A revision of the structure of sauvagnine

Article abstract of DOI:10.1021/np960209j

The alkaloid sauvagnine is not the α-hydroxytetradehydrocularine 1, but the phenolic benzoyl isoquinoline 4.

Full text of DOI:10.1021/np960209j

806
J . Nat. Prod. 1996, 59, 806-807
A Revision of th e Str u ctu r e of Sa u va gn in e
Alberto Garc´ıa, Luis Castedo,* and Domingo Dom´ınguez*
Departamento de Qu´ımica Orga´nica, Facultad de Quı´mica y Seccio´n de Alcaloides del C.S.I.C.,
15706 Santiago de Compostela, Spain
Received J anuary 29, 1996X
The alkaloid sauvagnine is not the R-hydroxytetradehydrocularine 1, but the phenolic benzoyl
isoquinoline 4.
The alkaloid sauvagnine, isolated from Corydalis
claviculata,1 was originally assigned the R-hydroxytet-
radehydrocularine structure 1 on the basis of its spec-
troscopic similarities to the alkaloid linaresine, for
which the structure 2 had been proposed.2 The ac-
companying alkaloid dihydrosauvagnine was assigned
the partially reduced structure 3.
F igu r e 1. Synthesis of compound 4.
The recent findings3 that linaresine does not have
structure 2, and that R-hydroxycularines are easily
oxidized by air, strongly suggested the necessity of
reexamining the structure of sauvagnine.
In conclusion, we have shown that the alkaloid
sauvagnine has the benzoyl isoquinoline structure 4.
1
Exp er im en ta l Section
Close inspection of the H-NMR spectrum of sauvag-
Gen er a l Exp er im en ta l P r oced u r es. 1H-, and 13C-
NMR spectra were recorded in CDCl3, at 250.13 and
62.83 MHz, respectively, on a Bruker WM-250 spec-
trometer; chemical shifts are reported in parts per
million (ppm) downfield from internal Me4Si. Mass
spectra were recorded at an ionization voltage of 70 eV.
Melting points are uncorrected.
1-[2-(Ben zyloxy)-3,4-(m eth ylen ed ioxy)p h en yl]-1-
[6,7-(m et h ylen ed ioxy)isoq u in olin yl]ca r b in ol (8).
80% NaH (0.03 g, 1.01 mmol) was suspended in 5 mL
of anhydrous DMF under Ar. To the cooled suspension
(-15 °C) was slowly added a solution of 5 (0.24 g, 0.78
mmol) in 4 mL of anhydrous DMF. After 10 min, 6 (0.20
g, 0.75 mmol, dissolved in 4 mL anhydrous DMF) was
added, and the reaction mixture was allowed to warm
to room temperature over 12 h. After addition of 5 mL
of MeOH, the mixture was evaporated to dryness,
leaving a residue that was dissolved in C6H6 (20 mL)
and washed with H2O (20 mL).
nine suggested the possibility that the signal at 7.16
ppm might belong to an aromatic proton rather than to
a benzylic one. On the other hand, the spectroscopic
data for sauvagnine are, to our understanding, clearly
in accordance with the presence of an isoquinoline
unit: its 1H-NMR spectrum shows two pyridinic dou-
blets at 7.64 and 8.44 ppm with a coupling constant of
5.5 Hz and two aromatic singlets at 7.35 and 7.16 ppm;
its UV spectrum undergoes a bathochromic shift in
acidic media; and in the EIMS spectrum the molecular
ion appears at 337 amu. In view of these data, we
tentatively hypothesized the benzoyl isoquinoline struc-
ture (4), which is also supported by the similarity the
1H-NMR data to those of other benzoyl isoquinolines.
To prove our hypothesis we undertook the total
synthesis of compound 4 by the pathway shown in
Figure 1.
The anion derived from the Reissert compound 54 was
alkylated with aldehyde 6.5 The crude condensation
product (7) was hydrolyzed under basic conditions
(NaOH, EtOH, ref), affording compound 8 in 68% overall
yield. Oxidation of 8 (Na2Cr2O7, AcOH, 100 °C) followed
by debenzylation of the phenol group (Me3SiI, CHCl3,
ref), afforded the desired compound 4.
The yellowish solid obtained after evaporation of the
C6H6 was suspended in a solution of 10 mL of EtOH,
5.5 mL of H2O, and 0.1 g of KOH, and the mixture was
refluxed for 3 h. Upon cooling, a precipitate appeared,
which was filtered out and washed with a small volume
of EtOH. The resulting solid (0.23 g, 68%) was identi-
fied as 8 and was recrystallized from EtOH: mp 189-
191 °C; IR (KBr) ν max 3358 (OH), 2894, 1623, 1586,
1
The H-NMR, EIMS, and UV spectra of compound 4
were identical to those reported for sauvagnine. The
IR spectrum (not provided by sauvagnine) showed the
1
1495, 1459 cm-1; H NMR δ 8.31 (1H, d, J ) 5.6, Ar -
carbonyl band at 1652 cm-1
.
H), 7.55 (2H, d, J ) 6.7, 2 × Ar - H), 7.43-7.33 (4H,
m, 4 × Ar - H), 7.13 (1H, s, Ar - H), 7.03 (1H, s, Ar -
H), 6.53 (1H, s, Ar - CH), 6.38 (1H, d, J ) 8.2, Ar - H),
6.33 (1H, d, J ) 8.2, Ar - H), 6.18 (1H, br s, OH), 6.04,
* To whom correspondence should be addressed. Phone: 34-9-81/
59-10-85. FAX: 34-9-81/59 50 12.
X Abstract published in Advance ACS Abstracts, August 1, 1996.
S0163-3864(96)00209-1 CCC: $12.00
© 1996 American Chemical Society and American Society of Pharmacognosy

Notes
J ournal of Natural Products, 1996, Vol. 59, No. 8 807
5.99 (2H, 2 × s, ArO-CH2-OAr), 5.94 (2H, s, ArO-
1-[2-Hyd r oxy-3,4-(m eth ylen ed ioxy)ben zoyl]-6,7-
(m eth ylen ed ioxy)isoqu in olin e (4). Me3SiI (0.2 mL)
was added to a solution of compound 9 (0.035 g, 0.08
mmol) in 5 mL of anhydrous CHCl3, and the mixture
was refluxed for 90 min. Because TLC showed the
continued presence of starting material, more Me3SiI
(0.2 mL) was added and reflux was continued for a
further 3 h. After cooling, the reaction mixture was
washed with H2O (10 mL), and a saturated solution of
NaHCO3 (10 mL), and was dried (Na2SO4). The residue
left by evaporation of the solvents was purified by
preparative TLC on SiO2 (3:7, EtOAc-hexane), afford-
ing 6 mg (21%) of 4 as a yellowish solid, mp 215-217
°C; IR (KBr) ν max 2920, 2853, 1652 (CO), 1610, 1578,
CH2-OAr), 5.47, 5.34 (2H, 2 × d, J ) 11.3, ArCH2); 13
C
NMR δ 158.0, 151.0, 149.2, 148.7, 140.6, 139.5 (CH),
137.6, 137.4, 135.3, 129.9, 128.9 (2 × CH), 128.6 (3 ×
CH), 122.7, 122.1 (CH), 120.7 (CH), 104.1 (CH), 103.4
(CH), 102.0 (CH2), 101.5 (CH2), 101.4 (CH), 74.7 (CH2),
66.3 (CH); EIMS m/z 429 [M]+ (1), 322 (100), 172 (21),
91 (36). Anal. Calcd for C25H19NO6: C, 69.92; H, 4.46;
N, 3.26. Found: C, 69.88; H, 4.42; N, 3.37.
1-[2-(Ben zyloxy)-3,4-(m eth ylen ed ioxy)ben zoyl]-
6,7-(m eth ylen ed ioxy)isoqu in olin e (9). A solution of
compound 8 (0.15 g, 0.35 mmol) in 1.5 mL of glacial
HOAc was treated with Na2Cr2O7 (0.11 g, 0.36 mmol)
in 1.5 mL of glacial HOAc. After being heated at 100
°C for 3 min, the mixture was poured on H2O, basified
with a saturated solution of NH4Cl, and extracted with
Et2O (3 × 20 mL) and CH2Cl2 (2 × 10 mL). The
combined organic extracts were washed with H2O (10
mL) and dried (Na2SO4). The residue left by evapora-
tion of the solvents was purified on an SiO2 column (97:
3, CH2Cl2-MeOH), affording 0.13 g (87%) of 9: mp
137-139 °C (EtOH); IR (KBr) ν max 3060-2914, 1670
1
1497, 1460 cm-1; H NMR δ 12.1 (1H, br s, OH), 8.43
(1H, d, J ) 5.5, Ar - H), 7.62 (1H, d, J ) 5.5, Ar - H),
7.33 (1H, s, Ar - H), 7.15 (1H, s, Ar - H), 7.08 (1H, d,
J ) 8.5, Ar - H), 6.39 (1H, d, J ) 8.5, Ar - H), 6.12
(2H, s, CH2), 6.11 (2H, s, CH2); EIMS m/z 337 [M]+ (73),
320 (39), 308 (39), 279 (100), 172 (46); UV (MeOH) λ
max 332, 306, 238, 212, nm; λ max (MeOH + H+) 345,
316, 242 nm; HREIMS calcd for C18H11NO6 337.0586,
found 337.0577.
1
(CO), 1618, 1464, 1267 cm-1; H NMR δ 8.23 (1H, d, J
) 5.5, Ar - H), 7.59 (1H, s, Ar - H), 7.47 (1H, d, J )
8.2, Ar - H), 7.36 (1H, d, J ) 5.5, Ar - H), 7.10 (1H, t,
J ) 7.4, Ar - H), 6.99 (3H, m, 3 × Ar - H), 6.70 (1H, d,
J ) 8.2, Ar - H), 6.63 (2H, d, J ) 7.4, 2 × Ar - H), 6.08
OAr), 4.90 (2H, s, ArCH2); 13C NMR δ 195.4 (CO), 156.3,
153.7, 151.0, 149.5, 142.7, 140.6, (CH), 137.2, 136.4,
135.8, 128.2 (2 × CH), 127.8 (CH), 127.4 (2 × CH), 126.8,
126.6 (CH), 123.5, 122.3 (CH), 104.0 (CH), 103.0 (CH),
102.8 (CH), 102.1 (CH2), 102.0 (CH2), 73.7 (CH2); EIMS
m/z 398 (5), 321 (21), 320 (100), 172 (14), 91 (48); UV
(MeOH) λ max 296, 234, 208 nm. Anal. Calcd for
C25H17NO6: C, 70.25; H, 4.01; N, 3.27. Found: C, 70.62;
H, 4.08; N, 3.37.
Ack n ow led gm en t. We thank the DGICYT for fi-
nancial support under project SAF 93-0607. A. Garc´ıa
thanks the CICYT for a fellowship.
(2H, s, ArO - CH2 - OAr), 6.02 (2H, s, ArO - CH2
-
Refer en ces a n d Notes
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(2) Firdous, S.; Freyer, A. J .; Shamma, M.; Urzu´a, A. J . Am. Chem.
Soc. 1984, 106, 6099.
(3) Garc´ıa, A.; Castedo, L.; Dom´ınguez, D. Tetrahedron Lett. 1993,
34, 1797.
(4) Chantimakorn, V.; Nimgirawath, S. Aust. J . Chem. 1989, 42,
209.
(5) Garc´ıa, A.; Castedo, L.; Dom´ınguez, D. Tetrahedron 1995, 51,
8585.
NP960209J