A simple and efficient synthetic route to chiral isopavines. Synthesis of (-)-O-methylthalisopavine and (-)-amurensinine

Article abstract of DOI:10.1021/jo9708102

The isopavinan alkaloids (-)-O-methylthalisopavine (7a) and (-)- amurensinine (7d) have been synthesized in good yield and high ee from the appropriate 1,2-diarylethylamine derivatives using optically active β-amino alcohols as chiral support. This synthetic route employs as key steps the alkylation reaction of the azomethine derivatives 2 with Grignard reagents 1 and-a novel one-pot double-intramolecular cyclization of the adequately functionalized 1,2-diarylethylamines 5 to afford a series of optically active isopavines 6a-d and 7a-d.

Full text of DOI:10.1021/jo9708102

6716
J . Org. Chem. 1997, 62, 6716-6721
Articles
A Sim p le a n d Efficien t Syn th etic Rou te to Ch ir a l Isop a vin es.
Syn th esis of (-)-O-Meth ylth a lisop a vin e a n d (-)-Am u r en sin in e
Luisa Carrillo, Dolores Bad´ıa,* Esther Dom´ınguez,*, J ose´ L. Vicario and Imanol Tellitu
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad del Pa´ıs Vasco,
Apdo. 644-48080 Bilbao, Spain
Received May 6, 1997X
The isopavinan alkaloids (-)-O-methylthalisopavine (7a ) and (-)-amurensinine (7d ) have been
synthesized in good yield and high ee from the appropriate 1,2-diarylethylamine derivatives using
optically active â-amino alcohols as chiral support. This synthetic route employs as key steps the
alkylation reaction of the azomethine derivatives 2 with Grignard reagents 1 and a novel one-pot
double-intramolecular cyclization of the adequately functionalized 1,2-diarylethylamines 5 to afford
a series of optically active isopavines 6a -d and 7a -d .
In tr od u ction
Over the last years we have been engaged in a major
effort to study the synthesis and reactivity of different
isoquinoline derivatives, such as 3-arylisoquinolines,
protoberberines, and benzo[c]phenanthridines.1 As a
result of our interest in this field, we have extended our
investigations to the synthesis of natural and non-natural
isopavines because of their important pharmacological
properties for the treatment of the nerve system disorders
recently reported: Alzheimer’s disease, Hungtington’s
chorea, amyotrophic lateral sclerosis, and Parkinson’s
and Down’s syndromes.2
F igu r e 1.
tion step takes place in moderate yields requiring rather
long reaction times.
In this paper, and in connection with our studies on
the asymmetric synthesis of isoquinoline alkaloids,5 we
describe a suitable and general route for the asymmetric
synthesis of optically pure isopavines starting from chiral
1,2-diarylethylamine precursors 4. Then, a sequence of
stereocontrolled transformations (N-alkylations and double
acid cyclization) was envisaged to prepare the isopavine
core. The described protocol is interesting from a syn-
thetic point of view taking into account the large number
of diarylethylamines of type 4 available by this method,
as it allows any arylic substitution pattern, thus leading
to the synthesis of a wide range of naturally and
unnaturally occurring isoquinoline derivatives.6
Isopavines are a small group of natural products
characterized by a tetracyclic skeleton with an isoquino-
line core, as shown below for natural (-)-O-methylthal-
isopavine and (-)-amurensinine (Figure 1). Few ex-
amples of syntheses of these compounds have been
reported to date.3 Moreover, the enantioselective syn-
thesis of isopavines has not been extensively developed
yet, although their interest for future pharmacological
studies should be emphasized. As far as we know, in the
literature there is only one example where the synthesis
of an enantiomerically enriched isopavine does not
involve a resolution step of any of the intermediates,4 and
furthermore, in all the cases reported, the final cycliza-
Resu lts a n d Discu ssion
The synthesis of 1,2-diarylethylamines 4 (see Scheme
1) started with the reaction between freshly prepared
Grignard benzylic reagents 1 and imines 2. These imines
were synthesized, in turn, in good yields by condensation
of the corresponding â-amino alcohol (readily prepared
by reduction of their respective R-amino acids7) with aryl
aldehydes in refluxing benzene. The S enantiomer of the
â-amino alcohol chiral auxiliary was employed because
it would eventually lead to the corresponding levogire
isopavines, the unique isomers found in nature.
X Abstract published in Advance ACS Abstracts, September 1, 1997.
(1) See, for example: (a) Tellitu, I.; Bad´ıa, D.; Dom´ınguez, E.;
Carrillo, L. Heterocycles 1996, 43, 2099-2112. (b) Bad´ıa, D.; Dom´ıngu-
ez, E.; Tellitu, I. Tetrahedron 1992, 48, 4419-4430.
(2) For pharmacological activities, see: (a) Weber, E.; Keana, J .;
Barmettler, P. PCT Int. Appl. WO 12575, 1990; Chem. Abstr. 1991,
115, 106019w. (b) Childers, W. E., J r.; Abou-Gharbia, M. A. U.S. Patent
4940789, 1990; Chem. Abstr. 1990, 113, 191190w.
(3) For syntheses of natural and non-natural isopavines, see, for
example: (a) Go¨zler, B. In The Alkaloids; Academic Press: New York,
1987; Vol. 31, pp 342-355. (b) Yasuda, M.; Hamasuna, S.; Yamano,
K.; Kubo, J .; Shima, K. Heterocycles 1992, 34, 965-977. (c) Kametani,
T.; Higashiyama, K.; Honda, T. Chem. Pharm. Bull. 1984, 32, 1614-
1618. (d) J ung, M. E.; Miller, S. J . J . Am. Chem. Soc. 1981, 103, 1984-
1992. (e) Dyke, S. F.; Kinsman, R. G.; Warren, P.; White, A. W .C.
Tetrahedron 1978, 34, 241-245 . (f) Dyke, S. F.; ; Ellis, A. C.; Kinsman,
R. G.; White, A. W .C. Tetrahedron 1974, 30, 1193-1199. (g) Rice, K.
C.; Ripka, W. C.; Reden, J .; Brossi, A. J . Org. Chem. 1980, 45, 601-
607.
(5) Tellitu, I.; Bad´ıa, D.; Dom´ınguez, E.; Garc´ıa, F. J . Tetrahedron:
Asymmetry 1994, 5, 1567-1578.
(6) Carrillo, L.; Bad´ıa, D.; Dom´ınguez, E.; Tellitu, I. Unpublished
results.
(7) (S)-(+)-Valinol and (S)-(+)-phenylglycinol were prepared by
reduction of L-valine and L-phenylglycine, respectively, using LiBH4-
Me3SiCl in THF at room temperature for 24 h. Nicola´s, E.; Russell, K.
C.; Hruby, V. J . J . Org. Chem. 1993, 58, 766-770.
(4) (a) Meyers, A. I.; Dickman, D. A.; Boes, M. Tetrahedron 1987,
43, 5095-5108. (b) Gottlieb, L.; Meyers, A. I. J . Org. Chem. 1990, 55,
5659-5662.
S0022-3263(97)00810-4 CCC: $14.00 © 1997 American Chemical Society

Synthetic Route to Chiral Isopavines
J . Org. Chem., Vol. 62, No. 20, 1997 6717
Sch em e 1
F igu r e 2.
Ta ble 2. Ch ir a l Am in es 4a -d a n d Isop a vin es 7a -d
P r ep a r ed
tR
tR
ee yield
substr prod R1
R2
R3
R4
OMe OMe
R5 R6 (min)a (min)b (%) (%)
3b 4a c OMe OMe H
13.6
9.7
10.2
10.7
15.9 95 92e
10.6 94 70f
13.3 94 80f
14.0 95 76e
19.1 95 96e
15.7 94 93f
14.5 94 88f
23.4 95 95e
3c
3d 4c
4b
H
H
OMe OMe OMe OMe
OMe H
OMe OMe
OCH2O
3e
6a
4d OMe OMe H
7a d OMe OMe H
OMe OMe Me 23.1
OMe OMe OMe OMe Me 23.3
Ta ble 1. Nu cleop h ilic Alk yla tion of Ch ir a l Im in e
6b 7b
6c 7c
H
H
Der iva tives 2a -c
OMe H
OMe OMe Me 18.9
OCH2O Me 21.6
yielda deb
R5 R6 (%) (%)
6d 7d OMe OMe H
entry substr prod R1
R2
R3
R4
a
Retention time for (S)-amines 4 or (5R,12S)-isopavines 7.
Retention time for (R)-amines 4 or (5S,12R)-isopavines 7. c The
OMe OMe iPr
OMe OMe Ph
OMe OMe OMe OMe Ph
80
80
b
1
2
3
4
5
1a + 2a 3a OMe OMe
1a + 2b 3b OMe OMe
H
H
80 >95
77 >95
76 >95
75 >95
HPLC conditions (Chiralcel OD, UV detector, n-hexane/2-propanol
1b + 2b 3c
1c + 2b 3d
H
H
50:50 as eluent; flow rate 0.9 mL/min) were optimized using a
racemic mixture of 4a .12 The HPLC conditions (Chiralcel OD,
d
OMe
H
H
OMe OMe Ph
1a + 2c 3e OMe OMe
OCH2O
Ph
UV detector, n-hexane/2-propanol 8:2 as eluent; flow rate 0.5 mL/
min) were optimized using a racemic mixture of 7a . e Crystallized.
f Oil.
a
b
Isolated yield of the mixture of diastereomers. Determined
by 1H NMR spectroscopy.
the group at the R position of the imines. Consequently,
the attack of the benzylic group occurs from the si-si
face (Figure 2), the less hindered face (Figure 2), of the
CdN bond leading to the (1S,1′S) isomer formation.11
This stereochemical proposal was a posteriori confirmed
on the heterocycles obtained by comparison with data
found in the literature.
Moreover, the chiral appendage was cleanly removed
from (1S,1S′)-3b-e by hydrogenolysis, thus providing the
corresponding primary (S)-amines 4a -d in high yield
without racemization. As shown in Table 2, the optical
purity in all the cases studied was shown to be greater
than 94% by HPLC.
In order to complete the synthesis (Scheme 2), the
amines 4a -d were alkylated with bromoacetaldehyde
diethyl acetal (BADA) to afford the corresponding acetals
5a -d . At this stage of the research, isopavines 6a -d
were successfully obtained in one step by acid-catalyzed
double cyclization. The observed behavior can be ex-
plained by assuming that the synthetic route involves
two sequential electrophilic cyclizations probably through
a 1-benzyltetrahydroisoquinoline intermediate.13 It is
noteworthy to point out that, when compared with other
previously reported synthesis of isopavines,3 the method
employed by our group, which uses H2SO4/HOAc as
cyclizing agent at room temperature, allows the prepara-
tion, in a short reaction time, of the isopavine framework
in almost quantitative yield. Besides, racemization
processes are not observed under the reaction conditions
chosen. These conditions gave better results than other
The so-obtained condensation derivatives were stable
and proved to consist of the typical imine-oxazolidine
tautomeric mixture.8 The aldimines 2 were assumed to
be in the E configuration on the basis of the report by
Hine9 and 13C NMR studies which showed only a single
resonance for the amino carbon (163 ppm). At this point,
imines 2a -c were submitted to addition reactions with
various Grignard reagents 1a -c, prepared in situ,10
exhibiting good to excellent levels of diasteroselection.
The transformations were carried out with 5 equiv of the
organometallic reagent at -10 °C; then, the crude was
later heated at 45-50 °C for 5 h, quenched with am-
monium chloride, and worked up in the usual manner.
The ratio of a diasteromeric mixture of amines 3 was
1
determined by H NMR spectroscopy, and it was found
to be dependent on the nature of the chiral support used
(see entries 1 and 2 in Table 1). Phenylglycinol-derived
imine 2b gave better stereoselectivity than the valinol-
derived imine 2a ; therefore phenylglycinol was selected
in order to prepare series of chiral (1S,1S′)-amines
3b-e. We presume that the remarkable stereocontrol
observed in the reported alkylation reactions can be
attributed to the formation of an internal chelate between
the magnesium atom of the Grignard reagent with the
hydroxy group and the lone pair electrons of the nitrogen
atom. Thus, the re and si faces are differentiated toward
the attack of the nucleophile because of the bulkiness of
(8) When the 1H NMR spectra were carried out in CDCl3, equilib-
rium mixtures of the imines 2 and the corresponding tautomeric
oxazolidines were observed, whereas the 1H NMR in CD3OD showed
resonances for only the open chain structures. For studies in imine-
oxazolidine tautomerism, see: (a) Lambert, J . B.; Majchrzak, M. W.
J . Am. Chem. Soc. 1980, 102, 3588-3591. (b) La´za´r, L.; Lakatos, A.
G.; Fu¨lo¨p, F.; Berna´th, G.; Riddell, F. G. Tetrahedron. 1997, 53, 1081-
1088 and references therein.
(9) Hine, J .; Yeh, C. H. J . Am. Chem. Soc. 1967, 89, 2669-2676.
(10) Obtained from activated magnesium by entrainment with 1,2-
dibromoethane and iodine. Hashigaki, K.; Kan, K.; Qais, N.; Takeuchi,
Y.; Yamato, M. Chem. Pharm. Bull. 1991, 39, 1126-1131.
(11) (a) Suzuki, Y.; Takahashi, H. Chem. Pharm. Bull. 1983, 31,
31-40. (b Takahashi, H.; Suzuki, Y.; Hori, T. Chem. Pharm. Bull. 1983,
31, 2183-2191.
(12) The 1,2-diarylethylamine 4a was prepared following the pro-
cedure described by Dyke, S. F.; Brown, D. W.; Sainsbury, M.; Hardy,
G. Tetrahedron 1971, 27, 3495-3502.
(13) Dyke, S. F.; Ellis, A. C.; Kinsman, R. G.; White, A. W .C.
Tetrahedron 1974, 30, 1193-1199.

6718 J . Org. Chem., Vol. 62, No. 20, 1997
Carrillo et al.
valinol [or (S)-(+)-phenylglycinol for 2b,c] (0.98 g, 8.5 mmol),
3,4-dimethoxybenzaldehyde (1.42 g, 9.5 mmol), and molecular
sieves (4 Å) in 60 mL of benzene was heated to reflux during
4 h. Then, after cooling, the mixture was filtered and the
solvent was distilled under vacuum to afford a residue that
was crystallized from Et2O-pentane (1.96 g, 92%): mp 102-
104 °C; [R]20D ) -42.0 (c ) 0.2, EtOH); 1H NMR (CD3OD) 0.89
(d, 3H, J ) 6.7), 0.97 (d, 3H, J ) 6.7), 1.87-1.95 (m, 1H), 3.28-
3.31 (m, 1H), 3.65 (dd, 1H, J ) 11.2, 8.4), 3.83 (dd, 1H, J )
11.2, 3.6), 3.86 (s, 3H), 3.87 (s, 3H), 6.99 (d, 1H, J ) 8.3), 7.24
(dd, 1H, J ) 8.3, 1.8), 7.52 (d, 1H, J ) 1.8), 8.17 (s, 1H); 13C
NMR (CD3OD) 19.7, 20.2, 31.1, 56.4, 64.8, 80.4, 110.8, 112.1,
124.8, 130.3, 150.7, 153.1, 163.9; IR (KBr) υ 3330-3100, 1680
cm-1; MS (EI) m/ z (rel intensity) 251 (M+, 11), 220 (M+ - 31,
100), 208 (21), 178 (12), 151 (28), 55 (12). Anal. Calcd for
C14H21NO3: C, 66.91; H, 8.42; N, 5.57. Found: C, 66.81; H,
8.62; N, 5.21.
Sch em e 2
(-)-(1′S)-(E)-N-(2-H yd r oxy-1-p h en ylet h yl)-3,4-d im e-
th oxyben zylid en ea m in e (2b). According to the typical
procedure imine 2b was obtained from (S)-(+)-phenylglycinol
and 3,4-dimethoxybenzaldehyde in 95% yield: mp 69-72 °C
(n-heptane); [R]20D ) -65.6 (c ) 0.2, EtOH); 1H NMR (CD3OD)
3.81 (s, 3H), 3.84 (s, 3H), 3.87 (d, 2H, J ) 6.5), 4.43 (t, 1H, J
) 6.5); 6.99 (d, 1H, J ) 8.0), 7.23-7.51 (m, 7H), 8.39 (s, 1H);
13C NMR (CD3OD) 56.3, 67.6, 78.1, 110.8, 112.1, 124.9, 128.4,
129.5, 130.5, 142.3, 150.7, 153.2, 163.9; IR (KBr) υ 3600-3200,
Sch em e 3
1638 cm-1; MS (EI) m/ z (rel intensity) 285 (M+, 4), 254 (M+
-
31, 100), 149 (12), 91 (8), 71 (8), 57 (11). Anal. Calcd for
C17H19NO3: C, 71.56; H, 6.71; N, 4.95. Found: C, 71.31; H,
6.93; N, 4.98.
(-)-(1′S)-(E)-N-(2-Hyd r oxy-1-p h en yleth yl)-3,4-(m eth yl-
en ed ioxy)-ben zylid en ea m in e (2c). According to the typical
procedure imine 2c was obtained from (S)-(+)-phenylglycinol
and 3,4-(methylenedioxy)benzaldehyde in 91% yield: mp 101-
103 °C (n-heptane); [R]20 ) -111.2 (c ) 1.0, EtOH); 1H NMR
D
(CD3OD) 3.92 (d, 2H, J ) 6.5), 4.46 (t, 1H, J ) 6.5), 6.04 (s,
2H), 6.91 (d, 1H, J ) 8.0), 7.24-7.56 (m, 7H), 8.36 (s, 1H); 13
C
NMR (CD3OD) 67.8, 77.9, 102.9, 107.5, 108.9, 126.2, 128.4,
129.5, 132.1, 142.4, 149.7, 151.5, 163.2; IR (KBr) υ 3330-3100,
1635 cm-1; MS (EI) m/ z (rel intensity) 269 (M+, 2), 238 (M+
-
methods previously reported for this kind of double
cyclization.14 Finally, in order to accomplish the final
products, a N-methylation reaction was carried out, thus
affording a series of N-methylated isopavines (7a -d )
with optical purities greater than 94% (see Table 2).
We would also like to report that an alternative
sequence of steps in the route toward the synthesis of
N-methylisopavines 7 was also studied. In this case (see
Scheme 3), when the methylation step was carried out
prior to the final cyclization process, a partial racemiza-
tion was detected in the final product. This low optical
purity was also observed in dialkylated amine 8 and was
calculated to be ca. 88% by HPLC (Chiralcel OD, UV
detector, n-hexane/2-propanol 75:25 as eluent; flow rate
0.5 mL/min; retention times 16.9 min for the R isomer,
19.4 min for the S isomer).
31, 100), 180 (9), 77 (15). Anal. Calcd for C16H15NO3: C, 71.36;
H, 5.61; N, 5.20. Found: C, 71.19; H, 5.59; N, 5.14.
Typ ica l P r oced u r e for th e Syn th esis of Am in es 3a -e.
Syn th esis of (+)-(1S,1′S)-1,2-Bis(3,4-d im eth oxyp h en yl)-
N-(2-h yd r oxy-1-isop r op yleth yl)-eth yla m in e (3a ). A solu-
tion of imine 2a (1.7 g, 6.77 mmol) in THF (20 mL) was added
to a freshly prepared solution of (3,4-dimethoxybenzyl)mag-
nesium chloride (1a ) (5 equiv) in 55 mL of the same solvent,
and the mixture was heated at 45-50 °C during 5 h. Then,
after cooling, the reaction was quenched with 20 mL of a
saturated solution of NH4Cl, and decanted, and the aqueous
layer was extracted twice with 20 mL of Et2O. The combined
organic extracts were dried over Na2SO4, and the solvent was
distilled under vacuum. The residue was column chromato-
graphed (hexanes/ethyl acetate, 1:1) to afford 3a (3.41 g, 80%)
as a colorless oil. An analytically pure sample was obtained
by crystallization from n-heptane: mp 94-95 °C; [R]20
)
D
+63.5 (c ) 0.1, EtOH); 1H NMR (CDCl3) 0.83 (d, 3H, J ) 6.8),
0.87 (d, 3H, J ) 6.8), 1.61-1.75 (m, 1H), 2.22-2.28 (m, 1H),
2.84 (d, 1H, J ) 7.1), 2.85 (d, 1H, J ) 7.1), 3.35 (dd, 1H, J )
11.0, 4.4), 3.55 (dd, 1H, J ) 11.0, 4.2), 3.77 (s, 3H), 3.80-3.86
(m, 10H), 6.52 (d, 1H, J ) 1.9), 6.62 (dd, 1H, J ) 8.0, 1.9),
6.68-6.80 (m, 4H); 13C NMR (CDCl3) 19.1, 19.5, 29.5, 44.8,
55.7, 55.8, 59.9, 61.1, 61.6, 109.9, 110.7, 110.9, 112.5, 119.5,
121.3, 131.3 136.4, 147.4, 147.9, 148.5, 148.9; IR (KBr) υ 3500-
3300 cm-1; MS (EI) m/ z (rel intensity) 300 (100), 285 (55),
234 (37), 205 (26), 181 (13), 151 (21), 128 (11), 91 (10). Anal.
Calcd for C23H33NO5: C, 68.46; H, 8.24; N, 3.47. Found: C,
68.07; H, 7.95; N, 3.80.
In summary, a simple and very efficient synthetic route
to obtain optically pure isopavine alkaloids has been
developed starting from chiral 1,2-diarylethylamines,
which, in turn, were obtained enantiomerically pure by
using phenylglycinol as chiral auxiliary, and it has been
applied with great success to the preparation of natural
(-)-O-methylthalisopavine (7a ) and (-)-amurensinine
(7d ).
Exp er im en ta l Section 15
(+)-(1S,1′S)-1,2-Bis(3,4-dim eth oxyph en yl)-N-(2-h ydr oxy-
1-p h en yl-eth yl)eth yla m in e (3b). According to the typical
procedure amine 3b was obtained from imine 2b and (3,4-
Typ ica l P r oced u r e for th e Syn th esis of Im in es 2a -c.
Syn th esis of (-)-(1′S)-(E)-N-(2-Hydr oxy-1-isopr opyleth yl)-
3,4-d im eth oxyben zylid en ea m in e (2a ). A mixture of L-
dimethoxybenzyl)magnesium chloride (1a ) in 80% yield: mp
1
104-106 °C (n-heptane); [R]20 ) +62.3 (c ) 0.1, EtOH); H
D
(14) See refs 3b, 3c, and 13.
(15) For general procedures, see: Sotomayor, N.; Dom´ınguez, D.;
Lete, E. J . Org. Chem. 1996, 61, 4062-4074.
NMR (CDCl3) 2.10 (br s, 2H), 2.88 (dd, 1H, J ) 13.4, 6.9), 2.97
(dd, 1H, J ) 13.4, 6.4), 3.53 (dd, 1H, J ) 10.6, 6.9), 3.66-3.88

Synthetic Route to Chiral Isopavines
J . Org. Chem., Vol. 62, No. 20, 1997 6719
(m, 15H), 6.44 (d, 1H, J ) 1.9), 6.51-6.73 (m, 5H), 7.14-7.29
(m, 5H); 13C NMR (CDCl3) 43.5, 55.6, 55.7, 55.8, 61.6, 61.8,
65.5, 110.2, 110.7, 110.8, 112.6, 119.3, 121.3, 127.1, 127.3,
128.4, 131.0, 136.0, 141.1, 147.3, 147.9, 148.4, 148.7; IR (KBr)
υ 3520-3200 cm-1; MS (EI) m/ z (rel intensity) 300 (100), 285
(51), 225 (16), 207 (9), 151 (12), 128 (9), 119 (8), 91 (7), 77 (5).
Anal. Calcd for C26H31NO5: C, 71.37; H, 7.14; N, 3.20.
Found: C, 71.15; H, 7.18; N, 3.16.
+32.0 (c ) 0.1, CH2Cl2); 1H NMR (CDCl3) 1.56 (br s, 2H), 2.82
(dd, 1H, J ) 13.1, 8.5), 2.98 (dd, 1H, J ) 13.1, 5.1), 3.79 (s,
3H), 3.83 (s, 6H), 3.84 (s, 3H), 4.18 (dd, 1H, J ) 8.5, 5.1), 6.67-
6.91 (m, 6H); 13C NMR (CDCl3) 40.8, 55.5, 55.7, 56.1, 60.3,
109.5, 110.6, 110.8, 118.1, 122.7, 123.5, 132.9, 138.7, 147.3,
147.7, 148.7, 152.6; IR (neat) υ 3260, 3240 cm-1; MS (EI) m/ z
(rel intensity) 316 (M+ - 1, 1), 166 (100), 139 (12), 124 (15).
Anal. Calcd for C18H23NO4: C, 68.11; H, 7.30; N, 4.41.
Found: C, 78.34; H, 7.42; N, 4.17.
(+)-(1S ,1′S )-1-(3,4-D im e t h o x y p h e n y l)-2-(2,3-d im e -
t h oxyp h en yl)-N-(2-h yd r oxy-1-p h en ylet h yl)et h yla m in e
(3c). According to the typical procedure, amine 3c was
obtained from imine 2b and (2,3-dimethoxybenzyl)magnesium
(+)-(1S)-1-(3,4-Dim et h oxyp h en yl)-2-(3-m et h oxyp h en -
yl)eth yla m in e (4c). According to the typical procedure,
amine 4c was obtained from amine 3d in 80% yield: [R]20
)
D
chloride (1b) in 77% yield: [R]20 ) +74.2 (c ) 0.5, EtOH); 1H
+25.0 (c ) 0.1, CH2Cl2); 1H NMR (CDCl3) 1.30 (br s, 2H), 2.78
(dd, 1H, J ) 13.2, 8.5), 2.95 (dd, 1H, J ) 13.2, 5.1), 3.75 (s,
3H), 3.85 (s, 6H), 4.15 (dd, 1H, J ) 8.5, 5.1), 6.70-6.89 (m,
6H), 7.18 (t, 1H, J ) 7.8); 13C NMR (CDCl3) 46.7, 55.1, 55.9,
56.0, 57.1, 110.1, 111.5, 111.8, 115.0, 118.5, 121.7, 129.3, 138.5,
140.7, 148.2, 149.1, 159.7; IR (neat) υ 3360, 3340 cm-1; MS
(EI) m/ z (rel intensity) 286 (M+ - 1, 1), 166 (100), 139 (12),
124 (15). Anal. Calcd for C17H20NO3: C, 71.06; H, 7.36; N,
4.87. Found: C, 71.04; H, 7.46; N, 4.59.
D
NMR (CDCl3) 2.25 (br s, 2H), 2.85 (dd, 1H, J ) 13.1, 7.1), 3.11
(dd, 1H, J ) 13.1, 6.9), 3.47 (dd, 1H, J ) 10.6, 7.2), 3.67-3.73
(m, 7H), 3.80-3.91 (m, 8H), 6.49-6.89 (m, 6H), 7.16-7.24 (m,
5H); 13C NMR (CDCl3) 38.3, 55.6, 55.7, 55.8, 60.4, 60.9, 65.6,
110.2, 110.6, 110.8, 119.0, 122.9, 123.5, 127.1, 127.3, 128.4,
132.7, 136.6, 141.4, 147.3, 147.8, 148.6, 152.6; IR (neat) υ
3500-3300 cm-1; MS (EI) m/ z (rel intensity) 438 (M++1, 4),
301 (23), 286 (100), 166 (81), 151 (13), 121 (17), 103 (20), 91
(18), 77 (14). Anal. Calcd for C26H31NO5: C, 71.37; H, 7.14;
N, 3.20. Found: C, 71.19; H, 7.22; N, 3.14.
(+)-(1S,1′S)-2-(3,4-Dim et h oxyp h en yl)-1-(3,4-(m et h yl-
en ed ioxy)p h en yl)-eth yla m in e (4d ). According to the typi-
cal procedure, amine 4d was obtained from amine 3e in 76%:
mp 220-222 °C (EtOH-Et2O as HCl salt) (lit.12 mp 225-226
(+)-(1S,1′S)-1-(3,4-Dim eth oxyp h en yl)-N-(2-h yd r oxy-1-
p h en yleth yl)-2-(3-m eth oxyp h en yl)eth yla m in e (3d ). Ac-
cording to the typical procedure, amine 3d was obtained from
°C, racemate); [R]20 ) +38.6 (c ) 1.0, CH2Cl2); 1H NMR
D
imine 2b and (3-methoxybenzyl)magnesium chloride (1c) in
(CDCl3) 1.61 (br s, 2H), 2.74 (dd, 1H, J ) 13.4, 8.5), 2.89 (dd,
1H, J ) 13.3, 5.1), 3.81 (s, 3H), 3.84 (s, 3H), 4.08 (dd, 1H, J )
8.5, 5.1), 5.92 (s, 2H), 6.60-6.68 (m, 6H); 13C NMR (CDCl3)
45.2, 55.6, 55.7, 57.2, 100.8, 106.8, 107.8, 111.0, 112.4, 119.5,
121.2, 130.7, 131.2, 146.3, 147.0, 147.5, 148.6; IR (neat) υ 3250,
3200 cm-1; MS (EI) m/ z (rel intensity) 301 (M+, 1), 150 (100),
123 (8), 93 (17), 65 (19). Anal. Calcd for C17H19NO4: C, 67.76;
H, 6.35; N, 4.65. Found: C, 67.88; H, 5.99; N, 4.44.
1
76% yield: [R]20 ) +57.0 (c ) 0.1, EtOH); H NMR (CDCl3)
D
2.22 (br s, 2H), 2.89 (dd, 1H, J ) 13.3, 6.9), 3.02 (dd, 1H, J )
13.3, 6.9), 3.52 (dd, 1H, J ) 10.7, 7.0), 3.63-3.69 (m, 12H),
6.55-6.83 (m, 6H), 7.10-7.29 (m, 6H); 13C NMR (CDCl3) 44.2,
55.0, 55.8, 55.9, 61.9, 65.6, 110.7, 111.3, 111.8, 115.1, 119.3,
121.8, 127.2, 127.3, 128.4, 129.0, 136.3, 140.3, 141.4, 148.2,
148.9, 159.5; IR (neat) υ 3550-3250 cm-1; MS (EI) m/ z (rel
intensity) 286 (100), 271 (17), 218 (32), 190 (10), 166 (66), 121
(17), 91 (13), 77 (13). Anal. Calcd for C25H29NO4: C, 73.68;
H, 7.17; N, 3.43. Found: C, 73.33; H, 7.39; N, 3.57.
Typ ica l P r oced u r e for th e Syn th esis of N-Alk yla ted
Am in es 5a-d. Syn th esis of (+)-(1S)-1,2-Bis(3,4-dim eth oxy-
p h en yl)-N-(2,2-d ieth oxyeth yl)eth yla m in e (5a ). Over a
stirred suspension of K2CO3 (0.97 g, 8.2 mmol) in 25 mL of
dry acetonitrile was added a solution of amine 4a (0.8 g, 2.52
mmol) in 15 mL of the same solvent and the mixture was
refluxed during 2 h. Then, BADA (1.52 mL, 10.1 mmol) was
added at once and the reflux was continued until the conver-
sion was completed (3 d). After cooling, the mixture was
quenched with water and dried over Na2SO4 and the solvent
was removed in vacuo to afford, after crystallization from
(+)-(1S,1′S)-2-(3,4-Dim et h oxyp h en yl)-1-(3,4-(m et h yl-
e n e d ioxy)p h e n yl)-N -(2-h yd r oxy-1-p h e n yle t h yl)e t h yl-
a m in e (3e). According to the typical procedure, amine 3e was
obtained from imine 2c and (3,4-dimethoxybenzyl)magnesium
chloride (1a ) in 75% yield: [R]20 ) +55.3 (c ) 1.0, EtOH); 1H
D
NMR (CDCl3) 2.61 (br s, 2H), 2.80 (dd, 1H, J ) 13.4, 7.3), 2.97
(dd, 1H, J ) 13.5, 6.2), 3.50 (dd, 1H, J ) 10.7, 7.2), 3.66-3.85
(m, 9H), 5.83 (s, 1H), 5.84 (s, 1H), 6.41-6.70 (m, 6H), 7.14-
7.25 (m, 5H); 13C NMR (CDCl3) 42.9, 55.4, 55.5, 61.4, 61.5, 65.3,
100.5, 107.2, 107.6, 110.7, 112.4, 120.3, 121.1, 126.9, 127.1,
128.2, 130.8, 137.3, 140.8, 146.2, 147.1, 147.3, 148.2; IR (neat)
υ 3550-3250 cm-1; MS (EI) m/ z (rel intensity) 422 (M+ + 1,
1), 285 (9), 270 (100), 150 (72). Anal. Calcd for C25H27NO5:
C, 71.24; H, 6.46; N, 3.32. Found: C, 71.19; H, 6.11; N, 3.14.
Typ ica l P r oced u r e for t h e Clea va ge of N-Ben zyl
Gr ou p s. Syn th esis of (+)-(1S)-1,2-Bis(3,4-d im eth oxyp h e-
n yl)eth yla m in e (4a ). A solution of the amine 3b (0.88 g, 2
mmol) in EtOH (20 mL) was hydrogenated in the presence of
10% Pd-C (0.8 g) and 8 mL of 10% HCl. After absorption of
hydrogen was complete (45-60 h), the catalyst was filtered
off, and the filtrate was made basic with a saturated NaHCO3
solution and extracted twice with 20 mL of CH2Cl2. The
combined organic layers were dried with Na2SO4, and the
solvent was evaporated off under reduced pressure. The
resulting residue was purified by flash column chromatogra-
phy to afford 4a as a colorless oil that was crystallized from
EtOH (580 mg, 92%): mp 101-103 °C (lit.12 mp 106-107 °C,
hexanes, pure amine 5a as a white solid (1.02 g, 93%): mp
1
73-75 °C; [R]20 ) +20.5 (c ) 0.4, CH2Cl2); H NMR (CDCl3)
D
0.98 (t, 6H, J ) 7.0), 1.67 (br s, 1H), 2.39-2.44 (m, 2H), 2.69-
2.74 (m, 2H), 3.25-3.40 (m, 2H), 3.42-3.48 (m, 2H), 3.60-
3.66 (m, 1H), 3.68 (s, 3H), 3.72 (s, 3H), 3.74 (s, 3H), 3.75 (s,
3H), 4.39 (t, J ) 5.1, 1H), 6.49-6.78 (m, 6H); 13C NMR (CDCl3)
14.9, 44.7, 49.5, 55.4, 55.5, 61.4, 61.5, 64.2 (C-1), 101.5, 109.9,
110.7, 111.0, 112.4, 119.3, 120.9, 131.2, 136.0, 147.3, 147.8,
148.5, 148.8; IR (KBr) υ 3310, 1260 cm-1
. Anal. Calcd for
C24H35NO6: C, 66.49; H, 8.13; N, 3.23. Found: C, 66.67; H,
8.29; N, 3.14.
(+)-(1S)-N-(2,2-Dieth oxyeth yl)-1-(3,4-dim eth oxyph en yl)-
2-(2,3-d im eth oxyp h en yl)eth yla m in e (5b). According to the
typical procedure, amine 5b was obtained from amine 4b in
55% yield: [R]20 ) +16.2 (c ) 1.0, CH2Cl2); 1H NMR (CDCl3)
D
1.07 (t, 6H, J ) 7.0), 2.00 (br s, 1H), 2.48-2.52 (m, 2H), 2.89
(d, 2H, J ) 6.8), 3.33-3.47 (m, 2H), 3.50-3.56 (m, 2H), 3.74-
3.79 (m, 4H), 3.82 (s, 9H), 4.49 (t, 1H, J ) 5.5), 6.60-6.91 (m,
6H); 13C NMR (CDCl3) 14.9, 39.3, 49.5, 55.3, 55.5, 60.2, 61.6,
61.7, 63.0, 101.5, 109.7, 110.5, 119.1, 122.6, 123.3, 128.0, 132.5,
racemate); [R]20 ) +30.0 (c ) 0.1, CH2Cl2); 1H NMR (CDCl3)
D
1.55 (br s, 2H), 2.75 (dd, 1H, J ) 13.4, 8.4), 2.89 (dd, 1H, J )
13.4, 5.2), 3.81 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 3.88 (s, 3H),
4.12 (dd, 1H, J ) 8.4, 5.2), 6.62-6.90 (m, 6H); 13C NMR
(CDCl3) 46.0, 55.7, 55.8, 55.9, 57.2, 109.5, 110.9, 111.1, 112.4,
118.4, 121.2, 131.5, 138.2, 147.5, 147.9, 148.6, 148.8; IR (KBr)
υ 3260, 3240 cm-1; MS (EI) m/ z (rel intensity) 316 (M+ - 1,
1), 166 (100), 139 (10), 124 (12). Anal. Calcd for C18H23NO4:
C, 68.11; H, 7.30; N, 4.41. Found: C, 68.02; H, 7.12; N, 4.05.
(+)-(1S)-1-(3,4-Dim eth oxyph en yl)-2-(2,3-dim eth oxyph e-
n yl)eth yla m in e (4b). According to the typical procedure,
136.3, 147.1, 147.6, 148.6, 152.5; IR (neat) υ 3310, 1270 cm-1
;
MS (EI) m/ z (rel intensity) 301 (15), 282 (53), 236 (100), 190
(32), 151 (30). Anal. Calcd for C24H35NO6: C, 66.49; H, 8.13;
N, 3.23. Found: C, 66.29; H, 8.29; N, 3.14.
(+)-(1S)-N-(2,2-Dieth oxyeth yl)-1-(3,4-dim eth oxyph en yl)-
2-(3-m eth oxyp h en yl)eth yla m in e (5c). According to the
typical procedure, amine 5b was obtained from amine 4b in
57% yield: [R]20 ) +17.2 (c ) 0.4, CH2Cl2); 1H NMR (CDCl3)
D
0.97 (t, 3H, J ) 7.0), 0.98 (t, 3H, J ) 7.0), 1.79 (br s, 1H),
2.38-2.44 (m, 2H), 2.73-2.78 (m, 2H), 3.23-3.33 (m, 2H),
3.36-3.48 (m, 2H), 3.61 (s, 3H), 3.64-3.69 (m, 1H), 3.72 (s,
amine 4b was obtained from amine 3c in 70% yield: [R]20
)
D

6720 J . Org. Chem., Vol. 62, No. 20, 1997
Carrillo et al.
3H), 3.74 (s, 3H), 4.39 (t, 1H, J ) 5.3), 6.58-6.79 (m, 6H), 7.05
(t, 1H, J ) 7.7); 13C NMR (CDCl3) 14.8, 45.1, 49.3, 54.5, 55.3,
61.3, 61.5, 63.9, 101.3, 109.5, 110.5, 111.4, 114.3, 119.1, 121.1,
128.8, 135.8, 139.9, 147.6, 148.6, 159.2; IR (neat) υ 3310, 1260
cm-1; MS (EI) m/ z (rel intensity) 358 (M+ - 45, 1), 309 (10),
282 (59), 271 (30), 236 (100), 190 (41), 151 (21). Anal. Calcd
for C23H33NO5: C, 68.46; H, 8.24; N, 3.47. Found: C, 68.29;
H, 8.51; N, 3.19.
) 11.2), 3.69 (d, 1H, J ) 3.8), 3.76 (s, 3H), 3.86 (s, 3H), 4.24
(t, 1H, J ) 3.5), 5.83 (d, 1H, J ) 1.1), 5.89 (d, 1H, J ) 1.1),
6.51 (s, 1H), 6.64 (s, 1H), 6.69 (s, 1H), 6.70 (s, 1H); 13C NMR
(CDCl3) 40.8, 45.8, 50.3, 54.5, 55.7, 55.8, 100.5, 106.1, 106.2,
111.1, 114.1, 126.4, 132.3, 134.7, 134.9, 145.8, 146.1, 146.5,
147.6; IR (KBr) υ 3310 cm-1; MS (EI) m/ z (rel intensity) 325
(M+, 26), 308 (M+ - 17, 11), 296 (M+ - 29, 93), 253 (27),174
(100). Anal. Calcd for C19H19NO4: C, 70.14; H, 5.88; N, 4.30.
Found: C, 70.19; H, 5.69; N, 4.34.
(+)-(1S)-N-(2,2-Dieth oxyeth yl)-2-(3,4-dim eth oxyph en yl)-
1-(3,4-(m eth ylen ed ioxy)p h en yl)eth yla m in e (5d ). Accord-
Typ ica l P r oced u r e for th e N-Meth yla tion of Isop a vi-
n a n es 6. Syn th esis of (-)-(5R,12S)-N-Meth yl-2,3,8,9-tet-
r am eth oxyisopavin an e (7a) [(-)-O-Meth ylth alisopavin e.].
Isopavinane 6a (0.15 g, 0.44 mmol) was dissolved in dry
acetonitrile (20 mL) under argon and 35% aqueous HCHO
(0.17 mL, 2.2 mmol) and NaBH3CN (0.055 g, 0.88 mmol) were
added in one portion. The solution was stirred at room
temperature until the conversion was complete (90 min).
Then, the mixture was quenched with water and extracted
twice with 15 mL of CH2Cl2. The organic extracts were
combined and dried over Na2SO4, and the solvent was removed
in vacuo. Isopavinane 7a was purified by crystallization from
ing to the typical procedure, amine 5d was obtained from
1
amine 4d in 57% yield: [R]20 ) +12.9 (c ) 1.0, CH2Cl2); H
D
NMR (CDCl3) 1.02 (t, 3H, J ) 7.0), 1.04 (t, 3H, J ) 7.0), 1.95
(br s, 1H), 2.41-2.47 (m, 2H), 2.71-2.77 (m, 2H), 3.32-3.45
(m, 2H), 3.47-3.50 (m, 2H), 3.64-3.71 (m, 1H), 3.74 (s, 3H),
3.76 (s, 3H), 4.43 (t, 1H, J ) 5.1), 5.84 (s, 2H), 6.51-6.69 (m,
6H); 13C NMR (CDCl3) 14.9, 44.7, 49.4, 55.4, 55.5, 61.5, 61.7,
64.3, 100.5, 101.5, 107.1, 107.6, 110.9, 112.1, 120.3, 120.9,
137.4, 139.9, 146.2, 147.2, 147.5, 148.4; IR (neat) υ 3300, 1270
cm-1. Anal. Calcd for C23H31NO6: C, 67.17; H, 7.48; N, 3.35.
Found: C, 67.19; H, 7.59; N, 3.14.
CCl4 (0.15 g, 96%): mp 157-159 °C (lit.4a mp 155 °C); [R]20
Typ ica l P r oced u r e for th e Syn th esis of Isop a vin a n es
6a -d . Syn th esis of (-)-(5R,12S)-2,3,8,9-Tetr a m eth oxy-
isop a vin a n e (6a ). H2SO4 (concentrated) (1.31 mL, 23.6
mmol) was added over a stirred solution of amino acetal 5a
(1.02 g, 2.36 mmol) in acetic acid (30 mL), and the mixture
was stirred at room temperature during 30 min. Then, the
solvent was removed under reduced pressure, and the residue
was basified with NH4OH and extracted twice with 30 mL of
CH2Cl2. The combined extracts were dried over Na2SO4 and
the solvent was evaporated in vacuo. Isopavine 6a was
purified by crystallization from EtOH (0.75 g, 93%): mp 169-
171 °C (EtOH) (lit.3d mp 149-159 °C, racemate); [R]20D ) -90.0
(c ) 0.1, EtOH); 1H NMR (CDCl3) 2.04 (br s, 1H), 3.11 (dd,
1H, J ) 17.2, 3.0), 3.22 (dd, 1H, J ) 11.1, 4.3), 3.33 (dd, 1H,
J ) 17.2, 3.9), 3.58 (d, 1H, J ) 11.1), 3.68 (d, 1H, J ) 3.9),
3.75 (s, 3H), 3.83 (s, 3H), 3.84 (s, 3H), 3.86 (s, 3H), 4.22 (t, 1H,
J ) 3.4), 6.51 (s, 1H), 6.66 (s, 1H), 6.74 (s, 2H); 13C NMR
(CDCl3) 41.6, 45.9, 50.9, 54.4, 55.8, 55.9, 56.0, 109.1, 109.2,
111.4, 114.4, 126.7, 131.8, 134.1, 135.1, 146.6, 147.6, 147.8;
D
) -103.6 (c ) 0.2, EtOH); 1H NMR (CDCl3) 2.48 (s, 3H), 2.85
(dd, 1H, J ) 10.4, 5.9), 2.90 (dd, 1H, J ) 17.3, 3.0), 3.45-3.63
(m, 3H), 3.76 (s, 3H), 3.85 (s, 6H), 3.86 (s, 3H), 3.89-3.93 (m,
1H), 6.52 (s, 1H), 6.65 (s, 1H), 6.74 (s, 1H), 6.76 (s, 1H); 13C
NMR (CDCl3) 38.4, 45.2, 46.0, 55.9, 56.1, 56.3, 60.1, 62.4, 109.3,
110.6, 111.8, 114.8, 126.9, 130.5, 134.2, 134.9, 146.8, 147.8,
147.9, 148.2; MS (EI) m/ z (rel intensity) 355 (M+, 16), 354 (M+
- 1, 19), 312 (M+ - 43), 204 (M+ - 151, 100). Anal. Calcd
for C21H25NO4: C, 70.95; H, 7.09; N, 3.94. Found: C, 70.83;
H, 7.15; N, 3.77.
(-)-(5R,12S)-N-Met h yl-2,3,9,10-t et r a m et h oxyisop a vi-
n a n e (7b). According to the typical procedure, isopavinane
7b was obtained from isopavinane 6b in 93% yield: [R]20
)
D
-109.6 (c ) 1.0, CH2Cl2); 1H NMR (CDCl3) 2.46 (s, 3H), 2.82-
2.92 (m, 2H), 3.42-3.52 (m, 2H), 3.68 (d, 1H, J ) 4.0), 3.73 (s,
3H), 3.75 (s, 3H), 3.81 (s, 3H), 3.84 (s, 3H), 3.90 (t, 1H, J )
3.5), 6.63 (d, 1H, J ) 8.3), 6.72 (s, 1H), 6.75 (s, 1H), 6.84 (d,
1H, J ) 8.3); 13C NMR (CDCl3) 32.9, 44.9, 45.5, 55.4, 55.7,
55.9, 59.3, 59.5, 61.6, 108.7, 109.6, 109.9, 122.3, 129.2, 130.1,
133.4, 135.7, 147.3, 147.7, 147.9, 151.0; MS (EI) m/ z (rel
intensity) 354 (M+ - 1, 30), 312 (39), 297 (31), 204 (100). Anal.
Calcd for C21H25NO4: C, 70.95; H, 7.09; N, 3.94. Found: C,
70.99; H, 7.19; N, 3.74.
IR (KBr) υ 3340 cm-1; MS (EI) m/ z (rel intensity) 340 (M+
-
1, 9), 339 (M+ - 2, 47), 312 (M+ - 29, 100), 308 (10), 269 (48),
156 (23). Anal. Calcd for C20H23NO4: C, 70.36; H, 6.79; N,
4.10. Found: C, 70.19; H, 6.59; N, 4.14.
(-)-(5R,12S)-2,3,9,10-Tetr a m eth oxyisop a vin a n e (6b).
According to the typical procedure, isopavinane 6b was
obtained from amino acetal 5b in 98% yield: [R]20D ) -60.5 (c
) 1.0, CH2Cl2); 1H NMR (CDCl3) 2.17 (br s, 1H), 3.10 (dd, 1H,
J ) 18.2, 3.2), 3.23 (dd, 1H, J ) 11.2, 4.5), 3.31 (dd, 1H, J )
18.2, 3.9), 3.57 (d, 1H, J ) 11.2), 3.73-3.78 (m, 7H), 3.84 (s,
6H), 4.30 (t, 1H, J ) 3.5), 6.67 (d, 1H, J ) 8.2), 6.73 (s, 1H),
6.74 (s, 1H), 6.88 (d, 1H, J ) 8.2); 13C NMR (CDCl3) 36.5, 45.8,
50.7, 54.0, 55.6, 55.9, 56.1, 59.5, 109.1, 109.8, 122.6, 129.5,
131.8, 133.7, 136.3, 147.5, 147.8, 148.1, 151.1; IR (neat) υ 3350
(-)-(5R,12S)-N-Meth yl-2,3,9-tr im eth oxyisopavin an e (7c).
According to the typical procedure, isopavinane 7c was
obtained from isopavinane 6c in 88% yield: [R]20 ) -111.6
D
(c ) 0.6, EtOH); 1H NMR (CDCl3) 2.50 (s, 3H), 2.89 (dd, 1H, J
) 10.8, 4.6), 2.98 (dd, 1H, J ) 17.8, 3.2), 3.54-3.70 (m, 6H),
3.84 (s, 3H), 3.85 (s, 3H), 3.95 (t, 1H, J ) 3.5), 6.57-6.61 (m,
2H), 6.74 (s, 1H), 6.77 (s, 1H), 7.03 (d, 1H, J ) 8.0); 13C NMR
(CDCl3) 38.0, 45.0, 55.1, 55.9, 56.1, 59.6, 62.2, 108.8, 110.2,
111.4, 116.3, 128.5, 129.0, 133.7, 134.6, 135.8, 147.6, 148.2,
158.4; MS (EI) m/ z (rel intensity) 325 (M+, 30), 324 (M+ - 1,
cm-1; MS (EI) m/ z (rel intensity) 340 (M+ - 1, 32), 312 (M+
-
29, 100), 297 (79), 190 (74). Anal. Calcd for C20H23NO4: C,
70.36; H, 6.79; N, 4.10. Found: C, 70.33; H, 6.69; N, 4.33.
(-)-(5R,12S)-2,3,9-Tr im et h oxyisop a vin a n e (6c). Ac-
cording to the typical procedure, isopavinane 6c was obtained
41), 282 (M+
- 43, 56), 204 (100). Anal. Calcd for
C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C, 73.79; H,
7.29; N, 4.44.
(-)-(5R ,12S )-N -Me t h yl-2,3-(m e t h yle n e d ioxy)-8,9-d i-
m eth oxyisop a vin a n e (7d ) [(-)-Am u r en sin in e]. According
to the typical procedure, amurensinine 7d was obtained from
from amino acetal 5c in 90% yield: mp 93-95 °C (EtOH/Et2O);
1
[R]20 ) -71.5 (c ) 1.0, CH2Cl2); H NMR (CDCl3) 2.71 (br s,
D
1H), 3.20 (dd, 1H, J ) 11.3, 4.5), 3.39 (dd, 1H, J ) 17.6, 3.5),
3.54 (d, 1H, J ) 11.3), 3.69 (s, 3H), 3.71-3.75 (m, 2H), 3.83 (s,
6H), 4.24 (t, 1H, J ) 3.2), 6.56-6.62 (m, 2H), 6.73 (s, 1H), 6.74
(s, 1H), 7.06 (d, 1H, J ) 8.2); 13C NMR (CDCl3) 41.5, 45.0, 50.3,
53.9, 54.7, 55.6, 55.8, 108.8, 110.9, 116.1, 128.4, 131.2, 133.8,
135.0, 136.0, 147.2, 147.5, 157.9; IR (KBr) υ 3360 cm-1; MS
(EI) m/ z (rel intensity) 309 (M+ - 2, 25), 282 (M+ - 29, 100),
251 (15), 239 (40), 208 (35). Anal. Calcd for C19H21NO3: C,
73.28; H, 6.79; N, 4.49. Found: C, 73.19; H, 6.58; N, 4.22.
(-)-(5R,12S)-8,9-Dim et h oxy-2,3-(m et h ylen ed ioxy)iso-
p a vin a n e (6d ). According to the typical procedure, isopavi-
nane 6d was obtained from amino acetal 5d in 95% yield: mp
129-131 °C (EtOH); [R]20D ) -54.0 (c ) 1.0, CH2Cl2); 1H NMR
(CDCl3) 2.56 (br s, 1H), 3.08 (dd, 1H, J ) 17.3, 3.1), 3.24 (dd,
1H, J ) 11.2, 4.5), 3.35 (dd, 1H, J ) 17.3, 3.8), 3.57 (d, 1H, J
isopavinane 6d in 95%: mp 160-163 °C (EtOH-Et2O) (lit.16
1
mp 162-164 °C); [R]20 ) -145.0 (c ) 1.0, CH2Cl2); H NMR
D
(CDCl3) 2.47 (s, 3H), 2.80-2.93 (m, 2H), 3.50-3.54 (m, 2H),
3.61 (d, 1H, J ) 3.4), 3.76 (s, 3H), 3.77-3.88 (m, 1H), 3.85 (s,
3H), 5.83 (d, 1H, J ) 1.2), 5.89 (d, 1H, J ) 1.2), 6.51 (s, 1H),
6.61 (s, 1H), 6.70 (s, 1H), 6.71 (s, 1H); 13C NMR (CDCl3) 37.9,
45.1, 45.8, 55.7, 55.8, 59.7, 62.3, 100.5, 106.0, 107.1, 111.1,
114.1, 126.3, 130.9, 134.4, 134.8, 145.8, 146.2, 146.5, 147.6;
MS (EI) m/ z (rel intensity) 339 (M+, 25), 322 (11), 296 (35),
188 (100). Anal. Calcd for C20H21NO4: C, 70.78; H, 6.23; N,
4.13. Found: C, 70.69; H, 6.49; N, 4.04.
(16) Santavy, F.; Hruban, L.; Maturova, M. Collect. Czech. Chem.
Commun. 1966, 31, 4286-4295.

Synthetic Route to Chiral Isopavines
J . Org. Chem., Vol. 62, No. 20, 1997 6721
Syn th esis of (+)-(1S)-1,2-Bis(3,4-d im eth oxyp h en yl)-N-
m eth yleth yla m in e (8). A solution of the amine 4a (0.50 g,
1.5 mmol) in formamide (10 mL) was stirred at 150 °C until
complete conversion. Water was added to the mixture, and
the resulting solution was then extracted twice with 20 mL of
CH2Cl and washed with H2O and brine. The organic layers
were collected, dried over Na2SO4, and filtered, and the solvent
was evaporated off under reduced pressure. A THF solution
of this crude was carefully added over a stirred solution of LAH
(0.114, 3.0 mmol) in the same solvent at 0 °C. The mixture
was refluxed until complete conversion (overnight) and then
was quenched with MeOH and filtered, water was added, and
the mixture was extracted with CH2Cl2. The organic layer was
washed with H2O and brine, dried over Na2SO4, and filtered,
and the solvent was removed in vacuo to provide, after flash
column chromatography (CH2Cl2/EtOAc 1:1), pure amine 8 as
refluxed during 2 h. Then, BADA (1.31 mL, 1.81 mmol) was
added and the reflux was continued until the conversion was
completed (3 d). After being cooled to room temperature, the
mixture was quenched with water and dried over Na2SO4 and
the solvent was removed in vacuo to provide, after flash
column chromatography (hexanes/EtOAc, 2:8), pure amine 9
as a colorless oil (0.67 g, 83%): [R]20D ) +38.5 (c ) 0.8, CH2Cl2);
1H NMR (CDCl3) 1.16 (t, 3H, J ) 7.1), 1.17 (t, 3H, J ) 7.1),
2.34 (s, 3H), 2.48 (dd, 1H, J ) 13.5, 5.1), 2.68 (dd, 1H, J )
13.5, 5.2), 2.86 (dd, 1H, J ) 13.4, 9.3), 3.20 (dd, 1H, J ) 13.4,
5.2), 3.41-3.62 (m, 4H), 3.69 (s, 3H), 3.78 (s, 3H), 3.81-3.84
(m, 7H), 4.52 (t, 1H, J ) 5.1), 6.46 (d, 1H, J ) 1.8), 6.54 (dd,
1H, J ) 8.1, 1.8), 6.63-6.86 (m, 4H); 13C NMR (CDCl3) 15.2,
38.7, 39.8, 55.6, 55.7, 55.8, 56.8, 61.6, 61.7, 70.7, 101.9, 110.3,
110.7, 111.9, 112.5, 121.1, 132.2, 132.4, 146.9, 147.8, 148.2,
148.4; IR (neat) υ 1130 cm-1; MS (EI) m/ z (rel intensity) 402
(3), 300 (90), 296 (100), 285 (47), 195 (52), 151 (40). Anal. Calcd
for C25H37NO6: C, 67.09; H, 8.33; N, 3.13. Found: C, 67.22;
H, 8.51; N, 3.24.
a colorless oil (1.12 g, 63%): [R]20 ) +40.0 (c ) 0.2, CH2Cl2);
D
1H NMR (CDCl3) 2.23 (s, 3H), 2.80 (d, 2H, J ) 7.0), 2.90 (br s,
1H), 3.58 (t, 1H, J ) 7.0), 3.69 (s, 3H), 3.74 (s, 3H), 3.76 (s,
3H), 3.77 (s, 3H), 6.51-6.81 (m, 6H); 13C NMR (CDCl3) 33.7,
43.9, 55.2, 55.3, 66.1, 110.1, 110.8, 111.1, 112.4, 119.3, 120.8,
130.6, 134.7, 147.2, 147.6, 148.3, 148.7; IR (KBr) υ 3600-3280
cm-1; MS (EI) m/ z (rel intensity) 330 (M+ - 1, 2), 300 (21),
180 (100), 151 (15). Anal. Calcd for C19H25NO4: C, 71.73; H,
7.69; N, 4.64. Found: C, 71.59; H, 7.59; N, 4.29.
Ack n ow led gm en t. The authors gratefully acknowl-
edge PETRONOR, S. A. (Muskiz, Bizkaia) for the gen-
erous gift of solvents. Financial support from the
Basque Government (Project GV PI 96/53 and a fellow-
ship to J .L.V.) and from the University of the Basque
Country (Project UPV 170.310-EA167/95) is gratefully
acknowledged.
Syn th esis (+)-(1S)-N-(2,2-Dieth oxyeth yl)-1,2-bis(3,4-d i-
m eth oxyp h en yl)-N-m eth yleth yla m in e (9). Over a stirred
suspension of K2CO3 (0.21 g, 1.81 mmol) in 25 mL of dry
acetonitrile a solution of amine 8 (0.15 g, 0.45 mmol) in 15
mL of the same solvent was added and the mixture was
J O9708102