Formal enantioselective synthesis of aplykurodinone-1

Article abstract of DOI:10.1002/anie.201301465

Step economy and simplicity were combined in the asymmetric formal synthesis of aplykurodinone-1 (see scheme; TBS=tert-butyldimethylsilyl). The key features of the strategy involve a one-pot aerobic and directed oxidation/deoxygenation and a late-stage co

Full text of DOI:10.1002/anie.201301465

Angewandte
Chemie
Communications
Natural Products
P. A. Peixoto, A. Jean, J. Maddaluno,
M. De Paolis*
&&&& — &&&&
Formal Enantioselective Synthesis of
Aplykurodinone-1
Step economy and simplicity were com-
bined in the asymmetric formal synthesis
of aplykurodinone-1 (see scheme; TBS=
tert-butyldimethylsilyl). The key features
of the strategy involve a one-pot aerobic
and directed oxidation/deoxygenation
and a late-stage controlled epimerization
to form the chiral architecture of the
molecule.
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DOI: 10.1002/anie.201301465
Natural Products
Formal Enantioselective Synthesis of Aplykurodinone-1**
Philippe A. Peixoto, Alexandre Jean, Jacques Maddaluno, and Michaꢀl De Paolis*
Dedicated to Professor Kozo Shishido
Aplykurodinone-1 (1) is a degraded sterol that can be isolated
from the skin of Syphonota geographica, a mollusc that
belongs to the Aplysiidae family (Scheme 1).[1] While the
centers.[8] Herein, we report the successful implementation of
this strategy, resulting in the concise formal enantioselective
synthesis of 1.
The structure of 1 inspired a synthetic approach in which
the formation of the quaternary carbon center C7 is pivotal to
the stereoselective assembly of the complete skeleton
(Scheme 2). In accordance with this plan, we envisaged the
Scheme 1. Molecules containing a hydrindane framework.
biological profile of this molecule remains unknown to date,
the closely related aplykurodinone-B (2) exhibits mild
cytotoxic activities.[2] Noteworthy, the structure of 1 features
six contiguous stereocenters, including a stereogenic quater-
nary center, embedded in an intriguing hydroindenone
system. As a typical feature of steroids, aplykurodinones
contain a lipophilic side chain with the stereocenter at C13
connected to the core. On the other hand, this class of
molecules features a cis hydrindane moiety (C7–C8 config-
uration), a structural framework that is also found in
pavidolide B (3).[3]
Scheme 2. Synthetic plan toward (+)-1. Bz=Benzoyl.
preparation of 7 by Michael coupling of 4 and 5, followed by
the enantioselective Robinson annulation of adduct 6. Next,
oxidation of 7 at C9 followed by the formal deoxygenation at
C11 was planned in order to access 8. A chemoselective
reduction of the olefin would lead to the stereocenters at C8
and C3 in 9. Our assumptions were that the cis relationship at
C8–C7 could be thermodynamically favored, while the trans
relationship at C8–C3 could be changed by epimerization.
Then, chemo- and diastereoselective reduction of 9 followed
by oxidative lactonization would lead to the known tricyclic
system 10. Overall, the stereocenter at C7 of 7 would control
the formation of the three other stereogenic centers.
To evaluate this strategy, rac-7 was produced on a multi-
gram scale from readily available 4 and 5.[9] In order to
perform the formal deoxygenation of 7, the reduction of the
ketone moiety at C11 was followed by the mesylation of the
resulting hydroxy group to facilitate the elimination step
(Scheme 3). Regarding the oxidation of C9, we anticipated
that a dienolate formed in the presence of bases such as 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) would steer the regio-
selectivity of the process. As it is compatible with this base,
molecular oxygen was the best oxidant for trapping the
dienolate, both in terms of practicability and regioselectivity.
Pleasingly, a screening of different conditions revealed that
exposure of 11 to DBU (1 equiv) in refluxing toluene under
an oxygen atmosphere allowed the isolation of 8 in 40%
yield.[9] In the absence of oxygen, the starting material was
The continued interest in steroids[4] is highlighted by
a recent total synthesis of rac-1 by Danishefsky and co-
workers, who employed an elegant strategy featuring an ionic
Diels–Alder reaction to form the racemic hyndrindane core.[5]
“Hajos–Parrish-type” ketones[6] are versatile scaffolds for
the formation of complex target molecules, as they are often
available in enantioenriched form.[7] As part of our current
program of natural product synthesis, we were interested in
the development of an oxidative process to expand the
potential of the Hajos–Parrish methodology to the synthesis
of chiral hydrindenediones with quaternary carbon stereo-
[*] Dr. P. A. Peixoto, A. Jean, Dr. J. Maddaluno, Dr. M. De Paolis
CNRS, Laboratoire COBRA, UMR 6014 and FR 3038
Universitꢀ et INSA de Rouen
76821 Mont Saint Aignan (France)
E-mail: michael.depaolis@univ-rouen.fr
Homepage: http://ircof.crihan.fr/
[**] We are grateful to the Rꢀgion Haute-Normandie for generous
support and to Morgan Cormier for valuable technical assistance.
Helpful discussions with Prof. H. Kotsuki (Kochi University, Japan)
are acknowledged. Dedicated to Prof. K. Shishido on the occasion of
the 2013 Award of the Pharmaceutical Society of Japan.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301465.
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Scheme 4. Comparison of epimerization of 14 and 15.
insufficient to shift the base-triggered equilibrium toward 9.
Methods to enhance these interactions could involve the
introduction of a substituent at C11 to exert vicinal repulsion,
as in 15. Provided the two substituents (R and CH3) are in
a cis configuration, the resulting repulsion could enhance the
1,3-diaxial interactions (C7/C3) and efficiently drive the base-
promoted epimerization toward 16. Incidentally, the imple-
mentation of this strategy was an opportunity to graft the side
chain of 1. Hence, the 1,4 addition of the pendant vinyl moiety
18 to 14/9 (3:2) furnished 15/16 (3:2) in 58% yield with facial
selectivity (Scheme 5).[15]
Scheme 3. Reagents and conditions: a) NaBH4, MeOH, À408C; MsCl,
CH2Cl2, RT, 80% over steps; b) DBU (1 equiv), PhMe, 1208C, O2,
120 h, [11] =0.3m, 40%; c) DBU (2 equiv), Cu(OAc)2 (10 mol%),
CH2Cl2, RT, O2, 3 h 30, [11]=0.025m, 52%; d) Zn (2.5 equiv), AcOH,
RT, 79% of 14:9 (3:2). MsCl=methanesulfonyl chloride.
recovered, implying that ketone 12 was formed first, and the
oxidation of C9 was followed by the elimination of the
mesylate.[10] Although the efficiency of the process remained
low, the unprecedented directed and metal-free aerobic
oxidation/deoxygenation was demonstrated.[11]
To improve the efficiency of the process, different
catalysts were screened. Pleasingly, the combination of Cu-
(OAc)2 (0.1 equiv) and DBU (2 equiv) under an atmosphere
of oxygen afforded 8 (52%) after reaction for only a few
hours at room temperature.[12] Again, when the reaction was
performed without oxygen, the starting material was recov-
ered, thus indicating that the formation of ketone 12 is the
first step of this process.[10] While the g-oxidation of g,d-
unsaturated ketones by copper(II)–amine complexes is
known,[13] there is no precedent for similar oxidations with
less acidic a,b-unsaturated ketones. To our knowledge, the
disclosed methodology is therefore the first example of
a directed and aerobic oxidation of hydroindenone in one
pot without preformation of a dienolate using an inexpensive
and ecologically benign catalyst.
With large quantities of 8 at our disposal, we turned our
attention to the chemo- and stereoselective reduction of the
enedione moiety, for which a smooth reductant was needed.
Upon treatment of 8 with zinc dust in acetic acid, the
chemoselective reduction proceeded in 79% yield via enolate
13. Out of four possible isomers, only 14 and 9 were produced
in a 3:2 ratio.[14] Importantly, both products were the result of
a stereoselective protonation of C8 from the convex side of
the bicyclic motif, thus enabling access to functionalized cis-
hydrindane structures directly from Hajos–Parrish-type
ketones in two steps. Unfortunately, numerous attempts to
convert 14 to 9 through epimerization met with failure.
Indeed, 14 remained the major isomer after the treatment of
a mixture of 14 and 9 under various basic or acidic conditions,
while the decomposition of the materials was observed upon
heating.[9]
Scheme 5. Reagents and conditions: a) 17, tBuLi, Et2O, À788C;
b) CuCN, Et2O/THF, À788C, 58%; c) DBU (5 equiv), THF, RT, 94% of
15:16 (1:3); d) NaBH4, CeCl3·7H2O, MeOH, À788C; e) LiOH·H2O,
THF/H2O/MeOH, RT; f) TEMPO, PhI(OAc)2, CH2Cl2, RT, 36% over
three steps. TBS=tert-butyldimethylsilyl, TEMPO=2,2,6,6-tetramethyl-
1-piperidinyloxy.
Gratifyingly, treatment of the mixture 15/16 (3:2) with
DBU shifted the equilibrium significantly toward 16 (15/16,
1:3, 94% yield). Once our epimerization strategy was
validated, we turned our attention to the reduction of the
ketone moiety at C4. Pleasingly, the combination of
CeCl3·H2O and NaBH4 was found to reduce 16 in a chemo-
and stereoselective manner. After removal of the benzoate
group of 19, the stage was set for the oxidative lactonization of
diol 20. Oxidation of the primary hydroxy group and the
lactol moiety by applying the conditions described by Forsyth
and co-workers[16] provided lactone 21. Importantly, 21 was
isolated as a single isomer in 36% overall yield (three steps
from 15/16) with spectroscopic data in agreement with those
reported.[9] From 21, only four steps are required to reach
aplykurodinone-1 (1).
Prompted to revise our initial strategy, we hypothesized
that a structural modification of 14/9 could steer the
epimerization toward the formation of the trans isomer. We
initially assumed that 1,3-diaxial interactions would destabi-
lize 14 (Scheme 4). However, this destabilization proved
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Scheme 6. Reagents and conditions: a) l-Phe (30 mol%), PPTS
(50 mol%), DMSO, 508C, 2 days, 68%, 91% ee. DMSO=dimethyl
sulfoxide, PPTS=pyridinium p-toluenesulfonate.
With a formal stereoselective approach to 1 in hand, the
asymmetric formation of the stereogenic quaternary carbon
center of 7 was undertaken (Scheme 6). In accordance with
our synthetic plan, the annulation of prochiral compound 6
was carried out by applying the conditions described by
Ohshima, Shibasaki, and co-workers.[7q] Hence, 6 was con-
verted to ketone (À)-7 (68% yield, 2 days) with high
enantioselectivity (91% ee) in the presence of l-phenyl-
alanine (l-Phe). As an appealing feature of our strategy,
a simple and commercially available catalyst is employed to
forge the chiral architecture of the aplykurodinone family,
thus allowing the first enantioselective approach to 1.
In summary, an asymmetric and formal synthesis of
aplykurodinone-1 (1) has been devised combining step
economy and simplicity.[17] Overall, 15 steps are required to
attain 21 in 4% yield from commercially available reagents
(22 steps for the previous racemic approach). The key
features of the strategy are 1) the directed and aerobic
oxidation of a Hajos–Parrish-type substrate, 2) a chemo- and
stereoselective reduction of an enedione, and 3) a controlled
epimerization based on vicinal repulsion to enhance existing
1,3-diaxial interactions. We believe that this study opens the
way to new strategies for the asymmetric preparation natural
products containing the hydrindane framework. Investiga-
tions on the scope and limitation of these methodologies and
their extensions to other natural products are ongoing.
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[10] Only 11 and 8 were observed during the reaction, see the
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(OAc)3 in combination with tBuOOH led to 8 in 32% and 38%,
respectively (see the Supporting Information for details).
[13] For pioneering studies on the aerobic g-oxidation of g,d-
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see: a) H. C. Volger, W. Brackman, Recl. Trav. Chim. Pays-Bas
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[14] The relative configuration of 14 and 9 was established by
2D NMR analyses after synthetic transformations (see the
Supporting Information for details).
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according to a slightly modified version of the procedure
reported in Ref. [5].
Received: February 19, 2013
Revised: March 27, 2013
Published online: && &&, &&&&
Keywords: epimerization · oxidation · oxygen ·
.
quaternary stereocenters · total synthesis
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