Using singlet oxygen to synthesise the CDE-ring system of the pectenotoxins

Article abstract of DOI:10.1039/c2ob27158c

A non-classical route to the key CDE-ring fragment of the pectenotoxins has been developed which showcases a remarkable singlet oxygen-mediated cascade reaction sequence to install the complete DE ring system.

Full text of DOI:10.1039/c2ob27158c

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Using singlet oxygen to synthesise the CDE-ring system
of the pectenotoxins†
Cite this: Org. Biomol. Chem., 2013, 11,
537
Antonia Kouridaki, Tamsyn Montagnon, Dimitris Kalaitzakis and
Georgios Vassilikogiannakis*
Received 6th November 2012,
Accepted 22nd November 2012
DOI: 10.1039/c2ob27158c
www.rsc.org/obc
A non-classical route to the key CDE-ring fragment of the pecteno-
toxins has been developed which showcases a remarkable singlet
oxygen-mediated cascade reaction sequence to install the com-
plete DE ring system.
The pectenotoxin (PTX, Fig. 1) family of natural products has
attracted a great deal of attention from different groups of
researchers in recent years, not only because of their biological
activity which has been shown to possess certain new and
exciting features, but also by reason of the structural chal-
lenges to synthesis that they exhibit. Originally isolated1a from
the host shellfish (a scallop named, Patinopecten yessoensis),
the pectenotoxins are actually produced by dinoflagellates
found worldwide in coastal waters.1 However, the scarcity of
samples available from natural sources has hindered the
pursuit of further studies into the PTXs’ potentially useful
cytotoxicity2 (achieved via a novel mode of F-actin disrup-
tion2b). Thus, finding effective new means to access these com-
pounds synthetically in larger quantities would serve a very
useful purpose.
In general, synthetic strategies towards polyoxygenated
targets frequently rely heavily on cumbersome redox shuttling
(manipulation and differentiation of the oxygen functionalities
by repeated back and forth alterations to their oxidation states
often using ungreen reagents) and on the use of an excessive
number of unconstructive oxygen functionality protections
and deprotections.3 The primary focus of our research of late4
has been to develop new singlet oxygen-based methods for the
synthesis of just such polyoxygenated motifs, which, by virtue
of the ability of singlet oxygen to orchestrate cascade reaction
sequences and its inherent selectivity, help us to avoid many
of these common pitfalls. Herein, we present one such effort
Fig. 1 The pectenotoxin family of natural products.
in the form of a non-classical route affording the key CDE-
ring5 fragment of the PTXs. When combined with our earlier
successful singlet oxygen-mediated one-pot “super-cascade”
which synthesised the ABC-ring section,6 this serves to illus-
trate the full synthetic potential of this powerful and green
oxidant.4a
PTXs 4 and 8 are the only members of the family which
have been successfully synthesised7 in the laboratory; however,
many efforts have been reported, which are directed towards
synthesis of specific fragments of these molecules.6,8 Our
current CDE-ring work joins the recent elegant efforts of
Pihko,9 Brimble,10 and Micalizio11 who have published their
own investigations (following on from earlier work undertaken
by the Roush group12) directed towards PTX fragments includ-
ing these particular rings. Furthermore, it should be noted
that the groups of both Paquette13 and Fujiwara14 have com-
pleted PTX sections which include the necessary but, as yet,
uncyclised backbone of the DE-bicycle section.
Department of Chemistry, University of Crete, Vasilika Vouton, 71003 Iraklion, Crete,
Greece. E-mail: vasil@chemistry.uoc.gr; Fax: +30 2810 545166;
Tel: +30 2810 545074
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, full spectroscopic data and copies of 1H and 13C NMR spectra for all
new compounds, as well as copies of the NOE experiments. See DOI:
10.1039/c2ob27158c
Our own synthetic blueprint (Scheme 1) was based on the
idea that a simple furanyl butanone unit could be united
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Scheme 1 Proposed synthetic plan.
readily with an intact pre-synthesised C-ring fragment (using
an aldol condensation) and then methylated in such a way as
to leave hydroxyl functionalities at the γ- and ε-positions of the
alkyl side chain appended to the 2-position of the furan B
(Scheme 1).
It was hoped that this newly acquired homochiral sub-
strate would then succumb to an ambitious singlet oxygen-
initiated reaction cascade sequence (in which these two
pendant hydroxyl functionalities would participate) that
would in a rapid and extremely efficient manner construct
the requisite DE-ring motif, and thus, afford the completed
CDE-ring section of the pectenotoxins (A, Scheme 1). We
had previously investigated such a cascade for accessing
simple 2,8-dioxabicyclo[3.2.1]octane model compounds and
had recorded successes both in organic solvents and in
water.15
To explore the practicality of this proposal we begun by
Scheme 2 Synthesis of the C-ring fragment.
developing
a C-ring synthesis in which we chose to
implement fairly obvious disconnections in the forward syn-
thetic sense. Thus, it was anticipated that a 5-exo-epoxide the now separable diastereoisomers 5a and 5b (5a : 5b, 1 : 1) in
opening (Scheme 1) of an appropriately substituted epoxide 88% overall yield. The relative stereochemistry of the two
by a hydroxyl group would be the easiest means by which to cyclised compounds was deconvoluted using NOE studies of
construct the desired tetrahydrofuran ring, and before selected derivatives. More specifically, both diastereoisomers
this cyclisation step, the requisite vicinal diol unit could be were advanced separately by, firstly, undertaking a double pro-
generated using
reaction.
a
Sharpless asymmetric dihydroxylation tection of alcohol residues as TBS ethers (yield from 5a 93%,
and from 5b, 46%), then by DIBALH-mediated reduction of
To this end, the commercially available and cheap homo- the ester to the primary alcohol (yielding either 6a or 6b, in
allylic alcohol 1 was oxidised using IBX and a solution of the yields of 82 and 89%, respectively). The reason for the low
resultant volatile aldehyde (not isolated) was treated directly yield obtained for the double protection of 5b is not immedi-
with the stabilised ylide Ph3PCHCO2Bn to afford diene 2 ately clear, but was anyway of little consequence because 6b
(trans : cis isomers = 9 : 1) in an overall yield for the two steps was needed only for NOE studies and not for progression of
1
of 83% (Scheme 2). Chemoselective epoxidation of diene 2 the synthesis. With a key area within the H NMR simplified
with m-CPBA in buffered (NaHCO3) DCM afforded epoxide 3 in and extra helpful protons also now introduced, extensive NOE
94% yield. AD-mix-β was then used to install the requisite studies were undertaken on both these compounds (6a and
vicinal diol unit at the site of the more electron deficient 6b) revealing that the relative stereochemistry was that which
double bond (3 → 4, 62% with 16% recovered starting is shown in Scheme 2. In addition, the primary alcohol of the
material). The benzoate ester had been chosen for inclusion in desired diastereoisomer 5a was selectively protected as the TBS
the substrate (from the earlier Wittig reaction) to improve the ether using standard conditions (yield 63%), the remaining
difficult isolation of the diol product from this aqueous dihy- secondary alcohol was then converted into each of the two
droxylation reaction; indeed, the analogous (to 4) methyl ester MPA esters separately and the resulting NMR spectra analysed.
had been synthesised, but could only be isolated in low yields, This confirmed that the expected absolute stereochemistry
and, furthermore, its quantities were further depleted on puri- had been obtained from the Sharpless asymmetric dihydroxy-
fication and manipulation due to its polarity and poor solubi- lation (for full details, see: ESI†).
lity in organic solvents. Catalytic acid (PPTS, 10 mol%) was
With our C-ring stereochemistry now fully analysed, the syn-
then used to effect the desired cyclisation reaction to afford thesis was advanced by oxidation of the primary alcohol of 6a
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Scheme 3 Synthesis of photooxidation substrate 10.
Scheme 5 Proposed mechanistic rationale.
this case, methylene blue, whilst irradiating the cooled solu-
tion (ice bath) with a Variac Eimac Cermax 300 W lamp. Fol-
lowing the completion of the initial oxidation steps, as
monitored by tlc, an excess of dimethyl sulfide was introduced
into the reaction vessel to effect the reduction of the newly
formed peroxy residue. Finally, and, once again when tlc moni-
toring indicated the reduction was complete, trace acid
(p-TsOH) was added to complete the cascade reaction
sequence (Scheme 4). Gratifyingly, each of these stages pro-
ceeded exceptionally smoothly and the final product, the com-
pleted pectenotoxin CDE-ring unit 11, was cleanly formed in
an extraordinary yield of 82%, as a single stereoisomer. Exten-
sive NOE experiments, as shown in Scheme 4, confirmed the
stereochemistry of the final cyclised compound 11. As
expected, a set of NOEs similar to those observed for 6a were
shown for the C-ring of 11. More importantly, the existence of
NOEs between H6 and both H9 and H10 proves the stereo-
chemistry of the DE-bicyclic ketal in the final compound 11. In
addition, this remarkable cascade reaction sequence could
also be adapted so that it could be conducted in water (in this
case, using rose bengal as sensitiser), albeit with a slightly
reduced yield of 74%, adding to its already excellent green
credentials.
Scheme 4 Key photooxidation cascade reaction.
using IBX (98%, Scheme 3). The resultant aldehyde 7 was then
used as the electrophile in an aldol reaction with the kinetic
enolate of furanyl butanone 8. This aldol reaction proceeded
in 70% yield and afforded the desired isomer as the major
product (dr 10 : 1).16 The conditions recently developed by
Pihko and co-workers9a were then employed to effect the last
remaining transformation prior to the key cascade reaction
sequence, namely, a stereoselective methylation reaction. The
reaction yielded photooxidation substrate 10, as the major dia-
stereoisomer, in a yield of 65% (the minor diastereoisomer
accounted for a further 17%).16
The stage was now set for implementation of the crucial
cascade reaction sequence (Scheme 4). Thus, photooxidation
substrate 10 was subjected to a set of singlet oxygen reaction
conditions that have been honed in our laboratory. These
include bubbling oxygen gently through the reaction solution
containing small quantities (10−4 M) of a photosensitiser, in
The mechanistic rationale for this highly complex
cascade reaction sequence is given in Scheme 5. Thus,
initial [4 + 2]-cycloaddition of singlet oxygen to the furan
fleetingly yields ozonide C, which is rapidly opened by the
pendant internal nucleophile (a hydroxyl group) to afford
the [5,5]-spirocyclic hydroperoxide D.4,6,15,17 All the charac-
teristic peaks corresponding to intermediate
D
were
observed in crude 1H NMR spectra of the photooxidation
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mixture, prior to the addition of dimethyl sulfide. Reduction
of the hydroperoxy residue of D to hemiketal E is followed
by acid catalysed rearrangement of the spirocycle and cis–
trans isomerisation of the double bond, to give the final
product 11 via intermediate F.
To summarise, an ambitious singlet oxygen-mediated
cascade reaction sequence has been successfully implemented
in a “real” system example, giving us rapid access (only 10
steps) to the complex and complete CDE-ring fragment of the
pectenotoxins. The cascade reaction sequence itself showcases
a remarkable increase in molecular complexity through an
easily implemented laboratory protocol and uses a green and
highly selective oxidant, thereby making it a powerful solution
to the intransigent problem of how to significantly improve
our efficiency when we seek to synthesise complex polyoxyge-
nated polycyclic molecules.
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5 There is some deviation in the assignment of the E-ring in
the published pectenotoxin literature. When we refer to the
E-ring throughout this manuscript we are referring to the
E-ring as it is depicted in Fig. 1.
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Acknowledgements
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. We also thank Prof. Robert
Stockman and Mr George Procopiou for their help in taking
HRMS.
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