Biomimetic synthesis of (±)-galanthamine and asymmetric synthesis of (-)-galanthamine using remote asymmetric induction

Article abstract of DOI:10.1248/cpb.54.1662

(±)-Galanthamine (1) was synthesized in excellent yield by applying PIFA-mediated oxidative phenol coupling of N-(4-hydroxy)phenethyl-N-(3′, 4′,5′-trialkoxy)benzyl formamide (15b) as a key step. Because of the symmetrical characteristics of the pyrogallol moiety in the substrate (15b), the phenol coupling resulted in a sole coupling product except for volatile components from the oxidizing agent. On the basis of the successful results of the above strategy, (-)-galanthamine (1) was synthesized by employing a novel remote asymmetric induction, where conformation of the seven-membered ring in the product of the phenol coupling was restricted by forming a fused-chiral imidazolidinone ring with D-phenylalanine on the benzylic C-N bond of the tri-O-alkylated gallyl amino moiety. The conformational restriction and successive debenzylation of the protected hydroxyl groups on the pyrogallol ring caused diastereoselective cyclization to yield a cyclic ether having the desired stereochemistry for the synthesis of (-)-1.

Full text of DOI:10.1248/cpb.54.1662

1662
Chem. Pharm. Bull. 54(12) 1662—1679 (2006)
Vol. 54, No. 12
Biomimetic Synthesis of (ꢀ)-Galanthamine and Asymmetric Synthesis of
(ꢁ)-Galanthamine Using Remote Asymmetric Induction
Manabu NODE,* Sumiaki KODAMA, Yoshio HAMASHIMA, Takahiro KATOH, Kiyoharu NISHIDE, and
Tetsuya KAJIMOTO
Department of Pharmaceutical Manufacturing Chemistry, 21st Century COE Program, Kyoto Pharmaceutical University;
1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607–8412, Japan.
Received August 2, 2006; accepted September 16, 2006; published online September 21, 2006
(ꢀ)-Galanthamine (1) was synthesized in excellent yield by applying PIFA-mediated oxidative phenol cou-
pling of N-(4-hydroxy)phenethyl-N-(3ꢂ,4ꢂ,5ꢂ-trialkoxy)benzyl formamide (15b) as a key step. Because of the sym-
metrical characteristics of the pyrogallol moiety in the substrate (15b), the phenol coupling resulted in a sole cou-
pling product except for volatile components from the oxidizing agent. On the basis of the successful results of
the above strategy, (ꢁ)-galanthamine (1) was synthesized by employing a novel remote asymmetric induction,
where conformation of the seven-membered ring in the product of the phenol coupling was restricted by forming
a fused-chiral imidazolidinone ring with D-phenylalanine on the benzylic C–N bond of the tri-O-alkylated gallyl
amino moiety. The conformational restriction and successive debenzylation of the protected hydroxyl groups on
the pyrogallol ring caused diastereoselective cyclization to yield a cyclic ether having the desired stereochemistry
for the synthesis of (ꢁ)-1.
Key words galanthamine; norbelladine; remote asymmetric induction; intramolecular phenol coupling; phenyliodine(III)
bis(trifluoroacetate) PIFA; biomimetic synthesis
(ꢀ)-Galanthamine (1), an alkaloid isolated from the Cau- Results and Discussion
casian snow drop, Galanthus woronowii,1) and another
A number of Amarylliaceae alkaloids were confirmed to
species of the Amaryllidaceae family, Lycoris radiate,2,3) has be biosynthesized by the phenol coupling reaction of norbel-
been reported to have many biological activities, e.g., acting ladine (2), which was derived from L-tyrosine in plants, and
as an allosteric modulator of the nicotinic receptor to secrete the multiple styles of the phenol couplings afford structural
acetylcholine as well as a competitive inhibitor of acetyl- diversities of the alkaloids.23—25) For example, the coupling
choline esterase.4) On the basis of these activities, (ꢀ)-1 was between the p-position of the phenol part and the oꢂ-position
developed as a medicine for Altzheimer’s disease, which is of the catechol portion affords galanthamine (1) alkaloids
considered to be caused by the functional deficiency of while p–pꢂ and o–pꢂ couplings respectively afford crinine (4)
cholinergic neural networks, and has been already purchased and lycorine (5) alkaloids. The first synthesis of (ꢁ)-1 em-
for clinical use in Europe and the United States.5) Owing to ployed the intramolecular phenol coupling of 2 with potas-
scarce supplies from the plant source and the significant in- sium ferricyanide but unfortunately preferentially yielded a
crease in demand due to the increased average life span in p–pꢂ coupling product rather than the desired p–oꢂ coupling
developed countries, the need for a practical total synthesis product due to steric repulsion.6) In order to avoid the unde-
of (ꢀ)-1 and its stable supply has increased. Synthesis of 1, sired coupling, the strategy was improved to mask the pꢂ-po-
where intramolecular oxidative phenol coupling of norbella- sition with a bromo or trimethylsilyl group. However, chemi-
dine (2) was adopted to afford narwedine (3), was first at- cal yields of the coupling could not be increased to more
tained by Barton and Kirby.6) Thereafter, much effort has than 50%.26—42) In addition, the coupling reaction using
been made to improve their method7,8) since it was accompa- metal oxidants had the practical disadvantages of releasing
nied by the successful preparation of an enantiomerically toxic chemicals as waste reagents, e.g., cyanides from potas-
pure form of (ꢀ)-1 by using resolutional crystallization of sium ferricyanide or heavy metal ions.
(ꢀ)-narwedine (3).9) However, the yield of the intramolecular
To overcome these disadvantages in the synthetic strate-
phenol coupling reaction in each synthetic route still remains gies of (ꢁ)-1, we referred to Koga’s procedure where the cat-
less than 50%, which hinders the overall yield from reaching echol moiety of 2 was replaced with a pyrogallol group be-
a satisfactory level.
cause the symmetrical characteristic of the pyrogallol moiety
While some excellent synthetic approaches of (ꢁ)-1 or in the precursor (6) made the p–oꢂ coupling afford the only
(ꢀ)-1 using intramolecular Heck reaction as a key step have possible coupling product.38,39) Moreover, phenyliodine(III)
been published recently,10—20) such routes required multiple bis(trifluoroacetate) (PIFA) was chosen as the oxidative
steps and their overall yields are unsatisfactory. Thus, bio- reagent for the phenol coupling based on reports that in addi-
mimetic approaches via the intramolecular phenol coupling tion to the coupling product only volatile products, i.e.,
reaction still remain a promising strategy in terms of chemi- iodobenzene and trifluoroacetic acid, remained after the
cal yield and regioselectivities. Based on this background, we PIFA-induced reaction.33—37,43—49)
have recently published the total synthesis of (ꢁ)-1 and the
At an initial stage of pretesting, we focused on the PIFA-
asymmetric synthesis of (ꢀ)-1.21,22) Here, we would like to induced phenol coupling of tri-O-methylated derivatives
report the details of the synthesis.
(7a, b) of pyrogallol-type norbelladine (6) to synthesize key
intermediates 8a and 8b, and began with the preparation of
∗ To whom correspondence should be addressed. e-mail: node@mb.kyoto-phu.ac.jp
© 2006 Pharmaceutical Society of Japan

December 2006
1663
7a and 7b. 3,4,5-Trimethoxybenzaldehyde (9) was treated etamide 12a. However, solubility of 12a in trifluoroethanol,
with tyramine in the presence of sodium borohydride to af- the most suitable solvent for PIFA-mediated reaction,33—37)
ford 10, which was derived to trifluoroacetamide 7a and for- was quite poor and the reaction attained in trifluoroacetic
mamide 7b. Next, the PIFA-mediated intramolecular phenol acid produced a low yield (12%) of 8a probably due to side-
couplings of 7a and 7b were attempted and were found to af- reactions triggered by the generation of a radical species on
ford good yields (75 and 95%, respectively) of dienone the pyrogallol moiety.
(11a, b) when the reaction was carried out at ꢀ40 °C in tri-
Thus, in order to increase solubility in trifluoroethanol and
fluoroethanol, where low nucleophilicity is believed to in- suppress side reactions, the derivatives 15a—g in which the
crease in the chemical yield of the oxidative coupling (Chart two hydroxyl groups on the pyrogallol moiety of 12a were
1).33—37)
protected with benzyl (Bn), allyl, methoxymethyl (MOM),
Herein, we were able to show that the use of the PIFA-me- or tert-butyldimethylsilyl (TBS) groups were synthesized
diated phenol coupling, where the substrates had a tri-O- by first protecting of the hydroxyl groups in 13b. First,
methyl pyrogallol ring instead of a catechol moiety in the monomethyl ether 13b was derived to 16a—d respectively,
norbelladine skeleton, could provide an excellent method for reduced with lithium aluminum hydride to primary alcohols
the synthesis of 1. However, the attempted demethylation of 17a—d, and oxidized with pyridium chlorochromate or oxy-
11a and 11b with boron tribromide at ꢀ78 °C to afford gen in the presence of palladium acetate and molecular
tetrahydrodibenzofuran derivatives (8a, b) was unsuccessful sieves resulting in aldehydes 18a—d. The aldehydes were
because of difficulties in the selective cleavage of methyl treated with tyramine under a reductive condition, i.e., in the
ethers and the occurrence of side-reactions such as dienone- presence of sodium borohydride, to afford norbelladine de-
phenol rearrangement.50)
rivatives 19a—d. A formyl group as well as a trifluoroacetyl
Therefore, we considered the synthesis of a substrate (12a) group were adopted to protecting the secondary amines
that had no protecting groups on the hydroxyl groups at C-3ꢂ 19a—d to afford N-protected pyrogallol type-norbelladines
and C-5ꢂ of the pyrogallol moiety and could be directly trans- 15a—g (Chart 2).
formed to tetrahydrodibenzofuran 8a once the coupling reac-
After running the phenol coupling of norbelladine deriva-
tion had proceeded smoothly. Namely, the p-hydroxyl group tives 15a—g with PIFA in trifluoroethanol ꢀ40 °C to afford
of methyl gallate (13a) was first methylated by conventional spirodienones 20a—g (Table 1), it was found that allyl ethers
methods to afford monomethyl ether 13b which was derived 15c—d, MOM ethers 15e—f, and TBS ether 15g were oxi-
to aldehyde 14a via primary alcohol 14b. Reductive amina- dized to the corresponding siprodienones 20c—g in moder-
tion of 14a with tyramine in the presence of sodium borohy- ate yields (Table 1, Entries 3—7), and the reaction using ben-
dride and successive treatment of the product 12b with triflu- zyl ether 15b as a substrate resulted in the highest yield
oroacetic anhydride produced a good yield of trifluoroac- (Table 1, Entry 2). The formyl group protected secondary
amines better than the trifluoroacetyl group in the reactions
with 15a and 15b with regard to chemical yield (Table 1, En-
tries 1, 2). The product 20b was especially easy to crystal-
lize, and was separated mainly by crystallization from a solu-
tion of the worked-up residue in ethyl acetate.
Since achieving phenol coupling attainable on a large scale
and satisfying economical and environmental issues were
crucial, reactions using dibenzyl ether 15b as a substrate
were attempted at 0 °C to room temperature by changing the
solvent from trifluoroethanol to other polar solvents and by
switching the oxidizing agent from PIFA to phenyliodine(III)
diacetate (PIDA) (Table 2). The reaction with PIDA pro-
duced a moderate yield of 20b, compared to the reaction
with PIFA (Table 2, Entries 2, 3, 5). As previously pre-
dicted,33—37) considerable amounts of by-products 21a—d
were obtained in cases using acetic acid, acetonitrile,
Fig. 1. Galanthamine (1) and Its Related Compounds
dimethoxyethane, and isopropanol as solvents due to the gen-
Chart 1. Synthesis of Norbelladine Derivatives (10, 7a, b) and Successive Phenol Coupling with PIFA

1664
Vol. 54, No. 12
Chart 2. Synthesis of Norbelladine Derivatives (15a—g)
Table 1. Phenol Coupling Reaction of Norbelladine Derivatives (15a—g)
undesired dienone-phenol rearrangements.50) The use of an
odorless sulfide instead of dimethyl sulfide made little differ-
ence (Table 3, Entries 3, 5). Deprotection of benzyl ethers
with boron trichloride55—58) could favorably afford in an ex-
cellent yield (95%) of 8b (Table 3, Entry 6).
Finally, conversion of the cyclic ether 8b in order to con-
vert it to (ꢁ)-1 was attained as follows. The extra phenolic
hydroxyl group on 8b was once transformed to triflate 23,
and successive reduction with palladium acetate in the pres-
ence of triphenylphosphine, triethylamine and formic acid af-
forded narwedine derivative 24.59) Reaction of 24 with L-
Selectride31,32) followed by reduction of the formyl group to a
methyl group with lithium aluminum hydride resulted in a
good yield of galanthamine (1) from 8b (Chart 3).
Our synthetic scheme, where the phenol coupling reaction
was especially revised by using a combination of the sym-
metrical substrate and PIFA, improved the overall yield from
the norbelladine derivative (19a) to (ꢁ)-galanthamine (1)
(44% overall yield, 7 steps).
Substrate
Entry
Time
Product Yield (%)
R1
R2
1
2
3
4
5
6
7
15a
15b
15c
15d
15e
15f
Bn
Bn
COCF3
CHO
COCF3
CHO
COCF3
CHO
COCF3
1 h
1 h
4 h
15 min
15 min
15 min
1 h
20a
20b
20c
20d
20e
20f
53
82
60
48
45
43
50
Allyl
Allyl
MOM
MOM
TBS
15g
20g
Herein, it is noteworthy that the successful resolution of
eration of a cation (22) or a radical followed by nucleophilic galanthamine (1) and narwedine (3) with di-p-toluoyl-D-tar-
attack of the solvents (Table 2, Entries 4—8). Fortunately, the taric acid has been reported.30,60) Moreover, the synthetic in-
best yield (85%) was obtained in the reaction conducted with termediate 3 was found recently to exist as a racemic con-
PIFA in trifluoroethanol at room temperature (Table 2, Entry glomerate, i.e., a yield of more than 70% of an enantiomeri-
1). Needless to say, metal oxidants such as manganese(III) cally pure form of 3 could be obtained from a supersaturated
acetate and copper(II) acetate gave no productive results.
solution of (ꢁ)-narwedine (3) in ethanol and triethylamine,
Next, debenzylation of dienones 20a and 20b was per- by seeding not only optically pure crystals of 3 but also for-
formed in order to afford cyclic ethers 8a and 8b, respec- eign substances such as (ꢃ)- and (ꢀ)-galanthamine (1).61)
tively, as the resulting products by spontaneous Michael ad- Thus, conversion of 24 to 3 was also examined to find an al-
dition of a deprotected hydroxyl group to the dienone moiety. ternative effective synthetic route of optically pure (ꢀ)-1.
Treatment of 20a and 20b with a combination of trifluo- The carbonyl group of 24 was protected with ethylene glycol
roacetic acid and dimethyl sulfide51—53) afforded good yields to give acetal 25, which was reduced with lithium aluminum
(85 and 81%, respectively) of 8a and 8b, respectively (Table hydride, followed by deprotection of the acetal group with
3, Entries 1, 2) in spite of an extended reaction time. Replac- acid to achieve an overall good yield (76%) of (ꢁ)-3.
ing trifluoroacetic acid with a stronger acid such as methane-
Encouraged by the success in the racemic synthesis of
sulfonic acid54) resulted in a faster reaction period, but, the (ꢁ)-1 and to provide an alternative synthesis of 3, which is a
chemical yield (62%) was reduced (Table 3, Entry 4) due to key intermediate for the practical synthesis of (ꢀ)-galan-

December 2006
1665
Table 2. Phenol Coupling Reaction of 15b in Several Kinds of Solvent
Product (%)
Entry
Oxidant
Solvent
Temp. (°C)
Time (min)
15b
20b
21a
21b
21c
21d
1
2
3
4
5
6
7
8
PIFA
PIDA
PIDA
PIFA
PIDA
PIFA
PIFA
PIFA
CF3CH2OH
CF3CH2OH
CF3CO2H
CF3CO2H
CF3CO2H
CH3CN
r.t.
r.t.
r.t.
0
r.t.
0
15
30
20
40
20
30
15
45
85
54
56
50
36
32
5
23
13
6
8
20
11
30
14
34
DME
i-PrOH
r.t.
0
13
5
24
11
Table 3. Debenzylation of 20a and 20b
Entry
Substrate
Reagent
Solvent
Temp.
Time
Product
Yield (%)
1
2
3
4
5
6
20a
20b
20b
20b
20b
20b
CF3CO2H
CF3CO2H
CF3CO2H
CH3SO3H
CH3SO3H
BCl3
CH3SCH3
CH3SCH3
C12H25SCH3
CH3SCH3
C12H25SCH3
CH2Cl2
r.t.
r.t.
r.t.
r.t.
r.t.
5 d
4 d
4 d
2 h
2 h
8a
8b
8b
8b
8b
8b
85
81
77
62
57
95
ꢀ78 °C
20 h
thamine (1), we next planned to establish a novel route for
the asymmetric synthesis of (ꢀ)-1 that could circumvent nar-
wedine (3) in view of the severe allergic responses caused. In
order to improve racemic synthesis for asymmetric synthesis,
the phenolic hydroxyl group should preferentially attack one
of the two b-olefinic carbons of the dienone in the intramole-
cular Michael addition since the symmetrical dienones
(20a, b) were converted to racemic mixtures (8a, b) by non-
selective intramolecular reaction (Table 3).
Remote asymmetric induction was used, restricting con-
formation of the seven-membered ring of 20a by introducing
chiral centers similar to Koga who put an alkoxycarbonyl
group onto the seven-membered ring for chiral synthesis of
(ꢃ)-galanthamine (1).39) Our strategy was designed so as to
introduce another C–N bond on the benzylic position of the
gallyl amino moiety of 20a to take advantage of the easily
cleavable properties of the benzylic C–N bond and the aza-
Chart 3. Synthesis of Galanthamine (1) and Narwedine (3)

1666
Vol. 54, No. 12
Chart 4
Fig. 2. PM3 Calculation of the Intermediate
acetal bond. We decided to link an optically pure a-amino
acid on the benzylic C–N bond of 20a to afford a chiral imi-
dazolidinone (A). Specifically, the conformation of the
seven-membered ring of the coupling product B would be re-
stricted by the fused-imidazolidinone composed of an amino
acid to afford C as a single Michael adduct (Chart 4).
Originally, synthesis of chiral 1,3-imidazolidin-5-one and
its application to chiral induction was reported by Seebach,
who proposed the concept as Self Regeneration of Stereocen-
ters (SRS).62—64)
Among naturally abundant amino acids, phenylalanine and
valine were chosen as the chiral auxiliary to form the fused
imidazolidinone because the bulky isopropyl and benzyl
groups on amino acid residues would provide promising
stereoselectivities. In the beginning, we simply expected that
the spontaneous Michael addition after deprotection of R1 in
B would progress diastereoselectively to afford cyclic ether
(C) with the desired configuration. As expected, PM3 calcu-
lation revealed that the most stable conformer of B (R1ꢄH,
R2ꢄBn, R3ꢄCF3CO), where the chiral imidazolodinone
Fig. 3. Heat of Formation of the Cyclic Ether (PM3)
On the basis of foregoing, this synthetic strategy began
moiety was composed of D-phenylalanine, had shorter dis- with the reaction of tyramine and N-Boc-D-phenylalanine
tance between the phenolic oxygen atom and Cb1 (2.61 Å) (26a) or N-Boc-D-valine (26b) in the presence of EDC·HCl
than that between the oxygen and Cb2 (3.15 Å) (Fig. 2).
and HOBt to afford amides 27a, b. Removal of the Boc-
Moreover, the calculation showed that the Michael adduct group of 27a and 27b with methanesulfonic acid to afford
from the former transition state was more stable than that amines 28a, b and following the formation of a Schiff base
from the latter transition state by 6.7 kcal/mol (Fig. 3). These with 18a, and the successive treatment with acid yielded imi-
results supported our expectation that the Michael addition dazolidinone (29a, b), respectively, while the acid treatment
of phenolic hydroxyl groups in B bearing a D-amino acid as a of 28a followed by treatment with 9 under acidic condition
chiral auxiliary, predominantly affords a diastereomer that resulted in 29c. The diastereoselectivity in the reaction pro-
could be led to the desired enantiomers of synthetic interme- viding 29a (ꢅ98% de) was much higher than those the oth-
diates.
ers (69% de in 29b and 86% de in 29c) and the stereochem-

December 2006
1667
istry of the major isomers was determined to be trans based forming imidazolidinone and the good chemical yield in the
on the NOESY spectrum. The configuration of the major iso- successive phenol coupling, imidazolidinone 29a with benzyl
mers was also supported by the experimental data in the syn- groups as the protecting groups (R1) and a side chain (R2) of
thesis of imidazolidinone derivatives, which was reported by a-amino acid is considered to be the most suitable synthetic
Seebach.62—64)
intermediate (Chart 5).
The amino group of 29a was next protected with a trifluo-
Thus, deprotection of the benzyl group of 31a with boron
roacetyl group to prepare 30a, a substrate of the phenol cou- trichloride at ꢀ78 °C afforded an excellent yield (95%) of
pling. The imidazolidinone derivatives 30b and 30c were 32.55—58) In the first strategy of transformation from 32 to
also prepared from 29b and 29c in order to compare the cou- (ꢀ)-1, we tried to remove the chiral imidazolidinone moiety
pling reactions. Among the intramolecular oxidative cou- in the early steps since the presence of a fused ring caused
plings of 30a—c with PIFA in trifluoroethanol, the reaction complexities and broadness of the NMR spectra, which inter-
of 30a at ꢀ40 °C afforded the highest yield of corresponding fered with structure analysis. Thus, 32 was first reduced with
spirodienone 31a. When the reaction was conducted at room L-Selectride to afford allyl alcohol 33, where hydrolysis with
temperature similar to that in Table 2, entry 1, the imidazo- sodium hydroxide to imine 34 via secondary amine 35 pro-
lidinone moiety seemed to decompose. In addition, the phe- ceeded smoothly at room temperature. Successive reduction
nol coupling of the compound with a formyl group instead of of 34 with sodium borohydride and protection of the amino
a trifluoroacetyl group in 30a with PIFA resulted only in a group with a Boc group resulted in 36, with an optical purity
low yield (33%). Although the yield (61%; the best record in of ꢅ99% e.e. could be secured by means of a chiral HPLC
our experiments) was not satisfactory in comparison with settled with a DAICEL CHIRALCEL OD column (Chart 6).
that obtained in the reaction of 20b, it was higher than any The high optical purity of 36 confirmed that the intramolecu-
other reported reactions using norbelladine derivatives as lar Michael addition progressed to afford cyclic ether 32 with
substrates.26—42) Because of the high stereoselectivity on high stereoselectivity. However, triflation of 36 with triflic
Chart 5
Chart 6

1668
Vol. 54, No. 12
perature. After the reaction, the reaction mixture was evaporated and crystal-
lized from methanol to afford 10 (7.77 g, 98%) as colorless crystals; mp
161—163 °C. 1H-NMR (400 MHz, CDCl3) d: 2.77 (2H, t, Jꢄ6.9 Hz, Ar-
CH2–CH2–N), 2.89 (2H, t, Jꢄ6.9 Hz, CH2–CH2–N), 3.74 (2H, s, Ar-
CH2–N), 3.80 (6H, s, OCH3ꢆ2), 3.82 (3H, s, OCH3), 6.50 (2H, s, Ar-H),
6.70 (2H, d, Jꢄ8.5 Hz, Ar-H), 7.03 (2H, d, Jꢄ8.5 Hz, Ar-H). 13C-NMR
(50 MHz , CDCl3) d: 35.3, 50.8, 54.4, 56.4, 61.2, 105.4, 115.9, 130.0, 131.2,
135.5, 137.2, 153.5, 155.0. IR (CHCl3) cmꢀ1: 3009, 1593, 1514, 1464, 1331,
1240, 1130, 1003. FAB-MS m/z: 318 (MꢃHꢃ). HR-MS m/z: 318.1701
(Calcd for C18H24NO4: 318.1705). Anal. Calcd for C18H23NO4: C, 68.12; H,
7.30; N, 4.41. Found: C, 67.99; H, 7.29; N, 4.45.
N-(4-Hydroxy)phenethyl-N-(3,4,5-trimethoxy)benzyltrifluoroacet-
amide (7a) Trifluoroacetic anhydride (0.13 ml, 0.9 mmol) was added to a
solution of 10 (110 mg, 0.56 mmol) in pyridine (1.0 ml) at 0 °C and the mix-
ture was stirred for 1 h at room temperature. After the reaction, the reaction
mixture was extracted with ethyl acetate and the organic layer was succes-
sively washed with 1 M hydrochloric acid, a saturated aqueous solution of
sodium bicarbonate, and a saturated aqueous solution of sodium chloride,
dried over sodium sulfate, and evaporated. The residue was purified by silica
gel column chromatography (chloroform : methanolꢄ50 : 1) to afford 7a
(96.5 mg, 95%) as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 2.78 (1H,
t, Jꢄ7.4 Hz, Ar-CH2–CH2), 2.83 (1H, t, Jꢄ8.1 Hz, Ar-CH2–CH2), 3.47 (1H,
anhydride and successive reduction of triflate with a palla-
dium catalyst in the presence of formate59) reduced the dou-
ble bond of the allylic alcohol moiety. In view negative re-
sults in the conversion of 32 to (ꢀ)-galanthamine (1), we re-
vised the synthetic strategy to deoxygenate the phenolic hy-
droxyl group of 32 via triflate 37 prior to the reduction of
a,b-unsaturated ketone, i.e., cyclic ether 32 was converted to
triflate 37 which was reduced with a palladium catalyst in the
presence of formate to afford narwedine derivative 3859) and
then, the conjugated ketone moiety of 38 was reduced with
L-Selectride31,32) resulting in allyl alcohol 39. The hydrolysis
of 39 under the same conditions adopted in the reaction of 33
did not yield any imine 40 because of the low solubility of
the deoxygenated intermediate 39 in an aqueous medium.
This was in good contrast with the fast hydrolysis of 33,
which could be explained by the higher solubility in an aque-
ous medium due to the presence of allylic and phenolic hy-
droxyl groups. Therefore, more drastic conditions were cho-
sen to achieve hydrolysis and the hydrolysis with potassium t, Jꢄ8.1 Hz, CH2–CH2–N), 3.52 (1H, t, Jꢄ7.4 Hz), 3.83 (6H, s, OCH3), 3.84
and 3.85 (3H, s, OCH3), 4.33 and 4.58 (2H, s, Ar-CH2N), 5.83 and 5.85 (1H,
hydroxide in aqueous ethanol under refluxed conditions in
the presence of a phase transfer, tetrabutylammonium bro-
mide (TBAB), finally resulted in imine 40. Imine 40 was re-
s, OH), 6.42 and 6.77 (2H, s, Ar-H), 6.78 and 6.80 (2H, d, Jꢄ8.5 Hz, Ar-H),
6.99 (d, Jꢄ8.5 Hz, Ar-H). 13C-NMR (100 MHz, CDCl3) d: 32.3, 34.7, 48.8,
50.2, 51.9, 52.0, 56.5, 56.5, 61.2, 61.2, 104.7, 105.4, 115.9, 116.1, 118.3,
duced with sodium borohydride, and the final N-methylation
to galanthamine (1) was attained by N-formylation using
ethyl formate and successive reduction of formamide 41 with
lithium aluminum hydride. All the spectral and physical data
of synthesized (ꢀ)-galanthamine (1) were identical with
those in publications.
118.5, 129.4, 130.1, 130.2, 130.7, 131.3, 138.0, 138.1, 153.9, 154.0, 155.1,
155.3. IR (CHCl3) cmꢀ1: 3009, 1686, 1595, 1516, 1464, 1240, 1196, 1167,
1150, 1132, 1001. FAB-MS m/z: 413 (Mꢃ). HR-MS m/z: 413.1454 (Calcd
for C20H22F3NO5: 413.1450).
N-(4-Hydroxy)phenethyl-N-(3,4,5-trimethoxy)benzylformamide (7b)
A suspension of 10 (2.00 g, 6.30 mmol) in ethyl formate (40 ml) was re-
fluxed for 4 d. After the reaction, the organic solvent was evaporated and the
residue was purified by recrystallization from ethyl acetate to afford 7b
(2.05 g, 94%) as colorless crystals; mp 117—119 °C. 1H-NMR (400 MHz,
CDCl3) d: 2.72 and 2.75 (2H, t, Jꢄ6.9 Hz, Ar-CH2–CH2–N), 3.38 and 3.48
(2H, t, Jꢄ6.9 Hz, Ar-CH2–CH2–N), 3.83 (6H, s, OCH3ꢆ2), 3.84 (3H, s,
OCH3), 4.20 and 4.48 (2H, s, Ar-CH2–N), 6.33 and 6.48 (2H, s, Ar-H), 6.74
and 6.77 (2H, d, Jꢄ8.5 Hz, Ar-H), 6.91 and 7.01 (2H, d, Jꢄ8.5 Hz, Ar-H),
7.83 and 8.23 (1H, s, CHO). 13C-NMR (100 MHz, CDCl3) d: 32.8. 34.1,
44.2, 46.3, 49.2, 52.4, 56.5, 56.5, 61.2, 104.7, 105.7, 115.8, 116.1, 129.1,
130.1, 130.2, 130.2, 131.7, 132.3, 137.9, 138.1, 153.8, 154.0, 155.4, 155.8,
163.4, 163.8. IR (CHCl3) cmꢀ1: 3007, 1665, 1595, 1516, 1464, 1240, 1130,
1003. FAB-MS m/z: 346 (MꢃHꢃ). HR-MS m/z: 346.1657 (Calcd for
C19H24NO5: 346.1654). Anal. Calcd for C19H23NO5: C, 66.07; H, 6.71; N,
4.06. Found: C, 66.14; H, 6.72; N, 4.32.
Conclusions
In conclusion, we succeeded in the synthesis of (ꢁ)-1 by
using a biomimetic approach, which took advantage of PIFA-
mediate oxidative phenol coupling of the structurally sym-
metrical norbelladine derivative 15b. Moreover, an asymmet-
ric synthesis of optically pure (ꢀ)-1, which could circumvent
allergenic intermediate 3, could be attained by using a new
type of remote asymmetric induction as a key step. Our syn-
thetic route of (ꢀ)-1 provided the highest overall yield (22%
from 26a, 13 steps) among the asymmetric synthesis re-
ported recently.
2-Trifluoroacetyl-6,7,8-trimethoxy-2,3,4,5-tetrahydro-1H-[2]ben-
zazepine-5-spiro-1ꢂ-cyclohexa-2ꢂ,5ꢂ-dien-4ꢂ-one (11a)
A solution of
PIFA (0.21 g, 0.50 mmol) in 2,2,2-trifluoroethanol (5.0 ml) was added to a
Experimental
solution of 7a (0.19 g, 0.45 mmol) in 2,2,2-trifluoroethanol (3.0 ml) at
General Infrared (IR) spectra were recorded on a Shimadzu FTIR-8300 ꢀ40 °C and the mixture was stirred for 2 h with keeping the temperature.
diffraction grating infrared spectrophotometer and 1H- and 13C-NMR spectra
After the reaction, the organic solvent in the reaction mixture was evapo-
were obtained on JEOL JNM-AL300, Varian Unity INOVA-400 and Varian rated and the residue was purified by silica gel column chromatography
GEMINI 200 spectrometers with tetramethylsilane as an internal standard.
Mass spectra (MS) were determined on a JEOL JMS-SX 102A QQ or a
(hexane : ethyl acetateꢄ1 : 1) to afford 11a (0.14 g, 75%) as colorless crys-
tals; mp 185—187 °C (ethyl acetate). H-NMR (400 MHz, CDCl3) d: 2.34
1
JEOL JMS-GC-mate mass spectrometer. Specific rotations were recorded on (2H, t, Jꢄ6.1 Hz, CH2–CH2–N), 3.63 and 3.64 (3H, s, OCH3), 3.77 and 3.79
a Horiba SEPA-200 automatic digital polarimeter. Wakogel C-200 (silica (3H, s, OCH3), 3.87 and 3.89 (3H, s, OCH3), 3.85 and 3.90 (2H, t,
gel) (100—200 mesh, Wako) was used for open column chromatography. Jꢄ6.1 Hz, CH2–CH2–N), 4.78 and 4.82 (2H, s, Ar-CH2–N), 6.31 (2H, d,
Flash column chromatography was performed by using Silica Gel 60N Jꢄ10.2 Hz), 6.45 and 6.63 (1H, s, Ar-H), 6.93 and 6.99 (2H, d, Jꢄ10.2 Hz).
(Kanto Chemical Co., Inc.) as a solid support of immobile phase. Kieselgel
60 F-254 plates (Merck) were used for thin-layer chromatography (TLC). 48.4, 49.2, 56.3, 56.4, 60.8, 60.9, 61.35, 61.37, 109.3, 110.1, 115.3, 118.1,
Preparative TLC (PTLC) was conducted with Kieselgel 60 F-254 plate 123.0, 123.4, 126.95, 126.98, 131.5, 131.6, 142.4, 142.6, 153.1, 154.3,
13C-NMR (100 MHz, CDCl3) d: 37.0, 38.5, 44.7, 45.5, 45.5, 47.3, 47.6,
(0.25 mm, Merck) or Silica gel 60 F-254 plate (0.5 mm, Merk). Unless pu-
154.4, 154.45, 154.53, 185.8, 185.9. IR (CHCl3) cmꢀ1: 1670, 1661, 1620,
rification with silica gel gave a pure enough compound, the compounds were 1595, 1466, 1332, 1184, 1150, 1128, 1001. FAB-MS m/z: 412 (MꢃHꢃ).
further treated with a recycle HPLC (JAI LC-908) on GPC column (JAIGEL HR-MS m/z: 412.1378 (Calcd for C20H21F3NO5: 412.1372).
1H and 2H). In the case it is possible, diastereomeric mixtures were also
2-Formyl-6,7,8-trimethoxy-2,3,4,5-tetrahydro-1H-[2]benzazepine-5-
separated by a recycle HPLC (JAI LC-908) on silica gel column (Kusano Si- spiro-1ꢂ-cyclohexa-2ꢂ,5ꢂ-dien-4ꢂ-one (11b) A solution of PIFA (47 mg,
10) after the purification mentioned above.
0.11 mmol) in 2,2,2-trifluoroethanol (0.5 ml) was added to a solution of 7b
(35 mg, 0.1 mmol) in 2,2,2-trifluoroethanol (0.5 ml) at ꢀ40 °C and the mix-
ture was stirred for 15 min with keeping the temperature. After the reaction,
the organic solvent in the reaction mixture was evaporated and the residue
was purified by silica gel column chromatography (hexane : acetoneꢄ15 : 1)
to afford 11b (32.8 mg, 95%) as colorless crystals; mp 157—159 °C (ethyl
N-(4-Hydroxy)phenethyl-N-(3,4,5-trimethoxy)benzylamine (10) Tyr-
amine (4.20 g, 30.6 mmol) was added to a solution of 9 (5.00 g, 25.5 mmol)
in methanol (50 ml) and the mixture was stirred for 2 d at room temperature.
After cooling the mixture at 0 °C, sodium borohydride (1.04 g, 27.5 mmol)
was added to the reaction mixture, which was stirred for 24 h at room tem-

December 2006
1669
acetate). 1H-NMR (400 MHz, CDCl3) d: 2.29 and 2.33 (2H, t, Jꢄ6.2 Hz,
CH2–CH2–N), 3.61 and 3.63 (3H, s, OCH3), 3.68 and 3.73 (2H, t, Jꢄ6.2 Hz,
CH2–CH2–N), 3.76 and 3.78 (3H, s, OCH3), 3.88 and 3.89 (3H, s, OCH3),
4.64 and 4.70 (2H, s, Ar-CH2–N), 6.31 (2H, d, Jꢄ10.1 Hz), 6.48 and 6.63
(1H, s, Ar-H), 6.96 and 7.01 (2H, d, Jꢄ10.1 Hz), 8.19 and 8.24 (1H, s,
CHO). 13C-NMR (100 MHz, CDCl3) d: 37.6, 38.8, 45.7, 45.9, 47.5, 50.6,
56.2, 56.3, 60.8, 60.9, 61.3, 61.4, 66.2, 108.4, 109.6, 123.4, 123.5, 126.6,
126.8, 133.3 133.5, 142.0, 142.3, 152.9, 153.0, 154.6, 154.7, 154.9, 162.1,
162.8, 186.1, 186.1. IR (CHCl3) cmꢀ1: 1663, 1620, 1593, 1427, 1332, 1126.
FAB-MS m/z: 344 (MꢃHꢃ). HR-MS m/z: 344.1494 (Calcd for C19H22NO5:
344.1498). Anal. Calcd for C19H21NO5: C, 66.46; H, 6.16; N, 4.08. Found:
C, 66.22; H, 6.26; N, 4.33.
Methyl 3,5-Dihydroxy-4-methoxybenzoate (13b) Potassium carbonate
(0.9 g, 6.5 mmol) was added to a solution of methyl gallate (13a) (1.0 g,
5.4 mmol) in N,N-dimethylformamide (10 ml) and the mixture was stirred
for 1 h at 85 °C. After cooling the reaction mixture to 0 °C, methyl iodide
(0.8 g, 5.6 mmol) was added and the reaction mixture was stirred for 30 min
at 0 °C and kept stirring for another 24 h at room temperature. After the re-
action, the mixture was filtered to remove precipitates and the filtrate was
extracted with ethyl acetate. The organic layer was washed with a saturated
aqueous solution of sodium chloride, dried over sodium sulfate, and evapo-
rated. The residue was purified by silica gel column chromatography (chlo-
roform : methanolꢄ50 : 1) to afford 13b (819.5 mg, 76%) as colorless nee-
dles; mp 147—148 °C (toluene). 1H-NMR (300 MHz, DMSO-d6) d: 3.75,
3.78 (each 3H, s, OMe), 6.96 (2H, d, Jꢄ0.7 Hz, Ar-H), 9.49 (2H, s, OH).
13C-NMR (75 MHz, DMSO-d6) d: 52.0, 59.7, 108.5 (2C), 124.5, 139.7,
150.7 (2C), 166.0. IR (CHCl3) cmꢀ1: 3531, 3265, 2952, 1714, 1595, 1438,
1337, 1236, 1198. EI-MS m/z: 198 (Mꢃ). HR-MS m/z: 198.0533 (Calcd for
C9H10O5: 198.0528). Anal. Calcd for C9H10O5: C, 54.55; H, 5.09. Found: C,
54.78, H, 5.33.
3,5-Dihydroxy-4-methoxybenzyl Alcohol (14b) A solution of 13b
(11.9 g, 60.0 mmol) in tetrahydrofuran (45 ml) was added to a suspension of
lithium aluminum hydride (9.1 g, 24.0 mmol) in tetrahydrofuran (240 ml) at
0 °C, and the mixture was stirred for 2 h at 55 °C. After the reaction, ethyl
acetate and saturated aqueous solution of sodium sulfate were added. The
mixture was filtered through celite, and the filtrate was extracted with ethyl
acetate. The organic layer was washed with a saturated aqueous solution of
sodium chloride, dried over sodium sulfate, and evaporated. The residue was
purified by silica gel column chromatography (chloroform : methanolꢄ
50 : 1) to afford 14b (7.48 g, 73%) as colorless needles (chloroform); mp
171—173 °C. 1H-NMR (300 MHz, DMSO-d6) d: 3.64 (3H, s, OMe), 4.25
(2H, d, Jꢄ5.5 Hz, CH2), 4.95 (1H, t, Jꢄ5.9 Hz, OH), 6.25 (2H, s, Ar-H),
8.90 (2H, s, OH). 13C-NMR (75 MHz, DMSO-d6) d: 60.1, 63.2, 105.9 (2C),
134.5, 138.3 (2C), 150.8 (2C). IR (CHCl3) cmꢀ1: 3435, 1601, 1528, 1433,
1346, 991, 961. EI-MS m/z: 170 (Mꢃ). HR-MS m/z: 170.0583 (Calcd for
C8H10O4: 170.0579).
N-(3,5-Dihydroxyl-4-methoxy)benzyl-N-(4-hydroxyphenyl)ethyltriflu-
oroacetamide (12a) Trifluoroacetic anhydride (0.15 ml, 1.04 mmol) was
added to a solution of 12b (100 mg, 0.35 mmol) in pyridine (1.5 ml) at 0 °C
and the mixture was stirred for 20 min. After the reaction, methanol was
added to the reaction mixture and the organic solvent was evaporated. The
residue was extracted with ethyl acetate and the organic layer was succes-
sively washed with 1 M hydrochloric acid, a saturated aqueous solution of
sodium bicarbonate, and a saturated aqueous solution of sodium chloride,
dried over sodium sulfate, and evaporated. The residue was purified by silica
gel column chromatography (chloroform : methanolꢄ50 : 1) to afford 12a
(114.2 mg, 86%) as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 2.96 and
2.81 (2H, t, Jꢄ6.6 Hz, Ar-CH2–CH2), 3.45 and 3.50 (2H, t, Jꢄ6.6 Hz,
CH2–CH2–N), 3.87 and 3.88 (3H, s, OMe), 4.22 and 4.48 (2H, s, Ar-
CH2–N), 4.98 (1H, br s, OH), 5.67 and 5.90 (2H, br s, OH), 6.28 and 6.38
(2H, s, Ar-H), 6.75 and 6.78 (2H, d, Jꢄ8.8 Hz), 7.00 (2H, d, Jꢄ8.8 Hz). 13C-
NMR (75 MHz, CDCl3) d: 29.7, 31.9, 34.3, 48.6, 49.4, 51.1, 61.15, 61.19,
107.0, 107.8, 115.6, 115.7, 118.4, 118.6, 129.3, 129.9, 130.0, 130.2, 131.6,
132.1, 134.3, 149.3, 149.4, 154.4, 154.6, 156.8, 157.2, 157.3, 157.7. IR
(CHCl3) cmꢀ1: 3312, 1686, 1599, 1516, 1458, 1439, 1366, 1263, 1192,
1165, 1061. EI-MS m/z: 385 (Mꢃ). HR-MS m/z: 385.1132 (Calcd for
C18H18NO5F3: 385.1137).
Methyl 3,5-Dibenzyloxy-4-methoxybenzoate (16a) Benzyl chloride
(3.81 ml, 33.3 mmol) and potassium carbonate (7.02 g, 50.8 mmol) were
added to a solution of 13b (2.81 g, 14.2 mmol) in N,N-dimethylformamide
(15 ml) and the mixture was stirred for 1.5 h at 150 °C. After the reaction,
precipitates were removed by filtration and the filtrate was evaporated, and
extracted with benzene. The organic layer was successively washed with 5%
aqueous solution of sodium hydroxide and a saturated aqueous solution of
sodium chloride, dried over sodium sulfate, and evaporated. The residue was
recrystallized from methanol (5.07 g, 95%) as colorless needles; mp 116—
118 °C (methanol). 1H-NMR (300 MHz, CDCl3) d: 3.88, 3.94 (3H, s, OMe),
5.16 (4H, s, 2ꢆCH2O), 7.32—7.48 (12-H, m, Ar-H). 13C-NMR (75 MHz,
CDCl3) d: 52.2, 61.0, 71.2 (2C), 109.2 (2C), 125.0, 127.4 (4C), 128.0 (2C),
128.5 (4C), 136.7 (2C), 143.6, 152.2 (2C), 166.6. IR (CHCl3) cmꢀ1: 3010,
2953, 1715, 1591, 1429, 1336, 1236, 1113. EI-MS m/z: 378 (Mꢃ). HR-MS
m/z: 378.1469 (Calcd for C23H22O5: 378.1467). Anal. Calcd for C23H22O5: C,
73.00, H, 5.86. Found: C, 73.33; H, 6.10.
Methyl 3,5-Diallyloxy-4-methoxybenzoate (16b) Allyl bromide
(4.0 ml, 46.0 mmol) and potassium carbonate (8.30 g, 60.0 mmol) were
added to a solution of 13b (3.95 g, 20.0 mmol) in N,N-dimethylformamide
(168 ml) and the mixture was stirred for 90 min at 50 °C. After the reaction,
the reaction mixture was evaporated to remove the organic solvent and ex-
tracted with ethyl acetate. The organic layer was washed with a saturated
aqueous solution of sodium chloride, dried over sodium sulfate, and evapo-
rated. The residue was purified by silica gel column chromatography
(hexane : ethyl acetateꢄ2 : 1) to afford 16b (5.9 g, quant.) as a colorless oil.
1H-NMR (300 MHz, CDCl3) d: 3.89, 3.93 (3H, s, OMe), 4.62, 4.64 (4H, dt,
Jꢄ5.4, 1.5 Hz, 2ꢆCH2O), 5.29 (2H, dq, Jꢄ10.6, 1.5 Hz, 2ꢆCH2ꢄCH–),
5.43 (2H, dq, Jꢄ17.2, 1.5 Hz, 2ꢆCH2ꢄCH–), 6.08 (2H, ddt, Jꢄ17.2, 10.6,
1.5 Hz, 2ꢆCH2ꢄCH–), 7.29 (2H, s, Ar-H). 13C-NMR (75 MHz, CDCl3) d:
52.2, 60.9, 69.9, 100.6, 108.8 (2C), 117.9 (2C), 124.9, 132.9 (2C), 143.2,
152.0, 166.6. IR (CHCl3) cmꢀ1: 2951, 1717, 1589, 1501, 1435, 1331, 1258,
1111, 1003. EI-MS m/z: 278 (Mꢃ). HR-MS m/z: 278.1157 (Calcd for
C15H18O5: 278.1154).
Methyl 3,5-Dimethoxymethoxyl-4-methoxybenzoate (16c) Chloro-
methyl methyl ether (8.98 g, 111.0 mmol) and potassium carbonate (20.5 g,
148.0 mmol) were added to a solution of 13b (7.37 g, 37.2 mmol) in N,N-
dimethylformamide (168 ml) at 0 °C and the mixture was stirred for 15 h
at 45 °C. After the reaction, the mixture was filtered and the filtrate was
evaporated to remove the organic solvent and then extracted with ethyl ac-
etate. The organic layer was washed with a saturated aqueous solution of
sodium chloride, dried over sodium sulfate, and evaporated. The residue was
purified by silica gel column chromatography (hexane : ethyl acetateꢄ2 : 1)
to afford 16c (9.35 g, 88%) as colorless needles; mp 69—79 °C (diethyl
ether); 1H-NMR (300 MHz, CDCl3) d: 3.53 (6H, s), 3.89 and 3.94 (each 3H,
s, OMe), 5.26 (4H, s, 2ꢆCH2O), 7.53 (2H, s, Ar-H). 13C-NMR (75 MHz,
CDCl3) d: 52.2, 56.4 (2C), 61.1, 95.3 (2C), 111.9 (2C), 125.5, 144.2, 150.5
(2C), 166.3. IR (CHCl3) cmꢀ1: 3020, 2955, 1717, 1593, 1501, 1435, 1331,
1231, 1049. EI-MS m/z: 286 (Mꢃ). HR-MS m/z: 286.1063 (Calcd for
C13H18O7: 286.1052). Anal. Calcd for C13H18O7: C, 54.54; H, 6.34. Found:
C, 54.53; H, 6.47.
3,5-Dihydroxy-4-methoxybenzaldehyde (14a)
A solution of 14b
(3.4 g, 20.0 mmol) in tetrahydrofuran (50 ml) was added to a suspension of
pyridinium chlorochromate (8.6 g, 40.0 mmol) and Celite® in tetrahydrofu-
ran (50 ml) at 0 °C, and the mixture was stirred for 1 d at room temperature.
After the reaction, the reaction mixture was filtered and the filtrate was evap-
orated. The residue was purified by silica gel column chromatography
(hexane : ethyl acetateꢄ1 : 1) to afford 14a (1.11 g, 33%) as colorless crys-
tals; mp 148—150 °C (chloroform). 1H-NMR (300 MHz, DMSO-d6) d: 3.77
(3H, s, OMe), 6.86 (2H, s, Ar-H), 9.62 (2H, s, OH), 9.71 (1H, s, CHO). 13C-
NMR (75 MHz, DMSO-d6) d: 59.7, 108.6 (2C), 131.7, 141.1, 151.3 (2C),
192.0. IR (CHCl3) cmꢀ1: 3260, 1693, 1597, 1524, 1350, 1126. EI-MS m/z:
168 (Mꢃ). HR-MS m/z: 168.0413 (Calcd for C31H29NO5: 168.0422).
N-(3,5-Dihydroxyl-4-methoxy)benzyl-N-(4-hydroxyphenyl)ethylamine
(12b) Tyramine (720 mg, 5.25 mmol) was added to a solution of 14a
(840 mg, 5 mmol) in methanol (15 ml) and the mixture was stirred for
25 min at room temperature. And then, sodium borohydride (190 mg,
5 mmol) was added to the reaction mixture, which was stirred for 20 min at
0 °C and for another 50 min at room temperature. After the reaction, dry ice
was added to the reaction mixture and precipitates were filtered off. The fil-
trate was evaporated and the residue was purified by silica gel column chro-
matography (chloroform : methanolꢄ1 : 1) to afford 12b (1.43 g, 99%) as
1
colorless crystals; mp 108—112 °C (methanol and diethyl ether). H-NMR
(300 MHz, DMSO-d6) d: 2.59—2.61 (4H, m, CH2CH2), 3.45 (2H, s, Ar-
CH2–N), 3.62 (3H, s, OMe), 6.23 (2H, s, Ar-H), 6.64, 6.95 (each 2H, d, AB
type, Jꢄ8.1 Hz, Ar-H). 13C-NMR (75 MHz, DMSO-d6) d: 35.0, 50.8, 52.8,
56.0, 106.8, 115.0, 129.3, 130.4, 134.0, 136.2, 150.3, 155.4. IR (CHCl3)
cmꢀ1: 3628, 1601, 1514, 1437, 1364, 1169, 1047, 1016. EI-MS m/z: 289
(Mꢃ). HR-MS m/z: 289.1317 (Calcd for C16H19NO4: 289.1314).
Methyl 3,5-Di-tert-butyldimethylsilyloxy-4-methoxybenzoate (16d)
A solution of tert-butyldimethylsilyl chloride (1.83 g, 12.1 mmol) and imida-
zole (1.38 g, 20.2 mmol) were stirred for 20 min at room temperature, and

1670
Vol. 54, No. 12
1350, 1254, 1092, 1007. EI-MS m/z: 398 (Mꢃ). HR-MS m/z: 398.2299
(Calcd for C20H38O4Si2: 398.2309).
13b (1.0 g, 5.05 mmol) was added to the solution. After stirring the reaction
mixture for 3 h at room temperature, 1 M hydrochloric acid was added to the
reaction mixture which was extracted with ethyl acetate. The organic layer
was washed with a saturated aqueous solution of sodium chloride, dried over
sodium sulfate, and evaporated. The residue was purified by silica gel col-
umn chromatography (hexane : ethyl acetateꢄ5 : 1) to afford 16d (2.0 g,
3,5-Dibenzyloxy-4-methoxybenzaldehyde (18a) Pyridinium chlorochro-
mate (1.32 g, 6.1 mmol) was added to a solution of 17a (1.43 g, 4.1 mmol) in
terahydrofuran (15 ml) and the mixture was stirred for 3 h at room tempera-
ture. After the reaction, the reaction mixture was filtered through Celite®,
concentrated in vacuo, and the residue was extracted with ethyl acetate. The
organic layer was successively washed with 1 M hydrochloric acid, a satu-
rated aqueous solution of sodium bicarbonate, and a saturated aqueous solu-
tion of sodium chloride, dried over sodium sulfate, and evaporated. The
residue was purified by recrystallization from ethanol to afford 18a (1.36 g,
1
93%) as a colorless oil. H-NMR (400 MHz, CDCl3) d: 0.19 (12H, s), 1.01
(18H, s), 3.77, 3.87 (each 3H, s, OMe), 7.19 (2H, s, Ar-H). 13C-NMR
(100 MHz, CDCl3) d: –4.7, 18.3 (2C), 25.7 (6C), 52.0, 60.0, 116.1 (2C),
125.1, 147.3, 149.6 (2C), 166.7. IR (CHCl3) cmꢀ1: 2955, 1717, 1493, 1427,
1354, 1092, 1011. EI-MS m/z: 426 (Mꢃ). HR-MS m/z: 426.2259 (Calcd for
C21H38O5Si2: 426.2258).
1
96%) as colorless needles; mp 75—77 °C, H-NMR (300 MHz, CDCl3) d:
3,5-Dibenzyloxy-4-methoxybenzyl Alcohol (17a) A suspension of 16a
(488 mg, 1.29 mmol) and lithium aluminum hydride (150 mg, 3.87 mmol) in
tetrahydrofuran (6 ml) was stirred for 3 h at 60 °C. After the reaction, excess
amount of lithium aluminum hydride was quenched with ethyl acetate and
ice water, and then the mixture was extracted with ethyl acetate. The organic
layer was successively washed with 1 M hydrochloric acid and saturated solu-
tion of sodium chloride, dried over sodium sulfate, and evaporated. The
residue was purified by recrystallization from a mixed solvent of hexane and
ethyl acetate to afford 17a (434 mg, 96%) as colorless needles; mp 103—
105 °C. 1H-NMR (400 MHz, CDCl3) d: 3.87 (3H, s, OMe), 4.49 (2H, s,
CH2OH), 5.08 (4H, s, 2ꢆPhCH2O), 6.61 (2H, s, Ar-H), 7.23—7.44 (10H,
m, Ar-H). 13C-NMR (100 MHz, CDCl3) d: 60.9, 65.1, 70.9 (2C), 106.2 (2C),
127.2 (4C), 127.8, 128.5 (4C), 136.6, 137.0 (2C), 138.5, 152.5 (2C). IR
(CHCl3) cmꢀ1: 3690, 3600, 1593, 1506, 1437, 1234. EI-MS m/z: 350 (Mꢃ).
HR-MS m/z: 350.1519 (Calcd for C22H22O4: 350.1518). Anal. Calcd for
C22H22O4: C, 75.41; H, 6.33. Found: C, 75.67; H, 6.39.
3.97 (3H, s, OMe), 5.19 (4H, s, 2ꢆCH2O), 7.17 (2H, s, Ar-H), 7.30—7.46
(10H, m, Ar-H), 9.78 (1H, s, CHO). 13C-NMR (75 MHz, CDCl3) d: 61.0,
71.2, 109.0 (2C), 127.3 (4C), 128.1 (2C), 128.6 (4C), 131.5 (2C), 136.4
(2C), 145.0, 152.9 (2C), 190.9. IR (CHCl3) cmꢀ1: 3010, 2943, 2359, 1693,
1585, 1499, 1439, 1327, 1115. EI-MS m/z: 348 (Mꢃ). HR-MS m/z:
348.1356 (Calcd for C22H20O4: 348.1361). Anal. Calcd for C22H20O4: C,
75.84; H, 5.79. Found: C, 75.48; H, 5.50.
3,5-Diallyloxy-4-methoxybenzaldehyde (18b) Molecular sieves 3A
(9.0 g) was added to a mixture of 17b (4.50 g, 18.0 mmol), palladium acetate
(0.20 g, 0.89 mmol) and pyridine (0.17 ml) in toluene (160 ml) and the mix-
ture was stirred for 5 h at 90 °C under the atmosphere of oxygen. After
the reaction, the reaction mixture was filtered and the filtrate was evapo-
rated. The residue was purified by silica gel column chromatography
(hexane : ethyl acetateꢄ2 : 1) to afford recovered 17b (1.65 g, 37%) and 18b
(2.30 g, 52%) as a colorless oil. 1H-NMR (300 MHz, CDCl3) d: 3.97 (3H, s,
OMe), 4.66 (4H, dt, Jꢄ5.1, 1.5 Hz, 2ꢆOCH2–CHꢄCH2), 5.31 (2H, dq,
Jꢄ10.5, 1.5 Hz, 2ꢆCH2ꢄCH–), 5.43 (2H, dq, Jꢄ17.3, 1.5 Hz,
2ꢆCH2ꢄCH–), 6.06 (2H, ddt, Jꢄ17.3, 10.5, 1.5 Hz, 2ꢆCH2ꢄCH–), 7.11
(2H, s, Ar-H), 9.82 (1H, s, CHO). 13C-NMR (75 MHz, CDCl3) d: 61.0, 70.0
(2C), 108.6, 118.1 (2C), 131.5, 132.7 (2C), 152.7 (2C), 191.0. IR (CHCl3)
cmꢀ1: 3013, 1690, 1585, 1497, 1443, 1393, 1327, 1111. EI-MS m/z: 248
(Mꢃ). HR-MS m/z: 248.1051 (Calcd for C14H16O4: 248.1048).
3,5-Dimethoxymethoxy-4-methoxybenzaldehyde (18c) Molecular
sieves 3A (10 g) was added to a mixture of 17c (5.17 g, 20.0 mmol), palla-
dium acetate (0.22 g, 1.00 mmol) and pyridine (0.16 g, 2.0 mmol) in toluene
(150 ml) and the mixture was stirred for 2.5 h at 90 °C under the atmosphere
of oxygen. After the reaction, the reaction mixture was filtered and the fil-
trate was evaporated. The residue was purified by silica gel column chro-
matography (hexane : ethyl acetateꢄ2 : 1) to afford 18c (5.05 g, quant.) as a
colorless oil. 1H-NMR (400 MHz, CDCl3) d: 3.53 (6H, s, 2ꢆOCH3), 3.98
(3H, s, OCH3), 5.28 (4H, s, 2ꢆOCH2O), 7.41 (2H, s, Ar-H), 9.86 (1H, s,
CHO). 13C-NMR (75 MHz, CDCl3) d: 56.4 (2C), 61.2, 95.3 (2C), 111.7
(2C), 131.9, 151.3 (2C), 190.9. IR (CHCl3) cmꢀ1: 2959, 1701, 1589, 1497,
1450, 1381, 1323, 1242, 1157. EI-MS m/z: 256 (Mꢃ); HR-MS m/z:
256.0951 (Calcd for C12H16O6: 256.0947).
3,5-Diallyloxy-4-methoxybenzyl Alcohol (17b)
A solution of 16b
(7.00 g, 25.2 mmol) in tetrahydrofuran (110 ml) was added to a suspension
of lithium aluminum hydride (2.86 g, 75.4 mmol) in tetrahedrofuran (25 ml)
at 0 °C and the mixture was stirred for 3 h at room temperature. After the re-
action, excess amount of lithium aluminum hydride was quenched with ethyl
acetate and saturated aqueous solution of sodium sulfate, and then the mix-
ture was filtered through Celite®. The filtrate was extracted with ethyl ac-
etate and the organic layer was washed with a saturated aqueous solution of
sodium chloride, dried over sodium sulfate, and evaporated. The residue was
purified by silica gel column chromatography (hexane : ethyl acetateꢄ1 : 1)
1
to afford 17b (5.60 g, 89%) as a colorless oil. H-NMR (400 MHz, CDCl3)
d: 3.86 (3H, s, OMe), 4.58 (6H, dt, Jꢄ5.2, 1.5 Hz, 2ꢆCH2–CHꢄCHꢃ
CH2Ar), 5.27 (2H, dq, Jꢄ10.4, 1.5 Hz, CH2ꢄCH–), 5.41 (2H, dq, Jꢄ17.2,
1.5 Hz, CH2ꢄCH–), 6.06 (2H, ddt, Jꢄ17.2, 10.4, 1.5 Hz, 2ꢆCH2ꢄCH–),
6.58 (2H, s, Ar-H). 13C-NMR (100 MHz, CDCl3) d: 60.7, 65.3, 69.8 (2C),
105.8 (2C), 117.5 (2C), 133.3 (2C), 136.4, 138.3, 152.4. IR (CHCl3) cmꢀ1
:
3422, 2939, 1589, 1504, 1435, 1327, 1238, 1111, 1003. EI-MS m/z: 250
(Mꢃ). HR-MS m/z: 250.1197 (Calcd for C14H18O4: 250.1205).
3,5-Dimethoxymethoxy-4-methoxybenzyl Alcohol (17c) A solution of
16c (9.30 g, 32.5 mmol) in tetrahydrofuran (35 ml) was added to a suspen-
sion of lithium aluminum hydride (3.70 g, 97.5 mmol) in tetrahydrofuran
(35 ml) and the mixture was stirred for 80 min at 60 °C. After the reaction,
the excess amount of lithium aluminum hydride was quenched with ethyl ac-
etate and a saturated aqueous solution of sodium sulfate, and then the mix-
ture was filtered through Celite®. The filtrate was evaporated and the residue
was purified by silica gel column chromatography (hexane : ethyl
acetateꢄ1 : 1) to afford 17c (8.00 g, 95%) as a colorless oil; 1H-NMR
(400 MHz, CDCl3) d: 3.51(6H, s, 2ꢆOMe), 3.87 (3H, s, OMe), 4.57 (2H, s,
ArCH2O), 5.21 (4H, s, 2ꢆOCH2O), 6.84 (2H, s, Ar-H). 13C-NMR
(100 MHz, CDCl3) d: 56.2 (2C), 61.0, 64.9, 95.1, 108.9, 136.9, 139.1, 150.8
(2C). IR (CHCl3) cmꢀ1: 3456, 2909, 1589, 1497, 1450, 1396, 1315, 1250.
EI-MS m/z: 258 (Mꢃ). HR-MS m/z: 258.1104 (Calcd for C12H18O6:
258.1103).
3,5-Di-tert-butyldimethylsilyloxy-4-methoxybenzaldehyde (18d)
Pyridinium chlorochromate (735.1 mg, 3.41 mmol) was added to a mixture
of 17d (679.8 mg, 1.70 mmol) and Celite® in chloroform (7 ml) and the mix-
ture was stirred for 2 h at room temperature. After the reaction, the reaction
mixture was filtered and the residue was washed with ethyl acetate. The fil-
trate was evaporated and the residue was purified by silica gel column chro-
matography (chloroform) to afford 18d (570.5 mg, 85%) as colorless nee-
1
dles; mp 75—77 °C (methanol), H-NMR (400 MHz, CDCl3) d: 0.20 (12H,
s), 1.01 (18H, s), 3.81 (3H, s, OMe), 7.03 (2H, s, Ar-H), 9.78 (1H, s, CHO).
13C-NMR (75 MHz, CDCl3) d: ꢀ4.6 (4C), 18.3, 25.7 (6C), 60.1, 115.9 (2C),
131.8, 148.9, 150.4 (2C), 191.1. IR (CHCl3) cmꢀ1: 2932, 1693, 1574, 1489,
1439, 1389, 1346, 1258, 1231, 1092, 1007. EI-MS m/z: 396 (Mꢃ). HR-MS
m/z: 396.2161 (Calcd for C20H36O4Si2: 396.2152).
N-(3,5-Dibenzyloxy-4-methoxy)benzyl-N-(4-hydroxyphenyl)ethyl-
amine (19a) Tyramine (2.05 g, 15.0 mmol) was added to a solution of 18a
(5.00 g, 14.4 mmol) in methanol (100 ml) and the mixture was stirred for
70 min at 70 °C. After cooling the mixture to 0 °C, sodium borohydride
(0.60 g, 15.8 mmol) was added to the reaction mixture, which was stirred for
30 min at 0 °C and for another 40 min at room temperature. After the reac-
tion, the reaction mixture was evaporated and extracted with ethyl acetate.
The organic layer was washed with a saturated aqueous solution of sodium
chloride, dried over sodium sulfate, and evaporated, the residue was purified
by recrystallization from methanol to afford 19a (5.5 g, 81%) as colorless
crytstals; mp 133—135 °C. 1H-NMR (400 MHz, CDCl3) d: 2.70 (2H, t,
Jꢄ6.4 Hz, Ar-CH2CH2), 2.78 (2H, t, Jꢄ6.4 Hz, CH2CH2N), 3.64 (2H, s, Ar-
CH2N), 3.86 (3H, s, OMe), 5.02 (4H, s, 2ꢆCH2O), 6.54 (2H, s, Ar-H), 6.66
(2H, d, Jꢄ8.4 Hz), 6.96 (2H, d, Jꢄ8.4 Hz), 7.26—7.41 (m, 10H). 13C-NMR
3,5-Di-tert-butyldimethylsilyloxy-4-methoxybenzyl Alcohol (17d)
A
solution of 16d (1.00 g, 2.3 mmol) in tetrahydrofuran (15 ml) was added to a
suspension of lithium aluminum hydride (266.8 mg, 7.0 mmol) in tetrahydro-
furan (15 ml) and the mixture was stirred for 3 h at room temperature. After
the reaction, the excess amount of lithium aluminum hydride was quenched
with ice water and saturated aqueous solution of sodium sulfate, and then
the mixture was filtered through Celite®. The filtrate was evaporated, dried
over sodium sulfate, and the residue was purified by silica gel column chro-
matography (hexane : ethyl acetateꢄ5 : 1) to afford 17d (931.9 mg, 94%) as a
1
colorless oil. H-NMR (400 MHz, CDCl3) d: 0.17 (12H, s), 1.00 (18H, s),
3.70 (3H, s, OMe), 4.52 (2H, br s, CH2), 6.51 (2H, s, Ar-H). 13C-NMR
(75 MHz, CDCl3) d: ꢀ4.7 (4C), 18.3, 25.7 (6C), 59.9, 65.1, 113.2 (2C),
136.2, 142.3, 149.9 (2C). IR (CHCl3) cmꢀ1: 2932, 1578, 1493, 1470, 1435,

December 2006
1671
(100 MHz, CDCl3) d: 34.8, 50.1, 53.8, 60.9, 70.9 (2C), 107.8 (2C), 115.6 (1H, br, –OH), 6.30 and 6.42 (2H, s), 6.72—6.78 (2H, m), 6.84—6.88 (2H,
(2C), 127.3 (4C), 127.8 (2C), 128.5 (4C), 129.8 (2C), 130.6, 134.8, 137.1 m), 7.24—7.40 (10H, m). 13C-NMR (100 MHz, CDCl3) d: 31.7, 34.2, 48.3,
(2C), 138.4, 152.5 (2C), 155.0. IR (CHCl3) cmꢀ1: 3310, 3013, 1593, 1512, 48.4, 49.7, 51.4, 60.9, 61.0, 71.0, 71.1, 107.0, 107.7, 115.0, 115.2, 115.5,
1435, 1327, 1111, 1007. EI-MS m/z: 469 (Mꢃ). HR-MS m/z: 469.2257 115.6, 117.9, 118.0, 127.16, 127.18, 127.9, 128.0, 128.5, 128.6, 128.9,
(Calcd for C30H31NO4: 469.2253). Anal. Calcd for C30H31NO4: C, 76.73; H, 129.66, 129.73, 129.8, 129.9, 130.7, 136.6, 136.7, 138.95, 139.04, 152.57,
6.65; N, 2.98. Found: C, 76.82; H, 6.68; N, 3.13.
152.64, 154.7, 154.9, 156.6, 157.0, 157.2, 157.5. IR (CHCl3) cmꢀ1: 3317,
N-(3,5-Diallyloxy-4-methoxy)benzyl-N-(4-hydroxyphenyl)ethylamine 3013, 1686, 1593, 1516, 1435, 1150, 1115. EI-MS m/z: 565 (Mꢃ). HR-MS
(19b) Tyramine (0.58 g, 4.2 mmol) was added to a solution of 18b (1.00 g,
4.0 mmol) in methanol (12 ml) and the mixture was stirred for 20 min at
room temperature. After cooling the mixture to 0 °C, sodium borohydride
m/z: 565.2077 (Calcd for C32H30F3NO5: 565.2076).
N-(3,5-Dibenzyloxy-4-methoxy)benzyl-N-(4-hydroxyphenyl)ethyl-
formamide (15b) A suspension of 19a (1.96 g, 4.2 mmol) in ethyl formate
(0.15 g, 4.0 mmol) was added to the reaction mixture, which was stirred for (40 ml) was refluxed for 6 h. After the reaction, the organic solvent was
20 min at room temperature. After the reaction, the reaction mixture was evaporated and the residue was purified by silica gel column chromatogra-
evaporated and extracted with ethyl acetate. The organic layer was washed phy (chloroform : methanolꢄ20 : 1) to afford 15b (2.0 g, 97%) as colorless
with a saturated aqueous solution of sodium chloride, dried over sodium sul- crystals; mp 125—126 °C. 1H-NMR (400 MHz, CDCl3) d: 2.54 and 2.61
fate, and evaporated, the residue was purified by silica gel column chro- (2H, t, Jꢄ6.9 Hz), 3.14 and 3.30 (2H, t, Jꢄ6.9 Hz), 3.90 (3H, s, OMe), 4.06
matography (chloroform : methanolꢄ10 : 1) to afford 19b (1.29 g, 87%) as
and 4.36 (2H, s), 5.10 (4H, s, 2ꢆOCH2Ph), 6.33 and 6.48 (2H, s, Ar-H),
colorless plates; mp 91—94 °C. 1H-NMR (400 MHz, CDCl3) d: 2.88 (4H, 6.74 and 6.82 (2H, d, A part of AB, Jꢄ8.5 Hz), 6.71 and 6.92 (2H, d, B part
br s, CH2CH2), 3.83 (3H, s, OMe), 3.84 (2H, s, Ar-CH2N), 4.55 (4H, d, of AB, Jꢄ8.5 Hz), 6.67 and 7.01 (1H, br s, –OH), 7.26—7.43 (10H, m), 7.74
Jꢄ5.1 Hz, 2ꢆCH2O), 5.23 (2H, dd, Jꢄ10.5, 1.4 Hz, CH2ꢄCH–), 5.38 (2H, and 8.13 (1H, s). 13C-NMR (100 MHz, CDCl3) d: 32.3, 33.6, 43.5, 45.7,
dd, Jꢄ17.3, 1.4 Hz, CH2ꢄCH–), 5.95—6.18 (2H, m, CH2ꢄCH–), 6.64 (2H, 48.6, 51.8, 60.9, 71.0, 71.1, 107.1, 108.1, 115.4, 115.6, 127.2, 127.3, 127.8,
s, Ar-H), 6.69, 6.92 (each 2H, d, AB type, Jꢄ8.4 Hz, Ar-H). 13C-NMR
128.0, 128.5, 128.6, 128.7, 129.6, 129.7, 129.8, 131.0, 131.5, 136.7, 136.9,
(100 MHz, CDCl3) d: 34.7, 50.1, 53.8, 60.7, 69.5, 107.3, 115.7, 117.4, 138.9, 139.1, 152.5, 152.7, 155.0, 155.4, 163.0, 163.3. IR (CHCl3) cmꢀ1
:
129.7, 130.4, 133.4, 134.5, 138.0, 152.3, 155.1. IR (CHCl3) cmꢀ1: 3310, 3310, 2939, 1663, 1593, 1516, 1435, 1238, 1115, 1007. EI-MS m/z: 497
2932, 1593, 1512, 1435, 1327, 1242, 1107, 1003; EI-MS m/z: 369 (Mꢃ). (Mꢃ). HR-MS m/z: 497.2207 (Calcd for C31H31NO5: 497.2202).
HR-MS m/z: 369.1951 (Calcd for C22H27NO4: 369.1940). Anal. Calcd for
C22H27NO4: C, 71.52; H, 7.37; N, 3.79. Found: C, 71.48; H, 7.21; N, 4.05.
N-(3,5-Diallyloxy-4-methoxy)benzyl-N-(4-hydroxyphenyl)ethyltrifluo-
roacetamide (15c) Trifluoroacetic anhydride (0.48 ml, 3.4 mmol) was
N-(3,5-Dimethoxymethoxy-4-methoxy)benzyl-N-(4-hydroxy- added to a solution of 19b (0.42 g, 1.13 mmol) in pyridine (4 ml) at 0 °C and
phenyl)ethylamine (19c) Tyramine (1.40 g, 10.5 mmol) was added to a so-
lution of 18c (2.60 g, 10.1 mmol) in methanol (30 ml) and the mixture was
stirred for 20 min at room temperature. After cooling the mixture to 0 °C,
the mixture was stirred for 10 min with keeping the temperature. After the
reaction, the reaction mixture was evaporated and the residue was purified
by silica gel column chromatography (hexane : ethyl acetateꢄ1 : 1) to afford
1
sodium borohydride (0.38 g, 10.0 mmol) was added to the reaction mixture, 15c (0.49 g, 93%) as a pale yellow oil. H-NMR (400 MHz, CDCl3) d: 2.75
which was stirred for 50 min at room temperature. After the reaction, the re- and 2.80 (2H, t, Jꢄ7.6 Hz), 3.45 and 3.47 (2H, t, Jꢄ7.6 Hz), 3.86 and 3.87
action mixture was evaporated and extracted with ethyl acetate. The organic (3H, s, OMe), 4.27 and 4.53 (2H, s), 4.55—4.58 (4H, m, 2ꢆCH2ꢄ
layer was washed with a saturated aqueous solution of sodium chloride, CH–CH2O), 5.25 and 5.28 (2H, dq, Jꢄ10.4, 1.5 Hz, 2ꢆCH2ꢄCH–), 5.39
dried over sodium sulfate, and evaporated, the residue was purified by silica and 5.40 (2H, dq, Jꢄ17.3, 1.5 Hz, 2ꢆCH2ꢄCH–), 6.00 and 6.05 (2H, ddt,
gel column chromatography (chloroform : methanolꢄ10 : 1) to afford 19c Jꢄ17.3, 1.5 Hz, CH2–CHꢄCH2), 6.32 and 6.43 (2H, s, Ar-H), 6.78 and 6.79
(3.80 g, quant) as a colorless oil. 1H-NMR (400 MHz, CDCl3) d: 2.75 (2H, t, (2H, d, Jꢄ8.5 Hz, Ar-H), 7.00 (2H, d, Jꢄ8.5 Hz, Ar-H). 13C-NMR
Jꢄ6.8 Hz, Ar-CH2CH2), 2.86 (2H, t, Jꢄ6.8 Hz, CH2CH2N), 3.50 (6H, s, (100 MHz, CDCl3) d: 31.9, 34.3, 48.4, 49.7, 51.4, 60.80, 60.83, 69.9, 70.0,
2ꢆOMe), 3.70 (2H, s, ArCH2N), 3.86 (3H, s, OMe), 5.18 (4H, s, 106.6, 107.3, 115.5, 115.7, 117.7, 117.8, 129.2, 129.8, 129.90, 129.94,
2ꢆOCH2O), 6.71 (2H, d, Jꢄ8.5 Hz, Ar-H), 6.76 (2H, s), 7.03 (2H, d,
130.1, 130.7, 133.0, 133.1, 138.8, 138.9, 152.6, 152.7, 154.5, 154.7. IR
Jꢄ8.5 Hz). 13C-NMR (75 MHz, CDCl3) d: 34.9, 50.3, 53.5, 56.2 (2C), 61.0, (CHCl3) cmꢀ1: 2939, 1690, 1663, 1593, 1493, 1462, 1435, 1327, 1150. EI-
95.3 (2C), 110.3 (2C), 115.5 (2C), 129.7 (2C), 131.0, 135.5, 138.9, 150.8 MS m/z: 465 (Mꢃ). HR-MS m/z: 465.1759 (Calcd for C24H26F3NO5:
(2C), 154.7. IR (CHCl3) cmꢀ1: 3314, 2935, 1593, 1512, 1435, 1323, 1242, 465.1763).
1111, 1042. EI-MS m/z: 377 (Mꢃ). HR-MS m/z: 377.1837 (Calcd for
C20H27NO6: 377.1838).
N-(3,5-Diallyloxy-4-methoxy)benzyl-N-(4-hydroxyphenyl)ethylform-
amide (15d) A solution of 19b (554 mg, 1.5 mmol) in ethyl formate
N-(3,5-Di-tert-butyldimethylsilyloxy-4-methoxy)benzyl-N-(4-hy- (10 ml) was refluxed for 33 h. After the reaction, the organic solvent was
droxyphenyl)ethylamine (19d) Tyramine (328 mg, 2.39 mmol) was added evaporated and the residue was purified by silica gel column chromatogra-
to a solution of 18d (950 mg, 2.39 mmol) in methanol (25 ml) and the mix-
ture was stirred for 2 h at room temperature. After cooling the mixture to yellow oil. 1H-NMR (400 MHz, CDCl3) d: 2.69 and 2.71 (2H, t, Jꢄ7.4 Hz),
0 °C, sodium borohydride (90.8 mg, 2.39 mmol) was added to the reaction
3.34 and 3.44 (2H, t, Jꢄ7.4 Hz), 3.86 (3H, s, OMe), 4.14 and 4.43 (2H, s),
phy (chloroform : methanolꢄ10 : 1) to afford 15d (570 mg, 97%) as a pale
mixture, which was stirred for 1 h at room temperature. After the reaction, 4.56 and 4.57 (4H, dt, Jꢄ5.1, 1.5 Hz, 2ꢆCH2ꢄCH–CH2), 5.26 and 5.27
the reaction mixture was evaporated and extracted with ethyl acetate. The (2H, dq, Jꢄ10.2, 1.5 Hz, 2ꢆCH2ꢄCH–), 5.39 (2H, dd, Jꢄ18.0, 1.5,
organic layer was washed with saturated aqueous solution of sodium chlo- 2ꢆCH2ꢄCH–), 5.99—6.05 (2H, m, 2ꢆCH2ꢄCH–), 6.32 and 6.46 (2H, s,
ride, dried over sodium sulfate, and evaporated, the residue was purified by Ar-H), 6.73 and 6.75 (2H, d, Jꢄ8.5 Hz), 6.91 and 7.01 (2H, d, Jꢄ8.4 Hz, Ar-
silica gel column chromatography (chloroform : methanolꢄ30 : 1) to afford H), 7.86 and 8.21 (1H, s, CHO). 13C-NMR (100 MHz, CDCl3) d: 32.4, 33.8,
19d (1.22 g, 98%) as colorless needles; mp 113—114 °C (n-hexane). 1H- 43.9, 45.8, 48.8, 52.0, 60.72, 60.74, 65.8, 67.9, 69.86, 69.90, 106.9, 107.5,
NMR (400 MHz, CDCl3) d: 0.14 (12H, s), 0.98 (18H, s), 2.74 (2H, t, 115.4, 115.7, 117.6, 117.7, 128.5, 129.5, 129.65, 129.71, 130.9, 131.5,
Jꢄ6.5 Hz, Ar-CH2CH2), 2.84 (2H, t, Jꢄ6.3 Hz, CH2CH2N), 3.64 (2H, s, Ar- 133.0, 133.1, 138.5, 138.7, 152.4, 152.6, 155.2, 155.5, 163.1, 163.3. IR
CH2N), 3.69 (3H, s, OMe), 6.42 (2H, s, Ar-H), 6.66 (2H, d, Jꢄ8.2 Hz, Ar- (CHCl3) cmꢀ1: 3316, 2936, 1663, 1593, 1516, 1423, 1238, 1111, 1103. EI-
H), 6.99 (2H, d, Jꢄ8.2 Hz, Ar-H). 13C-NMR (75 MHz, CDCl3) d: ꢀ4.7 MS m/z: 397 (Mꢃ). HR-MS m/z: 397.1892 (Calcd for C22H27NO5:
(4C), 18.3, 25.7 (6C), 35.0, 50.1, 53.2, 59.9, 114.4 (2C), 115.6 (2C), 129.7 397.1889).
(2C), 130.9, 134.7, 141.9, 149.7 (2C), 154.7. IR (CHCl3) cmꢀ1: 2932, 1578,
1516, 1431, 1350, 1254, 1092, 1007. EI-MS m/z: 517 (Mꢃ). HR-MS m/z: ethyltrifluoroacetamide (15e) Trifluoroacetic anhydride (5.35 ml, 37.9
517.3028 (Calcd for C28H47NO4Si2: 517.3043).
mmol) was added to a solution of 19c (4.77 g, 12.6 mmol) in pyridine
N-(3,5-Dimethoxymethoxy-4-methoxy)benzyl-N-(4-hydroxyphenyl)-
N-(3,5-Dibenzyloxy-4-methoxy)benzyl-N-(4-hydroxyphenyl)ethyltri- (40 ml) at 0 °C and the mixture was stirred for 20 min. After the reaction, the
fluoroacetamide (15a) Trifluoroacetic anhydride (0.36 ml, 2.56 mmol) reaction mixture was evaporated and the residue was purified by silica gel
was added to a solution of 19a (500 mg, 1.06 mmol) in pyridine (5 ml) at column chromatography (chloroform : methanolꢄ10 : 1) to afford 15e (5.1 g,
0 °C and the mixture was stirred for 10 min with keeping the temperature.
85%) as colorless needles; mp 95—97 °C (n-hexane–diethyl ether). 1H-
After the reaction, the reaction was quenched by adding methanol (5 ml) and NMR (400 MHz, CDCl3) d: 2.76 and 2.81 (2H, t, Jꢄ7.8 Hz), 3.48 and 3.50
the reaction mixture was evaporated. The residue was purified by silica (2H, t, Jꢄ7.8 Hz), 3.50 (6H, s, 2ꢆOMe), 3.87 and 3.88 (3H, s, OMe), 4.31
gel column chromatography (hexane : ethyl acetateꢄ2 : 1) to afford 15a
and 4.55 (2H, s), 5.18 (4H, s, 2ꢆOCH2O), 5.40 (1H, br s, OH), 6.63 and
(543 mg, 91%) as an amorphous powder. 1H-NMR (400 MHz, CDCl3) d: 6.71 (2H, s, Ar-H), 6.74 and 6.75 (2H, d, Jꢄ8.5 Hz), 6.99 and 7.00 (2H, d,
2.61 and 2.63 (2H, t, Jꢄ8.0 Hz), 3.26 and 3.30 (2H, t, Jꢄ8.0 Hz), 3.90 and Jꢄ8.5 Hz). 13C-NMR (100 MHz, CDCl3) d: 31.9, 34.3, 48.4, 48.5, 49.5,
3.91 (3H, s, OMe), 4.17 and 4.45 (2H, s), 5.09 (4H, s, 2ꢆOCH2Ph), 5.80 51.3, 56.26, 56.29, 61.05, 61.07, 95.4, 109.9, 110.4, 115.5, 115.7, 129.2,

1672
Vol. 54, No. 12
129.8, 129.9, 130.1, 130.5, 131.0, 136.6, 139.8, 139.9, 151.2, 151.3, 154.5,
154.7, 156.7, 156.8. IR (CHCl3) cmꢀ1: 3337, 2936, 1686, 1597, 1516, 1435,
1323, 1242, 1157, 1111, 1049, 1007. EI-MS m/z: 473 (Mꢃ). HR-MS m/z:
473.1654 (Calcd for C22H26F3NO7: 473.1661). Anal. Calcd for
C22H26F3NO7: C, 55.81; H, 5.54; N, 2.96. Found: C, 55.53; H, 5.61; N, 2.96.
OMe), 4.60 and 4.69 (2H, s), 4.84 and 4.88 (2H, s), 5.14 and 5.15 (2H, s),
6.14 and 6.15 (2H, d, Jꢄ10.2 Hz, A part of AB), 6.57 and 6.76 (1H, s, Ar-
H), 6.98 and 7.05 (2H, d, B part of AB, Jꢄ10.2 Hz), 7.22—7.47 (10H, m),
8.19 and 8.21 (1H, s, Ar-H). 13C-NMR (75 MHz, CDCl3) d: 38.1, 39.4, 40.8,
45.6, 45.7, 47.1, 50.4, 60.8, 60.9, 70.7, 71.0, 75.7, 110.3, 111.2, 124.2,
N-(3,5-Dimethoxymethoxoxy-4-methoxy)benzyl-N-(4-hydroxyphenyl)- 124.4, 126.5, 126.6, 127.3, 127.4, 127.7, 127.80, 127.82, 128.1, 128.2,
ethylformamide (15f) A solution of 19c (4.28 g, 11.3 mmol) in ethyl for- 128.31, 128.33, 128.6, 128.7, 133.0, 133.3, 136.3, 136.4, 136.7, 136.8,
mate (35 ml) was refluxed for 3.5 h. After the reaction, the organic solvent 142.2, 142.6, 151.81, 151.84, 153.1, 153.6, 154.1, 154.4, 161.7, 162.4,
was evaporated and the residue was purified by silica gel column chromatog- 185.1, 185.2. IR (CHCl3) cmꢀ1: 1663, 1620, 1593, 1493, 1329, 1123. EI-MS
raphy (chloroform : ethyl acetateꢄ1 : 1) to afford 15f (3.8 g, 83%) as color- m/z: 495 (Mꢃ). HR-MS m/z: 495.2052 (Calcd for C31H29NO5: 495.2045).
1
less crystals; mp 120—125 °C (ethyl acetate). H-NMR (400 MHz, CDCl3) Anal. Calcd for C31H29NO5: C, 75.13; H, 5.90; N, 2.83. Found: C, 75.26; H,
d: 2.71 and 2.72 (2H, t, Jꢄ6.0 Hz), 3.37 and 3.46 (2H, t, Jꢄ6.0 Hz), 3.51
(6H, s, 2ꢆOMe), 3.86 and 3.87 (3H, s, OMe), 4.16 and 4.46 (2H, s), 5.20
(4H, s), 6.63 and 6.73 (2H, s, Ar-H), 6.72 and 6.75 (2H, d, Jꢄ8.6 Hz), 6.90
and 7.00 (2H, d, Jꢄ8.6 Hz), 7.84 and 8.21 (1H, s, CHO). 13C-NMR
5.98; N, 2.92.
6,8-Diallyloxy-7-methoxy-2-trifluoroacetyl-2,3,4,5-tertahydro-1H-
[2]benzazepine-5-spiro-1ꢂ-cyclohexa-2ꢂ,5ꢂ-diene-4ꢂ-one (20c) A solution
of PIFA (47.3 mg, 0.12 mmol) in 2,2,2-trifluoroethanol (1 ml) was added to a
(100 MHz, CDCl3) d: 32.4, 33.8, 43.9, 45.6, 48.9, 51.8, 56.1, 56.3, 60.95, solution of 15c (50 mg, 0.11 mmol) in 2,2,2-trifluoroethanol (1.5 ml) at
61.03, 95.30, 95.34, 109.9, 110.5, 115.4, 115.7, 128.8, 129.7, 129.79,
129.81, 131.5, 131.9, 139.5, 139.8, 151.0, 151.2, 155.0, 155.4, 163.0, 163.3.
ꢀ40 °C and the mixture was stirred for 1 h with keeping the temperature.
After the reaction, the organic solvent in the reaction mixture was evapo-
IR (CHCl3) cmꢀ1: 3321, 2936, 1666, 1597, 1516, 1435, 1396, 1157, 1049, rated and the residue was purified by silica gel column chromatography
1107. EI-MS m/z: 405 (Mꢃ). HR-MS m/z: 405.1797 (Calcd for C21H27NO7:
405.1787). Anal. Calcd for C21H27NO7: C, 62.21; H, 6.71; N, 3.45. Found: oil. 1H-NMR (400 MHz, CDCl3) d: 2.31 (2H, t, Jꢄ5.5 Hz), 3.79 and 3.80
C, 62.34; H, 6.83; N, 3.27. (3H, s, OMe), 3.84 and 3.88 (2H, t, Jꢄ6.2 Hz), 4.37 and 4.39 (2H, dt,
(hexane : ethyl acetateꢄ1 : 1) to afford 20c (30.0 mg, 60%) as a pale yellow
N-(3,5-Di-tert-butyldimethylsilyloxy-4-methoxy)benzyl-N-(4-hydrox- Jꢄ4.4, 1.2 Hz, CH2ꢄCH–CH2), 4.59 and 4.61(2H, dt, Jꢄ4.4, 1.2 Hz,
yphenyl)ethyltrifluoroacetamide (15g) Trifluoroacetic anhydride (0.98 CH2ꢄCH–CH2), 4.76 and 4.80 (2H, s), 5.14 and 5.32 (2H, dm, Jꢄ10.4 Hz,
ml, 7.0 mmol) was added to a solution of 19d (1.2 g, 2.3 mmol) in pyridine 2ꢆCH2ꢄCH–), 5.20 and 5.43 (2H, dm, Jꢄ17.2 Hz, 2ꢆCH2ꢄCH–), 5.80
(20 ml) at 0 °C and the mixture was stirred for 3 h at room temperature.
and 6.06 (2H, m, 2ꢆCH2ꢄCH–), 6.27 (2H, d, Jꢄ10.0 Hz), 6.47 and 6.64
After the reaction, the reaction mixture was evaporated and extracted with (1H, s, Ar-H), 6.95 and 7.00 (2H, d, Jꢄ10.0 Hz). 13C-NMR (75 MHz,
ethyl acetate. The organic layer was successively washed with 10% hy- CDCl3) d: 37.2, 38.7, 44.4, 45.3, 47.0, 47.3, 48.2, 49.0, 60.67, 60.72, 69.6,
drochloric acid, saturated aqueous solution of sodium bicarbonate, and satu-
rated aqueous solution of sodium chloride, dried over sodium sulfate, and
69.8, 111.0, 111.5, 117.9, 118.05, 118.10, 123.2, 123.6, 126.9, 131.0, 131.2,
132.6, 132.7, 133.0, 133.1, 142.5, 142.7, 151.7, 152.6, 152.7, 153.8, 154.1,
evaporated. The residue was purified by silica gel column chromatography 185.39, 185.44; IR (CHCl3) cmꢀ1: 1690, 1663, 1620, 1593, 1466, 1327,
(hexane : ethyl acetateꢄ3 : 1) to afford 15g (1.19 g, 84%) as a pale yellow 1150, 1092. EI-MS m/z: 463 (Mꢃ). HR-MS m/z: 463.1600 (Calcd for
1
oil. H-NMR (400 MHz, CDCl3) d: 0.15 (12H, s), 0.99 (18H, s), 2.75 and C24H24F3NO5: 463.1606).
2.80 (2H, t, Jꢄ7.2 Hz), 3.44 and 3.46 (2H, t, Jꢄ7.2 Hz), 3.71 and 3.72 (3H,
6,8-Diallyloxy-2-formyl-7-methoxy-2,3,4,5-tertahydro-1H-[2]ben-
solution of
PIFA (155.8 mg, 0.36 mmol) in 2,2,2-trifluoroethanol (1.0 ml) was added to
13C-NMR (75 MHz, CDCl3) d: ꢀ4.7 (4C), 18.3, 25.7 (6C), 31.9, 34.3, 48.3, a solution of 15d (120 mg, 0.3 mmol) in 2,2,2-trifluoroethanol (0.5 ml) at
s, OMe), 4.20 and 4.49 (2H, s), 4.95 (1H, br, –OH), 6.28 and 6.37 (2H, s, zazepine-5-spiro-1ꢂ-cyclohexa-2ꢂ,5ꢂ-diene-4ꢂ-one (20d)
Ar-H), 6.75 and 6.77 (2H, d, Jꢄ8.6 Hz), 6.99 and 7.01 (2H, d, Jꢄ8.5 Hz).
A
49.1, 51.1, 51.2, 60.0, 113.8, 114.2, 115.5, 115.7, 129.3, 129.7, 129.8,
129.9, 130.1, 130.3, 142.6, 142.8, 150.1, 150.2, 154.5, 154.7, 156.61,
156.62, 157.1, 157.6. IR (CHCl3) cmꢀ1: 3337, 2932, 1686, 1578, 1516,
1497, 1431, 1358, 1258, 1150, 1092, 1107. EI-MS m/z: 613 (Mꢃ). HR-MS
m/z: 613.2881 (Calcd for C30H46F3N5Si2: 613.2866).
ꢀ40 °C and the mixture was stirred for 30 min with keeping the tempera-
ture. After the reaction, the organic solvent in the reaction mixture was evap-
orated and the residue was purified by silica gel column chromatography
(hexane : ethyl acetateꢄ2 : 1) to afford 20d (57.0 mg, 48%) as colorless crys-
tals. H-NMR (400 MHz, CDCl3) d: 2.28 and 2.31 (2H, t, Jꢄ6.3 Hz), 3.67
and 3.72 (2H, t, Jꢄ6.0 Hz), 3.78 and 3.79 (3H, s, OMe), 4.33 and 4.37 (2H,
1
6,8-Dibenzyloxy-7-methoxy-2-trifluoroacetyl-2,3,4,5-tertahydro-1H-
[2]benzazepine-5-spiro-1ꢂ-cyclohexa-2ꢂ,5ꢂ-diene-4ꢂ-one (20a)
A solu- dt, Jꢄ5.6, 1.2 Hz, 2ꢆCH2ꢄCH–CH2), 4.59—4.61 (2H, m), 4.61 and 4.68
tion of PIFA (1.70 g, 3.80 mmol) in 2,2,2-trifluoroethanol (15 ml) was added (2H, s), 5.13 and 5.33 (2H, dm, Jꢄ10.4 Hz, 2ꢆCH2ꢄCH–), 5.19 and 5.44
to a solution of 15a (1.8 g, 3.20 mmol) in 2,2,2-trifluoroethanol (4 ml) at
ꢀ40 °C and the mixture was stirred for 1 h with keeping the temperature.
(2H, dm, Jꢄ17.2 Hz, 2ꢆCH2ꢄCH–), 5.80 and 6.06 (2H, m, 2ꢆCH2ꢄCH–),
6.26 (2H, d, Jꢄ10.0 Hz), 6.49 and 6.64 (1H, s, Ar-H), 6.98 and 7.03 (2H, d,
After the reaction, the organic solvent in the reaction mixture was evapo- Jꢄ10.0 Hz), 8.19, 8.22 (1H, s, CHO). 13C-NMR (100 MHz, CDCl3) d: 37.8,
rated and the residue was purified by silica gel column chromatography 38.9, 40.8, 45.4, 45.6, 47.1, 50.3, 60.6, 60.7, 69.5, 69.7, 74.06, 74.13,
(hexane : ethyl acetateꢄ10 : 1) to afford 20a (960.7 mg, 53%) as colorless
109.92, 110.93, 117.90, 117.93, 118.01, 118.03, 123.7, 123.8, 126.6, 126.7,
1
amorphous powder. H-NMR (400 MHz, CDCl3) d: 2.28 (2H, m), 3.75 and 132.65, 132.71, 132.9, 133.0, 133.2, 142.1, 142.4, 151.5, 151.6, 152.5,
3.76 (3H, s), 3.80—3.88 (2H, m), 4.73 and 4.79 (2H, s), 4.89 and 4.91 (2H, 152.9, 154.2, 154.4, 161.7, 162.4, 185.6. IR (CHCl3) cmꢀ1: 1666, 1620,
s), 5.12 and 5.14 (2H, s), 6.12 (2H, d, Jꢄ10.1 Hz), 6.57 and 6.78 (1H, s), 1593, 1493, 1466, 1331, 1215, 1123, 1092; EI-MS m/z: 395 (Mꢃ). HR-MS
6.94 and 7.01 (2H, d, Jꢄ10.1 Hz), 7.22—7.47 (10H, m). 13C-NMR m/z: 395.1740 (Calcd for C23H25NO5: 395.1732).
(75 MHz, CDCl3) d: 37.2, 38.8, 44.3, 45.05, 45.10, 46.8, 47.08, 48.12,
48.85, 48.88, 60.6, 60.7, 70.7, 70.8, 75.4, 77.2, 111.2, 111.6, 114.1, 114.3,
6,8-Dimethoxymethoxy-7-methoxy-2-trifluoroacetyl-2,3,4,5-tertahy-
dro-1H-[2]benzazepine-5-spiro-1ꢂ-cyclo-hexa-2ꢂ,5ꢂ-diene-4ꢂ-one (20e)
117.9, 118.1, 121.7, 121.9, 123.6, 124.0, 126.52, 126.53, 127.1, 127.2, PIFA (72.6 mg, 0.16 mmol) was added to a solution of 15e (72.7 mg,
127.5, 127.58, 127.61, 127.9, 128.0, 128.1, 128.4, 128.5, 131.1, 131.2, 0.15 mmol) in 2,2,2-trifluoroethanol (1.5 ml) at ꢀ40 °C and the mixture was
136.1, 136.2, 136.6, 136.7, 142.5, 142.7, 151.7, 151.8, 152.9, 153.0, 153.7,
stirred for 15 min with keeping the temperature. After the reaction, the or-
153.9, 155.7, 156.0, 156.2, 156.5, 184.66, 184.73. IR (CHCl3) cmꢀ1: 1690, ganic solvent in the reaction mixture was evaporated and the residue was pu-
1663, 1593, 1466, 1331, 1150, 1123. EI-MS m/z: 563 (Mꢃ). HR-MS m/z: rified by silica gel column chromatography (hexane : ethyl acetateꢄ1 : 1) to
563.1924 (Calcd for C32H28F3NO5: 563.1919).
6,8-Dibenzyloxy-2-formyl-7-methoxy-2,3,4,5-tertahydro-1H-[2]ben-
afford 20e (32.3 mg, 45%) as a colorless oil. 1H-NMR (400 MHz, CDCl3) d:
2.33 (2H, m), 3.37 (3H, s, OMe), 3.52 (3H, s, OMe), 3.79 and 3.80 (3H, s,
zazepine-5-spiro-1ꢂ-cyclohexa-2ꢂ,5ꢂ-diene-4ꢂ-one (20b) (s-cis and s- OMe), 3.82—3.90 (2H, m), 4.77 and 4.80 (2H, s), 4.91 and 4.92 (2H, s),
transꢃ2 : 1)
A
solution of PIFA (1.90 g, 4.4 mmol) in 2,2,2-trifluo-
5.22 and 5.24 (2H, s), 6.32 (2H, d, Jꢄ10.1 Hz), 6.75 and 6.89 (1H, s, Ar-H),
6.95 and 7.00 (2H, d, Jꢄ10.1 Hz). 13C-NMR (75 MHz, CDCl3) d: 37.1, 38.6,
44.4, 45.17, 45.22, 47.0, 47.2, 48.1, 48.89, 48.94, 56.3, 56.4, 57.67, 57.69,
roethanol (10 ml) was added to a solution of 15b (2.00 g, 4.0 mmol) in triflu-
oroethanol (100 ml) at ꢀ40 °C and the mixture was stirred for 1 h with keep-
ing the temperature. After the reaction, the organic solvent in the reaction 60.70, 60.73, 95.0, 95.1, 99.2, 113.2, 113.8, 114.2, 114.4, 118.1, 118.2,
mixture was evaporated and the residue was purified by recrystallization 124.2, 124.5, 126.95, 126.99, 131.6, 131.8, 142.3, 142.4, 150.25, 150.29,
from ethyl acetate to afford 20b (1.29 g, 65%) and the mother liquid was 150.7, 150.8, 153.7, 154.0, 155.9, 156.3, 156.4, 156.7, 185.4, 185.5. IR
purified by silica gel column chromatography (chloroform : ethyl
(CHCl3) cmꢀ1: 3013, 1690, 1663, 1620, 1153, 1049. EI-MS m/z: 471 (Mꢃ).
HR-MS m/z: 471.1499 (Calcd for C22H24F3NO7: 471.1504).
6,8-Dimethoxymethoxy-2-formyl-7-methoxy-2,3,4,5-tertahydro-1H-
acetateꢄ20 : 1) to afford 20b (341.5 mg, 17%) as colorless crystals; mp
1
187—189 °C (ethyl acetate). H-NMR (400 MHz, CDCl3) d: 2.26 and 2.29
(2H, t, Jꢄ6.2 Hz), 3.65 and 3.71 (2H, t, Jꢄ6.2 Hz), 3.74 and 3.75 (3H, s, [2]benzazepine-5-spiro-1ꢂ-cyclohexa-2ꢂ,5ꢂ-diene-4ꢂ-one (20f) A solution

December 2006
1673
of PIFA (236 mg, 0.55 mmol) in 2,2,2-trifluoroethanol (2.5 ml) was added to organic solvent of the reaction mixture was removed in vacuo and the
a solution of 15f (203 mg, 0.5 mmol) in 2,2,2-trifluoroethanol (1.5 ml) at residue was extracted with ethyl acetate. The organic layer was successive-
ꢀ40 °C and the mixture was stirred for 10 min with keeping the tempera- ly washed with saturated aqueous solutions of sodium thiosulfate and
ture. After the reaction, the organic solvent in the reaction mixture was evap- sodium bicarbonate, dried over magnesium sulfate, and concentrated in
orated and partitioned between ethyl acetate and 5% aqueous solution of
vacuo. The residue was purified by silica gel column chromatography (chlo-
sodium bicarbonate. The organic layer was washed with saturated aqueous roform : methanolꢄ10 : 1) to afford 15b (20 mg, 8% recovered), 20b
solution of sodium chloride, dried over sodium sulfate, and evaporated. The (125 mg, 50%), and 21a (33 mg, 13%) as a colorless oil.
residue was purified by silica gel column chromatography (hexane : ethyl ac-
etateꢄ2 : 3) to afford 20f (87.0 mg, 43%) as a pale yellow oil. 1H-NMR 5) A solution of PIDA (194 mg, 0.6 mmol) in acetic acid (3.7 ml) was
(400 MHz, CDCl3) d: 2.29 and 2.32 (2H, t, Jꢄ6.5 Hz), 3.37 (3H, s, OMe), added dropwise to a solution of 15b (250 mg, 0.5 mmol) in acetic acid
Oxidative Coupling of 15b with PIDA in Acetic Acid (Table 2, Entry
3.52 and 3.53 (3H, s, OMe), 3.68 and 3.73 (2H, t, Jꢄ6.1 Hz), 3.78 and 3.79 (10 ml) and the mixture was stirred for 40 min at room temperature. The
(3H, s, OMe), 4.63 and 4.69 (2H, s), 4.86 and 4.90 (2H, s), 5.23 (2H, s), organic solvent of the reaction mixture was removed in vacuo and the
6.30 (2H, d, Jꢄ10.3 Hz), 6.76 and 6.88 (1H, s, Ar-H), 6.98 and 7.04 (2H, d, residue was extracted with ethyl acetate. The organic layer was successive-
Jꢄ10.3 Hz), 8.19 and 8.23 (1H, s). 13C-NMR (75 MHz, CDCl3) d: 37.3, ly washed with saturated aqueous solutions of sodium thiosulfate and
37.8, 38.9, 40.3, 45.8, 45.6, 47.1, 47.2, 50.2, 56.3, 56.4, 57.69, 57.71, 60.7,
60.8, 95.0, 95.1, 99.26, 99.33, 112.1, 113.3, 124.8, 126.7, 126.8, 132.3,
133.0, 133.5, 133.7, 142.0, 142.1, 150.2, 150.3, 150.6, 151.1, 154.1, 154.4,
sodium bicarbonate, dried over magnesium sulfate, and concentrated in
vacuo. The residue was purified by silica gel column chromatography (chlo-
roform : methanolꢄ20 : 1) to afford 20b (88 mg, 35.5%), and 21b (54 mg,
161.7, 162.5, 185.7. IR (CHCl3) cmꢀ1: 3514, 2939, 1659, 1620, 1593, 1493, 19.5%) as a colorless oil.
1427, 1323, 1157, 1045. EI-MS m/z: 403 (Mꢃ). HR-MS m/z: 403.1617
(Calcd for C21H25NO7: 403.1631).
6,8-Di-tert-butyldimethylsilyloxy-7-methoxy-2-trifluoroacetyl-2,3,4,5-
tertahydro-1H-[2]benzazepine-5-spiro-1ꢂ-cyclohexa-2ꢂ,5ꢂ-diene-4ꢂ-one
(20g) A solution of PIFA (2.15 g, 5.0 mmol) in 2,2,2-trifluoroethanol
(15 ml) was added to a solution of 15g (2.90 g, 4.7 mmol) in 2,2,2-trifluo-
roethanol (15 ml) at ꢀ40 °C and the mixture was stirred for 1 h with keeping
21b: 1H-NMR (400 MHz,CDCl3) d: 1.82 and 1.85 (2H, t, Jꢄ7.9 Hz), 2.02
and 2.04 (3H, s), 3.01 and 3.13 (2H, t, Jꢄ7.9 Hz), 3.90 and 3.91 (3H, s),
4.19 and 4.34 (2H, s), 5.11 and 5.12 (4H, s), 6.23 and 6.25 (2H, d,
Jꢄ10.2 Hz), 6.38 and 6.43 (2H, s), 6.66 and 6.73 (2H, d, Jꢄ10.2 Hz),
7.30—7.44 (10H, m), 8.09 and 8.15 (1H, s). 13C-NMR (100 MHz, CDCl3) d:
21.46, 21.48, 36.2, 37.5, 38.1, 41.8, 45.8, 51.8, 61.29, 61.32, 71.4, 71.5,
75.3, 75.6, 107.4, 108.3, 127.55, 127.59, 128.2, 128.3, 128.9, 129.0, 129.5,
the temperature. After the reaction, the organic solvent in the reaction mix- 129.7, 131.0, 131.4, , 137.1, 137.3, 139.8, 147.1, 147.6, 153.0, 153.2, 162.9,
ture was evaporated and the residue was purified by silica gel column chro- 169.3, 169.5, 184.8, 185.1. IR (CHCl3) cmꢀ1: 1751, 1670, 1593, 1435, 1371,
matography (hexane : ethyl acetateꢄ4 : 1) to afford 20g (1.44 g, 50%) as a
pale yellow oil. H-NMR (400 MHz, CDCl3) d: 0.07, 0.09, 0.17, and 0.19 (Calcd for C33H33NO7Na: 578.2155).
(12H, s), 0.74, 0.80, 1.008, and 1.011 (18H, s), 2.24—2.30 (2H, m), 3.67
1240, 1115, 1007. FAB-MS m/z: 578 (MꢃNaꢃ). HR-MS m/z: 578.2159
1
Oxidative Coupling of 15b with PIFA in CH3CN (Table 2, Entry 6)
A solution of PIFA (225 mg, 0.525 mmol) in acetonitrile (2.5 ml) was added
(3H, s), 3.80—3.84 (2H, m), 4.71 and 4.76 (2H, s), 6.26 (2H, d, Jꢄ10.1 Hz),
6.29 and 6.46 (1H, s), 6.96 (1H, d, Jꢄ10.1 Hz), 7.09 (1H, d, Jꢄ10.1 Hz). dropwise to a solution of 15b (250 mg, 0.5 mmol) in acetonitrile (10 ml) at
13C-NMR (100 MHz, CDCl3) d: ꢀ4.6, ꢀ4.4, ꢀ1.42, ꢀ1.38, 18.1, 19.6, 0 °C and the mixture was stirred for 50 min with keeping the temperature.
19.8, 25.5, 25.6, 27.05, 27.09, 40.2, 42.1, 44.9, 45.8, 46.9, 47.3, 48.8, 49.6, The organic solvent of the reaction mixture was removed in vacuo and the
60.1, 60.2, 114.8, 114.9, 115.1, 116.6, 117.7, 117.8, 122.4, 122.6, 127.5, residue was extracted with ethyl acetate. The organic layer was successive-
127.6, 130.7, 131.3, 141.8, 141.9, 148.1, 148.2, 149.5, 150.1, 155.2, 155.4, ly washed with saturated aqueous solutions of sodium thiosulfate and
185.6, 185.7. IR (CHCl3) cmꢀ1: 3275, 2932, 1659, 1616, 1585, 1470, 1431,
sodium bicarbonate, dried over magnesium sulfate, and concentrated in
vacuo. The residue was purified by silica gel column chromatography (chlo-
1385, 1254, 1150, 1115, 1088 1007. EI-MS m/z: 611 (Mꢃ).
Oxidative Coupling of 15b with PIDA in Trifluoroethanol (Table 2, roform : methanolꢄ10 : 1) to afford 15b (75 mg, 30%), 20b (80 mg, 32%),
Entry 2) A solution of PIDA (177 mg, 0.55 mmol) in 2,2,2-trifluo-
roethanol (6 ml) was added dropwise to a solution of 15b (250 mg,
0.5 mmol) in 2,2,2-trifluoroethanol (7 ml) and the mixture was stirred for
and 21c (30 mg, 11%) as a colorless oil.
21c: 1H-NMR (400 MHz, CDCl3) d: 1.69 (3H, t, Jꢄ7.2 Hz), 1.93 and
2.01 (3H, s), 2.88 and 3.09 (2H, t, Jꢄ7.2 Hz), 3.89 and 3.91 (3H, s), 4.21
30 min at room temperature. The organic solvent of the reaction mixture was and 4.33 (2H, s), 5.11 and 5.12 (4H, s), 6.23 (2H, d, Jꢄ10.2 Hz), 6.36 and
removed in vacuo and the residue was extracted with ethyl acetate. The or- 6.45 (2H, s), 6.71 (2H, d, Jꢄ10.2 Hz), 7.29—7.44 (10H, m), 8.02 and 8.16
ganic layer was successively washed with saturated aqueous solutions of (1H, s). 13C-NMR (100 MHz, CDCl3) d: 23.7, 37.9, 38.4, 52.7, 54.9, 61.3,
sodium thiosulfate and sodium bicarbonate, dried over magnesium sulfate,
71.4, 71.5, 107.5, 127.6, 127.7, 128.3, 128.4, 129.0, 129.3, 130.0, 130.6,
and concentrated in vacuo. The residue was purified by silica gel column 137.1, 139.9, 150.3, 153.2, 163.3, 170.5, 185.2. IR (CHCl3) cmꢀ1: 3009,
chromatography (chloroform : methanolꢄ10 : 1) to afford 20b (134 mg,
54%) as a colorless oil.
1670, 1628, 1593, 1506, 1115, 1078. FAB-MS m/z: 555 (Mꢃ). HR-MS m/z:
555.2500 (Calcd for C33H35N2O6: 555.2495).
Oxidative Coupling of 15b with PIDA in Trifluoroacetic Acid (Table 2,
Oxidative Coupling of 15b with PIFA in Dimethoxyethane (Table 2,
Entry 3) A solution of PIDA (210 mg, 0.65 mmol) in trifluoroacetic acid Entry 7) A solution of PIFA (280 mg, 0.65 mmol) in dimethoxyethane
(1 ml) was added dropwise to a solution of 15b (250 mg, 0.5 mmol) in triflu- (1.8 ml) was added dropwise to a solution of 15b (250 mg, 0.5 mmol) in
oroacetic acid (6 ml) and the mixture was stirred for 45 min at room temper- dimethoxyethane (6 ml) and the mixture was stirred for 60 min at room tem-
ature. The organic solvent of the reaction mixture was removed in vacuo and perature. The organic solvent of the reaction mixture was removed in vacuo
the residue was extracted with ethyl acetate. The organic layer was succes- and the residue was extracted with ethyl acetate. The organic layer was suc-
sively washed with saturated aqueous solutions of sodium thiosulfate and cessively washed with saturated aqueous solutions of sodium thiosulfate and
sodium bicarbonate, dried over magnesium sulfate, and concentrated in sodium bicarbonate, dried over magnesium sulfate, and concentrated in
vacuo. The residue was purified by silica gel column chromatography (chlo- vacuo. The residue was purified by silica gel column chromatography (chlo-
roform : methanolꢄ10 : 1) to afford 15b (15 mg, 6% recovered), 20b roform : methanolꢄ10 : 1) to afford 15b (34 mg, 14% recovered), 20b
(140 mg, 56%), and 21a (44 mg, 23%) as a colorless oil.
(13 mg, 5%), and 21a (33 mg, 13%) as a colorless oil.
Oxidative Coupling of 15b with PIFA in Isopropanol (Table 2, Entry
21a: 1H-NMR (400 MHz, CDCl3) d: 1.73 (2H, t, Jꢄ7.6 Hz), 3.04 and
3.15 (2H, t, Jꢄ7.6 Hz), 3.89 and 3.91 (3H, s), 4.21 and 4.33 (2H, s), 5.10 8) A solution of PIFA (225 mg, 0.525 mmol) in 2-propanol (3 ml) was
and 5.11 (4H, s), 6.11 and 6.13 (2H, d, Jꢄ10.3 Hz), 6.38 and 6.44 (2H, s), added dropwise to a solution of 15b (250 mg, 0.5 mmol) in 2-propanol
6.65 and 6.73 (2H, d, Jꢄ10.3 Hz), 7.30—7.43 (10H, m), 8.06 and 8.13 (1H, (16 ml) at 0 °C and the mixture was stirred for 50 min with keeping the tem-
s). 13C-NMR (100 MHz, CDCl3) d: 37.6, 38.0, 38.7, 41.9, 45.7, 52.1, 61.30, perature. The organic solvent of the reaction mixture was removed in vacuo
61.33, 68.5, 68.6, 71.3, 71.5, 107.5, 108.2, 127.56, 127.61, 128.2, 128.4, and the residue was extracted with ethyl acetate. The organic layer was suc-
128.5, 128.8, 128.9, 129.0, 131.0, 131.6, 137.1, 137.3, 139.3, 139.8, 150.1, cessively washed with saturated aqueous solutions of sodium thiosulfate and
150.7, 152.9, 153.2, 163.1, 163.4, 185.1, 185.4. IR (CHCl3) cmꢀ1: 3034, sodium bicarbonate, dried over magnesium sulfate, and concentrated in
1670, 1636, 1593, 1435, 1115, 1078. FAB-MS m/z: 513 (Mꢃ). HR-MS m/z: vacuo. The residue was purified by silica gel column chromatography (chlo-
513.2146 (Calcd for C31H31NO6: 513.2151).
roform : methanolꢄ20 : 1) to afford 15b (84 mg, 33.6% recovered), 20b
Oxidative Coupling of 15b with PIFA in Trifluoroacetic Acid (Table 2, (60 mg, 24%), and 21d (30 mg, 10.8%), and 21a (13 mg, 5%) as a colorless
Entry 4) A solution of PIFA (220 mg, 0.525 mmol) in trifluoroacetic acid oil.
(1 ml) was added dropwise to a solution of 15b (250 mg, 0.5 mmol) in triflu-
oroacetic acid (6 ml) and the mixture was stirred for 40 min at 0 °C. The
21d: 1H-NMR (400 MHz,CDCl3) d: 1.07 and 1.09 (6H, d, Jꢄ6.2 Hz),
1.71 and 1.75 (2H, t, Jꢄ7.9 Hz), 3.04 and 3.10 (2H, t, Jꢄ7.9 Hz), 3.49 and

1674
Vol. 54, No. 12
tion of 8b (200 mg, 0.634 mmol) in pyridine (4 ml) at 0 °C and the mixture
was stirred for 1 h with keeping the temperature. After the reaction, the reac-
tion mixture was evaporated and the residue was purified by silica gel col-
umn chromatography (chloroform : methanolꢄ5 : 1) to afford 23 (278.3 mg,
98%) as colorless needles; mp 229—231 °C (methanol). 1H-NMR
(400 MHz, CDCl3) d: 2.00—2.34 (2H, m), 2.79 and 2.80 (1H, dd, Jꢄ3.7,
17.8 Hz,), 3.13 (1H, dm, Jꢄ17.8 Hz), 3.28 and 3.70 (1H, br t, Jꢄ10.0 Hz),
3.99 and 4.00 (3H, s, OMe), 4.01 and 4.62 (1H, br d, Jꢄ12.0 Hz), 4.02
(0.5H, d, Jꢄ15.2 Hz, A part of AB type), 5.19 (0.5H, d, Jꢄ15.2 Hz, B part
of AB type), 4.52 (0.5H, d, Jꢄ17.0 Hz, Aꢂ part of AꢂBꢂ type), 4.55 (0.5H, d,
Jꢄ17.0 Hz, Bꢂ part of AꢂBꢂ type), 4.80 (1H, m), 6.13 and 6.14 (1H, d,
Jꢄ10.4 Hz), 6.81 and 6.87 (1H, dd, Jꢄ10.4, 2.0 Hz), 6.67 and 6.80 (1H, s),
8.16 and 8.19 (1H, s). 13C-NMR (100 MHz, CDCl3) d: 34.8, 37.09, 37.11,
38.2, 41.0, 46.3, 46.4, 48.56, 48.60, 52.1, 60.6, 60.7, 88.6, 88.7, 113.7,
115.0, 117.0, 120.2, 128.2, 128.4, 129.3, 129.6, 130.9, 131.0, 136.95,
137.04, 140.8, 140.9, 142.0, 142.5, 150.3, 150.6, 161.8, 162.3, 193.3, 193.4.
IR (CHCl3) cmꢀ1: 1678, 1423, 1234, 1200, 1045, 1022. EI-MS m/z: 447
(Mꢃ). HR-MS m/z: 447.0610 (Calcd for C18H16F3NO7S: 447.0599). Anal.
Calcd for C18H16F3NO7S: C, 48.32; H, 3.60; N, 3.13. Found: C, 48.49; H,
3.84; N, 2.91.
3.51 (1H, quint, Jꢄ6.2 Hz), 3.89 and 3.91 (3H, s), 4.20 and 4.33 (2H, s),
5.10 and 5.11 (4H, s), 6.26 and 6.27 (2H, d, Jꢄ10.3 Hz), 6.38 and 6.44 (2H,
s), 6.66 and 6.71 (2H, d, Jꢄ10.3 Hz), 7.30—7.44 (10H, m), 8.09 and 8.13
(1H, s,). 13C-NMR (100 MHz, CDCl3) d: 25.1, 37.0, 37.6, 38.9, 41.8, 45.6,
51.6, 61.30, 61.33, 68.4, 68.8, 71.4, 71.5, 74.1, 74.3, 107.4, 108.3, 127.57,
127.61, 128.2, 128.3, 128.9, 129.0, 130.8, 131.7, 137.1, 137.4, 150.8, 151.1,
153.0, 153.2, 162.9, 163.1, 185.5, 185.6. IR (CHCl3) cmꢀ1: 1670, 1636,
1593, 1435, 1117, 1005. FAB-MS m/z: 555 (Mꢃ). HR-MS m/z: 555.2626
(Calcd for C34H37NO6: 555.2621).
(ꢀ)-3-Hydroxy-N-trifluoroacetyl-N-nornarwedine
(8a) Trifluoro-
acetic acid (2 ml) was added to a solution of 20a (284 mg, 0.5 mmol) in di-
methyl sulfide (1 ml) at 0 °C and the mixture was stirred for 5 d at room tem-
perature. After the reaction, the reaction mixture was evaporated and the
residue was purified by silica gel column chromatography (hexane : ethyl ac-
etateꢄ2 : 1) to afford 8a (163 mg, 85%) as colorless needles; mp 250—
1
251 °C (ethyl acetate). H-NMR (400 MHz, CDCl3) d: 2.08—2.23 (2H, m),
2.75 and 2.79 (1H, dd, Jꢄ17.6, 3.6 Hz), 3.13 (1H, br d, Jꢄ17.6 Hz), 3.33
and 3.70 (1H, br t, Jꢄ14.0 Hz), 3.95 and 3.97 (3H, s, OMe), 4.10 and 4.49
(1H, d, Jꢄ16.0 Hz, A part of AB type), 4.34 and 4.72 (1H, br d, Jꢄ15.4 Hz),
4.81 and 5.21 (1H, d, Jꢄ16.0 Hz, B part of AB type), 4.73 (2H, br s), 5.73
(1H, br s), 6.40 and 6.56 (1H, s, Ar-H), 6.07 and 6.09 (1H, d, A part of AB,
Jꢄ10.3 Hz), 6.79 and 6.85 (1H, dd, B part of AB, Jꢄ10.3, 2.2 Hz). 13C-
NMR (400 MHz, CDCl3) d: 34.6, 37.37, 37.42, 37.6, 46.7, 46.9, 48.05,
48.09, 52.1, 52.9, 60.5, 88.3, 88.4, 107.7, 109.0, 114.8, 117.7, 121.6, 121.7,
127.2, 127.4, 128.3, 128.7, 131.3, 131.4, 142.8, 143.3, 148.8, 149.3, 193.94,
194.01. IR (CHCl3) cmꢀ1: 3530, 1690, 1601, 1512, 1443, 1150, 1072. EI-
MS m/z: 383 (Mꢃ). HR-MS m/z: 383.0979 (Calcd for C18H16F3NO5:
383.0980). Anal. Calcd for C18H16F3NO5: C, 56.46; H, 4.21; N, 3.65. Found:
C, 56.35; H, 4.47; N, 3.44.
(ꢀ)-N-Formyl-N-nornarwedine (24) Formic acid (6.17 mg, 0.134
mmol) and triethylamine (20 mg, 0.2 mmol) were added to a solution of 23
(30.0 mg, 0.067 mmol), palladium acetate (0.29 mg, 0.0013 mmol) and tri-
phenylphosphine (0.7 mg, 0.0027 mmol) in N,N-dimethylformamide (0.5 ml)
and the mixture was stirred for 3 h at 60 °C. After the reaction, the reaction
mixture was extracted with ethyl acetate. The organic layer was washed with
a saturated aqueous solution of sodium chloride, dried over sodium sulfate,
and evaporated. The residue was purified by silica gel column chromatogra-
phy (chloroform : methanolꢄ15 : 1) to afford 24 (19.4 mg, 97%) as colorless
1
crystals; mp 193—195 °C (hexane). H-NMR (400 MHz, CDCl3) d: 1.98—
(ꢀ)-3-Hydroxy-N-formyl-N-nornarwedine (8b) (s-cis and s-transꢃ
3 : 2) Trifluoroacetic acid (1 ml) was added to a solution of 20b (35.0 mg,
0.07 mmol) in dimethyl sulfide (0.5 ml) at 0 °C and the mixture was stirred
for 4 d at room temperature. After the reaction, the reaction mixture was
evaporated and the residue was purified by silica gel column chromatogra-
phy (ethyl acetate) to afford 8b (17.9 mg, 81%) as colorless plates; mp
249—251 °C (ethyl acetate). 1H-NMR (400 MHz, CDCl3) d: 1.94—2.24
(2H, m), 2.74—2.81 (1H, dm, Jꢄ17.0 Hz, A part of AB type), 3.09—3.15
(1H, dm, Jꢄ17.0 Hz, B part of AB type), 3.25 and 3.68 (1H, br t), 3.92 and
3.95 (3H, s), 4.01 (0.5H, d, Jꢄ17.0 Hz, A part of AB type), 5.16 (0.5H, d,
Jꢄ17.0 Hz, B part of AB type), 4.49 (1H, s), 4.00 and 4.63 (1 H, br d,
Jꢄ15.0 Hz), 4.70 (1H, br s), 6.06 and 6.07 (1H, d, Jꢄ10.3 Hz, A part of AB
type), 6.40 and 6.53 (1H, s), 6.83 and 6.87 (1H, d, Jꢄ10.3 Hz, B part of AB
type), 8.15 and 8.18 (1H, s). 13C-NMR (100 MHz, CDCl3) d: 35.0, 37.4,
38.5, 41.3, 46.7, 47.0, 48.2, 48.3, 52.9, 60.5, 88.2, 88.4, 106.8, 108.6, 129.8,
130.3, 131.2, 143.4, 143.8, 148.9, 149.0, 149.3, 149.5, 162.0, 162.5, 194.1,
194.2. IR (CHCl3) cmꢀ1: 1670, 1601, 1512, 1431, 1396, 1173, 1069. EI-MS
m/z: 315 (Mꢃ). HR-MS m/z: 315.1114 (Calcd for C17H17NO5: 315.1106).
Anal. Calcd for C17H17NO5: C, 64.75; H, 5.43; N, 4.44. Found: C, 64.50; H,
5.57; N, 4.35.
Methanesulfonic acid (67.9 mg, 0.7 mmol) was added to a solution of 20b
(35.0 mg, 0.07 mmol) in dimethyl sulfide (0.5 ml) at 0 °C and the mixture
was stirred for 2 h at room temperature. After the reaction, the reaction mix-
ture was evaporated and the residue was purified by silica gel column chro-
matography (chloroform : methnolꢄ10 : 1) to afford 8b (13.6 mg, 62%).
Trifluoroacetic acid (1 ml) was added to a solution of 20b (100 mg,
0.2 mmol) in dodecyl methyl sulfide (0.5 ml) at 0 °C and the mixture was
stirred for 4 d at room temperature. After the reaction, the reaction mixture
was evaporated and the residue was purified by silica gel column chromatog-
raphy (chloroform : methanolꢄ20 : 1) to afford 8b (49.0 mg, 77%).
Methanesulfonic acid (96.1 mg, 1.0 mmol) was added to a solution of 20b
(50.0 mg, 0.1 mmol) in dodecyl methyl sulfide (2.0 ml) at 0 °C and the mix-
ture was stirred for 2 h at room temperature. After the reaction, the reaction
mixture was evaporated and the residue was purified by silica gel column
chromatography (ethyl acetate) to afford 8b (17.8 mg, 57%).
2.12 (2H, m), 2.74 and 2.79 (1H, dd, Jꢄ5.4, 17.9 Hz), 3.20 (1H, dm,
Jꢄ17.9 Hz), 3.23 and 3.68 (1H, br t, Jꢄ13.0 Hz), 3.85 and 3.86 (3H, s,
OMe), 4.05 and 4.66 (each 0.5H, br d, Jꢄ10.1 Hz), 4.07 (0.5H, d,
Jꢄ15.4 Hz, A part of AB type), 5.27 (0.5H, d, Jꢄ15.4 Hz, B part of AB
type), 4.52 (0.5H, d, Jꢄ16.3 Hz, Aꢂ part of AꢂBꢂ type), 4.59 (0.5H, d,
Jꢄ16.3 Hz, Bꢂ part of AꢂBꢂ type), 4.73 (1H, m), 6.08 and 6.10 (1H, d,
Jꢄ10.5 Hz), 6.72—6.74 (1H, m), 6.88—6.90 (2H, m), 8.16 and 8.19 (1H, s).
13C-NMR (100 MHz, CDCl3) d: 35.3, 37.2, 38.7, 41.3, 46.7, 46.9, 48.97,
49.00, 52.8, 56.05, 56.08, 87.6, 87.7, 112.0, 112.1, 120.2, 121.9, 127.6,
127.8, 127.9, 128.3, 129.5, 129.7, 142.7, 143.1, 144.6, 144.8, 147.5, 147.9,
161.8, 162.4, 193.8, 193.9. IR (CHCl3) cmꢀ1: 1670, 1512, 1435, 1281, 1169,
1053. EI-MS m/z: 299 (Mꢃ). HR-MS m/z: 299.1165 (Calcd for C17H17NO4:
299.1157). Anal. Calcd for C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found:
C, 67.91; H, 5.82; N, 4.49.
(ꢀ)-Galanthamine (1) Lithium tri-sec-butylborohydride (L-Selectride)
(0.4 ml, 1.0 M solution in tetrahydrofuran, 0.4 mmol) was added to a solution
of 24 (40 mg, 0.17 mmol) in tetrahydrofuran (4 ml) at ꢀ78 °C and the mix-
ture was stirred for 6 h with keeping the temperature. And then, a suspension
of lithium aluminum hydride (15.2 mg, 0.40 mmol) in tetrahydrofuran
(1.0 ml) was added to the reaction mixture, and the mixture was stirred for
another 12 h at room temperature. After the reaction, an aqueous solution
of sodium sulfate was added to the reaction mixture which was
extracted with chloroform. The organic layer was washed with saturated
aqueous solution of sodium chloride, dried over sodium sulfate, and evapo-
rated. The residue was purified by silica gel column chromatography (chlo-
roform : methanolꢄ5 : 1) to afford (ꢁ)-1 (23.4 mg, 61%) as colorless crys-
tals; mp 123—124 °C (ethyl acetate) [lit. mp 121—123 °C].26) 1H-NMR
(400 MHz, CDCl3) d: 1.58 (1H, ddd, Jꢄ13.7, 4.0, 1.8 Hz), 2.01 (1H, ddd,
Jꢄ15.7, 3.5, 1.8 Hz), 2.09 (1H, dt, Jꢄ13.3, 3.2 Hz), 2.42 (3H, s), 2.44 (1H,
br s, OH), 2.69 (1H, ddt, Jꢄ15.7, 3.5, 1.8 Hz), 3.04 (1H, br d, Jꢄ13.7 Hz),
3.26 (1H, dt, Jꢄ13.7, 1.7 Hz), 3.68 (1H, d, A part of AB, Jꢄ15.2 Hz), 3.83
(3H, s), 4.09 (1H, d, B part of AB, Jꢄ15.2 Hz), 4.14 (1H, m), 4.61 (1H, br),
6.00 (1H, ddd, A part of AB, Jꢄ10.2, 5.0, 1.2 Hz), 6.07 (1H, dd, B part of
AB, Jꢄ10.2, 1.2 Hz), 6.62 (1H, d, A part of AB, Jꢄ8.3 Hz), 6.66 (1H, d, B
part of AB, Jꢄ8.3 Hz). 13C-NMR (100 MHz, CDCl3) d: 30.3, 34.2, 42.5,
48.6, 54.2, 56.2, 61.0, 62.4, 89.1, 111.5, 122.4, 127.2, 129.8, 133.4, 144.4,
146.2. IR (CHCl3) cmꢀ1: 3410, 2964, 2933, 1626, 1601, 1514, 1462, 1439,
1408, 1375, 1283, 1234, 1202, 1173, 1138, 1115, 1090, 1069, 1047, 1015.
EI-MS m/z: 287 (Mꢃ). HR-MS m/z: 287.1523 (Calcd for C17H21NO3:
287.1521).
Boron tricloride (6.1 ml, 1 M solution in CH2Cl2, 6.1 mmol) was added to a
solution of 20b (1.0 g, 2.0 mmol) in dichloromethane (20 ml) at ꢀ78 °C and
the mixture was stirred for 20 h with keeping the temperature. After the re-
action, the reaction mixture was poured into ice water and extracted with
chloroform. The organic layer was washed with a saturated aqueous solution
of sodium chloride, dried over sodium sulfate, and evaporated. The residue
was purified by recrystallization from ethyl acetate to afford 8b (605.3 mg,
95%).
2-Hydroxy-3-methoxy-11-formyl-4a,5,9,10,11,12-hexahydro-6H-ben-
zofuro[3a,3,2-ef][2]benzazepine-6-(1,2)-ethylenediol Ketal (25) Ethyl-
ene glycol and pyridinium p-toluenesulfonate were added to a solution of 24
(20.0 mg, 0.067 mmol) in benzene and the mixture was refluxed for 2 d.
(ꢀ)-3-Trifluoromethanesulfonyl-N-formyl-N-nornarwedine (23) Tri-
fluoromethanesulfonic anhydride (0.26 ml, 1.5 mmol) was added to a solu-

December 2006
1675
7.00 (2H, d, Jꢄ8.3 Hz). 13C-NMR (75 MHz, CDCl3) d: 18.0, 19.2 (2C), 28.3
(3C), 30.8, 34.8, 41.0, 60.2, 80.2, 115.6, 129.6 (2C), 129.8, 153.1, 155.1,
172.0. IR (CHCl3) cmꢀ1: 3339, 2976, 1705, 1670, 1514, 1456, 1369, 1238,
1171. EI-MS m/z: 336 (Mꢃ). HR-MS m/z: 336.2046 (Calcd for C18H28N2O4:
336.2049).
After the reaction, the reaction mixture was washed with a saturated aqueous
solution of sodium bicarbonate, and condensed in vacuo. The residue was
extracted with chloroform and the organic layer was washed with a saturated
aqueous solution of sodium chloride, dried over sodium sulfate, and evapo-
rated. The residue was purified by silica gel column chromatography (chlo-
roform : methanolꢄ10 : 1) to afford 25 (21.2 mg, 92%) as colorless crystals;
mp 253—254 °C (acetone). 1H-NMR (400 MHz, CDCl3) d: 1.83—2.07 (2H,
m), 2.19 (1H, dt, Jꢄ15.5, 3.7 Hz), 2.69 and 2.70 (1H, dd, Jꢄ15.5, 3.5 Hz),
3.15—3.23 (1H, m), 3.62—3.70 (1H, m), 3.82 and 3.83 (3H, s), 3.97—4.06
(4H, m), 4.48 and 4.54—4.62 (3H, m), 5.72 and 5.74 (1H, d, Jꢄ10.3 Hz),
6.10 and 6.15 (1H, d, Jꢄ10.4 Hz), 6.62—6.67 and 6.79 (2H, m), 8.10 and
8.14 (1H, s). 13C-NMR (100 MHz, CDCl3) d: 33.2, 33.3, 36.4, 38.8, 41.1,
46.8, 48.0, 48.1, 52.9, 55.7, 64.4, 65.3, 86.9, 87.0, 102.5, 111.1, 111.2,
119.4, 121.2, 127.0, 127.2, 128.1, 128.4, 131.0, 131.2, 144.6, 144.8, 147.2,
147.6, 161.8, 162.4. IR (CHCl3) cmꢀ1: 2935, 2889, 1668, 1626, 1591, 1510,
1465, 1431, 1286, 1171, 1132, 1057. EI-MS m/z: 343 (Mꢃ). HR-MS m/z:
343.1435 (Calcd for C19H21NO5: 343.1419).
2-(R)-Amino-N-2-(4-hydroxyphenethyl)ethyl-3-phenylpropionamide
(28a) Methanesulfonic acid (1.4 ml, 21.6 mmol) was added to a solution of
27a (4.20 g, 10.8 mmol) in methanol (40 ml) at room temperature and the
mixture was stirred at 40 °C for 3 h. The reaction mixture was then concen-
trated in vacuo and an aqueous solution of potassium carbonate was added
and extracted with ethyl acetate. The organic layer was washed with a satu-
rated aqueous solution of sodium chloride, dried over sodium sulfate, and
concentrated. The residue was recrystallized from diethyl ether to give 28a
(3.00 g, 97%) as colorless crystals, mp 87—88 °C (diethyl ether). [a]D26
ꢃ39.5° (cꢄ0.59, CHCl3). 1H-NMR (400M Hz, CDCl3) d: 2.64 (2H, dd,
Jꢄ13.7, 9.2 Hz), 2.71 (1H, t, Jꢄ7.2 Hz), 3.22 (1H, dd, Jꢄ13.7, 4.1 Hz), 3.45
(1H, dd, Jꢄ13.2, 7.2 Hz, A part of AB type), 3.50 (1H, dd, Jꢄ13.2, 7.2 Hz,
B part of AB type), 3.56 (1H, dd, Jꢄ9.2, 4.1 Hz), 6.77 (2H, d, Jꢄ8.6 Hz),
6.98 (2H, d, Jꢄ8.6 Hz), 7.13—7.33 (5H, m). 13C-NMR (100 MHz, CDCl3)
d: 34.8, 40.5, 41.0, 56.4, 115.5 (2C), 126.8, 128.7 (2C), 129.3 (2C), 129.7
(2C), 130.2, 137.7, 154.8, 174.5; IR (CHCl3) cmꢀ1: 3362, 1657, 1614, 1514,
1454, 1362, 1240, 1173, 1105. EI-MS m/z: 284 (Mꢃ). HR-MS m/z:
284.1522 (Calcd for C17H20N2O2: 284.1525). Anal. Calcd for C17H20N2O2:
C, 71.81; H, 7.09; N, 9.85. Found: C, 71.78; H, 7.06; N, 9.63.
(ꢀ)-Narwedine (3)
A suspension of lithium aluminum hydride
(9.95 mg, 0.262 mmol) in tetrahydrofuran (1.0 ml) was added to a solution of
25 (30.0 mg, 0.087 mmol) in tetrahydrofuran (0.5 ml) and the mixture was
stirred for 24 h. After the reaction, a saturated aqueous solution of sodium
sulfate was added to the reaction mixture, which was extracted with chloro-
form. The organic layer was washed with a saturated aqueous solution of
sodium chloride, dried over sodium sulfate and evaporated. The residue was
dissolved in tetrahydrofuran (1 ml), to which 1 M hydrochloric acid was
added, and the mixture was stirred for 24 h at room temperature. After the
reaction, the reaction mixture was extracted with chloroform. The organic
layer was washed with saturated aqueous solution of sodium chloride, dried
over sodium sulfate, and evaporated. The residue was purified by silica gel
column chromatography (chloroform : methanolꢄ10 : 1) to afford (ꢁ)-3 as
colorless crystals (20.6 mg, 83%); mp 198—199 °C (ethyl acetate) [lit. mp
188—190 °C].17) 1H-NMR (400 MHz, CDCl3) d: 1.84—1.89 (1H, m), 2.28
(1H, dt, Jꢄ13.2, 3.5 Hz), 2.45 (3H, s, NMe), 2.75 (1H, dd, Jꢄ17.9, 3.8 Hz),
3.19 (3H, m), 3.75 (1H, d, Jꢄ15.4 Hz, A part of AB type), 3.85 (3H, s,
OMe), 4.10 (1H, d, Jꢄ15.4 Hz, B part of AB type), 4.73—4.75 (1H, m),
6.05 (1H, d, Jꢄ10.4 Hz), 6.66 (1H, d, Jꢄ8.2 Hz, Ar-H), 6.70 (1H, d,
Jꢄ8.2 Hz, Ar-H), 6.95 (1H, d, Jꢄ10.4 Hz,). 13C-NMR (100 MHz, CDCl3) d:
33.6, 37.7, 42.8, 49.3, 54.5, 56.4, 61.0, 88.3, 112.2, 122.3, 127.5, 129.8,
130.9, 144.3, 144.7, 147.3, 194.8. IR (CHCl3) cmꢀ1: 1686, 1508, 1439,
1285, 1049. EI-MS m/z: 285 (Mꢃ). HR-MS m/z: 285.1371 (Calcd for
C17H19NO3: 285.1365).
2-(R)-tert-Butoxycarbonylamino-N-2-(4-hydroxyphenethyl)-3-phenyl-
propionamide (27a) EDC·HCl (4.3 g, 22.6 mmol) was added to a mixture
of N-Boc-D-phenylalanine (26a) (5.0 g, 18.9 mmol), tyramine (3.1 g,
22.0 mmol) and HOBt (254.6 mg, 1.88 mmol) in tetrahydrofuran (50 ml),
and the mixture was stirred for 2 h at room temperature. After the reaction,
the reaction mixture was concentrated in vacuo and the residue was ex-
tracted with ethyl acetate. The organic layer was successively washed with
1 M hydrochloric acid, saturated aqueous solution of sodium bicarbonate, sat-
urated aqueous solution of sodium chloride, dried over sodium sulfate, and
evaporated. The residue was recrystallized from diethyl ether to give 27a
(6.9 g, 95%) as colorless crystals; mp 102—104 °C (diethyl ether). 1H-NMR
(400 MHz, CDCl3) d: 1.39 (9H, s, t-Bu), 2.48—2.60 (2H, m), 3.00 (1H, d,
Jꢄ6.2 Hz), 3.22—3.29 (1H, m), 3.35—3.42 (1H, m), 4.25 (1H, q,
Jꢄ7.0 Hz), 5.16 (1H, s), 5.95 (1H, s), 6.73 (2H, d, Jꢄ8.4 Hz), 6.83—6.87
(2H, m), 7.16 (2H, d, Jꢄ8.4 Hz), 7.18—7.32 (3H, m). 13C-NMR (100 MHz,
CDCl3) d: 28.2, 34.6, 38.8, 40.9, 56.1, 80.4, 115.5, 127.0, 128.6, 129.3,
129.4, 129.6, 129.9, 136.6, 154.9, 171.3. IR (CHCl3) cmꢀ1: 3597, 3431,
3032, 1705, 1672, 1514, 1369, 1170. FAB-MS m/z: 385 (MꢃHꢃ). HR-MS
m/z: 385.2120 (Calcd for C22H29N2O4: 385.2127).
2-(R)-Amino-N-2-(4-hydroxyphenyl)ethyl-3-methylbutyramide (28b)
A mixture of 27b (3.84 g, 11.4 mmol), methanesulfonic acid (1.48 ml,
22.8 mmol) in methanol (32 ml) was stirred at room temperature for 24 h.
The reaction mixture was then concentrated in vacuo and an aqueous solu-
tion of potassium carbonate was added and extracted with ethyl acetate. The
organic layer was washed with a saturated aqueous solution of sodium chlo-
ride, dried over sodium sulfate, and concentrated in vacuo. The residue was
purified by silica gel column chromatography (chloroform : methanolꢄ5 : 1)
to give 28b (1.03 g, 38%) as colorless crystals; mp 134—136 °C (ethyl
1
acetate). H-NMR (400 MHz, CDCl3) d: 0.77 (3H, d, Jꢄ7.0 Hz), 0.96 (3H,
d, Jꢄ7.0 Hz), 2.24—2.32 (1H, m), 2.75 (2H, t, Jꢄ7.0 Hz), 3.19 (1H, d,
Jꢄ3.7 Hz), 3.43—3.58 (2H, m), 6.77 (2H, d, Jꢄ8.4Hz), 7.05 (2H, d,
Jꢄ8.4 Hz). 13C-NMR (100 MHz, CDCl3) d: 15.9 (2C), 19.7, 35.0, 40.3,
60.1, 115.4 (2C), 129.8 (2C), 130.7, 154.5, 174.4. IR (CHCl3) cmꢀ1: 3342,
2964, 1655, 1614, 1597, 1514, 1466, 1369, 1252, 1173, 829. EI-MS m/z:
236 (Mꢃ). HR-MS m/z: 236.1532 (Calcd for C13H20N2O2: 236.1525).
(2S,5R)-5-Benzyl-2-(3,5-dibenzyloxy-4-methoxyphenyl)-3-(4-hydrox-
yphenethyl)-imidazolidin-4-one (29a) A mixture of 3,5-dibenzyloxy-4-
methoxybenzaldehyde (18a) (100 mg, 0.29 mmol) and 28a (97.9 mg,
0.34 mmol) in dioxane (3.0 ml) was stirred at room temperature for 24 h.
And then, 4.0 M HCl in dioxane (1.5 ml) was added to the reaction mixture at
0 °C, which was stirred at room temperature for another 24 h. The reaction
mixture was then concentrated in vacuo and an aqueous solution of sodium
bicarbonate was added and extracted with ethyl acetate. The organic layer
was washed with saturated aqueous solution of sodium chloride, dried over
sodium sulfate, and concentrated in vacuo. The residue was purified by sil-
ica gel column chromatography (hexane : ethyl acetateꢄ2 : 1) to give 29a
(115.4 mg, 64%) as an amorphous powder. 1H-NMR (400 MHz, CDCl3) d:
2.38, 2.47 (each 1H, dd, Jꢄ13.7, 7.0 Hz, AB type), 2.59 (1H, dt, Jꢄ13.7,
7.2 Hz), 2.77 (1H, dd, Jꢄ13.7, 7.5 Hz, A part of AB type), 3.01 (1H, dd,
Jꢄ13.7, 3.8 Hz, B part of AB type), 3.70 (1H, dt, Jꢄ13.7, 7.2 Hz), 3.80—
3.93 (1H, m), 3.88 (3H, s, OCH3), 4.73 (1H, s), 5.07 (4H, s, 2ꢆPhCH2O),
6.34 (2H, s), 6.71 (2H, d, Jꢄ8.6 Hz), 6.79 (2H, d, Jꢄ8.6 Hz), 7.10—7.41
(16H, m). 13C-NMR (100 MHz, CDCl3) d: 32.6, 38.1, 41.7, 59.7, 60.9, 71.1
(2C), 75.9, 106.2 (2C), 115.4 (2C), 126.7, 127.3 (4C), 128.0 (2C), 128.5
(2C), 128.6 (4C), 129.6 (2C), 129.7 (2C), 129.8, 134.3, 136.7 (2C), 137.3,
140.0, 152.8 (2C), 154.9, 174.1. IR (CHCl3) cmꢀ1: 3595, 3007, 1686, 1595,
1516, 1445, 1327, 1240, 1113. FAB-MS m/z: 615 (MꢃHꢃ). HR-MS m/z:
615.2871 (Calcd for C39H39N2O5: 615.2859).
2-(R)-tert-Butoxycarbonylamino-N-2-(4-hydroxyphenethyl)-3-methyl-
butylamide (27b) EDC·HCl (4.18 g, 21.8 mmol) was added to a mixture
of N-Boc-D-valine (26b) (3.95 g, 18.2 mmol), tyramine (2.99 g, 21.8 mmol)
and HOBt (246 mg, 1.82 mmol) in tetrahydrofuran (45 ml) at 0 °C, and the
mixture was stirred for 24 h at room temperature. The reaction mixture was
condensed in vacuo, and extracted with ethyl acetate. The organic layer was
successively washed with 1 M hydrochloric acid, saturated aqueous solution
of sodium bicarbonate, saturated aqueous solution of sodium chloride, dried
over sodium sulfate, and concentrated in vacuo. The residue was purified by
silica gel chromatography (chloroform : methanolꢄ50 : 1) to give 27b
(3.84 g, 63%) as colorless crystals; mp 99—102 °C (diethyl ether). 1H-NMR
(300 MHz, CDCl3) d: 0.87, 0.89 (each 3H, d, Jꢄ7.7 Hz), 1.44 (9H, s), 1.71
(1H, m), 2.06 (1H, br), 2.71 (2H, t, Jꢄ7.0 Hz), 3.48 (2H, m), 3.77 and 3.80
(1H, d, Jꢄ7.0 Hz), 5.07 and 6.10 (each 1H, br s), 6.75 (2H, d, Jꢄ8.3 Hz),
(2S,5R)-2-(3,5-Dibenzyloxy-4-methoxyphenyl)-3-(4-hydroxy-
phenethyl)-5-isopropylimidazolidin-4-one (29b) A mixture of 3,5-diben-
zyloxy-4-methoxybenzaldehyde (18a) (653.9 mg, 1.90 mmol) and 28b
(300 mg, 1.27 mmol) in dioxane (6.0 ml) was stirred at room temperature for
24 h. And then, 4.0 M HCl in dioxane (6 ml) was added to the reaction mix-
ture at 0 °C, which was stirred at room temperature for another 48 h. The re-
action mixture was then concentrated in vacuo and an aqueous solution of
sodium bicarbonate was added and extracted with ethyl acetate. The organic
layer was washed with saturated aqueous solution of sodium chloride, dried
over sodium sulfate, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexane : ethyl acetateꢄ2 : 1) to give 29b

1676
Vol. 54, No. 12
1
(473.9 mg, 66%) as an amorphous powder. H-NMR (400 MHz, CDCl3) d:
0.74 (3H, d, Jꢄ6.8 Hz), 0.91 (3H, d, Jꢄ7.0 Hz), 1.70 (2H, br), 2.03—2.10
(1H, m), 2.46—2.68 (3H, m), 3.56 (1H, br s), 3.79—3.86 (1H, m), 3.92 (3H,
s), 5.04 (1H, br s), 5.11 (4H, s, 2ꢆOCH2O), 6.43 (2H, s), 6.73 (2H, d,
Jꢄ8.4 Hz), 6.91 (2H, d, Jꢄ8.4Hz), 7.28—7.43 (10H, m). 13C-NMR
(100 MHz, CDCl3) d: 16.2, 19.4, 30.8, 32.5, 41.4, 60.9, 63.6, 71.1 (2C),
76.7, 106.2 (2C), 115.4 (2C), 127.3 (4C), 128.0 (2C), 128.6 (4C), 129.7
(2H, d, Jꢄ8.5 Hz), 6.87 and 6.90 (2H, d, Jꢄ8.6 Hz), 7.26—7.41 (10H, m).
13C-NMR (100 MHz, CDCl3) d: 14.9, 15.9, 18.1, 18.6, 28.2, 32.4, 32.8,
34.2, 40.9, 40.9, 60.9, 61.1, 63.9, 64.2, 71.1, 71.4, 76.1, 107.5, 115.5, 127.2,
128.0, 128.3, 128.6, 128.7, 129.4, 129.7, 129.8, 130.2, 131.5, 136.3, 136.6,
140.5, 141.3, 152.7, 154.8, 154.8, 166.4, 166.8. IR (CHCl3) cmꢀ1: 3325,
2936, 1697, 1597, 1516, 1504, 1445, 1420, 1371, 1346, 1327, 1292, 1259,
1238, 1167, 1115, 1078, 1003, 826. FAB-MS m/z: 662 (Mꢃ). HR-MS m/z:
662.2608 (Calcd for C37H37F3N2O6: 662.2604).
(2C), 134.9, 136.7 (2C), 140.1, 152.9 (2C), 154.9, 174.4. IR (CHCl3) cmꢀ1
:
3327, 2964, 1682, 1595, 1516, 1445, 1369, 1352, 1327, 1259, 1240, 1113,
1078, 1003, 827. EI-MS m/z: 566 (Mꢃ). HR-MS m/z: 566.2784 (Calcd for
C35H38N2O5: 566.2780).
(2S,5R)-5-Benzyl-3-(4-hydroxyphenethyl)-1-(2,2,2-trifluoroacetyl)-2-
(3,4,5-trimethoxyphenyl)-imidazolin-4-one (30c) Trifluoroacetic anhy-
dride (0.23 ml, 1.62 mmol) was added to a solution of 29c (311.6 mg,
0.67 mmol) in pyridine (3.0 ml) at 0 °C and the mixture was stirred for
60 min. After the reaction, methanol (3 ml) was added to the mixture, which
was concentrated in vacuo. The residue was partitioned between ethyl ac-
etate and 1 M hydrochloric acid. The organic layer was washed with a satu-
rated aqueous solution of sodium bicarbonate, dried over sodium sulfate,
and concentrated in vacuo. The residue was purified by silica gel chromatog-
raphy (hexane : ethyl acetateꢄ1 : 1) to give 30c (358 mg, 95%) as colorless
(2S,5R)-5-Benzyl-3-(4-hydroxyphenethyl)-2-(3,4,5-trimethoxy-
phenyl)imidazolidin-4-one (29c) A mixture of 3,4,5-trimethoxybenzalde-
hyde (9) (2.6 g, 13.2 mmol) and 28a (2.5 g, 8.8 mmol) in dioxane (30 ml)
was stirred at room temperature for 12 h. And then, 4.0 M HCl in dioxane
(20 ml) was added to the reaction mixture at 0 °C, which was stirred at room
temperature for another 12 h. The reaction mixture was then concentrated in
vacuo and an aqueous solution of sodium bicarbonate was added and ex-
tracted with ethyl acetate. The organic layer was washed with a saturated
aqueous solution of sodium chloride, dried over sodium sulfate, and concen-
trated in vacuo. The residue was purified by silica gel column chromatogra-
phy (hexane : ethyl acetateꢄ2 : 1) to give 29c (1.75 g, 43%) as an amorphous
1
crystals. H-NMR (400 MHz, CDCl3) d: 2.17 (1H, br t, Jꢄ8.8 Hz), 2.26—
2.50 (3H, m), 3.34 (0.5H, dd, Jꢄ14.5, 4.6 Hz, A part of AB), 3.46 (0.5 H,
dd, Jꢄ14.5, 2.2 Hz, B part of AB), 3.36 (0.5H, dd, Jꢄ14.0, 2.2 Hz, Aꢂ part
of AB), 3.58 and 3.73 (1H, m), 3.72 (0.5H, dd, Jꢄ14.0, 4.9 Hz, Bꢂ part of
AꢂBꢂ), 3.76 (3H, s), 3.77 (3H, s), 3.82 (3H, s), 5.01 and 5.08 (1H, m), 5.52
and 5.59 (1H, br s), 6.04 and 6.21 (2H, s), 6.57 and 6.61 (2H, d, Jꢄ8.4 Hz),
6.67 (2H, d, Jꢄ8.4 Hz), 7.17 and 7.23 (2H, dd, Jꢄ7.4, 1.9 Hz), 7.36—7.40
(3H, m). 13C-NMR (100 MHz, CDCl3) d: 32.5, 33.1, 33.3, 38.7, 41.7, 41.8,
56.2, 56.3, 60.8, 60.9, 61.3, 76.2, 76.3, 104.2, 115.4, 127.6, 127.9, 128.7,
129.0, 129.6, 129.8, 130.15, 130.23, 130.3, 130.4, 131.6, 133.6, 134.7,
1
powder. H-NMR (400 MHz, CDCl3) d: 2.48—2.61 (2H, m), 2.78 (1H, m),
2.85 (1H, dd, Jꢄ13.8, 7.2 Hz, A part of AB), 3.05 (1H, dd, Jꢄ13.8, 3.9 Hz,
B part of AB type), 3.67 (1H, s), 3.80 (6H, s), 3.81 (3H, s), 3.74—3.93 (1H,
m), 4.02—4.05 (1H, m), 4.85 (1H, d, Jꢄ1.5 Hz), 6.34 (2H, s), 6.75 (2H, d,
Jꢄ8.6 Hz), 6.86 (2H, d, Jꢄ8.6 Hz), 7.22—7.38 (5H, m). 13C-NMR
(100 MHz, CDCl3) d: 32.7, 38.1, 42.1, 56.1 (2C), 59.9, 60.8, 76.3, 106.2
(2C), 115.5 (2C), 126.8, 128.5 (2C), 129.6 (2C), 129.66, 129.70 (2C), 134.5,
136.7, 138.5, 153.7 (2C), 155.1, 174.4. IR (CHCl3) cmꢀ1: 1686, 1597, 1516,
1447, 1425, 1329, 1238, 1130. EI-MS m/z: 462 (Mꢃ). HR-MS m/z:
462.2158 (Calcd for C27H30N2O5: 462.2154).
138.9, 139.6, 153.5, 153.7, 154.6, 154.7, 166.5, 167.1. IR (CHCl3) cmꢀ1
:
3323, 1701, 1597, 1516, 1466, 1425, 1350, 1329, 1240, 1169, 1130. EI-MS
m/z: 558 (Mꢃ). HR-MS m/z: 558.1977 (Calcd for C29H29F3N2O6: 558.1975).
Anal. Calcd for C29H29F3N2O6: C, 62.36; H, 5.23; N, 5.02. Found: C, 62.27;
H, 5.14; N, 4.90.
(2S,5R)-5-Benzyl-2-(3,5-dibenzyloxy-4-methoxyphenyl)-3-(4-hydroxy-
phenethyl)-1-(2,2,2-trifluoroacetyl)imidazolidin-4-one (30a) s-cis and s-
transꢃ2 : 1 Trifluoroacetic anhydride (0.89 ml, 6.33 mmol) was added to a
solution of 29a (1.63 g, 2.64 mmol) in pyridine (10 ml) at 0 °C and the mix-
ture was stirred for 15 min. After the reaction, methanol (10 ml) was added
to the mixture, which was concentrated in vacuo. The residue was parti-
tioned between ethyl acetate and 1 M hydrochloric acid. The organic layer
was washed with a saturated aqueous solution of sodium bicarbonate, dried
over sodium sulfate, and concentrated in vacuo. The residue was purified by
silica gel chromatography (hexane : ethyl acetateꢄ2 : 1) to give 30a (1.77 g,
94%) as colorless crystals; mp 118—135 °C. 1H-NMR (400 MHz, CDCl3) d:
1.96—2.09 (1H, m), 2.14—2.32 (2H, m), 3.25—3.33 (1H, m), 3.39—3.46
(1H, m), 3.53—3.60 (1H, m), 3.65 and 3.68 (1H, d, Jꢄ5.2 Hz), 3.86 and
3.87 (3H, s, OMe), 4.85 and 4.91 (1H, br s), 4.97—5.07 (4H, m,
2ꢆPhCH2O), 5.47 and 5.53 (1H, br s, –OH), 6.02 and 6.24 (2H, s), 6.47
(1H, d, Jꢄ8.5 Hz), 6.54 (1H, d, Jꢄ8.5 Hz), 6.63 and 6.65 (2H, d, Jꢄ8.5 Hz),
7.11—7.13 (1H, m), 7.18—7.20 (1H, m), 7.27—7.38 (13H, m). 13C-NMR
(100 MHz, CDCl3) d: 32.3, 33.0, 33.2, 38.6, 41.6, 60.8, 60.9, 61.0, 61.2,
71.2, 71.3, 76.0, 107.4, 113.5, 114.1, 115.4, 116.4, 116.7, 127.2, 127.2,
127.5, 127.9, 128.0, 128.1, 128.6, 128.6, 128.9, 129.6, 129.8, 130.0, 130.1,
130.2, 130.3, 131.2, 133.6, 134.6, 136.2, 136.6, 140.4, 141.2, 152.6, 154.6,
154.7, 155.2, 155.7, 156.1, 166.4, 167.0. IR (CHCl3) cmꢀ1: 3314, 1701,
1597, 1454, 1443, 1327, 1169, 1115. FAB-MS m/z: 711 (MꢃHꢃ). HR-MS
m/z: 711.2690 (Calcd for C41H38F3N2O6: 711.2682). Anal. Calcd for
C41H37F3N2O6: C, 69.29; H, 5.25; N, 3.94. Found: C, 69.13; H, 5.20; N,
3.82.
(2S,5R)-2-(3,5-Benzyloxy-4-methoxyphenyl)-3-(4-hydroxyphenethyl)-
5-isopropyl-1-(2,2,2-trifluoroacetyl)imidazolin-4-one (30b) Trifluoro-
acetic anhydride (0.02 ml, 0.147 mmol) was added to an ice-cooled solution
of 29b (34.8 mg, 0.06 mmol) in pyridine (1.0 ml) at 0 °C and the mixture was
stirred for 3 h. After the reaction, methanol (1.0 ml) was added to the mix-
ture, which was concentrated in vacuo. The residue was partitioned between
ethyl acetate and 1 M hydrochloric acid. The organic layer was washed with a
saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate,
and concentrated in vacuo. The residue was purified by silica gel chromatog-
raphy (chloroform : methanolꢄ10 : 1) to give 30b (30.5 mg, 77%) as color-
less crystals. 1H-NMR (400 MHz, CDCl3) d: 0.66 and 0.73 (3H, d,
Jꢄ6.9 Hz), 1.19 and 1.23 (3H, d, Jꢄ7.1 Hz), 2.13 and 2.43 (1H, m), 2.35—
2.49 (1H, m), 2.50—2.60 (1H, m), 3.71—3.82 (2H, m), 3.91 and 3.92 (3H,
s, OMe), 4.43 and 4.52 (1H, br s), 5.10 (2H, s, OCH2Ph), 5.06 (1H, d,
Jꢄ12.4 Hz, A part of AB type, OCH2Ph), 5.14 (1H, d, Jꢄ12.4 Hz, B part of
AB, OCH2Ph), 5.56 and 5.68 (1H, br s), 6.25 and 6.40 (2H, s), 6.72 and 6.75
Oxidative Coupling Reaction of 30a with PIFA PIFA (57.8 mg,
0.13 mmol) in 2,2,2-trifluoroethanol (3 ml) was added to a solution of 30a
(86.8 mg, 0.12 mmol) in 2,2,2-trifluoroethanol (3.0 ml) at ꢀ40 °C and the
mixture was stirred for 10 min. After the reaction, the mixture was concen-
trated in vacuo and the residue was purified by silica gel colum chromatog-
raphy (hexane : ethyl acetateꢄ2 : 1) to give 31a (51.8 mg, 61%) as an amor-
phous powder; 1H-NMR (400 MHz, CDCl3) d: 1.47 (0.5H, dd, Jꢄ16.5,
12.3 Hz, A part of AB type), 1.75 (0.5H, dd, Jꢄ16.5, 5.7 Hz, B part of AB
type), 1.88 (0.5H, dd, Jꢄ16.5, 5.5 Hz, Aꢂ part of AꢂBꢂ), 2.10 (0.5H, dd,
Jꢄ15.7, 12.6 Hz, Bꢂ part of AꢂBꢂ), 2.90 and 3.15 (1H, t, Jꢄ13.2 Hz), 3.27—
3.45 (1H, m), 3.57 (1H, dd, Jꢄ13.2, 5.2 Hz), 3.76 and 3.80 (3H, s, OMe),
3.75—3.85 (1H, m), 4.47 and 4.90 (1H, br s), 4.61 and 4.70 (1H, d,
Jꢄ10.6 Hz), 4.82 and 4.89 (1H, d, Jꢄ10.6 Hz), 4.99 and 5.04 (1H, d,
Jꢄ12.1 Hz), 5.08 and 5.21 (1H, d, Jꢄ12.1 Hz), 5.91 and 5.96 (1H, dd,
Jꢄ10.1, 1.7 Hz), 5.60 and 6.06 (1H, s), 6.14 and 6.15 (1H, d, Jꢄ10.1 Hz),
6.29 and 6.36 (1H, s), 6.69 and 6.78 (1H, dd, Jꢄ9.9, 3.0 Hz), 7.08—7.52
(15H, m). 13C-NMR (100 MHz, CDCl3) d: 32.6, 36.7, 37.2, 37.3, 39.1, 46.1,
46.5, 60.9, 62.7, 62.8, 70.4, 70.7, 70.9, 71.0, 75.8, 77.2, 104.4, 104.5, 121.4,
121.9, 122.6, 123.4, 126.0, 127.1, 127.2, 127.4, 127.5, 128.0, 128.1, 128.3,
128.4, 128.7, 128.9, 129.6, 129.8, 130.3, 133.2, 134.1, 136.0, 136.0, 136.2,
136.4, 143.7, 150.9, 152.5, 152.6, 153.4, 153.7, 155.9, 156.3, 156.8, 157.2,
164.7, 165.5, 184.6, 184.9. IR (CHCl3) cmꢀ1: 1707, 1660, 1456, 1333, 1184,
1171, 1117. FAB-MS m/z: 709 (MꢃHꢃ). HR-MS m/z: 709.2530 (Calcd for
C41H36F3N2O6: 709.2525).
Oxidative Coupling Reaction of 30b with PIFA PIFA (7.14 mg,
0.017 mmol) in 2,2,2-trifluoroethanol (0.5 ml) was added to a solution of
30b (10.0 mg, 0.015 mmol) in 2,2,2-trifluoroethanol (0.5 ml) at ꢀ40 °C and
the mixture was stirred for 15 min. After the reaction, the mixture was con-
centrated in vacuo and the residue was purified by silica gel column chro-
matography (chloroform : methanolꢄ1 : 1) to give 31b (4.5 mg, 45%) as an
amorphous powder; 1H-NMR (400 MHz, CDCl3) d: 0.86 and 0.94 (3H, d,
Jꢄ6.8 Hz), 1.23 and 1.30 (3H, d, Jꢄ7.0 Hz), 2.09 (1H, td, Jꢄ16.0, 5.5 Hz),
2.33 and 2.96 (1H, m), 2.59 (1H, dt, Jꢄ16.0, 5.5 Hz) , 3.17 and 3.20 (1H, t,
Jꢄ13.0 Hz), 3.74 and 3.90 (2H, dd, Jꢄ14.0, 5.5 Hz) 3.79 and 3.82 (3H, s),
4.06 and 4.41 (1H, br s), 4.72 and 4.73 (1H, d, Jꢄ10.5 Hz), 4.89 and 4.92
(1H, d, Jꢄ10.5 Hz), 5.01 and 5.03 (1H, d, Jꢄ12.5 Hz), 5.10 and 5.23 (1H, d,
Jꢄ12.5 Hz), 6.02 (1H, dd, Jꢄ10.1, 1.8 Hz), 6.22 and 6.24 (1H, dd, Jꢄ9.1,
1.8 Hz), 6.31 and 6.32 (1H, s), 6.71 and 6.75 (1H, s), 6.90 and 7.13 (1H, dd,
Jꢄ10.0, 3.0 Hz), 7.20—7.43 (10H, m). 13C-NMR (100 MHz, CDCl3) d:
15.0, 15.4, 17.9, 18.4, 25.8, 34.1, 36.9, 37.3, 37.4, 37.6, 46.7, 46.7, 60.9,
61.0, 65.6, 65.8, 70.5, 70.7, 70.8, 70.9, 75.8, 75.9, 104.3, 104.6, 121.6,

December 2006
1677
122.3, 123.2, 123.4, 126.5, 127.1, 127.2, 127.5, 127.6, 128.0, 128.1, 128.3, which 10% aqueous solution of sodium hydroxide (9.0 ml) was added. After
128.4, 128.4, 128.7, 128.9, 130.8, 135.9, 136.0, 136.3, 136.4, 143.6, 151.1, being stirred for 7 d, the mixture was neutralized with 1 M hydrochloric acid
151.4, 152.6, 153.7, 157.0, 157.2, 164.6, 165.7, 184.7, 184.9. IR (CHCl3) and extracted with chloroform. The organic layer was washed with saturated
cmꢀ1: 3007, 1707, 1661, 1622, 1593, 1487, 1456, 1437, 1423, 1366, 1321, aqueous solution of sodium chloride, dried over sodium sulfate, and concen-
1238, 1186, 1171, 1119, 1061, 1005, 854. EI-MS m/z: 660 (Mꢃ). HR-MS trated in vacuo. The residue was purified by silica gel chromatography (chlo-
m/z: 660.2254 (Calcd for C37H35F3N2O6: 660.2247).
roform : methanoꢄ10 : 1) to afford 34 (22.0 mg, 83%) as a yellow oil. 1H-
Oxidative Coupling Reaction of 30c with PIFA PIFA (84.0 mg, NMR (400 MHz, CDCl3) d: 2.00—2.08 (3H, m), 2.66 (1H, br d,
0.20 mmol) in 2,2,2-trifluoroethanol (3.5 ml) was added to a solution of 30c
(100 mg, 0.18 mmol) in 2,2,2-trifluoroethanol (3.0 ml) at ꢀ40 °C and the
Jꢄ15.6 Hz), 4.06 (3H, s), 4.01—4.16 (2H, m), 4.17 (1H, t, Jꢄ5.0 Hz), 4.71
(1H, br s), 5.56 (1H, d, Jꢄ9.9 Hz), 5.89 (1H, dd, Jꢄ9.9, 5.0 Hz), 6.63 (1H,
mixture was stirred for 90 min. After the reaction, the mixture was concen- s), 8.28 (1H, br s). 13C-NMR (100 MHz, CDCl3) d: 29.8, 36.8, 47.0, 50.0,
trated in vacuo and the residue was purified by silica gel column chromatog- 60.5, 61.9, 70.7, 89.8, 111.4, 127.0, 127.7, 129.9, 133.9, 146.7, 148.8,
raphy (hexane : ethyl acetateꢄ1 : 1) to give 31c (41.0 mg, 41%) as a colorless
powder; 1H-NMR (400 MHz, CDCl3) d: 1.55 (0.5H, t, Jꢄ13.9 Hz), 1.75
(0.5H, dd, Jꢄ16.3, 5.7 Hz), 1.91 (0.5H, dd, Jꢄ16.1, 5.1 Hz,), 2.13 (0.5H, t,
159.6. IR (CHCl3) cmꢀ1: 3533, 2934, 1601, 1504, 1404, 1369, 1269. EI-MS
m/z: 287 (Mꢃ). HR-MS m/z: 287.1151 (Calcd for C16H17NO4: 287.1157).
N-tert-Butoxycarbonyl-7-hydroxy-N-norgalanthamine (36) s-cis and s-
Jꢄ13.2 Hz), 3.00 and 3.24 (1H, t, Jꢄ13.2 Hz), 3.54 and 3.59 (3H, s), 3.76 transꢃ2 : 1 Sodium borohydride (4.6 mg, 0.123mmol) was added to a so-
and 3.77 (3H, s), 3.79 and 3.81 (3H, s), 3.31—3.86 (4H, m), 4.86 and 5.04 lution of 34 (8.8 mg, 0.031 mmol) in methanol (0.5 ml) at 0 °C and the mix-
(1H, br s), 5.63 and 6.09 (1H, s), 6.20 and 6.31 (1H, s), 6.17—6.25 (2H, m), ture was stirred at room temperature for 4 h. After the reaction, the reaction
6.68 and 6.74 (1H, dd, Jꢄ10.1, 2.7 Hz), 7.04—7.33 (5H, m). 13C-NMR
(100 MHz, CDCl3) d: 32.8, 36.0, 36.5, 36.8, 37.3, 39.3, 46.3, 46.7, 55.5,
mixture was concentrated and the residue was extracted with chloroform.
The organic layer was washed with saturated aqueous solution of sodium
55.9, 60.6, 60.7, 60.8, 62.8, 63.0, 70.7, 102.1, 122.7, 123.5, 126.0, 127.2, chloride, dried over sodium sulfate, and concentrated in vacuo. Di-tert-butyl
127.4, 127.6, 128.1, 128.5, 128.8, 129.6, 129.8, 130.4, 133.3, 134.1, 151.1, dicarbonate (21.1 mg, 0.096 mmol) was added to a solution of the residue in
153.2, 153.5, 156.7, 157.2, 164.9, 165.5, 185.1. IR (CHCl3) cmꢀ1: 1709, tetrahydrofuran (0.5 ml) and the mixture was stirred at room temperature for
1661, 1464, 1323, 1173, 1124. EI-MS m/z: 556 (Mꢃ). HR-MS m/z: 2 h. The reaction mixture was concentrated in vacuo and extracted with
556.1824 (Calcd for C29H27F3N2O6: 556.1821).
Debenzylation Reaction of 31a with BCl3 One molar solution of boron
trichloride in CH2Cl2 (0.085 ml, 0.085 mmol) was added to a solution of 31a
chloroform. The organic layer was washed with satureated aqueous solution
of sodium chloride, dried over sodium sulfate, and concentrated in vacuo.
The residue was purified by silica gel column chromatography (ethyl ac-
(20.0 mg, 0.028 mmol) in CH2Cl2 (0.5 ml) at ꢀ78 °C and the mixture was etate) to give 36 (7.0 mg, 58%) as a colorless oil. [100% ee, chiral HPLC
stirred for 20 h. The reaction was quenched by adding chilled water and the analysis; DICEL CHIRALCEL OD (25ꢆ0.46); eluent: n-hexane : iso-
mixture was stirred at room temperature for another 30 min. The reaction
propanolꢄ1 : 9; flow rate: 1 ml/min; temp. 25 °C; detector; 254 nm, (ꢀ)-36:
1
mixture was extracted with chloroform and the organic layer was washed 50.2 min, (ꢃ)-36: 74.0 min]; H-NMR (400 MHz, CDCl3) d: 1.39 and 1.43
with a saturated aqueous solution of sodium chloride, dried over sodium sul- (9H, s), 1.65—1.77 (2H, m), 1.90 (1H, dt, Jꢄ13.1, 3.1 Hz), 2.00 and 2.04
fate, and concentrated in vacuo. The residue was purified by silica gel col- (1H, dt, Jꢄ15.7, 2.4 Hz), 2.32 (1H, br), 2.65 (1H, d, Jꢄ15.7 Hz), 3.28 and
umn chromatography (chloroform : methanolꢄ10 : 1) to give 32 (14.1 mg,
3.37 (1H, t, Jꢄ13.0 Hz), 3.93 and 3.96 (3H, s, OMe), 4.09 and 4.28 (1H,
1
95%) as an amorphous powder; H-NMR (400 MHz, CDCl3) d: 1.26—1.37 br d, Jꢄ16.0 Hz, A part of AB type), 4.15 (1H, s), 4.27 (1H, d, Jꢄ14.8 Hz),
and 1.84—1.94 (2H, m), 2.01—2.06 (1H, m), 2.74 (1H, t, Jꢄ19.5 Hz), 3.07
(1H, t, Jꢄ18.0 Hz), 3.38 (2H, t, Jꢄ10.8 Hz), 3.46 (1H, t, Jꢄ11.8 Hz),
4.58 (1H, s), 4.60 and 4.79 (1H, d, Jꢄ16.0 Hz, B part of AB type), 5.71 and
5.95 (1H, br d, Jꢄ10.4 Hz), 5.72 and 5.98 (1H, br s), 6.34 and 6.45 (1H, s).
3.84—4.00 (1H, m), 3.92 and 4.00 (3H, s), 4.65—4.70 (1.5H, m), 4.94 and 13C-NMR (100 MHz, CDCl3) d: 28.3, 28.5, 30.0, 36.3, 37.3, 45.3, 46.0,
5.42 (0.5H, s), 5.93 and 6.20 (1H, s), 5.97 and 6.03 (1H, d, Jꢄ9.3 Hz), 6.32
47.6, 51.4, 52.0, 60.5, 62.0, 80.0, 89.0, 89.2, 107.5, 108.2, 124.4, 127.0,
and 6.54 (1H, d, Jꢄ9.3 Hz), 7.13—7.34 (5H, m). 13C-NMR (100 MHz,
127.2, 127.5, 130.8, 132.0, 147.8, 148.2, 154.9. IR (CHCl3) cmꢀ1: 3531,
CDCl3) d: 30.3, 32.3, 33.0, 36.5, 37.0, 37.6, 38.9, 46.8, 47.4, 60.4, 61.2, 2937, 1686, 1601, 1508, 1462, 1441, 1416, 1367, 1251, 1169. EI-MS m/z:
62.0, 71.3, 72.2, 77.2, 87.5, 88.0, 102.9, 103.4, 119.4, 125.7, 127.4, 127.9,
128.3, 128.4, 129.7, 129.9, 132.3, 133.5, 134.3, 142.9, 144.2, 149.3, 149.5,
389 (Mꢃ). HR-MS m/z: 389.1836 (Calcd for C21H27NO6: 389.1838).
Trifluoromethanesulfonation of 32 Trifluoromethanesulfonic anhy-
166.2, 167.2, 193.6. IR (CHCl3) cmꢀ1: 3526, 1693, 1510, 1456, 1437, 1238, dride (0.13 ml, 0.78 mmol) was added to a solution of 32 (343 mg,
1169. EI-MS m/z: 528 (Mꢃ). HR-MS m/z: 528.1508 (Calcd for
C27H23F3N2O4: 528.1514).
0.65 mmol) in pyridine (1.5 ml) at 0 °C and the mixture was stirred at the
temperature for 3 h. The reaction was quenched by adding methanol (3.0 ml)
Reduction of 32 with L-Selectride One molar solution of lithium tri- and the mixture was concentrated in vacuo. The residue was extracted with
sec-butylborohydride in tetrahydrofuran (0.64 ml, 0.64 mmol) was added to
a solution of 32 (141.2 mg, 0.27 mmol) in tetrahydrofuran (2.0 ml) at ꢀ78 °C
ethyl acetate and the organic layer was successively washed with 1 M hy-
drochloric acid and a saturated aqueous solution of sodium bicarbonate, a
and the mixture was stirred for 24 h with keeping the temperature. The reac- saturated aqueous solution of sodium chloride, dried over sodium sulfate,
tion was quenched by adding a saturated aqueous solution of sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column
to the reaction mixture, which was extracted with chloroform. The organic chromatography (ethyl acetate) to afford triflate 37 (354.3 mg, 83%) as a
1
layer was washed with a saturated aqueous solution of sodium chloride, crystalline powder; H-NMR (400 MHz, CDCl3) d: 1.46 and 1.95 (2H, m),
dried over sodium sulfate, and concentrated until a solid powder appeared, 2.76 (1H, t, Jꢄ15.8 Hz), 3.07—3.52 (4H, m), 3.89 (1H, m), 3.99 (3H, br s),
which was collected by vacuum filtration and purified by silica gel column 4.68 and 4.79 (1H, s), 4.73 and 4.95 (1H, s), 5.41 and 5.93 (1H, s), 6.08—
chromatography (chloroform : methanolꢄ50 : 1) to give 33 (131.7 mg, 92%)
as a colorless crystalline powder; 1H-NMR (400 MHz, CDCl3) d: 1.18— 32.4, 33.2, 36.3, 36.7, 37.7, 38.7, 39.0, 47.4, 48.2, 60.8, 61.1, 61.9, 71.0,
1.39 (1H, m), 1.66—2.04 (3H, m), 2.18 (1H, d, Jꢄ10.8 Hz), 2.62 (1H, t, 71.6, 88.0, 88.5, 110.3, 117.0, 120.2, 122.7, 123.4, 127.6, 128.0, 128.4,
6.54 (3H, m), 7.16—7.35 (5H, m). 13C-NMR (100 MHz, CDCl3) d: 30.8,
Jꢄ15.3 Hz,), 3.34—3.43 (2H, m), 3.82—3.93 (1H, m), 3.96 (3H, s), 4.11— 128.8, 129.9, 133.3, 133.9, 141.3, 142.6, 150.2, 150.6, 166.3, 167.0, 192.7.
4.14 (1H, m), 4.51 and 4.57 (1H, br s), 4.63 and 4.92 (1H, br s), 5.44 and IR (CHCl3) cmꢀ1: 1709, 1697, 1508, 1456, 1429, 1312, 1256, 1240, 1169,
5.69 (1H, d, Jꢄ10.4Hz), 6.02 (1H, dd, Jꢄ9.9, 4.8 Hz), 5.92 and 6.17 (1H, s), 1140, 1038, 1007. EI-MS m/z: 660 (Mꢃ). HR-MS m/z: 660.1000 (Calcd for
7.13—7.33 (5H, m). 13C-NMR (100 MHz, CDCl3) d: 29.3, 29.7, 31.7, 32.4, C28H22F6N2O8S: 660.0996).
34.2, 37.7, 38.8, 46.3, 47.1, 60.4, 61.2, 61.6, 61.9, 71.6, 72.4, 88.8, 102.8,
103.2, 114.0, 116.8, 121.9, 126.5, 127.3, 127.9, 128.3, 128.7, 129.7, 132.3, mmol) and triethylamine (0.355 ml, 2.55 mmol) were added to a solution of
133.5, 134.3, 148.7, 148.8, 155.6, 156.0, 166.3, 167.1. IR (CHCl3) cmꢀ1
37 (114.4 mg, 0.17 mmol), palladium acetate (7.86 mg, 0.035 mmol) and
3530, 2939, 1709, 1603. EI-MS m/z: 530 (Mꢃ). HR-MS m/z: 530.1660 triphenylphosphine (18.17 mg, 0.069 mmol) in N,N-dimethylformamide
Detrifluoromethanesulfonation of 37 Formic acid (0.064 ml, 1.7
:
(Calcd for C27H25F3N2O6: 530.1664).
(1.5 ml), and the mixture was stirred at 60 °C for 3 d. After the reaction, the
Hydrolysis of 33 A solution of 33 (50.0 mg, 0.094 mmol) in a mixed
mixture was concentrated in vacuo and the residue was extracted with ethyl
solvent composed of 10% aqueous solution of sodium hydroxide (0.5 ml) acetate. The organic layer was washed with a saturated aqueous solution of
and tetrahydrofuran (0.5 ml) was stirred at room temperature for 12 h. After sodium chloride, dried over sodium sulfate, and concentrated in vacuo. The
the reaction, the mixture was neutralized by 1 M hydrochloric acid and ex-
tracted with chloroform. The organic layer was washed with a saturated to give 38 (85.6 mg, 98%) as a colorless crystalline powder; 1H-NMR
aqueous solution of sodium chloride, dried over sodium sulfate, and concen- (400 MHz, CDCl3) d: 1.42—1.49 and 1.83—2.17 (2H, m), 2.76 (1H, dd,
trated in vacuo. The residue was purified by silica gel column chromatogra- Jꢄ17.6, 3.4 Hz), 2.70 and 3.20 (1H, m), 3.17 (1H, d, Jꢄ17.6 Hz), 3.37—
phy (chloroform : methanolꢄ10 : 1) to give the 35 (40.9 mg, quant.), to 3.48 (2H, m), 3.86 (3H, br s), 4.02 (1H, m), 4.65 and 4.72 (1.5H, br s), 4.96
residue was purified by silica gel column chromatography (ethyl acetate)

1678
Vol. 54, No. 12
sulfate to the reaction mixture, which was extracted with chloroform. The
organic layer was washed with a saturated aqueous solution of sodium chlo-
ride, dried over sodium sulfate, and concentrated in vacuo. The residue was
purified by silica gel chromatography (chloroform : methanolꢄ10 : 1) to give
(ꢀ)-1 (9.5 mg, 94%) as colorless crystals, [a]D22 ꢀ121.7° (cꢄ0.30, ethanol)
[lit. [a]D ꢀ121.4° (cꢄ0.99, ethanol)].7) 1H-NMR (400 MHz, CDCl3) d:
1.60—1.70 (1H, m), 1.89—2.04 (1H, m), 2.06—2.31 (1H, m), 2.43 (3H, s,
NCH3), 2.67—2.72 (1H, m), 3.09 (1H, d, Jꢄ14.5 Hz), 3.32 (1H, t,
Jꢄ13.0 Hz), 3.73 (1H, d, Jꢄ14.7 Hz), 3.84 (3H, s, OCH3), 4.14 (1H, d,
Jꢄ15.4 Hz), 4.15 (1H, t, Jꢄ4.8 Hz), 4.62 (1H, br s), 6.02 (1H, dd, Jꢄ10.5,
4.1 Hz), 6.06 (1H, d, Jꢄ10.3 Hz), 6.64 (1H, d, Jꢄ8.2 Hz), 6.68 (1H, d,
Jꢄ8.1 Hz). 13C-NMR (100 MHz, CDCl3) d: 29.8, 33.6, 41.8, 48.1, 53.6,
55.8, 60.4, 61.9, 88.6, 111.1, 122.0, 126.7, 127.6, 128.9, 132.9, 144.0,
145.5. IR (CHCl3) cmꢀ1: 3410, 2964, 2933, 1626, 1601, 1514, 1462, 1439,
1408, 1375, 1283, 1234, 1223, 1202, 1173, 1138, 1115, 1090, 1069, 1047,
1015, 988, 943, 922, 870, 826. EI-MS m/z: 287 (Mꢃ). HR-MS m/z:
287.1515 (Calcd for C17H21NO3: 287.1521).
and 5.50 (0.5H, s), 6.03 and 6.06 (1.5H, d, Jꢄ10.0 Hz), 6.29 and 6.34 (0.5H,
d, Jꢄ10.0 Hz), 6.53 and 6.59 (1H, d, Jꢄ9.3 Hz), 6.52 and 6.59 (1H, d,
Jꢄ9.0 Hz), 6.78 (1H, d, Jꢄ9.0 Hz), 7.14—7.35 (5H, m). 13C-NMR
(100 MHz, CDCl3) d: 30.9. 32.3, 33.6, 35.1, 36.3, 36.8, 37.8, 38.9, 39.8,
47.7, 48.6, 55.9, 56.1, 61.1, 61.9, 71.8, 72.6, 77.2, 87.0, 87.5, 88.0, 111.3,
112.1, 112.6, 116.4, 121.2, 123.5, 126.6, 127.4, 127.9, 128.1, 128.3, 128.7,
129.7, 129.9, 133.4, 134.2, 141.9, 143.3, 145.2, 145.8, 148.0, 155.8, 156.5,
166.4, 167.1, 193.2. IR (CHCl3) cmꢀ1: 2937, 1693, 1510, 1456, 1437, 1286,
1167, 1055. EI-MS m/z: 512 (Mꢃ); HR-MS m/z: 512.1553 (Calcd for
C27H23F3N2O5: 512.1559).
Reduction of 38 with L-Selectride One molar solution lithium tri-sec-
butylborohydride in tetrahydrofuran (0.937 ml, 0.937 mmol) was added to a
solution of 38 (200 mg, 0.39 mmol) in tetrahydrofuran (2 ml) at ꢀ78 °C and
the mixture was stirred at the temperature for 3 h. The reaction was
quenched by adding a saturated aqueous solution of sodium sulfate, and the
mixture was extracted with chloroform. The organic layer was washed with
a saturated aqueous solution of sodium chloride, dried over sodium sulfate,
and concentrated in vacuo. The residue was purified by silica gel column
chromatography (ethyl acetate) to give 39 (156.3 mg, 78%) as an amorphous
powder; 1H-NMR (400 MHz, CDCl3) d: 1.56—2.03 (4H, m), 2.67 (1H, t,
Jꢄ16.7 Hz), 3.40 (2H, t, Jꢄ12.5 Hz), 3.85 and 3.87 (3H, s), 3.80—3.89 (1H,
m), 3.98—4.03 (1H, m), 4.16 (1H, br s), 4.51 and 4.58 (1H, s), 4.63 and 4.93
(1H, br s), 5.73 (1H, d, Jꢄ8.6 Hz), 5.99 (1H, s), 6.05 and 6.07 (1H, d,
Jꢄ8.6 Hz), 6.26 and 6.49 (1H, d, Jꢄ8.2 Hz), 6.73 (1H, d, Jꢄ8.2 Hz), 7.12—
7.36 (5H, m). 13C-NMR (100 MHz, CDCl3) d: 29.1, 29.6, 32.4, 34.6, 37.9,
38.8, 47.3, 48.1, 55.9, 60.7, 61.1, 61.5, 61.9, 72.1, 72.7, 88.1, 111.3, 111.8,
114.0, 116.3, 125.6, 126.8, 127.3, 128.3, 128.7, 129.2, 129.7, 129.9, 134.4,
134.4, 145.9, 147.0, 167.1. IR (CHCl3) cmꢀ1: 3568, 2937, 1709, 1508, 1456,
1437, 1286, 1238, 1194, 1167, 1060. EI-MS m/z: 514 (Mꢃ). HR-MS m/z:
514.1711 (Calcd for C27H25F3N2O5: 514.1715).
Acknowledgements This research was financially supported in part by
Frontier Research Program and the 21st Century Center of Excellence Pro-
gram “Development of Drug Discovery Frontier Integrated from Tradition
to Proteome” of the Ministry of Education, Culture, Sport and Technology,
Japan, and Grant in Aid 16590022.
References
1) Proskurnina N. F., Yakovleva A. P., Zhur. Obschchei. Khim., 22,
1899—1902 (1952).
2) Uyeo S., Kobayashi S., Pharm. Bull., 1, 139—142 (1953).
3) Kobayashi S., Shingu T., Uyeno S., Chem. Ind., 1956, 177—178
(1956).
Hydrolysis of 39 A mixture of 39 (93.7 mg, 0.18 mmol), TBAB
(29.4 mg, 0.09 mmol) and 10% solution of potassium hydroxide in methanol
(3.0 ml) was stirred at 80 °C for 24 h. After the reaction, the mixture was
neutralized with 1 M hydrochloric acid and concentrated in vacuo. The
residue was extracted with chloroform, and the organic layer was washed
with saturated aqueous solution of sodium chloride, dried over sodium sul-
fate and concentrated in vacuo. The residue was purified by silica gel chro-
matography (chloroform : methanolꢄ10 : 1) to afford 40 (46.7 mg, 96%) as a
pale yellow oil. 1H-NMR (400 MHz, CDCl3) d: 1.98—2.09 (3H, m), 2.68—
2.73 (1H, m), 3.91 (3H, s, OMe), 4.01—4.18 (2H, m), 4.17 (1H, t,
Jꢄ5.0 Hz), 4.72 (1H, br s), 5.59 (1H, d, Jꢄ10.0 Hz), 6.01 (1H, ddd, Jꢄ10.0,
5.0, 1.1 Hz), 6.85 (1H, d, Jꢄ8.2 Hz), 7.04 (1H, d, Jꢄ8.4 Hz), 8.35 (1H, br s).
13C-NMR (100 MHz, CDCl3) d: 29.5, 35.9, 47.6, 49.7, 56.0, 61.7, 88.9,
111.7, 122.6, 126.4, 127.6, 128.7, 134.6, 145.2, 146.5, 158.9. IR (CHCl3)
cmꢀ1: 3564, 2930, 1620, 1506, 1454, 1437, 1406, 1286, 1173, 1090, 1063,
991. EI-MS m/z: 271 (Mꢃ). HR-MS m/z: 271.1214 (Calcd for C16H17NO3:
271.1208).
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N-Formyl-N-norgalanthamine (41) Sodium borohydride (13.4 mg,
0.35 mmol) was added to a solution of 40 (40.0 mg, 0.15 mmol) in methanol
(1.0 ml) at 0 °C, and the mixture was stirred at room temperature for 24 h.
After the reaction, the mixture was concentrated in vacuo and the residue
was extracted with CHCl3. The organic layer was washed with a saturated
aqueous solution of sodium chloride, dried over sodium sulfate and concen-
trated in vacuo. And then, ethyl formate (7.5 ml) was added to the residue,
and the mixture was refluxed for 2 d. The reaction mixture was concentrated
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(chloroform : methanolꢄ10 : 1) to give 41 (46.3 mg, quant.) as colorless
crystals; mp 117—118 °C (methanol). 1H-NMR (400 MHz, CDCl3) d:
1.77—1.92 (2H, m), 1.94—2.07 (2H, m), 2.68—2.75 (1H, dm, Jꢄ16.0 Hz),
3.21—3.28 (1H, br t, Jꢄ12.4 Hz), 3.66—3.74 (1H, br t, Jꢄ13.6 Hz), 3.84
and 3.85 (3H, s), 4.03 (0.5H, d, Jꢄ15.0 Hz, A part of AB type), 4.17 (1H, t,
Jꢄ4.6 Hz), 4.51 (1H, br s), 4.59 (1H, br s), 5. 21 (0.5H, d, Jꢄ15.0 Hz, B part
of AB type), 5.97—6.11 (2H, m), 6.69 and 6.86 (1H, d, Jꢄ8.2 Hz), 6.70
(1H, s), 8.12 and 8.16 (1H, s). 13C-NMR (100 MHz, CDCl3) d: 29.7, 29.8,
36.0, 39.3, 41.0, 46.5, 46.8, 48.2, 48.3, 52.8, 55.9, 61.8, 88.1, 88.2, 111.3,
111.4, 120.1, 121.8, 125.8, 126.1, 127.7, 128.4, 128.4, 128.6, 132.0, 132.1,
144.6, 144.8, 146.3, 146.7, 161.8, 162.4. IR (CHCl3) cmꢀ1: 3564, 2936,
1668, 1628, 1591, 1510, 1456, 1435, 1396, 1375, 1281, 1240, 1194, 1171,
1132, 1059, 1063, 993, 966. EI-MS m/z: 301 (Mꢃ). HR-MS m/z: 301.1317
(Calcd for C17H19NO4: 301.1314).
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