Interplay of cascade oxidative cyclization and hydride shifts in the synthesis of the ABC spiroketal ring system of pectenotoxin-4

Article abstract of DOI:10.1002/anie.201208919

Concepts: The formation of stereochemically defined bis-THF units through a double cyclization and a hydride-shift-initiated route to spiroketals is described (see scheme; Xc=chiral auxiliary). The resulting sequence has been used in a synthesis of the C1-16 fragment of the naturally occurring antitumor agent pectenotoxin-4. Copyright

Full text of DOI:10.1002/anie.201208919

Angewandte
Chemie
DOI: 10.1002/anie.201208919
Spiro Compounds
Interplay of Cascade Oxidative Cyclization and Hydride Shifts in the
Synthesis of the ABC Spiroketal Ring System of Pectenotoxin-4**
´
Timothy J. Donohoe* and Radosław M. Lipinski
The pectenotoxins (PTXs) are a family of cyclic polyether
macrolide toxins first isolated in 1985 by Yasumoto and co-
workers from the digestive glands of scallops (Patinopecten
yessoensis).[1] It has since been discovered that the producers
of pectenotoxins are toxic plankton (Dinophysis dinoflagel-
late) found in many coastal areas around the world. To date,
more than 20 members have been isolated and characterized,
with structural variations commonly involving the configu-
ration of the AB spiroketal (C7) as well as the oxidation state
at C43. Recent studies have demonstrated that the pecteno-
toxins exhibit potent biological activity, including selective
cytotoxicity against p53 mutant and p53-deficient tumors.[2]
The exquisite architectural complexity of these 26-mem-
bered macrolactones, which consist of either 19 or 20
stereogenic centers embedded within three tetrahydrofuran
rings, plus one spiroketal and one bicyclic ketal, poses
a synthetic challenge that has attracted considerable attention
from many research groups. While significant synthetic
endeavors have been directed toward the pectenotoxins,[3]
to date only one total synthesis of PTX-4 and PTX-8 has been
reported.[4]
Scheme 1. Two new concepts to be developed. LG=leaving group,
P=protecting group, Xc=chiral auxiliary.
onto the trisubstituted alkene, thus forming a THF ring (2).
The stereospecific (syn) addition of the two oxygen atoms
across the alkene will ensure the correct configuration in the
product. We then hoped that the metal chelate formed after
cyclization would translocate onto the hydroxy group at C10
and thus enable a second oxidative cyclization onto the
pendent C-6,7 alkene, forming 3 in the process. If successful,
this method would expand the limits of the catalytic oxidative
cyclization and form both THF rings of the target in one pot.
Our second point of interest was the notion of using the
exocyclic hydroxy group at C6 to initiate a hydride shift and
form an oxo-carbenium ion in situ (see 4!5).[6] If this
reaction were successful, we wanted to explore the role of
a pendent (protected?) hydroxy group in trapping the cation
and forming a spiroketal (6).[7] This sequence, which we called
hydride-shift-initiated spiroketalization, would be another
potentially general piece of methodology for organic syn-
thesis.
In particular we were drawn to the C1–16 fragment of the
pectenotoxins, because it contains a pair of THF rings
terminating with a spiroketal unit that could be derived
from a linear precursor; a synthesis would allow us to develop
two concepts that should find general use in organic synthesis.
Our first idea was to prepare a triol-containing linear diene,
such as 1 (Scheme 1), and carry out an oxidative cyclization[5]
in a cascade mode, catalyzed by osmium(VI). In the first
instance, we might expect the vicinal diol unit in 1 to chelate
to the osmium catalyst and facilitate an oxidative cyclization
´
[*] Prof. T. J. Donohoe, R. M. Lipinski
Department of Chemistry, University of Oxford
Chemistry Research Laboratory
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: timothy.donohoe@chem.ox.ac.uk
Initial results strongly suggested that the success of the
hydride shift depended on the relative configuration between
the exocyclic hydroxy group (activated as a leaving group)
and the ring junction.[8] Moreover, previous experiments with
deuterium labeling at the ring junction showed convincingly
the intramolecular nature of this hydride shift.[9] The relative
[**] We thank the Dulverton Trust for supporting this project and P. G.
Turner, A. E. Gatland, and X. Yang for carrying out some preliminary
experiments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208919.
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configuration that derives from syn oxidative cyclization onto
an E alkene was found to be optimal for the hydride shift;
clearly, this was the arrangement that we focused on.
tion chemistry to produce the target system. The precursor for
oxidative cyclization (17) was prepared in seven linear steps
(Scheme 2). One of the key steps was the Carreira reaction
Our first attempts concentrated on developing the hy-
dride-shift-initiated spiroketalization on a simpler system, so
that we could examine the parameters of leaving group,
reaction conditions, and protection of the remote oxygen
functionality. In particular we wanted to find a protecting
group that would not interfere with the hydride shift to form
an oxo-carbenium ion, but which could be easily deprotected
in order to form a spiroketal (in one-pot?).[10] Moreover, we
wanted to examine the viability of different leaving groups on
the exocyclic oxygen atom, and their response to solvolysis.
Table 1 shows the model system 7 and the various combina-
Table 1: Optimization of conditions for one- or two-step spiroketaliza-
tion initiated by hydride shift.[a]
Entry
OP
LG
Solvent
T [8C]
Product
Yield [%]
1
2
3
4
5
OTES
OTES
OTBS
OTES
OTBS
OMc
OMc
OMc
OMs
OMs
DMF (aq)
HFIPA
DMF (aq)
DMF (aq)
HFIPA
70–80
40
70–80
70–80
40
8
9
8
8
9
53
72
85
35
20
Scheme 2. Formation of the oxidative cyclization substrate using
a Carreira reaction, and methylation as described by Zhang and
Ready.[12] acac=acetylacetonate, dppe=ethane-l,2-diylbis(diphenyl-
phosphane), LDA=lithium diisopropylamide, NME=N-methylephe-
drine, PMB=p-methoxybenzyl, TBAF=tetra-n-butylammonium fluo-
ride, Tf=trifluoromethanesulfonyl.
[a] Entries in bold highlight optimized reaction conditions. Bn=benzyl,
DMF=N,N-dimethylformamide, HFIPA=hexafluoroisopropanol,
Mc=a-chloromesylate, Ms=methanesulfonyl, PPTS=pyridinium p-
toluenesulfonate, TBDPS=tert-butyldiphenylsilyl, TBS=tert-butyldime-
thylsilyl, TES=triethylsilyl.
between alkyne 12 and aldehyde 15, which proceeded with
excellent stereoselectivity (96:4) induced by the chiral ligand
(ꢀ)-N-methylephedrine (NME).[11] In addition, the catalytic
regio- and stereoselective methylation of alkyne 16 using
conditions recently developed by Zhang and Ready provided
the desired trisubstituted alkene 17 with the correct alkene
substitution pattern for the oxidative cyclization.[12]
We were now in a position to test the remaining
hypothesis underpinning our work, and subjected triol 17 to
oxidative cyclization conditions, aiming to produce the bis-
THF compound 18 through a double-oxidative-cyclization
cascade. The conditions used were those developed as a result
of intensive study of the reaction mechanism, and involved
the addition of catalytic amounts of potassium osmate
(K2[OsO2(OH)4]) in an aqueous acetonitrile solution with
pyridine-N-oxide (PNO) as a re-oxidant and a Lewis acid as
promoter (Table 2).[13] Initial studies showed that the addition
of a buffer (pH 6.5) to the system was essential in order to
prevent acid-promoted decomposition of the starting mate-
rial. The best set of conditions involved use of Zn(OTf)2
(50 mol%) at 808C, giving the desired bis-THF product 18 in
69% yield (entry 3). The double oxidative cyclization, which
occurs in a cascade fashion and in this case forms two rings
tions that were tested. The results showed that the general
concept worked, and that the biggest factor in deciding the
product distribution was the solvent, with aqueous solutions
trapping the oxo-carbenium ion followed by ring opening to
give ketone 8 (entry 1, compound 8 could be subsequently
cyclized under acidic conditions to give spiroketal 9 almost
quantitatively). Interestingly, the absence of water and the
presence of the polar solvent hexafluoroisopropanol (HFIPA)
allowed a one-pot hydride shift, oxygen deprotection, and
spiroketalization sequence to occur, forming 9 in 72% yield
(entry 2). Further studies showed that both TES and TBS
protecting groups gave acceptable yields in the spiroketaliza-
tion process (entry 3), and that the extra activation imparted
by an a-chloromesylate group (Mc)[6] was essential to the
success of the reaction (compare with entries 4 and 5). Our
conclusion was that we had found the correct balance of
protecting-group stability and leaving-group activation in this
prototype, and that this new method of spiroketal formation
was suitable for application in a more complex setting.
Next, we set about examining the cascade oxidative
cyclization and subsequent application of the spiroketaliza-
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Table 2: Cascade oxidative cyclization.
reported earlier (Table 1), we prepared the spiroketalization
precursor 23 by protecting the aldol adduct with a TES group,
removing the acetate group, and activating the liberated
hydroxy group at C6 as an a-chloromesylate derivative.
To finish our synthesis of the C1–16 fragment of
pectenotoxin-4, we investigated the hydride-shift-initiated
spiroketalization of 23 under the two sets of conditions that
had been previously identified (Scheme 4). Pleasingly, both
Entry
Lewis acid[a]
T [8C]
Solvent
Yield [%]
1
2
3
4
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Cu(OTf)2
60
60
80
80
MeCN (aq)
37[b]
33
69
55
MeCN (aq)/buffer
MeCN (aq)/buffer
MeCN (aq)/buffer
[a] 50 mol%. [b] Acid-promoted decomposition was also observed.
PNO=pyridine-N-oxide. Entries in bold highlight optimized reaction
conditions.
and four stereogenic centers, is unprecedented and shows the
power that this methodology holds for the formation of
complex THF-containing products with more than one ring.
Installation of the aldol-derived side chain involved
protecting-group manipulation of product 18, beginning
with protection of the primary hydroxy group (Scheme 3)
and followed by regioselective protection of the remaining
two hydroxy groups with an acetate (at C6) and then a TBS
group (at C11) to give 19.
Scheme 4. Hydride-shift-initiated spiroketalization.
the one- and two-step reaction sequences worked well and
produced the spiroketals 25 and 26 in good yields. Interest-
ingly, the one-pot reaction of 23 in HFIPA effected the
removal of the PMB group at C14 to give 25, while the two-
step protocol gave 26 with the PMB group intact (in the
natural product, the C14 position bears a ketone, so the
formation of 25 may be useful in the context of a total
synthesis). The structure of the spiroketal was confirmed by
nOe measurements, and these fit very well with the expected,
thermodynamically more stable spiroketal as shown.
In conclusion, we have developed two concepts that
should find use in organic synthesis, namely a hydride-shift-
initiated spiroketalization and a cascade oxidative cyclization
that enable the synthesis of bis-THFs. The utility of these
methodologies was tested successfully in a synthesis of the
C1–16 fragment of the complex and biologically active
natural product pectenotoxin-4.
Scheme 3. Installation of the spiroketal side chain. DIBAl-H= diisobu-
tylaluminum hydride, DMAP=4-dimethylaminopyridine, DMSO=di-
methyl sulfoxide, py=pyridine.
Received: November 7, 2012
Published online: January 30, 2013
Keywords: catalysis · cyclization · natural products ·
pectenotoxin · spiroketals
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oxidation to the aldehyde (20) and Evans aldol reaction with
oxazolidinone 21 gave the syn adduct 22 as a single diaste-
reoisomer.[14] Finally, and in accordance with the study
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