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Tetrahedron 64 (2008) 445e467www.elsevier.com/locate/tet

Tetrahedron report number 821

Total syntheses and synthetic studies of spongiane diterpenes

Miguel A. Gonzalez*

Departamento de Quımica Organica, 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4452. Structure, occurrence, and biological activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4463. Syntheses of spongiane diterpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446

3.1. Syntheses from other natural products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4463.2. Syntheses by biomimetic approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4563.3. Other approaches and total syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459

4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467

1. Introduction

Spongiane diterpenoids are bioactive natural products iso-lated exclusively from sponges and marine shell-less mollusks(nudibranchs), which are believed to be capable of

Abbreviations: AcCl, acetyl chloride; Ac2O, acetic anhydride; AIBN, azo-

bisisobutyronitrile; BuLi, buthyllithium; DIBAL-H, diisobutylaluminum hy-

dride; DHP, dihydropyrane; DMAD, dimethyl acetylenedicarboxylate;

DMAP, 4-(N,N-dimethylamino)pyridine; DMF, dimethylformamide; DMSO,

dimethylsulfoxide; Et3N, triethylamine; EVK, ethyl vinyl ketone; HMPA, hexa-

methyl phosphorotriamide; IBX, 2-iodoxybenzoic acid; LDA, lithium diisopro-

pylamide; LiHMDS, lithium hexamethyldisilylamide; MsCl, mesyl chloride;

MCPBA, m-chloroperbenzoic acid; NaHMDS, sodium hexamethyldisilyl-

amide; NMO, 4-methylmorpholine N-oxide; PCC, pyridinium chlorochromate;

PPTS, pyridinium p-toluenesulfonate; p-TSA, p-toluenesulfonic acid; PhH,

benzene; PhMe, toluene; Py, pyridine; TBDMSOTf, tert-butyl dimethylsilyl tri-

fluoromethanosulfonate; TBDPSCl, tert-butyldiphenylsilyl chloride; TBAF,

tetra-n-butylammonium fluoride; TFA, trifluoroacetic acid; TMSCl, trimethyl-

silyl chloride; TPAP, tetrapropylammonium perruthenate.

* Tel.: þ34 96 354 3880; fax: þ34 96 354 4328.

E-mail address: [email protected]

0040-4020/$ - see front matter � 2007 Elsevier Ltd. All rights reserved.

doi:10.1016/j.tet.2007.10.057

sequestering the spongian-derived metabolites from thesponges, soft corals, hydroids, and other sessile marine inver-tebrates on which they feed. Most of these compounds playa key role as eco-physiological mediators and are of interestfor 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-nary of Terpenoids.1 During the last two decades, many newmembers of this family of natural products have been isolatedand described in specific reviews on naturally occurring diter-penoids by Hanson,2 and the excellent reviewing work on ma-rine natural products by Faulkner,3,4 now continued by the teamof Blunt,5e7 all of which have covered mainly the isolation andstructural aspects of spongianes. A recent review on the chem-istry of diterpenes isolated from marine opisthobranchs has alsoincluded articles on isolation and structure determination ofspongianes up to 1999.8 The latter survey also covered somesynthetic studies of this class of substances. To the best of ourknowledge, there is only one more report dealing with the initialstudies toward the synthesis of spongianes.9

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446 M.A. Gonzalez / Tetrahedron 64 (2008) 445e467

We now provide full coverage of recent advances in thefield including a comprehensive description of the syntheticapproaches and syntheses reported in the literature on spon-gianes up to September 2007.

2. Structure, occurrence, and biological activity

The semisystematic naming of this family of diterpenoidswas introduced in 1979 after the isolation of the first membersof the family from sponges of the genus Spongia. Thus, inaccordance with the IUPAC recommendations the saturatedhydrocarbon I, named ‘spongian’, was chosen as the funda-mental parent structure with the numbering pattern as depictedin Figure 1.10

The first known member of the spongiane family, isoaga-tholactone (1), was discovered by Minale et al. from thesponge Spongia officinalis about 30 years ago, being the firstnatural compound with the carbon framework of isoagathicacid (2). Structure (1) was assigned based on spectroscopicdata and chemical correlation with natural grindelic acid (3).11

To date, there are nearly 200 known compounds belongingto this family of marine natural products, including those witha spongiane-derived skeleton.12 Most of them present a highdegree of oxidation in their carbon skeleton, particularly at po-sitions C17 and C19, as well as on all the rings AeD. Giventhe variety of chemical structures found in the spongiane fam-ily, we could group them according to the degree of oxidationas well as the degree of carbocyclic rearrangement of the par-ent 6,6,6,5-tetracyclic ring system.

Sponges are exposed to a variety of dangers in their envi-ronment and this has led to the development of chemical de-fense mechanisms against predation. Nudibranchs feed ona variety of sponges and are capable of storing selected meta-bolites, even transforming them, for their own self-defense.Thus, sponges and nudibranchs are a rich source of biologi-cally active metabolites, and the spongianes, in particular,have displayed a wide spectrum of interesting biological prop-erties including antifeedant, antifungal, antimicrobial, ichthyo-toxic, antiviral, antitumor, antihypertensive, fragmentation ofGolgi complex, as well as anti-inflammatory activity.12,13

2, isoagathic acid 3, grindelic acid

HO2C H H

H

I, spongiane skeleton

H

H

O

CO2HO

CO2H

1, isoagatholactone

H

H

O

O

HA

B

C D

17

19

1

7

12

3

16

2

4

5

6

8

9

10

11 13

14 15

18

20

Figure 1.

3. Syntheses of spongiane diterpenes

Several syntheses have appeared within the last 25 years andwe will classify them in three main groups. We will also includethe synthetic studies developed so far and, thus, we willdescribe the syntheses from other natural products, synthesesusing biomimetic approaches and, finally, other approaches in-cluding the total synthesis of rearranged spongianes.

Generally, despite the interesting molecular architecturesand biological properties of the spongianes, there have beenrelatively few synthetic studies toward their synthesis. In the1980s, most of the synthetic studies toward spongiane-type di-terpenes addressed mainly the synthesis of isoagatholactoneand the preparation of simple furanospongianes.

In the next decade, the syntheses of several pentacyclicspongianes were accomplished together with the developmentof biomimetic-like strategies for the synthesis of more com-plex furanospongianes and isoagatholactone derivatives.Over the last three or four years, some structureeactivity stud-ies have emerged together with several approaches toward themore complex oxygenated spongianes.

3.1. Syntheses from other natural products

Manool (4), copalic acid (5), sclareol (6), labdanolic acid(7), abietic acid (8), and carvones (9) (Fig. 2) have been usedfor the preparation of optically active spongianes. Naturally oc-curring racemic labda-8(20),13,dien-15-oic acid (copalic acid)has also been used for preparing racemic compounds.

These starting materials were converted into versatile tricy-clic intermediates having the characteristic ABC-ring system ofspongianes (Scheme 1) such as ent-methyl isocopalate (10), po-docarp-8(14)-en-13-one (11), and phenanthrenones (12,13).Several strategies have been reported to build up the necessaryring D from these key intermediates, preferably as a furan org-lactone ring. The choice of podocarpenone 11 as startingmaterial assures the absolute stereochemistry at C5, C9, and

4, manool

8, abietic acid

CO2H

H

H

H

5, copalic acid

O

OH

9, (+)- and (-)-carvone

H

CO2H

H

H

6, sclareol

H

H

OH

OH

7, labdanolic acid

CO2H

H

H OH

Figure 2.

447M.A. Gonzalez / Tetrahedron 64 (2008) 445e467

C10. Moreover, the selection of methyl isocopalate 10 andphenanthrenones 12,13 also assures the stereochemistry ofthe additional methyl group at C8 of the ring system.

manoolcopalic acidsclareollabdanolic acid

ent-methyl isocopalate (10)

(+)-carvone

H

H CO2Me

abietic acid

podocarp-8(14)-en-13-one (11)H

H

O

12

H

H O

TBSO

(-)-carvone

H

CO2Me

13a R = H13b R = OCO2Me

R

O

Scheme 1. Precursors of spongiane diterpenoids prepared from natural

sources.

In 1981, Ruveda et al. reported the first synthesis of a natu-ral spongiane diterpene.14 (þ)-Isoagatholactone (1) was syn-thesized from tricyclic ester 10 prepared from (þ)-manool(4) in three synthetic steps (Scheme 2). Two successive oxida-tions of manool followed by acid-catalyzed cyclization ofmethyl copalate 14 gave the known intermediate 10,15 also ob-tained from grindelic acid (3) by Minale et al. during the struc-tural elucidation of (þ)-1.11

(+)-manool(4)

1) PCC2) MnO2/HCN MeOH

10

1) 1O2, methylene blue EtOAc/EtOH2) P(OMe)3

17% H

H CO2Me

OH

15

6 N H2SO4

dioxane56%

H

H

O

O 72%LiAlH4

H

H 57%MnO2

16 17

CO2Me

H

HH+

14

OHOH (+)-1

Scheme 2. Ruveda’s synthesis of natural isoagatholactone.

The required functionalization of the allylic methyl groupwas achieved by sensitized photooxygenation to give allylicalcohol 15. The allylic rearrangement of 15 with simultaneous

lactonization to give lactone 16, followed by reductive open-ing of the lactone ring, gave the known degradation productof isoagatholactone, diol 17.11

Finally, allylic oxidation with MnO2 gave (þ)-isoagatho-lactone (1) in 3.9% yield from 10.

Contemporaneous studies by Nakano et al. described, soonafter, the synthesis of racemic isoagatholactone using a similarstrategy in which the reaction conditions were different, aswell as the starting material, which was racemic copalic acid(Scheme 3).16 Thus, (�)-isoagatholactone (1) was preparedin 11.6% yield from racemic methyl isocopalate 10.17

Unnatural (�)-isoagatholactone has also been prepared byRuveda et al. using the same sequence of steps starting frommethyl isocopalate (þ)-10, readily prepared from copalic acid(Scheme 4).18,19 Thus, sensitized photooxygenation gave alco-hol 18, which was subjected to allylic rearrangement with simul-taneous lactonization, using sulfuric acid, to give lactone 20.Then, reductive opening of the lactone ring, gave diol 21, whichwas oxidized with MnO2 to give (�)-isoagatholactone.

The interest in spongiane-type diterpenes possessing a furanring D led to the synthesis of (�)-12a-hydroxyspongia-13(16),14-diene (24) by Ruveda et al. using 19, also preparedfrom methyl isocopalate (Scheme 4).19 This unnatural spon-giane was designed as a precursor for other members with a dif-ferent functionality in ring D, since it contains, the requiredstereochemistry at C12. Compound (þ)-10 was converted into12,14-isocopaladiene (19) by LiAlH4 reduction, mesylation,and elimination. Photooxygenation of 19 and reduction pro-duced alcohol 22, which was submitted to a second photooxyge-nation reaction, and the resulting unsaturated cyclic peroxide 23was treated with ferrous sulfate to afford 12-hydroxyfuran 24.

Concurrent to this report, Nakano et al. described the synthesisof racemic 24 from hydroxy-isocopalane 15 (Scheme 5), which

1) HCOOH2) CH2N2/Et2O

(±)-1

70%

1) 3.5% H2SO4, dioxane, 83%2) LiAlH4, 95%

Collins reagent59%

5, copalic acid

CO2H

H

H

ent-methyl isocopalate (10)

H

H CO2Me

1O2, py,hematoporphyrin

25%

(±)-15

H

H CO2Me

OH

H

H

17

OHOH

H

H

O

O

Scheme 3. Nakano’s synthesis of racemic isoagatholactone.


copalicacid 1) CH2N2/Et2O

2) HCOOH

methyl isocopalate ent -10

(-)-1

H

H CO2Me

1) 1O2, methylene blue EtOAc/EtOH2) P(OMe)3

20% H

H CO2Me

OH

18

6 N H2SO4dioxane 88%

H

H

O

O 89%

H

H 64%MnO2

20 21

LiAlH4

85%

1) LiAlH42) MsCl/py3) EtO-Na+/EtOH

H

H

19

1) 1O2, rose bengal2) P(OMe)3

67%

H

H

OH

22

1O2, rose bengal14%

H

H

OH

23

75%

OO FeSO4·7H2O

H

H

OH

24

O

(ent-5)

OHOH

Scheme 4. Ruveda’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-oxidation of 15 gave epoxide 25 in quantitative yield, then, treat-ment with lithium diisopropylamide (LDA) led to b-eliminationand lactonization in one pot to give a,b-unsaturated g-lactone 26in 50% yield. When 26 was reduced with diisobutylaluminiumhydride, the furan (�)-24 was obtained in 19% yield. The majordrawback of Nakano’s synthesis of 24 is the yield of the photo-chemical reaction to functionalize C16 to give 15 (25% yield,based on recovered 10) and the final aromatization, which en-couraged further studies to solve these low-yielding steps.16,17

H

H CO2Me

OH

(±)-15

m-CPBA

H

H CO2Me

OH

25

LDA

H

H

O

O

26

OH

19%DIBAL-H

(±)-24

99%

50%

O

H

H

O

OH

Scheme 5. Nakano’s synthesis of (�)-13(16),14-spongiadien-12a-ol (24).

In 1984, another synthesis of natural isoagatholactone (þ)-(1) was reported by Vlad and Ungur (Scheme 6).20 The routeis identical to that of Ruveda, since the same diol 17 was oxi-dized by MnO2 to give isoagatholactone (see also Scheme 2).In this case, compound 17 was prepared in 48% yield by allylicoxidation of isocopalol 28 with SeO2 in EtOH, although Ruvedaet al. reported that this oxidation on isocopalate 10 and alcohol(isocopalol) 28 led to complex mixtures of products.19

Isocopalol 28 was prepared by Vlad et al. using an acid-catalyzed cyclization of an acetate mixture (27) (Scheme

6).21 These authors have used chiral isocopalol 28 and diol17 for the synthesis of sponge metabolites such as aldehydes29 and 30 by consecutive oxidations.22 The aldehydes havealso been prepared in racemic form starting from (�)-10(methyl isocopalate) via the racemic diol (�)-17.23

The same authors have also reported the synthesis of a fur-anoditerpene, methyl spongia-13(16),14-dien-19-oate (33), bycyclization of methyl lambertianate (32), which can beobtained from lambertianic acid (31), a diterpene acid of theSiberian cedar Pinus sibirica (Scheme 6).20

H

H

28

OH48%SeO2

95%MnO2 (+)-1

H27

OAc 10% H2SO4

HCOOH

H

H

17

OHOH

H

CHO

H

29

OAc

1) acetylation2) SeO2

H

CHO

H CHO

30

Swern oxid.

CO2RH

31 R = H32 R = Me

O H2SO4

MeNO2PhMe

CO2MeH

H

33

O

32%

Scheme 6. Vlad’s syntheses of natural isoagatholactone (þ)-1, aldehydes 29

and 30, and methyl spongia-13(16),14-dien-19-oate (33).


copalicacid

1) CH2N2

2) HCOOH

methyl isocopalate (±)-10H

H CO2Me

1) m-CPBA2) Al(iPrO)3

60%

H

H CO2Me

OH

15

H2SO4dioxane

H

H

O

O

16

H

H

38

O

(±-5)H

H

O

O

34

H2/Pt

80%

H

1) LiAlH42) (COCl)2/DMSO3) p-TsOH

20%

H

H CH2OH

OH

35

H2SO4dioxane

52%

LiAlH487%

H

H

O

36

42%

H

H

O

37

H2/PtO2

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

In 1985, Ruveda et al. reported the first synthesis of anaturally occurring furanospongiane, albeit in racemic form(Scheme 7).24 (�)-Spongia-13(16),14-diene (38) was preparedfrom (�)-methyl isocopalate (10) via the same unsaturated lac-tone (16) used in the synthesis of isoagatholactone (see Scheme2). It is worth mentioning that lactone 16 was similarly preparedfrom alcohol 15, but the latter was synthesized in an improvedmanner (60% overall yield) by epoxidation of 10 and subsequenttreatment with aluminium isopropoxide.23 Racemic lactone 16was then hydrogenated on Pt to give 34, which was reducedwith LiAlH4, oxidized under Swern conditions and treatedwith p-TsOH to afford the desired furan 38 in 20% overall yield.The tetracyclic diterpene, (�)-spongian 37, which is the tetrahy-drofuran derivative of 38 and possesses precisely the fundamen-tal parent structure I (Fig. 1), was synthesized in this work byhydrogenation of furan 36. Furan 36 was obtained by allylic re-arrangement with simultaneous cyclization of the diol 35, whichwas prepared by lithium aluminum hydride reduction of 15.

A few years later, Nakano et al. also described the synthesisof (�)-spongia-13(16),14-diene (38) from the same hydroxy-isocopalane 15 used in the synthesis of (�)-1 (Scheme 8).25

The starting material was, however, synthesized from (�)-methyl isocopalate (10) using the improved procedure devel-oped by Ruveda et al. for the synthesis of related tricyclicditerpenes (aldehydes 29 and 30).23 Thus, epoxidation of methylisocopalate 10 gave a-epoxide 39, which, upon treatment withaluminium isopropoxide, afforded hydroxy-isocopalane 15 in60% overall yield. Lactonization and b-elimination of 15 usingH2SO4, followed by isomerization with 10% ethanolic potas-sium hydroxide, gave a,b-unsaturated g-lactone 40, whichwas reduced with lithium aluminium hydride to give diol 41.Oxidation of 41 with pyridinium chlorochromate (PCC) gavethe desired (�)-furanospongian 38 in 55% yield (Scheme 8).

More recently, Urones et al. reported the preparation of theuseful intermediate in spongiane synthesis, ent-methyl isocopa-late (10), from sclareol26 (6) and labdanolic acid27 (7), two abun-dant bicyclic natural products (Scheme 9). Thus, sclareol (6),a major terpenic constituent of Salvia sclarea, was acetylatedquantitatively with acetyl chloride and N,N-dimethylaniline, af-fording the diacetyl derivative 42, the isomerization of whichwith bis(acetonitrile)palladium(II) chloride led to the diacetate

43 (89%). The selective hydrolysis of the allylic acetoxy groupof 43 led to hydroxy acetate 44, the oxidation of which withMnO2 gave aldehyde 45. Subsequent oxidation of 45 withNaClO2 followed by esterification with diazomethane affordedmethyl ester 46. Regioselective elimination of the acetoxy groupand cyclization with formic acid led to ent-methyl isocopalate(10) in 49% overall yield from sclareol (eight steps). Labdanolicacid (7), the main acid component of Cistus ladaniferus, is firstlyesterified with diazomethane, and then dehydrated and isomer-ized with I2 in refluxing benzene to give methyl labden-15-oate48. Ester 48 is converted into unsaturated ester 50 by eliminationof phenylselenic acid from 49, and then cyclized with formicacid to afford ent-methyl isocopalate (10) in 45% overall yieldfrom labdanolic acid.

The same authors showed how this material, ent-methylisocopalate (10), can be converted into 9,11-secospongianes,one of the most widespread subgroups of spongianes (Scheme10).28 To this end, the introduction of a D9,11 double bond andsubsequent cleavage was investigated. The method failed withtricyclic derivatives of 10, and no cleavage conditions weresuccessful. The strategy was then applied to other tetracyclicderivatives and led to the synthesis of secospongiane 54.The precursor of secospongiane 54 was the known hydroxy-

H

H

O

O

40

(±)-10m-CPBA

82%H

H CO2Me

O

72%Al(Oi-Pr)3

15

H2SO4dioxane

62%

39

16

KOHEtOH100%

H

H

41

55%PCC

H

H

O

38

100%LiAlH4

OHOH

Scheme 8. Nakano’s synthesis of (�)-spongia-13(16),14-diene, (38).


6, sclareolH

H

OH

OH 97%

AcCl,N

42

H

H

OAc

OAc 89%(MeCN)2PdCl2

43

H

H OAc

OAcK2CO3

MeOH98%

44

H

H OAc

OHMnO2

94%

45

H

H OAc

CHO 1) NaClO22) CH2N2

98%

46

H

H OAc

CO2MeSiO2/Δ90%

47

H

H

CO2MeHCOOH

70%

ent-methyl isocopalate (-)-10

H

H CO2Me

7, labdanolic acid

CO2H

H

H OH

1) CH2N22) I2/PhH

98%

48

CO2Me

H

LDA/PhSeCl85%

49

CO2Me

H

H2O2/AcOH57%

SePh

50

CO2Me

H

HCOOH 95%

Scheme 9. Urones’ syntheses of ent-methyl isocopalate (�)-10 from sclareol (6) and labdanolic acid (7).

isocopalane 15, which was again synthesized using Ruveda’smethod as outlined in Scheme 7.23 Treatment of 15 withOsO4 followed by oxidation with tetrapropylammonium per-

1) OsO4

2) TPAP

H

H

O

O

51

OOH

68%

1) PTAP

2) Li2CO3 LiBr

H

O

O

52

OOH

99%

1) LiAlH4

2) Ac2O, py39% H

O

O

53

OAcOAc

65%

O3

H

OO

O

54

OAcOAcOHC

15

Scheme 10. Urones’ synthesis of 9,11-secospongiane 54.

ruthenate (TPAP) gave the ketone 51 in 68% yield. The desireddouble bond was introduced by bromination with phenyltrime-thylammonium perbromide (PTAP) and subsequent elimina-tion with Li2CO3/LiBr to give the a,b-unsaturated ketone 52.Reduction of 52 and acetylation gave the compound 53, whichwas subjected to ozonolysis to afford the highly functionalizedsecospongiane 54 in 65% yield.

The readily available abietic acid (8) together with other nat-urally ocurring resin acids isolated from conifer oleoresins arecommon starting materials for the synthesis of natural productsand numerous diterpene derivatives.29,30 (þ)-Podocarp-8(14)-en-13-one 11 (Scheme 11) is a versatile chiral starting materialeasily prepared from commercially available (�)-abietic acidor colophony.31 Recently, the enantioselective biomimeticsynthesis of this chiral building block has been described.32

In the course of synthetic studies on the chemical conversion

H2O2/NaOH

H

H

O

11

abieticacid 86%

p-TsNHNH2

silica82%

H

H

O

55

O

H

OH

56

MeLi90%

H

H

57

OH CF3CO2H(CF3CO)2O

100%

H

H

OCOCF3

58

1) MeLi

2) HCHO75% H

H

O

59

OH NaOMe85%

H

H

O

60

OH1)

2) NaHMDS 3)

76%

O, PPTS

N N(SO2CF3)2

Cl H

H

OSO2CF3

OTHP

61

1) Pd(OAc)2, Ph3P, Et3N, DMF, CO2) PPTS

70%

(+)-1

Me3SiCN, ZnI297%

H

H

62

OTMSCN

OTMSHCl/AcOH

120 °C84%

H

H

63

O

O

1) DIBAL-H

2) H2SO486%

38

(8)

H

H

O

Scheme 11. Arno’s syntheses of (þ)-isoagatholactone (1) and (�)-spongia-13(16),14-diene (38) from 11.


of podocarpane diterpenoids into biologically active com-pounds, Arno et al. achieved an efficient synthesis of natural(þ)-isoagatholactone (1) and (�)-spongia-13(16),14-diene(38), starting from chiral podocarpenone 11.33 Compound 11was converted in six steps into the common intermediate 60(40% overall yield), appropriately functionalized for the elabo-ration of the D-ring system (Scheme 11).

The necessary 8b-methyl group was introduced by stereo-controlled acetylenic-cation cyclization of acetylenic alcohol57, which was prepared from 11 by epoxidation to give 55,followed by silica gel-catalyzed Eschenmoser ring-openingreaction to afford ketone 56, and addition of methyllithium.The instability of enol trifluoroacetate 58 (w70% overall yieldfrom 11) to hydrolysis required in situ incorporation of the hy-droxymethyl side chain to give hydroxy ketone 59, which wasisomerized at C14, to afford compound 60, upon treatmentwith methanolic sodium methoxide. This intermediate wasused in two separate approaches to complete the D ring ofthe targeted spongianes. In the first approach, the required ho-mologation at C13 was introduced by carbonylation of triflate61, and subsequent deprotection in acidic media afforded di-rectly the desired isoagatholactone (þ)-1 (20% overall yieldfrom 11). On the other hand, addition of trimethylsilyl cyanideprovided the carbon at C13, compound 62. Subsequent hydro-lysis with concomitant deprotection, lactonization, and dehy-dration occurred by treatment with a mixture of hydrochloricacid and acetic acid at 120 �C in a sealed tube to give lactone63, which was transformed into 38 via reduction to its

corresponding lactol, followed by dehydration and aromatiza-tion in acidic media (Scheme 11). (�)-Furanospongiane 38was thus prepared in 11 steps from 11 in 28% overall yield.

In the early 1990s, the same research group described thefirst enantioselective synthesis of pentacyclic spongianes.34,35

To date, the synthetic routes reported for these natural productsare based on this method. Chiral podocarpenone 11 was con-verted into the cyclobutene ester 65, via compound 64, by pho-tochemical reaction with acetylene, nucleophilic carboxylation,and reductive dehydroxylation, as indicated in Scheme 12.Compound 65 was hydrolyzed under alkaline conditions andthen cleaved with ozone to afford (�)-dendrillol-1 68 (R¼H),the simplest member of the pentacyclic spongianes. This syn-thetic sequence was later shortened by reductive cyanationwith tosylmethyl isocyanide (TosMIC) to give nitriles 67,which were subjected to alkaline hydrolysis in ethylene glycolethyl ether and ozonolysis. The key feature of the strategy is thecleavage of the cyclobutene ring to form a latent acid-dialde-hyde unit, compound 66, which spontaneously underwent inter-nal lactone-hemiacetal formation. Based on this synthetic plan,the same authors have prepared related C7-oxygenated conge-ners36 (aplyroseol-1 (68, R¼OCOPr), aplyroseol-2 (68, R¼OAc) and deacetylaplyroseol-2 (68, R¼OH)) upon stereoselec-tive introduction of a hydroxy function at the 7-position in thestarting material 11 (Scheme 13). Formation of the dienyl ace-tate of 69 followed by oxidation with m-chloroperbenzoic acidgave the hydroxy enone 70, in 74% yield, which was elaboratedto give hydroxy ester 72, precursor of the pentacyclic

H

H

65

1) C2H2/hν

2) CH(SMe)3 BuLi, CeCl3

~40%

CO2Me

1) KOH2) O3, then Me2S

H

H

64

C(SMe)3

OH 1) HgO,HgCl22) SmI23) 2% NaOMe

75%


70%

H

H

68, R = H

O

O

O

OHH

H

67

CN1) C2H2/hν

2) TosMIC/t-BuOK

H

H

66

CHOCHO

CO2H

40% 64%

66

R

H

H

O

11

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


H

H

O

O

O

OHH

H

75

CHOCHO

CO2H

H

H

OAc

1) m-CPBA2) Na2S2O3 NaHCO3

74% H

H

O

OH

69 70

1) C2H2/hν

2) (EtO)2P(O)CN3) SmI2/t-BuOH

52%H

H

CN

OH

71

AcCl/Ac2O

97%py

1) KOH2) CH2N2or Me2SO43) NaOMe

58%H

H

CO2Me

R

72, R = OH73, R = OAc74, R = OCOPr

R

68, R = OH68, R = OAc 68, R = OCOPr

R

Ac2O (PrCO)2O

H

H

O

11

Scheme 13. Arno’s syntheses of (�)-aplyroseol-1 (68, R¼OCOPr), (�)-aplyroseol-2 (68, R¼OAc) and (�)-deacetylaplyroseol-2 (68, R¼OH).


diterpenes. It is worthy of note that the homologation at C13was conducted more efficiently by cyanophosphorylation fol-lowed by reductive elimination to give nitriles 71.

The versatility of intermediate 65 also led to further inves-tigations, which culminated with the synthesis of acetylden-drillol-1 76 and revision of its stereochemistry at C17, aswell as the synthesis of tetracyclic spongianes functionalizedat C17 (Scheme 14).37 The introduction of a cyanophosphory-lation step improved the synthesis of 65, which was then con-verted into the intermediate dialdehyde 75. Acetylation ofcompound 75 with AcOH/Ac2O and sulfuric acid (1%) at65 �C gave exclusively the natural acetate 76, while reductionfollowed by lactonization led to (�)-spongian-16-oxo-17-al 78(Scheme 14). This compound was next converted into (�)-aplyroseol-14 80, having an unprecedented d-lactone unit forspongianes, and its structural isomer 81, which permittedthe structural reassignment of this natural product.38 Thisstructure was also confirmed by X-ray crystallography of com-pound 80.39

Recently, the same laboratory reported some structureeactivity relationship studies of the spongianes prepared inthe group including the synthesis and biological evaluationof novel C7,C17-functionalized spongianes (Scheme 15).40,41

Some of these new spongiane derivatives possess an a-acetoxygroup at C15 and were obtained from pentacyclic samples us-ing an optimized hemiacetal-ring opening under basic condi-tions. The synthetic protocol developed for the synthesis of78 was also used to convert hydroxy-cyclobutenone 72 intospongianals 84, 85, and 86, which were evaluated againstHeLa and HEp-2 cancer cells, compound 86 being the mostactive.

Arno et al. have also achieved the total synthesis of (�)-spongia-13(16),14-diene (38) starting from (þ)-carvone viathe phenanthrenone 89, which contains the two necessarymethyl groups at C8 and C10, and a useful carbonyl groupat C14 for the final assembly of the D ring (Scheme 16).42

The strategy is based on a C/ABC/ABCD ring annula-tion sequence in which the key step for the preparation of thetricyclic ABC-ring system was an intramolecular DielseAlder(IMDA) reaction. The whole sequence takes 13 steps to fur-nish the furanospongiane 38 in 9% overall yield. Carvone isfirst alkylated twice to introduce a three-carbon side chain,which is then elongated using a Wittig-type reaction to give87. Formation of the silyl enol ether of 88, followed byIMDA reaction in toluene at 190 �C during 7 days, providedstereoselectively compound 89 in 95% overall yield.

H

H

O

O

O

OAc

O3

then Me2S90% H

H

CO2Me

CHOCHO

75

Ac2O/AcOHH2SO4 cat.

85%

NaBH4

H

H

CO2Me

77

OOH

p-TSA

H

H

O

CHO

O

76

78

H

H

O

79, R = OH 80, R = OAc

NaBH4

99%

65%

O

R

90%

Ac2O

BF3, AcCl,Bu3SnH

45%H

H

O

O

81

OAc

H

H

65

CO2Me

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

O3

then Me2S99% H

H

CO2Me

CHOCHO

82

NaBH4

H

H

CO2Me

83

OOH

TFA

H

H

O

CHO

O

84

47%OH

H

H

O

O

O

OH

R= OH, OCOPrR

99%

OH OH

Ac2O/Et3N4-pyrrolidinopyridine

H

H

O

CHO

O

ROAc

H

H

CO2Me

72

OH

85 R = OAc86 R = OCOPr

Scheme 15. Gonzalez’s synthesis of C7,C17-functionalized spongianes.


O

(+)-carvone

1) LDA, then MeI2) LDA, then

I OEt

OEt

3) PPTS65%

O

87

1) POEtO

84%OHC

O OEt

2) Et3N, TBDMSOTfH

TBDMSO

O 97%Δ, 190 ºC

88

HRO

O

89, R = TBDMS

H

H

RO

90%TMSCl/ NaI

90, R = TBDMS

H

1) CH2I2, ZnEt22)

MeO PPhO Ph

OMe

83%

HRO

CHO 50%

91, R = TBDMS

H

LDA, then H2O

HRO

CHO

92, R = TBDMS

H

1) m-CPBA pH = 82) PTSA H

93

H

O

O40%

75%NH2NH2/KOH

H

38

H

O

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

The tricyclic system 89 is already a useful intermediate forthe synthesis of norspongianes and other spongianes function-alized in ring A, as well as other terpenes containing the sameABC-ring system. Cyclopropanation of the enol double bondfollowed by homologation of the carbonyl group at C14 ledto enol ether 90. After completing the desired carbon frame-work, functionalization at C16 was carried out by isomeriza-tion of the double bond in 91 to give aldehyde 92, and thencareful epoxidation followed by treatment with p-TSA gavethe furano ketone 93. Compound 93 is a potential precursorof other furanospongianes functionalized in ring A and has re-cently been isolated from natural sources.43 Finally, WolffeKishner reduction of 93 afforded 38 in 75% yield.

A new strategy toward oxygenated spongianes using (�)-carvone as starting material has recently been described byAbad et al., as outlined in Scheme 17.44 This synthetic sequencefollows a B/AB/ABC/ABCD approach in which carvoneis first converted into the decalone 95 (AB system) by alkylation

to give enone 94, and cyclization in acidic media. The construc-tion of the C ring needed an intramolecular DielseAlder reac-tion (IMDA) reaction to give the DielseAlder adduct 100.Therefore, decalone 95 was transformed into the IMDA precur-sor 99 by homologation at C9, epoxide opening, Wittig reac-tion, and introduction of the dienophile moiety. The desiredcycloaddition took place at 112 �C for 17 h to give theDielseAlder adduct 100 in 95% yield. This was next elaboratedusing a regioselective ring opening of a dihydrofuran ring togive the C7,C11-functionalized spongiane lactone 102 after hy-drolysis and epoxidation with tert-BuOOH and VO(acac)2.

Based on this synthetic plan, Abad et al. continued thedevelopment of several studies for the synthesis of spongianediterpenes related to natural dorisenones. Therefore, followingthe same strategy B/AB/ABC/ABCD for the ring-system construction they used the key epoxydecalone 96,which was further elaborated to the DielseAlder precursor99 (Scheme 17). Other DielseAlder precursors were also

(-)-carvone


Br

76% 94

1) KOH2) t-BuOOH VO(acac)2

100

H64%

101

H

O

O

Br

BrOO

Br

78%

CF3CO2H

O

87%

1) H2O2, NaOH2) H2, Pd/C

O

95 96

1)

2) NaH then HCO2H

MeO PPh

OPh

86%97

OH

O

70%

1) Ph3P=CH22) BrCH2CCH,

NaOH

98

O84%

BuLi thenCNCO2Me

99

O95%

Δ, 112 °C

O

CO2Me

100%ZnI2, Ac2O

O

OAc

102

H

O

O

OH

O

H H

H H H

CO2Me

Scheme 17. Abad’s synthesis of C7,C11-functionalized spongianes (102) from (�)-carvone.


synthesized from 96 for intermolecular DielseAlder reactionsbut provided low yields using dimethyl acetylenedicarboxylate(DMAD) as dienophile (Scheme 18).45 The synthesis startswith alkylation with LDA of the a-position of the enone. Fur-ther alkylation with an allyl bromide and acidic cyclizationgave 95. Epoxidation, followed by olefination, gave 97, andanother olefination led to 103, which after DesseMartin oxi-dation gave enone 104, then, sodium borohydride reductionand protection with TBDMS and reaction with dimethyl ace-tylenedicarboxylate (DMAD) gave a mixture of 105 in lowyield. Alternatively, 103 is propargylated with allyl propargylbromide. Introduction of the methoxycarboxylate and final re-action in toluene at 112 �C gave the desired DielseAlder diene100. Thus, by using an IMDA reaction the compound 100 wasformed and used to further introduce the required functional-ities and the construction of the D-ring system (Scheme 19).The regioselective ring opening of the dihydrofuran ring of

100 gave initially the corresponding 7-acetoxy-15-iodo-deriva-tive, which rapidly underwent lactonization to afford theg-lactone 101 in nearly quantitative yield. The structure of101 was initially assigned on the basis of a detailed spectro-scopic NMR study, and final proof of the structure was obtainedby single-crystal X-ray diffraction analysis. Unfortunately, all at-tempts to introduce the required oxygenated function present innatural dorisenones at C11 were unsuccessful. An oxygenatedfunction was introduced leading to epoxides 102, 110e112,but epoxide opening as desired was unsuccessful.

Following the above-mentioned extensive synthetic studiesfor the preparation of dorisenone diterpenes of the spongianefamily, Abad et al. have recently adapted their syntheticsequences for the synthesis of dorisenone C (127) (Scheme20).46 They have developed a B/AB/ABC/ABCDapproach starting from R-(�)-carvone, in which the knownhydroxy-aldehyde 97 (AB rings) (Scheme 18) is the key

(-)-carvone


Br

O

Br

BrO

60%3) CF3CO2H

O

84%

1) H2O2, NaOH2) H2, Pd/C

O

95 96

1)

2) NaH then HCO2H

MeO PPh

OPh

87%97

OH

O

94%Ph3P=CH2, THF

103

OH86%

Dess-Martinreagent

104

O

1) NaBH4

2) TBDMSOTf3) DMAD

105

OTBDMS

CO2Me

CO2Me

BrCH2CNaOH

98

OCH2 O

CO2CH3

100

9%

56%

1) BuLi, -78 °C2) CNCO2Me3) PhMe, 112 °C

80%

CH

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

O

CO2Me

OAc

O

O

R1

O

OZnI2, Ac2O

KOH, MeOH

OAc

O

Om-CPBA

O

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

OH

O

O

O

107 R1 = OH R2 = H (92%)

108 R1 = R2= =O (89%)

109 R1 = H, R2 = OH (99%)

R2

tBuO2H

VO(acac)2

100

98%

101

86%Swernoxid.1) BH32) H2O2

70%

O

O

O

O

102

110

m-CPBA

45%

Swernoxid.50%

Scheme 19. Abad’s synthesis of C7,C11-functionalized spongianes (102, 110, 111, and 112) from (�)-carvone.


(-)-carvone

O

82%75%

1) MeLi, -78 °C2) Swern oxid.

1) TBDSCl, Et3N2) LiHMDS then CNCO2Me

77%

97

OH

O

113

O

O

60% from241

PTSAacetone

117

O

O

H H

H

(see Scheme 17)

BrCH2CCH

NaOH

114

O

O

H

115

OH

TBDMSO CO2Me

PhMe,180 °C

116

OH

TBDMSO

114LDA-BuLi, -78 °Cthen MeOCOCl

67%118

OH

MeO2CO

MeO2CO

MeO2CO MeO2COCO2Me

PhMe, 195 °C

119, 56%

OH

+O

CO2CH3

120, 31%

82%

ZnI2, Ac2O

121

H

O

O

OAc96%

NaOMe-20 °C

122

H

O

O

OH

O

92%

Jonesreagent

123

H

O

O

O

O

99%

124

H

O

O

OH

O

BH3-THF

125

H

O

OH

OH

HODIBAL-H-78 °C

126

H

O

O

OH

HO

MnO2

71% from124

127, dorisenone C

H

O

O

OAc

AcOAc2ODMAP80%

H H H

H H H

Scheme 20. Abad’s synthesis of dorisenone C (127) from (�)-carvone.

intermediate for the preparation of different DielseAlder pre-cursors, since the key step for the formation of the C ring is anintramolecular DielseAlder reaction (Scheme 20). Firstly, theDielseAlder precursor 115 was prepared from 97 followingstandard reaction conditions used previously by the samegroup. Unfortunately, this precursor did not produce thedesired DielseAlder adduct, but a product of retro-hetero-ene rearrangement of the propargylic ether moiety. Thus, afterdesililation of 116 the enone 117 was formed in good yield. Toavoid the sterically demanding group of the diene moiety, thepreparation of the dienol carbonate 118 was undertaken andthe reduction of the retro-hetero-ene rearrangement productwas envisaged. In fact, the strategy did work, but the productof the rearrangement 119 was still the main product of the in-tramolecular DielseAlder reaction. Although in moderateyield, the desired compound 120 was obtained and the se-quence proceeded. Opening of the dihydrofuran ring of 120gave rise to the product 121 as a result of in situ lactonization.The cleavage of the ester groups gave 122, and subsequent ox-idation gave diketone 123, which was reduced with a boraneeTHF complex to give alcohol 124. Further reduction withDIBAL-H gave the triols 125 in which the lactol moiety wasre-oxidized with MnO2 to give the corresponding lactone126. Final diacetylation of 126 gave the synthetic natural prod-uct dorisenone C (127), the data for which, were in completeagreement with those reported earlier for the natural product

and hence established the absolute configuration of the naturalproduct. During these synthetic studies several unnatural fura-noditerpenes were also prepared from lactone 124 by reduc-tion and dehydration to give the furan ring present in 128and 129 (Scheme 21).

Finally, we describe how, recently, Ragoussis et al. haveconverted natural (�)-sclareol 6 into the furanoditerpene,(�)-marginatone (135) (Scheme 22).47 The authors convertedsclareol 6 into (þ)-coronarin E 132, using minor modificationsof reported procedures, which by regioselective hydrogenationand stereocontrolled-intramolecular electrophilic cyclizationgave the tetracyclic marginatane-type diterpene 134.Subsequent allylic oxidation of 134 afforded the synthetic(�)-marginatone 135, the spectroscopic data of which wereidentical to those reported for the natural product. The synthe-sis starts with the preparation of the ambergris odorant, (�)-g-bicyclohomofarnesal 130, from sclareol 6 in seven steps and

124

H

O

O

OH

O

1) DIBAL-H

2) H+

128 R = HH

O

OR

RO

H H

129 R = AcAc2O-DMAP

86%

95%

Scheme 21. Abad’s synthesis of furanoditerpenes 128, 129 from (�)-carvone.


6, sclareol

H

H

OH

OH

7 steps

52%

130

CHO

H

H3-bromofuran

BuLi79%

131

H

HHMPA, reflux

76%

OH

O

132

H

H

O

HCO2NH4

Pd/C 10%

77%

133

H

HBF3-Et2O

46%

O

134

H

Ht-BuOOHNaOCl33%

O

135

H

HO

O

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

52% overall yield. The coupling of 130 with 3-lithiofuran ledto a mixture of two diastereomeric alcohols 131 in 78% over-all yield. Dehydration of this mixture in refluxing HMPA gave(þ)-coronanin E 132 in high yield (76%) (Scheme 22). Reduc-tion of the side-chain double bond of 132 gave (þ)-dihydro-coronarin E 133 and subsequent intramolecular electrophiliccyclization furnished the tetracyclic derivative 134. Allylicoxidation with tert-BuOOH of 134 gave the target molecule,(�)-marginatone 135, albeit in low yield (33%).

3.2. Syntheses by biomimetic approaches

Inspired by nature, biologists and chemists have made poly-ene cyclizations a powerful synthetic tool for the one-step con-struction of polycyclic compounds, starting from acyclicpolyene precursors. Despite the impressive and economicalsyntheses achieved over the past 50 years by chemical simula-tion of polycyclic terpenoid biosynthesis,48,49 this area of re-search still remains a growing field of investigation. Thebiosynthetic transformations have been mimicked by cation-olefin and radical cyclization reactions and, more recently,by radical-cation cyclization cascades.

The first subgroup, commonly known as electrophilic cycli-zations of polyenes, has been intensively studied for the syn-thesis of steroids and a wide variety of polycyclic ringsystems, and is well documented in the literature.50,51 Indeed,their importance has increased over the past three decades, dueto the development of new routes to polyolefinic precursors,methods of asymmetric synthesis, and different conditionsfor the key cyclization step.52e58

In the early 1980s, Nishizawa’s research group describedthe biomimetic cyclization of a geranylgeraniol derivative136 to the racemic tricyclic alcohol 28 (Scheme 23),59,60

which had been previously converted into isoagatholactone(1) by Nakano and Hernandez17 and Ungur et al.20,21 Com-pound 28 has also been converted into 12a-hydroxyspongia-13(16),14-diene by Ruveda et al.19 The cyclization takes placeusing as the electrophile a mercury(II) triflate-N,N-dimethyl-aniline complex, which after reductive demercuration leads toalcohol 28 (22%), together with two bicyclic diterpenoids.

Contemporary synthetic studies by Ungur et al. also de-scribed the biomimetic synthesis of 28 by superacid cycliza-tion of geranylgeraniol 137 with fluorosulfonic acid.61 A fewyears later, the same group also reported the synthesis of

1) Hg(OTf)2·PhNMe22) aq. NaCl3) NaBH4/aq. NaOH

136

O

O

NO2

28

H

HOH

H22%

geranylgeraniol

OH

FSO3H/PrNO2-80 °C

87%

E,E,E-geranylgeranic methyl ester 138

CO2Me

FSO3H/PrNO2-55 °C 92%

10

H

HCO2Me

H

137

Scheme 23. Biomimetic syntheses of racemic isocopalol 28 and methyl isocopalate 10, precursors of spongiane diterpenoids.


racemic methyl isocopalate 10, from 138, using similar condi-tions (Scheme 23).62

Nishizawa et al. also used the mercury(II) reagent to cy-clize ambliofuran 139, leading to the tetracyclic isospongiane140 in 13% yield (Scheme 24).63 Compound 134, having themarginatane carbon skeleton, was obtained after the demercu-ration treatment of 140 with sodium borohydride. Amblio-furan 139 had also been cyclized to furanoditerpene 134 inhigh yield by Sharma et al. using SnCl4 as electrophile initia-tor (Scheme 24).64

1) Hg(OTf)2·PhNMe22) aq. NaCl

139

H

H13%O

ClHg

O

140

NaBH4

aq. NaOH

H

HO

134

SnCl4>90%

Scheme 24. Biomimetic synthesis of isospongiane 134 from ambliofuran 139.

Since the first investigations in the 1960s by Breslowet al.,65,66 biomimetic radical-mediated cyclization reactionshave become an excellent synthetic method for the synthesisof polycyclic natural products under mild conditions andwith high stereochemical control.67

In the early 1990s, Zoretic et al. developed a very efficientseries of triple and tetra cyclizations, leading to trans-decalinring systems. Their strategy68 was based on the Snider methodto cyclize intramolecularly unsaturated b-keto esters withMn(III) salts.69 Following the success of this approach, theyreported, in 1995, the first biomimetic-like synthesis of spon-giane diterpenes, particularly furanospongianes (Scheme

25).70 In their synthesis, an oxidative free-radical cyclizationof polyene 142 with a 2:1 mixture of Mn(OAc)3 and Cu(OAc)2

provided stereoselectively the tricyclic intermediate 143 in43% yield. Subsequent functional-group manipulation and ho-mologation at C13 of 143 allowed, in two independent syn-thetic sequences, the construction of the required furan ringD of the spongiane and marginatane carbon skeletons. Thus,starting from allylic alcohol 141, the necessary cyclizationprecursor 142 was obtained by treatment with allyl chloridefollowed by alkylation with ethyl 2-methylacetoacetate in49% overall yield. After securing the stereochemistry of 143by means of meticulous NMR studies,71 isospongiane 146was prepared by reduction, benzoylation, and ozonolysis lead-ing to ketone 145, which was alkylated with a THP-protectedhydroxyacetaldehyde and hydrolyzed with concomitant aro-matization and final debenzoylation by reduction.

On the other hand, ozonolysis of diol 144 and protection asits corresponding acetonide, compound 147, followed by furanring formation using Spencer’s method, gave unnatural furano-spongiane 149, via enone 148, in 8% overall yield from 141.

The same authors also reported an alternative route to 149 viathe tricyclic intermediate 152, which was prepared from the far-nesyl acetate derivative 150 in four steps, using a radical cascadeof polyolefin 151 (Scheme 26).72 Compound 152, possessing allof the carbons in the spongiane skeleton, was transformed intospongiane 149 in five steps, as detailed in Scheme 26. Thus, hy-drolysis, and epoxidation gave epoxide 153, subsequent Collinsoxidation and aromatization with p-TsOH gave furan 154. Finalreduction with LiAlH4 gave diol 149 in 2.8% overall yield from150. The synthetic sequence leading to diol 149 was later opti-mized (15% overall yield from 150), allowing the synthesis of(�)-isospongiadiol 156, via silyl enol ether 155, upon manipu-lation of the A-ring functionalization in 149.73

A few years later, Zoretic’s group reported an analogousstereoselective radical cascade cyclization introducing ana,b-unsaturated cyano group in the cyclization precursor

1) SOCl22) LiCH2C(O)CMe(Na)CO2Et

141

49%

Mn(OAc)3

Cu(OAc)2

142

CO2EtO

HO 43% HEtO2C

H

143

O

LiAlH4

H

H

144

HOHO

38%

1) PhCOCl

2) O3, then Ph3P

94%

H

H

145

BzO

O

BzO 56%

1) LDA, thenOHCCH2OTHP2) p-TsOH3) LiAlH4 H

H

146

HOHO

O

1) O3, then Me2S2) acetone oxalic acid

H

H

147

O

O

O

1) NaH, EtOCHO, then aq. HCl2) p-TsCl, py then n-BuSH

H

H

148

O

O

O

75%

SBu1) Me2S=CH2

2) HgSO457% from147

H

H

149

HOHO

O

Scheme 25. Zoretic’s biomimetic synthesis of isospongiane 146 and spongiane 149 from precursor 144.


1) MsCl2) LiCH2C(O)CMe(Na)CO2Et

3) Ac2O

150

29%

Mn(OAc)3

Cu(OAc)2

151

CO2EtO 23%

HEtO2C

H

152

O

OAcHO

OAc

OAc

89%

1) K2CO3

2) m-CPBA

HEtO2C

H

153

O

OH

55%

1) CrO3·2py

2) p-TsOH, then 10% HCl

O

HEtO2C

H

154

O

O

85%

LiAlH4149

67%

1) TBDMSCl2) CrO3·2py3) LDA/TMSCl

H

H

155

TMSO

O

TBDMSO35%

1) m-CPBA

2) n-Bu4NF

H

H

156

O

OHO

HO

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

(Scheme 27).74 They started from phosphonate 157, whichwas subjected to HornereEmmons olefination to give polyene158. This modification allows the synthesis of furanospon-gianes functionalized at C17, such as 163e166, through theadvanced intermediate 162. Compound 162 was prepared infour steps from tricyclic system exo 160, which was synthe-sized by an intramolecular radical cyclization of polyene 159.

Concurrent to these studies, Pattenden et al. applied their ex-pertise in polycyclic ring constructions, based on free-radical-mediated cyclizations of polyolefin selenyl esters,75,76 for thetotal synthesis of (�)-spongian-16-one 175 (6% overall yield)(Scheme 28).77,78 They completed the synthesis in a concisefashion via the cyclization precursor 173, which was preparedfrom alcohol 167, as shown in Scheme 28. Protection of167 as tetrahydropyranyl ether, followed by lithiation and

reaction with cyclopropyl methyl ketone, led to compound168. The next step was ring opening of the cyclopropane andformation of an E-homoallylic bromide using HBr, whichwas then used as its corresponding iodide 169 to alkylate 2-phe-nylthiobutyrolactone giving thioether 170. Removal of thethioether in 170 and subsequent manipulation of the tetrahydro-pyranyl ether led to selenoate 173. Treatment of the latter withBu3SnH and AIBN in refluxing degassed benzene led, aftermethylenation, to the tetracycle lactone 174 in 42% yield.Lactone 174 was then converted into 175 by SimmonseSmithcyclopropanation and hydrogenolysis.

Recently, Demuth et al. have developed a radical-typecascade cyclization for the synthesis of (�)-3-hydroxy-spon-gian-16-one 180, a precursor of 175 (Scheme 29).79 In theirstrategy, the photoinduced radical cation of the polyene

1) KN(SiMe3)22)

3) p-TsOH

157

64%

Mn(OAc)3

Cu(OAc)258%

CN

HEtO2C

H

160 8:2 exo/endo

O

THPO

OR

56%

1) n-Bu4NF

2) m-CPBA

CN

HEtO2C

H

161

O

OH

60%

1) CrO3·2py2) p-TsOH

O

HEtO2C

H

162

O

O

CNPO(OEt)2 H ORO

HOCN

158

OR

R = TBDPS

1) CBr4, PPh32) LiCH2C(O)CMe(Na)CO2Et

53%

CN

159

CO2EtO

OR

CN

HEtO2C

H

163

HO

O

CHO 96%

H

H

164

HO

O

HEtO2C

H

165

HO

O

CN

70%

1) CF3SO2Cl2) DMAP3) DIBAL-Hthen HOAc H

H

166

O

CHO

DIBAL-Hthen HOAc

73%

LiAlH4OH

HO

88%NaBH4

HO

R = TBDPS R = TBDPS

Scheme 27. Zoretic’s biomimetic synthesis of C17-functionalized furanospongianes.


1) DHP, PPTS2) Li then

167

76%

1) m-CPBA2) CaCO3

80%

O

170

OTHP

Br

OH

168

OTHP

HO

72%

1) HBr 2) DHP, PPTS 3) NaI, Me2CO

I

169

OTHP

71%

O

OPhS

O

OPhS1) PPTS2) Dess-Martin

84%

171

OTHP

O

O

1) NaClO22)

71%CHO

172

O

ON

O

O

SePh

CSePh

173

O

O

O

1) Bu3SnH AIBN2) Zn, TiCl4 CH2Br2

42%

174

O

O 1) Zn(Cu), CH2I22) PtO2, H2

76%H

H

175

O

O

H

H

Scheme 28. Pattenden’s biomimetic synthesis of (�)-spongian-16-one 175.

undergoes water addition in anti-Markovnikov sense, followedby cyclization cascades terminated by a 5-exo-trig ring closure.The overall reaction sequence mimics the non-oxidative biosyn-thesis of terpenes. The radical cation precursor 179 was synthe-sized from farnesyltri-n-butylstannane 176, which reacted withthe methylen-butyrolactone 177 via a Michael addition. Follow-ing the introduction of the double bond in 178, irradiation of 179in a Rayonet reactor with lmax¼300 nm afforded spongiane 180in 23% yield after purification. The structure of 180 was unam-bigously determined by NOE and X-ray analyses.

3.3. Other approaches and total syntheses

As mentioned previously, the studies toward the synthesis ofspongianes are scarce, especially of rearranged metabolites.The synthesis of furanospongiaditerpenoids has been embarkedupon starting from natural products and using biomimetic-likereaction sequences, both of which have provided in some casesthe synthesis of spongianes with a functionalized A-ring.Additionally, in the mid 1990s, Kanematsu’s group carriedout synthetic studies for the construction of an appropriate fur-anohydrophenanthrene ring system 194 (Scheme 30), which

later was converted into (�)-spongia-13(16),14-diene 38 and(�)-spongiadiosphenol 196 (Scheme 31).80,81

The route to the tetracyclic compound 194, the key inter-mediate for the synthesis of 38 and 196, starts with the conver-sion of furfuryl alcohol 181 into a propargyl ether 182, whichunderwent a furan ring transfer reaction to give the bicyclic al-cohol 183. Hydrogenation of 183 followed by Swern oxidationafforded the ketone 184. The ketone 184 was converted intothe allylic b-keto ester followed by methylation with iodome-thane to afford 185. Removal of the allyl ester gave ketone186, which was next annulated with ethyl vinyl ketone, via di-ketone 187, to give the tricyclic furan 188. The construction ofthe ring A was effected by reductive alkylation to introduce anallyl group, compound 189, which was then converted into anadequate side-chain ketone, compound 193, ready for the finalannulation to afford the tetracyclic intermediate 194. The ste-reochemical structure of 194 was assured by NOE effects be-tween the two angular methyl groups.

The synthesis of spongiane 38 was successfully completedby forming the gem-dimethyl moiety by reductive methylationof 194 to give ketone 93 and removal of the carbonyl group atC3. In parallel studies, compound 194 was reduced,

Sn(C4H9)3

176

180

O

O

H

H

O

O

O

O

+n-BuLi, CuI,LiBr, TMSCl

92%1) LiHMDS/PhSeBr2) m-CPBA, py

35%

O

O

177 178 179

Rayonet reactor λmax = 300 nm

1,4-dicyano-2,3,5,6-tetra-methylbenzene/biphenyl

23%

HO

O

OH2O

Scheme 29. Demuth’s biomimetic synthesis of (�)-3-hydroxy-spongian-16-one 180.


181

O OH

182

O O

183

O OO

HO

HC CCH2BrNaOH

t-BuOKt-BuOH

1) H2, 5% Pd-C

2) DMSO, TFA100% 78% from 182

184

OO

1) diallyl carbonate, NaH

2) MeI, K2CO374%

185

OO

80 °C

O

O

Pd(OAc)2

PPh3, HCO2H76%

186

OO

EVKDBU

187

OO

O

188

O

O

1) t-BuOK

2) p-TsOH74%

from 186189

O

O

Li, NH3(l)

allyl bromide62%

H

1) LiAlH4

2) TBSOTf94%

190

O

TBSOH

9-BBN thenNaOH/H2O2

96%

191

O

TBSOH

1) (COCl)2DMSO then Et3N2) EtMgBr3) TBAF

92%HO

192

O

HOH

HO

(COCl)2DMSO

then Et3N86%

193

O

OH

O73%

194

O

HO

KOH

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

194

O

HO

Li, NH3(l)

then MeI60%

O

HO H

1) LiAlH42) BuLi, CS2 then MeI3) (TMS)3SiH AIBN

50%38

O

H

H

1) Li, NH3(l)

36%

O

HO H

MeONaDMSO79%

HO

196

O

HHO H

O

2) LDA then MoOPH

93

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 affordthe desired (�)-spongiadiosphenol 196, which represents thefirst total synthesis of a furanospongiane diterpene with a func-tionalized A-ring (Scheme 31).

With regard to the synthesis of rearranged spongianes, thereare about three reported synthetic approaches to build up thebicyclic systems82e84 present and, to the best of our knowl-edge, only two published enantioselective total syntheses.85,86

Mehta and Thomas reported in 1992 how the abundant,commercially available (þ)-longifolene 197 can be degradedto a hydroazulene moiety, compound 200, present in rear-ranged spongianes (Scheme 32).82 Catalytic ruthenium oxida-tion of 197 led to the formation of longicamphenilone 198 in35e40% yield. Irradiation of 198 with a 450 W Hg lampthrough a Pyrex filter resulted in the expected Norrish-type Icleavage to the bicyclic aldehyde 199 in about 40% yield.

Reductive decarbonylation using the Wilkinson catalyst fur-nished the bicyclic hydroazulenic hydrocarbon (þ)-200 in52% yield (Scheme 32).

197

RuCl3-NaIO4

O

hν (pyrex)hexane35-40%40%

198

H

HOHC

toluene52%

H

H

(PPh3)3RhCl

199 200

Scheme 32. Mehta’s synthesis of hydroazulene 200.


Bhat et al. reported a common Lewis acid-catalyzed DielseAlder reaction to form decalin systems, present in spongianesand other terpenoids (Scheme 33).83

201 202

+

O

R

R`

R`

O R

AlCl3

203

Scheme 33. Bhat’s synthesis of decalins.

Diene 201 reacts with a series of dienophiles 202, in thepresence of AlCl3, to give a number of decalins 203, whichcan be further elaborated to build up the spongiane skeleton.

The last approach described for the synthesis of spongianesfeatures a synthetic route for the preparation of the cis-fused5-oxofuro[2,3-b]furan unit present in some rearranged spon-gianes. Reiser et al. reported a short and enantioselective syn-thesis of this furofuran unit starting from methyl 2-furoate(Scheme 34).84

The synthesis starts with a copper-bisoxazoline-catalyzed,enantioselective cyclopropanation of methyl 2-furoate 204 tocyclopropane 205, a versatile building block toward a broad va-riety of derivatives, which could be subsequently converted into5-oxofuro[2,3-b]furans. In fact, hydrogenation of 205 gave ex-clusively compound 206 as a single stereoisomer in 86% yield.Subsequent rearrangement to 207 using 2 M HCl in dioxanegave rise to the parent 5-oxofuro[2,3-b]furan framework inonly three steps from inexpensive methyl 2-furoate 204, andin enantiomerically pure form. Conversion of the carboxylicacid into the acetoxy derivative 209, typical in many spongianediterpenoids, was accomplished in a four-step sequence from207 via its methyl ketone 208, which underwent diastereoselec-tive BaeyereVilliger oxidation under retention of configuration.Alternatively, 207 could be photochemically decarboxylatedwith lead tetraacetate under copper(II) catalysis following a rad-ical pathway to directly yield a mixture of 209 and epi-209(210), which could be easily separated by chromatography.

To date, to the best of our knowledge, there has been re-ported only two enantioselective total syntheses of diterpeneswith a rearranged spongiane skeleton.

Firstly, in 2001, Overman et al. described the first enantio-selective synthesis of a rearranged spongiane, (þ)-shahamin K224 (Scheme 35),85 a spongian-derived metabolite havinga cis-hydroazulene unit and an attached highly oxidized six-carbon fragment.

One of the key steps of the synthesis was a Prins-pinacol re-action that produced the core of the carbon framework, the cis-hydroazulene system. The synthesis starts with the conversionof cyclohexanone 211 into the cyclization precursor 215 intro-ducing a kinetic resolution step with (R)-oxazaborolidine 213.Thus, oxidative cleavage of the double bond in 211, followedby thiocetalization, gave compound 212, which was subjectedto the chemical resolution to give enantioenriched ketone (S )-214 in 44% yield. Addition of (E )-1-propenyllithium to (S )-214 followed by silylation gave the silyl ether 215 in high yield.Treatment of 215 with dimethyl(methylthio)sulfonium tetra-fluoroborate (DMTSF) initiated the Prins-pinacol reaction togive the bicycle 216 in 80% yield as a mixture of sulfide epi-mers, the structure of which was confirmed by single-crystalX-ray analysis of the corresponding sulfone. Installation ofthe exocyclic methylene group, followed by oxidative desulfo-nylation, provided ketone 218, the thermodynamic lithium eno-late of which reacted with enantiopure sulfone 219 to givecompound 220, as a single isomer in 72% yield. To transformthe cyclopentanone ring in the side chain of the required pyra-none unit, keto sulfone 220 was reduced with SmI2 and the re-sulting enolate was acetylated to give enol acetate 221 in 88%yield. Reduction of the ketone of this intermediate with (R)-oxazaborolidine 213 and boraneeTHF complex, followed byacetylation, gave acetate 222 in 88% yield. Chemoselectivedihydroxylation of the enol acetate in 222 gave the a-hydroxyketone 223 in 87% yield. Cleavage of the hydroxy ketone in223 with Pb(OAc)4 followed by reduction of the resulting alde-hyde with NaBH4 and lactonization using the Mukaiyama re-agent, provided (þ)-shahamin K 224.

The second enantioselective total synthesis of a rearrangedspongian diterpene was achieved recently by Theodorakiset al.,86 who completed the sythesis of norrisolide 235 in2004. This molecule presents a rare g-lactone-g-lactol moietyas side chain, which has few synthetic precedents. This groupdeveloped initially an enantioselective synthesis of the sidechain, starting from D-mannose (Scheme 36).

204

OMeO2C OMeO2C

H

H

CO2Et

205 > 99% ee

Org. Lett.

2001 Pd/C H2 OMeO2C

H

H

CO2Et

2 M HCl1,4-dioxane86%

74%

O O

H

H

OHO2C

1) (COCl)22) CH2N2

3) HI

O O

H

H

OO 4) m-CPBA

31% (4 steps)

O O

H

H

OAcO

206 207

208 209

207

Pb(OAc)2, Cu(OAc)2HOAc,THF

hν88%

O O

H

H

OAcO

209

O O

H

H

OAcO

210

+

1 : 1.75

3, 1315

Scheme 34. Reiser’s synthesis of 5-oxofuro[2,3-b]furans.


O1) OsO4, NaIO4

2) PhSH, BF3·OEt289%

OSPh

SPh

N BO

HPh Ph

BH3·THF

OSPh

SPh

44%, 94% ee211 212

213

(S)-214

1) (E)-MeCH=CHLi

2) TMS-imidazole92%

SPhSPh

TMSODMTSF

80%

OH

H

SPh 1) TMSCH2Li

2) HF·py84%

215 216 (5:1; b:a)

H

H

SPh

217

1) m-CPBA

2) MoOPH, LDA80%

H

H

218

1) LDA, HMPA2)

72%

O

OAcO

SO2Ph

H

H

220

O

O

SO2PhH

AcO

SmI2Ac2O88%

H

H

221

O

OAc

H

AcO

N BO

HPh Ph

BH3·THF

213

88%

H

H

222

OAc

OAc

H

AcO

1)

2) Ac2O

OsO4, NMO87%

H

H

223

OAcH

AcOO

OH 1) Pb(OAc)4

2) NaBH43)

57%

N Cl+I-

DMAP

H

H

224

OAcH

O

OOAc

219

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

The preparation of the side chain begins with the transforma-tion of D-mannose to the known bisacetonide 225 with improvedconditions using iodine as catalyst to give 225 in 85% yield.Treatment of 225 with p-toluenesulfonyl chloride and triethyl-amine afforded the desired glycosyl chloride 226, which, uponelimination with a mixture of sodium naphthalenide in THF,gave rise to glycal 227 in 48% overall yield. Compound 227proved to be labile upon standing and was immediately benzy-lated to produce vinyl ether 228 in 90% yield. Syringe-pump ad-dition of ethyl diazoacetate (0.1 M in DCM) into a mixture of228 (2 M in DCM) and rhodium(II) acetate at 25 �C gave the cy-clopropanation ester 229 with the desired configuration at theC12 center. The only diastereomers acquired during this reac-tion were produced at the C13 center (4:1 ratio in favor of theexo adduct) and both were taken forward.

Exposure of 229 to a dilute ethanolic solution of sulfuric acidinduced acetonide deprotection and, followed by concomitantopening of the cyclopropane ring, afforded compound 230 in78% overall yield. After oxidative cleavage of diol 230, the re-sulting aldehyde was methylated by treatment with MeTi-(Oi-Pr)3 formed in situ to produce 231 in 63% combined yield.Oxidation of 231 under Swern conditions gave rise to ketone232 (79%). The best yields for the conversion of 232 in to233 were obtained using methanesulfonic acid, which at 0 �Cproduced bicycle 233 as a single isomer in 67% yield. The stagewas now set for the crucial BaeyereVilliger oxidation. Aftertesting several conditions, the conversion of 233 in to 234

was ultimately achieved using ureaehydrogen peroxide and tri-fluoroacetic anhydride and gave rise to the desired material in69% yield as a single isomer.

Theodorakis’s group described the total synthesis of norriso-lide 235 in 2004.86,87 In their strategy, they achieved the assem-bly of the two main fragments, 237 and 238, through theC9eC10 bond to give alkene 236 (Scheme 37). One of the frag-ments, the trans-fused hydrindane motif, could be preparedstarting from the enantiomerically enriched enone 239. Theother fragment was prepared from the lactone 240, which con-tains the desired cis stereochemistry at the C11 and C12 centers.

The synthesis began with the preparation of enone 239,which was available through an L-phenylalanine-mediatedasymmetric Robinson annulation (55e65% yield, >95% eeafter a single recrystallization). Selective reduction at themore reactive C9 carbonyl group, followed by protection ofthe resulting alcohol afforded, the silyl ether 241 in 76% yieldfor the two steps (Scheme 38). Methyl alkylation of the ex-tended enolate of 241 at the C5 center produced ketone 242(66%), the reduction and radical deoxygenation of which ledto the alkene 243 in 83% yield (from 242). The best resultsfor the conversion of alkene 243 into the trans-fused bicycle244 were obtained by hydroxylation of the double bond andsubsequent reduction of the resulting alcohol (52% yieldfrom 243). Fluoride-induced desilylation of 244 followed byPCC oxidation provided the ketone 245 in 91% yield. Treat-ment of 245 with hydrazine then produced the hydrazone


246. Finally, treatment of 246 with I2/Et3N led to the forma-tion of the desired vinyl iodide 237 (62% yield).

The preparation of the fragment 238 is highlighted inScheme 39. The C11 and C12 centers were connected bya DielseAlder reaction between butenolide 247 and butadiene(248). Under Lewis acid catalysis, this cycloaddition pro-ceeded exclusively from the opposite face to that with the

O

H

H

CO2EtBnO

229 (4:1 C13)

O

OHOHHO

OHHO

D-mannose

acetone, I285%

O

OO

O

O

X

X = OH 225X = Cl 226

TsCl60%O

RO

O

O

227 R = H228 R = Bn

BnBr90%

Na, naphthalene80%

Rh2(OAc)4N2CHCO2Et

45%

O

O

13EtOH, H+

78%

O

BnO230

HO

HO

OEt

CO2Et

O

BnO

231

OH

OEt

CO2Et

NaIO4MeTi(Oi-Pr)3

63%

Swernoxid.79%

O

BnO

232

O

OEt

CO2Et

MeSO3H 67%

O O

H

H

O

BnO

O

233

O O

H

H

OO

BnO234

O(H2N)2CO, H2O2

(CF3CO)2O69%

12

Scheme 36. Theodorakis’s synthesis of norrisolide side chain 234.

235 norrisolideH

O

O

O

O

O H

O

O

TBDPSO

OMe236

H

OO

O

TBDPSO

OMe

I

+

O O

910

TBDPSO

O

O

237 238 240239

Scheme 37. Theodorakis’ retrosynthesis of norrisolide 235.

bulky TBDPS group to afford 240 as a single isomer (85%yield). Reduction of the lactone, followed by oxidative cleav-age of the alkene, produced the fused lactol 249 in 63% yieldas a 1:1 mixture of isomers at C14. These isomers were sepa-rated after conversion into the corresponding methyl ether 250.Compound 250 was then converted into the selenide 251,which underwent oxidation and elimination to give alkene252 (61% yield from 250). Osmylation of 252, followed byoxidative cleavage of the resulting diol, furnished the aldehyde238 (two steps, 94% yield) as a crystalline solid, the structureof which was confirmed by X-ray analysis.

O OTBDPSO

240

O OTBDPSO

248

AlCl385%247

1) DIBAL-H2) OsO4, NMO3) Pb(OAc)4

63%

OO

TBDPSO

ORO

249 R = H250 R = Me

amberlist 15MeOH77%

1) NaBH42) PPh3, I23) PhSeNa

67%

OO

TBDPSO

OMe

PhSe 251

NaIO4 90%

OO

TBDPSO

OMe

252

O

OO

TBDPSO

OMe

238

1) OsO4, NMO2) Pb(OAc)4

94%

14

Scheme 39. Theodorakis’s synthesis of fragment 238 of norrisolide 235.

The remaining steps in the synthesis of norrisolide 235 areshown in Scheme 40. Lithiation of the vinyl iodide 237, fol-lowed by addition of the aldehyde 238 and DesseMartin(DM) oxidation of the resulting alcohol, afforded the enone253 in 71% yield. Hydrogenation of the double bond pro-ceeded exclusively from the more accessible a face of the bi-cyclic core to form the ketone 254 in 75% yield. After muchexperimentation, the conversion of ketone 254 into alkene236 was achieved by methylation with MeLi and treatment

OTBDPS

O239

1) NaBH42) TBDPSCl

59

OTBDPS

Ot-BuOK

MeI76%66%

1) NaBH42) nBuLi,CS2, MeI3) Bu3SnH/AIBN

OTBDPS1) BH3, H2O22) nBuLi,CS2, MeI3) Bu3SnH/AIBN

OTBDPS

H

1) TBAF2) PCC

O

H

241 242

243244

245

83%

52%91%

88%N2H4

N

H246

NH2

62%I2/Et3N

237

Scheme 38. Theodorakis’s synthesis of fragment 237 of norrisolide 235.


of the resulting alcohol with SOCl2 in the presence of pyridine(two steps, 64% yield). With the alkene 236 in hand, the stagewas now set for the final functionalization of the bicycle(Scheme 40). Deprotection of the silyl ether and oxidationof the resulting alcohol gave aldehyde 255, which was subse-quently converted into the ketone 256 via treatment withMeMgBr and DesseMartin (DM) oxidation (68% yield).Treatment of 256 with CrO3 in aqueous acetic acid producedthe lactone 257 in 80% yield. Finally, BaeyereVilliger oxida-tion of 257 (MCPBA, NaHCO3, 60% yield) led to insertion ofthe oxygen atom, as desired, with complete retention of con-figuration to produce norrisolide 235.

H

OO

O

TBDPSO

OMe253

H

OO

O

TBDPSO

OMe

I

+

237 238

1) tBuLi2) DM [O]

71%

H2, Pd/C85%

H

OO

O

TBDPSO

OMe254

1) MeLi2) SOCl2, py

H

O

O

TBDPSO

OMe236

1) TBAF2) IBX

64%

93%

H

O

O

O

OMe255

H

1) MeMgBr2) DM [O]

68%

H

O

O

O

X256 X = OMe,H 257 X = O

CrO380%

235

mCPBA60%

Scheme 40. Theodorakis’s synthesis of norrisolide 235.

After completion of their total synthesis of norrisolide, thisgroup has also explored the biological activities of some ana-logs of the parent molecule. Thus, the molecules 233, 234,245, and 257 from their previous synthetic studies were eval-uated together with 258e263, which were also synthesized(Scheme 41).

From the structure/function studies, it was suggested thatthe perhydroindane core of norrisolide is critical for bindingto the target protein, while the acetate unit is essential forthe irreversible vesiculation of the Golgi membranes. Com-pounds 261e263 have no effect on Golgi membranes. Thesame group has also studied the chemical origins of the norri-solide-induced Golgi vesiculation.88 To this end, the re-searchers studied the effect of fluorescent probes 264e269(Scheme 42) on the Golgi complex. While 265 had no effecton the Golgi apparatus, compound 264 was found to induceextensive Golgi fragmentation. In contrast to norrisolide 235,however, this fragmentation was reversed upon washing.

Competition experiments showed that compounds 264 and266 and norrisolide bind to the same receptor, which indicatesthat the perhydroindane core of norrisolide is essential andnecessary for such a binding. In the absence of the acetategroup of norrisolide, this binding induces a reversible Golgivesiculation, indicating that this group plays an essential rolein the irreversibility of the fragmentation, either by stabilizingthe binding or by creating a covalent bond with its target pro-tein. Compound 268, containing the core fragment of the nat-ural product, induced a similar vesiculation that was, however,reversible upon washing. In contrast, compound 269, in whichthe perhydroindane core was attached to a bisepoxide scaffold(suitable for protein labeling), induced an irreversible vesicu-lation of the Golgi membranes. On the other hand, compound267, lacking the perhydroindane motif, had no effect on theGolgi membranes, attesting to the importance of the norriso-lide core in Golgi localization and structure. Moreover, com-pound 269 induces an identical phenotype to that ofnorrisolide, suggesting that it may be used to isolate the bio-logical target of this natural product.

H

263

H

OO

HO

O

258

H

OO

O

O

H

OO

O

259 260

OO

O

O

O

261

OO

O

262

O

Scheme 41. Theodorakis’s analogs of norrisolide 235.

269

H

O

264

H

266

267 268

OO

O

O

OO

NMe2

O

O

O OMe2N

O

O

HO

O

265

OO

OONMe2

OO

OO

OO

H

OO

MeO

OMe

H

OO

O

O

O

O

Scheme 42. Theodorakis’s norrisolide-based fluorescent probes.


4. Conclusions

The scientific investigations of the spongiane family of di-terpenoids have been an active field during the last two de-cades, producing nearly 100 publications on the isolationand structural characterization of its members, including sev-eral preliminary biological studies. In spite of their biologicalproperties and the challenging variety of chemical entities thathave been found, however, the synthetic studies represent onlyone-third of the publications in the field. Until quite recently,researchers had not initiated any structure/function studies,and therefore this area also remains largely unexplored.

Acknowledgements

I gratefully acknowledge financial support from the SpanishMinistry of Science and Education under a ‘Ramon y Cajal’research grant.

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Biographical sketch

Miguel A. Gonzalez 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 Ramon J. Zaragoza, on the

Synthesis of Terpenes with Spongiane, Scopadulane and Estrane skeletons. Upon com-

pletion 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 ‘Ramon y

Cajal’ research contract at the University of Valencia. The synthesis of bioactive marine

natural products is his major interest.

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