Sesquiterpene isothiocyanates

A sesquiterpene isothiocyanate (240) was isolated from the Californian nudibranch Cadlina luteomarginata but was presumed to be concentrated from the Axinella species of sponge which constitutes much of its diet [249]. Famesyl isothiocyanate (241) was isolated from Pseudaxinyssa pitys [250], while theonellin isothiocyanate (242) was isolated from the sponge Theonella cf. swinhoei [251]. 

Two further sesquiterpene isothiocyanates were isolated from A. cannabina as minor metabolites. The first (243) is based on the epi-eudesmane skeleton while the next (244) is related to alloaromadendrene [252]. A third isothiocyanate (245) which is a ds-eudesmane derivative... 

The structure of 5-isothiocyanatopupukeanane (257), a sesquiterpene isothiocyanate from an Axinyssa species from Guam, was determined by X-ray analysis [260]. Two isomeric sesquiterpene thiocyanates, 2-thiocyanatoneopupukeanane (258) and 4-thiocyanatoneopupukeanane (259) were isolated from an unidentified sponge from Pohnpei and from Phycopsis terpnis from Okinawa [261]. A sample of Axinyssa (= Trachyopsis) aplysinoides from Palau yielded a rare thiocyanate, 2-thiocyanatopupukeanane (260), while two specimens from Pohnpei yielded 13-isothiocyanatocubebane (261), 1-isothiocyanatoaromadendrane (262) and 2-thiocyanatoneopupukeanane (258) [262]. This last compound had previously been assigned different stereochemistry at C2 [261]. (-)-4-Thiocyanatoneopupukeanane has been synthesised in an enantiospecific manner (259) [263]. Both enantiomers of 2-thiocyanatoneopupukeanane (258) have been synthesised from (7 )-carvone [264]. 

A sesquiterpene isothiocyanate, halipanicine (263) has been isolated from an Okinawan specimen of Halichondria panicea [265]. The relative stereochemistry of halipanicine (263) was established by synthesis [266] and later, a total synthesis was achieved [267]. 

Three new antiparasitic sesquiterpene isothiocyanates, 4-isothiocyanato-9-amorphene (264), 10-isothiocyanato-4,6-amorphadiene (265) and 10-isothiocyanato-5-amorphen-4-ol (266) were isolated from a Fijian specimen of Axinyssa fenestratus. The compounds were identified by spectral data interpretation [268]. Two isomeric isothiocyanates (267-268) were isolated from Acanthella klethra from the Great Barrier Reef and their structures were determined by X-ray crystallography and spectral data examination [269]. 

A sesquiterpene thiocyanate, cavemothiocyanate (269) was isolated from Acanthella cf. cavernosa and the structure was elucidated on the basis of spectral data. The nudibranch Phyllidia ocellata also contained cavemothiocyanate [270]. Acanthene B (270) is a sesquiterpene isothiocyanate isolated from a British Columbian Acanthella sp. [271]. The sesquiterpene thiol, T-cadinthiol (271) was isolated from Cymbastela hooperi from Kelso Reef on the Great Barrier Reef [272]. A sesquiterpene isothiocyanate that displayed modest in vitro antimalarial activity, (-)-9-isothiocyanatopupukeanane (272) was isolated from an Axinyssa sp. from the Great Barrier Reef [273]. Great Barrier Reef samples of A. cavernosa contained 10-isothiocyanatocadin-4-ene (273) [274],... 

Kalihinols G (277) and H (278) were trace components of a species of Acanthella from Guam and kalihinol X (279) was isolated from a Fijian species of Acanthella. All inhibited growth of Bacillus subtilis, Staphylococcus aureus and Candida albicans [278]. 10-Epi-isokalihinol H (280) and 15-isothiocyanato-l-epi-kalihinene (281) were isolated from Acanthella cavernosa from the Seychelles [279]. A Japanese specimen of A. cavernosa contained a sesquiterpene isothiocyanate (282) and 10 3-formamido-5p-isothiocyanatokalihinol A (283). Structures were assigned by spectral data interpretation [280]. Phakellia pulcherrima from the Philippines contained the minor diterpene isothiocyanates kalihinol L (284), 10-isothiocyanatokalihinol G (285), 10-epi-kalihinol H (286) and 10-isothiocyanatokalihinol C (287) [281]. 10-Epi-kalihinol I (288) and 5,10-bisisothiocyanatokalihinol G (289) were isolated from an Acanthella sp. from Okinawa [282]. 

Table 1. Bicyclic Sesquiterpene Isothiocyanates Isolated from Sponges...

Diterpene isothiocyanates fall into three distinct structural categories regarding their carbon skeletons the acyclic tetraenes (220 and 221), the biflorane framework (including the kalihinol family) (222-238), and the amphilectane framework (including the cyclo- and isocycloamphilectanes) (239-241). Like the sesquiterpene isothiocyanates, most of these compounds were isolated along with the corresponding isocyanate and formamide compounds. 

Nakamura, H., Deng, S., Takamatsu, M., Kobayashi, J., Ohizumi, Y, and Hirata, Y. (1991) Structure of halipanidne, a new sesquiterpene isothiocyanate from the Okinawan sponge Halichondria panicea (Pallas). Agric. Biol Chem., 55, 581-583. 

Sorek, H., Zelikoff, A.L., Benayahu, Y, and Kashman, Y. (2008) Axiplyns A-E, new sesquiterpene isothiocyanates from the marine sponge Axinyssa aplysinoides. Tetrahedron Lett., 49, 2200-2203. 

Nakamura, H Ye, B., and Mural, A. (1992) Synthesis of ( )-halipanicine, a marine sesquiterpene isothiocyanate isolated from an Okinawan marine sponge Hcdichondria panicea. Tetrahedron Lett., a, 8113-8116. 

Heating or irradiating alkenes in the presence of sulfur gives relatively low yields of thiiranes. For example, a mixture of sulfur and norbornadiene in pyridine-DMF-NHa at 110 °C gave a 19% yield of the monoepisulfide of norbornadiene as compared with a 78% yield by the method of Scheme 120 (79JCS(Pi)228). Often 1,2,3-trithiolanes are formed instead of thiiranes. The sesquiterpene episulfides in the essential oil of hops were prepared conveniently by irradiation of the terpene and sulfur in cyclohexane (Scheme 135) (80JCS(Pl)3li). Phenyl, methyl or allyl isothiocyanate may be used as a source of sulfur atoms instead of elemental sulfur. 

The structures and relative stereochemistry of epi-eudesmanes 25-27 from Axinella cannabina were formulated from 2D NMR and chemical correlation experiments [36]. The 500 MHz HNMR spectrum of 1 l-formamido-7/ H-eudesm-5-ene (27) measured in CDC13 showed a 2 3 cis.trans ratio of the -NHCHO group (cis 3 8.06 d, J = 2 Hz trans 5 8.20 d, J — 12 Hz). Isothiocyanate 26 was one of several sesquiterpenes reported from Acanthella pulcherrima [20]. 

Sesquiterpenes, sesterterpenes, dlbromotyrosine derivatives, isonitriles, isothiocyanates, polyalkylated indoles, macrolides, quinones, ancepsenolides, sterols... 

A species of Halichondria from the Marshall Islands contained an isothiocyanate (249) [255] and an isothiocyanate based on the guai-6-ene skeleton (250) was isolated from an unidentified sponge from Japanese waters [256]. Acanthella pulcherrima from Australia contained two isothiocyanates (251-252), in addition to known sesquiterpenes [257]. 

The first sesquiterpene thiocyanate to be isolated from a marine sponge was (15, 45, 65, 7/ )-4-thiocyanato-9-cadinene (253) from Trachyopsis aplysinoides. The structures of this compound and of an isothiocyanate with a new carbon skeleton (254), were determined by X-ray analysis and two additional isothiocyanates (255-256) were identified [258]. Isothiocyanate 254 was synthesised using an oxidative radical cyclisation reaction as a key step [259]. 

The marine isothiocyanates, with more than 80 compounds isolated so far, form the largest group of naturally occurring isothiocyanates. This well-established group of marine natural products is constituted mainly by terpene metabolites present as sesquiterpene and diterpene derivatives. The non-terpene isothiocyanate compounds include two cylindricine alkaloids and a series of long-chain aliphatic metabolites. Marine sponges constitute the main source of these compounds, although they are also found in nudibranches and tunicates. 

Although marine organisms produce a large number of isocyanates, isothiocyanates, and formamides, the corresponding thiocyanates have rarely been encountered. Indeed, the thiocyanate functionality has only been found in six sesquiterpenes (263-268), in four tricyclic quinoline alkaloids (271-274), and in psamaplin B (172) (included in the bromotyrosine derivatives discussed in the disulfide/polysulfide section). They have been found in marine sponges, as well as in nudibranches and tunicates. 

Dumdei, E. J., Flowers, A. E., Garson, M. J., and Moore, C. J., The biosynthesis of sesquiterpene isocyanides and isothiocyanates in the marine sponge A canthella cavernosa (Dendy) evidence for dietary tranfer to the dorid nudibranch Phyllidiella pustulosa, Comp. Biochem. Physiol., 113A, 1385, 1997. 

Compounds containing the isocyano group have fascinated natural products chemists ever since the first isocyanide xanthocillin was isolated from the fungus Penicillium notatum Westling in 1950 [1]. The existence of sesquiterpene isocyanides was first reported from the Mediterranean sponge Axinella cannabina in 1973 [2], closely followed by sesquiterpene isocyanides from the Mediterranean sponge Acanthella acuta by Minale et al. [3] and the Hawaiian sponge Halichondria sp. by Scheuer et al. [4]. These early reports also documented the presence of isothiocyanate [2] and formamide [4] functionality attached to the same carbon nucleus as the... 

Table 1 provides an update of the Chang-Scheuer summary and lists the structures of all new marine sesquiterpene isocyanides and related compounds including isothiocyanates, (1 - 67), by compound class,... 

---