Asymmetric synthesis of a tricyclic benzofuran motif: A privileged core structure in biologically active molecules

Article abstract of DOI:10.1039/c0ob00331j

An efficient synthetic strategy for the asymmetric synthesis of a hexahydrodibenzofuran core structure, with a quaternary stereogenic center, emerges by employing a chiral reduction using Corey's (S)-Me-CBS-oxazaborolidine reagent followed by a Mitsunobu reaction to set the stereochemistry. A Pd-mediated intramolecular Heck reaction concludes the tricyclic core structure. Finally, a Pd/C catalyzed reduction yields the target molecule in 21% overall yield over 6 steps.

Full text of DOI:10.1039/c0ob00331j

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COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Asymmetric synthesis of a tricyclic benzofuran motif: a privileged core
structure in biologically active molecules†
a
a,b
Henrik Sund e´ n and Roger Olsson*
Received 28th June 2010, Accepted 18th August 2010
DOI: 10.1039/c0ob00331j
An efficient synthetic strategy for the asymmetric synthesis of
a hexahydrodibenzofuran core structure, with a quaternary
stereogenic center, emerges by employing a chiral reduction
using Corey’s (S)-Me-CBS-oxazaborolidine reagent followed
by a Mitsunobu reaction to set the stereochemistry. A Pd-
mediated intramolecular Heck reaction concludes the tri-
cyclic core structure. Finally, a Pd/C catalyzed reduction
yields the target molecule in 21% overall yield over 6 steps.
difficult to synthesize on a reasonable scale and have traditionally
been obtained via classical resolution, similar to our original
2,8
strategy. Recently, however, asymmetric strategies toward these
15,16
molecules based on metal catalysis have been reported.
A retrosynthetic analysis of the tricyclic benzofuran ring system
as found in 6 identified the enantiomerically pure allylic alcohol 3
as a key intermediate, potentially obtained by an enantioselective
reduction of a,b-unsaturated ketone 2 (Scheme 1). A subsequent
Mitsunobu reaction between phenol 4 and the allylic alcohol 3
would yield ether 5 by an inversion of the stereochemistry at the
allylic carbon. However, the seemingly trivial Mitsunobu reaction
could be a challenge, due to the potential reaction path via a
stabilized cation which would erode the enantiopurity of the
compound. Nevertheless, these steps would set-up the synthesis
for a final ring-closing reaction generating the furan ring. An
intramolecular Mizoroki–Heck reaction would then be efficient
for the formation of the asymmetric congested quaternary center.
Tricyclic benzofurans incorporating an all-carbon asymmetric
quaternary center are featured in many biologically interesting
molecules and have therefore received considerable attention
1
–6
7–10
from the synthetic community, e.g., morphine, galantamine
and lunarine
11,12
(Fig. 1). These natural products have proven
to be highly potent drugs and are used in several different
11–13
therapies.
Recently, we disclosed a series of selective Estrogen
Receptor b (ERb) agonists based on the tricyclic benzofuran core
structure (Fig. 1). The reported synthesis gave a low yield and the
diastereomers and enantiomers were separated by crystallization
14
and chiral chromatography, respectively. Clearly, to be able to
efficiently establish a structure–activity relationship (SAR) and
to further evaluate these molecules’ biological activity it was
necessary to develop a more efficient enantioselective synthesis.
Compounds bearing these quaternary centers are in general
Scheme 1 Retrosynthetic analysis.
The synthesis of the tricyclic benzofurans starts from the a,b-
unsaturated ketone 7 that undergoes a DABCO-catalyzed iodo-
17,18
Baylis–Hillman reaction
yielding 8 in 82% yield (Scheme 2).
A convenient microwave assisted Pd/C-catalyzed Suzuki reaction
19
transforms iodo-carbonyl 8 into the aryl ketone 9 in 80% yield.
This reaction protocol is practical and fast with reaction times
between 15–20 min. In addition, the extractive work-up can readily
be performed in the microwave vial and gives the pure product
Fig. 1 Bioactive molecules containing the tricyclic benzofuran moiety.
a
Department of Chemistry/Medicinal Chemistry, University of Gothenburg,
SE-41296, Gothenburg, Sweden
b
ACADIA Pharmaceuticals AB, Medeon Science Park, S-20512, Malm o¨ ,
Sweden. E-mail: rolsson@acadia-pharm.com; Fax: +46 40 601 34 01;
Tel: +46 768 87 42 17
†
Electronic supplementary information (ESI) available: Detailed ex-
perimental procedures and compound characterization data. See DOI:
0.1039/c0ob00331j
23
1
Scheme 2 Synthesis of allylic alcohol 10.
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well within one hour. The enone 9 was thereafter subjected to an
enantioselective (S)-CBS catalyzed reduction. In order to obtain
optimal enantioselectivity the a,b-unsaturated ketone 9 was added
◦
with syringe pump to the reaction mixture at 0 C yielding
optically active alcohol 10 in an excellent ee of 98% and 83%
20,21
yield. Alternatively, reduction of 9 using the (R)- enantiomer of
22
the oxazaborolidine catalyst provided ent-10 in a similar yield.
Scheme 4 Mizoroki–Heck reaction on the 7-membered ether 15.
In addition, the reaction was chemoselective, hence no formation
of the corresponding saturated products was detected.
The enantioenriched allylic alcohol 10, was then reacted with 2-
iodophenol 11 under Mitsunobu conditions at room temperature
using diethyl azodicarboxylate (DEAD) and triphenyl phosphine
Conclusions
In summary, we have developed a practical and fast total synthesis
of compounds containing a tricyclic benzofuran core which are
abundant in many biologically active molecules. The six-step
sequence proceeds in 21% overall yield and high enantioselectivity.
The first asymmetric center is assembled in a highly enantio-
and chemo-selective oxaborolidine reduction of a cyclic a,b-
unsaturated ketone. Moreover, the final tricyclic benzofuran core
is constructed in a highly stereoselective intramolecular Mizoroki–
Heck reaction efficiently giving the all-carbon quaternary
center.
24
(
PPh ) (Scheme 3). Disappointingly, the reaction facilitated an
3
erosion of the enantiomeric excess; ether 12 was isolated in 83%
yield and 68% ee. As speculated, the enantio-detrimental outcome
was probably due to a competing cationic reaction path, which has
been observed in Mitsunobu reactions with benzylic and allylic
2
5–28
alcohols.
A series of optimization reactions found diisopropyl
◦
azodicarboxylate (DIAD) and PPh
3
in toluene at 0 C to be the
best reaction conditions. Compound 12 was obtained in 60% yield
29
and 90% ee. A palladium-mediated intramolecular Mizoroki–
Heck coupling using Pd(OAc) , Ag CO and PPh converted ether
2 to the tricyclic benzofuran 13 in excellent yield of 95% and
2
2
3
3
1
9
Acknowledgements
14 : 1 dr in preference for the cis-fused ring system. The relative
stereochemistry was assigned with a NOESY-NMR experiment
We thank the Michael J. Fox foundation for financial support.
30
(
see the ESI†). Notably, the all-carbon quaternary stereocenter is
formed with a high diastereoselectivity and only traces of double
31
Notes and references
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2
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Org. Biomol. Chem., 2010, 8, 4831–4833 | 4833