Synthesis of the macrocyclic core of rhizopodin

Article abstract of DOI:10.1002/asia.201300802

Rhizing star: A stereoselective synthesis of the fully functionalized macrocyclic core of rhizopodin, a cytotoxic 38-membered macrolide, has been disclosed. The key steps involve Sharpless epoxidation, Robinson-Gabriel oxazole synthesis, olefin cross-metathesis, Suzuki coupling, Yamaguchi esterificationn, and Shiina macrolactonization. Copyright

Full text of DOI:10.1002/asia.201300802

COMMUNICATION
DOI: 10.1002/asia.201300802
Synthesis of the Macrocyclic Core of Rhizopodin
[
a]
[a, b]
[a]
[b]
[a]
Liankai Song, Junyang Liu,
Honggang Gui, Chunngai Hui, Jingjing Zhou,
[a] [a, b] [b]
[
a]
Yian Guo, Pengpeng Zhang, Zhengshuang Xu,*
and Tao Ye*
Rhizopodin (1) is a recently discovered marine natural
product with impressive biological properties, including
potent cytostatic activity against a range of tumor cell lines
[1]
in the low nanomolar range. The mechanism of action is
known to involve interference with actin dynamics. Original-
ly isolated from the myxobacterium Myxococcus stipitatus in
[2]
1
993 and recently revised as shown in Scheme 1, this com-
pound possesses a novel molecular architecture, the central
domain of which consists of a 38-membered dilactone con-
taining two disubstituted oxazoles and two conjugated diene
systems. Our laboratory is engaged in a program devoted to
[3]
marine natural products and view their synthesis as a key
route to structural modification and subsequent activity con-
trol. Because of its important biological activity and novel
molecular features, rhizopodin (1) was selected as a prime
[3j]
target for our synthetic studies. Not surprisingly, rhizopo-
din has also attracted considerable attention from other syn-
thetic chemists. Over the past few years, several synthetic
approaches to fragments and advanced intermediates of rhi-
[4]
zopodin have been reported; these approaches include
Nicolaouꢀs synthesis of mono-rhizopodin and 16-epi-mono-
[5]
rhizopodin, and Mencheꢀs effects culminated in a complet-
[6]
ed total synthesis. While this manuscript was in prepara-
tion, Paterson and co-workers reported an elegant total syn-
[7]
thesis of rhizopodin that employs a conceptually similar
route towards the formation of the macrocyclic core. This
disclosure prompted us to present our own progress toward
the synthesis of rhizopodin. Herein, we describe our inde-
pendent synthesis of 2, which corresponds to the fully func-
tionalized macrocyclic core of rhizopodin.
Scheme 1. Retrosynthetic analysis.
+
+
[
a] L. Song, Dr. J. Liu, H. Gui, J. Zhou, Y. Guo, P. Zhang,
Prof. Dr. Z. Xu
Laboratory of Chemical Genomics, School of Chemical Biology and
Biotechnology, Peking University Shenzhen Graduate School
Xili, Nanshan District, Shenzhen, 518055 (China)
Fax : (+86)755-26032697
As outlined in our retrosynthetic analysis, rhizopodin
could be simplified by using the 38-membered macrodilac-
tone (2) as the advanced precursor with the side chains
being installed at a later stage in the total synthesis. It was
envisaged that 2 could be constructed by macrolactonization
of the corresponding precursor derived from intermediate 3,
which was envisaged to be assembled from fragments 4 and
E-mail: xuzs@pkusz.edu.cn
+
[
b] Dr. J. Liu, C. Hui, Prof. Dr. Z. Xu, Prof. Dr. T. Ye
Department of Applied Biology & Chemical Technology, The Hong
Kong Polytechnic University
Hung Hom, Kowloon, Hong Kong (China)
Fax : (+852)34008722
E-mail: tao.ye@polyu.edu.hk
5
(Scheme 1). This strategy would reduce the number of
protecting group manipulations and oxidation state adjust-
ments.
+
[
] These authors contributed equally to this work
The synthesis of fragment 5 involves elongation of diol 6
in two directions into the corresponding a,b-unsaturated
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300802.
Chem. Asian J. 2013, 00, 0 – 0
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Tao Ye, Zhengshuang Xu et al.
iodine, triphenylphosphine, and imidazole in THF and sub-
sequent reductive elimination of the iodo groups with acti-
[8]
vated Zn dust in EtOH provided the allylic alcohol 10 in
0% yield over two steps. Conversion of 10 into alcohol 12
9
was achieved by employing three straightforward transfor-
mations: (i) protection of the 1,3-diol moiety of 10 to the
corresponding PMP acetal, (ii) double hydroboration of two
terminal alkenes followed by an oxidative workup to give
rise to diol 11, and (iii) desymmetrization of diol 11 by
mono-tert-butyldimethyl-silylation. Oxidation of the primary
hydroxy group of 12 by the sequential action of TEMPO/
[
9]
NaClO and NaClO gave the corresponding acid, which
2
[10]
was then condensed with amino alcohol 13 to give rise to
1
1
4 in 74% yield. Dess–Martin oxidation of hydroxy amide
4 followed by one-pot cyclodehydration of the resulting al-
[11]
dehyde under Wipf conditions afforded the oxazole 15 in
6
2% yield. Further elaboration to the doubly protected diol
1
6 was then effected by an oxazole-directed acetal cleavage
[12]
using MgBr ·Et O and nBu SnH and protection of the re-
2
2
3
sulting C16 alcohol as its TES ether. The structure and re-
giochemistry of the acetal-cleavage adduct were confirmed
1
13
by H and C NMR spectroscopic experiments employing
COSY (correlation spectroscopy), HSQC (heteronuclear
single quantum coherence), and HMBC (heteronuclear mul-
tiple bond correlation) correlations (see the Supporting In-
formation). Olefin cross-metathesis of 16 with 17 in the
[13]
presence of additive 18 afforded vinyl boronate ester 19
in 72% yield with an E/Z ratio of 6:1. Building on the expe-
rience gained in our previous approach towards rhizopo-
[3j]
din, we elected to remove the PMB ether in 19 with DDQ
to give rise to alcohol 5, which would alleviate later chemo-
selectivity complications arising from oxidative conditions.
The synthesis of vinyl iodide 4 commenced from the
[14,6]
known ester 20.
Methyl ester 20 was subjected to succes-
sive reduction with DIBAL-H and oxidation with Dess–
Martin periodinane to afford the corresponding aldehyde.
The reaction of this aldehyde with Nagaoꢀs N-acetylthiazoli-
[15]
[16]
dine-2-thione (21) in the presence of tin triflate and N-
ethylpiperidine proceeded in high diastereoselectivity (d.r.=
10:1) to yield the corresponding b-hydroxy adduct 22 as the
major diastereomer. Protection of the resulting secondary
hydroxy group of 22 as its TBS ether, followed by displace-
ment of the thiazolidinethione auxiliary with methanol in
the presence of DMAP afforded 23 in 69% yield. Acidic
cleavage of primary TBS ether afforded alcohol 24 in 75%
yield. Oxidation of alcohol 24 with Dess–Martin periodinane
afforded the corresponding aldehyde, which was homologat-
Scheme 2. Synthesis of intermediate 5. DMSO=dimethylsulfoxide,
TEA=triethylamine, DIBAL-H=diisobutylaluminium hydride, DIPT=
diisopropyl tartrate, TBHP=tert-butyl hydroperoxide, MS=molec-
ular sieves, PPTS=pyridinium p-toluenesulfonate, PMP=p-methoxy-
phenyl, TBS=tert-butyldimethylsilane, DMPA=4-dimethylaminopyri-
dine, TEMPO=2,2,6,6-tetramethylpiperidine-1-oxyl, EDCI=1-ethyl-3-
(
3-dimethylaminopropyl)carbo-diimide, HOAT=1-hydroxy-7-azabenzo-
triazole, DIPEA=diisopropylethylamine, TES=triethylsilyl, Tf=tri-
fluoromethanesulfonate, PMB=p-methoxybenzyl, DDQ=2,3-dichloro-
5
,6-dicyano-1,4-benzoquinone.
[17]
ed using the Takai protocol
to furnish vinyl iodide 4 in
diester 8 (Scheme 2). Thus, Swern oxidation of diol 6 afford-
ed the corresponding dialdehyde, which was subjected to
Horner–Wadsworth–Emmons olefination with phosphonate
68% yield over two steps (Scheme 3).
With the key intermediates 4 and 5 in hand, we next
turned our attention to their coupling reaction (Scheme 4).
In the event, intermolecular coupling of vinyl iodide 4 and
vinyl boronate ester 5 proceeded smoothly in the presence
of a catalytic amount of tetrakis(triphenylphosphine)palladi-
7
to give 8 in 91% yield over the two steps. Reduction of 8
with DIBAL-H produced the corresponding allylic alcohol,
which was then subjected to a Sharpless asymmetric epoxi-
dation, using d-(À)-DIPT, to afford the diepoxy alcohol 9 in
very good yield (77%). The primary hydroxy groups of 9
were converted into the corresponding iodo groups with
[18]
um and silver oxide to provide the diene 25 in 84% yield.
Saponification of the methyl ester in the presence of
a number of sensitive functionalities was achieved by heat-
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Tao Ye, Zhengshuang Xu et al.
Scheme 3. Synthesis of intermediate 4. CSA=camphorsulfonic acid.
Scheme 4. Synthesis of intermediate 3. THF=tetrahydrofuran.
Scheme 5. Synthesis of macrocyclic core 2. TCEt=trichloroethanol,
TCE=trichloroethyl, TMS=trimethylsilyl, TCBC=2,4,6-trichlorobenzyl
chloride, MNBA=2-methyl-6-nitrobenzoic anhydride.
[19]
ing 25 with 5 equivalents of Me SnOH in toluene at 958C
3
for 36 h. Acid 3 was obtained in 83% yield and this moiety
was readily converted into compounds 26 and 27 for further
elaboration into macrodilactone 2.
acid intermediate was slowly added to a solution of DMAP
and 2-methyl-6-nitrobenzoic anhydride (MNBA) containing
powdered molecular sieves to give rise to macrodilactone
(2) in 44% yield.
In summary, the macrocyclic skeleton of the marine natu-
ral product rhizopodin has been prepared through a conver-
gent route that employed Sharpless epoxidation, Robinson–
Gabriel oxazole synthesis, olefin cross-metathesis, Suzuki
coupling, a Yamaguchi esterification, and Shiina macrolacto-
nization as the key steps. The elaboration of macrodilactone
2 and alternative synthetic strategies to natural rhizopodin
are ongoing in our laboratories and will be reported in due
course.
As shown in Scheme 5, 26 was obtained in 92% yield by
treatment of 3 with trimethylsilyl chloride and imidazole,
whereas 27 was produced by converting 3 into the corre-
sponding trichloroethyl ester in 83% yield through an EDC-
mediated esterification. Esterification between acid 26 and
alcohol 27 was achieved by using a modification of the Ya-
[20]
[21]
maguchi protocol, reported by Yonemitsu ; this afforded
8 in 63% yield. The secondary alcohol-bound TMS group
2
was selectively removed with a mixture of HCl (1m, aq)/
ethyl acetate (1:10) at ambient temperature and the trichlor-
oethyl ester was then reductively cleaved in a mixture held
[22]
at pH 4.7 using a buffer, and this provided the required
seco-acid, in preparation for the key macrolactonization
step. For our substrate, we found that the Shiina macrolacto-
[23]
nization
was the most effective. A solution of the seco-
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Tao Ye, Zhengshuang Xu et al.
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Experimental Section
2
HCl (1.2 mL, 1m in water) was added to a solution of 28 (18.6 mg,
0 mmol) in ethyl acetate (3 mL) at room temperature. The reaction was
stirred and monitored by TLC until the starting material was consumed
1
(
(
approx. 1.5 h). The reaction mixture was diluted with ethyl acetate
80 mL), washed with brine (10 mL), and dried over Na SO . The solu-
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2
4
tion was concentrated in vacuo to afford the desired alcohol, which was
employed in next step without further purification. The above alcohol
was dissolved in MeCN/KH PO (1m, 6 mL, v/v=1:1) at room tempera-
2 4
ture. After zinc dust (100 mg) was added, the reaction mixture was
stirred vigorously for 10 h. The reaction mixture was diluted with ethyl
2 4
acetate (100 mL), washed with brine (10 mL), dried over Na SO , and
2
977; b) H. Liu, Y. Liu, Z. Wang, X. Xing, A. R. Maguire, H.
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S. Kwong, Q. Ren, S. Tang, Y. Meng, Z. Xu, T. Ye, Synlett 2012, 19,
concentrated in vacuo. The residue was purified by silica-gel chromatog-
7
83; f) L. Wang, Z. Xu, T. Ye, Org. Lett. 2011, 13, 2506; g) H. Liu,
raphy (ethyl acetate/n-hexane=1:4 to 1:2) to give the seco-acid (14.0 mg)
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1
as a colorless oil. H NMR (400 MHz, CDCl
3
) d=7.50 (s, 1H), 7.49 (s,
1
H), 6.22–6.05 (m, 4H), 5.82–5.58 (m, 2H), 5.46–5.34 (m, 2H), 5.13–5.04
(
m, 1H), 4.34–4.25 (m, 2H), 4.25–4.15 (m, 4H), 3.92–3.79 (m, 3H), 3.81–
3
3
.71 (m, 2H), 3.65–3.58 (m, 1H), 3.57–3.49 (m, 1H), 3.35 (s, 3H), 3.34 (s,
H), 3.25 (s, 3H), 3.22 (s, 3H), 3.08 (dd, J=15.3, 3.2 Hz, 1H), 3.05–2.84
(
1
(
(
1
m, 3H), 2.72–2.47 (m, 8H), 1.98–1.82 (m, 3H), 1.79–1.66 (m, 3H), 1.6–
.54 (m, 2H), 0.96–0.85 (m, 66H), 0.58–0.34 (m, 12H), 0.12 (s, 6H), 0.10
s, 3H), 0.10 (s, 3H), 0.07 (s, 6H), 0.04 (s, 3H), 0.02 ppm (s, 3H). HRMS
+
+
ESI): m/z calc. for
638.0394.
MNBA (12.2 mg, 34 mmol), DMAP (10.3 mg, 82 mmol), and powdered
ꢂ molecular sieves (30.0 mg) were stirred in toluene (2.5 mL). After
the mixture was brought to 708C, a solution of the above seco-acid
14.0 mg, 8.5 mmol) in THF/toluene (2 mL, v/v=1:1) was added dropwise
84 2 6
C H161N O17Si : [M+H] : 1638.0405, found
[
4
(
with a syringe pump over 3 h. The reaction mixture was stirred at 708C
for an additional 12 h prior to being cooled to room temperature and
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quenched by saturated aqueous solution of NH
was diluted with ethyl acetate (200 mL) and the organic layer was
washed with brine (30 mL), dried over anhydrous Na SO , and concen-
trated in vacuo. The residue was purified by silica-gel chromatography
ethyl acetate/n-hexane=1:8 to 1:5) to give 2 (7.1 mg, 44%) as a colorless
4
Cl (1.0 mL). The mixture
2
4
[
(
2
012, 51, 5667.
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2
D
0
3
À1
À1
1
oil. [a] =À13 cm g dm
3
(c=0.2 in CHCl ); H NMR (400 MHz,
3
CDCl ) d=7.44 (s, 2H), 6.18–6.03 (m, 4H), 5.66 (dt, J=14.3, 7.1 Hz,
1
2
6
3
2
H), 5.36 (dd, J=14.5, 8.1 Hz, 2H), 5.07–4.99 (m, 2H), 4.20 (t, J=
[
[
.0 Hz, 2H), 4.18–4.07 (m, 4H), 3.76–3.63 (m, 2H), 3.64–3.52 (m, 2H),
.55–3.43 (m, 2H), 3.33 (s, 6H), 3.20 (s, 6H), 3.04 (dd, J=15.4, 2.8 Hz,
H), 2.89 (dd, J=15.3, 9.0 Hz, 2H), 2.62 (t, J=6.7 Hz, 4H), 0.94–0.76
1
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(
m, 66H), 0.49–0.29 (m, 12H), 0.05 (s, 12H), À0.00 ppm (s, 12H).
[
1
3
C NMR (125 MHz, CDCl ) d=170.6, 163.6, 140.6, 135.0, 133.1, 131.9,
3
1
31.8, 129.9, 79.2, 76.3, 76.0, 74.6, 66.4, 60.3, 56.8, 55.9, 43.0, 42.4, 37.7,
[
[
3
3.8, 32.8, 29.7, 25.9, 25.9, 20.8, 19.9, 18.2, 18.0, 7.0, 5.0, À4.4, À4.6, À5.4,
2
and
+
+
À5.4 ppm. HRMS (ESI): m/z calc. for
84 159 2 6
C H N O16Si : [M+H] :
3
1
620.0300, found 1620.0382.
[
[
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Keywords: antitumor agents
macrocycles · natural products · polyketides
· asymmetric synthesis ·
1
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Tao Ye, Zhengshuang Xu et al.
[
[
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Received: June 18, 2013
Published online: && &&, 0000
22] G. Just, K. Grozinger, Synthesis 1976, 457.
Chem. Asian J. 2013, 00, 0 – 0
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COMMUNICATION
Natural Products
Rhizing star: A stereoselective synthe-
sis of the fully functionalized macrocy-
clic core of rhizopodin, a cytotoxic 38-
membered macrolide, has been dis-
closed. The key steps involve Sharpless
epoxidation, Robinson–Gabriel oxa-
zole synthesis, olefin cross-metathesis,
Suzuki coupling, Yamaguchi esterifica-
tionn, and Shiina macrolactonization.
Liankai Song, Junyang Liu,
Honggang Gui, Chunngai Hui,
Jingjing Zhou, Yian Guo,
Pengpeng Zhang, Zhengshuang Xu,*
Tao Ye*
&&&& — &&&&
Synthesis of the Macrocyclic Core of
Rhizopodin
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