Tetrat~edron Letters, Vo132, No 40, lap 5555-5558, 1991 0040-4039/91 $3.0£Printed m Great Britain Pergamon Press plc

F A V E L A N O N E , A N O V E L T E T R A C Y C L I C C Y C L O P R O P A N E D E R I V A T I V E

F R O M THE B R A Z I L I A N P L A N T , Cnidosco lus phyllacanthus

Yulchi Endo, Tomihisa Ohta, and Shigeo Nozoe*

Faculty of Pharmaceutical Sciences, Tohoku Umverslty,

Aoba-ku, Sendal 980, Japan

Abstract : A novel tetracyclic cyclopropane denvatlve, favelanone (1), having cytotoxic actwities, wasisolated from the bark of Cmdoscolus phyllacanthus and the structure was elucidated on the basis of itsspectroscopic data.

During the invest~gatlon on antltumor compounds from natural sources, we have reported the isolation

of three cytotoxlc tncyclic benzocycloheptene derivatives, favehne, favelme methyl ether, and deoxofaveline,

from the Brazilian plant, Favela, Cnidoscolus phyllacanthus (MART.) PAX et K. HoFFM.(Euphorblaceae) 1.

Our continuous study on the cytotoxic pnnclples in tlus plant led to the isolation of a novel tetracyclic

cyclopropane derivative, favelanone (1). We wish to report here the isolation and the structure elucidation

of this compound.

The combined n-hexane and EtOAc soluble fractions from the MeOH extract of the dried bark of

Favela (30 g) was subjected to silica gel chromatography with n-hexane-EtOAc mixtures of increacmg

polarity (100:0 to 0:100). The fraction eluted with n-hexane-EtOAc (20: l) was chromatographed again on

silica gel with n-hexane-EtOAc (10:1). The fraction thus obtained was successively purified by HPLC on

Inertsil PREP-ODS (Gasukuro Kogyo) with 85% aq. MeOH to isolate favelanone (1, 112 rag) as colorless

needles, mp 152-153 °C, [Ct]o +57.9° (c = 0.92, CHCI3), after recrystallization from n-hexane. Its ICs0

value was 24.9 I.tg/ml against P-388 murine leukemia cells in vitro.

The molecular formula C19H2203 for favelanone (1), indicating nine degrees of unsaturatlon, was

determined by HREIMS (m/z 298.1572, M+, A 0.4 mmu)2. The presence of a benzene nng with two

conjugated ketones was suggested by UV maxima (MeOH) at 246 (log e 4.49), 293 (3.78), and 316 (3.71)

O

18 1

O

16

CH3 17

CH3 : "

13

1 favelanone

5555

5556

nm; IR absorption (CHCI3) at 1675, 1660 (sh) , 1600 and 1500 cm-1 , 13C NMR signals (CDCI~) at 8 194 8

(s), 194.1 (s), 162 5 (s), 133.8 (s), 132.5 (s), 128.9 (d), 125.4 (s), and 107 1 (d) ; IH NMR signals

(CDCI3) for two aromatic protons at 8 7 74 (d, J = 1 0 Hz) and 7,40 (s). The 1H and 13C NMR spectra of

favelanone (1) also revealed the presence of a methoxyl (SH 3 95 / 8c 55 9), three tertmry methyls (SH / ~ :

I ~06 / 29.2 ~ t.08 / 30 2 ; 2.28 / ! 6.5), three m~thylene~ (SJ~ / 86" t 27 / 34 6 ; t 47 / t7 8 ; t 5273.02 /

22 1), two methmes (Su / 8c • 1 80 / 48 0 , 2 . 4 0 / 40 0), and two quaternary carbons (8c 29.8 and 39 3).

The substitution pattern of the benzene ring was s~mdar m the 1H and 1~C NMR chemical shift data to those

of favehne methyl etherI. The 1H-1H COSY spectrum m&cated the two pamal structures, CH-CH and

CH2-CHe-CH2-C(CH3)2 , which v~ere pointed to be joined each other by HMBC~ analysis Namely, the

following connectwmes were found two methyls (Su 1.06 and 1.08) to a methme (8¢ 48 0, C-9) , a

methme (Su 1 80, H-9) to a quaternary carbon (8c' 29.8, C- 15) and a methylene (8c 34,6, C- 14), another

methme (SH 2 40, H-8) to a quaternary carbon (C-15) The above 2D NMR data as well as the large one-

bond carbon proton couphng constants, JCsH = 170.6 Hz and JC9H = 156.0 Hz, permitted the presence of a

partml structure including a cyclopropane nng, blcyclo[4.1.0]heptane system (2) The small couphng

constant, J8,9 = 5 .4 Hz, suggested lhe t r a n s stereochem~stry for the cyclopropane nng protons4. The

connective pattern of the b~cyclo system to the conjugated system was determnIed w~th the observed cross

peaks in HMBC and C O L O C spectra, Le, between C-6 and H-8, C-7 and H-9, H-9 and C-11, H-4 and C-

11, and C-11 and H-12 (Table 1) The gross structure of favelanone is lhus represented by 1

89 OH3

r r ~ ~ CH3

0 "~IH-tH COSY

2

~ " ~ H O

H30o ,7 3 ~ : NOE

The relatwe stereochemlstry of favelanone (1) was confirmed by &fferentlal NOE experiment as

shown m 3. Namely, irradiation of the H-8 signals resulted in 5.1% of NOE for H-12, while irradlatmn of

the H-9 signal caused 5.3% of NOE for H-J6

Favelanone (1) Is a new class of fused tetracyclic system containing a cyclopropane nng, and an origin

and a b~osynthetic pathway of th~s compound are of interest to be resolved Besides fundamental terpeno~ds

having a cyclopropane rang such as cycloartanol, fused tncyclic cyclopropane terpenolds, cubebene,

cubebol, and their derivatives have been isolated from terrestrial plants5, blown alga6, and soft coral7.

5557

Table 1. 13C and 1H NMR Spectral Data for 1 in CDCI3a

Carbon No. 13Cb lH HMBC COLOC

1 128.9 d 7.74 d (1.0) H-18 H-18

2 133.8 s H-4, H-18 H-4, H-18

3 162.5 s H-l, H-18, OMe H-i, H-18, OMe

4 107.1 d 7.40 s

5 132.5 s H-1 H-1

6 125.4 s H-4 H-4, H-8

7 194.8 s H-1 H-I, H-9

8 40.0 d (170.6)c 2.40 d (5.4) H-12 H-12

9 48.0 d (156.0) 1.80 d (5.4) H-16, H-17 H-16, H-17

10 39.3 s H-12, H-13

11 194.1 s H-4, H-9 H-4, H-9, H-12

12 22.1 t 3.02 m

1.52 m

13 17.8 t 1.47 m

14 34.6 t 1.27 m H-9, H-12, H-16, H-17

15 29.8 s H-8, H-9, H-16, H-17 H-16, H-17

16(15-Me) 29.2 q 1.06 s H-17

17 (15-Me) 30.2 q 1.08 s H-16

18 (2-Me) 16.5 q 2.28 s H-I

OMe 55.9 q 3.95 s

a 13C and 1H NMR spectra were recorded at 125 MHz and 500 MHz, respectively.

Coupling constants, 1Jc.n and JH-H (in Hz) are gaven in parentheses.

b Multiphcitles were determined by DEPT experimems.

c Coupling constants were determined by INEPT experiments.

Acnowledgement : We wish to thank Dr. Toshihiko Naito (Botanical Garden, Faculty of Science, Tohoku

Umversity) for collection of the bark of ttns plant, and Fuji Chemical Industry Co., Ltd. for carrying out the

biological assay. We also thank the Ministry of Education, Science and Culture for a Grant-in-Aid for

Scientific Research (B)-01470135.

5558

References and Notes

1 Y. Endo, T. Ohta, and S. Nozoe, Tetrahedron Lett , 32, 3083 (1991)

2. E I M S o f l . m / z ( % ) 2 9 8 ( M +. 17), 217 (20),178 (100),161(35),133 (18), 89 (9), and 77 (l l)

3 A. Bax, and M. F Summers, J Am Chem Soc, 108, 2093 (1986).

4. Jc~s of the cyclopropane ring protons are generally larger than Jtrans (a) M. Qllka Y Yoshlda, Y.

Nakayama, and K. Yamada, Tetrahedron Lett , 31, 4907 (1990) ; (b) M D. Hlggs and L J. Mulhelrn,

Tetrahedron, 37, 4259 (1981 ).

5 (a) F. Vanasek, V. Herout, and F. Sonn, Coll Cze~ h Chem Commun, 25, 919 (1960) : (b) Y.

Ohta, T. Sakal, and Y Hlrose, Tetrahedron Lett , 51, 6365 (1966), (c) F. Bohlmann, J. Jakupovlc,

M. Ahmed, M. Wallmeyer, H. Robinson, and R. M. King, Phytochemtstry, 20, 2383 (1981) ; (d) F

Bohlmann, M Wallmeyer, J Jakupovlc, and J Zlesche, Phytochemlstr~, 22, 1645 (1983) ; (e) C.

Pizza and N. De Tommasl, J Nat Prod, 50, 784 (1987)

6. (a) M. Suzuki, N. Kowata, and E, Kurosawa, Bull Chem Soc Jpn, 54, 2366 (1981) ; (b) B N.

Ravl~ and lL J. Wells~ Au~.t I Chem ~35,129 (1982) ; (c) K K~ata~ K Shtralsht~ T~ Takano, K~

Tanlguchl, and M. Suzuki, Chem Lett , 1629 (1988) ; (d) K Kurata, K Tamguch~, K. ShlralshJ, and

M Suzuki, Phytochemtstry, 29, 3453 (1990).

7 (a) B F. Bowden, J.C. Coll, andD M. Taplolas, Aust J Chem, 36,211 (1983), (b) D.E.

Wdhams, R. J. Andersen, J F Kingston, and A. G. Falhs, Can .I Chem, 66, 2928 (1988)

(Received In Japan 20 June 1991)