Intramolecular Heck cyclization to the galanthamine-type alkaloids: Total synthesis of (±)-lycoramine

Article abstract of DOI:10.1016/j.tet.2004.09.044

A novel approach towards the construction of the galanthamine skeleton was demonstrated by the total synthesis of (±)-lycoramine. The key steps include a Pd-catalyzed intramolecular cyclization to form the seven-membered azepane ring and a spontaneous int

Full text of DOI:10.1016/j.tet.2004.09.044

Tetrahedron 60 (2004) 11655–11660
Intramolecular Heck cyclization to the galanthamine-type
alkaloids: total synthesis of (G)-lycoramine
†
*
Pi-Hui Liang, Jing-Ping Liu, Ling-Wei Hsin and Chen-Yu Cheng
Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Room 1336,
Taipei 10018, Taiwan, ROC
Received 27 April 2004; revised 5 August 2004; accepted 6 September 2004
Available online 2 October 2004
Abstract—A novel approach towards the construction of the galanthamine skeleton was demonstrated by the total synthesis of
(G)-lycoramine. The key steps include a Pd-catalyzed intramolecular cyclization to form the seven-membered azepane ring and a
spontaneous intramolecular Michael addition to afford the five-membered furan ring. This synthetic route has also been demonstrated to be
useful for the preparation of novel derivatives with simplified galanthamine skeletons.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
palladium-catalyzed cyclization to build the quaternary
center of galanthamine-type alkaloids.22–26
Galanthamine ((K)-1),1 an alkaloid isolated from the
Amaryllidaceae species, has been shown to be a potent
acetylcholinesterase (AChE) inhibitor and significantly
enhances cognitive functions in patients who suffered
from Alzheimer’s disease (AD).2–4 Galanthamine was first
approved in Austria and most recently in the rest of Europe
and in the United States for the treatment of AD.
Galanthamine is structurally related to morphine in topology
(Chart 1). Morphine and its simplified analogs morphinan,
benzomorphan, and 4-phenylpiperidine derivatives, remain
the most widely used analgesics for the treatment of severe
pain. Therefore, derivatives containing simplified galantha-
mine skeleton may be potential candidates for the develop-
ment of novel AChE inhibitors. Prior research in this
laboratory has focused on the development of novel synthetic
strategies for the efficient preparation of compounds
Galanthamine is produced by isolation from botanical
sources (e.g., Galanthus nivalis, G. narcissus, G. leucojum,
or G. crinium) and these sources are limited.5 Thus,
synthetic approaches to the large-scale production of
galanthamine have been sought and a number of total
syntheses of galanthamine have appeared in the litera-
tures.6–26 Most of them utilized a biomimetic oxidative
bisphenol coupling to create the critical spiroquarternary
carbon of galanthamine.6–19 Lycoramine ((K)-2, 1,2-
dihydrogalanthamine), another galanthamine-type alkaloid,
has been claimed to have significant activities in inhibiting
the formation of peptide bond in protein synthesis.20 In a
formal synthesis of 2, the intramolecular Heck reaction was
used to construct the quaternary carbon center via a 6-exo
cyclization.21 From then on, several groups have utilized
Keywords: Galanthamine; Lycoramine; Intramolecular cyclization; Heck
reaction.
* Corresponding author. Tel.: C886 2 2395 2310; fax: C886 2 2351 2086;
e-mail: lwh@ntumc.org
† Present address: Formosa Laboratories, Inc., No. 36-1, Hoping Street,
Chart 1.
Louchu County, Taoyuan 338, Taiwan, ROC.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.044

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P.-H. Liang et al. / Tetrahedron 60 (2004) 11655–11660
possessing morphine partial structures.27–32 The Heck
reaction was one of the key reactions used for construction
of the O ring in the ANO and ACNO ring systems of
morphine.28 This experience has prompted us to extend our
methodology to the synthesis of structurally simplified
galanthamine analogs, including the 12-aza-benzo[h]spiro
[5.6]dodecane (G)-3, which retains most of the rigidity of
galanthamine and demonstrated the desired, albeit weak
AChE inhibition.33 To further explore the utilities of our
methodology, we have achieved the total synthesis of the
galanthamine-type alkaloid lycoramine ((G)-2). Here, we
report in detail the novel synthetic strategy for the
preparation of (G)-2.
The starting amine 6 was prepared from diol 7 via a reaction
sequence of Mitsunobu reaction with phthalimide, dehy-
dration, and deprotection. Diol 7 was obtained from
cyclohexane-1,4-dione monoethylene ketal, as previously
described.33 Reductive amination of 2-halobenzaldehydes
with amine 6, followed by protection of the secondary amine
intermediates with (Boc)2O afforded compounds 10 and 11,
respectively (Scheme 2). However, all attempts to effect the
intramolecular Heck reaction to prepare the desired cyclized
product 12 failed, resulting primarily in dehalogenated
products. Earlier reports suggested that compounds with an
endo-amide group may favor the intramolecular Heck
reaction due to the added conformational restriction.34,35
Therefore, we turned our attention to the use of endo-amide
intermediates, such as compound 14.
2. Results and discussion
Treatment of compound 7 with MsCl, followed by
methylamine, resulted in nucleophilic substitution and
dehydration to afford the secondary amine 13. The
advantage of this alternative process for the preparation of
the said amines was to avoid the use of very toxic reagents,
DEAD and hydrazine, for the Mitsunobu and the subsequent
deprotection steps, respectively. Compound 14 was pre-
pared by the coupling of 2-iodobenzoic acid with amine 13.
To our delight, compound 14 underwent the desired
intramolecular Pd-catalyzed cyclization smoothly to pro-
vide spiro-amide 15 in 67% yield. However, the desired
cyclization was not observed when the bromo-analog of
Retrosynthetic consideration led us to propose the route as
shown in Scheme 1. The dihydrofuran ring in 2 could be
generated by an intramolecular Michael addition of the
phenol group to the enone functionality of 4. The seven-
membered tetrahydroazepine ring in compound 4 could be
formed via a Pd-catalyzed 7-exo-trig cyclization of the key
intermediate 5. Compound 5 can be synthesized from the
coupling of a 2-haloisovanillin and 2-(1,4-dioxa-spiro[4,5]
dec-7-en-8-yl)ethylamine (6) via a reductive amination
reaction.
Scheme 1. Retrosynthetic analysis of galanthamine-type alkaloids (XZBr or I).
Scheme 2. Reagentsandconditions:(a)phthalimide,DEAD, PPh3, THF,rt;(b)p-TsOH, toluene,reflux;(c)N2H4$H2O,ethanol,reflux;(d)2-bromobenzaldehydeor
2-iodobenzaldehyde, CH2Cl2, rt; then NaBH4, MeOH, rt; (e) (Boc)2O, NaHCO3, MeOH, rt; (f) Heck reaction conditions; (g) MsCl, CH2Cl2, K23 8C to rt; (h) 40%
CH3NH2, reflux; (i) 2-iodobenzoic acid, SOCl2, THF, K23 8C to rt; (j) Pd(OAc)2, PPh3, K2CO3, CH3CN, 130 8C; (k) 1 N HCl, rt.

P.-H. Liang et al. / Tetrahedron 60 (2004) 11655–11660
11657
compound 14 was subjected to the same Heck reaction
condition. Hydrolysis of the ketal function in 15 with HCl
afforded enone 16 in 63% yield.
spectrum, which is identical to that of an authentic sample of
lycoramine.
In summary, we have demonstrated a novel synthetic route
to the galanthamine skeleton and its simplified analogs, such
as 16. To our knowledge, the direct construction of the
seven-membered ring of galanthamine-type alkaloids via an
intramolecular Heck reaction as exemplified by the total
synthesis of (G)-2 has not been documented yet. The total
synthesis starts from simple cyclohexane-1,4-dione mono-
ethylene ketal and isovanillin, and completes in eight steps
with an overall yield of 3%. Notable features of this
synthetic route include a Pd-catalyzed intramolecular
cyclization and a spontaneous intramolecular Michael
addition to form the seven-membered azepane ring and
the five-membered furan ring, respectively. This synthetic
strategy may be developed into an alternative process for
galanthamine production, and provide derivatives posses-
sing simplified galanthamine skeleton as potential drug
candidates. Further work towards the synthesis of novel
galanthamine-related compounds and their pharmacological
studies are in progress.
With the success in the synthesis of compound 16, we then
turned our efforts to the construction of the complete
tetracyclic skeleton of galanthamine. Thus, 2-iodoisovanil-
lin (18) was prepared from isovanillin in four steps
according to the literature.36 The aldehyde and phenol
groups of isovanillin were protected by reacting with
trimethyl orthoformate and chloromethyl methyl ether,
respectively, to afford compound 17. Treatment of 17 with
n-butyl lithium and I2, followed by acidic work-up furnished
compound 18. Direct oxidation of 18 to the corresponding
acid failed due to the sensitivity of its phenol group.
Therefore, the phenol group of 18 was first protected as a
benzyl ether, and then the protected aldehyde was oxidized
with KMnO4 to give acid 19. Coupling of compound 19
with amine 13 afforded amide 20 in 73% yield (Scheme 3).
When compound 20 was subjected to Heck reaction
condition using Pd(OAc)2, Ph3P, and K2CO3 in CH3CN,
the desired intramolecular cyclization was achieved to
provide dispiro-compound 21. Other reaction conditions,
with different phosphine ligands (Ph3As, BINAP), bases
(NEt3, Ag2CO3, proton sponge), and solvents (THF, DMF),
resulted in the formation of 21 from 20 in lower yields.
Longer reaction time or higher reaction temperature resulted
in significant decomposition of the starting compound 20.
The ethylene ketal group of 21 was removed easily when put
in contact with silical gel in methanol to give ketone 22 in
95% yield. Subsequent removal of the benzyl group in 22
with SnCl4 was accompanied by a spontaneous intramole-
cular Michael addition to afford the tetracyclic oxolycor-
aminone (23)37 in 75% yield. Simultaneous reduction of
both the ketone and amide groups of 23 with LiAlH4
afforded (G)-237,38 with excellent diastereoselectivity
(de O95%). The hydroxyl group of (G)-2 was assigned
to be cis to the oxide ring based on analysis of its 1H NMR
3. Experimental
3.1. General procedures
Melting points were taken in capillary tubes on a
MEL-TEMP II apparatus by Laboratory Devices and are
uncorrected. NMR spectra were recorded on Bruker
DPX-200 and AMX-400 FT-NMR spectrometers; chemical
shifts were recorded in parts per million downfield from
Me4Si. Mass spectra were recorded on a Jeol JMS-D300
mass spectrometer; HRMS was obtained with a Jeol-HX110
mass spectrometer. Elemental analyses were performed
with a Perkin–Elmer 2400-CHN instrument. TLC was
performed on Merck (art. 5715) silica gel plates and
visualized under UV light (254 nm), upon treatment with
iodine vapor or upon heating after treatment with 5%
Scheme 3. Reagents and conditions: (a) trimethy orthoformate, CH2Cl2, rt; (b) LDA, MOMCl, THF, K78 8C; (c) n-butyllithium, I2, K78 8C; (d) 3 N HCl, rt;
(e) benzyl bromide, K2CO3, acetone, rt; (f) KMnO4, acetone–H2O, rt; (g) SOCl2, THF, K23 8C; then 13, NEt3, THF, K23 8C to rt; (h) Pd(OAc)2, PPh3,
K2CO3, CH3CN, 130 8C; (i) silical gel, MeOH, rt; (j) SnCl4, CH2Cl2, rt; (k) LAH, THF, reflux.

11658
P.-H. Liang et al. / Tetrahedron 60 (2004) 11655–11660
phosphomolybdic acid in ethanol. Flash column chroma-
tography was performed with Merck (art. 9385) 40–63 mm
silical gel 60. Anhydrous tetrahydrofuran was distilled from
sodium-benzophenone prior to use.
(t, JZ8.6 Hz, 2H), 2.15–2.22 (m, 4H), 2.37–2.43 (t, JZ
8.6 Hz, 2H), 2.97 (s, 3H), 3.91–3.96 (m, 4H), 4.23–4.30
(m, 2H), 5.40–5.41 (m, 1H); 13C NMR (50 MHz, CDCl3) d
27.6, 30.9, 35.6, 36.4, 37.4, 64.3, 68.3, 107.6, 121.8, 132.1.
To a stirred mixture of the mesylate (1.29 g, 4.92 mmol) and
Et3N (1 mL) in THF (10 mL) was added methylamine (40%
in water, 2.55 mL). The reaction mixture was heated at
reflux overnight and the solvent was evaporated. The
residue was treated with water (15 mL) and then extracted
with a solution of IPA/CHCl3 (1:4; 3!15 mL). The
combined organic layers were dried over MgSO4, filtered,
and evaporated to afford 13 (870 mg, 90%) as a yellow oil:
1H NMR (200 MHz, CDCl3) d 1.70–1.75 (m, 3H), 2.15–
2.20 (m, 5H), 2.40 (s, 3H), 2.63 (t, JZ7.4 Hz, 2H), 3.94 (s,
4H), 5.33 (s, 1H); 13C NMR (50 MHz, CDCl3) d 27.8, 31.0,
33.5, 35.6, 41.4, 55.5, 64.3, 107.8, 119.8, 134.7; MS
(EI, 70 eV) m/z 198 (MCC1), 157 (base); HRMS calcd for
C11H19NOC2 : 197.1416, found 197.1432.
3.1.1. (2-Bromobenzyl)-[2-(1,4-dioxa-spiro[4.5]dec-7-en-
8-yl)ethyl]carbamic acid tert-butyl ester (10). A mixture
of 633 (355 mg, 1.94 mmol) and 2-bromobenzaldehyde
(390 mg, 2.13 mmol) in CH2Cl2 (30 mL) was stirred at rt
for 30 min. The mixture was evaporated and was added
MeOH (20 mL) and NaBH4 (232 mg, 5.82 mmol). The
resulting mixture was stirred at rt for 1 h. The solution was
evaporated and the residue was partitioned with EtOAc
(3!15 mL) and H2O (10 mL). The combined extract was
dried over MgSO4, filtered, and evaporated. The residue was
chromatographed (silical gel; EtOAc) to afford 8 (442 mg,
65%) as a yellow oil: 1H NMR (200 MHz, CDCl3) d 1.24–
1.78 (m, 4H), 1.92–2.02 (m, 4H), 2.67 (t, JZ6.5 Hz, 2H),
3.83 (s, 2H), 3.94 (s, 4H), 5.04 (s, 1H), 7.08 (t, JZ7.0 Hz,
1H), 7.24 (t, JZ7.0 Hz, 1H), 7.35 (d, JZ6.5 Hz, 1H), 7.50
(d, JZ7.8 Hz, 1H); 13C NMR (50 MHz, CDCl3) d 27.7,
31.5, 36.0, 37.7, 47.0, 54.1, 64.7, 108.4, 109.9, 120.4, 124.3,
127.8, 128.9, 130.7, 133.1, 135.4. To a solution of 8
(442 mg, 1.26 mmol) in MeOH (30 mL) was added (Boc)2O
(330 mg, 1.51 mmol) and NaHCO3 (260 mg, 3.05 mmol)
and stirred at rt for 2 h. The mixture was evaporated and the
residue was partitioned with EtOAc (2!20 mL) and H2O
(10 mL). The combined extract was dried over MgSO4,
filtered, and evaporated. The residue was chromatographed
(silical gel; EtOAc/n-hexane 2:3) to afford 10 (368 mg,
64%) as a yellow oil: 1H NMR (200 MHz, CDCl3) d 1.36–
1.47 (m, 9H), 1.75 (t, JZ6.4 Hz, 2H), 2.16–2.22 (m, 6H),
3.23–3.27 (m, 2H), 3.93 (s, 4H), 4.45–4.49 (m, 2H), 5.30
(s, 1H), 7.04–7.29 (m, 3H) 7.49 (d, JZ7.8 Hz, 1H); MS
(EI, 70 eV) m/z 451 (MC), 298, 168; HRMS calcd for
C22H30BrNOC4 : 451.1358, found 451.1356.
3.1.4. N-[2-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-ethyl]-2-
iodo-N-methyl-benzamide (14). To a solution of 2-iodo-
benzoic acid (1.50 g, 6.04 mmol) in THF (50 mL) was
added SOCl2 (0.7 mL, 6.64 mmol) at K78 8C and stirred for
30 min. The temperature was allowed to raise to K20 8C,
and then a solution of 13 (1.20 g, 6.56 mmol) and Et3N
(2.3 mL, 18.1 mmol) in THF (15 mL) was added. The
mixture was stirred for 6 h and the reaction temperature was
slowly raised to rt. The solvent was evaporated and the
residue was partitioned with CH2Cl2 (50 mL) and H2O
(20 mL). The organic layer was dried over MgSO4, filtered,
and evaporated. The residue was chromatographed (silica
gel; EtOAc/n-hexane 3:2) to afford 14 (1.62 g, 63%) as a
yellow oil: 1H NMR (200 MHz, CDCl3) d 1.60 (t, JZ
6.0 Hz, 1H), 1.72 (t, JZ6.0 Hz, 1H), 1.84–1.88 (m, 1H),
2.0–2.3 (m, 5H), 2.72 and 3.04 (s, 3H), 3.06–3.11 (m 1H),
3.51–3.65 (m, 1H), 3.87 and 3.90 (s, 4H), 5.16 and 5.38
(s, 1H), 6.91–7.05 (m, 1H), 7.12–7.17 (m, 1H), 7.27–7.31
(m, 1H), 7.71–7.77 (m, 1H); 13C NMR (50 MHz, CDCl3) d
27.3, (30.9, 32.4), 34.0, (35.6, 36.3), 45.3, 49.4, 64.2, (92.1,
92.6), (107.4, 107.7), (120.2, 120.8), (126.8, 127.2), (128.0,
128.2), (129.8, 129.9), (133.3, 134.4), 138.9, (142.4, 142.8),
(170. 170.6); IR (neat) cmK1 3450, 2926, 1636, 1488; MS
(EI, 70 eV) m/z 427 (MC), 166; HRMS calcd for
C18H22INOC3 : 427.0644, found 427.0621. (Since the
amide group in 14 could adopt either a cis or trans
3.1.2. [2-(1,4-Dioxa-spiro[4.5]dec-7-en-8-yl)ethyl]-(2-
iodobenzyl)carbamic acid tert-butyl ester (11). [2-(1,4-
Dioxa-spiro[4.5]dec-7-en-8-yl)ethyl]-(2-iodobenzyl)amine
(9) was synthesized using compound 6 and 2-iodobenzal-
dehyde as described above to afford 9 in 55% yield as a
yellow oil. Compound 11 was then synthesized from
compound 9 as described above to afford 11 in 53% yield
1
as a yellow oil: H NMR (200 MHz, CDCl3) d 1.36–1.49
1
configuration, some of the H and 13C signals appear as
(m, 9H), 1.90–1.94 (m, 2H), 2.10–2.16 (m, 6H), 3.20–3.21
(m, 2H), 3.93 (s, 4H), 4.35–4.44 (m, 2H), 5.30 (s, 1H), 6.91
(t, JZ7.4 Hz, 1H), 7.11 (d, JZ7.4 Hz, 1H), 7.27 (t, JZ
7.4 Hz, 1H), 7.78 (d, JZ7.5 Hz, 1H); MS (EI, 70 eV) m/z
499 (MC), 398, 216; HRMS calcd for C22H30INOC4 :
499.1220, found 499.1233.
pairs.)
3.1.5. 12-Methyl-12-aza-benzo[h]spiro[5.6]dodec-1-en-
3,11-dione (16). A solution of 14 (950 mg, 2.22 mmol),
Pd(OAc)2 (54 mg, 0.22 mmol), triphenylphosphine
(233 mg, 0.89 mmol), and K2CO3 (618 mg, 4.44 mmol) in
acetonitrile (150 mL) was heated in a sealed round bottle at
130 8C for 36 h. The mixture was cooled, filtered, and
evaporated to afford crude 14-methyl-1,4-dioxa-14-aza-
benzo[j]dispiro[4.2.6.2]hexadec-6-en-13-one (15). The
crude 15 was treated with 1 N HCl for 30 min. The resulting
mixture was evaporated and partitioned with CH2Cl2
(50 mL) and H2O (20 mL). The organic layer was dried
over MgSO4, filtered, and evaporated. The residue was
purified by chromatography (silica gel; EtOAc/n-hexane
3:2) to afford 16 (349 mg, 63%). Compound 16 was
3.1.3. [2-(1,4-Dioxa-spiro[4,5]dec-7-en-8-yl)ethyl]-meth-
ylamine (13). To a stirred solution of diol 733 (3.44 g,
17 mmol) and Et3N (12 mL) in CH2Cl2 (125 mL) was added
MsCl (2.64 mL, 34 mmol). The resulting mixture was
stirred at rt under N2 for 1 h. The solvent was evaporated
and then water (100 mL) was added to the residue. The
solution was extracted with CH2Cl2 (100 mL !2) and the
combined extract was dried over MgSO4, filtered, and
evaporated to afford methanesulfonic acid 2-(1,4-dioxa-
spiro[4,5]dec-7-en-8-yl)ethyl ester (2.37 g, 53%) as a
colorless oil: 1H NMR (200 MHz, CDCl3) d 1.71–1.77
1
recrystallized from EtOAc as colorless crystals: H NMR

P.-H. Liang et al. / Tetrahedron 60 (2004) 11655–11660
11659
(200 MHz, CDCl3) d 2.11–2.39 (m, 6H), 3.15 (s, 3H), 3.18–
3.38 (m, 1H), 3.38–3.50 (m, 1H), 6.06 (d, JZ10.6 Hz, 1H),
6.91 (dd, JZ10.4, 1.0 Hz, 1H), 7.21–7.25 (m, 1H), 7.35–
7.40 (m, 2H), 7.71–7.75 (m, 1H); 13C NMR (50 MHz,
CDCl3) d 34.3, 34.4, 38.0, 42.4, 43.7, 48.2, 126.5, 127.9,
129.0, 130.4, 130.7, 135.6, 138.9, 156.5, 170.6, 198.8; IR
(KBr) cmK1 3478, 1680, 1639; MS (EI, 70 eV) m/z 255
(MC, base). Anal. Calcd for C16H17NO2: C, 75.27; H, 6.71;
N, 5.49. Found: C, 75.21; H, 6.65; N, 5.26.
(Since the amide group in 20 could adopt either a cis or
1
trans configuration, some of the H and 13C signals appear
as pairs.)
3.1.8. 9-Benzyloxy-10-methoxy-14-methyl-1,4-dioxa-14-
aza-benzo[j]dispiro[4.2.6.2]hexadec-6-en-13-one (21).
A mixture of 20 (250 mg, 0.44 mmol), Pd(OAc)2 (9 mg,
0.04 mmol), triphenylphosphine (23 mg, 0.088 mmol), and
K2CO3 (123 mg, 0.86 mmol) in CH3CN (40 mL) was
heated in a sealed round bottle at 130 8C for 5 days. The
resulting mixture was filtered, evaporated, and partitioned
with CH2Cl2 (50 mL) and H2O (20 mL). The organic extract
was dried over MgSO4, filtered, and evaporated. The residue
was purified with prepared TLC (silica gel; EtOAc/n-
hexane/NH3(conc) 3:2:0.005) to afford compound 21 (53 mg,
28%) as an oil with recovered starting material 20 (21%)
and de-iodinated by-product (15%). Compound 21: 1H
NMR (200 MHz, CDCl3) d 1.58–1.95 (m, 4H), 2.12–2.29
(m, 2H), 2.96–3.03 (m, 1H), 3.09 (s, 3H), 3.29–3.43 (m,
1H), 3.87 (s, 3H), 3.92–4.00 (m, 4H), 4.68 (d, JZ10.3 Hz,
1H), 4.87 (d, JZ10.3 Hz, 1H), 5.32 (d, JZ10.6 Hz, 1H),
6.30 (d, JZ10.1 Hz, 1H), 6.88 (d, JZ8.4 Hz, 1H), 7.24–
7.38 (m, 3H), 7.42–7.50 (m, 3H); 13C NMR (50 MHz,
CDCl3) d 30.9, 34.2, 38.5, 43.3, 44.0, 48.1, 55.6, 64.2, 64.4,
74.0, 105.7, 110.1, 121.9, 126.3, 127.9, 128.1, 132.0, 135.3,
138.1, 141.6, 146.2, 155.3, 171.1; MS (EI, 70 eV) m/z 435
(MC), 91 (base); HRMS calcd for C26H29NOC5 : 435.2046,
found 435.2030.
3.1.6. 3-Benzyloxy-2-iodo-4-methoxybenoic acid (19).
A
solution of 2-iodo-isovanillin (18)36 (1.50 g,
5.39 mmol), benzyl bromide (2.0 mL, 7.54 mmol), and
K2CO3 (3.75 g, 27.1 mmol) in acetone (60 mL) was heated
at reflux for 2 h. The solvent was evaporated and the crude
was purified by recrystallization from EtOAc to give
3-benzyloxy-2-iodo-4-methoxy-benaldehyde (1.97 g, 99%)
as a light yellow solid. To a solution of 3-benzyloxy-2-iodo-
4-methoxy-benaldehyde (1.30 g, 3.53 mmol) in acetone
(60 mL) was added KMnO4 (19.5 g, 12.3 mmol) in water
(30 mL) and stirred for 24 h. The mixture was filtered to
remove MnO2 and the filtrate was partitioned with 1 N
NaOH (20 mL) and CH2Cl2 (100 mL). The organic layer
was collected to recover the starting material. The aqueous
layer was separated, acidified with 3 N HCl (20 mL), and
extracted with a solution of IPA/CHCl3 (1:4; 80 mL !2).
The combined organic layers were dried over MgSO4,
filtered, and evaporated to afford 19 (1.55 g, 75%) as a
yellow solid. This solid was recrystallized from CH2Cl2 to
give colorless crystals: mp 176–178 8C; 1H NMR
(400 MHz, CDCl3) d 3.92 (s, 3H), 5.0 (s, 3H), 6.93
(d, JZ8.7 Hz, 1H), 7.33–7.41 (m, 3H), 7.58–7.60
(m, 2H), 7.87 (d, JZ8.7 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 56.1, 74.2, 95.8, 111.2, 125.9, 128.1, 128.3, 128.5,
129.5, 136.8, 148.6, 156.1, 171.0; IR (neat) cmK1 1687,
1577, 1274; MS (EI, 70 eV) m/z 384 (MC), 91 (base);
HRMS calcd for C15H13IO4C: 383.9859, found 383.9847.
3.1.9. 7-Benzyloxy-8-methoxy-12-methyl-12-aza-ben-
zo[h]spiro[5.6]dodec-1-en-3,11-dione (22). To a solution
of 21 (53 mg, 0.12 mmol) in methanol (10 mL) was added
silical gel (20 mg) and stirred at rt for 1 h. The mixture was
filtered and evaporated. The residue was partitioned with
CH2Cl2 (50 mL) and H2O (20 mL). The organic layer was
dried over MgSO4, filtered, and evaporated to afford
compound 22 (45 mg, 95%) as a light yellow oil: 1H
NMR (400 MHz, CDCl3) d 1.89 (dd, JZ14.4, 1.4 Hz, 1H),
2.09 (ddd, JZ12.0, 9.6, 2.8 Hz, 1H), 2.19–2.23 (m, 1H),
2.24–2.32 (m, 2H), 2.41–2.44 (m, 1H), 3.05–3.11 (m, 1H),
3.11 (s, 3H), 3.39–3.48 (m, 1H), 3.90 (s, 3H), 4.40 (d, JZ
10.8 Hz, 1H), 4.98 (d, JZ10.8 Hz, 1H), 5.69 (d, JZ
10.0 Hz, 1H), 6.94 (d, JZ10.0 Hz, 1H), 7.23 (d, JZ8.4 Hz,
1H), 7.25–7.34 (m, 5H), 7.50 (d, JZ8.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 34.3, 34.7, 39.7, 42.2, 44.0, 48.0, 55.7,
74.1, 110.9, 123.4, 126.8, 127.7, 127.9, 128.5, 129.2, 133.4,
136.8, 145.5, 155.0, 158.5, 170.5, 200.0; IR (neat) cmK1
3428, 2938, 1672, 1635; MS (EI, 70 eV) m/z 391 (MC), 91
(base); HRMS calcd for C24H25NOC4 : 391.1784, found
391.1773.
3.1.7. 3-Benzyloxy-N-[2-(1,4-dioxa-spiro[4.5]dec-7-en-8-
yl)-ethyl]-2-iodo-4-methoxy-N-methyl-benzamide (20).
A mixture of 19 (355 mg, 0.93 mmol), SOCl2 (0.11 mL,
1.02 mmol), and DMF (three drops) in THF (30 mL) was
stirred at K78 8C for 30 min. The reaction temperature was
raised to K40 8C and then a solution of 13 (240 mg,
1.21 mmol) and Et3N (0.36 mL, 2.77 mmol) in THF
(10 mL) was added. The resulting mixture was stirred and
the temperature was slowly raised to rt. The solution
was evaporated and the residue was partitioned with EtOAc
(3!15 mL) and H2O (10 mL). The combined extract was
dried over MgSO4, filtered, and evaporated to afford 20
(382 mg, 73%) as a yellow oil: 1H NMR (400 MHz, CDCl3)
d 1.60–1.68 (m, 1H), 1.73–1.77 (m, 1H), 1.80–1.93 (m, 1H),
2.16–2.34 (m, 5H), 2.72 and 3.05 (s, 3H), 3.12–3.20 (m,
1H), 3.60–3.62 (m, 1H), 3.83 (s, 3H), 3.90–3.93 (m, 4H),
4.91–4.97 (m, 2H), 5.19 and 5.40 (s, 1H), 6.90–6.92
(m, 2H), 7.30–7.35 (m, 3H), 7.49–7.55 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 27.4, 31.0, (32.6, 32.4), (35.5, 36.5),
45.6, 49.7, 64.3, 74.4, (92.1, 92.5), (107.6, 107.9), (112.7,
112.9), (120.2, 120.8), (122.8, 123.2), (128.1, 128.3),
(128.5, 128.6), 131.9, (132.1, 132.6), (135.9, 136.3),
136.9, 147.8, 152.4, (170.2, 170.6); IR (neat) cmK1 2927,
1633, 1261; MS (EI, 70 eV) m/z 563 (MC), 367 (base);
HRMS calcd for C26H30INO5C: 563.1169, found 563.1143.
3.1.10. Oxylycoramone (23).37 To s solution of compound
22 (29 mg, 0.074 mmol) was added SnCl4 (72 mg,
0.27 mmol) in CH2Cl2 (5 mL). After 30 min, the mixture
was evaporated and partitioned with CH2Cl2 (20 mL) and
NH3(conc) (10 mL). The organic layer was dried over
MgSO4, filtered, and evaporated to afford compound 23
1
(16.7 mg, 75%) as a light yellow oil: H NMR (400 MHz,
CDCl3) d 1.80–1.88 (m, 1H), 1.92–1.99 (m, 1H), 2.01–2.08
(m, 2H), 2.17–2.22 (m, 1H), 2.45 (td, JZ7.0, 2.2 Hz, 1H),
2.76 (dd, JZ8.6, 1.4 Hz, 1H), 2.99 (dd, JZ8.6, 1.4 Hz, 1H),
3.13 (s, 3H), 3.15–3.20 (m, 1H), 3.67–3.78 (m, 1H), 3.88
(s, 3H), 4.91 (s, 1H), 6.87 (d, JZ8.4 Hz, 1H), 7.39 (d, JZ

11660
P.-H. Liang et al. / Tetrahedron 60 (2004) 11655–11660
8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 34.8, 35.8,
36.7, 40.7, 43.0, 48.0, 49.5, 56.0, 91.0, 112.3, 123.8, 123.9,
130.7, 146.1, 146.6, 168.9, 207.8; IR (neat) cmK1 2928,
1719, 1636; MS (EI, 70 eV) m/z 301 (MC, base); HRMS
calcd for C17H19NOC4 : 301.1314, found 301.1301.
12. Vlahov, R.; Krikorian, D.; Spassov, G.; Chinoua, M.;
Ulahov, F.; Parushev, S.; Snatzke, G.; Ernst, L.; Klieslich,
K.; Abraham, W.-R.; Sheldrick, W. S. Tetrahedron 1989, 45,
3329–3345.
13. Szewczyk, J.; Wilson, J. W.; Lewin, A. H.; Carroll, F. I.
J. Heterocycl. Chem. 1995, 32, 195–199.
3.1.11. Lycoramine (2).37,38 To a solution of 23 (20 mg,
0.066 mmol) in THF (15 mL) was added LAH (5 mg,
0.13 mmol) and heated at reflux for 24 h. The mixture was
evaporated and the residue was chromatographed (silica gel;
CH2Cl2/MeOH 8:1) to afford 2 (10 mg, 53%) as a light
yellow oil: 1H NMR (400 MHz, CDCl3) d 1.51–1.56
(m, 1H), 1.63–1.71 (m, 1H), 1.73–1.80 (m, 2H), 1.83–1.89
(m, 1H), 1.91–1.98 (m, 1H), 2.36 (s, 3H), 2.34–2.49
(m, 2H), 3.04 (d, JZ14.4 Hz, 1H), 3.21 (t, JZ12.8 Hz,
1H), 3.62 (d, JZ14.8 Hz, 1H), 3.81 (s, 3H), 4.01 (d, JZ
14.8 Hz, 1H), 3.99–4.05 (m, 1H), 4.34 (s, 1H), 6.57 (d, JZ
8.4 Hz, 1H), 6.63 (d, JZ8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 23.8, 27.7, 31.0, 31.6, 41.5, 46.7, 54.0, 55.9, 60.3,
65.4, 90.0, 110.8, 122.0, 128.1, 136.2, 144.3, 146.0; IR
(neat) cmK1 3365, 2932, 1506; MS (EI, 70 eV) m/z 289
(MC, base); HRMS calcd for C17H23NOC3 : 289.1678, found
289.1678.
14. Chaplin, D. A.; Fraser, N.; Tiffin, P. D. Tetrahedron Lett. 1997,
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This research was supported by the National Science
Council of the ROC under grant no. NSC 91-2320-B-002-
205 and NSC 89-2113-M002-019.
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