (S)-oxazaborolidinium was obtained. α-
Substituted acrolein (4, 1.25 mmol) was then added in one portion to
the cooled (−78 °C) solution of catalyst. After 20 min of stirring at
−78 °C, ethyl propiolate (6.25 mmol, 0.63 mL) and TMSI (1.5 mmol,
215 μL) were added to the mixture sequentially. After reaction
completion, the reaction mixture was quenched with aq HCl (2 M, 6
mL) and ethyl acetate (6 mL) and vigorously stirred for 35 min at 0
°C. After complete removal of TMS group, the aqueous layer was
extracted with CH2Cl2. The combined organic extracts were washed
with brine, dried (Na2SO4), and filtered, and the solvent was removed
under reduced pressure to produce the crude product. Purification by
flash chromatography on silica gel (hexane/ethyl acetate = 10:1)
afforded the corresponding (R)-(Z)-β-iodo MBH ester 5 as a colorless
oil.
Scheme 4. Synthesis of (Z)-α-Alkylidene-β-hydroxy-γ-
butyrolactone Natural Product (−)-Litsenolide A1, C1, and
(+)-Dihydromahubenolide A
(R,Z)-Ethyl 3-Hydroxy-2-(iodomethylene)-4-methylpent-4-
enoate (5a). Prepared according to the general procedure. Colorless
1
oil, 94% yield (1.18 mmol, 348 mg). H NMR (300 MHz, CDCl3): δ
1.34 (t, J = 7.2 Hz, 3H), 1.70 (d, J = 0.3 Hz, 3H), 2.67 (d, J = 6.0 Hz,
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Note
1H), 4.29 (q, J = 7.2 Hz, 2H), 4.88 (d, J = 6.0 Hz, 1H), 4.98−4.99(m,
1H), 5.08 (d, J = 0.6 Hz, 1H), 7.18 (s, 1H). 13C NMR (75 MHz,
CDCl3): δ: 14.1, 18.3, 61.6, 77.7, 85.5, 113.5, 143.6, 144.4, 166.2. IR
νmax: 3454, 2981, 1714, 1304, 1188, 1044, 906, 738 cm−1. LRMS
(APCI): m/z = 297 (M + 1, 4), 279 (100), 246 (30), 152 (35), 124
(33). HRMS (EI): m/z calcd for C9H13IO3 295.9909, found 295.9906.
GC: Cyclosil-B, 130 °C, flow: 3 mL/min, tR = 44.7 min (minor) and tR
extracted with CH2Cl2 (3 × 10 mL). The combined organic phase was
dried over Na2SO4, filtered, and concentrated. Without column
chromatography, the reduction was performed with crude product.
The crude product in 15 mL of THF was cooled to −30 °C and
zinc borohydride (1.0 M in THF, 1.84 mL, 1.84 mmol, 1.0 equiv)
added. The reaction was monitored by TLC. The reaction mixture was
quenched with ammonium chloride (5 mL) and extracted with ethyl
acetate (3 × 10 mL). Purification by flash column chromatography
(hexane/ethyl acetate = 2:1) afforded the desired product 7 as a
colorless oil.
= 46.4 min (major). [α]20 = −10.76 (c 1.0, CHCl3).
D
(R,Z)-Ethyl 3-Hydroxy-2-(iodomethylene)-4-methylenehexa-
noate (5b). Prepared according to the general procedure. Colorless
1
oil, 84% yield (1.05 mmol, 326 mg). H NMR (300 MHz, CDCl3): δ
(3S,4R,Z)-Ethyl 3,4-Dihydroxy-2-(iodomethylene)-
1.05 (t, J = 7.5 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H), 1.92−2.14 (m, 2H),
2.78 (br s, 1H), 4.28 (q, J = 7.2 Hz, 2H), 4.91 (d, J = 6.3 Hz, 1H),
4.99(m, 1H), 5.11−5.12 (m, 1H), 7.19 (m, 1H). 13C NMR (75 MHz,
CDCl3): δ 12.1, 14.2, 24.7, 61.6, 77.3, 85.6, 111.1, 144.6, 149.6, 166.3.
IR νmax: 3494, 2971, 1715, 1371, 1188, 1036, 909, 736 cm−1. LRMS
(APCI): m/z = 310 (M + 1, 3), 295 (51), 249 (64), 166 (53), 123
pentanoate (anti-7a). Prepared according to the general procedure.
1
Colorless oil, 72% yield (1.32 mmol, 378 mg). H NMR (300 MHz,
CDCl3): δ 1.17 (d, J = 6.6 Hz, 3H), 1.38 (t, J = 7.2 Hz, 3H), 2.14 (d, J
= 5.7 Hz, 1H), 2.89 (d, J = 5.7 Hz, 1H), 3.93−3.98 (m, 1H), 4.33 (q, J
= 7.2 Hz, 2H), 4.33−4.38 (m, 1H), 7.17 (d, J = 0.9 Hz, 1H). 13C NMR
(75 MHz, CDCl3): δ 14.2, 18.0, 62.0, 69.3, 78.6, 86.2, 143.5, 167.0. IR:
νmax 3435, 2980, 2927, 1710, 1314, 1191, 1072, 1015 cm−1. LRMS
+
(51), 93 (100), 91 (87). HRMS (FAB): m/z calcd for C10H16IO3
311.0144, found 311.0143. GC: Cyclosil-B, 150 °C, flow: 3 mL/min,
(APCI): m/z = 301 (M + 1, 1), 289 (8), 197 (7), 127 (100). HRMS
tR = 30.8 min (minor) and tR = 31.6 min (major). [α]20 = 2.40 (c
+
(FAB): m/z calcd for C8H14IO4 300.9937, found 300.9939. [α]20
=
D
D
0.64, CHCl3).
10.26 (c 1.0, CHCl3).
(R,Z)-Ethyl 3-Hydroxy-2-(iodomethylene)-5-methyl-4-meth-
ylenehexanoate (5c). Prepared according to the general procedure.
Colorless oil, 82% yield (1.02 mmol, 332 mg). H NMR (300 MHz,
(3S,4R,Z)-Ethyl 3,4-Dihydroxy-2-(iodomethylene)hexanoate
(anti-7b). Prepared according to the general procedure. Colorless oil,
78% yield (1.44 mmol, 451 mg). 1H NMR (300 MHz, CDCl3): δ 0.98
(t, J = 7.5 Hz, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.46−1.61 (m, 1H), 2.68
(br s, 1H), 3.47 (br d, J = 5.4 Hz, 1H), 3.60−3.66 (m, 1H), 4.32 (q, J =
7.2 Hz, 2H), 4.39 (br t, J = 4.2 Hz, 1H), 7.14 (d, J = 0.9 Hz, 1H). 13C
NMR (75 MHz, CDCl3): δ 10.4, 14.2, 25.0, 62.0, 74.8, 77.8, 85.9,
144.0, 167.25. IR: νmax 3444, 2968, 2935, 2878, 1708, 1306, 1019, 978,
735 cm−1. LRMS (APCI): m/z = 315 (M + 1, 4), 282 (100), 251 (57),
1
CDCl3): δ 1.06 (d, J = 6.9 Hz, 3H), 1.07 (t, J = 6.9 Hz, 3H), 1.33 (t, J
= 7.2 Hz, 3H), 2.28 (spd, JAB = 6.9 Hz, JAC = 0.9 Hz, 1H), 2.55 (d, J =
6.9, 1H), 4.28 (q, J = 7.2 Hz, 2H), 4.94 (dt, JAB = 6.9 Hz, JAC = 0.9 Hz,
1H), 5.04 (m, 1H), 5.11 (m, 1H), 7.22 (d, J = 1.2 Hz, 1H). 13C NMR
(75 MHz, CDCl3): δ 14.2, 22.4, 22.8, 30.6, 61.6, 76.3, 85.9, 110.2,
114.8, 154.9, 166.3. IR: νmax 3503, 2964, 2097, 1716, 1312, 1188, 1033,
951 cm−1. LRMS (APCI): m/z = 325 (M + 1, 2), 295 (17), 249 (20),
180 (26), 124 (45), 107 (54), 105 (100). HRMS (EI): m/z calcd for
+
223 (49), 205 (19), 149 (28). HRMS (FAB): m/z calcd for C9H16IO4
315.0093, found 315.0092. [α]20 = 22.9 (c 1.79, CHCl3).
D
+
C11H18IO3 325.0301, found 325.0302. GC: Cyclosil-B, 130 °C, flow:
(3S,4R,Z)-Ethyl 3,4-Dihydroxy-2-(iodomethylene)-5-methyl-
hexanoate (anti-7c). Prepared according to the general procedure.
Colorless oil, 78% yield (1.44 mmol, 471 mg). H NMR (300 MHz,
3 mL/min, tR = 49.5 min (minor) and tR = 51.5 min (major). [α]20
21.23 (c +2.61, CHCl3).
=
D
1
(R,Z)-Ethyl 4-Cyclohexyl-3-hydroxy-2-(iodomethylene)pent-
CDCl3): δ 0.94 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.6 Hz, 3H), 1.39 (t, J
= 7.2 Hz, 3H), 1.79−1.92 (m, 1H), 2.30 (d, J = 5.7 Hz, 1H), 3.15 (d, J
= 6.9 Hz, 1H), 3.44 (q, J = 5.7 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 4.39
(t, J = 6.3 Hz, 1H), 7.12 (d, J = 0.6 Hz, 1H). 13C NMR (75 MHz,
CDCl3): δ 14.2, 16.8, 19.7, 29.7, 62.0, 76.8, 78.2, 85.9, 144.8, 167.7. IR:
νmax 3452, 2964, 2875, 1708, 1307, 1192, 1008, 734 cm−1. LRMS
(APCI): m/z = 329 (M + 1, 6), 318 (26), 290 (38), 282 (90), 265
(100), 209 (65), 149 (58), 109 (73). HRMS (FAB): m/z calcd for
C10H18IO4+ 329.0250, found 329.0249. [α]20D = 11.0 (c 2.00, CHCl3).
General Procedure for the Synthesis of (Z)-α-Iodomethy-
lene-β-hydroxy-γ-butyrolactones 8. To anti-diol 7 (1.24 mmol) in
CH2Cl2 (20 mL) was added a CF3COOH (0.62 mmol). The reaction
was stirred under the indicated conditions and monitored by TLC.
After completion of the reaction, trifluoroacetic acid was quenched
with saturated aqueous NaHCO3 (5 mL), and the product was
extracted with CH2Cl2 (3 × 5 mL) and dried with Na2SO4. The
volatiles were evaporated, and the residue was purified on silica gel
(hexane/ethyl acetate = 3:1) to give 8 as a white solid which was
recrystallized from dichloromethane/hexanes to afford enantiopure 8.
(4S,5R,Z)-4-Hydroxy-3-(iodomethylene)-5-methyldihydro-
furan-2(3H)-one (8a). The reaction was refluxed for 3 h. Flash
chromatography purification afforded the desired product as a white
4-enoate (5d). Prepared according to the general procedure.
1
Colorless oil, 87% yield (1.09 mmol, 396 mg). H NMR (300 MHz,
CDCl3): δ 1.11−1.29 (m, 5H), 1.32 (t, J = 7.2 Hz, 3H), 1.67−1.77 (m,
5H), 1.88 (tt, JAB = 11.1 Hz, JAC = 3.0 Hz, 1H), 2.70 (d, J = 6.6, 1H),
4.27 (q, J = 7.2 Hz, 2H), 4.93 (d, J = 6.6 Hz, 1H), 5.00 (s, 1H), 5.09
(s, 1H), 7.22 (d, J = 1.2 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 14.2,
26.3, 26.78, 26.83, 33.0, 33.5, 41.0, 61.5, 76.2, 85.6, 110.9, 144. 8,
154.1, 166.3. IR: νmax 3486, 2925, 2852, 1714, 1447, 1310, 1281, 1131,
1033, 891 cm−1. LRMS (APCI): m/z = 365 (M + 1, 3), 347 (44), 282
(77), 219 (27), 173 (36), 145 (100), 117 (45). [α]20 = 6.2 (c 2.05,
D
+
CHCl3). HRMS (FAB): m/z calcd for C14H22IO3 365.0614, found
365.0612. HPLC: Chiralcel OD-H, n-hexane/(n-hexane/2-propanol =
1:9) = 80:20, 1.0 mL/min, 256 nm UV detector, tR = 10.3 min (major)
and tR = 11.1 min (minor).
(R,Z)-Ethyl 3-Hydroxy-2-(iodomethylene)-4-methylenenona-
noate (5e). Prepared according to the general procedure. Colorless
1
oil, 72% yield (0.90 mmol, 319 mg). H NMR (300 MHz, CDCl3): δ
0.89 (t, J = 6.6 Hz, 3H), 1.24−1.35 (m, 4H), 1.33 (t, J = 7.2 Hz, 3H),
1.40−1.49 (m, 2H), 1.89−2.09 (m, 2H), 2.96 (d, J = 6.3, 1H), 4.27 (q,
J = 7.2 Hz, 2H), 4.89 (d, J = 6.0 Hz, 1H), 4.98 (s, 1H), 5.10 (s, 1H),
7.18 (d, J = 0.9 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 14.11, 14.14,
22.6, 27.5, 31.6, 31.9, 61.5, 77.0, 85.5, 112.0, 144.7, 148.2, 166.3. IR:
νmax 3471, 2929, 1714, 1307, 1186, 1039, 908, 732 cm−1. LRMS
(APCI): m/z = 353 (M + 1, 2), 335 (78), 208 (44), 179 (33), 133
1
solid, 96% yield (1.19 mmol, 302 mg). H NMR (300 MHz, CDCl3):
δ 1.45 (d, J = 6.9 Hz, 3H), 2.21 (d, J = 6.9 Hz, 1H), 4.30 (dq, JAB = 6.3
Hz, JAC = 4.8 Hz, 1H), 4.54 (ddd, JAB = 6.9 Hz, JAC = 4.8 Hz, JAD = 1.8
Hz, 1H), 7.75 (d, J = 1.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ
18.8, 78.1, 81.8, 92.8, 141.0, 168.8. IR: νmax 3707, 3511, 2969, 2864,
1736, 1171, 1053 cm−1. LRMS (APCI): m/z 255 (M + 1, 100), 256
(7), 237 (75), 209 (21). HRMS (EI): m/z calcd for C6H7IO3
(100), 105 (93). [α]20 = 1.3 (c 1.29, CHCl3). HRMS (FAB): m/z
D
calcd for C13H22IO3+ 353.0614, found 353.0614. HPLC: Chiralcel OD-
H, n-hexane/(n-hexane/2-propanol = 1:9) = 95:5, 1.0 mL/min, 256
nm UV detector, tR = 28.0 min (minor) and tR = 30.2 min (major).
General Procedure for the Synthesis of anti-Diol 7. To a
solution of 5 (1.84 mmol) in 30 mL of HPLC-grade CH2Cl2 was
cooled to −78 °C and ozonolyzed until color of reaction mixture
converted to blue (<2 min). The resulting solution was treated with
dimethyl sulfide (5 mL), stirred for 50 min at −78 °C and 10 min at rt
with N2 bubbling, and then quenched with H2O (10 mL) and
253.9440, found 253.9437. Mp: 102−104 °C. [α]20 = 10.75 (c 1.0,
D
MeOH). HPLC: Chiralcel AS-H column, n-hexane/2-propanol =
85:15, 1.0 mL/min, 256 nm UV detector, tR = 12.07 min (major) and
tR = 14.23 min (minor).
(4S,5R,Z)-5-Ethyl-4-hydroxy-3-(iodomethylene)dihydro-
furan-2(3H)-one (8b). The reaction was stirred at room temperature
773
dx.doi.org/10.1021/jo302369q | J. Org. Chem. 2013, 78, 770−775

The Journal of Organic Chemistry
Note
for 2.5 h. Flash chromatography purification afforded the desired
product as white solid, 95% yield (1.18 mmol, 316 mg). 1H NMR (300
MHz, CDCl3): δ 1.06 (t, J = 7.2 Hz, 3H), 1.65−1.87 (m, 2H), 2.28 (br
s, 1H), 4.10−4.16 (m, 1H), 4.52 (dd, JAB = 4.5 Hz, JAC = 1.8 Hz, 1H),
7.76 (d, J = 1.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 9.4, 26.5,
75.8, 85.3, 94.2, 139.1, 167.5. IR: νmax 3427, 3050, 2970, 2937, 1742,
1623, 1165, 1081, 968, 657 cm−1. LRMS (APCI): m/z 269 (M + 1,
27), 251 (93), 223 (84), 163 (51), 149 (91), 135 (100), 121 (83).
3H), 1.42−1.51 (m, 1H), 1.51−1.62 (m, 1H), 2.26 (br, 1H), 2.75 (m,
2H), 3.64(m, 1H), 4.3−4.4 (br, 1H), 6.54 (td, JAB = 7.5 Hz, JAC = 1.2
Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 14.4, 19.5, 23.0, 28.2, 29.2,
29.6, 29.7, 29.8, 29.9, 29.98 (×2), 30.01 (×2), 32.2, 75.9, 81.7, 129.1,
149.7, 168.7. IR: νmax 3708, 3455, 2918, 2851, 1730, 1256, 1055 cm−1.
LRMS (APCI): m/z 311 (M + 1, 100), 312 (14), 294(4), 293 (22),
247 (5). HRMS (EI): m/z calcd for C19H34O3 310.2508, found
310.2507. [α]20D = −9.70 (c 0.5, dioxane; lit.7 [α]24D = −9.4, dioxane).
Mp: 160−162 °C.
+
HRMS (FAB): m/z calcd for C7H10IO3 268.9675, found 268.9675.
Mp: 40 °C. [α]20 = 5.58 (c 1.35, CHCl3). HPLC: Chiralcel AS-H
(4R,5S,Z)-3-Butylidene-4-hydroxy-5-methyldihydrofuran-
2(3H)-one (10). Prepared according to the general procedure to
afford of the desired product 10 in 97% yield (30 mg, 0.179 mmol) as
colorless oil. 1H NMR (300 MHz, CDCl3): δ 0.91 (t, J = 7.5 Hz, 3H),
1.39 (d, J = 6.3 Hz, 3H), 1.50 (qt, JAB = 7.5 Hz, JAC = 7.5 Hz, 2H),
2.6−2.84 (m, 2H), 3.07 (d, J = 4.5 Hz, 1H) 4.37 (br, 2H), 6.56 (td, JAB
= 7.8 Hz, JAC = 1.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 13.8,
19.2, 22.2, 75.5, 81.6, 129.0, 149.4, 168.9. IR: νmax 3432, 2929, 1741,
1673, 1373, 1195, 1124, 1046, 931 cm−1. LRMS (APCI): m/z 170 (M
+ 1, 17), 153 (74), 149 (39), 135 (30), 125 (41). HRMS (FAB): m/z
calcd for C9H15O3 171.1021, found 171.1024. HPLC: Chiralcel OD-H
column, n-hexane/2-propanol = 9:1, 1.0 mL/min, 256 nm UV
D
column, n-hexane/2-propanol = 85:15, 1.0 mL/min, 256 nm UV
detector, tR = 11.57 min (major) and tR = 14.97 min (minor).
(4S,5R,Z)-4-Hydroxy-3-(iodomethylene)-5-isopropyldihydro-
furan-2(3H)-one (8c). The reaction was stirred at room temperature
for 45 min. Flash chromatography purification afforded the desired
product as white solid, 98% yield (1.21 mmol, 343 mg). 1H NMR (300
MHz, CDCl3): δ 1.01 (d, J = 2.1 Hz, 3H), 1.04 (d, J = 2.1 Hz, 3H),
1.85−2.01 (m, 1H), 2.29 (br s, 1H), 3.95 (dd, JAB = 6.6 Hz, JAC = 4.8
Hz, 1H), 4.59 (br s, 1H), 7.77 (d, J = 1.8 Hz, 1H). 13C NMR (75
MHz, CDCl3): δ 17.7, 17.9, 31.3, 74.0, 88.7, 94.3, 139.3, 167.5. IR:
νmax 3445, 2966, 2876, 1741, 1622, 1165, 1004, 825, 672 cm−1. LRMS
(APCI): m/z 283 (M + 1, 22), 282 (89), 209 (70), 149 (100), 121
detector, TR = 8.13 min (major) and tR = 7.43 min (minor). [α]20
18.19 (c 1.18, CHCl3).
=
D
+
(57). HRMS (FAB): m/z calcd for C8H12IO3 282.9831, found
282.9834. mp: 50 °C. [α]20D = 7.12 (c 1.38, CHCl3). HPLC: Chiralcel
AS-H column, n-hexane/2-propanol = 85:15, 1.0 mL/min, 256 nm UV
detector, tR = 10.30 min (major) and tR = 12.40 min (minor).
(S,Z)-Ethyl 3-Hydroxy-2-(iodomethylene)-4-methylpent-4-
enoate (ent-5a). Prepared according to the general procedure for
5a. Colorless oil, 94% yield (1.18 mmol, 348 mg). GC: Cyclosil-B, 130
°C, flow: 3 mL/min, tR = 38.1 min (major) and tR = 40.1 min (minor).
[α]20 = 10.93 (c 1.16 CHCl3)
(4R,5S,Z)-3-Hexylidene-4-hydroxy-5-methyldihydrofuran-
2(3H)-one (11). Prepared according to the general procedure to
afford of the desired product 11 in 85% yield (72 mg, 0.36 mmol) as a
colorless oil. 1H NMR (300 MHz, CDCl3): δ 0.89 (t, J = 6.9 Hz, 3H),
1.35 (br m, 6H), 1.38 (d, J = 6.3 Hz, 3H), 1.42−1.56 (m, 2H), 2.11 (s,
1H), 2.72 (m, 2H), 4.35 (br m, 2H), 6.56 (td, JAB = 7.8 Hz, JAC = 1.5
Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 14.0, 19.2, 22.5, 27.8, 28.6,
31.4, 75.6, 81.4, 128.8, 149.5, 168.3. IR: νmax 3847, 3449, 2958, 2925,
2858, 1737, 1673, 1184, 1051 cm−1. LRMS (APCI): m/z 197 (M − 1,
100), 198 (17), 181 (17), 153 (9), 138 (11). HRMS (EI): m/z calcd
for C11H18O3 198.1256, found 198.1258. HPLC: Chiralcel OD-H
column, n-hexane/2-propanol = 9:1, 1.0 mL/min, 256 nm UV
(3DR,4S,Z)-Ethyl 3,4-Dihydroxy-2-(iodomethylene)-
pentanoate (ent-7a). Prepared according to the general procedure
for 7. Colorless oil, 72% yield (two steps). [α]20 = −10.5 (c 1.0
D
CHCl3)
detector, tR = 13.60 min (major) and tR = 10.77 min (minor). [α]20
−20.14 (c 0.7, CHCl3).
=
(4R,5S,Z)-4-Hydroxy-3-(iodomethylene)-5-methyldihydro-
D
furan-2(3H)-one (ent-8a). Prepared according to the general
procedure for 8. White solid, 96% yield. [α]20 = −10.79 (c 1.11
(+)-Dihydromahubenolide (2). Prepared according to the
general procedure to afford the desired product (+)-dihydromahube-
nolide (2) in 83% yield (88 mg, 0.26 mmol) as a white solid. 1H NMR
(300 MHz, CDCl3): δ 0.88 (t, J = 6.8 Hz, 3H), 1.25 (br m, 18H), 1.39
(d, J = 6.3 Hz, 3H), 1.40−1.52 (m, 2H), 2.04 (m, 1H), 2.16 (br s, 1H),
2.75(q, 7.5 Hz, 2H), 4.36 (m, 2H), 4.96 (m, 2H), 5.82 (ddt, JAB = 17
Hz, JAC = 10.2 Hz, JAD= 6.6 Hz, 1H). 6.55 (dt, JAB = 7.8 Hz, JAC = 1.2
Hz, 1H) 13C NMR (75 MHz, CDCl3): δ 19.3, 28.0, 29.0, 29.1, 29.3,
29.4, 29.55, 29.65, 29.68 (×2), 29.76 (×2), 29.79, 34.0, 75.7, 81.5,
114.2, 128.9, 139.4, 149.6, 168.4. IR: νmax 3454, 2917, 2849, 1730,
1208, 1055 cm−1. LRMS (APCI): m/z 337 (M + 1, 100), 338 (30),
320 (23), 319 (68). HRMS (FAB): m/z calcd for C21H37O3 337.2743,
found 337.2742. [α]20 = 8.51 (c 0.66, dioxane; lit.7 [α]24 = 8.5,
D
CHCl3).
General Procedure for the Synthesis of (Z)-α-Alkylidene-β-
hydroxy-γ-butyrolactones. A THF solution (3 mL) of vinyl iodide
(0.31 mmol) was cooled to −40 °C, LiCuBr2 (0.5 M in THF, 0.13 mL,
0.065 mmol) added, and then alkylmagnesium bromide (1.0 M in
THF, 0.94 mL, 0.94 mmol) slowly added dropwise. The resulting
solution was quenched by addition of NH4Cl (2 mL) and H2O (1 mL)
and stirred while the aqueous layer turned blue. The organic layer was
extracted with ethyl acetate (2 mL) and CH2Cl2 (2 × 2 mL), and the
combined organic layers were dried over Na2SO4, filtered, and
concentrated. The crude product was purified by silica gel (hexane/
ethyl acetate = 5:1) to afford the desired product.
D
D
(−)-Litsenolide A1 (1). Prepared according to the general
procedure to afford the desired product (−)-litsenolide A1 (1) in
56% yield (24 mg, 0.086 mmol) as a colorless oil. 1H NMR (300 MHz,
CDCl3): δ 1.28−1.54 (br, 14H), 1.38 (d, J = 6.3 Hz, 3H), 2.04 (br q, J
= 6.6 Hz, 2H), 2.38 (br, 1H), 2.75 (m, 2H), 4.3−4.4 (m, 2H), 4.93
dioxane).
(+)-Blastmycinolactol (12). To a dichloromethane solution (2
mL) of 10 (20 mg, 0.115 mmol) was added 10% Pd/C (12 mg, 0.012
mmol) and the flask sealed with a hydrogen balloon. The solution was
stirred for 3 h at room temperature. The resulting solution was filtered
with a Celite bed and concentrated. The crude product was purified by
silica gel (hexane/ethyl acetate = 2:1) to afford the (+)-blastmycino-
lactol (12) in 96% yield (19 mg, 0.11 mmol) as white solid. 1H NMR
(300 MHz, CDCl3): δ 0.92 (t, J = 7.2 Hz, 3H), 1.3−1.56 (m, 4H),
1.45 (d, J = 6.3 Hz, 3H), 1.56−1.68 (m, 1H), 1.78−1.92 (m, 1H), 2.57
(ddd, JAB = 8.7 Hz, JAC = 7.4 Hz, JAD = 6.0 Hz, 1H), 2.78 (d, J = 5.1
Hz, 1H), 3.78−3.91 (br m, 1H), 4.22 (dq, JAB = 7.1 Hz, JAC = 6.3 Hz,
1H). 13C NMR (75 MHz, CDCl3): δ 14.1, 18.5, 22.9, 28.4, 29.1, 48.8,
79.1, 80.4, 176.8. IR: νmax 3472, 2946, 2863, 1733, 1186, 1057 cm−1.
LRMS (APCI): m/z 173 (M + 1, 29), 155 (57), 149 (28), 109 (100),
69 (26). HRMS: (FAB) m/z calcd for C9H16O3 172.1099, found
(dq, JAB = 10.2 Hz, JAC = 1.2 Hz, 1H), 4.99 (m, 1H), 5.81 (ddt, JAB
17 Hz, JAC = 10.2 Hz, JAD = 6.6 Hz, 1H), 6.54 (td, JAB = 7.8 Hz, JAC
=
=
1.2 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 19.3, 27.9, 28.96, 29.05,
29.2, 29.4, 29.5, 29.6, 33.9, 75.7, 81.5, 114.2, 128.9, 139.4, 149.6, 168.5.
IR: νmax 3434, 3075, 2980, 2924, 2855, 2361, 1742, 1178, 1112, 1051,
913 cm−1. LRMS (APCI): m/z 281 (M + 1, 100), 282 (24), 263 (55),
217 (18), 147 (11). HRMS (EI): m/z calcd for C17H28O3 280.2038,
found 280.2038. [α]20 = −15.79 (c 0.7, dioxane; lit.7 [α]24 = −2.4,
D
D
dioxane). HPLC: Chiralcel OD-H column, n-hexane/2-propanol
=95:5, 1.0 mL/min, 256 nm UV detector, tR = 9.97 min (major)
and tR = 14.57 min (minor).
(-)-Litsenolide C1 (9). Prepared according to the general procedure
to afford of the desired product (−)-litsenolide C1 (9) in 78% yield
(28 mg, 0.092 mmol) as a white solid. 1H NMR (300 MHz, CDCl3): δ
0.88 (t, J = 6.3 Hz, 3H), 1.18−1.36 (br, 20H), 1.38 (d, J = 6.3 Hz,
172.1095. Mp: 49−51 °C. [α]20 = −25.43 (c 1.08, CHCl3; lit.11a
D
[α]25 = −19.4, c = 1.01, CDCl3).
D
(+)-Blastmycinone (14). To a CH2Cl2 solution (2 mL) of
(+)-blastmycinolactol (12) (21 mg, 0.122 mmol) were added DMAP
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The Journal of Organic Chemistry
Note
(59 mg, 0.488 mmol) and isovaleryl chloride (0.096 mL, 0.732 mmol).
The mixture was stirred for 24 h at room temperature. The resulting
solution was quenched by addition of NaHCO3 (2 mL). The organic
layer was extracted with CH2Cl2 (3 × 2 mL), and the combined
organic layer were dried over Na2SO4, filtered, and concentrated. The
crude product was purified by silica gel (hexane/ethyl acetate = 10:1)
to afford the desired product (+)-blastmycinone (14) in 91% yield (28
ACKNOWLEDGMENTS
■
This work has supported by grants NRF-2012R1A6A1040282
(Priority Research Centers Program), NRF-20110029186
(Midcareer Researcher Program), and the Korea Basic Science
Institute (T33409).
1
REFERENCES
mg, 0.111 mmol) as a colorless oil. H NMR (300 MHz, CDCl3): δ
■
0.91 (t, J = 7.2 Hz, 3H), 0.97 (d, J = 6.6 Hz, 6H), 1.25−1.45(m, 4H),
1.47(d, J = 6.6 Hz, 3H), 1.65 (m, 1H), 1.86 (m, 1H), 2.12 (m, 1H),
2.23 (d, J = 6.9 Hz, 2H), 2.69 (dt, JAB = 8.1 Hz, JAC = 6.0 Hz, 1H), 4.37
(qd, JAB = 6.6 Hz, JAC = 4.5 Hz, 1H), 4.95 (dd, JAB = 5.7 Hz, JAC = 4.8
Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 13.8, 19.4, 22.29, 22.33,
22.36, 25.7, 28.9, 29.0, 43.1, 46.4, 78.4, 79.4, 172.5, 176.0. IR: νmax
2959, 2866, 1783, 1740, 1175, 1114, 1036, 752 cm−1. LRMS (APCI):
m/z 257 (M + 1, 20), 155 (100), 109 (25). HRMS (FAB): m/z calcd
for C14H25O4 257.1753, found 257.1755. [α]20D = 11.21 (c 0.7, CHCl3;
lit.11a [α]25 = 11.3, c = 1.18, CHCl3).
(1) (a) Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K. Angew. Chem.,
Int. Ed. 2009, 48, 9426. (b) Lepoittevin, J.-P.; Berl, V.; Gimen
́
ez-Arnau,
E. Chem. Record 2009, 9, 258. (c) Bandichhor, R.; Nosse, B.; Reiser, O.
Top. Curr. Chem. 2005, 243, 43. (d) Li, Y.; Pattenden, G. Nat. Prod.
Rep. 2011, 28, 429. (e) Ahmed, A. F.; Shiue, R.-T.; Wang, G.-H.; Dai,
C.-F.; Kuo, Y.-H.; Sheu, J.-H. Tetrahedron 2003, 59, 7337. (f) Tsai, I.-
L.; Hung, C.-H.; Duh, C.-Y.; Chen, J.-H.; Lin, W.-Y.; Chen, I.-S. Planta
Med. 2001, 67, 865.
(2) (a) Adam, W.; Renze, J.; Wirth, T. J. Org. Chem. 1998, 63, 226.
(b) Chen, M.-J.; Lo, C.-Y.; Chin, C.-C.; Liu, R.-S. J. Org. Chem. 2000,
NFX-2 (D13). To a dichloromethane solution (2 mL) of compound
11 (23 mg, 0.115 mmol) was added 10% Pd/C (12 mg, 0.012 mmol)
and the flask sealed with a hydrogen balloon. The solution was stirred
for 3 h at room temperature. The resulting solution was filtered with a
Celite bed and concentrated. The crude product was purified by silica
gel (hexane/ethyl acetate = 2:1) to afford the desired product NFX-2
(13) in 96% yield (22 mg, 0.11 mmol) as a white solid. 1H NMR (300
MHz, CDCl3): δ 0.89 (t, J = 6.9 Hz, 3H), 1.2−1.56 (m, 8H), 1.45 (d, J
= 6.3 Hz, 3H), 1.56−1.67 (m, 1H), 1.8−1.92 (m, 1H), 2.49 (d, J = 5.4
Hz, 1H), 2.56 (ddd, JAB = 8.1 Hz, JAC = 7.3 Hz, JAD = 5.6 Hz, 1H), 3.84
(ddd, JAB = 8.1 Hz, JAC = 7.2 Hz, JAD = 5.4 Hz, 1H), 4.21 (dq, JAB = 7.2
Hz, JAC = 6.3 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 14.0, 18.2, 22.6,
26.7, 28.5, 29.2, 31.6, 48.6, 79.0, 80.0, 176.3. IR: νmax 3469, 2921, 2857,
1732, 1299, 1186, 1058 cm−1. LRMS (APCI): m/z 201 (M + 1, 100),
183 (91), 165 (40), 149 (39), 137 (86), 95 (46). HRMS: m/z calcd
65, 6362. (c) Harcken, C.; Bruckner, R. Tetrahedron Lett. 2001, 42,
̈
3967. (d) Tamura, S.; Tonokawa, M.; Murakami, N. Tetrahedron Lett.
2010, 51, 3134. (e) Song, J.; Shen, Q.; Xu, F.; Lu, X. Org. Lett. 2007, 9,
2947.
(3) For recent selected examples for oxazaborolidinium catalysts, see:
(a) Corey, E. J. Angew. Chem., Int. Ed. 2009, 48, 2100. (b) Ryu, D. H.;
Corey, E. J. J. Am. Chem. Soc. 2005, 127, 5384. (c) Senapati, B. K.;
Gao, L.; Lee, S. I.; Hwang, G.-S.; Ryu, D. H. Org. Lett. 2010, 12, 5088.
(d) Gao, L.; Hwang, G.-S.; Ryu, D. H. J. Am. Chem. Soc. 2011, 133,
20708. (e) Gao, L.; Kang, B. C.; Hwang, G.-S.; Ryu, D. H. Angew.
Chem., Int. Ed. 2012, 51, 8322.
(4) Senapati, B. K.; Hwang, G.-S.; Lee, S.; Ryu, D. H. Angew. Chem.,
Int. Ed. 2009, 48, 4398.
(5) (a) Nakata, T.; Tanaka, T.; Oishi, T. Tetrahedron Lett. 1983, 24,
2653. (b) Husain, S. M.; Stillger, T.; Dunkelmann, P.; Lodige, M.;
Walter, L.; Breitling, E.; Pohl, M.; Burchner, M.; Krossing, I.; Muller,
M.; Romano, D.; Molinari, F. Adv. Synth. Catal. 2011, 353, 2359.
̈
̈
for C11H20O3: 200.1412, found: 200.1410. mp 56−58 °C. [α]20
=
D
̈
̈
−16.19 (c 1.3, CHCl3; lit.11a [α]25 = −15.1, c 1.20, MeOH).
D
(+)-Antimycinone (15). To a CH2Cl2 solution (2 mL) of NFX-2
(13) (22 mg, 0.11 mmol) were added DMAP (54 mg, 0.44 mmol) and
isovaleryl chloride (0.08 mL, 0.67 mmol). The mixture was stirred for
24 h at room temperature. The resulting solution was quenched by
adding NaHCO3 (2 mL). The organic layer was extracted with
CH2Cl2 (3 × 2 mL), and the combined organic layers were dried over
Na2SO4, filtered, and concentrated. The crude product was purified by
silica gel (hexane/ethyl acetate = 5:1) to afford the desired product
(+)-antimycinone (15) in 87% yield (27 mg, 0.096 mmol) as a
colorless oil. 1H NMR (300 MHz, CDCl3): δ 0.88 (t, J = 6.6 Hz, 3H),
0.97 (d, J = 6.3 Hz, 6H), 1.22−1.44(m, 8H), 1.47(d, J = 6.6 Hz, 3H),
1.64 (m, 1H), 1.86 (m, 1H), 2.11 (m, 1H), 2.23 (d, J = 6.6 Hz, 2H),
(6) Lee, S. I.; Hwang, G.-S.; Shin, S. C.; Lee, T. G.; Jo, R. H.; Ryu, D.
H. Org. Lett. 2007, 9, 5087.
(7) (a) Martinez V., J. C.; Yoshida, M.; Gottlieb, O. R. Tetrahedron
Lett. 1979, 20, 1021. (b) Martinez V., J. C.; Yoshida, M.; Gottlieb, O.
R. Phytochemistry 1981, 20, 459.
(8) (a) Takeda, K.; Sakurawi, K.; Ishii, H. Tetrahedron 1972, 28,
3757. (b) Tanaka, H.; Nakamura, T.; Ichino, K.; Ito, K.; Tanaka, T.
Phytochemistry 1990, 29, 857.
(9) (a) Chang, S.-Y.; Cheng, M.-J.; Peng, C.-F.; Chang, H.-S.; Chen,
I.-S. Chem. Biodivers. 2008, 5, 2690. (b) Chen, I.-S.; Lai-Yaun, I.-L.;
Duh, C.-Y.; Tsai, I.-L. Phytochemistry 1998, 49, 745.
(10) (S)-β-iodo MBH ester was prepared using ent-3d by following
the same procedure.
(11) (a) Sibi, M. P.; Lu, J.; Talbacka, C. L. J. Org. Chem. 1996, 61,
7848. (b) de Azevedo, M. B. M.; Greene, A. E. J. Org. Chem. 1995, 60,
4940. (c) Ferrarini, R. S.; Dos Santos, A. A.; Comasseto, J. V.
Tetrahedron Lett. 2010, 51, 6843.
2.69 (dt, JAB = 8.1 Hz, JAC = 5.7 Hz, 1H), 4.37 (qd, JAB = 6.6 Hz, JAC
=
4.5 Hz, 1H), 4.95 (dd, JAB = 5.7 Hz, JAC = 4.8 Hz, 1H). 13C NMR (75
MHz, CDCl3): δ 14.2, 19.6, 22.5, 22.7, 25.9, 27.0, 29.1, 29.5, 31.7,
43.3, 46.6, 78.6, 79.6, 172.6, 176.1. IR: νmax 2954, 2866, 1784, 1741,
1175, 1112, 1037 cm−1. LRMS (APCI): m/z 285 (M + 1, 56), 286
(12), 231 (12), 184 (15), 183 (100), 137(18). HRMS (FAB): m/z
calcd for C16H29O4 285.2066, found 285.2064. [α]20 = 10.64 (c 1.0,
(12) (a) Uchiyama, H.; Kobayashi, Y.; Sato, F. Chem. Lett. 1985, 467.
(b) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2001, 3, 675.
(c) Chakraborty, T. K.; Chattopadhyay, A. K.; Ghosh, S. Tetrahedron
Lett. 2007, 48, 1139.
D
CHCl3; lit.11a [α]25 = 10.8, c 0.50, CHCl3).
D
ASSOCIATED CONTENT
* Supporting Information
■
(13) (a) Esteve, J.; Jimen
Urpí, F. Tetrahedron 2011, 67, 6045. (b) Esteve, C.; Ferrero,
Romea, P.; Urpí, F.; Vilarrasa, J. Tetrahedron Lett. 1999, 40, 5083.
́
ez, C.; Nebot, J.; Velasco, J.; Romea, P.;
M.;
S
́
Chiral GC data for compounds 5; chiral HPLC data for
compounds 1, 8; NMR spectra for compounds 1, 2, 5, and 7−
15. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: dhryu@skku.edu; gshwang@kbsi.re.kr.
■
Notes
The authors declare no competing financial interest.
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dx.doi.org/10.1021/jo302369q | J. Org. Chem. 2013, 78, 770−775