Total Syntheses and Synthetic Studies of Spongiane Diterpenes

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Tetrahedron 64 (2008) 445e467 www.elsevier.com/locate/tet Tetrahedron report number 821 Total syntheses and synthetic studies of spongiane diterpenes

Miguel A. Gonza´lez*

Departamento de Quı´mica Orga´nica, Universidad de Valencia, E-46100 Burjassot, Valencia, Spain Received 2 October 2007 Available online 22 October 2007

Keywords: Diterpenes; Spongiane; Marine natural products; Synthesis

Contents

1. Introduction ...... 445 2. Structure, occurrence, and biological activity ...... 446 3. Syntheses of spongiane diterpenes ...... 446 3.1. Syntheses from other natural products ...... 446 3.2. Syntheses by biomimetic approaches ...... 456 3.3. Other approaches and total syntheses ...... 459 4. Conclusions ...... 465 Acknowledgements ...... 465 References and notes ...... 465 Biographical sketch ...... 467

1. Introduction sequestering the spongian-derived metabolites from the sponges, soft corals, hydroids, and other sessile marine inver- Spongiane diterpenoids are bioactive natural products iso- tebrates on which they feed. Most of these compounds play lated exclusively from sponges and marine shell-less mollusks a key role as eco-physiological mediators and are of interest (nudibranchs), which are believed to be capable of for potential applications as therapeutic agents. Spongianes having the characteristic carbon skeleton I (Fig. 1) have been reviewed up to 1990 and listed in the Dictio- Abbreviations: AcCl, acetyl chloride; Ac2O, acetic anhydride; AIBN, azo- 1 bisisobutyronitrile; BuLi, buthyllithium; DIBAL-H, diisobutylaluminum hy- nary of Terpenoids. During the last two decades, many new dride; DHP, dihydropyrane; DMAD, dimethyl acetylenedicarboxylate; members of this family of natural products have been isolated DMAP, 4-(N,N-dimethylamino)pyridine; DMF, dimethylformamide; DMSO, and described in specific reviews on naturally occurring diter- 2 dimethylsulfoxide; Et3N, triethylamine; EVK, ethyl vinyl ketone; HMPA, hexa- penoids by Hanson, and the excellent reviewing work on ma- methyl phosphorotriamide; IBX, 2-iodoxybenzoic acid; LDA, lithium diisopro- rine natural products by Faulkner,3,4 now continued by the team pylamide; LiHMDS, lithium hexamethyldisilylamide; MsCl, mesyl chloride; 5e7 MCPBA, m-chloroperbenzoic acid; NaHMDS, sodium hexamethyldisilyl- of Blunt, all of which have covered mainly the isolation and amide; NMO, 4-methylmorpholine N-oxide; PCC, pyridinium chlorochromate; structural aspects of spongianes. A recent review on the chem- PPTS, pyridinium p-toluenesulfonate; p-TSA, p-toluenesulfonic acid; PhH, istry of diterpenes isolated from marine opisthobranchs has also benzene; PhMe, toluene; Py, pyridine; TBDMSOTf, tert-butyl dimethylsilyl tri- included articles on isolation and structure determination of fluoromethanosulfonate; TBDPSCl, tert-butyldiphenylsilyl chloride; TBAF, spongianes up to 1999.8 The latter survey also covered some tetra-n-butylammonium fluoride; TFA, trifluoroacetic acid; TMSCl, trimethylsilyl chloride; TPAP, tetrapropylammonium perruthenate. synthetic studies of this class of substances. To the best of our * Tel.: þ34 96 354 3880; fax: þ34 96 354 4328. knowledge, there is only one more report dealing with the initial 9 E-mail address: [email protected] studies toward the synthesis of spongianes.

O 3. Syntheses of spongiane diterpenes 12 16 11 13 20 1 9 C D O O 2 14 Several syntheses have appeared within the last 25 years and A 10H 8 15 H H 5 17 3 B 7 we will classify them in three main groups. We will also include 4 H 6 H the synthetic studies developed so far and, thus, we will 19 18 I, spongiane skeleton 1, isoagatholactone describe the syntheses from other natural products, syntheses using biomimetic approaches and, ﬁnally, other approaches in- CO2H cluding the total synthesis of rearranged spongianes. O CO H Generally, despite the interesting molecular architectures H 2 and biological properties of the spongianes, there have been H H HO2C relatively few synthetic studies toward their synthesis. In the 2, isoagathic acid 3, grindelic acid 1980s, most of the synthetic studies toward spongiane-type di- Figure 1. terpenes addressed mainly the synthesis of isoagatholactone and the preparation of simple furanospongianes. In the next decade, the syntheses of several pentacyclic spongianes were accomplished together with the development We now provide full coverage of recent advances in the of biomimetic-like strategies for the synthesis of more com- ﬁeld including a comprehensive description of the synthetic plex furanospongianes and isoagatholactone derivatives. approaches and syntheses reported in the literature on spon- Over the last three or four years, some structureeactivity stud- gianes up to September 2007. ies have emerged together with several approaches toward the more complex oxygenated spongianes.

2. Structure, occurrence, and biological activity 3.1. Syntheses from other natural products

The semisystematic naming of this family of diterpenoids Manool (4), copalic acid (5), sclareol (6), labdanolic acid was introduced in 1979 after the isolation of the first members (7), abietic acid (8), and carvones (9)(Fig. 2) have been used of the family from sponges of the genus Spongia. Thus, in for the preparation of optically active spongianes. Naturally oc- accordance with the IUPAC recommendations the saturated curring racemic labda-8(20),13,dien-15-oic acid (copalic acid) hydrocarbon I, named ‘spongian’, was chosen as the funda- has also been used for preparing racemic compounds. mental parent structure with the numbering pattern as depicted 10 These starting materials were converted into versatile tricy- in Figure 1. clic intermediates having the characteristic ABC-ring system of The first known member of the spongiane family, isoaga- spongianes (Scheme 1) such as ent-methyl isocopalate (10), po- tholactone (1), was discovered by Minale et al. from the docarp-8(14)-en-13-one (11), and phenanthrenones (12,13). sponge Spongia officinalis about 30 years ago, being the first Several strategies have been reported to build up the necessary natural compound with the carbon framework of isoagathic ring D from these key intermediates, preferably as a furan or acid (2). Structure (1) was assigned based on spectroscopic 11 g-lactone ring. The choice of podocarpenone 11 as starting data and chemical correlation with natural grindelic acid (3). material assures the absolute stereochemistry at C5, C9, and To date, there are nearly 200 known compounds belonging to this family of marine natural products, including those with a spongiane-derived skeleton.12 Most of them present a high OH CO H degree of oxidation in their carbon skeleton, particularly at po- H H 2 sitions C17 and C19, as well as on all the rings AeD. Given H H the variety of chemical structures found in the spongiane fam- 4, manool 5, copalic acid ily, we could group them according to the degree of oxidation as well as the degree of carbocyclic rearrangement of the par- OH ent 6,6,6,5-tetracyclic ring system. CO2H Sponges are exposed to a variety of dangers in their envi- H OH H OH ronment and this has led to the development of chemical de- H H fense mechanisms against predation. Nudibranchs feed on 6, sclareol 7, labdanolic acid a variety of sponges and are capable of storing selected metabolites, even transforming them, for their own self-defense. Thus, sponges and nudibranchs are a rich source of biologically active metabolites, and the spongianes, in particular, H O have displayed a wide spectrum of interesting biological prop- H erties including antifeedant, antifungal, antimicrobial, ichthyo- CO2H 9, (+)- and (-)-carvone 8 toxic, antiviral, antitumor, antihypertensive, fragmentation of , abietic acid 12,13 Golgi complex, as well as anti-inflammatory activity. Figure 2. M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467 447

C10. Moreover, the selection of methyl isocopalate 10 and lactonization to give lactone 16, followed by reductive open- phenanthrenones 12,13 also assures the stereochemistry of ing of the lactone ring, gave the known degradation product the additional methyl group at C8 of the ring system. of isoagatholactone, diol 17.11 Finally, allylic oxidation with MnO2 gave (þ)-isoagatholactone (1) in 3.9% yield from 10. manool Contemporaneous studies by Nakano et al. described, soon CO Me copalic acid H 2 after, the synthesis of racemic isoagatholactone using a similar sclareol labdanolic acid H strategy in which the reaction conditions were different, as ent-methyl isocopalate (10) well as the starting material, which was racemic copalic acid 16 O (Scheme 3). Thus, ()-isoagatholactone (1) was prepared in 11.6% yield from racemic methyl isocopalate 10.17 abietic acid H Unnatural ()-isoagatholactone has also been prepared by H Ru´veda et al. using the same sequence of steps starting from podocarp-8(14)-en-13-one (11) methyl isocopalate (þ)-10, readily prepared from copalic acid (Scheme 4).18,19 Thus, sensitized photooxygenation gave alcohol 18, which was subjected to allylic rearrangement with simul- O (+)-carvone H taneous lactonization, using sulfuric acid, to give lactone 20. TBSO H Then, reductive opening of the lactone ring, gave diol 21, which 12 was oxidized with MnO2 to give ()-isoagatholactone. R CO2Me The interest in spongiane-type diterpenes possessing a furan ring D led to the synthesis of ()-12a-hydroxyspongia- (-)-carvone 13(16),14-diene (24)byRu´veda et al. using 19, also prepared O 19 H from methyl isocopalate (Scheme 4). This unnatural spon- 13a R = H giane was designed as a precursor for other members with a dif- 13b R = OCO2Me ferent functionality in ring D, since it contains, the required Scheme 1. Precursors of spongiane diterpenoids prepared from natural stereochemistry at C12. Compound (þ)-10 was converted into sources. 12,14-isocopaladiene (19) by LiAlH4 reduction, mesylation, and elimination. Photooxygenation of 19 and reduction pro- In 1981, Ru´veda et al. reported the ﬁrst synthesis of a natu- duced alcohol 22, which was submitted to a second photooxyge- ral spongiane diterpene.14 (þ)-Isoagatholactone (1) was syn- nation reaction, and the resulting unsaturated cyclic peroxide 23 thesized from tricyclic ester 10 prepared from (þ)-manool was treated with ferrous sulfate to afford 12-hydroxyfuran 24. (4) in three synthetic steps (Scheme 2). Two successive oxida- Concurrent to this report, Nakano et al. described the synthesis tions of manool followed by acid-catalyzed cyclization of of racemic 24 from hydroxy-isocopalane 15 (Scheme 5), which methyl copalate 14 gave the known intermediate 10,15 also obtained from grindelic acid (3) by Minale et al. during the struc- 11 1) HCOOH tural elucidation of (þ)-1. CO H CO Me H 2 H 2 2) CH2N2/Et2O 70% H H 5 ent-methyl isocopalate (10) 1) PCC H+ , copalic acid (+)-manool CO Me 10 H 2 OH (4) 2) MnO2/HCN MeOH 1 H O2, py, 14 hematoporphyrin CO2Me OH 25% H H 1 1) O2, methylene blue (±)-15 EtOAc/EtOH CO Me 6 N H2SO4 H 2 2) P(OMe)3 dioxane OH 17% H 56% 15 1) 3.5% H2SO4, dioxane, 83% OH 2) LiAlH , 95% H OH 4 O LiAlH OH MnO H 4 2 (+)-1 17 H H O 72% 57% O H H 16 17 O Collins reagent Scheme 2. Ru´veda’s synthesis of natural isoagatholactone. 59% H H The required functionalization of the allylic methyl group (±)-1 was achieved by sensitized photooxygenation to give allylic alcohol 15. The allylic rearrangement of 15 with simultaneous Scheme 3. Nakano’s synthesis of racemic isoagatholactone. 448 M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467

1) 1O , methylene blue copalic 2 1) CH N /Et O EtOAc/EtOH acid 2 2 2 CO Me CO Me H 2 2) P(OMe) H 2 (ent-5) 2) HCOOH 3 H 20% H methyl isocopalate ent -10 18 1) LiAlH4 6 N H2SO4 2) MsCl/py 88% 85% dioxane 3) EtO-Na+/EtOH

OH O LiAlH OH MnO 4 2 (-)-1 H H H O 89% 64% H H H 19 20 21

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 22 23 24

Scheme 4. Ru´veda’s synthesis of ent-isoagatholactone ()-(1) and ent-13(16),14-spongiadien-12a-ol (24). was prepared as outlined in Scheme 3 from ()-copalic acid. Ep- 6).21 These authors have used chiral isocopalol 28 and diol oxidation of 15 gave epoxide 25 in quantitative yield, then, treat- 17 for the synthesis of sponge metabolites such as aldehydes ment with lithium diisopropylamide (LDA) led to b-elimination 29 and 30 by consecutive oxidations.22 The aldehydes have and lactonization in one pot to give a,b-unsaturated g-lactone 26 also been prepared in racemic form starting from ()-10 in 50% yield. When 26 was reduced with diisobutylaluminium (methyl isocopalate) via the racemic diol ()-17.23 hydride, the furan ()-24 was obtained in 19% yield. The major The same authors have also reported the synthesis of a fur- drawback of Nakano’s synthesis of 24 is the yield of the photo- anoditerpene, methyl spongia-13(16),14-dien-19-oate (33), by chemical reaction to functionalize C16 to give 15 (25% yield, cyclization of methyl lambertianate (32), which can be based on recovered 10) and the ﬁnal aromatization, which en- obtained from lambertianic acid (31), a diterpene acid of the couraged further studies to solve these low-yielding steps.16,17 Siberian cedar Pinus sibirica (Scheme 6).20

OH OH O OAc 10% H2SO4 OH SeO2 m-CPBA HCOOH H 48% CO2Me CO2Me H 99% H H H 27 28 H H 1) acetylation (±)-15 25 2) SeO2 OH OH CHO OH OH MnO2 OAc O O (+)-1 LDA DIBAL-H H 95% H 50% H 19% H O H H H H 17 Swern oxid. 29 26 (±)-24 CHO

Scheme 5. Nakano’s synthesis of ()-13(16),14-spongiadien-12a-ol (24). CHO H H In 1984, another synthesis of natural isoagatholactone (þ)- 30 (1) was reported by Vlad and Ungur (Scheme 6).20 The route is identical to that of Ru´veda, since the same diol 17 was oxi- O O dized by MnO to give isoagatholactone (see also Scheme 2). H2SO4 2 H MeNO2 In this case, compound 17 was prepared in 48% yield by allylic PhMe H H oxidation of isocopalol 28 with SeO2 in EtOH, although Ru´veda CO2R 32% CO2Me 33 et al. reported that this oxidation on isocopalate 10 and alcohol 31 R = H (isocopalol) 28 led to complex mixtures of products.19 32 R = Me Isocopalol 28 was prepared by Vlad et al. using an acid- Scheme 6. Vlad’s syntheses of natural isoagatholactone (þ)-1, aldehydes 29 catalyzed cyclization of an acetate mixture (27)(Scheme and 30, and methyl spongia-13(16),14-dien-19-oate (33). M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467 449

OH H 1) m-CPBA H SO 2 4 O H /Pt O copalic 1) CH2N2 2) Al(iPrO) dioxane 2 3 CO Me CO2Me 2 H H acid 2) HCOOH H 60% H O 80% O (±-5) H H H H methyl isocopalate (±)-10 15 16 34

1) LiAlH4 2) (COCl) /DMSO 20% OH LiAlH4 2 87% 3) p-TsOH H SO 2 4 O O O dioxane H2/PtO2 CH2OH H 52% H 42% H H H H H H 35 36 37 38

Scheme 7. Ru´veda’s synthesis of ()-spongian (37) and ()-spongia-13(16),14-diene (38).

In 1985, Ru´veda et al. reported the first synthesis of a O naturally occurring furanospongiane, albeit in racemic form 24 m-CPBA Al(Oi-Pr) (Scheme 7). ()-Spongia-13(16),14-diene (38) was prepared 10 3 15 (±)- H CO2Me from ()-methyl isocopalate (10) via the same unsaturated lac- 82% 72% H tone (16) used in the synthesis of isoagatholactone (see Scheme 39 2). It is worth mentioning that lactone 16 was similarly prepared from alcohol 15, but the latter was synthesized in an improved H2SO4 KOH O dioxane EtOH LiAlH manner (60% overall yield) by epoxidation of 10 and subsequent 16 4 H treatment with aluminium isopropoxide.23 Racemic lactone 16 62% 100% O 100% H was then hydrogenated on Pt to give 34, which was reduced 40 with LiAlH4, oxidized under Swern conditions and treated OH O with p-TsOH to afford the desired furan 38 in 20% overall yield. OH PCC The tetracyclic diterpene, ()-spongian 37, which is the tetrahy- H 55% H drofuran derivative of 38 and possesses precisely the fundamen- H H tal parent structure I (Fig. 1), was synthesized in this work by 41 38 hydrogenation of furan 36. Furan 36 was obtained by allylic re- Scheme 8. Nakano’s synthesis of ()-spongia-13(16),14-diene, (38). arrangement with simultaneous cyclization of the diol 35, which was prepared by lithium aluminum hydride reduction of 15. A few years later, Nakano et al. also described the synthesis 43 (89%). The selective hydrolysis of the allylic acetoxy group of ()-spongia-13(16),14-diene (38) from the same hydroxy- of 43 led to hydroxy acetate 44, the oxidation of which with 25 isocopalane 15 used in the synthesis of ()-1 (Scheme 8). MnO2 gave aldehyde 45. Subsequent oxidation of 45 with The starting material was, however, synthesized from ()- NaClO2 followed by esterification with diazomethane afforded methyl isocopalate (10) using the improved procedure devel- methyl ester 46. Regioselective elimination of the acetoxy group oped by Ru´veda et al. for the synthesis of related tricyclic and cyclization with formic acid led to ent-methyl isocopalate diterpenes (aldehydes 29 and 30).23 Thus, epoxidation of methyl (10) in 49% overall yield from sclareol (eight steps). Labdanolic isocopalate 10 gave a-epoxide 39, which, upon treatment with acid (7), the main acid component of Cistus ladaniferus, is firstly aluminium isopropoxide, afforded hydroxy-isocopalane 15 in esterified with diazomethane, and then dehydrated and isomer- 60% overall yield. Lactonization and b-elimination of 15 using ized with I2 in refluxing benzene to give methyl labden-15-oate H2SO4, followed by isomerization with 10% ethanolic potas- 48. Ester 48 is converted into unsaturated ester 50 by elimination sium hydroxide, gave a,b-unsaturated g-lactone 40, which of phenylselenic acid from 49, and then cyclized with formic was reduced with lithium aluminium hydride to give diol 41. acid to afford ent-methyl isocopalate (10) in 45% overall yield Oxidation of 41 with pyridinium chlorochromate (PCC) gave from labdanolic acid. the desired ()-furanospongian 38 in 55% yield (Scheme 8). The same authors showed how this material, ent-methyl More recently, Urones et al. reported the preparation of the isocopalate (10), can be converted into 9,11-secospongianes, useful intermediate in spongiane synthesis, ent-methyl isocopa- one of the most widespread subgroups of spongianes (Scheme late (10), from sclareol26 (6) and labdanolic acid27 (7), two abun- 10).28 To this end, the introduction of a D9,11 double bond and dant bicyclic natural products (Scheme 9). Thus, sclareol (6), subsequent cleavage was investigated. The method failed with a major terpenic constituent of Salvia sclarea, was acetylated tricyclic derivatives of 10, and no cleavage conditions were quantitatively with acetyl chloride and N,N-dimethylaniline, af- successful. The strategy was then applied to other tetracyclic fording the diacetyl derivative 42, the isomerization of which derivatives and led to the synthesis of secospongiane 54. with bis(acetonitrile)palladium(II) chloride led to the diacetate The precursor of secospongiane 54 was the known hydroxy- 450 M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467

N OAc OH OH AcCl, OAc K2CO3 MnO2 (MeCN)2PdCl2 H OH 97% H OAc 89% H OAc MeOH H OAc 94% 98% H H H H 6, sclareol 42 43 44

CHO CO Me CO Me 1) NaClO2 2 2 Δ 2) CH2N2 SiO2/ HCOOH CO2Me H OAc 98% H OAc 90% H 70% H H H H H 45 46 47 ent-methyl isocopalate (-)-10

HCOOH 95% 1) CH N 2 2 SePh 2) I2/PhH LDA/PhSeCl H2O2/AcOH CO2H CO2Me CO2Me CO2Me H OH 98% 85% 57% H H H H 7, labdanolic acid 48 49 50

Scheme 9. Urones’ syntheses of ent-methyl isocopalate ()-10 from sclareol (6) and labdanolic acid (7). isocopalane 15, which was again synthesized using Ru´veda’s ruthenate (TPAP) gave the ketone 51 in 68% yield. The desired method as outlined in Scheme 7.23 Treatment of 15 with double bond was introduced by bromination with phenyltrime- OsO4 followed by oxidation with tetrapropylammonium per- thylammonium perbromide (PTAP) and subsequent elimina- O O tion with Li2CO3/LiBr to give the a,b-unsaturated ketone 52. OH OH Reduction of 52 and acetylation gave the compound 53, which 1) OsO O 1) PTAP O 15 4 was subjected to ozonolysis to afford the highly functionalized 2) TPAP H 2) Li CO O 2 3 O secospongiane 54 in 65% yield. 68% LiBr H 99% H The readily available abietic acid (8) together with other nat- 51 52 urally ocurring resin acids isolated from conifer oleoresins are OAc OAc OAc OHC OAc common starting materials for the synthesis of natural products O and numerous diterpene derivatives.29,30 (þ)-Podocarp-8(14)- O O O 1) LiAlH4 3 en-13-one 11 (Scheme 11) is a versatile chiral starting material 2) Ac2O, py O 65% O 39% easily prepared from commercially available ()-abietic acid H H or colophony.31 Recently, the enantioselective biomimetic 53 54 synthesis of this chiral building block has been described.32 Scheme 10. Urones’ synthesis of 9,11-secospongiane 54. In the course of synthetic studies on the chemical conversion

O O OH CF3CO2H abietic H2O2/NaOH p-TsNHNH2 MeLi O (CF3CO)2O acid H 86% H O silica H 90% H (8) 82% 100% H H H H 11 55 56 57

OCOCF3 O O OSO2CF3 1) , PPTS 1) MeLi OH NaOMe OH O OTHP H 2) HCHO H 85% H 2) NaHMDS H H 75% H H 3) Cl H 58 59 60 61 N N(SO2CF3)2 76% Me3SiCN, ZnI2 97% 1) Pd(OAc) , Ph P, 2 3 70% Et3N, DMF, CO 2) PPTS OTMS O HCl/AcOH CN O O OTMS 120 °C 1) DIBAL-H (+)-1 H 84% H 2) H2SO4 H H H 86% H 62 63 38

Scheme 11. Arno´’s syntheses of (þ)-isoagatholactone (1) and ()-spongia-13(16),14-diene (38) from 11. M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467 451 of podocarpane diterpenoids into biologically active com- corresponding lactol, followed by dehydration and aromatiza- pounds, Arno´ et al. achieved an efficient synthesis of natural tion in acidic media (Scheme 11). ()-Furanospongiane 38 (þ)-isoagatholactone (1) and ()-spongia-13(16),14-diene was thus prepared in 11 steps from 11 in 28% overall yield. (38), starting from chiral podocarpenone 11.33 Compound 11 In the early 1990s, the same research group described the was converted in six steps into the common intermediate 60 first enantioselective synthesis of pentacyclic spongianes.34,35 (40% overall yield), appropriately functionalized for the elabo- To date, the synthetic routes reported for these natural products ration of the D-ring system (Scheme 11). are based on this method. Chiral podocarpenone 11 was con- The necessary 8b-methyl group was introduced by stereo- verted into the cyclobutene ester 65, via compound 64, by pho- controlled acetylenic-cation cyclization of acetylenic alcohol tochemical reaction with acetylene, nucleophilic carboxylation, 57, which was prepared from 11 by epoxidation to give 55, and reductive dehydroxylation, as indicated in Scheme 12. followed by silica gel-catalyzed Eschenmoser ring-opening Compound 65 was hydrolyzed under alkaline conditions and reaction to afford ketone 56, and addition of methyllithium. then cleaved with ozone to afford ()-dendrillol-1 68 (R¼H), The instability of enol trifluoroacetate 58 (w70% overall yield the simplest member of the pentacyclic spongianes. This syn- from 11) to hydrolysis required in situ incorporation of the hy- thetic sequence was later shortened by reductive cyanation droxymethyl side chain to give hydroxy ketone 59, which was with tosylmethyl isocyanide (TosMIC) to give nitriles 67, isomerized at C14, to afford compound 60, upon treatment which were subjected to alkaline hydrolysis in ethylene glycol with methanolic sodium methoxide. This intermediate was ethyl ether and ozonolysis. The key feature of the strategy is the used in two separate approaches to complete the D ring of cleavage of the cyclobutene ring to form a latent acid-dialde- the targeted spongianes. In the first approach, the required ho- hyde unit, compound 66, which spontaneously underwent inter- mologation at C13 was introduced by carbonylation of triflate nal lactone-hemiacetal formation. Based on this synthetic plan, 61, and subsequent deprotection in acidic media afforded di- the same authors have prepared related C7-oxygenated conge- rectly the desired isoagatholactone (þ)-1 (20% overall yield ners36 (aplyroseol-1 (68,R¼OCOPr), aplyroseol-2 (68,R¼ from 11). On the other hand, addition of trimethylsilyl cyanide OAc) and deacetylaplyroseol-2 (68,R¼OH)) upon stereoselec- provided the carbon at C13, compound 62. Subsequent hydro- tive introduction of a hydroxy function at the 7-position in the lysis with concomitant deprotection, lactonization, and dehy- starting material 11 (Scheme 13). Formation of the dienyl ace- dration occurred by treatment with a mixture of hydrochloric tate of 69 followed by oxidation with m-chloroperbenzoic acid acid and acetic acid at 120 C in a sealed tube to give lactone gave the hydroxy enone 70, in 74% yield, which was elaborated 63, which was transformed into 38 via reduction to its to give hydroxy ester 72, precursor of the pentacyclic

C(SMe)3 O CO2Me CO2H ν OH 1) C2H2/h 1) HgO,HgCl2 1) KOH CHO H H H H 2) CH(SMe)3 2) SmI2 2) O3, then CHO BuLi, CeCl 3) 2% NaOMe Me S H 3 H H 2 H 11 ~40% 64 75% 65 70% 66

O CN O 1) C H /hν 1) KOH 2 2 66 H 2) TosMIC/t-BuOK H 2) O3, then Me2S O 40% 64% H H R OH 67 68, R = H

Scheme 12. Arno´’s syntheses of ()-dendrillol-1 (68,R¼H).

O OAc O CN 1) C H /hν AcCl/Ac2O 1) m-CPBA 2 2 H py H 2) Na2S2O3 H 2) (EtO)2P(O)CN H 97% NaHCO3 OH 3) SmI2/t-BuOH OH H H 74% H H 11 69 70 52% 71 O CO2Me CO2H O 1) KOH 1) KOH CHO H 2) CH2N2 H 2) O3, then Me2S H CHO O or Me SO 2 4 R OH 3) NaOMe H H R H R 58% 72, R = OH 75 68, R = OH Ac2O 73 , R = OAc (PrCO)2O 68, R = OAc 74, R = OCOPr 68, R = OCOPr

Scheme 13. Arno´’s syntheses of ()-aplyroseol-1 (68,R¼OCOPr), ()-aplyroseol-2 (68,R¼OAc) and ()-deacetylaplyroseol-2 (68,R¼OH). 452 M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467 diterpenes. It is worthy of note that the homologation at C13 Some of these new spongiane derivatives possess an a-acetoxy was conducted more efficiently by cyanophosphorylation fol- group at C15 and were obtained from pentacyclic samples us- lowed by reductive elimination to give nitriles 71. ing an optimized hemiacetal-ring opening under basic condi- The versatility of intermediate 65 also led to further inves- tions. The synthetic protocol developed for the synthesis of tigations, which culminated with the synthesis of acetylden- 78 was also used to convert hydroxy-cyclobutenone 72 into drillol-1 76 and revision of its stereochemistry at C17, as spongianals 84, 85, and 86, which were evaluated against well as the synthesis of tetracyclic spongianes functionalized HeLa and HEp-2 cancer cells, compound 86 being the most at C17 (Scheme 14).37 The introduction of a cyanophosphory- active. lation step improved the synthesis of 65, which was then con- Arno´ et al. have also achieved the total synthesis of ()- verted into the intermediate dialdehyde 75. Acetylation of spongia-13(16),14-diene (38) starting from (þ)-carvone via compound 75 with AcOH/Ac2O and sulfuric acid (1%) at the phenanthrenone 89, which contains the two necessary 65 C gave exclusively the natural acetate 76, while reduction methyl groups at C8 and C10, and a useful carbonyl group followed by lactonization led to ()-spongian-16-oxo-17-al 78 at C14 for the final assembly of the D ring (Scheme 16).42 (Scheme 14). This compound was next converted into ()- The strategy is based on a C/ABC/ABCD ring annula- aplyroseol-14 80, having an unprecedented d-lactone unit for tion sequence in which the key step for the preparation of the spongianes, and its structural isomer 81, which permitted tricyclic ABC-ring system was an intramolecular DielseAlder the structural reassignment of this natural product.38 This (IMDA) reaction. The whole sequence takes 13 steps to fur- structure was also confirmed by X-ray crystallography of com- nish the furanospongiane 38 in 9% overall yield. Carvone is pound 80.39 first alkylated twice to introduce a three-carbon side chain, Recently, the same laboratory reported some structuree which is then elongated using a Wittig-type reaction to give activity relationship studies of the spongianes prepared in 87. Formation of the silyl enol ether of 88, followed by the group including the synthesis and biological evaluation IMDA reaction in toluene at 190 C during 7 days, provided of novel C7,C17-functionalized spongianes (Scheme 15).40,41 stereoselectively compound 89 in 95% overall yield.

O CO2Me CO2Me O O 3 Ac2O/AcOH CHO H then Me2S H CHO H2SO4 cat. H O 90% H H 85% H OAc 65 75 76 O NaBH4 O 99% R O NaBH4 H CO2Me 90% O H p-TSA 79 , R = OH Ac O H O 65% H CHO 80, R = OAc 2 H OH H O 77 78 BF3, AcCl, O Bu3SnH 45% H OAc H 81

Scheme 14. Arno´’s syntheses of ()-acetyldendrillol-1 (76), ()-spongian-16-oxo-17-al (78), ()-aplyroseol-14 (80) and ()-isoplyroseol-14 (81).

O CO2Me CO2Me CO2Me O O3 NaBH TFA CHO 4 H then Me2S H CHO 99% H O 47% H CHO OH 99% OH OH H H H OH H OH 72 82 83 84 O O

O O Ac2O/Et3N H O 4-pyrrolidinopyridine H CHOOAc H R OH H R R= OH, OCOPr 85 R = OAc 86 R = OCOPr

Scheme 15. Gonza´lez’s synthesis of C7,C17-functionalized spongianes. M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467 453

O O 1) OEt 1) LDA, then MeI POEt 2) LDA, then Δ, 190 ºC OEt 2) Et N, TBDMSOTf O 97% O O 3 H I OEt OHC 84% (+)-carvone 3) PPTS TBDMSO 87 88 65% 1) CH2I2, LDA, then H O ZnEt2 TMSCl/ NaI 2 OMe O 2) O 90% CHO 50% H Ph H H MeO PPh RO RO H RO H H 83% 89, R = TBDMS 90, R = TBDMS 91, R = TBDMS

1) m-CPBA O NH2NH2/KOH O CHO pH = 8 75% H 2) PTSA H H RO O H 40% H H

92, R = TBDMS 93 38

Scheme 16. Arno´’s synthesis of ()-spongia-13(16),14-diene (38) from (þ)-carvone.

The tricyclic system 89 is already a useful intermediate for to give enone 94, and cyclization in acidic media. The construc- the synthesis of norspongianes and other spongianes function- tion of the C ring needed an intramolecular DielseAlder reac- alized in ring A, as well as other terpenes containing the same tion (IMDA) reaction to give the DielseAlder adduct 100. ABC-ring system. Cyclopropanation of the enol double bond Therefore, decalone 95 was transformed into the IMDA precur- followed by homologation of the carbonyl group at C14 led sor 99 by homologation at C9, epoxide opening, Wittig reac- to enol ether 90. After completing the desired carbon frame- tion, and introduction of the dienophile moiety. The desired work, functionalization at C16 was carried out by isomeriza- cycloaddition took place at 112 C for 17 h to give the tion of the double bond in 91 to give aldehyde 92, and then DielseAlder adduct 100 in 95% yield. This was next elaborated careful epoxidation followed by treatment with p-TSA gave using a regioselective ring opening of a dihydrofuran ring to the furano ketone 93. Compound 93 is a potential precursor give the C7,C11-functionalized spongiane lactone 102 after hy- of other furanospongianes functionalized in ring A and has re- drolysis and epoxidation with tert-BuOOH and VO(acac)2. cently been isolated from natural sources.43 Finally, Wolffe Based on this synthetic plan, Abad et al. continued the Kishner reduction of 93 afforded 38 in 75% yield. development of several studies for the synthesis of spongiane A new strategy toward oxygenated spongianes using ()- diterpenes related to natural dorisenones. Therefore, following carvone as starting material has recently been described by the same strategy B/AB/ABC/ABCD for the ring- Abad et al., as outlined in Scheme 17.44 This synthetic sequence system construction they used the key epoxydecalone 96, follows a B/AB/ABC/ABCD approach in which carvone which was further elaborated to the DielseAlder precursor is ﬁrst converted into the decalone 95 (AB system) by alkylation 99 (Scheme 17). Other DielseAlder precursors were also

O O O O 1) LDA, then MeI 1) H O , Br Br 2 2 2) LDA, then CF3CO2H NaOH O Br 78% 2) H2, Pd/C H 87% H Br (-)-carvone 76% 94 95 96

1) O O CO2Me Ph 1) Ph3P=CH2 BuLi then MeO PPh 2) BrCH CCH, Δ 2 CNCO2Me , 112 °C 2) NaH then NaOH 84% 95% HCO H 70% 2 H OH H O H O 86% 97 98 99

O O CO2Me O O O ZnI2, Ac2O 1) KOH 100% 2) t-BuOOH O OAc VO(acac) OH H H 2 H 64% 100 101 102

Scheme 17. Abad’s synthesis of C7,C11-functionalized spongianes (102) from ()-carvone. 454 M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467 synthesized from 96 for intermolecular DielseAlder reactions 100 gave initially the corresponding 7-acetoxy-15-iodo-deriva- but provided low yields using dimethyl acetylenedicarboxylate tive, which rapidly underwent lactonization to afford the (DMAD) as dienophile (Scheme 18).45 The synthesis starts g-lactone 101 in nearly quantitative yield. The structure of with alkylation with LDA of the a-position of the enone. Fur- 101 was initially assigned on the basis of a detailed spectro- ther alkylation with an allyl bromide and acidic cyclization scopic NMR study, and final proof of the structure was obtained gave 95. Epoxidation, followed by olefination, gave 97, and by single-crystal X-ray diffraction analysis. Unfortunately, all at- another olefination led to 103, which after DesseMartin oxi- tempts to introduce the required oxygenated function present in dation gave enone 104, then, sodium borohydride reduction natural dorisenones at C11 were unsuccessful. An oxygenated and protection with TBDMS and reaction with dimethyl ace- function was introduced leading to epoxides 102, 110e112, tylenedicarboxylate (DMAD) gave a mixture of 105 in low but epoxide opening as desired was unsuccessful. yield. Alternatively, 103 is propargylated with allyl propargyl Following the above-mentioned extensive synthetic studies bromide. Introduction of the methoxycarboxylate and final re- for the preparation of dorisenone diterpenes of the spongiane action in toluene at 112 C gave the desired DielseAlder diene family, Abad et al. have recently adapted their synthetic 100. Thus, by using an IMDA reaction the compound 100 was sequences for the synthesis of dorisenone C (127)(Scheme formed and used to further introduce the required functional- 20).46 They have developed a B/AB/ABC/ABCD ities and the construction of the D-ring system (Scheme 19). approach starting from R-()-carvone, in which the known The regioselective ring opening of the dihydrofuran ring of hydroxy-aldehyde 97 (AB rings) (Scheme 18) is the key

O O O O 1) Ph O 1) LDA, then MeI 1) H O , MeO P Br 2 2 Ph 2) LDA, then NaOH O 2) NaH then Br 2) H2, Pd/C HCO H OH Br 2 84% 87% (-)-carvone 3) CF3CO2H 95 96 97 60% CO Me Dess-Martin 2 1) NaBH Ph3P=CH2, THF reagent 4 CO2Me 94% 86% 2) TBDMSOTf OH O 3) DMAD OTBDMS 9% 103 104 105

CO2CH3 1) BuLi, -78 °C BrCH2C CH 2) CNCO Me NaOH 2 CH 3) PhMe, 112 °C 56% 2 O O 80% 98 100

Scheme 18. Abad’s synthesis of advanced intermediates for the preparation of C7,C11-functionalized spongianes from ()-carvone.

CO2Me

O 100

ZnI2, Ac2O 98% O O O O O O KOH, MeOH O tBuO2H

VO(acac)2 R1 70% OH OAc R 2 102 Swern 101 107 O oxid. Swern R1 = OH R2 = H (92%) 50% m-CPBA 86% oxid. 108 m-CPBA O R1 = R2= =O (89%) O 1) BH3 O 109 45% 2) H2O2 R1 = H, R2 = OH (99%) O O O 110 OAc

111 9α,11α-epoxy (46%) 112 9β,11β-epoxy (40%)

Scheme 19. Abad’s synthesis of C7,C11-functionalized spongianes (102, 110, 111, and 112) from ()-carvone. M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467 455

O O O O 1) MeLi, -78 °C BrCH2CCH 2) Swern oxid. NaOH 75% (see Scheme 17) OH O O H 82% H H 97 113 114 (-)-carvone

TBDMSO CO2Me TBDMSO O PTSA 1) TBDSCl, Et3N PhMe,180 °C acetone 2) LiHMDS then 60% from CNCO Me O 241 O 2 H H O H 77% 115 116 117

MeO2CO CO2Me MeO2CO MeO2CO CO2CH3

PhMe, 195 °C ZnI2, Ac2O 114 LDA-BuLi, -78 °C + then MeOCOCl O 82% O O 67% H H 118 119, 56% 120, 31% O O O O MeO CO O O O 2 NaOMe Jones O O reagent O O -20 °C BH3-THF 96% H 92% H 99% H OAc OH O OH H H H H 121 122 123 124 OH O O HO HO AcO DIBAL-H O O Ac2O O -78 °C MnO2 DMAP H 71% from H 80% H OH 124 OH OAc H H H 125 126 127, dorisenone C

Scheme 20. Abad’s synthesis of dorisenone C (127) from ()-carvone. intermediate for the preparation of different DielseAlder pre- and hence established the absolute conﬁguration of the natural cursors, since the key step for the formation of the C ring is an product. During these synthetic studies several unnatural fura- intramolecular DielseAlder reaction (Scheme 20). Firstly, the noditerpenes were also prepared from lactone 124 by reduc- DielseAlder precursor 115 was prepared from 97 following tion and dehydration to give the furan ring present in 128 standard reaction conditions used previously by the same and 129 (Scheme 21). group. Unfortunately, this precursor did not produce the Finally, we describe how, recently, Ragoussis et al. have desired DielseAlder adduct, but a product of retro-hetero- converted natural ()-sclareol 6 into the furanoditerpene, ene rearrangement of the propargylic ether moiety. Thus, after ()-marginatone (135)(Scheme 22).47 The authors converted desililation of 116 the enone 117 was formed in good yield. To sclareol 6 into (þ)-coronarin E 132, using minor modiﬁcations avoid the sterically demanding group of the diene moiety, the of reported procedures, which by regioselective hydrogenation preparation of the dienol carbonate 118 was undertaken and and stereocontrolled-intramolecular electrophilic cyclization the reduction of the retro-hetero-ene rearrangement product gave the tetracyclic marginatane-type diterpene 134. was envisaged. In fact, the strategy did work, but the product Subsequent allylic oxidation of 134 afforded the synthetic of the rearrangement 119 was still the main product of the in- ()-marginatone 135, the spectroscopic data of which were tramolecular DielseAlder reaction. Although in moderate identical to those reported for the natural product. The synthe- yield, the desired compound 120 was obtained and the se- sis starts with the preparation of the ambergris odorant, ()-g- quence proceeded. Opening of the dihydrofuran ring of 120 bicyclohomofarnesal 130, from sclareol 6 in seven steps and gave rise to the product 121 as a result of in situ lactonization. The cleavage of the ester groups gave 122, and subsequent ox- O idation gave diketone 123, which was reduced with a boranee O RO O O THF complex to give alcohol 124. Further reduction with 1) DIBAL-H H H DIBAL-H gave the triols 125 in which the lactol moiety was 2) H+ OH 95% OR re-oxidized with MnO2 to give the corresponding lactone H H 124 128 R = H 126. Final diacetylation of 126 gave the synthetic natural prod- Ac2O-DMAP 129 R = Ac uct dorisenone C (127), the data for which, were in complete 86% agreement with those reported earlier for the natural product Scheme 21. Abad’s synthesis of furanoditerpenes 128, 129 from ()-carvone. 456 M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467

O O

CHO OH OH 7 steps 3-bromofuran HMPA, reflux HCO2NH4 H H H H OH BuLi 76% Pd/C 10% 52% H H 79% H H 77% 6, sclareol 130 131 132 O

O BF3-Et2O O t-BuOOH O H H H 46% NaOCl H H 33% H 133 134 135

Scheme 22. Ragoussis’s synthesis of ()-marginatone 135 from ()-sclareol.

52% overall yield. The coupling of 130 with 3-lithiofuran led The first subgroup, commonly known as electrophilic cycli- to a mixture of two diastereomeric alcohols 131 in 78% over- zations of polyenes, has been intensively studied for the syn- all yield. Dehydration of this mixture in refluxing HMPA gave thesis of steroids and a wide variety of polycyclic ring (þ)-coronanin E 132 in high yield (76%) (Scheme 22). Reduc- systems, and is well documented in the literature.50,51 Indeed, tion of the side-chain double bond of 132 gave (þ)-dihydro- their importance has increased over the past three decades, due coronarin E 133 and subsequent intramolecular electrophilic to the development of new routes to polyolefinic precursors, cyclization furnished the tetracyclic derivative 134. Allylic methods of asymmetric synthesis, and different conditions oxidation with tert-BuOOH of 134 gave the target molecule, for the key cyclization step.52e58 ()-marginatone 135, albeit in low yield (33%). In the early 1980s, Nishizawa’s research group described the biomimetic cyclization of a geranylgeraniol derivative 59,60 3.2. Syntheses by biomimetic approaches 136 to the racemic tricyclic alcohol 28 (Scheme 23), which had been previously converted into isoagatholactone 17 20,21 Inspired by nature, biologists and chemists have made poly- (1) by Nakano and Hernańdez and Ungur et al. Com- pound 28 has also been converted into 12a-hydroxyspongia- ene cyclizations a powerful synthetic tool for the one-step con- 19 struction of polycyclic compounds, starting from acyclic 13(16),14-diene by Ru´veda et al. The cyclization takes place polyene precursors. Despite the impressive and economical using as the electrophile a mercury(II) triflate-N,N-dimethyl- syntheses achieved over the past 50 years by chemical simula- aniline complex, which after reductive demercuration leads to tion of polycyclic terpenoid biosynthesis,48,49 this area of re- alcohol 28 (22%), together with two bicyclic diterpenoids. search still remains a growing field of investigation. The Contemporary synthetic studies by Ungur et al. also described the biomimetic synthesis of 28 by superacid cycliza- biosynthetic transformations have been mimicked by cation- 61 olefin and radical cyclization reactions and, more recently, tion of geranylgeraniol 137 with fluorosulfonic acid. Afew by radical-cation cyclization cascades. years later, the same group also reported the synthesis of

NO 2 1) Hg(OTf)2·PhNMe2 2) aq. NaCl O 3) NaBH4/aq. NaOH O 136 22% OH H H

FSO3H/PrNO2 H -80 °C 28

OH 87%

geranylgeraniol 137

FSO3H/PrNO2 -55 °C CO Me CO2Me 2 92% H H H E,E,E-geranylgeranic methyl ester 138 10

Scheme 23. Biomimetic syntheses of racemic isocopalol 28 and methyl isocopalate 10, precursors of spongiane diterpenoids. M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467 457 racemic methyl isocopalate 10, from 138, using similar condi- 25).70 In their synthesis, an oxidative free-radical cyclization 62 tions (Scheme 23). of polyene 142 with a 2:1 mixture of Mn(OAc)3 and Cu(OAc)2 Nishizawa et al. also used the mercury(II) reagent to cy- provided stereoselectively the tricyclic intermediate 143 in clize ambliofuran 139, leading to the tetracyclic isospongiane 43% yield. Subsequent functional-group manipulation and ho- 140 in 13% yield (Scheme 24).63 Compound 134, having the mologation at C13 of 143 allowed, in two independent syn- marginatane carbon skeleton, was obtained after the demercu- thetic sequences, the construction of the required furan ring ration treatment of 140 with sodium borohydride. Amblio- D of the spongiane and marginatane carbon skeletons. Thus, furan 139 had also been cyclized to furanoditerpene 134 in starting from allylic alcohol 141, the necessary cyclization high yield by Sharma et al. using SnCl4 as electrophile initia- precursor 142 was obtained by treatment with allyl chloride tor (Scheme 24).64 followed by alkylation with ethyl 2-methylacetoacetate in 49% overall yield. After securing the stereochemistry of 143 by means of meticulous NMR studies,71 isospongiane 146 1) Hg(OTf)2·PhNMe2 2) aq. NaCl was prepared by reduction, benzoylation, and ozonolysis lead- O 13% O ing to ketone 145, which was alkylated with a THP-protected H hydroxyacetaldehyde and hydrolyzed with concomitant aro- SnCl ClHg 4 H 139 >90% matization and ﬁnal debenzoylation by reduction. 140 On the other hand, ozonolysis of diol 144 and protection as

NaBH4 its corresponding acetonide, compound 147, followed by furan O aq. NaOH H ring formation using Spencer’s method, gave unnatural furanospongiane 149, via enone 148, in 8% overall yield from 141. H 134 The same authors also reported an alternative route to 149 via the tricyclic intermediate 152, which was prepared from the far- Scheme 24. Biomimetic synthesis of isospongiane 134 from ambliofuran 139. nesyl acetate derivative 150 in four steps, using a radical cascade of polyolefin 151 (Scheme 26).72 Compound 152, possessing all Since the first investigations in the 1960s by Breslow of the carbons in the spongiane skeleton, was transformed into et al.,65,66 biomimetic radical-mediated cyclization reactions spongiane 149 in five steps, as detailed in Scheme 26. Thus, hy- have become an excellent synthetic method for the synthesis drolysis, and epoxidation gave epoxide 153, subsequent Collins of polycyclic natural products under mild conditions and oxidation and aromatization with p-TsOH gave furan 154. Final 67 with high stereochemical control. reduction with LiAlH4 gave diol 149 in 2.8% overall yield from In the early 1990s, Zoretic et al. developed a very efficient 150. The synthetic sequence leading to diol 149 was later opti- series of triple and tetra cyclizations, leading to trans-decalin mized (15% overall yield from 150), allowing the synthesis of ring systems. Their strategy68 was based on the Snider method ()-isospongiadiol 156, via silyl enol ether 155, upon manipu- to cyclize intramolecularly unsaturated b-keto esters with lation of the A-ring functionalization in 149.73 Mn(III) salts.69 Following the success of this approach, they A few years later, Zoretic’s group reported an analogous reported, in 1995, the first biomimetic-like synthesis of spon- stereoselective radical cascade cyclization introducing an giane diterpenes, particularly furanospongianes (Scheme a,b-unsaturated cyano group in the cyclization precursor

1) SOCl2 Mn(OAc) LiAlH 2) LiCH2C(O)CMe(Na)CO2Et 3 4 H 49% Cu(OAc)2 94% O O 43% H HO EtO C CO2Et 2 141 142 143

1) LDA, then 1) PhCOCl OHCCH OTHP O 2 O H H H 2) O3, then Ph3P 2) p-TsOH HO BzO 3) LiAlH HO H 38% H 4 H HO BzO 56% HO 144 145 146

1) O3, then Me2S 2) acetone 75% oxalic acid 1) NaH, EtOCHO, SBu O then aq. HCl 1) Me2S=CH2 O O H 2) p-TsCl, py H 2) HgSO4 H O then n-BuSH O 57% from HO H H H O O 147 HO 147 148 149

Scheme 25. Zoretic’s biomimetic synthesis of isospongiane 146 and spongiane 149 from precursor 144. 458 M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467

1) MsCl 2) LiCH2C(O)CMe(Na)CO2Et OAc Mn(OAc)3 OAc HO 3) Ac2O Cu(OAc)2 29% O 23% CO Et 150 2 151

1) K2CO3 O 1) CrO3·2py O OAc OH H 2) m-CPBA H 2) p-TsOH, H 89% then 10% HCl O O O H H 55% H EtO2C EtO2C EtO2C 152 153 154 1) TBDMSCl LiAlH 2) CrO ·2py O 1) m-CPBA O 4 149 3 HO 85% 3) LDA/TMSCl H 2) n-Bu4NF H 35% 67% TMSO O H H TBDMSO HO 155 156

Scheme 26. Zoretic’s biomimetic synthesis of ()-isospongiadiol 156.

(Scheme 27).74 They started from phosphonate 157, which reaction with cyclopropyl methyl ketone, led to compound was subjected to HornereEmmons olefination to give polyene 168. The next step was ring opening of the cyclopropane and 158. This modification allows the synthesis of furanospon- formation of an E-homoallylic bromide using HBr, which gianes functionalized at C17, such as 163e166, through the was then used as its corresponding iodide 169 to alkylate 2-phe- advanced intermediate 162. Compound 162 was prepared in nylthiobutyrolactone giving thioether 170. Removal of the four steps from tricyclic system exo 160, which was synthe- thioether in 170 and subsequent manipulation of the tetrahydro- sized by an intramolecular radical cyclization of polyene 159. pyranyl ether led to selenoate 173. Treatment of the latter with Concurrent to these studies, Pattenden et al. applied their ex- Bu3SnH and AIBN in refluxing degassed benzene led, after pertise in polycyclic ring constructions, based on free-radical- methylenation, to the tetracycle lactone 174 in 42% yield. mediated cyclizations of polyolefin selenyl esters,75,76 for the Lactone 174 was then converted into 175 by SimmonseSmith total synthesis of ()-spongian-16-one 175 (6% overall yield) cyclopropanation and hydrogenolysis. (Scheme 28).77,78 They completed the synthesis in a concise Recently, Demuth et al. have developed a radical-type fashion via the cyclization precursor 173, which was prepared cascade cyclization for the synthesis of ()-3-hydroxy-spon- from alcohol 167, as shown in Scheme 28. Protection of gian-16-one 180, a precursor of 175 (Scheme 29).79 In their 167 as tetrahydropyranyl ether, followed by lithiation and strategy, the photoinduced radical cation of the polyene

1) KN(SiMe3)2 2) PO(OEt) OR 2 O H CN 1) CBr , PPh CN OR 4 3 THPO 3) p-TsOH HO 2) LiCH2C(O)CMe(Na)CO2Et 64% 53% 157 158 R = TBDPS

CN 1) n-Bu NF CN O OR Mn(OAc)3 OR 4 OH

Cu(OAc)2 H CN 2) m-CPBA H O 58% O 56% O H H CO2Et EtO2C EtO2C 159 R = TBDPS 160 8:2 exo/endo R = TBDPS 161

O O DIBAL-H LiAlH4 then HOAc H CHO 96% H OH 73% HO HO H H EtO C HO 1) CrO3·2py O 2 163 164 2) p-TsOH H CN 60% 1) CF SO Cl O NaBH O 3 2 O H 4 2) DMAP EtO2C 88% 162 H CN 3) DIBAL-H H CHO HO H then HOAc H EtO C 70% HO 2 165 166

Scheme 27. Zoretic’s biomimetic synthesis of C17-functionalized furanospongianes. M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467 459

1) DHP, PPTS 2) Li O then 1) HBr I HO 2) DHP, PPTS PhS Br O O 3) NaI, Me2CO 76% 72% 71% OH 167 OTHP OTHP 168 169 1) NaClO2 2) O PhS O O O N SePh 1) m-CPBA 1) PPTS O O O 2) CaCO3 2) Dess-Martin O 80% 84% 71% CHO OTHP OTHP 170 171 172 1) Bu SnH O 3 O O AIBN H 1) Zn(Cu), H 2) Zn, TiCl CH I O 4 O 2 2 O CH2Br2 2) PtO2, H2 42% H 76% H CSePh O 173 174 175

Scheme 28. Pattenden’s biomimetic synthesis of ()-spongian-16-one 175. undergoes water addition in anti-Markovnikov sense, followed later was converted into ()-spongia-13(16),14-diene 38 and by cyclization cascades terminated by a 5-exo-trig ring closure. ()-spongiadiosphenol 196 (Scheme 31).80,81 The overall reaction sequence mimics the non-oxidative biosyn- The route to the tetracyclic compound 194, the key inter- thesis of terpenes. The radical cation precursor 179 was synthe- mediate for the synthesis of 38 and 196, starts with the conver- sized from farnesyltri-n-butylstannane 176, which reacted with sion of furfuryl alcohol 181 into a propargyl ether 182, which the methylen-butyrolactone 177 via a Michael addition. Follow- underwent a furan ring transfer reaction to give the bicyclic al- ing the introduction of the double bond in 178, irradiation of 179 cohol 183. Hydrogenation of 183 followed by Swern oxidation in a Rayonet reactor with lmax¼300 nm afforded spongiane 180 afforded the ketone 184. The ketone 184 was converted into in 23% yield after puriﬁcation. The structure of 180 was unam- the allylic b-keto ester followed by methylation with iodome- bigously determined by NOE and X-ray analyses. thane to afford 185. Removal of the allyl ester gave ketone 186, which was next annulated with ethyl vinyl ketone, via di- 3.3. Other approaches and total syntheses ketone 187, to give the tricyclic furan 188. The construction of the ring A was effected by reductive alkylation to introduce an As mentioned previously, the studies toward the synthesis of allyl group, compound 189, which was then converted into an spongianes are scarce, especially of rearranged metabolites. adequate side-chain ketone, compound 193, ready for the ﬁnal The synthesis of furanospongiaditerpenoids has been embarked annulation to afford the tetracyclic intermediate 194. The ste- upon starting from natural products and using biomimetic-like reochemical structure of 194 was assured by NOE effects be- reaction sequences, both of which have provided in some cases tween the two angular methyl groups. the synthesis of spongianes with a functionalized A-ring. The synthesis of spongiane 38 was successfully completed Additionally, in the mid 1990s, Kanematsu’s group carried by forming the gem-dimethyl moiety by reductive methylation out synthetic studies for the construction of an appropriate fur- of 194 to give ketone 93 and removal of the carbonyl group at anohydrophenanthrene ring system 194 (Scheme 30), which C3. In parallel studies, compound 194 was reduced,

O O Sn(C H ) 4 9 3 O n-BuLi, CuI, O O + LiBr, TMSCl 1) LiHMDS/PhSeBr O 92% 2) m-CPBA, py 35% 176 177 178 179

H O O Rayonet reactor λ = 300 nm max H2O 23% O 1,4-dicyano-2,3,5,6-tetra- O methylbenzene/biphenyl H HO 180

Scheme 29. Demuth’s biomimetic synthesis of ()-3-hydroxy-spongian-16-one 180. 460 M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467

HC CCH Br t-BuOK 1) H2, 5% Pd-C 2 O O OH NaOH O O t-BuOH O O HO 2) DMSO, TFA 100% 80 °C 78% from 182 181 183 182

1) diallyl carbonate, NaH Pd(OAc)2 EVK O O O O 2) MeI, K2CO3 O PPh3, HCO2H O DBU O 76% 184 74% O 186 185

O 1) t-BuOK O Li, NH3(l) O 1) LiAlH4 O 2) p-TsOH allyl bromide 2) TBSOTf H O 74% 62% 94% from 186 O O 187 188 189

1) (COCl)2 O O O 9-BBN then DMSO then Et3N

H NaOH/H2O2 H 2) EtMgBr H 96% HO 3) TBAF HO TBSO TBSO HO 92% 190 191 192

(COCl) O O 2 KOH DMSO H 73% H then Et N 3 O O O 86% 193 194

Scheme 30. Kanematsu’s synthesis of spongian precursor 194.

1) LiAlH4 O 2) BuLi, CS2 O Li, NH3(l) then MeI H H then MeI 3) (TMS)3SiH 60% O H AIBN H 50% O 93 38 H O O O HO O 194 1) Li, NH3(l) H MeONa H 2) LDA then DMSO O H HO H MoOPH 79% 196 36% 195

Scheme 31. Kanematsu’s synthesis of ()-spongia-13(16),14-diene 38 and ()-spongiadiosphenol 196. hydroxylated to give ketone 195 and then oxidized to afford Reductive decarbonylation using the Wilkinson catalyst fur- the desired ()-spongiadiosphenol 196, which represents the nished the bicyclic hydroazulenic hydrocarbon (þ)-200 in ﬁrst total synthesis of a furanospongiane diterpene with a func- 52% yield (Scheme 32). tionalized A-ring (Scheme 31). With regard to the synthesis of rearranged spongianes, there are about three reported synthetic approaches to build up the 82e84 bicyclic systems present and, to the best of our knowl- RuCl3-NaIO4 hν (pyrex) 85,86 edge, only two published enantioselective total syntheses. 35-40% hexane O 40% Mehta and Thomas reported in 1992 how the abundant, 197 198 commercially available (þ)-longifolene 197 can be degraded to a hydroazulene moiety, compound 200, present in rear- H H 82 ranged spongianes (Scheme 32). Catalytic ruthenium oxida- (PPh3)3RhCl tion of 197 led to the formation of longicamphenilone 198 in toluene H 52% H 35e40% yield. Irradiation of 198 with a 450 W Hg lamp OHC through a Pyrex ﬁlter resulted in the expected Norrish-type I 199 200 cleavage to the bicyclic aldehyde 199 in about 40% yield. Scheme 32. Mehta’s synthesis of hydroazulene 200. M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467 461

Bhat et al. reported a common Lewis acid-catalyzed Dielse Firstly, in 2001, Overman et al. described the first enantio- Alder reaction to form decalin systems, present in spongianes selective synthesis of a rearranged spongiane, (þ)-shahamin K and other terpenoids (Scheme 33).83 224 (Scheme 35),85 a spongian-derived metabolite having a cis-hydroazulene unit and an attached highly oxidized six- carbon fragment. O R O One of the key steps of the synthesis was a Prins-pinacol re- R` AlCl action that produced the core of the carbon framework, the cis- R 3 + hydroazulene system. The synthesis starts with the conversion R` of cyclohexanone 211 into the cyclization precursor 215 intro- 201 202 203 ducing a kinetic resolution step with (R)-oxazaborolidine 213. Scheme 33. Bhat’s synthesis of decalins. Thus, oxidative cleavage of the double bond in 211, followed by thiocetalization, gave compound 212, which was subjected Diene 201 reacts with a series of dienophiles 202, in the to the chemical resolution to give enantioenriched ketone (S )- presence of AlCl3, to give a number of decalins 203, which 214 in 44% yield. Addition of (E )-1-propenyllithium to (S )- can be further elaborated to build up the spongiane skeleton. 214 followed by silylation gave the silyl ether 215 in high yield. The last approach described for the synthesis of spongianes Treatment of 215 with dimethyl(methylthio)sulfonium tetra- features a synthetic route for the preparation of the cis-fused fluoroborate (DMTSF) initiated the Prins-pinacol reaction to 5-oxofuro[2,3-b]furan unit present in some rearranged spon- give the bicycle 216 in 80% yield as a mixture of sulfide epi- gianes. Reiser et al. reported a short and enantioselective syn- mers, the structure of which was confirmed by single-crystal thesis of this furofuran unit starting from methyl 2-furoate X-ray analysis of the corresponding sulfone. Installation of (Scheme 34).84 the exocyclic methylene group, followed by oxidative desulfo- The synthesis starts with a copper-bisoxazoline-catalyzed, nylation, provided ketone 218, the thermodynamic lithium eno- enantioselective cyclopropanation of methyl 2-furoate 204 to late of which reacted with enantiopure sulfone 219 to give cyclopropane 205, a versatile building block toward a broad va- compound 220, as a single isomer in 72% yield. To transform riety of derivatives, which could be subsequently converted into the cyclopentanone ring in the side chain of the required pyra- 5-oxofuro[2,3-b]furans. In fact, hydrogenation of 205 gave ex- none unit, keto sulfone 220 was reduced with SmI2 and the re- clusively compound 206 as a single stereoisomer in 86% yield. sulting enolate was acetylated to give enol acetate 221 in 88% Subsequent rearrangement to 207 using 2 M HCl in dioxane yield. Reduction of the ketone of this intermediate with (R)- gave rise to the parent 5-oxofuro[2,3-b]furan framework in oxazaborolidine 213 and boraneeTHF complex, followed by only three steps from inexpensive methyl 2-furoate 204, and acetylation, gave acetate 222 in 88% yield. Chemoselective in enantiomerically pure form. Conversion of the carboxylic dihydroxylation of the enol acetate in 222 gave the a-hydroxy acid into the acetoxy derivative 209, typical in many spongiane ketone 223 in 87% yield. Cleavage of the hydroxy ketone in diterpenoids, was accomplished in a four-step sequence from 223 with Pb(OAc)4 followed by reduction of the resulting alde- 207 via its methyl ketone 208, which underwent diastereoselec- hyde with NaBH4 and lactonization using the Mukaiyama re- tive BaeyereVilliger oxidation under retention of configuration. agent, provided (þ)-shahamin K 224. Alternatively, 207 could be photochemically decarboxylated The second enantioselective total synthesis of a rearranged with lead tetraacetate under copper(II) catalysis following a rad- spongian diterpene was achieved recently by Theodorakis ical pathway to directly yield a mixture of 209 and epi-209 et al.,86 who completed the sythesis of norrisolide 235 in (210), which could be easily separated by chromatography. 2004. This molecule presents a rare g-lactone-g-lactol moiety To date, to the best of our knowledge, there has been re- as side chain, which has few synthetic precedents. This group ported only two enantioselective total syntheses of diterpenes developed initially an enantioselective synthesis of the side with a rearranged spongiane skeleton. chain, starting from D-mannose (Scheme 36).

Org. Lett. H O O H O H O O MeO C 2001 MeO C Pd/C H2 MeO C 2 M HCl 2 2 2 HO C O 86% 1,4-dioxane 2 3, 1315 CO Et CO Et 2 2 74% H 204 H H 205 > 99% ee 206 207 H H 1) (COCl)2 O 2) CH N O O 4) m-CPBA O O 2 2 O AcO O 3) HI 31% (4 steps) H H 208 209 Pb(OAc) , Cu(OAc) H H 2 2 O O O O HOAc,THF 207 AcO O + AcO O hν 88% H H 209 1 : 1.75 210

Scheme 34. Reiser’s synthesis of 5-oxofuro[2,3-b]furans. 462 M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467

HPh Ph O O O O N SPh B SPh 1) OsO4, NaIO4 213 1) (E)-MeCH=CHLi

2) PhSH, BF3·OEt2 SPh BH3·THF SPh 2) TMS-imidazole 89% 92% 211 212 (S)-214 44%, 94% ee

O TMSO H H 1) TMSCH Li DMTSF SPh 2 SPh 1) m-CPBA SPh 80% 2) HF·py 2) MoOPH, LDA SPh H 84% H 80% 215 216 (5:1; b:a) 217

Ph AcO AcO H Ph O OAc 1) O H N B O 1) LDA, HMPA H H 213 H SO Ph SmI2 H O 2 O 2) AcO Ac2O BH3·THF H 219 O 88% 2) Ac2O H H 88% 218 72% SO2Ph 220 221 O AcO AcO OAc OAc O O H H OH H H OsO , NMO H 1) Pb(OAc)4 H OAc 4 OAc OAc 87% 2) NaBH4 3) H H DMAP H + NCl 222 223 I- 224 57%

Scheme 35. Overman’s synthesis of (þ)-shahamin K 224.

The preparation of the side chain begins with the transforma- was ultimately achieved using ureaehydrogen peroxide and tri- tion of D-mannose to the known bisacetonide 225 with improved ﬂuoroacetic anhydride and gave rise to the desired material in conditions using iodine as catalyst to give 225 in 85% yield. 69% yield as a single isomer. Treatment of 225 with p-toluenesulfonyl chloride and triethyl- Theodorakis’s group described the total synthesis of norriso- amine afforded the desired glycosyl chloride 226, which, upon lide 235 in 2004.86,87 In their strategy, they achieved the assem- elimination with a mixture of sodium naphthalenide in THF, bly of the two main fragments, 237 and 238, through the gave rise to glycal 227 in 48% overall yield. Compound 227 C9eC10 bond to give alkene 236 (Scheme 37). One of the frag- proved to be labile upon standing and was immediately benzy- ments, the trans-fused hydrindane motif, could be prepared lated to produce vinyl ether 228 in 90% yield. Syringe-pump ad- starting from the enantiomerically enriched enone 239. The dition of ethyl diazoacetate (0.1 M in DCM) into a mixture of other fragment was prepared from the lactone 240, which con- 228 (2 M in DCM) and rhodium(II) acetate at 25 C gave the cy- tains the desired cis stereochemistry at the C11 and C12 centers. clopropanation ester 229 with the desired conﬁguration at the The synthesis began with the preparation of enone 239, C12 center. The only diastereomers acquired during this reac- which was available through an L-phenylalanine-mediated tion were produced at the C13 center (4:1 ratio in favor of the asymmetric Robinson annulation (55e65% yield, >95% ee exo adduct) and both were taken forward. after a single recrystallization). Selective reduction at the Exposure of 229 to a dilute ethanolic solution of sulfuric acid more reactive C9 carbonyl group, followed by protection of induced acetonide deprotection and, followed by concomitant the resulting alcohol afforded, the silyl ether 241 in 76% yield opening of the cyclopropane ring, afforded compound 230 in for the two steps (Scheme 38). Methyl alkylation of the ex- 78% overall yield. After oxidative cleavage of diol 230, the re- tended enolate of 241 at the C5 center produced ketone 242 sulting aldehyde was methylated by treatment with MeTi- (66%), the reduction and radical deoxygenation of which led (Oi-Pr)3 formed in situ to produce 231 in 63% combined yield. to the alkene 243 in 83% yield (from 242). The best results Oxidation of 231 under Swern conditions gave rise to ketone for the conversion of alkene 243 into the trans-fused bicycle 232 (79%). The best yields for the conversion of 232 in to 244 were obtained by hydroxylation of the double bond and 233 were obtained using methanesulfonic acid, which at 0 C subsequent reduction of the resulting alcohol (52% yield produced bicycle 233 as a single isomer in 67% yield. The stage from 243). Fluoride-induced desilylation of 244 followed by was now set for the crucial BaeyereVilliger oxidation. After PCC oxidation provided the ketone 245 in 91% yield. Treat- testing several conditions, the conversion of 233 in to 234 ment of 245 with hydrazine then produced the hydrazone M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467 463

O OTBDPS OTBDPS O OH 1) NaBH HO acetone, I 4 2 O X 2) TBDPSCl 9 t-BuOK O 239 85% 5 HO OH 76% O MeI O 66% OH O O 241 242 D-mannose 1) NaBH4 O 225 TsCl X = OH 2) nBuLi,CS2, MeI 83% 60% X = Cl 226 O 3) Bu3SnH/AIBN O 1) BH , H O Na, naphthalene 3 2 2 OTBDPS 2) nBuLi,CS , MeI OTBDPS 80% 1) TBAF 2 RO 2) PCC 3) Bu3SnH/AIBN BnBr 227 R = H 90% 228 R = Bn 52% 91% H 244 243 Rh2(OAc)4 45% N CHCO Et 2 2 O N NH2 O HO N H I /Et N 2 4 2 3 237 O H + O O EtOH, H HO OEt 88% 62% 13 12 78% H H CO Et BnO 2 BnO 245 246 H CO2Et 229 230 (4:1 C13) Scheme 38. Theodorakis’s synthesis of fragment 237 of norrisolide 235. 63% NaIO4 MeTi(Oi-Pr)3 O Swern OH O OEt oxid. O OEt bulky TBDPS group to afford 240 as a single isomer (85% 79% yield). Reduction of the lactone, followed by oxidative cleav- BnO BnO CO Et CO2Et 2 age of the alkene, produced the fused lactol 249 in 63% yield 232 231 as a 1:1 mixture of isomers at C14. These isomers were sepa- MeSO H 67% 3 rated after conversion into the corresponding methyl ether 250. H O H Compound 250 was then converted into the selenide 251, O O O (H N) CO, H O O O O 2 2 2 2 O O which underwent oxidation and elimination to give alkene (CF3CO)2O 252 (61% yield from 250). Osmylation of 252, followed by BnO H 69% BnO H 233 234 oxidative cleavage of the resulting diol, furnished the aldehyde 238 (two steps, 94% yield) as a crystalline solid, the structure Scheme 36. Theodorakis’s synthesis of norrisolide side chain 234. of which was conﬁrmed by X-ray analysis.

TBDPSO TBDPSO 1) DIBAL-H 246 246 O O . Finally, treatment of with I2/Et3N led to the forma- O O 2) OsO4, NMO 3) Pb(OAc) tion of the desired vinyl iodide 237 (62% yield). AlCl3 4 The preparation of the fragment 238 is highlighted in 247 85% 63%

Scheme 39. The C11 and C12 centers were connected by 240 248 a DielseAlder reaction between butenolide 247 and butadiene 1) NaBH TBDPSO 4 TBDPSO (248). Under Lewis acid catalysis, this cycloaddition pro- O 2) PPh3, I2 O O O 3) PhSeNa 14 ceeded exclusively from the opposite face to that with the O OMe 67% OR 251 amberlist 15 249 R = H PhSe MeOH 250 R = Me NaIO 90% 77% O 4 TBDPSO TBDPSO TBDPSO O O 1) OsO , NMO O O 4 O 2) Pb(OAc)4 O O OMe OMe 10 94% O 252 O 9 O 238 Scheme 39. Theodorakis’s synthesis of fragment 238 of norrisolide 235. H O H OMe 235 norrisolide 236 The remaining steps in the synthesis of norrisolide 235 are TBDPSO shown in Scheme 40. Lithiation of the vinyl iodide 237, fol- TBDPSO lowed by addition of the aldehyde 238 and DesseMartin O O O I O O (DM) oxidation of the resulting alcohol, afforded the enone + 253 in 71% yield. Hydrogenation of the double bond pro- O O ceeded exclusively from the more accessible a face of the bi- H OMe cyclic core to form the ketone 254 in 75% yield. After much 239 237 238 240 experimentation, the conversion of ketone 254 into alkene Scheme 37. Theodorakis’ retrosynthesis of norrisolide 235. 236 was achieved by methylation with MeLi and treatment 464 M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467

O of the resulting alcohol with SOCl2 in the presence of pyridine HO O 236 (two steps, 64% yield). With the alkene in hand, the stage O O O O O O was now set for the ﬁnal functionalization of the bicycle O (Scheme 40). Deprotection of the silyl ether and oxidation of the resulting alcohol gave aldehyde 255, which was subse- O quently converted into the ketone 256 via treatment with MeMgBr and DesseMartin (DM) oxidation (68% yield). H H H Treatment of 256 with CrO3 in aqueous acetic acid produced 258 259 260 257 e the lactone in 80% yield. Finally, Baeyer Villiger oxida- O O tion of 257 (MCPBA, NaHCO3, 60% yield) led to insertion of the oxygen atom, as desired, with complete retention of con- O O O ﬁguration to produce norrisolide 235. O O O O H TBDPSO TBDPSO 261 262 263

O O Scheme 41. Theodorakis’s analogs of norrisolide 235. I O 1) tBuLi O 2) DM [O] + O 71% O Competition experiments showed that compounds 264 and H 266 and norrisolide bind to the same receptor, which indicates OMe H OMe 237 238 253 that the perhydroindane core of norrisolide is essential and

85% H2, Pd/C necessary for such a binding. In the absence of the acetate group of norrisolide, this binding induces a reversible Golgi TBDPSO TBDPSO vesiculation, indicating that this group plays an essential role O O 1) MeLi O in the irreversibility of the fragmentation, either by stabilizing 2) SOCl2, py the binding or by creating a covalent bond with its target pro- O 64% O tein. Compound 268, containing the core fragment of the nat-

H OMe H OMe ural product, induced a similar vesiculation that was, however, 236 254 reversible upon washing. In contrast, compound 269, in which 1) TBAF 93% the perhydroindane core was attached to a bisepoxide scaffold 2) IBX (suitable for protein labeling), induced an irreversible vesicu- O O H lation of the Golgi membranes. On the other hand, compound 267, lacking the perhydroindane motif, had no effect on the O 1) MeMgBr O 2) DM [O] mCPBA 235 Golgi membranes, attesting to the importance of the norriso- O 68% O 60% lide core in Golgi localization and structure. Moreover, compound 269 induces an identical phenotype to that of H OMe H X 255 256 norrisolide, suggesting that it may be used to isolate the bio- CrO3 X = OMe,H 80% 257 X = O logical target of this natural product. Scheme 40. Theodorakis’s synthesis of norrisolide 235. O O O NMe2 NMe2 After completion of their total synthesis of norrisolide, this O group has also explored the biological activities of some ana- O O O O logs of the parent molecule. Thus, the molecules 233, 234, O O 245, and 257 from their previous synthetic studies were eval- HO O e O O uated together with 258 263, which were also synthesized O (Scheme 41). O O From the structure/function studies, it was suggested that H H the perhydroindane core of norrisolide is critical for binding Me2N O O to the target protein, while the acetate unit is essential for 264 265 266 O the irreversible vesiculation of the Golgi membranes. Com- OMe O O pounds 261e263 have no effect on Golgi membranes. The O same group has also studied the chemical origins of the norri- O 88 MeO O solide-induced Golgi vesiculation. To this end, the re- O O O O searchers studied the effect of ﬂuorescent probes 264e269 O O (Scheme 42) on the Golgi complex. While 265 had no effect O on the Golgi apparatus, compound 264 was found to induce O H H extensive Golgi fragmentation. In contrast to norrisolide 235, 267 268 269 however, this fragmentation was reversed upon washing. Scheme 42. Theodorakis’s norrisolide-based ﬂuorescent probes. M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467 465

4. Conclusions 25. Nakano, T.; Hernańdez, M. I.; Gomez, M.; Domingo Medina, J. J. Chem. Res., Synop. 1989,54e55. The scientific investigations of the spongiane family of di- 26. Urones, J. G.; Marcos, I. S.; Basabe, P.; Gomez, A.; Estrella, A.; Lithgow, A. M. Nat. Prod. Lett. 1994, 5, 217e220. terpenoids have been an active field during the last two de- 27. Urones, J. G.; Sexmero, M. J.; Lithgow, A. M.; Basabe, P.; Gomez, A.; cades, producing nearly 100 publications on the isolation Marcos, I. S.; Estrella, A.; Diez, D.; Carballares, S.; Broughton, H. B. and structural characterization of its members, including sev- Nat. Prod. Lett. 1995, 6, 285e290. eral preliminary biological studies. In spite of their biological 28. Basabe, P.; Go´mez, A.; Marcos, I. S.; Martıń, D. D.; Broughton, H. B.; e properties and the challenging variety of chemical entities that Urones, J. G. Tetrahedron Lett. 1999, 40, 6857 6860. 29. Abad, A.; Agullo´, C.; Arno´, M.; Domingo, L. R.; Zaragoza´,R.J.Org. have been found, however, the synthetic studies represent only Prep. Proced. Int. 1991, 23, 321e356. one-third of the publications in the field. Until quite recently, 30. Lee, H.-J.; Ravn, M. M.; Coates, R. M. Tetrahedron 2001, 57, 6155e6167. researchers had not initiated any structure/function studies, 31. Abad, A.; Arno´, M.; Domingo, L. R.; Zaragoza´,R.J.Tetrahedron 1985, and therefore this area also remains largely unexplored. 41, 4937e4940. 32. Ishihara, K.; Ishibashi, H.; Yamamoto, H. J. Am. Chem. Soc. 2001, 123, 1505e1506. Acknowledgements 33. Abad, A.; Agullo´, C.; Arno´, M.; Marıń, M. L.; Zaragoza´,R.J.J. Chem. Soc., Perkin Trans. 1 1996, 2193e2199. ´ ´ ´ e I gratefully acknowledge financial support from the Spanish 34. Abad, A.; Arno, M.; Marın, M. L.; Zaragoza,R.J.Synlett 1991, 789 791. 35. Abad, A.; Arno´, M.; Cunat,~ A. C.; Marıń, M. L.; Zaragoza´,R.J.J. Org. Ministry of Science and Education under a ‘Ramoń y Cajal’ Chem. 1992, 57, 6861e6869. research grant. 36. Abad, A.; Arno´, M.; Marin, M. L.; Zaragoza´,R.J.J. Chem. Soc., Perkin Trans. 1 1993, 1861e1867. 37. Arno´, M.; Gonza´lez, M. A.; Marıń, M. L.; Zaragoza´,R.J.Tetrahedron References and notes Lett. 2001, 42, 1669e1671. 38. Arno´, M.; Gonza´lez, M. A.; Zaragoza´,R.J.J. Org. Chem. 2003, 68, 1. Connolly, J. D.; Hill, R. A. Dictionary of Terpenoids; Chapman and Hall: 1242e1251. London, 1991; Vol. 2, pp 895e899. 39. Blake, A. J.; Gonza´lez, M. A.; Gil-Gimeno, M. J. Acta Crystallogr. 2006, 2. Hanson, J. R. Nat. Prod. Rep. 2006, 23, 875e885 and former reviews in C62, 208e210. this series. 40. Betancur-Galvis, L.; Zuluaga, C.; Arno´, M.; Gonza´lez, M. A.; Zaragoza´, 3. Faulkner, D. J. Nat. Prod. Rep. 2002, 19,1e49 and former reviews in this R. J. J. Nat. Prod. 2002, 65, 189e192. series. 41. Arno´, M.; Betancur-Galvis, L.; Gonza´lez, M. A.; Sierra, J.; Zaragoza´,R.J. 4. Faulkner, D. J.; Newman, D. J.; Cragg, G. M. Nat. Prod. Rep. 2004, 21, Bioorg. Med. Chem. 2003, 11, 3171e3177. 50e76. 42. Arno´, M.; Gonza´lez, M. A.; Zaragoza´,R.J.Tetrahedron 1999, 55, 5. Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, 12419e12428. M. R. Nat. Prod. Rep. 2005, 22,15e61. 43. Somerville, M. J.; Mollo, E.; Cimino, G.; Rungprom, W.; Garson, M. J. 6. Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, J. Nat. Prod. 2006, 69, 1086e1088. M. R. Nat. Prod. Rep. 2006, 23,26e78. 44. Abad, A.; Agullo´, C.; Cunat,~ A. C.; Garcıá, A. B. Tetrahedron Lett. 2002, 7. Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro, M. H. G.; Northcote, P. T.; 43, 7933e7936. Prinsep, M. R. Nat. Prod. Rep. 2007, 24,31e86. 45. Abad, A.; Agullo´, C.; Cunat,~ A. C.; Garcıá, A. B.; Gimeńez-Saiz, C. 8. Gavagnin, M.; Fontana, A. Curr. Org. Chem. 2000, 4, 1201e1248. Tetrahedron 2003, 59, 9523e9536. 9. Goldsmith, D. The Total Synthesis of Tri- and Tetracyclic Diterpenes; 46. Abad, A.; Agullo´, C.; Cunat,~ A. C.; Garcıá, A. B. Tetrahedron 2005, 61, ApSimon, J., Ed.; John Wiley and Sons: New York, NY, 1992; Vol. 8, 1961e1970. pp 228e230. 47. Kolympadi, M.; Liapis, M.; Ragoussis, V. Tetrahedron 2005, 61, 2003e 10. Kazlauskas, R.; Murphy, P. T.; Wells, R. J.; Noack, K.; Oberhaensli, W. E.; 2010. Schoenholzer, P. Aust. J. Chem. 1979, 32, 867e880. 48. Eschenmoser, A.; Ruzicka, L.; Jeger, O.; Arigoni, D. Helv. Chim. Acta 11. Cimino, G.; De Rosa, D.; De Stefano, S.; Minale, L. Tetrahedron 1974, 1955, 38, 1890e1904. 30, 645e649. 49. Stork, G.; Burgstahler, A. W. J. Am. Chem. Soc. 1955, 77, 5068e5077. 12. Keyzers, R. A.; Northcote, P. T.; Davies-Coleman, M. T. Nat. Prod. Rep. 50. Bartlett, P. A. Asymmetric Synthesis; Morrison, J. D., Ed.; Academic: New 2006, 23, 321e334. York, NY, 1984; Vol. 3, pp 341e409. 13. Gonza´lez, M. A. Curr. Bioact. Comp. 2007, 3,1e36. 51. Sutherland, J. K. Comprehensive Organic Synthesis; Trost, B. M., 14. Imamura, P. M.; Sierra, M. G.; Ru´veda, E. A. J. Chem. Soc., Chem. Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 341e377. Commun. 1981, 734e735. 52. Corey, E. J.; Lee, J.; Roberts, B. E. Tetrahedron Lett. 1997, 38, 8915e8918. 15. Bory, S.; Fe´tizon, M.; Laszlo, P. Bull. Soc. Chim. Fr. 1963, 2310e2322. 53. Corey, E. J.; Roberts, B. E. Tetrahedron Lett. 1997, 38, 8919e8920. 16. Nakano, T.; Hernańdez, M. I. Tetrahedron Lett. 1982, 23, 1423e1426. 54. Corey, E. J.; Wood, H. B., Jr. J. Am. Chem. Soc. 1996, 118, 11982e11983. 17. Nakano, T.; Hernańdez, M. I. J. Chem. Soc., Perkin Trans. 1 1983, 135e 55. Huang, A. X.; Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 9999e 139. 10003. 18. Imamura, P. M.; Ru´veda, E. A. J. Org. Chem. 1980, 45, 510e515. 56. Ishihara, K.; Nakamura, S.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 19. De Miranda, D. S.; Brendolan, G.; Imamura, P. M.; Gonza´lez Sierra, M.; 4906e4907. Marsaioli, A. J.; Ru´veda, E. A. J. Org. Chem. 1981, 46, 4851e4858. 57. Bogensta¨tter, M.; Limberg, A.; Overman, L. E.; Tomasi, A. L. J. Am. 20. Vlad, P. F.; Ungur, N. D. Khim. Prir. Soedin. 1984, 6, 725e731. Chem. Soc. 1999, 121, 12206e12207. 21. Vlad, P. F.; Ungur, N. D.; Koltsa, M. N. Tetrahedron 1983, 39, 3947e 58. Ungur, N.; Kulcitki, V.; Gavagnin, M.; Castelluccio, F.; Vlad, P. F.; 3958. Cimino, G. Tetrahedron 2002, 58, 10159e10165. 22. Ungur, N. D.; Vlad, P. F. Khim. Prir. Soedin. 1985, 1,45e51. 59. Nishizawa, M.; Takenaka, H.; Hayashi, Y. Chem. Lett. 1983, 1459e1460. 23. Mischne, M. P.; Gonza´lez Sierra, M.; Ru´veda, E. A. J. Org. Chem. 1984, 60. Nishizawa, M.; Takenaka, H.; Hayashi, Y. J. Org. Chem. 1986, 51, 806e 49, 2035e2037. 813. 24. Gonza´lez Sierra, M.; Mischne, M. P.; Ru´veda, E. A. Synth. Commun. 61. Vlad, P. F.; Ungur, N. D.; Perutskii, V. B. Khim. Prir. Soedin. 1986, 4, 1985, 15, 727e735. 514e515. 466 M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467

62. Ungur, N. D.; Van Nguyen, T.; Vlad, P. F. Khim. Prir. Soedin. 1991, 5, 75. Boehm, H. M.; Handa, S.; Pattenden, G.; Roberts, L.; Blake, A. J.; Li, W.-S. 726e728. J. Chem. Soc., Perkin Trans. 1 2000, 3522e3538. 63. Nishizawa, M.; Yamada, H.; Hayashi, Y. J. Org. Chem. 1987, 52, 4878e 76. Handa, S.; Nair, P. S.; Pattenden, G. Helv. Chim. Acta 2000, 83, 2629e 4884. 2643. 64. Pandey, U. C.; Sarmah, P.; Sharma, R. P. Tetrahedron 1984, 40, 3739e 77. Pattenden, G.; Roberts, L. Tetrahedron Lett. 1996, 37, 4191e4194. 3748. 78. Pattenden, G.; Roberts, L.; Blake, A. J. J. Chem. Soc., Perkin Trans. 1 65. Breslow, R.; Barrett, E.; Mohacsi, E. Tetrahedron Lett. 1962, 3, 1207e1211. 1998, 863e868. 66. Breslow, R.; Olin, S. S.; Groves, J. T. Tetrahedron Lett. 1968, 9, 1837e 79. Goeller, F.; Heinemann, C.; Demuth, M. Synthesis 2001, 8, 1114e1116. 1840. 80. Baba, Y.; Sakamoto, T.; Kanematsu, K. Tetrahedron Lett. 1994, 35, 67. Malacria, M. Chem. Rev. 1996, 96, 289e306. 5677e5680. 68. Zoretic, P. A.; Weng, X.; Caspar, M. L.; Davis, D. G. Tetrahedron Lett. 81. Sakamoto, T.; Kanematsu, K. Tetrahedron 1995, 51, 5771e5780. 1991, 32, 4819e4822. 82. Mehta, G.; Thomas, A. Synth. Commun. 1992, 22, 1831e1838. 69. Snider, B. B. Chem. Rev. 1996, 96, 339e363. 83. Mayelvaganan, T.; Hadimani, S.; Bhat, S. V. Tetrahedron 1997, 53, 70. Zoretic, P. A.; Shen, Z.; Wang, M.; Ribeiro, A. A. Tetrahedron Lett. 1995, 2185e2188. 36, 2925e2928. 84. Weisser, R.; Yue, W.; Reiser, O. Org. Lett. 2005, 7, 5353e5356. 71. Ribeiro, A. A.; Shen, Z.; Wang, M.; Zhang, Y.; Zoretic, P. A. Magn. 85. Lebsack, A. D.; Overman, L. E.; Valentekovich, R. J. J. Am. Chem. Soc. Reson. Chem. 1998, 36, 325e335. 2001, 123, 4851e4852. 72. Zoretic, P. A.; Zhang, Y.; Ribeiro, A. A. Tetrahedron Lett. 1995, 36, 86. Brady, T. P.; Kim, S. H.; Wen, K.; Theodorakis, E. A. Angew. Chem., Int. 2929e2932. Ed. 2004, 43, 739e742. 73. Zoretic, P. A.; Wang, M.; Zhang, Y.; Shen, Z.; Ribeiro, A. A. J. Org. 87. Brady, T. P.; Kim, S. H.; Wen, K.; Kim, C.; Theodorakis, E. A. Chem. 1996, 61, 1806e1813. Chem.dEur. J. 2005, 11, 7175e7190. 74. Zoretic, P. A.; Zhang, Y.; Fang, H.; Ribeiro, A. A.; Dubay, G. J. Org. 88. Guizzunti, G.; Brady, T. P.; Malhotra, V.; Theodorakis, E. A. J. Am. Chem. Chem. 1998, 63, 1162e1167. Soc. 2006, 128, 4190e4191. M.A. Gonza´lez / Tetrahedron 64 (2008) 445e467 467

Biographical sketch

Miguel A. Gonza´lez was born in Valencia, Spain, in 1972. He received his B.S. degree in Chemistry in 1995 and a M.Sc. (Honours) degree in Chemistry from the University of Valencia, in 1997. He then remained at the same University to undertake Ph.D. studies, under the direction of Professor Manuel Arno´ and Professor Ramoń J. Zaragoza´, on the Synthesis of Terpenes with Spongiane, Scopadulane and Estrane skeletons. Upon completion of his Ph.D. in 2001, he undertook postdoctoral research first in the group of Professor Gerald Pattenden at the University of Nottingham (UK), on the synthesis of Phorboxazole, and then in the group of Professor Emmanuel A. Theodorakis at the Uni- versity of California, San Diego (USA), on the synthesis of norzoanthamine. After three years of postdoctoral research abroad, he returned to Spain to work with a ‘Ramońy Cajal’ research contract at the University of Valencia. The synthesis of bioactive marine natural products is his major interest.