Current Bioactive Compounds 2007, 3, 1-36 1 Spongiane Diterpenoids†

Miguel A. González*

Department of Organic Chemistry/Institute of Molecular Science, Dr Moliner 50, E-46100 Burjassot, Valencia, Spain

Abstract: In this review we cover the structures, occurrence, biological activities and synthesis of all the spongianes and rearranged spongianes since their discovery in 1974. We have given special attention to structure revisions and biological properties of these polycyclic terpenoids of exclusive marine origin. However, an important part of the review describes the synthetic efforts in the field. Thus, this part has been subdivided into syntheses from other natural products, syntheses by biomimetic approaches and other approaches including enantioselective total syntheses.

INTRODUCTION the family from sponges of the genus Spongia [9]. Thus, in Marine terpenoids are typical constituents of the secondary accordance with the IUPAC recommendations the saturated metabolite composition of marine flora and fauna. These hydrocarbon I, named ‘spongian’, was choosen as the fundamental isoprenoid-derived compounds are common in almost all marine parent structure with the numbering pattern as depicted in Fig. 1. phyla and show a wide range of novel structures. Although most of them are also present in terrestrial organisms, the occurrence of a O few skeletons is restricted to certain marine species. In this review 12 16 11 13 we focus our attention to diterpenoids characterized by polycyclic 20 1 C D O O structures having either the spongiane (I, C20) (Fig. 1) carbon 9 framework or several degraded or rearranged spongiane-derived 2 14 A 10 H 8 15 H H skeletons. 5 17 3 B Spongiane diterpenoids are bioactive natural products isolated 7 4 H 6 H exclusively from sponges and marine shell-less mollusks (nudibranchs), which are believed to be able of sequestering the 19 18 spongian-derived metabolites from the sponges, soft corals, I, spongiane skeleton 1, isoagatholactone hydroids and other sessile marine invertebrates on which they feed. Most of these compounds play a key role as eco-physiological mediators and are of interest for potential applications as CO2H therapeutic agents. O Spongianes having the characteristic carbon skeleton I (Fig. 1) CO H have been reviewed up to 1990 and listed in the Dictionary of H 2 terpenoids [1]. During the last two decades, many new members of this family of natural products have been isolated and described in H H specific reviews on naturally occurring diterpenoids by Professor HO2C Hanson [2], and the excellent reviewing work on marine natural products by Professor Faulkner [3,4], now continued by the team of 2, isoagathic acid 3, grindelic acid Professor Blunt [5,6], all of which have mainly covered the isolation and structural aspects of spongianes. A recent review on Fig. (1). the chemistry of diterpenes isolated from marine opisthobranchs, has also included articles on isolation and structure determination of The first known member of the spongiane family, isoaga- spongianes up to 1999 [7]. The latter also covered some synthetic tholactone (1), was discovered by Minale et al. from the sponge studies of this class of substances. To the best of our knowledge, Spongia officinalis about thirty years ago, being the first natural there is only one more report dealing with the initial studies towards compound with the carbon framework of isoagathic acid (2). the synthesis of spongianes [8]. We now provide full coverage of Structure (1) was assigned based on spectroscopic data and recent advances in the field including a comprehensive description chemical correlation with natural grindelic acid (3) [10]. of the synthetic approaches and syntheses reported in the literature To date, there are nearly 200 known compounds belonging to on spongianes up to march 2006. this family of marine natural products, including those with a spongiane-derived skeleton. Most of them present a high degree of STRUCTURE, OCCURRENCE AND BIOLOGICAL oxidation in their carbon skeleton, particularly at positions C-17 ACTIVITY and C-19 as well as on all the rings A-D. Given the variety of The semisystematic naming of this family of diterpenoids was chemical structures found in the spongiane family, we could group introduced in 1979 following the isolation of the first members of them according to the degree of oxidation as well as the degree of carbocyclic rearrangement of the parent 6,6,6,5-tetracyclic ring system. Thus, we have integrated most of them into two main *Address correspondence to this author at the Department of Organic groups: compounds having the intact spongiane skeleton and Chemistry/Institute of Molecular Science, Dr Moliner 50, E-46100 compounds either with an incomplete skeleton or resulting from an Burjassot, Valencia, Spain; Fax: +34 96 3544328; E-mail: [email protected] hypothetical rearrangement process, which has been proposed several times from a biosynthetic point of view. †An invited review in the series of bioactive compounds.

1573-4072/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd. 2 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González

Sponges are exposed to a variety of dangers in their environ- R4= H; R1= OAc, R2= R3= R 4= H; R1= OH, R2= R3= H, R4= OH; ment and this has led to the development of chemical defense R1= H, R2= R4= OH, R3= H) were isolated from the sponge Spongia mechanisms against predation. Nudibranchs feed on a variety of officinalis [27], whose methanol extract is active against sponges and are able of storing selected metabolites, even transform Staphylococcus aureus, Pseudomonas aeruginosa and Bacillus them, for their own self defense. Thus, sponges and nudibranchs are sphaericus. It also inhibits the cell growth of HeLa cells with values a rich source of biologically active metabolites, and the spon- of ID50 1-5 mg/mL [11]. gianes, in particular, have displayed a wide spectrum of interesting Dorisenones A, B and D (5, R1= OAc, R2= H, R3= OH, R4= biological properties including antifeedant, antifungal, anti- OAc; R 1= OAc, R2= R4= H, R3= OH; R1= R 4= OAc, R2= R 3= H) microbial, ichthyotoxicity, antiviral, antitumor, antihypertensive, and dorisenone C (6, D13 R= Me) (Fig. 3) were isolated from the fragmentation of Golgi complex, as well as anti-inflammatory mollusk Chromodoris obsoleta [17], and sponges from the Aegean activity (see Table 1). Sea [28]. These compounds have displayed cytotoxic activities, in particular, dorisenone A has shown strong cytotoxicity against Intact Spongiane Skeleton L1210 and KB cancer cells [17]. The first subgroup contains compounds derived formally from the antimicrobial isoagatholactone (1) [11], and therefore O characterized by the functionalization present in ring D, a g-lactone AcO H ring D, in this case (Fig. 2). R O O O R1 R2 H H R1 R O O OAc 2 H H H R 3 (6) R3 R4 D13 R= Me H H D12 R= CHO (4) (5) R= CHO

R1= H, R2 = Me, R3 = OAc R1= OH, R2 = R3 = R4 = H R1= H, R2 = CH2OAc, R3 = OAc R1= OAc, R2 = R3 = R4 = H Fig. (3). R1= H, R2 = Me, R3 = OH R1= OH, R2 = R3 = H, R4 = OH R = H, R = CHO, R = H R = H, R = R = OH, R = H 1 2 3 1 2 4 3 From the african mollusk Chromodoris hamiltoni [29], new R = R = H, R = CH OAc R = OAc, R = H, R = OH, R = OAc 1 3 2 2 1 2 3 4 spongianes having a functionalised C-17 such as compounds 6 (D12 R1= OH, R2 = CH2OAc, R3 = OAc R1= OAc, R2 = R4 = H, R3 = OH R = H, R = Me, R = H R = R = OAc, R = R = H R= CHO) and 6 (R= CHO) have been isolated. Their biological 1 2 3 1 4 2 3 activity has not yet been investigated. Fig. (2). During the past few years, new spongiane lactones characterised by an acid group at C-19 and like 6 (D13 R= Me) with For example, aplyroseol-1 (4, R1= H, R2= Me, R3= OAc), was a double bond between C-13 and C-14 (Fig. 4). For example, isolated from the dendroceratid sponges Aplysilla rosea [12,13], compound 7 (R= H) was isolated from the sponge Spongia Dendrilla rosea [14] Aplysilla polyrhapis [15], and Chelonaplysilla matamata along with the hemiacetal lactone 7 (R= a -OMe) and the violacea [16] and also from the nudibranches Chromodoris isomeric lactones 8 [30]. Compound 7 and 8 (R=H) have also been obsoleta [17] and Chromodoris inopinata [18]. Anti-tumor activity found in the sponge Coscinoderma mathewsi along with the lactol 7 against the P388 mouse leukaemia cell line in vivo showed no (R=OH) [31]. Lactol 7 (R=OH) also called spongiabutenolide A significant activity. and its hydroxy C-19 derivative, spongiabutenolide B, together with isomeric lactols, spongiabutenolides C-D, having the carbonyl group of the lactone moiety at C-16 have been found in a The sponge Aplysilla rosea also contained the lactone 4 (R1= H, Philippines marine sponge of the genus Spongia [32]. R2= CH2OAc, R3= OAc). From the tentatively identified mollusk Ceratosoma brevicaudatum, it was isolated the simplest member of O R the series with a functionalised C-17 (4, R1= H, R2= CHO, R3= H) [19]. The mollusk resulted to be Ceratosoma epicuria [20] and the synthetic compound showed some cytotoxicity against HeLa and O O HEp-2 cancer cells [21].

Aplyroseol-14 (4, R1= R3= H, R2= CH2OAc) and aplyroseol-16 H R H O (4, R1= OH, R2= CH2OAc, R3= OAc) have been isolated more recently also from the sponge Aplysilla rosea [24], whereas the H H cytotoxic g-lactone spongian-16-one (4, R1= H, R2= Me, R3= H) has HO2C HO2C been found in several species such as Dictyodendrilla cavernosa (7) (8) [22], Chelonaplysilla violacea [16,23], Aplysilla var. sulphurea R= H R= H [24], and also in the mollusks Chromodoris obsoleta [17], C. R= a -OMe R= a -OMe petechialis [25], and C. inopinata [18]. The structure for R= OH R= b-OMe aplyroseol-14 was corrected a few years later by spectroscopic means, chemical synthesis (see synthesis section) and also by X-ray diffraction analysis [26]. Thus, structure 4 (R1= R3= H, R2= Fig. (4). CH2OAc) was renamed as isoaplyroseol-14. Several members containing the unsaturated g-lactone ring have Other related metabolites such as zimoclactones A 9 (R=OH), B 9 (R=H) and C 10 (Fig. 5) have been isolated recently from the shown antimicrobial properties. Compounds 5 (R1= OH, R2= R3= Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 3 marine sponge Spongia zimocca subspecies irregularia [33,34]. the corresponding hydroxy derivative 13 (R1= OH, R2= H, R3= H) Zimoclactone A showed a moderate cytotoxic activity against P388 [37], which has also been found in the sponge Spongia zimocca cell lines. [38], together with 12-deacetyl aplysillin 13 (R1= H, R2= OH, R3= H). They have shown antifeedant properties and therefore they are O OH suggested to be part of the chemical defense of these organisms. 12- epi-aplysillin 13 (R1= OAc, R2= H, R3= H) has also been found in the nudibranch Chromodoris geminus, along with the 7-acetoxy O O derivatives 13 (R = R = H, R = OAc) and 7a -acetoxy-12-epi- O HO 1 2 3 aplysillin 13 (R = OAc, R = H, R = OAc) [18]. More recently, a H H 1 2 3 R O new member of this group has been isolated and is characterised by HO OH HO OH a b-epoxide between the positions C-11 and C-12, compound 14. H H HOH C This metabolite was isolated from the mollusk Chromodoris 2 obsoleta and presents a strong cytotoxicity against L1210 and KB (9) (10) cancer cells [17]. R= OH This group, also includes a number of furanospongianes which R= H presents a furan ring D instead of the g-lactone ring D (Fig. 7-9). Fig. (5). There are several examples which are charac-terised by different substituents at C-19, compounds 15. These molecules were isolated In this first subgroup, we can also include examples where the from the sponge Spongia officinalis and this dichloromethane D-ring system is an anhydride, a lactol, or a double hemiacetal extract displayed antifungal activity [39]. Compound 15 (R= functionality which is acetylated (Fig. 6). For example, compound CO2Me) was synthesised during that work by esterification with 11 was isolated from the sponge Dictyodendrilla cavernosa and is ethereal the first anhydride isolated from a marine sponge [22]. Lactol 12 also called aplyroseol-15, was isolated from Aplysilla rosea and is characterised by an oxidation pattern between a lactone and an O O anhydride [24]. O Compound 13 (R1= R2= R3= H) was isolated from the sponges H H Spongia officinalis [35], Chelonaplysilla violacea [23] and Aplysilla var. sulphurea [24]. Aplysillin (13, R = H, R = OAc, RO OR 1 2 H H R ROH2 C O O (15) (16) R= CH3 R= H R= CHO R= Ac O O R= COOH R= COOMe H H R= CH2OAc O OH OAc H H O O R O (11) (12) H H

R R OAc OAc O RO 1 2 O H H HOH2C HOH2C O O (17) (18) R= H R= b-Ac R= OH R= H H OAc H OAc

H H Fig. (7). R3 (14) (13) diazomethane of 15 (R= CO2H), and recently has been isolated as a metabolite of an unidentified sponge of the family Demospongiae, R1= R2= R3= H together with known 15 (R= CO2H) and a new furanospongiane, R1= H, R2= OAc, R3= H compound 15 (R= CH 2OAc) [40]. During this work the inhibition R1= OAc, R2= H, R3= H R = OH, R = H, R = H of DNA polymerase b lyase was demonstrated by compounds 15 1 2 3 (R= CO Me, CO H and CH OAc), being ester 15 (R= CO Me) the R1 = H, R2= OH, R3= H 2 2 2 2 R1 = H, R2= H, R3= OAc most active. In addition, compound 15 (R= Me) was also found in R1 = OAc, R2 = H, R3= OAc the sponge Hyatella intestinalis [41], as well as compound 15 (R= CO2H) has also been isolated from the sponges Spongia matamata Fig. (6). [30] and Coscinoderma mathewsi [31]. Other furanospongianes are characterised by a highly R3= H) has been found in the sponge Aplysilla rosea [36], though functionalised A-ring, for instance, compounds 16-23. The series of later other studies demonstrated that the sponge was Darwinella sp. compounds 16 has been isolated from similar species of the genus [14], and also in the sponge Spongia officinalis [27]. The molecule Spongia [9], and their stereochemistry was confirmed by single was inactive in a number of antimicrobial assays. crystal X-ray analysis, in addition to their absolute configuration measured by circular dichroism. Spongiatriol 16 (R=H) causes Compound 13 (R1= OAc, R2= H, R3= H)(12-epi-aplysillin) was found in the marine organism Chromodoris luteorosea, along with falling of blood pressure in hypertensive rats and also reduces the 4 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González heart rate of anesthetised cats [42]. Compounds 16 and other acetate derivatives have been isolated from the nudibranch Casella O O atromarginata as well [43]. However, compounds 17 and 18 were O Hyatella intestinalis O found in the sponge [41]. The two epimers of R2 H H compound 18 (R=H), 3a and 3b, named spongiadiol and R CH OR O CH OH epispongiadiol, respectively, were also isolated from Australian 1 H 2 3 H 2 Spongia 17 AcOH2C HOH2C species [9], and together with the compound (R=OH), (24) (25) named isospongiadiol and found in Caribbean Spongia species [44], are active against herpes simplex virus type 1 and P388 cancer R1= OH, R2= H, R3 = Ac R1= OAc, R2= H, R3= H cells. They have also shown induction of apoptosis in human R = H, R = OAc, R = H melanoma cells [45]. This series of compounds are also present in 1 2 3 the sponge of the genus Rhopaloeides odorabile and it was demonstrated that the environmental conditions generates a O O O considerable chemical variation [46]. O O From a Great Barrier Reef sponge of the genus Spongia, two H R1 H new metabolites were isolated, compounds 19 and 20 (Fig. 8). Both O were inactive in antitumor tests against P388 H H CO2R2 R2 R1 (26) (27)

R1= CH2OH, R2= H R1= OH, R2= H O O R1= CH3, R2= H R1= H, R2 = OH HO O H H Fig. (9). HO OH HO H H HOH2C Spongiolactone A 26 (R 1= CH3, R 2= H) is structurally related and (19) (20) was isolated from Spongia officinalis var. arabica [50]. Finally, lactones 27 were isolated from the sponge Spongia zimocca sensu [51], which was erroneously identified as Spongia matamata [30]. O O The last subgroup is composed by pentacyclic compounds, such R O 1 R2 as 28-29, having and additional ring E, which is a peculiar group of H H R1 highly oxygenated metabolites (Fig. 10). O OR O OH H 2 H O O R2OH2 C (21) (22) O O R1= H, R2 = Ac R1 = OH, R2= H R1= R2= H R1 = H, R2= OH H O H O

OH OR2 R3 O H R2 H O R1 R1

R2 H (28) (29) R = H, R = OCOPr R = OCOPr, R = OH R = OCOPr, R = H, 17-b R1 1 2 1 2 1 2 H R1= H, R2 = OAc R1= OCOPr, R2 = OAc R1 = OAc, R2 = H, 17-b R1= H, R2 = OH R1= R2= H R1 = OAc, R2 = Ac, 17-a (23) R1= OH, R2= OCOPr R1= R2= OAc R1 = OCOPr, R2= Ac, 17-a R = OAc, R = OCOPr R = H, R = Ac, 17-b R1= OH, R2 = H, R3= CH2OH 1 2 1 2 R1= H, R2= OH, R3= CH2OH Fig. (10). R1= H, R2= OH, R3= CH3

Fig. (8). Schmitz and co-workers established the structure 28 (R1= H, R2= OCOPr) by X-ray analysis and suggested that the oxygenated cancer cells [47]. Compounds 21 were isolated from the nud- positions of these compounds might act as a complexing moiety for ibranch Casella atromarginata [43], whereas compounds 22 and 23 cations and such complexation might play a role in the biological were found in other australian Spongia species [48]. activity of these compounds. Compound 28 (R1= H, R2= OCOPr) also known as aplyroseol-1 is mildly cytotoxic in lymphocytic More recently, Fontana and co-workers isolated several leukemia PS cells [52]. Taylor and co-workers have also confirmed furanospongiane acetates, compounds 24 (Fig. 9), from the mollusk the absolute stereochemistry of 28 (R1= H, R2= OCOPr), except one Glossodoris atromarginata [49]. They also found the corresponding stereocenter, by X-ray diffraction methods of the p-bromobenzoyl tetracetate of tetraol 19. Several of these acetates had been derivative [53]. Aplyroseol-1 (28, R = H, R = OCOPr) and previously found in the related mollusk Casella atromarginata [43]. 1 2 aplyroseol-2 (28, R1= H, R2= OAc) have been found in the sponges Finally, within the group of furanospongianes it is worth to Igernella notabilis [52], Aplysilla rosea [12] and Dendrilla rosea mention several metabolites characterised by a lactone ring forming [13], and recently aplyroseol-2 (28, R1= H, R2= OAc) was isolated the A-ring, compounds 25-27. For example, compounds 25 and 26 from the mollusk Chromodoris obsoleta showing cytotoxic activity (R1= CH2OH, R2= H) were isolated from a Great Barrier Reef (but no relevant anti-tumor activity in vivo) [17], as well as from sponge of the genus Spongia [47], in particular, compound 25 has Chromodoris inopinata [18]. shown certain cytotoxicity against P388 cancer cells. Compound 28 (R1= H, R2= OH) was also isolated from Igernella notabilis [52], and aplyroseol-3 (28, R1= OH, R2= Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 5

OCOPr), aplyroseol-4 (28, R1= OAc, R2= OCOPr), aply-roseol-5 Degraded or Rearranged Spongiane Skeleton (28, R1= OCOPr, R2= OH) and aplyroseol-6 (28, R1= OCOPr, R2= The second main group is formed by a number of norspon- OAc) were isolated from Aplysilla rosea [12] and also from gianes, secospongianes and other compounds with a rearranged Dendrilla rosea (except aplyroseol-4) [13], though the known carbon skeleton. aplyroseol-3 (28, R1= OH, R2= OCOPr) was isolated for the first time from Aplysilla sp. [54]. In addition, aplyroseol-1 (28, R = H, Norrisolide (33) is the first known member of rearranged 1 spongiane diterpenes. It was firstly isolated by Faulkner and Clardy R2= OCOPr), aplyroseol-5 (28, R1= OCOPr, R2= OH), and aplyroseol-6 (28, R = OCOPr, R = OAc) are inhibitors of the from the dorid nudibranch Chromodoris norrisi and its structure 1 2 was determined by single-crystal X-ray diffraction analysis [61]. enzyme phospholipase A2 (PLA2), an enzyme involved in inflammation processes [55]. Structurally, norrisolide belongs to a family of natural products that share a fused g-lactone-g-lactol ring system attached to a hydro- Dendrillol-1 (28, R1= R2= H) and dendrillol-2 (28, R1= R2= phobic bicyclic core and includes dendrillolide A (34), initially OAc) were isolated from Dendrilla rosea [13], and the former was assigned to dendrillolide B and dendrillolide C (35) (Fig. 12), for also found later in the mollusk identified as Ceratosoma brevicau- example, which were found in the Palauan sponge Dendrilla sp., datum [19], along with compounds 29 (R1= OCOPr, R2= H, 17-b), later reidentified as Chelonaplysilla sp. [62], along with norrisolide 29 (R1= OAc, R2= H, 17-b), 29 (R1= OAc, R2= Ac, 17-a ) and 29 (33) as a minor constituent and dendrillolide B whose structure is (R1= OCOPr, R2= Ac, 17-a ). The mollusk was ultimately identified still unknown [63,64]. to be Ceratosoma epicuria [20]. Dendrillol-1 (28, R1= R2= H) has proved to have cytotoxic activity on tumor cells.[21] More recently, AcO AcO it has been isolated compound 29 (R1= H, R2= Ac, 17-b), called acetyldendrillol-1, from the mollusk Cadlina luteomarginata [56], O H O which was missasigned a 17-a configuration during its isolation [57]. H O O Finally, several compounds with a derived intact spongian structure merit mention. For example, haumanamide 30 (Fig. 11), based on a nitrogenous amide was isolated from a Pohnpei Spongia O O sp. [58], which is active against KB cancer cells and LoVO (colon H H cancer). Polyrhaphin D 31 is also a novel isospongian diterpene in 33 34 which a 2,3-fused tetrahydrofuran ring replaces the 3,4-fused ( ) norrisolide ( ) dendrillolide A tetrahydrofuran ring normally found in spongiane diterpenes, which O was isolated from the sponge Aplysilla polyrhaphis in 1989 [15]. H O

O N O Ph O H H H H O (35) dendrillolide C H H HOOC (30) (31) Fig. (12). R2 Norrisolide (33) has also been found in other marine species R1 (see below) and displays PLA2 inhibition [55], ichthyotoxicity to O H Gambusia affinis [65], as well as Golgi fragmentation [66]. Dendrillolide A (34) has also been found in other marine H species (see below) and biologically inactivates PLA2 at 2 mg/mL (32) [55].

R1= CH3, R2 = O Aplyviolene (36) was also isolated from Palauan sponge R1= COOH, R2= H2 Dendrilla sp. though this structure was initially assigned to den- R1= CH2OAc, R2 = O drillolide A. The X-ray analysis of 36 isolated from the sponge Chelonaplysilla violacea confirmed this initial misassignment Fig. (11). [23,67,68]; aplyviolacene (37) was also found in this sponge (Fig. 13). Also, it is worth mentioning several structures with a iso- The chemical investigation of the sponge Aplysilla sulphurea spongian skeleton, which was named marginatane skeleton. For yielded as major component aplysulphurin (38) (Fig. 13) and a example, marginatafuran 32 (R1= COOH, R2= H2) is a small amount of aplysulphuride whose structure was not elucidated. furanoditerpene isolated from the dorid nudibranch Cadlina The structure 38 was confirmed by a single-crystal X-ray luteomarginata, whose structure was solved by X-ray diffraction determination [13]. analysis [59]. This compound has also been found later in sponges The studies of the constituents of the Mediterranean sponge of the genus Aplysilla [56], together with a derivative of Spongionella gracilis led to the structure elucidation by spectral marginatone 32 (R = CH , R = O), which was isolated from the 1 3 2 analysis of gracilin A (39) and gracilin B (40), which represents the sponge Aplysilla glacialis [60], the 20-acetoxy marginatone 32 (R = 1 first bis-nor-diterpene observed from a marine sponge, together CH OAc, R = O) was isolated, however, from the skin extracts of 2 2 with two gracilin A derivatives (41-42) and spongionellin (43) the nudibranch Cadlina luteomarginata [56]. which possess a new carbocyclic skeleton (Fig.14) [70-72]. Gracilin A inactivates PLA2 at 2mg/mL [55]. 6 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González

OAc OAc O O H H OAc AcO OAc O O O O O O H H H H O O H H

O O (44) tetrahydroaplysulphurin-1 (45) tetrahydroaplysulphurin-2 H H OAc (36) aplyviolene (37) aplyviolacene H

OAc O

O H H O

O O (46) tetrahydroaplysulphurin-3 O Fig. (15). (38) aplysulphurin

Fig. (13). O O

R O O H 1 O O H O O OAc OAc H O O H H OR2 H O (47) macfarlandin A (48) macfarlandin B AcO OAc O O (39) R1=OAc R2= Ac, gracilin A (40) gracilin B (41) R1=H R2= Ac, gracilin E O OAc (42) R1=H R2= H, gracilin F O O O O O H H H OAc H O

H OAc (49) macfarlandin C (50) macfarlandin D Fig. (16).

(43) spongionellin Further chemical studies of the sponge Spongionella gracilis led to the discovery of spongiolactone (51) (Fig. 17) whose struc- Fig. (14). ture was deduced from chemical and physico-chemical evidence [76]. Also the two minor norditerpenes (52) and (53) were charac- The sponges Darwinella sp. and Darwinella oxeata contain the terised by spectral data and derivatisation reactions [77]. known rearranged spongiane aplysulphurin 38 and the new From the antarctic sponge Dendrilla membranosa two new compounds tetrahydroaplysulphurins-1 (44), -2 (45), and -3 (46) rearranged spongianes were isolated and identified by spectral data (Fig.15) [14]. The structure of tetrahydro-aplysulphurin-1 (44) was and chemical correlations. 9,11-dihydrogracillin A (54) and confirmed by X-ray studies [73], and also it has been isolated from membranolide (55) (Fig. 18) showed growth inhibition of Bacillus the dorid nudibranch Cadlina luteomarginata [60]. subtilis, also membranolide was mildly active against S. aureus The chemical study of dorid nudibranchs of the genus [78]. Chromodoris, in particular, Chromodoris macfarlandi yielded five The X-ray analysis of a keto derivative of 9,11-dihydro- new rearranged spongianes, macfarlandins A-E (47-50, 37), whose gracillin A (54) confirmed the structure fixing the previous structures were elucidated from spectral data (Fig. 16). unknown stereochemistry at C-10 [79]. 9,11-dihydrogracillin A Macfarlandin E (37) has been named aplyviolacene, see above. (54) has also been isolated from the Northeastern Pacific dorid Only the structure of macfarlandin C (49) was determined by a nudibranch Cadlina luteomarginata and the sponge Aplysilla sp single-crystal X-ray diffraction analysis. Macfarlandin E is identical [56]. to aplyviolacene 37 and was marginally active against Vibrio anguillarum and Beneckea harveyi. Macfarlandin A, B and D showed antimicrobial activity against Bacillus subtilis [74,75]. Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 7

O O OCOCH2CH(CH3)2 OH H H OCH3 H AcO OCH3 H O H O O H H H H O OH (51) spongiolactone O H H H OAc H (56) shahamin A (57) shahamin B O O H OAc OAc OAc OH H H OAc OAc O O H H O O (52) (53) H H H H Fig. (17).

H H H OAc (58) shahamin C (59) shahamin D O O OH OH O OAc H H O OAc O H R R H CO Me 1 2 O O 2 O H H (54) 9,11-dihydrogracilin A (55) membranolide H H

Fig. (18). H The investigation of two Red Sea Dysidea sponges yielded ten (61) shahamin F R =R =H new rearranged spongianes, shahamins A-J (56-65), together with (60) shahamin E 1 2 (62) shahamin G R1=H,R2=OH known aplyviolacene (37). Structures of all compounds were (63) shahamin H R =OH, R =H elucidated from spectral data, mass spectra, and by comparison with 1 2 other related known diterpenes (Fig. 19) [80,81]. Shahamin F (61) O has also been found in the nudibranch Chromodoris annulata [18]. AcO OAc From the Californian sponge Aplysilla polyrhaphis were R R H isolated the known compounds norrisolide (33), aplyviolene (36), 1 2 O O macfarlandin E (37), shahamin C (58), and three novel rearranged diterpenes, polyrhaphins A-C (66-68) (Fig. 20) [15]. Norrisolide H (33), macfarlandin E (37), shahamin C (58), and polyrhaphin A (66) H were also found in the dorid nudibranch Chormodoris norrisi collected in the same locality as Aplysilla polyrhaphis, which is the presumed dietary source. Shahamin C (58), and polyrhaphin C (68) inhibited feeding by the Gulf of California rainbow wrasse (64) shahamin I R1=R2=H Thalossoma lucasanum. Polyrhaphin C (68) also showed (65) shahamin J R1=OH,R2=H antimicrobial activity against Staphylococcus aureus and Bacillus subtilis while aplyviolene (36) was also active against B. subtilis. Polyrhaphin C (68) has also been isolated from the Cantabrian Fig. (19). nudibranch Chromodoris luteorosea and displayed ichthyotoxic activity to Gambusia affinis [65]. The degraded and rearranged diterpenoid glaciolide (75) (Fig. A reinvestigation of the Palauan sponge Dendrilla sp. led to the 22) was isolated from the dorid nudibranch Cadlina luteomarginata isolation of four novel rearranged spongiane diterpenes (69-72) and the sponge Aplysilla glacialis. The structure was solved by (Fig. 21) in addition to known norrisolide (33), dendrillolide A (34), extensive spectroscopic analysis and chemical derivatisation and dendrillolide C (35). The structure of the four novel metabolites [60,84]. were determined by interpretation of spectral data [64]. The chemical study of the nudibranch Chromodoris luteorosea The skin chemistry of the Indian Ocean Nudibranch yielded luteorosin (76) (Fig. 23), along with the known Chromodoris cavae was examined leading to the isolation of macfarlandin A (47). Both compounds presented ichthyotoxic chromodorolide A (73) (Fig. 22), a putative repellent which disp- activity [65,85]. lays both cytotoxic and antimicrobial activities [82]. A few years later, the same authors reported the isolation of chromodorolide B (74) from the same nudibranch [83]. 8 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González

The encrusting sponge Aplysilla tango gave five degraded AcO H spongian diterpenes, including the known gracilin A (39), AcO O MeO2C AcO aplytandiene-1 (77), aplytandiene-2 (78), aplytan-gene-1 (79) and O aplytangene-2 (80) (Fig. 23) [86]. O H H H H O OAc

O H H

(66) polyrhaphin A (67) polyrhaphin B OAc O OAc

(76) luteorosin H O H H O O O O O

H O H OAc H

(68) polyrhaphin C (77) aplytandiene-1 (78) aplytandiene-2 Fig. (20). O OAc OAc CO2 Me O O AcO H O O H O O O O H H H H H H H O H

H H (79) aplytangene-1 (80) aplytangene-2

(69) 12-desacetoxypolyrhaphin A (70) 12-desacetoxyshahamin C Fig. (23).

O CO Me 2 Three new rearranged spongiane-type diterpenes were isolated AcO O O from a Red Sea Dysidea species along with known norrisolide (33). O Thus, the structures of norrlandin (81), seco-norrisolide B (82) and OAc H seco-norrisolide C (83) (Fig. 24) were elucidated from intensive O NMR experiments and both norrisolide (33) and norrlandin (81) displayed cytotoxic activities [87]. H H The Pohnpeian sponge Chelonaplysilla sp. contains the known (71) dendrillolide D (72) dendrillolide E spongiane-derived diterpenes norrisolide (33), dendrillolide A (34), dendrillolide D (71), aplyviolene (36), and 12-desacetoxyshahamin Fig. (21). C (70). Three novel rearranged spongiane-type diterpenes, chelona- plysins A-C (84-86) (Fig. 24) were identified by interpretation of spectral data and chemical correlation with known compounds. O O Aplyviolene (36), chelonaplysin B (85), and chelonaplysin C (86) OAc HO O AcO O exhibited antimicrobial activity against the bacterium Bacillus AcO AcO subtilis [62]. Chelonaplysin C (86) is also a consti-tuent of the O O Cantabrian nudribranch Chromodoris luteorosea, presents ichthyotoxicity to Gambusia affinis [65] and its structure has been H H OAc confirmed by a single-crystal X-ray study [88]. H H The skin extracts of the Sri Lankan dorid nudibranch Chromodoris gleniei contained dendrillolide A (34), 12- H H desacetoxyshahamin C (70) and the new shahamin K (87) (Fig. 25) (73) chromodorolide A (74) chromodorolide B [18]. O The sponge Aplysilla glacialis gave four new rearranged and/or degraded “spongian” terpenoids: cadlinolide A (88), cadlinolide B (89), aplysillolide A (90), and aplysillolide B (91) (Fig. 26). The O structures were determined by extensive spectroscopic analysis and chemical interconversions, the structure of cadlinolide A (88) was H further confirmed by X-ray diffraction analysis [60].

(75) glaciolide The New Zealand sponge Chelonaplysilla violacea contains known norrisolide (33), dendrillolide A (34), aplyviolene (36), Fig. (22). chelonaplysin C (86), and a series of new rearranged spongianes: Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 9

cheloviolenes A-F (92-97) and chelo-violin (98) (Fig. 27) [16]. The H O structures were established by analysis of the spectroscopic data. O O H O H This study indicated that the structure assignment for chelonaplysin O B (85) was incorrect, since its 1H NMR spectrum was identical to OAc that of cheloviolene A (92). Separate proof for the structure of H OAc H cheloviolene A (92) was obtained by a single-crystal X-ray CO2Me determination [89]. Another investigation on the antarctic sponge Dendrilla H H membranosa led to the isolation of dendrillin (99) (Fig. 28), a (81) norrlandin (82) seco-norrisolide B spongiane-derived norditerpene related to 9,11-dihydro-gracillin A (54). Dendrillin (99) displayed no deterrent effect towards the O major sponge predator, the sea star Perknaster fuscus [90]. i O Pr H CH2OAc O H AcO O H O O O H O O HO O H H O H H O H CH2OAc H H R

(83) seco-norrisolide C (84) chelonaplysin A H H OAc HO (92) R= a -OH, cheloviolene A (94) cheloviolene C O O H (93) R= b-OH, cheloviolene B O CH2CO2Me H O H O CH2CO2Me H H O O H O H H H H O (85) chelonaplysin B (86) chelonaplysin C O H Fig. (24). H (95) cheloviolene D (96) cheloviolene E OAc OAc O O OAc H O O H H H O O H O OAc H H H H H (87) shahamin K (97) cheloviolene F (98) cheloviolin Fig. (25).

O Fig. (27). H H OH

O O The chemical study of the South African nudibranch Chromodoris hamiltoni led to the isolation of the chlorinated homo- H diterpenes hamiltonins A-D (100-103) (Fig. 28), which possess an O O unusual 3-homo-4,5-seco-spongiane carbon framework [69]. Hamiltonins A (100) and B (101) showed no significant activity in O O antimicrobial and cytotoxicity bioassays. (88) cadlinolide A (89) cadlinolide B The chemical investigation of skin extracts of North-eastern Pacific nudibranch Cadlina luteomarginata led to the isolation of H H O O the novel seco-spongian (104) (Fig. 29) [56]. O O A number of seco-spongianes were isolated from Aplysilla rosea and are characterised by an g-lactone between C15 and C17 H H H [24]. Thus, aplyroseols -8 to -12 and dendrillol-3 and dendrillol-4 OH present the structure as drawn in 105, typical of ent-isocopalanes (Fig. 29). Aplyroseol-13 (106) was also isolated from this sponge (90) aplysillolide A (91) aplysillolide B and possess a carbon skeleton similar to several norditerpenoids isolated from the sponge Aplysilla pallida: aplypallidenone (107), Fig. (26). 10 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González aplypallidoxone (108), aplypallidione (109), and aplypalli-dioxone carbonyl group of the lactone ring of 113 for a hemiketal carbon. (110) (Fig. 30). The structures were elucidated by spectroscopic Finally, compound 115 can be seen as a derivative of 114 by the studies and the crystal structures of aplypallidenone and aplypal- lidoxone were determined by X-ray diffraction methods [91]. CO2Me Further studies on the Antarctic sponge Dendrilla membranosa by different research groups have led to the isolation of novel CHO H H OAc H OAc O (106) aplyroseol-13 H O H O OAc AcO CO2Me AcO CO2Me

(99) dendrillin O O H H

O O H H H H H H O OH (107) aplypallidenone (108) aplypallidoxone Cl Cl OH OH O O CO2Me AcO CO2Me (100) hamiltonin A (101) hamiltonin B O O O O O CHO H O CHO H H H H H O Cl Cl (109) aplypallidione (110) aplypallidioxone OH OH (102) hamiltonin C (103) hamiltonin D Fig. (30).

Fig. (28).

O CO2Me CO2Me H H O OAc H O H O (111) dendrinolide OMe H OAc H R H 1 CO Me R2 2 (104) (105) O

R1= OCOC3H7, R2= H aplyroseol-8 O H H R1= OCOCH3, R2 = H aplyroseol-9 O O R1= OH, R2= OCOC3H7 aplyroseol-10 CO2Me R1= OCOCH3, R2 = OCOC3H7 aplyroseol-11 R1= OCOC3H7, R2= OCOCH3 aplyroseol-12 (112) (113) R1= H, R2= H dendrillol-3 R1= OH, R2= OH dendrillol-4 Fig. (29). H H rerranged spongiane members. For example, dendrinolide (111) O O (Fig. 31) which was isolated together with known 9,11-dihydro- gracilin A (54). H H H OMe O This structure was elucidated by interpretation of spectral data CO2H and comparison with data for similar compounds [92]. O Other researchers found in the same sponge, the new com- (114) (115) pounds 112-115 (Fig. 31). Compound 112 is a nor-diterpene related to known gracilin A (39) and its structure containing a g-methyl Fig. (31). butenolide moiety, was determined by spectroscopic data interpre- tation. Compound 113 is a rearranged diterpene related to known loss of methanol as a consequence of an intramolecular displace- tetrahydroaplysul-phurin-1 (44). Compound 114 is very similar to ment of the hemiketalic methoxy group by the free carboxylic acid 113, the main difference between them is the substitution of the to give the corresponding d-lactone [93]. Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 11

Also another research group working with Dendrilla B (124) and cadlinolide C (119) showed moderate anti-inflam- membranosa were able to discover new rearranged spongia-nes matory activity. Pourewic acid A (122) has been found simulta- related to membranolide (55). Thus, membranolides B-D (116-118) neously in the sponge Dendrilla membranosa, see compound 114, (Fig. 32) were isolated along with known membranolide (55), however, the reported optical rotation was of opposite sign. aplysulphurin (38), and tetrahydroaply-sulphurin (44). Membra- Similarly, also cadlinolide C (119) has been found in the sponge nolides C (117) and D (118) display Gram-negative antibiotic and Dendrilla membranosa, see compound 115. antifungal activities [94]. The first chemical study of patagonian nudibranchs, in parti- cular the dorid nudibranch Tyrinna nobilis has led to the isolation of R2 R1 a new seco-11,12-spongiane, named tyrinnal (125) (Fig. 34) [96]. CHO O O OMe HO O OAc OMe AcO O O CO2H CHO O O H OAc (116) membranolide B (117) R1= OMe, R2 = H membranolide C H OAc H (118) R1= H, R2= OMe membranolide D

Fig. (32). H H (125) tyrinnal (126) chromodorolide C In the course of a NMR-directed sponge extract screening program, an extract of Chelonaplysilla violacea was found to Fig. (34). contain compounds of interest. After intensive isolation work, eight new spongiane diterpenes were identified, including the known The small scale extract of an Aplysillid sponge exhibited potent tetrahydroaplysulphurin-1 (44) and cadlinolide B (89). cytotoxicity. The isolation of the bioactive substances of the whole Two of the new metabolites are related to cadlinolide B and sponge, tentatively identified as Aplysilla sulfurea, led to the were therefore reported as cadlinolides C (119) and D (120) (Fig. isolation of known chromodorolide diterpenes chromodorolide A 33). Pourewanone (121) presents a new carbon skeleton, being the (73) and B (74), which were reported from the nudibranch first example of a formate compound of marine origin, while Chromodoris cavae, along with the new derivative chromodorolide compounds 122-124 are lactone seco-acid derivatives of cadlinolide C (126) (Fig. 34). All chromodorolides displayed significant B (Fig. 33) [95]. cytotoxicity against P388 cell line but not useful at low concentrations (1 mg/mL). Chromodorolide A (73) also showed nematocidal activity against the free-living larval stages of the H H OMe parasitic nematodes Haemonchus contortus and Trichostrongylus colubriformis [97]. O O Using an assay to detect inhibitors of the lyase activity of DNA H H polymerase b, the bioassay-directed fractionation of an extract of an O O unidentified sponge of the family Demospon-giae led to the isolation of two new and bioactive bis-norditerpenoids, compounds O O (127) and (128) (Fig. 35) [40]. (119) cadlinolide C (120) cadlinolide D

R H H 2 OCHO O O H O H OH OMe CO2H R1 O (127) R = CO Me, R = OH (121) pourewanone (122) pourewic acid A 1 2 2 (128) R = CO H, R = OH O O 1 2 2 H H Fig. (35). O O H H H H Two new rearranged spongiane diterpenes named omriolide A OMe OH (129) and omriolide B (130) (Fig. 36) have been isolated from the CO2H CO2Me southern Kenyan sponge Dictyodendrilla aff. retiara [98]. Omriolide A (129) possesses a unique trioxatricyclodecane ring (123) 15-methoxypourewic acid B (124) methylpourewate B system. The structures of both diterpenes were elucidated by interpretation of MS results and NMR data. Both omriolide A and Fig. (33). B lacked cytotoxicity against several tumor lines as well as any activity on the Golgi membrane, on which norrisolide (33) was Pourewic acid A (122) was inactive in both leukaemia cell line found to be highly active [66]. and in antimicrobial tests. Pourewic acid A (122), methylpourewate 12 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González

H Aplyroseol-2 HO O Cytotoxic AcO H H O (28, R1=H, R2=OAc) H O O Aplyroseol-5 H PLA2 inhibition H (28, R1= OCOPr, R2=OH) O O AcO Aplyroseol-6 PLA2 inhibition H H (28, R1= OCOPr, R2=OAc) O (129) omriolide A (130) omriolide B Dendrillol-1 Cytotoxic (28, R1= R2=H) Fig. (36). Haumanamide 30 Cytotoxic

Norrisolide 33 Golgi fragmentation, PLA Table 1. Biological Activity Found in Compounds 1-130 2 inhibition, ichthyotoxic

Dendrillolide A 34 PLA2 inhibition Compound Biological Activity

Gracilin A 39 PLA2 inhibition Isoagatholactone, 1 Antimicrobial Macfarlandins A 47, B 48 and D 50 Antimicrobial, ichthyotoxic Aplyroseol-7 Antifeedant and cytotoxic Macfarlandin E 37 Antimicrobial (4, R1=H, R2=Me, R3=OAc) Aplyviolene 36 Antimicrobial Spongianal Cytotoxic (4, R1=R3=H, R2=CHO) 9,11-Dihydrogracillin A 54 Antimicrobial

Spongian-16-one Membranolide 55 Antimicrobial Cytotoxic (4, R1=H, R2=Me, R3=H) Shahamin C 58 Antifeedant Lactones 5 Antimicrobial and cytotoxic Antifeedant, antimicrobial and Polyrhaphin C 68 Dorisenone A ichthyotoxic Cytotoxic (5,R1=R4=OAc,R2=H,R3=OH) Cytotoxic, antimicrobial, Chromodorolide A 73 Dorisenone B antinematocidal Cytotoxic (5,R1=OAc,R2=R4=H,R3=OH) Luteorosin 76 Ichthyotoxic Dorisenone C Cytotoxic Norrlandin 81 Cytotoxic (6, D13 R= Me) Chelonaplysin B 85 Antimicrobial Dorisenone D Cytotoxic (5,R1=R4=OAc, R2=R3=H) Chelonaplysin C 86 Antimicrobial, ichthyotoxic

Zimoclactone A, 9 (R=OH) Cytotoxic Membranolide C 117 Antimicrobial, antifungal

12-epi-aplysillin Membranolide D 118 Antimicrobial, antifungal Antifeedant 13 (R1=OAc, R2=R3=H) Cadlinolide C 119 Antiinflammatory 12-epi-deacetyl-aplysillin Antifeedant Pourewic acid A 122 Antiinflammatory 13 (R1=OH, R2=R3=H)

12-deacetyl-aplysillin Methylpourewate B 124 Antiinflammatory Antifeedant 13 (R1=H, R2=OH, R3=H) Inhibition of DNA polymerase b Bis-norditerpenoids 127, 128 Epoxide 14 Cytotoxic lyase

Antifungal and inhibition of DNA Furans 15 polymerase b lyase SYNTHESIS OF SPONGIANE DITERPENOIDS

Spongiatriol 16 (R=H) Antihypertensive Several syntheses have appeared within the last twenty five years and we will classify them in three main groups. We will also Spongiadiols 17 and 18 Antiviral and cytotoxic include the synthetic studies developed so far, thus, we will describe the syntheses from other natural products, syntheses using Furanolactone 25 Cytotoxic biomimetic approaches and finally other approaches including the total synthesis of rearranged spongianes. Aplyroseol-1 Cytotoxic and phospholipase A 2 Generally, despite the interesting molecular architectures and 28 ( , R1=H, R2=OCOPr) (PLA2) inhibition biological properties of spongianes, there have been relatively few synthetic studies towards their synthesis. In the 1980s, most of the Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 13 synthetic studies towards spongiane-type diterpenes addressed mainly the synthesis of isoaga-tholactone and the preparation of simple furanospongianes. manool copalic acid CO Me In the next decade, syntheses of several pentacyclic spongianes H 2 were accomplished together with the development of biomimetic- sclareol labdanolic acid like strategies for the synthesis of more complex furanospongianes H and isoagatholactone derivatives. Over the last three or four years, some structure-activity studies have emerged together with several ent-methyl isocopalate (137) approaches towards more complex oxygenated spongianes. O Syntheses from Other Natural Products Manool (131), copalic acid (132), sclareol (133), labdanolic acid (134), abietic acid (135), and carvones (136) (Fig. 37) have abietic acid H been used for the preparation of optically-active spongianes. Naturally occurring racemic labda-8(20),13, dien-15-oic acid H (copalic acid) has also been used for preparing racemic compounds. podocarp-8(14)-en-13-one (138)

OH

CO H H 2 H O (+)-carvone H H H TBSO H 131, manool 132, copalic acid 139

OH R CO2Me

CO H H H 2 OH OH (-)-carvone

H H O H

133, sclareol 134, labdanolic acid 140a R= H 140b R= OCO2 Me Scheme 1. Precursors of spongiane diterpenoids prepared from natural sources.

H acid (3) by Minale et al. during the structure elucidation of (+)-1 O [10]. The required functionalization of the allylic methyl group was achieved by sensitized photooxygenation to give allylic alcohol H CO H 2 136, (+)- and (-)-carvone

135, abietic acid + 1) PCC H (+)-manool CO Me 137 2) MnO /HCN 2 Fig. (37). (131) 2 H MeOH H These starting materials were converted into versatile tricyclic 141 intermediates having the characteristic ABC ring system of spongianes (Scheme 1) such as ent-methyl isocopalate (137), OH podocarp-8(14)-en-13-one (138) and phenanthrenones (139-140). Several strategies have been reported to build up the necessary ring 1) 1 O , methylene blue D from those key intermediates, preferably as a furan ring or a g- 2 EtOAc/EtOH CO2Me 6N H2SO4 lactone ring. The choice of podocarpenone 138 as starting material H dioxane assures the absolute stereochemistry at C-5, C-9 and C-10. 2) P(OMe)3 17% 56% Moreover, the election of methyl isocopalate-137 phenanthrenones H 139-140 also assures the stereochemistry of the additional methyl 142 group at C-8 of the ring system. OH O In 1981, Rúveda et al. reported the first synthesis of a natural LiAlH4 OH MnO2 spongiane diterpene [99]. (+)-Isoagatholactone (1) was synthesized (+)-1 H from tricyclic ester 137 prepared from (+)-manool (131) in three H O 72% 57% synthetic steps (Scheme 2). Two successive oxidations of manool H H followed by acid-catalyzed cyclization of methyl copalate 141 gave 143 144 the known intermediate 137 [100], also obtained from grindelic Scheme 2. Rúveda´s synthesis of natural isoagatholactone. 14 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González

142. The allylic rearrangement of 142 with simultaneous lactoni- reduced with diisobutylaluminium hydride, the furan (±)-151 was zation to give lactone 143, followed by reductive opening of the obtained in 19% yield. The major drawback of Nakano´s synthesis lactone ring gave the known degradation product of isoagatho- of 151 is the yield of the photochemical reaction to functionalize C- lactone, diol 144 [10]. Finally, allylic oxidation with MnO2 gave 16 to give 142 (25% yield based on recovered 137) and the final (+)-isoagatholactone (1) in 3.9% yield from 137. aromatization, which encouraged further studies to solve these low Contemporaneous studies by Nakano et al. described soon after yielding steps [101,102]. the synthesis of racemic isoagatholactone using a similar strategy in In 1984, another synthesis of natural isoagatholactone (+)-(1) which the reaction conditions were different as well as the starting was reported by Vlad and Ungur (Scheme 6) [105]. The route is material, which was racemic copalic acid (Scheme 3) [101]. Thus, identical to that of Rúveda since the same diol 144 was oxidized by (±)-isoagatholactone (1) was prepared in 11.6% yield from racemic MnO2 to give isoagatholactone (see also Scheme 2). In this case methyl isocopalate 137 [102]. compound 144 was prepared in 48% yield by allylic oxidation of Unnatural (-)-isoagatholactone has also been prepared by isocopalol 155 with SeO2 in EtOH, though Rúveda and colleagues Rúveda et al. using the same sequence of steps starting from methyl reported that this oxidation on isocopalate 137 and isocopalate (+)-137 readily prepared from copalic acid (Scheme 4) alcohol(isocopalol) 155 led to complex mixtures of products [104]. [103,104]. The interest in spongiane-type diterpenes possessing a Isocopalol 155 was prepared by acid-catalyzed cycliza-tion of furan ring D led to the synthesis of (-)-12a -hydroxyspongia- an acetate mixture (154) (Scheme 6) [106]. These authors have used 13(16),14-diene (151) by Rúveda et al. using 148 also prepared chiral isocopalol 155 and diol 144 for the synthesis of sponge from methyl isocopalate (Scheme 4) [104]. This unnatural metabolites such as aldehydes 156 and 157 by consecutive spongiane was designed as a precursor for other members with oxidations [107]. These aldehydes have also been prepared in different functionality in ring D since it contains, the required racemic form starting from (±)-137 (methyl isocopalate) via the stereochemistry at C-12. Compound (+)-137 was converted into racemic diol (±)-144 [108]. 12,14-isocopa-ladiene (148) by LiAlH4 reduction, mesylation, and The same authors also reported the synthesis of a elimina-tion. Photooxygenation of 148 and reduction produced furanoditerpene, methyl spongia-13(16),14-dien-19-oate (160), by alcohol 149 which was submitted to a second photooxygena-tion cyclization of methyl lambertianate (159), which can be obtained reaction, and the resulting unsaturated cyclic peroxide 150 was from lambertianic acid (158), a diterpene acid of the Siberian cedar treated with ferrous sulfate to afford 12-hydroxy-furan 151. Pinus sibirica (Scheme 6) [105]. Concurrent to this report, Nakano et al. described the synthesis In 1985, Rúveda et al. reported the first synthesis of a naturally of racemic 151 from hydroxy-isocopalane 142 (Scheme 5), which occurring furanospongiane, albeit in racemic form (Scheme 7) was prepared as outlined in Scheme 3 from (±)-copalic acid. [109]. (±)-Spongia-13(16),14-diene (15, R= CH3) was prepared Epoxidation of 142 followed by treatment with lithium diisopro- from (±)-methyl isocopalate (137) via the same unsaturated lactone pylamide (LDA) led to b-elimination and lactonization in one-pot (143) used in the synthesis of isoagatholactone (see Scheme 2). It is to give a,b - unsaturated g-lactone 153 in 50% yield. When 153 was worth mentioning that lactone 143 was similarly prepared from alcohol 142, however, the latter was synthesized in an improved manner (60% overall yield) by epoxidation of 137 and subsequent 1) HCOOH treatment with aluminium isopropoxide [108]. Racemic lactone 143 CO2H CO Me H H 2 was then hydrogenated on Pt to give 161, which was reduced with 2) CH N /Et O 2 2 2 LiAlH4, oxidized under Swern conditions and treated with p-TsOH H 70% H to afford the desired furan 15 (R= CH3) in 20% overall yield. The tetracyclic diterpene (±)-spongian 164, which is the tetrahydrofuran 132, copalic acid ent-methyl isocopalate (137) derivative of 15 (R= CH 3) and possesses precisely the fundamental OH parent structure I (Fig. 1), was synthesized in this work by hydrogenation of furan 163. Furan 163 was obtained by allylic 1 rearrangement with simultaneous cyclization of the diol 162, which O2, py, hematoporphirin was prepared by lithium aluminum hydride reduction of 142. CO2Me 25% H A few years later, Nakano et al. also described the synthesis of (±)-spongia-13(16),14-diene (15, R= CH 3) from the same hydroxy- H isocopalane 142 used in the synthesis of (±)-151 (Scheme 8) [110], however, that starting material was synthesized from (±)-methyl (±)-142 isocopalate (137) using the improved procedure developed by Rúveda et al. for the synthesis of related tricyclic diterpenes OH (aldehydes 156 and 157) [108]. Thus, epoxidation of methyl 1) 3.5% H2SO4 , dioxane, 83% OH isocopalate 137 gave a -epoxide 165 which upon treatment with H aluminium isopropoxide afforded hydroxy-isocopalane 142 in 60% 2) LiAlH4 , 95% overall yield. Lactonization and b-elimination of 142 using H2SO4, H followed by isomerization with 10% ethanolic potassium hydroxide 144 gave a ,b-unsaturated g-lactone 166, which was reduced with O lithium aluminium hydride to give diol 167. Oxidation of 167 with pyridinium chlorochromate gave the desired (±)-furanospongian 15 O (R= CH3) in 55% yield (Scheme 8). Collins reagent More recently, Urones et al. reported the preparation of the 59% H useful intermediate in spongiane synthesis, ent-methyl isocopalate (137), from sclareol [111] (133) and labdanolic acid [112] (134), H two abundant bicyclic natural products (Scheme 9). Thus, sclareol (±)-1 (133), a major terpenic constituent of Salvia sclarea, was acetylated quantitatively with acetyl chloride and N,N-dimethylaniline, Scheme 3. Nakano´s synthesis of racemic isoagatholactone. Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 15

OH

1 1) O2, methylene blue copalic 1) CH2N2/Et2 O EtOAc/EtOH CO Me CO Me acid 2 H 2 2) HCOOH H 2) P(OMe)3 (ent-132) 20% H H

methyl isocopalate (+)-137 145 1) LiAlH 4 6N H2 SO4 2) MsCl/py dioxane 88% 85% 3) EtO- Na+/EtOH

OH O LiAlH4 OH MnO2 H H H (-)-1 O 89% 64% H H H 148 146 147

1 1) O2 , rose bengal 67% OH OH OH 2) P(OMe)3 O 1 O O2 , rose bengal O FeSO4·7H2O H 14% H 75% H

H H H 149 150 151

Scheme 4. Rúveda´s synthesis of ent-isoagatholactone (-)-(1) and ent-13(16),14-spongiadien-12a-ol (151).

OH OH O SeO OAc 10% H2SO4 OH 2 HCOOH H 48% m-CPBA CO Me CO Me H 2 99% H 2 H H 154 155 H H 1) acetylation 2) SeO (±)-142 152 2 OH OH CHO OH MnO OH 2 OAc O O (+)-1 LDA DIBAL-H H 95% H 50% H 19% H O H H 156 H H 144 Swern oxid. CHO 153 (±)-151

CHO Scheme 5. Nakano´s synthesis of (±)-13(16),14-spongiadien-12a -ol (151). H

H affording the diacetyl derivative 168, whose isomerization with 157 bis(acetonitrile)palladium (II) chloride led to the diacetate 169 (89%). The selective hydrolysis of the allylic acetoxy group of 169 O led to hydroxy acetate 170, whose oxidation with MnO2 gave O H SO aldehyde 171. Subsequent oxidation of 171 with NaClO followed 2 4 2 H by esterification with diazomethane afforded methyl ester 172. MeNO2 PhMe Regioselective elimination of the acetoxy group and cyclization H 32% H with formic acid led to ent-methyl isocopalate (137) in 49% overall CO2R CO2Me yield from sclareol (8 steps). Labdanolic acid (134), the main acid 158 R= H 159 160 component of Cistus ladaniferus, is firstly esterified with R= Me diazomethane, and then dehydrated and isomerized with I2 in Scheme 6. Vlad´s syntheses of natural isoagatholactone (+)-1, aldehydes refluxing benzene to give methyl labden-15-oate 174. Ester 174 is 156 and 157, and methyl spongia-13(16),14-dien-19-oate (160). 16 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González

OH H

1) m-CPBA H2SO4 O O 1) CH N copalic 2 2 2) Al(iPrO)3 dioxane H2/Pt CO Me CO Me acid 2 H 2 H H 2) HCOOH H 60% O 80% O (±-132) H H H H

methyl isocopalate (±)-137 142 143 161

1) LiAlH4 LiAlH 2) (COCl)2/DMSO 20% OH 4 3) p-TsOH 87%

H2SO4 O O O dioxane H2/PtO2 CH2OH H 52% H 42% H H

H H H H R 162 163 164 15, R= CH3 Scheme 7. Rúveda´s syntheses of (±)-spongia-13(16),14-diene (15, R= CH3) and (±)-spongian (164).

O ammonium perbromide (PTAP) and subsequent elimination with Li2CO3/LiBr to give the a ,b-unsaturated ketone 178. Reduction of 178 and acetylation gave the compound 179 which was subjected to ozonolysis to afford the highly functionalized secospongiane 180 in m-CPBA Al(i-PrO)3 (±)-137 H CO2Me 142 65% yield. 72% 82% The readily available abietic acid (135) together with other H naturally ocurring resin acids isolated from conifer oleoresins are 165 common starting materials for the synthesis of natural products and numerous diterpene derivatives [114,115]. (+)-Podocarp-8(14)-en- 13-one 138 (Scheme 11) is a versatile chiral starting material easily prepared from commercially available (-)-abietic acid or colophony H2SO4 KOH O LiAlH [116]. Recently, the enantioselective biomimetic synthesis of this dioxane EtOH 4 chiral building block has been described [117]. In the course of 143 H 62% 100% O 100% synthetic studies on the chemical conversion of podocarpane diterpenoids into biologically active compounds, Arnó et al. H achieved an efficient synthesis of natural (+)-isoagatholactone (1) 166 and (-)-spongia-13(16),14-diene (15, R= CH3) starting from chiral OH podocarpenone 138 [118]. Compound 138 was converted in six O steps into the common intermediate 186 (40% overall yield), OH PCC appropriately functionalized for the elaboration of the D-ring H H system (Scheme 11). 55% The necessary 8b-methyl group was introduced by H H stereocontrolled acetylenic-cation cyclization of acetylenic alcohol R 167 15, R= CH3 183, which was prepared from 138 by epoxidation, silica gel catalysed eschenmoser ring-opening reaction and addition of Scheme 8. Nakano´s synthesis of (±)-spongia-13(16),14-diene. methyllithium. The instability of enol trifluoro-acetate 184 (~70% overall yield from 138) to hydrolysis required in situ incorporation of the hydroxymethyl side chain to give hydroxy ketone 185 which converted into unsaturated ester 176 by elimination of phenyl- 186 selenic acid from 175, and then cyclized with formic acid to afford was isomerized at C-14, to afford compound , upon treatment ent-methyl isocopalate (137) in 45% overall yield from labdanolic with methanolic sodium methoxide. This intermediate was used in two separate approaches to complete the D ring of targeted acid (5 steps). spongianes. In the first approach, the required homologation at C- The same authors showed how this material, ent-methyl 13 was introduced by carbonylation of triflate 187, subsequent isocopalate (137), can be converted into 9,11-secospon-gianes, one deprotection in acidic media afforded directly the desired of the most widespread subgroups of spongianes (Scheme 10) 9-11 isoagatholactone (+)-1 (20% overall yield from 138). On the other [113]. To this end, the introduction of a D double bond and hand, addition of trimethylsilyl cyanide provided the carbon at C- subsequent cleavage was investigated. The method failed with 13, compound 188. Subsequent hydrolysis with concomitant tricyclic derivatives of 137, no cleavage conditions were successful. deprotection, lactonization, and dehydration occurred by treatment The strategy was then applied to other tetracyclic derivatives and with a mixture of hydrochloric acid and acetic acid at 120 ºC in a led to the synthesis of secospongiane 180. The precursor of sealed tube to give lactone 189, which was transformed into (15, R= secospongiane 180 was the known hydroxy-isocopalane 142, which CH3) via reduction to its corresponding lactol, followed by was again synthesized using Rúveda´s method as outlined in dehydration and aromatization in acidic media (Scheme 11). (-)- Scheme 7 [108]. Treatment of 142 with OsO followed by oxidation 4 Furanospongiane 15 (R= CH3) was thus prepared in eleven steps with TPAP gave the ketone 177 in 68% yield. The desired double from 138 in 28% overall yield. bond was introduced by bromination with phenyltri-methyl- Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 17

N OAc OH OH AcCl , OAc (MeCN)2 PdCl2 K2CO3 MnO2 MeOH H OH 97% H OAc 89% H OAc H OAc 94% 98% H H H H 133, sclareol 168 169 170

CHO CO2Me CO2Me 1) NaClO2 ) CH N SiO /D HCOOH 2 2 2 2 CO Me H H H H 2 OAc 98% OAc 90% 70%

H H H H

171 172 173 ent-methyl isocopalate (-)-137

HCOOH 95%

1) CH2N2 SePh 2) I2 /PhH LDA/PhSeCl H2O2/AcOH CO2H CO2Me CO2Me CO2Me H OH 98% 85% 57%

H H H H

134, labdanolic acid 174 175 176

Scheme 9. Urones´ syntheses of ent-methyl isocopalate (-)-137 from sclareol (133) and labdanolic acid (134).

introduction of a hydroxy function at the 7-position in the starting O O OH OH material 138 (Scheme 13). Formation of the dienyl acetate of 194 followed by oxidation with m-chloroperbenzoic acid gave the O 1) PTAP O 1) OsO4 hydroxy enone 195 in 74% yield which was elaborated to give 142 hydroxy ester 197, precursor of the pentacyclic diterpenes. It is 2) TPAP H 2) Li2 CO3 O LiBr O worth mentioning that the homologation at C-13 was conducted 68% H 99% H more efficiently by cyanophosphorylation followed by reductive 196 177 178 elimination to give nitriles . The versatility of intermediate 191 also led to further investi- OAc OAc OAc OHC OAc gations which culminated with the synthesis of acetyldendrillol-1 O 202 and revision of its stereochemistry at C-17, as well as the O O synthesis of tetracyclic spongianes functionalized at C-17 (Scheme 1) LiAlH4 O 3 14) [57]. The introduction of a cyanophosphorilation step improved 65% 2) Ac2 O,py O O the synthesis of 191 which was then converted into the intermediate 39% dialdehyde 201. Acetylation of compound 201 with AcOH/Ac O H H 2 and sulfuric acid (1%) at 65 ºC gave exclusively natural acetate 179 180 202, while reduction followed by lactonization led to (-)-spongian- 16-oxo-17-al 204 (Scheme 14). This compound was next converted Scheme 10. Urones´ synthesis of 9,11-secospongiane 180. into (-)-aplyroseol-14 206, having an unpredented d-lactone unit for spongianes, and its structural isomer 207 which permitted the structural reassignment of this natural product [122]. This fact was In the early 1990s, the same research group described the first also confirmed by X-ray crystallography of compound 206 [26]. enantioselective synthesis of pentacyclic spongianes [119,120]. To date the synthetic routes reported for these natural products are Recently, the same laboratory reported a couple of structure- based on this one. Chiral podocarpenone 138 was converted into the activity relationship studies of the spongianes prepared in the group cyclobutene-ester 191 by photo-chemical reaction with acetylene, including the synthesis and biological evaluation of novel C7,C17- nucleophilic carboxylation and reductive dehydroxylation as functionalized spongianes (Scheme 15) [21,123]. Some of these indicated in Scheme 12. Compound 191 was hydrolized under new spongiane derivatives possess an a -acetoxy group at C-15 and alkaline conditions and then cleaved with ozone to afford (-)- were obtained from pentacyclic samples using an optimized dendrillol-1 28 (R1= R2= H), the simplest member of the hemiacetal-ring opening under basic conditions. The synthetic pentacyclic spongianes. This synthetic sequence was later shortened protocol developed for the synthesis of 204 was also used to by reductive cyanation with tosylmethyl isocyanide (TosMIC) to convert hydroxy-cyclobutenone 197 into spon-gianal 210, 211 and give nitriles 193, which were subjected to alkaline hydrolysis in 212 which were evaluated against HeLa and HEp-2 cancer cells ethylene glycol ethyl ether and ozonolysis. The key feature of the being compound 212 the most active. strategy is the cleavage of a cyclobutene ring to form a latent acid- Arnó et al. have also achieved the total synthesis of (-)-spongia- dialdehyde unit, compound 192, which spontaneously underwent 13(16),14-diene (15, R = CH3) starting from (+)-carvone via the internal lactone-hemiacetal formation. Based on this synthetic plan, phenanthrenone 215, which contains the two necessary methyls the same authors have prepared related C7-oxygenated congeners groups at C-8 and C-10, and an useful carbonyl group at C-14 for [121] (aplyroseol-1 (28, R= OCOPr), aplyroseol-2 (28, R= OAc) the final assembly of the D ring (Scheme 16) [124]. and deacetyla-plyroseol-2 (28, R= OH)) upon stereoselective 18 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González

O O CF CO H OH 3 2 MeLi (CF CO) O abietic H2 O2 /NaOH p-TsNHNH2 O 3 2 acid silica H 86% H H 90% H 100% (135) O 82% H H H H 138 181 182 183

OCOCF3 O O OSO2CF3 1) , PPTS 1) MeLi OH NaOMe OH O OTHP H H H H 2) HCHO 85% 2) NaHMDS 75% Cl H H H 3) H

184 185 186 N N(SO2CF3)2 187 76% Me SiCN, ZnI 3 2 1) Pd(OAc) , Ph P, 97% 2 3 Et3N, DMF, CO 70% O 2) PPTS OTMS

CN HCl/AcOH O O OTMS 120˚C 1) DIBAL-H (+)-1 H 84% H 2) H2 SO4 H 86% H H H R 188 189 15, R= CH3

Scheme 11. Arnó´s syntheses of (+)-isoagatholactone (1) and (-)-spongia-13(16),14-diene (15, R= CH3) from 138.

C(SMe)3 O CO2Me CO2H OH

1) C2H2/hn 1) HgO,HgCl2 1) KOH 2) SmI CHO H 2) CH(SMe)3 H 2 H 2) O3, then H CHO BuLi,CeCl3 3) 2% NaOMe Me2S H H H H ~40% 75% 70% 138 190 191 192

O CN O 1) C H /hn 1) KOH 2 2 192 2) TosMIC/t-BuOK H 2) O3 , then Me2S H O 40% 64% H OH H R2 R 193 1 28, R1 = R2 = H Scheme 12. Arnó´s synthesis of (-)-dendrillol-1 (28, R1= R2= H).

The strategy is based on a C® ABC® ABCD ring annulation was carried out by isomerization of the double bond in 217, then sequence in which the key step for the preparation of the tricyclic careful epoxidation followed by treatment with p-TSA gave the ABC-ring system present there was an intramolecular Diels-Alder furanoketone 219. Compound 219 is a potential precursor of other (IMDA) reaction [125]. The whole sequence takes 13 steps to furanospongianes functionalized in ring A. Finally, Wolff-Kishner furnish the furanospongiane (15, R=CH3) in 9% overall yield. reduction of 219 afforded (15, R=CH3) in 75% yield. Carvone is first alkylated twice to introduce a three carbon side- A new strategy towards oxygenated spongianes using (-)- chain which is then elongated using a wittig-type reaction to give carvone as starting material has recently been described by Abad et 213. Formation of the silylenolether of 214, which upon IMDA al. [126] as outlined in Scheme 17. This synthetic sequence follows reaction in toluene at 190 ºC during 7 days provided stereo- a B® AB® ABC® ABCD approach in which carvone is first selectively compound 215 in 95% overall yield. The tricyclic converted into the decalone 220 (AB system) by alkylation and system 215 is already an useful intermediate for the synthesis of cyclization in acidic media. The construction of the C ring needed norspongianes and other spongianes functionalized in ring A as an intramolecular Diels-Alder reaction (IMDA) reaction to give well as other terpenes containing the same ABC-ring system. Diels-Alder adduct 226. Therefore, decalone 220 was transformed Cyclopronation of the enol double bond followed by homologation into the IMDA precursor 225 by homologation at C-9, epoxide of the carbonyl group at C-14 led to enol ether 216. After opening, wittig reaction and introduction of the dienophile moiety. completing the desired carbon framework, functionalization at C-16 The desired cycloaddition took place at 112ºC for 17 h to give the Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 19

O OAc O CN

AcCl/Ac2O 1) m-CPBA 1) C2H2/hn H py H 2) Na2S2O3 H 2) (EtO)2P(O)CN H NaHCO3 3) SmI2/t-BuOH 97% OH OH H H 74% H 52% H 138 194 195 196 O

CO2Me CO2H O 1) KOH 1) KOH 2) CH N CHO 2 2 H 2) O3, then Me2S H CHO H O or Me2SO4 3) NaOMe R R OH H H H R 58% 197, R= OH 198, 200 28, R= OH 28, Ac2O R= OAc 199, R= (PrCO)2O R= OAc 28, R= OCOPr OCOPr

Scheme 13. Arnó´s syntheses of (-)-aplyroseol-1 (28, R= OCOPr), (-)-aplyroseol-2 (28, R= OAc) and (-)-deacetylaplyroseol-2 (28, R= OH).

O

CO2Me CO2Me O O3 Ac2 O/AcOH CHO H then Me2S H CHO H2 SO4 cat. H O 90% 85% H H H OAc 191 201 202 O NaBH4 O 99% R O NaBH4 H CO2 Me 90% O H p-TSA 205, R=OH 206, H H Ac2O O 65% CHO R=OAc O H OH H 203 204 O BF3 , AcCl, Bu3SnH H 45% OAc H 207 Scheme 14. Arnó´s syntheses of (-)-acetyldendrillol-1 (202), (-)-spongian-16-oxo-17-al (204), (-)-aplyroseol-14 (206) and (-)-isoaplyroseol-14 (207).

O

CO2 Me CO2Me CO2Me

O O 3 NaBH4 TFA CHO H H H H then Me2S CHO 99% O 47% CHO OH 99% OH OH H H H OH H OH

197 208 209 210

O O

O O Ac2O/Et3 N H O H 4-pyrrolidinopyridine CHO OAc OH R H R H

R= OH, OCOPr 211,212 R= OAc, OCOPr

Scheme 15. González´s synthesis of C7,C17-functionalized spongianes. 20 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González

O O OEt 1) P 1) LDA, then MeI OEt 2) LDA, then D, 190˚C OEt 2) Et3N, TBDMSTf O 97% O O H I OEt OHC 84% TBDMSO (+)-carvone 3) PPTS 65% 213 214

1) CH2I2, TMSCl NaI LDA, then H2 O ZnEt2 OMe 2) O O Ph 90% CHO 50% H MeO P H H Ph RO RO RO H H H 83% 215, R= TBDMS 216, R= TBDMS 217, R= TBDMS

1) m-CPBA O NH2NH2 /KOH O pH=8 CHO H 2) PTSA H 75% H

RO O H 40% H H R 218, R= TBDMS 219, R= TBDMS 15, R = CH3

Scheme 16. Arnó´s synthesis of (-)-spongia-13(16),14-diene (15, R= CH3) from (+)-carvone.

O O O O 1) LDA, then MeI Br Br CF CO H 1) H2 O2, 2) LDA, then 3 2 NaOH O 2) H2 , Pd/C Br 78% H 87% H Br (-)-carvone 76% 220 221 222

O O CO2Me Ph 1) MeO P 1) Ph3P=CH2 BuLi then Ph 2) BrCH2CCH, D, 112˚C CNCO2Me 2) NaH then NaOH 84% 95% 70% HCO2H OH O O H H H 86% 223 224 225

O O

CO2Me O O O ZnI2, Ac2O 1) KOH 2) t-BuOOH 100% VO(acac) O 2 OAc OH H H H 64% 226 227 228

Scheme 17. Abad´s synthesis of C7,C11-functionalized spongianes (228) from (-)-carvone.

Diels-Alder adduct 226 in 95% yield. This was next elaborated Based on this synthetic plan, Abad and co-workers continued using a regioselective ring-opening of a dihydrofuran ring to give the development of several studies for the synthesis of spongiane the C7,C11-functionalized spongiane lactone 228 after hydrolysis diterpenes related to natural dories-nones (see Fig. 3). Therefore, and epoxidation with t-BuOOH and VO(acac)2. following the same strategy B® AB® ABC® ABCD for the ring- system construction they used the key epoxydecalone 222, which Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 21 was further elaborated to the Diels-Alder precursor 225 (Scheme Introduction of the methoxycarboxylate and final reaction in 17). Other Diels-Alder precursors were also synthesized from 223 toluene at 112 ºC gave the desired Diels-Alder diene 226. Thus, by for intermolecular Diels-Alder reactions but provided low yields using an IMDA reaction the compound 226 was formed and used to using dimethyl acetylene-dicarboxylate (DMAD) as dienophile further introduce the required functionalities and the construction of (Scheme 18) [127]. The synthesis starts with alquilation with LDA the D ring system (Scheme 19). The regioselective ring-opening of of the a -position of the enone. Further alquilation with an allyl the dihydrofuran ring of 226 gave initially the corresponding 7- bromide gave 221. Epoxidation, followed by olefination gave 223, acetoxy-15-iodo-derivative, which rapidly underwent lactonization another olefination led to 229 which after Dess-Martin oxidation, to afford the g-lactone 227 in nearly quantitative yield. The sodium borohydride reduction and protection with TBDMS and structure of 227 was initially assigned on the basis of a detailed reaction with DMAD gave mixture of 231 in low yield. spectroscopic NMR study, and final proof of the structure was Alternatively, 229 is propargylated with allyl propargyl bromide. obtained by single-crystal X-ray diffraction analysis.

O O O O O 1) Ph MeO P Ph 1) LDA, then MeI Br 1) H2O2, 2) LDA, then NaOH O 2) H , Pd/C 2) NaH then Br 2 HCO2H OH Br 84% 87% (-)-carvone 3) CF3CO2 H 221 222 223 60% CO2Me Dess-Martin 1) NaBH4 Ph3 P=CH2,THF reagent CO Me 2) TBDMSOTf 2 94% 86% 3) DMAD OH O OTBDMS 9% 229 230 231

CO2CH3 1) BuLi, -78˚C BrCH2C CH 2) CNCO2Me NaOH CH2 3) PhMe, 112˚C 56% O O 80% 224 226 Scheme 18. Abad´s synthesis of advanced intermediates for the preparation of C7,C11-functionalized spongianes from (-)-carvone.

CO2 CH3

O

226

ZnI2,Ac2O 98% O O O O O O tBuO H O KOH,MeOH 2

VO(acac)2 OH R1 70% OAc R2 237 swern 227 O 50% 234 R1= OH R2 =H (92%) swern m-CPBA 86% m-CPBA O 235 R1= R2= =O (89%) O O 1)BH3 2)H2O2 236 R1= H, R2=OH (99%) 45%

O O O

238

OAc

232 9a ,11a -epoxy (46%) 233 9b,11b-epoxy (40%) Scheme 19. Abad´s synthesis of C7,C11-functionalized spongianes (232,233,237,238) from (-)-carvone. 22 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González

O O O O 1) MeLi, -78˚C BrCH2CCH 2) swern NaOH 75% (see Scheme 17) OH O O H 82% H H 223 239 240 (-)-carvone

TBDMSO CO2Me TBDMSO O PTSA PhCH ,180˚C 1) TBDSCl,Et3N 3 acetone 2) LiHMDS then CNCO Me 60% from 2 241 O O O 77% H H H 241 242 243

MeO2CO CO2Me MeO2CO MeO2CO CO2CH3

LDA-BuLi, -78˚C PhCH ,195˚C ZnI2, Ac2 O 240 3 + then CH OCOCl 3 O 82% O O 67% H H 244 245, 56% 246, 31%

O O O O

MeO2CO O O O O NaOCH3 O Jones O O -20˚C reagent BH3-THF 96% H 92% H 99% H OAc OH O OH H H H H 247 248 249 250 OH O O HO HO AcO DIBAL-H O O Ac2O O -78˚C MnO2 DMAP H H H 71% from 80% OH 250 OH OAc H H H 251 252 6,D13 dorisenone C Scheme 20. Abad´s synthesis of dorisenone C (6,D13 R= Me) from (-)-carvone.

Unfortunately, all attempts to introduce the required oxygenated the reduction of the retro-hetero-ene rearrangement product. In fact, function present in natural dorisenones at C-11 were unsuccessful. the strategy did work but the product of the rearrangement 245 was Following the above mentioned extensive synthetic studies for the still the main product of the intramolecular Diels-Alder reaction. preparation of dorisenone diterpenes of the spongiane family, Abad Though in moderate yield the desired compound 246 was obtained and co-workers have recently adapted their synthetic sequences for and the sequence proceeded with it. Opening of the dihydrofuran the synthesis of dorisenone C (6, D13 R= Me) (Fig. 3) [128]. ring of 246 gave rise to product 247 as a result of in situ lactoni- They have developed a B® AB® ABC® ABCD app-roach zation. The cleavage of the ester groups and oxidation gave starting from R-(-)-carvone, in which the known hydroxyaldehyde diketone 249 which was reduced with borane-THF complex to give 223 (AB rings) (Scheme 18) is the key intermediate for the alcohol 250. Further reduction with DIBAL-H gave triols 251 in preparation of different Diels-Alder precursors, since the key step which the lactol moiety was reoxidized with MnO2 to give the corresponding lactone 252. Final diacetylation of 252 gave the for the formation of the C ring is an intramolecular Diels-Alder 13 reaction (Scheme 20). Firstly, the Diels-Alder precursor 241 was synthetic natural product dorisenone C (6, D R = Me, Fig. 3) prepared from 223 following standard reaction conditions used whose data were in complete agreement with those reported earlier previously by the same group. Unfortunately, this precursor did not for the natural product and hence establishing the absolute produce the desired Diels-Alder adduct but a product of retro- configuration of the natural product. hetero-ene rearrangement of the propargylic ether moiety instead. During these synthetic studies several unnatural furanodi- Thus, the enone 242 was formed in good yield. To avoid the terpenes were also prepared from lactone 250 by reduction and sterically demanding group of the diene moiety, the preparation of dehydration to give the furan ring present in 253 and 254 (Scheme the dienol carbonate 244 was undertaken and thus it was envisaged 21). Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 23

O biosynthesis [129,130], this area of research still remains a growing O RO field of investigation. The biosynthetic transformations have been mimicked by cation-olefin and radical cyclization reactions, and O O more recently by radical-cation cyclization cascades. 1) DIBAL-H H + H The first subgroup, commonly known as electrophilic cycliza- 2) H tions of polyenes, has been intensively studied for the synthesis of OH OR H 95% H steroids and a wide variety of polycyclic ring systems, and is well 250 253 R= H documented in the literature [131,132]. Indeed, their importance has Ac2O-DMAP 254 R= Ac increased over the past three decades due to the development of 86% new routes to polyolefinic precursors, methods of asymmetric syn- Scheme 21. Abad´s synthesis of furanoditerpenes 253-254 from (-)-carvone. thesis, and different conditions for the key cyclization step [133- 139]. In the early 1980s, Nishizawa´s research group described the Finally, we describe how recently Ragoussis and co-workers biomimetic cyclization of a geranylgeraniol derivative 260 to the have converted natural (-)-sclareol 133 into the furanoditerpene (-)- racemic tricyclic alcohol 155 (Scheme 23) [140,141], which had marginatone 32 (R1= CH3, R2= O, Fig. 11) (Scheme 22) [172]. The been previously converted into isoagatholactone (1) by Nakano and authors converted sclareol 133 into (+)-coronarin E 257, using Hernández [102] and Ungur et al. [105,106]. Compound 155 has minor modifications of reported procedures, which by regio- also been converted into 12a -hydroxyspongia-13(16),14-diene by selective hydrogenation and stereocontrolled-intramolecular elec- Rúveda et al. [104]. The cyclization takes place using as the trophilic cyclization gave the tetracyclic marginatane-type diterpene electrophile a mercury (II) triflate-N,N-dimethylaniline complex, 259. Subsequent allylic oxidation of 259 afforded the synthetic (-)- which after reductive demercuration leads to alcohol 155 (22%) marginatone 32 whose spectroscopic data were identical to those together with two bicyclic diterpenoids. Contemporary synthetic reported for the natural product. The synthesis starts with the studies by Ungur et al. also described the biomimetic synthesis of preparation of the ambergris odorant, (-)-g-bicyclohomofarnesal 155 by superacid cyclization of geranylgeraniol with fluorosulfonic 255 from sclareol 133 in 7 steps and 52% overall yield. The acid [142]. The same group also reported the synthesis of racemic coupling of 255 with 3-lithiofuran led to a mixture of two methyl isocopalate 137 by using similar conditions a few years later diastereomeric alcohols in 78% overall yield. Dehydration of this (Scheme 23) [143]. mixture in refluxing HMPA gave (+)-coronanin E 257 in high yield Nishizawa et al. also used the mercury (II) reagent to cyclize (76%) (Scheme 22). Partial reduction of the side chain double bond ambliofuran 261 leading to the tetracyclic isospon-giane 262 in of 257 gave (+)-dihydrocoronarin E 258 and a subsequent 13% yield (Scheme 24) [144]. Compound 263, having the margi- intramolecular electrophilic cyclization with BF3 etherate furnished natane carbon skeleton [59], was obtained after the demercuration the desired tetracyclic derivative 259 with the marginatane skeleton, treatment of 262 with sodium borohydride. Ambliofuran 261 had on which an allylic oxidation with t-BuOOH gave the target also been cyclized to furanoditerpene 263 in high yield by Sharma molecule (-)-marginatone 32, albeit in low yield (33%). et al. using SnCl4 as electrophile initiator (Scheme 24) [145]. Since the first investigations in the 1960s by Breslow et al. Syntheses by Biomimetic Approaches [146,147], biomimetic radical-mediated cyclization reactions have Inspired by Nature, biologists and chemists have made polyene become an excellent synthetic method for the synthesis of cyclizations a powerful synthetic tool for the one-step construction polycyclic natural products under mild conditions and with high of polycyclic compounds starting from acyclic polyene precursors. stereochemical control [148]. Despite the impressive and economical syntheses achieved over the past 50 years by chemical simulation of polycyclic terpenoid

O O

CHO OH OH 7 steps 3-bromofuran HMPA, reflux HCO2NH4 H OH H H H BuLi 76% Pd/C 10% 52% H H 79% H H 77%

133, sclareol 255 256 257 O

O

BF3 -Et2O O t-BuOOH O H H H NaOCl 46% H H 33% H

258 259 32

Scheme 22. Ragoussis´s synthesis of (-)-marginatone 32 from (-)-sclareol. 24 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González

NO2 1) Hg(OTf)2 ·C6H5NMe2 2) aq. NaCl O 3) NaBH4 / aq. NaOH

O 22% 260 OH H H

FSO3H/PrNO2 H -80˚C 155

OH 87%

geranylgeraniol

FSO3H/PrNO2 -55˚C CO Me CO2Me 2 H H 92% H E,E,E-geranylgeranic methyl ester 137

Scheme 23. Biomimetic syntheses of racemic isocopalol 155 and methyl isocopalate 137, precursors of spongiane diterpenoids.

was prepared by reduction, benzoylation, ozonolysis, alkylation 1) Hg(OTf)2 ·C6H5NMe2 with a THP-protected hydroxyacetaldehyde, subsequent hydrolysis 2) aq. NaCl with concomitant aromatization and final debenzoylation by O O 13% H reduction. ClHg On the other hand, ozonolysis of diol 267 and protection as its SnCl4 H corresponding acetonide, followed by furan ring formation using 261 >90% 262 Spencer´s method gave unnatural furanos-pongiane 272 in 8% overall yield from 264. The same authors also reported an alternative route to 272 via NaBH4 aq. NaOH O the tricyclic intermediate 275, which was prepared from the H farnesyl acetate derivative 273 in four steps (Scheme 26) [153]. Compound 275 possessing all of the carbons in the spongiane H skeleton was transformed into spongiane 272 in five steps as 263 detailed in Scheme 26. Thus, hydrolysis, epoxidation, collins oxidation, aromatization with p-TsOH and final reduction gave diol Scheme 24. Biomimetic synthesis of isospongiane 263 from ambliofuran 272 in 2.8% overall yield from 273. The synthetic sequence leading 261. to diol 272 was later optimized (15% overall yield from 273) allowing the synthesis of (±)-isospongiadiol 17 upon manipulation In the early 1990s, Zoretic and co-workers developed a very of the A-ring functionalization in 272 [154]. efficient series of triple and tetra cyclizations leading to trans- A few years later, Zoretic´s group reported an analogous decalin ring systems. Their strategy [149] was based on the Snider stereoselective radical cascade cyclization introducing an a ,b- method to cyclize intramolecularly unsaturated b-keto esters with unsaturated cyano group in the cyclization precursor (Scheme 27) Mn(III) salts [150]. Following the success of this approach they [155]. This modification allows the synthesis of furanospongianes reported, in 1995, the first biomimetic-like synthesis of spongianes functionalized at C-17, such as 285-288, through the advanced diterpenes, particularly furanospongianes (Scheme 25) [151]. In intermediate 284. Compound 284 was prepared in four steps from their synthesis, an oxidative free-radical cyclization of polyene 265 tricyclic system 282 exo, which was synthesized by intramolecular with a 2:1 mixture of Mn(OAc) and Cu(OAc) provided stereose- 3 2 radical cyclization of polyene 281. lectively the tricyclic intermediate 266 in 43% yield. Subsequent functional group manipulation and homologation at C-13 of 266 Concurrent to these studies, Pattenden and co-workers applied allowed, in two independent synthetic seq-uences, the construction their expertise in polycyclic ring constructions, based on free of the required furan ring D of the spongiane and marginatane radical-mediated cyclizations of polyolefin selenyl esters [156,157], carbon skeletons. Thus, starting from allylic alcohol 264, the for the total synthesis of (±)-spongian-16-one 4 (6% overall yield) necessary cyclization precursor 265 was obtained by treatment with (Scheme 28) [158,159]. They completed the synthesis in a concise allyl chloride followed by alkylation with ethyl-2-methyl-aceto- fashion via the cyclization precursor 295, which was prepared from acetate in 49% overall yield. After securing the stereochemistry of alcohol 289 as shown in Scheme 28. Protection of 289 as 266 by means of meticulous NMR studies [152], isospongiane 269 tetrahydropyranyl ether, followed by lithiation and reaction with Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 25

1) SOCl2 2) LiCH2 C(O)CMe(Na)CO2Et LiAlH4 Mn(OAc)3 Cu(OAc)2 H 49% 94% O 43% O HO H CO2Et EtO2C 264 265 266

1) LDA, then 1) PhCOCl OHCCH OTHP O 2 O H 2) O3, then Ph3 P H 2) p-TsOH H 3) LiAlH4 HO 38% BzO HO H H H HO BzO 56% HO 267 268 269

1) O3, then Me2S 2) acetone 75% oxalic acid

SBu 1) NaH, EtOCHO, O then aq. HCl 1) Me2S=CH2 O O 2) HgSO H 2) p-TsCl, py H 4 H then n-BuSH O O 57% from HO H H 270 H O O HO 270 271 272

Scheme 25. Zoretic´s biomimetic synthesis of isospongiane 269 and spongiane 272 from precursor 265.

1) MsCl 2) LiCH2C(O)CMe(Na)CO2Et OAc OAc Mn(OAc)3 HO Cu(OAc)2 3) Ac2O 29% O 23%

CO2Et 273 274

O 1) CrO3·2py O OAc 1) K2CO3 OH 2) p-TsOH, H 2) m-CPBA H H 89% then 10% HCl O O 55% O H H H EtO2 C EtO2 C EtO2 C 275 276 277

1) TBDMSCl O 1) m-CPBA LiAlH4 2) CrO3·2py O 272 HO H 85% 3) LDA/TMSCl 2) n-Bu4 NF H 67% 35% TMSO H O H TBDMSO HO 278 17

Scheme 26. Zoretic´s biomimetic synthesis of (±)-isospongiadiol 17. 26 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González

1) KN(SiMe3)2 2) PO(OEt) 2 OR CN CN O H OR 1) CBr4 , PPh3 THPO 3) p-TsOH HO 2) LiCH2C(O)CMe(Na)CO2 Et

64% 53% 279 280 R=TBDPS

CN CN O OR Mn(OAc)3 OR 1) n-Bu4NF OH Cu(OAc) m 2 H CN 2) -CPBA H O 58% O 56% O H H CO2Et EtO2C EtO2C 281 R=TBDPS 282 8:2 exo/endo R=TBDPS 283

O O LiAlH4 DIBALH H CHO H OH then HOAc 96% HO HO 73% H H O EtO2C HO 1) CrO3·2py 285 286 2) p-TsOH H CN 60% O NaBH O O H 4 1) CF3 SO2Cl EtO2C 88% 2) DMAP H CN 3) DIBALH H CHO 284 then HOAc HO H 70% H EtO2C HO 287 288

Scheme 27. Zoretic´s biomimetic synthesis of C17-functionalized furanospongianes. cyclopropyl methyl ketone led to compound 290. Ring-opening of synthesis of furanospongiaditerpenoids has been embarked starting the cyclopropane and formation of a E-homoallylic bromide using from natural products and using biomimetic-like reaction HBr, which was then used as its corresponding iodide 291 to sequences. Both of them have provided in some cases the synthesis alkylate 2-phenylthio-butyrolactone. Removal of the thioether and of spongianes with a functionalized A-ring. Also, in the mid 1990s, subsequent manipulation of the tetrahydropyranyl ether led to Kanematsu´s group carried out synthetic studies for the construc- selenoate 295. The treatment of the latter with Bu3SnH and AIBN tion of an appropriate furanohydrophenanthrene ring system 316 in refluxing degassed benzene led, after methylenation, to the (Scheme 30), which later was converted into (±)-spongia-13(16), tetracycle lactone 296 in 42% yield. Lactone 296 was then 14-diene 15 and (±)-spongiadiosphenol 20 (Scheme 31) [161,162]. converted into 4 by Simmons-Smith cyclopropanation and The route to the tetracyclic compound 316, the key intermediate hydrogenolysis. for the synthesis of 15 and 20, starts with the conversion of furfuryl Recently, Demuth and co-workers have developed a radical- alcohol 303 into a progargyl ether 304, which underwent a furan type cascade cyclization for the synthesis of (±)-3-hydroxy- ring transfer reaction to give the bicyclic alcohol 305. spongian-16-one 302, a precursor of 4 (Scheme 29) [160]. In their Hydrogenation of 305 followed by Swern oxidation afforded the strategy, the photoinduced radical cation of the polyene undergoes ketone 306. The ketone 306 was converted into the allylic b-keto water addition in anti-Markovnikov sense, followed by cyclization ester followed by methylation with iodomethane to afford 307. cascades terminated by a 5-exo-trig ring closure. The overall Removal of the allyl ester gave ketone 308 which was next reaction sequence mimics the non-oxidative biosynthesis of ter- annulated with ethyl vinyl ketone to give the tricyclic furan 310. penes. The radical cation precursor 301 was synthesized from far- The construction of the ring A was effected by reductive alkylation nesyltri-n-butylstannane 297, which reacted with the methylenbu- to introduce an allyl group which was then converted into an tyrolactone 298 via a Michael addition. Following the introduction adequate side-chain ketone, compound 315, ready for the final of the double bond in 300, irradiation of 301 in a Rayonet reactor annulation to give the tetracyclic intermediate 316. The stereo- with l max=300nm afforded spongiane 302 in 23% yield after chemical structure of 316 was assured by NOE effects between the purification. The structure of 302 was unambigously determined by two angular methyl groups. NOE and X-ray analyses. The synthesis of spongiane 15 was successfully completed forming the gem-dimethyl moiety by reductive methylation of 316 Other Approaches and Total Syntheses to give ketone 219 and removal of the carbonyl group at C-3. In As we mentioned before, the studies towards the synthesis of parallel studies, compound 316 was reduced, hydroxylated to give spongianes are scarce, specially of rearranged metabolites. The ketone 317 and then oxidized to afford the desired (±)- Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 27

1) DHP, PPTS 2) Li O 1) HBr I then HO PhS Br 2) DHP, PPTS O O 3) NaI, Me2CO

76% 72% 71% OH 289 OTHP OTHP 290 291 1) NaClO2 2) O O O O PhS N SePh 1) m-CPBA O O 1) PPTS O 2) CaCO3 2) Dess-Martin O 80% 84% 71% CHO OTHP OTHP 292 293 294

O O O H H 1) Bu3SnH AIBN 1) Zn(Cu), O 2) Zn, TiCl4 O CH2 I2 O CH2Br2 2) PtO2, H2 H H 42% 76% CSePh

O 295 296 4

Scheme 28. Pattenden´s biomimetic synthesis of (±)-spongian-16-one 4.

O O

Sn(C4 H9)3 O n-BuLi, CuI, O O 1) LiHMDS/PhSeBr + LiBr, TMSCl O 92% 2) m-CPBA, py 35% 298 297 300 301

O H O H O Rayonet reactor lmax= 300nm 2 23% O 1,4-dicyano-2,3,5,6-tetra- O methylbenzene/biphenyl H HO

302 Scheme 29. Demuth´s biomimetic synthesis of (±)-3-hydroxy-spongian-16-one 302. spongiadiosphenol 20, which represents the first total synthesis of a formation of longicamphenilone 319 in 35-40%. Irradiation of 319 furanospon-giaditerpenoid with a functionalized A-ring (Scheme with a 450 W Hg lamp through a pyrex filter resulted in the 31). expected Norrish-type I cleavage to the bicyclic aldehyde 320 in With regard to the synthesis of rearranged spongianes, there are about 40%. Reductive decarbonylation using the Wilkinson catalyst about three synthetic approaches to build up bycyclic systems [163- furnished the bicyclic hydroazulenic hydrocarbon (+)-321 in 52% 165] present in those and, to the best of our knowledge, only two yield (Scheme 32). enantioselective total syntheses [166,167]. Bhat and co-workers reported a common Lewis acid catalyzed Mehta and Thomas reported in 1992 how the abundant, Diels-Alder reaction to form decalin systems, present in spongianes commercially available (+)-longifolene 318 can be degraded to a and other terpenoids (Scheme 33) [164]. hydroazulene moiety, compound 321, present in rearranged spongianes [163]. Catalytic ruthenium oxidation of 318 led to the 28 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González

HC CCH2 Br t-BuOK O 1) H2 , 5% Pd-C NaOH t-BuOH 2) DMSO, TFAA O OH O O O O HO 100% 80˚C 78% from 304 303 305 304

O 1) diallylcarbonate, NaH O Pd(OAc)2 O EVK 2) MeI, K2CO3 PPh3, HCO2H DBU O O O 74% O 76% 306 O 308 307

O O Li, NH (l) O O 1) t-BuOK 3 1) LiAlH4 2) p-TsOH allyl bromide 2) TBSOTf H 74% O 62% 94% from 308 O O 309 310 311

O O 1) (COCl)2 O 9-BBN then DMSO then Et3N NaOH/H O 2) EtMgBr H 2 2 H H 3) TBAF HO HO TBSO 96% TBSO HO 312 313 92% 314

O O (COCl)2 KOH DMSO H H then Et N 73% 3 O 86% O O

315 316 Scheme 30. Kanematsu´s synthesis of spongian precursor 316.

1) LiAlH4 O O Li, NH (l) 2) BuLi, CS2 3 then MeI H H then MeI 3) (TMS)3 SiH AIBN O 60% H 50% H O 219 15

H O O O HO O MeONa 316 1) Li, NH3 (l) H H 2) LDA then O DMSO HO H H MoOPH 79% 317 20 36%

Scheme 31. Kanematsu´s synthesis of (±)-spongia-13(16),14-diene 15 and (±)-spongiadiosphenol 20.

The last approach described for the synthesis of spongianes Reiser and co-workers reported a short and enantio-selective features a synthetic route for the preparation of the cis-fused 5- synthesis of the above mentioned unit starting from methyl 2- oxofuro[2,3-b]furan unit present in some rearranged spongianes. furoate (Scheme 34) [165]. Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 29

under retention of configuration. Alternatively, 328 could be photochemically decarboxylated with lead tetraacetate under copper RuCl -NaIO hn (pyrex) (II) catalysis following a radical pathway to directly yield a mixture 3 4 of 330 and epi-330 (331), which could be easily separated by 35-40% hexane chromatography. O 40% Following this general strategy, the authors next looked for a 318 319 flexible way to stereoselectively introduce substituents into the 3- position of 5-oxofuro[2,3-b]furans (Scheme 35).

H H To date, to the best of our knowledge, there has been reported only two enantioselective total syntheses of diterpenes with (PPh3)3RhCl rearranged spongiane skeleton. Firstly, in 2001, Overman et al. described the first enantioselective synthesis of a spongian- derived toluene metabolite, (+)-shahamin K 353 (Scheme 36) [166], a rearranged H 52% H OHC spongiane having a cis- hydroazulene unit and an attached highly oxidized six-carbon fragment. 320 321 One of the key steps of the synthesis was a Prins-Pinacol reaction that produced the core of the carbon framework, the cis- Scheme 32. Mehta´s synthesis of hydroazulene 321. hydroazulene system. The synthesis starts with the conversion of cyclohexanone 340 into the cyclization precursor 344 introducing a O kinetic resolution step with (R)-oxazaborolidine 342. Thus, oxi- R dative cleavage of the double bond in 340, followed by thio- O cetalization gave compound 341, which was subjected to the R` chemical resolution to give enantioenriched ketone (S)-344 in 44% AlCl3 + R yield. Addition of (E)-1-propenyllithium to (S)-343 followed by silylation gave the silyl ether 344 in high yield. The treatment of R` 344 with dimethyl(methylthio)sulfonium tetrafluoroborate (DM- TSF) initiated the Prins-pinacol reaction to give the bicycle 345 in 322 323 324 80% yield as a mixture of sulfide epimers, whose structure was confirmed by single-crystal X-ray analysis of the corres-ponding Scheme 33. Bhat´s synthesis of decalins. sulfone. Installation of the exocyclic methylene group, followed by oxidative desulfonylation provided ketone 347, whose thermo- The synthesis starts with a copper-bisoxazoline-catalyzed, dynamic lithium enolate reacted with enantiopure sulfone 348 to enantioselective cyclopropanation of methyl 2-furoate 325 to give compound 349, as a single isomer in 72% yield. To transform cyclopropane 326, a versatile building block toward a broad variety the cyclopentanone ring in the side chain to the required pyranone of derivatives, which could be subsequently converted into 5-oxo- unit, keto sulfone 349 was reduced with SmI2 and the resulting furo[2,3-b]furans. In fact, hydrogenation of 326 gave exclusively enolate was acetylated to give enol acetate 350 in 88% yield. compound 327 as a single stereoisomer in 86% yield. Subsequent Reduction of the ketone of this intermediate with (R)-oxaza- rerrangement to 328 using 2 M HCl in dioxane gave rise to the borolidine 342 and borane complex, followed by acetylation gave parent 5-oxofuro[2,3-b]furan framework in only three steps from acetate 351 in 88% yield. Chemoselective dihydroxylation of the inexpensive methyl 2-furoate 325, and in enantiomerically pure enol acetate in 351 gave the a -hydroxy ketone 352 in 87% yield. form. Conversion of the carboxylic acid to the acetoxy derivative Cleavage of the hydroxy-ketone in 352 with Pb(OAc) 4 followed by 330, being typical in many spongiane diterpenoids, was accom- reduction of the resulting aldehyde with NaBH4 and lactonization plished in a four-step sequence from 328 via its methyl ketone 329, using the Mukaiyama reagent provided (+)-shahamin K 353. which underwent diastereo-selective Baeyer-Villiger oxidation

OL, 2001 H H H O 3, 1315 O O O O MeO2C MeO2C Pd/C H2 MeO2C 2M HCl HO2C O 86% 1,4-dioxane CO2 Et CO2Et 74% H H H 325 326 >99% ee 327 328 H H 1) (COCl) O 2 O O 4) m-CPBA O O 2) CH N 2 2 O AcO O 3)HI 31% (4 steps) H H 329 330 H H Pb(OAc)2, Cu(OAc)2 O O O O HOAc,THF 328 AcO O + AcO O hn 88% H H 330 1 : 1.75 331

Scheme 34. Reiser´s synthesis of 5-oxofuro[2,3-b]furans. 30 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González

Br the cyclopropane ring afforded compound 359 in 78% overall yield. O H O H Br2 E DBU E Acetonide 358 can also be converted into the desired fused lactone- 326 lactol in one step using methanesulfonic acid [169]. After oxidative 70% 94% CO Et CO Et cleavage of diol 359, the resulting aldehyde was methylated by Br 2 Br 2 H H treatment with MeTi(i-OPr)3 formed in situ to produce 360 in 63% E=CO2Me combined yield. Oxidation of 360 under Swern conditions gave rise 332 333 to ketone 361 (79%). The best yields for the conversion of 361 to 362 were obtained using methane-sulfonic acid, which at 0ºC Pd(PPh ) produced bicycle 362 as a single isomer in 67% yield. The stage 3 4 Ar-B(OH) Ph Pd(OAc)2 K CO 2 was now set for the crucial Baeyer-Villiger oxidation. After testing 2 3 PPh3, Et3N, DMF several conditions, the conversion of 362 to 363 was ultimately 71% O H O H achieved using urea-hydrogen peroxide and trifluoroacetic E E anhydride and gave rise to the desired material in 69% yield as a single isomer. CO2Et CO2 Et Ar The Theodorakis´s group described the total synthesis of H H norrisolide 33 in 2004 [167,170]. In their strategy, they did the 334 Ph 335 assembly of the two main fragments, 365 and 366, through the C9- Ar = Ph (86%) C10 bond (Scheme 38). One of the frag-ments, the trans-fused Ar = 2-naphtyl (77%) hydrindane motif, could be prepared starting from the 67% Pd/C H2 Ar = o-MeO-C6H4 (83%) enantiomerically enriched enone 367. The other fragment was prepared from the lactone 368, which contains the desired cis Pd/C H2 stereochemistry at the C11 and C12 centers. O H E The synthesis began with the preparation of enone 367, which O H E was available through an L-phenylalanine-mediated asymmetric CO2 Et Robinson annulation (55-65% yield, >95% ee after a single CO Et H recrystallization). Selective reduction at the more reactive C9 2 Ph Ar H 337 carbonyl group, followed by protection of the resulting alcohol afforded the silyl ether 369 in 76% yield for the two steps (Scheme 336 6M HCl 39). Methyl alkylation of the extended enolate of 369 at the C5 Ar = Ph (93%) 1,4-dioxane Ar = 2-naphtyl (46%) center produced ketone 370 (66%) the reduction and radical deoxygenation of which led to the alkene 371 in 83% yield (from 6M HCl H 370). The best results for the conversion of alkene 371 into the 1,4-dioxane O O trans-fused bicycle 372 were obtained by hydroxylation of the HO2 C O double bond and subsequent reduction of the resulting alcohol (52% H yield from 371). Fluoride-induced desilylation of 372 followed by O O H PCC oxidation provided the ketone 373 in 91% yield. The treatment

HO2C O Ph 339 of 373 with hydrazine then produced the hydrazone 374. Finally, treatment of 374 with I2/Et3N led to the formation of the desired Ar H vinyl iodide 365 (62% yield). 338 The preparation of the fragment 366 is highlighted in Scheme 40. The C11 and C12 centers were connected by a Diels-Alder Scheme 35. Reiser´s synthesis of 3-substituted 5-oxofuro[2,3-b]furans. reaction between butenolide 375 and butadiene (376). Under Lewis acid catalysis this cycloaddition proceeded exclusively from the The second enantioselective total synthesis of a rearranged opposite face to that with the bulky TBDPS group to afford 368 as a spongian diterpene was achieved recently by Theodorakis et al. single isomer (85% yield). Reduction of the lactone, followed by [167]. They completed the sythesis of norrisolide 33 in 2004. This oxidative cleavage of the alkene produced the fused lactol 377 in molecule presents a rare g-lactone-g-lactol moiety as side chain 63% yield as a 1:1 mixture of isomers at C14. These isomers were which has few synthetic precedents. This group developed initially separated after conversion into the corresponding methyl ether 378. an enantio-selective synthesis of the side chain starting from D- Compound 378 was then converted into the selenide 379, which mannose (Scheme 37) [168]. The preparation of the side chain underwent oxidation and elimination to give alkene 380 (61% yield begins with the transformation of D-mannose to the known from 378). Osmylation of 380, followed by oxidative cleavage of bisacetonide 354 with improved conditions using iodine as catalyst the resulting diol, furnished the aldehyde 366 (two steps, 94% to give 354 in 85% yield. Treatment of 354 with p-toluenesulfonyl yield) as a crystalline solid whose structure was confirmed by X-ray chloride and triethylamine afforded the desired glycosyl chloride analysis. 355, which upon elimination with a mixture of sodium The remaining steps in the synthesis of norrisolide 33 are naphthalenide in THF gave rise to glycal 356 in 48% overall yield. shown in Scheme 41. Lithiation of the vinyl iodide 365, followed Compound 356 proved to be labile upon standing and was by addition of the aldehyde 366 and oxidation of the resulting immediately benzylated to produce vinyl ether 357 in 90% yield. alcohol, afforded the enone 381 in 71% yield. Hydrogenation of the Syringe pump addition of ethyl diazoacetate (0.1M in DCM) into a double bond proceeded exclusively from the more accessible a face mixture of 357 (2M in DCM) and rhodium (II) acetate at 25ºC gave of the bicyclic core to form the ketone 382 in 75% yield. After the cyclopropanation ester 358 with the desired configuration at C- much experimentation, the conversion of ketone 382 into alkene 12 center. The only diastereomers acquired during this reaction 364 was achieved by methylation with MeLi and treatment of the were produced at the C-13 center (4:1 ratio in favor of the exo resulting alcohol with SOCl 2 in the presence of pyridine (two steps, adduct) and both were taken forward. 64% yield). Exposure of 358 to a dilute ethanolic solution of sulfuric acid With the alkene 364 in hand, the stage was now set to final induced acetonide deprotection followed by concomitant opening of functionalization of the bicycle (Scheme 41). Deprotection of the Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 31

H Ph Ph

O O O O N B SPh SPh 1) (E)-MeCH=CHLi 1) OsO4 , NaIO4 342

2) PhSH, BF3·OEt2 SPh BH3·THF SPh 2) TMS-imidazole 89% 92%

340 341 (S)-343 44%, 94% ee

O TMSO H H

DMTSF SPh 1) TMSCH2Li SPh 1) m-CPBA SPh 80% 2) HF·py 2) MoOPH, LDA SPh H 84% H 80%

344 345 (5:1; b:a) 346

AcO AcO H Ph Ph O OAc 1) H O N B O H H 1) LDA, HMPA H SO2Ph SmI2 H 342 O O 2) AcO Ac2O BH3·THF H O 88% 2) Ac2O 348 H H 88% 347 72% SO2Ph 349 350 O AcO AcO OAc O OAc O

H H OH H H OsO4, NMO H 1) Pb(OAc) H OAc OAc 4 OAc 2) NaBH4 87% 3) DMAP H H H + N Cl I- 351 352 353 57%

Scheme 36. Overman´s synthesis of (+)-shahamin K 353. silyl ether and oxidation of the resulting alcohol gave aldehyde 383, chemical origins of the norrisolide-induced Golgi vesiculation which was subsequently converted into the ketone 384 via [171]. To this end, the researchers studied the effect of fluorescent treatment with MeMgBr and Dess-Martin oxidation (68% yield). probes 392-397 (Scheme 43) on the Golgi complex. While 393 had Treatment of 384 with CrO3 in aqueous acetic acid produced the no effect on the Golgi apparatus, compound 392 was found to lactone 385 in 80% yield. Finally, Baeyer–Villiger oxidation of 385 induce extensive Golgi fragmentation. However, in contrast to (MCPBA, NaHCO3, 60% yield) led to insertion of the oxygen atom norrisolide 33, this fragmentation was reversed upon washing. as desired with complete retention of configuration to produce Competition experiments showed that compound 392 and 394 and norrisolide 33. norrisolide bind to the same receptor, which indicates that the After completion of their total synthesis of norrisolide, this perhydroindane core of norrisolide is essential and necessary for group has also explored the biological activities of some analogs of such a binding. In the absence of the acetate group of norrisolide, the parent molecule. Thus, the molecules 362, 363, 373 and 385 this binding induces a reversible Golgi vesiculation, indicating that from previous synthetic studies were evaluated together with 386- this group plays an essential role in the irreversibility of the 391 which were also synthesized (Scheme 42) [66]. fragmentation either by stablizing the binding or by creating a covalent bond with its target protein. Compound 396, containing From the structure/function studies it was suggested that the the core fragment of the natural product, induced a similar perhydroindane core of norrisolide is critical for binding to the vesiculation that was, however, reversible upon washing. In target protein, while the acetate unit is essential for the irreversible contrast, compound 397, in which the perhydroindane core was vesiculation of the Golgi membranes. Compounds 389-391 have no effect on Golgi membranes. This group has also studied the 32 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González

O OTBDPS OTBDPS O OH HO 1) NaBH4 acetone, I2 O 9 O X 2) TBDPSCl t-BuOK 367 5 HO OH 85% 76% O MeI O OH 66% O O 369 370 D-mannose 1) NaBH4 O 2) nBuLi,CS2, MeI 83% TsCl X= OH 354 3) Bu3 SnH/AIBN 355 O 60% X= Cl O OTBDPS 1) BH3, H2O2 OTBDPS 2) nBuLi,CS , MeI Na, naphtalene 1) TBAF 2 2) PCC 3) Bu3SnH/AIBN 80% RO 52% BnBr 356 R= H 91% H 90% 357 R= CH Ph 2 372 371 Rh2(OAc)4 45% NH2 N2CHCO2Et O N N2H4 I2/Et3 N O HO 365 88% 62% O H O OEt O EtOH, H+ HO H H 13 373 374 CO Et 78% BnO 2 BnO H CO2Et Scheme 39. Theodorakis´ synthesis of fragment 365 of norrisolide 33. 358 (4:1 C13) 359 NaIO 63% 4 MeTi(i-OPr) 3 TBDPSO TBDPSO O OH O O 1) DIBAL-H O O 2) OsO , NMO O OEt Swern O OEt 4 AlCl3 3) Pb(OAc)4 79% 375 85% 63% BnO BnO CO2Et CO2Et 361 360 368 376 MeSO H 67% 3 TBDPSO 1) NaBH4 TBDPSO O O 2) PPh3, I2 O 3) PhSeNa O O 14 H H O O O O O O OMe OR (H2N)2CO, H2O2 67% O O O amberlist 15 377 R=H (CF3 CO)2O 379 PhSe MeOH 378 R=Me BnO H 69% BnO H NaIO 90% 77% 362 363 4 Scheme 37. Theodorakis´ synthesis of norrisolide side chain 363. TBDPSO TBDPSO O 1) OsO4, NMO O O O 2) Pb(OAc)4 O OMe OMe TBDPSO 94% O O 380 366 O O Scheme 40. Theodorakis´ synthesis of fragment 366 of norrisolide 33. 10 9 O O attached to a bisepoxide scaffold (suitable for protein labeling), induced an irreversible vesiculation of the Golgi membranes. On H O H OMe the other hand, compound 395, lacking the perhydroindane motif, 33 norrisolide 364 had no effect on Golgi membranes, attesting to the importance of the norrisolide core in Golgi localization and structure. Moreover, compound 397 induces an identical phenotype to that of norrisolide, TBDPSO suggesting that it may be used to isolate the biological target of this TBDPSO natural product. O O O I O O CONCLUSION

+ The scientific investigations of the spongiane family of diter- O penoids has been an active field during the last two decades O H producing nearly 100 publications on isolation and structural OMe characterisation of its members, including several preliminary 367 368 365 366 biological studies. However, in spite of their biological properties and the challenging variety of chemical entities that have been Scheme 38. Theodorakis´ retrosynthesis of norrisolide 33. Spongiane Diterpenoids Current Bioactive Compounds 2007, Vol. 3, No. 1 33

TBDPSO TBDPSO O O NMe NMe O 2 O O 2 I O 1) tBuLi O O 2) DM [O] O + O O O O O 71% O H O OMe H OMe HO O O O 365 366 381 O O 85% H2, Pd/C O

TBDPSO TBDPSO H H Me2N O O O 392 393 394 O O 1) MeLi O 2) SOCl2, py O O OMe O O 64% O H OMe H OMe O MeO O 364 382 O 1) TBAF O O 93% O 2) IBX O O

O O H O O H H O 1) MeMgBr O 395 396 397 2) DM [O] mCPBA 33 Scheme 43. Theodorakis´ norrisolide-based fluorescent probes. O 68% O 60%

H OMe H X ACKNOWLEDGMENTS

383 CrO3 384 X=OMe,H I am grateful to Prof. Ramón J. Zaragozá, my teacher and 80% 385 X=O friend, for his encouragement and suggestions in the preparation of this review. I also gratefully acknowledge financial support from Scheme 41. Theodorakis´ synthesis of norrisolide 33. the Spanish Ministry of Science and Education under a “Ramón y Cajal” research grant. The anonymous reviewers are thanked for helpful comments and suggestions. O HO O O REFERENCES O O O [1] Connolly, J. D.; Hill, R. A. (1991) Dictionary of Terpenoids. In: O O O Diterpenoids. London, Chapman & Hall, 2, pp. 895-899. [2] Hanson, J. R. (2005) Diterpenoids. Nat. Prod. Rep., 22, 594-602 and former reviews in this series. O [3] Faulkner, D. J. (2002) Marine Natural Products. Nat. Prod. Rep., 19, 1-49 and former reviews in this series. [4] Faulkner, D. J.; Newman, D. J.; Cragg, G. M. (2004) Investigations of the Marine Flora and Fauna of the Islands of Palau. Nat. Prod. Rep., 21, 50-76. H H H [5] Blunt J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. (2005) Marine Natural Products. Nat. Prod. Rep., 22, 15-61. [6] Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. 386 387 388 (2006) Marine Natural Products. Nat. Prod. Rep., 23, 26-78. [7] Gavagnin, M.; Fontana, A. (2000) Diterpenes from Marine Opisthobranch O 4 O Molluscs. Curr. Org. Chem., , 1201-1248. [8] Goldsmith, D. (1992) The Total Synthesis of Natural Products. In: The Total O O O Synthesis of Tri- and Tetracyclic Diterpenes. New York, ApSimon, J., John Wiley and Sons, 8, pp. 228-230. O O [9] Kazlauskas, R.; Murphy, P. T.; Wells, R. J.; Noack, K.; Oberhaensli, W. E.; Schoenholzer, P. (1979) A New Series of Diterpenes from the Australian Spongia Species. Aust. J. Chem., 32, 867-880. O O H [10] Cimino, G.; De Rosa, D.; De Stefano, S.; Minale, L. (1974) Isoagatholactone, a Diterpene of a new structural type from the Sponge 389 390 391 Spongia officinalis. Tetrahedron, 30, 645-649. [11] González, A. G.; Darias, V.; Estevez, E. (1982) Contribution to the Scheme 42. Theodorakis´ analogues of norrisolide 33. Biological Study of Spongia officinalis. Il Farmaco, 37, 179-183. [12] Karuso, P.; Taylor, W. C. (1986) The Constituents of Marine Sponges. II The Isolation from Aplysilla Rosea (Dendroceratida) of (5R*,7S*,8R*,9S*,10R*, found, the synthetic studies represent only one third of the public- 13S*,14S*,15S*)-15,17-Epoxy-17-hydro-xy-16-oxospongian-7-yl Butyrate cations in the field. Until quite recently researchers had not initiated (Aplyroseol-1) and Related Diterpenes (Aplyroseol-2 to -6). Aust. J. Chem., any structure/function studies, and therefore this area also remains 39, 1629-1641. [13] Karuso, P.; Skelton, B. W.; Taylor, W. C.; White, A. H. (1984) The largely unexplored. The work listed in the review justifies the Constituents of Marine Sponges. I. The Isolation from Aplysilla Sulphurea potential for discovery of novel pharmaceutical agents and (Dendroceratida) of (1R*,1'S*,1"R*,3R*)-1-acetoxy-4-ethyl-5-(1,3,3- biological probes in this area of research. 34 Current Bioactive Compounds 2007, Vol. 3, No. 1 Miguel A. González

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Received: July 5, 2006 Revised: August 1, 2006 Accepted: September 15, 2006