Studies towards the synthesis of tedanolide C. Construction of the C13-epi C1-C15 fragment

Article abstract of DOI:10.1039/c6ob00896h

The preparation of an advanced intermediate on route towards the synthesis of tedanolide C is reported here. It is based on the coupling of two fragments of similar size and complexity, which in turn are prepared by highly stereoselective substrate-contro

Full text of DOI:10.1039/c6ob00896h

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Studies towards the synthesis of tedanolide
C. Construction of the C13-epi C1–C15 fragment†
Cite this: DOI: 10.1039/c6ob00896h
Received 26th April 2016,
Accepted 17th May 2016
Joana Zambrana, Pedro Romea* and Fèlix Urpí*
DOI: 10.1039/c6ob00896h
www.rsc.org/obc
The preparation of an advanced intermediate on route towards the
synthesis of tedanolide C is reported here. It is based on the coup-
ling of two fragments of similar size and complexity, which in turn
are prepared by highly stereoselective substrate-controlled
titanium-mediated aldol reactions from chiral ketones.
Tedanolides are a family of structurally complex natural
marine products that feature in vitro cytotoxicities in the nano-
molar to picomolar range.1 The combination of this biological
activity and their unique structure have led to considerable
efforts to synthesize them, which have resulted in the com-
pletion of several total tedanolide synthesis (Fig. 1).2,3
However, and in sharp contrast to the other efforts to date, no
total synthesis and only a few approaches towards small frag-
ments of tedanolide C (Fig. 1) have been reported so far.4
Tedanolide C, isolated by Ireland in 2005 from a marine
sponge of the Ircinia species found in Papua New Guinea,5
exhibits potent cytotoxic activity against HCT-116 cells in vitro
and produces important S-phase arrest. These remarkable pro-
perties grant it a prominent position among the lead com-
pounds for the inhibition of protein biosynthesis. Structurally,
tedanolide C resembles other members of the tedanolide
family since a side chain bearing an epoxide and an alkene is
attached to a highly oxygenated 18-membered macrolactone
from a primary alcohol. In turn, it is distinguished by a
geminal dimethyl group and eight stereocentres, including a
tertiary alcohol. This structure and the relative stereochemistry
shown in Fig. 1 have been determined by NMR studies, mole-
cular modelling and DFT calculations, but its absolute con-
figuration is still unknown. In fact, this has often been called
into question and most of the synthetic studies reported to
date target the enantiomer or any of its epimers.4
Fig. 1 Tedanolides.
Given this uncertainty and considering the need for
efficient routes to tedanolide C, we launched a project devoted
precisely to the synthesis of such a challenging structure.
Initially, we planned to synthesize an advanced C1–C15 inter-
mediate by coupling two fragments, which in turn might
result from the novel and highly stereoselective substrate-
controlled aldol reactions developed by our group.6,7 Such an
approach entailed the opposite configuration for the C13
stereocentre; but we were first interested in testing the syn-
thetic potential of our basic methods and exploring the feasi-
bility of the overall strategy. As represented in Scheme 1, our
retrosynthetic analysis for the C13-epimeric C1–C15 fragment
of tedanolide C (1) hinges on the disconnection of the C7–C8
bond, which yields two fragments of similar size and complex-
ity. The synthesis of the C1–C7 northern fragment takes advan-
tage of a titanium-mediated aldol reaction based on a chiral
isopropyl ketone;6 whereas the C8–C15 southern fragment
results from the aldol reaction of a chiral methyl ketone with a
Secció de Química Orgànica, Departament de Química Inorgànica i Orgànica,
and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de
Barcelona, Carrer Martí i Franqués 1-11, 08028 Barcelona, Catalonia, Spain.
E-mail: pedro.romea@ub.edu, felix.urpi@ub.edu
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization of products and copies of 1H and 13C spectra of new
compounds. See DOI: 10.1039/c6ob00896h
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Scheme 1 Retrosynthetic analysis of tedanolide C.
chiral aldehyde.7 Interestingly, both ketones may be prepared methylsilyloxypropanal proceeded smoothly to produce
from the same starting material: the methyl (S)-Roche ester, 94 : 6 mixture of diastereomers from which the desired adduct
which is the single chiral source for all the stereocentres. 5 was isolated in 84% yield. Having completed the backbone
a
According to this plan, the chiral isopropyl ketone 2 of the northern C1–C7 fragment, we envisaged that the
required for the construction of the C1–C7 fragment was pre- removal of the TBS protecting group could trigger the simul-
pared in a three-step sequence from commercially available taneous protection of the ketone and the resultant primary
methyl (S)-3-hydroxy-2-methylpropionate by standard trans- alcohol, which would facilitate further transformations.8 As
formations (Scheme 2).6 A quick glance at 2 indicated that the planned, deprotection of 5 produced the dihydroxy ketone 6
enolization would be troublesome due to the close similarity with an excellent yield; but the carbonyl group turned out to
of the two α-positions flanking the carbonyl bond. Contrary be completely unreactive and the desired pyran 7 (Scheme 2)
to what might be expected, the chelating capacity of TiCl4 was never observed in the reaction mixtures. This lack of reac-
permitted outstanding regioselective enolization and the sub- tivity is probably due to syn-pentane interactions developed by
sequent Lewis acid-mediated aldol addition to 3-tert-butyldi- the geminal dimethyl group in the cyclic form. Other attempts
to protect the carbonyl group as a ketal also failed, which
forced us to revise our approach.
Since the protection of the ketone proved to be difficult, it
was necessary to reduce it to install the required aldehyde at
C7 securely. Indeed, protection of the C3 alcohol and removal
of the benzyl protecting group produced pure hydroxy ketone 9
in a straightforward manner (Scheme 3). The subsequent sub-
strate-controlled reduction9 of the carbonyl proceeded with
excellent stereocontrol to provide diol 10 as a 92 : 8 mixture of
diastereomers and in 93% combined yield, whose treatment
with TESOTf gave fully protected polyol 11 in 89% yield.
Finally, the selective oxidation of the TES-protected primary
alcohol10 furnished the desired aldehyde, 12, in 83% yield.
Therefore, the northern fragment was synthesized in six steps
and with 45% overall yield from isopropyl ketone 2.
Once the aldehyde 12 was prepared, we focused our atten-
tion on the southern fragment. The starting chiral methyl
ketone 3 was readily available from Weinreb amide 4, pre-
viously prepared for the synthesis of isopropyl ketone 2
(Scheme 4). So, double differentiating aldol addition of 3 to
the chiral aldehyde 13 led to the anti-Felkin aldol adduct 14 in
79% yield and 94 : 6 diastereomeric ratio. This was a remark-
able result since the anti-Felkin relationship corresponds to
Scheme 2 First approach to the synthesis of the northern fragment.
a putative mismatched pair.7 Next, we assessed the stereo-
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Scheme 3 Synthesis of the C1–C7 northern fragment.
Scheme 4 Synthesis of the C8–C15 southern fragment.
selective reduction of the carbonyl group. Preliminary attempts that mild experimental conditions were employed to avoid the
based on Narasaka–Prasad conditions11 were disappointing epimerization of the sensitive aldehyde 18. Indeed, treatment
and syn diol 15 was obtained with a modest combined yield of 18 with dimethyl (acetyldiazomethyl)phosphonate and
(60%) and a low diastereomeric ratio (dr 70 : 30). Thus, we NaOMe at −40 °C16 gave enantiomerically pure terminal
were pleased to observe that the use of DIBALH under Kiyooka alkyne 20 in 69% overall yield over the three steps. Finally,
conditions12 led to an 85 : 15 mixture, from which enantio- methylation of 20 and hydrozirconation of the resultant alkyne
merically pure syn diol 15 was isolated with 80% yield. The 21 with Cp2ZrHCl, followed by treatment of the vinylzirconium
protection of the resulting diol and the accurate hydrogenoly- intermediate with iodine, provided the desired iodoalkene 22
sis of the benzyl ether 16 produced the primary alcohol 17, with 89% combined yield. Thus, the southern fragment 22
which was immediately oxidized without further purification had been synthesized in eight steps and 30% yield from
with Dess–Martin periodinane13 to give aldehyde 18. Then, the methyl ketone 3.
conversion of the carbonyl into a terminal alkyne was evalu-
With both fragments 12 and 22 in hand, we next tackled
ated. Application of the Corey–Fuchs conditions14 to 18 pro- their assembly. Surprisingly and in spite of the synthetic
duced the dibromoalkene 19 with a certain epimerization importance of the metal-mediated asymmetric additions of
(dr 93 : 7) and in modest yield (53%). The Ohira–Bestmann halo alkenes to aldehydes, there is still a lack of models to
method15 turned out to be much more effective provided predict their stereochemical outcome. This limitation probably
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Scheme 5 Coupling of northern and southern fragments: synthesis of the C13-epi C1–C15 fragment.
stems from the large number of variables that determine the and transmetalation of the resultant intermediate with
configuration of the new stereocentre, which involves the geo- ZnMe2 produced a vinylzincate that, added to aldehyde
metry of the olefin, the metal, the structure of both partners, 12, gave the desired C13-epi C1–C15 fragment 24‡ as a
and the influence of other chiral additives.17
Facing such a daunting task, we initially examined the con- (Scheme 5).§
60 : 40 mixture of two diastereomers in 70% combined yield
version of iodo olefin 22 into a vinylzinc compound and the
Aiming to simplify the overall procedure, we then focused
subsequent addition to aldehyde 12. Marshall reported that our attention on the addition of trisubstituted alkenyl lithium
the addition of vinyl zinc bromide intermediates to α-chiral intermediates to aldehydes. The stereocontrol of such reac-
aldehydes in the presence of lithiated (+)- or (−)-N-methyl- tions is usually poor, but occasionally they proceed with mod-
ephedrine under non-chelation conditions proceeded stereose- erate to high diastereoselectivity.23 Indeed, some examples
lectively to afford the corresponding anti or syn adducts with reported by Smith were encouraging since they involved alde-
predominant reagent control.18–20 Thus, we considered that hydes and iodo olefins that are structurally close to our north-
the appropriate choice of the enantiomer of the easily available ern and southern fragments respectively.24 These Smith
N-methylephedrine might permit the stereocontrolled coup- conditions proved to be highly effective and produced the C13-
ling of the northern and southern fragments. Unfortunately epi C1–C15 fragment 24 in 76% yield and 60 : 40 diastereo-
and despite intensive efforts, such a transformation did not meric ratio (Scheme 5).
produce the desired C1–C15 fragment. Instead, we always
In summary, we have achieved the stereocontrolled synthe-
recovered the starting aldehyde 12 and dehalo derivative 23 ses of aldehyde 12 and iodo olefin 22, two fragments of
(Scheme 5), which suggests that the chiral NME complex is not similar size and complexity on route towards the synthesis of
efficiently formed or turns out to be too bulky to attack the tedanolide C. Both approaches are based on highly efficient
carbonyl.
substrate-controlled titanium-mediated aldol reactions from
Interestingly, related vinylzincates, prepared by transmetala- chiral ketones derived from the (S)-Roche ester. Addition of
tion of vinyllithium intermediates with ZnMe2, can also par- the alkenyl lithium intermediate from 22 to aldehyde 12 pro-
ticipate in highly diastereoselective substrate-controlled vides alcohol 24, an advanced C13-epi C1–C15 fragment of
reactions of halo alkenes and aldehydes and have already been tedanolide C, in high yield but modest stereocontrol. Further
employed in the total syntheses of natural products.21 Particu- studies on such a coupling and other improvements are cur-
larly, comprehensive studies by Gennari have established that rently underway in our group and will be reported in due
double asymmetric additions of chiral lithium vinylzincates to course.
chiral aldehydes usually proceed in high yields, although the
stereocontrol depends heavily on the structure of the nucleo-
phile and is difficult to rationalize.17,22 With this conceptual
Acknowledgements
framework in mind, we next assessed its application to
the synthesis of the C1–C15 fragment. Thus, we were pleased
to observe that treatment of iodo olefin 22 with t-BuLi
Financial support from the Spanish Ministerio de Economía y
Competitividad and Fondos Feder (Grant No. CTQ2012-31034
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