A Synthesis of (±)-Aplydactone

Article abstract of DOI:10.1002/anie.201604102

Aplydactone is an unusual brominated sesquiterpenoid isolated from the sea hare Aplysia dactylomela. Its highly strained skeleton contains two four- and three six-membered rings and features three adjacent quaternary carbon atoms. Although it is most likely of photochemical origin, attempts to generate it from a chamigrane precursor have failed thus far. In this work, we present a total synthesis of aplydactone that relies on two photochemical key steps that are not biomimetic but highly effective in establishing the two cyclobutane rings. Our synthesis also features an unusual Barbier-type cyclization and culminates in new radical conditions to install the sterically hindered secondary bromide of the natural product.

Full text of DOI:10.1002/anie.201604102

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International Edition: DOI: 10.1002/anie.201604102
German Edition: DOI: 10.1002/ange.201604102
Natural Product Synthesis
A Synthesis of (ꢀ)-Aplydactone
Robin Meier and Dirk Trauner*
Dedicated to Professor Samuel J. Danishefsky on the occasion of his 80th birthday
Abstract: Aplydactone is an unusual brominated sesquiterpe-
noid isolated from the sea hare Aplysia dactylomela. Its highly
strained skeleton contains two four- and three six-membered
rings and features three adjacent quaternary carbon atoms.
Although it is most likely of photochemical origin, attempts to
generate it from a chamigrane precursor have failed thus far. In
this work, we present a total synthesis of aplydactone that relies
on two photochemical key steps that are not biomimetic but
highly effective in establishing the two cyclobutane rings. Our
synthesis also features an unusual Barbier-type cyclization and
culminates in new radical conditions to install the sterically
hindered secondary bromide of the natural product.
fore, it is reasonable to assume that the cyclobutane rings in
1 are formed from 2 by intramolecular photochemical [2+2]
[
5]
cycloaddition. Nevertheless, Stonik et al. reported that 2
could not be converted into 1 under “long-term UV
[
3]
irradiation”. Although this result is worthy of revisiting
using modern theoretical and photochemical methods, we
decided to explore alternative approaches to synthesize 1.
From a synthetic point of view, the polycyclic structure of
1 provides a considerable challenge owing to the high ring
strain and steric congestion of the unique tetracy-
1
,6 3,11
clo[4.4.2.0 .0 ]dodecane skeleton. This framework features
[
6]
an unprecedented [2]-ladderane moiety, which is connected
to a cis-decalin system comprising four quaternary centers
and a secondary neopentyl bromide. As a result of this
bridged core structure, the bond lengths and angles within the
four-membered rings are highly distorted from the usual
values of puckered cyclobutanes. Indeed, aplydactone (1)
readily undergoes a Wagner–Meerwein rearrangement under
P
hotochemical steps are rare in biosynthesis but can give
[
1]
rise to natural products with unusual architectures. They
seem to be especially relevant in organisms that live in
shallow seawater and at latitudes where solar irradiation is
[2]
comparatively intense.
[
3]
In 2001, Stonik and co-workers reported the isolation of
acidic conditions to relieve ring strain.
aplydactone (1), an intriguing cyclobutane-containing natural
To the best of our knowledge, just one synthetic study
towards 1 has been reported despite its intriguing structure.
Herein, we disclose the first total synthesis of aplydactone (1),
which hinges on photochemical transformations.
[3]
[7]
product, from Aplysia dactylomela (Figure 1). This sea hare
also produces dactylone (2) and the brominated chamigranes
[
4]
3
and 4. The biological specimens were collected at a water
depth of 3–5 m at the northern coast of Madagascar. There-
A survey of the literature suggested that either a [2+2]
[6,8]
cycloaddition of a transient cyclobutadiene or a contraction
[6,8d,9]
of a bicyclo[3.2.0]heptane ring system
suitable for the establishment of the central bicyclo-
2.2.0]hexane moiety of aplydactone (1). As cyclobutadiene
would be most
[
cycloaddition proved to be non-viable, we based our retro-
synthetic analysis on a photochemical [2+2] cycloaddition
and a ring contraction (Scheme 1). Late-stage bromination
and disconnection of one of the six-membered rings would
suggest 5 as a suitable intermediate, which could be traced
back to 6 by a Wolff ring contraction and methylation.
Furthermore, we rationalized that intermediate 6 could be
prepared in one step through an intramolecular [2+2] photo-
cycloaddition from cyclopentenone 7, which can be derived
from known ester 8.
Figure 1. Aplydactone (1) and the brominated chamigranes 2–4, iso-
lated from the sea hare Aplysia dactylomela.
Our actual synthesis began with the preparation of alkyl
bromide 10 starting from known ester 8, which was prepared
on decagram scale by a Johnson–Claisen rearrangement
[
10]
[10b]
(
Scheme 2). A reaction sequence involving ozonolysis,
[*] R. Meier, Prof. Dr. D. Trauner
[11]
allylation with subsequent lactonization, a second ozonol-
Department of Chemistry
Ludwig-Maximilians-Universitꢀt Mꢁnchen
ysis with full reduction, and protection afforded lactone 9.
[
12]
Methenylation,
reduction, and double benzylation of
81377 Munich (Germany)
lactone 9 were followed by selective deprotection of the
E-mail: dirk.trauner@lmu.de
[13]
SEM group and bromination to obtain 10. This opening
sequence was scalable and provided bromide 10 from ester 8
in 43% overall yield on multigram scale. For the installation
Supporting information and the ORCID identification numbers for
the authors of this article can be found under http://dx.doi.org/10.
1002/anie.201604102.
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To establish the ladderane motif of aplydactone (1), the
cyclopentanone ring of 6 had to be contracted. To our
surprise, the formation of a-diazo ketone 13 turned out to be
more challenging than expected. Activation of 6 through
[
16]
[17]
formylation or trifluoroacetoxylation followed by diazo
[
18]
transfer as well as direct-transfer conditions suffered from
low yield. However, 13 could be prepared by treatment of
[
9a,19]
enaminone 12 with pABSA.
The subsequent photo-
proceeded smoothly and
[
20]
chemical Wolff rearrangement
provided ladderane 14 in good yield as a 3:1 diastereomeric
mixture (major diastereomer shown). Following deprotona-
tion, methylation occurred from the less hindered face of the
bicyclo[2.2.0]hexane scaffold generating ester 5, which fea-
tures all requisite quaternary stereocenters, in very good
yield. The structure of 5 was established by NOESY experi-
ments and was ultimately confirmed by X-ray structure
analysis of diol 15, which was obtained by double debenzy-
lation.
Scheme 1. Retrosynthetic analysis of aplydactone (1).
The next phase of our synthesis required the closure of the
six-membered ring to obtain the full carbon skeleton of 1.
Whereas selective functionalization of the primary neopentyl
alcohol was not feasible, we were able to selectively deprotect
the secondary alcohol of 5 under reductive conditions
(Scheme 3). Reprotection as a silyl ether and deprotection
of the primary alcohol followed by conversion of the ester
into the Weinreb amide gave 16. Iodination of 16 under
of the cyclopentenone moiety, we used a method introduced
[
14]
by Yoshida and Saito. Coupling of sulfone 11 with bromide
0 followed by acid-induced deprotection and elimination
1
gave precursor 7 in excellent yield. With gram quantities of 7
in hand, we turned our attention to the photochemical [2+2]
cycloaddition, which needed to build up two quaternary
stereocenters next to a sterically hindered gem-dimethyl
[
5b,15]
[21]
moiety.
After some optimization, key intermediate 6
Garegg–Samuelsson conditions produced the highly sensi-
[22]
could be obtained in decent yield and very good diastereo-
selectivity upon irradiation of 7 with UV light. The relative
configuration of the complex ring system was established by
NOESY experiments.
tive iodide 17, which readily rearranged to cyclopentene 18.
Conducting the reaction and the quenching at low temper-
ature suppressed the ring expansion and provided the desired
iodide 17 as the major reaction product. Treatment of iodide
Scheme 2. Synthesis of key intermediate 5. a) O , CH Cl /MeOH, ꢁ788C; then PPh , ꢁ788C!RT, 95%; b) Zn, allyl bromide, THF, 08C!RT,
3
2
2
3
7
8%; c) O , CH Cl /MeOH, ꢁ788C; then PPh , ꢁ788C!RT; then NaBH , 08C!RT; d) SEMCl, DIPEA, CH Cl , 08C!RT, 80% over 2 steps;
3
2
2
3
4
2
2
+ ꢁ
e) LHMDS, CH NMe I , THF, ꢁ788C!RT; then MeI, MeOH, 08C!RT; then DBU, NaHCO , CH Cl /H O, 08C!RT, 92%; f) DIBAL-H, THF,
2
2
3
2
2
2
0
9
8C!RT, 94%; g) NaH, BnBr, TBAI, THF, 08C!508C, 90%; h) nBuSH, MgBr ·OEt , K CO , Et O, RT, quant.; i) PPh , NBS, CH Cl , 08C!RT,
2
2
2
3
2
3
2
2
4%; j) 11, LDA, THF, ꢁ788C; then 10, ꢁ788C!RT; k) HCl, THF, 608C, 93% over 2 steps; l) medium-pressure Hg lamp (150 W), pyrex filter,
EtOAc, ꢁ788C, 55% (13:1 d.r.); m) MeOCH(NMe ) , THF, N stream (open flask), 608C; then pABSA, dioxane, 708C, 61%; n) NEt , Rayonet
2
2
2
3
lamp (300 nm), MeOH, RT, 77% (3:1 d.r.); o) LDA, THF, ꢁ788C; then MeI, ꢁ788C!ꢁ508C, 86% (20:1 d.r.); p) Pd/C, H (1 atm), MeOH, RT,
2
6
6%. Bn=benzyl, DIBAL-H=diisobutylaluminum hydride, DIPEA=diisopropylethylamine, LDA=lithium diisopropylamide, LHMDS=lithium
hexamethyldisilazide, NBS=N-bromosuccinimide, pABSA=4-acetamidobenzenesulfonyl azide, SEMCl=[2-(trimethylsilyl)ethoxy]methyl chloride,
[30]
TBAI=tetra-n-butylammonium iodide, Ts=para-toluenesulfonyl.
2
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Scheme 3. Completion of the synthesis of aplydactone (1). a) Pd/C, H (1 atm), EtOH, RT; b) TIPSOTf, 2,6-lutidine, CH Cl , 08C!RT, 83% over
2
2
2
2
ꢁ
steps; c) Pd(OH) , H (1 atm), MeOH, RT, 97%; d) LHMDS, Me(OMe)NH Cl, THF, ꢁ788C!08C, 87%; e) PPh , I , imidazole, CH Cl ,
2
2
2
3
2
2
2
208C!ꢁ158C; f) tBuLi (reverse addition), pentane/Et O, ꢁ1158C!ꢁ608C, 42% over 2 steps; g) TBAF, THF, 08C!RT, 91%; h) 22, DMAP,
2
THF, 608C, 91%; i) 24 (4 equiv, syringe pump), 25 (5 equiv), benzene, 608C, 58% (1.6:1 d.r.). DMAP=4-(dimethylamino)pyridine, TBAF=tetra-n-
[
30]
butylammonium fluoride, TIPSOTf=triisopropylsilyl trifluoromethanesulfonate.
1
7 with 2.2 equiv tBuLi at ꢁ1158C in an ether/pentane solvent
atom from 25 to afford aplydactone (1) and its C8 epimer 27
in 36% and 22% yield, respectively. The applied combination
of radical initiator and bromine source was essential for the
success of this transformation. Di-tert-butyl hyponitrite (24)
enabled low-temperature initiation, thereby preventing com-
petitive thermal elimination of the thiocarbonylimidazole.
Furthermore, a-bromo acid 25 showed better reactivity than
bromotrichloromethane and was more easily removed from
the reaction mixture than a-bromo esters and malonates. The
two epimers 1 and 27 were separable by standard flash
column chromatography, and the analytical data of synthetic
1 were in full accordance with those reported for the isolated
natural product. Incidentally, 8-epi-aplydactone (27) may
emerge as a natural product arising from the photocycload-
dition of 10-epi-dactylone (4), which was isolated together
with dactylone (2) and aplydactone (1) from Aplysia dacty-
lomela.
In summary, we have achieved the first total synthesis of
the unusual brominated sesquiterpenoid aplydactone (1) in
racemic form. Our approach relies on two non-biomimetic
photoreactions to construct the [2]-ladderane scaffold. An
initial diastereoselective [2+2] cycloaddition generated the
three adjacent quaternary centers present in the natural
product. A photochemical Wolff rearrangement followed by
late-stage Barbier-type ring closure provided the core struc-
ture of 1. New reaction conditions were developed for the
radical conversion of a sterically hindered thiocarbonylimi-
dazole into an alkyl bromide to complete the synthesis.
Further investigations on the substrate scope of this reaction
and the biosynthesis of 1 are underway.
mixture afforded the desired ketone 20 in 42% overall yield
from 16. This unusual ring closure warrants further analysis.
Under the chosen conditions, first organolithium species 19
[
23]
[24]
should form via an ionic ate complex,
thus preventing
[
25]
a radical ring opening or expansion. Subsequently, 19 must
undergo a substantial conformational rearrangement (19!
1
9’) to bring the nucleophilic site into close proximity to the
electrophilic Weinreb amide. This rearrangement entails an
inversion of the cyclohexane ring that brings the silyl-
protected alcohol into an axial position. The resulting
conformation is clearly visible in the crystal structure of
product 20, which already possesses the full carbon skeleton
of aplydactone (1). Subsequent silyl deprotection with TBAF
afforded alcohol 21.
Unsurprisingly, attempts to convert activated derivatives
of the secondary neopentyl alcohol into the desired bromide
by nucleophilic displacement were unsuccessful owing to
[
26]
steric hindrance. This prompted us to seek radical bromi-
nation conditions as an alternative method for the final CꢁBr
bond formation. The conversion of alcohols and their
derivatives into alkyl halides under radical conditions has
been rarely explored, and the known methods failed in our
[27]
hands. Therefore, we decided to develop new conditions for
this transformation based on the work of Zard et al. on the
conversion of S-alkyl-O-ethyl xanthates into alkyl bro-
[
28]
mides.
To this end, alcohol 21 was converted into the
corresponding imidazole 23. Slow addition of di-tert-butyl
hyponitrite (24) to a solution of 23 and a-bromo acid 25 led
to the formation of radical 26, which abstracted a bromine
[29]
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[
[
We thank the Center for Integrated Protein Science Munich
(
CIPSM) for financial support. We would like to acknowledge
169 – 182.
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Communications
Chemie
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[30] CCDC 1475334 (15) and 1475333 (20) contain the supplemen-
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[
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Received: April 27, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Natural Product Synthesis
R. Meier, D. Trauner*
&&&& — &&&&
A Synthesis of (ꢀ)-Aplydactone
The unusual sesquiterpenoid aplydactone
was obtained by total synthesis. The core
skeleton was constructed by two non-
biomimetic photochemical reactions,
a diastereoselective [2+2] cycloaddition,
a photochemical Wolff rearrangement,
and a Barbier reaction. New radical con-
ditions were developed for installing the
sterically hindered secondary bromide.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!