Rhodium-catalysed vinyl 1,4-conjugate addition coupled with Sharpless asymmetric dihydroxylation in the synthesis of the CDE ring fragment of pectenotoxin-4

Article abstract of DOI:10.1039/c9sc01761e

Our synthesis of the CDE ring fragment of pectenotoxin-4 utilised two key steps to make the complex bicyclic ketal unit: (i) a rhodium-catalysed vinyl group 1,4-addition as the major C-C bond forming step; (ii) a stereoselective Sharpless Asymmetric Dihydroxylation (SAD) of the resulting 1,1-disubstituted homoallylic alcohol. Subsequent acid-catalysed cyclisation afforded the desired [5,6]-bicyclic ketal of the target molecule. This methodology was shown to be compatible with the desired E ring fragment 35 in order to construct the CDE fragment 37 of pectenotoxin-4.

Full text of DOI:10.1039/c9sc01761e

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Rhodium-catalysed vinyl 1,4-conjugate addition
coupled with Sharpless asymmetric
Cite this: DOI: 10.1039/c9sc01761e
dihydroxylation in the synthesis of the CDE ring
fragment of pectenotoxin-4†
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Melodie S. W. Richardson,a Christopher J. Tame,b Darren L. Pooleb
a
*
and Timothy J. Donohoe
Our synthesis of the CDE ring fragment of pectenotoxin-4 utilised two key steps to make the complex
bicyclic ketal unit: (i) a rhodium-catalysed vinyl group 1,4-addition as the major C–C bond forming step;
(ii) a stereoselective Sharpless Asymmetric Dihydroxylation (SAD) of the resulting 1,1-disubstituted
homoallylic alcohol. Subsequent acid-catalysed cyclisation afforded the desired [5,6]-bicyclic ketal of the
target molecule. This methodology was shown to be compatible with the desired E ring fragment 35 in
order to construct the CDE fragment 37 of pectenotoxin-4.
Received 10th April 2019
Accepted 17th May 2019
DOI: 10.1039/c9sc01761e
rsc.li/chemical-science
40 EFG fragment via stereodivergent catalytic cobalt and
osmium oxidative cyclisations (Scheme 1a).8
Introduction
The major challenge remaining in our synthesis of PTX-4 is
uniting these two complex fragments to synthesise the nal
[5,6]-bicyclic ketal, the D ring. A handful of approaches to this
bicyclic structure for PTX-2 (ref. 4o, s, t, x, y, z and 6) and PTX-4
The pectenotoxins (PTXs) are a family of polyether macrolides
containing a spiroketal (AB ring), three substituted tetrahydro-
furans (C, E and F rings) and 19 or more stereocentres deco-
rating the 40-carbon chain.1 These intriguing natural products
were rst isolated in 1985 by Yasumoto and coworkers,2 and
have been shown to exhibit potent biological activity, including
selective cytotoxicity against tumour cell lines.3
The architectural complexity of these highly functionalised
macrolactones have garnered signicant interest within the
synthetic chemistry community,4 however only two total
syntheses of these molecules have been completed to date: PTX-
4 by Evans in 2002 (ref. 5) and PTX-2 by Fujiwara in 2014.6
The Donohoe group has made several signicant advances
towards the total synthesis of PTX-4. We have successfully
synthesised the C-1 to C-16 ABC fragment via a double osmium
catalyzed oxidative cyclisation together with a hydride-shi-
initiated spiroketalisation,7 as well as preparing the C-21 to C-
aDepartment of Chemistry, University of Oxford, Chemistry Research Laboratory,
Manseld Road, Oxford, OX1 3TA, UK. E-mail: timothy.donohoe@chem.ox.ac.uk
bGlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1
2NY, UK
Scheme 1 Previously synthesised fragments and key disconnections
proposed in this work for the CDE fragments: (a) previous work; (b) this
work.
† Electronic supplementary information (ESI) available: Synthetic procedures,
compounds' characterisation data and NMR spectra. See DOI: 10.1039/c9sc01761e
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(ref. 4d, x and 5) have been published in the literature. Herein,
we propose a novel route which proceeds via an unusual
rhodium-catalysed vinyl 1,4-addition9 as the key C–C bond
formation step to join the ABC and E ring fragments. It is
important to note that this key reaction has the potential to
allow complex molecular fragments to be joined under rela-
tively mild conditions and without using a large excess of either,
extremely valuable, component. A subsequent stereoselective
dihydroxylation–ketalisation sequence should then afford the
desired [5,6]-bicyclic ketal structure of the D ring of PTX-4
(Scheme 1b). Note here that the sensitive diene containing FG
ring fragment will be constructed as it is attached to the E-ring
by a Julia reaction, aer cyclisation of the D ring, because the
1,3-diene fragment itself would be unlikely to survive the
conditions needed for dihydroxylation and/or cyclisation.
Scheme 3 Synthesis of the model E ring enone 19. Reagents and
conditions: (i) DMSO, (COCl)2, Et3N, CH2Cl2, À78 ꢀC; (ii) vinyl
magnesium bromide, Et2O, À78 ꢀC, 35% over two steps, 1.15 : 1 dr; (iii)
DMP, CH2Cl2, 89%.
added to afford volatile allyl alcohol 18 in 35% yield (1.15 : 1 dr
at the hydroxyl centre) over two steps. Oxidation using DMP
furnished the model E ring enone 19 in 89% yield.
Using rhodium-catalysed 1,4-addition conditions9 on model
C ring boronate 15 with 19 was successful and afforded the
desired adduct 20 in approximately 40% yield. However, the use
of methanol as the solvent formed the methanol 1,4-addition
adduct of compound 19 as a by-product, which oen co-eluted
with the desired products. Pleasingly, we found that replacing
methanol with THF as the solvent prevented the formation of
this by-product and improved the yield to 63% for the reaction
between 15 and 19 (Scheme 4).
Results and discussion
To begin, we chose to use model C ring boronate 15 as
a substitute for the real ABC ring fragment required in the
synthesis of PTX-4 (Scheme 2). Starting from commercially
available enantiopure furanose 8, the hemiacetal was reduced
to the corresponding THF 9, and the primary benzyl group
removed in two steps, via acetate 10, to reveal 11.10 Oxidation of
the primary alcohol to the aldehyde followed by a Hosomi–
Sakurai reaction11 with bromoallylsilane 12 (ref. 12) afforded the
(R)-homoallylic alcohol 13 as a single diastereoisomer in 56%
yield over two steps. The stereochemistry arises from Felkin–
Ahn-controlled addition of the bromoallylsilane 12 and was
conrmed via Mosher's ester analysis.13 Direct conversion of the
bromide to the desired boronate was unsuccessful; therefore
protection of the secondary alcohol 13 with TESOTf was
necessary. Miyaura borylation of TES-protected bromide 14 to
the model C ring boronate 15 was then accomplished in 79%
yield.14
In order to ensure that no epimerisation had taken place
adjacent to the ketone carbonyl, we repeated the coupling
between 15 and racemic 19 (compound S6 prepared separately,
see ESI† for details). This reaction gave two diastereoisomeric
compounds (in an approximately 1 : 1 ratio) and from the 13C
NMR spectrum of this mixture we could rule out epimerisation
in compound 20 formed from enantiopure 19.
In order to construct the bicyclic acetal D-ring system we next
required a facially selective dihydroxylation of the alkene within
20 (to set the stereochemistry at C7, Scheme 5) followed by
a ketalisation reaction. Although the stereochemical outcome of
dihydroxylation of 1,1-disubstituted alkenes are difficult to
predict,15 we chose to use the Sharpless Asymmetric Dihydrox-
ylation (SAD) to control diol formation. It is worth noting that
the original mnemonic proposed by Sharpless for the SAD
reaction16 is oen problematic when applied to 1,1-disubsti-
tuted alkenes, as rst shown by Hale.15a In the case of substrate
20, even if we could achieve near “perfect” facial selectivity for
the correct diol 21, acid-catalysed cyclisation could then result
in three possible isomeric bicyclic ketal structures: the desired
[5,6]-ketal 23, [6,7]-ketal 24 and [5,5]-ketal 25 (Scheme 5).
Similarly, we started with a less substituted THF ring in place
of the desired E ring fragment in our initial studies (Scheme 3).
Therefore, (R)-tetrahydrofurfuryl alcohol 16 was oxidised to the
corresponding aldehyde 17, and vinyl Grignard reagent was
Scheme 2 Synthesis of the model C ring boronate 15. Reagents and
conditions: (i) Et3SiH, BF3$OEt2, MeCN, 95%; (ii) Ac2O, TFA; (iii) NaOMe,
MeOH, 89% over two steps; (iv) DMSO, SO3$py, Et3N, CH2Cl2, 0 ꢀC; (v)
12, BF3$OEt2, CH2Cl2, À78 ꢀC, 56% over two steps; (vi) TESOTf, imid-
azole, CH2Cl2, 85%; (vii) (B(pin))2, PdCl2(PPh3)2 (3 mol%), PPh3 (6 mol%), Scheme 4 Rhodium-catalysed 1,4-addition reaction of model C ring
KOPh, PhMe, 50 ꢀC, 79%.
boronate 15 with model E ring enone 19.
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Scheme 6 Sharpless asymmetric dihydroxylation and acid-catalysed
cyclisation of 20. Reagents and conditions: (i) K2OsO2(OH)4, (DHQ)2-
PHAL, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH/H2O (1 : 1), 0 ꢀC then
PPTS, CH2Cl2/MeOH (1 : 1); (ii) K2OsO2(OH)4, (DHQD)2PHAL,
K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH/H2O (1 : 1), 0 ꢀC then PPTS,
CH2Cl2/MeOH (1 : 1), 91%; (iii) 4-bromobenzoic acid, DIC, DMAP,
CH2Cl2, 5% over two steps for 27, 53% for 28.
Scheme 5 Possible bicyclic ketal structures arising from diols 21 and
22.
At rst the dihydroxylation of 1,1-disubstituted alkene 20
was attempted using Upjohn conditions17 to reveal any
substrate bias during oxidation, however purication and
identication of the desired diol was difficult as a complex
mixture of products were obtained, possibly due to TES group
migration. It was proposed to cyclise the crude diol using mildly
acidic conditions5b while also removing the TES group; however
the use of this procedure still produced in a complex mixture.
Undeterred, we chose the Sharpless Asymmetric Dihydrox-
ylation (SAD) conditions to obtain the desired diol stereo-
chemistry. As it is difficult to predict which ligand is required,
we used both (DHQ)2PHAL and (DHQD)2PHAL separately.
According to the mnemonic,16 we predicted (DHQ)2PHAL would
produce the desired diol. However, using (DHQ)2PHAL ligand in
the dihydroxylation and acid-induced cyclisation sequence
produced a mixture of products (Scheme 6). Nevertheless, upon
derivatisation of the mixture with 4-bromobenzoic acid we
identied [5,6]-bicyclic ketal 27, with a characteristic 13C NMR
peak at 108.4 ppm.4d The connectivity, supported by COSY/
HSQC/HMBC experiments, was shown to be the [5,6]-ketal
over the [6,7] or [5,5] isomers. Moreover, the relative stereo-
chemistry of dihydroxylation could also be assigned as shown,
because within the [5,6]-ketal structure we did not observe an
nOe enhancement across the ring system (i.e. between C-5 to
either C-8 or C-9); this would be expected in the desired ketal
structure. Looking at the full set of data we concluded that
compound 27 contained the [5,6]-bicyclic ketal but with the
opposite stereochemistry at C-7 (as set by the initial
dihydroxylation).
However, this time the molecule did exhibit key nOe enhance-
ments across the bicyclic ring (C-5 to C-8 and C-9), showing it to
be the desired [5,6]-bicyclic ketal 23 originating from the correct
stereochemistry at C7. Further derivatisation of 23 with 4-bro-
mobenzoic acid gave compound 28 which was different to the
related ketal (27) formed from the (DHQ)2PHAL derived
experiments.
We note that other bicyclic ketals ([6,7] and [5,5]) were not
isolated in any reaction, however there have been reports that
these types of structures may undergo facile degradation upon
purication and may not be isolatable.4d Our studies show that
in this system it is the (DHQD)2PHAL ligand that delivers the
correct facial selectivity during dihydroxylation, and that acid-
catalysed ketalisation then forms the desired [5,6]-ketal
system as found in the natural product. The fact that
(DHQD)2PHAL has formed the (S)-diol 21 during dihydrox-
ylation is consistent with the reversed stereoselectivity that has
been reported during the SAD reaction of 1,1-disubstituted
alkenes.15a–e,i
To further test this methodology in the synthesis of
pectenotoxin-4, we converted the desired E ring fragment 29
(ref. 8) into the desired enone 35, with the unsaturated ethyl
ester side chain serving as a precursor for a Julia olenation
coupling with the FG ring fragment. Therefore, the previously
reported E fragment enantiopure 29 (ref. 8) was deprotected
with TBAF, before Parikh–Doering oxidation to the aldehyde
and vinyl Grignard reagent was added to afford allyl alcohol 30
(Scheme 7). The hydroxyl group was protected with TBSCl,
before the Weinreb amide was reduced to the aldehyde with
DIBAL-H and a Horner–Wadsworth–Emmons reaction with
ylide 32 furnished (E)-unsaturated ethyl ester 33 (stereochem-
istry proven by nOe analysis). Finally, removal of the TBS group
Interestingly, the use of (DHQD)2PHAL in the dihydrox-
ylation–cyclisation sequence (oxidation being followed by
treatment with acid) also provided one bicyclic ketal diaste-
reoisomer 23 with a 13C NMR peak at 108.8 ppm (Scheme 6).
Upon detailed NMR (COSY/HSQC/HMBC) analysis, 23 was
again conrmed to have the [5,6]-bicyclic ketal connectivity.
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NMR peak at 108.0 ppm. Other ligands tested in the osmium
catalyzed dihydroxylation of 36, such as (DHQD)2PYR and
(DHQD)2AQN, did not improve the yield. It should be noted that
the omission of methanesulfonamide and careful monitoring of
the reaction progress was required to avoid over-oxidation of the
ethyl ester substituted alkene. Moreover, the structure of 37 was
conrmed with COSY/HSQC/HMBC NMR experiments to be the
desired [5,6]-ketal and the stereochemistry was then assigned by
the nOes observed across the bicyclic ring system (C-16 to C-19
and C-20) as was the case for compound 23. In this case,
experiments performed to dihydroxylate and cyclise 36 using
the opposite chiral ligand (i.e. (DHQ)2PHAL) only resulted in the
formation of a complex mixture of products.
Conclusions
Scheme 7 Synthesis of the E ring enone 35. Reagents and conditions:
(i) TBAF, THF, 0 ꢀC, 96%; (ii) SO3$py, Et3N, DMSO, CH2Cl2, 0 ꢀC; (iii) vinyl
In conclusion, we have developed a novel route to the CDE
magnesium bromide, Et2O, 0 ꢀC, 69% over two steps; (iv) TBSCl, fragment (C-12 to C-30) of PTX-4. The key C–C bond forming
imidazole, DMAP, CH2Cl2, 88%; (v) DIBAL-H, THF, À78 ꢀC; (vi) 32,
step was a rhodium catalysed 1,4-vinyl group addition to an
enone which used a close to equimolar ratio of the two key
components. Model studies revealed a reversal of ligand-facial
benzene, D, 87% over two steps; (vii) TBAF, THF, 78%; (viii) DMP,
NaHCO3, CH2Cl2, 90%.
selectivity during the SAD reaction of a 1,1-disubstituted
homoallylic alcohol, resulting in the isolation of two different
[5,6]-bicyclic ketals depending on the chiral ligand used. This
methodology was then extended to incorporate the desired E
ring fragment of PTX-4 in the synthesis of a CDE fragment of
PTX-4. Further work is ongoing to utilise this methodology and
complete the total synthesis of PTX-4.
with TBAF followed by oxidation with DMP afforded the E ring
enone 35.
Initial rhodium-catalysed 1,4-addition reaction conditions
between model C ring boronate 15 and E ring enone 35 were
moderately successful, affording adduct 36 in 30% yield
(Scheme 8). Repeating the reaction with a more active catalyst
system, [Rh(cod)OH]2,18 improved the yield of 36 to 53%.
Conflicts of interest
Pleasingly, the dihydroxylation–cyclisation sequence (using
(DHQD)2PHAL ligand) then afforded the desired CDE fragment
There are no conicts to declare.
37 in 40% yield, as a single compound, with a characteristic 13
C
Acknowledgements
M. S. W. R. is grateful to the EPSRC Centre for Doctoral Training
in Synthesis for Biology and Medicine (EP/L015838/1) for
studentships, generously supported by AstraZeneca, Diamond
Light Source, Defence Science and Technology Laboratory,
Evotec, GlaxoSmithKline, Janssen, Novartis, Pzer, Syngenta,
Takeda, UCB and Vertex. We are grateful to T. Kwok and Y. Liu
for assistance with the preparation of compound 29.
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Scheme 8 Rhodium-catalysed 1,4-addition reaction of the model C
ring boronate 15 with E ring enone 35, followed by the Sharpless
asymmetric dihydroxylation and acid-catalysed cyclisation sequence
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