Indian Journal of Chcmist ry Vol. 4 1 B. NovembL'r 2002. pp. 2333-234 1

Synthesis of new tetracyclic aristotelia alkaloids

Mel Abul Hashem "' & Zannatul Fereloush

Dcpartmcnt of Chcmistry, Jahangirnagar Univcrsity, Sayar, Dhaka- 1342, Bangladcsh

Receil'ed 4 Febrllary 2000 .. accepled (revised) 17 l illi e 2002

A symhcs is of an analogue of thc rarc ari stotelia indole alkaloids has been reported . The monoterpene R( -)curvone 6 on nitromethyla ti on gives the Michacl add ition produc t 6-nitromcthyl- I ,6-dihydrocarvonc 7. The kctonic group of thc Michael adduc t 7 is protcc ted th rough ketal formati on by trca tmcnt with ethylene glycol. The reaction yie lds two isomeric products of nitrometh ylcarvonc aceta l , Irans-8a and cis-8b . The rcaction of compound 8a,b with grammine [3-(N,N-dimethylamino­methy l)indolc] affords three isomeric condensati on products, the nitroketa ls 9a. 9b and 9c. The treatmem of nitroketal 9a with Zn-Hg/HCI gives two products, one is the hydrolyzed product, nitroketone Ib and the other is the alkaloid l a, the amino cyclized product , where both reduct ion of -N02 to -NH2 and cyc li za tion of amino to olefinic double bond has taken place simu ltaneously. The reducti on of compound 9c furni shes the aminoketal 10 which on hydrolys is yields two products, one is the aminoindole cycl ized product 2a and the other is the aminoketone 2b.

Ari stote li a alk aloids are an emerging class of indole alkaloids1.2 . Over the las t decade quite a number of aris toteli a alkaloids have been isolated. But at present their iso lati on and sy ntheses are attracting more inter­est, since some of them have been fo und to be bio­logica ll y ac ti ve3

. Recentl y more of these types of ari s­totelia alkaloids have been isolated . Some of their sy nthesis have already been reported~. The ari stoteli a alka loids ex ist in pl ants in very minute quantity. Thus, it is quite difficult to study their prec ise pharmacol­ogica l act ivity. Therefore, they have to be sy nthesized in reaso nable quantity so as to study their pharmacol­og ica l act ivity. For thi s purpose our aim was to sy n­thesize some of the monoterpenoid tetracyc lic aristo­telia alkaloids and their analogues. The basic skeleton of monoterpenoid ari stoteli a indole alkaloids consists of all indole nucleus and a monoterpene unit. A join­ing of the two parts constitute the ari stoteli a alkaloids. From thi s laboratory a sy nthesis of an analogue of Fruticoso line has just been reporteds. We are · inter­es ted in sy nthesizing more of these types of ar istote li a indole alkaloids. In thi s paper we report the sy nthesis of two more aristoteli a indole alkaloids, 1a and 2a (Scheme J). The alkaloid 1a is the key intermedi ate for the sy nthesis of a large number of natura lly abun­dant aristote li a alkaloids like Hobartinc 3, Mako­makine 4 and Sorelline 5 etc.

Results and Discussion For the sy nthesis of new tetracyc l ic ari stotel ia al ka­

loids, we have used R(-) carvone 6 as the starting

terpenoid unit, which was transformcd to nitromethyl carvone-ketals 8a ,b before the condensati on was done with the indole skeleton, grammine (Scheme I). The Michael add ition of nitromethane to carvone 6 yielded the glimmy type product, which on chromatographic separat ion gave light yellowish liquid of the pure product 7 (70%). The IR spectrum of compound 7 showed the req uired absorption band fo r saturated >C=O group at 1713 cm'! and strong -N02 absorpti on band at 1551 cm' ! for asymmetric N=O stretching and at 138 1 cm'! for sy mmetric N=O stretching. The !H NMR spectrum of compo und 7 showed the C- I methy l as a doublet at 8 1.1 8 (1=6.8 Hz) and C-8 methyl appeared as singlet at 8 1.74. Each of the me­thylene protons attached to -N02 group appeared as doubl et of doublet at 84.38 (1=12.3, 8.3 Hz) and at 8 4.50 (1=1 2.3, 4.8 Hz). In !3C NMR spectra the peaks at 8 78.8 clearl y indicates the carbon of CH2-N02.

The mass spectra of compound 7 showed the molecu­lar ion peak at mlz 2 11 (8%) which corresponded to the molecul ar formula C II H17N03 and confirmed the ass igned structure for compound 7. The other impor­tant peaks at mlz 165 (M- O2), 150 (M-NOr Me, 13%), 135 (M-N0 2-2Me, 12%), 12 1 (M-CH2 O2-

2Me, 23 %), 107 (M-CH2N02-2Me, 4 1 %), 95 (Me­CH2NOr Me-C3Hs, 50%) and a base peak at mlz 41 (CH3-CH=CH2) were also present in the mass spectra.

The glyco l protection of nitromethyl cal'vone 7 gave a mi xture of two compounds 8a,b in about 1: 1 ratio (yield 64%). This mixture of compounds on co l­umn chromatography gave two pure compounds 8a

2334

6

INDIAN J. CHEM ., SEC B, NOVEM BER 2002

H

7 H

+

H

1a -+-

H

H 1b

Reagents

(i) MeN02, K~03, MeCN/MeOH(3: 1), rfl., 12 hrs.

(ii) CHzOH-CHzOH, p-Iol uene s ulphonic acid, Cf116, rfl., 8 hrs . (iii) Na/EIOH, grammine , rfl. , 8 hrs. (iv) Zn -H g/conc.HCI, r. l, 12 hrs. (v) Li Al H4, d ry elher, r.l , 16 hrs.

(vi) 2N -HzSOJCH~OCH3, r. l, 12 hrs.

Scheme I

H 3

+

+

N02

H 8b

9c

H 10

and 8b. In the IR spectrum of both tl e co mpounds 8a and 8b, the characteri sti c band at 171 3 cm·1 for >C=O group was absent , i.e. >C=O group is protec ted by ketali sati on. The IH NMR spectrum of compound 8a

showed a signal at 8 0.96 as doubl et (1 = 6.84 Hz) fo r 3 protons of I-M e group. The singlet at 8 1.71 repre­sents 8-meth yl group. The 3-H proton appeared at 8 1.36 as doublet of doublet (1=1 2.83, 13.75 Hz). The another 3-H proton appeared at 8 1.75 as dde! (1=2.44, 2.75, 13.75 Hz). The two methylene protons of 5,5-H appeared as three doubl et at 8 1.40 (1=4.58, 12.83, 13.75 Hz) and at 8 1.86 (1=2.44, 3.67, ] 2.83 Hz),

HObartine~

HN,~

~ I ~N/ H 5

Sorell ine

iii --~

H 4

Makomakine

ABUL HAS HEM e l al.:SY TH ES IS OF TETRACYCLI C AR ISTOTELI A ALKALOIDS 2335

respectively. The I-H proton appeared as doublet of quartet at 8 2.11 (1=5.50, 6.84 Hz). The 4-H proton appeared as triplet triplet at 8 2.35 (1=2.75 , 12.83 Hz). The 6-H proton appeared at 8 2.72 as four doubl ets (1=2.93,3.67,4.58 and 5.50 Hz) . The four methylene protons of the ketal gave mutiplet at 8 3.80-4.00. The peaks at 8 4.50 (dd, I H, J=3.67, 12.83 Hz) and at 8 4.67 (del , 1 H, J=2.93, 12.83 Hz) were ass igned for the two protons of CH2- O2. The two olefinic geminal protons =CH 2 appeared as doublet at 8 4.70 (1= 1.46 Hz) and at 8 4.74 (J= 1.46 Hz). The coupling constants and the pos itions of the protons in each isomer 8a and 8b were clearly evaluated from the 20-'H_ 'H cosy NMR spectra (Figure 1).

On the basis of IH NMR analys is, the st ructure of 8a was assigned as trans- isomer, because the cou­pling constant between the I-H proton and the 6- H proton is 5.5 Hz. The IH MR spectrum of compound 8b showed I-methyl as doublet at 8 1.1 2 (1=7.32 Hz) and 8-meth yl as singlet at 8 1.72. The I-H proton ap-

COS,( (H~S007)

. • 1 '-'-'-1 . 1 • . . 1 . . 1 . ~ . 5 4 .0 3.5 3 .0 2. 5

~ Q

U . ,

Q

0JO ~ QJ

.<il ~ 0 0

°0 G! -@

peared as mutiplet at 8 1.76. The four methylene pro­tons of the ketal 0-CHr CH2-0 gave mutiplet at 8 3.80-4.00. The two methylene protons of CHr O2

appeared as mutiplet at 8 4.70. The two olefini c geminal protons =CH2 appeared as Goublet at 8 4.73 (1= 1.46 Hz) and at 8 4.75 (1= 1.46 Hz) . The other pro­ton signals also fit the spectrum that corresponds to the ass igned structure for 8b. On the bas is of above IH NMR analys is the structure of compound 8b was ass igned as cis-isomer. The 1JC NMR spectrum of 8a ,b also showed carbon signals of thirteen carbon atoms each with almost same intensity. The CHr O2

signal s are shown at 8 75.5 and at 8 79.4 for 8a and 8b, respecti vely.

The four methy lene carbon signals of ketal ap­peared at 8 63.9,64.5 and 64.7, 65 .6 respecti vely. The other carbon signals were closely related to the struc­ture 2. Thus, the I3C NMR values also fit the ass igned structure for 8a and 8b. The molec ul ar ion peak at mlz 255 ( I 1 %) was observed in the mass spectrum

PPM . 1 . I . ,...-.-r 2.0 1. 5 1.0

C> 0

Cl.

f-VI

0 ~ .. 0

1.0 W U,

'" 0

re 0

r\J

;~Q u.

;

I 0

U1

~~ I.,'Q 0 0

Figure 1- 20. 1 H, 1 H Cosy 45 speclruill of 8a

2336 INDIAN J. CHEM ., SEC B, NOVEMBER 2002

corresponding to the molecular formu la CIJH21 N04

fo r both 8a and 8b. The important peaks were at mlz 214 (M-C3HS, 16%), 209 (M-N02, 45 %), 195 (M­CH2N02, 22%), 153 (M-NOr C3Hs-CH3, 35%), 139 (M-CH2N02-C3Hs-CH}, 97%) and the base peak at mlz 86 was due to the fo llowing fragment :

m/z 86(100%)

The reac ti on of the compound 8a,b with Grammine [3-(N,N-dimethylaminomethyl)indole] in the presence of Na-metal in dry ethanol at reflux temperature for 8 hr yielded a gummy prod uct, which on chroma­tographic separation gave three crysta lline condensed products, 9a , 9b and 9c with different polarity and melting point. The total yield was 52%. Compound 9a was obtained as colourl ess crystals( 18%), m.p. 158-60°C. The IR spectrum of compound 9a showed a strong sharp band at 3480 cm-I due to indolic N-H stretching band. The absence of >C=O absorption in­dicated that the ketal was not hyd rolyzed. The IH 'MR spectrum showed the different proton signals

due to both the indole ring and the terpenoid (ali­phatic) portion of the molecule. In the indole ring sys­tem the IH NMR showed a broad peak at 8 8.03 fo r indolic -NH proton. The 2-H appeared as doublet at 8 7.0 (1=2.4 Hz). The 5,6,7 and 8-H appeared as three doublets at 8 7.34 (1= 1.6, 7.2, 1.2 Hz), 7.20 (1= 1.6, 7.2,7.2 Hz), 7.12 (1=1.6, 8,7.2 Hz) and 7.54 (1=1.2, 8, 1.6 Hz) respectively. In the terpenoid portion the four protons of 15, IS , 17 , 17-H gave mutiplet at 8 0.96-1 .03. The 13-methyl appeared as doublet at 8 1.05 (1=7.2 Hz). The 13-H appeared as doublet of quartet at 8 2.05 (1 = 6.8,7.2 Hz). The 12-H appeared as mutiplet at 8 2. 11-2.24. The 19-methyl appeared as singlet at 8 2.18. The 16-H appeared as mutiplet at 2.66. The two methylene protons of 10,10-H appeared as doublet of doublet at 8 3.34 (1=14.8 , 4.4 Hz) and at 83.50 (1= 14.8, 10 Hz) respect ively. The fo ur methyl­ene protons of the ketal showed mutipl et at 8 3.96-4.02. The CH-N02 proton appeared as triple doublet at 8 5.20 (1= 4.4, 6.8, 10Hz) . The two olefinic gem i­nal protons appeared as doublet at 8 5.34 (1=1 .2 Hz) and 5.36 (1=1 .2 Hz) respectively . The 13C NMR spec­trum of compound 9a indicate the presence of twenty- two carbon signals, and also fro m DEPT spec­trum it is clear that the compound con tains three me­thylene carbons (downward signals) of C-15 , C-17, C-

10 appeared at 8 2 1 .1, 28.0, 34.4 and also the two me­thylene carbons of ketal (O-CHrCHr O) at 8 64.6 and 65. 1 respectively. It also contains four mcthyne car­bons (upward signa ls) of C- 13, C- I 6. C- 12 and C- I I (CH-N02) whi ch appeared at (5 34.8, 37. I, 46 .6 and 90.9 respectively, and also conta ins two meth yl ca r­bons (upward signals) of 13-Me an 19-Me whi ch appeared at 8 14. 1 and 2 1.0 respectively. The quater­nary carbon C- 14 gave signal at 8 110.0. The two ole­fini c carbon of C- 19 (H2C=C<) and C-20 (>C=CH2)

gave signa ls at 8 144.5 and II 1.4 respectively. In the indole portion 13C NM R gave signals for eight car­bons and also from DEPT spectrum it is show n th at the methyne carbons gave onl y five signal s at 8 122.8, 1 19.6, 122.3, 11 8. 1 and 11 2.5 for C-2, C-5 , C-6 , C-7 and C-8 respectively , and other three terti ary carbon gave signals at 8 110.2, 126.8 and 136.2 for C-3, C-4 and C-9, respecti vely. The intense molecul ar ion peak at mlz 384 (51 %) was observed in the mass spectru m corresponding to the molecular formula Cn H28N20 .j . The important mass fragments are at mlz 338 (M­N02, 43 %), 252 (C9HsN-H2, 19%), 195 (M-CHN02-

C9HSN, 12%), 139 (M-C9HgN-CHNOrCHr C3Hs, 66%) and the base peak at mlz 130 indicates indoli c compound hav ing CH2 attached to pos ition-3. From the above inves ti gations the structure of the com­pound 9a was ass igned as l rans-i so lll er, on the basi s of the position of the attachment to the indolic porti on with respect to 13-methyl of the terpcnoid unit. Com­pou nd 9b was obtained as co lourless crystals (15 %), m.p. 90-93°C. The IR spectrum of compound 9b showed a medium band at 3420 crn·1 du e to indolic -NH stretching and a very strong band at 1549 cm·1

and a medium band at 1375 cm·1 due to asymmet ri c and symmetric N=O stretching of - O2 group. The I H NMR spectrum of compound 9b sho'wed a broad peak at 8 8.03 fo r indoli c -NH. The 2-H appea red as dou­blet at 8 6.97 (1=2.44 Hz) . The 6 and 7-H appeared as tripl et at 8 7.15 (1=7.81 Hz) and at 8 7.20 (1=7.81 Hz) respectively. The 8 and 5-H appeared as doublet at 8 7.34 (1=7 .8 1 Hz) and at 8 7.53 (J=7.8 1 Hz) respec­ti vely. In the terpenoid portion of the molecule the 13-Me appeared as doublet at 8 1.09 U=7.32 Hz). The 13-H appeared as multiplet at 8 2.35··2.41, the va lue is hi gher than 9a (82.05) . The two methylene protons of 10,10-H appeared as doublet of doublet at 8 3.16 (1=11.23 , 14.65 Hz) and at 8 3.37 (1=3.41,14.65 Hz), these values also appeared at sli ghtl y hi gher field than 9a . The I1-H appeared as triple doublet at 8 5.62 (1=3.41,10.75,11.23 Hz), the va lLie is shifted to

AI3UL HAS HEM 1'1 al.SYNTII ES IS OF TETRACYC LIC AR ISTOTELIA ALKALOIDS 2337

lower fi eld than 9a. The 12- H for 9b appeared as mul­

tiplet at 8 1.92 whereas in 9a this value appeared at

lower fi eld at 8 2. 11-2.24 i .e., the position of these protons in 9a and 9b are quite different, one is closer to - O2 and the other is far from -N02. The other pro­ton signals also fi t the I H N M R spectrum that corre­spond to the ass igned structure fo r 9b. The IJC NM R spectrum of compound indicated the presence of twenty- two carbon signals. The two meth yl carbons of 13-Me and 19-Me appeared at 8 16.8 and at 8 20.8. The three meth ylene carbons of C- 15, C- 17 and C- I 0

gave signals at 8 27.3 , 28.5 and 34.4 respecti ve ly and

the two methy lene carbons of ketal gave signals at 8 64.0 and 64.8. Three meth yne carbon signals of C- 13,

C-1 6 and C- 12 appeared at 8 37.4,37.4 and 44.8 re­

spectively and the CH- O2 appeared at 8 9 1.5. The

quaternary carbon C- 14 signal appeared at 0 109.2. The two olefini c carbon of C-19 (H2C=C<) and C-20 (>C=CH2,) gave signals at 8 148.2 and 11 0.2 respec­ti ve ly. In the indole rin g the LIC MR gave signals

for methyne carbon C-2, C-5, C-6, C-7 and C-8 at 8 122.9, 119.5, 122 .2, 11 8.3 and 111.3, respect ively, and the other three tertiary carbon signals for C-3, C-4

and C-9 at 8 11 1.3, 126.9 and 136.2, respecti ve ly. The intense molecular ion peak at mlz 384 (M +, 95 0/£) was observed in the mass spect rum corresponding to a molecular formula C22H 2XN 20~ . The important mass fragments have identical va lue to the 9a but differ in intensity. From the above spectral data ana lys is and the shielding and deshielding of 10, II and 12-H, the structure of compound 9b has been ass igned as cis­isomer. Thi s is also confinned by the nex t step reac­ti on, reduct ion of nitro group, in which only cis­isomer is obtained. Compou nd 9c was obtained as co lourless crys tals ( 19%), m. p. 160-62°C. The I R spectrum of compound 9c showed a medium broad band at 34 18 cm-I indicating -NH stretching. The IH NM R spectrum of compound 9c showed dillerent proton signal s due to both the indole and the terpenoid (ali phatic) porti on of the mo lecule. The spectral pat­tern of compounds 9b and 9c is almost similar but the position, intensity and coupling constant slightl y dif­fered. In the indole ring system a broad peak appeared at 8 8.0 for indoli c - H. The 2-H appeared as doublet

at 8 6.95 (1 = 2.35 Hz). The 6 and 7-H appeared as doublet of doublet at 8 7. 13 and at 8 7. 19 (1 = 7.8 1, 8.30 Hz) respectively. The 8 and 5-H appeared as doublet at 0 7. 32 (1 = 8.3 1 Hz) and at 8 7.64 (1 = 7.8 1 Hz) respect ive ly . In the terpcnoid unit the 13- M e ap­

peared as doublet at 8 1.24 (1=7.33 Hz), the val ue is

shifted to lower fi eld than both 9a and 9b i .e., thi s methyl proton is slightl y deshielded by -N02 group.

The 13-H appeared as doublet quartet at 8 2.2 1 (1 =

2.44, 7.33 Hz). The 12-H appeared as mutiplet at 8 2.48, which is deshielded by -N02 group compared to

9b. The two methylene protons of 10, 10- H appeared

as doublet of doublet at 8 3. 19 (1= 11.23, 14.65 Hz);

and at 8 3.5 1 (1=2.93 , 14.65 Hz), thi s va lue also ap­

peared at lower fi eld th an 9b. The II-H appeared at 8 5.6 1 as tripl e doublet (1=2.93 , 11 .23, 11 .72 Hz); thi s is also at lower f ield. T he other proton signals also fit the IH NMR spectrum th at corresponds to the as­signed structure for 9c. The 13C NMR spectru m of compound 9c indica ted the presence of t wenty-t \VO carbon signal s. The two meth y l carbon of 13-Me and

19-M e gave signals at 8 16.3 and at 8 20.7. The three methy lene carbon of C-1 5, C-17 and C- I O gave sig­

nals at 8 26.3,29.0 and 35.7 respecti ve ly and the t\Vo

methylene carbons of ketal gave signals at 8 64.0 and 64.5. The three methyne carbons of C- 13, C-16 and

C- 12 gave signals at 8 36.7, 38.4 and 44.8 respec­

ti ve ly and the C- II (CH-N02) gave signal at 89 1.-L The two olefini c carbon of C- 19 (H2C=C<) and C-20

(>C=CI-h ) gave signals at 8 148.0 and I 10.0 respec­tive ly. The other 13C MR signal of indole ring showed almost identical va l ue correspondi ng to the compound 9b. From the above analysis and the de­shielding of the 10, II and 12-H protons and the cou­pling constant between 13- H and 12- H (1=2.44 Hz) , the structure of the compound 9c has been ass igned as cis- isomer, which is obta ined by rota ti on o f the terpe­

noid unit by an angle of around 60° rr0111 9b configu­rat ion.

The reacti on or compound 9a with Zn- Hg/HCI in methanol at r00111 temperature fo r 12 hI' y ielded a number of products, which on chromatograph ic sepa­rat ion furnished only two pure products la and 1 b in 25 % and 10% y ield respecti vely.

The IR spectrum of compound l a showed a 111e­dium broad band at 3350 cm-I indica ting -N H stretch­ing and a strong band at 171 3 cm-I due to the >C=O group absorption . The absence of nitro group absorp­tion in the region 1550 C111-1 indicates that - I O2 is re­duced. A medium band at 12 17cm-1 w ith s111all dou­

blet indicate y-s tretching o f >C (CH3h group. The 11-1 NMR spectrum of compound ]a showed a broad peak at 0 7.88 clue to incloli c-NH. The 2- H appeared as

doublet at 8 7.09. The 6 and 7- H appeared as doublet of doublet at 8 7. 14 (1=7.6, 7.6 Hz) and at 0 7.47 (1=7.6,7 .6 Hz) respecti ve ly . The 5 and 8-H appeared

2338 I DIA J. CHEM , SEC B, NOVEMBER 2002

as doublet at 8 7.25 (1=7.6 Hz) and at 8 7.26 (1=7.6 Hz) respectively. [n the aliphatic reg ion the 17-

M e appeared as doublet at 8 0.88 (1=7 Hz). The two geminal methy l of 2 1-Me and 22-Me appeared as

singlet at 8 1.25 and 1.26 respectively . The 17-H ap­

peared as doublet of quartet at 8 1.67 (1= 13.2, 7.2 Hz). Each of the Illeth y lene protons of 19, 19-H ap­

peared as doublet of doublet at 8 2.33 (1= 16.8, 6 Hz)

and at 8 2.47 (1= 16.8, 4.8 Hz) . The two meth y lene protons of 10, 10- H also appeared as doublet of dou­

blet at 8 4.02 (1= 16.8, 6 Hz) and at 8 4.29 (1= 16.8 , 7.2 Hz) . The low field shift of these protons is clue to the fi eld effect of carbony l group. The II-H (CH-NH)

appeared as Illutiplet at 8 3.8 1. The aliphatic -NH ap­

peared as broad singlet at 8 5.8. The other proton sig­nals al so fit the 'H MR spectrum for th e ass igned structure for la . The Uc MR spectrum clearly indi­cated the presence of twenty carbon signal s. The three me thy l carbon signals for 17-Me, 2 1-M e and 22-Me

appeared at 8 16.3, 16.7 and 16.9 respectively . The three methylene carbon signal s of C-19, C- 15 , and C-

10 appeared at 8 23 .7, 26.2 and 35. 1, respectively. The three methy lene carbon signals o f C-17 , C-14 and

C- 16 appeared at 840.2,43 .5 and 49.8, respectively

and the CH- 'H signal is at 8 50.2. The quaternary

carbon signal fo r C- 13 appeared at 8 6 1.0. The >C=O signal appeared at 8 194.0. The other DC N M R val ues also fit the spectrum that correspond s to the assigned structure for 1a. The [R , 'H NMR and I:lC NMR data are in good agreement for the ass igned structure for la , which is obtained by the simultaneous reduction and cyc li za ti on of the reduced product.

The IR spectrum of compound Ib showed a strong band at 1705 cm-I due to the >C= 0 group indicat ing that the ketal is hydrolyzed to ketone. The IH NMR spectrum of Ib showed different proton signals due to both the indole ring and the terpenoid (a liphatic) por­ti on of the molecule. [n the indole ri ng system the 1 H

NMR showed a broad peak at 8 8.1 for indoli c-N H. The 2-H appeared as doublet at 8 7.02 (1=2.4 Hz) .

The 6 and 7-H appeared as doublet of doublet at 8 7.15 (1=8, 8 Hz) and at 8 7.22 (1=8.8 Hz), respec­

tively. The 5 and 8- H appeared as doublet at 8 7.37 (1=8 Hz) and at 87.49 (1=8 Hz), respecti ve ly. [n the aliphat ic porti on of the molecule the 19-methy l ap­peared as doublet at 8 1.1 3 with very small coupling (J=2Hz) due to all y li c coupling. The 13-Me appeared

as doublet at 8 1.3 1 (1=6.8 Hz). The 13-H appeared as multiplet downfield at 8 4.80 than the reactant 9a

(8 2.05) due to the presence of adjacent C=O group. Also the absence of four methylene proton signals of keta l indicate th at ketal is hydrolyzed to ketone. The two methylene protons 10, 10-H appeared as doublet

of doublet at 8 3.30 (1=4.8 , 15.2 Hz) and at 8 3.56 (1=9.6 , 15.2 Hz). The II -H appeared as tripl e doublet

at 8 5.06 (1=4.8, 9.6, 9.6 Hz) . The 12-H appeared as

multiplet at 8 2.96. The other proton ~ i g nal s also fit the 1 H NMR spectrum th at corresponds to the as­signed structure for lb. The I:lC NMR spectrum of compound Ib showed the presence of twenty carbon signals. The spectru m showed two methy l carbon sig­nals of 13-Me and 19-Me at 8 12.5 ,md 19.5, respec­tively . The three methyl ene ca rbon signals of C-15 ,

C-1 7 and C- I 0 appeared at 8 19.6, 26 .1 and 26.3 re­spectively. The four methyne carbon signals of C-1 6,

C-13 , C-1 2 and C- II (CH- O2) appeared at 8 34.6, 42.1 , 42.7 and 89.4, respecti ve ly. T he two olefinic carbons C-19 (H2C=C<) and C-20 (>C=CH2) gave signals at 8 166.8 and 108.4, respect ively . The 13C NMR value of indole ring gave also identi ca l va lue corresponding to the starting materi al 9a. Thus the IR, IH NMR and Uc NM R values are in good agreemen t with the structure ass igned for compound lb.

The reduction of the condensed ni tro compound 9c with LiAIH~ in diethy l ether gave the reduced am ino compound 10 (26%). The [R spectru m of compound 10 showed a medium sharp band at 3480 cm-I indicat­ing indolic -N H absorption. A weak band at around 3250 cm·1 w ith small doublet indicates ·· NI-l stretching of primary aliphati c amine. The absence of nitro group absorpti on in the reg ion 1550 cm-I indicates that -N02 is reduced to -NH 2. In the fi nger print re­gion a medium band at 12 12 cm-' indicate C-N stretching. The IH NMR spectrum of compound 10 showed the 13-meth y l as doublet at 8 1.1 2 (1=6.83 Hz). T he 12- H for 10 appeared as multiplet at slightl y higher field at 8 1.8 1. The two methy lene protons of

10, IO-H for 10 appeared as doublet of doublet at 8 2.54 (1=10.26,14.16 Hz) and at 8 3.32 (1=2.93, 14. 16 Hz) . T he va lue is !>hifted to higher fiel d i.e. these pro­tons are slightly shielded by NH2 group. The II-H also appeared at higher fi eld as dou b l r~t of triplet at 8 3.67 (1=10.26,2.93 Hz) . The NI-h proton appeared as

broad singlet at 8 2.92. The hydro lys is of the am ino ketal 10 with 2N

H2SO,1 in acetone at room temperature y ielded a mi x­ture o f compounds, which on chromatographi c sepa­ration gave two pure products 2a (48%) and 2b (22%) . Both the compounds gave pos iti ve alkaloid

ABU !. HAS HEM el al.:SYNTHES IS OF TETRACYCLIC AR ISTOTELI A ALKALOIDS 2339

test. The IR spectrum of compound 2a showed a strong band at 1705 cm-I indicating the >C=O group absorpt ion. A broad band at 3480 cm-I indica ted the -NH absorpti on. A medium sharp band near 3000 cm-

I

indicated =C-H stretching. The IH MR spectrum showed di fferent proton signa ls due to both the indole ring and the aliphati c port ion of the molecule. In the indole ring system, the IH NM R showed a broad peak

at 8 7.68 for indoli c - H. One major difference is that in thi s region it gave signals for other four pro­

tons of phenyl at 87.08,7. 14,7.3 1 and 7.46 for 7-H, 6- H, 8-H and 5- H, respecti ve ly, but 2- H proton of indole is mi ss ing. In the aliphat ic reg ion the 14-M e

appeared as doublet at 8 1. 17 (1= 6.84 Hz). The ali ­

phatic amino proton appeared as broad singlet at 8 I _54 and corresponding intensity as single proton. The two meth y lene protons of' 10, 10-H appeared as dou­

blet of doublet at 82.55 (1= 10.75, 15.13 Hz) and at 8 2.65 (J=6.35, 15.13 Hz). Each of the methy lene pro­tons of 16, 16-H also appeared as doublet or doublet

at 8 2.47 (1=5.86, 14.65 Hz) and at 8 2.69 (1=3.91, 14.65 Hz), these va lue appeared at low fie ld th an re­actant due to the presence of adjacent C=O group _

The II -H proton appeared as doublet or triplet at 8 3.1 9 (1=6.35, 10.75 Hz). The other prOlon signal also ritthe IH NMR spectrum 1'01' the ass igned structu re or 2a. The L1 C NMR spectrum or compound 2a clear ly indicated the pn.:sence of twen ty carbon signals in the molecu le. The two meth y l carbon signals or 14-Me

and 20-Me appeared at 8 14.2 and at 8 2 1. 7. Thc three methy lene carbon signals o f C- 16, C- 18 and C- IO

appeared at 8 26.7, 27. 1 and 29.7, respect i ve ly. The rour meth yne carbon signal s of C-17, C- 13, C- 14 ap­

peared at 8 29.9 , 40.4 , -+6.7 , respect ive ly and C-II

(CH- H) appeared at 8 50.0. The C-2 appeared at 8

108. 1 and >C=O signal appeared at 8 192.4. T he other carbon signals or indole rin g also fit in the spectrum that corresponds to the ass igned structure 1'01' 2a .Mass spectrulll showed a very sma ll peak at m/z 308 (M +) corresponding to the molecular formula C2l1H }~ N }O .

The important mass rragments arc al m/z 279 (M-Cl-IO) , 223 (M-CIIO-C1H,, -CH"\ ), 199 (M-CHO­Cc,Hx) and a bas<.: peak at m/z 17 1. The I R sp<.:c tru m of compound 2h showed a mediulll sharp band at 34 5 cm-I due lO indoli c -N H absorpti on and a broad weak band around 3285 C lll -

I indicatcd -NH } stretch­i ng or al i phati c am i ne. A strong band at 17 1 () Clll -

I

indicated C=O absorpti on, i.e., ketal is hydrolyzed to ketone. The II I NMR spectrum or compound 2b showed thc dirferent proton signals due to both the

indole ring and the terpenoid (a liphatic) porti on of the molecule. In the indole rin g system a broad peak ap­

peared as singlet at 8 8.05 for indolie - H. The 2- H

appeared as doublet w ith sma ll coupling at 8 7.06 (1 = 1.95 Hz). The 6 and 7-H appeared as three doublet at

87. 13 (1=7 .8 1,6.83,0.98 Hz) and at 8 7.2 1 (1= 7.8 1, 6.83, 0.98 Hz) respecti ve ly . The 8-H and 5-H ap­

peared as doublet at 87 .37 (1=7.8 1 Hz) and at 8 7.57 (1=7.8 1 Hz) respecti ve ly. In the aliphatic portion of

the molecule the 13-Me appeared as doublet at 8 1.12

(1 = 6.83 Hz). The 19-Me appeared as singlet at 8

1.74. The 12-H appeared as multiplet at 8 1.70- 1.74.

The -N H2 protons appeared as broad singlet at 8 1.85. The two methy lene proton s of 10, IO-H appeared as

doublet of doublet at 8 2.46 (1= 6.84, 14.65 Hz) and at

8 2.58 (1 = 4.39, 14.65 Hz). The 13-H appeared as

doublet of quartet at 8 2.54 (1=6.84, 1.46 Hz). This

va lue shifted to the downfield th an the reactant 10 (8 2. 18) due to the presence of adjacen t elec tron with­drawi ng C=O group, from thi s it is clear th at the ketal is hydrolyzed. Each of the methy lene protons of I S, 15- H also appeared at low ri eld as doublet of dou­

blet at 8 2.77 (1=9 .76, 14 .1 6 Hz) and at 8 2.93

(1=3.9 1, 14. 16 Hz) than the reactant 10 (8: 1.54-1.71 ) due to the presence to C=O group. The II -H appeared

as doublet tripl et at 8 3.32 (1 = 4.39, 6.84 Hz). The two ole finic protons of 20, 20-H appeared as singlet at

84.72 and 84.85, respecti ve ly. The oth er proton sig­nals also fit the spectrum that corresponds to the as­signed structure fo r compound 2b.

Ex perimental Section

Fischer John's electrothermal mclting point appara­tu s was used for recorcli ng the melti ng poi 11lS. I R spectra were recorded either as solution in CHCl 3 or CCI~ or as mull in nujol or in K Br disc using Shima­clzu FT IR-8 10 1 ; IH NNR spectra of 10 and 20 - ( IH, IH, cosy) in COCl ] using a Bruker WH 200, 400 and 500 spectrometer with TMS as internal standard ; l.lC

MR spectra on a Bruker WH 100 and 500 spectro­photometer with OEPT programme in COCl ] using TMS as internal standard, and mass spectra on a Var­ian MAT 7 11 (70 eV) and Varian MAT -+45 with GC eombi nat ion. Col umn chromatograpl y was perrormed on k iese l ge l 60 GF 254 (E Merck). A Va ri an 3700 type GC was used for analysis or the compounds. All reacti ons were carri ed out in dry nitrogen atmosphere. A ll organic so lutions after wo rk-up were dried over anhydrous sodiu1l1 sulphate. Pel. et her rders to I'rac-

2340 I DIAN J. CHEM .. SEC B, NOVEMBER 2002

tion of b.p. 40-60°C. For test of alkaloids5 Dragen­dorff and Mayer's reagents were used.

Preparation of 6-nitromethyl-l ,6-dihydl"O-carvonc 7. itromethane ( 14.64 g, 240 ITlmoles) of potass ium carbonate (20 g) were taken in a mixture of dry acetonitrile (90 mL) and meth anol (30 mL) so l­ven ts in a ratio o f 3: I . A suspension of carvone 6 ( 18 g, 120 mmoles) was added drop by drop to it w ith stirring at room temperature . The reacti on mixture was rerluxed at 120°C for 12 hr. The reaction mixture was then coo led and filtered off and the fi ltrate was evaporated ill VOC IIO, when a gummy concentrate was obta ined . Finall y the gummy concentrate was ex ­tracted with bcn zene to remove more K2CO, . A brown co loured liquid (22.46 g) was obtained on re­mova l of the so lvent. The crude product was chroma­tographed over a co lumn of kiesel ge l using pet. ether:ethy l acetate (9 : I ) as solven t system to obta in pure 7 as slightl y ye llow ish liquid ( 17.5 g, 70%). In pel. ether:ethy l acetate ( 17:3) so lvent system the Rr va lue of compound 7 was 0.55. The compound 7 was characteri zed from its spectral data.

Glycol protection of 6-nitromcthyl-l ,6-dihydrocarvone (8a, 8b). To a mixed so lution of 6-nitromethyl-I,6-dihydrocarvone 7 (5 g, 23.69 Il1moles) and freshly disti lled ethy lene glyco l ( 14.67 g, 236.9 mmoles) in 300 mL of dry benzene, p­toluenesulfonic acid ( 11 .25 g) was added with con­tinuous stirring under nitrogen atmosphere. The reac­ti on mi xture was rerluxed in a dean-stark apparat us for 8 hr. The comp leti on o f the reacti on was moni­tored by TLC. Water from the reaction mixture was scparated from the bottom of the benzene layer. A f"ter 8 hr no i"urther progress of the react ion was observed. The reaction mixture was then coo led and succes­si ve ly washed w ith 5% NaHC03 so lution and then \\l ith distill ed water to remove excess ethy lene glycol. The organic layer was separated, dried over anhy­drous Na2S0~ and evaporated ill VOCIIO to y ield crude prod uct (5.47 g). The crude product on TLC exam ina­tion gave two maj or spots one of them was reactant 7. The crude liquid \vas chromatographed over a co lumn of sili ca gel (60-120 mesh) using pet. ether:ethyl ace­tate (9: I ) and successive ly eluted with the so lvents of increasing polarity . From the co lumn ch romatogra­phy, two pure fract ions were collected. Fract ion ( 1-9) y ielded the product 8 (4 .0 g, 64%) and fract ion ( 13-IS) was the reactant 7 (0. 12 g) . The compound 8 was a pale ye llow liquid ; TLC examinati on of the com­pound 8 showed a single spot in PE:EA (4: I ) so lvent sys tem, and Rr value is 0.66. But in PE:EA (9: I ) sol-

vent system showed two adjacent spots with Rr va lues 0.54 and 0.46. Moreover GC of thi s compound also showed it to be a mixture of two isomers 8a and 8b in about I : I rati o. This mixture of compounds was sepa­rated by flash column chromatography (s ilica ge l 230-400 mesh) elu ting f irst w ith II-hexane, then w ith 3% EA-hexane. Fract ion (32-48) gave compound 8a (0.62 g, 10.2%) with Rr val ue 0.54 in the so lvent system PE:EA (9: I ). Fractions (49-57) gave a mixture of compounds 8a and 8b (2.70 g, 44.7CX: ) and fract ions (58-68) gave compound 8b (0.55 g, 9. 1 %) vvith Rr va lue 0.46 in the so l vent system PE: EA (9: I ). The compounds Sa and Sb were charac ter ized by spectral ana lys is.

Reaction of compounds 8a,b with grammine (3-(N,N-dimethy laminomethy l) indole). First I g (39.2 Illlllo les) of a-Ille tal was added to 100 IllL of dry ethanol taken in a 250 IllL three-nec ' ,~d flask and was refluxcd for hal f an hour under nitrogen atlllosphere. Then I g (3 .92 Illllloles) of compound 8a,b was added slow ly and the Ill ix ture was refluxed for another I hr with constant sti rrin g. Finall y grammine (0.682 g, 3.92 mlllolcs) was added to it. Reflu x ing was cont in­ued for 8 hr. The reaction mixtu re was then coo led and acidified wi th 10% acetic acid. T he resulring mi x­ture was then diluted w ith 40 mL of dry ether and washed w ith much water to remove cthanol. The wa­ter so lution was ex tracted with ether once again and then Illixed w ith the organic solu l i n. The organic port ion was then dried and evaporated ill vaCIIO , when a brown co loured gummy product ( 1.38 g) was ob­tained. The crude on TLC examina ti on gave five spots, one of them was reactant 8a,b . The crude prod­uct was chromatographed over a co lumn of silica ge l (60- 120 mesh) using pet. ether:ethy l acetate ( 19: I ) as solvent system and the polarity of the solvents were increased accQl'ding to th e TLC behav iour of the frac­ti ons. From the co lumn chromatography fi ve pure fract ions were co llec ted. First frac tioll gave the start ­ing mater ial 8a,b. The second fracti on gave the com­pound 9a ( 18 1 mg, 12%). The third frac tion gave the compound 9b ( 15 1 mg, 10%), the fourth fracti on gave the cOIllPound 9c ( 196 Illg, 13%). Compounds 8a,b and 9a-c were characteri zed by speclt'al anal ys is.

Reaction and cyclization of compound 9a with Zn-HglHCI. Zn powder (0.325 g, 5 Illllloles) was taken in a flask and washed with cone:. HCI acid. To this was added HgCI2 ( 1.355 g, 5 mmoles) and 5 mL of 2N HCI while stirring. Compound 9a ( 100 mg, 0.26 mmoles) in methanol was then added dropwisc and the mixture stirred at room temperature for 12 hr.

ABUL HASHEM el al.:SYNTI-IESIS OF TETRACYCLIC AR ISTOTELIA ALKALOIDS 234 1

After completion of the reaction the methanol was removed, water was added and neutrali zed with 5% K2C03. The solution was ex tracted with chloroform. The organic layer was dried and evaporated in V{f ClIO.

Finall y a redd ish brown co loured gummy product (86 mg) was obtained. The crude product on TLC ex­amination gave five spots, one of them corresponded to the reactant 9a. The crude product was then chro­matographed over a co lumn of silica-ge l (60- 120 mesh) using pet. ether:ethyl acetate (9: I ) as a so lvent and success ive ly eluted w ith the so lvents of increas­ing polar ity . From the co lumn chromatography, two new pure fractions were co llec ted. Fracti on ( 10- 13) yielded the compound I b (9.8 mg, 10%) and fracti on (46-53) was found to be the compound la ( 19.5 mg, 25 %). The compounds la and Ib were characteri zed by spectral anal ys is.

Reduction of the condensed product 9c with Li­AIH4, To a stirred suspension of LiAIH4 in 10 mL dry ether, a so lution of the condensed product 9c (56 mg, 0.15 mmoles) in 5 mL dry ether was added dropwi se at room temperature under nitrogen atmos­phere. Stirring was continued for further 16 hr. After completion o f the reacti on, a saturated so lution of

H4C1 was added dropwise to avo id coagulation. The solu ti on was decanted and ex tracted w ith dichloro­methane. The organic layer was separated, dried over anhydrous Na2S04 and the solvent was evaporated ill

vaCl/O to iso late crude product (55 mg). The crude product on TLC examination gave five spots. The crude product was chromatographed over a co lumn of silica ge l (230-400 mesh) eluting first with 80% eth y l acetate in M eOH and success ively eluted with the solvents of increas ing polarity. From the co lumn chromatograph y two pure fractions were collec ted. Fraction (4-5 ) gave compound 10 (7 mg, 26%) with Rr value 0.89 in the so lvent system EtOAc:MeOH (2: I ). The compound 10 was characterized by spectral anal ys is.

Hydrolysis of the reduced product 10, To a stirred so lution of reduced compound 10 ( 13 mg, 0.04 mmoles) in 10 mL acetone, 0.3 mL of 2N H2S04 was added. Stirring was continued for 12 hI' at room tem­perature. The reaction mixture was then neutrali zed

with 5% K2C03 and extracted with CHCl 3 (3x20 mL). The organic portion was separated, washed with water and dried over anhydrous a2S04. Finally, on re­moval of the so l vent ill va llCO, a crude product ( 16 mg) was obtained. The crude product on TLC ex­aminat ion gave three spots. The crude product \Vas flash chromatographed over a column of silica gel (230-400 mesh) eluting first with ethyl acetate, then with 90% EtOAc in M eOH. Fraction (3-5) gave com­pound 2a (5 .5 mg; 48%) wi th Rr va lue 0.85 in pet.ether:MeOH (2: I ), and fracti on 15-26) gave com­pound 2b (2.5 mg; 22%) with Rr va lue 0.44 in the same sol vent system. The compounds 2a and 2b were characteri zed by spectral anal ys is.

Acknowledgement The authors are thankful to Y Tschuda and F

Kiuchi , Department of Pharmaceutical Sciences, Kanazawa University , Japan and also to A Kirschning, Institute of Organic Chemistry, Technica l University Clausthal , Germany for recording the spectras and for their helpful suggestions during the inves ti gati on. The authors are al so grateful to the German Technica l Co-operation for their donat ion of Laboratory Instruments to Prof. Md Abul Hashem, Department of Chemistry , Jahangirnagar Universi ty, Savar, Dhaka, Bangladesh, which made it eas ier to carry out the research work. One of the authors (Z F) is al so grateful to the Ministry of Science & Technology , Bangladesh for the grant of fellowship.

Rcfcl'cnccs I Bick I R C & Hai M A, in The Alkaloids, Vol. 24. cditcd by A.

Bross i, (Acadcmic Prcss, Ncw York), 1985, p 11 3. 2 Borschberg 1-1 J, in The Chell/islry of I-Ielerocyciic COII/pol/I/ds

Vol. 25 , cdited by J E Saxton , (Wiley, Chichcstcr), 1994. piS . 3 (a) Usher G, A diCliol/ary oj' plal/ls I/sed by 111(111, (Constabk,

London), 1974,pS9. (b) Macdonald C. Medicill es of lhe Maori, (Co llin s, Auckland ), 1973, pSD. (c)BrookcrSG&CoopcrR C,Ecolli301, IS, I96I , I. (d) Brookcr S G, Cambic R C R & Coopcr R C, in Nell' Zea lalld Medicillal plal/ls, (Heinemann, Auck l,1I1d ), 198 I , pSD.

4 Borschbcrg H J, in Th e Alkaloids, Vol. 48, cditcd by (G A Cor­dell , (Acadcmic Prcss, cw York ), 1996, Chapter 3.

5 Hashem M A, Sultana I & Hai M A. IlIliiall J Chell/.38B , 1999. 789.