Toward general access to the Aspidosperma-type terpenoid indole alkaloids: Synthesis of the key 3,3-disubstituted piperidones through enantioselective intramolecular Heck-type reaction of chloroformamides

Article abstract of DOI:10.1248/cpb.56.1567

An enantioselective intramolecular Heck-type reaction of chloroformamides has been developed for the synthesis of 3,3-disubstituted piperidones. The desired piperidone was formed in the presence of a palladium catalyst, an optically active phosphoramidite ligand, K₃PO₄ and Ag ₃PO₄. The obtained piperidone was converted to epieburnamonine.

Full text of DOI:10.1248/cpb.56.1567

November 2008
Chem. Pharm. Bull. 56(11) 1567—1574 (2008)
1567
Toward General Access to the Aspidosperma-Type Terpenoid Indole
Alkaloids: Synthesis of the Key 3,3-Disubstituted Piperidones through
Enantioselective Intramolecular Heck-Type Reaction of
Chloroformamides
Yoshizumi YASUI, Hiroshi TAKEDA, and Yoshiji TAKEMOTO*
Graduate School of Pharmaceutical Sciences, Kyoto University; Yoshida, Sakyo-ku, Kyoto 606–8501, Japan.
Received July 4, 2008; accepted August 21, 2008
An enantioselective intramolecular Heck-type reaction of chloroformamides has been developed for the syn-
thesis of 3,3-disubstituted piperidones. The desired piperidone was formed in the presence of a palladium cata-
lyst, an optically active phosphoramidite ligand, K3PO4 and Ag3PO4. The obtained piperidone was converted to
epieburnamonine.
Key words enantioselective reaction; total synthesis; terpenoid indole alkaloid
The terpenoid indole alkaloids are a class of natural prod- strates: usually, the reaction needs to start from aryl or vinyl
ucts that are biosynthetically derived from tryptamine and a halides. In context of our recent studies on transition-metal-
monoterpene unit.1) Classification has been made by the fea- catalyzed reactions of carbamoyl derivatives,15—18) we
ture of the terpenoid origin part.2) A group of compounds planned to develop an enantioselective Heck-type reaction of
with a quaternary carbon in the terpenoid region forms a carbamoyl chlorides (Fig. 2b). By this reaction, a lactam ring
large subclass that are called aspidosperma-type alkaloids with a quaternary carbon was expected to be obtained.
(Fig. 1). Motivated by their bioactivities and attractive poly- Though racemic Heck-type reaction of carbamoyl chlorides
cyclic structures, enormous synthetic studies on this class of was reported briefly in 1986,19) further study does not exist.
compounds have been carried out.3—9) Since the bond for-
We set up our goal to synthesize formyl piperidone 1 that
mation between the indole and the terpenoid moiety had could be a useful intermediate for the synthesis of the aspi-
been well resolved, much effort has been made to enhance dosperma-type terpenoid indole alkaloids (Fig. 3). Chloro-
the stereoselective construction of the quaternary carbon. formamide 2 possessing an allyl ether moiety was designed
Among these studies, strategies based on chiral auxiliary are as a substrate for the key Heck-type cyclization. Compound
dominant, and catalytic enantioselective method remains as a 2 can be synthesized from Boc-protected tryptamine 3 and
challenging task.10—13)
alkenyl acetal 4.
Enantioselective Heck reaction has been well recognized
At the initial stage of this project, the key Heck-type reac-
as a powerful method to construct quaternary carbon centers tion was tested with simple chloroformamide 8 (Fig. 4).
(Fig. 2a).14) Scope of this reaction is a limitation on the sub- Compound 8 was obtained from known allyl alcohol 520)
through Johnson–Claisen rearrangement, reduction of the re-
sultant ester to alcohol, oxidation with IBX,21) reductive ami-
nation, and chlorocarbonylation with triphosgene. Chloro-
formamide 8 was found to be stable for aqueous extraction,
silica gel column chromatography and storage in refrigerator
for several weeks, as expected.
Heck reaction of chloroformamide 8 was performed with
Pd(PPh3)4 (10 mol%) and a base in xylene at 130 °C (Table
1). In contrast to the previously reported 5-exo cyclization,19)
the desired 6-membered lactam 9 was formed in poor yield
Fig. 1. Examples of the Aspidosperma-Type Terpenoid Indole Alkaloids
Fig. 2. Comparison of Heck Reaction and Heck-Type Reaction of Chloro-
Fig. 3. Synthetic Plan
formamides
∗ To whom correspondence should be addressed. e-mail: takemoto@pharm.kyoto-u.ac.jp
© 2008 Pharmaceutical Society of Japan

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Vol. 56, No. 11
Fig. 4. Synthesis of Chloroformamide 8
Fig. 5. Synthesis of Alkene (E)-4
Table 1. Heck-Type Reaction of Chloroformamide 8
Base
(eq)
Ag3PO4
(eq)
Yield
(%)a)
Entry
1
2
3
Bu3N (1.5)
—
—
—
0.5
0.5
0.5
7 (61)
16 (49)
10 (64)
60
59
—
K3PO4 (1.2)
Collidine (2.6)
K3PO4 (1.5)
K3PO4 (2.0)
Collidine (1.7)
4
5b)
6c)
Fig. 6. Synthesis of Alkene (Z)-4
a) The yield in parentheses shows the recovered yield of compound 8. b) In-
stead of Pd(PPh3)4, Pd2(dba)3 (5 mol%) and (S)-BINAP (15 mol%) were used. c) In-
stead of Pd(PPh3)4, Pd(OAc)2 (10 mol%) and 1,3-bis(2,6-diisopropylphenyl)imida-
zolium chloride (10 mol%) were used.
under normal conditions (entries 1—3). However, lactam 9
was isolated in 60% yield when Ag3PO4 was added to the re-
action (entry 4). The combination of Pd2(dba)3 and BINAP
was also able to promote the cyclization in the presence of
Ag3PO4 (entry 5). Nolan’s NHC catalyst was not effective
(entry 6).
With these results in hand, syntheses of each cis–trans iso-
mer of alkenyl chloroformamide 2 were performed. Alkene
(E)-4 was synthesized through hydroalumination as a key
step (Fig. 5). 4-Pentyn-1-ol (10) was transformed into alco-
hol 11 through oxidation, acetalization, and hydroxymethyla-
Fig. 7. Synthesis of Chloroformamides
tion using benzotriazolylmethanol (BtCH2OH).22) Alcohol 11 pounds were converted to the corresponding chloroform-
was then subjected to the hydroalumination–iodination se- amides (E)-2 and (Z)-2 by treating with triphosgene and
quence23,24) to give (Z)-iodo alkene 12, whose configuration Et3N.
was confirmed by NOE experiment. Ethylation by Suzuki
coupling, followed by benzylation gave the desired alkene reaction was attempted to find out a suitable palladium
(E)-4. source (Table 2). The cyclized product 1 was isolated after
Before the enantioselective Heck-type reaction, a racemic
Change of the starting material afforded the alternative hydrolysis of the resultant enol ether. At the early stage, poor
stereoisomer (Fig. 6). (Z)-Iodoalkene 14 was synthesized reproducibility was a serious problem. After several attempts,
from 2-pentyn-1-ol (13) through hydroalumination and iodi- it was found that the activity of the catalyst is highly associ-
nation. Since benzylation of the hydroxy group under either ated with the conditions used to mix palladium sources and
basic or acidic conditions competed with decomposition of ligands prior to the addition of chloroformamide 2. When
the starting material, protection by THP group was carried [Pd(h3-C3H5)Cl]2 was premixed with (p-tol)3P at 30 °C for
out. The resultant THP ether 15 underwent Negishi coupling 30 min, the disappearance of 2 was slow and the yield was
with 3,3-(dimethoxy)propylzinc chloride 16.25) Selective hy- 30% after 24 h (entry 1). In contrast, the starting material dis-
drolysis of the THP ether and benzylation afforded the de- appeared in 3 h and yield reached 49% when premixing was
sired alkene (Z)-4.
performed at 40 °C for 30 min (entry 2). Longer time and
Alkenyl acetals (E)-4 and (Z)-4 were coupled with trypta- higher temperature gave less-active catalyst (entry 3).
mine 326) through hydrolysis and reductive amination to give [Pd(h3-C3H5)Cl]2 was found to be a better source than
amines (E)-17 and (Z)-17, respectively (Fig. 7). These com- Pd2(dba)3·CHCl3 or PdCl2(MeCN)2 (entries 4, 5).

November 2008
1569
Table 2. The Effects of Premixing Conditions of Palladium Sources and (p-tol)3P
Entry
“Pd”
Time A (h)
Temp. (°C)
Time B (h)
Yield (%)
b)
1a)
2a)
3a)
4
[Pd(h3-C3H5)Cl]2b)
[Pd(h3-C3H5)Cl]2b)
[Pd(h3-C3H5)Cl]2
0.5
0.5
1
0.5
0.5
30
40
80
40
40
24
3
24
4
30
49
29
31
8
b)
Pd2(dba)3·CHCl3
c)
5
PdCl2(MeCN)2
24
a) t-BuOK (0.11—0.15 mol%) was added. b) 5 mol%. c) 10 mol%.
Table 3. Enantioselective Heck-Type Reaction of Chloroformamide 2a)
Entry
Configuration of 2
Ligand (mol%)
Time (h)
Yield (%)
Dominant enantiomer of 1
ee (%)
1
2
3
4
5
6
7
8
9
E
E
E
E
E
E
E
Z
E
Z
E
E
L1 (20)
L2 (20)
L3 (20)
L4 (20)
L5 (40)
L6 (40)
L7 (40)
L7 (40)
L8 (40)
L8 (40)
L9 (40)
L10 (40)
24
9
22
6
3
3
11
24
4
23
11
5
16
32
35
50
51
31
52
16
43
24
30
30
R
R
S
3
8
5
18
0
5
43
43
21
64
47
52
S
—
R
R
S
S
10
11
12
R
R
R
a) [Pd(h3-C3H5)Cl]2, ligand, t-BuOK, Ag3PO4 and K3PO4 were premixed at 40 °C for 30 min prior to the addition of chloroformamide 2.
The enantioselective Heck-type reaction of chloroform- performed with phosphoramidite L732) that was synthesized
amide 2 was performed by combining [Pd(h3-C3H5)Cl]2 with from (R)-BINOL and bis[(R)-1-phenylethyl]amine, piperi-
optically active phosphorous ligands in the presence of done (R)-1 was isolated in 52% and the selectivity reached to
Ag3PO4 and K3PO4 (Table 3). Initial attempts to react (E)-2 43% ee (entry 7). By changing the starting material to (Z)-2,
by using bisphosphine ligands (L1—L4)27—29) gave poor se- the opposite enantiomer, (S)-1, was obtained dominantly
lectivity, though these ligands have been shown to be effec- (entry 8). The corresponding diastereomeric ligand, L8, gave
tive for normal enantioselective Heck reactions (entries 1— (S)-1 in 21% ee from (E)-2, and (R)-1 in 64% ee from (Z)-2
4).14) Representative optically active monophosphines, (R)- (entries 9, 10). Though Z-isomer of chloroformamide 2
MeO-MOP (L5)30) and (ꢀ)-NMDPP (L6),31) did not improve showed better selectivities in some cases, the reactions took
the selectivity (entries 5, 6). However, when the reaction was longer period and the yields were lower than those of the E-

1570
Vol. 56, No. 11
Fig. 8. Proposed Reaction Mechanism
isomer. Further screening of phosphoramidites33,34) did not
give dramatic improvements (entries 11, 12).
A reaction mechanism similar to that of the normal Heck
reaction with halogen scavengers is proposed (Fig. 8). Oxida-
tive addition followed by chloride abstraction generates
cationic intermediate B. The side reactions are likely to occur
by direct reaction of the silver salt with the starting chloro-
formamide 2, which generates highly reactive intermediates
such as E. Achieving the selective chloride abstraction from
the complex A or avoiding the use of halogen scavengers will
be a key for further improvements.
The utility of piperidone 1 as an intermediate for the ter-
penoid indole alkaloid synthesis was briefly demonstrated by
converting 1 to epieburnamonine (Fig. 9). Oxidation and
methylation followed by removal of the Boc group under mi-
crowave irradiation afforded methyl ester 19, from which
syntheses of eburnamonine, eburnamine and vincamine have
been reported.35—37) Methyl ester 19 was converted to epi-
eburnamonine (20) through Bischler–Napieralski reaction
and reduction with NaBH4. It is known that reduction of the
related compounds with NaBH4 gives a mixture in which the
trans isomer is in excess of the cis isomer.38—41) In our sys-
tem, trans isomer 20 was obtained as a sole product. Com-
parison of the optical rotation with that reported42) showed
that the product was (ꢁ)-epieburnamonine (20).
In conclusion, an enantioselective Heck-type reaction of
chloroformamides has been developed for the construction of
3,3-disubstituted piperidones, and applied toward the synthe-
sis of monoterpene indole alkaloids. The addition of silver
salts was essential for the 6-exo cyclization. Phosphoramidite
L7 that was synthesized from (R)-BINOL and bis[(R)-1-
phenylethyl]amine showed the best yield and selectivity. Fur-
ther improvements of the current Heck-type reaction will
lead to convenient and efficient access to a variety of com-
pounds containing quaternary carbons.
Fig. 9. Conversion of 1 to Epieburnamonine
cially available reagents and solvents were used as received without further
purification.
Analytical thin-layer chromatography was performed with Merck silica
gel 60 F254 and Merck 25 DC-Alufolein (alumina). Flash silica gel column
chromatography was performed with Kanto silica gel 60 (particle size
0.063—0.210 mm). Flash alumina column chromatography was performed
with deactivated (5% water) Merck aluminum oxide 90 (particle size
0.063—0.200 mm). Proton nuclear magnetic resonance (1H-NMR) spectra
were recorded on a JEOL JNM-LA500 at 500 MHz or JEOL JNM-AL400 at
400 MHz, and chemical shifts were reported relative to Me4Si (d 0.00). Car-
bon nuclear magnetic resonance (13C-NMR) spectra were recorded on a
JNM-ECA500 at 125 MHz or JNM-AL400 at 100 MHz, and chemical shifts
were reported relative to CDCl3 (d 77.2). Infrared spectra were recorded on
a JASCO FT/IR-410. Optical rotations were recorded on a JASCO DIP-360
polarimeter. Enantiomeric excess (ee) was determined by HPLC analysis on
a SHIMADZU SCL-10A. All microwave irradiation experiments were car-
ried out in a CEM Discover microwave apparatus.
(E)-4-Ethylhex-4-en-1-ol (6) A mixture of 3-ethylbut-3-en-2-ol (5)
(3.92 g, 39.2 mmol), MeC(OEt)3 (25.0 ml, 137 mmol) and propionic acid
(0.30 ml, 4.03 mmol) in a sealed tube was stirred at 150 °C for 3 d, and the
solution was poured into a mixture of MeOH (30 ml) and aqueous 1 M HCl
(30 ml).The resulting mixture was stirred for 2 h at room temperature. After
adding brine, the mixture was extracted with EtOAc. The combined extracts
were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4,
Experimental
All reactions were performed under argon. Pd(PPh3)4 was prepared by
using the reported protocol.43) K3PO4 was dried by heating under vacuum.
Bu3N, diisopropylamine and xylene were distilled from CaH2. Phosphor-
amidites were synthesized according to the literatures.32—34) Other commer-

November 2008
1571
and concentrated in vacuo. The resulting residue was dissolved in THF removed by filtration. To the filtrate, MeOH (60 ml) and p-TsOH·H2O
(135 ml), and LiAlH4 (80% purity, 2.42 g, 63.7 mmol) was added portion
wise at 0 °C. After stirring for 15 min at 0 °C, the mixture was diluted with
(557 mg, 2.93 mmol) were added, and resultant solution was stirred for 3 h at
40 °C. After adding aqueous NaHCO3, the mixture was extracted with Et2O.
Et2O. Potassium sodium tartrate tetrahydrate was added, and the mixture was The combined extracts were washed with saturated aqueous NaHCO3 and
stirred for 3 h at room temperature. Insoluble materials were removed by brine, dried over Na2SO4, and resulting solution was filtered through silica
filtration, and the filtrate was concentrated in vacuo. Purification by silica gel pad. Et2O was removed by distillation to afford a solution of dimethyl
gel column chromatography (hexane/Et2Oꢂ1/0→6/4) afforded alcohol 6 acetal in THF. This solution was added to a solution of LDA at ꢁ78 °C,
(3.33 g, 66%) as a colorless oil. Rf 0.59 (silica gel, hexane/EtOAcꢂ8/2). 1H-
NMR (CDCl3, 500 MHz) d: 5.22 (1H, q, Jꢂ6.8 Hz), 3.64 (2H, q, Jꢂ6.4 Hz),
2.08—2.03 (4H, m), 1.66 (2H, tt, J1ꢂJ2ꢂ6.4 Hz), 1.59 (3H, d, Jꢂ6.8 Hz),
1.30—1.27 (1H, m), 0.97 (3H, t, Jꢂ7.3 Hz). 13C-NMR (CDCl3, 100 MHz)
which was generated from diisopropylamine (41.1 ml, 294 mmol) and n-
butyl lithium (1.63 M in hexane, 185 ml, 301 mmol) in anhydrous THF
(16 ml). After stirring for 15 min at ꢁ78 °C, 1H-benzotriazole-methanol
(18.6 g, 125 mmol) in anhydrous THF (500 ml) was added dropwise over
d: 141.5, 118.4, 62.9, 32.9, 31.1, 22.7, 13.0, 12.8. IR (NaCl) cmꢁ1: 3332, 45 min. After stirring for 4 h at room temperature, aqueous NaOH was added
2964, 2935, 2872, 1456. LR-MS (EI) m/zꢂ128 (Mꢀ). Anal. Calcd for at 0 °C and the mixture was extracted with EtOAc. The combined extracts
C8H16O: C, 74.94; H, 12.58. Found: C, 74.98; H, 12.84.
were washed with aqueous 1 M HCl, saturated aqueous NaHCO3 and brine,
(E)-N-Benzyl-4-ethylhex-4-en-1-amine (7) A suspension of alcohol 6 dried over Na2SO4, and concentrated in vacuo. Purification by silica gel col-
(713 mg, 5.57 mmol) and IBX (2.35 g, 8.39 mmol) in THF (20 ml) was re-
fluxed for 2.5 h. The reaction mixture was diluted with Et2O, filtered through
umn chromatography (hexane/EtOAcꢂ6/4) afforded alcohol 11 (4.61 g,
40%) as a yellow oil. Rf 0.24 (silica gel, hexane/EtOAcꢂ6/4). 1H-NMR
alumina pad, and concentrated in vacuo. The residue was dissolved in THF (CDCl3, 400 MHz) d: 4.48 (1H, t, Jꢂ5.8 Hz), 4.25 (2H, dt, J1ꢂ2.2 Hz,
(19.3 ml), and benzylamine (0.65 ml, 5.96 mmol) and MS4A (3.39 g) were J2ꢂ6.1 Hz), 3.34 (6H, s), 2.29 (2H, tt, J1ꢂ2.2 Hz, J2ꢂ7.3 Hz), 1.81 (2H, dt,
added. After stirring for 2.5 h at room temperature, insoluble materials were J1ꢂ5.8 Hz, J2ꢂ7.3 Hz). 13C-NMR (CDCl3, 125 MHz) d: 103.3, 84.7, 79.0,
removed by filtration. To the filtrate was added a solution of NaBH4 (95%
purity, 264 mg, 6.60 mmol) in MeOH (22 ml) at 0 °C. After stirring for 1 h at
53.0, 50.9, 31.4, 14.2. IR (NaCl) cmꢁ1: 3426, 2940, 2225. LR-MS (FAB)
m/zꢂ157 (Mꢀꢁ1). Anal. Calcd for C8H14O3: C, 60.74; H, 8.92. Found: C,
room temperature, water was added, and the mixture was extracted with 60.51; H, 8.64.
CH2Cl2. The combined extracts were washed with water and brine, dried
(Z)-3-Iodo-6,6-dimethoxyhex-2-en-1-ol (12) To a solution of Red-Al
over Na2SO4, and concentrated in vacuo. Purification by silica gel column
(3.05 M in toluene, 28.9 ml, 88.1 mmol) in anhydrous Et2O (30 ml) was
chromatography (hexane/EtOAc/EtOHꢂ1/0/0→0/5/5) afforded amine
7
added alcohol 11 (5.57 g, 35.3 mmol) in Et2O (75 ml) at 0 °C. After stirring
(1.02 g, 84%) as a light yellow oil. Rf 0.35 (alumina, CH2Cl2/MeOHꢂ9/1). for 4.5 h at 30 °C, EtOAc (8.6 ml, 88.2 mmol) and a solution of iodine
1H-NMR (CDCl3, 500 MHz) d: 7.34—7.30 (4H, m), 7.27—7.22 (1H, m), (10.7 g, 42.2 mmol) in THF (90 ml) were added successively at 0 °C. Reac-
5.17 (1H, q, Jꢂ6.7 Hz), 3.78 (2H, s), 2.62 (2H, t, Jꢂ7.1 Hz), 2.05—2.00 tion mixture was stirred for 2 h at room temperature, and was added satu-
(4H, m), 1.60 (2H, tt, J1ꢂJ2ꢂ7.1 Hz), 1.57 (3H, d, Jꢂ6.7 Hz), 0.95 (3H, t,
rated aqueous potassium sodium tartrate tetrahydrate and 10% aqueous
Jꢂ7.6 Hz). 13C-NMR (CDCl3, 100 MHz) d: 141.7, 140.8, 128.6 128.3, sodium thiosulfate at 0 °C. The mixture was extracted with EtOAc, and the
127.1, 118.2, 54.2, 49.4, 34.4, 28.6, 22.7, 13.1, 12.9. IR (NaCl) cmꢁ1: 2963, combined extracts were washed with 10% aqueous sodium thiosulfate and
2931, 1454. LR-MS (EI) m/zꢂ217 (Mꢀ). Anal. Calcd for C15H23N: C,
82.89; H, 10.67; N, 6.44. Found: C, 82.82; H, 10.88; N, 6.31.
brine, dried over Na2SO4, and concentrated in vacuo. Purification by silica
gel column chromatography (hexane/EtOAcꢂ6/4→4/6) afforded iodide 12
1
(E)-N-Benzyl-N-(4-ethylhex-4-enyl)chloroformamide (8) To a solu-
tion of amine 7 (597 mg, 2.75 mmol) and Et3N (0.55 ml, 4.2 mmol) in THF
(6.0 ml) was added a solution of triphosgene (317 mg, 1.07 mmol) in THF
(8.21 g, 81%) as a yellow oil. Rf 0.28 (silica gel, hexane/EtOAcꢂ6/4). H-
NMR (CDCl3, 400 MHz) d: 5.89 (1H, tt, J1ꢂ1.2 Hz, J2ꢂ5.9 Hz), 4.37 (1H,
t, Jꢂ5.8 Hz), 4.19 (2H, t, Jꢂ5.9 Hz), 3.33 (6H, s), 2.57 (2H, dt, J1ꢂ1.2 Hz,
(4.0 ml) at ꢁ78 °C. The reaction mixture was warmed to room temperature, J2ꢂ7.7 Hz), 1.87—1.82 (2H, m). 13C-NMR (CDCl3, 125 MHz) d: 134.6,
followed by stirring for 2.5 h at 60 °C. EtOAc, water, and aqueous 1 M HCl
108.1, 103.0, 67.1, 52.9, 40.3, 32.1. IR (NaCl) cmꢁ1: 3406, 2934, 1127,
were added successively at 0 °C. The layers were separated, and the aqueous 1055. LR-MS (FAB) m/zꢂ285 (Mꢀꢁ1). Anal. Calcd for C8H15IO3: C,
phase was extracted with EtOAc. The combined extracts were washed with 33.58; H, 5.28. Found: C, 33.72; H, 5.13.
aqueous 1 M HCl, water, saturated aqueous NaHCO3, and brine, dried over
Na2SO4, and concentrated in vacuo. Purification by silica gel column chro-
matography (hexane/Et2Oꢂ1/0→9/1) afforded chloroformamide 8 (565 mg,
74%) as a light yellow oil. Rf 0.40 (silica gel, hexane/Et2Oꢂ9/1). 1H-NMR*
(E)-1-Benzyloxy-3-ethyl-6,6-dimethoxyhex-2-ene (4) A mixture of io-
dide 12 (3.59 g, 12.6 mmol), triethylborane (1.0 M in hexane, 15.0 ml,
15.0 mmol), PdCl2(dppf)·CH2Cl2 (317 mg, 0.388 mmol) and NaOH (1.13 g,
28.3 mmol) in THF (27 ml) and water (5.5 ml) was stirred for 2 h at 30 °C.
(CDCl3, 500 MHz) d: 7.40—7.30 (3H, m), 7.27—7.25 (2H, m), 5.14 (1H, After adding aqueous H2O2 at 0 °C, the mixture was extracted with EtOAc.
m), 4.71 (2H, s), 4.57 (s), 3.32 (2H, m), 2.03—1.94 (4H, m), 1.72—1.64 The combined extracts were washed with water and brine, dried over
(2H, m), 1.56 (3H, m), 0.95—0.91 (3H, m). 13C-NMR* (CDCl3, 100 MHz)
Na2SO4, and concentrated in vacuo. Filtration through silica gel pad
d: 150.4, 149.5, 140.4, 140.2, 136.1, 135.9, 129.1, 129.0, 128.8, 128.30, (hexane/EtOAcꢂ5/5) and concentration in vacuo afforded crude olefin. This
128.25, 128.19, 127.3, 119.1, 118.9, 54.5, 52.5, 50.3, 49.5, 33.6, 33.5, 26.2, crude material was dissolved with DMF (40 ml) and water (1.0 ml), and
25.4, 22.6, 13.0, 12.8. IR (NaCl) cmꢁ1: 2964, 2933, 2872, 1735. LR-MS sodium hydride (55% purity, 1.64 g, 37.6 mmol) was added portion wise at
(EI) m/zꢂ279 (Mꢀ). Anal. Calcd for C16H22ClNO: C, 68.68; H, 7.93; N, 0 °C. After stirring for 10 min, benzyl bromide (97% purity, 1.85 ml,
5.01. Found: C, 68.88; H, 7.84; N, 5.00 (* ca. 1 : 1 mixture of rotamers).
1-Benzyl-3-ethyl-3-vinylpiperidin-2-one (9) A suspension of chloro-
formamide 8 (58.7 mg, 0.210 mmol), K3PO4 (106 mg, 0.490 mmol), Ag3PO4
(45.5 mg, 0.107 mmol) and Pd(PPh3)4 (24.3 mg, 0.0210 mmol) in xylene
(3.0 ml) were stirred for 2 h at 130 °C. After cooling to 0 °C, aqueous 1 M
15.1 mmol) was added and the suspension was stirred for 1 h at 30 °C. Water
was added at 0 °C, and the mixture was extracted with Et2O. The combined
extracts were washed with water and brine, dried over Na2SO4, and con-
centrated in vacuo. Purification by silica gel column chromatography
(hexane/EtOAcꢂ1/0→9/1) afforded benzyl ether (E)-4 (2.57 g, 74%) as a
HCl were added, and the mixture was extracted with EtOAc. The combined colorless oil. Rf 0.49 (silica gel, hexane/EtOAcꢂ8/2). 1H-NMR (CDCl3,
extracts were washed with aqueous 1 M HCl, water, saturated aqueous
400 MHz) d: 7.35—7.25 (5H, m), 5.38 (1H, t, Jꢂ6.7 Hz), 4.50 (2H, s), 4.37
NaHCO3, and brine, dried over Na2SO4, and concentrated in vacuo. Purifica- (1H, t, Jꢂ5.7 Hz), 4.04 (2H, d, Jꢂ6.7 Hz), 3.32 (6H, s), 2.12—2.03 (4H, m),
tion by silica gel column chromatography (hexane/Et2Oꢂ1/0→8/2) afforded 1.76—1.70 (2H, m), 0.97 (3H, t, Jꢂ7.7 Hz). 13C-NMR (CDCl3, 125 MHz)
piperidone
9
(30.6 mg, 60%) as
a
yellow oil. Rf 0.38 (silica gel,
d: 145.3, 138.6, 128.3, 127.7, 127.5, 120.7, 104.2, 72.1, 66.3, 52.6, 31.2,
hexane/EtOAcꢂ8/2). 1H-NMR (CDCl3, 400 MHz) d: 7.31 (2H, dd, 30.9, 23.8, 13.4. IR (NaCl) cmꢁ1: 2933, 1454, 1365, 1126, 1067. LR-MS
J1ꢂJ2ꢂ7.0 Hz), 7.27—7.23 (3H, m), 5.94 (1H, dd, J1ꢂ10.7 Hz, J2ꢂ (FAB) m/zꢂ277 (Mꢀꢁ1). Anal. Calcd for C17H26O3: C, 73.34; H, 9.41.
17.5 Hz), 5.16 (1H, d, Jꢂ10.7 Hz), 5.08 (1H, d, Jꢂ17.5 Hz), 4.62 (1H, d, Found: C, 73.44; H, 9.38.
J1ꢂ14.7 Hz), 4.57 (1H, d, J1ꢂ14.7 Hz), 3.24—3.13 (2H, m), 1.94—1.63
(Z)-3-Iodopent-2-en-1-ol (14) To a solution of Red-Al (3.05 M in
(6H, m), 0.86 (3H, t, Jꢂ7.4 Hz). 13C-NMR (CDCl3, 100 MHz) d: 173.2, toluene, 19.9 ml, 60.7 mmol) in anhydrous Et2O (20 ml) at 0 °C, was added a
142.8, 137.9, 128.8, 128.3, 127.5, 114.2, 50.6, 49.4, 47.8, 31.8, 28.8, 19.3,
solution of 2-pentyn-1-ol (13) (2.04 g, 24.3 mmol) in Et2O (30 ml). After
stirring for 2.5 h at 30 °C, EtOAc (6.0 ml, 61.5 mmol) and a solution of io-
8.6. IR (NaCl) cmꢁ1: 2966, 2939, 2874, 2240, 1628. LR-MS (EI) m/zꢂ243
(Mꢀ). Anal. Calcd for C16H21NO: C, 78.97; H, 8.70; N, 5.76. Found: C, dine (7.44 g, 29.3 mmol) in THF (60 ml) was added at 0 °C. The reaction
78.81; H, 8.92; N, 5.49.
6,6-Dimethoxyhex-2-yn-1-ol (11) A mixture of 4-pentyn-1-ol (10) rated aqueous potassium sodium tartrate tetrahydrate and 10% aqueous
(7.00 ml, 73.5 mmol), DMSO (1.04 ml) and IBX (31.3 g, 112 mmol) in THF sodium thiosulfate were added successively. The mixture was extracted with
(75 ml) was refluxed for 22 h. After adding Et2O, insoluble materials were EtOAc. The combined extracts were washed with brine, dried over Na2SO4,
mixture was stirred for 2 h at room temperature, cooled to 0 °C, and satu-

1572
Vol. 56, No. 11
and concentrated in vacuo. Purification by silica gel column chromatography with microwave at 180 °C for 25 min with 50 W as max irradiation power.
(hexane/EtOAcꢂ1/0→7/3) afforded iodide 14 (4.18 g, 81%) as a light
yellow oil. Rf 0.58 (silica gel, hexane/EtOAcꢂ6/4). 1H-NMR (CDCl3,
The combined reaction mixtures were added aqueous 1 M HCl and extracted
with CHCl3. The combined organic extracts were washed with water, satu-
400 MHz) d: 5.84 (1H, t, Jꢂ5.9 Hz), 4.20 (2H, d, Jꢂ5.9 Hz), 2.55 (2H, q, rated aqueous NaHCO3 and brine, dried Na2SO4, and concentrated in vacuo.
Jꢂ7.3 Hz), 1.10 (3H, t, Jꢂ7.3 Hz). 13C-NMR (CDCl3, 125 MHz) d: 132.6, Recrystallization from CHCl3 and hexane afforded 2-[2-(1H-indol-3-
111.7, 67.2, 39.0, 14.8. IR (NaCl) cmꢁ1: 3320, 2969, 1644, 1019. Anal.
Calcd for C5H9IO: C, 28.32; H, 4.28. Found: C, 28.37; H, 4.21.
(Z)-2-(3-Iodopent-2-enyloxy)tetrahydro-2H-pyran (15) A solution of
yl)ethyl]isoindoline-1,3-dione (14.9 g, 89%) as a yellow solid. Rf 0.31 (alu-
mina, CH2Cl2). mp 167.0—167.8 °C (lit. 164 °C).44) 1H-NMR (CDCl3,
500 MHz) d: 7.99 (1H, br s), 7.84 (2H, dd, J1ꢂ3.0 Hz, J2ꢂ5.4 Hz), 7.74 (1H,
iodide 14 (2.44 g, 11.5 mmol), dihydropyran (1.57 ml, 17.2 mmol) and p- d, Jꢂ7.6 Hz), 7.70 (2H, dd, J1ꢂ3.0 Hz, J2ꢂ5.4 Hz), 7.35 (1H, d, Jꢂ7.6 Hz),
TsOH·H2O (222 mg, 1.17 mmol) in CH2Cl2 (38 ml) was stirred for 1.5 h at 7.19 (1H, dd, J1ꢂJ2ꢂ7.6 Hz), 7.13 (1H, dd, J1ꢂJ2ꢂ7.6 Hz), 7.10 (1H, s),
30 °C. After adding aqueous NaHCO3, the mixture was extracted with 4.01 (2H, t, Jꢂ7.8 Hz), 3.16 (2H, t, Jꢂ7.8 Hz). 13C-NMR (CDCl3, 100
CHCl3. The combined extracts were washed with brine, dried over Na2SO4, MHz) d: 168.7, 136.4, 134.1, 132.4, 127.6, 123.4, 122.33, 122.25, 119.7,
and concentrated in vacuo. Purification by silica gel column chromatography 119.1, 112.6, 111.3, 38.6, 24.6. IR (KBr) cmꢁ1: 3355, 1707, 1396, 1103,
(hexane/EtOAcꢂ1/0→94/6) afforded THP ether 15 (3.05 g, 89%) as a color-
745, 713. LR-MS (FAB) m/zꢂ290 (Mꢀ).
tert-Butyl 3-[2-(1,3-Dioxoisoindolin-2-yl)ethyl]-1H-indole-1-carboxyl-
less oil. Rf 0.36 (silica gel, hexane/EtOAcꢂ94/6). 1H-NMR (CDCl3, 400
MHz) d: 5.82 (1H, tdd, J1ꢂ1.2 Hz, J2ꢂ5.6 Hz, J3ꢂ7.6 Hz), 4.65 (1H, dd, ate A solution of 2-[2-(1H-indol-3-yl)ethyl]isoindoline-1,3-dione (5.33 g,
J1ꢂ2.9 Hz, J2ꢂ3.9 Hz), 4.29 (1H, tdd, J1ꢂ1.2 Hz, J2ꢂ5.6 Hz, J3ꢂ13.2 Hz), 18.4 mmol) in DMF (60 ml) was added sodium hydride (55% purity, 1.08 g,
4.06 (1H, tdd, J1ꢂ1.2 Hz, J2ꢂ7.6 Hz, J3ꢂ13.2 Hz), 3.89 (1H, ddd, J1ꢂ3.2 24.8 mmol) at 0 °C. After stirring for 20 min, di-tert-butyl dicarbonate
Hz, J2ꢂ7.8 Hz, J3ꢂ11.4 Hz), 3.56—3.51 (1H, m), 2.54 (2H, dddq, J1ꢂJ2ꢂ (4.87 g, 22.3 mmol) and DMF (20 ml) was added. The suspension was
J3ꢂ1.2 Hz, J4ꢂ7.3 Hz), 1.87—1.79 (1H, m), 1.76—1.69 (1H, m), 1.64— stirred for 45 min at 40 °C, cooled to 0 °C, and then hexane and water were
1.50 (4H, m), 1.10 (3H, t, Jꢂ7.3 Hz). 13C-NMR (CDCl3, 125 MHz) d: added. The appeared brown solid was collected by filtration and dissolved
130.7, 111.8, 98.4, 71.8, 62.3, 39.1, 30.6, 25.5, 19.5, 14.7. IR (NaCl) cmꢁ1
:
with CHCl3. This solution was washed with brine, dried over Na2SO4, and
concentrated in vacuo. Recrystallization from CHCl3 and Et2O afforded tert-
butyl 3-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-1H-indole-1-carboxylate (4.48 g,
62%) as a light brown crystal. Rf 0.44 (alumina, CH2Cl2). mp 149.0—
2938, 1648, 1455, 1121, 1028. LR-MS (FAB) m/zꢂ297 (MꢀHꢀ). Anal.
Calcd for C10H17IO2: C, 40.56; H, 5.79. Found: C, 40.78; H, 5.59.
(Z)-2-(3-Ethyl-6,6-dimethoxyhex-2-enyloxy)tetrahydro-2H-pyran To
a mixture of magnesium turning (455 mg, 18.7 mmol) in anhydrous THF
(3.0 ml), was added a small portion of 1-bromo-3,3-dimethoxypropane
(3.23 g, 17.7 mmol) in anhydrous THF (8.0 ml) and 3 drops of 1,2-dibro-
methane. As soon as the reaction started, remainder of the bromide solution
is added dropwise, and the resulting mixture was stirred for 1 h at room tem-
perature. This solution was diluted with anhydrous THF (8.0 ml), and added
to a solution of anhydrous ZnCl2 (2.57 g, 18.5 mmol) in anhydrous THF
1
149.8 °C. H-NMR (CDCl3, 500 MHz) d: 8.13 (1H, br d, Jꢂ7.7 Hz), 7.86
(2H, dd, J1ꢂ3.0 Hz, J2ꢂ5.5 Hz), 7.73 (2H, dd, J1ꢂ3.0 Hz, J2ꢂ5.5 Hz),
7.68 (1H, d, Jꢂ7.7 Hz), 7.48 (1H, br s), 7.32 (1H, ddd, J1ꢂ0.9 Hz,
J2ꢂJ3ꢂ7.7 Hz), 7.26 (1H, ddd, J1ꢂ0.9 Hz, J2ꢂJ3ꢂ7.7 Hz), 4.00 (2H, t,
Jꢂ7.9 Hz), 3.08 (2H, t, Jꢂ7.9 Hz), 1.66 (9H, s). 13C-NMR (CDCl3,
125 MHz) d: 168.5, 149.9, 135.8, 134.2, 132.4, 130.5, 124.7, 123.6, 123.5,
122.8, 119.2, 117.1, 115.5, 83.6, 37.8, 28.3, 24.4. IR (KBr) cmꢁ1: 1773,
(48 ml) at ꢁ78 °C. The reaction mixture was warmed up to room tempera- 1737, 1712, 1395, 1371, 765, 744, 716. LR-MS (FAB) m/zꢂ390 (Mꢀ).
ture, and added to a solution of THP ether 15 (2.64 g, 8.92 mmol) and
Pd(PPh3)4 (836 mg, 0.723 mmol) in anhydrous THF (10 ml). After stirring
for 20 h at 30 °C, water was added, and the mixture was extracted with
Anal. Calcd for C23H22N2O4: C, 70.75; H, 5.68; N, 7.17. Found: C, 70.51; H,
5.61; N, 7.17.
Tryptamine 3 A solution of tert-butyl 3-[2-(1,3-dioxoisoindolin-2-
EtOAc. The combined extracts were washed with water and brine, dried over yl)ethyl]-1H-indole-1-carboxylate (2.41 g, 6.17 mmol) and hydrazine mono-
Na2SO4, and concentrated in vacuo. Purification by silica gel column hydrate (0.46 ml, 9.3 mmol) in 2-propanol (40 ml) and THF (10 ml) was re-
chromatography (hexane/EtOAcꢂ1/0→8/2) afforded (Z)-2-(3-ethyl-6,6-
fluxed. After 4 h, hydrazine monohydrate (0.095 ml, 1.92 mmol) was added
dimethoxyhex-2-enyloxy)tetrahydro-2H-pyran (1.43 g, 59%) as a yellow oil. and reflux was continued for additional 3.5 h. The reaction mixture was di-
Rf 0.42 (silica gel, hexane/EtOAcꢂ8/2). 1H-NMR (CDCl3, 400 MHz) d: luted with CHCl3, insoluble materials were removed by filtration, and the fil-
5.37 (1H, t, Jꢂ6.8 Hz), 4.63 (1H, t, Jꢂ3.7 Hz), 4.33 (1H, t, Jꢂ5.6 Hz), 4.27
(1H, dd, J1ꢂ6.8 Hz, J2ꢂ11.9 Hz), 4.04 (1H, dd, J1ꢂ6.8 Hz, J2ꢂ11.9 Hz),
3.89 (1H, ddd, J1ꢂ3.4 Hz, J2ꢂ7.6 Hz, J3ꢂ11.2 Hz), 3.54—3.51 (1H, m),
trate was concentrated in vacuo. The residue was solved with CHCl3, and
aqueous NaHCO3 was added. The layers were separated, and the aqueous
phase was extracted with CHCl3. The combined organic extracts were
3.32 (6H, s), 2.19—2.04 (4H, m), 1.89—1.76 (1H, m), 1.76—1.48 (7H, m), washed with brine, dried over Na2SO4, and concentrated in vacuo. Purifica-
1.03 (3H, t, Jꢂ7.5 Hz). 13C-NMR (CDCl3, 125 MHz) d: 144.9, 120.3, 104.1, tion by alumina column chromatography (hexane/CHCl3/MeOHꢂ1/1/0→
98.0, 63.5, 62.2, 52.6, 31.4, 30.8, 29.5, 25.7, 25.6, 19.6, 12.4. IR (NaCl) 0/9/1) afforded tryptamine 345) (1.50 g, 94%) as a yellow oil. Rf 0.22 (alu-
1
cmꢁ1: 2941, 1459, 1383, 1127, 1025. LR-MS (FAB) m/zꢂ271 (Mꢀꢁ1). mina, CH2Cl2/MeOHꢂ5/5). H-NMR (CDCl3, 500 MHz) d: 8.13 (1H, br s),
Anal. Calcd for C15H28O4: C, 66.14; H, 10.36. Found: C, 66.23; H, 10.65.
(Z)-1-Benzyloxy-3-ethyl-6,6-dimethoxyhex-2-ene (4) To a solution of
7.54 (1H, d, Jꢂ7.9 Hz), 7.43 (1H, br s), 7.32 (1H, dd, J1ꢂJ2ꢂ7.9 Hz), 7.24
(1H, dd, J1ꢂJ2ꢂ7.9 Hz), 3.05 (2H, t, Jꢂ6.8 Hz), 2.84 (2H, t, Jꢂ6.8 Hz),
(Z)-2-(3-ethyl-6,6-dimethoxyhex-2-enyloxy)tetrahydro-2H-pyran (913 mg, 1.67 (9H, s), 1.25 (2H, br s). 13C-NMR (CDCl3, 100 MHz) d: 150.0, 135.8,
3.35 mmol) and Sc(OTf)3 (48.4 mg, 98.4 mmol) in MeOH (22.0 ml) and
130.8, 124.6, 123.4, 122.6, 119.2, 118.5, 115.5, 83.6, 41.7, 29.3, 28.3. IR
water (0.5 ml) was stirred for 3 h at 40 °C. The solution was poured onto ice-
(NaCl) cmꢁ1: 3372, 1732, 1607, 1454, 1379, 1255, 1159, 1090, 746. LR-MS
cooled saturated aqueous NaHCO3, and the resultant mixture was extracted (FAB) m/zꢂ261 (MꢀHꢀ).
with EtOAc. The combined extracts were washed with saturated aqueous
Amine (E)-17 A solution of benzyl ether (E)-4 (751 mg, 2.70 mmol)
NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. This and p-TsOH·H2O (1.03 g, 5.42 mmol) in acetone (15 ml) and water (1.0 ml)
residue was dissolved with DMF (11 ml), and cooled to 0 °C. Sodium hy- was stirred for 3.5 h at 40 °C. After aqueous NaHCO3 was added, the mix-
dride (55% purity, 297 mg, 6.81 mmol) and benzyl bromide (97% purity, ture was extracted with EtOAc. The combined extracts were washed with
0.49 ml, 4.00 mmol) were added and stirred for 1 h at room temperature.
saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated
After adding water at 0 °C, the mixture was extracted with Et2O. The com- in vacuo. This residue was dissolved with THF (9.0 ml), and added trypta-
bined extracts were washed with water and brine, dried over Na2SO4, and mine 3 (857 mg, 3.30 mmol) and MS4A (3.77 g). After stirring for 2 h at
concentrated in vacuo. Purification by silica gel column chromatography 40 °C, MS4A was removed by filtration. To the filtrate, was added a solution
(hexane/Et2Oꢂ1/0→9/1) afforded benzyl ether (Z)-4 (546 mg, 59%) as a
of NaBH4 (158 mg, 4.07 mmol) in MeOH (10 ml) at 0 °C. After stirring for
20 min at room temperature, water was added, and the mixture was extracted
colorless oil. Rf 0.50 (silica gel, hexane/EtOAcꢂ8/2). 1H-NMR (CDCl3,
400 MHz) d: 7.36—7.27 (5H, m), 5.41 (1H, t, Jꢂ6.7 Hz), 4.51 (2H, s), 4.29 with EtOAc. The combined extracts were washed with water and brine, dried
(1H, t, Jꢂ5.8 Hz), 4.05 (2H, d, Jꢂ6.7 Hz), 3.29 (6H, s), 2.11—2.04 (4H, m), over Na2SO4, and concentrated in vacuo. Purification by alumina column
1.67—1.62 (2H, m), 1.03 (3H, t, Jꢂ7.4 Hz). 13C-NMR (CDCl3, 125 MHz)
chromatography (hexane/CHCl3ꢂ5/5→0/1) afforded amine (E)-17 (1.07 g,
d: 145.2, 138.7, 128.5, 128.0, 127.7, 120.6, 104.2, 72.4, 66.6, 52.8, 31.4, 83%) as a colorless oil. Rf 0.39 (alumina, CH3Cl/MeOHꢂ9/1). 1H-NMR
29.5, 25.9, 12.6. IR (NaCl) cmꢁ1: 2962, 1455, 1126, 1067. LR-MS (FAB) (CDCl3, 400 MHz) d: 8.13 (1H, br d, Jꢂ8.0 Hz), 7.55 (1H, d, Jꢂ7.6 Hz),
m/zꢂ277 (Mꢀꢁ1). Anal. Calcd for C17H26O3: C, 73.34; H, 9.41. Found: C, 7.42 (1H, br s), 7.34—7.21 (7H, m), 5.34 (1H, t, Jꢂ6.6 Hz), 4.49 (2H, s),
73.07; H, 9.20.
4.02 (2H, d, Jꢂ6.6 Hz), 2.95 (2H, t, Jꢂ5.8 Hz), 2.89 (2H, t, Jꢂ5.8 Hz), 2.64
(2H, t, Jꢂ7.4 Hz), 2.08—2.01 (4H, m), 1.66—1.57 (11H, m), 0.94 (3H, t,
Jꢂ7.6 Hz). 13C-NMR (CDCl3, 125 MHz) d: 149.9, 146.0, 138.7, 135.7,
2-[2-(1H-indol-3-yl)ethyl]isoindoline-1,3-dione A mixture of trypta-
mine (9.26 g, 57.9 mmol), phthalic anhydride (9.01 g, 60.9 mmol) and DMF
(9 ml) was divided into six microwave reactor vials. Each vial was irradiated 130.8, 128.5, 127.9, 127.6, 124.5, 123.1, 122.5, 120.7, 119.1, 118.9, 115.4,

November 2008
1573
73.8 mmol), K3PO4 (83.2 mg, 0.385 mmol) and Ag3PO4 (39.1 mg, 91.5 mmol)
in xylene (1.0 ml) was stirred for 30 min at 40 °C. To this suspension, a solu-
tion of chloroformamide (E)-2 (100 mg, 0.186 mmol) in xylene (3.0 ml) was
added. After stirring for 5 h at 130 °C, the reaction mixture was cooled to
room temperature, and water was added, and the product was extracted with
EtOAc. The combined organic extracts were washed with water and brine,
dried over Na2SO4, and concentrated in vacuo. Purification by silica gel col-
umn chromatography (hexane/CHCl3/Et2Oꢂ1/0/0→60/16/24) afforded a
mixture containing enol ether, which was added acetone (3.0 ml), water
(0.1 ml) and p-TsOH·H2O (36.5 mg, 0.192 mmol). After stirring for 100 min
at 30 °C, aqueous NaHCO3 was added, and the product was extracted with
EtOAc. The combined organic extracts were washed with saturated aqueous
NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. Purifica-
tion by silica gel column chromatography (hexane/EtOAcꢂ1/0→6/4) af-
forded piperidone 1 (39.8 mg, 52%) as a light yellow oil. Enantiomeric ex-
cess (ee) was measured by HPLC analysis with chiralcel AS-H column
(hexane/2-propanolꢂ95/5, 0.5 ml/min, 254 nm) tR: 36.9 min (S, minor),
83.5, 72.1, 66.4, 49.9, 49.3, 34.3, 28.5, 28.4, 25.9, 23.7, 13.5. IR (NaCl)
cmꢁ1: 2932, 1730, 1453, 1374, 1254, 1159, 1088. LR-MS (FAB) m/zꢂ477
(MꢀHꢀ). Anal. Calcd for C30H40N2O3: C, 75.59; H, 8.46; N, 5.88. Found: C,
75.41; H, 8.65; N, 5.89.
Amine (Z)-17 A solution of benzyl ether (Z)-4 (425 mg, 1.53 mmol) and
p-TsOH·H2O (576 mg, 3.03 mmol) in acetone (10 ml) and water (0.5 ml)
was stirred for 3 h at 40 °C. After adding aqueous NaHCO3, the mixture was
extracted with EtOAc. The combined extracts were washed with saturated
aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo.
To a solution of this residue in THF (5.1 ml), were added tryptamine 3
(615 mg, 2.37 mmol) and MS4A (2.12 g). After stirring for 2 h at 40 °C,
MS4A was removed by filtration. To the filtrate, was added a solution of
NaBH4 (98% purity, 88.6 mg, 2.28 mmol) in MeOH (8.0 ml) at 0 °C. After
stirring for 1 h at room temperature, water was added, and the mixture was
extracted with EtOAc. The combined extracts were washed with water,
brine, dried over Na2SO4, and concentrated in vacuo. Purification by alu-
mina column chromatography (hexane/CHCl3ꢂ5/5→CHCl3/MeOHꢂ9/1)
afforded amine (Z)-17 (451 g, 62%) as a colorless oil. Rf 0.45 (alumina,
CH3Cl/MeOHꢂ9/1). 1H-NMR (CDCl3, 400 MHz) d: 8.13 (1H, br d,
Jꢂ7.8 Hz), 7.54 (1H, d, Jꢂ7.8 Hz), 7.41 (1H, br s), 7.35—7.22 (7H, m),
5.38 (1H, t, Jꢂ6.7 Hz), 4.48 (2H, s), 4.01 (2H, d, Jꢂ6.7 Hz), 2.95—2.86
(4H, m), 2.58 (2H, t, Jꢂ7.2 Hz), 2.07—2.01 (4H, m), 1.66 (9H, s), 1.58—
1.49 (2H, m), 1.01 (3H, t, Jꢂ7.5 Hz). 13C-NMR (CDCl3, 125 MHz) d:
149.8, 145.7, 138.6, 135.6, 130.7, 128.4, 127.9, 127.6, 124.4, 123.0, 122.4,
120.1, 119.0, 118.8, 115.4, 83.4, 72.2, 66.4, 49.8, 49.3, 29.4, 29.0, 28.5,
28.3, 25.8, 12.5. IR (NaCl) cmꢁ1: 2932, 1731, 1453, 1373, 1254, 1159,
1088. LR-MS (FAB) m/zꢂ477 (MꢀHꢀ). Anal. Calcd for C30H40N2O3: C,
75.59; H, 8.46; N, 5.88. Found: C, 75.85; H, 8.55; N, 5.83.
1
44.9 min (R, major) (43% ee). Rf 0.30 (silica gel, hexane/EtOAcꢂ6/4). H-
NMR (CDCl3, 400 MHz) d: 9.79 (1H, dd, J1ꢂ1.2 Hz, J2ꢂ2.4 Hz), 8.13 (1H,
br d, Jꢂ7.8 Hz), 7.62 (1H, d, Jꢂ7.8 Hz), 7.43 (1H, br s), 7.31 (1H, dd,
J1ꢂJ2ꢂ7.8 Hz), 7.24 (1H, dd, J1ꢂJ2ꢂ7.8 Hz), 3.69—3.57 (2H, m), 3.40—
3.34 (1H, m), 3.25—3.20 (1H, m), 2.96 (2H, t, Jꢂ7.6 Hz), 2.86 (1H, dd,
J1ꢂ1.2 Hz, J2ꢂ16.4 Hz), 2.43 (1H, dd, J1ꢂ2.4 Hz, J2ꢂ16.4 Hz), 1.85—1.68
(6H, m), 1.66 (9H, s), 0.90 (3H, t, Jꢂ7.5 Hz). 13C-NMR (CDCl3, 100 MHz)
d: 201.7, 173.8, 149.9, 135.7, 130.7, 124.5, 123.3, 122.7, 119.2, 118.0,
115.4, 83.5, 51.5, 49.0, 48.3, 43.7, 31.0, 30.1, 28.3, 22.8, 19.6, 8.3. IR
(NaCl) cmꢁ1: 2937, 1727, 1629, 1454, 1377, 1255, 1158. LR-MS (FAB)
m/zꢂ413 (MꢀHꢀ). [a]D ꢁ0.9 (cꢂ1.0, CHCl3). Anal. Calcd for
C24H32N2O4: C, 69.88; H, 7.82; N, 6.79. Found: C, 69.58; H, 8.00; N, 6.56.
Methyl Ester 18 A mixture of piperidone 1 (149 mg, 0.361 mmol),
2-methyl-2-butene (1.0 ml), NaClO2 (80% purity, 143 mg, 1.27 mmol),
NaH2PO4·2H2O (141 mg, 0.904 mmol) in t-BuOH (3.0 ml) and water
(1.5 ml) was stirred for 2 h. After adding saturated aqueous NH4Cl, the mix-
ture was extracted with CHCl3. The combined extracts were washed with
water and brine, dried over Na2SO4, and concentrated in vacuo. This residue
was dissolved in CH3CN (3.0 ml), and Cs2CO3 (142 mg, 0.436 mmol) and
MeI (0.025 ml, 0.40 mmol) were added at 0 °C. After stirring for 2.5 h, water
was added, and. the mixture was extracted with CHCl3. The combined
extracts were washed with water and brine, dried over Na2SO4, and con-
centrated in vacuo. Purification by silica gel column chromatography
(hexane/EtOAcꢂ1/0→6/4) afforded methyl ester 18 (144 mg, 90%) as a col-
orless oil. Rf 0.41 (silica gel, hexane/EtOAcꢂ6/4). 1H-NMR (CDCl3,
400 MHz) d: 8.13 (1H, br d, Jꢂ7.5 Hz), 7.65 (1H, d, Jꢂ7.5 Hz), 7.44 (1H,
br s), 7.31 (1H, dd, J1ꢂJ2ꢂ7.5 Hz), 7.24 (1H, dd, J1ꢂJ2ꢂ7.5 Hz), 3.71—
3.57 (5H, m), 3.46—3.40 (1H, m), 3.22—3.18 (1H, m), 3.02—2.91 (3H, m),
2.43 (1H, d, Jꢂ16.1 Hz), 1.98—1.55 (15H, m), 0.89 (3H, t, Jꢂ7.6 Hz). 13C-
NMR (CDCl3, 125 MHz) d: 174.1, 172.6, 149.9, 135.7, 130.7, 124.5, 123.3,
122.6, 119.3, 118.3, 115.3, 83.4, 51.5, 49.1, 48.5, 43.5, 42.2, 31.6, 29.4,
28.4, 22.8, 20.0, 8.7. IR (NaCl) cmꢁ1: 2942, 1733, 1635, 1454, 1377, 1255,
1160. LR-MS (FAB) m/zꢂ443 (MꢀHꢀ). [a]D ꢁ0.4 (cꢂ0.99, CHCl3). Anal.
Calcd for C25H34N2O5: C, 67.85; H, 7.74; N, 6.33. Found: C, 67.42; H, 7.78;
N, 6.24.
Chloroformamide (E)-2 To
a solution of triphosgene (349 mg,
1.18 mmol) in THF (10 ml) was added triethylamine (0.59 ml, 4.22 mmol)
followed by amine (E)-17 (1.42 g, 2.98 mmol) in THF (10 ml) at ꢁ78 °C.
The reaction mixture was warmed to room temperature, stirred for 1.5 h at
70 °C, and aqueous 1 M HCl was added at 0 °C. The mixture was extracted
with EtOAc, and the combined organic extracts were washed with 1 M HCl,
saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated
in vacuo. Purification by silica gel column chromatography (hexane/
EtOAcꢂ1/0→9/1) afforded chloroformamide (E)-2 (1.29 g, 80%) as a color-
less oil. Rf 0.45 (silica gel, hexane/EtOAcꢂ8/2). 1H-NMR* (CDCl3,
400 MHz) d: 8.14 (1H, br d, Jꢂ7.3 Hz), 7.56 (1H, dd, J1ꢂ7.8 Hz,
J2ꢂ10.5 Hz), 7.42 (1H, br s), 7.34—7.22 (7H, m), 5.35 (1H, t, Jꢂ6.8 Hz),
4.50 (2H, s), 4.02 (2H, d, Jꢂ6.8 Hz), 3.72—3.61 (2H, m), 3.38—3.32 (2H,
m), 3.06—3.00 (2H, m), 2.06—2.00 (4H, m), 1.78—1.70 (2H, m), 1.67 (9H,
s), 0.95 (3H, t, Jꢂ7.6 Hz). 13C-NMR* (CDCl3, 125 MHz) d: 149.8, 149.3,
149.1, 144.7, 144.4, 138.6, 138.6, 135.7, 130.3, 130.2, 128.5, 127.9, 127.7,
124.83, 124.76, 123.5, 122.8, 121.6, 121.4, 118.9, 118.7, 116.9, 116.6,
115.6, 115.5, 83.9, 83.8, 72.43, 72.36, 66.3, 51.9, 51.4, 50.4, 50.3, 33.4,
33.3, 28.4, 26.7, 25.8, 24.7, 23.7, 23.4, 13.5. IR (NaCl) cmꢁ1: 2971, 1733,
1454, 1375, 1255, 1157, 1088. LR-MS (FAB) m/zꢂ538 (Mꢀ). Anal. Calcd
for C31H39ClN2O4: C, 69.06; H, 7.29; N, 5.20. Found: C, 69.08; H, 7.09; N,
5.18 (* ca. 1 : 1 mixture of rotamers).
Chloroformamide (Z)-2 To
a solution of triphosgene (69.8 mg,
0.235 mmol) in THF (1.0 ml) was added a solution of triethylamine (0.11 ml,
0.786 mmol) and amine (Z)-17 (273 mg, 0.573 mmol) in THF (4.0 ml) at
ꢁ78 °C. The reaction mixture was warmed up to 70 °C, and stirred for 2 h.
After successive addition of water and 1 M HCl at 0 °C, the mixture was ex-
tracted with EtOAc. The combined organic extracts were washed with 1 M
HCl, saturated aqueous NaHCO3 and brine. The organic layer was dried over
Na2SO4, and concentrated in vacuo. Purification by silica gel column chro-
matography (hexane/EtOAcꢂ1/0→9/1) afforded chloroformamide (Z)-2
(282 mg, 91%) as a colorless oil. Rf 0.46 (silica gel, hexane/EtOAcꢂ8/2).
1H-NMR* (CDCl3, 400 MHz) d: 8.14 (1H, br d, Jꢂ7.1 Hz), 7.54 (1H, dd,
J1ꢂ7.8 Hz, J2ꢂ10.7 Hz), 7.41 (1H, br s), 7.36—7.23 (7H, m), 5.45—5.40
(1H, m), 4.49 (2H, s), 3.98—3.94 (2H, m), 3.67—3.56 (2H, m), 3.29—3.25
(2H, m), 3.02—2.97 (2H, m), 2.05—1.99 (4H, m), 1.67 (11H, s), 1.01 (3H,
t, Jꢂ7.4 Hz). 13C-NMR* (CDCl3, 125 MHz) d: 149.7, 149.2, 148.9, 144.7,
144.5, 138.4, 138.4, 135.6, 130.2, 130.1, 128.4, 127.9, 127.70, 127.66,
124.76, 124.68, 123.4, 122.8, 120.9, 120.8, 118.8, 118.6, 116.8, 116.5,
115.54, 115.45, 83.8, 83.7, 72.4, 66.2, 66.1, 51.8, 51.2, 50.3, 50.2, 29.3,
28.29, 28.26, 27.8, 27.7, 27.2, 26.3, 24.6, 23.3, 12.5. IR (NaCl) cmꢁ1: 2968,
1734, 1454, 1376, 1256, 1158, 1088. LR-MS (FAB) m/zꢂ538 (Mꢀ). Anal.
Calcd for C31H39ClN2O4: C, 69.06; H, 7.29; N, 5.20. Found: C, 69.06; H,
7.35; N, 5.19 (* ca. 1 : 1 mixture of rotamers).
Indole 19 A solution of methyl ester 18 (144 mg, 0.325 mmol) in
CH3CN (4.0 ml) was irradiated microwave for 4 h at 200 °C, using a
maximum irradiation power of 150 W. The reaction mixture was con-
centrated in vacuo, and purification by silica gel column chromatography
(hexane/EtOAcꢂ1/0→6/4) afforded indole 19 (110 mg, 99%) as a colorless
oil. Rf 0.53 (silica gel, hexane/EtOAcꢂ3/7). 1H-NMR (CDCl3, 400 MHz) d:
8.19 (1H, br s), 7.68 (1H, d, Jꢂ7.8 Hz), 7.35 (1H, d, Jꢂ7.8 Hz), 7.18 (1H,
dd, J1ꢂJ2ꢂ7.8 Hz), 7.11 (1H, dd, J1ꢂJ2ꢂ7.8 Hz), 7.06 (1H, s), 3.67—3.63
(5H, m), 3.42—3.36 (1H, m), 3.22—3.17 (1H, m), 3.03 (2H, t, Jꢂ7.7 Hz),
2.96 (1H, d, Jꢂ16.1 Hz), 2.35 (1H, d, Jꢂ16.1 Hz), 1.99—1.60 (6H, m), 0.88
(3H, t, Jꢂ7.7 Hz). 13C-NMR (CDCl3, 125 MHz) d: 174.0, 172.7, 136.5,
127.7, 122.3, 122.1, 119.4, 119.1, 113.6, 111.3, 51.6, 49.1, 49.0, 43.6, 42.2,
31.7, 29.4, 23.1, 20.1, 8.8. IR (NaCl) cmꢁ1: 3268, 2946, 1736, 1615, 1492,
1457, 1435, 1355, 1198, 742. LR-MS (FAB) m/zꢂ343 (MꢀHꢀ). [a]D ꢁ1.9
(cꢂ1.0, CHCl3). Anal. Calcd for C20H26N2O3: C, 70.15; H, 7.65; N, 8.18.
Found: C, 69.92; H, 7.83; N, 7.88.
(ꢀ)-Epieburnamonine (20)
A solution of indole 19 (110 mg,
0.321 mmol) and POCl3 (0.120 ml, 1.28 mmol) in anhydrous CH3CN
(4.0 ml) was irradiated microwave for 3.5 h at 120 °C, using a maximum ir-
radiation power of 150 W. Then the reaction mixture was added dropwise
into a solution of NaBH4 (248 mg, 6.40 mmol) in MeOH (16 ml) at 0 °C.
After stirring for 25 min, water was added, and the mixture was extracted
Piperidone 1 A suspension of [Pd(h3-C3H5)Cl]2 (3.63 mg, 9.72 mmol),
t-BuOK (90% purity, 3.59 mg, 28.8 mmol), phosphoramidite L7 (39.8 mg,

1574
Vol. 56, No. 11
with CHCl3. The combined extracts were washed with water and brine, dried
Y., Tetrahedron, 63, 2978—2989 (2007).
over Na2SO4, and concentrated in vacuo. Purification by silica gel col- 19) Henin F., Muzart J., Pete J.-P., Tetrahedron Lett., 27, 6339—6340
umn chromatography (hexane/CHCl3ꢂ2/8→0/1) afforded (ꢁ)-epieburna-
monine (20) (55.8 mg, 59%) as a light yellow solid. Rf 0.51 (silica gel,
hexane/EtOAcꢂ6/4). mp 125.7—127.0 °C. H-NMR (CDCl3, 400 MHz) d:
8.33 (1H, dd, J1ꢂ2.0 Hz, J2ꢂ6.3 Hz), 7.41 (1H, dd, J1ꢂ2.0 Hz, J2ꢂ6.3 Hz),
7.31—7.06 (2H, m), 3.12—3.05 (3H, m), 2.92—2.83 (1H, m), 2.80 (1H, d,
Jꢂ15.6 Hz), 2.66 (1H, br d, Jꢂ15.9 Hz), 2.53 (1H, ddd, J1ꢂ4.4 Hz,
J2ꢂJ3ꢂ11.4 Hz), 2.36 (1H, dd, J1ꢂ1.9 Hz, J2ꢂ15.6 Hz), 2.31 (1H, dd,
(1986).
20) Marvel C. S., Myers R. L., Saunders J. H., J. Am. Chem. Soc., 70,
1694—1699 (1948).
21) Frigerio M., Santagostino M., Sputore S., Palmisano G., J. Org.
Chem., 60, 7272—7276 (1995).
22) Deguest G., Bischoff L., Fruit C., Marsais F., Org. Lett., 9, 1165—
1167 (2007).
1
J1ꢂ2.9 Hz, J2ꢂ11.0 Hz), 1.95—1.83 (3H, m), 1.66—1.57 (1H, m), 1.24— 23) Corey E. J., Kirst H. A., Katzenellenbogen J. A., J. Am. Chem. Soc.,
1.16 (1H, m), 0.87—0.76 (4H, m). 13C-NMR (CDCl3, 125 MHz) d: 167.8,
135.2, 133.5, 130.1, 124.2, 124.0, 118.3, 116.4, 113.1, 66.1, 55.6, 52.4,
44.4, 39.6, 32.0, 21.7, 21.4, 20.9, 7.5. IR (KBr) cmꢁ1: 2928, 1706, 1655,
1457, 1365, 751. LR-MS (FAB) m/zꢂ295 (MꢀHꢀ). [a]D ꢁ62.3 (cꢂ1.0,
CHCl3). Anal. Calcd for C19H22N2O: C, 77.52; H, 7.53; N, 9.52. Found: C,
77.24; H, 7.52; N, 9.23.
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Acknowledgment This work was supported in part by a Grant-in-Aid
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