Stereocontrolled synthesis of the C8-C22 fragment of rhizopodin

Article abstract of DOI:10.1021/ol203130b

A convergent synthesis of the central C8-C22 core of the potent macrolide antibiotic rhizopodin is reported. Notable features of the stereocontrolled approach include an asymmetric reverse prenylation of an alcohol using a method of Krische, a thiazolium catalyzed transformation of an epoxyaldehyde as described by Bode, and a late-stage oxazole formation from advanced intermediates. This route demonstrates the applicability of these methodologies in complex natural product synthesis.

Full text of DOI:10.1021/ol203130b

ORGANIC
LETTERS
2012
Vol. 14, No. 1
382–385
Stereocontrolled Synthesis of the
C8ÀC22 Fragment of Rhizopodin
Manuel Kretschmer† and Dirk Menche*,‡
ꢀ
Kekule-Institut fur Organische Chemie und Biochemie der Universitat Bonn,
Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany, and Universitat Heidelberg,
€
€
€
Institut fu€r Organische Chemie, INF 270, D-69120 Heidelberg, Germany
dirk.menche@uni-bonn.de
Received November 22, 2011
ABSTRACT
A convergent synthesis of the central C8ÀC22 core of the potent macrolide antibiotic rhizopodin is reported. Notable features of the
stereocontrolled approach include an asymmetric reverse prenylation of an alcohol using a method of Krische, a thiazolium catalyzed
transformation of an epoxyaldehyde as described by Bode, and a late-stage oxazole formation from advanced intermediates. This route
demonstrates the applicability of these methodologies in complex natural product synthesis.
€
In 1993, the Hofle group reported the structure of
Schubert and co-workers through an X-ray structure of
rabbit-actin bound rhizopodin.5
rhizopodin (1, Scheme 1) from the myxobacterium
Myxococcus stipitatus.1 Thismacrolidedisplaysimpressive
biological properties including antifungal and antiproli-
ferative activities at low nanomolar concentrations. This
potency has been attributed to its ability to specifically
bind to globular actin (G-actin) and thus impede its poly-
merization to filamentous actin (F-actin).1b Rhizopodin
has also been shown to hamper the phagocytic efficiency of
yeast cells.2
While originally reported as a monomeric compound,1
its structure was revised in 2008 to a C2-symmetric dimer
during studies aimed at determining its absolute config-
uration.3 Based on extensive NMR analyses, in combina-
tion with derivatization and molecular modeling experi-
ments, a complete stereochemical assignment was made
by our group,4 which was independently confirmed by
The unique structure of rhizopodin which consists of
a total of 18 stereogenic centers within a 38-membered
macrolide ring incorporates two oxazole rings and two
diene systems. The macrocyclic core bears two side chains
with labile N-vinyl-formamide motifs, which are believed
to be critical parts of the pharmacophore unit.5 The com-
bination of remarkable structure and potent bioactivity,
together with its low availability from natural sources, make
rhizopodin an attractive target, and several fragment syn-
theses have been reported.6À8 However, despite these
efforts, an efficient and, in particular, concise and stereo-
selective route to the central C8ÀC22 fragment (2, Scheme 1)
has not been achieved. This central fragment is character-
ized by five stereogenic centers, a highly hindered stereo-
tetrad centered around the quaternary carbon at C17 in
combination with the oxazole core. Retrosynthetically, we
anticipated this central building block arising from amine
3 and acid 4 with assembly of the oxazole unit via a
cyclodehydration strategy.
†
€
€
Universitat Heidelberg.
Universitat Bonn.
(1) (a) Sasse, F.; Steinmetz, H.; Hofle, G.; Reichenbach, H.
‡
€
€
J. Antibiot. 1993, 46, 741. (b) Gronewold, T. M. A.; Sasse, F.; Lunsdorf,
H.; Reichenbach, H. Cell Tissue Res. 1999, 295, 121.
(2) Klippel, N.; Bilitewski, U. Anal. Lett. 2007, 40, 1400.
(3) Jansen, R.; Steinmetz, H.; Sasse, F.; Schubert, W. D.; Hageluken,
(6) Cheng, Z.; Song, L.; Xu, Z.; Ye, T. Org. Lett. 2010, 12, 2036.
(7) (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.
(8) 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.
€
€
G.; Albrecht, S. C.; Muller, R. Tetrahedron Lett. 2008, 49, 5796.
(4) Horstmann, N.; Menche, D. Chem. Commun. 2008, 41, 5173.
(5) Hagelueken, G.; Albrecht, S. C.; Steinmetz, H.; Jansen, R.; Heinz,
D. W.; Kalesse, M.; Schubert, W. D. Angew. Chem., Int. Ed. 2009, 48,
595.
r
10.1021/ol203130b
Published on Web 12/13/2011
2011 American Chemical Society

alcohol 712 to 1,1-dimethyl allene (8) in the presence of
propionaldehyde and catalytic amounts of iridium com-
plex 9 smoothly delivered 10 in quantitative yield in an
enantiomeric excess of 82%.13À15 Notably, in contrast to
previous routes to this fragment, our approach enables a
stereoselective construction of both stereogenic centers
adjacent to C17 by employing chiral catalysts.
Scheme 1. Synthetic Approach to the Central Fragment 2 of
Rhizopodin (1)
Scheme 2. Synthesis of Amine Building Block 3
After protection of the alcohol as silyl ether 11 (TBS
triflate, lutidine, 96%), the olefin was cleaved oxidatively
(O3, dimethyl sulfide) to afford aldehyde 12. A likewise
tested alternative effort to transform 12 more directly into
17 by an asymmetric allylation and subsequent oxidative
cleavage resulted in only low yields and/or stereoselec-
tivities in the allylation step, in agreement with previous
results,6 presumably due to steric hindrance of the carbon-
yl group of 12. We therefore decided to pursue a different
strategy.16
To this end, 12 was treated with methyl diethyl phos-
phonoacetate/NaHMDS to give the corresponding unsa-
turated ester in84% yield overboth steps. Reduction of the
product ester (86%) with di-iso-butyl aluminum hydride
(DiBAlH) furnished an allylic alcohol that was subjected
to Sharpless’ asymmetric epoxidation.17 Epoxide 13 was
isolated in good yield in a diastereomeric ratio of 7.5:1 in
The synthesis of amine 3, illustrated in Scheme 2,
started from commercially available N-Boc-D-serine (5).
O-Protection as a TBS-ether (79%) followed by treatment
of the respective lithium carboxylate with allyl magnesium
chloride afforded a configurationally instable homoallylic
ketone 69 which was directly exposed to NaBH4. At À78 °C,
a high level of stereoselectivity (11:1) was obtained, pre-
sumably through substrate chelation control.10 After re-
moval of the undesired isomer by column chromatography,
the aminoalcohol (not shown) was obtained diastereomeri-
cally pure in 61% yield over three steps. The elaboration
into 3 was straightforward. Selective O-methylation was
achieved using carefully controlled amounts of NaH and
methyl iodine in THF, followed by subsequent deprotec-
tion of the carbamate and the TBS-ether using aqueous
TFA in 96% yield.
(12) Shibahara, S.; Fujino, M.; Tashiro, Y.; Okamoto, N.; Esumi, T.;
Takahashi, T.; Ishihara, J.; Hatakeyama, S. Synthesis 2009, 2935.
(13) The ee and the configuration of the new stereogenic center were
determined using Mosher’s ester analysis. See the Supporting Informa-
tion for full details.
(14) After completion of the synthesis of 4, Krische and co-workers
reported an improved procedure for the purification of structurally
related catalysts: Gao, X.; Townsend, I. A.; Krische, M. J. J. Org. Chem.
2011, 76, 2350.
(15) In principle, the central core of fragment 4 may also be accessible
by Krische’s method of a double enantioselective allylation. However,
such an approach may have resulted in ensuing difficulties in selective
differentiation of the resulting two hydroxyls and alkenes. Therefore, it
was was not pursued: Lu, Y.; Kim, I. S.; Hassan, A.; Del Valle, D. J.;
Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 5018.
Witha scalable route toward3 in hand, an entry toacid 4
was required. Our final and successful strategy, as outlined
in Scheme 3, commenced with an asymmetric reverse
prenylation following a method developed by the group of
Krische.11 In detail, exposure of known PMB-protected
(9) Knudsen, C .G.; Rapoport, H. J. Org. Chem. 1983, 48, 2260.
(10) Toumi, M.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2007,
46, 572.
(16) Related sequences have been previously employed, see e.g.: (a)
Hillier, M. C.; Price, A. T.; Meyers, A. I. J. Org. Chem. 2001, 66, 6037.
(b) Reference 6.
(11) (a) Han, S. B.; Kim, I. S.; Han, H.; Krische, M. J. J. Am. Chem.
Soc. 2009, 131, 6916. (b) Correction: Han, S. B.; Kim, I. S.; Han, H.;
Krische, M. J. J. Am. Chem. Soc. 2010, 132, 12517.
(17) (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. (b) Hanson, R. M.;
Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
Org. Lett., Vol. 14, No. 1, 2012
383

Scheme 3. Successful Strategy for the Construction of 4
€
favor of the isomer with the desired configuration at C18,
as judged from 1H NMR.
15 in the presence of Hunig’s base to afford a β-hydroxyester
in high yield (86%) which, in turn, was transformed into
the TES-congener 16 (TES triflate, lutidine, 85%).
After routine oxidation state manipulations, which
enhanced the diastereomeric purity of the material (12:1)
following careful chromatography of the intermediates,
the stage was set for an aldol reaction between aldehyde
17 and oxazolidinone 18. After variable results with boron
enolates,21 exposure of 17 to the titanium enolate of
18 according to Crimmins’ conditions22 afforded the de-
sired C20/C21-syn-isomer 19 exclusively in reproducibly
high yields (95%). Reductive removal of the auxiliary under
Soai’s conditions (88%),23 followed by selective silylation of
the primary alcohol and subsequent methylation, provided
20 incorporating the complete C16ÀC21-stereotetrad in
88% yield over two steps.
With epoxide 13 in hand, various conditions to re-
ductively open this compound with different hydride
sources (RedAl, DiBAlH, LiAlH4, AlH3 among others)
were tested, but all met with failure giving product mix-
tures. These resulted mainly from silyl migration which
occurred under the basic reaction conditions or the for-
mation of regioisomeric diols with only traces of the desi-
18
red 1,3-diol. In contrast, exposure to NaBSePh(OEt)3
gave a β-hydroxyaldehyde in excellent yield, which could
not be protected orthogonally. All attempts to install an
acetate, benzoate, orTESgroupledtodecompositionofthe
labile compound.
We thus turned our attention to alternative possibilities
totransform 13intoa syntheticallyuseful intermediateand
took note of a method introduced by the group of Bode19
which allows the conversion of enantioenriched 2,3-epoxy-
aldehydes to chiral β-hydroxyesters.
Next, the PMB-ether was selectively cleaved by means
of DDQ in a buffered aqueous media, and the liberated
intermediary alcohol was sequentially oxidized using
DMP and NaClO2/NaH2PO4 to furnish 4 in good yields
(76% over three steps).
Consequently, 13 was oxidized to the corresponding epoxy-
aldehyde 14 by means of the Dess-Martin-periodinane
(DMP)20 (68%) and directly treated with thiazolium salt
(18) Miyashita, M.; Suzuki, T.; Hoshino, M.; Yoshikoshi, A. Tetra-
hedron 1997, 53, 12469.
(21) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127.
(19) Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126.
(20) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(22) Crimmins, M. T.; She, J. Synlett 2004, 1371.
(23) Soai, K.; Ookawa, A. J. Org. Chem. 1986, 51, 4000.
384
Org. Lett., Vol. 14, No. 1, 2012

To this end, building blocks 3 and 4 were coupled in the
presence of 3-(diethoxyphosphoryloxy)-1,2,3-benzotria-
zin-4(3H)-one (DEPBT),24 giving rise to β-hydroxy amide
21 in good yield (73%) without the requirement for addi-
tional protection/deprotection steps. For the conversion
into the desired oxazole motif, 21 was first oxidized with
DMP to an intermediary aldehyde which was directly
exposed to iodine and triphenylphosphine.25 Gratifyingly,
ring closure and elimination took place, as expected,
and finally enabled access to the complete fragment 2 in
87% yield.
Scheme 4. Completion of the Synthesis of Fragment 2
Insummary, wehaveachieved a stereoselective synthesis
of the C8ÀC22 fragment of rhizopodin in an overall yield
of 8.1% based on a convergent approach which compares
favorably to previous routes with respect to the number of
steps and/or stereoselectivity. Notable features of the
present route are the creation of the stereogenic center at
C16 via the Krische asymmetric reverse prenylation from
an alcohol precursor and the organocatalytic conversion
of a derived epoxyaldehyde into a synthetically useful
β-hydroxyester using a method of Bode, together with a
late-stage oxazole formation from advanced and elabo-
rated intermediates. This route demonstrates the true
applicability of these strategies in complex natural product
synthesis and may be useful in devising a scalable synthetic
route toward rhizopodin.
Acknowledgment. This work was generously supported
by the ’Deutsche Forschungsgemeinschaft’ and the ’Wild-
Stiftung’. M.K. is grateful for a PhD fellowship on behalf
of the ’Graduiertenkolleg 850’ (’Modeling of Molecular
Properties’). We thank Daniela Jacob (bachelor student)
for technical support.
With sufficient amounts of 3 and 4 now prepared, we
proceeded with their assembly en route to 2 (Scheme 4).
Supporting Information Available. Experimental de-
tails, spectral data, and copies of NMR spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(24) Li, H.; Jiang, X.; Ye, Y.; Fan, C.; Romoff, T.; Goodman, M.
Org. Lett. 1999, 1, 91.
(25) This reaction may be regarded as a modified RobinsonÀGabriel
reaction. See: Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604.
Org. Lett., Vol. 14, No. 1, 2012
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