Marine Natural Products 1986

Marine Natural Products D. J. Faulkner Scripps Institution of Oceanography, A- 0 12F, University of California, San Diego, La Joila, CA 92093, USA ~ ~~~ ~~~ Reviewing the literature published between October 1983 (Algal Metabolites) or July 1984 (invertebrate Metabolites) and July 1985 (Continuing the coverage of literature in Natura/ Product Reports, 1984, Vol. 1, pp. 251 and 551) 1 2 3 4 5 6 7 8 8.1 8.2 8.3 9 10 1 1 12 13 14 Introduction Marine Micro-organisms and Phytoplankton Blue-green Algae (Cyanobacteria) Green Algae Brown Algae Red Algae Sponges Coe len t e rates Soft Corals Gorgonians Other Coelenterates Bryozoans Marine Molluscs Tunicates Echinoderms Miscellaneous References 1 Introduction This Report provides an update of the two-part review of the literature of marine natural products that was published in Natural Product Reports during 1984. The first part of that review covered the literature published between 1977 and October 1983 concerning metabolites of marine algae and herbivorous marine molluscs.’ The second part reviewed publications reporting metabolites of marine invertebrates during the period 1977 to July 1984.’ Both areas are now combined into a single Report that continues the coverage until approximately July 1985.3 A few papers that were omitted from the previous reviews have been included in this Report. Two comprehensive reviews have appeared during this reporting period, on the subjects ‘Chemical and Biological Aspects of Marine Monoterpenes’j and ‘Paralytic Shellfish Poisons’.s A ‘Symposium-in-Print’ that is devoted to the chemistry of marine natural products has provided a showcase for research in this field. The papers cover many topics and are reviewed in the appropriate sections. One of the most satisfying aspects of research into marine natural products is the high level of interest that is exhibited by researchers outside the field. The natural symbiosis between marine biology and marine natural products chemistry is noticeably stronger, and the interest of the pharmaceutical industry in the pharmacology of marine metabolites has grown to gratifying proportions. Marine natural products are often the target of research in synthetic organic chemistry. While there are many interesting studies being directed toward the- synthesis of marine metabolites, this review will concentrate on examples of total synthesis rather than partial synthesis. 2 Marine Micro-organisms and Phytoplankton Three aromatic acids, rubrenoic acids A (l), B (2), and C (3), from the marine bacterium Alteromonas rubra showed broncho- dilator activity iv: zitro.b The structures of acids (1)-(3) were elucidated by interpretation of spectral data, and rubrenoic acid C (3) was synthesized by a relatively inefficient route. The antibiotic SS-228Y, from a species of the genus Chuinicr that had been isolated from shallow sea mud, was originally assigned the structure (4).’ On exposure to light, or if heated, the antibiotic rearranged to a naphthacene derivative ( 5 ) . Further studies suggested that structures (4) and ( 5 ) should be replaced by (6 ) and (7), respectively.8 The synthesis of both ( 5 ) and (7) has clearly confirmed the correct structure of the rearrangement product, SS-228R (7), and, by inference, of SS- 228Y (6).9 The antimicrobial activity of the diatom Nariculu delognei f. elliptica was shown to be due to (E)-phytyl (5Z,8Z, 1 l Z , 142,17Z)-icosa-5,8,11,14,17-pentaenoate (8), (62,92,122,15Z)-hexadeca-6,9,12,15-tetraenoic acid, (6Z,92,12Z,15Z)-octadeca-6,9,12,15-tetraenoic acid, and (62,92,122)-hexadeca-6,9,12-trienoic acid. The mild antimi- crobial activity of polyunsaturated fatty acids may account for the erratic antimicrobial activity that is associated with the crude extracts of many marine organisms. 0 0 0 0 0 2 N A T U R A L PRODUCT REPORTS, 1986 CHO H ( 9 ) X = O H , R ’ = H , R 2 = O S 0 3 - , R 3 = SO, (10) x = O H , R ’ = O S O , - , R ~ = H , R ~ = SO, ( 1 1 ) X = H , R ’ = R 2 = H , R 3 = SO3- (12) X = OH, R’ = R2 = H I R3= SO3- (13) X = R2= H I R ’ = OSO,, R 3 = SO, (14) X = R ’ = R 2 = R 3 = H ‘ O ’ A U \ H H \ H H H (15) R = A c (17) R = H \ \ H H H . OH H 0 2 C W I 1 R‘ (18) R’ = R2= H (19) R ’ = H , R 2 = Me (20) R’ = a c y l , R 2 = Me The chemistry and biological significance of paralytic shellfish poisons has been reviewed in detail.’ There are three new papers describing carbamoyl-N-sulphate derivatives of saxitoxin and neosaxitoxin. The structures of 1 lcr-hydroxy- carbamoyl-N-sulphoneosaxitoxin sulphate (9) and 1 lp-hydroxy- carbamoyl-N-sulphoneosaxitoxin sulphate (1 0) from the dino- flagellate Protugonyaulax catenella were first deduced from their electrophoretic behaviour and from the hydrolysis products. The physicochemical data for these compounds appeared under the new names toxin C3 (9) and toxin C4 (1 0), and the structure of toxin C4 was confirmed by X-ray analysis. The isolation of the carbamoyl-N-sulphates GTX-V (1 l ) , GTX-VI (12), and GTX-VIII ( 1 3) has been described in a full paper that expands on previous communications and in which a molecular basis for the interaction between saxitoxins and an excitable membrane is proposed.I3 Saxitoxin (14) has been synthesized by a new route that involved a 1,3-dipolar addition as the key ring-forming reaction.’-‘ Studies of the biosynthesis of saxitoxin (14) and its derivatives in Aphanizo- menun flus-aquae have provided evidence for an unexpected pathway involving two molecules of acetate, one of which is incorporated into arginine through the tricarboxylic acid cycle.’ At least two carbon atoms remain unassigned and, in particular, the possibility that two molecules of arginine are incoporated does not appear to have been eliminated. Two new polycyclic ethers, GB-5 (1 5 ) and GB-6 ( I 6), have been isolated from cultures of Gymnodinium brew Davis (= Ptychodiscus brecis Davis), which is the ‘red tide’ organism of the Gulf Coast of Florida.I6 The ether GB-5 (15) is the 37-0- acetate of brevetoxin-B (17). The structure of GB-6 (16) was determined by X-ray analysis and proved to be (27S,28R)- 27,28-epoxy-27,28-di hydrobrevetoxin-B. The dinoflagellate Dinophysis jortii produces, and transmits to shellfish, the toxins that are responsible for diarrhetic shellfish poisoning, which is a non-fatal but widely occurring gastroenteritis;’ ’ the dinophysistoxins are closely related to okadaic acid (18), which is a toxin that was first found in sponges’ * and later traced to the dinoflagellate Prorocentrum lima.I9 Dinophysistoxin-1 (19) is a 35-methyl derivative of okadaic acid (1 8) while dinophysistoxin-3 (20) is a mixture of 7- 0-acyl derivatives of dinophysistoxin- 1 ’ The pectenotoxins are a new group of diarrhetic shellfish toxins. Five pectenotox- ins were recognized in extracts of the scallop Patinopecten yessoensis, and they are presumed to arise from a dinoflagellate source. The structure of pectenotoxin-1 (21) was determined by X-ray analysis and the structure of pectenotoxin-2 (22) was assigned by comparison of spectral data. l 7 3 Blue-green Algae (Cyanobacteria) The absolute stereochemistries of the aplysiatoxins and oscillatoxin A have been determined as a result of extensive H n.m.r. and c.d. studies, and have been confirmed by an X-ray- crystallographic analysis of 19,2 1 -dibromoaplysiatoxin (23). ?* Deep-water specimens of Lyngbya majuscula from Enewetak Atoll contained three minor constituents, which were oscilla- NATURAL PRODUCT REPORTS, 1986 - D. J . FAULKNER 3 ‘. (21) R = OH (22) R = H OH OH ( 2 4 ) R = Me ; 4a - OH ( 2 5 ) R = Me; 4p - OH (27) R = H H 0’ OH (23) OH (26) R = Me (28) R = H OAc CHO &pg= H-- / CHO JCH0 OAc OAc (32) ( 3 3 ) ( 3 4 ) toxin B1 (24), oscillatoxin B2 (25), and 30-methyloscillatoxin D (26).’ Two related 3 1-nor-derivatives, i.e. 3 1 -noroscillatoxin B (27) and oscillatoxin D (28), were obtained as minor metabo- lites of a mixture of Schizothrix calcicola and Oscillatoria nigroviridis. The structures of (24)-(28) were elucidated by analysis of spectral data and by partial chemical degradation.2 Majusculamide C (29) is a cyclic depsipeptide, from the deep- water variety of L. majuscula, that inhibits the growth of fungal plant pathogen^.^^?^^ The structure of majusculamide C was determined by interpretation of spectral data. Hydrolysis of majusculamide C gave glycine, L-alanine, N-methyl-L-valine, N-methyl-L-isoleucine, N,O-dimethyl-L-tyrosine, racemic 2- amino-4-methylpentan-3-one, N-[(2S,3S)-2-hydroxy-3-methyl- pentanoyl]glycine, and 3-amino-2-methylpentanoic acid of unknown absolute stereochemistry.22 Two stereoselective syntheses of malyngolide (30) have been presented. ( )-Malyngolide (30) was synthesized with good stereoselectivity, using the catalytic hydrogenation of 2,3- didehydromalyngolide as the final step.24 A second route permitted the synthesis of all four possible diastereoisomers of malyngolide (30) in high diastereomeric and enantiomeric purity.25 4 Green Algae Green algae of the genera Halimeda, Penicillus, and Udotea contain unstable but extremely bioactive sesquiterpenes and diterpenes. An investigation of twelve species of Halimeda, all of which were subjected to extraction of their constituents in the field, gave various combinations of four diterpenes. In addition to halimedatrial(3 1),26 4,9-diacetoxyudoteal(32) was present in most samples, although halimedalactone (33) and the aromatic bisnor-diterpene aldehyde (34) were found in only two or three samples.’’ 4,9-Diacetoxyudoteal (32) had previously been reported from H . opuntia,28 but neither group of investigators has determined the stereochemistry of the molecule. The diterpenes (31F(34) exhibit antimicrobial activity and are c y t o t ~ x i c . ~ ~ 4 N A T U R A L P R O D U C T REPORTS. 1986 Penicillus dumetosus has been found to contain four diter- penes (35)--(38), all of which have a 1,4-diacetoxybutadiene moiety, while Penici1lu.r capitatus contains the triacetoxy- sesquiterpene (39) and an aldehyde (40) that is formally a hydrolysis product of (39).’” The only metabolite that was isolated from Ucjotea conglutinata was the known sesquiterpene flexilin (4 l) ,”) while lidotea cj.athi#ormi.r produced the same metabolites (39) and (40) as P. capitatu.s.2” A sample of Uchteu Jabellum from the Bahamas contained two dialdehydes (42) and (43).” One dialdehyde was identical to petiodial (42), which had earlier been isolated from the Mediterranean alga lidotea p e t i o l a t ~ . ~ ’ N o attempt was made to elucidate the relative stereochemistry of petiodial (42).2”.3 I The green alga C1aclophora.fascic.ulrri.r contains 4,6-di bromo- 2-(2,4-dibromophenoxy)anisole (44),32 which is a polybromin- ated diphenyl ether that resembles a class of sponge met a bol i te s . s3 The sea grass Arnphibolis antartica (not a green alga, but reviewed here for convenience) produces sandaracopimara- diene (45), isopimaradiene (46), and a new cleistanthene hydrocarbon (47). 3 4 5 Brown Algae Studies of the attractants that are released by the female gametes of brown algae to attract the motile male gametes continue to produce interesting results. The female gametes of Chorda tomento.sa secrete a mixture of multifidene (48), 3-butyl- 4-vinylcyclopentene (49), ectocarpene (50), and ( - )- dictyopterene C’ ( 5 1 ) that triggers an explosive discharge of spermatozoids from ripe antheridia prior to chemotaxis.35 The sperm attract ants of Cystop hora siliy uosa and Hormosiru hank sii were identified as cystophorene (52) and hormosirene ( 5 3 ) , respectively.”” Since the natural gamete attractants are produced in such small quantities, confirmation of the proposed structures and studies of the mechanisms of their action require synthetic materials. The absolute configuration of viridiene (54), which is the attractant for the male gametes of \OAc (35) AcO, (39) R = OAc (41 ) R = H OAc (40) C H O OR ( 4 2 ) R = Ac ( 4 3 ) R = H ( 4 4 ) Br ( 4 6 ) ( 4 8 ) (50) OAc (36) C H O ( 5 4 ) (45) ( 4 7 ) ( 4 9 ) (55) OH (56) N A T I I R A L . P R O D U C T R E P O R T S . 1986 D. J . F A U L K N E R 5 :T1,riti~otkirnin ptiinrwj.i. was determined by comparison of its behaciour with that of synthetic material on enantiospecific complexat;on gas ~hro rna tog raphy .~ ’ A synthesis of racemic multifidene (48) employs a fragmentation of ;i bicyclo[3.2.0]heptan-6-o1 as the key transformation.38 A series of compounds that mimic the gamete attractants multifidene (48). viridiene (54), and ectocarpene (50) has been syn- thesized:”’ ( + )-Dictyopterene A (55) and (+)-dictyopterene C’ have been synthesized, using the palladium-catalysed cyclization of a chiral allylic benzoate as the key An enant ioselect ive synthesis of (6S,7S,9R, 1 OR)-6,9- epoxynonadec-18-ene-7,lO-diol (56), which is an unusual lipid from Nothoiri urioninlu,4‘ has been described.l’ The racemic form of (56) has also been synthesized.13 Although no new sesquiterpenes from brown algae have been described, syntheses of (-)-zonarene (57) (a sesquiter- pene hydrocarbon from Dicr.tvptcvis zonurioitle.si4) and of ( )- p-dictyopterol (58) (purported to be a metabolite of Dictjwptm‘s dii~ciric*rrtuJi 1 have appeared. ( - )-Zonarene (57) was synthe- sized from the photo-adducts of (-)-piperitone and 1- substituted cyclobutenes.sh The proposed structure of p- dictyopterol (58) has been syn thes i~ed .~ ’ The physicochemical data of the synthetic sample are identical with those in the literature,i’ but attempts to re-isolate the natural compound for direct comparison were unsuccessful.s8 Although the majority of new diterpenes from brown algae belong t o established structural classes, two new diterpene carbon skeletons have recently been discovered. a-Dictalediol monoacetate (59) is an unusual tricyclic diterpene from an unidentified species of Dictjwta that is found in the Canary Islands.4” I t appears to be unrelated biosynthetically to dictyols [cf pachydictyol A (60)], with which it co-occurs. Dictyo- H I OH (58) (57) H \ \ OH tetraene (611, which is a metabolite of a drift-specimen of a species of Dictj~itu from the Brittany Coast, appears to be derived by further cyclization of the dictyol skeleton. The structure of dictyotetraene (61) was proposed on the basis of spectral data, particularly the ‘ H n.m.r. spectrum.i’) The latest member of the dictyol series, i.e. dictyol H (62) (a nietabolite of Dictj~otu &titutu from Barbados), co-occurs with pachydictyol A (60) and dictyol C (63).5’ The stereochemistry about the tetrahydrofuran ring of dictyol H (62) was not determined. Dihphus Iigulurus contains dictyol C (63)52 and dictyoxide (64),53 while dictyol F (65), epidictyol F (66), epoxypachydictyol A (67), and methoxydictydiene (68) have been isolated from Dictj*ota ciichotoma. Dictyol C (63) and the two allylic alcohols (65) and (66) exhibited antimicrobial activity . Dictjvta birrghamiae (from British Columbia) produces pachydictyol A (60), dictyoxide (64), and three new com- pounds, which are dictyol G acetate (69), dictyoxide A (70), and dictyotriol A diacetate (71).55 Dictyoxide A (70) is thought to be an artifact that is formed from dictyol G acetate (69) during the isolation process. Two C-14 epimers, namely dictyotriol A (73) and dictyotriol B (74), have been isolated from Dic’tj’otu indzcu.57 The physical data that were previously reported’h for dictytriol(72) are not identical with those ofeither dictyotriol A (73) or dictyotriol B (74). It should be noted that dictyoxide A (70) is not the same as dictyoxide (64) and that dictyotriol A diacetate (71) is not related to dictytriol (72), dictyotriol A (73), or dictyotriol B (74). Several new xenicane-class diterpenes have been isolated from brown algae. Hydroxydictyodial (75) is an antimicrobial metabolite of Diczyora spinulosa that inhibits feeding in the omnivorous fish Tilupiu niossunihicu at a concentration of 10; in food.s8 Three of the four new diterpenes that have been (60) 3- A c 0 (59) (66) (67) H ‘, (61 1 H \\ (68) (69) 9 H O -- @+ OH 11 l4 OH \ (72) 11R ( ” ) } epimers at C-14 \ )-2 H OH (75) R = OH (70 ) (71 1 (74) (80) R = H 6 NATURAL PRODUCT REPORTS. 1986 isolated from Pachydictyon coriaceurn, namely neodictyolactone (76), 18-acetoxydictyolactone (77), and isodictyoacetal (78), have the familiar xenicane carbon but pachyaldehyde (79)h0 is a norditerpene that may formally be derived by decarbonylation of dictyodial (80).h’ Pachylactone (81) is a minor metabolite of P. coriaceurn6’ that is related to ace to~ycrenul ide .~~ The structure of pachylactone was derived by interpretation of spectral data, particularly H n.m.r. n.0.e. measurements. Reference 62 gives a structure of ‘isoacetoxycrenulatin’ that was reported at a symposium in 1980 but which has not yet appeared in the literature. Three new tricarbocyclic cyclopropanoid diterpenes, which have been named tricyclodictyofuran A (82), tricyclodictyofuran B (83), and tricyclodictyofuran C (84), have been isolated, in very low yields, from Dictyota dichotorna.hS The structures were proposed on the basis of spectral evidence. The absolute configuration that has been proposed is based on a comparison with dilophol (85)hs rather than with the xenicanes from which the tricyclodictyofurans are probably derived : it might there- fore be erroneous. The absolute stereochemistry of dilophol (85), which is a metabolite of Dilophus ligulutu.qh6 was determined by a single- crystal X-ray diffraction study of the corresponding p - bromobenzoate.6s Dilophol (85) and 3-acetoxyacetyldilophol (86) were both isolated from a Japanese sample of Dicfyota dichotoma.6 Three ichthyotoxic and phytotoxic dolabellane-class diterp- enes, which are a diacetate (87), a triacetate (88), and the tetra- acetate (89) of the same tetraol, were isolated from a collection of Di/ophus,fusciola from the North Adriatic Sea.h7 A total of eight new diterpenoids (90)-(97) that are based on the dolabellane skeleton have been isolated from an unidentified species of D i c t ~ * o t a . ~ ~ - ~ ~ ) The major difference between these and other dolabellane derivatives is that the sites of unsatura- tion in the eleven-membered ring are at positions 4 and 8 rather than at 3 and 7 or at 2 and 7. Metabolite (90) is the only one that exhibits significant cytotoxicity.h8 Although no new dolastane diterpenes have been described during the reporting period, the absolute stereochemistry of isoamijiol (98) was determined by the c.d. allylic benzoate method.” The same technique has been used to determine the absolute configuration of crinitol (99), which is an acyclic diterpene (from Sargassum tor ti/^^^) that inhibits the growth of insect^.'^ The total synthesis of (+)- spata-13,17-dien-5-01 (loo), which is a metabolite of Stoecho- spermurn rn~rgimturn , ’~ is the first synthesis of a member of the spatane class of d i te rpene~. ’~ There have been some particularly interesting developments in the chemistry and pharmacology of prenylated aromatic compounds. A new chromenol, dictyochromenol (1 01), was isolated from Dictyopteris undulata and was shown to be ichthyotoxic at 27 ~ . p . m . ’ ~ The known metabolites zonarol(l7 p.p.m.), isozonarol (1 7 p.p.m.), zonarone (7 p.p.m.), isozonar- M e 0 (76) (78) (77) OHC/ R’ 0 R2 (79) [structure (80) is w i t h (7511 (81 1 R’ R2 (85) R’= R2 = H (86)