chemists. Recently, several groups, including us,4 have
independently accomplished the total synthesis of 1.5 This
work not only confirmed its chemical structure but also
defined the absolute stereochemistry. However, further
chemical studies are required to uncover the structure-
activity relationships (SAR) of 1, which may lead to
development of more selective GluR ligands.
We therefore searched for minor neuroactive components
in the aqueous extract of D. herbacea using the mouse assay
as a guide and found a new dysiherbaine analogue, neo-
dysiherbaine A (2), as a minor constituent. We now report
the isolation, structure determination, and total synthesis of
2 (Figure 1).
overall spectral pattern of 2 was similar to that of 1,
indicating that the structure of 2 is closely related to that of
1, although a significant difference, lack of a methyl signal,
was evident. A COSY experiment assigned all the non-
exchangeable proton signals, whereby large differences in
chemical shifts were observed in some signals for 1 and 2;
H-8 (∆δ1-2 ) -0.2), H-7 (+0.2), and H-9 (+0.3). These
shifts along with the difference in molecular formulas
between 1 and 2 (less CH3N with an additional oxygen in 2
in comparison with 1) allowed us to assign a hydroxyl group
at C8. The relative stereochemistry of the perhydrofuro[b]-
pyran ring is assigned to be the same as that for 1, since the
coupling pattern of all the protons on this ring system is
nearly identical to that of 1. However, we could not
determine the stereochemistry at quaternary C4 and correlate
stereochemistry at C2 to the bicyclic portion because a
minute amount of 2 hampered further 2D NMR studies. We
thus carried out the total synthesis of 2 to resolve the
remaining stereochemical ambiguities and ultimately provide
access to additional material for biological evaluation.
We decided to synthesize 2a as the most likely candidate.
The present synthesis relied on a strategy developed for the
total synthesis of 1,5 which was designed to be applicable
to a variety of its analogues. We envisioned that 2a would
be constructed by cross-coupling of organozinc compound
3 and vinyl triflate 4, which would be accessed from a
carbohydrate precursor (Scheme 1).
Figure 1. Structures of dysiherbaine (1) and neodysiherbaine A
(2).
Dysidea herbacea collected in Yap State, Micronesia, in
July 1998 was homogenized with water. The aqueous extract
was separated by a series of gel filtration chromatography
(Sephadex LH20 and BioGel P2). Fractions were pooled
according to their TLC profile and bioactivity. Purification
of the most active fraction afforded 1 (70 ppm of the wet
sponge). Another bioactive fraction eluted before 1 on the
BioGel P2 column was separated by DE52 anion exchange
Scheme 1. Retrosynthesis of NeodysiherbaineA (2a)
chromatography (Whattman). The UV (342 nm), 1H and 13
C
NMR, and ESIMS (m/z 330) spectra of the bioactive fraction
indicated that it contained shinorine (or mytilin A), a
ubiquitous mycosporine,6 as a major component. However,
an authentic compound presented by Prof. H. Nakamura of
Nagoya University confirmed that shinorine was not the
bioactive principal of this fraction. We thus suspected the
presence of a minor active principal, and finally, purification
by HPLC (C18) of this fraction afforded a small amount of
the active component, neodysiherbaine A (2, 0.26 mg).7
FABMS of 2 showed a molecular ion at m/z 290. From high-
resolution FABMS data, m/z 290.0865 ([M - H]-), its
formula was deduced to be C11H17NO8. In the1H NMR, the
Synthesis of vinyl triflate 4 commenced with tri-O-acetyl-
D-glucal (5), which was converted into olefin 6 by a three-
step sequence of reactions in 84% overall yield (Scheme 2).
Dihydroxylation of 6 proceeded stereoselectively to give
R-diol 7 in 79% yield along with 17% yield of the
corresponding â-diol. Routine protective group manipulations
led to alcohol 8 (76% overall), which upon oxidation and
Wittig reaction provided terminal olefin 9 in 83% yield.
Hydroboration followed by oxidative workup afforded
primary alcohol 10 (95% yield), which was then converted
to methyl ketone 11 in 83% overall yield. Kinetic deproton-
ation (KHMDS, THF, -78 °C) followed by treatment of
the derived enolate with Tf2NPh provided the desired enol
triflate 4, which was immediately used in the crucial coupling
reaction.
(4) Sasaki, M.; Koike, T.; Sakai, R.; Tachibana, K. Tetrahedron Lett.
2000, 3923-3926.
(5) (a) Snider, B. B.; Hawryluk, N. A.Org. Lett. 2000, 2, 635-638. (b)
Masaki, H.; Maeyama, J.; Kamada, K.; Esumi, T.; Iwabuchi, Y.; Hatakeya-
ma, S. J. Am. Chem. Soc. 2000, 122, 5216-5217.
(6) Chioccara, F.; Misuraca, G.; Novellino, E.; Prota, G. Tetrahedron
lett. 1979, 3181-3182.
1
(7) CD (H2O) λext 204 nm, ∆ꢀ ) 1.7; H NMR (400 MHz, D2O at 20
°C, HOD at δ 4.65 as an internal reference) δ 4.07 (brs, 1H, H-7), 3.99
(brs, 1H, H-6), 3.76 (t, 1H, J ) 3.7 Hz, H-8), 3.71 (dd, 1H, J ) 1 2.6, 2.5
Hz, H-10a), 3.55 (brs, 1H, H-9), 3.42 (brd, 2H, J ) 12.7 Hz, H-10b, H-2),
2.50 (dd, 1H, J ) 14.9, 1.5 Hz, H-3a), 2.42 (d, 1H, J ) 14.2 Hz, H-5a),
2.01(dd, 1H, J ) 14.0, 3.4 Hz, H-5b), 1.81 (dd, 1H, J ) 15.1, 12.1 Hz,
H-3b).
Treatment of 4 with organozinc reagent 38 in the presence
of PdCl2(PPh3)2 in THF-DMA (1:1) according to the
reported method4 furnished the desired cross-coupled product
1480
Org. Lett., Vol. 3, No. 10, 2001