Bruneton, J.

Duval, O.

Fournet, Alain

Guinaudeau, H.

Oger, J.M.

Richomme, P.

Horizon / Pleins textes

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HETEROCYCLES, Vol 34. No. I ,  i392 
(R)-( +)-NORANICANINE 
A NEW TYPE OF TRIOXYGENATED 
BENZYLISOQUINOLINE 
ISOLATION AND SYNTHESIS 
p 
t f  
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Jean Michel Oger, Olivier Duval, Pascal Richomme, Jean Bruneton, and Hélène 
Guinaudeau* 
CEPM, U. F. R. des Sciences Mtdicales ct Pharmaceutiques, 16 Boulevard Daviers. 49045 Angers, France 
and Alain ournet i'; 
ORSTOM.213 me La Fayette, 75480 Paris Cedex 10, France 
Abstract - (R)-(+)-Noranicanine (la), a new typc of bcnzylisoquinoline precursor was isolated from Anibo canelilla 
(Lauraccae) and its structure was determincd by means of spoctroscopic data as well as by synlhesis. 
l-Benzylisoquinolines and their derivatives represent one of the preeminent group of alkaloids in plants.1 The 
benzylisoquinoline skeleton is known to be produced, in vivo, via cyclization of Schiff bases formed from 
condensation of dopamine with either 4-hydroxyphenylacetaldehyde or 3,4-dihydroxyphenyIacetaldehyde.2 
Natural known l-benzyltetrahydroisoquinolines with a monosubstituted benzyl group therefore always exhibit 
apara  functionality in ring C. We now have isolated from a Bolivian Lauraceae, Aniba canefilla ,3 (+)- 
noranicanine (l), a tioxygenated benzyltetrahydroisoquinoline with a different substitution pattern in ring C, 
the oxygenated substituent being in the mefa position. The structure of this new alkaloid has been firmly 
established by synthesis. 
The EI mass spectrum of 1 , C18H21N03, exhibited a typical benzyltetrahydroisoquinoline type fragmentation 
pattern4 with a very weak molecular ion at m/z 299 and a base peak at m/z 192 representing the isoquinoline 
moiety. The nmr spectrum of (+)-noranicanine (CDC13, 200 MHz, TMS=O) has been summarized around 
structure la.  Noteworthy were the absence of a N-methyl singlet and the presence of two methoxy singlets at 6 
3.79 and 3.85 ppm and two aromatic singlets at 6 6.57 and 6.50 ppm for the isoquinoline moiety. Unlike 
coclaurine or other compounds monosubstituted in ring C, H-I3 was there in evidence as a deshielded doublet 
of doublets at 6 7.09 ppm (J12,13=513,14=7.5 H z ) .  However, the unresolved multiplet centered at 6 6.67 ppm 
corresponding to the three remaining aromatic protons did not allow us to unambiguously establish the 
substitution pattern of the benzene ring, 
cote's ' 3  @ 
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HETEROCYCLES. Vol. 34. No. I ,  1992 
2.80 m 
Dam with * are inlerchangeable f2 7.5 7.w 7 5  
la 
Different assays of' solvent effects failed in  offering a betrer resolution than CDC1-j. however the hydroxyl 
substituent of ring C should be undoubtedly locared either in the mera ( la)  or in  the ortho position (lb).  We 
thus undertook the synthesis of both possible compounds via a classical route 5 5  in order to confirm the 
assigned smcrure 1 (Scheme 1). 
2a : R,=H, R,=OH 
3a : Rl=H, R2=OBz 
2b : R,=OH, R,=H 
3b : R,=OBz, R 2 = H  
reflux. 2 h J 
i:t R2 
4a : R,=H, R,=OBz 
4b : R,=OBz, R 2 = H  
Sa : A,=H, R,=OBz 
5b : R,=OBz, R2=H 
l a  : R,=H, R,=OH 
l b  : R,=OH, R p H  
c 
Scheme 1 
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HETEROCYCLES Vol 34. No I 1992 
.+ 
Condensation of 3,4-dimethoxyphenethylmine with m-hydroxyphenylacetic acid or o-hydroxyphenylacetic 
acid respectively led to amides (2a) (89%,mp 149-150 OC) and 2b (97%, mp 108-109°C) which were 
benzylated to give 3a (72%, mp 89-90 OC) and 3b (85%, trip 112-1 13°C). A Bischler-Napieralski cyclization 
with 33 and 3b then provided 3,4-dihydroisoquinolines (4a) (71%, mp 79-80 "C) and (4b) (73%, mp 184- 
185OC) which were further reduced with sodium borohydride into 5a (86%, mp 160-161°C) and 5b (82%, mp 
165-166"C), respectively..Debenzylation of Sa and 5b gave the corresponding phenol (la) (61%, mp 155-156 
"C) and (lb) (76%, mp 147-148 OC) as their hydrochlorides.7Compound (la),  in its base form, finally was 
spectroscopically identical with natural (+)-noranicanine.8 
The 1-R configuration of the natural (+)-noranicanine is suggested by the positive optical rotation 9 and 
confi ied by the cd curve which presents a negative Cotton effect at 284 nm and a negative tail at 240 nm .lo 
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To our knowledge, this is the first report of a natural benzyltetrahydroisoquinoline monosubstituted in ring C 
with the hydroxyl group being in the meta position. Due to the number of alkaloids derived from this basic 
skeleton, (+)-noranicanine may be therefore regarded as a new type of benzylisoquinoline precursor. 
REFERENCES AND NOTES 
1 D. W. Hughes, and D. B. MacLean, "The alkaloids : The 13C-nmr spectra of isoquinoline alkaloids", Vol. 
18, ed. by R. G. A. Rodrigo , Academic Press, Inc., New York, 1981, pp. 217-262. 
R. Stadler and M. H. Zenk, Liebig Ann. Chem,, 1990,555. 
Plant collection, extraction and alkaloid isolation- The stem barks of Aniba canelilla (1.1 Kg) were 
2 
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t collected in 1988 at Fatima de Chimanes, Bolivia. A voucher specimen (ref AF855) was deposited at the 
herbarium of ORSTOM-IBBA center of La Paz. The crude alkaloids (1.04%) were obtained from the 
powdered defatted stem barks following a classical procedure. Specific extraction was followed by 
MPLC (CHCI3 gradually enriched with MeOH) and preparative TLC (CHC13-MeOH 13%) on silica gel. 
This way, 16 mg of amorphous (+)-noranicanine were isolated. 
M. Tomita, H.Furukawa, T. Kikuchi, A. Kato, and T. Ibuka, Chem. Pharm. Bull., 1966,u ,  232. 
S. Kubota, T. Matsui, E. Fujita, and S. M. Kupchan, J. &E. Chem., 1966,2,516. 
S. Teitel and A. Brossi, J. Heterocycl. Chem.,1968,5,825. 
Eims data (70 eV) for compounds 2a-Sa and 2b-+5b : 2a m/z : 315 (M+, CigH21N04,8.7%), 165 
(10.4%), 164 (loo%), 152 (4.8%), 151 (20%), 149 (8.8%), 108 (3.1%), 107 (14.8%), 91 (3.1%), 78 (4.8 
%), 77 (&.4%), 44 (3.4%) ; 3a m/z : 405 (M+, C25H27N04, 7.6%), 165 (12.3%), 164 (loo%), 151 
(ES%),  149 (4.5%), 134 (3.9%), 107 (3%), 92 (3.8%), 91 (42.3%), 65 (5%) ; 4a m/z : 387 (Mf, 
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20 HETEROCYCLES. Vol. 34. No. i .  1992 
CzsHzsN03, 5.7%), 386 (6.9%), 297 (22.3%), 296 (100%), 280 (4.6%), 268 (11.5%), 252 (3.5%), 192 
(2.1%), 152 (1.7%), 92 (5.7%), 91 (53.1%), 77 (3.9%), 65 (7.4%), 38 (7%), 36 (18.9%), 35 (3.2%) ; 5a 
m/z : 389 (M+, CyjH27N03,0.06%), 280 (1.3%). 193 (12.7%), 192 (loo%), 176 (5.8%), 148 (3.5%), 147 
(1.6%), 91 (9.5%) ; 2b m/z : 315 (M', ClsH2lN04,9.6%), 165 (12.6%), 164 (100%), 152 (4.4%), 151 
(15.6%), 107 (12.8%), 106 (3.2%). 91 (3.1%), 79 (3.9%). 78 (4.8%), 77 (8.6%) ; 3b m/z : 405 (M+, 
C25H27N04. 0.8%), 165 (13.5%), 164 (la)%), 151 (13.5%), 149 (5.4%), 107 (12.8%), 106 (4.4%), 92 
(5.5%), 91 (62.0%), 79 (3.4%). 78 @.O%), 77 (6.9%), 65 (13.0%) ; 4b m/z : 387 (M+, CzsH25N03, 
0.4%), 377 (3.4%), 296 (6.7%), 281 (13.7%), 280 (71.9%), 264 (5.1%), 128 (5.6%), 126 (15.0%), 92 
(8.1%), 91 (loo%), 89 (7.5%), 65 (12.5%), 63 (7.1%), 52 (3.1%), 51 (4.7%), 50 (6.2%), 38 (3.2%). 36 
(4.5%) ; 5b m/z : 389 (M+, C=H27NO3,0.03%), 280 (3.0%), 193 (13.0%), 192 (loo%), 176 (7.0%), 148 
(3.0%). 91 (11.3%). 
Spectral data for compounds l a  and l b  : h : CisH21N03, uv h max (MeOH) nm (log E) : 207 (4.53, 
229 sh (4.03), 282 (3.71), h max (MeOH-KOH) nm (log E) : 212 (4.66), 235 sh (3.96), 288 (3.61) ; ir v 
max (KBr) : 3450, 3260, 1610, 1585 cm-l ; eims (70 eV) m/z : 299 (Mf, 0.2%), 193 (12.5%), 192 
(loo%), 177 (3.7%), 148 (4.0%), cims (NH3) m/z : 300 ([MH]+, loo%), 193 (3.1%), 192 (24.2%) ; 1H- 
nmr  (200 MHz, CDC13,6 ppm) : see la, l3C-nmr (68 MHz, CDC13,6 ppm) : 56.3 (C-1), 40.3 (C-3), 28.5 
(C-4), 126.5 ((2-44, 11 1.7 (C-5), 147.1 and 147.7 (C-6 and C-7), 109.3 (C-S), 128.9 (C-8a), 41.9 ( C a ) ,  
139.4 (C-9), 116.2 (C-lo), 157.6 (C-ll), 114.7 (C-12), 130.0 (C-l3), 120.4 (C-14). 55.8 and 55.9 (2 
OCH3) ; spectral data for natural (+)-noranicanine, [aj~+36"(c=I, CHC13 ), cd (MeOH) LSE (nm) O (299), 
-0.15 (284), -0.04 (255), negative tail at 240 nm. fi : C18H21N03, uv h max (MeOH) nm (log E) : 206 
(4.63), 230 sh (4.06), 281 (3.79), h max (MeOH-KOH) nm (log E )  : 210 (4.76), 233 sh (4.11), 286 (3.80) 
; ir v max (KBr) : 3440,3290, 1610, 1585 cm-1 ; eims (70 eV) m/z : 299 (M+, 0.2%), 193 (15.7%), 192 
(loo%), 178 (8.7%), 177 (4.0%), 176 (10.9%), 148 (5.7%), 131 (4.6%), 77 (7.8%), cims (NH3) m/z : 300 
([MH]+, 100%), 286 (6.7%), 193 (3.2%), 192 (23.9%), 178 (1.7%) ; 'H-nmr (200 MHz, CDCl3,6 ppm) : 
2.83 and 3.35 (Zm, 6H, 3 CH2), 3.83 and 3.85 (2s, 6H, 2 OCH3), 4.36 (dd, lH, J=8.0, 1.0 Hz, H-l), 6.54 
8 
(s, lH, H-8), 6.60 (s, lH, H-3, 6.73 (dd, lH, 5~7.0,  7.0 Hz, H-13), 6.87 (d, Jz7.0 Hz, H-ll), 7.03 (d, 
J=7.0 Hz, H-14), 7.10 (dd, J=7.0,7.0 Hz, H-12) ; 13C-nm (68 MHz, CDC13, 6 ppm) : 55.9 (C-I), 38.5 
(C-3), 27.1 (C-4), 125.6 and 127.1 and 125.0 (C-4a and C-8a and C-9), 11 1.0 (C-5), 147.6 and 147.9 (C-6 
and C-7), 109.9 (C-8), 40.3 (C-CL), 156.7 (C-lo), 117.4 (C-ll), 128.4 (C-12), 119.1 (C-13), 131.6 (C-14), 
55.8 and 55.9 (2OCH3). 
J. E. Leet, S. F. Hussin, R. D. Minard, and M. Shamma, Heterocvcles, 1982, E, 2355. 
J. C. Craig, M. Martin-Smith, S. K. Roy, and J. B. Stenlake, Tetrahedron, 1966,=, 1335. 
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Received, 14th October, 1991 


(R)-(+)-noranicanine a new type of trioxygenated benzylisoquinoline isolation and synthesis

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