Total syntheses of (-)-vallesamidine and related Aspidosperma and Hunteria type indole alkaloids from the common intermediate

Article abstract of DOI:10.1016/j.tet.2004.02.015

A new synthetic method of (-)-vallesamidine, including a unique 2,2,3-trialkylindoline skeleton, was developed by reductive radical cyclization reaction from the 2,3-dialkylindole derivative, which has been known to be an intermediate for the synthesis of

Full text of DOI:10.1016/j.tet.2004.02.015

Tetrahedron 60 (2004) 3273–3282
Total syntheses of (2)-vallesamidine and related Aspidosperma
and Hunteria type indole alkaloids from the common intermediate
*
Hideo Tanino, Kazuhisa Fukuishi, Mina Ushiyama and Kunisuke Okada
Faculty of Pharmacy, Meijo University, Tenpaku, Nagoya 468-8503, Japan
Received 22 December 2003; accepted 2 February 2004
Dedicated to Professor A. Ian Scott on the occasion of his 75th birthday
Abstract—A new synthetic method of (2)-vallesamidine, including a unique 2,2,3-trialkylindoline skeleton, was developed by reductive
radical cyclization reaction from the 2,3-dialkylindole derivative, which has been known to be an intermediate for the synthesis of
aspidospermidine.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2,3-disubstituted indole 3 is not generally useful, because of
the propensity of the resulting cation to rearrange to the
more stable 2,3,3-trialkylindolenium ion. In fact, Harley-
Mason,5 Fuji6 and Schultz7 have succeeded in the synthesis
of the aspidosperidine skeleton from 3, being used as a key
intermediate, in the cyclization which includes the interest-
ing rearrangement as shown in Scheme 2.
Vallesamidine 1 is one of 28 alkaloids isolated from
Vallesia dichotoma Ruiz and Pav in 1965 and its structure
and absolute configuration were determined by Djerassi in
1968.1 The defined structure shows a unique and abnormal
indole alkaloid including a 2,2,3-trialkylindoline skeleton,
which differs from (þ)-aspidospermidine 2, a typical indole
alkaloid, having 2,3,3-trialkylindoline chromophore
(Scheme 1). The stereochemistry of vallesamidine at C-5
and C-19 is identical to that of aspidospermidine, suggesting
that these two alkaloids are possibly biosynthesized from
the same intermediate. A great amount of research has been
reported on the synthesis of 2,3,3-trialkylated indoline
alkaloids such as Aspidosperma and Strychnos families,2 but
little research has been carried out on 2,2,3-trialkylated
indoline alkaloids such as vallesamidine.3
On the other hand, Levy’s elegant transformation of the
pentacyclic vallesamidine skeleton from tabersonine was
achieved by treatment with Zn powder in acetic acid.8 It has
been proposed that 2,2,3-trialkylindoline intermediate 6 is
included in the equilibrium reaction mixture, in addition to
2,3,3-trialkylindoline 4 and quebrachamine chromophore 5
(Scheme 3). In this way, enantiomeric (þ)-vallesamidine
was obtained in 24% yield.
Because of the above discussion, we have been interested in
investigating a new synthetic approach to vallesamidine
wherein the reductive radical cyclization of the known 2,3-
dialkylindole derivative 3a provides the 2,2,3-trialkyl-
indoline skeleton. Although many novel ring systems and
In 1990, Heathcock reported the first total synthesis of (^)-
vallesamidine via newly developed methodology, wherein
the indolenine skeleton is formed in the late stage of its
synthesis.4 In his paper, it is noted that alkylation at C-2 of a
Scheme 1.
Keywords: Radical reaction; Cyclization; Indole; Asymmetric synthesis.
*
Corresponding author. Tel.: þ81-52-832-1781x250; fax: þ81-52-834-8780; e-mail address: kokada@ccmfs.meijo-u.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.015

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H. Tanino et al. / Tetrahedron 60 (2004) 3273–3282
Scheme 2.
Scheme 3.
natural products have been synthesized by radical reactions,
a small amount of research has been devoted to the synthesis
of indoline alkaloids.9 In this article, we first describe a
successful total synthesis of (2)-vallesamidine 1 from 3a,
prepared by the following line (Scheme 4),10 and second the
additional transformation of 3a into (þ)-aspidospermidine 2
and (þ)-dihydroeburnamenine 24a from the common
intermediate 3a.
2. Results and discussion
2.1. Synthesis of (2)-vallesamidine
The synthesis of the chiral key intermediate 3a was started
from 7, which was obtained from the double alkylation of
(S)-g-trityloxymethyl-g-butyrolactone by using the method
reported by Koga.11 Detritylation of 7 afforded an alcohol 8
Scheme 4. Reagents and conditions: (a) 80% AcOH, 80 8C, 1 h; (i) 4 M aq. NaOH, dioxane, 100 8C, 1 h; (ii) CO2; (iii) aq. NaIO4, rt, 3 h; (iv) 1 M HCl; (c) (i)
NaBH4, MeOH, rt, 1 h; (ii) 4 M HCl–MeOH, 70 8C, 1 h; (d) (i) DiBAL–H, Et2O, 278 8C, 1 h; (ii) CH(OMe)3, p-TsOH, MeOH, 80 8C, 40 min; (e) (i) 9-BBN,
THF, rt, overnight; (ii) 30% H2O2, 3 M aq. NaOH, THF, rt, 1 h; (f) SO3-Py, DMSO, TEA, CH2Cl2, rt, 0.5 h; (g) NaClO2, t-BuOH, aq. NaH2PO4,
Me2CvCHMe, rt, 1 h; (h) tryptamine, AcOH, 125 8C, 6 days; (i) 20% aq. NaOH, MeOH, rt, 1 h.

H. Tanino et al. / Tetrahedron 60 (2004) 3273–3282
3275
Scheme 5. Reagents and conditions: (a) MsCl, pyridine, 0 8C, 2 h; (b) (PhSe)2, NaBH4, EtOH, 0 8C!rt, 3 h; (c) n-Bu3SnH, AlBN, toluene, 100 8C, 0.5 h; (d)
35% HCHO, NaBH3CN, CH3CN, then AcOH, rt, 1 h; (e) LAH, THF, 70 8C, 0.5 h.
in 98% yield, which was hydrolyzed with 4 M aqueous
NaOH in dioxane followed by neutralization with CO2. The
resulting mixture was oxidized with sodium periodate to
give hemiacetal 9 in 95% yield. Reduction of 9 with sodium
borohydride in methanol gave g-lactones 10 (92%). The
lactone was then converted to methylacetal 11 by reduction
with diisobutylaluminum hydride at 278 8C, followed by
treatment with trimethyl orthoformate and p-toluene-
sulfonic acid in methanol, in 84% yield in two steps.
Transformation of the double bond in 11 into primary
alcohols 12a,b was performed by following successive
reactions of hydroboration with 9-BBN in THF and
oxidation with hydrogenperoxide in alkali in 87% yield.
The alcohols 12a,b were further oxidized to carboxylic
acids 14a,b (95% yield)12 via 13a,b in the usual way.
converted into mesylate by using MsCl–DMAP in pyridine
at 0 8C in 92% yield. The resulting mesylate 17a was treated
with diphenydiselenide and NaBH4 in EtOH at room
temperature, giving the desired selenide 18a in 68% yield
together with N-alkylated product (4% yield, Hunteria type
chromophore). Treatment of the selenide 18a with a mixture
of tributyltin hydride (n-Bu3SnH) and 2,20-azobisisobutyro-
nitrile (AIBN) in toluene at 100 8C under argon for 30 min
gave a single product in 91% yield, the structure of which
was assumed to be pentacyclic compound 19 based on the
following physical data; in 1H NMR (d): the signal at
4.77 ppm (lH, s; C19-proton) of 18a moved to 3.28 ppm
(lH, s); in 13C NMR (d): two sp2 carbon signals at 126–
136 ppm, corresponding to a and b-carbon in the indole
ring of 18a, disappeared and in place of these signals, two
new signals were observed at 44.6 ppm (–CH–) and
76.3 ppm (quaternary carbon). N-Methylation of 19 with
the mixture of HCHO–NaBH3CN–AcOH in acetonitrile
gave 20 in 87% yield.
The next condensation reaction was performed by heating
the mixture of carboxylic acids 14a,b with tryptamine in
AcOH at refluxing temperature. In this reaction mixture, the
intermediate 15 was always detected on a silica gel TLC.
The structure of 15 was proposed by spectral data and
further confirmed by its chemical transformation into the
same products 16a,b. After 6 days, the intermediate 15
completely disappeared and then, the reaction mixture was
separated by using a silica gel column chromatography to
give a tetracyclic indole lactam derivatives 16a (43%) and
16b (44%)6 as acetates. Exposure of 16a to 20% aqueous
NaOH in MeOH solution afforded the desired alcohol 3a,
corresponding to the natural form, and 16b gave another
stereoisomer 3b under the same conditions. The stereo-
chemistry of each product was characterized by
comparison with 1H NMR spectra of the authentic samples.6
The structure of 3a was further confirmed by the
conversion into the known compound (þ)-aspidospermi-
dine 2 under the usual acidic conditions followed by LAH
reduction.6 The next approach from 3a to 1 is outlined in
Scheme 5.
Finally, reduction of the lactam 20 by using LAH in THF
under refluxing temperature for 30 min was achieved to
provide (2)-vallesamidine 1 in 82% yield. The structure of
the synthetic material was confirmed by comparison with
the physical data reported by Heathcock.4b
2.2. Radical reduction of the epimer 18b
Another stereoisomer 3b was also converted into phenyl-
selenide 18b through mesylate 17b as shown in Scheme 6.
Exposure of the isomer 18b with n-Bu3SnH and AIBN in
toluene at 100 8C for 1 h under an argon atmosphere gave a
single product 22 in 70% yield. None of the cyclized
product was detected on silica gel TLC. The 1H NMR
spectrum of 22 indicated the presence of two methyl groups.
This observation may reflect a reduction of the radical
intermediate generated from the 20-phenylselenylethyl side
chain in 18b, because the location of the radical is separated
from indole ring as depicted in 21.
The primary hydroxy group in the side chain of 3a was

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H. Tanino et al. / Tetrahedron 60 (2004) 3273–3282
Scheme 6. Reagents and conditions: (a) MsCl, DMAP, pyridine, 0 8C, 2 h; (b) (PhSe)2, NaBH4, EtOH, 0 8C, 0.5 h!rt, 3 h; (c) n-Bu3SnH, AlBN, toluene,
100 8C, 1 h.
2.3. Syntheses of (1)-dihydroeburnamenine 24a and
(2)-epidihydroeburnamenine 24b
5, 12, 19, which may suggest one route for biosynthesis of
these alkaloids is carried out from the common intermediate
3a.
It is interesting to note that the mesylate 17b was readily
converted into N-alkylated pentacyclic product 23b by
treatment with NaOH in THF at room temperature in 88%
yield, although ring closure of 18b was not observed under
radical reaction conditions as described above. The other
stereoisomer of the masylate 17a was also converted into a
cyclization product 23a in 94% yield with alkali. (þ)-
Dihydroeburnamenine 24a was obtained from 23a on
reduction with LiAlH4 in THF under refluxing temperature
in 91% yield. Reduction of another isomer 23b was not
succeeded under the same conditions because of decompo-
sition. However, when 23b was treated with an excess
amount of NaBH4–TFA in dioxane, the desired (2)-
epidihydroeburnamenine 24b was obtained in 87% yield
(Scheme 7). The structures of 24a6 and 24b3,6,13 were
characterized by comparison with the physical data reported
in the literature, respectively.
4. Experimental
4.1. General information
All melting points were uncorrected. 1H NMR spectra
(600 MHz) and 13C NMR spectra (150 MHz) were recorded
on a JEOL JNM-A 600 spectrometer. 13C NMR assignments
were carried out using DEPT experiments. IR spectra were
recorded on a JASCO IR-810 spectrometer. UV spectrum
was recorded on a JASCO UVIDEC-6100 spectrometer. MS
spectra were recorded on a JEOL-MS700. Optical rotations
were measured on a JASCO DIP-370 polarimeter. Separ-
ation of the products by flash column chromatography was
carried out on silica gel (Fuji Silysia Chem. Co., BW-300).
Separation of the products by TLC was carried out on silica
gel (MERCK 1.05744).
3. Conclusions
4.1.1. (2R)-2,3-Dideoxy-2-ethyl-2-(2-propenyl)-D-
glyceropentanoic acid g-lactone (8). A solution of 7
(1.96 g, 4.60 mmol) in 80% AcOH (15.5 mL) was stirred at
80 8C for 1 h. After the mixture was concentrated under
reduced pressure, the residue was diluted with AcOEt. The
organic phase was washed with saturated aqueous NaHCO3
and brine, dried over anhydrous Na2SO4 and concentrated.
The residual oil was purified by flash column chromato-
graphy on silica gel with hexane–AcOEt (1:1) as eluant to
give 8 (827 mg, 98%) as a colorless oil; [a]2D0 þ22.38 (c 1.7,
We have developed a new strategy for preparation of the
2,2,3-trialkylindoline skeletons via reductive radical
cyclization reaction, and demonstrated five steps for the
synthesis of vallesamidine 1 from the intermediate 3a,
which has been known to be a common substrate for the
synthesis of Aspidosperma and Hunteria type indole
alkaloids. It is noteworthy that vallesamidine 1 and the
co-occurring aspidosperma-type indole alkaloids have been
shown to have the same absolute configuration at carbon 2,
1
CHCl3); IR (neat) 3450, 1760, 1645, 1195, 930 cm21; H
Scheme 7. Reagents and conditions: (a) NaOH, THF, rt, 20 min; (b) LAH, TAF, 70 8C, 0.5 h; (c) NaBH4, TFA, dioxane, 100 8C, 45 min.

H. Tanino et al. / Tetrahedron 60 (2004) 3273–3282
3277
NMR (CDCl3): d 0.93 (3H, t, J¼7.3 Hz), 1.58–1.73 (2H,
m), 2.03 (1H, dd, J¼13.2, 7.8 Hz), 2.09 (1H, dd, J¼13.2,
9.3 Hz), 2.30 (1H, dd, J¼13.7, 7.8 Hz), 2.37 (1H, dd,
J¼13.7, 7.3 Hz), 3.59 (1H, dd, J¼12.7, 4.9 Hz), 3.88 (1H,
dd, J¼12.7, 2.9 Hz), 4.44–4.54 (1H, m), 5.13–5.22 (2H,
m), 5.71–5.86 (1H, m); 13C NMR (CDCl3; DEPT) d 8.6
(CH3), 29.2 (CH2), 31.6 (CH2), 41.5 (CH2), 48.6 (C), 63.9
(CH2), 77.7 (CH), 119.5 (CH2), 132.6 (CH), 180.8 (C); MS
(EI): 184 (Mþ); HRMS (EI), calcd for C10H16O3: 184.1099;
found: 184.1122.
hydride in hexane (0.95 mol/L, 6.0 mL, 5.70 mmol) was
added dropwise to a stirred solution of 10 (385 mg,
2.50 mmol) in anhydrous ether (19.0 mL) at 278 8C under
nitrogen. The mixture was stirred at the same temperature
for 1 h. After the reaction mixture was allowed to warm to
room temperature, MeOH (12 mL), methyl orthoformate
(1.0 mL, 9.14 mmol) and p-toluenesulfonic acid (1.59 g,
8.36 mmol) were added to the mixture, and the resulting
solution was heated at refluxing temperature for 40 min.
After cooling, the mixture was diluted with AcOEt and the
organic solution was washed with saturated aqueous
NaHCO3, brine, and dried over anhydrous Na2SO4 and
then concentrated. The residual oil was purified by flash
column chromatography on silica gel with hexane–AcOEt
(10:1) as eluant to afford 11 (355 mg, 84%) as an
inseparable mixture of diastereoisomers (17:14). IR (neat)
4.1.2. (3R)-3-Ethyldihydro-5-hydroxy-3-(2-propenyl)-
2(3H)-furanone (9). To
a solution of 8 (827 mg,
4.49 mmol) in dioxane (113 mL) was added 4 M aqueous
NaOH (45 mL) and the mixture was heated at 100 8C for
1 h. After cooling, the reaction mixture was neutralized with
dry ice. To the milky suspension was added a solution of
NaIO4 (2.42 g, 11.3 mmol) in H2O (20 mL) and the
suspension was stirred at room temperature for 3 h. After
quenched with 1 M HCl–H2O (180 mL), the reaction
mixture was extracted with CH2Cl2 (3£100 mL). The
combined extracts were washed with saturated aqueous
NaHCO3, brine, and dried over anhydrous Na2SO4 and
concentrated. The residual oil was purified by flash column
chromatography on silica gel with hexane–AcOEt (2:1) as
eluant to afford diastereoisomers 9 (727 mg, 95%) as
colorless oil. The ratio of the diastereoisomeric mixture
could not be determined because of broad signals observed
in the 1H NMR spectrum; IR (neat) 3400, 1750, 1645, 1195,
930 cm21; 1H NMR (CDCl3): d 0.94 (3H, br s), 68 (2H, br
s), 2.07 (1H, br s), 2.35 (2H, br s), 4.98 (1H, br s), 5.10–5.20
(2H, br m), 5.73 (1H, br s), 5.83 (1H, br s); 13C NMR
(CDCl3; DEPT) d 8.7 (CH3), 29.8 (CH2), 38.4 (CH2), 41.0
(CH2), 48.4 (C), 96.9 (CH), 119.7 (CH2), 132.8 (CH), 180.6
(C); MS (EI): 170 (Mþ); HRMS (EI), calcd for C9H14O3:
170.0943; found: 170.0932.
1
1645, 1455, 1105, 1030, 915 cm21; H NMR (CDCl3): d
0.87 and 0.88 (3H, t, J¼7.3 Hz), 1.25–1.59 (2H, m), 1.66–
1.81 (2H, m), 2.03–2.34 (2H, m), 3.33 and 3.34 (3H, s),
3.84–3.92 (1H, m), 3.93–3.98 (1H, m), 4.47 and 4.48 (1H,
s), 5.00–5.10 (2H, m), 5.72–5.83 (1H, m); 13C NMR
(CDCl3; DEPT) d 8.2 and 9.2 (CH3), 24.5 and 26.8 (CH2),
33.7 and 33.8 (CH2), 36.0 and 37.9 (CH2), 49.5 and 50.0
(C), 54.6 and 54.7 (CH3), 65.9 and 65.9 (CH2), 108.6 and
108.8 (CH), 116.7 and 117.7 (CH2), 134.4 and 135.8 (CH);
MS (EI): 170 (Mþ); HRMS (EI), calcd for C10H18O2:
170.1307; found: 170.1332.
4.1.5. (3R)-3-Ethyltetrahydro-2-methoxy-3-furanpro-
panol (12a,b). To a solution of 11 (976 mg, 5.73 mmol)
in absolute THF (23 mL) was added a solution of 0.5 M
9-borabicyclo[3,3,1]nonane (9-BBN; 36.7 mL, 18.4 mmol)
in hexane dropwise for a period of 15 min under nitrogen
atmosphere and the mixture was stirred at room temperature
overnight. The mixture was allowed to cool to 0 8C. To the
cold solution was added H2O (20 mL), 3 M aqueous NaOH
(31.2 mL, 93.6 mmol), and 30% H2O2 (8.33 mL,
81.5 mmol) and the mixture was warmed again to room
temperature. After stirring for 1 h, the mixture was extracted
with ether (twice). The combined organic extracts were
washed with H2O and brine, and dried over anhydrous
Na2SO4 and concentrated to give an oil that was purified by
flash column chromatography on silica gel with hexane–
AcOEt (1:1) as eluant to afford 12a,b (567 mg, 87% as
collected yield) as a mixture of diastereomers (17:14) and
recovered 11 (377 mg, 39%). The sample for physical
analysis was separated by repeated TLC on silica gel with
hexane–AcOEt (2:3). 12a: [a]2D0 þ79.98 (c 1.6, CHCl3); IR
4.1.3. (3R)-3-Ethyldihydro-3-(2-propenyl)-2(3H)-fura-
none (10). Sodium borohydride (156 mg, 4.12 mmol) was
added to a solution of 9 (350 mg, 2.06 mmol) in MeOH
(7.7 mL). After stirring at room temperature for 1 h, the
reaction mixture was acidified with 4 M HCl–MeOH
(0.94 mL) and heated at 70 8C for 1 h. After the reaction
mixture was allowed to cool to room temperature, the
resulting mixture was diluted with CH2Cl2 and the solution
was washed with saturated aqueous NaHCO3, brine, and
dried over anhydrous Na2SO4 and concentrated. The
residual oil was purified by flash column chromatography
on silica gel with hexane–AcOEt (4:1) as eluant to afford 10
(293 mg, 92%) as a colorless oil; [a]2D0 223.38 (c 1.6,
(neat) 3400, 1460, 1100, 1055, 920 cm21 1H NMR
;
(CDCl3): d 0.86 (3H, t, J¼7.3 Hz), 1.34 (1H, dq, J¼14.7,
7.3 Hz), 1.43 (1H, dq, J¼14.7, 7.3 Hz), 1.48–1.53 (4H, m),
1.67–1.77 (2H, m), 3.33 (3H, s), 3.58–3.70 (2H, m), 3.87
(1H, q, J¼8.4 Hz), 3.93 (1H, td, J¼8.4, 4.3 Hz), 4.47 (1H,
s); 13C NMR (CDCl3; DEPT) d 8.2 (CH3), 26.2 (CH2), 26.9
(CH2), 28.1 (CH2), 34.1 (CH2), 49.4 (C), 54.5 (CH3), 63.4
(CH2), 65.8 (CH2), 108.9 (CH); MS (EI): 187 (Mþ21);
HRMS (EI), calcd for C10H19O3 (Mþ21): 187.1334; found:
187.1342. 12b: [a]2D0 283.78 (c 0.99, CHCl3); IR (neat)
1
CHCl3); IR (neat) 2980, 1770, 1375, 1190, 1030 cm21; H
NMR (CDCl3): d 0.96 (3H, t, J¼7.3 Hz), 1.65 (2H, qd,
J¼7.3, 1.5 Hz), 2.10 (1H, dq, J¼14.6, 7.3 Hz), 2.19 (1H, dq,
J¼14.6, 7.3 Hz), 2.30 (1H, ddt, J¼13.7, 8.3, 1.0 Hz), 2.17
(1H, ddt, J¼13.7, 6.8, 1.5 Hz), 4.22 (2H, t, J¼7.3 Hz),
5.12–5.19 (2H, m), 5.68–5.82 (1H, m); 13C NMR (CDCl3;
DEPT) d 8.7 (CH3), 29.2 (CH2), 30.8 (CH2), 40.4 (CH2),
46.5 (C), 65.3 (CH2), 119.3 (CH2), 132.9 (CH), 180.8 (C);
MS (EI): 154 (Mþ); HRMS (EI), calcd for C9H14O2:
154.0994; found: 154.0985.
1
3400, 1460, 1100, 1055, 920 cm21; H NMR (CDCl3) d
0.85 (3H, t, J¼7.3 Hz), 1.31–1.39 (1H, m), 1.40–1.46 (1H,
m), 1.46–1.60 (4H, m), 1.67–1.78 (2H, m), 3.33 (3H, s),
3.64 (2H, t, J¼6.6 Hz), 3.88 (1H, q, J¼8.4 Hz), 3.94 (1H, td,
J¼8.4, 4.0 Hz), 4.47 (1H, s); 13C NMR (CDCl3; DEPT): d
4.1.4. (3R)-3-Ethyltetrahydro-2-methoxy-3-(2-pro-
penyl)furan (11). A solution of 0.95 M diisobutylalminum

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H. Tanino et al. / Tetrahedron 60 (2004) 3273–3282
9.2 (CH3), 24.2 (CH2), 27.3 (CH2), 29.6 (CH2), 34.4 (CH2),
49.5 (C), 54.7 (CH3), 63.5 (CH2), 65.8 (CH2), 109.0 (CH);
MS (EI): 187 (Mþ21); HRMS (EI), calcd for C10H19O3
(Mþ21): 187.1334; found: 187.1353.
1.2, CHCl3); IR (KBr) 1710, 1450, 1190, 1100, 1025 cm21
;
1H NMR (CDCl3): d 0.86 (3H, t, J¼7.3 Hz), 1.47 (1H, dq,
J¼14.7, 7.3 Hz), 1.56 (1H, dq, J¼14.7, 7.3 Hz), 1.65–1.81
(4H, m), 2.27–2.37 (2H, m), 3.33 (3H, s), 3.90 (1H, q,
J¼8.1 Hz), 3.95 (1H, td, J¼8.1, 4.4 Hz), 4.48 (1H, s); 13C
NMR (CDCl3; DEPT) d 9.1 (CH3), 24.2 (CH2), 28.3 (CH2),
29.2 (CH2), 34.1 (CH2), 49.3 (C), 54.8 (CH3), 65.7 (CH2),
108.5 (CH), 179.7 (C); MS (EI): 201 (Mþ21). Anal. calcd
for C10H18O4: C, 59.39; H, 8.97. Found: C, 58.99; H, 8.99.
4.1.6. (3R)-3-Ethyltetrahydro-2-methoxy-3-furanpro-
panal (13a,b). Surfur trioxide pyridine complex (1.90 g,
11.9 mmol) was added to a solution of 12a,b (274 mg,
1.46 mmol), methyl sulfoxide (14.0 mL, 197 mmol) and
triethylamine (5.5 mL, 39.5 mmol) in CH2Cl2 (5.5 mL) and
the mixture was stirred at room temperature for 0.5 h under
nitrogen atmosphere. The resulting mixture was diluted with
AcOEt and washed with H2O, saturated aqueous NH4Cl,
saturated aqueous NaHCO3, and brine and dried over
anhydrous Na2SO4. Concentration of the solvent under
reduced pressure provided crude aldehyde 13a,b which was
used for next reaction without any purification; 13a
(prepared from 12a): [a]2D0 þ89.68 (c 1.4, CHCl3); IR
4.1.8. (1R,12bR)-1-Ethyl-2,3,6,7,12,12b-hexahydro-1-(2-
acetoxyethyl)-indolo[2,3-a]quinolizin-4 (1H)-one (16a)
and (1R,12bS)-1-ethyl-2,3,6,7,12,12b-hexahydro-1-(2-
acetoxyethyl)-indolo[2,3-a]quinolizin-4(1H)-one (16b).
A mixture of 14a,b (205 mg, 1.01 mmol) and tryptamine
(211 mg, 1.32 mmol) in AcOH (3.0 mL) was heated at
125 8C for 6 days. After the solvent was removed under
reduced pressure, the resulting residue was purified by flash
column chromatography on silica gel with CH2Cl2–MeOH
(20:1) as eluant to afford 16a (154 mg, 43%) and 16b
(158 mg, 44%) as a crystalline solid. Additional product 15
was isolated as an intermediate in this reaction; 16a
(recrystallization from AcOEt–hexane): mp 79–81 8C;
[a]2D0 þ77.88 (c 1.3, CHCl3); IR (KBr) 1740, 1620, 1240,
(neat) 1730, 1460, 1100, 1055, 920 cm21 1H NMR
;
(CDCl3): d 0.86 (3H, t, J¼7.3 Hz), 1.34 (1H, dq, J¼14.7,
7.3 Hz), 1.42 (1H, dq, J¼14.7, 7.3 Hz), 1.68–1.78 (2H, m),
1.79–1.89 (2H, m), 2.30–2.44 (2H, m), 3.30 (3H, s), 3.88
(1H, q, J¼8.1 Hz), 3.94 (1H, td, J¼8.1, 5.1 Hz), 9.74 (1H, t,
J¼2.2 Hz); 13C NMR (CDCl3; DEPT) d 8.2 (CH3), 23.7
(CH2), 26.4 (CH2), 33.8 (CH2), 39.8 (CH2), 49.1 (C), 54.5
(CH3), 65.8 (CH2), 108.7 (CH), 202.7 (CH); MS (EI): 186
(Mþ); HRMS (EI), calcd for C10H18O3: 186.1256; found:
186.1237. 13b (prepared from 12b): [a]2D0 291.48 (c 1.5,
CHCl3); IR (neat) 1730, 1460, 1380, 1100, 1060,
1135, 745 cm21 1H NMR (DMSO-d6): d 1.08 (3H, t,
;
J¼7.3 Hz), 1.16 (1H, ddd, J¼14.7, 9.9, 5.9 Hz), 1.51 (1H,
ddd, J¼14.7, 9.9, 5.9 Hz), 1.52–1.59 (1H, m), 1.78 (1H, dq,
J¼14.7, 7.3 Hz), 1.87 (3H, s), 1.89–1.96 (1H, m), 1.99 (1H,
dq, J¼14.7, 7.3 Hz), 2.31–2.44 (2H, m), 2.54–2.61 (1H,
m), 2.65 (1H, td, J¼11.7, 2.2 Hz), 2.72 (1H, br d,
J¼14.3 Hz), 3.79 (1H, td, J¼10.6, 5.9 Hz), 3.95 (1H, td,
J¼10.6, 5.9 Hz), 4.88 (1H, s), 4.88–4.91 (1H, m), 6.99 (1H,
td, J¼7.7, 1.0 Hz), 7.07 (1H, td, J¼7.7, 1.0 Hz), 7.42 (1H,
dd, J¼7.7, 1.0 Hz), 7.45 (1H, dd, J¼7.7, 1.0 Hz), 10.31 (1H,
br s); 13C NMR (CDCl3; DEPT) d 8.2 (CH3), 20.9 (CH3),
21.1 (CH2), 27.5 (CH2), 28.9 (CH2), 30.3 (CH2), 30.5 (CH2),
38.8 (C), 41.2 (CH2), 60.3 (CH2), 60.7 (CH), 111.1 (CH),
113.5 (C), 118.3 (CH), 119.9 (CH), 122.4 (CH), 126.4 (C),
130.4 (C), 136.3 (C), 169.8 (C), 171.1 (C); MS (EI): 354
(Mþ). Anal. calcd for C21H26N2O3: C, 71.16; H, 7.39; N,
7.90. Found: C, 70.74; H, 7.51; N, 7.86. 16b (recrystalliza-
tion from AcOEt–hexane): mp 75–77 8C; [a]2D0 284.08 (c
1
1030 cm21; H NMR (CDCl3): d 0.85 (3H, t, J¼7.3 Hz),
1.48 (1H, dq, J¼14.7, 7.3 Hz), 1.56 (1H, dq, J¼14.7,
7.3 Hz), 1.62–1.72 (3H, m), 1.73–1.82 (1H, m), 2.35–2.45
(2H, m), 3.31 (3H, s), 3.89 (1H, q, J¼8.1 Hz), 3.95 (1H, td,
J¼8.1, 4.0 Hz), 9.80 (1H, t, J¼1.5 Hz); 13C NMR (CDCl3;
DEPT) d 9.1 (CH3), 24.3 (CH2), 25.5 (CH2), 34.2 (CH2),
39.1 (CH2), 49.2 (C), 54.7 (CH3), 65.7 (CH2), 108.6 (CH),
202.0 (CH); MS (EI): 186 (Mþ); HRMS (EI), calcd for
C10H18O3: 186.1256; found: 186.1243.
4.1.7. (3R)-3-Ethyltetrahydro-2-methoxy-3-furanpro-
panoic acid (14a,b). To a solution of aldehydes 13a,b in
tert-butylalcohol (11.8 mL) was added 2-methyl-2-butene
(0.68 mL, 6.42 mmol), sodium dihydrogenphosphate
dihydrate (228 mg, 1.46 mmol) and H2O (3.0 mL) and
sodium chlorite (544 mg, 6.02 mmol) portionwise over 1 h
under vigorous stirring. After cooling to 0 8C, the mixture
was acidified with 1 M HCl, and then extracted with CH2Cl2
(three times). The combined extracts were dried over
anhydrous Na2SO4 and concentrated to give an oil which
was purified by flash column chromatography on silica gel
with hexane–AcOEt (1:1) as eluant to afford 14a,b
(280 mg, 95%) as a mixture of diastereomers (17:14). 14a
(prepared from 13a): [a]D20 þ77.88 (c 1.3, CHCl3); IR (neat)
1.3, CHCl3); IR (KBr) 1720, 1630, 1235, 1035, 740 cm21
;
1H NMR (DMSO-d6): d 0.64 (3H, t, J¼7.3 Hz), 0.89 (1H,
dq, J¼14.7, 7.3 Hz), 1.28 (1H, dq, J¼14.7, 7.3 Hz), 1.60
(1H, ddd, J¼13.6, 6.2, 4.4 Hz), 1.90–2.02 (2H, m), 2.06
(3H, s), 2.18 (1H, ddd, J¼15.0, 8.8, 6.6 Hz), 2.26 (1H, ddd,
J¼17.6, 11.0, 6.2 Hz), 2.38 (1H, ddd, J¼17.6, 6.2, 4.4 Hz),
2.53–2.60 (1H, m), 2.65 (1H, td, J¼11.7, 3.0 Hz), 2.68–
2.74 (1H, m), 4.29 (1H, ddd, J¼11.0, 8.8, 6.6 Hz), 4.39 (1H,
ddd, J¼11.0, 8.8, 5.9 Hz), 4.88 (1H, dd, J¼11.7, 3.0 Hz),
4.94 (1H, s), 6.99 (1H, td, J¼7.3, 1.0 Hz), 7.07 (1H, td,
J¼7.3, 1.0 Hz), 7.41 (1H, dd, J¼7.3, 1.0 Hz), 7.42 (1H, dd,
J¼7.3, 1.0 Hz), 10.32 (1H, br s); 13C NMR (CDCl3; DEPT)
d 6.9 (CH3), 21.2 (2 carbons: CH3 and CH2), 23.8 (CH2),
27.2 (CH2), 28.9 (CH2), 34.9 (CH2), 38.9 (C), 40.8 (CH2),
60.5 (CH), 61.4 (CH2), 111.4 (CH), 112.9 (C), 117.9 (CH),
119.4 (CH), 122.0 (CH), 126.2 (C), 129.8 (C), 136.7 (C),
169.7 (C), 172.8 (C); MS (EI): 354 (Mþ). Anal. calcd for
C21H26N2O3: C, 71.16; H, 7.39; N, 7.90. Found: C, 71.09;
H, 7.48; N, 7.89.
1
1710, 1460, 1100, 1050, 975 cm21; H NMR (CDCl3): d
0.87 (3H, t, J¼7.3 Hz), 1.33 (1H, dq, J¼14.7, 7.3 Hz), 1.42
(1H, dq, J¼14.7, 7.3 Hz), 1.69–1.80 (2H, m), 1.80–1.90
(2H, m), 2.26–2.37 (2H, m), 3.32 (3H, s), 3.88 (1H, q,
J¼8.1 Hz), 3.95 (1H, td, J¼8.1, 5.1 Hz), 4.46 (1H, s); 13C
NMR (CDCl3; DEPT) d 8.2 (CH3), 26.3 (CH2), 26.4 (CH2),
29.9 (CH2), 33.8 (CH2), 49.1 (C), 54.6 (CH3), 65.8 (CH2),
108.7 (CH), 180.0 (C); MS (EI): 201 (Mþ21); HRMS (EI),
calcd for C10H17O4 (Mþ21): 201.1127; found: 201.1119.
14b (prepared from 13b): mp 41–42 8C; [a]2D0 283.28 (c
Compound 15. [a]2D0 þ27.48 (c 1.2, CHCl3); IR (neat) 3300,

H. Tanino et al. / Tetrahedron 60 (2004) 3273–3282
3279
1635, 1460, 1040, 740 cm21; 1H NMR (DMSO-d6): d 0.75
(3H, t, J¼7.3 Hz), 1.23 (1H, dq J¼14.7, 7.3 Hz), 1.30 (1H,
dq, J¼14.7, 7.3 Hz), 1.50 (1H, ddd, J¼13.6, 9.9, 5.5 Hz),
1.67 (1H, dt, J¼13.6, 5.5 Hz), 1.73 (1H, ddd, J¼12.8, 8.4,
6.6 Hz), 1.83 (1H, ddd, J¼12.8, 8.1, 5.9 Hz), 2.21 (1H, dt,
J¼17.2, 5.5 Hz), 2.33 (1H, ddd, J¼17.2, 9.9, 5.5 Hz), 2.85
(1H, ddd, J¼13.9, 9.2, 4.8 Hz), 2.95 (1H, ddd, J¼13.9, 9.5,
7.0 Hz), 3.40 (1H, ddd, J¼13.2, 9.2, 7.0 Hz), 3.65 (1H, ddd,
J¼13.2, 9.5, 4.8 Hz), 3.69 (1H, td, J¼8.4, 5.9 Hz), 3.79 (1H,
q, J¼8.4 Hz), 4.50 (1H, s), 6.98 (1H, t, J¼7.3 Hz), 7.06 (1H,
t, J¼7.3 Hz), 7.13 (1H, d, J¼2.2 Hz), 7.33 (1H, d,
J¼7.3 Hz), 7.57 (1H, d, J¼7.3 Hz), 10.80 (1H, br s); 13C
NMR (DMSO-d6; DEPT) d 8.4 (CH3), 23.5 (CH2), 26.4
(CH2), 28.2 (CH2), 29.7 (CH2), 34.1 (CH2), 42.9 (C), 46.1
(CH2), 64.1 (CH2), 94.7 (CH), 111.3 (CH), 111.5 (C),
118.1 (CH), 118.2 (CH), 120.8 (CH), 122.6 (CH), 127.2 (C),
136.2 (C), 169.7 (C); MS (EI): 312 (Mþ2H20); HRMS (EI),
calcd for C19H24N2O2 (Mþ2H20): 312.1838; found:
312.1837.
J¼13.9, 2.2 Hz), 3.71–3.80 (1H, br m), 3.82–3.90 (1H, br
m), 4.87–4.93 (1H, m), 5.03 (1H, br s, OH), 5.06 (1H, s),
6.98 (1H, t, J¼7.3 Hz), 7.06 (1H, t, J¼7.3 Hz), 7.41 (1H, d,
J¼7.3 Hz), 7.43 (1H, d, J¼7.3 Hz), 10.29 (1H, br s); 13C
NMR (DMSO-d6; DEPT) d 7.0 (CH3), 20.8 (CH2), 24.4
(CH2), 26.8 (CH2), 28.8 (CH2), 38.2 (CH2), 38.4 (C), 40.1
(CH2), 56.6 (CH2), 60.2 (CH), 110.9 (C), 111.5 (CH), 117.3
(CH), 118.5 (CH), 120.9 (CH), 125.9 (C), 132.0 (C), 136.0
(C), 169.0 (C); MS (EI): 312 (Mþ). Anal. calcd for
C19H24N2O2: C, 73.05; H, 7.74; N, 8.97. Found: C, 72.81;
H, 7.90; N, 8.80.
4.1.10. (1R,12bR)-1-Ethyl-2,3,6,7,12,12b-hexahydro-1-
[2-[(methanesulfonyl)oxy]ethyl]indolo[2,3-a]quinolizin-
4(1H)-one (17a) and (1R,12bS)-1-ethyl-2,3,6,7,12,12b-
hexahydro-1-[2-[(methanesulfonyl)oxy]ethyl]-
indolo[2,3-a]quinolizin-4(1H)-one
(17b).
Methane-
sulfonyl chloride (40.7 mg, 0.355 mmol) was added drop-
wise to a solution of 3a (11.1 mg, 0.0355 mmol) and
4-(dimethylamino)pyridine (14.7 mg, 0.120 mmol) in
pyridine (1.3 mL) at 0 8C under N2 atmosphere. After
stirring at 0 8C for 2 h, the reaction mixture was diluted with
AcOEt. The solution was washed with saturated aqueous
NaHCO3 and brine, dried over anhydrous Na2SO4, and
concentrated. The residue was purified by preparative TLC
on silica gel with CH2Cl2–MeOH (25:1) to afford 17a
(12.7 mg, 92%) as a colorless oil; [a]2D0 þ110.08 (c 0.69,
4.1.9. (1R,12bR)-1-Ethyl-2,3,6,7,12,12b-hexahydro-1-(2-
hydroxyethyl)-indolo[2,3-a]quinolizin-4 (1H)-one (3a)
and (1R,12bS)-1-ethyl-2,3,6,7,12,12b-hexahydro-1-(2-
hydroxyethyl)-indolo[2,3-a]quinolizin-4(1H)-one (3b).
To a solution of 16a (72.2 mg, 0.204 mmol) in MeOH
(2.0 mL) was added 20% aqueous NaOH solution (80 mL,
0.40 mmol). After stirring at room temperature for 1 h, the
reaction mixture was neutralized with AcOH. The resulting
mixture was diluted with AcOEt and washed with saturated
aqueous NaHCO3 and brine, dried over anhydrous Na2SO4,
and concentrated. The resulted crystalline solid was washed
with AcOEt and collected by filtration to give 3a (45.9 mg,
72%); 3a (recrystallization from CH2Cl2–MeOH): mp
264–268 8C decomp.; [a]2D0 þ188.18 (c 0.15, CH3OH); IR
1
CHCl3); IR (neat) 1630, 1355, 1175, 955, 745 cm21; H
NMR (CDCl3): d 1.22 (3H, t, J¼7.3 Hz), 1.53 (1H, dq,
J¼14.7, 7.3 Hz), 1.69 (1H, ddd, J¼13.9, 6.6, 2.9 Hz), 1.82–
1.98 (2H, m), 1.99–2.07 (1H, m), 2.52 (1H, ddd, J¼14.9,
11.7, 6.6 Hz), 2.60 (1H, ddd, J¼18.3, 6.6, 2.9 Hz), 2.71–
2.82 (3H, m), 2.81 (3H, s), 3.94–4.02 (1H, m), 4.06–4.15
(1H, m), 4.82 (1H, s), 5.13–5.19 (1H, m), 7.14 (1H, t,
J¼7.3 Hz), 7.22 (1H, t, J¼7.3 Hz), 7.38 (1H, d, J¼7.3 Hz),
7.52 (1H, d, J¼7.3 Hz), 7.98 (1H, br s); 13C NMR (CDCl3;
DEPT) d 8.3 (CH3), 21.1 (CH2), 28.0 (CH2), 29.0 (CH2),
30.4 (CH2), 31.1 (CH2), 37.2 (CH3), 39.3 (C), 40.8 (CH2),
60.3 (CH), 65.7 (CH2), 111.1 (CH), 113.7 (C), 118.3 (CH),
120.1 (CH), 122.7 (CH), 126.3 (C), 130.1 (C), 136.2 (C),
169.7 (C); MS (EI): 294 (Mþ2MsOH); HRMS (EI), calcd
for C19H22N2O (Mþ2MsOH): 294.1732; found: 294.1744.
(KBr) 3300, 1610, 1415, 1155, 745 cm21 1H NMR
;
(DMSO-d6): d 1.01–1.07 (1H, m), 1.06 (3H, t, J¼7.3 Hz),
1.39 (1H, ddd, J¼13.9, 10.3, 5.9 Hz), 1.54 (1H, dt, J¼13.2,
5.1 Hz), 1.76 (1H, dq, J¼14.7, 7.3 Hz), 1.87 (1H, ddd,
J¼13.2, 10.3, 7.3 Hz), 1.96 (1H, dq, J¼14.7, 7.3 Hz), 2.32–
2.40 (2H, m), 2.52–2.60 (1H, m), 2.60–2.68 (1H, m), 2.68–
2.74 (1H, m), 3.22 (1H, td, J¼10.3, 5.9 Hz), 3.30 (1H, td,
J¼10.3, 5.5 Hz), 4.83 (1H, s), 4.87–4.93 (1H, m), 6.98 (1H,
t, J¼7.3 Hz), 7.06 (1H, t, J¼7.3 Hz), 7.41 (1H, d,
J¼7.3 Hz), 7.45 (1H, d, J¼7.3 Hz), 10.30 (1H, br s); 13C
NMR (DMSO-d6; DEPT) d 8.3 (CH3), 20.8 (CH2), 27.2
(CH2), 28.8 (CH2), 29.4 (CH2), 35.0 (CH2), 38.2 (C), 40.0
(CH2), 56.3 (CH2), 60.0 (CH), 110.9 (C), 111.6 (CH), 117.3
(CH), 118.5 (CH), 120.9 (CH), 125.8 (C), 131.6 (C), 136.5
(C), 169.0 (C); MS (EI): 312 (Mþ). Anal. calcd for
C19H24N2O2: C, 73.05; H, 7.74; N, 8.97. Found: C, 72.73;
H, 7.84; N, 8.93.
The preparation of 17b was carried out under the same
procedure described above in 90% yield; 17b (colorless oil):
[a]2D0 277.88 (c 1.0, CHCl3); IR (neat) 3400, 1625, 1355,
;
1180, 955 cm21 1H NMR (CDCl3): d 0.75 (3H, t,
J¼7.3 Hz), 0.99 (1H, dq J¼14.7, 7.3 Hz), 1.52 (1H, dq,
J¼14.7, 7.3 Hz), 1.73 (1H, ddd, J¼13.9, 6.6, 3.7 Hz), 1.90
(1H, td, J¼13.9, 6.6 Hz), 2.20 (1H, ddd, J¼14.7, 8.8,
5.8 Hz), 2.42 (1H, dt, J¼15.4, 8.1 Hz), 2.49 (1H, ddd,
J¼17.6, 11.7, 6.6 Hz), 2.55 (1H, ddd, J¼17.6, 6.6, 3.7 Hz),
2.69–2.83 (2H, m), 3.11 (3H, s), 4.50–4.59 (1H, m), 4.70
(1H, dt, J¼15.4, 8.1 Hz), 4.91 (1H, s), 5.12–5.17 (1H, m),
7.12 (1H, t, J¼7.3 Hz), 7.19 (1H, t, J¼7.3 Hz), 7.39 (1H, d,
J¼7.3 Hz), 7.51 (1H, d, J¼7.3 Hz), 8.72 (1H, br s); 13C
NMR (CDCl3; DEPT) d 7.0 (CH3), 21.1 (CH2), 24.0 (CH2),
27.2 (CH2), 28.8 (CH2), 36.4 (CH2), 38.2 (CH3), 39.3 (C),
40.9 (CH2), 60.7 (CH), 66.3 (CH2), 111.3 (CH), 113.7 (C),
118.1 (CH), 119.8 (CH), 122.3 (CH), 126.3 (C), 129.8 (C),
136.6 (C), 169.6 (C); MS (EI): 294 (Mþ2MsOH); HRMS
(EI), calcd for C19H22N2O (Mþ2MsOH): 294.1732; found:
294.1776.
The preparation of 3b was carried out under the same
procedure described above in 85% yield; 3b (recrystalliza-
tion from CH2Cl2–MeOH): mp 123–127 8C; [a]2D0 2141.28
(c 0.24, CH3OH); IR (KBr) 3380, 1615, 1440, 1305,
745 cm21; 1H NMR (DMSO-d6): d 0.74 (3H, t, J¼7.3 Hz),
1.21 (1H, dq, J¼14.7, 7.3 Hz), 1.29 (1H, dq, J¼14.7,
7.3 Hz), 1.52 (1H, ddd, J¼13.2, 6.6, 3.7 Hz), 1.79 (1H, dt,
J¼15.4, 5.9 Hz), 1.94–2.02 (1H, m), 2.05 (1H, ddd,
J¼15.4, 8.1, 5.9 Hz), 2.24 (1H, ddd, J¼17.6, 11.0,
6.6 Hz), 2.38 (1H, ddd, J¼17.6, 6.6, 3.7 Hz), 2.51–2.59
(1H, m), 2.62 (1H, td, J¼11.7, 2.2 Hz), 2.70 (1H, dt,

3280
H. Tanino et al. / Tetrahedron 60 (2004) 3273–3282
4.1.11. (1R,12bR)-1-Ethyl-2,3,6,7,12,12b-hexahydro-1-
[2-[(phenylseleno)ethyl]-indolo[2,3-a]quinolizin-4(1H)-
one (18a) and (1R,12bS)-1-ethyl-2,3,6,7,12,12b-hexa-
hydro-1-[2-[(phenylseleno)ethyl]-indolo[2,3-a]quino-
lizin-4(1H)-one (18b). Sodium borohydride (11 mg,
0.29 mmol) was added to a solution of 17a (29.3 mg,
0.065 mmol) and diphenyl diselenide (47.9 mg,
0.153 mmol) in EtOH (2.5 mL) at 0 8C and the mixture
was stirred at 0 8C for 30 min and then allowed to warm to
room temperature. Sodium borohydride (20 mg,
0.53 mmol) was frequently added to the reaction mixture
during 3 h. The mixture was allowed to cool to 0 8C,
neutralized with AcOH, and then diluted with AcOEt. The
organic phase was washed with saturated aqueous NaHCO3
and brine, and dried over anhydrous Na2SO4 and concen-
trated. The residue was purified by preparative TLC on
silica gel with AcOEt–hexane (3:1) to afford 18a (23.0 mg,
68%) and 23a (0.8 mg, 4%) as a colorless oil; 18a
(recrystallized from MeOH): mp 180–181 8C; [a]D20
þ151.98 (c 0.40, CHCl3); IR (CDCl3) 1630, 1440, 1420,
0.0041 mmol) in toluene (0.75 mL) was added tributyltin
hydride (19.4 mg, 0.067 mmol), and the mixture was stirred
at 100 8C for 0.5 h under argon atmosphere. After the
solvent was removed under reduced pressure, the residual
crude material was purified by preparative TLC on silica gel
with CH2Cl2–MeOH (25:1) to afford 19 (4.5 mg, 91%) as a
colorless needles (re-crystallization from benzene); mp
194–195 8C; [a]2D0 þ26.68 (c 0.23, CHCl3); IR (neat) 3340,
1635, 1465, 1270, 750 cm21; UV (MeOH, log 1) 245.8
1
(3.57), 296.4 (3.18) nm; H NMR (CDCl3): d 0.96 (3H, t,
J¼7.3 Hz), 1.63–1.96 (9H, m), 1.96–2.03 (1H, m), 2.27
(1H, ddd, J¼17.2, 10.6, 5.1 Hz), 2.38 (1H, dt, J¼17.2,
4.8 Hz), 2.75 (1H, ddd, J¼12.8, 8,1, 4.8 Hz), 3.15 (1H, t,
J¼5.9 Hz), 3.28 (1H, s), 4.34 (1H, dt, J¼12.8, 6.6 Hz), 6.63
(1H, d, J¼7.3 Hz), 6.78 (1H, t, J¼7.3 Hz), 7.06 (1H, t,
J¼7.3 Hz), 7.17 (1H, d, J¼7.3 Hz); 13C NMR (CDCl3;
DEPT) d 9.1 (CH3), 24.6 (CH2), 28.8 (CH2), 29.1 (CH2),
35.2 (CH2), 36.2 (CH2), 36.5 (CH2), 40.1 (CH2), 43.6 (C),
44.6 (CH), 69.7 (CH), 76.3 (C), 109.7 (CH), 119.4 (CH),
123.5 (CH), 127.9 (CH), 130.8 (C), 149.1 (C), 171.0 (C);
MS (EI): 296 (Mþ); HRMS (EI), calcd for C19H24N2O:
296.1889; found: 296.1867.
1
1305 cm21; H NMR (CDCl3): d 1.15 (3H, t, J¼7.3 Hz),
1.50 (1H, dt, J¼13.9, 4.4 Hz), 1.62 (1H, ddd, J¼13.9, 6.6,
3.7 Hz), 1.74 (1H, dt, J¼13.9, 4.4 Hz), 1.81 (1H, dq,
J¼14.7, 7.3 Hz), 1.85–1.94 (2H, m), 2.37 (1H, ddd,
J¼18.3, 11.6, 6.6 Hz), 2.46–2.55 (2H, m), 2.61–2.76 (4H,
m), 4.77 (1H, s), 5.05–5.13 (1H, m), 7.08–7.19 (4H, m),
7.22 (1H, t, J¼7.3 Hz), 7.24–7.30 (2H, m), 7.33 (1H, d,
J¼7.3 Hz), 7.52 (1H, d, J¼7.3 Hz), 7.78 (1H, br s); 13C
NMR (150 MHz, CDCl3; DEPT) d 8.2 (CH3), 21.0 (CH2),
21.9 (CH2), 27.8 (CH2), 28.9 (CH2), 30.0 (CH2), 33.1 (CH2),
40.5 (C), 40.9 (CH2), 60.4 (CH), 111.0 (CH), 113.5 (C),
118.3 (CH), 120.0 (CH), 122.4 (CH), 126.4 (C), 127.2 (CH),
129.0 (CH), 129.5 (C), 130.5 (C), 133.3 (C), 136.1 (C),
169.8 (C); MS (EI): 452 (Mþ). Anal. calcd for
C25H28N2OSe: C, 66.51; H, 6.25; N, 6.21. Found: C,
66.28; H, 6.31; N, 6.21.
4.1.13. (6aR,11aS,13aS,13bR)-13a-Ethyl-1,2,5,6,6a,11,
12,13,13a,13b-decahydro-11-methyl-3H-cyclopenta[ij]-
indolo[2,3-a]quinolizin-3-one (20). To a solution of 19
(4.4 mg, 0.015 mmol) and 35% formaldehyde (24 mL,
0.30 mmol) in acetonitrile (0.66 mL) was added sodium
cyanoborohydride (2.8 mg, 0.045 mmol) and the mixture
was stirred at room temperature. After 10 min, acetic acid
(30 mL, 0.50 mmol) was added to the reaction mixture,
which was further stirred at room temperature for 1 h. The
mixture was diluted with AcOEt and washed with saturated
aqueous NaHCO3 and brine, dried over anhydrous Na2SO4
and concentrated. The residue was purified by preparative
TLC on silica gel with CH2Cl2–MeOH (20:1) to afford 20
(4.0 mg, 87%) as a colorless oil; [a]2D0 237.58 (c 0.40,
1
The preparation of 18b was carried out under the same
procedure described above in 88% yield and 23b at 5.6%
yield as a by-product; 18b (a colorless oil): [a]2D0 220.88 (c
CHCl3); IR (neat) 2880, 1645, 1480, 1210, 755 cm21; H
NMR (CDCl3): d 0.93 (3H, t, J¼7.3 Hz), 1.58–1.68 (2H,
m), 1.69–1.86 (6H, m), 1.96–2.06 (2H, m), 2.28–2.40 (2H,
m), 2.56 (1H, ddd, J¼13.2, 11.0, 5.1 Hz), 2.80 (3H, s), 3.06
(1H, t, J¼6.6 Hz), 3.40 (1H, s), 4.46 (1H, ddd, J¼13.2, 6.6,
3.7 Hz), 6.55 (1H, d, J¼7.3 Hz), 6.77 (1H, t, J¼7.3 Hz),
7.03 (1H, d, J¼7.3 Hz), 7.12 (1H, t, J¼7.3 Hz); 13C NMR
(CDCl3; DEPT) d 8.9 (CH3), 26.2 (CH2), 27.6 (CH2), 28.4
(CH2), 31.4 (CH2), 32.5 (CH2), 32.8 (CH3), 34.5 (CH2), 39.7
(CH2), 44.3 (C), 44.4 (CH), 70.3 (CH), 78.5 (C), 110.2
(CH), 119.4 (CH), 122.8 (CH), 127.7 (CH), 134.8 (C), 152.0
(C), 170.4 (C); MS (EI): 310 (Mþ); HRMS (EI), calcd for
C20H26N2O: 310.2045; found: 310.2046.
0.64, CHCl3); IR (neat) 3320, 1620, 1440, 1310, 740 cm21
;
1H NMR (CDCl3): d 0.69 (3H, t, J¼7.3 Hz), 0.89 (1H, dq
J¼14.7, 7.3 Hz), 1.40 (1H, dq, J¼14.7, 7.3 Hz), 1.67 (1H,
ddd, J¼13.9, 6.6, 3.7 Hz), 1.92 (1H, td J¼13.9, 6.6 Hz),
2.04 (1H, ddd, J¼14.7, 12.5, 5.1 Hz), 2.23 (1H, ddd,
J¼14.7, 12.5, 5.1 Hz), 2.44 (1H, ddd, J¼18.3, 11.7, 6.6 Hz),
2.52 (1H, ddd, J¼18.3, 6.6, 3.7 Hz), 2.65–2.77 (3H, m),
3.05 (1H, dt, J¼12.5, 5.1 Hz), 3.12 (1H, td, J¼12.5, 5.1 Hz),
4.85 (1H, s), 5.12 (1H, dt, J¼11.7, 2.9 Hz), 7.07–7.12 (2H,
m), 7.16 (1H, t, J¼7.3 Hz), 7.33 (1H, br s), 7.40 (2H, t,
J¼7.3 Hz), 7.43 (1H, d, J¼7.3 Hz), 7.47 (1H, d, J¼7.3 Hz),
7.67 (2H, d, J¼7.3 Hz); 13C NMR (CDCl3; DEPT) d 7.0
(CH3), 21.1 (CH2), 22.1 (CH2), 24.1 (CH2), 26.9 (CH2), 28.9
(CH2), 38.4 (CH2), 40.5 (C), 40.9 (CH2), 60.1 (CH), 111.0
(CH), 113.5 (C), 118.1 (CH), 119.8 (CH), 122.2 (CH), 126.2
(C), 128.2 (CH), 129.0 (C), 129.7 (CH), 130.4 (C), 134.1
(CH), 136.0 (C), 169.8 (C); MS (EI): 452 (Mþ); HRMS (EI),
calcd for C25H28N2OSe: 452.1386; found: 452.1378.
4.1.14. (2)-Vallesamidine (1). To a solution of 20 (6.9 mg,
0.022 mmol) in anhydrous THF (1.5 mL) was added lithium
aluminum hydride (6.0 mg, 0.16 mmol), and the mixture
was heated with stirring at 70 8C for 0.5 h under an argon
atmosphere. After cooling to 0 8C, two drops of water were
added to the reaction mixture, which was then diluted with
AcOEt, and filtered through a hyflo super-cel. Evaporation
of the solvent afforded an oil. The crude material was
purified by preparative TLC on silica gel with CH2Cl2–
MeOH (10:1) to afford (2)-vallesamidine (1) (5.4 mg, 82%)
as a colorless oil; [a]D20 276.68 (c 0.25, CHCl3); IR (neat)
2750, 1610, 1485, 1115, 735 cm21; UV (MeOH, log 1)
4.1.12. (6aR,11aS,13aS,13bR)-13a-Ethyl-1,2,5,6,6a,11,
12,13,13a,13b-decahydro-3H-cyclopenta[ij]-indolo[2,3-
a]quinolizin-3-one (19). To a solution of 18a (7.5 mg,
0.017 mmol) and 2,20-azobisisobutyronitrile (0.67 mg,

H. Tanino et al. / Tetrahedron 60 (2004) 3273–3282
3281
1
258.6 (3.69), 302.4 (3.18) nm; H NMR (CDCl3): d 0.90
HRMS (EI), calcd for C19H22N2O: 194.1732; found:
194.1746.
(3H, t, J¼7.3 Hz), 1.35–2.15 (12H, m), 2.25–2.50 (3H, m),
2.78 (3H, s), 2.70–3.00 (3H, br m), 6.44 (1H, br d,
J¼7.3 Hz), 6.67 (1H, br t, J¼7.3 Hz), 7.03 (1H, d,
J¼7.3 Hz), 7.07 (1H, t, J¼7.3 Hz); 13C NMR (CDCl3;
DEPT) d 9.1 (CH3), 18.1 (CH2), 26.4 (CH2), 27.3 (CH2),
30.1 (CH2), 31.0 (CH3), 31.2 (CH2), 35.4 (CH2), 44.0 (CH),
44.4 (C), 49.6 (CH2), 50.1 (CH2), 72.6 (CH), 78.6 (C), 107.6
(CH), 117.7 (C), 122.9 (CH), 127.3 (CH), 134.6 (C), 151.3
(C); MS (EI): 296 (Mþ); HRMS (EI), calcd for C20H28N2:
296.2252; found: 296.2216.
4.1.17. 14,15-Dihydroeburnamenine (24a). Lithium
aluminum hydride (11.1 mg, 0.298 mmol) was added to a
solution of 23a (9.3 mg, 0.032 mmol) in anhydrous THF
(4.5 mL) and the mixture was stirred at 70 8C for 0.5 h under
argon atmosphere. After cooling, two drops of water were
added to the reaction mixture, which was then diluted with
AcOEt. The mixture was filtered through hyflo super-cel
and the filtrate was dried over anhydrous Na2SO4 and then
concentrated. The residue was purified by preparative TLC
on silica gel with CH2Cl2–MeOH (10:1) to afford 24a
(8.1 mg, 91%) as a colorless oil; [a]2D0 þ17.38 (c 0.23,
4.1.15. (12bS)-1,1-Diethyl-2,3,6,7,12,12b-hexahydro-
indolo[2,3-a]quinolizin-4(1H)-one
(22).
Tributyltin
1
hydride (20.4 mg, 0.070 mmol) was0 added to a solution of
18b (8.9 mg, 0.020 mmol) and 2,2 -azobisisobutyronitrile
(1.8 mg, 0.011 mmol) in toluene (0.9 mL), and the mixture
was stirred at 100 8C for 1 h under an argon atmosphere.
After the solvent was removed under reduced pressure,
obtained the residue was purified by preparative TLC on
silica gel with CH2Cl2–MeOH (25:1) to afford 22 (4.1 mg,
70%) as a colorless needles (recrystallization from
CH2Cl2–MeOH); mp 293–294 8C; [a]2D0 291.88 (c 0.41,
CH3OH); IR (neat) 2940, 1460, 1355, 1100, 740 cm21; H
NMR (CDCl3): d 0.93 (3H, t, J¼7.3 Hz), 1.09 (1H, dt,
J¼13.9, 4.4 Hz), 1.31 (1H, dt, J¼13.9, 1.5 Hz), 1.38 (1H, dt,
J¼13.9, 1.5 Hz), 1.56 (1H, dq, J¼14.7, 7.3 Hz), 1.73–1.83
(1H, m), 1.90–2.02 (2H, m), 2.15 (1H, dq, J¼14.7, 7.3 Hz),
2.47 (1H, td, J¼11.7, 2.9 Hz), 2.55–2.65 (2H, m), 2.95–
3.05 (1H, m), 3.24–3.37 (2H, m), 3.78 (1H, td, J¼11.7,
5.9 Hz), 3.93 (1H, s), 4.16 (1H, ddd, J¼11.7, 5.9, 1.5 Hz),
7.11 (1H, t, J¼7.3 Hz), 7.17 (1H, t, J¼7.3 Hz), 7.29 (1H, d,
J¼7.3 Hz), 7.49 (1H, d, J¼7.3 Hz); 13C NMR (CDCl3;
DEPT) d 7.5 (CH3), 17.0 (CH2), 20.6 (CH2), 23.8 (CH2),
28.9 (CH2), 31.9 (CH2), 34.1 (C), 38.4 (CH2), 44.5 (CH2),
51.2 (CH2), 59.2 (CH), 104.3 (C), 109.2 (CH), 118.1 (CH),
119.3 (CH), 120.6 (CH), 127.9 (C), 136.3 (C); MS (EI): 280
(Mþ); HRMS (EI), calcd for C19H24N2: 280.1939; found:
280.1919.
CHCl3); IR (neat) 3270, 1620, 14440, 1310, 750 cm21; H
1
NMR (CDCl3): d 0.74 (3H, t, J¼7.3 Hz), 0.99 (1H, dq
J¼14.7, 7.3 Hz), 1.20 (1H, t, J¼7.3 Hz), 1.48 (1H, dq,
J¼14.7, 7.3 Hz), 1.62 (1H, ddd J¼11.7, 6.6, 2.9 Hz), 1.81
(1H, dq, J¼14.7, 7.3 Hz), 1.86–1.96 (2H, m), 2.46 (1H,
ddd, J¼17.6, 11.7, 6.6 Hz), 2.53 (1H, ddd, J¼17.6, 6.6,
2.9 Hz), 2.53 (1H, ddd, J¼17.6, 6.6, 2.9 Hz), 2.70–2.80
(3H, m), 4.85 (1H, s), 5.17 (1H, ddd, J¼10.3, 3.7, 1.5 Hz),
7.13 (1H, t, J¼8.1 Hz), 7.19 (1H, t, J¼8.1 Hz), 7.35 (1H, d,
J¼8.1 Hz), 7.51 (1H, d, J¼8.1 Hz), 7.80 (1H, br s); 13C
NMR (CDCl3; DEPT) d 7.1 (CH3), 8.2 (CH3), 21.1 (CH2),
24.3 (CH2), 26.5 (CH2), 28.9 (CH2), 29.9 (CH2), 39.1 (C),
40.9 (CH2), 60.4 (CH), 110.8 (CH), 113.2 (C), 118.2 (CH),
119.8 (CH), 122.2 (CH), 126.4 (C), 131.2 (C), 136.0 (C),
170.0 (C); MS (EI): 296 (Mþ); HRMS (EI), calcd for
C19H24N2O: 296.1889; found: 296.1903.
4.1.18. (3R,16S)-14,15-Dihydroeburnamenin-19-one
(23b). The synthesis of 23b was carried out under the
same procedure described above in 88% yield; 23b
(colorless oil): [a]2D0 2132.68 (c 0.49, CHCl3); IR (neat)
1
2930, 1650, 1460, 1310, 740 cm21; H NMR (CDCl3): d
0.62 (1H, dq, J¼14.7, 7.3 Hz), 0.79 (3H, t, J¼7.3 Hz), 1.35
(1H, dq, J¼14.7, 7.3 Hz), 1.63 (1H, td, J¼13.2, 7.3 Hz),
1.87 (1H, td, J¼13.9, 7.3 Hz), 2.01 (1H, ddd. J¼13.2, 7.3,
0.7 Hz), 2.21 (1H, dd, J¼13.9, 5.9 Hz), 2.47–2.61 (2H, m),
2.70–2.88 (2H, m), 3.07 (1H, ddd, J¼13.2, 10.3, 5.1 Hz),
3.79 (1H, td, J¼11.7, 5.9 Hz), 4.22 (1H, dd, J¼11.7,
6.6 Hz), 4.44 (1H, s), 4.90 (1H, ddd, J¼13.2, 5.1, 2.2 Hz),
7.14 (1H, t, J¼7.3 Hz), 7.21 (1H, t, J¼7.3 Hz), 7.29 (1H, d,
J¼7.3 Hz), 7.50 (1H, d, J¼7.3 Hz); 13C NMR (CDCl3;
DEPT) d 7.1 (CH3), 16.9 (CH2), 20.2 (CH2), 28.7 (CH2),
29.3 (CH2), 30.4 (CH2), 35.7 (C), 38.9 (CH2), 39.8 (CH2),
60.0 (CH), 106.5 (C), 109.7 (CH), 118.5 (CH), 119.9 (CH),
121.4 (CH), 127.7 (C), 132.1 (C), 138.3 (C), 169.7 (C); MS
(EI): 294 (Mþ); HRMS (EI), calcd for C19H22N2O:
294.1732; found: 294.1703.
4.1.16. (3R,16R)-14,15-Dihydroeburnamenin-19-one
(23a). A powder of NaOH (2 mg, 0.05 mmol) was added
to a solution of 17a (12.4 mg, 0.0318 mmol) in THF
(1.0 mL) and the mixture was stirred at room temperature
for 20 min. The reaction mixture was diluted with AcOEt
and then washed with saturated aqueous NaHCO3 and brine,
dried over anhydrous Na2SO4, and concentrated. The
residue was purified by preparative TLC on silica gel with
CH2Cl2–MeOH (25:1) to afford 23a (8.8 mg, 94%) as a
colorless oil; [a]2D0 þ81.98 (c 0.45, CHCl3); IR (neat) 2930,
1650, 1460, 1010, 750 cm21; 1H NMR (CDCl3): d 1.01 (3H,
t, J¼7.3 Hz), 1.45–1.60 (3H, m), 2.03–2.11 (2H, m), 2.11–
2.18 (1H, m), 2.26 (1H, ddd, J¼17.6, 5.1, 1.5 Hz), 2.45 (1H,
ddd, J¼17.6, 13.2, 5.9 Hz), 2.70 (1H, dd, J¼15.4, 5.1 Hz),
3.03 (1H, td, J¼12.5, 5.1 Hz), 3.07–3.15 (1H, m), 3.69 (1H,
td, J¼11.7, 5.2 Hz), 4.23 (1H, ddd, J¼11.7, 5.9, 1.5 Hz),
4.36 (1H, s), 4.96 (1H, dd, J¼12.5, 5.9 Hz), 7.13 (1H, t,
J¼7.3 Hz), 7.20 (1H, t, J¼7.3 Hz), 7.29 (1H, d, J¼7.3 Hz),
7.47 (1H, d, J¼7.3 Hz); 13C NMR (CDCl3; DEPT) d 7.3
(CH3), 20.8 (CH2), 22.3 (CH2), 28.7 (CH2), 28.9 (CH2), 31.0
(CH2), 33.4 (C), 38.6 (CH2), 43.3 (CH2), 60.7 (CH), 107.7
(C), 109.6 (CH), 118.4 (CH), 120.0 (CH), 121.4 (CH), 128.2
(C), 133.8 (C), 136.8 (C), 169.5 (C); MS (EI): 294 (Mþ);
4.1.19. (3S)-14,15-Dihydroeburnamenine (24b). Sodium
borohydride (9.0 mg, 0.24 mmol) was added to a solution of
23b (7.0 mg, 0.024 mmol) and TFA (19.0 mL, 0.25 mmol)
in absolute dioxane (1.2 mL), and the mixture was stirred at
100 8C for 45 min under nitrogen atmosphere. Concen-
tration of the solvent under reduced pressure to give a
residual oil which was purified by preparative TLC on silica
gel with CH2Cl2–MeOH (20:1) to afford 24b (5.8 mg, 87%)
as a colorless oil; [a]D20 254.48 (c 0.55, CH3OH); IR (neat)
1
2940, 1635, 1470, 1135, 740 cm21; H NMR (CDCl3): d
0.76 (3H, t, J¼7.3 Hz), 0.74–0.84 (1H, m), 1.12 (1H, td,

3282
H. Tanino et al. / Tetrahedron 60 (2004) 3273–3282
4. (a) Dickman, D. A.; Heathcock, C. H. J. Am. Chem. Soc. 1989,
111, 1528–1530. (b) Heathcock, C. H.; Norman, M. H.;
Dickman, D. A. J. Org. Chem. 1990, 55, 798–811.
5. Harley-Mason, J.; Kaplan, M. J. Chem. Soc., Chem. Commun.
1967, 915–916.
J¼13.2, 4.4 Hz), 1.60 (1H, br d, J¼13.6 Hz), 1.68–1.82
(2H, m), 1.88 (1H, br dt, J¼12.8, 2.2 Hz), 1.91–2.02 (1H,
m), 2.06 (1H, dd. J¼13.9, 5.1 Hz), 2.24 (1H, td, J¼12.8,
2.2 Hz), 2.47 (1H, td, J¼12.1, 4.4 Hz), 2.71 (1H, dt, J¼15.4,
2.6 Hz), 2.90–2.99 (1H, m), 2.95 (1H, s), 3.02–3.12 (2H,
m), 3.77 (1H, td, J¼12.1, 5.5 Hz), 4.11 (1H, dd, J¼11.7,
6.6 Hz), 7.09 (1H, t, J¼7.3 Hz), 7.14 (1H, t, J¼7.3 Hz), 7.25
(1H, d, J¼7.3 Hz), 7.46 (1H, d, J¼7.3 Hz); 13C NMR
(CDCl3; DEPT) d 7.3 (CH3), 18.5 (CH2), 21.4 (CH2), 21.6
(CH2), 31.4 (CH2), 32.0 (CH2), 35.2 (C), 39.3 (CH2), 53.5
(CH2), 56.1 (CH2), 68.0 (CH), 105.2 (C), 109.1 (CH), 118.1
(CH), 119.2 (CH), 120.3 (CH), 127.9 (C), 134.0 (C), 137.3
(C); MS (EI): 280 (Mþ); HRMS (EI), calcd for C19H24N2:
280.1939; found: 280.1910.
6. (a) Fuji, K.; Node, M.; Nagasawa, H.; Naniwa, Y.; Terada, S.
J. Am. Chem. Soc. 1986, 108, 3855–3856. (b) Node, M.;
Nagasawa, H.; Fuji, K. J. Org. Chem. 1990, 55, 517–521.
7. Schultz, A. G.; Pettus, L. J. Org. Chem. 1997, 62, 6855–6861.
8. Levy, J.; Mauperin, P.; Maindreville, M. D.; Le Men, J.
Tetrahedron Lett. 1971, 1003–1006.
9. (a) Zhang, W. Tetrahedron 2001, 57, 7237–7262, and
references cited therein. (b) Ziegler, F. E.; Belema, M.
J. Org. Chem. 1994, 59, 7962–7967.
10. Tanino, H.; Fukuishi, K.; Ushiyama, M.; Okada, K.
Tetrahedron Lett. 2002, 43, 2385–2388.
References and notes
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1621–1624.
1. (a) Walser, A.; Djerassi, C. Helv. Chim. Acta 1965, 48,
391–404. (b) Brown, S. H.; Djerassi, C.; Simpson, P. G. J. Am.
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12. In Ref. 6, it is noted that optical purity of (3S,2E)-3-
ethyltetrahydro-3-(2-nitroethenyl)-2H-Pyran-2-one, a starting
material for the synthesis of indole alkaloids, is 82% ee. Our
starting material 7 utilized for the synthesis of vallesamidine is
,100% optically pure.
2. (a) Cordell, G. A. The alkaloids; Manske, R. H. F., Rodrigo,
R., Eds.; Academic: New York, 1979; Vol. XVII, pp 199–384.
(b) Smith, G. F. The alkaloids; Manske, R. H. F., Ed.;
Academic: New York, 1960; Vol. VIII, pp 591–671.
3. Padwa, A.; Harring, S. R.; Semones, M. A. J. Org. Chem.
1998, 63, 44–54.
13. Coffen, D. L.; Katonak, D. A.; Wong, F. J. Am. Chem. Soc.
1974, 96, 3966–3973.