Divergent approach to building a latrunculin family derived hybrid macrocyclic toolbox

Article abstract of DOI:10.1021/ol503465p

A divergent approach to obtain a latrunculin family based hybrid macrocyclic toolbox is developed. A practical, stereoselective synthesis of a common substructure present in latrunculin A and latrunculol A was achieved. This was further utilized in the ma

Full text of DOI:10.1021/ol503465p

Letter
pubs.acs.org/OrgLett
Divergent Approach to Building a Latrunculin Family Derived Hybrid
Macrocyclic Toolbox
Madhu Aeluri, Bhanudas Dasari, and Prabhat Arya*
Dr. Reddy’s Institute of Life Sciences (DRILS), University of Hyderabad Campus, Hyderabad 500046, India
S
* Supporting Information
ABSTRACT: A divergent approach to obtain a latrunculin
family based hybrid macrocyclic toolbox is developed. A
practical, stereoselective synthesis of a common substructure
present in latrunculin A and latrunculol A was achieved. This
was further utilized in the macrocyclic diversity synthesis. The
amino acid moiety embedded in the 15-membered macrocyclic
ring allows for the exploration of various chiral side chains as
one of the diversity sites.
solated from Red Sea sponges Negombata magnifica and
other unrelated species, the latrunculin natural products
family is structurally unique and exhibits biological responses as
highly potent inhibitors of actin polymerization and cytotoxicity
against a wide variety of cancer cell lines.1 One of the first
compounds isolated in this series is a latrunculin A (1, Figure
1),1a and in 2008, another interesting member, latrunculol A
monomer binding to latrunculin A revealed that the
interactions made by the pyran ring containing thiazolidinone
substitution with actin are crucial for the biological activity.3
Because of the excellent biological properties that are shown
by this family of natural products and the scarcity of accessing
these compounds in sufficient amounts from the natural
sources, several groups worked on the synthesis of
latrunculins.1c,4 In 2013, the Smith group reported the first
total synthesis of epimeric latrunculol A.5 As part of our
continuous interest in developing modular approaches to
building a toolbox having different types of natural product-
inspired macrocyclic compounds,6 we focused our attention on
the common southern part of latrunculin A and latrunculol A
and on utilizing this scaffold in obtaining a diverse set of hybrid
macrocyclic natural product-based small molecules (3). Having
a diverse set of chemical toolbox in hand, our interest is in
exploring the value of these hybrid compounds to search for a
new family of cytoskeleton modulators as well as in other
selected pathways involved in cytoskeleton and cell migration
biology.7 Our long-term goal in this exercise is to identify novel
sets of compounds as selective modulators of protein−protein
interactions8,9 and, in some of the signaling pathways.
Keeping in mind the importance of the southern region of
latrunculin family, we planned our synthesis with the following
objectives, and these are (i) to develop a novel and practical
route to access sufficient amounts of the southern scaffold and
(ii) to utilize this key scaffold in building a diverse set of
macrocyclic architectures with an embedded amino acid
moiety. The incorporation of an amino acid moiety in the
macrocyclic ring would allow exploring the variation in the
chiral side chain functionality as one of the diversity sites. Our
approach to obtaining latrunculin-derived hybrid macrocycles is
outlined in Scheme 1. The first objective is to develop a
stereoselective synthesis for obtaining the southern scaffold
I
Figure 1. Latrunculin A (1), latrunculol A (2), and the proposed
hybrid macrocyclic natural products 3.
(2),1d was further reported. The structures of latrunculin A and
B (note: the structure is shown only for latrunculin A) were
assigned on the basis of extensive spectroscopic studies and the
single-crystal X-ray of the methyl glycoside derivative of
latrunculin A.2 Several members of the latruculin family, such
as latrunculin A, latrunculin B, and latrunculol A, bear a
common southern substructure having a stereodefined
tetrahydropyran ring coupled to a thiazolidinone moiety. In
some cases, the northern macrocyclic substructures vary in the
ring sizes (for example, 14- and 16-membered rings). There are
also slight variations in the functional groups of the northern,
macrocyclic region among several family members. Latruncu-
lins are known to disrupt the microfilament organization by
binding specifically to a cytoskeleton protein called actin
through forming a 1:1 complex without affecting the micro-
tubule dynamics.1a,b The X-ray crystal structure of the actin
Received: December 1, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503465p
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ketone 10 gave β-hydroxy ketone 12 as an inseparable 5:2
(from 1H NMR) diastereomeric mixture in 88% yield.
Desilylation of the secondary hydroxyl group protected as
−OTBS at C-13 followed by an asymmetric ketolization of the
aldol product 12 in the presence of pyridinium p-toluenesul-
fonate (PPTS) and methanol smoothly furnished the separable
mixture of methylacetals 13 (50%) and 14 (20%).
Scheme 1. Our Plan To Obtain Latrunculin-Derived Hybrid
Macrocycles (4) from the Southern Scaffold 5 Which Can Be
Obtained from 6 by Ketolization
The stereochemical assignments of the major and minor
products were made by NOE experiments (see Figure 2). The
NOE between two protons at C-13 and C-15 and proton at C-
13 and C-17 OMe in 13 was observed, whereas 14 did not
show any NOE between two protons at C-13 and C-15.
(both series having α- and β-OH group at C-15) in large
quantities having two orthogonally protected hydroxyl groups
on the pyran moiety. The primary −OH group at C-13 can be
acylated using an amino acid moiety, which after the coupling
could be subjected to ring-closing metathesis as the stitching
approach for obtaining a 15-membered ring. The scaffolds
having α- and β-OH groups at C-15 would allow building
macrocyclic rings utilizing cis and trans orientations of two
functional groups at C-13 and C-15, respectively. In our plan,
we aimed at accessing 5 from 6 by an asymmetric ketolization.
The synthesis of 6 can be achieved by an aldol reaction (see the
disconnection).
Figure 2. Stereochemical assignment through NOE studies.
Allylation of the secondary hydroxyl group at C-15 of the
pyran fragment 13 with allyl bromide and NaH followed by a
removal of the TBDPS group with tetrabutylammonium
fluoride gave the primary alcohol 15 in 75% yields (Scheme
3). Coupling of N-alloc-amino acid 16 with primary alcohol 15
Scheme 3. Synthesis of 15-Membered Macrocyclic Ring
Using Cis Oriented Hydroxyls at C-15 and C-13
Synthesis of the southern scaffold as pyran fragments 13 and
14 is shown in Scheme 2. The thiazolidinone acid 8 was
Scheme 2. Synthesis of the Southern Scaffold of Latrunculins
13 and 14
in the presence of EDCI and DMAP gave the bisallyl precursor
17 which was then subjected to ring-closing metathesis using
Grubbs’ II catalyst (10 mol %). This was then followed by
hydrogenation of an olefin with 10% Pd−C in the presence of
hydrogen gas to obtain the macrocycle 18 in a very good yield.
To explore the generality of 15-membered ring formation using
a ring-closing metathesis approach and to obtain several
analogues with a variation in the chiral side chain, five amino
acids were tried. In all cases, the large ring formation using the
cis orientation of the stitching substituents at C-13 and C-15
(17), did occur without any problem. The synthesis details and
a full structural characterization are provided in the
experimental details in the Supporting Information. Although
not shown here, compound 18 having a PMB group on the
obtained from L-cysteine (7) in two steps following the
reported protocol (see the Supporting Information). The
coupling of hydroxylamine hydrochloride with acid 8 using
EDCI reagent gave Weinreb amide 9, which was further treated
with methylmagnesium bromide to obtain methyl ketone 10 in
a good yield. Titanium tetrachloride mediated aldol reaction10
between the aldehyde 11, which was obtained from S-malic acid
in four steps (see the Supporting Information), and methyl
B
DOI: 10.1021/ol503465p
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
thiazolidinone moiety can further be utilized in building the
second diversity site.
latrunculin-derived hybrid macrocyclic architectures. Further,
biological investigations using these compounds are ongoing,
and these studies will be made available when complete.
In a similar manner, we also succeeded in the synthesis of
macrocycles 19 starting from the pyran fragment 14 having
trans stitching functional groups at C-13 and C-15. In this
series, we faced no problem, and the 15-membered macrocyclic
ring formation appeared to be independent of the stereo-
chemistry of the functional group at C-15. Again, in this series,
five amino acids were used to validate the generality of this
reaction and to explore one of the diversity sites on the
macrocyclic ring skeleton. Although not attempted yet, the
utilization of β-amino acid moieties in our macrocyclic
synthesis planning in both series shown in Schemes 3 and 4
can lead to accessing 16-membered ring architectures.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental section and spectral data are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: prabhata@drils.org.
Notes
Scheme 4. Similar Approach to Obtain Latrunculin-Based
Hybrid Macrocycles (19) Epimeric at C-15 of the Pyran
Moiety
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank DST and DBT (funding agencies from India) for the
financial support. M.A. and B.D. thank CSIR, India, for the
award of a Senior Research Fellowship. Our sincere thanks to
the DRILS analytical facility team for providing excellent
technical support.
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