Synthetic studies of the tridentatols

Article abstract of DOI:10.1021/ol9907421

(Matrix presented) The tridentatols are conjugated tyramine derivatives isolated from the Atlantic hydroid Tridentata marginata and have potentially useful properties in sunscreen applications. Preparations of tridentatol C and two tridentatol A analogues

Full text of DOI:10.1021/ol9907421

ORGANIC
LETTERS
1999
Vol. 1, No. 4
661-662
Synthetic Studies of the Tridentatols
Gamini S. Jayatilake and Bill J. Baker*
Department of Chemistry, Florida Institute of Technology, 150 West UniVersity
BouleVard, Melbourne, Florida 32901
bbaker@fit.edu
Received June 16, 1999
ABSTRACT
The tridentatols are conjugated tyramine derivatives isolated from the Atlantic hydroid Tridentata marginata and have potentially useful properties
in sunscreen applications. Preparations of tridentatol C and two tridentatol A analogues bearing the unusual N-[bis(methylthio)methylene]
functional group are described.
The tridentatols are N-[(dialkylthio)methylene] tyramine
derivatives isolated from hydroids found among the floating
Sargassum patches off the coast of North Carolina by
Lindquist et al.1 Tridentatol A (1) displays a linear arrange-
ment of the unusual N-[bis(methylthio)methylene] functional
group while in tridentatol C (2) the group has cyclized to
form a thiazole ring. Because of their UV absorption
dithiocarbamate for elaboration into the desired functional
group.4 In studies toward a model tridentatol phenyl deriva-
tive, the dithiocarbamate adduct proved elusive, suggesting
an unfavorable enamine/imine equilibrium. The inaccessibil-
ity of the methyl dithiocarbamate from the enamine neces-
sitated introduction of the N-[bis(methylthio)methylene]
group separately from the vinyl group.
Amino alcohol 3 (Scheme 1) was converted via the
dithiocarbamate to intermediate 4. Several attempts at
dehydration of the benzylic alcohol 4 were made; best results
were obtained by the use of diethylaminosulfur trifluoride
(DAST), yielding a 2:1 mixture of E and Z isomers of 5
which could be separated by HPLC.1 Our initial (unopti-
mized) efforts produced 20% of 5 from 3.
properties (λmax 313-337 nm), the tridentatols may serve
the hydroid as natural sunscreens.2 In an effort to study the
potential of these compounds for use in sunscreen applica-
tions,3 we have developed a preparation of tridentatol C and
two tridentatol derivatives as model sunscreens. This is the
first reported tridentatol synthesis.
Scheme 1
N-Bis(alkylthio)methylene functional groups have been
prepared from amines via the corresponding alkyl dithio-
carbamate.4 Therefore, we envisioned a synthesis of triden-
tatol A (1) based on trapping an enamine as the methyl
(1) Lindquist, N.; Lobkovsky, E.; Clardy, J. Tetrahedron Lett. 1996, 37,
9131-9134.
(2) Stachowicz, J. J.; Lindquist, N. Mar. Ecol. Prog. Ser. 1997, 155,
115-126.
(3) Lindquist, N. U.S. Patent 5705146; Chem. Abstr. 1998, 128, 119431.
(4) Cativiela, C.; Diaz de Villegas, M. D. Tetrahedron 1993, 49, 497-
506.
Having established a method to the vinyl N-[bis(meth-
ylthio)methylene] functional group, we attempted to elaborate
10.1021/ol9907421 CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/20/1999

tridentatol A (1) from the corresponding phenol, DL-octo-
pamine (6) (Scheme 2). On treatment with CS2/MeI, rather
Scheme 3
Scheme 2
achieved with phosphorus pentoxide, resulting in the E
isomer of methoxy tridentatol A (10) in 70% yield.
Thus tridentatol C (2), deoxytridentatol A (5), and meth-
oxytridentatol A (10) have been prepared, the latter of which
displays enhanced UVB absorption properties (λmax 334, ꢀ
31 500) relative to the natural product. We are currently
engaged in optimizing these synthetic pathways and in the
preparation of additional derivatives for a systematic study
of the physical properties of the extended conjugated system.
We evaluated tridentatol C in the NCI 60 cell line panel and
found it to be devoid of cytotoxicity, an important consid-
eration for a potential sunscreen.
than the expected dithiocarbamate, the cyclic product 7 was
obtained; the increased benzylic electrophilicity induced by
the phenol group apparently enabled nucleophilic attack of
the thiocarbonyl, resulting in a 4,5-dihydrothiazole (thiazo-
line) ring. Although such nucleophilic substitution has been
used in the construction of thiazoline rings,5 this result is
interesting to contrast to the work of Cativiela and Diaz de
Villegas who found that the C-8 carboxylate of 4 cyclizes
to the oxazoline. This unexpected cyclization provided a
route to the skeleton of tridentatol C (2). Aromatization of
the thiazoline ring was carried out by treatment of 7 with
DDQ to yield tridentatol C (2).
A scheme to the linear tridentatols therefore had to
moderate the benzylic electrophilicity induced by the phenol
group. The methyl ether was chosen for this task, and a
suitable candidate (8) was prepared in three steps from
p-methoxybenzaldehyde in 40% overall yield.
Acknowledgment. This work was undertaken as a
collaboration with Dr. Niels Lindquist, University of North
Carolina at Chapel Hill, whose input was invaluable. The
staff of the National Cancer Institute and Dr. R Somanathan,
San Diego State University, are gratefully acknowledged for
bioassay and mass spectral determinations, respectively. This
work was funded in part by a grant from the National Science
Foundation (OCE-9725040 to B.J.B.).
Treatment of 8 (Scheme 3) under conditions developed
above for the introduction of the vinyl N-[bis(methylthio)-
methylene] functional group produced intermediate 9 in 60%
yield. Elimination of the benzylic methoxy group could be
Supporting Information Available: Experimental pro-
cedures and characterization of compounds 4, 5, 7-10. This
material is available free of charge via the Internet at
http://www.pubs.acs.org.
(5) Crawhall, J. C.; Elliott, D. F. J. Chem. Soc. 1952, 3094-3102.
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Org. Lett., Vol. 1, No. 4, 1999