Stereoselective synthesis of the monomeric unit of actin binding macrolide rhizopodin

Article abstract of DOI:10.1021/ol301103d

An efficient, scalable, and stereocontrolled synthesis of the entire carbon framework of an actin binding dimeric macrolide rhizopodin has been accomplished in its protected form. The key features of our synthesis include a titanium catalyzed anti acetal

Full text of DOI:10.1021/ol301103d

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2858–2861
Stereoselective Synthesis of the
Monomeric Unit of Actin Binding
Macrolide Rhizopodin†
Kiran Kumar Pulukuri and Tushar Kanti Chakraborty*
CSIR-Central Drug Research Institute, Lucknow 226001, India
chakraborty@cdri.res.in
Received April 25, 2012
ABSTRACT
An efficient, scalable, and stereocontrolled synthesis of the entire carbon framework of an actin binding dimeric macrolide rhizopodin has been
accomplished in its protected form. The key features of our synthesis include a titanium catalyzed anti acetal aldol reaction, a substrate controlled
diastereoslelective prenyl stannylation, a Mukaiyama aldol reaction, an indium mediated diastereoselective propargylation, and an advanced
stage Stille coupling reaction.
Myxobacteria were found to be a rich source of novel
secondary metabolites, which includes several biologically
active cytotoxic compounds such as epothilone, chondra-
mide, tubulysin A, etc.1 Rhizopodin (1) (Figure 1) is
another such novel and unique polyketide isolated in
1993 from the culture broth of the Myxococcus stipitatus.2
Initially, the structure of 1 was found to be a 19-membered
macrolide, which was later revised as a C2-symmetric 38-
membered dilactone exhibiting 18 stereogenic centers, two
conjugated diene systems in combination with two disub-
stituted oxazoles, and two enamide side chains.3 Impor-
tantly, 1 shows potent cytotoxic activity against various
cancer cell lines in low nanomolar concentration and also
displays activity against certain fungi.4 The cytotoxic activity
of 1 results from its ability to bind, thereby inhibiting the
polymerization of G-actin. The effects of 1 resemble those of
latrunculin but are elicited at a 10-fold lower concentration.
In contrast to lantrunculin, the effects of 1 are irreversible on
the cytoskeleton of actin and take a little longer to appear.
The scarcity of 1 together with its intriguing biological
activity and challenging architecture make it an attractive
target for total synthesis. As part of our continuous interest
in the development of C2-symmetric peptidomimetics, and
the total synthesis of biologically active C2-symmetric
diolides,5 we embarked on the total synthesis of rhizopodin
1. The first total synthesis of 1 has just appeared.6 Earlier
† CDRI Communication no. 8250.
(1) Reichenbach, H. J. Ind. Microbiol. Biotechnol. 2001, 27, 149.
€
(2) Sasse, F.; Steinmetz, H.; Hofle, G.; Reichenbach, H. J. Antibiot.
1993, 46, 741.
(3) (a) Hagelueken, G.; Albrecht, S. C.; Steinmetz, H.; Jansen, R.;
Heinz, D. W.; Kalesse, M.; Schubert, W.-D. Angew. Chem., Int. Ed.
2009, 48, 595. (b) Horstmann, N.; Menche, D. Chem. Commun. 2008, 41,
5173. (c) Jansen, R.; Steinmetz, H.; Sasse, F.; Schubert, W.-D.;
Hageluken, G.; Albrecht, S. C.; Muller, R. Tetrahedron Lett. 2008, 49,
5796.
Figure 1. Structure of rhizopodin 1.
(4) Gronewold, T. M. A.; Sasse, F.; Lunsdorf, H.; Reichenbach, H.
Cell Tissue Res. 1999, 295, 121.
r
10.1021/ol301103d
Published on Web 05/18/2012
2012 American Chemical Society

Scheme 1. Retrosynthesis of Rhizopodin 1
Scheme 2. Synthesis of Ketophosphonate Fragment 6
dilactone could be synthesized from cyclodimerization of
suitably protected monomer 2, which could be obtained
from a palladium catalyzed CꢀC bond formation between
vinyl iodide 3 and vinyl stannane 4. We previously reported
the synthesis of vinyl stannane 4 via an iterative acetate aldol
reaction.9a Vinyl iodide 3 would arise from the Hornerꢀ
WadsworthꢀEmmons (HWE) olefination with keto phos-
phonate 6and aldehyde 5containing oxazole and vinyl iodide.
Aldehyde 5, in turn, would be obtained from oxazole assem-
bly of amino alcohol 7 and carboxylic acid 8 via an amide
bond formation, oxidation, and cyclodehydration strategy.
Our synthetic endeavor began from the synthesis of keto
phosphonate 6 (Scheme 2) which started with the direct
installation of anti β-methoxy-R-methyl stereocenters in a
single operation by utilizing the Urpi diastereoselective anti
acetal aldol reaction.10 Treatment of dimethyl acetal 911
with the titanium enolate generated from (S)-valine derived
N-propionylthiozolidine thione 10 provided the desired
aldol product in 86% yield (anti/syn = 93:7, dr). Optically
pure anti isomer 11 was isolated in 79% yield by simple
column chromatography. Treatment of 11 with lithiated
methyl dimethylphosphonate (generated using n-BuLi) di-
rectly furnished the β-keto phosphonate 6 in 92% yield.12
Next, the synthesis of amino alcohol 7 started from the
(R)-Garner aldehyde 12 (Scheme 3) which was prepared
from D-serine following a reported procedure.13 An asym-
metric indium mediated propargylation of aldehyde 12,
using (1S,2R)-(þ)-2-amino-1,2-diphenylethanol 13 as a
chiral auxiliary developed by Singaram et al.,14 produced
the homo propargyl alocohol 14 in 83% yield with good
diastereoselectivity (10:1 dr, HPLC).15 Selective methyla-
tion of the secondary hydroxyl group followed by one-pot
hydrozirconationꢀiodination using a Schwartz reagent
(generated in situ from Cp2ZrCl2 and DIBAL-H),
Nicolaou et al. reported the synthesis of mono rhizopodin,7
while others described fragment synthesis.8 We also reported
the synthesis of C1ꢀC15 and C16ꢀC28 fragments of the
molecule.9 Herein, we describe an efficient, stereoselective,
and highly convergent synthesis of the entire monomeric unit
of rhizopodin in its protected form 2.
Our retrosynthetic analysis of 1 is depicted in Scheme 1.
With our previous experience in the synthesis of C2-
symmetric diolides, we envisaged that the 38-membered
(5) (a) Chakraborty, T. K.; Roy, S.; Koley, D.; Dutta, S. K.;
Kunwar, A. C. J. Org. Chem. 2006, 71, 6240. (b) Chakraborty, T. K.;
Ghosh, S.; Rao, M. H. V. R.; Kunwar, A. C. ARKIVOC 2005, xi, 89. (c)
Chakraborty, T. K.; Srinivasu, P.; Kumar, S. K.; Kunwar, A. C. J. Org.
Chem. 2002, 67, 2093. (d) Chakraborty, T. K.; Reddy, V. R. Tetrahedron
Lett. 2006, 47, 2099. (e) Chakraborty,T.K.;Reddy,V.R.;Chattopadhyay,
A. K. Tetrahedron Lett. 2006, 47, 7435. (f) Chakraborty, T. K.; Reddy,
V. R.; Gajula, P. K. Tetrahedron 2008, 64, 5162.
(10) (a) Cosp, A.; Romea, P.; Talavera, P.; Urpı
Font-Bardia, M.; Solans, X. Org. Lett. 2001, 3, 615. (b) Galvez, E.;
´
, F.; Vilarrasa, J.;
ꢀ
ꢀ
Parello, R.; Romea, P.; Urpı, F. Synlett 2008, 2951.
´
(11) Okada, H.; Mori, T.; Saikawa, Y.; Nakata, M. Tetrahedron Lett.
2009, 50, 1276.
(6) Dieckmann, M.; Kretschmer, M.; Li, P.; Rudolph, S.; Herkommer,
D.; Menche, D. Angew. Chem., Int. Ed. DOI: 10.1002/anie.201201946.
(7) Nicolaou, K. C.; Jiang, X.; Lindsay-Scott, P. J.; Corbu, A.;
Yamashiro, S.; Bacconi, A.; Fowler, V. M. Angew. Chem., Int. Ed.
2011, 50, 1139.
(12) Crimmins, M. T.; Siliphaivanh, P. Org. Lett. 2003, 5, 4641.
(13) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361.
(14) (a) Hirayama, L. C.; Dunham, K. K.; Singaram, B. Tetrahedron
Lett. 2006, 47, 5173. (b) Haddad, T. D.; Hirayama, L. C.; Buckley, J. J.;
Singaram, B. J. Org. Chem. 2012, 77, 889.
(8) (a) Cheng, Z.; Song, L.; Xu, Z.; Ye, T. Org. Lett. 2010, 12, 2036.
(b) Kretschmer, M.; Menche, D. Org. Lett. 2012, 14, 382.
(9) (a) Chakraborty, T. K.; Pulukuri, K. K.; Sreekanth, M. Tetra-
hedron Lett. 2010, 51, 6444. (b) Chakraborty, T. K.; Sreekanth, M.;
Pulukuri, K. K. Tetrahedron Lett. 2011, 52, 59.
(15) (a) Stereochemistry of the product was confirmed by comparing
with reported data. See: Koviach, J. L.; Chappell, M. D.; Halcomb, R. L.
J. Org. Chem. 2001, 66, 2318. (b) The diastereomeric ratio was deter-
mined by HPLC of the benzoate prepared by treatment with benzoyl
chloride, NEt3, and DMAP.
Org. Lett., Vol. 14, No. 11, 2012
2859

Scheme 3. Synthesis of Amino Alcohol Fragment 7
Scheme 4. Synthesis of Carboxylic Acid Fragment 8
following Negishi’s protocol,16 provided exclusively
E-vinyl iodide 15 in 78% yield in two steps. Treatment of 15
with 4 M HCl in dioxane furnished the desired amino
alcohol 7.17 Due to the high sensitivity of 7 for workup as
well as chromatography, the product was confirmed by 1H
NMR of the crude reaction mixture after removal of
reaction volatiles and was used as such for the next reaction.
On the other hand, carboxylic acid 8 was synthesized
(Scheme 4) in a stereocontrolled manner starting from
protected compound 17, which was prepared in four steps
from PMB protected aldehyde 16 following a literature
procedure.9b Oxidative removal of the PMB group in 17
using DDQ gave the primary alcohol 18 in 94% yield.
DessꢀMartin periodinane oxidation18 of the resultant
primary alcohol yielded the corresponding aldehyde,
which was then subjected to methoxy directed19 chelation
controlled prenyl stannylation using TiCl4 to obtain the
alcohol in 86% yield with a 9:1 ratio (determined by the 1H
NMR integration) of separable diastereomers in favor of
the desired anti isomer 20. Lower selectivities were ob-
the monodentate Lewis acid BF3 Et2O was identified to
3
promote the desired aldol addition in toluene to give the
required β-hydroxyl ester 23in 82% yield (three steps) with
3.4:1 diastereoselectivity in favor of the desired anti
isomer.22 Noteworthy is that the use of bidentate Lewis
acid TiCl4 provided the aldol product in a reversal of the
diastereoselectivity (1:1.7, dr).23 Since the resultant diaste-
reomers were not separable at this stage we continued
further as such for the silyl protection of hydroxyl group
followed by saponification of methyl ester to obtain the
acid 8 in 90% yield (anti/syn = 3.4:1).
With both amino alcohol 7 and carboxylic acid 8 in
hand, we endeavored to combine them through an oxazole
synthesis (Scheme 5). First, an amide coupling between
amino alcohol 7 and carboxylic acid 8 using EDCI,
HOBt, and NEt324 afforded a mixture of hydroxyl amide
(anti/syn = 3.2:1) in 76% yield. At this stage both C16
epimers were separated by column chromatography and
optically pure anti isomer 24 was isolated in 58% yield.
DessꢀMartin periodinane mediated oxidation of hydroxyl
amide 24 followed by one-pot cyclodehydration of the
resultant aldehyde and subsequent elimination of HBr
from the bromooxazoline intermediate following Wipf
conditions25 afforded the oxazole 25 in 74% yield. Selec-
tive primary silyl deprotection using acetic acid buffered
served with other Lewis acids such as MgBr2 Et2O, ZnBr2,
and BF3 Et2O. This transformation establishes the C17
3
3
geminal dimethyl and C18 stereocenter with a good level
of 1,3-anti stereoinduction. The C18 hydroxyl group was
protected as p-methoxybenzyl ether to obtain 21 using
PMBOC(dNH)CCl3 and La(OTf)3.20 Dihydroxylation
of olefin followed by oxidative cleavage of the resulting
diol provided the corresponding aldehyde in good yield.
To install the β-hydroxy ester, a Lewis acid mediated
Mukaiyama aldol reaction21 between the aldehyde and
commercially available silyl enol ether 22 was investigated.
After various Lewis acids and conditions were screened,
(16) Huang, Z.; Negishi, E.-I. Org. Lett. 2006, 8, 3675.
(22) (a) The absolute configuration of the major C16 stereogenic
center was determined as (16S) by 1H NMR analysis of the correspond-
ing (R)- and (S)-MTPA esters. See: Supporting Information for details.
(b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
(17) Han, G.; Tamaki, M.; Hruby, V. J. J. Peptide Res. 2001, 58, 338.
(18) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(19) (a) Keck, G. E.; Castellino, S.; Wiley, M. R. J. Org. Chem. 1986, 51,
5478. (b) Keck, G. E.; Castellino, S. J. Am. Chem. Soc. 1986, 108, 3847. (c)
Keck, G. E.; Abbott, D. E. Tetrahedron Lett. 1984, 25, 1883. (d) For
methoxy directed allylation, see: Paterson, I.; Coster, M. J.; Chen, D. Y.-K.;
Gibson, K. R.; Wallace, D. J. Org. Biomol. Chem. 2005, 3, 2410.
(20) Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267.
(21) (a) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc.
1974, 96, 7503. (b) Paterson, I.; Smith, J. D. J. Org. Chem. 1992, 57, 3261.
(c) Paterson, I.; Smith, J. D.; Ward, R. A. Tetrahedron 1995, 51, 9413. (d)
Mutou, T.; Suenaga, K.; Fujita, T.; Itoh, T.; Takada, N.; Hayamizu, K.;
Kigoshi, H.; Yamada, K. Synlett 1997, 199. (e) Evans, D. A.; Dart, M. J.;
Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322. (f) Evans,
D. A.; Allison, B. D.; Yang, M. G. Tetrahedron Lett. 1999, 40, 4457.
(23) Other Lewis acids, i.e. TiCl2(O-iPr)2, MgBr2 Et2O, ZnBr2, and
3
LiClO4, were also investigated but were less effective. Under these condi-
tions either no reaction or decomposition of aldehyde was observed.
(24) Sheehan, J.; Cruickshank, P.; Boshart, G. J. Org. Chem. 1961,
26, 2525.
(25) (a) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604. (b) Wipf,
P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558.
(26) Higashibayashi, S.; Shinko, K.; Ishizu, T.; Hashimoto, K.;
Shirahama, H.; Nakata, M. Synlett 2000, 1306.
(27) Parikh, J. R.; Doering, W. V. E. J. Am. Chem. Soc. 1967, 89,
5505.
2860
Org. Lett., Vol. 14, No. 11, 2012

Scheme 5. Assembly of Fragments 7, 8, 6, and 4 To Complete the Synthesis of 2
TBAF26 furnished the primary alcohol 26 in 84% yield.
ParikhꢀDoering oxidation27 of primary alcohol 26 furn-
ished the corresponding aldehyde which was subjected to
HWE olefination with keto phosphonate 6 in the presence
of copper thiophene-2-carboxylate (CuTc) in a DMF/THF
(1:1) mixture31 gave the coupled product 2 in 88% yield.
In summary, a concise and scalable synthesis of the pro-
tected monomeric unit 2 of rhizopodin, suitable for sub-
sequent steps and a late-stage introduction of the enamide
side chains, was achieved in a highly convergent way in 21
steps (longest linear sequence) starting from 16. Notable
features of our synthesis include a diastereoselective anti
acetal aldol reaction, a highly diastereoselective propargyla-
tion of the Garner aldehyde, a substrate controlled anti
stereoselective prenyl stannylation, a Mukaiyama aldol
reaction, an advanced oxazole synthesis, and Stille coupling.
Further work toward the total synthesis of rhizopodin 1 and
its simplified structural analogs is in progress.
28
of Ba(OH)2 to achieve the enone 27 in 86% yield.
Selective 1,4-reduction of enone using Stryker’s reagent29
followed by oxidative cleavage of PMB ether gave the
alcohol 3 (C8ꢀC29 fragment) in 78% yield.
With key fragment 3 in hand, the stage was now set for
coupling with vinyl stannane 4 through C7ꢀC8 bond
formation using the Stille reaction.30 Initial attempts to
accomplish the Stille coupling of vinyl iodide 3 and vinyl
stannane 4 with standard Stille conditions using 10 mol %
of Pd (0, II) catalysts were less effective and gave the
desired diene only in 30% yield, along with a byproduct
resulting from the homocoupling of vinyl iodide 3. After
several conditions were examined by using various combi-
nations of palladium catalysts (Pd(PPh3)4, PdCl2(CH3CN)2,
Pd2(dba)3,PdCl2(PPh3)2), transmetalation ligands (As(PPh3)3,
TFP), transmetalation catalysts (CuCl, CuI, CuTc), and
solvents (NMP, DMF, THF), it was found, to our delight,
that use of 5 mol % Pd(PPh3)4 and a stoichiometric amount
Acknowledgment. The authors wish to thank CSIR, New
Delhi for a research fellowship (K.K.P.). K.K.P. also thanks
Drs. A. Ravi Sankar, Dipankar Koley, and M. Sridhar
Reddy for their support, Mr. R. K. Purshottam for HPLC
data, and the SAIF, CDRI for providing the spectroscopic
and analytical data.
Supporting Information Available. Experimental pro-
cedures, spectral data, 1H and 13C spectral data of
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(28) Paterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993, 774.
(29) (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am.
Chem. Soc. 1988, 110, 291. (b) Terminal olefin resulting from the
reduction of vinyl iodide appeared as a side product in 5ꢀ10% yield.
(30) (a) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813. (b)
Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748. (c)
(31) Both Pd and CuTc are required for this coupling.
The authors declare no competing financial interest.
€
Furstner, A.; Funel, J.-A.; Tremblay, M.; Bouchez, L. C.; Nevado, C.;
Waser, M.; Ackerstaff, J.; Stimson, C. C. Chem. Commun. 2008, 2873.
Org. Lett., Vol. 14, No. 11, 2012
2861