Total syntheses of crinine and related alkaloids

Article abstract of DOI:10.1016/j.tet.2006.07.005

Cyclizations of a bicyclic amine via an intramolecular Heck reaction followed by an oxidation reaction generated a tetracyclic spirocyclohexadione. From this useful intermediate, different crinine alkaloids such as crinine, buphanisine, flexinine, and aug

Full text of DOI:10.1016/j.tet.2006.07.005

Tetrahedron 62 (2006) 9043–9048
Total syntheses of crinine and related alkaloids
*
Claire Bru and Catherine Guillou
Institut de Chimie des Substances Naturelles, Bt 27, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 31 May 2006; revised 26 June 2006; accepted 1 July 2006
Available online 25 July 2006
Abstract—Cyclizations of a bicyclic amine via an intramolecular Heck reaction followed by an oxidation reaction generated a tetracyclic
spirocyclohexadione. From this useful intermediate, different crinine alkaloids such as crinine, buphanisine, flexinine, and augustine could
be synthesized. Dienol/benzene or dienone/phenol rearrangement of this tetracyclic spirodienone afforded apogalanthamine analogs.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
as the main step for the construction of the skeleton by
simultaneous creation of the B and D rings. The approach in-
volving the sequence A/C/B/D requires the construc-
tion of an angular substituted phenanthridine, and the
elaboration of the pyrrolidine D ring is achieved by the
formation of a carbon/nitrogen bond via alkylation.
The
2,3,4,4a-tetrahydro-1H,6H-5,10b-ethanophenanthri-
dine (cis-3a-aryloctahydroindole nucleus) skeleton charac-
terizes the crinine alkaloids such as crinine 1, buphanisine
2, flexinine 3, and augustine 4, which represent an important
sub-class within the large family of Amaryllidaceae alka-
loids (Fig. 1).1 Many members of this sub-class display inter-
esting biological properties including immuno-stimulatory,2
cytotoxic,3 antimalarial,4 and anticholinergic activities.5
The key intermediates in the A/C/D/B and A/D/
C/B approaches are 3a-arylhydroxyindoles and the
formation of the B ring is generally achieved by using a
Pictet–Spengler reaction.
O
OR
OR
The biomimetic approach is based on an intramolecular oxi-
dative phenolic coupling of norbelladine analogs using vana-
dium oxyfluoride,7 vanadium oxytrichloride,8 thallium(III)
trifluoroacetate,9 anodic oxidation,10 hypervalent iodine
reagent (PIFA)11 or on photolysis of bromophenolic
compounds.12
D
O
O
O
O
H
C
N
H
A
B
N
3 flexinine (R=H)
4 augustine (R=Me)
1 crinine (R=H)
2 buphanisine (R=Me)
Figure 1. Structures of Amaryllidaceae alkaloids.
An alternate synthetic route could in principle be based on
intramolecular Heck cyclization.6b,13 Our approach derives
from a general program underway in the laboratory by which
application of the Heck reaction followed by an oxidative
step to produce spiro tricyclic dienones.14,15 The intramolec-
ular Heck reaction leading to 7-exo-trigonal cyclization has
not often been described and ipso facto has rarely been used
for the creation of a spiro quaternary center.
Several approaches have been developed to synthesize this
skeleton, which includes a quaternary carbon. The incorpo-
ration of this sterically congested quaternary center is the
critical element in the total synthesis of crinine-type alka-
loids and numbers of synthetic efforts have emerged to solve
this challenging problem.
The most common and generally useful syntheses developed
thus far may be classified into four principal types based on
the sequence of ring construction: AB/BD (biogenetic),
A/C/B/D, A/C/D/B, A/D/C/B.1,6 In the
biosynthetic approach, amino spirodienones are the key
intermediates, and an internal Michael cyclization serves
2. Results and discussions
Our synthesis started from the known aldehyde 516 and
amine 6.17 Reductive amination of these two components
followed by functional transformation of the enol ether
gave the amine 8. Subsequent protection of the amine func-
tion with di-tert-butyl dicarbonate furnished compound 9
(75%), the precursor for the intramolecular Heck reaction
* Corresponding author. Tel.: +33 1 69 82 30 75; fax: +33 1 69 07 72 47;
e-mail: catherine.guillou@icsn.cnrs-gif.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.005

9044
C. Bru, C. Guillou / Tetrahedron 62 (2006) 9043–9048
OMe
(Scheme 1). The key carbon bond-forming reaction was
achieved by heating 9, catalytic amounts of 10%
[Pd2(dba)3], 20% dppe, and thallium acetate (1.2 equiv) in
acetonitrile. After removal of the dioxolane group with hy-
drochloric acid to give 10 (56% for both steps), oxidation
of the a,b-unsaturated ketone function of the latter to the
corresponding dienone 11 was accomplished in 79% yield
by using selenium dioxide and acetic acid in t-BuOH. Re-
moval of the N-Boc group of 11 with trifluoroacetic acid re-
sulted in spontaneous Michael addition to afford oxocrinine
12 (65%) (Scheme 1). A direct diastereoselective reduction
of 12 to crinine 1 was not possible. However, enone 12 was
stereoselectively reduced with the Luche reagent18 to give
epicrinine 13 (94%). Finally, Mitsunobu inversion of the
C-3 hydroxyl provided (ꢀ)-crinine 1 (63%), which had spec-
tral data in accordance with published values (Scheme 2).19
OH
a
O
O
O
O
H
H
N
N
( )-13
( )-2 (buphanisine)
b
O
O
OR
OH
O
O
O
O
H
H
N
N
( )-3 flexinine (R=H)
( )-4 augustine (R=Me)
( )-14
Scheme 3. Synthetic route of buphanisine 2, flexinine 3, and augustine 4: (a)
(i) MsCl, NEt3, CH2Cl2, rt; (ii) MeOH, rt, 40 h (41%); (b) CCl3CN, H2O2
(3 equiv), TFA/CH2Cl2 (1/5), 24 h (42%).
OMe
I
O
O
a
b
Compound 12 also proved to be a valuable precursor for the
synthesis of flexinine 3 and augustine 4. These alkaloids
have never been synthesized but have been isolated from
different plants.21,22 The antimalarial activities of (ꢂ)-
augustine 4 in both chloroquine-sensitive and chloroquine-
resistant strains of Plasmodium falciparum are probably
due to the presence of the epoxide functionality. Epoxidation
of epicrinine 13 was performed with peroxymidic acid in
the presence of trifluoroacetic acid to avoid oxidation of
the nitrogen atom. The epoxide 14 was obtained only as the
expected isomer (42%).
+
7
8
CHO
5
c
NH2
6
O
O
O
I
O
O
O
d
Boc
N
O
NBoc
9
10
e
Finally, the synthesis of apogalanthamine analogs from
spirodienone 11 via dienol/benzene23 or dienone/phenol24
rearrangement was examined. Reduction of 11 affords
dienol 15, which undergoes acid-catalyzed rearrangement
to 16.25 In the same way, the dienone 11 was treated with
HCl to convert it to the new biaryl 17 by dienone/phenol
rearrangement (Scheme 4).
O
O
O
f
O
O
H
O
N
NBoc
( )-12
11
OH
Scheme 1. Synthetic route of oxocrinine 12: (a) MeOH, D, 1 h then NaBH4,
MeOH, AcOH, 0 ꢁC–rt (100%); (b) (CH2OH)2, BF3$Et2O, THF, rt (93%);
(c) Boc2O, NaOH, t-BuOH/H2O, rt (75%); (d) (i) Pd2(dba)3, dppe, TIOAc,
MeCN, D, 3 days; (ii) 1 N HCl, THF, rt (56%); (e) SeO2, AcOH, t-BuOH, D,
27 h (79%); (f) TFA, CH2Cl2, rt then NaOH, MeOH, rt (65%).
a
b
O
11
NH
O
O
NBoc
c
O
OH
15
16
HO
O
a
b
O
O
( )-12
( )-1 (crinine)
H
N
NH
( )-13
O
Scheme 2. Synthetic route of (ꢀ)-crinine 1: (a) NaBH4, CeCl3$7H2O,
MeOH, rt (94%); (b) DEAD, PPh3, HCO2H, THF, 3 days then 2 N
NaOH, THF, rt (63%).
17
Scheme 4. Synthetic route of apogalanthamine analogs 16 and 17: (a)
NaBH4, CeCl3$7H2O, MeOH, 2 h, rt (68%); (b) concd HCl, MeCN,
95 ꢁC, 24 h (65%); (c) concd HCl, MeCN, 1.5 h, rt (73%).
We next attempted to synthesize (ꢀ)-buphanisine 2, which
has been previously prepared via an A/C/D/B,
sequence.20 It should be noted that diastereoselective re-
duction of an enone function (precursor of the allylic
methoxy) present in the N-benzyl indolone is not possible.19
Buphanisine 2 was thus prepared by methanolysis of the
allylic mesylate of (ꢀ)-epicrinine 13 with concomitant
inversion of stereochemistry in 41% yield (Scheme 3).
3. Conclusion
In summary, an intramolecular Heck reaction followed by
a dehydrogenation reaction provided the key intermediate
spirocyclohexanone 11 and an efficient strategy for the

C. Bru, C. Guillou / Tetrahedron 62 (2006) 9043–9048
9045
construction of numerous alkaloids in the crinine and apoga-
lanthamine series. An asymmetric route to these alkaloids
from the valuable prochiral dienone intermediate 11 is in
progress.
75 MHz) d (ppm): 148.5, 147.5, 135.8, 135.1, 120.1,
118.6, 110.0, 108.0, 101.6, 87.0, 64.4, 58.0, 46.6, 37.3,
35.7, 31.2, 27.4. IR (CHCl3) n (cmꢂ1): 2958, 2927, 1503,
1476, 1261, 1234, 1102, 1040.
4.2.3. [2-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-ethyl]-[2-
iodo-4,5-methylenedioxybenzyl]carbamic acid tert-butyl
ester (9). To a solution of 8 (2.15 g, 4.86 mmol) in 1/1 mix-
ture of t-BuOH/H2O (260 ml) were added Boc2O (1.27 g,
5.84 mmol, 1.2 equiv) and 1 N aqueous NaOH (6.8 ml,
1.4 equiv). After being stirred at room temperature for 4 h,
the solvents were evaporated. The residue was extracted
with AcOEt. The combined organic layers were washed
with water and brine, dried (MgSO4), and evaporated. The
residue was purified by flash chromatography (elution with
heptane/AcOEt 90/10, 80/20, 70/30) to give 9 (1.98 g,
75%) (rotamers) as a pale yellow oil. HRMS (ESI, m/z) calcd
for C23H30NIO6Na (MNa+): 566.1004, found: 566.1016. 1H
NMR (CDCl3, 300 MHz) d (ppm): 7.22 (1H, s), 6.72 (1H,
4. Experimental
4.1. General
NMR spectra were determined on Brucker Avance-300 with
tetramethylsilane as internal reference. HMRS mass spectra
were obtained on a MALDI-TOF spectrometer. Infrared (IR)
spectra were recorded on a Fourier Perkin–Elmer Spectrum
BX FT-IR. Elemental analyses were performed by the ‘Ser-
vice de microanalyses’ (ICSN, CNRS, Gif-sur-Yvette).
4.2. Materials
0
m), 5.95 (2H, s), 5.30 (1H, s, H7 ), 4.39 and 4.32 (2H, s),
THF was distilled from sodium/benzophenone, CH3CN
from CaH2, MeOH from Mg/I2, CH2Cl2 from P2O5, and
NEt3 from KOH. All separations were carried out under flash
chromatographic conditions on Merck silica gel 60 (70–230
mesh) at medium pressure (200 mbar). TLC was done on
Merck silica gel plates (60 F254) with a fluorescent indicator.
3.93 (4H, s), 3.29 and 3.19 (2H, m), 2.23–2.20 (6H, m),
1.78–1.72 (2H, m), 1.54 and 1.43 (9H, s). 13C NMR
(CDCl3, 75 MHz) d (ppm): 155.8, 155.3, 148.8, 147.6,
134.7, 133.8, 120.6, 120.4, 118.5, 108.2, 107.9, 107.7,
101.6, 86.0, 79.9, 64.4, 55.3, 54.7, 46.0, 45.4, 35.9, 35.2,
35.7, 31.2, 28.4, 27.5. IR (CHCl3) n (cmꢂ1): 2957, 1685,
1503, 1477, 1234, 1157, 1107, 1040.
4.2.1. [2-Iodo-4,5-methylenedioxybenzyl]-[2-(4-methoxy-
cyclohexa-1,4-dienyl)-ethyl]amine (7). A solution of 5
(1.45 g, 5.25 mmol) and amine 6 (813.5 mg, 5.32 mmol) in
dry MeOH (80 ml) was refluxed for 1 h. The solution was
cooled at room temperature, then NaBH4 (397 mg,
10.5 mmol, 2 equiv) was added and the pH was adjusted to
4–5 using acetic acid. The reaction mixture was stirred at
room temperature for 30 min. The solvent was removed in
vacuo. The residue was diluted with AcOEt and washed
with saturated aqueous Na2CO3. The combined organic
layers were washed with water and brine, dried (Na2SO4),
and evaporated. Compound 7 (2.34 g, 100%) was isolated
as a yellow oil. HRMS (ESI, m/z) calcd for C17H21NIO3
(MH+): 414.0553, found: 414.0542. 1H NMR (CDCl3,
300 MHz) d (ppm): 7.23 (1H, s), 6.91 (1H, s), 5.95 (2H,
s), 5.46 (1H, s), 4.61 (1H, s), 3.78 (2H, s), 3.72 (3H, s),
2.71 (6H, m), 2.22 (2H, t, J¼6.8). 13C NMR (CDCl3,
75 MHz) d (ppm): 153.0, 148.5, 147.5, 135.8, 133.1,
119.3, 118.6, 110.0, 101.6, 90.4, 87.1, 58.1, 53.9, 46.6,
37.0, 29.2. IR (CHCl3) n (cmꢂ1): 2962, 2831, 1697, 1664,
1504, 1261, 1234, 1099, 1040, 1015.
4.2.4. tert-Butyl-7,8-(methylenedioxy)-40-oxo-2,3,4,5-
tetrahydro-1H-[2]-benzazepine-5-spiro-10-cyclohexa-20-
ene-2-carboxylate (10). A mixture of Pd2(dba)3 (218.5 mg,
0.24 mmol, 0.1 equiv) and dppe (190.1 mg, 0.48 mmol,
0.2 equiv) in dry CH3CN (30 ml) was stirred at room tem-
perature for 1 h. Then TlOAc (753.6 mg, 2.86 mmol,
1.2 equiv) and 9 (1.29 g, 2.38 mmol) in CH3CN (50 ml)
were added. After being stirred at 90 ꢁC for 72 h, the reac-
tion mixture was filtered through Celite (elution with
AcOEt) and evaporated. The residue was dissolved in THF
(60 ml), then 1 N aqueous HCl (32 ml) was added. After
being stirred at room temperature for 12 h, the solvent was
evaporated and the residue was extracted with AcOEt. The
combined organic layers were washed with water and brine,
dried (MgSO4), and evaporated. Flash chromatography of
the residue (elution with heptane/AcOEt 90/10, 80/20, 70/
30) afforded 10 (494.3 mg, 56%) (rotamers) as a pale yellow
solid. HRMS (ESI, m/z) calcd for C21H25NO5Na (MNa+):
1
394.1602, found: 371.4269. H NMR (CDCl3, 300 MHz)
d (ppm): 6.79 (1H, d, J¼10.4), 6.72 (1H, s), 6.64 (1H, s),
6.09 (1H, d, J¼10.2), 5.93 (2H), 4.48, 4.41 (2H, s), 3.74
(2H, m), 2.42–2.17 (3H, m), 1.92 (1H, m), 1.43, 1.37 (9H,
s). 13C NMR (CDCl3, 75 MHz) d (ppm): 199.1, 157.7,
154.9, 154.6, 146.8, 146.1, 145.9, 135.9, 135.4, 132.0,
131.7, 127.3, 111.0, 110.5, 109.7, 101.3, 80.0, 50.4, 49.7,
44.7, 44.0, 43.5, 36.4, 35.9, 34.1, 33.3, 33.0, 28.4. IR
(CHCl3) n (cmꢂ1): 2961, 2930, 1682, 1506, 1488, 1261,
1162, 1041.
4.2.2. [2-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)-ethyl]-[2-
iodo-4,5-methylenedioxybenzyl]amine (8). To a solution
of 7 (2.28 g, 5.53 mmol) in dry THF (160 ml) were added
at 0 ꢁC ethylene glycol (0.62 ml, 0.11 mmol, 2 equiv) and
BF3$OEt2 (0.72 ml, 5.53 mmol, 1 equiv). After being stirred
for 12 h at room temperature, the reaction mixture was
quenched with saturated aqueous NaHCO3 and extracted
with CH2Cl2. The combined organic layers were washed
with water and brine, dried (Na2SO4), filtered, and evapo-
rated. Compound 8 (2.33 g, 93%) was isolated as a yellow
oil. HRMS (ESI, m/z) calcd for C20H23NIO4 (MH+):
4.2.5. tert-Butyl-7,8-(methylenedioxy)-40-oxo-2,3,4,5-
tetrahydro-1H-[2]-benzazepine-5-spiro-10-cyclohexa-
20,50-diene-2-carboxylate (11). A mixture of a,b-unsaturated
ketone 10 (1.03 g, 2.78 mmol), SeO2 (1.24 g, 11.1 mmol,
4 equiv), acetic acid (5.6 ml) in t-BuOH (76 ml) was heated
at reflux for 27 h. After cooling at room temperature, the
1
444.0671, found: 444.0672. H NMR (CDCl3, 300 MHz)
d (ppm): 7.23 (1H, s), 6.91 (1H, s), 5.95 (2H, s), 5.30 (1H,
s), 3.98 (4H, s), 3.72 (2H, s), 2.69 (2H, t, J¼6.6), 2.26–
2.14 (6H, m), 1.76 (2H, t, J¼6.6). 13C NMR (CDCl3,

9046
C. Bru, C. Guillou / Tetrahedron 62 (2006) 9043–9048
reaction mixture was filtered through Celite (elution with
AcOEt) and extracted with AcOEt. The combined organic
layers were washed with water and brine, dried (MgSO4),
and evaporated. Flash chromatography of the residue (elution
with heptane/AcOEt 90/10, 80/20, 70/30) yielded 11
(806.8 mg, 79%) (rotamers) as a yellow solid. HRMS (ESI,
m/z) calcd for C21H23NO5Na (MNa+): 392.1471, found:
4.2.8. ( )-Crinine (1). To a solution of 13 (40.2 mg,
0.148 mmol) in dry THF (1.5 ml) were added PPh3
(78.0 mg, 0.297 mmol, 2 equiv), distilled formic acid
(25 ml, 0.663 mmol, 4.5 equiv), and DEAD (55 ml,
0.302 mmol, 2 equiv). The reaction was allowed to proceed
under argon at room temperature for 3 days, while adding
every 24 h extra portions of PPh3 (78.0 mg), formic acid
(25 ml), and DEAD (55 ml). The reaction mixture was then
evaporated. Flash chromatography (elution with CH2Cl2/
MeOH 97/3, 92/8, 90/10) yielded 3-O-formyl epicrinine
(11.4 mg, 26%) as a white powder, a mixture (5.9 mg,
3-O-formyl epicrinine/3-O-formyl-crinine 35/65), and 3-
O-formyl-crinine (28.9 mg, 65%) as a white powder. To a
solution of 3-O-formyl-crinine (28.9 mg, 0.097 mmol) in
THF (3 ml) was added 2 N aqueous NaOH (2.2 ml). After
1.5 h at room temperature, the solvent was evaporated.
The residue was dissolved in CHCl3, washed with 33%
aqueous NH3, and extracted with CHCl3. The combined or-
ganic layers were washed with saturated aqueous NaHCO3,
dried (MgSO4), and evaporated. (ꢀ)-Crinine 1 (25.3 mg,
97%) was yielded as a white powder. HRMS (ESI, m/z) calcd
for C16H18NO3 (MH+): 272.1287, found: 272.1287. 1H
NMR (CDCl3, 300 MHz) d (ppm): 6.78 (1H, s), 6.59 (1H,
d, J¼9.8), 6.42 (1H, s), 5.97 (1H, dd, J1¼5.1, J2¼9.8),
5.83 (2H, ABq), 4.42 (1H, d, J¼16.8), 4.36 (1H, m), 3.75
(1H, d, J¼16.8), 3.39–3.27 (2H, m), 2.85 (1H, ddd,
J1¼5.9, J2¼8.9, J3¼13.9), 2.19 (1H, ddd, J1¼4.2, J2¼9.0,
J3¼12.7), 1.97–1.88 (2H, m), 1.75 (1H, ddd, J1¼4.2,
J2¼J3¼13.6). 13C NMR (CDCl3, 75.5 MHz) d (ppm):
146.2, 145.8, 138.2, 132.3, 127.5, 126.2, 107.0, 102.9,
100.8, 64.2, 62.9, 62.1, 53.6, 44.3, 44.2, 32.8. IR (CHCl3)
n (cmꢂ1): 3690, 3343, 2853, 1602, 1504, 1262, 1004, 938.
1
392.1474. H NMR (CDCl3, 300 MHz) d (ppm): 6.97 (2H,
d, J¼10.1), 6.74, 6.62 (1H, s), 6.54 (1H, s), 6.28 (2H, d,
J¼10.1), 5.94 (2H), 4.57, 4.48 (2H, s), 3.73 (2H, m), 2.27
(2H, t, J¼6.1), 1.47 and 1.39 (9H, s). 13C NMR (CDCl3,
75.5 MHz) d (ppm): 185.6, 155.0, 154.7, 153.8, 147.0,
146.9, 132.7, 132.3, 129.3, 126.8, 110.5, 110.0, 109.6,
101.5, 80.4, 80.2, 48.9, 48.6, 47.8, 44.5, 43.6, 35.8, 35.5,
28.5, 28.4. IR (CHCl3) n (cmꢂ1): 2981, 2930, 1686 (C]O),
1665 (C]O), 1624 (C]C), 1487, 1234, 1040.
4.2.6. ( )-Oxocrinine (12). To a solution of 11 (602.3 mg,
1.63 mmol) in CH2Cl2 (45 ml) was added trifluoroacetic
acid (14 ml). After 30 min at room temperature, the mixture
was basified with solid NaOH and dissolved in aqueous
MeOH. After 1 h, the solvents were evaporated and the
residue was extracted with CH2Cl2. The combined organic
layers were washed with water and brine, dried (MgSO4),
and evaporated. Flash chromatography (elution with
CH2Cl2/MeOH 95/5) yielded 12 (286.3 mg, 65%) as white
powder. HRMS (ESI, m/z) calcd for C16H16NO3 (MH+):
1
270.1133, found: 270.1130. H NMR (CDCl3, 300 MHz)
d (ppm): 7.61 (1H, d), 6.9 (1H, s), 6.51 (1H, s), 6.08 (1H,
d, J¼10.4), 5.91 (2H, ABq), 4.39 (1H, d, J¼16.9), 3.79
(1H, d, J¼16.9), 3.63 (1H, dd, J1¼5.6, J2¼13.0), 3.53
(1H, ddd, J1¼3.8, J2¼10.4, J3¼13.7), 3.00 (1H, ddd,
J1¼6.2, J2¼8.8, J3¼13.3), 2.68 (1H, dd, J1¼5.6,
J2¼16.8), 2.46 (1H, dd, J1¼13.0, J2¼16.8), 2.36 (1H, ddd,
J1¼3.8, J2¼8.8, J3¼12.8), 2.16 (1H, ddd, J1¼6.2,
J2¼10.4, J3¼12.8). 13C NMR (CDCl3, 75 MHz) d (ppm):
198.2, 149.5, 146.6, 146.4, 136.0, 128.8, 126.4, 107.3,
102.5, 101.0, 68.9, 61.9, 54.1, 44.8, 44.7, 40.2. IR
(CHCl3) n (cmꢂ1): 2929, 2890, 1682, 1505, 1484, 1248,
1234, 1042.
4.2.9. ( )-Buphanisine (2). To a solution of 13 (45.1 mg,
0.17 mmol) in dry CH2Cl2 (4.4 ml) were added Et3N
(60 ml, 0.43 mmol, 2.5 equiv) and MsCl (33 ml, 0.43 mmol,
2.5 equiv). After 2 h at room temperature, the solvent was
evaporated, and the residue was dissolved in dry MeOH
(5 ml). After 40 h at room temperature, the solvent was
evaporated, the residue was dissolved in CHCl3, washed
with saturated aqueous NaHCO3, and extracted with
CHCl3. The combined organic layers were washed with sat-
urated aqueous NaHCO3, dried (MgSO4), and evaporated.
Preparative thin-layer chromatography (elution with
CH2Cl2/MeOH 9/1) yielded (ꢀ)-buphanisine 2 (19.6 mg,
41%) as a white powder. HRMS (ESI, m/z) calcd for
4.2.7. ( )-Epicrinine (13). To a solution of (ꢀ)-oxocrinine
12 (50.5 mg, 0.188 mmol) in dry MeOH (5 ml) were added
NaBH4 (14.9 mg, 0.394 mmol, 2.1 equiv) and CeCl3$7H2O
(146.9 mg, 0.394 mmol, 2.1 equiv). After 1 h at room tem-
perature, the mixture was filtered through Celite (elution
with MeOH) and evaporated. The residue was dissolved in
CH2Cl2, washed twice with saturated aqueous NaHCO3,
and extracted with CHCl3. The combined organic layers
were dried (MgSO4) and evaporated. (ꢀ)-Epicrinine 13
(48.1 mg, 94%) was isolated as a white powder. HRMS
(ESI, m/z) calcd for C16H18NO3 (MH+): 272.1282, found:
272.1287. 1H NMR (CDCl3, 300 MHz) d (ppm): 6.77
(1H, s), 6.44 (1H, s), 6.36 (1H, dd, J1¼2.3, J2¼10.2), 5.77
(2H, s), 5.66 (1H, d, J¼10.4), 4.26 (1H, d, J¼16.8), 3.71
(1H, m), 3.31 (1H, ddd, J1¼4.7, J2¼10.4, J3¼14.3), 3.17
(1H, dd, J1¼3.8, J2¼13.4), 2.87 (1H, ddd, J1¼6.4, J2¼8.5,
J3¼14.7), 2.13–1.94 (3H, m), 1.51 (1H, ddd, J1¼10.7,
J2¼11.9, J3¼13.2). 13C NMR (CDCl3, 75.5 MHz)
d (ppm): 147.9, 147.4, 139.6, 132.8, 129.3, 126.3, 107.9,
103.9, 102.1, 68.1, 62.6, 53.7, 46–50, 45.8, 35.1. IR
(CHCl3) n (cmꢂ1): 3603, 2956, 2856, 1504, 1483, 1250,
1236, 1041.
1
C17H20NO3 (MH+): 286.1438; found: 286.1443. H NMR
(CDCl3, 300 MHz) d (ppm): 6.81 (1H, s), 6.59 (1H, d,
J¼10.0), 6.45 (1H, s), 5.94 (1H, ddd, J1¼1.0, J2¼5.1,
J3¼10.0), 5.86 (2H, d, J¼1.3), 4.38 (1H, d, J¼16.9), 3.81
(1H, m), 3.75 (1H, d, J¼16.9), 3.34 (3H, s), 3.39–3.29
(2H, m), 2.87 (1H, ddd, J1¼5.8, J2¼9.2, J3¼12.8), 2.19–
2.03 (2H, m), 1.89 (1H, ddd, J1¼5.8, J2¼10.6, J3¼12.0),
1.58 (1H, ddd, J1¼4.0, J2¼J3¼13.6). 13C NMR (CDCl3,
75 MHz) d (ppm): 146.0, 145.6, 138.5, 133.0, 126.4,
125.3, 106.9, 102.9, 100.7, 72.7, 63.0, 62.4, 56.4, 53.6,
44.3, 28.9. IR (CHCl3) n (cmꢂ1): 2962, 2930, 1602, 1505,
1261, 1092, 1041, 1014.
4.2.10. ( )-1b,2b-Epoxy-epicrinine (14). A solution of
CCl3CN (26 ml, 0.26 mmol, 3 equiv) and 30% aqueous
H2O2 (30 ml, 0.26 mmol, 3 equiv) in dry CH2Cl2 (0.5 ml)
was stirred at room temperature for 1.5 h. Then, the solution

C. Bru, C. Guillou / Tetrahedron 62 (2006) 9043–9048
9047
was transferred via syringe to a flask containing 13 (23.5 mg,
0.09 mmol, 1 equiv) in a mixture of CH2Cl2/TFA (1.1 ml/
0.3 ml). After 24 h at room temperature, the reaction mixture
was basified with 33% aqueous NH3 (pH 10) and extracted
with CHCl3. The combined organic layers were washed
with saturated aqueous NaHCO3, dried (MgSO4), and evapo-
rated. Preparative thin-layer chromatography (elution with
CH2Cl2/MeOH 9/1) yielded 14 (10.4 mg, 42%) as a white
powder. HRMS (ESI, m/z) calcd for C16H17NO4 (MH+):
CH2Cl2/MeOH 9/1) afforded 16 (18.6 mg, 73%) as a white
solid. HRMS (ESI, m/z) calcd for C16H16NO2 (MH+):
254.1187; found: 254.1183. H NMR (CDCl3, 300 MHz)
1
d (ppm): 7.37–7.22 (4H, m), 6.88 (1H, s), 6.80 (1H, s),
6.00 (2H, ABq, J¼1.0), 3.87 (1H, d, J¼13.9), 3.42 (1H,
dd, J1¼6.8, J2¼13.9), 3.11 (1H, d, J¼13.9), 2.86–2.78
(2H, m), 2.41 (1H, m). 13C NMR (CDCl3, 75 MHz)
d (ppm): 147.6, 146.7, 140.7, 139.9, 133.4, 133.1, 129.4,
129.3, 128.1, 126.1, 109.5, 109.4, 101.2, 50.2, 49.0, 36.3.
IR (CHCl3) n (cmꢂ1): 3064, 2928, 1702, 1675 (Ar), 1601
(Ar), 1504, 1262, 1011.
1
288.1236; found: 288.1225. H NMR (CDCl3, 300 MHz)
d (ppm): 6.89 (1H, s), 6.49 (1H, s), 5.91 (2H, s), 4.38 (1H,
d, J¼16.9), 4.14 (1H, ddd, J1¼10.6, J2¼5.4, J3¼1.6), 3.84
(1H, d, J¼3.8), 3.72 (1H, d, J¼16.9), 3.46 (1H, d, J¼3.8),
3.30 (1H, ddd, J1¼4.5, J2¼10.9, J3¼15.3), 2.91 (1H, dd,
J1¼3.1, J2¼13.3), 2.84 (1H, ddd, J1¼5.8, J2¼9.2,
J3¼13.0), 2.48 (1H, ddd, J1¼5.8, J2¼10.9, J3¼13.4), 2.0
(1H, ddd, J1¼4.7, J2¼9.2, J3¼13.4), 1.84 (1H, ddd,
J1¼3.4, J2¼4.5, J3¼12.1), 1.39 (1H, ddd, J1¼10.9,
J2¼J3¼12.1). 13C NMR (CDCl3, 75 MHz) d (ppm): 146.5,
146.1, 137.1, 126.0, 107.2, 102.7, 101.0, 68.2, 67.5, 62.0,
58.5, 55.1, 52.5, 41.4, 38.7, 30.5. IR (CHCl3) n (cmꢂ1):
3690, 2926, 1505, 1483, 1314, 1262, 1002, 938.
4.2.13. 2,3-Methylenedioxy-5,6,7,8-tetrahydrodibenzo-
[c,e]-azocin-11-ol (17). To a solution of 11 (50.5 mg,
0.188 mmol) in dry CH3CN (7 ml) was added 35% aqueous
HCl (4.6 ml) at room temperature. After 24 h at 95 ꢁC, the
reaction mixture was cooled at room temperature, basified
with 33% aqueous NH3 (pH 10), and extracted with
CHCl3. The combined organic layers were washed with sat-
urated aqueous NaHCO3, dried (MgSO4), and evaporated.
Flash chromatography (alumina, elution: CH2Cl2, CH2Cl2/
MeOH 97.5/2.5, 96/4, 90/10) afforded 17 (49.9 mg, 62%)
as a white powder. HRMS (ESI, m/z) calcd for C16H16NO3
(MH+): 270.1120, found: 270.1130. 1H NMR (CD3OD,
300 MHz) d (ppm): 7.04 (1H, d, J¼8.3), 6.85 (1H, s), 6.75
(1H, dd, J1¼2.6, J2¼8.3), 6.70 (1H, s), 6.63 (1H, d,
J¼2.6), 5.95 (2H, ABq, J¼1.0), 3.73 (1H, d, J¼13.8), 3.23
(1H, dd, J1¼7.0, J2¼13.8), 3.02 (1H, d, J¼13.8), 2.74–
2.59 (2H, m), 2.20 (1H, dd, J1¼10.0, J2¼14.0). 13C NMR
(CD3OD, 75.5 MHz) d (ppm): 156.6, 149.0, 148.3, 142.1,
135.6, 133.6, 133.2, 131.5, 116.7, 116.3, 110.7, 109.9,
101.2, 50.7, 50.2, 35.6. IR (CHCl3) n (cmꢂ1): 3691 (O–H),
3599 (O–H), 3290 (NH), 2961, 2855, 1604 (Ar), 1572
(Ar), 1503, 1261, 1040 (C–O), 1015 (C–O).
4.2.11. tert-Butyl-7,8-(methylenedioxy)-40-hydroxy-
2,3,4,5-tetrahydro-1H-[2]-benzazepine-5-spiro-10-cyclo-
hexa-20,50-diene-2-carboxylate (15). To a solution of 11
(104.4 mg, 0.283 mmol) in dry MeOH (7 ml) were added
CeCl3$7H2O (221.3 mg, 0.594 mmol, 2.1 equiv) and
NaBH4 (22.5 mg, 0.595 mmol, 2.1 equiv). After 1 h at
room temperature, the mixture was filtered though Celite
(elution with MeOH) and evaporated. The residue was
diluted with CHCl3, washed with 33% aqueous NH3, and
extracted with CHCl3. The combined organic layers were
washed saturated aqueous NaHCO3, dried (MgSO4), and
evaporated. Preparative thin-layer chromatography (elution:
heptane/AcOEt 1/1) yielded a 1/1 separable diastereoiso-
meric mixture 15 (74.0 mg, 71%) (rotamers) as a white solid.
HRMS (ESI, m/z) calcd for C21H28NO5Na (MNa+):
394.1626; found: 394.1630. IR (CHCl3) n (cmꢂ1): 3691,
3586, 2959, 1684, 1602, 1505, 1416, 1261, 1099 (C–O),
Acknowledgements
The authors thank the CNRS for financial support and
Robert Dodd for carefully reading the manuscript and for
helpful comments.
1
1011 (C–O). Fraction 1: 15a: H NMR (CDCl3, 300 MHz)
d (ppm): 6.60, 6.57 (1H, s), 6.65, 6.53 (1H, s), 5.9–5.86
(6H, m), 4.61 (1H, m), 4.47, 4.39 (2H, s), 3.63 (2H, m),
2.09 (2H, m), 1.42, 1.34 (9H, s). 13C NMR (CDCl3,
75 MHz) d (ppm): 155.1, 146.7, 145.6, 136.1, 135.8,
135.7, 135.3, 131.5, 131.2, 125.3, 125.1, 110.9, 110.6,
109.9, 109.5, 101.2, 79.8, 62.2, 49.0, 48.1, 45.1, 43.8,
43.5, 37.9, 37.8, 28.5, 28.4. Fraction 2: 15b: 1H NMR
(CDCl3, 300 MHz) d (ppm): 6.74, 6.70 (1H, s), 6.67, 6.55
(1H, s), 5.9–5.87 (6H, m), 4.54 (1H, m), 4.49, 4.40 (2H, s),
3.63 (2H, m), 2.04 (2H, m), 1.44, 1.36 (9H, s). 13C NMR
(CDCl3, 75 MHz) d (ppm): 155.0, 146.5, 145.6, 135.6,
131.5, 131.1, 125.4, 111.1, 110.7, 109.9, 109.4, 101.2,
79.8, 61.7, 49.0, 48.1, 45.4, 43.3, 42.5, 38.2, 38.0, 28.5, 28.4.
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