Indian Journal of Chemistry Vol. 38B, April 1999, pp. 511 - 514

Note

Synthesis of 8-(3' -butenyl)-9 ,9-dimethyl-2-oxaspiro[ 4.4 ]non-7 -en-I-one, an advanced

intermediate for terpenes of the marine sponge Dysidea herbacea

Anjan Ghatak & Subrata Ghosh*

Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Calcutta 700 032 , India.

Received 28 December 1998, accepted 24 March /999

A short synthesis of the spirolactone 6 has been achieved for the total synthesis of the nor-sesquiterpene herbasolide 1 and other structurally related sesquiterpenes of the marine sponge Dysidea herbacea.

The marine sponge Dysidea herbacea contains a number of structurally novel terpenes, namely herbasolide 1,1 herbadysidolide 2, I spirodysin 3,2 furodysin 43 and furodysinin 5.3 Biosynthetically herbasolide 1 is the oxidative catabolite of herbadysidolide 2, while furodysin and furodysinin originate from the rearrangement of spirodysin. As part of our continued interest4 on the synthesis of cyclopentanoid natural products, we have undertaken the synthesis of the structurally related compounds 1-3 which to date has eluded synthesis .s Herein, we describe the synthesis of the title compound 6 as an advanced intermediate to the natural products 1-3.

A common structural feature of these compounds is a gem-dimethylated cyclopentane ring having a spiro lactone functionality. Thus, we anticipated that the spiro lactone 6 (Scheme I) could serve as an intermediate for all the three compounds . The lactone 6 could be generated by spirolactonisation of the ester 7 which in tum could be obtained from the gem-

H 0

'CpO H AcO H

~ 2 3

H H

'CQO: I~ - 0 H ~ 4 5

6 7 8

Scheme I

dimethylated cyclopentanone 8. The cyclopentanone 8 was prepared following a novel methodology developed in this laboratory for the construction of highly substituted cyclopentanones 7 and spiro cyclopentanones4

. ,b which has been extensively employed for the synthesis of the sesquiterpenes

d 4',b II 4c u-ce rene, capne ene and the monoterpene ~-necrodoI.8 Introduction of a four-carbon chain was achieved the by addition of butenyl bromomagnesium to the protected hydroxycyclopentanone 9 in the presence of anhydrous teCI) at 0 °c to afford, after deprotection, a single diastereoisomer of the diol 10, mp 84-85 °c, in 58% yield (Scheme II). The stereo­chemical assignment to 10 was dictated by addition of the alky1cerium from the face opposite to the ~ydrox~methyl group to avoid l,3-eclipsing mteractlOn. The diol 10 was selectively dehydrated by heating in DMSO to afford an inseparable mixture of the dienol 11 and its exo-double bond isomer in 70% yield in ca. 9: 1 ratio. In order to convert the diene 11 to the spirolactone 16, it was necessary to oxidise the CH20H group. However, all attempts to oxidise it with a variety of oxidising agents led to a complex mixture of products or the reaction did not proceed at all. Thus, we decided to carry out the alky1cerium addition on to the keto-ester 12. Reaction of the keto-ester 127b with butenyl bromomagnesium under the conditions used for addition to the ketone 9 led to isolation of the trans-adduct 13, mp 110-1 14 °C in 34% yield, Dehydration of the hydroxyester 13 was achieved by heating in DMSO at 165°C to afford an inseparable mixture (ca , 2: I ratio) of the diene 7 and its exo-double bond isomer in 55% yield. Subsequent steps conversion of the diene ester 7 to the lactone 6 was carried out with this mixture hoping separation to be possible at a later stage,

For annulation of the lactone ring, lithium enol ate generated (LDA) from the ester 7 was alkylated with bromoacetaldehyde diethyl acetal to produce the ester 14 in 22% isolable yield . Deacetalisation of the acetal

51 2 INDIAN J CHEM, SEC B, APRIL 1999

q: R (i),(ii) (for R = CH 20lHP) (i), (iii) , (iv ). (v) (for R = C02Me)

"'" ... o

9, R = CH 20lHP 12, R = C02Me

(vii)

14

w:,::~ OH

10, R = CH20H 13, R = C02Me

(viii) , (ix) •

"') ~ dt:::~ 11 , R = CH20H 7, R = C02Me

o ~O

o:f.? 6

Scheme II - Reagents and conditions (i) H2C:CHCH2CH2MgBr, CeCi l, THF; (i i) PTSA, MeOH, room temperature, 6hr; (iii ) 10%

KOH-EtOH , reflux , 5hr; (iv) HCI; (v) CH2N2• Et20 ; (vi) DMSO, 160- 165 IiC, 3hr; (vii ) LDA, THF-HMPA, BrCH2CH(OEth; (vi ii)

CH}COOH-H20 (3: 1). room temperature, 12hr; (ix) NaB H4 , MeOH, room temperature, 15 min.

14 with aqueous acetic ac id followed by NaBH4 reduction of the resulting aldehyde led to spontaneous lactoni sation to afford the spirolactone 6 in 4Q% yield . The spirolactone 6 contains all the carbon atoms and necessary functional groups for transformation to the nor-sesquiterpenic natural product herbasolide 1. Necessary modification for increasing the efficiency of the overall reaction sequence described above for the synthesis of the natural products 1-3 is underway and wi ll be reported ·elswhere .

Experimental Section

General. Melting points were taken in open capi llaries in sulphuric acid bath and are uncorrected . Column chromatography was performed over sil ica sel (60- 120 mesh). Petroleum refers to the fraction of boil ing point 60-80 DC. Ether refers to diethyl ether. Organic extracts were dried with anhydrous Na2S04. IR spectra were recorded as neat for liquids and in CHCb solutions or in KBr pellets fo r solids. Peak pos itions in IH and uCNMR spectra are indicated in ppm downfield from internal TMS in 8 units. I H NMR and DC NMR spectra were recorded in CDCh solutions at 300 MHz and 75 MHz respectively. Elemental analyses were carried out at the microanalytical laboratory of this department.

2, 2- Dimethyl-la-hydroxy-3a-hydroxymethyl-1~- (3/-butenyl)-cyclopentane 9. A mixture of the alcohol 8 ( l.l g, 7.74 mmoles), 3,4-dihydro-2H-pyran ( 1.3 g, 15.49 mmoles) and PPTS (0.05 g) in 20 rnL CH2Ch was stirred at room temperature under nitrogen atmosphere for 12hr. After evaporation of the

solvent, the crude mass was subjected to chromatography us ing ether-pet roleum ( I :9) as eluent to afford the tetrahydropyranyl deri vative 9 ( 1.66 g, 95%) as a colourless thick liquid ; IH NMR: 80.91 (s) and 0.94 (s, total 3H), 1.11 (3H, s), 1.54-2.37 ( II H, m), 3.38-3.54 (2H, m), 3.79-3.90 (2H, m), 4.57-4.60 (t H, m).

Cerium(III) chloride heptahydrate (CeCI3.7H20) (7 .9 1 g, 2 1.26 mmoles) was dried in vacuo (0.2 mm) for 5hr at ISO-160 °C and finall y kept under argon. It was cooled to 0 °c and THF (50 mL) added to it. The white suspension was stirred at room temperature for 12 hr. A solut ion of the ke tone 9 (2.67 g, I 1.8 mmoles) in THF (20 mL) was added to the suspension and the mjxture was stirred at room temperature for I hr. The reaction mixture was cooled to 0 °c and butenylmagnesiu m bromide, prepared from ac ti vated magnesium ( 1.43 g, 59.0 mmoles) and 4-bromo-l­butene (6.37 g, 47.2 mmoles) in THF (30 rnL), was added dropwise to it. The mixture was sti rred at that temperature for 3hr and allowed to warm to room temperature. After stirring for an additional 1 hr the reaction mixture was cooled to 0 °c and quenched by dropwise addition of cold saturated NH4C1 solution . The mixture was filtered through a pad of Celite. The filtrate was extracted with ether (3x40 rnL), and the combined ether extract washed successively with cold 10% HCI solution, saturated NaHC0 3 solution and brine, and dried . Evaporation of the solvent afforded a thick oily residue (3.44 g) which was dissolved in MeOH (25 rnL) and PTSA (0.1 g) added to it. The mixture was stirred under nitrogen atmosphere at room temperature for 6hr. Evaporation of the solvent

+

NOTES 513

followed by column chromatography [ether-petroleum (2:3)] afforded the diollO (1.35 g, 58%), mp 84-85 °c (ether-petroleum); IH NMR: 8 0.9 (3H, s), 0.98 (3H, s), 1.46-1.64 (3 H, m), 1.75-1.89 (5 H, m) , 2.12-2.33 (2H, m), 3.47 ( IH, dd, J = 10.8 and 2.4 Hz), 3.72 (IH, d, J = 10.8 Hz), 3.76 (I H, bs), 4.94-5 .08 (2H, m) , 5.81-5.94 (IH, m) ; I' C NMR: 8 17 .77 (CH,), 22.14 (CH2), 29.00 (CH2), 29 .26 (CH,), 34.3 1 (CH2) , 35.73 (CH2), 47 .59, 50.69 (CH), 62.57 (OCH2), 83.54, 114.26(CH2) , 139.48 (CH). Anal. Calcd For C I2Hn 0 2:

C, 72.67; H, 11 .19%. Found: C, 72.5 I; H, 11 .26%.

Dehydration of the diol 10. A solution of the diol 10 (0.25 g, 1.26 mmoles) in DMSO (3 mL) was heated under argon atmosphere for 3hr at 160-165 DC. It was cooled, poured carefully into cold water (5 mL) and extracted with ether (2x20 mL). The combined ether extract. was washed with water, dried and concentrated. The residue was chromatographed [ether-petroleum (I :9)] to afford a mjxture of the dienes 11 and its exo-isomer (0.16 g, 70%) (in ca. 9: I ratio from 13C NMR) ; IH NMR: 8 0.86 (3 H, s), 1.08 (3H, s), 1.95-2.08 (4H, m), 2.21-2.41 (3H, m), 3.61-3.67 ( IH, m) , 3.76-3.82 ( IH, m), 4.94-5 .07 (2H, m), 5.26 (IH, s) , 5.82-5 .87 (IH, m) ; I' C NMR: 8 (for the major isomer) 20.27 (CH,), 25 .75 (CH2), 27 .02 (CH,), 31.87 (CH2), 33.45 (CH2), 46.83 , 52.09 (CH), 64.20 (OCH2), 114.38 (CH2) , 119.90 (CH), 138 .86 (CH), 151.88.

Methyl-2, 2-dirnethyl- 1a-hydroxy- 1~-( 3' -but­enyl)-cycIopentane-3a-carboxylate 13. Cerium(III) chloride heptahydrate (CeCi, .7H20) (8.53 g, 22.94 mmoles) was dried in vacuo (0.2 mm) for 5hr at 150-160 °C and finally kept under argon atmosphere . It was cooled to 0 °c and THF (65 mL) added to it. The white suspension was stirred at room temperature for 12hr. A solution of the keto-ester 12 (2.6 g, 15.29 mmoles) in THF (25 mL) was added to the suspens'ion and the mixture stirred at room temperature for I hr. The mixture was cooled to 0 °c and butenylmagne­sium bromide, prepared from activated magnesium ( 1.85 g, 76.45 mmoles) and 4-bromo-l-butene (8.25 g, 61 .16 mmoles) in THF (30 mL) added to it dropwise. It was allowed to stir at that temperature for 3.5 hr and quenched by addition of cold saturated NH4CI solution at 0 DC. The mixture was filtered through a pad of Celite, and the filtrate extracted with ether (3x50 mL). The combined ether extract was washed with brine and dried . Evaporation of the solvent afforded a thick oily residue (3 .1 g) which was dissolved in 10% ethanolic KOH solution and the mixture refluxed under nitrogen atmosphere for 5hr. It

was then cooled and made slightly acidic with cold I: 1 aqueous HCI. Ethanol was removed under reduced pressure and the residue diluted with water to about 60 mL. Solid NaHC03 was then added in small portions till the mixture became alkaline. The aqueous part was extracted with ether (2x30 mL). The combined ether extract was dried and concentrated to afford a thick yellow liquid which was discarded . The aqueous part was then acidified with cold concentrated HCI and extracted with ethyl acetate (3x30 mL) . The combined organic ex tract was washed repeatedly with brine, dried and concentrated to afford a yellowish solid (1.Ig, 34%), mp 110-114 °c (ethyl acetate-petroleum); IR(CHCI ,): 34 12, 2940, 2361, 1699,1451,1216 em-I; IH NMR: 8 1.01 (3H, s), l.08 (3H, s), 1.47- 1.53 (lH, m), 1.58-1.64 (lH, m), 1.93-2.17 (5H, m), 2.28-2.31 ( I H, m), 2.73 (I H, t, J = 6.9 Hz), 4.96-5.10 (2H, m), 5.80-5 .94 ( I H, m).

The crude acid, obtained above, on treatment with an ethereal diazomethane afforded the ester 13 (0.95 g, 28% overall from keto-ester 12) as a colourless liquid; IR (Neat): 3471 , 2953, 1711 , 1639, 1437, 1362, 1173 cm-I; IH NMR: 8 0 .91 (3H, s), 0.94 (3H, s), 1.32-1.38 (I H, m), 1.46-1.52 ( I H, m) , 1.86-2.03 (6H, m), 2.25-2.35 (lH, m), 2.58-2.61 (I H, m), 3.63 (3H, s), 4.85-5.00 (2H, m), 5.79-5 .9 (I H, m); 13C NMR, 8 18.35 (CH,), 24.26 (CH2), 28 .0 I (CH3), 28.85 (CH2), 34.08 (CH2), 36.48 (CH2) , 49.30; 57.89 (OCH,), 54.90 (CH) , 84.11, 113.92 (CH2), 139.50 (CH), 179.42 (CO). Anal. Calcd For C 13H220 , :C, 68 .98; H, 9.80%. Found: C, 68.57 ; 9.78%.

Dehydration of the alcohol 13. A solution of the alcohol 13 (0.1 g, 0.44 mmole) in DMSO ( 1.5 mL) was heated under argon atmosphere for 6hr at 160-165 DC. Usual work-up as described for dehydration of 10 afforded the diene 7 and its exo-isomer (0.05 g 55 %) as a light yellow liquid in ca. 2: 1 ratio (from the integration of COOMe protons in IH NMR); IR(Neat): 2928,1732, 1437 cm-I; IH NMR: 80.84 (s) and 1.21 (s) (Me's for major regio isomer), 0.91 (s) and 1.22 (s) (Me's for minor regio isomer) (total 6H), 1.94-2.84 (7H, m) , 4.93-5 .07 (2H, m), 5.14-5.20 (m) (for exo­olefin) and 5.24-5 .25 (m) (for endo-olefin) (total IH) , 5.74-5.92 (lH, m) ; 13C NMR: 8 (for the major regio isomer) : 21.33 (CH3), 25 .71 (CH2), 26.74 (CH3),

31.67 (CH2), 33.70 (CH2), 48 .88, 51.19 (OCH,), 55.03 (CH), 114.43 (CH2), 119.41 (CH), 138.40 ' (CH), 149.42, 174.41 (CO) (for the minor regio isomer), 24.92 (CH,), 25.00 (CH2), 26.89 (CH2), 28 .12 (CH,), 33.12 (CH2), 45 .03, 51.14 (OCH3), 55 .22 (CH),

514 INDIAN J CHEM, SEC B, APRIL 1999

11 4.09 (CH2), 116.40 (CH), 136.88 (CH), 151.28, 174.31 (CO) .

8-( 3'-Butenyl )-9, 9-dimethyl-2-oxa-spiro[4.4]­non-7 -en-I-one 6. To a magnetically stirred cooled (-78 °C) solution of LDA [prepared from diisopropyl­amine (0.2 g, 1.87 mmoles) and n-BuLi (0.7 mL, 1.73 mmoles, 2.5 M in hexane)] was added a solution of the ester 7 (0.3 g, 1.44 mmoles) in THF (3 mL) . The reaction mixture was then slowly warmed to -25°C and stirred at that temperature for 2hr. HMPA (I mL) was added and the reaction mixture brought down again to -78°C and bromoacetaldehyde diethylacetal (0.37 g, 1.87 mmoles) in THF (1.5 mL) added to it dropwise. The reaction mixture was allowed to attain room temperature and stirred overnight (12-16hr) . After quenching with aturated NH4CI solution, the reaction mixture was extracted with ether (3x15 mL). The combined organic extract was washed successively with 10% aqueous HCI (2x5 mL), saturated NaHC03, brine and dried. After evaporation of the solvent, the residue was chromatographed [ether-petroleum (l: 19)] to afford the unreacted ester (0.1 8 g, 60%). FUlther elution with ether-petroleum (l :9) afforded the alkylated product 14 (0.04 g, 22% based on recovered ester) as a light yellow liquid ; III NMR: 8 0.84 (s) (Me for the major diastereomer) and 0.89 (s) (Me for the minor isomer) (total 3H), 1.09 (s) , 1.15-1.29 (m) (total 9H), 1.78-2.3 (7H, m), 2.68-2.74 (lH, m), 3.42-3 .66 (4H, m) , 3.67 (s) (OMe for minor isomer) and 3.68 (OMe for major isomer) (total 3H), 4.47-4 .51 (I H, m), 4.94-5.08 (2H, m), 5.l8-5.19 (m) (for ex~-o lefin) and 5.22-5.23 (m) (for endo-olefin) (total HI) , 5.75-5 .93 (lH, m).

A solution of the acetal 14 (0.04 g, 0.12 mmole) in acetic acid (1.2 mL) and water (0.4 mL) was stirred at room temperature under nitrogen atmosphere for 12hr. The reaction mixture was warmed at 50-60°C for 30 min . and cooled to room temperature. It was diluted' with water (2 mL) and neutralised with solid Na2COJ .

The mixture was extracted with ether (3x 10 mL), and the combined ether extract washed with brine and dried. Evaporation of the solvent afforded the crude aldehyde (0.03 g); IH NMR: 8 0.87 (s) (Me for major isomer) and 0.92 (s) (Me for minor isomer) (total 3H), 1.08 (s) (Me for major i.somer) and 1.10 (s) (Me for the 1T1jnor isomer) (total 3H), 1.93-2.74 (7H, m), 2.91-3.07 (1 H, m), 3.68 (s) (OMe for minor isomer) and 3.7 (s) (OMe for the major isomer) (total 3H), 4.95-5.07 (2H. m), 5. 18-5.19 (m) (for exo-olefin) and 5.22-5.23 (m) (for endo-olefin (total I H), 5.78-5 .89 (I H, m), 9.57 (d, J = 1.5 Hz) (CHO for major isomer) and

9.69 (d, J = 1.6 Hz) (CHO for the minor isomer (total IH).

To a magnetically stirred solution of the crude aldehyde (0.03 g) in MeOH (1 .5 mL), cooled to 0 DC, was added NaBH4 (0.01 g, 0.26 mmole). The mixture was allowed to stir at room temperature for 15 min . Water (3 mL) was added and methanol removed under reduced pressure. The mixture was extracted with ether (3x I 0 mL), and the combined ether layer washed with brine, dried and solvent evaporated. Chromatography of the residue [ether-petroleum (l :9)] afforded the lactone 6 (0.0 1 g, 40% from the acetal 14) as a colourless thick liqu id; IR (Neat): 2922,2573, 1766, 1126, 1032 cm- I; IH NMR: 8 1.01 (s) (Me for major isomer) and 1.02 (s) (Me for the minor isomer) (total 3H), 1.09 (s) (Me for the major isomer) and 1.12 (s) (Me for the minor isomer) (total 3H), 1.96-2.72 (8H, m), 4.1 5-4.25 (2H, m), 4.96-5 .08 (2H, m), 5.]8-5.23 (m) (for exo-regio isomer) and 5.28-5.29 (m) (for endo-regio isomer) (total I H), 5.76-5 .94 (lH, m) .

Acknowledgement

Financial support from DST, New Delhi, IS

gratefully acknowledged.

References

I Charles C, Brackman J C, Daloze D, Tursch B, Declerq J P, Germani G & Van Meerssche M, Bull Soc Chim Belg, 87 , 1978,481.

2 Kazlauskas R, Murphy P T & Well s R J, Tetrahedrol! Lell , 1978, 495 1.

3 Kazlauskas R, Murphy P T & Wells R J, Tetrahedron Lett, 1978,4949.

4 (a) Ghosh S, Patra D & Saha G, J Chem Soc Chem Commun , 1993, 783. (b) Ghosh S & Patra D, J Chem Soc Perkin Tral!s l , 1995. 2635. (c) Samajdar S, Patra D & Ghosh S, Tetrahedron , 54, 1998. 1789.

5 Synthesis of herbasolide, furodysin and fu rody~ in i n has recently been reported : (a) Ho T L: Liang F S, J Chem Soc Chem Commull , 1996, 1882. (b)Ho T L; Lee K Y Tetrahedroll Leu , 36, 1995,947. (c) Ho T. L; Chein R J, J Chem Soc Chem Commlln, 1996, 1147.

6 Patra D & Ghosh S, S) l! th Comlllun, 1994. 1623. 7 (a) Ghosh S & Patra D, Tctrah edron Leu, 34, 1993,4565 .

(b) Palra D & Ghosh S, J Org Chem, 60, 1995, 2526. (c) Ghosh S & Palra D, Pure Appl Chem. 68, 1996,597 (d) Ghosh S, Palra D & Samajdar S, Tetrahedron Leu, 37, 1996, 2073. (e) Haque A, Ghatak A, Ghosh S & Ghosal N, J Org Chern . 62, 1997, 5211 .

8 Ghatak A, Samajdar S & Ghosh S, J Indian Chem Soc (Special issue),75 , 1998,628.

+