Synthetic studies toward potent cytostatic macrolide rhizopodin: Stereoselective synthesis of the C16-C28 fragment

Article abstract of DOI:10.1016/j.tetlet.2010.10.142

A stereoselective synthesis of the C16-C28 fragment of cytostatic C ₂-symmetric macrolide rhizopodin is described. Enantioselective addition of a chiral thiazolidinethione derived titanium enolate to acetal, Evans' aldol reaction, Horner-Wadsworth-Emmons reaction, and Mukaiyama aldol reaction were applied as key steps.

Full text of DOI:10.1016/j.tetlet.2010.10.142

Tetrahedron Letters 52 (2011) 59–61
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic studies toward potent cytostatic macrolide rhizopodin:
stereoselective synthesis of the C16–C28 fragment q
Tushar Kanti Chakraborty a, , Midde Sreekanth b, Kiran Kumar Pulukuri a
⇑
a Central Drug Research Institute, CSIR, Lucknow 226 001, India
b Indian Institute of Chemical Technology, CSIR, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective synthesis of the C16–C28 fragment of cytostatic C2-symmetric macrolide rhizopodin is
described. Enantioselective addition of a chiral thiazolidinethione derived titanium enolate to acetal,
Evans’ aldol reaction, Horner–Wadsworth–Emmons reaction, and Mukaiyama aldol reaction were
applied as key steps.
Received 30 September 2010
Revised 25 October 2010
Accepted 27 October 2010
Available online 31 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Rhizopodin
Cytostatic
Actin polymerization
Inhibitor
Diolides
Aldol reaction
Myxobacteria produce a wide variety of secondary metabolites
with interesting biological activities and distinct structures.1 Rhiz-
opodin (1) is one such example, which was isolated from the cul-
ture broth of the myxobacterium, Myxococcus stipitatus in 1993
by Sasse et al.2
Initially it was proposed that rhizopodin was a 16-membered
macrolide.2 But later the structure was revised as a C2-symmetric
38-membered dilactone bearing 18 stereogenic centers, two disub-
stituted oxazole rings, two conjugated diene systems, and two ena-
mide side chains by X-ray analysis of its complex with rabbit
muscle G-actin and extensive NMR studies.3–5
It showed potent cytostatic activity against a range of tumor cell
lines in the low nanomolar range.6 The cytostatic activity was
attributed to the formation of a ternary complex with two G-actin
molecules where the enamide side chains play a key role. It specif-
ically binds to select sites of G-actin and disrupts the cytoskeleton
thereby inhibiting the actin polymerization.5 Biological studies7
further revealed that rhizopodin affects the dynamics of actin skel-
eton of macrophages thereby showing significant changes in the
phagocyte efficiency for yeast cells.
opment of C2-symmetric peptidomimetics9 and total synthesis of
biologically active C2-symmetric diolides,10 we undertook the total
synthesis of rhizopodin.
Scheme 1 discloses the retrosynthetic analysis of rhizopodin (1).
Inspection of the structure of rhizopodin revealed that it could be
synthesized by the macrolactonization/cyclodimerization of suit-
ably protected compound 2 which in turn could be obtained from
the two key intermediates 3 and 4. Herein, we report the synthesis
of C16–C28 fragment (3) of the molecule.
Our synthesis commenced with the addition of boron enolate of
(R)-4-benzyl-3-propionyloxazolidin-2-one (5) to aldehyde 6,
which was prepared by the oxidation of mono-PMB protected
1,3-propanediol to furnish compound 7 in 90% yield (Scheme
2).11 Reductive removal of the chiral auxiliary12 using NaBH4 gave
a 1,3-dihydroxy compound 8 in 76% yield. Selective O-silylation of
the primary hydroxyl group using TBDPSCl and Et3N furnished the
secondary alcohol 9, which on etherification using NaHMDS and
MeI afforded compound 10 in 81% yield over two steps. Desilyla-
tion with TBAF gave a primary alcohol, which on oxidation under
Swern conditions13 produced aldehyde 12 in excellent yield.
Synthesis of ketophosphonate 16 was started with the enantiose-
lective addition14a,b of titanium enolate of (S)-1-(4-isopropyl-2-thi-
oxothiazolidin-3-yl)propan-1-one (14) to the known14c dimethyl
acetal 13 to furnish compound 15 in 82% yield (Scheme 3). Displace-
ment of thiazolidinethione auxiliary of compound 15 by the anion
generated from dimethyl methylphosphonate14d using nBuLi re-
sulted in the formation of b-keto phosphonate 16 in 90% yield. Keto
Unique architecture coupled with interesting biological activi-
ties makes rhizopodin an attractive target for synthetic organic
chemists.8 In connection with our continuing interest in the devel-
q
CDRI Communication No. 7980
⇑
Corresponding author. Tel.: +91 522 2623286; fax: +91 522 2623405/938.
E-mail address: chakraborty@cdri.res.in (T.K. Chakraborty).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.142

60
T. K. Chakraborty et al. / Tetrahedron Letters 52 (2011) 59–61
O
OMe
OMe
N
O
S
OMe
O
OMe O
S
O
BnO
13
N
S
BnO
N
S
O
OMe OH
OMe
a
iPr
14
iPr
OMe
O
15
N
HO
N
O
OH
H3C P OMe
OMe
OMe O
O
P
OMe
OMe
O
O
MeO
BnO
O
OH OMe
OMe
b
16
Rhizopodin (1)
OMe O
OMe O
OMe
OMe
O
MeO
N
c
O
BnO
OPMB
OPMB
OMe OTIPS
28
17
18
OMe OTIPS
BnO
BnO
OMe
OMe
TESO
d
BnO
HO
TBSO
N
16
3
HO
HO
+
15
N
O
O
OMe OH
OMe
OMe
HO
1
MeO
e
O
OMe
OTBS
OMe
O
OMe
OTBS
OMe
2
BnO
OPMB
OPMB
4
19
Scheme 1. Retrosynthetic analysis of rhizopodin (1).
OMe OTIPS
f
BnO
O
20
O
O
OH
O
O
OPMB
OPMB
6
N
N
OPMB
OH
O
O
a
OMe OTIPS
OMe
Bn
Bn
7
5
g
BnO
OH
OH
21
b
c
TBDPSO
OPMB
HO
9
8
OMe OTIPS
OMe
OMe
h
BnO
e
d
TBDPSO
OPMB
HO
OPMB
OMe
10
11
22
HO
OMe
f
COOMe
OPMB
O
OMe OTIPS
12
i
BnO
Scheme 2. Synthesis of 12: Reagents and conditions: (a) nBu2BOTf, DIPEA, CH2Cl2,
0 °C, 1 h, ꢁ78 °C, then 6, 1.5 h at ꢁ78 °C, then 0 °C, 30 min, 90%; (b) NaBH4, THF/H2O
(5:1), 0 °C to rt, overnight, 76%; (c) TBDPSCl, Et3N, DMAP, CH2Cl2, 0 °C to rt,
overnight, 90%; (d) NaHMDS, MeI, THF, 0 °C to rt, 4 h, 89%; (e) TBAF, THF, 0 °C to rt,
7 h, 78%; (f) (COCl)2, DMSO, Et3N, CH2Cl2, ꢁ78–0 °C, quant.
OMe
TESO
23
COOMe
j
3
phosphonate coupling between 16 and the aldehyde 12 using
Ba(OH)2ꢀ8H2O as a base15 gave the
a,b-unsaturated ketone 17 in
Scheme 3. Synthesis of 3: Reagents and conditions: (a) TiCl4, CH2Cl2, 0 °C, 5 min,
ꢁ78 °C, DIPEA, ꢁ40 °C, 2 h, SnCl4, then 13, 2 h, 82%; (b) nBuLi, THF, ꢁ78 °C, 30 min
then 15, 30 min, 90%; (c) Ba(OH)2ꢀ8H2O, THF, 30 min, then 12 (as a solution in 40:1
mixture of THF and H2O), 30 min, rt, 77%; d) Pd-C/H2, nBuNH2, EtOAc, 15 min,
quant.; (e) (R)-B-Me-CBS, BH3ꢀSMe2, THF, ꢁ40 °C to 0 °C, 15 h, 88%; (f) TIPSOTf, 2,6-
lutidine, CH2Cl2, 0 °C to rt, 10 min, 85%; (g) DDQ, CHCl3/buffer (pH 7, 20:1), rt,
20 min, 64%; (h) (i) Dess–Martin periodinane, NaHCO3, CH2Cl2, 0 °C to rt, 1 h,
quant.; (ii) methyl trimethylsilyl dimethylketene acetal, BF3ꢀEt2O, CH2Cl2, ꢁ78 °C,
1 h, 64%; (i) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C to rt, 10 min, 80%; (j) DIBAL-H, CH2Cl2,
ꢁ78 °C, 30 min, 79%.
77% yield. Chemoselective hydrogenation16 of the double bond pro-
vided compound 18 in quantitative yield. The keto functionality was
then reduced under standard CBS conditions17 to give 19 in 88%
yield. Protection of the secondary hydroxyl group as its TIPS ether
using TIPSOTf and 2,6-lutidine resulted in the formation of orthogo-
nally protected compound 20 in 85% yield. Oxidative cleavage of
PMB ether with DDQ18 under buffered conditions gave the primary
alcohol 21 in 64% yield. Oxidation of the primary alcohol using

T. K. Chakraborty et al. / Tetrahedron Letters 52 (2011) 59–61
61
Dess–Martin periodinane19 furnished a b-methoxy aldehyde in
quantitative yield and was directly subjected to a 1,3-anti diastereo-
facial selective Mukaiyama aldol reaction20 with methyl trimethyl-
silyl dimethylketene acetal to provide 22 as the major diasteromer
in 64% yield (dr P 8:1). The hydroxyl group was then protected as
TES ether using TESOTf and 2,6-lutidine to get compound 23 in
80% yield. Reduction of the methyl ester using DIBAL-H delivered
the C16–C28 fragment (3) of the rhizopodin21 in an overall yield of
13.4% starting from 15 in a linear sequence of 10 steps.
9. (a) Chakraborty, T. K.; Roy, S.; Koley, D.; Dutta, S. K.; Kunwar, A. C. J. Org. Chem.
2006, 71, 6240–6243; (b) Chakraborty, T. K.; Ghosh, S.; Rao, M. H. V. R.;
Kunwar, A. C. Arkivoc 2005, xi, 89–101; (c) Chakraborty, T. K.; Srinivasu, P.;
Kumar, S. K.; Kunwar, A. C. J. Org. Chem. 2002, 67, 2093–2100.
10. (a) Chakraborty, T. K.; Reddy, V. R. Tetrahedron Lett. 2006, 47, 2099–2102; (b)
Chakraborty, T. K.; Reddy, V. R.; Chattopadhyay, A. K. Tetrahedron Lett. 2006, 47,
7435–7438; (c) Chakraborty, T. K.; Reddy, V. R.; Gajula, P. K. Tetrahedron 2008,
64, 5162–5167.
11. (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127–
2129; (b) Reaction conditions were adopted wherein ent-7 was described. See:
Williams, D. R.; Clark, M. P.; Berliner, M. A. Tetrahedron Lett. 1999, 40, 2287–
2290.
In conclusion we have synthesized the C16–C28 fragment of
rhizopodin by using enantioselective addition of a chiral thiazoli-
dinethione derived titanium enolate to an acetal, Evans’ aldol reac-
tion, Horner–Wadsworth–Emmons reaction, and Mukaiyama aldol
reaction as key steps. The efforts toward total synthesis of the mol-
ecule are underway in our laboratory and will be reported in due
course.
12. Prashad, M.; Har, D.; Kim, H.-Y.; Repic, O. Tetrahedron Lett. 1998, 39, 7067–
7070.
13. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480–2482.
14. (a) Gálvez, E.; Parelló, R.; Romea, P.; Urpí, F. Synlett 2008, 2951–2954; (b) Cosp,
A.; Romea, P.; Talavera, P.; Urpí, F.; Vilarrasa, J.; Font-Bardia, M.; Solans, X. Org.
Lett. 2001, 3, 615–617; (c) Panek, J. S.; Yang, M. J. Org. Chem. 1991, 56, 5755–
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17. (a) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986–2012; (b) Even
though the C24-OH was to be converted into a keto at a late stage of the
synthesis, in order to avoid the possible complexity of the synthesis and
spectroscopic analysis, asymmetric reduction of the ketone moiety was
preferred instead of the normal reduction.
Acknowledgments
The authors wish to thank DST, New Delhi for the Ramanna Fel-
lowship (SR/S1/RFOC-06/2006; T.K.C.) and CSIR, New Delhi for re-
search fellowships (M.S. and K.K.P.).
18. Wipf, P.; Graham, T. H. J. Am. Chem. Soc. 2004, 126, 15346–15347.
19. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
20. (a) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118,
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Diastereomers obtained were separable by silica gel column chromatography
and the observed dr refers to chromatographically pure compounds.
21. Analytical and spectral data of compound 3: Rf = 0.3 (silica gel, 10% ethyl
References and notes
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M.; Schubert, W.-D. Angew. Chem. Int. Ed. 2009, 48, 595–598.
6. Gronewold, T. M. A.; Sasse, F.; Lünsdorf, H.; Reichenbach, H. Cell Tissue Res.
1999, 295, 121–129.
7. Klippel, N.; Bilitewski, U. Anal. Lett. 2007, 40, 1400–1411.
8. Chakraborty, T. K.; Pulukuri, K. K.; Sreekanth, M. Tetrahedron Lett. 2010, 51,
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acetate in petroleum ether); ½a D24
ꢂ
= ꢁ17.7 (c 0.7, CHCl3); IR (neat): mmax 3473,
2950, 2870, 1461, 1379, 1090, 1009, 734, 674 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d 7.32–7.18 (m, 5H), 4.44 (ABq, 2H), 3.92 (m, 1H), 3.68 (dd, J = 7.55, 0.76 Hz,
1H), 3.56–3.41 (m, 3H), 3.29–3.12 (m, 9H), 1.96–1.72 (m, 3H), 1.64–1.05 (m,
7H), 0.99 (s, 21H), 0.96–0.85 (m, 12H), 0.84–0.71 (m, 9H), 0.65–0.52 (m, 6H);
13C NMR (75 MHz, CDCl3): d 138.6, 128.3, 127.6, 127.5, 82.9, 79.6, 77.1, 73.5,
73.0, 70.4, 66.9, 57.6, 56.4, 42.4, 39.5, 34.1 33.3, 31.6, 31.0, 26.7, 22.6, 21.5,
18.3, 15.9, 12.9, 10.3, 7.1, 5.6; MS (ESI): m/z (%) 726 (80) [M+H]+, 748 (25)
[M+Na]+; HRMS (ESI): calcd for C41H80O6NaSi2 [M+Na]+ 747.5391, found
747.5394.