Stereoselective total synthesis of cytotoxic sporiolide A

Article abstract of DOI:10.1016/j.tetlet.2010.08.014

A simple and highly efficient stereoselective total synthesis of cytotoxic agent sporiolide A has been achieved starting from d-mannitol; the strategy of synthesis utilizes stereoselective zinc-mediated allylation, aldol coupling and ring-closing metathes

Full text of DOI:10.1016/j.tetlet.2010.08.014

Tetrahedron Letters 51 (2010) 5440–5442
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Stereoselective total synthesis of cytotoxic sporiolide A
⇑
D. Kumar Reddy, K. Rajesh, V. Shekhar, D. Chanti Babu, Y. Venkateswarlu
Organic Chemistry Division-I, Natural Products Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and highly efficient stereoselective total synthesis of cytotoxic agent sporiolide A has been
Received 21 June 2010
Revised 2 August 2010
Accepted 5 August 2010
Available online 12 August 2010
achieved starting from D-mannitol; the strategy of synthesis utilizes stereoselective zinc-mediated ally-
lation, aldol coupling and ring-closing metathesis as key steps.
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Dr. J. Madhusudhana Rao on
his 60th birthday and for his excellent
contributions in natural products
Keywords:
Sporiolide A
Zinc-mediated allylation
Aldol coupling
Ring-closing metathesis
1. Introduction
OH
OH
O
OH
O
Marine fungi are attractive sources for anticancer, antifungal
and antibacterial secondary metabolites with various exotic struc-
tural features.1 Sporiolide A (1), sporiolide B (2) and pandangolide
1 (3) are 12-membered lactones isolated from the cultured fungal
broth of Cladosporium sp. of an Okinawan brown alga Actinotrichia
fragilis and the Red sea sponge Niphates rowi, respectively.2 Sporio-
lides A and B were found to exhibit cytotoxicity against L1210 cells
O
O
O
O
OBZ
O
OMe
O
OH
O
1
2
3
with IC50 values of 0.13 and 0.81
assays revealed that sporiolide A exhibits antifungal activity
against Candida albicans (MIC 16.7 g/mL), Cryptococcus neofor-
g/mL) and Neurospora
g/mL) and showed antibacterial activity against Micro-
g/mL), while sporiolide B (2) had antibacterial
lg/mL, respectively. Further
Our planned approach to sporiolide A (1) involved the stereo
selective zinc-mediated allylation, aldol coupling and ring-closing
metathesis as key steps from D-mannitol as a chiral starting mate-
rial. The retro synthesis is depicted in Scheme 1.
l
mans (8.4
crassa (8.4
coccus luteus (16.7
l
l
g/mL), Aspergillus niger (16.7
l
l
2. Results and discussion
activity against M. luteus (16.7 lg/mL). Its structure was deter-
mined on the basis of spectroscopic methods.3 To our knowledge,
The synthesis of sporiolide A (1) was achieved starting from the
readily available D-mannitol diacetonide, which was oxidized fol-
only one synthesis was reported on sporiolide A (1) starting from
D
-glucal by Yuguo Du et al.4a Yuguo Du et al. also reported synthe-
lowing a known procedure,6 to give (R)-2,3-O-isopropylidene alde-
hyde 4 (Scheme 2). Compound 4 was subjected to the Zn-mediated
allylation in aqueous medium following operationally simple
Luche’s7 procedure to afford highly diastereoselective anti homoal-
lylic alcohol8 (syn/anti = 5%:95%) which was protected as the ben-
zyl ether 5. The acetonide protection group in 5 was removed on
treatment with aqueous TFA to afford diol 6 which was selectively
protected with TBSCl to afford monosilyl ether 7. The secondary
hydroxyl in 7 was protected with p-methoxy benzyl bromide to af-
ford p-methoxybenzyl ether 8. The tert-butyldimethylsilyl ether in
sis of sporiolide B.4b Our continued interest towards the total
synthesis of biologically active natural products5 prompted us to
undertake the synthesis of this demanding target from commer-
cially available D-mannitol.
⇑
Corresponding author. Tel.: +91 40 27193167; fax: +91 40 27160512.
E-mail address: luchem@iict.res.in (Y. Venkateswarlu).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.014

D. Kumar Reddy et al. / Tetrahedron Letters 51 (2010) 5440–5442
5441
OH
O
OPMB
O
O
O
O
O
H
O
OH
OBn
OBZ
O
10
1
4
Scheme 1.
O
O
O
a
OH
OH
b
O
OH
c
OTBS
H
OBn
O
OBn
OBn
4
5
6
7
PMB
PMB
O
O
PMB
OTBS
O
O
d
e
f
OH
O
OBn
OBn OH
OBn
9
8
10
PMB
O
OH
i
h
O
O
g
O
O
OBZ
OBn
11
OBZ
OBn
12
O
OH
OBn
O
j
K
O
O
O
O
O
OBZ
OBn
OBZ
O
OBZ
O
13
14
1
Scheme 2. Reagents and conditions: (a) (i) Zn, allyl bromide, THF, saturated solution of NH4Cl (cat), 6 h, 90%; (ii) BnBr, NaH, TBAI, THF.0 °C to rt, 2 h, 85%; (b) TFA–water, rt,
5 h, 90%; (c) TBDMSCl, imidazole, dry CH2Cl2, 4 h, 93%; (d) PMBCl, NaH, DMF, 2 h, 82%; (e) TBAF, THF, 0 °C to rt, 85%; (f) (i) 2-iodoxybenzoic acid, DMSO, CH2Cl2, 3 h, 92%; (ii)
16, LiHMDS, dry THF, ꢀ78 °C, 6 h, 54%; (g) BzCl, Pyr, DMAP, 4 h, 92%; (h) DDQ, CH2Cl2/H2O, 2 h, 85%; (i) Dess–Martin periodinane, CH2Cl2, 3 h, 80%; (j) 30% Grubbs I catalyst
CH2Cl2, reflux, 24 h, 70%; (k) H2, Pd/C, MeOH, 24 h, 95%.
compound 8 was removed using TBAF to afford primary alcohol 9.9
The primary alcohol in 9 was oxidized using IBX (2-iodoxybenzoic
acid) in DMSO to afford the corresponding aldehyde, which was
subjected to the aldol coupling with ester 16 (Scheme 3)10 using
LiHMDS as base11 to furnish secondary alcohol compound 10 with
high diastereoselectivity (syn/anti = 20%:80%) favoring anti-isomer.
The pure anti-isomer was separated by column chromatography.
The absolute stereochemistry of the newly generated center in
compound 10 bearing the hydroxyl group was determined by
modified Mosher’s method12 and found to be in R-configuration
(Fig. 1). The negative chemical shift difference to the left side of
MTPA plane and positive chemical shift differences to the right side
of MTPA plane determined that hydroxyl stereochemistry is in R-
configuration (Fig. 1).
O
O
The hydroxyl group was subjected to benzoylation with BzCl in
pyridine to afford benzoyl ester 11. The deprotection of PMB group
in 11 with DDQ afforded secondary alcohol 12 which was oxidized
following the Dess–Martin periodinane oxidation to afford keto
diene 13. We also tried the same conversion with known proce-
dures using IBX oxidation and Swern oxidation, without success.
The diene was then subjected to ring-closing metathesis (RCM)
O
a, b
15
16
Scheme 3. Reagents and conditions: (a) allyl chloride, Mg, CuCN, THF, 0 °C to rt,
overnight; (b) Ac2O, pyridine, 0 °C to rt, 3 h, 92%.

5442
D. Kumar Reddy et al. / Tetrahedron Letters 51 (2010) 5440–5442
3. Shigemori, H.; Kasai, Y.; Komatsu, K.; Tsuda, M.; Mikami, Y.; Kobayashi, J. Mar.
-0.2
Drugs 2004, 2, 164–169.
4. (a) Du, Y.; Chen, Q.; Linhardt, R. J. J. Org. Chem. 2006, 71, 8446–8451; (b) Chen,
Q.; Du, Y. Tetrahedron Lett. 2006, 47, 8489–8492.
O
0.1
0.1
OMTPA
-0.19
-0.2
0.08
5. (a) Selvam, J. J. P.; Rajesh, K.; Suresh, V.; Chanti Babu, D.; Venkateswarlu, Y.
Tetrahedron: Asymmetry 2009, 20, 1115–1119; (b) Suresh, V.; Selvam, J. J. P.;
Rajesh, K.; Venkateswarlu, Y. Tetrahedron: Asymmetry 2008, 19, 1509–1533; (c)
Shekhar, V.; Kumar Reddy, D.; Suresh, V.; Chanti Babu, D.; Venkateswarlu, Y.
Tetrahedron Lett. 2010, 51, 946–948.
O
R
0.02
H
-0.07
O
0.03
O
-0.3 H
H
-0.1
6. Schmid, C. R.; Bryant, J. D. Org. Synth. 1993, 72, 6–13.
7. (a) Petrier, C.; Luche, J. L. J. Org. Chem. 1985, 50, 910; (b) Einhorn, C.; Luche, J. L.
J. Organomet. Chem. 1987, 322, 177.
8. Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104–6107.
OMe
9. Toshima, K.; Yamaguchi, H.; Jyojima, T.; Noguchi, Y.; Nakata, M.; Matsumura,
M. Tetrahedron Lett. 1996, 37, 1073–1076. and references cited therein.
10. Acetyl fragment 16 was synthesized (Scheme 3) from commercially available
epoxide 15, which was subjected to copper (I) cyanide-promoted regioselective
nucleophilic ring-opening with allyl magnesium chloride to provide the
corresponding alcohol in 85% yield; acetylation of alcohol by use of acetic
anhydride and pyridine yielded 16.
11. (a) Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pirrung, M. C.; White, C. T.;
VanDerveer, D. J. Org. Chem. 1980, 45, 3846–3856; (b) Oikawa, H.; Oikawa, M.;
Ueno, T.; Ichihara, A. Tetrahedron Lett. 1994, 35, 4809–4812.
12. (a) KumarReddy, D.; Shekhar, V.; Srikanth Reddy, T.; Purushotham Reddy, S.;
Venkateswarlu, Y. Tetrahedron: Asymmetry 2009, 20, 2315–2319; (b) Ohtani, I.;
Kusumi, J.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092–4096;
(c) Yoshido, W. Y.; Bryan, P. J.; Baker, B. J.; McClintock, J. B. J. Org. Chem. 1995,
60, 780–782.
Figure 1. Determination of absolute configuration and
MTPA ester derivatives of 10 (
d = dS ꢀ dR).
Dd values for the S and R-
D
using Grubbs 1st generation catalyst13 to afford macrolide 14. Fi-
nally, the reduction of the double bond and debenzylation in 14
was achieved by hydrogenation over Pd/C to afford sporiolide A
(1)14 (Scheme 2). The physical and spectral data of compound 1
were found to be identical with that of reported natural product3
{½a 2D5
ꢁ
ꢀ15.2 (c 0.1, MeOH), reported ½a D25
ꢀ14 (c 0.1, MeOH)}.
ꢁ
In conclusion, an efficient stereoselective total synthesis of spo-
13. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450.
14. Spectral data for selected compounds:
riolide A (1) has been achieved in 13 steps with a 7.00% overall
yield from D-mannitol.
Compound 10: ½a 2D5
ꢁ
ꢀ13.6 (c 1, CHCl3); IR (neat): 3480, 3072, 2932, 1723, 1612,
1513, 1454, 1248, 1175, 1085,1034, 914, 768, 699 cmꢀ1
.
1H NMR (300 MHz,
CDCl3): d 7.35–7.16 (m, 7H), 6.87–6.79 (m, 2H), 5.97–5.67 (m, 2H), 5.17–5.00
(m, 3H), 4.99–4.87 (m, 2H), 4.64 (d, 1H, J = 10.9 Hz), 4.58 (d, 1H, J = 10. 7), 4.57–
4.51 (m, 2H), 4.14 (t, 1H, J = 6.3 Hz), 3.77 (s, 3H), 3.74–3.67 (m, 1H), 3.59–3.52
(m, 1H), 3.08 (br s, OH), 2.61–2.56 (m, 1H), 2.51–2.40 (m, 3H), 2.12–2.97 (m,
2H), 1.75–1.59 (m, 1H), 1.48–1.61(m, 1H), 1.21 (d, 3H, J = 6.2 Hz). 13C NMR
(75 MHz, CDCl3): d 172.7, 159.1, 138.2, 137.5, 135.1, 130.4, 129.5, 128.2, 127.7,
127.5, 117.1, 115.1, 113.6, 96.1, 81.4, 79.0, 73.3, 70.6, 68.5, 55.0, 37.5, 35.0,
34.5, 29.6, 19.9. MS-ESIMS: m/z = 483 [M+H]+.
Acknowledgement
The authors D.K.R., K.R., V.S. and D.C.B. are thankful to CSIR,
New Delhi, for the financial support.
References and notes
Compound 1: ½a 2D5
ꢁ
ꢀ15.2 (c 0.1, MeOH); IR (neat): 3447, 2934, 1722, 1452,
1263, 1173, 1110, 766, 713 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d 8.07–8.01 (m,
1. (a) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat.
Prod. Rep. 2004, 21, 1–49; (b) Faulkner, D. Nat. Prod. Rep. 2002, 19, 1–48; (c)
Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat.
Prod. Rep. 2005, 22, 15–61; (d) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.;
Northcote, P. T.; Prinsep, P. R. Nat. Prod. Rep. 2006, 23, 26–78; (e) Tsuda, M.;
Mugishima, T.; Komatsu, K.; Sone, T.; Tanaka, M. J. Nat. Prod. 2003, 66, 412–415.
2. Kobayashi, J.; Tsuda, M. Phytochem. Rev. 2004, 3, 267–274.
2H), 7.62–7.55 (m, 1H), 7.49–7.41 (m, 2H), 5.99 (d, 1H, J = 10.3 Hz), 5.04–4.90
(m, 1H), 4.41 (t, 1H, J = 5.2 Hz), 3.47 (dd, 1H, J = 10.2, 16.8 Hz), 2.81 (d, 1H,
J = 16.8 Hz), 2.06–1.95 (m, 1H), 1.71–1.54 (m, 1H), 1.51–1.36 (m, 3H), 1.35–
1.28 (m, 3H), 1.27 (d, 3H, J = 5.6 Hz), 1.26–1.22 (m, 1H), 1.20–1.06 (m, 1H).
13CNMR (75 MHz, CDCl3): d 207.4, 168.3, 165.2, 134.0, 129.9, 128.6, 128.3, 75.6,
73.5, 67.6, 39.9, 34.9, 31.5, 26.0, 20.7, 19.7. MS-ESIMS: m/z = 371 [M+Na]+.