Synthesis of (-)-dysiherbaine.

Article abstract of DOI:10.1021/ol991393d

[reaction: see text] The first synthesis of (-)-dysiherbaine has been accomplished using intramolecular SN2 substitutions of a carbamate anion on an epoxide and an alkoxide on a secondary mesylate to efficiently construct the bicyclic skeleton stereospecifically from xylose. A general sequence has been developed to introduce an allyl group and convert it to the alanine side chain that should be useful for the construction of dysiherbaine analogues.

Full text of DOI:10.1021/ol991393d

ORGANIC
LETTERS
2000
Vol. 2, No. 5
635-638
Synthesis of (−)-Dysiherbaine
Barry B. Snider* and Natalie A. Hawryluk
Department of Chemistry MS015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
snider@brandeis.edu
Received December 22, 1999
ABSTRACT
The first synthesis of (−)-dysiherbaine has been accomplished using intramolecular SN2 substitutions of a carbamate anion on an epoxide and
an alkoxide on a secondary mesylate to efficiently construct the bicyclic skeleton stereospecifically from xylose. A general sequence has
been developed to introduce an allyl group and convert it to the alanine side chain that should be useful for the construction of dysiherbaine
analogues.
(-)-Dysiherbaine (1) is a novel neurotoxic amino acid
isolated from the Micronesian marine sponge Dysidea
herbacea by Sakai and co-workers in 1997.1 It is a potent
neurotoxin reminiscent of domic acid that appears to function
as an agonist for non-NMDA type glutamate receptors in
the central nervous system. The structure of dysiherbaine
was assigned on the basis of one- and two-dimensional NMR
studies. The relative configuration of the bicyclic portion was
determined by coupling constant analysis and NOE studies.
The relative stereochemistry at C2 was determined by careful
analysis of proton-proton and proton-carbon coupling
constants, which suggested that 1 exists preferentially in the
conformation with intramolecular hydrogen bonding between
the basic tetrahydrofuran oxygen and the ammonium group,
giving rise to coupling constants for H2 of 11.5 and 2.5 Hz.
This assignment is supported by comparison to lycoperdic
acid (2), in which H2 absorbs as a dd, J ) 10.3, 3.3 Hz,
while in the diastereomer 3 H2 absorbs as a dd, J ) 5.9, 5.1
Hz.2 The absolute stereochemistry of dysiherbaine was not
determined but is most likely as shown with S stereochem-
istry at C2, since non-NMDA type glutamate receptors bind
preferentially to S amino acids.3
The potent biological activity and structural novelty of
dysiherbaine prompted us to undertake its synthesis. Dysi-
herbaine contains six chiral centers on a novel bicyclic
skeleton, making it a challenging synthetic target. The
polarity of the molecule vastly increases the synthetic
challenge since suitable protecting groups must be chosen
to make the intermediates sufficiently lipophilic that they
can be separated from inorganic reagents and purified
chromatographically.
We envisioned that the three-carbon side chain of 1 could
be introduced stereospecifically by alkylation of ester 4 from
the less hindered R-face as shown in Scheme 1. Ester 4
(1) Sakai, R.; Kamiya, H.; Murata, M.; Shimamoto, K. J. Am. Chem.
Soc. 1997, 119, 4112-4116.
(2) Yoshifuji, S.; Kaname, M. Chem. Pharm. Bull. 1995, 43, 1617-
1620.
(3) Watkins, J. C.; Krogsgaard-Larsen, P.; Honore´, T. Trends Pharmacol.
Sci. 1990, 11, 25-33.
10.1021/ol991393d CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/08/2000

was now inverted by conversion to the nosylate with nosyl
chloride, DMAP, and Et3N in CH2Cl2 at 0 °C. Displacement
of the nosylate with CsOAc and DMAP in toluene at reflux
for 8 h and hydrolysis of the acetate with K2CO3 and
NaHCO3 in MeOH at room temperature for 1 h gave 9 in
83% yield from 8. Use of NaHCO3 as a buffer was necessary
to prevent Payne rearrangement of the epoxy alcohol.
Reaction of 9 with NaH and methyl isocyanate in THF
by Roush’s procedure5 afforded the oxazolidinone alcohol,
which was treated with MsCl and Et3N in CH2Cl2 to form
mesylate 10 in 67% yield from 9. Dihydroxylation with OsO4
and NMO afforded a mixture of diols that was heated in
pyridine at reflux for 4 h to form the tetrahydrofuran ring.4
Dess-Martin oxidation gave aldehydes 11 as a 2:1 mixture
of diastereomers in 78% yield from 10. The mixture of
isomers is of no consequence since the stereocenter will be
set during the introduction of the three-carbon side chain.
The formation of aldehydes in the Dess-Martin oxidation
establishes unambiguously that the intramolecular SN2 reac-
tion gave only tetrahydrofuranmethanols since oxidation of
a tetrahydropyranol would have given a ketone, not an
aldehyde.
Having prepared the fully functionalized bicyclic frame-
work efficiently and stereospecifically, we turned our atten-
tion to the introduction of the three-carbon side chain. While
this work was in progress, Sasaki and Tachibana reported
the synthesis of a dysiherbaine model lacking the hydroxy
and methylamino groups.7 Their route proceeded through an
aldol reaction with the enolate of 12, which, surprisingly,
gave only 18% of the desired diastereomer 13 and 75% of
the diastereomer in which the aldehyde reacted with the
enolate from the â face, which had been expected to be more
hindered (Scheme 3). This was cause for concern, although
Scheme 1
should be readily available from diol mesylate 5, which
should undergo an intramolecular SN2 reaction regiospecifi-
cally to give the tetrahydrofuran rather than the tetrahydro-
pyran.4 Mesylate 5 can be prepared by Roush’s procedure
involving attack of the carbamate anion on the epoxide of
6.5 Epoxide 6 can be prepared from allylic alcohol 7, which
has been prepared from diacetyl-L-xylal by reaction with
allyltrimethylsilane and TiCl4.6 This approach should be
useful for the preparation of analogues since both enanti-
omers of xylose are readily available.
Hydroxy-directed epoxidation of 7 with m-CPBA in CH2-
Cl2 for 7 d at -20 °C afforded 73% of epoxide 8, 15% of
the bis epoxide, and 8% of recovered 7 (Scheme 2). More
Scheme 2
Scheme 3
we anticipated that the presence of the oxazolidinone in 11
would improve selectivity for the desired isomer.
Model studies for the attachment of the side chain were
carried out with 2-tetrahydrofurancarboxylic acid. Since
initial attempts at allylation of the ester enolate proceeded
in low yield, we turned our attention to the Ireland Claisen
rearrangement.8 Reaction of allyl ester 14 with LDA and
TMSCl/Et3N afforded 94% of Claisen rearrangement product
15, which was converted to the primary amide by reaction
bis epoxide was formed at higher temperatures. Hydroxy-
directed epoxidation with VO(acac)2 and t-BuOOH gave
mixtures containing mainly enone. The hydroxy group of 8
(4) Yazbak, A.; Sinha, S. C.; Keinan, E. J. Org. Chem. 1998, 63, 5863-
5868.
(5) Roush, W. R.; Adam, M. A. J. Org. Chem. 1985, 50, 3752-3757.
(6) (a) Sabol, J. S.; Cregge, R. J. Tetrahedron Lett. 1989, 30, 6271-
6274. (b) Hosokawa, S.; Kirschbaum, B.; Isobe, M. Tetrahedron Lett. 1998,
39, 1917-1920.
(7) Sasaki, M.; Maruyama, T.; Sakai, R.; Tachibana, K. Tetrahedron Lett.
1999, 40, 3195-3198.
(8) (a) Ireland, R. E.; Norbeck, D. W. J. Am. Chem. Soc. 1985, 107,
3279-3285. (b) Di Florio, R.; Rizzacasa, M. A. J. Org. Chem. 1998, 63,
8595-8598.
636
Org. Lett., Vol. 2, No. 5, 2000

calculated by MM2 for the conformation shown. The amide
hydrogens of 21 absorb at δ 5.79 and 5.84, which indicates
that they are not hydrogen bonded. H2 absorbs as a dd, J )
8.4, 4.4 Hz, as calculated by MM2 for the conformation
shown.
Scheme 4
Unfortunately, benzyl lactams 18b, 20, or 21 could not
be hydrolyzed,11 although N-unsubstituted lactams can be
hydrolyzed with HCl. Since hydrogenolysis of benzyl lactams
is not possible, we replaced the benzyl group with a 2,4-
dimethoxybenzyl group, which should be cleaved by the
acidic hydrolysis conditions needed to hydrolyze the nitrile
and lactam.12 Nitriles 18c were prepared analogously to that
of 18b using 2,4-dimethoxybenzylamine. We were delighted
to find that reaction of 18c in 6 M HCl at reflux for 2 d
afforded the desired amino acids 19 in 90% yield, thereby
providing a protocol that should be suitable for conversion
of 11 to dysiherbaine.
with oxalyl chloride and then ammonia (Scheme 4). Ozo-
nolysis gave aldehyde 16a, which was treated with base to
give an equilibrium 1:1 mixture of lactam alcohol 17a and
amide aldehyde 16a. We prepared a secondary amide to
increase the lipophilicity and with the hope that it would
form a lactam alcohol more readily than the primary amide.
Benzyl amide 16b was prepared in 70% yield from 15
analogously to the preparation of 16a with the expectation
that it could be cleaved hydrogenolytically at the end of the
synthesis. We were delighted to find that treatment of 16b
with K2CO3 afforded lactam alcohol 17b quantitatively.
Treatment of 17b with ZnI2 and TMSCN9 afforded cyano
lactam 18b as a separable 2:1 mixture of isomers in 90%
yield.
Initial attempts at the Ireland Claisen rearrangement of
the allyl ester obtained from 11 proceeded in low yield,
possibly due to interference by the oxazolidinone. Fortu-
nately, a Claisen variant reported by Secrist for allylation of
carbohydrate aldehydes was successful.13 Reaction of the
pyrrolidine enamine of 11 with allyl bromide in acetonitrile
at room temperature to 80 °C afforded 58% of an inseparable
3:1 mixture of aldehydes 22 after hydrolysis of the iminium
salt (Scheme 6). Oxidation of 22 with NaClO2 afforded 69%
Scheme 6
Mild hydrolysis of the major and minor nitriles 18b with
basic hydrogen peroxide afforded amides 20 and 21,
respectively (Scheme 5) in 92% yield. The structure of the
Scheme 5
of acid 23 and 24% of the undesired diastereomer 24, which
were easily separated chromatographically. The structures
were tentatively assigned on the basis of the chromatographic
behavior. The desired major product 23 was substantially
less polar [23, Rf ) 0.34; 24, Rf ) 0.14 (77:23 EtOAc/
MeOH)] since the acid group of 23 is on the more hindered
concave face and is intramolecularly hydrogen bonded to
the tetrahydropyran oxygen.
desired major diastereomer 20, which has the same relative
stereochemistry as 1, was established by examination of its
NMR spectrum. The amide hydrogens of 20 absorb at δ 5.46
and 6.91. The downfield shift of the hydrogen at δ 6.91 is
indicative of an intramolecular hydrogen bond to the tet-
rahydrofuran ring.10 H2 absorbs as a dd, J ) 8.4, 1.8 Hz, as
(11) For a similar observation see: Ohta, T.; Shiokawa, S.; Sakamoto,
R.; Nozoe, S. Tetrahedron Lett. 1990, 31, 7329-7332.
(12) Schlessinger, R. H.; Bebernitz, G. R.; Lin, P.; Poss, A. J. J. Am.
Chem. Soc. 1985, 107, 1777-1778.
(13) Secrist, J. A., III.; Winter, W. J., Jr. J. Am. Chem. Soc. 1978, 100,
2554-2555.
(9) Tung, R. D.; Rich, D. H. Tetrahedron Lett. 1987, 28, 1139-1142.
(10) Boiadjiev, S. E.; Person, R. V.; Lightner, D. A. Tetrahedron:
Asymmetry 1993, 4, 491-510.
Org. Lett., Vol. 2, No. 5, 2000
637

The 2,4-dimethoxybenzyl amide was introduced in 86%
yield by reaction of 23 with EDC, HOBt, and 2,4-
dimethoxybenzylamine in wet MeCN (Scheme 7). Cleavage
dimethoxybenzyl group, and hydrolyze the resulting N-
unsubstituted lactam. We were delighted to find that reaction
of nitrile 26a in 6 M HCl for 4 d at reflux, concentration
under reduced pressure, and washing the residue with CH2-
Cl2 to remove byproducts from the dimethoxybenzyl group
afforded dysiherbaine 1 cleanly as the hydrochloride salt
(Scheme 8). Although the natural product is the free amino
Scheme 7
Scheme 8
1
acid, the H and 13C NMR spectral data of the synthetic
material are identical to those of an authentic sample kindly
provided by Prof. Sakai.16 The rotation, [R]25 -5°, corre-
D
sponds closely to that of the natural product, [R]25 -3°.
D
This suggests that the absolute configuration of dysiherbaine
is as shown, although the small magnitude of the rotation
and the possibility of pH effects on the rotation preclude
definitive assignment.
of the double bond with OsO4 and then NaIO4 provided 99%
of aldehyde 25.14 Cyclization with K2CO3 in wet acetone
afforded 99% of the lactam alcohols, which were treated with
TMSCN and ZnI2 in CH2Cl2 to provide 99% of a 1:1 mixture
of readily separable nitriles 26a and 27a.
In conclusion, we have completed the first synthesis of
dysiherbaine using intramolecular SN2 substitutions of a
carbamate anion on an epoxide and an alkoxide on a
secondary mesylate to efficiently construct the bicyclic
skeleton stereospecifically from L-xylose. A general sequence
that should be useful for the construction of dysiherbaine
analogues has been developed to introduce an allyl group
and convert it to the alanine side chain. Preparation and
biological evaluation of the stereoisomers at C2 and C4 are
in progress.
The stereochemistry at C4 was confirmed by the NOEs
between H3 and H7 in both 26a and 27a. The stereochemistry
at C2 was established by analysis of the 1H NMR spectra of
amides 26b and 27b, which were prepared by hydrolysis of
the nitriles with H2O2 and K2CO3 in acetone, as described
above for 20 and 21. The amide hydrogens of the desired
isomer 26b absorb at δ 5.33 and 6.10, indicating the presence
of an intramolecular hydrogen bond. H2 absorbs as a dd, J
) 9.2, <1 Hz. The amide hydrogens of the diastereomer
27b absorb at δ 5.32 and 5.65; H2 absorbs as a dd, J ) 7.6,
5.6 Hz. The coupling constants of both 26b and 27b
correspond closely to those calculated by MM2 and observed
in model amides 20 and 21.
Acknowledgment. We are grateful to the National
Institutes of Health (GM-46470) for generous financial
support. We thank Ms. Christine Hofstetter for assistance in
obtaining NMR spectra and Professor Sakai for an authentic
sample of dysiherbaine.
Supporting Information Available: Experimental pro-
cedures for the preparation of 8-11, 22-27, and 1. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The final step in the synthesis was hydrolysis with 6 M
HCl at reflux, which was expected to hydrolyze the oxazo-
lidinone,15 hydrolyze the nitrile to an acid, cleave the
OL991393D
(14) Ozone oxidized the electron rich aromatic ring.
(15) Knapp, S.; Sebastian, M. J.; Ramanathan, H. J. Org. Chem. 1983,
48, 4786-4788.
(16) The pH of a dilute solution of 1 (1 mg/mL) in D2O may be controlled
by dissolved CO2.
638
Org. Lett., Vol. 2, No. 5, 2000