Synthesis of trans-perhydroisoquinolines by 6-endo-trig radical cyclization of amino-tethered vinyl bromides and cyclohexenes

Article abstract of DOI:10.1016/j.tet.2006.11.087

Bu₃SnH-promoted cyclization of several N-(2-bromoprop-2-enyl)-N-[(4-oxocyclohex-1-enyl)methyl]alkylamines is reported. It has been found that the generated vinyl radicals evolve through a 6-endo-cyclization pathway giving rise to the correspond

Full text of DOI:10.1016/j.tet.2006.11.087

Tetrahedron 63 (2007) 1372–1379
Synthesis of trans-perhydroisoquinolines by 6-endo-trig radical
cyclization of amino-tethered vinyl bromides and cyclohexenes
*
Josefina Quirante, Xavier Vila, Laura Paloma, Josep M. Guiu and Josep Bonjoch
*
Laboratori de Quꢀımica Orgaꢁnica, Facultat de Farmaꢁcia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028-Barcelona, Spain
Received 17 October 2006; revised 27 November 2006; accepted 30 November 2006
Available online 20 December 2006
Abstract—Bu3SnH-promoted cyclization of several N-(2-bromoprop-2-enyl)-N-[(4-oxocyclohex-1-enyl)methyl]alkylamines is reported. It
has been found that the generated vinyl radicals evolve through a 6-endo-cyclization pathway giving rise to the corresponding 4,6-function-
alized perhydroisoquinolines in a prevalent trans-relative configuration.
Ó 2006 Elsevier Ltd. All rights reserved.
R
N
R
N
1. Introduction
6-endo
5-exo
or 6-exo
3-Azacarboradicals centered at a vinyl carbon have been lit-
tle used for the synthesis of nitrogen-containing six-mem-
bered rings.1,2 Since Padwa’s pioneering studies in this
field about the 5-exo versus 6-endo regioselectivity,3 work-
ing with vinyl halides and Bu3SnH, and Crich’s reevaluation
of this process,4 few valuable syntheses have been reported
involving either 6-endo5 or 6-exo cyclizations.6 Different
competitive pathways encountered in attempts to form a six-
membered ring through a radical process are depicted in
Scheme 1. The aforementioned 5-exo versus 6-endo dichot-
omy appears when starting from 1-alkenyl-3-aza-5-hexenyl
radicals, while 1-alkenyl-3-aza-6-heptenyl radicals some-
times result in a competition between a 1,5-hydrogen trans-
location followed by a five-membered cyclization7 and the
6-exo cyclization process. Additionally, a problem in this
type of radical cyclizations is that the high reactivity of the
vinyl radical increases the rate of hydrogen abstraction
from the stannane resulting in simple reduction.
R2
R2
R
N
R1
R1
R3
R3
Br
R2
R1
R3
reduction
R
R
N
translocation/
cyclization
N
R2
R2
R1
R1
R3
R3
Scheme 1.
yohimbine10,11 and related indole alkaloids,12 and is found
in some synthetic compounds that exhibit several pharmaco-
logical activities.13
R
N
R
N
In this work, we decided to explore the radical process orig-
inating in vinyl radicals coming from cyclohexene-tethered
2-bromopropenylamines of structure A in order to evaluate
its regioselectivity and stereoselectivity (Scheme 2). The re-
sults reported in this paper introduce a new synthetic entry to
trans-perhydroisoquinoline derivatives.8,9 The trans-perhy-
droisoquinoline nucleus is part of the pentacyclic structure
of the potent and selective a2 adrenergic receptor antagonist
radical process
H
O
Br
H
O
O
O
A
N
N
H
H
H
H
MeO2C
OH
Keywords: Vinyl radicals; Decahydroisoquinolines; Radical cyclization;
Nitrogen heterocycles.
* Corresponding authors. Tel.: +34 934024540; fax: +34 934024539 (J.B.);
e-mail: josep.bonjoch@ub.edu
yohimbine
Scheme 2.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.087

J. Quirante et al. / Tetrahedron 63 (2007) 1372–1379
1373
2. Results and discussion
8(a–d) as the main product through a 6-endo radical process.
The corresponding cis isomers (9a–d) were also detected
through NMR and GC–MS experiments but they could not
be isolated in pure form. The yields of the ring closure varied
from 45% from 7a to 80% from 7d, the ratio of trans/cis
isomers (8/9) being around 7:1 in all the series.
Initially, we decided to prepare four vinyl halides (7a–d) to
test the aforementioned radical process. The syntheses were
carried out as outlined in Scheme 3. For the N-methyl
substituted amine 7a, the known benzylamine 1 (R¼Me)14
was subjected to Birch reduction to give the dihydroanisole
2a, which after alkylation with 2,3-dibromopropene and
treatment of the resulting enol ether 3a with ethylene glycol
in acid medium afforded the required amino alkene 7a. For
the N-benzyl derivative 7b, the Birch reduction was carried
out using the primary amine 1 (R¼H), and the resulting di-
hydroanisole15 was submitted to a reductive amination with
benzaldehyde to give 2b, which following the same syn-
thetic sequence as from 2a gave the tertiary amine 7b. The
syntheses of the amino derivatives 7c and 7d started from
p-anisyl alcohol 4, which was transformed to aldehyde 516
in a three-step sequence using a described protocol: (i) Birch
reduction, (ii) conversion of the generated enol ether into its
ethylene acetal, and (iii) oxidation with PCC. Reductive
amination of aldehyde 5 with sec-butylamine and trypt-
amine, using NaBH(OAc)3 as a reducing agent, furnished
secondary amines 6c and 6d, respectively, which in turn
were alkylated with 2,3-dibromopropene to afford the
required vinyl halides 7c and 7d.
This regiochemical outcome is probably the result of a direct
6-endo cyclization of the initially formed vinyl radical that
gives the fused radical adduct, since the amount of reducing
agent used precluded the possibility of an initial 5-exo pro-
cess and rearrangement of an homoallyl radical through a
cyclopropylcarbinyl radical. In other words, as the endo
product was formed in the presence of 2 equiv of hydride,
we assumed that its formation reflected a kinetic control
rather than the equilibration between radical intermediates
through an intramolecular rearrangement.17,18 The alkene
substitution pattern present in the radicals derived from 7 re-
tarded the usually favored 5-exo cyclization mode in benefit
of the 6-endo mode.19,20
The stereochemistry of azabicyclic compounds synthesized
was elucidated by 2D NMR spectra (COSY, HSQC). The
key evidence for the relative configuration of trans-decahy-
droisoquinolines 8 was found in the 13C NMR chemical shift
of C-1 (d 61.8 for 8a), as well as that of the methine carbons
at C-4a and C-8a (d 42.4 and 41.2, respectively, for 8a).21
The 13C NMR chemical shifts for these methine carbons
of the minor cis-decahydroisoquinolines 9a–d appear be-
tween 31.7–33.7 and 40.6–42.3.
Treatment of vinyl halides 7 (1 equiv) with Bu3SnH (2 equiv)
in refluxing benzene (100 mL) at 0.01 M concentration,
using AIBN (0.3 equiv) as the initiator, in all cases gave
the corresponding trans-perhydroisoquinoline derivative
R
N
CH2NHR
CH2NHR
(i)
Br
(ii)
R
N
(iii)
(73%) for 2a
(61%) for 2b
(58%) for 3a
(76%) for 3b
Bu3SnH, AIBN
C6H6, rfx
OMe
OMe
OMe
(66%) for 7a
(67%) for 7b
Br
1
2
3
O
O
7
R
NH
(iii)
CH2OH
CHO
(iv)
(v)
(52%) for 6c
(57%) for 6d
ref 16
(93%) for 6c
(95%) for 6d
O
O
O
O
OMe
6
4
5
R
N
R
ratio 8/9
6:1
overall yield
N
H
a R = Me
45%
57%
55%
78%
H
+
b R = Bn
7:1
CH2
CH2
H
H
c R = sec-Bu
7:1
O
O
O
O
8
9
8:1
d R = CH2CH2(3-indolyl)
Scheme 3. Synthesis of cis-decahydroquinolines. Reagents and conditions: (i) for series a: NH3 liq, Li, EtOH, ꢀ78 ꢁC. For series b: from 1 (R¼H) after the
Birch reduction, C6H5CHO, then NaBH4; (ii) 2,3-dibromopropene, LiI, K2CO3, CH3CN, rfx; (iii) (CH2OH)2, BF3$Et2O, THF, rt, 24 h; (iv) NH3 liq, Na, EtOH,
ꢀ78 ꢁC; (CH2OH)2, BF3$Et2O, THF, rt, 24 h; PCC/Celite, CH2Cl2, rfx, 2.5 h; (v) sec-butylamine (series c) or tryptamine (series d), NaBH(OAc)3, CH2Cl2,
rt, 18 h.

1374
J. Quirante et al. / Tetrahedron 63 (2007) 1372–1379
CO2Me
CO2Me
With the aim of extending the above regioselective 6-endo
cyclizations to the preparation of enantiopure compounds,
we next turned our attention to vinyl bromide 12 (Scheme 4).
Allylic mesylate 10, prepared from the corresponding alco-
hol previously used in the synthesis of aldehyde 5, was
treated with the methyl ester of tryptophan to give the enan-
tiopure secondary amine 11. Subsequent alkylation fur-
nished the required proradical compound 12, which under
the aforementioned radical conditions efficiently gave the
corresponding trans-perhydroisoquinoline ring in 75%
yield. In contrast, from the diastereoselective point of view
O
N
(i)
(ii)
(73%)
O
N
N
H
N
H
11
(80%)
CCl3
O
O
14
15
O
O
(iii)
(86%)
CO2Me
CO2Me
O
1
N
the result was disappointing, since H NMR showed the
N
(ii)
(65%)
N
H
O
N
H
crude cyclization product to be a nearly equimolecular mix-
ture of the corresponding trans-perhydroisoquinolines 13a
and 13b.
CCl3
16
17
O
O
Scheme 5. Reagents and conditions: (i) Cl3CCOCl, CH2Cl2, Et3N, rfx; (ii)
Bu3SnH, AIBN, benzene, rfx; (iii) 3 N HCl, rt.
OR
CO2Me
(i)
(iii)
HN
O
N
H
4
(42%)
3. Experimental
3.1. General
O
O
O
R = H
11
10
(ii)
R = Ms
All reactions were carried out under an argon atmosphere
with dry, freshly distilled solvents under anhydrous condi-
tions. Analytical TLC was performed on SiO2 (silica gel
60 F254, Merck) or Al2O3 (ALOX N/UV254, Polygram),
and the spots were located with 1% aqueous KMnO4. Chro-
matography refers to flash chromatography and was carried
out on SiO2 (silica gel 60, SDS, 230–240 mesh ASTM) or
Al2O3 (aluminum oxide 90, Merck). Drying of organic ex-
tracts during workup of reactions was performed over anhy-
drous Na2SO4. Chemical shifts of 1H and 13C NMR spectra
are reported in parts per million downfield (d) from Me4Si.
In 13C NMR analysis, always a DEPT experiment was
included. Two-dimensional NMR experiments (gCOSY
and gHSQC) were performed in a Varian Mercury 400
instrument.
CO2Me
N
(v)
N
(iv)
(83%)
H
(75%)
Br
O
O
12
CO2Me
H
CO2Me
H
N
O
N
N
H
N
H
+
H
H
O
13a
13b
O
O
3.1.1. N-[(4-Methoxy-2,5-dihydrophenyl)methyl]methyl-
amine (2a). A solution of N-methyl-p-methoxybenzyl-
amine14 (1a, 2.94 g, 19.4 mmol) in EtOH (59 mL) was
added to liquid ammonia (60 mL) at ꢀ78 ꢁC. To this mixture
was added portionwise Li (136 mg, 7 equiv) over 1 h. After
quenching with NH4Cl (4 g) in H2O (15.6 mL), the solvents
were removed, the aqueous suspension was extracted with
CH2Cl2, and the organic extracts were dried and concen-
trated to give 2.25 g (73%) of 2a, which was used without
Scheme 4. Reagents and conditions: (i) mesyl chloride, TEA, THF, 0 ꢁC,
45 min; (ii) tryptophane methyl ester, Na2CO3, CH3CN, 40 ꢁC, overnight;
(iii) 2,3-dibromopropene, LiI, K2CO3, CH3CN, rfx, 24 h; (iv) Bu3SnH,
AIBN, benzene, rfx, 3 h.
At this point, we decided to use another type of proradical to
check if it was possible to increase the diastereoselectivity
while maintaining the 6-endo regioselectivity. Thus, we pre-
pared the trichloroacetamide 14 to test the radical cycliza-
tion.22 In this new series, the regioselectivity changed, and
azaspirane 15 being isolated as the only cyclized com-
pound.23 When the reaction was carried out with trichloro-
acetamide 16, which might have a slightly different
geometry, the synthetic result disappointingly was similar
leading to azaspirane 17 (Scheme 5).24
1
further purification. H NMR (300 MHz) 2.40 (br s, 4H,
H-3 and H-6), 2.77 (s, 3H, NCH3), 2.31 (s, 2H, NCH2),
3.56 (s, 3H, OCH3), 4.67 (s, 1H, H-5), 5.37 (s, 1H, H-2);
13C NMR (75 MHz) 27.9 and 28.9 (C-6 and C-9), 35.7
(NCH3), 53.8 (OCH3), 57.1 (NCH2), 90.2 (C-5), 119.1 (C-
2), 133.6 (C-1), 152.7 (C-4).
In summary, a new synthetic entry to functionalized trans-
decahydroisoquinolines has been reported. Since the
observed stereoselectivity in the radical cyclization of
N-alkyl-1-vinyl-3-aza-5-hexenyl radicals bearing a cyclo-
hexenone ring gives access to yohimbine-type stereochemis-
tries, decahydroisoquinolines 8d and 13 could be applied to
the synthesis of yohimban indole alkaloids.
3.1.2. N-[(4-Methoxy-2,5-dihydrophenyl)methyl]benzyl-
amine (2b). A mixture of benzaldehyde (1.31 g, 106 mmol)
and dihydroanisole 2 (R¼H,15 1.93 g, 13.9 mmol) in CH2Cl2
˚
(12 mL) was stirred at rt for 3 h with activated 4 A molec-
ular sieves. The mixture was filtered through a short pad of
Celite and concentrated. The resulting crude imine in MeOH
(32 mL) was treated with NaBH4 (0.93 g, 37.8 mmol), and

J. Quirante et al. / Tetrahedron 63 (2007) 1372–1379
1375
the reaction mixture was stirred for 4 h. After quenching
with H2O (30 mL), MeOH was evaporated, and the resulting
aqueous suspension was extracted with CH2Cl2 and washed
with brine. The organic extracts were dried, concentrated,
and the residue was purified by chromatography (EtOAc/
hexane 9:1) to afford 1.93 g (61%) of 2b. 1H NMR
(200 MHz) 2.78 (br s, 4H, H-3 and H-6), 3.20 (s, 2H,
NCH2), 3.55 (s, 3H, OCH3), 3.75 (s, 2H, CH2Ph), 4.65 (m,
W1/2¼8 Hz, 1H, H-5), 5.60 (m, W1/2¼8 Hz, 1H, H-2),
7.20–7.40 (m, 5H, ArH); 13C NMR 28.0 and 28.9 (C-3 and
C-6), 53.0 (CH2Ph), 53.9 (OCH3), 54.4 (NCH2), 90.4
(C-5), 119.1 (C-2), 126.8, 128.1, 128.3 (C-o, C-m, C-p),
134.5 (C-1), 140.4 (C-ipso), 152.8 (C-4).
aldehyde 5 (768 mg, 4.6 mmol) and tryptamine (737 mg,
4.60 mmol), and after workup, 1.37 g (95%) of 6d was iso-
lated, which was used without further purification. 1H NMR
(200 MHz) 1.65 (t, J¼7 Hz, 2H, H-5), 2.24 (m, 4H, H-3 and
H-6), 2.65 and 2.85 (2m AA0BB0 system, 4H, InCH2CH2N),
3.97 (s, 4H, OCH2), 5.5 (m, W1/2¼8 Hz, 1H, H-2), 6.98 (d,
J¼2 Hz, 1H, H-20), 7.00–7.22 (m, 2H, H-50 and H-60), 7.30
(d, J¼7 Hz, 1H, H-70), 7.60 (d, J¼7 Hz, 1H, H-40), 7.90
(br s, 1H, NH); 13C NMR 23.0 (CH2In), 26.0 (C-5), 31.0
and 35.7 (C-3 and C-6), 53.8 (NCH2), 60.1 (CH2CBr),
64.4 (OCH2), 108.3 (C-4), 111.0 (C-70), 114.5 (C-30), 117.7
(]CH2), 118.9 (C-50), 119.1 (C-60), 121.6 (C-2), 121.9 (C-
20), 127.5 (C-3a), 132.8 (BrC]), 135.8 (C-7a), 136.2 (C-1).
3.1.3. N-(2-Bromoprop-2-enyl)-N-[(4-methoxy-2,5-dihy-
drophenyl)methyl]methylamine (3a). To a solution of
amine 2a (0.5 g, 3.26 mmol) in acetonitrile (11 mL) were
added 2,3-dibromopropene (1.01 mL, 9.8 mmol), LiI
(568 mg, 4.84 mmol), and K2CO3 (1.03 g, 7.5 mmol), and
the reaction mixture was heated at reflux temperature for
24 h. After filtration and concentration, the residue was par-
titioned between H2O and CH2Cl2 and the aqueous layer was
extracted with CH2Cl2. The dried organic extracts were con-
centrated and the residue was purified by chromatography to
yield 0.52 g (58%) of 8a: 1H (400 MHz) 2.72–2.79 (m, 2H,
H-6), 2.79–2.85 (m, 2H, H-3), 2.93 (s, 2H, NCH2), 3.10 (s,
2H, CH2CBr), 3.55 (s, 3H, OCH3), 4.65 (m, W1/2¼8 Hz,
1H, H-5), 5.56 (s, 1H, ]CH), 5.59 (m, W1/2¼8 Hz, 1H,
H-2), 5.85 (d, J¼1.2 Hz, 1H, ]CH); 13C NMR (100 MHz)
28.0 and 29.1 (C-3 and C-6), 41.9 (NCH3), 53.9 (OCH3),
63.5 (NCH2), 65.0 (CH2CBr), 90.8 (C-5), 118.1 (]CH2),
121.0 (C-2), 124.8 (]CBr), 133.5 (C-1), 152.5 (C-4).
3.1.7. N-(2-Bromoprop-2-enyl)-N-[(4-oxocyclohex-1-
enyl)methyl]methylamine ethylene acetal (7a). To a
cooled solution (0 ꢁC) of the enol ether 8a (0.14 g,
0.52 mmol) in THF (0.9 mL) were added ethylene glycol
(35 mL, 0.62 mmol) and BF3$OEt2 (66 mL, 0.52 mmol).
After stirring overnight, saturated aqueous NaHCO3 was
added, and the reaction mixture was extracted with EtOAc.
The organic extracts were dried and concentrated to give
0.10 g (66%) of 7a, which was used without further purifica-
tion in the next step. 1H NMR (400 MHz) 1.76 (t, J¼6.4 Hz,
1H, H-5), 2.18 (s, 3H, CH3), 2.04–2.07 (m, 4H, H-3 and
H-6), 2.90 (s, 2H, NCH2), 3.09 (s, 2H, CH2CBr), 3.97 (s,
4H, OCH2), 5.50 (br s, 1H, H-2), 5.54 (s, 1H, ]CH), 5.83
(s, 1H, ]CH); 13C NMR (100 MHz) 25.8 (C-5), 31.0 (C-6),
35.7 (C-3), 41.9 (CH3), 63.4 (CH2CBr), 64.3 (CH2O), 65.1
(CH2N), 108.2 (C-4), 118.2 (]CH2), 121.9 (C-2), 132.1
(C-1), 135.5 (]CBr).
3.1.8. N-(2-Bromoprop-2-enyl)-N-[(4-oxocyclohex-1-
enyl)methyl]benzylamine ethylene acetal (7b). Operating
as above, starting from enol ether 3b (400 mg, 1.15 mmol)
and after chromatography (EtOAc/hexane 9:1), 289 mg
3.1.4. N-(2-Bromoprop-2-enyl)-N-[(4-methoxy-2,5-dihy-
drophenyl)methyl]benzylamine (3b). Operating as above,
starting from 2b (390 mg, 1.31 mmol) and after chromato-
1
1
graphy, tertiary amine 3b (0.35 g, 76%) was isolated. H
(67%) of acetal 7b was isolated. H NMR 1.67 (m, 2H,
NMR (200 MHz) 2.85–3.00 (m, 4H, H-3 and H-6), 2.97 (s,
2H, NCH2), 3.20 (s, 2H, CH2CBr), 3.55 (s, 3H, OCH3),
3.56 (s, 2H, CH2Ph), 4.63 (m, W1/2¼8 Hz, 1H, H-5), 5.58
(s, 1H, ]CH), 5.60 (m, W1/2¼8 Hz, 1H, H-2), 5.93 (s, 1H,
]CH), 7.20–7.40 (m, 5H, ArH).
H-5), 2.30 (m, 4H, H-3 and H-6), 2.98 (s, 2H, NCH2), 3.10
(s, 2H, CH2CBr), 3.60 (s, 2H, CH2Ph), 4.00 (s, 4H,
OCH2), 5.50 (br s, 1H, H-2), 6.00 (s, 1H, ]CH), 5.90 (s,
1H, ]CH), 7.20–7.40 (m, 5H, ArH); 13C NMR 25.9
(C-5), 31.0 (C-6), 35.7 (C-3), 57.6 (NCH2), 59.7 (CH2CBr),
61.7 (CH2Ph), 64.2 (OCH2), 108.2 (C-4), 118.3 (]CH2),
121.9 (C-2), 132.4 (C-1), 135.5 (]CBr), 139.2 (C-ipso).
HRMS (ESI-TOF) calcd for C19H25BrNO2 (M++1)
378.1063, found 378.1076.
3.1.5. N-[(4-Oxocyclohex-1-enyl)methyl]sec-butylamine
ethylene acetal (6c). To a solution of aldehyde 516 (848 mg,
5.08 mmol) and sec-butylamine (0.51 mL, 5.08 mmol) in
dichloroethane, NaBH(OAc)3 (1.51 g, 7.11 mmol) was
added and the mixture was stirred at rt for 18 h. The reaction
mixture was quenched with aqueous saturated NaHCO3
solution, and extracted with Et2O. The ethereal extracts were
dried and concentrated to give a residue, which was submit-
ted to chromatography (SiO2, EtOAc) yielding 1.06 g (93%)
of 6c. 1H NMR (400 MHz) 0.90 (t, J¼7 Hz, 3H, CH3), 1.05
(d, J¼7 Hz, 3H, CH3), 1.35 and 1.55 (2m, 2H, CH2-sec
butyl), 1.80 (t, J¼7 Hz, 2H, H-5), 2.20–2.30 (m, 4H, H-3
and H-6), 2.60 (m, 1H, CHN), 3.10 (m, 2H, NCH2), 5.55
(m, W1/2¼8 Hz, 1H, H-2); 13C NMR (100 MHz) 10.2
(CH3), 20.0 (CH3), 26.0 (C-5), 29.5 (CH2-sec-butyl), 31.5
and 36.0 (C-3 and C-6), 52.0 (NCH2), 54.0 (NCH), 108.0
(C-4), 120.0 (C-2), 136.0 (C-1).
3.1.9. N-(2-Bromoprop-2-enyl)-N-[(4-oxocyclohex-1-
enyl)methyl]sec-butylamine ethylene acetal (7c). To a
solution of amine 6c (583 mg, 4.37 mmol) in acetoni-
trile (65 mL) were added 2,3-dibromopropene (0.59 mL,
5.68 mmol), LiI (760 mg, 5.68 mmol), and K2CO3 (785 mg,
5.68 mmol), and the reaction mixture was heated at reflux
temperature for 3 h. After filtration and concentration of
the filtrate, the residue was partitioned between H2O and
CH2Cl2, and the aqueous layer was extracted with CH2Cl2.
The dried organic extracts were concentrated and purified
1
by chromatography to yield 0.79 g (52%) of amine 7c. H
NMR 0.90 (t, J¼6.3 Hz, 3H, CH3), 0.93 (t, J¼7.2 Hz, 3H,
CH3), 1.25 and 1.50 (2m, 2H, CH2-sec-butyl), 2.10–2.52
(m, 4H, H-3 and H-6), 2.64 (q, J¼6.6 Hz, 1H, CHN), 2.84
and 3.03 (2d, J¼13.2 Hz, 2H, NCH2), 3.04 and 3.26 (2d,
J¼15.6 Hz, 2H, CH2CBr), 3.98 (s, 4H, OCH2), 5.51 (m,
3.1.6. N-[(4-Oxocyclohex-1-enyl)methyl]tryptamine eth-
ylene acetal (6d). Operating as above, starting from

1376
J. Quirante et al. / Tetrahedron 63 (2007) 1372–1379
2H, H-2 and ]CH), 5.90 (s, 1H, ]CH); 13C NMR 11.8
(CH3), 13.2 (CH3), 25.7 (C-5), 26.7 (CH2-sec-butyl), 31.0
(C-6), 35.7 (C-3), 54.7 (CHN), 55.2 (NCH2), 57.6 (CH2CBr),
64.3 (CH2O), 108.2 (C-4), 117.0 (]CH2), 121.3 (C-2), 133.9
(]CBr), 136.0 (C-1). HRMS (ESI-TOF) calcd for
C16H27BrNO2 (M++1) 344.1220, found 344.1209.
3.2.2. 2-Benzyl-4-methylene-trans-perhydroisoquinolin-
6-one ethylene acetal (8b). Operating as in the general pro-
cedure, starting from 87 mg (0.236 mmol) of 7b and after
chromatography (SiO2, hexane/EtOAc 4:6), 39 mg (57%)
of 8b, containing a 15% of cis-isomer 9b, was obtained. 1H
NMR (400 MHz, gCOSY) 1.20–2.00 (m, 6H), 1.25 (m, 1H,
H-8a), 1.90 (m, 2H, H-1 and H-4a), 2.63 (d, J¼12 Hz, 1H,
H-3), 2.89 (d, J¼11.4 Hz, 1H, H-1eq), 3.31 (dd, J¼11.4,
1.8 Hz, 1H, H-3), 3.52 and 3.58 (2d, J¼12 Hz, 2H,
CH2Ph), 3.90–4.00 (m, 4H, OCH2), 4.63 (s, 1H, ]CH),
4.78 (d, J¼1.5 Hz, 1H, ]CH), 7.20–7.40 (5H, ArH); 13C
NMR (100 MHz, gHSQC) 26.8 (C-8), 34.4 (C-5), 36.7
(C-7), 40.7 (C-8a), 42.9 (C-4a), 59.4 (C-1), 60.9 (C-3),
62.6 (CH2Ph), 64.3 and 64.5 (OCH2), 106.6 (]CH2),
109.5 (C-6), 127.0, 128.2, 129.1 (C-o, C-m, C-p), 138.0
(ipso-C), 147.0 (C-4).
3.1.10. N-(2-Bromoprop-2-enyl)-N-[(4-oxocyclohex-1-
enyl)methyl]tryptamine ethylene acetal (7d). Operating
as above, starting from 6d (1.37 g, 4.60 mmol) and after
1
chromatography, amine 7d (1.12 g, 57%) was isolated. H
NMR (200 MHz) 1.70 (t, J¼6.5 Hz, 2H, H-5), 2.20–2.40
(m, 4H, H-3 and H-6), 2.80 and 2.90 (2m AA0BB0 system,
4H, InCH2CH2N), 3.08 (s, 2H, NCH2), 3.31 (s, 2H, CH2CBr),
3.97 (s, 4H, OCH2), 5.54 (m, 2H, H-2 and ]CH), 5.90 (s, 1H,
]CH), 7.00–7.40 (m, 4H), 7.60 (d, J¼7 Hz, 1H), 7.90 (br s,
1H, NH); 13C NMR 23.0 (CH2In), 26.0 (C-5), 31.0 and 35.7
(C-3 and C-6), 53.8 (NCH2), 60.1 (CH2CBr), 62.2
(NCH2C]), 64.4 (OCH2), 108.3 (C-4), 111.0 (C-70), 114.5
(C-30), 117.7 (]CH2), 118.9 (C-50), 119.1 (C-60), 121.6
(C-2), 121.9 (C-20), 127.5 (C-30a), 132.8 (]CBr), 135.8
(C-70a), 136.2 (C-1). HRMS (ESI-TOF) calcd for
C22H28BrN2O2 (M++1) 431.1329, found 431.1321.
3.2.3. 2-sec-Butyl-4-methylene-6,6-ethylenedioxy-trans-
perhydroisoquinolin-6-one ethylene acetal (8c). Operat-
ing as in the general procedure, starting from 100 mg
(0.29 mmol) of 7c and after chromatography (SiO2,
CH2Cl2/MeOH 95:5), 48 mg (62%) of 8c, containing a
1
15% of cis-isomer 9c, was obtained. H NMR (400 MHz,
gCOSY) 0.91 (t, J¼7.2 Hz, 3H, CH3), 1.05 (d, J¼6.8 Hz,
2H, CH2-sec-butyl), 1.20–1.75 (m), 1.78 (dd, J¼12.8,
1.6 Hz, 1H, H-5eq), 1.88 (t, J¼10 Hz, H-4a), 1.91 (d,
J¼13 Hz, H-7eq), 2.05–2.25 (m, 1H, H-1), 2.57 (m, 1H,
CH-sec-butyl), 2.80–3.00 (m, 2H, H-1 and H-3), 3.23–3.33
(m, 1H, H-3), 3.80–4.00 (m, 4H, OCH2), 4.66 (s, 1H,
]CH), 4.86 (s, 1H, ]CH); 13C NMR (100 MHz, gHSQC)
11.4 (CH3), 13.5 (CH3), 25.6 (CH2), 28.0 (C-8), 34.3 (C-
5), 36.7 (C-7), 40.9 (C-8a), 43.1 (C-4a), 53.4 and 55.1 (C-
1), 55.8 and 57.5 (C-3), 60.9 (CH-sec-butyl), 64.3 and
64.4 (OCH2), 107.1 (]CH2), 109.4 (C-6), 146.5 (C-4).
HRMS (ESI-TOF) calcd for C16H28NO2 (M++1) 266.2115,
found 266.2112.
3.2. General procedure for the synthesis of trans-per-
hydroisoquinolines (8a–d) by radical cyclization
of the corresponding vinyl bromides (7a–d)
A solution of vinyl halide (1 equiv) and AIBN (0.3 equiv) in
benzene (100 mL) was heated at reflux. Then, Bu3SnH
(2 equiv) was added dropwise and the reaction mixture
was stirred at this temperature for 3 h. After removal of
the solvent, the residue was dissolved in EtOAc and ex-
tracted with aqueous 1% HCl. The aqueous phase was basi-
fied with saturated Na2CO3 and extracted with CH2Cl2.
Concentration of the dried organic extracts afforded a residue
that was purified by chromatography.
3.2.4. 2-[2-(3-Indolyl)ethyl]-4-methylene-trans-perhy-
droisoquinolin-6-one ethylene acetal (8d). Operating
as in the general procedure, starting from 125 mg
(0.29 mmol) of 7d and after chromatography (Al2O3,
CH2Cl2/MeOH 95:1), 80 mg (78%) of 8d, containing a
H
H
8a
1
N
R
O
H
1
15% of cis-isomer 9d, was obtained. H NMR (400 MHz,
4a
3
H
H
gCOSY) 0.9–1.9 (m), 1.98 (dd, J¼12, 2 Hz, 1H, H-4a),
2.02–2.30 (m, 1H, H-1), 2.80–2.95 (m, 3H, H-3 and NCH2),
3.16 (t, J¼8.4 Hz, 2H, CH2In), 3.23 (d, J¼10.8 Hz, 1H, H-
1eq), 3.66 (dd, J¼11.6, 1.6 Hz, 1H, H-3), 4.06–4.20
(m, 4H, OCH2), 4.84 (s, 1H, ]CH), 5.04 (s, 1H, ]CH),
7.16 (br s, 1H, H-20), 7.27 (t, J¼7.4 Hz, 1H, H-50), 7.37 (t,
J¼7.4 Hz, 1H, H-60), 7.49 (d, J¼8 Hz, 1H, H-7), 7.77
(d, J¼7.6 Hz, 1H, H-40), 8.5 (br s, 1H, NH); 13C NMR
(100 MHz, gHSQC) 23.1 (CH2In), 27.1 (C-8), 34.4 (C-5),
36.8 (C-7), 41.0 (C-8a), 43.0 (C-4a), 58.9 (NCH2), 59.7
(C-1), 61.2 (C-3), 64.2 and 64.3 (OCH2), 106.7 (]CH2),
109.3 (C-6), 111.1 (C-70), 114.2 (C-30), 118.7 (C-40), 119.1
(C-50), 121.5 (C-60), 121.8 (C-20), 127.4 (C-3a), 136.3 (C-
7a), 147.0 (C-4). HRMS (ESI-TOF) calcd for C22H29N2O2
(M++1) 353.2224, found 353.2213.
O
H
8 (a-d)
3.2.1. 2-Methyl-4-methylene-trans-perhydroisoquinolin-
6-one ethylene acetal (8a). Operating as above, starting
from 100 mg (0.3 mmol) of 7a and after chromatography
(Al2O3, hexane/EtOAc 7:3), 30 mg (45%) of 8a, containing
a 15% of cis-isomer 9a, was obtained. 1H NMR (400 MHz,
gCOSY) 1.32 (m, 1H, H-8a), 1.50–1.80 (m), 1.93 (dt,
J¼12.8, 2.8 Hz, 1H, H-7), 2.17 (s, 3H, NCH3), 2.53 (d,
J¼11.6 Hz, 1H, H-3), 2.85 (d, J¼10.4 Hz, 1H, H-1eq),
3.26 (dd, J¼11.6, 1.6 Hz, 1H, H-3), 3.90–4.05 (m, 4H,
OCH2), 4.63 (s, 1H, ]CH), 4.83 (d, J¼1.2 Hz, 1H,
]CH); 13C NMR (100 MHz, gHSQC) 27.9 (C-8), 34.4
(C-5), 36.7 (C-7), 41.2 (C-8a), 42.4 (C-4a), 45.9 (NCH3),
61.8 (C-1), 63.1 (C-3), 64.3 and 64.4 (OCH2), 106.5
(]CH2), 109.5 (C-6), 147.1 (C-4). HRMS (ESI-TOF) calcd
for C13H22NO2 (M++1) 224.1645, found 224.1648.
3.2.5. (2S)-N-[(4-oxocyclohex-1-enyl)methyl]tryptophan
ethylene acetal methyl ester (11). To a cooled solution
(0 ꢁC) of 4-hydroxymethylcyclohex-3-enone ethylene ace-
tal16 (1.08 g, 6.37 mmol) in THF (118 mL) were added

J. Quirante et al. / Tetrahedron 63 (2007) 1372–1379
1377
TEA (0.98 mL, 7.0 mmol) and mesyl chloride (0.5 mL,
6.37 mmol). After stirring for 1 h 30 min, the reaction mix-
ture was filtered and concentrated to give crude mesylate 10,
which was used without further purification in the next step.
To a mixture of tryptophan methyl ester (927 mg,
4.25 mmol) and Na2CO3 (675 mg, 6.37 mmol) in CH3CN
(100 mL) was added a solution of the crude mesylate 10 in
CH3CN (27 mL). The reaction mixture was heated at
45 ꢁC overnight and then filtered and concentrated to give
a residue, which was purified by chromatography (EtOAc)
(400 MHz) 1.20–1.92 (m, 6H), 1.27 (m, 1H, H-8a), 1.86
(m, 1H, H-4a), 2.10 (t, J¼10 Hz, 0.5H, H-1, diastereomer
B), 2.20 (t, J¼10 Hz, 0.5H, H-1, diastereomer A), 2.85 (d,
J¼10 Hz, 0.5H, H-3, diastereomer A), 2.86 (t, J¼10 Hz,
0.5H, H-1, diastereomer A), 2.92 (d, J¼10 Hz, 0.5H, H-3,
diastereomer B), 3.00–3.10 (m, 1.5H, CH2-In and H-1, dia-
stereomer B), 3.20–3.30 (m, 1H, CH2-In), 3.48 and 3.49 (2s,
3H, OCH3), 3.50–3.60 (m, 1H, CHN), 3.84–3.94 (m, 4H,
OCH2), 4.59 (br s, 1H, ]CH), 4.78 and 4.80 (2s, 1H,
]CH), 6.95 (br s, 1H, H-2), 7.03 (t, J¼7 Hz, 1H, H-5),
7.10 (t, J¼7 Hz, 1H, H-6), 7.25 (d, J¼8 Hz, 1H, H-7),
7.54 (dd, J¼7.6, 2.4 Hz, 1H, H-40), 7.99 (br s, 1H, NH);
13C NMR (100 MHz) diastereomer A 25.5 (CH2In), 28.1
(C-8), 34.7 (C-5), 37.0 (C-7), 41.8 (C-8a), 43.3 (C-4a),
51.2 (OCH3), 58.9 (C-1), 60.5 (C-3), 64.7 (CH2O), 68.7
(CHN), 106.9 (CH2]), 109.3 (C-acetal), 111.4 (C-7),
112.2 (C-3), 119.0 (C-4), 119.6 (C-5), 122.2 (C-6), 123.0
(C-2), 127.7 (C-3a), 136.3 (C-7a), 147.0 (C]), 172.2
(CO); diastereomer B 25.8 (CH2In), 28.2 (C-8), 34.7
(C-5), 37.0 (C-7), 41.7 (C-8a), 43.3 (C-4a), 51.3 (OCH3),
53.9 (C-1), 55.7 (C-3), 64.6 (CH2O), 68.6 (CHCOO),
106.9 (]CH2), 109.3 (C-acetal), 111.4 (C-7), 112.2 (C-3),
119.0 (C-4), 119.6 (C-5), 122.2 (C-6), 122.9 (C-2), 127.7
(C-3a), 136.3 (C-7a), 147.4 (]C), 172.2 (CO). HRMS
(ESI-TOF) calcd for C24H31N2O4 (M++1) 411.2278, found
411.2271.
1
to give 876 mg (56%) of 11. H NMR 1.60 (m, 2H, H-5),
2.10 (m, 2H, H-6), 2.20 (s, 2H, H-3), 2.98–3.20 (m, 4H,
CH2In and CH2N), 3.61 (dd, J¼7.2, 6.1 Hz, 1H, CHN),
3.64 (s, 3H, OCH3), 3.95 (s, 4H, OCH2), 5.40 (m, W1/2
¼
8 Hz, 1H, H-2), 7.07 (d, J¼2.4 Hz, 1H, H-2), 7.12 (td,
J¼7.8, 0.9 Hz, 1H, H-5), 7.19 (td, J¼7.8, 0.9 Hz, 1H,
H-6), 7.35 (d, J¼7.8, 1.3 Hz, 1H, H-7), 7.61 (dd, J¼7.8,
1.3 Hz, 1H, H-4), 8.01 (br s, 1H, NH); 13C NMR 25.8 (C-
5), 29.3 (CH2In), 30.8 and 35.4 (C-3 and C-6), 51.7
(OCH3), 53.3 (NCH2), 60.8 (CHN), 64.2 (OCH2), 108.0
(C-4), 111.1 (C-7), 118.6 (C-3), 119.2 (C-4), 120.2 (C-5),
121.9 (C-2 and C-6), 122.8 (C-20), 127.3 (C-3a), 135.2 (C-
10), 136.1 (C-7a), 175.3 (CO).
3.2.6. (2S)-N-(2-Bromoprop-2-enyl)-N-[(4-oxocyclohex-
1-enyl)methyl]tryptophan ethylene acetal methyl ester
(12). To a solution of amine 11 (140 mg, 0.57 mmol) in ace-
tonitrile (1.7 mL) were added K2CO3 (181 mg, 1.31 mmol)
and 2,3-dibromopropene (0.18 mL, 1.71 mmol). The reac-
tion mixture was heated at 55 ꢁC overnight and concentrated
to dryness. The residue was taken up in water and extracted
with CH2Cl2. Concentration of the dried organic extracts
gave a residue, which was purified by chromatography to
give 173 mg (83%) of 12. IR 3409, 2950, 1730, 1210,
1166, 1114, 1011, 1059, 742; 1H NMR 1.40–1.75 (m),
2.90–2.30 (m), 3.63 (s, 3H, OCH3), 3.80 (m, 1H, CHN),
3.95 (s, 4H, OCH2), 5.48 (m, W1/2¼8 Hz, 1H, H-2), 5.53
(s, 1H, ]CH), 5.8 (d, J¼0.6 Hz, 1H, ]CH), 7.02 (d,
J¼2.4 Hz, 1H, H-2), 7.11 (td, J¼7.5, 1.2 Hz, 1H, H-5),
7.18 (td, J¼6.9, 1.2 Hz, 1H, H-6), 7.33 (dm, J¼7.5 Hz,
1H, H-7), 7.60 (dm, J¼7.2 Hz, 1H, H-4), 7.97 (br s, 1H,
NH); 13C NMR 26.7 (CH2In), 25.9 (C-5), 30.8 and 35.6
(C-3 and C-6), 51.0 (OCH3), 56.9 (NCH2), 58.5 (CH2CBr),
61.5 (CHN), 64.2 and 64.3 (OCH2), 108.2 (C-7), 111.0 (C-
40), 111.9 (C-3), 118.2 (]CH2), 118.6 (C-4), 119.2 (C-5),
121.8 (C-6), 122.8 (C-20), 123.0 (C-2), 127.3 (C-3a), 132.5
(]CBr), 134.8 (C-10), 136.1 (C-7a), 172.7 (CO). HRMS
(ESI-TOF) calcd for C24H30BrN2O4 (M++1) 489.1383,
found 489.1379.
3.2.8. Methyl (S)-N-[(4-oxocyclohex-1-enyl)methyl]-N-
(trichloroacetyl)tryptophan ethylene acetal (14). To a so-
lution of amine 11 (267 mg, 0.72 mmol) in CH2Cl2 (1 mL)
was added triethylamine (0.11 mL, 0.79 mmol). To this
cooled solution (0 ꢁC) was added dropwise trichloroacetyl
chloride (0.121 mL, 1.08 mmol) and the reaction mixture
was heated at reflux for 15 h. After cooling, CH2Cl2 was
added and the organic solution was washed with saturated
aqueous K2CO3, dried, and concentrated. The resulting res-
idue was purified by chromatography (hexane/EtOAc 3:7) to
give trichloroacetamide 14 (297 mg, 80%) as a yellow solid.
IR (NaCl) 3374, 1742, 1666; 1H NMR (300 MHz) 1.50–2.50
(m, 6H), 2.94 (d, J¼14.4 Hz, 1H, CHN), 3.60 (d, J¼7.2 Hz,
2H, CH2In), 3.79 (s, 3H, OCH3), 3.86–3.96 (m, 4H, OCH2),
4.32 (dd, J¼6.6 Hz, 1H, CH), 4.37 (d, J¼14.4 Hz, 1H,
CHN), 4.88 (m, W1/2¼10 Hz, 1H, H-30), 7.04 (d,
J¼2.1 Hz, 1H, H-2), 7.13 (td, J¼7.4, 1.1 Hz, 1H, H-5),
7.20 (td, J¼7.4, 1.1 Hz, 1H, H-6), 7.38 (d, J¼7.8 Hz, 1H,
H-7), 7.58 (d, J¼7.8 Hz, 1H, H-4), 8.03 (br s, 1H, NH);
13C NMR (75 MHz) 23.7 (CH2In), 25.1 (C-60), 30.5 (C-
50), 35.6 (C-20), 52.4 (OCH3), 57.6 (CH2N), 59.8 (CH),
64.2 and 64.3 (OCH2), 92.9 (CCl3), 107.4 (C-1), 111.0 (C-
3), 111.4 (C-7), 118.4 (C-4), 119.4 (C-5), 122.2 (C-6),
123.7 (C-2), 127.0 (C-3 and C-3a), 131.7 (C-4), 136.2
(C-7a), 160.2 (CON), 170.0 (COO). Anal. Calcd for
C23H25Cl3N2O5: C, 53.55; H, 4.85; N, 5.43. Found: C,
53.23; H, 4.98; N, 5.36.
3.2.7. 2-[2-(3-Indolyl)-1(S)-methoxycarbonylethyl]-4-
methylene-trans-perhydroisoquinolin-6-one ethylene
acetal (13). A solution of 12 (123 mg, 0.25 mmol) and
AIBN (8 mg, 0.05 mmol) in benzene (25 mL) was heated
at reflux. Bu3SnH (90 mL, 0.34 mmol) was added dropwise
and the reaction mixture was stirred at this temperature for
3 h. After evaporation of the solvent, the residue was parti-
tioned between CH3CN and hexane, and extracted several
times with CH3CN. Concentration of the dried organic
extracts afforded a residue that was purified by chroma-
tography (SiO2, hexane/EtOAc 98:2) to give isoquinoline
13 (75 mg, 75%) as a mixture of two diastereomers. IR
3290, 2952, 1728, 1249, 853, 744, 691, 611; 1H NMR
3.2.9. 2-[(1S)-2-(1H-Indol-3-yl)-1-(methoxycarbonyl)-
ethyl]-2-azaspiro[4.5]decan-3,8-dione ethylene acetal
(15). To a boiling solution of 14 (96 mg, 0.19 mmol) and
AIBN (9 mg, 0.06 mmol) in benzene (1.60 mL) was added
Bu3SnH (0.175 mL, 0.65 mmol), and the mixture was heated
under reflux for 3 h. After the solvent had been evaporated,
the residue was purified by chromatography (EtOAc) to give
15 (55 mg, 73%) as a yellow oil. IR (NaCl) 3400, 1741,

1378
J. Quirante et al. / Tetrahedron 63 (2007) 1372–1379
1
1674; H NMR (300 MHz) 1.16–1.46 (m, 8H), 2.12–2.27
(2d, J¼16.7 Hz, 1H each, CH2CO), 3.07–3.24 (2d,
J¼9.6 Hz, 1H each, NCH2), 3.21 (m, 1H, CHIn), 3.43
(ddd, J¼15.5, 4.8, 1 Hz, 1H, CHIn), 3.74 (s, 3H, OCH3),
3.87 and 3.88 (2s, OCH2), 5.26 (dd, J¼11.5, 5.4 Hz, 1H,
CHCO), 7.00 (d, J¼1.8 Hz, 1H, H-2), 7.11 (td, J¼11.1,
1.2 Hz, 1H, H-5), 7.15 (td, J¼8, 1.1 Hz, 1H, H-6), 7.33
(dd, J¼8.1, 0.9 Hz, 1H, H-7), 7.50 (d, J¼7.5 Hz, 1H, H-4),
8.54 (br s, 1H, NH); 13C NMR (75 MHz) 24.7 (CH2In),
31.4, 33.3, 33.4, 35.7 (C-20, C-30, C-50, C-60), 43.0
(CH2CO), 52.3 (OCH3), 53.3 (CHCO), 54.0 (NCH2), 64.1
(OCH2), 107.9 (C), 110.3 (C-3), 111.2 (C-7), 118.1 (C-4),
119.4 (C-5), 121.8 (C-6), 122.0 (C-2), 127.1 (C-3a), 136.0
(C-7a), 171.2 (CON), 174.4 (CO). Anal. Calcd for
C23H28N2O5: C, 67.65; H, 6.86; N, 5.88. Found: C, 67.38;
H, 6.96; N, 5.76.
52.4 (OCH3), 53.3 (CHCO), 53.4 (CH2N), 110.5 (C-3),
111.3 (C-7), 118.1 (C-4), 119.7 (C-5), 121.8 (C-6), 122.4
(C-2), 127.2 (C-3a), 136.0 (C-7a), 171.3 (CON), 173.8
(CO2Me), 209.9 (CO).
Acknowledgements
This research was supported by the MEC (Spain)-FEDER
through project CTQ2004-04701/BQU. Thanks are also
due to the DURSI (Catalonia) for Grant 2005SGR-00442
and the University of Barcelona for a fellowship to L.P.
References and notes
3.2.10. Methyl (S)-N-[(4-oxocyclohex-1-enyl)methyl]-N-
(trichloroacetyl)tryptophan (16). A solution of acetal 14
(300 mg, 0.68 mmol) in 3 N HCl (30 mL) was stirred over-
night at rt. The reaction mixture was basified and extracted
with CH2Cl2. The organic extracts were dried and concen-
trated to give ketone 16 (190 mg, 86%) as a yellow oil. An
analytical sample was obtained by chromatography (hex-
1. For reviews covering the radical-mediated synthesis of nitrogen
heterocycles, see: (a) Zhang, W. Tetrahedron 2001, 57, 7237–
7262; (b) Bowman, W. R.; Fletcher, A. J.; Potts, G. B. S.
J. Chem. Soc., Perkin Trans. 1 2002, 2747–2762; (c)
Ishibashi, H.; Sato, T.; Ikeda, M. Synthesis 2002, 695–713;
(d) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P.
Tetrahedron 2005, 61, 10603–10642.
2. For seminal works of carbocyclization from vinyl radicals, see:
(a) Stork, G.; Baine, N. H. J. Am. Chem. Soc. 1982, 104, 2321–
2323; (b) Beckwith, A. L. J.; O’Shea, D. M. Tetrahedron Lett.
1986, 27, 4525–4528; (c) Stork, G.; Mook, R., Jr. Tetrahedron
Lett. 1986, 27, 4529–4532.
1
ane/EtOAc 75:25). IR (NaCl) 3400, 1740, 1673; H NMR
(300 MHz, gCOSY) 2.16–2.34 (m, 2H, H-50), 2.54–2.80
(m, 4H, H-3 and H-6), 2.96 (d, J¼15 Hz, 1H, CHN), 3.56–
3.68 (d, J¼7.7 Hz, 2H, CH2In), 3.81 (s, 3H, OCH3), 4.31
(dd, J¼8.4, 6.6 Hz, 1H, CH), 4.42 (d, J¼15 Hz, 1H,
CHN), 5.03 (m, W1/2¼9 Hz, 1H, H-20), 7.04 (d, J¼2.4 Hz,
1H, H-2), 7.13 (ddd, J¼7.8, 7, 1.1 Hz, 1H, H-5), 7.21 (td,
J¼7.5, 1.1 Hz, 1H, H-6), 7.39 (d, J¼8.1 Hz, 1H, H-7),
8.22 (br s, 1H, NH); 13C NMR (75 MHz, gHSQC) 23.7
(CH2In), 25.8 (C-60), 38.0 (C-50), 39.3 (C-20), 52.6
(OCH3), 57.1 (NCH2), 60.2 (CH), 92.7 (CCl3), 111.1 (C-
3), 111.6 (C-7), 118.3 (C-4), 119.6 (C-5), 122.4 (C-6),
123.7 (C-2), 126.1 (C-3), 126.9 (C-3a), 132.8 (C-4), 136.2
(C-7a), 160.1 (CON), 169.7 (CO2Me), 209.2 (CO). Anal.
Calcd for C21H21Cl3N2O4: C, 53.47; H, 4.49; N, 5.94.
Found: C, 53.40; H, 4.67; N, 5.54.
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3.2.11. 2-[(1S)-2-(1H-Indol-3-yl)-1-(methoxycarbonyl)-
ethyl]-2-azaspiro[4.5]decan-3,8-dione (17). To a boiling
solution of 16 (73 mg, 0.16 mmol) and AIBN (8 mg,
0.05 mmol) in benzene (1.3 mL) was added Bu3SnH
(0.145 mL, 0.54 mmol), and the mixture was heated under
reflux for 3 h. After the solvent had been evaporated, the res-
idue was purified by chromatography (EtOAc) to give 17
(42 mg, 65%) as a yellow oil. IR (NaCl) 3304, 1740, 1682;
1H NMR (400 MHz) 1.35 (ddd, J¼13.7, 7.9, 5.7 Hz, 1H,
H-30 or H-50), 1.49 (ddd, J¼13.7, 8.1, 5.7 Hz, 1H, H-30 or
H-50), 1.85 (t, J¼6.8 Hz, 2H, H-20 or H-60), 1.96 (ddd,
J¼14.2, 8.6 Hz, 1H, H-30 or H-50), 2.05 (ddd, J¼14.8, 7.2,
6 Hz, 1H, H-30 or H-50), 2.24–2.31 (m, 2H, H-20 or H-60),
2.19 and 2.39 (2d, J¼16.6 Hz, 2H, CH2CO), 3.19 and 3.40
(2d, J¼9.4 Hz, 2H, NCH2), 3.28 (dd, J¼15.6, 12 Hz, 1H,
CHIn), 3.45 (ddd, J¼15.6, 6, 1.2 Hz, 1H, CHIn), 5.29 (dd,
J¼11.4, 5 Hz, 1H, CHCO), 7.06 (d, J¼2.4 Hz, 1H, H-2),
7.13 (td, J¼7.5, 0.9 Hz, 1H, H-5), 7.20 (td, J¼7.6, 0.9 Hz,
1H, H-6), 7.35 (d, J¼8 Hz, 1H, H-7), 7.58 (d, J¼8 Hz, 1H,
H-7), 8.20 (br s, 1H, NH); 13C NMR (100 MHz) 24.7
(CH2In), 35.5 (C-30 or C-50), 35.7 (C-20 or C-60), 36.0 (C-
40), 37.5 (C-30 or C-50), 37.8 (C-20 or C-60), 42.6 (CH2CO),
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