Synthesis of sporiolide B from d-glucal

Article abstract of DOI:10.1016/j.carres.2007.04.013

A total synthesis of the 12-membered ring natural macrolide, sporiolide B, was achieved from d-glucal in 17 steps with 4.8% overall yield. The required stereochemical configuration at C-3 and C-5 in sporiolide B was easily introduced by applying a Mitsuno

Full text of DOI:10.1016/j.carres.2007.04.013

Carbohydrate Research 342 (2007) 1405–1411
Synthesis of sporiolide B from D-glucal
Qi Chen and Yuguo Du*
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences,
Chinese Academy of Sciences, Beijing 100085, PR China
Received 4 March 2007; received in revised form 19 April 2007; accepted 20 April 2007
Available online 29 April 2007
Abstract—A total synthesis of the 12-membered ring natural macrolide, sporiolide B, was achieved from D-glucal in 17 steps with
4.8% overall yield. The required stereochemical configuration at C-3 and C-5 in sporiolide B was easily introduced by applying a
Mitsunobu reaction on the chiral template D-glucal. Yamaguchi esterification and ring closing metathesis greatly improved the
access to the target compound.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Keywords: Total synthesis; Macrolides; Sporiolide B; D-Glucal; Natural products
1. Introduction
5
S
OH
O
Marine microorganisms, such as bacteria, fungi, and
microalgae, which have proved to be a rich source of
structurally novel and biologically active secondary
metabolites, are attracting increasing attention as a
potential source of new pharmaceuticals and pharma-
ceutical leads.1 In 2004, from the culture broth of a fun-
gus Cladosporium sp. separated from an Okinawan
marine brown alga Actinotrichia fragilis, Kobayashi
reported the isolation of a 12-membered ring macrolide
sporiolide B (1) and proposed that structurally it corre-
sponds to the 3-O-methyl ether of pandangolide 1 (2)2
based on spectroscopic analyses (Chart 1).3
Sporiolide B exhibits cytotoxicity against L1210 cells
(IC50 = 0.81 lg/mL) and antibacterial activity against
Micrococcus luteus (MIC = 16.7 lg/mL). Attracted by
its various biological activities, we already completed
the first total synthesis of sporiolide B from D-xylose
in 3.5% overall yield.4 In our ongoing project, we needed
to synthesize larger quantities of sporiolide B for bio-
activity screening. However, in large scale preparations
with our previous procedure, we realized that a number
S
R
O
3
O
OR
1 R = Me (Sporiolide B)
2 R = H (Pandangolide 1)
Chart 1. Structures of sporiolide B (1) and pandangolide 1 (2).
of toxic reagents (HgAc2 and KCN) were used. We thus
decided to explore an alternative strategy toward the
target molecule. Herein, a facile total synthesis of spo-
riolide B from 1,5-anhydro-2-deoxy-D-arabino-hex-1-
enitol (D-glucal) as starting material is now reported.
2. Results and discussion
As outlined in Chart 2, sporiolide B (1) could be
prepared from the lactone precursor 3 available from
intramolecular ring closure metathesis of diene 4 after
Yamaguchi esterification of alcohol 5 and acid 6. Key
intermediate 6 could be derived from the well function-
alized lactone 7, which would be prepared from com-
mercially available D-glucal.
*
Corresponding author. Tel.: +86 10 62849126; fax: +86 10
62923563; e-mail: duyuguo@rcees.ac.cn
0008-6215/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.04.013

1406
Q. Chen, Y. Du / Carbohydrate Research 342 (2007) 1405–1411
9
7
OBn
11
OH
O
RCM
OMe
OBn
5
O
1
O
3
O
O
O
O
O
4
OMe
O
OMe
OBn
1
3
O
O
OMe
Esterification
+
D-Glucal
HOOC
OPMB
OH
OPMB
OMe
5
6
7
Chart 2. Retrosynthetic analysis of sporiolide B (1).
O
O
OPMB
OH
+
OH
OPMB
OMe
11
OMe
O
O
10
O
OH
a
c
45%
50%
40%
30%
OH
O
PhOMe
d
OH
OR
e
O
O
8 R = H
D-Glucal
OH
b
OPMB
9 R = Me
+
OPMB
OH
12
13
trace
90%
Scheme 1. Attempted cleavage of p-anisaldehyde acetal by regioselective reduction. Reagents and conditions: (a) Ref. 5; (b) MeI, NaH, DMF, 2 h;
95%; (c) DIBAL-H, DCM, ꢀ78 ꢁC to rt, 2 h, 45% for 10, 40% for 11; (d) LiAlH4, AlCl3, THF, 75 ꢁC, 6 h, 50% for 10, 30% for 11; (e) NaCNBH3,
TMSCl, MeCN, 4 h, 90% for 12.
Initially, we tried to prepare 10 from 9, which was
obtained by methylation of the known D-glucal derivative
8,5 through regioselective reductive cleavage of p-anisal-
dehyde acetal as illustrated in Scheme 1. Unfortunately,
a poor selectivity was obtained using either DIBAL-H5,6
or LiAlH4–AlCl37 as reducing agents. When 9 was trea-
ted with NaCNBH3–TMSCl,8 12 involving double bond
migration was obtained unexpectedly in an excellent
yield (90%), and its structure was confirmed unambigu-
yield (67% in three steps). Treatment of 7 with NaOMe
in MeOH gave the methyl ester 17, in which the free (R)-
OH was inverted into the precursor (S)-benzoate under
Mitsunobu reaction conditions.11 Debenzoylation of
this precursor with NaOMe in methanol (!18), fol-
lowed by benzylation with benzyl 2,2,2-trichloroacetim-
idate (!19),12 and hydrolysis with LiOH, furnished acid
6. Esterification of 6 with (S)-6-hepten-2-ol (5)13 under
Yamaguchi’s conditions14 afforded the diene derivative
20 (78% from 19), which was subjected to PMB cleavage
with DDQ15 and Dess–Martin periodinane16 oxidation,
to give the key intermediate 4 in 77% yield and two
steps. Diene 4 was then exposed to the Grubbs catalyst
[PHCH@RuCl(PCy3)2, 30 mol %]17 undergoing an
intramolecular ring closure metathesis (RCM) to pro-
duce macrolactone 3 as a E,Z mixture (E/Z = 2:1).
Final hydrogenation of 3 with H2 in the presence of
Pd/C simultaneously cleaved the benzyl ether and
1
ously by H NMR spectroscopy.
To solve this problem, we turned our attention to
another synthetic route as shown in Scheme 2. Silylated
14 was easily obtained from D-glucal in five steps
according to our previous report.9 Thus, desilylation
with TBAF gave alcohol 15, which was methylated with
MeI and NaH resulting in the glucal derivative 16. Com-
pound 16 was subjected to PCC oxidation10 at 45 ꢁC in
the presence of silica gel to give the key lactone 7 in good

Q. Chen, Y. Du / Carbohydrate Research 342 (2007) 1405–1411
1407
O
O
O
d
a
e
D-Glucal
OPMB
OPMB
OMe
OR
14 R = TBS
15 R = H
16 R = Me
7
b
c
OMe OR
OPMB
OMe OH
OMe
OBn
f
h
MeOOC
O
MeOOC
O
OPMB
17
OR
18 R = H
19 R = Bn
g
20 R = PMB
21 R = H
i
OBn
O
l
k
j
OMe
Sporiolide B (1)
OBn
O
O
O
O
OMe
O
4
3
Scheme 2. Reagents and conditions: (a) Ref. 10, 44%; (b) TBAF, THF, 2 h, 95%; (c) MeI, NaH, DMF, 2 h, 95%; (d) PCC, silica gel, DCM, 45 ꢁC,
6 h, 70%; (e) NaOMe, MeOH, 3 h, 83%; (f) (i) Ph3P, DEAD, PhCOOH, THF, 2 h; (ii) NaOMe, MeOH, 3 h, 81% in two steps; (g) BnOC(NH)CCl3,
TMSOTf, DCM, 3 h, 75%; (h) (i) LiOH, THF/water, 12 h; (ii) (s)-6-hepten-2-ol, 2,4,6-trichlorobenzoyl chloride, TEA, DMAP, THF, 18 h, 78% in
two steps; (i) DDQ, DCM/water, 2 h, 93%; (j) Dess–Martin periodinane, DCM, 3 h, 83%; (k) 30% PhCH@RuCl2(PCy3)2, DCM, refluxing, 24 h, 70%
(E/Z = 2:1); (l) H2, Pd/C, MeOH, 12 h, 81%.
saturated the double bond yielding sporiolide B, identi-
cal in every respect to the natural product.3
and [a]D-values are in units of 10ꢀ1 deg cm2 gꢀ1 1H
.
NMR, 13C NMR, and H–1H, H–13C COSY spectra
were recorded with a Bruker ARX 400 spectrometer
for solns in CDCl3. Chemical shifts are given in parts
per million downfield from internal Me4Si. Mass spectra
were measured using a MALDI TOF mass spectrometer
with a-cyano-4-hydroxycinnamic acid (CCA) as matrix,
or recorded with a VG PLATFORM mass spectrometer
using the ESI(ꢀ) technique to introduce the sample.
TLC was performed on silica gel HF254 with detection
by charring with 30% H2SO4 in MeOH or in some cases
by UV detection. Column chromatography was con-
ducted by elution of a column of silica gel (100–200
mesh) with EtOAc–petroleum ether (60–90 ꢁC). Solns
were concentrated at <60 ꢁC under diminished pressure.
1
1
The effects of sporiolide B against human MDA231,
BEL-7402, and Hela cell growth were investigated with
different methods.3,18 Unfortunately, under these testing
conditions, sporiolide B did not show significant inhibi-
tion on proliferation of either human MDA231, BEL-
7402, or Hela cell lines at 0.25–1.0 lg/mL for 24, 48,
and 72 h, respectively.
In summary, we have achieved the total synthesis of
sporiolide B in 17 steps and 4.8% overall yield. The
required stereochemical configuration at C-3 and C-5
in sporiolide B was successfully controlled by using a
Mitsunobu reaction to invert the stereochemistry at
C-5 of a glucal-derived compound. Yamaguchi esterifi-
cation and ring closing metathesis greatly improved
the target synthesis.
3.2. (2R,3S)-2-Hydroxymethyl-3-(4-methoxybenzyloxy)-
3,6-dihydro-2H-pyran (12)
3. Experimental
To a stirred soln of 85 (2.2 g, 8.4 mmol) in anhyd DMF
(15 mL) was added NaH (400 mg, 16.4 mmol) at 0 ꢁC,
30 min later, methyl iodide (0.6 mL, 9 mmol) was added
dropwise under the same reaction conditions. After
stirring at rt for 2 h, the reaction mixture was poured
into ice water (30 mL) and extracted with EtOAc
3.1. General methods
Optical rotations were determined at 25 ꢁC with a
Perkin–Elmer Model 241-Mc automatic polarimeter,

1408
Q. Chen, Y. Du / Carbohydrate Research 342 (2007) 1405–1411
(2 · 50 mL). The combined organic layers were dried
over anhyd Na2SO4 and concentrated under diminished
pressure. Purification of the residue on column chroma-
tography (7:1 petroleum ether–EtOAc) afforded 9 (2.2 g,
95%) as a solid. To a stirred soln of 9 (0.5 g, 1.8 mmol)
in anhyd MeCN (10 mL) at 0 ꢁC was added TMSCl
(1.5 mL, 10.8 mmol) portionwise, and then NaCNBH3
(754 mg, 10.8 mmol) was added under the same condi-
tions. The resulting mixture was diluted with CH2Cl2
(50 mL) 4 h later and washed with satd aq NaHCO3
and aq NaCl. After drying over anhyd Na2SO4 and con-
centration under diminished pressure, the residue was
purified by column chromatography (3:1 petroleum
ether–EtOAc) to give 12 (400 mg, 90%) as a colorless
wise at 0 ꢁC and 30 min later, methyl iodide (0.3 mL,
4.5 mmol) was added dropwise under the same condi-
tions. After stirring at rt for 2 h, the reaction mixture
was poured into ice water (20 mL) and extracted with
EtOAc (2 · 40 mL). The combined organic layer was
dried over anhyd Na2SO4 and concentrated under
diminished pressure. Purification of the residue by col-
umn chromatography (7:1 petroleum ether–EtOAc)
25
afforded 16 (1.1 g, 95%) as a solid: ½aꢁD ꢀ18 (c 0.5,
1
CHCl3); H NMR (CDCl3): d 7.27 (d, 2H, J 8.4 Hz,
Ph), 6.87 (d, 2H, J 8.3 Hz, Ph), 6.41 (d, 1H, J 6.1 Hz,
OCH@C), 6.07–5.93 (m, 1H, CH@CH2), 5.40 (d, 1H,
J 17.2 Hz, CH@CHaHb), 5.29 (d, 1H, J 10.5 Hz,
CH@CHaHb), 4.86 (dd, 1H, J 2.5, 6.1 Hz, OCH@CH),
4.71 (d, 1H, J 11.0 Hz, PhCH), 4.62 (d, 1H, J 11.0 Hz,
PhCH), 4.29 (t, 1H, J 7.5 Hz, CHOPMB), 3.96 (d, 1H,
J 6.0 Hz, OCHCH@CH2), 3.80 (s, 3H, OCH3 in
PMB), 3.49 (dd, 1H, J 6.7, 8.5 Hz, CHOMe), 3.39 (s,
3H, OCH3); 13C NMR (100 MHz, CDCl3): d 159.7,
143.7, 133.7, 129.6, 128.9 (2C), 118.6, 113.1 (2C), 99.2,
98.8, 77.1, 76.6, 72.4, 55.8 (PhOCH3), 54.5 (OCH3).
Anal. Calcd for C16H20O4: C, 69.54; H, 7.30. Found:
C, 69.81; H, 7.22.
25
syrup: ½aꢁD ꢀ10 (c 1, CHCl3); 1H NMR (CDCl3): d
7.26 (d, 2H, J 8.5 Hz, Ph), 6.88 (d, 2H, J 8.6 Hz, Ph),
5.93 (d, 1H, J 10.4 Hz, H-3), 5.85 (d, 1H, J 10.5 Hz,
H-2), 4.60, 4.47 (2d, 2H, J 11.2 Hz, PhCH2), 4.24–4.15
(m, 2H, H-1a and H-1b), 3.99 (d, 1H, J 8.7 Hz, H-4),
3.86 (dd, 1H, J 2.9, 11.6 Hz, H-6b), 3.81 (s, 3H,
OCH3), 3.68 (dd, 1H, J 5.6, 11.6 Hz, H-6a), 3.49–
3.45 (m, 1H, H-5), 1.86 (br s, 1H, OH). Anal. Calcd
for C14H18O4: C, 67.18; H, 7.25. Found: C, 67.33; H,
7.31.
3.5. (4R,5S,6R)-4-Methoxy-5-(p-methoxybenzyloxy)-6-
vinyl-tetrahydropyran-2-one (7)
3.3. (2R,3S,4R)-3-(4-Methoxybenzyloxy)-2-vinyl-3,4-
dihydro-2H-pyran-4-ol (15)
To a soln of 16 (880 mg, 3.2 mmol) in CH2Cl2 (100 mL)
was added PCC (2.1 g, 9.6 mmol) and silica gel (2.6 g).
The stirred suspension was refluxed for 6 h, then cooled
and filtered through Celite. The Celite pad was washed
several times with EtOAc and the combined filtrates
were concentrated. The crude product was purified by
column chromatography (4:1 petroleum ether–EtOAc)
To a soln of silyl ether 149 (4.5 g, 12 mmol) in THF
(50 mL) was added TBAF (24 mL of a 1 M soln in
THF, 24 mmol) at 0 ꢁC. The mixture was stirred under
these conditions for 30 min, followed by additional 2 h
stirring at rt, at the end of which time, TLC indicated
completion of the reaction. Then the reaction mixture
was concentrated under diminished pressure and the res-
idue was subjected to column chromatography (4:1
petroleum ether–EtOAc) to furnish 15 (3.0 g, 95%) as
25
to give 7 (650 mg; 70%) as a colorless syrup: ½aꢁD ꢀ15
(c 0.8, CHCl3); 1H NMR (CDCl3): d 7.25 (d, 2H, J
8.2 Hz, Ph), 6.90 (d, 2H, J 8.2 Hz, Ph), 5.98–5.82 (m,
1H, CH@CH2), 5.43 (d, 1H, J 17.2 Hz, CH@CHaHb),
5.30 (d, 1H, J 10.6 Hz, CH@CHaHb), 4.62 (d, 1H, J
11.0 Hz, PhCH), 4.61–4.57 (m, 1H, CHOPMB), 4.55
(d, 1H, J 11.0 Hz, PhCH), 3.81 (s, 3H, PhOCH3),
3.76 (dd, 1H, J 3.6, 7.8 Hz, OCHCH@CH2), 3.54 (dd,
1H, J 3.4, 7.5 Hz, CHOMe), 3.36 (s, 3H, OCH3), 2.83
(dd, 1H, J 4.5, 16.3 Hz, COCHaHb), 2.73 (dd, 1H, J
4.2, 16.4 Hz, COCHaHb); 13C NMR (100 MHz,
CDCl3): d 168.7 (C@O), 158.3, 132.9, 128.9 (2C),
128.0, 117.8, 113.2 (2C), 98.8, 79.1, 77.8, 71.6, 56.0
(PhOCH3), 54.5 (OCH3), 32.4 (COCH2). Anal. Calcd
for C16H20O5: C, 65.74; H, 6.90. Found: C, 65.35; H,
6.82.
25
a colorless syrup: ½aꢁD ꢀ17 (c 1, CHCl3); 1H NMR
(CDCl3): d 7.28 (d, 2H, J 8.1 Hz, Ph), 6.89 (d, 2H, J
7.7 Hz, Ph), 6.39 (d, 1H, J 6.0 Hz, OCH@CH), 6.05–
5.92 (m, 1H, CH@CH2), 5.47 (d, 1H, J 17.3 Hz,
CH@CHaHb), 5.34 (d, 1H, J 10.6 Hz, CH@CHaHb),
4.78 (dd, 1H, J 2.6, 6.0 Hz, OCH@CH), 4.74 (d, 1H, J
11.3 Hz, PhCH), 4.61 (d, 1H, J 11.2 Hz, PhCH), 4.35
(t, 1H, J 7.2 Hz, CHOPMB), 4.28 (s, 1H, OCHCH@
CH2), 3.80 (s, 3H, OCH3), 3.43 (t, 1H, J 6.9 Hz,
CHOH); 13C NMR (100 MHz, CDCl3): d 159.9, 144.6,
134.5, 130.5, 130.0 (2C), 118.6, 114.4 (2C), 103.2, 80.5,
78.1, 73.8, 68.7, 55.7 (OCH3). Anal. Calcd for
C15H18O4: C, 68.68; H, 6.92. Found: C, 69.09; H, 6.84.
3.4. (2R,3S,4R)-4-Methoxy-3-(p-methoxybenzyloxy)-2-
vinyl-3,4-dihydro-2H-pyran (16)
3.6. Methyl (3R,4R,5R)-5-hydroxy-3-methoxy-4-(p-
methoxybenzyloxy)-hept-6-enoate (17)
To a stirred soln of 15 (1.1 g, 4.2 mmol) in anhyd DMF
To a soln of 7 (600 mg, 2.0 mmol) in anhyd MeOH
(15 mL) was added NaH (200 mg, 8.2 mmol) portion-
(15 mL) was added M NaOMe in MeOH until pH 9–

Q. Chen, Y. Du / Carbohydrate Research 342 (2007) 1405–1411
1409
10. The reaction mixture was stirred at rt for 3 h, then
3.8. Methyl (3R,4S,5S)-5-benzyloxy-3-methoxy-4-(p-
methoxybenzyloxy)-hept-6-enoate (19)
neutralized with Amberlite IR-120 (H+), and filtered.
The filtrate was concentrated to dryness under dimin-
ished pressure. Purification of the residue by column
chromatography (4:1 petroleum ether–EtOAc) gave 17
To a soln of 18 (250 mg, 0.77 mmol) and benzyl 2,2,2-
trichloroacetimidate (380 mg, 1.5 mmol) in dry CH2Cl2
(15 mL) at ꢀ25 ꢁC was added TMSOTf (3.0 lL,
0.008 mmol) under N2 atmosphere. The reaction was
monitored by TLC until all the starting material was
consumed, then quenched with Et3N and concentrated
to dryness. The residue was subjected to silica gel col-
umn chromatography (petroleum ether–EtOAc, 6:1) to
25
(550 mg, 83%) as a colorless syrup: ½aꢁD ꢀ20 (c 0.5,
1
CHCl3); H NMR (CDCl3): d 7.26 (d, 2H, J 8.6 Hz,
Ph), 6.88 (d, 2H, J 8.6 Hz, Ph), 6.00–5.90 (m, 1H,
CH@CH2), 5.44 (d, 1H, J 17.2 Hz, CH@CHaHb), 5.25
(d, 1H, J 10.5 Hz, CH@CHaHb), 4.64, 4.50 (2d, 2H, J
11.3 Hz, PhCH2), 4.39 (t, 1H, J 5.3 Hz, CHOPMB),
4.02–3.98 (m, 1H, OCHCH@CH2), 3.81 (s, 3H,
PhOCH3), 3.65 (s, 3H, CH3OOC), 3.45 (dd, 1H, J 3.4,
5.9 Hz, CHOMe), 3.33 (br s, 1H, OH), 3.38 (s, 3H,
OCH3), 2.69 (dd, 1H, J 5.9, 16.1 Hz, COCHaHb), 2.61
(dd, 1H, J 7.0, 16.1 Hz, COCHaHb); 13C NMR
(100 MHz, CDCl3): d 172.1 (O@COMe), 159.4, 137.9,
129.8 (2C), 129.6, 116.1, 113.9 (2C), 78.8, 78.4, 72.3,
72.0, 58.0 (COOCH3), 55.3 (PhOCH3), 51.7 (OCH3),
34.7 (OOCCH2). Anal. Calcd for C17H24O6: C, 62.95;
H, 7.46. Found: C, 62.67; H, 7.60.
25
give 19 (240 mg, 75%) as a colorless syrup: ½aꢁD ꢀ16 (c
1
0.8, CHCl3); H NMR (CDCl3): d 7.34–7.23 (m, 7H,
Ph), 6.84 (d, 2H, J 8.4 Hz, Ph), 5.99–5.91 (m, 1H,
CH@CH2), 5.41 (d, 1H, J 17.1 Hz, CH@CHaHb), 5.40
(d, 1H, J 10.6 Hz, CH@CHaHb), 4.65, 4.62 (2d, 2H, J
11.4 Hz, PhCH2), 4.46, 4.34 (2d, 2H, J 11.3 Hz, PhCH2),
4.05 (t, 1H, J 6.9 Hz, CHOPMB), 3.96–3.92 (m, 1H,
OCHCH@CH2), 3.79 (s, 3H, PhOCH3), 3.64 (s, 3H,
CH3OOC), 3.57 (dd, 1H, J 3.5, 6.3 Hz, CHOMe), 3.31
(s, 3H, OCH3), 2.58–2.41 (m, 2H, COCH2); 13C NMR
(100 MHz, CDCl3): d 172.6 (O@COMe), 158.9, 138.6,
135.5, 130.4, 129.1 (2C), 127.6 (2C), 127.0 (2C), 126.8,
119.5, 113.5 (2C), 81.6, 80.1, 72.6, 70.0, 69.3, 58.1
(COOCH3), 54.6 (PhOCH3), 50.8 (OCH3), 34.3
(OOCCH2). Anal. Calcd for C24H30O6: C, 69.54; H,
7.30. Found: C, 69.91; H, 7.21.
3.7. Methyl (3R,4R,5S)-5-hydroxy-3-methoxy-4-(p-
methoxybenzyloxy)-hept-6-enoate (18)
To a soln of 17 (520 mg, 1.6 mmol) in dry THF
(15 mL) was added Ph3P (839 mg, 3.2 mmol), benzoic
acid (391 mg, 3.2 mmol), and diethylazodicarboxylate
(DEAD, 0.50 mL, 3.2 mmol) at 0 ꢁC. The resulting
mixture was stirred at rt for 2 h. After removing the
solvent under diminished pressure, the residue was dis-
solved in EtOAc (100 mL) and washed with N aq HCl,
satd aq NaHCO3, and aq NaCl. After drying over an-
hyd Na2SO4 and concentration under diminished pres-
sure, the residue was dissolved in anhyd MeOH
(15 mL), and M NaOMe in MeOH was added until
pH 9–10. The reaction mixture was stirred at rt for
3 h under these conditions, neutralized with Amberlite
IR-120 (H+), filtered, and concentrated. The residue
was purified by silica gel column chromatography
(4:1 petroleum ether–EtOAc) to yield 18 (421 mg,
3.9. (S)-Hept-6-en-2-yl (3R,4S,5S)-5-benzyloxy-3-meth-
oxy-4-(p-methoxybenzyloxy)-hept-6-enoate (20)
Methyl ester 19 (210 mg, 0.51 mmol) was dissolved in
4:1 THF–water (15 mL) and the soln was cooled in an
ice-water bath. To this was added LiOHÆH2O (84 mg,
2 mmol), and the resulting mixture was stirred at room
temperature for 12 h, neutralized with 1 N HCl, and
then extracted with EtOAc. The combined organic
phases were dried with anhyd Na2SO4 and concentrated
to afford acid 6. Without further purification, the crude
acid was dissolved in anhyd THF (15 mL) and treated
with Et3N (82 lL, 0.6 mmol) and 2,4,6-trichlorobenzoyl
chloride (78 lL, 0.5 mmol) successively. After stirring at
rt for 1 h, a soln of (S)-6-hepten-2-ol (68 mg, 0.6 mmol)
and DMAP (73 mg, 0.6 mmol) in THF (5 mL) was
added. The reaction mixture was stirred at rt for another
18 h, then diluted with aq NH4Cl. The aq soln was
extracted with EtOAc (2 · 25 mL). The combined organic
extracts was dried and evaporated. Purification of the
residue by column chromatography (6:1 petroleum
ether–EtOAc) gave 20 (196 mg, 78% in two steps) as a
25
81%) as a colorless syrup: ½aꢁD ꢀ14 (c 0.6, CHCl3);
1H NMR (CDCl3): d 7.25 (d, 2H, J 8.4 Hz, Ph), 6.89
(d, 2H, J 8.4 Hz, Ph), 6.05–5.96 (m, 1H, CH@CH2),
5.46 (d, 1H, J 17.0 Hz, CH@CHaHb), 5.28 (d, 1H, J
10.5 Hz, CH@CHaHb), 4.66, 4.51 (2d, 2H, J 11.0 Hz,
PhCH2), 4.44–4.40 (m, 1H, CHOPMB), 4.02 (t, 1H, J
6.9 Hz, OCHCH@CH2), 3.80 (s, 3H, PhOCH3), 3.68
(s, 3H, CH3OOC), 3.48 (dd, 1H, J 3.6, 6.5 Hz,
CHOMe), 3.40 (s, 3H, OCH3), 2.70–2.55 (m, 2H,
COCH2); 13C NMR (100 MHz, CDCl3): d 172.0
(O@COMe), 159.5, 137.8, 129.8 (2C), 129.5, 116.2,
113.8 (2C), 78.8, 78.3, 72.3, 71.9, 58.1 (COOCH3),
55.2 (PhOCH3), 51.8 (OCH3), 34.6 (OOCCH2). Anal.
Calcd for C17H24O6: C, 62.95; H, 7.46. Found: C,
62.70; H, 7.35.
25
colorless syrup: ½aꢁD ꢀ22 (c 0.5, CHCl3); 1H NMR
(CDCl3): d 7.34–7.24 (m, 7H, Ph), 6.84 (d, 2H, J
8.0 Hz, Ph), 5.97–5.92 (m, 1H, CH@CH2), 5.78–5.74
(m, 1H, CH@CH2), 5.42 (d, 1H, J 9.0 Hz CH@CHaHb),
5.38 (d, 1H, J 18.0 Hz, CH@CHaHb), 5.00 (d, 1H, J
17.4 Hz, CH@CHaHb), 4.98–4.90 (m, 2H, CH@CHaHb,

1410
Q. Chen, Y. Du / Carbohydrate Research 342 (2007) 1405–1411
CHOOC), 4.65, 4.48 (2d, 2H, J 10.5 Hz, PhCH2), 4.62,
4.36 (2d, 2H, J 11.2 Hz, PhCH2), 4.02 (t, 1H, J 6.8 Hz,
CHOPMB), 3.97–3.95 (m, 1H, OCHCH@CH2), 3.80
(s, 3H, PhOCH3), 3.57–3.55 (m, 1H, CHOMe), 3.32 (s,
3H, OCH3), 2.60–2.47 (m, 2H, COCH2), 2.04 (dd, 2H,
J 6.7, 13.3 Hz, CH2CH@CH2), 1.55–1.41 (m, 4H,
CH2CH2), 1.21 (d, 3H, J 6.0 Hz, CH2CH3); 13C NMR
(100 MHz, CDCl3): d 171.5 (O@COCH), 159.2, 138.4
(2C), 136.2, 133.3, 130.4 (2C), 129.8, 128.2 (2C), 127.7,
127.4 (2C), 119.4, 114.7, 113.6 (2C), 81.8, 80.1, 77.5,
74.0, 70.9, 58.6 (OCH3), 55.2 (PhOCH3), 36.5, 35.3,
33.4, 24.5, 19.9. Anal. Calcd for C30H40O6: C, 72.55;
H, 8.12. Found: C, 72.81; H, 8.01.
CH@CH2), 5.50 (d, 1H, J 17.3 Hz, CH@CHaHb), 5.42
(d, 1H, J 10.3 Hz, CH@CHaHb), 5.00 (d, 1H, J
17.2 Hz, CH@CHaHb), 4.97–4.92 (m, 2H, CH@CHaHb,
CHOOC), 4.62 (d, 1H, J 6.7 Hz, OCHCH@CH2), 4.67,
4.54 (2d, 2H, J 11.9 Hz, PhCH2), 4.48 (dd, 1H, J 3.6,
8.2 Hz, CHOMe), 3.34 (s, 3H, OCH3), 2.77 (dd, 1H, J
3.7, 16.1 Hz, COCHaHb), 2.52 (dd, 1H, J 8.4, 16.1 Hz,
COCHaHb), 2.04 (dd, 2H,
J
7.0, 13.8 Hz,
CH2CH@CH2), 1.53–1.43 (m, 4H, CH2CH2), 1.20 (d,
3H, J 6.1 Hz, CH2CH3); 13C NMR (100 MHz, CDCl3):
d 206.6 (C@O), 169.9 (O@COCH), 138.4, 137.2, 132.3,
128.5 (2C), 128.0, 127.9 (2C), 120.1, 114.7, 83.1, 80.5,
71.6, 71.4, 58.7 (OCH3), 37.1, 35.3, 33.4, 24.5, 19.9.
Anal. Calcd for C22H30O5: C, 70.56; H, 8.07. Found:
C, 70.91; H, 7.88.
3.10. (S)-Hept-6-en-2-yl (3R,4S,5S)-5-benzyloxy-4-
hydroxy-3-methoxy-hept-6-enoate (21)
3.12. Lactone 3
A soln of ester 20 (170 mg, 0.33 mmol) in CH2Cl2
(10 mL) at 0 ꢁC was treated with water (1 mL) and
DDQ (150 mg, 0.66 mmol), and then stirred at rt for
2 h. Satd aq NaHCO3 was added, and the aq layer
was extracted with CH2Cl2 (2 · 20 mL). The combined
organic extracts were dried over anhyd Na2SO4 and
concentrated to dryness. Column chromatography of
the residue (4:1 petroleum ether–EtOAc) gave 21
Diolefin 4 (550 mg, 1.4 mmol), dissolved in dry degassed
CH2Cl2 (100 mL), was added dropwise within 2 h to a
refluxing soln of ruthenium catalyst17 (360 mg,
0.4 mmol) in dry degassed CH2Cl2 (2 L). The mixture
was heated at reflux until complete consumption of the
starting material (20–24 h, TLC monitoring). After sol-
vent removal under diminished pressure, the residue
was purified by column chromatography (8:1 petroleum
ether–EtOAc) yielding first (Z)-3 (120 mg, 23.5%) and
then (E)-3 (250 mg, 46.5%) as colorless syrups: for the
25
(120 mg, 93%) as a colorless syrup: ½aꢁD ꢀ25 (c 0.5,
1
CHCl3), H NMR (CDCl3): d 7.34–7.26 (m, 5H, Ph),
5.86–5.82 (m, 1H, CH@CH2), 5.77–5.73 (m, 1H,
CH@CH2), 5.43 (d, 1H, J 10.2 Hz, CH@CHaHb), 5.38
(d, 1H, J 17.3 Hz, CH@CHaHb), 5.00 (d, 1H, J
17.3 Hz, CH@CHaHb), 4.96–4.91 (m, 2H, CH@CHaHb,
CHOOC), 4.63, 4.36 (2d, 2H, J 11.6 Hz, PhCH2),
3.99 (br s, 1H, CHOH), 3.81 (t, 1H, J 7.4 Hz,
OCHCH@CH2), 3.49 (d, 1H, J 6.5 Hz, CHOMe), 3.34
(s, 3H, OCH3), 2.67–2.55 (m, 2H, COCH2), 2.04 (dd,
2H, J 6.8, 13.6 Hz, CH2CH@CH2), 1.55–1.36 (m, 4H,
CH2CH2), 1.20 (d, 3H, J 6.1 Hz, CH2CH3); 13C NMR
(100 MHz, CDCl3): d 171.3 (O@COCH), 138.4, 138.1,
136.1, 128.3 (2C), 128.0 (2C), 127.6, 120.2, 114.7, 80.5,
76.1, 74.7, 71.1, 70.2, 58.7 (OCH3), 37.0, 35.3, 33.4,
24.6, 19.9. Anal. Calcd for C22H32O5: C, 70.18; H,
8.57. Found: C, 69.89; H, 8.48.
25
1
Z-isomer, ½aꢁD ꢀ28 (c 0.5, CHCl3); H NMR (CDCl3):
d
7.35–7.26 (m, 5H, Ph), 5.83–5.79 (m, 1H,
CH2CH@CH), 5.62 (t, 1H, J 9.5 Hz, CH2CH@CH),
4.89 (d, 1H, J 8.7 Hz, CHOOC), 4.83 (dd, 1H, J 6.3,
11.8 Hz, CHOBn), 4.62 (d, 1H, J 11.7 Hz, PhCH),
4.52 (d, 1H, J 11.5 Hz, PhCH), 3.40 (s, 3H, OCH3),
4.34 (dd, 1H, J 2.7, 9.4 Hz, CHOMe), 2.91 (dd, 1H, J
2.6, 14.8 Hz, OOCCHaHb), 2.70 (dd, 1H, J 9.3,
14.8 Hz, OOCCHaHb), 2.08 (dd, 2H, J 9.7, 16.9 Hz,
CH2CH@CH), 1.53–1.44 (m, 4H, CH2CH2), 1.20 (d,
3H, J 6.1 Hz, CH2CH3); 13C NMR (100 MHz, CDCl3):
d 205.6 (C@O), 169.1 (O@COCH), 137.3, 128.3 (2C),
128.1, 128.0 (2C), 127.8, 125.3, 79.5, 76.1, 72.3, 71.1,
58.2 (OCH3), 37.1, 32.7, 27.0, 22.7, 20.6; for the E-iso-
25
mer, ½aꢁD ꢀ26 (c 0.5, CHCl3), 1H NMR (CDCl3): d
3.11. (S)-Hept-6-en-2-yl (3R,5S)-5-benzyloxy-3-meth-
oxy-4-oxo-hept-6-enoate (4)
7.39–7.31 (m, 5H, Ph), 5.91–5.87 (m, 1H, CH2CH@CH),
5.42 (dd, 1H, J 4.7, 15.7 Hz, CH2CH@CH), 4.87 (t, 1H,
J 5.6 Hz, CHOOC), 4.63 (d, 1H, J 11.9 Hz, PhCH), 4.61
(d, 1H, J 7.0 Hz, CHOBn), 4.54 (d, 1H, J 11.8 Hz,
PhCH), 3.42 (s, 3H, OCH3), 4.19 (dd, 1H, J 3.1,
6.7 Hz, CHOMe), 3.11 (dd, 1H, J 3.0, 16.2 Hz, OOC-
CHaHb), 2.85 (dd, 1H, J 6.7, 16.3 Hz, OOCCHaHb),
2.19–2.17 (m, 1H, CHaHbCH@CH), 1.92–1.89 (m, 1H,
CHaHbCH@CH), 1.55–1.47 (m, 4H, CH2CH2), 1.14
(d, 3H, J 6.5 Hz, CH2CH3); 13C NMR (100 MHz,
CDCl3): d 204.3 (C@O), 169.0 (O@COCH), 137.5,
133.7, 128.5 (2C), 127.9, 127.6 (2C), 124.4, 83.5, 79.6,
71.9, 71.2, 58.4 (OCH3), 35.9, 32.1, 31.6, 21.7, 19.1;
To a soln of 21 (970 mg, 2.6 mmol) in dry CH2Cl2
(150 mL), Dess–Martin periodinane (1.65 g, 3.9 mmol)
was added and the reaction mixture was stirred for 3 h
at rt. After extraction with satd aq NaHCO3, the organ-
ic layer was separated, dried, and concentrated. The res-
idue was subjected to column chromatography on silica
gel (6:1 petroleum ether–EtOAc) to furnish compound 4
25
(802 mg, 83%) as a colorless syrup: ½aꢁD ꢀ30 (c 0.5,
1
CHCl3); H NMR (CDCl3): d 7.40–7.30 (m, 5H, Ph),
5.90–5.86 (m, 1H, CH@CH2), 5.77–5.74 (m, 1H,

Q. Chen, Y. Du / Carbohydrate Research 342 (2007) 1405–1411
1411
ESI(+)MS: m/z 347 [M+H]+, 369 [M+Na]+. Anal. Calcd
References
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3.13. Sporiolide B (1)
To a suspension of Pd/C (5% Pd, 100 mg) in MeOH
(50 mL) was added a soln of 3 (E/Z mixture, 250 mg,
0.72 mmol) in MeOH (20 mL). The mixture was allowed
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25
25
amorphous solid: ½aꢁD ꢀ32 (c 0.5, MeOH); lit.4 ½aꢁD ꢀ29
25
D
25
(c 0.5, CHCl3), ½aꢁ ꢀ33 (c 0.5, MeOH); lit.3 ½aꢁD ꢀ33 (c
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11), 4.44 (d, 1H, J 8.7 Hz, H-3), 4.30 (d, 1H, J 5.7 Hz,
H-5), 3.53 (s, 3H, OCH3), 3.43 (t, 1H, J 12.6 Hz, H-
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1H, H-6b), 1.58–1.69 (m, 2H, H-10b, H-6a), 1.48–1.57
(m, 2H, H-7b, H-9b), 1.38–1.47 (m, 2H, H-8b, H-9a),
1.25–1.36 (m, 2H, H-8a, H-10a), 1.23 (d, 3H, J 6.4 Hz,
H-12), 1.07–1.09 (m, 1H, H-7a); 13C NMR (100 MHz,
CDCl3): d 208.8 (C-4), 170.6 (C-1), 76.1 (C-5), 74.4 (C-
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12); MALDI-FTMS: calcd for C13H22O5: 258.1467
[M]+; found: 281.1403 [M+Na]+.
´
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.carres.
2007.04.013.