Total synthesis and stereochemical revision of the chlorinated sesquiterpene (±)-gomerone C

Article abstract of DOI:10.1002/anie.201207203

Red algae from the genus Laurencia (Ceramiales) are the source of over 500 halogenated terpenes, cyclic ethers, and acetogenides, which in some cases have been suggested to serve as chemical defence agents because of their activity against pathogenic marine bacteria and herbivores. In 2008 a Spanish research group reported the isolation and structural elucidation of three novel chlorinated sesquiterpenes, gomerones A-C, from samples of Laurencia majuscula collected at the southern coast of La Gomera, Canary Islands (Scheme 1). The structurally interesting and unprecedented gomerane skeleton in combination with their unexplored biological activity as well as the halogenated nature of these natural products rendered them noteworthy targets for synthesis. Herein, we report a total synthesis of gomerone C (1), which not only represents the first synthesis of a member of this novel class of chlorinated sesquiterpenes, but also resulted in the revision of the relative stereochemistry of gomerone C (1) and hence to a stereochemical reassignment of gomerone B (2).

Full text of DOI:10.1002/anie.201207203

.
Angewandte
Communications
DOI: 10.1002/anie.201207203
Natural Product Synthesis
Total Synthesis and Stereochemical Revision of the Chlorinated
Sesquiterpene (Æ)-Gomerone C**
Nikolas Huwyler and Erick M. Carreira*
Red algae from the genus Laurencia (Ceramiales) are the
source of over 500 halogenated terpenes, cyclic ethers, and
acetogenides, which in some cases have been suggested to
serve as chemical defence agents because of their activity
The synthetic challenges encountered in the gomerones
include the angular, tricyclic carbon skeleton, two contiguous
quaternary centers at C6 and C11, as well as two chloride-
substituted tertiary carbon centers, one of which is positioned
at the bridgehead of a bicyclo[3.2.1]octane. Consideration of
Bredtꢀs rule thus suggests that the bridgehead chloride would
be precluded from being introduced by enolate chemistry
once both rings have been formed. With this limitation in
mind, we became intrigued by the possibility of forging the
bicyclic scaffold by a late-stage Conia-ene reaction involving
an a-chlorinated silyl enol ether and an alkyne. Such a trans-
formation, if successful, would install the required 6-mem-
bered ring and also concomitantly generate an exocyclic
olefin that could be employed as a flexible handle for further
[1,2]
against pathogenic marine bacteria and herbivores. In 2008
a Spanish research group reported the isolation and structural
elucidation of three novel chlorinated sesquiterpenes, gomer-
ones A–C, from samples of Laurencia majuscula collected at
the southern coast of La Gomera, Canary Islands
[
3]
(
Scheme 1). The structurally interesting and unprecedented
[
5]
elaboration toward the natural products (Scheme 2). Struc-
ture 3, the necessary precursor for the ene reaction, could be
further simplified retrosynthetically, as indicated, to arrive at
intermediate 4, which could arise from a [4+2] cycloaddition
reaction.
Scheme 1. A) Proposed structures of gomerones A–C; B) gomerane
skeleton; C) structural revision and reassignment.
Scheme 2. Retrosynthetic analysis of gomerone C.
gomerane skeleton in combination with their unexplored
biological activity as well as the halogenated nature of these
natural products rendered them noteworthy targets for
The synthesis commenced with a Diels–Alder reaction
between silyloxydiene 7 and commercially available 1-acetyl-
1-cyclopentene (6), thereby allowing for the rapid formation
of the fused 5,6-membered ring system and the concomitant
installation of the two adjacent quaternary centers at the very
beginning of the synthetic route (Scheme 3). Despite the
hindered character of the diene and the sometimes limited
reactivity of cyclopentene dieneophiles in cycloaddition
reactions, the reaction was found to proceed well, delivering
[
4]
synthesis. Herein, we report a total synthesis of gomerone C
1), which not only represents the first synthesis of a member
(
of this novel class of chlorinated sesquiterpenes, but also
resulted in the revision of the relative stereochemistry of
gomerone C (1) and hence to a stereochemical reassignment
of gomerone B (2).
[6]
the desired product in 69% yield. The structure and relative
configuration of the Diels–Alder adduct obtained was
confirmed by X-ray crystallography (see the Supporting
Information). Subsequent cleavage of the TBS enol ether
under acidic conditions followed by regioselective mono-
acetalization of the obtained diketone 4 delivered methyl
[
*] N. Huwyler, Prof. Dr. E. M. Carreira
Laboratorium fꢀr Organische Chemie, ETH Zꢀrich, HCI H335
Wolfgang-Pauli Strasse 10, 8093 Zꢀrich (Switzerland)
E-mail: carreira@org.chem.ethz.ch
Homepage: http://www.carreira.ethz.ch
[
**] We are grateful to Dr. B. Schweizer and M. Solar for X-ray
crystallographic analysis, and to Dr. M.-O. Ebert, R. Arnold, R.
Frankenstein, and P. Zumbrunnen for NMR measurements.
[
7]
ketone 9 in 58% overall yield (three steps).
Next, we turned our attention to the introduction of the
but-3-ynyl side chain. Preliminary experiments revealed that
the sterically hindered carbonyl carbon atom of the methyl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207203.
1
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desired but-3-ynyl side chain and efficiently delivered ketone
4 in 28% overall yield from the starting materials.
With a viable route for the synthesis of ketone 14 in hand,
1
the remaining challenge toward the preparation of the key
Conia-ene precursor 3 was the introduction of the proper
oxidation pattern in the northern quadrant of the molecule.
To address this task, ketone 14 was first transformed into the
corresponding enone by means of the Mukaiyama-dehydro-
genation procedure, furnishing the targeted compound in
[
12]
9
4% yield. Subsequent treatment with TBSOTf and 2,6-
lutidine in dichloromethane then selectively delivered silyl-
oxydiene 16. Inspired by a single preliminary report involving
an 1-acetoxy diene, we found that subjection of dienol silane
1
6 to an excess of CrO ·3,5-dimethylpyrazole complex in
3
dichloromethane directly led to the formation of the enedione
[13]
1
7 in a single step (66% overall yield for steps j and k).
The chlorination of enedione 17 at the a-position of the 5-
membered ring ketone turned out to be surprisingly difficult.
Selective formation of the lithium enolate at the sterically less
hindered C2-position of the molecule and subsequent treat-
ment with TsCl preferentially gave the corresponding tosyl
enol ether in 60% yield, instead of the chlorinated product,
which is usually observed under these conditions. Treat-
ment with TfCl, on the other hand, led to complex mixtures of
products. After quite some experimentation with many other
chlorinating agents, we eventually found that silyl enol ether
Scheme 3. Reagents and conditions: a) Me AlCl (20 mol%), toluene/
2
CH Cl (2:1), À158C, 24 h; then 08C, 24 h, 69%; b) F CCO H, CH Cl ,
2
2
3
2
2
2
RT, 2 h, 89%; c) 2-methyl-2-ethyl-1,3-dioxolane, TsOH·H O (25 mol%),
2
ethylene glycol (12 mol%), RT, 45 min, 95%; d) phosphazene base
P tBu (3.0 equiv), F C SO F (1.3 equiv), DMF, À108C to RT, 2 h; then
2
9
4
2
[
14]
RT for 24 h, 92%; e) nBuLi, THF, À788C to RT, 40 min; then BF ·OEt ,
3
2
À788C, 10 min; then DMF (3.3 equiv), 60 min, 78%; f) Pd/C
10 mol%), H (1 atm), EtOAc, RT, 2 h, 84%; g) dimethyl-1-diazo-2-
(
2
oxopropylphosphonate, K CO , MeOH, 2.5 h, 88%; h) nBuLi, Me SiCl,
2
3
3
THF, À788C to RT; then RT, 20 h; then 0.1m aq. HCl, THF, reflux, 4 h,
2%; i) LiN(SiMe ) , THF, À788C; then PhS(=N-tBu)Cl, 2 h, 94%;
1
8, upon exposure to Bu NCl (Mioskowskiꢀs reagent), was
4 3
9
3
2
directly transformed into a-chlorinated silyl enol ether 3,
j) TBSOTf, 2,6-lutidine, CH Cl , 08C, 1.5 h; k) CrO (15 equiv), 3,5-
2
2
3
[15]
without loss of the silyl group. This welcome result renders
dimethylpyrazole (15 equiv), CH Cl , À208C, 20 min, 66% for 2 steps.
2
2
unnecessary steps that would otherwise be required to
regenerate the silyl enol ether (Scheme 4).
Ts =toluene-4-sulfonyl, DMF=N,N-dimethylformamide, TBS=tert-
butyldimethylsilyl.
ketone in 9 was relatively inert towards attack by nucleo-
philes. Consequently, we opted to transform the methyl
ketone into the corresponding terminal acetylene via an
elimination reaction. To this end, two well-established
procedures were attempted in which the ketone is first
converted into its enol phosphate or enol triflate, before it is
treated, in a second step, with amide base to effect elimi-
[
8]
nation. However, after some unsuccessful experimentation
with the above protocols, a novel one-step procedure was
examined that had been reported to allow for the direct
conversion of methyl ketones into simple, terminal alkynes.
Scheme 4. Reagents and conditions: a) KN(SiMe ) (1.3 equiv), TBSCl
3
2
(
2.0 equiv), THF, À788C to RT, 3 h; b) Bu NCl (2.4 equiv), CH Cl ,
4
3
2
2
Treatment of methyl ketone 9 with phosphazene base P tBu
2
À788C to RT, 5 h, 51% for 2 steps; c) (MeCN)[(2-biphenyl)di-tert-
(
(
Schwesingerꢀs base) and nonafluorobutanesulfonyl fluoride
butylphosphine]gold(I) hexafluoroantimonate (0.5 equiv), acetone,
NfF) in dry DMF cleanly afforded terminal alkyne 10 in 92%
4
58C, 6 h, 65%; d) HCl (gas), SnCl (30 equiv), CH Cl , sealed tube,
4
2
2
[
9]
yield in a single step. Lewis acid promoted formylation of
the corresponding lithium acetylide with DMF followed by
the reduction of the intermediate propiolaldehyde with
catalytic Pd/C under an atmosphere of hydrogen then
À788C to RT, 5 h, 67%.
We then turned our attention to the crucial Conia-ene
reaction. After a few preliminary experiments with related
precursors (e.g. 18) and some minor optimization, we were
pleased to observe that treatment of 3 with acetonitrile[(2-
biphenyl)di-tert-butylphospine]gold(I) hexafluoroantimonate
(Echavarrenꢀs catalyst) in dry acetone at 458C effected both
the desired cyclization as well as the concomitant removal of
[
10]
furnished aliphatic aldehyde 12.
Transformation of the
aldehyde into the terminal acetylene 13 could subsequently
be brought about by means of the Ohira–Bestmann proce-
[
11]
dure. Finally, the sequence was completed by a one-pot
reaction, which included the protection of the terminal
acetylene with trimethylsilyl chloride and subsequent cleav-
age of the 1,3-dioxolane by using aqueous HCl. The sequence
described above reliably allowed for the introduction of the
[
16]
the silyl protecting group on the alkyne. It is worth noting
that although haloalkynes have been studied in gold-medi-
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Angewandte
Communications
ated Conia-ene cyclizations by Toste and co-workers, to our
knowledge, chlorinated silyl enol ethers have not been
ical revision of the structure of the natural product and hence
also led to reassignment of the related gomerone B (2). The
synthesis relies on a key, late-stage Conia-ene reaction of
a chlorinated enol silane and an alkyne, which efficiently
provides access to the novel gomerane skeleton with the
attendant bridgehead chloride. The formed bicyclo[3.2.1]-
octane core is set up for the subsequent introduction of the
second tertiary chloride. Additional salient features of the
synthesis include a Diels–Alder reaction, which introduces
two contiguous quaternary centers with concomitant con-
struction of the fused perhydroindene core. Moreover, in the
context of the total synthesis we showcase in a complex
setting the use of Schwesingerꢀs base/NfF for the convenient
one-step conversion of a ketone into an alkyne as well as the
selective oxygenation of a 1-silyloxydiene mediated by
[17,18]
examined.
Tricyclic product 19 was obtained in good
yield, and the stage was set to address the final hydro-
chlorination reaction. The exocyclic olefin in 19 was found to
be unreactive towards addition of hydrogen chloride under
mild conditions (e.g. treatment of 19 with AcCl/EtOH), which
is most likely due to the proximal electron-withdrawing
[19]
functional groups.
We thus had to resort to vigorous
conditions for the installation of the chloride substituent. In
the experiment, saturation of a dichloromethane solution of
substrate 19 at À788C with gaseous hydrogen chloride in the
presence of an excess of SnCl followed by slow warm-up to
4
ambient temperature, brought about the desired transforma-
[
20]
tion.
1
13
The H and C NMR spectra of the product obtained
from the hydrochlorination reaction were in very good
agreement with those assigned to nominal gomerone C.
This, however, was rather puzzling, because it suggested
that the double bond in 19 had undergone selective hydro-
chlorination from the endo-face of the bicyclo[3.2.1]octane
substructure; which molecular modeling indicated is the more
hindered face (Scheme 5). Consistent with our hesitation, no
CrO ·3,5-dimethylpyrazole. Efforts to expand the strategy to
3
the synthesis of the other two members of the family as well as
preliminary biological testing of the obtained gomerone C (1)
are currently ongoing and will be reported in due course.
Received: September 5, 2012
Published online: November 14, 2012
Keywords: conia-ene reaction · gold · natural products ·
.
pericyclic reactions · total synthesis
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2
011, 13, 908 – 911.
[
21]
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