Indian Journal of Chemistry Vol. 398, October 2000, pp. 738- 745

Diels-Alder approach for the synthesis of spiro compounds related to Fredericamycin A

Ravinder R Sudini , t Uday R Khire, Rajesh K Pandey & Pradeep Kumar*

Di vision of Organic Chemis try: Technology, National Chemical Laboratory, Pune-4 11 008, India

Received 7 Jun e 1999; accepted (revised) 7 January 2000

The synthesis of a vari ety of spirodiones 7,12 related to frederi camycin A I has been reported. The preparati on of Diels­Alder adducts employing the nonfunctionalised and functionali sed isobenzofurans 13, 14 as dienes and spirodiones 7 , 12 as dienophi les has been described. The subsequent acid induced rearrangement of Diels- Alder adducts 15, 17, 19, 21 leads to the formation of spiro compounds 16, 18, 20, 22 related to fredericamycin A.

Fredericamyc in A 1 is an antitumor antibiotic produced by a strain of Streptomyces griseus. T he molecule contains a cyclopentanoisoquinolone moiety fused to a cyclopentanonaphthoquinone nuc leus in a spiro fashion.1 The presence of a novel spiro I , 3-di one system, undoubtedly makes th is molecule unique for this class of natura l pm ducts. The spiro system imparts certa in interesti ng spati al charac­teristi cs to the molecul e and may be significant in determining its biological actt vtttes. Numerous synthetic approaches have been reported in the literature for its partial2 and/or total synthes is3

. Most interestingly, the unusual I ,4-diketo spiro[ 4.4 ]nonane skeleton has triggered worldwide interes t in the recent literature describ ing strategies directed towards the synthes is of model spiro compound4

. It has shown acti vity aga in st asc ites, mammary tumors, leukemj a ce ll s and marg inal ac ti vity aga in st me lanoma tumors 1

c .

We have reported an effi c ient methodology for spiro creation by the reaction of cycl ic ketals with I ,2-disi lyloxycycl obutene5

. Furthermore, we have ex tended thi s meth odology for the synthes is of a variety of spirodi ones which were subsequentl y utili sed as dienophile precursor in the Die ls-Aider reacti on leading to the spi ro co mpounds related to fredericamyc in A. Our syntheti c strategy for the preparati on of spiro compounds in vo lves Diels-A ider approach usmg spirodi one as dienophil e and

tPresenl add ress: Depart ment of Chemistry and Chemical Bio­logy, Harvard Uni versity, Cambridge, Massachu setts, 02 138, USA.

OMe

0

spirodi one was synthes ized by the reaction of the corresponding cyclic ketals with I ,2-disilyl oxycyclo­butene .

Results and Discussion Synthesis of spirodiones 7, 12: The ketals of

cyc lopentanone and cyclohexanone were prepared following standard synthetic pwcedure. Thus, cyclopentanone 2a and cyclohexan one 2b on treat­ment with e thylene glycol in the presence of p-TSA gave excellent yields of the respec tive ketals 4a and 4b . These ketals were reacted with I ,2-di silyl­oxycyc lobutene 5 in the presence o f excess BF, . Et20 to g ive the corresponding spirod ione 6 which was subsequentl y converted into spiroe nedione 7 by followin g the brominati on-dehydrobromination sequence (Scheme I) . T he sp iroened iones 7 were charac teri sed by the ir spec troscop ic data which were in full agreement with those desc ribed in the literature7

'8

.

The reac ti on of 1-indanone 8a or a.-tetralone 8b

SUDINI eta/. : SYNTHESIS OF SPIRO COMPOUNDS RELATED TO FREDERICAM YCIN A 739

2

a : n = 1 b : n = 2

0

a) 8

a : n = 1 b : n = 2

n HO OH

) n

3

0

r:J7 iii--

+

7

Rx2

HO OH

9

a : R1 = R2 =Me b : R1 = R2 = Et

iv

;:__=C)=o W)n

12

4 5

6

10

a: n = 1, R 1 = R2 = Me b: n = 2, R1 = R2 = Me c: n = 2, R1 = R2 = Et

iii

+

5

11

Scheme I : Synthesis of spirodiones. Reagents : i) p-toluenesulphonic acid, benzene, reflux.; ii) BF3.Et20, dichloromethane, -78• C-room temp.;ii i) Br2 / AcOH, room temp.; iv) pyrid inium

p-toluenesulphonate, benzene, reflux.

with ethylene glyco l in the presence of catalytic amount of p-TSA was not very sati sfactory and gave onl y low yield of the prod uct. In an alternative route, the protecting group such as 2, 2-dimethyJ-1, 3-propa­nediol 9a gave moderate yield of the product while the ketone protec ti on of indanone and a-tetralone was success full y ca rri ed out by the use of 2,2-diethyl-1 ,3-propaned iol 9b and pyridinium p-toluenesulphonate (PPTS) in reflu xing benzene in about 95% yield. (Scheme 1) . The cyclic ketal JO then was allowed to react with I, 2-di silyloxycyc lobutene 5,'; in the presence of excess of BF1.Et20 at -78°C foll owed by overni ght stirring at room temperature to give the spi rodione II in good yield . The sp irod ione JJ was then convened in to spiroenedi one 12 by bromination and dehydrobromi nat ion react ion. It should be mentioned here that the syntheti c approach described

for 12, a di enophil e precursor for Diels-A lder reaction , is short , effici ent and hi gh yielding as

d h I. 4[8 compare to t e tterature report · .

Diels-Alder reaction. The Diels-Aider reacti on was carri ed out at room temperature using spirodione as di enophile and isobenzofuran as diene. The additi on of spirodione 7a, 12 to isobenzofuran 13 led to the formati on of the endo/exo mixture of Diels­Aider adducts 15, 19 respecti ve ly. The endo and exo isomers were not separated as both of them on ac id induced rearran gement were ex pected to end up in the same aromati zed product. Indeed, the endo-exo mixture of adducts 15 and 19 on heating with p-TS A in toluene gave compounds 16 and 20 respecti ve ly as single product in exce llent yie lds. (Scheme II).

Similarly, under the above reaction conditi ons, the spirodiones 7a and 12a were allowed to react with

740 INDIAN J CHEM, SEC 8 , OCTOBER 2000

7a + ~ 0 H

~ '/~

0 13

15

7 +

14

12 + 13 i -19

12a + 14

21

iv -----

iv --

16

(~ 0

OH

18 a : n = 1 b · n = 2

20 a : n = ·: b : n = 2

22 Scheme II : Diels-Aider reaction and synthesis of spiro compounds related to Fredericamycin-A.

Reagents : i) benzene, room temp.; ii) p-toluene sulphonic acid, toluene.; iii) THF. room temp. iv) CHC/ 3 , trifluoroacetic acid, reflux

active diene 14 (whi c h was generated in situ) to give

the corresponding Die ls-A ider ad ucts 17a and 21 respective ly in good yie lds. The endo: exo ratio for I 7a as dete rmined by 1 H-NMR was 90: I 0 whereas in the case of 21, the rati o was found to be 80: 20.

Similarly, the reaction of the substituted diene 7b with J4 at room temperature led t the format ion of

Diels-Aider adducts 17b in 66% yie ld. The ratio of endo: exo was 92: 8 as dete rmined by

1 H-NMR

spectrum. Here aga in the mi xtures of endo and exo isomers were not separated as both o f them were ex pected to end up in the same aromatized product by ac id induced rearrangemen t. Subsequently, the Diels­Aider adduc ts 17, 2J on treatment with trifluoroacetic

ac id in CHCI 1 gave the des ired products 18 and 22 re:>pec tive ly in good y ie lds.

Experimental Section General information. Me lting poin ts were

dete rmined w ith a Me l-Temp apparatus and are

uncorrected. Infrared spec tra were recorded on a Pe rki n-Elmer mode l 683 grating infrared spectrometer. Proton and uC NMR spectra were recorded on Varian FT-80A, Bruker WH-90 FT MR and Bruker AC-200 NMR spectrometers (chemical

shifts in 8, ppm) usin g tetramethy lsil ane as an internal standard and mass spectra o n a Finnigan MAT-

I 0208-70-e V mass spectrometer. E lemental analy es were carried out on a Carlo Erba CHNS-0 ana lyzer.

General procedure for the preparation of kctals 4a, b. A mi xture of ke tone (0.0 I mo le), p-toluene­su lphoni c acid (20mg) and ! ,2-ethanediol (0.0 15

mo le) in 50 mL of dry benzene was heated under re flux for 3-5 hr using a Dean- Mtark water separator. The progress of the reac ti on was monitored by TLC. The mixture was cooled to room temperature and benzene layer was washed with aqueous sod ium

bicarbonat e so luti on (2x20 mL), foll owed by washing

w ith brine (2x I 0 mL) and water (2x I 0 mL). The organ ic layer was separated and dried o ver anhydrous

SUDI I et a/. SYNTHESIS OF SPIRO COMPOUNDS RELATED TO FREDER ICAMYCIN A 741

sodium su lphate . Removal of so lvent gave crude keta ls, whi ch were purified by di s till ati on under

reduced pressure. 1,4-Dioxaspiro[4.4]nonane 4a: Co lorless liquid ;

yield 86%, b.p . 59°CII8mm (lit. 10 57°C/18mm); 1H­

NMR (CDC! _~): o 1.65 (s, 8H), 3 .9 (s, 4H).

1 ,4-Dioxaspiro[4.5]decan~ 4b: Co lorless liquid ;

90%, b.p. 73°C/ 16mm (Lit. 10 73°C/ 16 mm) ; I H-NM R

(C DCI 3): o 1.60 (s, I OH), 3.9 (s, 4H).

General procedure for the preparation of 1-

indanone and a -tetralone ketals lOa,b,c. A mixture

of 1-indanone Sa or a-tetra lone 8b (0 .0 I mo le), pyridinium p-to luenesulphonate (25 mg) and one of these di o ls (2,2-d imethy l -I ,3-propanediol 9a or 2,2-

d iethyl-1 ,3-propaned io l 9b) (0.0 I 5 mo le) in 50 mL of dry benzene was hea ted unde r re flux for 5 hr using a Dean-S tark water separator. The mi xture was coo led and washed with saturated sod ium bicarbonate

so lution (2x 15 mL) and wate r (2x I 5 mL) . The organic layer was separated and dried over anh ydrous sod ium sulphate. Remova l of so lvent unde r reduced pressure led to a res idue, which was purified by neutra l alum in a co lumn using pe t. e ther as e luent and recrystalli sati on from n-hexane.

Spiro(indanc-2, 1'-5, 5-dimethyl-1 , 3-dioxane) lOa: Colorless c rysta lline so lid ; y ie iJ 46%; m. p.

78°C ; 1 H-N MR (CDC ! _~ ): o 0 .9 (s, 3H), 1.3 (s, 3H), 2.4 (t, 2H), 2.9 (t, 2 H), 3.6-3 .8 (q, 4H), 7. 2 (m, 3H), 7.5 (m, I H); MS (m/z, rei. int. %): M+ 2 18 (8 %), 133

( I 00), 11 5 (7), I 04 (2 1 ), 91 (5), 77 (8), 69 (5), 55 (5). Anal. Found : C. 76.75; H, 8.52. Calcd for C 14 H 180 2

(2 18.28): C . 77.03; H, 8.31 % .

Spiro (tctrala ne-2, 1'-5, 5-dimethy l-1 ,3-dioxane) lOb: Colorless crystalline solid; y ie ld 47 % ; m.p.

62°C; 1H-NMR (CDC I3): 8 0 .92 (s, 3H), 1. 3 1 (s, 3H), 2.52-2.92 (m, 6H), 3 .7 1-3 .91 (q, 4 H). 7.22 (m, 3H),

7.5 I (m, I H). Anal. Found : C, 77.32 ; H, 8 .92. Ca lcd

for C,5H2o0 2 (232 .3 1 ): C, 77 .55; H, 8.68%. Spiro (tctralanc-2, l'-5, 5-diethyl-1, 3-c\ioxanc)

lOc: Colorless c rysta lline so lid ; yie ld 95 % ; m.p.

34°C; ' H-NMR (CDC! ,): o 0.65- 1. 34 (m, 8H), 1.66-

2. 11 (m, 4 1-1 ), 2. 17-2 .5 1 (m, 2 H), 2.68-2.92 (t, 2 H), 3 .55-4.00 (q, 41-1), 7.0-7.4~ (m, 31-1 ), 7 .86-8 .0 (m, I H); MS (m/z, rei. int. %) : M+ 260 (25 %), 232 (65), 147 (74), 11 8 ( 100), 90 (46), 69 (30). 55 (75). Anal. Found: C, 78 . 13 ; H. 9.49. C tl cd for C 17 H240 2

(260.36): C, 78.42; H, 9.29%.

Typical one pot proccdm·c for the conversion of ketals into sp iro (4.n) dione sys tem. In an oven-

dried 50 mL two-nec ked round-bottomed flask conta ining a magne tic stirrin g bar was placed the ke ta l (0 .00 l mole). The flask was flu shed with ni trogen and sealed with a rubbe r septum. Dry

dichl oromethane (25 mL) and l ,2-b is-(trimeth yl­

s il y loxy)cyclobutene 5 (0.003 mo le) were added success ive ly with the he lp of a syringe. The flask was

coo led to -78°C and BF,. Et20 ( 10 eq .) was added slow ly with the he lp of a syri nge. The reaction mixture was stirred at the same temperature for 6-8 hr and a ll owed to attain room te mperature by overnight stirring. After monito ring the progress of the reaction by TLC, in w hic h no rma ll y a ll the ketal d isappC'ars, the reac ti on mixture was worked up by washing with saturated NaHCO, soluti on and fina ll y with brine.

The organ ic layer was dri ed over anhydrous sodium sulphate and so lve nt was re moved to y ie ld essenti ally pure spiro(4. n) diones which were fur the r purified by pass ing through a sma ll s ili ca ge l column and e luting with pe t. e the r: ace to ne mi xture.

S piro (4.4) nonane-1 ,4-dione 6a~ : Eluti on usin g 3o/c acetone in pet. e the r during column chromato­

graphy and rec rysta lli sati on from pet.ether afforded the product as a co lo rl ess so li d. yie ld 92%; m.p.

68°C; !R (N uj ol): 1720. 1440. 1270 em·'; ' H- MR

(CDC ! _~ ): o 1. 8 (brs, 8H), 2.75 (s, 4H) ; MS (m/z, re i. int. %): M+ 152 ( 100%), I 53 (72), 124 (32), 68 (32 ).

56 (22).

Spiro (4.5) decane-1 ,4-dione 6b: Elution using 3 % acetone in pet. et he r during column chromato­graph y and recrystallisation fro m pet. ethe r affo rded

the product in 93 % yie ld . m .p. 62°C (lit11

62-6-I-°C ). IR (N ujol ): !720, 1450, 1220, 11 80 em·'.

1H-NMR

(CDC13): o 1.6 (brs, IOH), 2.7 (s, 4H); MS (m/z, rei. int. %): M+ 166 ( 100% ), 137 (24), 124 (36), 11 2 (87), Ill (83), 109 (27), 85 (38). 8 1 (-+8), 67 (95). 59 (48).

54 (45), 53 (42), 4 1 (58) . 30 (6-1- ).

Spiro ( cyclopentane-l-1 ' -indan)-2,5-dione ll a: Eluti on us ing 6clc acetone in pet. e ther during column ch romatography and recrysta ll is at ion from hexane and e thyl acetate (90: I 0) affo rded the product as

ye ll ow solid, yie ld 64% ; m.p. 109°C (lit 7 107-

1080C); IR (N uj o l): 1720, 1478 . 1456 em· '; 11-1 -NMR

(C DC!,) : o 2 .37-2.42 (t, 2H ), 2.80-2.95 (m, 2H), 2 .9-3. 1 (m, 2 H), 3. 15-3.20 ( I, 2 H), 6.8.">-6.9 (d. I H). 7 . 12-7. 15 (t, I H). 7.20-7.25 (m, I H), 7.3-7.35 (d, IH )

S piro (cyclopentane-1, 11-tc trala n )-2 , 5-dione 11 b: E lution us ing 5% acetone in pe t. e the r during co lumn chromatography and rec rys talli sa tion from n-

742 INDIAN J CHEM, SEC B, OCTOBER 2000

hexane:ethyl acetate (90: I 0) afforded the product as a

co lorless so lid , yield 70%; m.p. ll O- I2°C ; IR (Nujol ): 1735 , 1705 , 1510, 1465, 1230 cm-1; 1H-NMR

(CDCI,): 8 1.87-2.08 (t, 4H), 2.72-3. 14 (m, 6H), 6 .52-

6.72 (d, IH), 7 .08-7.4 (m, 3H); L'C-NMR (CDCI3): 8 2 14 .46 (s), 138.39 (s) , 131.82 (s), 129.53 (d), 128. 19 (d), 127.34 (d), 126. 10 (d), 62.08 (s) , 35. 12 (t) , 3 1.32 (t), 28.59 (t), 17.82 (t); Ms (m/z, re l.int%) M+ 214 ( 100%), 186 ( 13), 157 (24), 129 (43), 115( 17). Anal. Found : C, 78.3 1; H, 6.61 . Ca lcd . for C 14H 1402 (2 14.25): C, 78.48; H 6 .59%.

General Procedure for the creation of double bond in spiro (4.n) dione system. To a solution of spiro di one 6, 11 ( 1.7 mmole) in g lac ial acetic acid ( I 0 mL) at room temperature was added bromine 0.09 mL ( 1.77 mmole). The reaction mixture was allowed to stir fo r I hr and then poured into water ( I 0 mL). The aqueous layer was ex tracted with

dichl oromethane (3x I 0 mL) and the combined or<>ani c ex trac ts were washed with saturated sodium

b

bicarbonate so luti on (2x I 0 mL), brine (2x I 0 mL),

water (2x I 0 mL) and dried over anhydrous sodium sul phate. Removal of solvent under reduced pressure fol lowed by chromatograph y on s ili ca ge l using acetone : pet. ether mixture yie lded the product.

Spiro ( 4.4)non-2,3-ene-1 ,4-dione 7a: Elution using I% acetone in pet. e th er during column ch romatography and recrystalli sati on from n-hexane afforded the product as a col ourless crystalline solid,

yield 70%; m.p. 46°C (lit. 8 46-4rC); IR (Nuj o l): 1720, 1460, 1380 cm-1; 1H-NMR (CDC I3): 8 1.68-

1.86 (m, 8H), 7 .24 (s, 2H); 13C-NMR (CDCb) 8: 207.70 (s), 148 .07 (d), 55 .79 (s), 34.02 (t) , 26.88 (t); MS (m/z, re i. int. %): M+ 150 (50 %), 122 ( 15), 109 (58), 94 (45 ), 82 ( 100), 67 (30), 54 (85).

Spiro ( 4.5)dec-2,3-ene-1,4-dione 7b: E luti on us ing I% acetone in pet. e ther during column

chromatography and recrystal li sati on from n-hexane afforded the product as a yel low crystalline solid ,

yield 72%; m.p. 90-9 1°C; IR (Nuj o l): 1710, 1680,

1580, 1470 cnf 1; 1H-N MR (C DC h ): 8 1.4-1.8 (m,

IOH), 7:21 (s , 2H); 13C-NMR (C DC!_,) 8: 207.02 (s), 146 .42 (d), 48.8 1 (s), 28.78 (t), 24.59 (t), 20.64 (t); MS (m/z, re i. int. %): M+ 164 ( 100%), 136 (34), 122 ( I 0), I I 0 (28), 97 (34), 82 (62). 54 ( 18) . Anal. Found: C, 73.06; H, 7 .33, Calcd for C 10H 120 2 ( 164. 20): C , 73 .14 ; H 7.37 %.

Spiro (3-cyclopcntene-1,11-indan)-2,5-dione 12a: E lution us ing 3% acetone in pet. ether during column

chromatography and recrystall isati on from n-hexane afforded the product as a ye ll ow crys talline solid,

yie ld 55 % ; m.p . 82°C (lit7 80-81 °C); IR (Nuj ol): 3062, 2980, 1700, 1672, 1470. 1455 cm-1; 1H-NMR

(CDCI3): 8 2.4-2.45 (t, 2H), 3.2-3.3 (t, 2H), 6 .75-6.80 (d , IH), 7. 1- 7.5 (t, IH), 7 .2-7.3 (m, IH), 7.32-7.35 (d , I H), 7.5 (s, 2H).

Spiro (3-cyclopentene-1, 1'-tetralan)-2, 5-dione 12b: E luti on us ing 3% acetone in pet. ether during col umn chromatography and recrysta lli sati on from n-hexane afforded the product as a ye llow crys talline

solid , yie ld 65%; m. p. 94.5°C; lR (Nuj ol) :17 18,

1640, 1230 cm-1. 1H-NMR (CDCI_;) : 8 1.92-2.2 (m, 4H), 2.78-3.04 (t, 2H), 6.63-6.78 ( , IH), 7 .12-7 .36

(m, 3H), 7 .54 (s, 2H); 13C-NMR (CDC b) : 8 205.50 (s), 149.37 (d), 138.75 (s), 13 1.1 2 (s), 129.86 (d), 127 .39 (d), 126 .68 (d), 126. 14 (d), 54.18 (s), 29.75 (t) , 28.82 (t), 18 .54 (t) . MS (m/z, re i. int. %): M+ 21 2 ( 100%) , 194 ( 17), 184 (24), 166 ( 18), 129 (41 ), 11 5 (26). An al. Found : C, 78.92 ; H, 5.96. Calcd . for C14 H1 20 2 (2 12.24) : C,79.22; H, 5.70%.

General procedure for the preparation of isobenzofuran 13 in situ and successive reaction with spiro (4.n) enedione to prepare the endo and exo Diels-Aidcr adducts 15, 19. To an ice-cooled so luti on of dii sopropylamine 0.49g (0 .7 mL, 5mmole) in 4 mL of d ry benzene was added 2.64 mL of 1.6M hexane so luti on of n-butyl li thiu m (4 .2 mmole). The stirred li thium dii sopro pylamide (LOA) solution was a ll owed to warm to room temperature and then 1-methoxy- I , 4-dihyd roisobenzofuran6

" (0 .25g, 1.66 mrno le) in 5 mL of dry benzene was added within a few minutes. After I 0 min of stirr ing, the reacti on mixture was quenched by add ing 6 mL of aqueous NH 4CI soluti on. The benzene layer was separated and dri ed over anhydrous sodi um su lpha te. After 30 min , the benzene so lution was fi ltered and one of the spiro

(4. n)-ened iones 7a, 12 (0 .85-0.95 mmole) was added to it; reacti on mixture was kept stirring and progress of the reac tion was moni to red by TLC. After 5 to 6 hr, some so lid was separated out from the reacti on

mi xture. T he solvent was the n removed under reduced pressure. Dichl oromethane (20 mL) was added. T he organic layer was washed with water

(2x I 0 mL) and brine (2x I 0 mL) and dri ed over anhydrous sod ium sulphate. Removal of solvent gave a mixture of endo and exo Die ls-Aider adducts in 66- 74% yie lds.

The qu antity of reactant spiro ( 4. n )-ened ione used

SUD INI eta/. : SYNTHESIS OF SPIRO COMPOUNDS RELATED TO FREDERICAMYCIN A 743

in the above reaction and various adducts obtained are given below. Formation of adducts ( endo+exo) were confirmed by the absence of enone protons correspond ing to the ene dione in their 1H-NMR spectra.

Spiro (4.4) non-2, 3-ene-1 , 4-dione 7a (128 mg, 0.85mmol) gave 168 mg of adduct 15.

Adduct 15: Yield 74% ; IR (CHCI 1): 1720, 1450,

I 330 cm·1; 1H-NMR (CDC! .~ ): 8 1.6-1.88 (m, 8H), 3.55 (s, 2H), 5 .54 (s, 2H) , 7.41-7 .65 (m, 4H) .

Spiro (3-cyclopentene-1-1 1-indan)-2 ,5-dione 12a ( 178 mg, 0.9 mmole) gave 187 mg of adduct 19a.

Adduct 19a: Yie ld 66%; IR (Nujol ): 1720, 1460,

1380 cm.1; 1H-NMR (CDCI,): 8 2.4-2.6 (t, 2H), 3.2-3.4 (t, 2H), 4 .0-4. 1 (m, 2H), 5. 8-6 .0 (dd , 2H), 6 .8-

7.5 (m, 8H). Spiro(3-cyclopentene- l-1 1-tetral an)-2,5-dione 12b

(200mg, 0.95 mmole) gave 212mg of adduct 19b. Adduct 19b: Yie ld 68% ; IR (Nujol ): 1720, 1470,

1460 cm-1; 1H-NMR (CDCI 1) : 8 1.82-2 .22 (m, 4H), 2.72-3 .05 (m, 2H), 3 .3 1 (s, 2H), 5 .8 (s, 2H), 6 .53-6 .68 (d, I H), 7.0-7 .55 (m, 7H); MS (m/z, re i. int. %): M+ 330 (4%), 312 (5), 23 1 (7), 2 12 ( 100), 174 ( 12), 159 ( I 0), 127 ( 18) , 118 (38), 89 ( I 0) .

2,2-Tetramethylene-benz(f)indane-1,3-dione 16. The mixture of Die ls-Alder adduct 15 ( 120mg, 0.45 mmole) in dry toluene ( I 0 mL) containing 5 mg of PTSA was re flu xed for 3 hr under nitrogen atmos­phere . The progress of the reacti on was monitored by TLC. The reac tion mi xture was cooled to room temperature; to luene laye r was washed with water

(2x5 mL) , brine (2x 5 mL) and dried over anhydrou s sodium sulphate. Removal of so lvent led to a residue which on purification by s ili ca ge l co lumn chromatography using 4% acetone in pet. ether and subsequent recrystalli sation form n-hex ane yie lded 99 mg (8 5%) of pure 16 as a co lorl ess crys talline solid ,

m.p. 131 - 132°C. (lit. 128- 129°C) ; IR (Nuj o l): 1720,

1705 cm-1; 1H- NMR (C DC I1) : 8 2.04 (b rs, 8H), 7.72-7.92 (m, 2H), 8. 13-8.33 (m, 2H), 8.62 (s, 2 H); MS (m/z, re i. int. 9'c): M+ 250 (64), 209 (100), 194 (23),

165 (41 ), 154 (35), 139 ( 18) . 127 (35) , 126 (90), 125 (36), 112 (20), 55 ( I 0 ).

Spiro [2H-henz(f)-indene-2, 11-indan]-1, 3-dione 20a. The mixture of Di e ls-A IJe r add uct 19a ( 155 mg, 0.5 mmole) in dry toluene ( I 0 mL) cont aining 5 mg of p-TSA was rc flu xcd fo r 3 hr under nitrogen atmosphere. T he progress of the reac ti on was mor,it ored by TLC. The reacti on mi xtu re was cooled

to room temperature; toluene layer was washed with

water (2x 5 mL), brine (2x5 mL) and dried over anhydrous sodium sulphate. Removal of solvent led to a residue, which on purification by silica ge l column chromatography using 5% acetone in pet. ether and subsequent recrystalli sation form n-hexane yielded 119 mg (82%) of pure 20a as a yellow

crystalline compound; m.p. 218• C (lit. 8 215-216°C) .

IR (Nujol) : 1725, 1710 cm·1; 1H-NMR (CDCb): 8 2.61-2.65 (t, 2H), 3.33-3.4 (t, 2H), 6.6-6 .62 (d, I H), 7.0-7.8 (m, 2H) , 8.1-8.2 (m, 2H), 8.6 (s, 2H) ; MS (m/z, re i. int. %) : M+ 298 (100), 281 (19) , 269 (8), 252 ( I 0), 239 ( 18), 183 ( I 0) , I 15 ( I 0).

Spiro [2H-benz(f)-indene-2, 11-tetralan]-1, 3-

dione 20b. The mixture of Die ls-Aider adduct 19b (200 mg, 0 .61 mmole) in dry toluene ( 15 mL) containing 5 mg of p-TSA was re fluxed for 4 hr under nitroge n atmosphere. The progress of the reacti on was monitored by TLC. The reac tion mixture was cooled to room te mperature, toluene layer was

washed with brine (2x l0 mL), water (2x l0 mL) and dried over anhydrou s sodium sulphate . Removal of solvent led to a residue, which on purification by sili ca ge l column chromatography using 2% acetone in pe t. ether and recrystalli sation form n-hexane yie lded 172 mg (8 9%) of pure 20b as a yellow

crys talline so lid , m.p. 231 °C; lR (Nujol): 1740, 1710, 1630, 1610 1480, 1470, 1390, 1255 cm.1; iH-NMR

(CDC1 1): 8 2.1-2.31 (t, 4H) , 2. 89-3.16 (m, 2H), 6.56-6.72 (d , IH), 6.94-7.16 (m, !H), 7 . 18-7.38 (m, 2H), 7.4-7.96 (m, 2H), 8 .12-8.36 (m, 2H), 8.69 (s , 2H); 11C-NMR (CDCI 1) : 8 203.02 (s), 138.73 (s), 136.65 (s), 133. 11 (s), 130.54 (d) , 129.93 (d), 129.65 (d), 127 .79 (d), 127.36 (d), 126.25 (d), 125.05 (d), 59.4 1 (s), 30. 84 (t), 29 .06 (t) , 18 .84 (t); MS (m/z, re i. int. %): M+ 3 12 ( 100%), 297 (20), 284 (24), 265 ( 15), 183 ( 12), 155 (20), 126 (35), 77 (8). Anal. Found : C,

84.36; H, 5.04. Calcd for C22H 160 2 (312.35): C, 84.59 : H 5 . 16%.

General Procedure for the preparation of 1-tl"imethylsilyl-3-trimethylsilyloxy isobenzofuran

14 in situ and its successive reaction with spiro( 4.n )-enediones to p1·epare the Diets-Alder adducts 18 and 22. In an oven-dried 50 mL two ncc kL:d round bottomed fl ask, equipped in an inert atmosphere was charged a so luti on of phthalide (208 mg. 1.6 mmole) in dry THF (3 mL). To thi s, LOA ( 1.8 mmole) [whi ch is prepared at ooc by mi xing dii sopropyl amine ( 18 1 mg) in dry T HF

744 INDIAN J CHEM, SEC 8 , OCTOBER 2000

(2mL), butyl lithium I .5 mL (I .2M)] was added at -78°C where by the solution turned yellow. After 30 min , a freshly distilled and dried chlorotrimethyl­silane 0 .6 g (5.5 mmole) was added and the solution warmed to 0°C for I .5 hr. The solution was reduced to one third of its original volume in vacuo while warming gently . The solution was cooled to -78°C and LDA ( 1.8 mmole) (preparation as above) was added where by the solution became dark red. After I .5 hr, chlorotrimethylsilane 0.6 g (5.5 mmole) was added and th e solution warmed to 0°C for I .5 to 2 hr (t ill the solution became lightened). To this , one of the spiro (4.n)-enediones 7a, 7b, 12a (0.74-0.91 mmole) was added and the reaction mixture was stirred for 6 hr. The solvent was then removed under diminished pressure. Dichloromethane (20 ml) was added . The organic layer was washed with brine (2x I 0 mL) , water (2x I 0 mL) , and dried over anhy­drous sodium sulphate. Removal of so lvent gave the endo and exo mixture of Die ls-Aider adducts in 55-66% yields.

The quantity of reactant spiro(4. n)-enedione used in the above reaction and the va ri ous adducts obtai ned are given below. Formation of adducts (endo+exo) was confirmed by the absence of enone protons corresponding to the ene diane in their 1H­NMR spectra.

Spiro (4.4) non-2, 3-ene-1, 4-dione 7a (136 mg, 0.91 mmole) gave 225 mg of adduct 17a.

Adduct 17a: Yield 58%; 1H-NMR (CDCI3): 8 0.05-0.30 (m, 18H), 2.00 (s, 8H), 3.65-3 .81 (m, 2H), 7.22-7.38 (t, I H), 7.44-7.51 (t, IH), 7.62-7 .71 (d, IH) , 7.87-8 .00 (d, I H).

Spiro ( 4.5) dec-2, 3-ene-1, 4-dione 7b ( 140 mg, 0.85 mmole) gave 250 mg of adduct 17b.

Adduct 17b: Yie ld 66%; 1H-NMR (CDCI3): 8 0.05-0.25 (m, 18H), 1.38-1.92 (m, I OH), 3.70-3 .85

(m, 2H), 7.25-7.40 (t, IH), 7.47-7.52 (t, IH), 7.65-7.73 (d, I H), 7.9-8.0 (d, I H).

Spiro (3-cyc lopentene-1- 1-indan)-2, 5-dione 12a ( 146 mg, 0.74 mmole) gave 193 mg of adduct 21.

Adduct 21: Yie ld 55 %; 1H-NMR (CDCI3): 8 0.1-0.35 (m, 18H), 2.35-2 .50 (t, 2H), 2.60-2.72 (t, 2H), 3.16-3.28 (t. 2H), 3.30-3 .45 (t, 2H), 4 .10-4.42 (dd, 2H). 6.70-6.83 (d , I H), 7.05-7.85 (m, 5H), 8.05-8 .25 (m, 2H).

Cyclopcntane-1-spiro-2'-[ 41, 91-dihydroxy-2H­

benz (/)inden]-1 1,31-dione 18a. Tri fluoro-acetic acid (I mL) was added to a so lution of Diels-Aider adduct

17a (210 mg, 0 .5 mmole) in chloroform (15 mL) and the reaction mixture was refluxed for 6-8 hr under nitrogen atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction , the solution was cooled to room tempera­ture; organic layer was washed with sodium bicarbonate solution (2xl0 mL), brine (2xl0 mL) and water (2x I 0 mL) . The organic layer was dried over anhydrou s sodium sulphate. Remova l of solvent led to a residue, which on purification by silica gel column chromatography using 4% acetone in pet. ether yielded 90 mg (65 %) of pure 18a as a yellow crystalline solid , m.p. 160-16 l°C (l it. 12 163-164°C); IR (CHCh ): 3350, 1730, 1680, 1625, 1600 cm·1. 1H­NMR (CDCI3): 8 2 .00 (s, 8H), 7.65-7.82 (m, 2H), 7.90-8.10 (rn, IH), 8.40-8.55 (m, I H), 9.90 (brs, 2H). MS (m/z, re i. int. %): M+ 282 (2%), 266 (74), 248 (12), 225 ( 100), 194 (12), 18 1 (l 3), 171 (15), 142 ( 13), I 14 ( 10).

Cyclohexanc-1-spiro-2'-[ 41, 91-dihydroxy-2H­

benz-(/)inden]-11,31-dione 18b. Tn fluoroacetic ac id ( I mL) was added to a soluti on of Diels-Aider adduct 17b (230 mg, 0.52 mniole) in ch loroform (15 mL) and the reaction mix ture was retluxed for 6-7 hr under nitrogen atmosphere. The progress of the reac tion was monitored by TLC. After completion of the reaction , the so lution was cooled to room temperature; organic layer was washed with sodium bi carbonate soluti on (2x I 0 mL) and water (2x I 0 mL). The organic layer was sepa rated and dried over anhydrous sodium sulphate. Removal of so lvent led to a res idue, which on purification by si li ca ge l co lumn chromatography using 8% acetone in pet. ether yielded 112 mg (73%) of pure 18b as a yellow crystalline solid . It was further recrystalli sed from acetone: n-hexane (0.5:9.5) mi xture, m.p. 159-160°C ; IR (Nuj o l) : 3380-3300, 1740, 1685 , 1630, 1600, 1460

cm.1; 1H-NM R (CDCI3): 8 1.45-2.02 (m, IOH), 7.58-7.85 (m, 2H), 7.90-8.03 (m, IH), 8.35-8.57 (m, IH), I 0.00 (brs, 2H); 13C-NMR (CDCI .:.): 8 208.45 (s), 203.95 (s), 156.13 (s), I 38.73 (s), I 34.33 (s), 130.84

(d) , 130.71 (d), 128.63 (d), 124.46 (d), 116.5 1 (s), 115 .93 (s), 54.64 (s), 30.06 (t), 25 .36 (t), 21.38 (t); MS (m/z, re i. int.%): M+ 296 (5 %), 280 (100), 262 ( 12), 252 ( 12) , 238 (14), 225 (6 1), 212 (48), 199 (12) , 171 (25), 165 (13), 152 (14), I 14 (29), 55 ( 14). Anal. Found: C, 72.63; H, 5.2 1. Calcd . for C1 8H1 604 (296 .3 1 ): C, 72 .96; H, 5.44% .

4, 9-Dihyd roxyspiro [2H-benz(f) inden-2',1'-

SUDINI eta!. : SYNTHESIS OF SPIRO COMPOUNDS RELATED TO FREDERICAMYCIN A 745

indan]-1,3-dione 22. Trifluoroacetic acid (I mL) was added to a solution of Diels-Aider adduct 21 ( 170 mg, 0.35 mmole) in dry chloroform ( 15 mL) and the reaction mixture was refluxed with stirring for 5-6 hr under nitrogen atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the solution was cooled to room temperature, organic layer was washed with sodium bicarbonate solution (2x10 mL) and with water (2xl0 mL), The organic layer was separated and dried over anhydrous sodium sulphate. Removal of solvent led to a residue, which on purification by silica gel column chromatography using 20% acetone in pet. ether yielded 67 mg (57%) of pure 22 as crystalline solid, m.p . 250°C (dec .) (lit.7 248°C) ; IR (CHCI3):

3400-3300, 1703, 1680 em-' . 1H-NMR (CDCb): 8 2.57-2.62 (t, 2H), 3.25-3 .30 (t, 2H), 6.87-6.90 (d, lH), 7.08-7 . 13 (t, IH), 7.24-7.28 (t, lH), 7.37-7.40 (d, lH) , 7.88-7 .91 (m, 2H), 8.47-8 .50 (m, 2H), 9.52 (brs , 2H); MS (rn/z, rei. int.%): M+ 330 (5%), 314 ( 10), 205 ( 12), 175 (13), 149 (20), 133 (30), I 04 (34 ), 97 (.55) , 83 (52), 69 ( I 00), 67 (22).

I

Acknowledgement One of us (RKP) thanks Director, NCL, Pune to

all ow him to work as a guest worker. We are grateful to Dr T Ravindranathan for hi s support and encouragement. Thi s is NCL Communication No. 6471 .

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