Total synthesis of amaryllidaceae alkaloid buflavine

Article abstract of DOI:10.1021/jo0202379

A concise synthesis of the amaryllidaceae alkaloid buflavine (1) and its regioisomer (2) involving sequential Meyers' biaryl coupling, enecarbamate formation, and hydrogenation followed by ultimate intramolecular reductive amination is presented.

Full text of DOI:10.1021/jo0202379

3 and 4 equipped with appropriate functionalities liable
to secure the biaryl coupling reaction (retrosynthetic
Scheme 1, path a). However, rare literature precedent2
did not give sound support to the feasibility of such an
approach, and it was decided to adopt the alternative
synthetic tactic depicted in the retrosynthetic Scheme 1
(path b).
Tota l Syn th esis of Am a r yllid a cea e
Alk a loid Bu fla vin e
Christophe Hoarau, Axel Couture,* Eric Deniau, and
Pierre Grandclaudon
Laboratoire de Chimie Organique Physique, UPRESA 8009,
Universite´ des Sciences et Technologies de Lille,
Baˆtiment C3, DUSVA,
Critical to the success of this strategy then was the
ability to identify a temporary auxiliary Z in the diaryl-
alkylamines 5 and 6 that could be capable not only of
allowing and, if feasible, facilitating the aryl-aryl bond
formation but also could serve as a latent functionality
to react ultimately with a remote alkylamino group. Our
synthetic approach was dictated by reliance on the
elegant Meyers’ protocol7 and an oxazoline-mediated
unsymmetrical biaryl coupling was then employed to
form the pivotal biaryl carbon-carbon bond of the benzo-
[c,e]azocine system.
59655 Villeneuve d’Ascq Cedex, France
axel.couture@univ-lille1.fr
Received April 5, 2002
Abstr a ct: A concise synthesis of the amaryllidaceae alka-
loid buflavine (1) and its regioisomer (2) involving sequential
Meyers’ biaryl coupling, enecarbamate formation, and hy-
drogenation followed by ultimate intramolecular reductive
amination is presented.
The first facet of the synthesis then started with the
assembly of the biphenyl derivatives 10 and 11 equipped
with the appropriate functionalities (Scheme 2). This
operation was readily accomplished when the 2-aryl-4,4-
dimethyl-2-oxazolines 8 and 9 readily obtained from the
corresponding benzoic acids7 were allowed to react with
the Grignard reagent derived from the acetal 7 of
2-bromobenzaldehyde. The bulky size of the different
substituents at the 2 and 2′ positions had no steric impact
on the biaryl coupling reaction since usual workup and
chromatography provided the corresponding biaryls 10
and 11 in excellent yields of 76% and 81%, respectively.
Regeneration of the carboxaldehyde function delivered
almost quantitatively the corresponding benzaldehyde
derivatives 12 and 13. Horner reaction between the
metalated carbamate 15 obtained by coupling N-[(diphen-
ylphosphinoyl)methyl]-N-methylamine 14 with di-tert-
butyl dicarbonate and compounds 12 and 13 proceeded
uneventfully to furnish the enecarbamates 16 and 17,
which were isolated in high yields (85% and 81%,
respectively) as a mixture of Z and E isomers with the E
isomer predominating by a large margin (>90%) (Scheme
3). Hydrogenation8 of the polysubstituted enecarbamates
16 and 17 delivered the protected biarylalkylamines 18
and 19 with very good yields (97% and 95%, respec-
tively).9 Gratifyingly, all these operations spared the
oxazoline unit and its presence in the elaborated models
was rewarded here: reductive cleavage of the oxazoline
ring of 18 and 19 following the mild high-yield procedure
developed by Meyers10 gave rise to the benzaldehyde
derivatives 20 and 21 in satisfactory yields (79% and
Buflavine 1 constitutes an eminent example of the odd
natural amaryllidaceous alkaloids that have been iso-
lated from Boophane flava, an endemic Amaryllidaceae
species growing in the winter rainfall area in Southern
Africa.1 This alkaloid possesses an unique 5,6,7,8-tet-
rahydrobenzo[c,e]azocine skeleton present in the apogal-
anthamine series2 and seems to be endowed with an
interesting profile of biological activities, namely adren-
olytic and anti-serotonin properties.3 As far as we are
aware, the first synthesis of buflavine 1 was incidentally
reported 25 years ago,4 but curiously, this report predated
its isolation and structural elucidation.1 Consequently,
the skillful synthetic approach recently reported by
Snieckus et al.5 can arguably be deemed as the first total
synthesis of this natural product.
Herein, we delineate a tactically new six-step total
synthesis of the alkaloid buflavine 1 that relies upon our
long-standing experience in the field of N-acylenamine
chemistry,6 and we wish to disclose the success of our
concept by describing the synthesis of its regioisomer 2.
A contentious issue in the elaboration of the target
compounds 1 and 2 was judging the proper strategy for
the formation of the heteroring unit embedded in the
polyhydrobenzoazocine skeleton. The formation of the
eight-membered ring could be a priori triggered by the
ring closure of the arylmethylarylethylamine derivatives
(1) Viladomat, F.; Bastida, J .; Codina, C.; Campbell, W. E.; Mathee,
S. Phytochemistry 1995, 40, 307.
(2) Kihara, M.; Itoh, J .; Iguchi, S.; Imakura, Y.; Kobayashi, S. J .
Chem. Res., Synop. 1988, 8.
(3) (a) Ishida, Y.; Sasaki, Y.; Kimura, Y.; Watanabe, K. J . Pharma-
cobio-Dyn. 1985, 8, 917; Chem. Abstr. 1986, 104, 45660. (b) Manoury,
P. M.; Binet, J . L.; Dumas, A. P.; Lefevre-Borg, F.; Cavero, I. J . Med.
Chem. 1986, 29, 19. (c) Campbell, S. F.; Davey, M. J .; Hardstone, J .
D.; Lewis, B. N.; Palmer, M. J . J . Med. Chem. 1987, 30, 49.
(4) Kobayashi, S.; Kihara, M.; Shizu, S.; Katayama, S.; Ikeda, H.;
Kitahiro, K.; Matsumoto, H. Chem. Pharm. Bull. 1977, 25, 3312.
(5) Patil, P. A.; Snieckus, V. Tetrahedron Lett. 1998, 39, 1325.
(6) (a) Couture, A.; Lebrun, S.; Deniau, E.; Grandclaudon, P. Eur.
J . Org. Chem. 1999, 2345. (b) Couture, A.; Deniau, E.; Grandclaudon,
P.; Hoarau, C. Tetrahedron 2000, 56, 1491. (c) Hoarau, C.; Couture,
A.; Deniau, E.; Grandclaudon, P. J . Org. Chem. 1998, 63, 3128. (d)
Hoarau, C.; Couture, A.; Cornet, H.; Deniau, E.; Grandclaudon, P. J .
Org. Chem. 2001, 66, 8064.
(7) For leading references and examples, see: Hutchings, R. H.;
Meyers, A. I. J . Org. Chem. 1996, 61, 1004.
(8) (a) Sonesson, C.; Wikstroem, H.; Smith, M. W.; Svensson, K.;
Carlsson, A.; Waters, N. Bioorg. Med. Chem. Lett. 1997, 7, 241. (b)
Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S.; Leonce, S.;
Renard, P.; Pfeiffer, B. Bioorg. Med. Chem. 2000, 8, 2113.
(9) Attempts to assemble compounds 18 and 19 by applying the
Meyers' coupling reaction to 8, 9 and N-methyl-N-tert-butoxycarbonyl-
2-bromophenethylamine met with limited success since the preparation
of the Grignard reagent was accompanied by the formation of undesir-
able inter- and intra-self-condensation products.
(10) Meyers, A. I.; Willemsen, J . J . Tetrahedron 1998, 54, 10493.
10.1021/jo0202379 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/04/2002
5846
J . Org. Chem. 2002, 67, 5846-5849

SCHEME 1
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were conducted under an
argon atmosphere with magnetic stirring. Solvents were dried
according to established protocols by distillation under argon
from an appropriate drying agent. Dichloromethane and dichlo-
roethane were distilled from CaH2. Tetrahydrofuran (THF) was
distilled over sodium benzophenone ketyl and stored over sodium
before use. Methanol and ethanol were distilled from magnesium
turnings. 1H, 13C, and 31P NMR spectra were recorded at 300,
75, and 121 MHz, respectively. Elemental analyses were per-
formed by the CNRS microanalysis center. For flash chroma-
tography, Merck silica gel 60 (230-400 mesh ASTM) was used.
Ma ter ia ls. Compounds 7,12 8,13 9,10 and phosphorylated
amine 1414 were synthesized according to already reported
procedures.
N-(ter t-Bu toxyca r bon yl)-N-[(d ip h en ylp h osp h in oyl)m e-
th yl]m eth yla m in e (15). A solution of di-tert-butyl dicarbonate
(12 g, 55 mmol) in THF (10 mL) was added dropwise to a solution
of the phosphorylated amine 14 (12.25 g, 50 mmol) in THF (20
mL), and the mixture was refluxed for 3 h under Ar. The solvent
was removed under vacuum, and recrystallization of the residue
from hexane-toluene afforded the phosphorylated carbamate
15 as a white solid (13.45 g, 78%): mp 83-84 °C; 1H NMR
(CDCl3, mixture of rotational isomers, 75:25) δ (major rotational
isomer) 1.23 (s, 9H), 2.97 (s, 3H), 4.18 (d, J ) 4.4 Hz, 2H), 7.33-
7.56 (m, 6H), 7.66-7.90 (m, 4H); δ (minor rotational isomer) 1.16
(s, 9H), 3.00 (s, 3H), 4.12 (d, J ) 4.2 Hz, 2H), 7.33-7.56 (m,
6H), 7.66-7.90 (m, 4H); 13C NMR (CDCl3) δ (major rotational
SCHEME 2. Meyer s’ Cou p lin g Rea ction
isomer) 28.1, 35.8, 48.7 (d, J CP ) 79.5 Hz), 80.1, 128.5 (d, J CP
)
11 Hz), 131.0 (d, J CP ) 97 Hz), 131.1 (d, J CP ) 10 Hz), 132.0 (d,
J CP ) 2.5 Hz), 155.4; 31P NMR (CDCl3, mixture of rotational
isomers, 75:25) δ (minor rotational isomer) 31.0, δ (major
rotational isomer) 27.6. Anal. Calcd for C19H24NO3P: C, 66.08;
H, 7.00; N, 4.06. Found: C, 66.30; H, 6.91; N, 3.89.
Syn th esis of th e Bia r yls 10, 11. To a suspension of the
bromo derivative 7 (2.5 g, 10.9 mmol) and granular magnesium
(292 mg, 12 mmol) in THF (10 mL) was added 1,2-dibromotet-
rafluoroethane (1.3 g, 5 mmol) in portions over a period of 1 h.
The resulting Grignard reagent was transferred via cannula to
a solution of the oxazoline 8, 9 (2.9 g, 10.9 mmol) in THF (10
mL), and the reaction mixture was stirred overnight. The
reaction was quenched with saturated aqueous NH4Cl and
filtered over a Celite pad. Water was added, and the reaction
mixture was extracted with AcOEt (3 × 20 mL), dried over
MgSO4, and concentrated in vacuo to give the crude biaryl, which
was purified by silica gel column chromatography (acetone/
hexanes, 40:60) to afford 10 and 11 as light yellow solid. Final
purification was carried out by recrystallization from EtOH.
2-(2-(2-[1,3]Dioxol-2-ylp h en yl)-4,5-d im et h oxyp h en yl)-
4,4-d im eth yl-4,5-d ih yd r o[1,3]oxa zole (10): 3.17 g, 76%; mp
77%, respectively). This protocol allowed the tailored
incorporation of a carboxaldehyde function into the
dimethoxylated aromatic part of the models (compared
to 12 and 13). N-Deprotection of carbamates 20 and 21
with trifluoroacetic acid and subsequent reductive ami-
nation11 afforded straightforwardly the target natural
product buflavine 1 and its regioisomer 2 with overall
yields of 35% and 33% for the seven steps (starting from
the precursors of 8 and 9).
In summary, the new synthetic protocol consisting of
sequential Meyers’ biaryl coupling reaction, enecarbam-
ate formation, subsequent hydrogenation, and ultimate
reductive amination has been applied to an efficient
construction of the 5,6,7,8-tetrahydrodibenzo[c,e]azocine
framework, and the synthetic potential of this method
has been illustrated by the second known total synthesis
of the alkaloid buflavine.
1
114-115 °C; H NMR (CDCl3) δ 1.15 (s, 3H), 1.17 (s, 3H), 3.53
(d, J ) 8.0 Hz, 1H), 3.66 (d, J ) 8.0 Hz, 1H), 3.73-4.04 (m, 2H),
3.82 (s, 3H), 3.90 (s, 3H), 3.97-4.04 (m, 2H), 5.47 (s, 1H), 6.76
(s, 1H), 7.11 (dd, J ) 1.8, 6.6 Hz, 1H), 7.24-7.31 (m, 2H), 7.30
(s, 1H), 7.58 (dd, J ) 1.8, 7.6 Hz, 1H); 13C NMR (CDCl3) δ 27.8,
28.1, 55.9, 56.0, 65.1, 65.3, 66.8, 79.2, 101.4, 112.0, 114.2, 120.5,
126.0, 127.3, 128.3, 129.5, 132.8, 134.9, 141.3, 147.7, 149.7, 163.2.
Anal. Calcd for C22H25NO5: C, 68.91; H; 6.57; N, 3.65. Found:
C, 69.04; H, 6.72; N, 3.51.
2-(2-(2-[1,3]Dioxol-2-ylp h en yl)-3,4-d im et h oxyp h en yl)-
4,4-d im eth yl-4,5-d ih yd r o[1,3]oxa zole (11): 3.38 g, 81%; mp
1
104-105 °C; H NMR (CDCl3) δ 1.12 (s, 3H), 1.18 (s, 3H), 3.47
(s, 3H), 3.55 (d, J ) 8.0 Hz, 1H), 3.63 (d, J ) 8.0 Hz, 1H), 3.80-
3.83 (m, 2H), 3.89 (s, 3H), 3.98-4.03 (m, 2H), 5.55 (s, 1H), 6.91
(d, J ) 8.6 Hz, 1H), 7.15 (dd, J ) 1.8, 6.8 Hz, 1H), 7.32-7.37
(m, 2H), 7.56 (d, J ) 8.6 Hz, 1H), 7.61 (dd, J ) 1.8, 7.6 Hz, 1H);
(12) Tanaka, K.; Katsurada, M.; Ohno, F.; Shiga, Y.; Oda, M.;
Miyagi, M.; Takehara, J .; Kazuya, O. J . Org. Chem. 2000, 65, 432.
(13) Meyers, A. I.; Gabel, R.; Mihelich, E. D. J . Org. Chem. 1978,
43, 1372.
(11) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J . Org. Chem. 1996, 61, 3849.
(14) Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Tetra-
hedron Lett. 1996, 37, 7749.
J . Org. Chem, Vol. 67, No. 16, 2002 5847

SCHEME 3. Tota l Syn th esis of Bu fla vin e
13C NMR (CDCl3) δ 27.8, 28.1, 55.8, 60.4, 65.2, 66.7, 79.3, 101.6,
111.1, 122.0, 125.8, 126.1, 127.5, 128.0, 129.9, 134.3, 135.7, 136.3,
146.5, 154.6, 163.0. Anal. Calcd for C22H25NO5: C, 68.91; H, 6.57;
N, 3.65. Found: C, 68.80; H, 6.74; N, 3.79.
2-(4,5-Dim eth oxy-2-(2-(2-m eth yl-ter t-bu toxycar bon ylam i-
n o-(E)-1-eth en yl)p h en yl)p h en yl)-4,4-d im eth yl-4,5-d ih yd r o-
[1,3]oxa zole (16): 2.30 g, 85%; 1H NMR (CDCl3) δ 1.18 (s, 6H),
1.48 (s, 9H), 2.90 (s, 3H), 3.55-3.72 (m, 2H), 3.87 (s, 3H), 3.98
(s, 3H), 5.52 (d, J ) 14.6 Hz, 1H), 6.73 (s, 1H), 7.19 (s, 1H), 7.18-
7.29 (m, 2H), 7.42-7.55 (m, 2H), 7.68 (d, J ) 14.6 Hz, 1H); 13C
NMR (CDCl3) δ 28.0, 28.2, 34.2, 56.0, 56.1, 66.8, 79.5, 81.4, 107.3,
112.2, 113.7, 120.2, 123.6, 125.5, 127.4, 129.4, 129.8, 134.3, 135.5,
139.6, 147.7, 150.2, 154.9, 163.2.
Syn th esis of th e Bia r ylca r boxa ld eh yd es 12, 13. A solution
of the biaryl 10, 11 (3 g, 7.8 mmol) and iron(III) chloride
hexahydrate (6 g, 22.2 mmol) in a mixture acetone/dichlo-
romethane (1:4, 50 mL) was vigorously stirred over a period of
2 h at room temperature. The crude mixture was poured onto a
saturated aqueous NH4Cl solution (20 mL), filtered on Celite,
and extracted with CH2Cl2 (3 × 20 mL). The organic extracts
were washed successively with water and brine and dried over
MgSO4. The solvents were removed in vacuo, and the crude
residue was recrystallized from hexane-toluene to afford 12 and
13 as colorless powder.
2-(3,4-Dim eth oxy-2-(2-(2-m eth yl-ter t-bu toxycar bon ylam i-
n o-(E)-1-eth en yl)p h en yl)p h en yl)-4,4-d im eth yl-4,5-d ih yd r o-
[1,3]oxa zole (17): 2.19 g, 81%; 1H NMR (CDCl3) δ 1.12 (s, 6H),
1.46 (s, 9H), 2.86 (s, 3H), 3.46 (s, 3H), 3.56-3.61 (m, 2H), 3.90
(s, 3H), 5.46 (d, J ) 14.6 Hz, 1H), 6.91 (d, J ) 8.6 Hz, 1H), 7.14-
7.15 (m, 2H), 7.25-7.30 (m, 1H), 7.40-7.59 (m, 2H), 7.53 (d, J
) 8.6 Hz, 1H); 13C NMR (CDCl3) δ 28.0, 28.2, 34.0, 55.8, 60.5,
67.5, 79.5, 81.2, 107.5, 110.9, 123.4, 123.5, 125.0, 125.9, 127.5,
129.3, 130.2, 135.4, 135.8 (two peaks overlapping), 146.8, 154.8,
155.4, 162.9.
2-(2-(4,4-D im e t h y l-4,5-d ih y d r o [1,3]o x a zo l-2-y l)-4,5-
d im eth oxyp h en yl)ben za ld eh yd e (12): 2.43 g, 92% after
recrystallization; mp 87-88 °C; 1H NMR (CDCl3) δ 1.08 (s, 3H),
1.10 (s, 3H), 3.57 (d, J ) 8.1 Hz, 1H), 3.61 (d, J ) 8.0 Hz, 1H),
3.82 (s, 3H), 3.91 (s, 3H), 6.70 (s, 1H), 7.26 (d, J ) 7.4 Hz, 1H),
7.33 (s, 1H), 7.39 (t, J ) 7.5 Hz, 1H), 7.51 (t, J ) 7.4 Hz, 1H),
7.89 (d, J ) 7.7 Hz, 1H), 9.76 (s, 1H); 13C NMR (CDCl3) δ 27.9,
28.0, 56.0, 56.1, 67.2, 79.1, 112.1, 113.7, 121.2, 126.4, 127.6,
130.5, 130.8, 133.0, 134.2, 148.4, 150.2, 154.2, 162.1, 192.0. Anal.
Calcd for C20H21NO4: C, 70.78; H, 6.24; N, 4.13. Found: C, 70.92;
H, 6.29; N, 3.97.
Syn th esis of th e Ca r ba m a tes 18, 19. A solution of com-
pound 16, 17 (1.4 g, 3 mmol) in MeOH (100 mL) was stirred
with activated Pd/C (10%, 50 mg) and ammonium formate (1.90
g, 3 mmol) was added portionwise. The reaction mixture was
refluxed for 0.5 h, filtered on Celite, and evaporated to dryness.
The crude residue was dissolved in CH2Cl2 (100 mL), and the
organic phase was washed with water, dried (MgSO4), and
concentrated in vacuo to afford the carbamates 18 and 19 as
colorless oils that were sufficiently pure to be used directly for
the next step without further purification.
2-(2-(4,4-D im e t h y l-4,5-d ih y d r o [1,3]o x a zo l-2-y l)-3,4-
d im eth oxyp h en yl)ben za ld eh yd e (13): 2.35 g, 89% after
recrystallization; mp 109-110 °C; 1H NMR (CDCl3) δ 1.08 (s,
3H), 1.10 (s, 3H), 3.44 (s, 3H), 3.48 (d, J ) 8.0 Hz, 1H), 3.64 (d,
J ) 8.0 Hz, 1H), 3.82 (s, 3H), 6.98 (d, J ) 8.6 Hz, 1H), 7.24 (dd,
J ) 1.1, 7.6 Hz, 1H), 7.45 (dt, J ) 0.9, 7.5 Hz, 1H), 7.53 (dt, J )
0.9, 7.5 Hz, 1H), 7.57 (d, J ) 8.6 Hz, 1H), 7.97 (dd, J ) 1.1, 7.7
Hz, 1H), 9.78 (s, 1H); 13C NMR (CDCl3) δ 27.8, 28.0, 55.9, 60.3,
67.2, 79.1, 111.8, 122.2, 126.0, 126.5, 127.8, 130.7, 132.7, 134.2,
2-(4,5-Dim eth oxy-2-(2-(2-m eth yl-ter t-bu toxycar bon ylam i-
n oe t h yl)p h e n yl)p h e n yl)-4,4-d im e t h yl-4,5-d ih yd r o[1,3]-
oxa zole (18): 1.36 g, 97%; 1H NMR (CDCl3) δ 1.15 (s, 3H), 1.16
(s, 3H), 1.40 (s, 9H), 2.45 (s, 3H), 2.59-2.61 (m, 2H), 3.13-3.18
(m, 2H), 3.59 (s, 2H), 3.84 (s, 3H), 3.90 (s, 3H), 6.64 (s, 1H), 7.08
(s, 1H), 7.06-7.20 (m, 4H); 13C NMR (CDCl3) δ 28.0, 28.3, 31.5,
33.9, 50.1, 56.0, 56.1, 66.8, 79.0, 79.2, 112.1, 113.3, 120.2, 125.5,
127.3, 129.2, 129.6, 134.4, 137.0, 141.1, 147.6, 150.1, 155.4, 163.5.
Anal. Calcd for C27H36N2O5: C, 69.21; H, 7.74; N, 5.98. Found:
C, 69.14; H, 7.61; N, 6.15.
134.4, 140.5, 146.7, 154.6, 162.0, 192.0. Anal. Calcd for C20H21
-
NO4: C, 70.78; H, 6.24; N, 4.13. Found: C, 70.98; H, 6.10; N,
4.05.
Syn th esis of En eca r ba m a tes 16, 17. A solution of BuLi (3.6
mL, 1.6 M in hexanes, 5.8 mmol) was added dropwise to a
solution of the phosphorylated carbamate 15 (2 g, 5.8 mmol) in
THF (50 mL) at -78 °C under Ar. The orange solution was kept
at this temperature for 15 min, and a solution of the biarylcar-
boxaldehyde 12, 13 (1.97 g, 5.8 mmol) in THF (5 mL) was then
added by syringe. The reaction mixture was allowed to warm to
room temperature over a period of 2 h followed by addition of
aqueous NH4Cl and extraction with Et2O (3 × 25 mL). The
organic layer was purified by flash column chromatography with
acetone/hexanes (70:30) as eluent to afford 16 and 17 as a
mixture of E and Z isomers.
2-(3,4-Dim eth oxy-2-(2-(2-m eth yl-ter t-bu toxycar bon ylam i-
n oe t h yl)p h e n yl)p h e n yl)-4,4-d im e t h yl-4,5-d ih yd r o[1,3]-
oxa zole (19): 1.33 g, 95%; 1H NMR (CDCl3) δ 1.12 (s, 3H), 1.13
(s, 3H), 1.40 (s, 9H), 2.55 (s, 3H), 2.47-2.63 (m, 2H), 3.21-3.23
(m, 2H), 3.48 (m, 4H), 3.63-3.65 (m, 1H), 3.92 (s, 3H), 3.93 (d,
J ) 8.6 Hz, 1H), 7.09-7.23 (m, 4H), 7.51 (d, J ) 8.6 Hz, 1H);
13C NMR (CDCl3) δ 27.9, 28.0, 28.4, 32.2, 34.2, 49.6, 55.8, 60.5,
66.9, 78.9, 79.1, 110.9, 122.2, 125.1, 125.8, 127.4, 128.8, 129.6,
135.6, 136.2, 137.9, 146.2, 154.5, 155.6, 162.8. Anal. Calcd for
C27H36N2O5: C, 69.21; H, 7.74; N, 5.98. Found: C, 69.40; H, 7.89;
N, 6.02.
5848 J . Org. Chem., Vol. 67, No. 16, 2002

Syn th esis of th e F or m yla ted Ca r ba m a tes 20, 21. To a
flame-dried flask containing a solution of oxazoline 18, 19 (1.40
g, 3 mmol) in CH2Cl2 (25 mL) was added methyl trifluo-
romethanesulfonate (985 mg, 0.68 mL, 6 mmol), and the solution
was stirred at room temperature overnight. The solution was
cooled to 0 °C and treated dropwise with a solution of NaBH4
(226 mg, 6 mmol) in THF/MeOH (4:1, 30 mL). After the mixture
was stirred for 1 h, saturated aqueous NH4Cl (30 mL) was added.
The layers were separated, the organic layer was washed with
CH2Cl2 (3 × 25 mL), and the combined organic extracts were
dried (Na2SO4) and concentrated to dryness. Filtration through
a short plug of silica and evaporation of the solvent left a crude
residue that was dissolved in a solution of THF/H2O (4:1, 50
mL) and treated with oxalic acid dihydrate (1.0 g, 8 mmol). The
solution was stirred overnight, Et2O (50 mL) was added, and
then the solution was washed successively with saturated
aqueous NaHCO3 (50 mL) and brine (50 mL). The combined
organic extracts were dried (Na2SO4) and concentrated in vacuo
to provide a colorless oil that was finally purified by flash column
chromatography using acetone/hexanes (1:1) as eluent.
4,5-Dim eth oxy-2-(2-(2-m eth yl-ter t-bu toxyca r bon yla m i-
n oeth yl)p h en yl)ben za ld eh yd e (20): 945 mg, 79%; 1H NMR
(CDCl3) δ 1.20 (s, 9H), 2.47 (s, 3H), 2.59-2.61 (m, 2H), 3.09-
3.30 (m, 2H), 3.92 (s, 6H), 6.68 (s, 1H), 7.13-7.32 (m, 4H), 7.46
(s, 1H), 9.50 (s, 1H); 13C NMR (CDCl3) δ 28.2, 31.3, 34.0, 50.3,
56.0, 56.3, 79.2, 107.9, 112.8, 126.0, 127.2, 128.5, 129.8, 130.7,
137.2, 138.0, 140.3, 148.7, 153.5, 155.3, 190.7. Anal. Calcd for
C23H29NO5: C, 69.15; H, 7.32; N, 3.51. Found: C, 68.98; H, 7.20;
N, 3.73.
Syn th esis of th e Tetr a h yd r od iben zo[c,e]a zocin es 1, 2.
To a solution of the formylated carbamate 20, 21 (40 mg, 0.1
mmol) in CH2Cl2 (10 mL) was added, by syringe under Ar,
trifluoroacetic acid (114 mg, 1 mmol), and the mixture was
stirred for 2 h. The solvent and excess reagent were removed
under vacuum, and the crude salt was dissolved in Cl(CH2)2Cl
(50 mL). Sequential addition of Et3N (101 mg, 1 mmol) and
NaBH(OAc)3 (25 mg, 0.12 mmol) was followed by stirring at room
temperature under Ar for 12 h. The reaction mixture was then
treated with saturated aqueous NaHCO3 (2 × 10 mL) and
washed with water and brine. The organic phase was dried over
MgSO4 and concentrated in vacuo, and the crude product was
purified by chromatography on silica gel (eluent CH2Cl2/MeOH,
90:10) to afford the annulated product 1, 2, which was finally
recrystallized from hexane.
2,3-Dim eth oxy-6-m eth yl-5,6,7,8-tetr a h yd r od iben zo[c,e]-
a zocin e (Bu fla vin e, 1): 24.3 mg, 86%; mp 106-107 °C (lit.1
mp 106-108 °C). Analytical and spectral data matched those
reported for the natural product.
1,2-Dim eth oxy-6-m eth yl-5,6,7,8-tetr a h yd r od iben zo[c,e]-
a zocin e (2): 23.5 mg, 83%; mp 62-63 °C; 1H NMR (CDCl3) δ
2.41 (s, 3H), 2.47-2.51 (m, 2H), 2.65-2.69 (m, 1H), 2.98 (d, J )
13.5 Hz, 1H), 3.17-3.20 (m, 1H), 3.44 (s, 3H), 3.47 (d, J ) 13.5
Hz, 1H), 3.88 (s, 3H), 6.92 (d, J ) 8.4 Hz, 1H), 7.10 (d, J ) 8.4
Hz, 1H), 7.21-7.24 (m, 2H), 7.31-7.33 (m, 2H); 13C NMR (CDCl3)
δ 35.3, 45.6, 55.9, 57.5, 58.9, 60.4, 111.7, 125.3, 126.1, 126.3,
129.2, 130.5, 131.6, 134.5, 135.1, 141.5, 146.1, 151.9. Anal. Calcd
for C18H21NO2: C, 76.30; H, 7.47; N, 4.94. Found: C, 76.46; H,
7.30; N, 5.09.
3,4-Dim eth oxy-2-(2-(2-m eth yl-ter t-bu toxyca r bon yla m i-
n oeth yl)p h en yl)ben za ld eh yd e (21): 920 mg, 77%; 1H NMR
(CDCl3) δ 1.36 (s, 9H), 2.45-2.59 (m, 5H), 3.11-3.18 (m, 2H),
3.52 (s, 3H), 3.97 (s, 3H), 7.05 (d, J ) 8.6 Hz, 1H), 7.15 (d, J )
7.4 Hz, 1H), 7.23-7.29 (m, 2H), 7.35 (d, J ) 6.7 Hz, 1H), 7.83
(d, J ) 8.6 Hz, 1H), 9.46 (s, 1H); 13C NMR (CDCl3) δ 28.3, 32.0,
34.2, 49.7, 56.0, 60.7, 79.1, 111.4, 124.7, 125.8, 128.2, 128.5,
129.6, 130.6, 132.8, 138.3, 139.4, 146.0, 155.5, 157.7, 190.6. Anal.
Calcd for C23H29NO5: C, 69.15; H, 7.32; N, 3.51. Found: C, 69.05;
H, 7.44; N, 3.56.
Ack n ow led gm en t. This research was supported by
the Centre National de la Recherche Scientifique and
MENESR (grant to C.H.). We also acknowledge helpful
discussions and advice from Dr. T. G. C. Bird (Astra-
Zeneca Pharma).
J O0202379
J . Org. Chem, Vol. 67, No. 16, 2002 5849