Synthesis of the C9-C25 Subunit of Spirastrellolide B

Article abstract of DOI:10.1021/acs.orglett.6b01248

The synthesis of the C9-C25 subunit of the marine natural product spirastrellolide B is reported. The key synthetic features included the union of the two key fragments 5 and 6 via a Suzuki-Miyaura coupling reaction and a late-stage, one-pot sequential de

Full text of DOI:10.1021/acs.orglett.6b01248

Letter
pubs.acs.org/OrgLett
Synthesis of the C9−C25 Subunit of Spirastrellolide B
Soma Maitra,† Mahipal Bodugam,‡ Salim Javed, and Paul R. Hanson*
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045-7582, United States
S
* Supporting Information
ABSTRACT: The synthesis of the C9−C25 subunit of the
marine natural product spirastrellolide B is reported. The key
synthetic features included the union of the two key fragments 5
and 6 via a Suzuki−Miyaura coupling reaction and a late-stage,
one-pot sequential deprotection/cascade Achmatowicz rear-
rangement−spiroketalization to install the key spirocyclic
intermediate present in the C9−C25 fragment of spirastrellolide
B. The synthesis of the C9−C16 fragment 6 was accomplished
via a phosphate tether mediated ring-closing metathesis (RCM),
a subsequent hydroboration−oxidation protocol, followed by
other stereoselective transformations in a facile manner. The
spirocyclic intermediate was further functionalized utilizing a
Lindlar/NaBH4 reduction protocol to furnish the C9−C25
subunit 3.
pirastrellolide A (1, Figure 1) was the first member of the
spirastrellolide family to be isolated in 2003 by Andersen and
carboxylic acid group. Spirastrellolide A methyl ester 1 exhibited
potent activity in a cell-based (human carcinoma MCF-7 cells)
antimitotic assay with IC50 value of 100 ng/mL, and its unique
cytotoxicity has been linked to the phosphatase-inhibition
mechanism (a PP2A inhibitor).3 Irregularities in protein
phosphorylation are known to contribute to many human
diseases such as cancer and diabetes;4 therefore, it is imperative
to identify inhibitors of phosphatases in order to understand their
role in such biological problems and aid in detecting potential
drug targets. The interesting biological activity and novel
structural features of the spirastrellolide family have culminated
in many elegant synthetic efforts toward the syntheses of
spirastrellolides A, B, E, and F.5 The total synthesis of
S
spirastrellolide A was accomplished by both the Furstner and
̈
the Paterson groups.6,7 Initially, no biological activity was
reported for spirastrellolide B; however, in 2012, both of the
family members, spirastrellolides A and B, were reisolated as free
acids from a marine sponge Epipolasis sp. and tested against HeLa
cancer cell lines.8 The IC50 values of the free acids of
spirastrellolides A and B were found to be 20 and 40 nM,
respectively, comparable to the corresponding methyl ester of
spirastrellolides A and B, which exhibited IC50 values of 30 and 70
nM, respectively. However, unlike spirastrellolide A, the
cytotoxicity of spirastrellolide B has not been linked to the
phosphatase inhibition mechanism. Additionally, no total
synthesis has been reported so far for spirostrellolide B. Given
the structural similarities between spirastrellolides A and B (1
and 2 in Figure 1), we believe that the total synthesis of
spirastrellolide B will serve not merely as another synthetic
campaign but also for the identification of the pharmacophore of
Figure 1. Structures of spirastrellolides A and B and retrosynthetic
analysis of the C9−C25 fragment of spirastrellolide B.
co-workers from the extracts of the Caribbean marine sponge
Spirastrella coccinea.1 Subsequently, in 2007, Andersen and co-
workers isolated spirastrellolide B (2) (Figure 1) from the same
extract.2 The key structural features of these macrolides include a
47-carbon linear polyketide backbone, a highly functionalized 38-
membered lactone that contains a tetrahydropyran, and two
spiro-bispyran substructures, as well as a side chain containing
Received: April 28, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01248
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Letter
spirastrellolides A/B, which could, in turn, serve as an excellent
biological tool to investigate protein phosphatase-mediated
cellular regulation. Herein, we disclose a pot-efficient, phosphate
tether mediated synthesis of the C9−C25 fragment of
spirastrellolide B.
To further streamline the synthesis, we also attempted a one-
pot RCM/hydroboration−oxidation protocol.13 Accordingly,
triene (R,R)-814 was treated with 3 mol % of the G-II catalyst in
refluxing CH2Cl2. Upon completion of the reaction, the solvent
was evaporated and treated with 4 equiv of BH3·DMS in THF at
0 °C for 3 h. The reaction was quenched with NaBO3·4H2O to
generate alcohol 9 in an overall 31% yield (over two reactions in
one pot, 56% average/reaction, unoptimized). It should be noted
that the yield of this one-pot sequential protocol was low
compared to that of the individual reactions. Therefore, further
optimization studies will be necessary. However, the feasibility of
combining the phosphate tether mediated RCM and hydro-
boration−oxidation into a single pot is promising.15 Taken
collectively, the synthesis of the C9−C16 fragment was achieved
over 8 LLP (longest linear pot sequence) and 8 TPC (total pot
count) (Scheme 2).
Our group has focused on developing efficient synthetic
strategies utilizing phosphate tether mediated desymmetrization
of C2-symmetric 1,3-diene diols en route to 1,3-antidiol group
containing bioactive natural products.9 Our interest in
developing modular and library-amenable strategies to access
polyketide natural products has led to the completion of the total
synthesis of (−)-tetrahydrolipstatin, dolabelide C, (+)-strictifo-
lione, a formal total synthesis of (−)-salicylihalamides A and B,
the macrolactone core of lyngboulloside, and a recent total
synthesis of Sch-725674, as well as simplified analogues bearing
diverse α,β-unsaturated chemotypes.10 Aligned with this goal, we
attempted the synthesis of the C9−C25 fragment of
spirastrellolide B, in which we envisioned to utilize the temporary
phosphate tethered system, bicyclo[4.3.1]phosphate (R,R,RP)-7,
to construct the C9−C16 fragment 6 in a facile manner (Figure
1). The proposed retrosynthetic route for the C9−C25 fragment
of spirastrellolide B relies on a late-stage Achmatowicz
spirocyclization of the key furan-containing subunit 4, previously
utilized by Deshong and Tong11 to generate the crucial
spirocyclic intermediate. The key fragment was planned to be
derived via a Suzuki−Miyaura coupling of furan substrate 5 with
the 1,3-diol-containing synthon 6. Overall, successful imple-
mentation of this route would achieve the synthesis of the C9−
C25 fragment of spirastrellolide B (3).
Scheme 2. One-Pot, Sequential RCM/BH3-(ox) Protocol
Toward the aforementioned goal, we initiated our synthesis of
the C9−C16 polyol-containing fragment 6 (Scheme 1). The
The synthesis of the C17−C25 fragment commenced with the
PMB protection of (S)-Roche ester (13), followed by the
conversion to Weinreb amide16 14 in the presence of
(MeO)NH(Me)·HCl and i-PrMgCl (Scheme 3). Subsequent
Scheme 1. Synthesis of the C9−C16 Fragment
Scheme 3. Synthesis of the C17−C25 Furan Fragment
corresponding borate ester synthesis started with the ring-closing
metathesis (RCM) of triene (R,R)-8 furnishing bicyclo[4.3.1]-
phosphate (R,R,RP)-7 in the presence of the Grubbs second-
generation catalyst (G-II)12 in refluxing dichloromethane.
Bicyclo[4.3.1]phosphate 7 was further converted to alcohol 9
via a regioselective hydroboration−oxidation protocol. Subse-
quent benzylation produced benzylated bicyclo[4.3.1]phosphate
10 (Scheme 1). Regio- and diasteroselective allylic cuprate
displacement followed by tether removal of 10 resulted in olefin
11. Subsequent acetonide protection followed by cross-meta-
thesis (CM) with vinyl pinacolatoboron provided the C9−C16
coupling partner, fragment 6.
Grignard addition, followed by the CBS reduction,17 generated
the olefinic cross-partner, substituted allylic alcohol 15 in 8:1
diastereomeric ratio. Further, CM with furan substrate 17,
generated via the Wittig reaction of 5-bromo-2-furaldehyde (16),
in the presence of Hoveyda−Grubbs second-generation (HG-
II)18 catalyst produced furan-substituted allylic alcohol 18 in
75% yield. Subsequent TBS-protection of the C23 hydroxyl
B
DOI: 10.1021/acs.orglett.6b01248
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Letter
group furnished 19, which was dihydroxylated with high
diastereoslectivity (>20:1)5r to deliver the C17−C25 bromofur-
an coupling partner 5 in 7 LLP and 8 TPC.
Scheme 5. Alternative Synthesis of the C9−C25 Fragment
Suzuki−Miyaura coupling of the C9−C16 boronic ester
fragment 6 and furan intermediate 5 in the presence of
Pd(PPh3)4 and K3PO4 furnished the coupling product 20 in
50% yield (Scheme 4). Subsequent hydrogenation using o-
Scheme 4. Synthesis of the C9−C25 Fragment
facilitate the application of a two-pot protocol combining olefin
and ketone reductions. Lindlar catalyst was chosen for the olefin
hydrogenation, since simple filtration would be sufficient and the
crude intermediate could be subjected to the ketone reduction
step without any quenching/workup procedure. Accordingly,
compound 24 was subjected to the Lindlar catalyst in MeOH;
subsequent filtration followed by the treatment with NaBH4 in a
mixed solvent system MeOH/CH2Cl2 (7:3 ratio) furnished the
desired product, the C9−C25 fragment 3, in a two-pot,
sequential manner with 88% ds.
In conclusion, the synthesis of the C9−C25 fragment 3 was
achieved over 14 longest linear pots and 22 total pots. The
highlights of the synthesis included phosphate tether-mediated
facile synthesis of the C9−C16 fragment, a Suzuki−Miyaura
coupling unifying the C9−C16 and C17−C25 subunits, and a
late-stage, one-pot sequential deprotection/cascade Achmato-
wicz rearrangement−spiroketalization to reveal the key
spirocyclic intermediate. Taken collectively, this synthesis further
corroborates the utility of the temporary phosphate tether
toward the synthesis of complex 1,3-diol containing natural
products. Synthetic efforts toward the construction of the C26−
C40 fragment are currently in progress and will be reported in
due course. Additional efforts directed toward the design and
synthesis of the C1−C8 subunit to complete the total synthesis
campaign toward spirastrellolide B are also underway.
NBSH19 yielded the Achmatowicz precursor 21 in 84% yield.
Next, we performed the Achmatowicz cyclization by subjecting
the hydrogenated product 21 to NBS, NaHCO3, and NaOAc·
3H2O in a THF/H2O (4:1) mixture to produce α,β-unsaturated
pyran 2220 in 82% yield. Our next goal was to protect the
secondary hydroxyl group at C22 as an acetate prior to
spiroketalization to prevent the possible formation of bridged
product during spirocyclization.21 However, when subjected to
Ac2O and pyridine/DMAP, no diacetate product was observed.
To eliminate the possibility of other side product formation,
we envisioned a one-pot, cascade Achmatowicz/spiro-ketaliza-
tion reaction, whereby the spiroketalization would occur in the
same pot under acidic condition after the formation of α,β-
unsaturated pyran in situ. Furthermore, to ensure the formation
of desired spirocyclic product in Achmatowicz/spiroketalization
reaction, we also aimed to perform acetonide deprotection prior
to the Achmatowicz cyclization. Since both of the reactions could
be theoretically performed under acidic conditions, we also
viewed this as an opportunity to implement a one-pot sequential
protocol by combining the deprotection and Achmatowicz
cyclization steps. Accordingly, we attempted the acetonide
deprotection in the presence of CSA, MeOH, evaporated the
solvent and treated the crude mixture to m-CPBA and CSA
(sequential addition). Gratifyingly, this one-pot, sequential
deprotection/cascade Achmatowicz-spiroketalization reaction
sequence furnished the critical spirocyclic intermediate 23 in
an excellent overall yield of 51% over three reactions in one pot
(Scheme 5). The formation of the spirocycle was confirmed by
NOE experiments on the C9−C25 fragment 3. Subsequent TBS
protection produced spirocycle 24 in 84% yield.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01248.
Experimental details and spectroscopic data of new
compounds (PDF)
AUTHOR INFORMATION
■
With 24 in hand, we aimed efforts at the reduction of the
olefinic double bond followed by diastereoselective ketone
reduction. After a couple of optimization studies on model
substrates, we realized that it would be better to reduce the
olefinic bond first followed by the reduction of ketone to avoid
the complication of forming 1,4- and 1,2-reduction products. In
addition, we believed that the order of the reactions would also
Corresponding Author
*E-mail: phanson@ku.edu.
Present Addresses
†Soma Maitra, Postdoctoral Associate, University of Minnesota.
‡Mahipal Bodugam, Principal Scientist, Escientia Bio-Pharma
Pvt. Ltd., Hyderabad, India.
C
DOI: 10.1021/acs.orglett.6b01248
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Notes
Letter
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The authors declare the following competing financial interest:
P.R.H. is on the Scientific Advisory Board of Materia, Inc.
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ACKNOWLEDGMENTS
■
This investigation was generously supported by funds provided
by NIGMS (NIH R01GM077309). We acknowledge Dr.
Rambabu Chegondi, a former postdoctoral associate in the
Hanson lab (current affiliation: Division of Natural Products
Chemistry, CSIR-Indian Institute of Chemical Technology,
Hyderabad, India) for his suggestions and insights into this
project. We are grateful to the University of Kansas and the State
of Kansas for support of our program. We gratefully thank Justin
Douglas and Sarah Neuenswander at the University of Kansas
NMR Laboratory for their help and suggestions and Todd
Williams at the University of Kansas for HRMS analysis. Support
for the NMR instrumentation was provided by NSF Grant Nos.
9512331, 9977422, and 0320648 and NIH Center Grant Nos.
P20 GM103418, S10RR024664, and S10 OD016360. We also
thank Materia, Inc., for supplying metathesis catalyst.
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