Synthesis of the C9-C23 (C9′-C23′) fragment of the dimeric natural product rhizopodin

Article abstract of DOI:10.1021/ol100515m

Figure presented A stereoselective assembly of the C9-C23 (C9′-C23′) fragment of rhizopodin, a 38-membered bis-lactone natural product, has been developed. A highly efficient approach to this fragment assembles >50% of the carbon skeleton and the stereoch

Full text of DOI:10.1021/ol100515m

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2036-2039
Synthesis of the C9-C23 (C9′-C23′)
Fragment of the Dimeric Natural Product
Rhizopodin
Zheng Chen,† Liankai Song,† Zhengshuang Xu,*,†,‡ and Tao Ye*,†,‡
Laboratory of Chemical Genomics, Peking UniVersity Shenzhen Graduate School,
UniVersity Town of Shenzhen, Xili, Nanshan District, Shenzhen, China, 518055, and
Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic
UniVersity, Hung Hom, Kowloon, Hong Kong, China
bctaoye@inet.polyu.edu.hk; xuzs@szpku.edu.cn
Received March 2, 2010
ABSTRACT
A stereoselective assembly of the C9-C23 (C9′-C23′) fragment of rhizopodin, a 38-membered bis-lactone natural product, has been developed. A
highly efficient approach to this fragment assembles >50% of the carbon skeleton and the stereochemical elements present in the natural product.
Rhizopodin is a structurally unique polyketide that was
isolated from the myxobacterium Myxococcus stipitatus in
1993.1 Being originally considered as a monomeric lactone,
its structure and absolute stereochemistry were recently
revised as shown in Figure 1.2-4 The planar structure of
rhizopodin is distinguished by a C2-symmetric, 38-membered
dilactone exhibiting 18 stereogenic centers, two conjugated
diene systems in combination with two disubstituted ox-
azoles, and two enamide side chains.2-4 Rhizopodin displays
impressive biological properties including potent cytostatic
activity against a range of tumor cell lines in the low
nanomolar range.1,5 It bears two enamide side chains, each
of which binds a single G-actin molecule, resulting in a
ternary rhizopodin/G-actin complex.2 The ability of rhizopo-
din to interfere with actin cytoskeleton dynamics has allowed
it to play important roles as a probe molecule for chemical
biology. The low supply of rhizopodin, together with its
interesting biological activity and intriguing structure, makes
it an attractive target for total synthesis. As part of our
research program directed toward the total synthesis,6
stereochemical and structural studies,7 and biological evalu-
ation of natural products,8 we have embarked on the synthesis
(5) Gronewold, T. M.; Sasse, F.; Lu¨nsdorf, H.; Reichenbach, H. Cell
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† Peking University Shenzhen Graduate School.
‡ The Hong Kong Polytechnic University.
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65, 2695–2702. (c) Ren, Q.; Dai, L.; Zhang, H.; Tan, W.; Xu, Z. S.; Ye, T.
Synlett 2008, 2379–2383. (d) Chen, Z. Y.; Ye, T. New J. Chem. 2006, 30,
518–520. (e) Pang, H. W.; Xu, Z. S.; Chen, Z. Y.; Ye, T. Lett. Org. Chem.
2005, 2, 699–702. (f) Pang, H. W.; Xu, Z. S.; Ye, T. Lett. Org. Chem.
2005, 2, 703–706. (g) Chen, H. L.; Xu, Z. S.; Ye, T. Tetrahedron 2005,
61, 11132–11140. (h) Chen, Z. Y.; Deng, J. G.; Ye, T. ARKIVOC 2003,
(Part VII), 268–285.
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10.1021/ol100515m  2010 American Chemical Society
Published on Web 04/09/2010

of rhizopodin. Herein we report a highly stereocontrolled
synthesis of fragment 3, corresponding to the C9-C23
(C9′-C23′) fragment of the natural product.
under standard Wittig conditions with methylenetriph-
enylphosphorane to provide terminal alkene 6 in 87% yield.
Protection of the primary alcohol in 6 by using tert-
butyldimethylsilyl chloride, followed by alkene hydrobora-
tion/oxidation11 with 9-borabicyclo[3.3.1]nonane (9-BBN)
and alkaline hydrogen peroxide furnished the corresponding
alcohol 7 in 82% yield (over the two steps).
Scheme 1. Synthesis of the C16-C23 Fragment
Figure 1. Synthetic strategy for the synthesis of rhizopodin.
Our synthetic approach, which is shown in Figure 1, would
exploit the dimeric nature of 1. The acid-labile N-methyl-
N-vinylformamide moiety at the terminus was designed to
be introduced at the final stage of the synthesis and the
macrocyclic ring was envisioned to be constructed through
a sequential esterification/lactonization from the monomeric
subunit 2. The required monomer ultimately would be
derived from the C9-C23 (C9′-C23′) fragment 3 via a
sequence of reactions involving dithiane alkylation and Stille
reaction9 (or a Wittig-type reaction10).
A stereocontrolled synthesis of fragment 3 commenced
with the protection of D-Pantolactone as its p-methoxybenzyl
ether 5 (Scheme 1). DIBAL-H reduction of 5 in THF at -78
°C afforded the corresponding lactol that was homologated
Treatment of alcohol 7 with the Dess-Martin reagent12
provided the aldehyde 8 in 92% yield, which was subse-
quently reacted with Brown’s (Z)-crotyldiisopinocampheyl-
borane13 prepared from (+)-diisopinocampheyl(methoxy)bo-
rane, and yielded the syn homoallylic alcohol 9 in 78% yield,
with distereomeric ratio higher than 97:3. O-Methyl-
ation of homoallylic alcohol 9 with iodomethane in the
presence of LiHMDS afforded 10 in 90% yield. Hydrobo-
ration/oxidation11 of the terminal alkene with 9-BBN and
H2O2 provided the corresponding alcohol, which was then
protected as its pivaloate 11 in 79% yield over the two steps.
Selective cleavage of the tert-butyldimethylsilyl (TBS) ether
from 11 with pyridinium p-toluenesulfonate (PPTS) in
methanol, followed by oxidation of the resulting primary
hydroxyl with the Dess-Martin periodinane gave aldehyde
12.12 With aldehyde 12 in hand, efforts were focused on the
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Org. Lett., Vol. 12, No. 9, 2010
2037

led only to decomposition of the starting material. We believe
the problem here is steric in origin.
Scheme 2. Allylation of Aldehyde12
Since the allylation-based route was operationally jeopardized
by the steric hindrance of the aldehyde, we turned to the use of
an epoxide-opening-based approach16 so as to generate the
required precursor for the synthesis of the oxazole fragment
(Scheme 3). Thus, treatment of TBS ether 10 with TBAF
afforded primary alcohol 14 in 80% yield. Alcohol 14 was
oxidized with Dess-Martin periodinane12 to provide the
corresponding aldehyde, which was subjected to a Horner-
Wadsworth-Emmons olefination17 with ethyl diethylphospho-
noacetate to afford (E)-R,ꢀ-unsaturated ethyl ester 15 in 87%
yield over the two steps. DIBAL-H reduction of ester 15
afforded allylic alcohol 16, which was subjected to a Sharpless
asymmetric epoxidation18 with use of (-)-diisopropyl tartrate
to obtain the epoxy alcohol 17 in 87% yield with 94%
diastereomeric excess. As expected, hydroxyl-directed reductive
opening of epoxide 17 with sodium bis(2-methoxyethoxy)alu-
minum hydride (Red-Al) at 0 °C in THF produced alcohol 18
in 90% yield.19 Selective protection of the primary hydroxyl
introduction of the homoallylic alcohol functionality that
would serve as a precursor for the construction of the oxazole
unit. Unfortunately, all attempts to effect allylation of
aldehyde 12 under the influence of various Lewis acids did
not succeed (Scheme 2).14,15 In most cases, the reactions
Scheme 3. Assembly of the C9-C23 Fragment 3
2038
Org. Lett., Vol. 12, No. 9, 2010

group in 18 with pivaloyl chloride in the presence of DMAP
furnished the corresponding pivaloate 19 in 85% yield. The
terminal alkene in 19 was converted into the corresponding
primary alcohol via a hydroboration/oxidation process;11 this
was then protected as its TBS ether 20 in 76% yield over the
two steps. Selective removal of the pivaloate functionality in
20 by DIBAL-H reduction afforded the free alcohol 21 in 90%
yield. Sequential Dess-Martin12 and Pinnick20 oxidations of
primary alcohol 21 afforded the corresponding carboxylic acid,
which was then activated by Mukaiyama reagent21 and coupled
with L-serine methyl ester to give dipeptide 22 in 86% yield
over the three steps. Activation of hydroxy amide 22 with
diethylaminosulfur trifluoride (DAST) in CH2Cl2 at -78 °C
afforded the oxazoline,22 which was then treated with bromo-
trichloromethane (BTCM) and 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU)23 at 0 °C to produce oxazole 23 in 75% yield.
DIBAL-H reduction of the ester group in 23 furnished the
corresponding alcohol 24 in 73% yield. Dess-Martin oxida-
tion12 of alcohol 24 afforded an aldehyde, which was subjected
to Keck allylation14 to produce the homoallylic alcohol 25 with
>94% diastereoselectivity and 65% yield over the two steps
(78% yield based on recovered starting material). Finally,
O-methylation of homoallylic alcohol 25 with iodomethane in
the presence of sodium hydride afforded 3 in 93% yield.
In summary, we have accomplished an efficient and highly
stereoselective synthesis of 3 corresponding to the C9-C23
fragment of rhizopodin (28 steps, 4.1% overall yield). Key
transformations in the sequence include installation of the
C(20) and C(21) stereogenic centers via asymmetric crotyl-
boration and hydroxyl-directed reductive opening of an
epoxide, construction of the oxazole via Williams’ oxazoline
dehydrogenation protocol, and introduction of the C(11)
stereogenic center via an asymmetric Keck allylation.
Progress toward the development of an efficient total
synthesis of rhizopodin will be reported in due course.
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Acknowledgement. We acknowledge financial support
from the Hong Kong Polytechnic University and financial
support from the Shenzhen Bureau of Science, Technology
& Information (JC200903160367A, ZD200806180051A). Xu
thanks the support from the Shenzhen Foundation for R&D
(SY200806300179A, JC200903160372A) and Nanshan Sci-
ence & Technology (NANKEYUAN2009083).
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Supporting Information Available: Full details for
experimental procedures for compounds 3, 5, 5a, 6, 6a,
7-10, 10a, 11, 11a, 12, 14-19, 19a, 20-22, 22a, and 23-25,
and 1H and 13C NMR spectra for compounds 3, 5, 5a, 6, 6a,
7, 9-10, 10a, 11, 11a, 12, 14-19, 19a, 20-22, 22a, and
23-25. This material is available free of charge via the
Internet at http://pubs.acs.org.
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