Total Synthesis and Structure Revision of Halioxepine

Article abstract of DOI:10.1002/chem.202004847

The first total synthesis of halioxepine is accomplished using a 1,4-addition for constructing the quaternary center at C10 and a halo etherification for the generation of the tertiary ether at C7. The correct structure of halioxepine was determined by assembling different enantiomeric building blocks and by changing the relative configuration between C10 and C15.

Full text of DOI:10.1002/chem.202004847

Accepted Article
Accepted Article
Title: Total Synthesis and Structure Revision of Halioxepine
Authors: Markus Kalesse and Caroline Poock
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To be cited as: Chem. Eur. J. 10.1002/chem.202004847
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01/2020

10.1002/chem.202004847
Chemistry - A European Journal
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Total Synthesis and Structure Revision of Halioxepine
Caroline Poock,[a] and Markus Kalesse*[a, b, c]
[a]
C. Poock, Prof. Dr. M. Kalesse
Institute for Organic Chemistry
Gottfried Wilhelm Leibniz Universität Hannover
Schneiderberg 1B, 30167 Hannover (Germany)
markus.kalesse@oci.uni-hannover.de
Prof. Dr. M. Kalesse
Centre of Biomolecular Drug Research (BMWZ)
Gottfried Wilhelm Leibniz Universität Hannover
Schneiderberg 38, 30167 Hannover (Germany)
Prof. Dr. M. Kalesse
[b]
[c]
Helmholtz Centre for Infection Research (HZI)
Inhoffenstrasse 7, 38124 Braunschweig (Germany)
Supporting information for this article is given via a link at the end of the document.
Abstract: The first total synthesis of halioxepine is accomplished
using a 1,4-addition for constructing the quaternary center at C10 and
a halo etherification for generation of the tertiary ether at C7. The
correct structure of halioxepine was determined by assembling
different enantiomeric building blocks and by changing the relative
configuration between C10 and C15.
In the course of our ongoing program of accessing natural
products through total synthesis,[4] we started the synthesis of
halioxepine with the aim of confirming its proposed structure and
to access this family of natural products for further biological
investigation. Retrosynthetically, the stereoselective addition of
the hydroquinone moiety should take place in the endgame of the
synthesis and take advantage of the stereochemical controlling
properties of the alpha chiral center. The tetrahydrooxepine ring
should be constructed via an iodine-mediated ether formation
which leads back to fragments 4 and 5. Compound 5 in turn,
which should allow access to both, the syn- and anti-configured
tetrahydrooxepine, can be assembled from Weinreb amide 6 and
iodide 7. Both fragments can be obtained rapidly from simple
starting materials 8, 9 and 10.
Halioxepine (1) is a new meroditerpene isolated from the
indonesian sponge Haliclona sp. by Tanaka and co-workers in
2011.[1] It shows moderate cytotoxic and antioxidant activity and
the structure was determined to comprise a hydroquinone, a
tetrahydrooxepine and
a cyclohexene moiety. The major
challenge in the structure elucidation was the fact that the
hydroquinone-tetrahydrooxepine and the cyclohexene spin
systems were difficult to relate to each other. Consequently, there
was some degree of uncertainty about the relative configuration
of both regions with respect to each other so that two possible
relative configurations were proposed: 1S*,2S*,7R*,10S*,15S* or
1S*,2S*,7R*,10R*,15R*. In 2018, the group of Rodriguez[2]
reported two additional halioxepins, namely halioxepine B (2) and
C (3) (Figure 1). In addition to NMR-experiments, they used DFT
calculations to determine the stereochemical relationship of the
two stereoclusters separated by two methylene units (C8, C9).
Their analysis suggested 1S*,2S*,7R*,10R*,15R* to be the
relative configuration of halioxepine (1) (Figure 1). In addition,
they confirmed for halioxepine C (1) the absolute configuration at
position C1 with the aid of the Mosher[3] ester method.
Scheme 1. Retrosynthetic analysis of halioxepine.
The synthesis of fragment 6 commenced with an enantioselective
1,4-addition[5] followed by acylation and subsequent methylation
as reported by Herzon.[6] This sequence already generated the
two chiral centers of this fragment in very high selectivities and
61% yield over three steps. Addition of methyl magnesium
bromide and subsequent elimination using pTsOH established
Figure 1. Proposed structures of the halioxepines. For halioxepine (1) and
halioxepine B (2) only the relative configuration was proposed.
1
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the trisubstituted double bond between C11 and C12. The ester olefination and removal of the TES protecting group provided the
was reduced to its corresponding alcohol using LiAlH4 and finally, starting material for the tetrahydrooxepine cyclization. This was
[15]
IBX oxidation followed by HWE-olefination introduced the two
carbons which will separate the two chiral clusters (Scheme 2).
accomplished with I(2,4,6-collidine)2PF6
to provide
a
non-separable mixture of the syn- and anti-isomers
(syn:anti = 1.2:1). Removal of the terminal iodide was achieved
with “super hydride” (LiEt3BH) and the primary TBS group was
removed with TBAF, which made separation of both
diastereomers possible. At this stage nOe-experiments could
unambiguously identify the syn-tetrahydrooxepine which was part
of the proposed structure. For the endgame of the synthesis, an
aldol-type addition of TBS hydroquinone 23 to aldehyde 24 was
envisioned.[16] For this, alcohol syn-22 was oxidized and treated
with a magnesium salt derived from deprotonation of mono-
protected hydroquinone 23.[17] The addition proceeded with high
selectivity for the expected syn-diol which is proposed to proceed
via a chelation-controlled transition state. Removal of the
remaining TBS group with the aid of TBAF led to target molecule
1 (Scheme 4). Unfortunately, the NMR spectra significantly
deviated from the ones of the authentic material (see Figure 3 and
SI).
Scheme 2. Synthesis of western fragment 6 (o2s = over two steps).
The synthesis of eastern fragment 7 started with aldehyde 9[9]
which was converted to its corresponding Z-vinyl iodide 16 using
a Zhao–Stork olefination. Subsequent halide-metal exchange
generated the nucleophile which was added to aldehyde 10[10] to
generate a racemic mixture. Allylic alcohol 17 was oxidized using
IBX and selectively reduced with (+)-DIPCl[3] to obtain the
required Z-configured allylic alcohol in good yields and
selectivities. TES protection and transformation of the PMB ether
to its corresponding iodide completed the synthesis of eastern
fragment 7 (Scheme 3).
Scheme 3. Synthesis of eastern fragment 7 (o2s = over two steps).
Scheme 4. Coupling of both hemispheres and endgame of the synthesis of 1
(o2s = over two steps).
The fragment coupling started with the halide-metal exchange
of iodide 7 and addition to Weinreb amide 6. The desired ,-
unsaturated ketone 19 was formed in good yield along with small
amounts of undesired ketone 25. Optimization of the reaction
conditions partially led to suppression of byproduct formation, but
only with diminishing yield of 19. As the byproduct could be
removed during further steps, the conditions shown were applied.
For reduction of the ,-unsaturated ketone, different conditions
were investigated (e.g. Strykers reagent,[11] Raney-Ni,[12]
Since the isolation papers covered in detail the relative
orientation of both stereoclusters to each other, we believed that
the differences in the NMR spectra were the result of the opposite
relative orientation of both stereoclusters. As the configuration of
the eastern hemisphere depends on the configuration at C2 we
reoxidized intermediate (S)-20 and reduced[3] the ,-unsaturated
ketone with (−)-DIPCl. With the so obtained inversion at C2 the
steps carried out for the former isomer were repeated. Fortunately,
the cyclization proceeds with higher selectivities (syn:anti = 2.3:1)
DiBAlH+HMPA+CuI+MeLi[13]
Co(acac)2 and DiBAlH gave full conversion.[14] Subsequent Wittig
) but only the combination of
2
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and the aldol-type addition of hydroquinone gave again good
yields and selectivities for diol 28 (Scheme 5). TBAF-mediated
removal of the TBS group provided iso-halioxepine 29. However,
even the NMR spectra of this isomer did not match the ones of
the authentic material. So the problems in the configurational
assignment were obviously not solved by changing the
stereoclusters.
1,4-addition was performed generating a 1.3:1 isomeric mixture
of bis-methylated compound 31.[5] However, the isomeric mixture
was inconsequential as subsequent enamine formation and
1,4-addition led to stereoselective formation of the quaternary
center.[19] The ester and the keto-carbonyl groups were reduced
and the primary alcohol was TBDPS-protected.[20] Then, the
secondary alcohol was re-oxidized and methyl addition followed
by elimination generated the double bond in an endo- and exo-
mixture. This was isomerized to the desired endo-olefin with
rhodium(III)-chloride,[21] which also removed the silicon protecting
group (Scheme 6).
Scheme 5. Synthesis of iso-halioxepine 29 (o2s = over two steps).
A closer look into NMR spectra of compounds with fragments
similar to the cyclohexene-fragment revealed, that there is a
significant difference in 1H- and 13C-shifts for different relative
orientations of the methyl groups corresponding to C20 and C18
(compare Figure 2, top).[18] Comparing those shifts to the ones of
authentic halioxepine and the synthesized isomers 1 and 29
(Figure 2, bottom), we suggest a syn-relationship of Me-20 and
Me-18 for authentic halioxepine. Consequently, our next target
was the proposed structure but with an inverted configuration at
the quaternary carbon at C10.
Scheme 6. Synthesis of altered western fragment 34, coupling with eastern
fragment 7 and synthesis of iso-halioxepine 41 (o2s = over two steps, o3s =
over three steps).
Figure 2. Comparison of 1H- and 13C-NMR shifts for cyclohexene-parts similar
to those in halioxepine.
Oxidation of the so generated primary alcohol set the stage
for coupling with eastern segment 7. As a byproduct alcohol 42
was formed, but it could be removed during further steps. Alcohol
35 was then oxidized and transformed to its corresponding exo-
methylene derivative. At this stage, PPTS removed selectively the
The synthesis of the new western hemisphere (C7-C15)
required
a slightly altered route. Again, an asymmetric
3
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TES group in the presence of the TBS group. As in the synthesis
of the previous isomers, treatment with I(2,4,6-collidine)2PF6
induced the tetrahydrooxepine formation in favor of the desired
isomer with a 1.6:1-ratio. After TBAF deprotection, both isomers
could be separated and alcohol 39 was oxidized and transformed
in the above mentioned aldol-type addition of mono-protected
hydroquinone 23. Finally, TBAF-mediated removal of the
remaining TBS group provided compound 41 which again did not
exhibit matching NMR spectra. However, analyzing the NMR
signals derived from the methyl groups at C17, C18 and C20 we
could clearly see that these are in better agreement with the ones
of the authentic material (Figure 3).
analysis looks quite conclusive, however, things are not so
obvious if one does not have isomers for comparison.
Nevertheless, it could still be that we had to switch the relative
configuration of the two stereoclusters in relation to each other.
This we could achieve by oxidizing alcohol (S)-37 and reducing
the so obtained ketone with (−)-DIPCl. The desired allylic alcohol
(R)-37[3] was obtained in very good yield and selectivity and the
subsequent tetrahydrooxepine cyclization succeeded in 88%
yield. Removal of the iodide was achieved by treatment with
LiEt3BH (85%). The final steps, namely the removal of the TBS
group, oxidation followed by aldol-type addition (configuration at
C1 was confirmed via Mosher ester analysis;[3] see SI) and final
deprotection provided isomer 46 which NMR spectra were in very
good accordance with the ones of the authentic material (see
Figure 3 and SI). However, the optical rotation value had the
opposite sign as reported in the isolation papers. We therefore
had synthesized the enantiomer of halioxepine.
Figure 3. Comparison of the 1H-NMR shifts of the methyl groups of different
halioxepine isomers to the one from natural halioxepine.
In summary, we were able to complete the first total synthesis
of halioxepine and by doing so to revise its configuration at C10.
The synthesis takes advantage of an asymmetric 1,4-addition and
stereoselective Michael addition to control the configuration at the
quaternary center and the one at C15. The stereocenters of the
eastern stereocluster are consecutively derived from
a
stereoselective DIPCl reduction of a prochiral ketone. The
iodonium-induced ether cyclization occurred in modest
selectivities of 1.6:1. However, both isomers could be separated
easily on the subsequent stage. The final aldol-type addition of
the mono-protected hydroquinone occurred with high selectivities
(>19:1). In the light of these findings, it seems very likely that the
configuration at C10 of halioxepine C also needs some additional
examination. Due to the different carbon skeleton in halioxepine
B, the situation is not as clear cut as for halioxepine and
halioxepine C. Our ongoing investigation in this direction will be
reported in due course.
Acknowledgements
We are very grateful to Prof. J. Tanaka (University of the Ryukyus)
for providing NMR-Spectra of authentic halioxepine. We also
thank Prof. J. Rodriguez (Universidade da Coruña) for
cooperation with respect to NMR-spectra. We thank Dr. J. Fohrer,
M. Rettstadt and D. Körtje for detailed NMR analysis and A.
Schulz and R. Reichel for mass spectra. In terms of preparation
of the manuscript we thank Alina Eggert, Giada Tedesco,
Alexandru-Adrian Sara and Daniel Lücke.
Scheme 7. Endgame in the synthesis of ent-Halioxepine (46) (o2s = over two
steps).
Keywords: halo etherification • natural product synthesis •
A comparison of the 1H-NMR spectra of the here described
synthetic compounds with the one obtained from the authentic
material is a clear indication of the refined configuration of the
halioxepines. Additionally, even if the stereoclusters are
separated they obviously influence the chemical shifts
significantly. It should be pointed out here that in retrospect the
quarternary stereocenter • structure elucidation • terpenoids
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Entry for the Table of Contents
Assemble and reassign: The first total synthesis of halioxepine is presented, along with a structural revision. Due to two
stereoclusters separated by two methylene groups, there was some uncertainty about the relative configuration for halioxepine.
Mismatched spectroscopic data for both suggested structures caused a new analysis and led to reassignment of the relative
configuration between C10 and C15.
6
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