Enantioselective Synthesis of (-)-Dysiherbaine

Article abstract of DOI:10.1021/acs.orglett.5b01821

Dysiherbaine, a natural product isolated from the Marine sponge Dysidea herbacea, has been shown to be a selective agonist of non-NMDA type glutamate receptors, kainate receptors. An enantioselective synthesis of dysiherbaine is reported. Metathesis of th

Full text of DOI:10.1021/acs.orglett.5b01821

Letter
pubs.acs.org/OrgLett
Enantioselective Synthesis of (−)-Dysiherbaine
Ha Do, Chang Won Kang, Joon Hyung Cho, and Scott R. Gilbertson*
Department of Chemistry, University of Houston, Houston, Texas 77204, United States
S
* Supporting Information
ABSTRACT: Dysiherbaine, a natural product isolated from
the Marine sponge Dysidea herbacea, has been shown to be a
selective agonist of non-NMDA type glutamate receptors,
kainate receptors. An enantioselective synthesis of dysiher-
baine is reported. Metathesis of the diene followed by
conversion of the resulting alkene to the amino alcohol and addition of the amino acid provides the natural product. This
synthesis differs from previous approaches to the molecule in that the functionality on the tetrahydropyran ring is installed late in
the route.
he use of molecules that selectively interact with central
nervous system (CNS) receptors is one of the
Scheme 1. Retrosynthetic Analysis
T
fundamental approaches that has been used to elucidate the
role of various receptors. Kainate receptors (KAR) may be
among the least understood of the ionotropic receptors, in part
because of the lack of molecules that selectively interact with
the different types of KARs. A series of neurotoxic amino acids,
dysiherbaine and neodysiherbaine, have been isolated from the
marine sponge Dysidea herbacea by Sakai and co-workers
(Figure 1).1−4 A study of these molecules revealed that they
allow for introduction of functionality at C-8 and C-9 toward
the end of the synthetic sequence. After introduction of the
amine and hydroxyl groups the amino acid is added.3,10,12,14−16
Dihydropyran 4 is derived from a metathesis reaction on
diene 5 which is synthesized by epoxide opening of 6. The
epoxide is formed by directed epoxidation of homoallylic
alcohol 7. Asymmetry of the system is set by the use of optically
active commerically available methyl glycidate 8.18
Figure 1. Dysiherbaine and neodysiherbaine A.
The opening of glycidic methyl ester was attempted with a
number of acetylides with the aluminum acetylide proceeding
in good yield (Scheme 2). Following the removal of the
trimethylsilyl group, the acetylene 9 was converted to enyne 10
by Sonogashira coupling. The reduction of the enyne to the
required cis-diene required considerable optimization. Lindlar
conditions generally failed to provide the desired product in
good yield. The major product using a variety of different
“Lindlar” conditions either resulted in over reduction or no
reaction. Reaction with zinc/copper/silver amalgam in
methanol/water provided the desired cis-diene 7 in good
yield.19,20 The stereogenic center α to the ester was then used
to perform a regio- and diastereoselective epoxidation (12:1
ratio of diastereomers) of the diene 7. The selective opening of
epoxide 6 with formation of the desired tetrahydrofuran was
first performed using BF3·Et2O; however, after extensive
optimization the yield was only 53%. The approach reported
by Hirama, using palladium-catalyzed opening of the epoxide,
possess unique agonist activity with the non-NMDA type
glutamate receptors, kainate receptors.5−10 Initial studies
examining simple analogues of dysiherbaine and neodysiher-
baine have found that the glutamate section of the molecule is
responsible for much of the binding to the receptor, while the
conformation and functionality of the tetrahydropyran ring are
key in determining the activity profile (agonist vs antagonist) of
these molecules.9 Since the functionality of the tetrahydropyran
ring appears to be important in controlling the receptor
response of these molecules, an approach to dysiherbaine and
neodysiherbaine analogues was embarked on that would pass
through an intermediate that allows the modification the
tetrahydropyran ring at a late stage in the synthesis.
The previous routes to these molecules have generally
utilized starting materials that have the amino alcohol or the
diol at C-8 and C-9 in place.10−17 Starting with such
tetrahydropyran-containing starting materials limits the ability
to make molecules where the functionality at C-8 and C-9 is
varied. The approach described here forms the pyran ring at a
late stage, as dihydropyran 4 (Scheme 1), and is designed to
Received: June 24, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01821
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of the Furopyran Ring Skeleton
followed by addition of the α-hydroxyl group to the allyl
palladium intermediate provided the desired furan ring with the
inverted stereochemistry (11), consistent with the reported
literature for similar substrates.21,22 Allylation of the free
alcohol with allyl bromide and silver oxide provided the diene
metathesis substrate (5). Reaction with Grubbs II catalyst
provided the 1,5-dioxaoctahydroindene (4) system in excellent
yield.
The next step in the planned approach was to install the
amino acid using one of the methods reported in the literature
or by a new approach developed by us. The approach taken
possesses elements of both (Scheme 3). Addition of form-
bromobenzenesulfonic ester with the wrong diastereomer for
dysiherbaine providing crystals that were used for an X-ray
crystal structure to confirm the stereochemistry (data provided
in the Supporting Information).
Introduction of the amino alcohol to the alkene was critical
for the entire approach. Dihydroxylation of 14 gave diol 15. Bis
hydroxylation of the double bond functionalized carbons 8 and
9 but with the opposite configuration from dysiherbaine.
Substitution at C-8 with a variety of nitrogen nucleophiles
proved to be difficult due to the equatorial position of the
hydroxyl group. It was necessary to introduce the amine
nitrogen in an intramolecular fashion. This was accomplished
by bis mesylation followed by selective substitution of with
azide at C-9 (16). Treatment of 16 with PPh3 and DIPEA
successfully provided aziridine which was protected with Boc
due to the ease of purification. Reaction of 17, protected as the
Boc carbamate, with copper(II) triflate provided the rearranged
produce (18) which efficiently introduced both amine group at
C-8 and hydroxyl group at C-9.24−27 To the best of our
knowledge this is the first example of a regioselective opening
of a carbamate protected aziridine not directed by a carboxyl
group somewhere in the molecule.25−27 The regio- and
stereochemistry of 18 was confirmed by COSY and NOESY
NMR, respectively. Methylation of the nitrogen followed by
oxidation of the primary alcohol set the stage for the
introduction of amino acid by olefination of the newly formed
aldehyde providing 21. Asymmetric hydrogenation using
rhodium DuPhos in ethanol provided the protected version
of dysiherbaine. Hydrolysis of 22 with 40% NaOH in MeOH,
followed by ion exchange and reverse phase chromatography
provided dysiherbaine. The 1H and 13C NMR spectra of
synthetic product matched well to those of the synthesized and
natural product reported in literature.
Scheme 3. Functionalization of Ester 4
aldehyde provided a primary alcohol that would ultimately be
oxidized and then converted to the amino acid by asymmetric
hydrogenation. Reaction of 4 with LDA followed by quenching
with formaldehyde proved the desired alcohol in limited yield
but 5:1 selectivity.23 When the scale of this reaction was
increased the yield decreased significantly. Consequently, an
alternate approach was taken where the formaldehyde addition
was carried out before the metathesis ring closure. This results
in significantly better yield but poorer selectivity (2:1);
however, the two diastereomeric alcohols (13) are easily
separated by column chromatography. Following separation,
the metathesis reaction proceeds in high yield with both
diastereomers. Both diastereomers were converted to a 4-
In conclusion, we have completed the enantioselective
synthesis of dysiherbaine by using the optically active readily
available methyl glycidate. The approach of building a pyran
ring at a late stage in the synthesis will allow for modification of
functionality at C-8 and C-9 from a common intermediate in a
late stage of the synthesis, thus providing a more efficient route
to access to analogs of dysiherbaine.
B
DOI: 10.1021/acs.orglett.5b01821
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Introduction of Amino Alcohol and Addition of Amino Acid
(8) Sanders, J. M.; Ito, K.; Settimo, L.; Pentikainen, O. T.; Shoji, M.;
Sasaki, M.; Johnson, M. S.; Sakai, R.; Swanson, G. T. J. Pharmacol. Exp.
Ther. 2005, 314, 1068−1078.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01821.
■
S
(9) Lash, L. L.; Sanders, J. M.; Akiyama, N.; Shoji, M.; Postila, P.;
Pentikainen, O. T.; Sasaki, M.; Sakai, R.; Swanson, G. T. J. Pharmacol.
Exp. Ther. 2008, 324, 484−496.
(10) Shoji, M.; Akiyama, N.; Tsubone, K.; Lash, L. L.; Sanders, J. M.;
Swanson, G. T.; Sakai, R.; Shimamoto, K.; Oikawa, M.; Sasaki, M. J.
Org. Chem. 2006, 71, 5208−5220.
(11) Sasaki, M.; Koike, T.; Sakai, R.; Tachibana, K. Tetrahedron Lett.
2000, 41, 3923−3926.
(12) Snider, B. B.; Hawryluk, N. A. Org. Lett. 2000, 2, 635−638.
(13) Phillips, D.; Chamberlin, A. R. J. Org. Chem. 2002, 67, 3194−
3201.
General methods, experimental procedures, spectro-
scopic data, and 1H and 13C NMR spectra for all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: srgilbe2@central.uh.edu.
Notes
(14) Shoji, M.; Shiohara, K.; Oikawa, M.; Sakai, R.; Sasaki, M.
Tetrahedron Lett. 2005, 46, 5559−5562.
(15) Sasaki, M.; Maruyama, T.; Sakai, R.; Tachibana, K. Tetrahedron
Lett. 1999, 40, 3195−3198.
The authors declare no competing financial interest.
(16) Kang, S. H.; Lee, Y. M. Synlett 2003, 993−994.
(17) Huang, J.-M.; Xu, K.-C.; Loh, T.-P. Synthesis 2003, 755−764.
(18) Stevenson, C. P.; Nielsen, L. P. C.; Jacobsen, E. N. Organic
Synthesis 2006, 83, 162−169.
ACKNOWLEDGMENTS
Acknowledgment is made to the Robert A. Welch Foundation
and NIGMS GM089173 for support of this work.
■
(19) Khrimian, A.; Klun, J. A.; Hijji, Y.; Baranchikov, Y. N.; Pet’ko, V.
M.; Mastro, V. C.; Kramer, M. H. J. Agric. Food Chem. 2002, 50, 6366−
6370.
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DOI: 10.1021/acs.orglett.5b01821
Org. Lett. XXXX, XXX, XXX−XXX