An approach toward constructing the trioxadispiroketal core in the DEF-ring of (+)-spirastrellolide A

Article abstract of DOI:10.1021/ol502103b

A concise and stereoselective synthesis of the trioxadispiroketal motif that embodies the DEF-ring of the marine macrolide (+)-spirastrellolide A is described. The synthetic approach features a sequence of cyclic acetal tethered ring-closing metathesis an

Full text of DOI:10.1021/ol502103b

Letter
pubs.acs.org/OrgLett
An Approach toward Constructing the Trioxadispiroketal Core in the
DEF-Ring of (+)-Spirastrellolide A
Yi-Biao Wu,† Yu Tang,*,† Guo-Ying Luo,† Yang Chen,† and Richard P. Hsung*,‡
†School of Pharmaceutical Science and Technology, Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative
Innovation Center of Chemical Science and Engineering, Tianjin University, Tianjin, 300072 P. R. China
‡Division of Pharmaceutical Sciences, School of Pharmacy, and Department of Chemistry, University of Wisconsin, Madison,
Wisconsin 53705 United States
S
* Supporting Information
ABSTRACT: A concise and stereoselective synthesis of the trioxadispiroketal motif that embodies the DEF-ring of the marine
macrolide (+)-spirastrellolide A is described. The synthetic approach features a sequence of cyclic acetal tethered ring-closing
metathesis and Suarez oxidative cyclization, thereby constituting a viable strategy for constructing the Northern Half.
́
profile resembles other well-known Ser/Thr phosphatase
he spirastrellolides are a family of structurally unprece-
Tdented marine macrolides that are protein phosphatase inhibitors, fostriecin and okadaic acid.5 Despite lagging behind
the development of cancer therapeutics based on kinase
inhibitors because of the perceived notion that kinases are
more highly regulated and specific, there has been a renewed
interest in protein phosphatase inhibitors in recent years.1,2,6
Phosphatases work in concert with kinases to maintain the all too
critical reversibility in protein phosphorylations. Consequently,
they signify “the other half” of checkpoints in cell cycles and
assume an equally important role in regulating cellular signal
transductions and should not be ignored.
inhibitors, thereby representing valuable lead compounds for
developing new anticancer therapeutics.1,2 (+)-Spirastrellolide A
was first isolated from the Caribbean sponge Spirastrella coccinea
off the coast of Dominica (see Scheme 1),3a and this was followed
by six structurally related congeners (spirastrellolide B−-G) and
their respective methyl ester derivatives.3c,d (+)-Spirastrellolide
A exhibits an impressive inhibitory activity against protein PP2A
(IC50 ca. 1 nm) with an excellent selectivity for PP2A over PP1
(∼50:1), while showing no inhibition of PP2C.4 Such a biological
To date, there have been many papers describing elegant
synthetic efforts toward these natural products7−11 including two
Scheme 1. Our Synthetic Plan for (+)-Spirastrellolide A
monumental total syntheses by Paterson10 and Furstner.11
̈
Our12 long-standing synthetic strategy toward (+)-spirastrel-
lolides has featured cyclic acetal-tethered transformations for
constructing spiroketals.13,14 Specifically, the use of cyclic acetal-
tethered ring-closing metathesis (RCM)15,16 has allowed us to
complete a synthesis of the BC-ring (see 2)12 and ultimately the
assembly of the entire Southern Half or the C1−C23 fragment
through connection with A-ring via Mukaiyama antialdol (see
1).12b−e On the other hand, fragment 3, or the Northern Half,
contains a challenging trioxadispiroketal motif that embodies the
DEF-ring. Nevertheless, we want to showcase our cyclic acetal-
Received: July 17, 2014
© XXXX American Chemical Society
A
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Letter
tethered RCM method in a synthesis of the Northern Half of
(+)-spirastrellolide A. We report here an approach toward the
trioxadispiroketal core of the DEF-ring that would employ a
Scheme 4. Synthesis of C33−C40 Fragment 17
sequence of cyclic acetal tethered RCM along with the Suar
́
ez
oxidative cyclization.17−19
A general design of our approach is shown in Scheme 2. We
intend to build the trioxadispiroketal core 4 through use of
Scheme 2. Approach to DEF-Ring
afford protected tetraol 16. Subsequent oxidation and allylation
using allylmagnesium bromide would give the homoallylic
alcohol 17 as a mixture of diastereomers. It is noteworthy that
diastereomeric control of the allylation is not critical because any
stereochemical information at C35 will be lost during the
oxidative cyclization.
In the presence of 1.0 equiv of Tf2NH,25,26 cyclic acetal
formation proceeded smoothly to afford 18 in 78% yield
(Scheme 5). RCM using Grubbs’ Gen-II catalyst27 took place in
́
Suarez oxidative cyclization of spiroketal 5 to close the F-ring and
Scheme 5. Attempted Cyclic Acetal Tethered RCM−Suarez
́
adoption of the RCM of cyclic acetal 7 to construct the DE-ring.
Cyclic acetal 7 should be readily accessible from diol 8 and lactol
9. While we could use simpler lactols and diols such as shown
with 8 and 9 to quickly establish the concept of a DEF-ring
construction involving cyclic acetal tethered RCM, we chose D-
glucose as the starting point because it contains the stereo-
chemical information that could be translated to that in the D-
ring.
Oxidative Cyclization Sequence
Our synthesis commenced with D-glucose, which was
converted into tri-O-acetyl-D-glucal 10 using known procedures
(Scheme 3).20 After standard deacetylation was followed by
Scheme 3. D-Ring Synthesis from D-Glucose
monoprotection at C26, diol 11 could be obtained and was
further protected as methyl ethers using NaH and MeI (see
12).21 PCC-oxidation of 12 would give the corresponding
lactone,22 which was converted to the key lactol intermediate 13
upon exposure to excess vinyl magnesium bromide. Lactol 13
exists in equilibrium with its ring-opened ketone form at room
temperature. It is noteworthy that while it is capped as a simple
methyl ether here, it is known that the C29-OH group can be
selectively protected.23 From this would emerge the possibility of
converting the unprotected C28-OH into the desired chloride in
the D-ring of spirastrellolide A.
With lactol 13 in hand, we proceeded to prepare the alcohol
needed for the cyclic acetal formation. As shown in Scheme 4, we
selected Paterson’s lactone 1424 because we had hoped to bring
in as many side-chain (C39−C46) carbons and stereochemical
elements as possible. A sequence of protection, LAH reduction,
methyl ether formation, and standard debenzylation would
high yield to give the desired DE-ring spiroketal 19. Hydro-
genation and removal of the MOM group at C38 led to alcohol
21 being ready for Suar
could not carry out this transformation using the Suar
́
ez oxidative cyclization. However, we
ez modified
́
conditions, which involve PhI(OAc)2 and irradiation with a LED
lamp.18 Although we are not sure at this point what the reasons
are, we do observe one product that consistently appears in
modest yield. Unfortunately, we could not assign its structure
unambiguously using available spectroscopic data, and neither is
it crystalline. However, this unassigned product is most likely
associated with competing hydrogen abstractions as shown in A
with half arrows shown for the desired 1,5-hydrogen abstraction
for the red hydrogen atom and blue hydrogen atoms being the
possible competing ones.
With this assumptive analysis of possible byproduct in mind,
we decided to simplify the alcohol piece because using the more
elaborate fragment 17 might have been a detriment for the
B
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Letter
cyclization. As shown in Scheme 6, monoprotected diol 23,
which could be accessed quickly from 1,4-butanediol, was used
In summary, we have developed here a concise and
stereoselective approach toward the trioxadispiroketal motif in
DEF-ring of the marine macrolide (+)-spirastrellolide A. This
synthetic approach features a sequence of cyclic acetal tethered
Scheme 6. Successful Trioxadispiroketal Construction
́
ring-closing metathesis and Suarez oxidative cyclization and
employs the readily available and inexpensive D-glucose for the
D-ring synthesis. It constitutes a viable strategy for constructing
the Northern Half. These efforts are currently underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures as well as NMR spectra, character-
izations, and X-ray structural files (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yutang@tju.edu.cn.
*E-mail: rhsung@wisc.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
R.P.H. thanks the NSF (CHE1012198) for financial support.
Y.T. thanks the National Natural Science Foundation of China
(Nos. 21172169 and 21172168) and The National Basic
Research Project (No. 2014CB932201) for generous funding.
We also thank Dr. Haibin Song of Nankai University for
providing X-ray structure and data analysis.
for the cyclic acetal formation. The ensuing RCM of 24 with
Grubbs’ Gen-II catalyst led to the DE-ring spiroketal 25 in 90%
yield. Hydrogenation of the E-ring olefin concomitant with
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́
ez
■
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́
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