Singlet oxygen-mediated synthesis of bis -spiroketals found in azaspiracids

Article abstract of DOI:10.1021/ol501301w

Conversion of a simple furan into the ABCD-ring skeleton of the azaspiracids via a singlet oxygen-initiated one-pot process has been accomplished.

Full text of DOI:10.1021/ol501301w

Letter
pubs.acs.org/OrgLett
Singlet Oxygen-Mediated Synthesis of Bis-spiroketals Found in
Azaspiracids
Myron Triantafyllakis, Maria Tofi, Tamsyn Montagnon, Antonia Kouridaki,
and Georgios Vassilikogiannakis*
Department of Chemistry, University of Crete, Vasilika Vouton, 71003 Iraklion, Crete, Greece
S
* Supporting Information
ABSTRACT: Conversion of a simple furan into the ABCD-
ring skeleton of the azaspiracids via a singlet oxygen-initiated
one-pot process has been accomplished.
any natural products such as the ionophore antibiotics1
Msalinomycin and narasin, or the marine toxins
pinnatoxins/pteriatoxins,2 spirolides,3 and azaspiracids,4 contain
bis-spiroketal motifs.5 These molecules have become increas-
ingly popular as synthetic targets due to the combination of
their promise as new anticancer therapies (a consequence of
their potent cytotoxicity) and the fact that they possess
complex, yet fragile, 3D-architectures that offer a number of
challenges which synthetic chemists find hard to resist. The
traditional approach to such structures has the stepwise
construction of a linear precursor precede an acid-catalyzed
ketalization−cyclization event (or, more usually, several
events), and many syntheses have been accomplished in this
manner.5 Others have sought to design new methods to make
bis-spiroketals that avoid some of the efficiency pitfalls (e.g., the
heavy use of concessionary steps,6 protections/deprotections,7
and nonstrategic redox manipulations8) that abound in the
more traditional chemistry of polyoxygenated polycycles.
Among these alternative ideas, we were inspired by the use
of furan oxidations as a starting point for the synthesis of bis-
spiroketals.9−12 The application of this approach, however, has
frequently been limited to simple substrates in response to the
harsh/nonselective oxidants employed (Br2,9 NBS,10 electro-
chemical oxidation11). A noteworthy exception to the “simple
substrate”-limitation is to be found within the investigations
that culminated in elegant total syntheses of salinomycin by
1
Scheme 1. Synthesis of Bis-spiroketals Using O2
basic substrates for [6,5,6]-bis-spiroketals) we now hoped to
extend the work and to design a more advanced cascade. This
would include additional and potentially competing hydroxyl
functionalities that would efficiently deliver new ring systems,
such as the ABCD-rings of the azaspiracids.
Azaspiracid-1 (1, Figure 1) was first isolated from the blue
mussel Mytilus edulis in 1998 by Yasumoto et al.17 Two closely
related analogues of 1, azaspiracids-2 and 3 (2 and 3, Figure 1),
were isolated by the same team one year later.18 The
Kocien
́
ski’s group published in the 1990s.10b,12
We believed that we could use singlet oxygen as a clean and
selective oxidant13 to synthesize this key motif, and in addition,
we felt that we could do it in a way that formed both of the
rings flanking the central five-membered ring of the bis-
spiroketal unit in one operation. Indeed, this turned out to be
the case so that, starting from simple and readily accessible
furan substrates, we were able to obtain either [5,5,5]- or
[6,5,6]-bis-spiroketals directly in high yield (Scheme 1).14,15
This method could be successfully adapted to include a further
rearrangement during the course of the reaction sequence such
that it now gave access to a [6,6,5]-bis-spiroketal motif16
(Scheme 1) of the type found in salinomycin as NBS-precedent
had suggested was possible.10b,12 With these simple examples
delineated (just one substrate for [5,5,5]-bis-spiroketal and two
Figure 1. Azaspiracids.
Received: May 7, 2014
© XXXX American Chemical Society
A
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azaspiracids have shown a range of interesting biological
activities,19 including the recently discovered inhibition of the
hERG ion channel.20 A synthesis of the structure originally
proposed for azaspiracid-1 was reported by Nicolaou et al. in
2003. However, it was found that the spectroscopic data for this
synthetic compound did not match those of the natural
isolate.21 The same team then revised the structure to that
shown in Figure 1 based on degradation studies, the synthesis
of different diastereoisomers, and, as a final confirmation, the
first total synthesis of azaspiracid-1 (1).22 They also completed
total syntheses of the revised structures of azaspiracid-2 and -3
(2 and 3) in 2006,23 as well as shorter second generation total
syntheses of all three azaspiracids (1−3).4a In the following
year, a concise total synthesis of ent-azaspiracid-1 (ent-1) was
accomplished by Evans et al.4b,24 Different approaches to the
ABCD-domain of these complex molecules have been
reported.25
Scheme 2. A Model Study: Formation of a [6,5,5]-Bis-
spiroketal
The strategy we were now seeking to implement for the
construction of the ABCD-ring skeleton of the azaspiracids
involved the photooxygenation of furan precursors of type 4
(Figure 2) followed by a cyclization cascade reaction sequence,
came from the oxidation of 10 to the corresponding ketone
(not shown), which resulted in a downfield shift of the −CH2−
protons “α” to the newly formed carbonyl, as well as
simplification of their coupling patterns.
The unwanted outcome for this singlet oxygen-initiated
spiroketalization of the model furan 4a indicated to us that the
γ-OH group of the photooxidation precursor needed to be
protected such that only the δ-positioned hydroxyl was left free
to ketalize and form the desired [6,5,6]-bis-spiroketal. Wishing
to avoid the use of concessionary steps6 and classical protecting
groups, we opted to pursue another idea, namely, that the
presence of an epoxide (4b, Figure 2), or an α,β-unsatutated
ester (4c), in the starting substrate could serve a dual purpose,
“protection” of the γ-positioned oxygen atom as well as offering
a means to construct the requisite 5-membered D-ring.
Figure 2. Photooxidation precursors.
as its key step. The presence in the substrate of unprotected
hydroxyl functionalities and an electron-rich allylic alcohol are
notable as these would interfere with most other oxidation−
cyclization strategies. Furthermore, the presence of both a γ-
and a δ-hydroxyl, either of which could engage with the initially
formed intermediate endoperoxide to afford the [6,5,5]-bis-
spiroketal, or the [6,5,6]-bis-spiroketal, respectively, had
introduced a possible competition within the cascade reaction
sequence, for which the outcome was uncertain as it had not
been investigated as part of the original and much more basic
bis-spiroketal formation study.14
The first task for this investigation was therefore to clarify
which of these two possible products would dominate in the
key step of the proposed approach. To answer this question, a
simple model system that was easily synthesized (in just 4 steps
from furan) furan triol 4a (Scheme 2) was used. It is important
to note that the dihydroxylation reaction of deprotected 9 was
completely regioselective leaving the double bond of the allylic
alcohol untouched. Furan 4a was then subjected to the singlet
oxygen (1O2) oxidation conditions routinely used in our
laboratories to affect such transformations. Oxygen was bubbled
through the reaction solution that had 10−4 M methylene blue
added as a sensitizer, and the solution was irradiated with
visible spectrum light until complete consumption of the
starting material was observed by TLC (1.5 min). After the
addition of dimethyl sulfide, as an in situ reductant for the
intermediate spiro-hydroperoxide (not shown),14 and addition
of catalytic p-TsOH·H2O, the [6,5,5]-bis-spiroketal 10 was
isolated as the product of the reaction (consisting of four
partially separable diastereoisomers).26 The assignment of the
final bis-spiroketal as being the [6,5,5]-bis-spiroketal instead of
the desired [6,5,6]-variant derived from comparisons between
the 13C NMR chemical shifts of the ketal carbons in this and
known [5,5,5]- and [6,5,6]-bis-spiroketals.14,27 Further proof
To access the furan-tetrol 4b, 2,5-disubstituted furan 13
(Scheme 3) was prepared by two sequential ortho-alkylations of
furan (7). Deprotection of the TBS-ether was followed by
Dess-Martin periodinane (DMP) oxidation of the resulting
primary alcohol affording the corresponding aldehyde, and
then, by in situ Wittig reaction with a stabilized ylide, the α,β-
unsaturated ester 14 (55% overall yield over 3 steps) was
accessed. Reduction of the ester group using Dibal-H was
followed by Sharpless epoxidation of the resulting allylic
alcohol. Deprotection of the TBDPS-ether afforded the epoxide
15. Regioselective dihydroxylation of 15 resulted in the
formation of a complicated mixture of tetrol 4b and its
diastereoisomer accompanied by THF-ethers 16a and 16b,
products of the desired 5-exo epoxide opening. This
complicated mixture was treated with PPTS, which encouraged
exclusive formation of the diastereoisomeric THF-ethers 16a
and 16b in a ratio which varied from 3:2 to 2:1. The fact that
the major diastereoisomer 16a had the desired stereochemistry
was unambiguously confirmed by extensive NOE-studies of
both diastereoisomers.27 This diastereoisomeric ratio directly
reflects the diastereoselectivity of the dihydroxylation reaction.
The stage was now set, with only the δ-positioned hydroxyl
1
left free to ketalize, for the key O2-mediated reaction. When
the inseparable mixture of 16a and 16b was subjected to the
photooxidation conditions in MeOH (tetrols 16a and 16b were
not very soluble in CH2Cl2), using Rose Bengal as a
photosensitizer, an inseparable mixture of tetracycles 17a and
B
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the formation of two inseparable diastereomers 16a,b. Despite
the fact that the major diastereoisomer has the desired
stereochemistry at the newly formed THF-ring (D-ring), it
would have been a more attractive approach if the crucial
photooxidation/bis-spiroketalization step could be run on only
the correct isomer. This led us to explore the use of compound
4c (Figure 2). TBDPS-protected 4c was synthesized by
regioselective dihydroxylation of triene 14. MeONa-mediated
intramolecular oxa-Michael reaction followed by TBAF-
mediated deprotection of the allylic alcohol resulted in the
formation of two separable THF-ethers 18 in an 8:1 ratio
(Scheme 4). Extensive NOE studies proved that the major
Scheme 3. Synthesis of the ABCD-Ring Skeleton of
Azaspiracids in the Form of 17a
Scheme 4. Synthesis of the ABCD-Ring Skeleton of
Azaspiracids in the Form of 19
diastereomer was the correct one.27 With the desired
diastereomer now separated from its minor isomer and in
hand, the key singlet oxygen-initiated bis-spiroketalization
cascade reaction sequence was again tested. This reaction
now afforded a mixture of only two, and, in this case, almost
completely separable, diastereoisomers of 19 in a 1:1 ratio.
Extensive 2D-NMR experiments and NOE studies were run on
both diastereoisomers. No NOEs were seen between the A-
and C-ring protons; thus, any stereochemical assignment at the
spiroketal centers would be tentative. These observations are in
keeping with precedent in other similar systems.25,26 Attempts
at obtaining crystals for X-ray diffraction were unsuccessful.
The synthetic strategy developed herein to access this type of
tetracycle is highly advantageous since it rapidly constructs the
carbon backbone of the targeted molecular fragment (the
ABCD-ring system of azaspiracid), in the form of furan 14,
leaving the inclusion of the central oxygens to the two (or
three) chemoselective oxidations (epoxidation, dihydroxylation
17b was isolated in 61% yield. It is important to note that when
the complicated mixture of 4 compounds (from before
1
treatment with PPTS) was subjected to the O2 oxidation
conditions, exactly the same mixture of desired [6,5,6]-bis-
spiroketals 17a and 17b was isolated and none of the undesired
[6,5,5]-bis-spiroketal of type 10 (as had been seen in the model
study) was observed. At this point, it is important to mention
that both 17a and 17b appear in the NMR as a 1:1 mixture of
two diastereoisomers27 which means that the spiroketalization
reaction led to only two out of the four possible
diastereoisomers. This could arise as a result of the anomeric
effect, or from energy differences between the cis- and trans- bis-
spiroketals.25e,g,j−l
1
and O2 furan oxidation) that terminate the sequence. The
strategy uses a minimal number of concessionary steps,6
nonstrategic redox manipulations,8 and protecting groups,7 thus
taking a step closer to the sustainable ideal. Lastly, the final one-
pot reaction sequence initiated by 1O2 is particularly notable for
its rapid increase in three-dimensional molecular complexity
from a very simple starting point.
The drawback of this very short synthetic sequence is the low
diastereselectivity of the dihydroxylation of 15 which resulted in
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, full spectroscopic data, and copies of
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
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L.; Sanguinetti, M. C. Chem. Res. Toxicol. 2012, 25, 1975.
*E-mail: vasil@chemistry.uoc.gr.
(21) (a) Nicolaou, K. C.; Li, Y.; Uesaka, N.; Koftis, T. V.; Vyskocil,
S.; Ling, T.; Govindasamy, M.; Qian, W.; Bernal, F.; Chen, D. Y. K.
Angew. Chem., Int. Ed. 2003, 42, 3643. (b) Nicolaou, K. C.; Chen, D. Y.
K.; Li, Y.; Qian, W.; Ling, T.; Vyskocil, S.; Koftis, T. V.; Govindasamy,
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Rodriquez, M.; Sarlah, D.; Zou, N. J. Am. Chem. Soc. 2006, 128, 2244.
(d) Nicolaou, K. C.; Chen, D. Y. K.; Li, Y.; Uesaka, N.; Petrovic, G.;
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(22) (a) Nicolaou, K. C.; Vyskocil, S.; Koftis, T. V.; Yamada, Y. M.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The research leading to these results has received funding from
the European Research Council under the European Union’s
Seventh Framework Programme (FP7/2007-2013)/ERC Grant
Agreement No. 277588.
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