Synthetic Studies of the TridentatolsGamini S. Jayatilake and Bill J. Baker*

Department of Chemistry, Florida Institute of Technology, 150 West UniVersityBouleVard, 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 propertiesin sunscreen applications. Preparations of tridentatol C and two tridentatol A analogues bearing the unusual N-[bis(methylthio)methylene]functional group are described.

The tridentatols areN-[(dialkylthio)methylene] tyraminederivatives isolated from hydroids found among the floatingSargassumpatches off the coast of North Carolina byLindquist et al.1 Tridentatol A (1) displays a linear arrange-ment of the unusualN-[bis(methylthio)methylene] functionalgroup while in tridentatol C (2) the group has cyclized toform a thiazole ring. Because of their UV absorption

properties (λmax 313-337 nm), the tridentatols may servethe hydroid as natural sunscreens.2 In an effort to study thepotential of these compounds for use in sunscreen applica-tions,3 we have developed a preparation of tridentatol C andtwo tridentatol derivatives as model sunscreens. This is thefirst reported tridentatol synthesis.

N-Bis(alkylthio)methylene functional groups have beenprepared 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

dithiocarbamate for elaboration into the desired functionalgroup.4 In studies toward a model tridentatol phenyl deriva-tive, the dithiocarbamate adduct proved elusive, suggestingan unfavorable enamine/imine equilibrium. The inaccessibil-ity of the methyl dithiocarbamate from the enamine neces-sitated introduction of theN-[bis(methylthio)methylene]group separately from the vinyl group.

Amino alcohol 3 (Scheme 1) was converted via thedithiocarbamate to intermediate4. Several attempts atdehydration of the benzylic alcohol4 were made; best resultswere obtained by the use of diethylaminosulfur trifluoride(DAST), yielding a 2:1 mixture ofE and Z isomers of5which could be separated by HPLC.1 Our initial (unopti-mized) efforts produced 20% of5 from 3.

Having established a method to the vinylN-[bis(meth-ylthio)methylene] functional group, we attempted to elaborate

(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.Tetrahedron1993, 49, 497-

506.

Scheme 1

ORGANICLETTERS

1999Vol. 1, No. 4

661-662

10.1021/ol9907421 CCC: $18.00 © 1999 American Chemical SocietyPublished on Web 07/20/1999

tridentatol A (1) from the corresponding phenol,DL-octo-pamine (6) (Scheme 2). On treatment with CS2/MeI, rather

than the expected dithiocarbamate, the cyclic product7 wasobtained; the increased benzylic electrophilicity induced bythe phenol group apparently enabled nucleophilic attack ofthe thiocarbonyl, resulting in a 4,5-dihydrothiazole (thiazo-line) ring. Although such nucleophilic substitution has beenused in the construction of thiazoline rings,5 this result isinteresting to contrast to the work of Cativiela and Diaz deVillegas who found that the C-8 carboxylate of4 cyclizesto the oxazoline. This unexpected cyclization provided aroute to the skeleton of tridentatol C (2). Aromatization ofthe thiazoline ring was carried out by treatment of7 withDDQ to yield tridentatol C (2).

A scheme to the linear tridentatols therefore had tomoderate the benzylic electrophilicity induced by the phenolgroup. The methyl ether was chosen for this task, and asuitable candidate (8) was prepared in three steps fromp-methoxybenzaldehyde in 40% overall yield.

Treatment of8 (Scheme 3) under conditions developedabove for the introduction of the vinylN-[bis(methylthio)-methylene] functional group produced intermediate9 in 60%yield. Elimination of the benzylic methoxy group could be

achieved with phosphorus pentoxide, resulting in theEisomer 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 whichdisplays enhanced UVB absorption properties (λmax 334, ε31 500) relative to the natural product. We are currentlyengaged in optimizing these synthetic pathways and in thepreparation of additional derivatives for a systematic studyof the physical properties of the extended conjugated system.We evaluated tridentatol C in the NCI 60 cell line panel andfound it to be devoid of cytotoxicity, an important consid-eration for a potential sunscreen.

Acknowledgment. This work was undertaken as acollaboration with Dr. Niels Lindquist, University of NorthCarolina at Chapel Hill, whose input was invaluable. Thestaff of the National Cancer Institute and Dr. R Somanathan,San Diego State University, are gratefully acknowledged forbioassay and mass spectral determinations, respectively. Thiswork was funded in part by a grant from the National ScienceFoundation (OCE-9725040 to B.J.B.).

Supporting Information Available: Experimental pro-cedures and characterization of compounds4, 5, 7-10. Thismaterial is available free of charge via the Internet athttp://www.pubs.acs.org.

OL9907421(5) Crawhall, J. C.; Elliott, D. F.J. Chem. Soc. 1952, 3094-3102.

Scheme 2

Scheme 3

662 Org. Lett., Vol. 1, No. 4, 1999