General and systematic synthetic entry to carotenoid natural products

Article abstract of DOI:10.1016/j.tet.2004.09.002

A general synthetic method of carotenoid natural products has been developed, in which the systematic chain extension and termination processes were applied. The syntheses of the chain extension and termination units were greatly improved by the use of the common intermediate, 1-bromo-4-chloro-3- methyl-2-butene (8), in a short and highly efficient way. The C₁₀ chain initiation β-cyclogeranyl sulfone (3) was coupled with the C ₅ chain extension unit to give the C₁₅ chain-extended allylic sulfone after chemoselective sulfide oxidation. This chain-extended C₁₅ allylic sulfone underwent the Julia olefination reaction with the C₅ and the C₁₀ chain termination units to give retinol (1) and β-carotene (2), respectively. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.09.002

Tetrahedron 60 (2004) 10181–10185
General and systematic synthetic entry to carotenoid
natural products
Young Cheol Jeong, Minkoo Ji, Jun Sup Lee, Jae-Deuk Yang, Jingquan Jin, Woonphil Baik
*
and Sangho Koo
Department of Chemistry, Myong Ji University, San 38-2, Nam-Dong, Yongin, 449-728 Kyunggi-Do, South Korea
Received 4 August 2004; revised 2 September 2004; accepted 2 September 2004
Abstract—A general synthetic method of carotenoid natural products has been developed, in which the systematic chain extension and
termination processes were applied. The syntheses of the chain extension and termination units were greatly improved by the use of the
common intermediate, 1-bromo-4-chloro-3-methyl-2-butene (8), in a short and highly efficient way. The C10 chain initiation b-cyclogeranyl
sulfone (3) was coupled with the C5 chain extension unit to give the C15 chain-extended allylic sulfone after chemoselective sulfide oxidation.
This chain-extended C15 allylic sulfone underwent the Julia olefination reaction with the C5 and the C10 chain termination units to give retinol
(1) and b-carotene (2), respectively.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
structures systematically into the chain initiation allylic
sulfone 3, the chain extension C5 unit 4, and the chain
termination C5 and C10 units, 5 and 6, respectively (Scheme
1). We herein report the details of our systematic studies on
Carotenoids are biologically, medicinally, and commer-
cially important natural products, which include retinol
(vitamin A), retinoic acid, b-carotene, canthaxanthin, and
astaxanthin etc.1 Retinol is an essential nutrient for higher
animals required for cell growth and differentiation,
fertilization, and visual action. Retinoic acid shows broad
treatment effects on skin disorders including acne and even
on emphysema.2 b-Carotene and astaxanthin have wide
industrial applications especially in animal feeds and the
coloration of foodstuffs. These carotenoids belong to the
isoprenoid family according to their biogenetic origin,
which are enzymatically assembled by repeated uses of
isopentenyl pyrophosphate (IPP) or dimethylallyl pyropho-
sphate (DMAP) as building blocks.1 Chemical syntheses of
these carotene compounds,3 therefore, can be generalized in
a systematic way by utilizing ‘the C5 building blocks,’ as
chemical mimics for IPP or DMAP. The Julia sulfone
olefination protocol4 is the best method to construct these
highly unstable carotenoid structures through the much
more stable allylic sulfone intermediates that can be
transformed to the fully conjugated polyene chains in the
final stage. Retrosynthetic analyses of the two representative
carotenoid compounds, retinol (1) and b-carotene (2)
utilizing the sulfone chemistry disintegrate these carotenoid
Keywords: Carotenoid; Olefination; Retinol; b-Carotene; Total synthesis.
* Corresponding author. Tel.: C82 31 330 6185; fax: C82 31 335 7248;
e-mail: sangkoo@mju.ac.kr
Scheme 1. Disconnection approaches to retinol (1) and b-carotene (2).
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.002

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Y. Cheol Jeong et al. / Tetrahedron 60 (2004) 10181–10185
the efficient syntheses of each unit, the chain extension
process, and the total syntheses of retinol (1) and
b-carotene (2).
The ambidextrous allylic halide 8 was prepared from readily
available isoprene in two steps: chlorohydrin formation
using N-chlorosuccinimide in H2O-DMF (78% yield),
followed by PBr3-promoted bromination of the resulting
chlorohydrin 7 under CuCl catalyst (84% yield), where the
allylic-transposed bromination product 8 was exclusively
obtained with a high E:Z ratio of 10:1.10
2. Results and discussion
b-Cyclogeranyl sulfone (3)5 which can be readily prepared
by the electrophilic cyclization of geranyl sulfone was used
as a chain initiation unit for our carotenoid synthesis. The
C5 chain extension unit was so designed as to give the
1,5-arrangement of the methyl substituents, which is
the general substitution pattern of the carotenoid com-
pounds, and to give the chain-extended allylic sulfones
again after the Julia coupling reaction with the chain-
initiating allylic sulfone 3. 4-Halo-3-methyl-2-butenyl
sulfide 4 instead of the corresponding sulfone compound
was selected in order to facilitate the Julia coupling reaction
with b-cyclogeranyl sulfone 3, where the undesirable
dehydrohalogenation reaction could be prevented.6 The
resulting chain-extended allylic sulfide can be oxidized to
the corresponding allylic sulfone. The chain-extended
allylic sulfone then undergoes olefination process with the
C5 and the C10 chain termination units 5 and 6 to give retinol
(1) and b-carotene (2), respectively. Bis(haloallylic) sulfide
6 has proven to be a stable substitute for highly unstable
1,8-dihalo-2,7-dimethyl-2,4,6-octatriene as the C10 chain
termination unit for b-carotene and lycopene syntheses.6,7
The chain extension unit 4 that was proposed as a chemical
mimic for IPP or DMAP was then utilized in the chain
extension process. The Julia coupling reaction of b-cyclo-
geranyl sulfone (3) with the C5 chain extension unit 4
produced the chain-extended allylic sulfides 9 (Scheme 3).11
This coupling reaction works well (87% yield) with n-BuLi
as a base. Chemoselective sulfur oxidation of 9 proceeded
smoothly with 2.5 equiv H2O2 under LiNbMoO6 catalyst12
to give the C15 disulfone compound 10 (90% yield), where
no epoxidation at the tetra-substituted double bond in the
cyclohexene ring was observed contrary to the case of
the conventional electrophilic oxidant such as MCPBA. The
white crystalline disulfone compound 10 was easily purified
by washing with diethyl ether.
Scheme 3. Chain extension process to obtain the C15 disulfone compound
10.
It was envisioned that the chain extension unit 48 and the
chain termination units 59 and 66,7 might be obtained in a
highly efficient and convenient way from the common
intermediate 8 in proviso that the ambidextrous allylic
halide 8 could show different electrophilic reactivity
(Scheme 2). In fact, the nucleophiles of PhSK (PhSH,
K2CO3 in acetone), AcOK (AcOK in DMF) and S2K (Na2S
in CH3OH) discriminated allylic bromide from allylic
chloride of 1-bromo-4-chloro-3-methyl-2-butene (8) to
directly give rise to the C5 chain extension unit, phenyl
4-chloro-3-methyl-2-butenyl sulfide (4)10 in 89% yield and
the C5 and the C10 chain termination units, 4-chloro-3-
methyl-2-butenyl acetate (5)10 and bis(4-chloro-3-methyl-
2-butenyl) sulfide (6) in 94 and 81% yields, respectively.
The Julia olefination reaction of the chain-extended allylic
sulfone 10 with the C5 chain termination unit 5 produced
retinol (1). The coupling reaction of the C15 disulfone 10
and the C5 unit 5 under t-BuOK/DMF condition provided
the C20 compound 11 in 85% yield (Scheme 4). Deprotona-
tion at the a-carbons to the benzenesulfonyl groups of the
disulfone 10 can be completed by the use of 2 equiv of a
strong base such as t-BuOK or n-BuLi, where the coupling
reaction proceeded only at the less-substituted secondary
carbanion. The dehydrosulfonation reaction of the C20
coupling product 11 using NaOH as a base in EtOH then
produced all-(E)-retinol (1) in 82% yield after chromato-
graphic separation of a small amount (less than 10%) of
13-(Z)-retinol.13 It is beneficial to use NaOH as a base in
EtOH and to operate the reaction initially at room
temperature and then at the reflux temperature of EtOH to
facilitate the hydrolysis of acetate first, and then promote
dehydrosulfonation reaction in order to minimize the
possibility of the base-promoted elimination of
acetate producing anhydro vitamin A. Base-promoted
Scheme 2. Syntheses of the chain-extension unit 4 and the chain-
termination units 5 and 6.
Scheme 4. Retinol synthesis.

Y. Cheol Jeong et al. / Tetrahedron 60 (2004) 10181–10185
10183
dehydrosulfonation reaction produces a E-double bond in
4. Experimental
4.1. General information
the Julia sulfone olefination.14 Dehydrosulfonation at C(7,8)
in the compound 11 proceeded rapidly even at room
temperature presumably due to steric congestion, however,
dehydrosulfonation at C(11,12) requires a stronger con-
dition of boiling EtOH.
1H (300 MHz) and 13C NMR (75.5 MHz) spectra were
recorded in deuterated chloroform (CDCl3). Solvents for
extraction and chromatography were reagent grade and used
as received. The column chromatography was performed by
the method of Still with silica gel 60, 230–400 mesh ASTM
supplied by Merck. Solvents used as reaction media were
The Julia olefination reaction of the chain-extended allylic
sulfone 10 with the C10 chain termination unit 6 in
¨
combination with the Ramberg-Backlund reaction produced
b-carotene (2). The coupling reaction of the C15 disulfone
10 (2 equiv) with the C10 unit 6 (1 equiv) provided the C40
compound 12 (Scheme 5). To complete the deprotonation
and the coupling reaction at the secondary a-carbon to the
benzenesulfonyl group in compound 10, 2 equiv n-BuLi
was used as a base to give the optimized yield of 82%.
Chemoselective oxidation of the bisallylic sulfide 12 to the
corresponding bisallylic sulfone 13 proceeded by H2O2
(2.5 equiv) under LiNbMoO6 catalyst (0.05 equiv) in 80%
yield,12 where MeCN was used as a solvent to improve the
solubility of the compound 12 containing tetra-benzenesul-
˚
dried over pre-dried molecular sieve (4 A) by microwave
oven. All reactions were performed under a dry argon
atmosphere in oven-dried glassware except for those used
H2O as a reaction medium.
4.2. Bis(4-chloro-3-methyl-2-butenyl) sulfide (6)
To a stirred solution of 1-bromo-4-chloro-3-methyl-2-
butene (8) (15.6 g, 80.7 mmol) in THF (100 mL) at 0 8C
was added Na2S (6.76 g, 40.3 mmol). The reaction mixture
was stirred at that temperature for 6 h, and H2O was added.
The mixture was extracted with ether, washed with H2O,
dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified
by SiO2 flash column chromatography to give 6 [7.83 g,
32.7 mmol; (E,E):(E,Z)Z5:1] in 81% yield.
¨
fonyl groups. The Ramberg-Backlund reaction of bisallylic
sulfone 13 under Meyers condition15 produced the C40
compound 14 containing the central triene moiety. It was
necessary to apply the dehydrosulfonation reaction to the
crude product 14 without purification because the C40
compound 14 was not stable under air, and furthermore,
some of the premature dehydrosulfonation products at C(7)
4.2.1. Data for (E,E)-6.7 1H NMR d 1.78 (s, 6H), 3.10 (d,
JZ7.6 Hz, 4H), 4.03 (s, 4H), 5.62 (t, JZ7.6 Hz, 2H) ppm.
Data for (E,Z)-6: 1H NMR d 1.78 (s, 3H), 1.83 (s, 3H), 3.10
(d, JZ7.6 Hz, 2H), 3.12 (d, JZ8.1 Hz, 2H), 4.01 (s, 2H),
4.03 (s, 2H), 5.44 (t, JZ8.1 Hz, 1H), 5.62 (t, JZ7.6 Hz, 1H)
ppm.
¨
were also observed at the Ramberg-Backlund reaction stage.
Dehydrosulfonation reaction of the crude product 14 under
excess NaOEt in refluxing EtOH, which presumably
allowed thermal isomerization of the (Z)-isomers, then
produced all-(E)-b-carotene (2) in 71% overall yield after
two steps from the bisallylic sulfone 13.
4.3. 3-Methyl-5-(2,6,6-trimethyl-1-cyclohexenyl)-1,5-
dibenzenesulfonyl-2-pentene (10)
To a stirred solution of 3 (2.78 g, 10.00 mmol) in THF
(50 mL) at 0 8C was added 1.6 M solution of n-BuLi in
hexane (7.5 mL, 12.00 mmol). The mixture was stirred for
1 h, and a solution of 4 (2.55 g, 12.00 mmol) in THF
(10 mL) was added. The mixture was stirred at 0 8C for
1.5 h, quenched with 1 M HCl (20 mL), and extracted with
ether. The organic layer was washed with 1 M HCl and
H2O, dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The crude product was
purified by silica gel column chromatography to give 911
(2.96 g, 8.71 mmol) in 87% yield.
Scheme 5. b-Carotene synthesis.
3. Conclusion
To a stirred solution of 9 (2.94 g, 6.50 mmol) in CH3OH
(30 mL) and benzene (10 mL) at 0 8C were added
LiNbMoO6 (94 mg, 0.30 mmol) and 30% H2O2 solution
(1.84 g, 16.25 mmol). The reaction mixture was warmed up
and stirred at 25 8C for 6 h, and most of solvent was
removed under reduced pressure. The crude material was
diluted with CHCl3 (50 mL), washed with H2O, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by silica gel flash
column chromatography to give 10 (2.83 g, 5.80 mmol) in
90% yield. The product was further purified by recrystalli-
zation with ether to give the (E)-10 (2.55 g, 5.23 mmol) in
72% yield.
We have developed a general and systematic synthetic
method of carotenoid natural products. This biomimetic
approach highlights the use of the C5 chain extension unit 4
and the C5 and the C10 chain termination units 5 and 6 that
are prepared from the common intermediate 8 in a highly
efficient way. The usefulness and general applicability of
our systematic approach have been demonstrated in the
synthesis of retinol (1) and b-carotene (2). This approach for
carotenoid syntheses can be applied to the systematic
syntheses of other isoprenoid natural products including
terpenoids and steroids, which have the same biogenetic
origin as the carotenoid compounds.

10184
Y. Cheol Jeong et al. / Tetrahedron 60 (2004) 10181–10185
4.3.1. Data for (E)-10. 1H NMR d 0.76 (s, 3H), 0.98 (s, 3H),
1.11 (s, 3H), 1.33–1.60 (m, 4H), 1.95–2.18 (m, 2H), 1.99 (s,
3H), 2.57 (d of ABq, JABZ14.6 Hz, JdZ6.2 Hz, 1H), 3.10
(d of ABq, JABZ14.6 Hz, JdZ7.1 Hz, 1H), 3.64 (d of ABq,
4.6. Bis[3,7-dimethyl-5,9-dibenzenesulfonyl-9-(2,6,6-
trimethyl-1-cyclohexenyl)-2,6-nonadienyl] sulfide (12)
To a stirred solution of 10 (4.00 g, 8.21 mmol) in THF
(50 mL) at 0 8C was added 1.6 M solution of n-BuLi in
hexane (11.3 mL, 18.1 mmol). The mixture was stirred at
that temperature for 20 min, and a solution of 6 (1.18 g,
4.11 mmol) in THF (15 mL) was added. The resulting
mixture was stirred at 0 8C for 1 h, quenched with 1 M HCl
solution, extracted with ether, washed with H2O, dried over
anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The crude product was purified by silica gel flash
column chromatography to give 12 (3.85 g, 6.75 mmol) in
82% yield. This coupling product was composed of a
mixture of diastereomers, which were not easily separable.
JABZ15.4 Hz, JdZ7.8 Hz, 1H), 3.70 (d of ABq, JAB
Z
15.4 Hz, JdZ7.8 Hz, 1H), 3.87 (dd, JZ7.1, 6.2 Hz, 1H),
5.23 (dt, JdZ1.0 Hz, JtZ7.8 Hz, 1H), 7.43–7.70 (m, 6H),
7.76–7.93 (m, 4H) ppm; 13C NMR d 15.7, 18.9, 23.3, 28.4,
28.9, 34.5, 36.0, 39.6, 41.1, 55.9, 65.2, 114.7, 128.2, 128.5,
128.8, 129.1, 130.5, 133.2, 133.7, 138.2, 138.7, 141.6 ppm;
IR (KBr) 1448, 1385, 1144, 1084 cmK1; HRMS (CIC)
calcd for C27H35O4S2 487.1977, found 487.1990.
4.4. 1-Acetoxy-5,9-dibenzenesulfonyl-3,7-dimethyl-9-
(2,6,6-trimethyl-1-cyclohexenyl)-2,6-nonadiene (11)
4.6.1. Data for the major diastereomer of 12. 1H NMR d
0.77 (s, 6H), 0.82 (s, 6H), 1.16 (s, 6H), 1.23–1.43 (m, 4H),
1.43–1.52 (m, 4H), 1.50 (s, 6H), 1.86–2.12 (m, 4H), 1.97 (s,
6H), 2.03–2.32 (m, 2H), 2.44–3.00 (m, 6H), 2.90–3.20 (m,
4H), 3.72–3.99 (m, 4H), 4.83–5.00 (m, 2H), 5.12–5.27 (m,
2H), 7.43–7.68 (m, 12H), 7.74–7.95 (m, 8H) ppm; 13C NMR
d 15.8, 18.7, 23.2, 28.5, 28.7, 34.4, 35.5, 35.7, 38.4, 39.4,
40.9, 41.4, 62.6, 65.4, 120.7, 124.3, 124.9, 128.6, 128.9,
129.0, 129.0, 131.3, 133.4, 133.7, 137.4, 137.7, 140.9,
141.8 ppm; IR (KBr) 2931, 1447, 1304, 1144 cmK1; HRMS
(FABC) calcd for C52H71S3O4 [C64H83S5O8K2!
(C6H6SO2)] 855.4514, found 855.4511.
To a stirred solution of 10 (0.50 g, 1.03 mmol) in DMF
(20 mL) at K20 8C was added t-BuOK (0.29 g, 2.47 mmol).
The mixture was stirred at that temperature for 1 h, and a
solution of C5 chloroacetate 5 (0.25 g, 1.54 mmol) in
DMF (5 mL) was added. The resulting mixture was stirred
at K20 8C for 3 h, and 2 M HCl solution (10 mL) was added
to quench the reaction. The mixture was extracted with
ether, washed with H2O, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by silica gel flash column chroma-
tography to give 11 (0.54 g, 0.88 mmol) in 85% yield, which
was a 2:1 mixture of diastereomers
4.7. Bis[3,7-dimethyl-5,9-dibenzenesulfonyl-9-(2,6,6-
trimethyl-1-cyclohexenyl)-2,6-nonadienyl] sulfone (13)
4.4.1. Data for the major isomer of 11. 1H NMR d 0.68 (s,
3H), 0.80 (s, 3H), 1.12 (s, 3H), 1.27–1.68 (m, 4H), 1.57 (s,
3H), 1.95–2.09 (m, 2H), 1.96 (s, 3H), 2.01 (s, 3H), 2.24 (dd,
JZ14.3, 11.3 Hz, 1H), 2.62 (dd, JZ15.0, 5.9 Hz, 1H), 2.87
(br d, JZ14.3 Hz, 1H), 3.05 (dd, JZ15.0, 5.9 Hz, 1H), 3.78
(t, JZ5.9 Hz, 1H), 3.91 (ddd, JZ11.3, 10.3, 3.3 Hz, 1H),
4.38–4.55 (m, 2H), 4.95 (d, JZ10.3 Hz, 1H), 5.28 (t, JZ
6.7 Hz, 1H), 7.47–7.70 (m, 6H), 7.75–7.95 (m, 4H) ppm;
13C NMR d 15.9, 16.3, 18.9, 20.9, 23.5, 28.7, 28.7, 34.5,
35.6, 38.4, 39.5, 41.6, 60.9, 63.0, 65.6, 120.8, 122.3, 128.8,
129.0, 129.0, 129.4, 131.5, 133.4, 133.8, 136.2, 137.3,
138.0, 140.9, 142.1, 170.9 ppm; IR (KBr) 2934, 1737, 1446,
1304, 1233, 1145 cmK1; HRMS (FABC) calcd for
C22H33O2 (C34H45O6S2K2C6H6SO2) 329.2481, found
329.2485.
To a stirred solution of 12 (1.61 g, 1.41 mmol) in MeCN
(20 mL) at 0 8C were added LiNbMoO6 (20 mg, 0.07 mmol)
and a 35% aqueous solution of H2O2 (0.34 g, 3.53 mmol).
The resulting mixture was stirred at 0 8C for 1 h and at room
temperature for 12 h. The mixture was then extracted with
CH2Cl2, washed with 1 M HCl and H2O, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by silica gel
column chromatography to give 13 (1.36 g, 1.13 mmol) in
80% yield. This coupled product was composed of a mixture
of diastereomers, which were not easily separable.
4.7.1. Data for the major diastereomer of 13. 1H NMR d
0.67 (s, 6H), 0.79 (s, 6H), 1.28 (s, 6H), 1.23–1.54 (m, 8H),
1.67 (s, 6H), 1.93–2.03 (m, 4H), 2.00 (s, 6H), 2.05–2.66 (m,
4H), 2.71–2.92 (m, 2H), 2.98–3.32 (m, 2H), 3.42–3.70 (m,
4H), 3.74–4.02 (m, 4H), 4.86–5.10 (m, 2H), 5.13–5.40 (m,
2H), 7.45–7.69 (m, 12H), 7.72–7.92 (m, 8H) ppm; 13C NMR
d 15.8, 18.9, 23.4, 28.4, 28.7, 34.6, 35.7, 36.1, 38.4, 39.5,
41.5, 51.7, 62.3, 65.4, 113.8, 114.5, 120.4, 128.6, 129.0,
129.0, 129.2, 131.1, 133.5, 133.8, 137.2, 137.8, 140.8,
142.2 ppm; IR (KBr) 2931, 1447, 1305, 1144 cmK1; HRMS
(FABC) calcd for C46H65S2O4 [C64H83S5O10K3!
(C6H6SO2)] 745.4324, found 745.4333.
4.5. Retinol (1)4
To a stirred solution of 11 (7.53 g, 12.27 mmol) in 99.9%
EtOH (100 mL) was added NaOH (4.91 g, 0.12 mol). The
mixture was stirred at room temperature for 1 h and then
heated to reflux for 15 h. The reaction mixture was cooled to
room temperature, and most of the solvent was removed
under reduced pressure. The mixture was carefully treated
with H2O and 3 M HCl (40 mL) solution, extracted with
CHCl3, washed with H2O, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The crude
product which contained a small amount (less than 10%) of
13-(Z)-retinol was purified by silica gel flash column
chromatography to give all-(E)-retinol (1) (2.88 g,
10.06 mmol) in 82% yield.
4.8. b-Carotene (2)3,7
To a stirred solution of 13 (0.98 g, 0.84 mmol, 1 equiv) in
CCl4 (15 mL) and t-BuOH (10 mL) at 0 8C was added
pulverized KOH (0.47 g, 8.36 mmol, 10 equiv). The result-
ing mixture was stirred at 0 8C for 1 h and at room

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10185
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temperature for 10 h, and carefully quenched with H2O. The
mixture was then neutralized with 1 M HCl (10 mL),
extracted with CH2Cl2, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The crude
product (1.15 g) was not stable and directly used for the next
dehydrosulfonation reaction without purification.
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A solution of the crude product 14 (1.15 g) in 99.9% EtOH
(20 mL) was added to a solution of NaOEt which was
prepared by adding Na (1.20 g, 52.14 mmol) to 99.9%
EtOH (50 mL). The resulting mixture was heated to reflux
for 12 h, and cooled to room temperature. Most of the
solvent was removed under reduced pressure. The crude
mixture was treated with 1 M HCl solution, extracted with
CHCl3, washed with H2O, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by silica gel flash column chroma-
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Acknowledgements
This work was supported by the RRC (Regional Research
Center) program of MOST (Ministry of Science and
Technology), KOSEF (Korea Science and Engineering
Foundation), and Kyunggi-Do.
10. Lee, J.-S.; Jeong, Y. C.; Ji, M.; Baik, W.; Lee, S.; Koo, S.
Synlett 2004, 1937–1940.
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J. S.; Park, M.; Koo, S. Helv. Chim. Acta 2003, 86, 2620–2628.
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