The first total synthesis of sporiolide B

Article abstract of DOI:10.1016/j.tetlet.2006.09.145

The first total synthesis of natural cytotoxic agent, sporiolide B, is described. d-Xylose was used as the chiral template to pre-control the absolute configuration during the synthesis. Yamaguchi esterification and ring closing metathesis greatly facilit

Full text of DOI:10.1016/j.tetlet.2006.09.145

Tetrahedron Letters 47 (2006) 8489–8492
The first total synthesis of sporiolide B
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, Beijing, PR China
Received 6 July 2006; revised 27 September 2006; accepted 28 September 2006
Available online 17 October 2006
Abstract—The first total synthesis of natural cytotoxic agent, sporiolide B, is described. D-Xylose was used as the chiral template to
pre-control the absolute configuration during the synthesis. Yamaguchi esterification and ring closing metathesis greatly facilitate
the target compound accomplishment.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Kobayashi and co-workers at Hokkaido University
recently reported a new cytotoxic 12-membered macro-
lide, designated sporiolide B (1).1 It was isolated from
the cultured broth of a fungus Cladosporium sp., which
was separated from an Okinawan marine brown alga
Actinotrichia fragilis. The spectroscopic data based
structure elucidation supposed that sporiolide B corre-
sponds to 3-O-methyl pandangolide 1 (2), a hexaketide
lactone whose absolute configuration has been deter-
mined very recently.2 Sporiolide B exhibits cytotoxicity
against L1210 cells (IC50 = 0.81 lg/mL) and antibacte-
rial activity against Micrococcus luteus (MIC =
16.7 lg/mL). The biological potential as well as the
uncertainty of its absolute structural configuration
marked it as a synthetic target for us. We report herein
the first total synthesis of sporiolide B starting from
D-xylose.
D-xylofuranosyl derivative 8,3 followed by one-pot allyl
isomerization (t-BuOK in DMSO) and cleavage
(Hg(OAc)2 in THF/H2O),4 gave hemiacetal 10 in a good
yield (80% from 8). The standard Wittig reaction of 10
and methyltriphenylphosphonium bromide in anhy-
drous THF at ꢀ50 ꢁC generated olefin 11, in which
the secondary alcohol was subsequently methylated with
MeI and NaH in DMF (!12). The acid hydrolysis of 12
with TsOH hydrate (!13), and regioselective iodin-
ation5 with Ph3P and I2 furnished iodide 14 in a 52% iso-
lated yield over four steps. SN2 substitution of iodide
with KCN,6 followed by acid hydrolysis in methanol
gave methyl ester 15. The secondary hydroxyl of 15
was oxidized with Dess–Martin periodinane7 to give
ketone 16 in an excellent yield (90%). Unfortunately,
free acid formation from 16 was troublesome under
basic conditions8 and the double bond migrated
analogue 17 was gained unambiguously. This migration
was confirmed by a correlated quartet (d 6.49 ppm, J =
7.1 Hz, @CHCH3) and doublet (d 1.79 ppm, J = 7.1 Hz,
CH3CH@) in NMR spectra.
As outlined in Scheme 1, we decided to prepare sporio-
lide B (1) by intercepting olefinic intermediate 3 that we
envisaged would be made available from ring closing
metathesis (RCM) of diene 4 after esterification of alco-
hol 5 and acid 6 (or its precursor 7). Key intermediate 6
(or 7) could be derived from D-xylose in order to keep
the proposed absolute configurations at C-3 and C-5
in sporiolide B (Fig. 1).
Alternatively, the secondary hydroxyl group of 15 was
protected by 4-methoxybenzyl (PMB) using 4-meth-
oxybenzyl trichloroacetimidate9 in the presence of
TMSOTf to give 18, which was hydrolyzed with LiOH,
furnished acid 7. The esterification of acid 7 and (S)-6-
hepten-2-ol (5)10 under Yamaguchi’s conditions11 affor-
ded diene derivative 19 (70% from 15), which was
subjected to cleavage of PMB group with DDQ12 and
oxidation with Dess–Martin periodinane, to form key
intermediate 4 in a 77% yield in two steps. Diene 4
was then exposed to the Grubbs catalyst
[PHCH@RuCl(PCy3)2, 30 mol %, 1.4 · 10ꢀ4 M in
The synthesis began with the preparation of acid 6 as
illustrated in Scheme 2. Thus, benzylation of known
Keywords: Sporiolide B; Macrolide; Natural product; Xylose; Cyto-
toxic agent.
*
Corresponding author. Tel.: +86 10 62914475; fax: +86 10
62923563; e-mail: duyuguo@rcees.ac.cn
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.145

8490
Q. Chen, Y. Du / Tetrahedron Letters 47 (2006) 8489–8492
OBn
OH
O
OMe
OBn
O
O
O
O
O
O
O
OMe
OMe
O
1
4
3
OMe
OBn
HOOC
or
D-xylose
+
OH
O
6
5
OMe
OBn
HOOC
OPMB
7
Scheme 1. Retrosynthetic analysis of sporiolide B (1).
presence of Pd/C reduced both benzyl group and double
bond to accomplish the total synthesis of sporiolide B,
identical in all physical data to that of reported for the
natural product14 (Scheme 3).
5
OH
O
OH
O
S
S
R
R
O
O
3
In summary, we have accomplished the first total syn-
thesis of sporiolide B in 15 linear steps and a 3.5% over-
all yield. The required stereochemical configurations at
C-3 and C-5 in sporiolide B were pre-controlled by using
D-xylose as the chiral template. Yamaguchi esterification
and ring closing metathesis greatly facilitate the target
accomplishment. The current report also provides an
attractive way for the preparation of other natural prod-
ucts, such as pandangolide 1a, pandangolide 1, and
sporiolide A.1,2,15
O
O
OMe
OH
1
2
Figure 1. Chemical structures of sporiolide B (1) and pandangolide 1
(2).
CH2Cl2]13 undergoing a ring closing metathesis (RCM)
to produce macrolide 3 in a form of E,Z mixture
(E/Z = 2/1). The hydrogenation of 3 with H2 in the
O
O
O
O
OAll
O
O
a
c
d
OH
D-xylose
OR
8 R = H
9 R = Bn
OBn
b
10
OMe
OBn
OR
OBn
OMe
OBn
f
h
MeOOC
R
O
O
OH
15
OH
13 R = OH
14 R = I
11 R = H
12 R = Me
g
e
OMe
OBn
OMe
OBn
j
i
MeOOC
HOOC
O
O
17
16
Scheme 2. Reagents and conditions: (a) Ref. 3; (b) BnBr, NaH, DMF, 2 h, 95% (a/b = 1.5/1); (c) (i) t-BuOK, DMSO, 80 ꢁC, 15 min; (ii) Hg(OAc)2,
THF/H2O, 30 min, 84% over two steps (a/b = 2/1); (d) n-BuLi, Ph3PCH3Br, THF, ꢀ50 ꢁC to rt, 12 h, 75%; (e) MeI, NaH, DMF, 2 h, 96%; (f)
TsOHÆH2O, MeOH/H2O, 3 h, 95%; (g) Ph3P, I2, Imidazole, THF, 12 h, 76%; (h) (i) KCN, MeOH/H2O, 12 h; (ii) aq 6 N HCl, MeOH/H2O, 80 ꢁC,
6 h, 63% in two steps; (i) Dess–Martin periodinane, CH2Cl2, 3 h, 90%; (j) LiOH, THF/H2O, 12 h, 85%.

Q. Chen, Y. Du / Tetrahedron Letters 47 (2006) 8489–8492
8491
OMe OBn
c
a
e
OMe
OBn
ROOC
15
O
O
OPMB
OR
18 R = Me
7 R = H
b
19 R = PMB
20 R = H
d
OH
O
OBn
O
f
g
OMe
OBn
O
O
O
O
O
OMe
O
OMe
O
4
Sporiolide B (1)
3 (E/Z = 2/1)
Scheme 3. Reagents and conditions: (a) PMBOC(NH)CCl3, TMSOTf, CH2Cl2, 2 h, 75%; (b) LiOH, THF/H2O, 12 h; (c) (S)-6-hepten-2-ol, 2,4,6-
trichlorobenzoyl chloride, TEA, DMAP, THF, 18 h, 78% in two steps; (d) DDQ, CH2Cl2/H2O, 2 h, 93%; (e) Dess–Martin periodinane, CH2Cl2, 3 h,
83%; (f) 30% PhCH@RuCl2(PCy3)2, CH2Cl2, reflux, 24 h, 70% (E/Z = 2/1); (g) H2, Pd/C, MeOH, 12 h, 81%.
1H), 7.30–7.39 (m, 5H); For compound 17: 1H NMR
Acknowledgments
(CDCl3): d 1.79 (d, 3H, J = 7.1 Hz), 2.55 (dd, 1H, J = 8.5,
16.0 Hz), 2.65 (dd, 1H, J = 4.6, 15.8 Hz), 3.29 (s, 3H), 4.62
This work was supported by the National Basic
Research Program of China (2003CB415001) and the
(dd, 1H, J = 4.7, 8.4 Hz), 4.87 (s, 2H), 6.49 (q, 1H, J =
1
7.1 Hz), 7.31–7.41 (m, 5H); For compound 19: H NMR
NNSF of China (20372081, 30330690).
(CDCl3): d 1.21 (d, 3H, J = 6.0 Hz), 1.41–1.55 (m, 4H),
2.04 (dd, 2H, J = 6.7, 13.3 Hz), 2.47–2.60 (m, 2H), 3.32 (s,
3H), 3.55–3.57 (m, 1H), 3.80 (s, 3H), 3.95–3.97 (m, 1H),
References and notes
4.02 (t, 1H, J = 6.8 Hz), 4.36 (d, 1H, J = 11.7 Hz), 4.48
(d, 1H, J = 10.9 Hz), 4.62 (d, 1H, J = 10.8 Hz), 4.65 (d,
1H, J = 9.6 Hz), 4.90–4.98 (m, 2H), 5.00 (d, 1H,
J = 17.4 Hz), 5.38 (d, 1H, J = 18.0 Hz), 5.42 (d, 1H, J =
9.0 Hz), 5.75–5.77 (m, 1H), 5.94–5.96 (m, 1H), 6.84 (d, 2H,
J = 8.0 Hz), 7.24–7.34 (m, 7H); 13C NMR (CDCl3): d
19.91, 24.54, 33.40, 35.27, 36.51, 55.19, 58.63, 70.86, 70.92,
74.04, 77.54, 80.06, 81.79, 113.59, 114.70, 119.35, 127.40,
127.65, 128.24, 129.78, 130.44, 133.29, 136.15, 138.36,
138.42, 159.17, 171.47; For compound 20: 1H NMR
(CDCl3): d 1.20 (d, 3H, J = 6.1 Hz), 1.36–1.55 (m, 4H),
2.04 (dd, 2H, J = 6.8, 13.6 Hz), 2.55–2.67 (m, 2H), 3.34 (s,
3H), 3.49 (d, 1H, J = 6.5 Hz), 3.81 (t, 1H, J = 7.4 Hz),
3.99 (br s, 1H), 4.36 (d, 1H, J = 11.7 Hz), 4.63 (d, 1H,
J = 11.6 Hz), 4.91–4.96 (m, 2H), 5.38 (d, 1H,
J = 17.3 Hz), 5.43 (d, 1H, J = 10.2 Hz), 5.74–5.76 (m,
1H), 5.84–5.86 (m, 1H), 6.84 (d, 2H, J = 8.0 Hz), 7.26–
7.34 (m, 5H); 13C NMR (CDCl3): d 19.92, 24.57, 33.42,
35.27, 37.04, 58.68, 70.18, 71.14, 74.69, 76.11, 80.53,
114.74, 120.17, 127.62, 127.96, 128.34, 136.10, 138.08,
138.38, 171.29; For compound 4: 1H NMR (CDCl3):
d 1.20 (d, 3H, J = 6.1 Hz), 1.34–1.53 (m, 4H), 2.04
(dd, 2H, J = 7.0, 13.8 Hz), 2.52 (dd, 1H, J = 8.4, 16.1 Hz),
2.77 (dd, 1H, J = 3.7, 16.1 Hz), 3.34 (s, 3H), 4.48 (dd, 1H,
J = 3.6, 8.2 Hz), 4.54 (d, 1H, J = 11.9 Hz), 4.62 (d, 1H,
J = 6.7 Hz), 4.67 (d, 1H, J = 11.8 Hz), 4.92–4.97 (m, 2H),
5.00 (d, 1H, J = 17.2 Hz), 5.42 (d, 1H, J = 10.3 Hz), 5.50
(d, 1H, J = 17.3 Hz), 5.75–5.77 (m, 1H), 5.87–5.89 (m,
1H), 7.30–7.40 (m, 5H); 13C NMR (CDCl3): d 19.88,
24.52, 33.41, 35.26, 37.08, 58.67, 71.38, 71.57, 80.53, 83.11,
114.73, 120.14, 127.87, 127.96, 128.49, 132.34, 137.21,
138.38, 169.93, 206.55; For compound 3 (Z-isomer): 1H
NMR (CDCl3): d 1.20 (d, 3H, J = 6.1 Hz), 1.44–1.53 (m,
4H), 2.08 (dd, 2H, J = 9.7, 16.9 Hz), 2.70 (dd, 1H, J = 9.3,
14.8 Hz), 2.91 (dd, 1H, J = 2.6, 14.8 Hz), 3.40 (s, 3H), 4.34
(dd, 1H, J = 2.7, 9.4 Hz), 4.52 (d, 1H, J = 11.5 Hz), 4.62
(d, 1H, J = 11.7 Hz), 4.83 (dd, 1H, J = 6.3, 11.8 Hz), 4.89
(d, 1H, J = 8.7 Hz), 5.62 (t, 1H, J = 9.5 Hz), 5.80–5.82
(m, 1H), 7.26–7.35 (m, 5H); 13C NMR (CDCl3): d 20.61,
1. Shigemori, H.; Kasai, Y.; Komatsu, K.; Tsuda, M.;
Mikami, Y.; Kobayashi, J. Mar. Drugs 2004, 2, 164–169.
2. Gesner, S.; Cohen, N.; Iian, M.; Yarden, O.; Carmeli, S.
J. Nat. Prod. 2005, 68, 1350–1353.
3. Ireland, R. E.; Norbeck, D. W. J. Am. Chem. Soc. 1985,
107, 3279–3285.
4. Gigg, R.; Warren, C. D. J. Chem. Soc. C 1968, 1903–1911.
5. Uehara, H.; Oishi, T.; Inoue, M.; Shoji, M.; Nagumo, Y.;
Kosaka, M.; Brazidec, J. L.; Hirama, M. Tetrahedron
2002, 58, 6493–6512.
6. Muratake, H.; Natsume, M. Tetrahedron 2006, 62, 7056–
7070.
7. Dess, P. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–
4156.
8. Chakraborty, T. K.; Ghosh, S.; Laxman, P.; Dutta, S.;
Samanta, R. Tetrahedron Lett. 2005, 46, 5447–5450.
9. Andrus, M. B.; Shih, T. J. Org. Chem. 1996, 61, 8780–
8785.
10. Takahata, H.; Yotsui, Y.; Momose, T. Tetrahedron 1998,
54, 13505–13516.
11. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yama-
guchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
12. (a) Oikawa, Y.; Tanaka, T.; Horita, K.; Yonemitsu, O.
Tetrahedron Lett. 1984, 25, 5397–5400; (b) Tanaka, T.;
Oikawa, Y.; Hamada, T.; Yonemitsu, O. Tetrahedron
Lett. 1986, 27, 3651–3654.
13. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–
4450.
14. Yields refer to isolated and chromatographically pure
compounds. All the compounds exhibited spectral data
(1H, 13C NMR, and mass or elemental analysis) consistent
with their structures. Selected spectral data for compound
1
16: H NMR (CDCl3): d 2.58 (dd, 1H, J = 8.1, 16.3 Hz),
2.81 (dd, 1H, J= 4.2, 16.3 Hz), 3.34 (s, 3H), 3.68 (s, 3H),
4.48 (dd, 1H, J = 4.2, 8.1 Hz), 4.55 (d, 1H, J = 11.8 Hz),
4.62 (d, 1H, J= 6.6 Hz), 4.68 (d, 1H, J = 11.8 Hz), 5.42 (d,
1H, J = 10.4 Hz), 5.49 (d, 1H, J = 17.3 Hz), 5.86–5.88 (m,

8492
Q. Chen, Y. Du / Tetrahedron Letters 47 (2006) 8489–8492
22.69, 26.98, 32.69, 37.14, 58.19, 71.11, 72.31, 76.13, 79.46,
1H NMR (CDCl3): d 1.07–1.09 (m, 1H), 1.23 (d, 3H,
J = 6.4 Hz), 1.25–1.36 (m, 2H), 1.38–1.47 (m, 2H), 1.48–
1.57 (m, 2H), 1.58–1.69 (m, 2H), 2.04–2.06 (m, 1H), 2.60
(dd, 1H, J = 8.8, 13.9 Hz), 3.43 (t, 1H, J = 12.6 Hz), 3.53
(s, 3H), 4.30 (d, 1H, J = 5.7 Hz), 4.44 (d, 1H, J = 8.7 Hz),
4.81–4.83 (m, 1H); 13C NMR (CDCl3): 20.83, 22.15, 23.82,
26.54, 29.96, 33.42, 41.35, 58.41, 73.31, 74.37, 76.12,
170.63, 208.76; ESI(+)-MS: Calcd for C13H22O5: 258.15
[M]; Found 281.3 [M+Na]+.
125.30, 127.84, 128.01 ,128.12, 128.38, 128.44, 137.59,
137.28, 169.08, 205.57; For E-isomer: 1H NMR (CDCl3): d
1.14 (d, 3H, J = 6.5 Hz), 1.47–1.55 (m, 4H), 1.91–1.93 (m,
1H), 2.17–2.19 (m, 1H), 2.85 (dd, 1H, J = 6.7, 16.3 Hz),
3.11 (dd, 1H, J = 3.0, 16.2 Hz), 3.42 (s, 3H), 4.19 (dd, 1H,
J = 3.1, 6.7 Hz), 4.54 (d, 1H, J = 11.8 Hz), 4.61 (d, 1H,
J = 7.0 Hz), 4.63 (d, 1H, J = 11.9 Hz), 4.87 (t, 1H,
J = 5.6 Hz), 5.42 (dd, 1H, J = 4.7, 15.7 Hz), 5.88–5.90
(m, 1H), 7.31–7.39 (m, 5H); 13C NMR (CDCl3): d 19.10,
21.74, 31.57, 32.12, 35.90, 58.42, 71.20, 71.87, 79.59, 83.45,
124.39, 127.62, 127.92, 128.51, 133.66, 137.47, 168.97,
204.29; ESI(+)-MS: Calcd for C20H26O5: 346.18 [M];
Found 347 [M+H]+, 369 [M+Na]+; For compound 1,
15. (a) Smith, C. J.; Abbanat, D.; Bernan, V. S.; Maiese, W.
M.; Greenstein, M.; Jompa, J.; Tahir, A.; Ireland, C. M. J.
Nat. Prod. 2000, 63, 142–145; (b) Jadulco, R.; Proksch, P.;
Wray, V.; Berg, A.; Grafe, U. J. Nat. Prod. 2001, 64, 527–
530; (c) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.;
Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2006, 23,
26–78.
25
25
½aꢁD ꢀ29 (c 0.5, CHCl3), ½aꢁD ꢀ33 (c 0.5, MeOH);
25
{reported value for 1 in Ref. 1: ½aꢁD ꢀ33 (c 0.3, MeOH)};