Carbohydrate-based first stereoselective total synthesis of bioactive cytospolide P

Article abstract of DOI:10.1039/c4ob00323c

A facile carbohydrate-based highly stereoselective synthetic route has been developed for the cytospolide P (1) from d-ribose for the first time. Key steps of the synthesis include Wittig homologation, regioselective epoxide ring opening, Sharpless asymmetric epoxidation, Evans aldol reaction, and Yamaguchi macrolactonization. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00323c

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Carbohydrate-based first stereoselective total
synthesis of bioactive cytospolide P†
Cite this: Org. Biomol. Chem., 2014,
12, 3358
Pathi Suman and Bhimapaka China Raju*
Received 12th February 2014,
Accepted 18th March 2014
DOI: 10.1039/c4ob00323c
www.rsc.org/obc
A facile carbohydrate-based highly stereoselective synthetic route
has been developed for the cytospolide P (1) from D-ribose for the
first time. Key steps of the synthesis include Wittig homologation,
regioselective epoxide ring opening, Sharpless asymmetric epoxi-
dation, Evans aldol reaction, and Yamaguchi macrolactonization.
The pharmaceutical industry has been continuously searching
for new biologically active compounds. The main goal of this
research is to synthesize the compounds with potential bio-
logical applications particularly for cancer. Macrolides, par-
ticularly lactones with medium-sized rings (8–10 membered),
are scarce, and continue to attract the attention of chemists
due to their interesting biological properties.1 Zhang et al. iso-
lated cytospolides A–E,2 cytospolides F–Q and decytospolides
A–B3 from the endophytic fungus Cytospora sp. Cytospolides
(A–E) have an unprecedented 15-carbon skeleton with a
unique C-2 methyl group. These structures were elucidated by
spectroscopic analysis, chemical interconversion, and X-ray
single crystal diffraction studies. Cytospolide P (Fig. 1) with
(2S) configuration was cytotoxic against A549, QGY, and U973
cell lines. It is interesting to note that the cytospolide P has
different functional groups (keto at C-3, acetate at C-5 and
hydroxy at C-8) when compared to other cytospolides. The
design and synthesis of any molecule is sensible by imple-
menting important protocols and suitable protecting groups
to accomplish the target molecule in an efficient manner.
Though cytospolide P is an interesting molecule, there has
been no report of its successful total synthesis. We have long
term interest in total synthesis of natural products4 and bio-
logically active heterocyclic compounds.5 Herein, we report the
first stereoselective total synthesis of cytospolide P starting
from D-ribose.
Fig. 1 Structures of cytospolide A–D, E, and P (1).
The hypothesized retrosynthetic analysis indicated that
cytospolide P (1) can arise via the Yamaguchi lactonization of
seco acid 3 followed by selective deprotection and oxidation.
Seco acid 3 in turn could be accessed from chiral primary
alcohol 4 by means of the Evans aldol reaction. The chiral
primary alcohol 4 could be synthesized by a six step sequence
from olefin 5 using the Sharpless epoxidation protocol, which
in turn could easily be accessed from commercially available
D-ribose. Accordingly, a retrosynthetic analysis is delineated in
Scheme 1.
Synthesis of olefin 5 (Scheme 2) having two stereo centres
was accomplished from D-ribose in an efficient manner. Aceto-
nide protection of D-ribose followed by reduction with NaBH4
and oxidation using NaIO4 furnished 2,3-O-isopropylidene-L-
erythrose 6 in 79% yield.6 Four carbon Wittig homologation of
6 and subsequent hydrogenation with Pd/C led to primary
alcohol 7.7 The alcohol was treated with TsCl in the presence
of DMAP to yield a tosylated compound and subsequent aceto-
nide deprotection with p-TsOH in methanol to obtain diol 8 in
82% yield. Compound 8 was treated with K2CO3–MeOH8 to
give epoxy alcohol and protection of the secondary alcohol
with PMB-Br led to 9. Initially, we opened the terminal epoxide
with ally magnesium bromide in the presence of CuI, which
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500 007, India. E-mail: chinaraju@iict.res.in; Fax: (+91)-40-27160512
†Electronic supplementary information (ESI) available: Experimental details and
scanned copies of 1H and 13C NMR spectra for new compounds. See DOI:
10.1039/c4ob00323c
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Scheme 3 Reagents and conditions: (a) (1) O3, CH2Cl2, −78 °C; (2)
Ph3PvCHCO2C2H5, benzene, r.t., 2 h, 85% over two steps; (b) DIBAL-H,
CH2Cl2, 0 °C to r.t., 3 h, 78%; (c) (−)-DIPT, Ti(OiPr)4, TBHP, CH2Cl2,
−20 °C, 3 h, 87%; (d) (1) Red-Al, THF, 0 °C to r.t., 2 h; (2) PhCH(OMe)2,
PPTS, CH2Cl2, 0 °C, 3 h, 85% over two steps; (e) DIBAL-H, CH2Cl2,
−20 °C, 2 h, 86%; (f) Dess–Martin periodinane, CH2Cl2, 0 °C to r.t., 1 h.
Scheme 1 Retrosynthetic analysis of cytospolide P (1).
Scheme 4 Reagents and conditions: (a) propionyloxazolidinone,
Bu2BOTf, DIPEA, CH2Cl2, −78 °C, 25% yield; (b) propionyloxazolidinone
(1.0 mmol), TiCl4 (1.2 mmol), 5 min, 0 °C, DIPEA, 30 min, NMP, CH2Cl2,
−78 °C to 0 °C, 1 h; (c) propionyloxazolidinone (1.0 mmol), TiCl4
(1.0 mmol), 25 min, 0 °C, DIPEA, 45 min, NMP, CH2Cl2, −78 °C to
0 °C, 1 h.
Scheme 2 Reagents and conditions: (a) (1) acetone, conc. H2SO4, r.t.,
2.5 h; (2) NaBH4, MeOH, 0 °C, 1 h then NaIO4, t-BuOH, H2O, 25 °C, 79%
over two steps; (b) (1) n-BuPh3PBr, n-BuLi, THF, −78 °C to r.t., 3 h; (2)
Pd/C, H2, EtOH, r.t., 4 h, 83% over two steps; (c) (1) TsCl, Et3N, cat.
DMAP, CH2Cl2, 0 °C to r.t., 4 h; (2) p-TsOH, MeOH, 0 °C to r.t., 2 h, 82%
over two steps; (d) (1) K2CO3, MeOH, 0 °C, 2 h; (2) PMB-Br, NaH, TBAI,
THF, 0 °C to r.t., 4 h, 80% over two steps; (e) allyl magnesium bromide,
CuBr, THF, 0 °C, 3 h, 87%; (f) MOMCl, DIPEA, CH2Cl2, 0 °C to r.t.,
8 h, 85%.
Scheme 5 Reagents and conditions: (a) TBSOTf/2,6-lutidine, CH2Cl2,
−78 °C, 2 h, 92%; (b) (1) DDQ, CH2Cl2, 0 °C, 30 min; (2) LiOH, H2O2,
THF–H2O (4 : 1), 0 °C, 5 h, 87% over two steps.
resulted in lower yields of product 10. However, on further
optimization, we observed the formation of product 10 with
CuBr in good yield (87%).8a The resulting secondary alcohol
was then protected with MOMCl to obtain 5.
After the successful synthesis of compound 5, we focused
on creating two other stereo centres (at C-5 and C-2) to obtain
seco acid 3 (Schemes 3–5). Accordingly, ozonolysis9 of terminal
olefin 5 afforded the corresponding aldehyde and subsequent
two carbon Wittig homologation led to α,β-unsaturated ester
11 (E-isomer, 85% yield), which was subjected to DIBAL-H
reduction, resulting in allylic alcohol 12. Sharpless asymmetric
epoxidation of 12 in the presence of (−)-diisopropyl tartrate,
Ti(OiPr)4 and TBHP at −20 °C gave epoxy alcohol 13 in
87% yield.10 Regioselective ring opening of epoxide 13 in the
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presence of Red-Al yielded the corresponding 1,3-diol11 and major role in obtaining the target molecule. To deprotect
subsequent protection with benzyl dimethoxyl acetal in the these groups delicately, we have planned selective debenzyla-
presence of a catalytic amount of PPTS furnished cyclic phenyl tion and desilylation procedures. Using the Pd/C hydrogenoly-
acetal 14. The regioselective reductive ring opening of the sis method, compound 2 was converted to 19 followed by
cyclic phenyl acetal 14 with DIBAL-H afforded alcohol 4 in acylation19 using acetic anhydride to obtain 20. Silyl ether on
86% yield.12 In order to generate seco acid 3, primary alcohol 4 20 was removed by TBAF to obtain the corresponding alcohol
was converted to aldehyde 15 by employing Dess–Martin con- 21. Oxidation of secondary alcohol 21 under Dess–Martin con-
ditions (Scheme 3).13
ditions yielded ketone 22, which was purified by crystalliza-
Initially, the Evans aldol reactions with boron enolate tion. Finally, MOM deprotection with BF3·Et2O20 was adopted
afforded aldol adduct 16 in moderate yield (25%, Scheme 4). to get the target molecule cytospolide P (1). Physical and spec-
However, over the past few years it has been reported14 that tral data of compound 1 are identical to those reported in the
TiCl4 has replaced Bu2BOTf. Switching from boron to titanium literature.3
(TiCl4) mediated aldol reaction under Crimmins conditions15
In summary, the first stereoselective total synthesis of cyto-
resulted in the formation of two products 16 (58% yield) and spolide P (1) was accomplished from commercially available
17 (22% yield). The required aldol product 16 was confirmed D-ribose. Four stereogenic centres were created by employing
by spectral analysis and the other product was confirmed as 17 Wittig homologation, regioselective epoxide ring opening,
(benzyloxy eliminated product). Next, a series of experiments Sharpless asymmetric epoxidation and Evans aldol reaction.
were carried out selectively to obtain 16 from 15. We found Finally, Yamaguchi macrolactonization was adopted to accom-
that the mole ratio of TiCl4 and the reaction time play a major plish the target molecule. The obtained product 17 has a
role in forming a titanium enolate complex to get the desired unique C2–C5 carbon skeleton of the cytospolide A–E family
compound 16 (83% yield, >20 : 1 d.r., see ESI†).
with appropriate chirality and functional groups. Further
TBS protection of secondary alcohol 16 with TBSOTf/ studies towards the synthesis of cytospolides are ongoing.
2,6-lutidine afforded 18 (Scheme 5). The PMB protected
hydroxyl derivative 18 was freed by DDQ,16 and the Evans
chiral auxiliary was removed under basic conditions17 (LiOH,
H2O2, THF–H2O (4 : 1)) to get the seco acid 3 (87% yield over
Acknowledgements
two steps).
Having established all the required four stereogenic for their constant encouragement. We thank Dr Anthony
centres, Yamaguchi macrolactonization18 of seco acid
Addlagatta and Mr G. Saidachary, CSIR-IICT, for useful discus-
We thank the Director, CSIR-IICT, and the Head, NPC division
3
resulted in 2 in 76% yield (Scheme 6). With three protecting sions. B.C.R. thanks CSIR, New Delhi for financial support as
groups on 2 (benzyl, silyl and methoxymethyl ether), sequen- part of the XII Five Year plan programme (ORIGIN, CSC-0108).
tial and selective functional group interconversions play a P.S. thanks CSIR, New Delhi, India for a research fellowship.
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