Synthetic Studies toward the C32-C46 Segment of Hemicalide. Assignment of the Relative Configuration of the C36-C42 Subunit

Article abstract of DOI:10.1021/acs.orglett.5b00955

The synthesis of five diastereomeric model compounds incorporating the C32-C46 segment of the antitumor marine natural product hemicalide has been achieved through a convergent approach relying on the 1,4-addition of an alkenyl boronate to an α,β-unsaturated δ-lactone followed by α-hydroxylation of an enolate and a Julia-Kocienski olefination. Comparison of the ¹H and ¹³C NMR data of the model compounds with those of hemicalide enabled the assignment of the relative configuration of the C36-C42 subunit. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b00955

Letter
pubs.acs.org/OrgLett
Synthetic Studies toward the C32−C46 Segment of Hemicalide.
Assignment of the Relative Configuration of the C36−C42 Subunit
†
‡
†
‡
‡
‡
Simon Specklin, Guillaume Boissonnat, Camille Lecourt, Geoffroy Sorin, Marie-Isabelle Lannou,
§
§
,†
,†
Janick Ardisson, Franc o̧ is Sautel, Georges Massiot, Christophe Meyer,* and Janine Cossy*
†Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI), ESPCI ParisTech, CNRS (UMR8231),
PSL Research University, 10 rue Vauquelin, 75231 Paris Cedex 05, France
‡
Faculte
́
de Pharmacie, Universite
Pharmacochimie de la Regulation Epigen
Developpement Pierre Fabre, 3 avenue Hubert Curien, 31035 Toulouse Cedex 01, France
S Supporting Information
́
Paris Descartes, CNRS (UMR8638), 4 avenue de l’observatoire, 75270 Paris Cedex 06, France
§
́
́ ́
etique du Cancer (ETac), CNRS/Pierre Fabre (USR3388), Centre de Recherche et de
́
*
ABSTRACT: The synthesis of five diastereomeric model compounds
incorporating the C32−C46 segment of the antitumor marine natural
product hemicalide has been achieved through a convergent approach
relying on the 1,4-addition of an alkenyl boronate to an α,β-unsaturated δ-
lactone followed by α-hydroxylation of an enolate and a Julia−Kocienski
1
13
olefination. Comparison of the H and C NMR data of the model
compounds with those of hemicalide enabled the assignment of the
relative configuration of the C36−C42 subunit.
he discovery of antitumor agents acting by new
mechanisms is of prime importance in cancer chemo-
T
therapy for the development of alternative or synergistic
anticancer drugs, and in this context, natural products have
1
always played a prominent role. The naturally occurring
complex polyketide hemicalide, recently isolated from extracts
of the marine sponge Hemimycale sp. collected around the
Torres Islands (Vanuatu), exhibits highly potent antiprolifer-
ative activity against several human cancer cell lines at
2
subnanomolar concentrations. The exact mechanism by
which hemicalide disrupts the α/β microtubule network, as
2
observed in immunocytochemistry assays, is not yet fully
understood, but its mode of action differs from the other well-
Figure 1. Structure of hemicalide.
known natural products targeting the mitotic spindle such as
3
Vinca alkaloids or taxoids. The new mode of action of
segment of hemicalide and the assignment of the relative
configuration of the α-hydroxy-δ-lactone C36−C42 subunit of
this antitumor marine natural product.
hemicalide as a mitotic blocker, its extreme scarcity, and its
challenging structure led us to embark in a research program
devoted to the total synthesis of this marine natural product
and simplified analogues thereof.
The nuclear Overhauser effects (NOE) observed in the
NOESY spectrum of hemicalide between H37 and the methyl
group at C42, as well as with H40, enabled the determination of
the relative configuration of the three stereocenters (C37, C39,
The planar structure of hemicalide was assigned by NMR
spectroscopy, but the configuration of the 21 stereocenters
contained in the 46 carbon atom backbone was initially
7
2
and C40) in the δ-lactone ring. To assign the relative
unknown (Figure 1). The relative configuration of the
configuration of the adjacent methyl-substituted stereocenters
stereocenters embedded in the C8−C13 and C18−C24
segments of hemicalide was subsequently assigned by the
synthesis of appropriate model compounds for the C1−C17
and C18−C25 subunits, combined with careful analysis and
comparison of NMR spectra as well as computational
(
C36 and C42) and possibly that of the C45 remote
stereocenter, the synthesis of diastereomeric model compounds
A, structurally related to the C32−C46 subunit, was undertaken
with the goal of comparing their NMR data with those of
2
4
,5
hemicalide. The C34−C35 disubstituted alkene in model
conformational analysis. These initial synthetic endeavors
also resulted in the development of a convergent approach
6
toward the C1−C25 fragment of hemicalide. Herein, we
Received: April 2, 2015
report synthetic studies toward the yet unexplored C32−C46
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00955
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Letter
compound A would be formed by a Julia−Kocienski olefination
applied to an aldehyde at C35, generated by oxidation of the
corresponding protected primary alcohol in compound B. The
introduction of the C42 stereocenter was envisaged by
hydrogenation of the C42−C43 trisubstituted alkene C. This
latter transformation, which may not proceed with high
diastereocontrol, would provide an easy access to both epimers
Scheme 2. Synthesis of α,β-Unsaturated δ-Lactones 4 and 5
2
at C42 from a common precursor. The presence of an sp -
hybridized carbon at C42 and the trans relative relationship of
the substituents at C37, C39, and C40 in δ-lactone C further
guided the retrosynthetic analysis. Installation of the hydroxyl
at C40 would be achieved by a diastereoselective α‑hydrox-
ylation of a disubstituted lactone which, in turn, would result
from the diastereoselective 1,4-addition of the trisubstituted
alkenyl boronate E to the α,β-unsaturated δ-lactone D. This
synthetic approach would be flexible as the configuration of
C36, C37, and C45 could be initially varied in the coupling
partners D and E and since both epimers would be later
generated at C42, once the C39 and C40 stereocenters have
been controlled (Scheme 1).
afforded (S)-7 (92%, two steps from (S)-10). Subsequent
cross-metathesis with isopropenyl boronate 8 eventually
produced the enantiomeric alkenyl boronate (S)-9 (56%)
Scheme 1. Retrosynthetic Analysis of Model Compounds A
(
Scheme 3).
Scheme 3. Synthesis of Alkenyl Boronates (R)-9 and (S)-9
The coupling of the C35−C41 and C42−C46 subunits was
then investigated. After a slight optimization, the 1,4-addition of
the trisubstituted alkenyl boronate (S)-9 to the α,β-unsaturated
lactone 4 could be successfully carried out in the presence of
The synthesis of the two possible epimeric lactones D was
achieved from both enantiomers of the Roche ester 1.
Enantiomer (S)-1 was protected as a PMB ether and converted
into the Weinreb amide 2 (87%) which was reduced with
[Rh(COD)Cl] (3 mol %) and a stoichiometric quantity of
2
1
4
LiOH in dioxane/H O (10:1) at 40 °C. This reaction
proceeded with moderate diastereoselectivity and produced
2
8
,9
DIBAL-H. The resulting aldehyde was engaged in a reagent-
15
controlled face-selective allylation using Hafner−Duthaler’s
lactones 11 and 11′ in an 83:17 ratio (74%). Introduction of
the hydroxyl group at C40 was achieved by enolization of the
mixture of 11/11′ with NaHMDS followed by addition of
10
allyltitanium complex (R,R)-[Ti]-I to provide homoallylic
alcohol 3 (dr >96:4) in 92% yield. Acylation of 3 with acryloyl
chloride followed by ring-closing metathesis in the presence of
Grubbs’ second-generation catalyst (Grubbs-II) provided the
1
6
Davis oxaziridine. The trisubstituted lactone 12 was
reproducibly obtained as a single diastereomer (72%) because
the minor epimer 11′ did not undergo hydroxylation under
these conditions. The relative configuration of 12 was
11
α,β-unsaturated δ-lactone 4 (72%, two steps from 3). Lactone
(C35−C41 subunit) was synthesized in six steps from (S)-1
4
12
7
(
58% overall yield), and application of a similar sequence to
unambiguously assigned by NMR spectroscopy (NOESY)
enantiomer (R)-1 afforded lactone 5 (47% overall yield) which
is the epimer of 4 at C36 (Scheme 2).
and confirmed that the 1,4-addition of alkenyl boronate (S)-9
to lactone 4 occurred preferentially trans to the substituent at
C37, whereas the hydroxyl group at C40 was subsequently
introduced trans to the alkenyl residue at C39. The creation of
the sixth stereocenter at C42 was then envisaged by
hydrogenation of the trisubstituted C42−C43 alkene. Under
an atmospheric pressure of hydrogen and in the presence of
Pd/C, hydrogenation of 12 did not proceed. This trans-
formation was achieved using an H-cube flow reactor under
harsher conditions (Pd/C, 40 bar, 50 °C) to produce a mixture
of epimeric lactones 13a/13b (76%) with low diastereoselec-
The enantiomers of alkenyl boronate E (C42−C46 subunit)
were prepared from either commercially available (R)-pent-4-
en-2-ol or (S)-propylene oxide. Protection of alcohol (R)-6 as a
TBS ether afforded (R)-7 (96%) which was involved in a cross-
13
metathesis with isopropenyl pinacol boronate 8. A mixture of
geometric isomers (Z/E = 85:15) was obtained from which the
major product (R)-9 was isolated in 55% yield. Alternatively,
ring opening of epoxide (S)-10 with vinylMgCl in the presence
of CuI followed by protection of the alcohol as a TBS ether
B
DOI: 10.1021/acs.orglett.5b00955
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Letter
tivity (13a/13b = 45:55). It was envisaged to take advantage of
Scheme 5. Model Compounds 17a and 17b
the homoallylic alcohol at C40 and perform a directed
17
reduction. In the presence of Crabtree’s catalyst [Ir]-I,
hydrogenation of the C42−C43 alkene proceeded readily and
led to a 63:37 mixture of lactones 13a/13b presumably due to a
lack of significant conformational restriction around the C39−
C42 bond. Lactones 13a (45%) and 13b (27%) were separated
by medium pressure liquid chromatography, and the absolute
configuration at C42 was reliably assigned by Vibrational
Circular Dichroism analysis of the corresponding epimers
18
obtained after cleavage of the protecting groups (Scheme 4).
Scheme 4. Creation of the C39, C40, and C42 Stereocenters
Scheme 6. Model Compounds 17c, 17d, and 17e
The next task was to install the C34−C35 disubstituted
alkene in model compounds A. Protection of the alcohol at
C40 in 13a as a TBS ether followed by cleavage of the PMB
ether led to a primary alcohol at C35 which was oxidized with
Dess-Martin periodinane (DMP). The resulting aldehyde 14a
(
92%, three steps from 13a) was engaged in a Julia−Kocienski
19
olefination using sulfone 15 and KHMDS as the base which
produced the disubstituted olefin 16a (E/Z = 95:5) in 70%
yield. Subsequent cleavage of the TBS ethers at C40 and C45
led to a first model compound 17a for the C32−C46 subunit of
hemicalide. Compound 13b was engaged in the same sequence
of reactions as described for 13a that led to 17b (13% overall
yield, unoptimized), which is the epimer of 17a at C42
(
Scheme 5). Following the same strategy, lactones 17c and 17d
which are the epimers at C45 of compounds 17a and 17b,
respectively, were prepared from α,β-unsaturated lactone 4 and
the enantiomeric alkenyl boronate (R)-9. Compound 17e,
which is the epimer of 17c at C36, was also synthesized from
Figure 2. Δδ (ppm) between diastereomeric model compounds 17c,
7
lactone 5 and alkenyl boronate (S)-9 (Scheme 6).
13
1
7d, 17e and hemicalide in C NMR (CD OD).
3
The NMR spectra of 17a and 17c, as well as those of 17b
and 17d, were nearly indistinguishable thereby preventing the7
configurational assignment of the remote C45 stereocenter.
17c and 17d (epimers at C42) and, conversely, no significant
variations are observed in the chemical shifts of the C43−C37
region for 17c and 17e (epimers at C36). This indicates that
the modification of the configuration of C36 or C42 does not
affect the chemical shifts of the atoms in the opposite chains (at
C39 and C37, respectively) on the δ-lactone. Thus, it can be
concluded that hemicalide has the same configuration at C42 as
in model compounds 17c and 17e. Although C36 experienced
a more pronounced upfield shift (−1.5 ppm) in 17e than in 17c
(−0.5 ppm) relative to hemicalide, further discrimination was
1
3
Comparison of the C NMR spectra of model compounds
1
7c, 17d, and 17e with those of hemicalide turned out to be
7
particularly informative (Figure 2). For selected representative
atoms leading to distinguishable signals, the best agreement
with hemicalide was obtained with compound 17c (|Δδ| ≤ 0.5
ppm) whereas significant deviations (|Δδ| > 4 ppm) were
observed for 17d (epimer at C42) at C43 and the methyl group
at C42 [Me(42)]. It is worth noting that the chemical shifts of
C37, C36 and the methyl group at C36 [Me(36)] are similar in
C
DOI: 10.1021/acs.orglett.5b00955
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
achieved by comparison of the H NMR spectra (Figure 3).
Slight differences in chemical shifts (Δδ) were observed
between hemicalide and model compounds 17c, 17d, and
Letter
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2
(
17e. The best agreement was again observed for model
compound 17c, whereas the epimer at C36 17e led to a
difference of 0.12 ppm for H37. Additionally, inspection of the
signal corresponding to H37 was particularly meaningful. The
splitting pattern observed in hemicalide (ddd, J = 11.0, 7.7, 3.5
Hz) is almost identical with that in 17c (ddd, J = 11.0, 7.5, 3.9
Hz), is comparable to that in 17d (ddd, J = 10.0, 7.5, 4.4 Hz),
but is significantly different in the case of 17e (dt, J = 11.1, 4.3
Hz), as a consequence of the conformational change induced
by inversion of C36 in the latter compound. Thus, the relative
configuration of the C36−C42 subunit of hemicalide appears to
be the same as that in model compound 17c.
(
́
(
(
(
(
Massiot, G.; Specklin, S.; Meyer, C.; Cossy, J.; Lannou, M.-I.; Ardisson,
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(
(
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5
(
́
B.; Hennequin, L.
(
(
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(
3
Figure 3. Δδ (ppm) between diastereomeric model compounds 17c,
1
1
7d, 17e and hemicalide in H NMR (CD OD).
3
(
3
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In summary, comparison of the NMR data of five
6
(
4
(
diastereomeric model compounds for the C32−C46 segment
of hemicalide has allowed the assignment of the relative
configuration of the C36−C42 δ-lactone subunit. These
synthetic efforts also indicated the possibility to construct the
C34−C35 olefin by a Julia−Kocienski olefination which will be
exploited in our ongoing convergent total synthesis of this
antitumor marine natural product and analogues thereof.
1
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(
15) The diastereoselectivity was improved (11/11′ = 91:9) when
ASSOCIATED CONTENT
Supporting Information
the 1,4-addition was achieved under double stereodifferentiating
conditions with (R)-BINAP as a chiral ligand (matched manifold) at
the expense of a lower yield (51%).
■
*
S
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) Davis, F. A.; Haque, M. S.; Ulatowski, T. G.; Towson, J. C. J.
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AUTHOR INFORMATION
Corresponding Authors
(18) De Gussem, E.; Herrebout, W.; Specklin, S.; Meyer, C.; Cossy,
■
*
*
J.; Bultinck, P. Chem.Eur. J. 2014, 20, 17385−17394.
(
19) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
́
E-mail: christophe.meyer@espci.fr.
E-mail: janine.cossy@espci.fr.
Synlett 1998, 26−28. (b) Aïssa, C. Eur. J. Org. Chem. 2009, 1831−
1844.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
S.S. and G.S. thank the CNRS for a postdoctoral fellowship.
Financial support from the ANR is gratefully acknowledged
■
(AMICAL project, ANR-BLAN-2013).
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DOI: 10.1021/acs.orglett.5b00955
Org. Lett. XXXX, XXX, XXX−XXX