Formal synthesis of actin binding macrolide rhizopodin

Article abstract of DOI:10.1021/ol5008179

Formal synthesis of an actin binding macrolide rhizopodin was achieved in 19 longest linear steps. The key features of the synthesis include a stereoselective Mukaiyama aldol reaction, dual role of a Nagao auxiliary (first, as a chiral auxiliary of choice for installing hydroxy centers and, later, as an acylating agent to form an amide bond with an amino alcohol), late stage oxazole formation, and Stille coupling reactions.

Full text of DOI:10.1021/ol5008179

Letter
pubs.acs.org/OrgLett
Formal Synthesis of Actin Binding Macrolide Rhizopodin
Kiran Kumar Pulukuri† and Tushar Kanti Chakraborty*,†,‡
†CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
‡Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
S
* Supporting Information
ABSTRACT: Formal synthesis of an actin binding macrolide rhizopodin was
achieved in 19 longest linear steps. The key features of the synthesis include a
stereoselective Mukaiyama aldol reaction, dual role of a Nagao auxiliary (first, as a
chiral auxiliary of choice for installing hydroxy centers and, later, as an acylating
agent to form an amide bond with an amino alcohol), late stage oxazole formation,
and Stille coupling reactions.
Scheme 1. Retrosynthesis of Rhizopodin 1
ctin, one of the major components of cytoskeleton in
eukaryotic cells and responsible for many important
A
cellular functions such as cell shape, cell division, motility, and
adhesion, is found to be an attractive target for the
development of drugs for various diseases.1 Small natural
products that disrupt the dynamics of actin cytoskeleton serve
as valuable molecular probes for understanding the complex
mechanisms associated with its function.2 Cytochalasins B, D
and latrunculins A, B are some of the earliest actin binding
molecules that have been studied extensively.1 Rhizopodin (1,
Figure 1) is another such novel actin binding polyketide
isolated from the culture broth of the Myxococcus stipitatus.3
Based on extensive NMR studies and the crystal structure of its
complex with rabbit G-actin, the structure was found to be a C2-
symmetric 38-membered dilactone exhibiting 18 stereogenic
centers, two conjugated diene systems in combination with two
disubstituted oxazoles, and two enamide side chains.4
Rhizopodin displays potent antiproliferative activity against
various cancer cell lines in low nanomolar concentration and
also displays activity against certain fungi.5 Most importantly,
rhizopodin displays irreversible effects on actin cytoskeleton by
binding with a few critical sites of actin. Its impressive biological
activity and complex architecture make it a challenging target
for the synthetic community.
To date, two total syntheses of rhizopodin have been
reported. Menche’s group achieved the first total synthesis and
confirmed the absolute configuration of rhizopodin.6 This was
followed by the elegant synthesis by the Paterson group7 and
synthesis of several fragments, including monorhizopodin and
Received: March 19, 2014
Published: April 10, 2014
Figure 1. Structure of rhizopodin 1.
© 2014 American Chemical Society
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Scheme 2. Preparation of C1−C7 Fragments 4 and 5
Scheme 5. Synthesis of Seco Acid 2
Scheme 3. Preparation of C8−C13 Fragment 6
Scheme 4. Preparation of C8−C22 Fragment 4
the macrocyclic core of rhizopodin by others.8 We have also
reported the syntheses of C1−C15, C16−C27 fragments and
later the entire monomeric unit of rhizopodin in its protected
form.9 In continuation of our efforts toward the synthesis of
rhizopodin, we now report a new approach to the synthesis of
C1−C7, C8−C14, and C16−C23 fragments and an advanced
intermediate 2 in Paterson’s total synthesis of rhizopodin.
Our retrosynthetic plan involves a highly convergent route to
the seco acid 2, as shown in Scheme 1. We envisaged that the
seco acid 2 could be prepared from vinyl iodide 3 and vinyl
stannane 4 and 5 by a sequential cross-coupling, esterification,
and cross-coupling reactions. Vinyl iodide 3 could be prepared
by an oxazole formation, which involves a direct amide bond
formation between amino alcohol 6 and the thiozolidine
auxiliary 7, followed by oxidation and cyclodehydration.
Synthesis of vinylstannane 5 started with an acetate aldol
reaction of known aldehyde 8,8f with a titanium enolate derived
from chiral auxiliary 910 (Scheme 2). The resulting aldol adduct
was immediately converted to methyl ester 10 using imidazole
in methanol to get the chromatographically separable mixture
of diastereomers in a 5:1 ratio. Diastereomerically pure product
10 was isolated in 61% yield. Protection of the secondary
alcohol as its TBS ether, followed by selective primary silyl
deprotection using PPTS in methanol, gave the hydroxy
compound 11 in 82% yield.
Oxidation of 11 followed by treatment of the resultant
aldehyde with Bestmann−Ohira reagent11 12 gave the alkyne
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13 in 78% yield. Hydrostannylation of alkyne with Pd(dppf)Cl2
and Bu3SnH afforded the vinylstannane 4 in 86% yield with a
95:5 (E/gem) ratio. Methyl ester hydrolysis of 4 gave the
carboxylic acid 5 in good yield.
conditions24 to gain the vinyl stannane 26 in 86% yield,
which was subjected to another Stille coupling with the vinyl
iodide 12 to give the bis-diene methyl ester 27 in 74% yield.
Unfortunately, basic hydrolysis of methyl ester using various
bases, such as LiOH, Ba(OH)2, etc., was quite problematic, as
under these conditions deprotection of TES ethers at C16,
C16′ was observed prior to the hydrolysis of the methyl ester.
After a brief survey of various conditions, treatment of methyl
ester with Me3SnOH25 in dichloroethane enabled a clean
saponification to give the carboxylic acid 2 in 76% yield.26
In conclusion, we have completed the formal synthesis of
actin binding macrolide rhizopodin in 19 longest linear steps in
a highly convergent manner. The notable features of our
synthesis include a stereoselective Mukaiyama aldol reaction,
dual role of a Nagao auxiliary, first as a chiral auxiliary for
installing hydroxy centers on complex substrates and, later, as
an acid activating agent to form an amide bond with an amino
alcohol, late stage oxazole formation, and Stille coupling
reactions. Further studies are currently in progress.
n
Previously, we reported9c the synthesis of the amino alcohol
fragment using an asymmetric indium mediated homopropar-
gylation of Garner aldehyde 14,12 which proved to be less
viable on a multigram scale. An alternative route (Scheme 3) to
this fragment was undertaken. An indium mediated Barbier
type addition of propargyl bromide to aldehyde 14 gave an
inseparable mixture of homopropargyl alcohols which were
subjected to silyl protection followed by one-pot hydro-
zirconation and iodination13 to gain vinyl iodide 15 as a
separable mixture of C11 epimers in 71% yield (2:1 dr). Silyl
deprotection followed by O-methylation of pure C11 hydroxy
gave the methyl ether 16 in 90% yield. The C11 epimer was
also converted to methyl ether 16, by a sequence of reactions as
shown in Scheme 3, in 68% yield. Treatment of 16 with 4 M
HCl in dioxane gave the desired amino alcohol fragment 6.
Synthesis of key C8−C22 fragment 3 started with the
Mukaiyama aldol reaction14 between TBDPS protected (S)-
Roche aldehyde 1715 and silyl ketene acetal 18,16 as shown in
Scheme 4. Previously, similar aldol reactions of aldehyde 17
with boron and lithium enolates derived from methyl ketone
were reported, but gave the aldol products in lower
selectivities.17 We anticipated that the geminal dimethyl
group in ketene acetal 18 would induce better Felkin−Anh
selectivity. As expected, treatment of the aldehyde 17 with silyl
enol ether 18 in the presence of BF3·Et2O gave the desired β-
hydroxyl ketone 19 in 92% yield with very good diaster-
eoselectivity (dr 10:1).18 The selection of protecting groups
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details as well as characterization data and copies
of the NMR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: tushar@orgchem.iisc.ernet.in.
Notes
was critical for the stereoselectivity of the aldol reaction.19
A
The authors declare no competing financial interest.
stereoselective reduction of 19 using Me4NB(OAc)3H20 gave
the anti 1,3-diol in very good yield with excellent
diastereoselectivity, which was subjected to one-pot selective
deprotection of TBS ether and regioselective protection of the
resultant triol as PMP acetal to obtain the compound 20 in 66%
yield. PMP acetal 20 was converted to aldehyde 21 in 65% yield
in three steps, which involved methylation, regioselective
opening of PMP acetal, and oxidation of the resultant alcohol.
Selective removal of TBDPS ether at a later stage of synthesis
was found to be problematic; hence, it was changed to TBS
ether in a two-step sequence to give rise to TBS protected
aldehyde 22 in 86% yield. Next, compound 22 was subjected to
an acetate aldol reaction with tin enolate, generated from
thiazolidinethione auxiliary 23,21 which gave the desired aldol
product with excellent diastereoselectivity (dr 12:1), which was
further transformed into the triethylsilyl ether 7 in 85% yield
(two steps). With gram quantities of 6 and 7 in hand, their
coupling was carried out by an oxazole formation. First, direct
displacement of the thiazolidinethione auxiliary in 7 by the
amino alcohol 6 was carried out to get the hydroxyl amide,
which was subjected to oxidation, subsequent cyclodehydration,
and elimination using modified Wipf conditions22 to obtain the
desired oxazole 24 in 67% yield. Oxidative removal of C18
PMB ether gave the C8−C22 fragment 3 in 92% yield. This key
C8−C22 fragment was synthesized in 13 linear steps, with an
overall yield of 17%.
ACKNOWLEDGMENTS
■
The authors wish to thank CSIR, New Delhi for a research
fellowship (K.K.P.), Dr. A. Ravi Sankar, CDRI for his support,
and the SAIF, CDRI for providing the spectroscopic and
analytical data.
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