Cross-coupling reactions in Cinchona alkaloid chemistry: Aryl-substituted and dimeric quinine, quinidine, as well as quincorine and quincoridine derivatives

Article abstract of DOI:10.1039/b004693k

Cross-coupling reactions of modified Cinchona alkaloids provide access to a wide variety of novel arylated and dimeric derivatives of quinine and quinidine containing a single and double 1,2-amino alcohol functionality. Sonogashira and Heck reactions allow functionalization of ethynyl and 11-iodovinyl precursors. The role of bystander functionality is investigated.

Full text of DOI:10.1039/b004693k

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Cross-coupling reactions in Cinchona alkaloid chemistry: aryl-
substituted and dimeric quinine, quinidine, as well as quincorine
and quincoridine derivatives
1
Jens Frackenpohl,† Wilfried M. Braje‡ and H. Martin R. Hoffmann*
Department of Organic Chemistry, Universität Hannover, Schneiderberg 1B, D-30167
Hannover, Germany. E-mail: hoffmann@mbox.oci.uni-hannover.de; Fax: ϩ(0) 511 762 3011
Received (in Cambridge, UK) 13th June 2000, Accepted 28th September 2000
First published as an Advance Article on the web 11th December 2000
Cross-coupling reactions of modified Cinchona alkaloids provide access to a wide variety of novel arylated and
dimeric derivatives of quinine and quinidine containing a single and double 1,2-amino alcohol functionality.
Sonogashira and Heck reactions allow functionalization of ethynyl and 11-iodovinyl precursors. The role of
bystander functionality is investigated.
Introduction
In recent years, the study of transition-metal mediated
reactions has facilitated progress in organic synthesis and vice
versa.1 Metal-catalyzed cross-coupling reactions have been
extensively employed, spanning the range of complex natural
products to supramolecular chemistry and materials science.
Among the many transition metals used, palladium2,3 com-
plexes are probably most valuable. At the outset of our work
it was not clear whether the basic bridgehead amine and other
functionality of the alkaloids including the C9-hydroxy and its
protection groups would help or hinder the planned carbon–
carbon coupling reactions.
The quest for novel ligands of neuronal receptors has been a
further incentive, as the quinuclidine nucleus has been found to
be a good mimic for the quaternary nitrogen in acetylcholine.
Unlike acetylcholine, the quaternary nitrogen of which is
necessarily charged, the unprotonated form of quinuclidines is
able to cross the blood–brain barrier.4 Quinuclidine derivatives
with aromatic substituents in the 3-position are able to block
Fig. 1 Quinuclidine lead structures.
M1 (1 and 2), 5-HT3 (3) and NK1-receptors5,6 and to act as
squalene synthase inhibitors (4) (Fig. 1).7 In contrast to de novo
syntheses which provide the desired target molecules only in
poor yields and as racemic mixtures, cross-coupling reactions
of quinuclidine derivatives offer an efficient access to the
desired lead structures.8
Dimeric alkaloids, e.g. vincristine and vinblastine, have been
used as potent antitumor agents.9 Dimeric Cinchona alkaloids
are decisive as ligands in the AD reaction. Thus, dimeric
quinine- and quinidine-based phthalazine- and pyrimidine-
bridged ligands have outperformed monomeric ligands in most
reactions.10 Chloroquine is still one of the main antimalarial
drugs, but its efficacy is being steadily eroded by the spread of
resistant parasites. The development of alternative agents
remains a major goal. Dimeric quinoline-based antimalaria
agents such as piperaquine-like quinine derivative 5 (Fig. 2)
are of current interest11 since some of these compounds
exhibit high activity against chloroquine-resistant parasites.12
Further examples of dimeric Cinchona alkaloid derivatives are
† Current address: J. Frackenpohl, ETH, Laboratorium für Organische
Chemie, Universitätsstrasse 16, CH-8092 Zürich, Switzerland.
‡ Current address: W. Braje, BASF AG, Hauptlaboratorium, D-67056
Ludwigshafen, Germany.
Fig. 2 Dimerized Cinchona alkaloids.
DOI: 10.1039/b004693k
J. Chem. Soc., Perkin Trans. 1, 2001, 47–65
47
This journal is © The Royal Society of Chemistry 2001

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chiral symmetrical pentamethinium cyanine dyes with hexa-
hydroquininyl and -quinidinyl end groups (6).13
In the course of our work we have prepared a wide variety
of arylated and dimeric derivatives from acetylenic and
vinylic precursors. The acetylenic derivatives of the diyne
and enediyne type described herein represent an entirely new
class of Cinchona alkaloids.
Results and discussion
A useful route to arylalkynes and conjugated enynes is the
Pd-catalyzed coupling of terminal alkynes with aryl or alkenyl
halides as described by Sonogashira et al.14 Numerous appli-
cations have been reported, especially in the construction of
complex unsaturated frameworks of enediyne antibiotics with
(Z)-1,2-dichloroethylene.15 To explore the application of this
cross-coupling reaction to Cinchona alkaloids we have used
10,11-didehydro-derivatives 9, 10, 18, 20 of quinine 8, quinidine
7, Quincorine (QCI) 13 and Quincoridine (QCD) 19,
vinyl iodides 11, 12, 17 and vinylstannane 15 as precursors
(Schemes 1 and 2). The series of terminal alkynes 9, 10, 18,
20 was prepared efficiently in two steps from the naturally
occurring Cinchona alkaloids and from QCI (13) and QCD
Scheme 2 Synthesis of precursors for quincorine and quincoridine
cross-coupling. Reagents and conditions: i, 1. Br2, CHCl3–CCl4, 0 ЊC,
2 h, 2. Et3N, CHCl3, rt, 2 h, 3. KOH, aliquat 336, THF, 6–20 h,
rt or 70 ЊC; ii, 1. 2,4,6-triisopropylbenzenesulfonyl hydrazide, Et2O,
rt, 16 h, 2. n-BuLi, TMEDA, hexane, Ϫ78 ЊC→0 ЊC, 1 h; 3. Bu3SnCl,
0 ЊC→rt, 2 h; iii, 1. TBDSCl, Et3N, DMAP, DCM, rt, 14 h, 2.
K3[Fe(CN)6], K2CO3, OsO4, tBuOH–H2O (1:1), rt, 8 h; iv, NaIO4, SiO2,
H2O, DCM, rt, 15 min; v, CrCl2, CHI3, THF, 0 ЊC→rt, 3 h.
(19).16 Iodinated alkynes were easily transformed into corre-
sponding (Z)-vinyl iodides 11, 12, 17 by p-tolylsulfonyl
hydrazide-mediated hydrogenation. (E)-Vinyl iodide 17 was
obtained upon treatment of C10-aldehyde 16 with CrCl2 and
CHI3.17 Vinylstannane 15 was prepared from ketone 14 via
hydrazide reduction.18
Usually, the Sonogashira coupling is carried out in the
presence of catalytic amounts of a Pd()-complex and CuI
in an amine as solvent. The use of cosolvents like THF or DMF
has also been reported.19
In view of differences in reactivity of halides and alkynes
we have optimized the (Ph3P)2PdCl2-mediated coupling of
unprotected 10,11-didehydroquinidine 9a with iodo- and
bromobenzene with respect to amine, solvent, temperature
and reaction time. In accord with other optimization studies20
reaction of the coupling precursors with (Ph3P)2PdCl2 (0.05 eq.)
and CuI (0.1 eq.) in a mixture (1:1) of Et3N and THF proved to
be suitable (Scheme 3, Table 1). Due to strong basicity of the
bridgehead nitrogen and the presence of a quinoline nitrogen,
Sonogashira coupling of 9a is also feasible without addition
of an external amine furnishing the desired internal alkyne in
moderate yield (44%).
Scheme 1 Synthesis of precursors for quinine and quinidine cross-
coupling. Reagents and conditions: i, 1. Br2, CHCl3–CCl4, 0 ЊC, 2 h,
2. Et3N, CHCl3, rt, 2 h, 3. KOH, aliquat 336, THF, 6–20 h, rt or 70 ЊC;
ii, AcCl, Et3N, DCM, 0 ЊC→rt, 16 h; iii, I2, morpholine, toluene, 55 ЊC,
10 h, 91–97%; iv, TsNHNH2, NaOAc, THF, H2O, 55 ЊC, 4–6 h, 56–65%.
48
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Table 1 Optimization of Sonogashira coupling of 10,11-didehydro-
quinidine and -quinine with phenyl halides
Ph-X
Alkyne (eq.)
Solvent,
basea
Yield
(%)
Entry
Time/h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21a
21b
22a
22b
Ph-I (1.0)
THF, Et2NH
THF, iPr2NH
—, Et3N
THF, Et3N
THF, Et3N
Et2O, Et3N
Dioxan, Et3N
DMF, Et3N
THF, —
THF, Et3N
THF, Et3N
THF, Et3N
THF, Et3N
THF, Et3N
6
6
60
66
51
73
80
68
63
65
44
53
71
94
70
86
Ph-I (1.5)
Ph-I (1.5)
Ph-I (1.5)
Ph-I (1.5)
Ph-I (1.5)
Ph-I (1.5)
Ph-I (1.5)
Ph-I (1.5)
Ph-Br (1.5)
Ph-Br (1.5)
Ph-I (1.5)
Ph-I (1.5)
Ph-I (1.5)
16b
6
14
14
14
14
72
6
20
14
16
16
a Typically, reactions were carried out at rt. b Temperature: 60 ЊC.
Scheme 4 Sonogashira coupling of 10,11-didehydroquinidine 9a,b
with substituted aryl and vinyl halides. Reagents and conditions: i,
(Ph3P)2PdCl2 (0.05 eq.), CuI (0.1 eq.), aryl or vinyl halide (1.0–1.5
eq.), THF, Et3N, 16 h.
exclusively by a tandem reaction involving cross-coupling
and intramolecular cyclization. The corresponding coupling
of 10,11-didehydroquinidine 9b with 2-iodoaniline furnished
the substituted alkyne 21n.21 Indoles can only be obtained
under forcing conditions.22
Pd-mediated cross-coupling was also applied to polar
1,2-amino alcohols didehydro-QCI and didehydro-QCD
(Scheme 5). Unprotected alkynes 18a and 20a coupled under
Scheme
3
Optimized Sonogashira coupling of 10,11-didehydro-
quinidine 9a,b and -quinine 10a,b. Reagents and conditions: i, (Ph3P)2-
PdCl2 (0.05 eq.), CuI (0.1 eq.), phenyl halide (1.0–1.5 eq.), THF,
amine.
Although an unprotected 1,2-amino alcohol unit was present
in terminal alkyne 9a the desired coupling product 21a
was obtained in 80% yield using iodobenzene and in 71%
yield using bromobenzene (Table 1, entries 5 and 11). Likewise,
coupling of 10,11-didehydroquinine 10a with iodobenzene
furnished internal alkyne 22a in 70% yield. Protection of the
C9-hydroxy group by acetylation as in Cinchona alkaloid pre-
cursors 9b and 10b gave higher yields of up to 94% (Schemes 1
and 4, Tables 1 and 2). Reaction with less reactive bromo-
benzene required longer reaction times, but was also feasible
under mild conditions (Table 1, entries 10, 11). Formation of
symmetrical diyne side products by oxidative homocoupling
was not observed in the optimized Sonogashira couplings
of 10,11-didehydro-derivatives of quinine, quinidine, QCI and
QCD. Moreover, ordinary, nondegassed reagent-grade sol-
vents could be used without decrease in yield. Optimized
Sonogashira coupling of 10,11-didehydroquinidine 9a,b with
various substituted aryl and vinyl halides furnished the desired
internal alkynes 21c–n with yields from 67 to 94%. When 2-
iodophenol was used as halide benzofuran 21o was obtained
Scheme 5 Sonogashira coupling of 10,11-didehydroquincorine 18a,c
and 10,11-didehydroquincoridine 20a,b with substituted aryl and
vinyl halides. Reagents and conditions: i, (Ph3P)2PdCl2 (0.05 eq.),
CuI (0.1 eq.), aryl or vinyl halide (1.0–1.5 eq.), THF, Et3N, 16 h.
standard conditions to the desired internal alkynes in yields
from 62 to 77% (Table 3, entries 1, 3, 4, 9, 10). Nevertheless,
O-silylation and O-acylation of the 1,2-amino alcohol gave
a considerable increase in yield (up to 92%, Table 3, entry 5).
Moreover, no significant difference in reactivity between aryl
iodides and aryl bromides was observed, although yields of
coupling reactions with aryl bromides turned out to be slightly
lower (Table 3, entries 6, 10, 12, 14, 15). Vinylic chlorides are
inert for many coupling reactions.23 We were pleased to find
that TBDS-protected 10,11-didehydroquincoridine 20b coupled
smoothly when using diisopropylamine or piperidine instead of
Et3N (Table 3, entries 16 and 17).
J. Chem. Soc., Perkin Trans. 1, 2001, 47–65
49

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Table 2 Sonogashira coupling of 10,11-didehydroquinidine with aryl and vinyl halides
Internal
alkyne
Yield
(%)
Entry
1
Alkyne
Ar-X
R2-Br
R1
H
R2 a
9a
21c
77
2
3
9b
9a
R2-Br
R2-Br
21d
21e
Ac
H
94
67
4
5
6
9b
9b
9b
R2-I
21f
21g
21h
Ac
Ac
Ac
86
83
90
R2-Br
R2-Br
7
8
9b
9b
R2-Br
R2-I
21i
21j
Ac
Ac
88
94
9
9b
9b
R2-I
R2-I
21k
21l
Ac
Ac
85
82
10
11
12
13
14
9b
9b
9b
9a
R2-I
R2-I
R2-I
R2-I
21m
21n
21o
21p
Ac
Ac
Ac
H
82
92
78
79
15
9a
R2-I
21q
H
71
a Numbering shown is used in the NMR analysis.
50
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Table 3 Sonogashira coupling of 10,11-didehydroquincorine 18a–c and -quincoridine 20a,b with various aryl and vinyl halides
Internal
alkyne
Yield
(%)
Entry
Alkyne
Ar-X
R2-I
R1
H
R2 c
QCI-series
1
18a
23a
23b
23c
23d
74
84
77
71
2
3
4
18b
18a
18a
R2-I
R2-I
R2-I
TBDS
H
H
5
6
18c
18b
R2-I
23e
23f
Bz
92
86
R2-Br
TBDS
7
8
18b
18b
R2-I
R2-I
23g
23h
TBDS
TBDS
84
78a
QCD-series
9
20a
20a
R2-I
24a
24b
H
H
65
62
10
R2-Br
11
12
20b
20b
R2-I
24c
24d
TBDS
TBDS
91
82
R2-Br
13
20b
R2-I
24e
TBDS
89
14
15
20b
20b
R2-Br
R2-Br
24f
TBDS
TBDS
83
80
24g
16
17
20b
20b
R2-Clb
R2-Clb
24h
24i
TBDS
TBDS
78
83
a Yield after cyclization to benzofuran 23h. b Pri2NH and piperidine were used instead of Et3N. c Numbering shown is used in the NMR analysis.
J. Chem. Soc., Perkin Trans. 1, 2001, 47–65
51

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Homocoupling of simple 10,11-didehydroquincorine 18a and
10,11-didehydroquincoridines 20a,b afforded the correspond-
ing diynes (64–85%) without by-products. Moreover, further
spacers could be introduced giving enediyne 32 and quin-
coridine-based diyne 33 with a benzene spacer. Interestingly,
enediyne 32 underwent a Bergman cycloaromatization at
moderately elevated temperature (60–70 ЊC) in CHCl3 (86%
yield), although the enediyne moiety was not incorporated into
a strained medium sized ring (Scheme 8).
Scheme 6 Sonogashira coupling of (Z)-vinyl iodides 11b, 12 and
vinylstannane 15 with alkylated alkynes. Reagents and conditions:
i, (Ph3P)2PdCl2 (0.05 eq.), CuI (0.1 eq.), aryl or halide (1.0 eq.), THF,
Et3N, 16 h.
Quinidine- and quinine-based vinyl iodides 11a,b and 12
coupled with terminal alkynes (Scheme 6) giving (Z)-enynes
25a–c and 26 in fair yield (78–86%). Likewise, vinylstannane 15
was transformed into α-amino enyne 27.
Homocoupling of 10,11-didehydro-quinidine and -quinine
furnished the novel class of dimeric Cinchona alkaloids which
are linked via the C10–C11-side chain. This is in contrast to
AD-ligands of the second generation which incorporate hetero-
aromatic spacers (phthalazine or pyrimidine) between C9-
oxygen atoms. A variety of synthetic methods is available for
the homocoupling.24 Although being suitable for the synthesis
of porphyrin oligomers, the classic approach to diynes, the
Glaser coupling, afforded the desired quinidine dimerics 28a,b
only in poor yield (<15%). Modified Sonogashira coupling
was more suitable for the synthesis of symmetrical diynes 28
and 29.25 10,11-Didehydroquinidine 9a,b and 10,11-didehydro-
quinine 10a,b underwent self-coupling in the presence of
(Ph3P)2PdCl2, CuI, I2 (0.5 eq.) and Et3N to give the correspond-
ing diynes 28a,b and 29a,b exclusively (yields from 71 to 95%).
The resulting products exhibit strongly enhanced basicity com-
pared with parent quinine and quinidine (Scheme 7).
Scheme 8 Pd-mediated dimerization of 10,11-didehydroquincorine
and 10,11-didehydroquincoridine. Reagents and conditions: i, (Ph3P)2-
PdCl2 (0.05 eq.), CuI (0.1 eq.), I2 (0.5 eq.), THF, Et3N, 16 h;
ii, (Ph3P)2PdCl2 (0.05 eq.), CuI (0.1 eq.), 1,4-diiodobenzene or (Z)-1,2-
dichloroethene (0.5 eq.), THF, Et3N, 16 h; iii, CHCl3, 60–70 ЊC, 4 h.
Over the years the Heck reaction has emerged as a powerful
method for the formation of carbon–carbon bonds. Hallmarks
of Heck reactions are excellent functional group tolerance
and predictable regio- and stereochemistry. A telling indication
of the utility of intramolecular Heck reactions is their recent
use as the key step in the synthesis of many complex natural
products, especially alkaloids.26 Various protocols have been
introduced, and tetraalkylammonium salts in particular have
been highly successful in enhancing reactivity and selectivity of
Scheme 7 Pd-mediated dimerization of 10,11-didehydroquinine and
10,11-didehydroquinidine. Reagents and conditions: i, (Ph3P)2PdCl2
(0.05 eq.), CuI (0.1 eq.), I2 (0.5 eq.), THF, Et3N, 16 h.
52
J. Chem. Soc., Perkin Trans. 1, 2001, 47–65

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inter- and intramolecular Heck-type reactions. We therefore
used the optimized phase-transfer protocol developed by Jeffery
(Pd(OAc)2, K2CO3, n-Bu4NI, DMF).27 Under these con-
ditions quinidine-(Z)-vinyl iodides 11a,b and quincoridine-
based (E)-vinyl iodide could be coupled stereoselectively
with α,β-unsaturated carbonyl compounds to give conjugated
alkenes 35a–e and 36 at room temperature. O-Protection of
the 1,2-amino alcohol unit was not essential. Heck coupling
of vinyl iodide 11a with methyl acrylate furnished dienoic ester
35b (84%) (Scheme 9).
was freshly prepared before use. Coupling precursors 9–12, 18
and 20 were prepared as described previously.16
(1S,2S,4S)-2-Hydroxymethyl-5-tributylstannanyl-1-azabicyclo-
[2.2.2]oct-5-ene 15
Ketone 1418 (1.0 eq.) and 2,4,6-triisopropylbenzenesulfonyl
hydrazide (1.05 eq.) were dissolved in Et2O at rt. The resulting
yellow reaction mixture was stirred for 16 h at rt, sat. aq.
NaHCO3 was added and the aqueous layer was extracted with
DCM. The collected organic layer was dried over MgSO4,
filtered and the solvent removed in vacuo. The residue was
purified by column chromatography (EtOAc–MeOH 10:1)
and redissolved (300 mg, 0.45 mmol, 1 eq.) in a 1:1 mixture
of TMEDA (2 ml) and cyclohexane (2 ml). After stirring for
10 min at rt, the homogeneous solution was cooled to Ϫ78 ЊC
and treated with n-BuLi (0.84 ml, 1.34 mmol, 3 eq.) and
Bu3SnCl (0.24 ml, 0.89 mmol, 2 eq.). The reaction mixture
was stirred for 2 h at 0 ЊC, treated with sat. aq. NaHCO3 and
extracted with CH2Cl2. The collected organic layer was dried
(MgSO4), filtered and concentrated under reduced pressure.
The resulting crude product was purified by column chrom-
atography (EtOAc–MeOH 6:1) to afford vinylstannane 15
(80%, 152 mg, 0.36 mmol); νmax(CHCl3)/cmϪ1 3304, 2960, 2929,
2872, 1564, 1463, 1419, 1379, 1362, 1342, 1292, 1230, 1150,
1082, 1050, 1007, 939 and 878; δH(400 MHz; CDCl3) 6.93 (s, 1 H,
H-6), 3.94–3.90 (m, 1 H, H-9), 3.81–3.74 (m, 1 H, H-9), 3.40–
3.32 (m, 1 H, H-2), 2.90–2.76 (m, 2 H, H-7, H-7), 1.90–1.81 (m,
1 H, H-4), 1.62–1.54 (m, 2 H, H-3, H-8), 1.48–1.42 (m, 2 H, H-
8, H-3), 1.32–1.16 (m, 9 H, SnBu3) and 0.88–0.82 (m, 18 H,
SnBu3); δC(100 MHz; CDCl3) 135.93 (CH, C-6), 121.95 (C,
C-5), 62.61 (CH, C-2), 61.07 (CH2, C-9), 43.16 (CH2, C-7),
34.32 (CH, C-4), 29.37 (CH2, SnBu3), 28.15 (CH2, SnBu3),
27.12 (CH2, SnBu3), 26.93 (CH2, SnBu3), 26.19 (CH2, C-8),
24.94 (CH3, SnBu3), 24.55 (CH3, SnBu3), 23.86 (CH3, SnBu3),
23.09 (CH2, C-3), Ϫ9.02 (CH2, SnBu3), Ϫ9.13 (CH2, SnBu3)
and Ϫ9.22 (CH2, SnBu3); m/z (MAT, 70 ЊC) (EI) 429.2054 (Mϩ,
C20H39N1O1120Sn requires 429.2054), 313 (Mϩ Ϫ 2 Bu, 15%),
292 (7), 269 (100), 239 (10), 213 (20), 195 (1), 177 (27), 155 (23)
and 121 (12).
Scheme 9 Heck reactions of (E)- and (Z)-vinyl iodides. Reagents
and conditions: i, Pd(OAc)2 (0.05 eq.), K2CO3 (2.5 eq.), TBAI (1.0 eq.),
α,β-unsatd. compound (4.0 eq.), DMF, RT, 12 h.
Conclusion
Cinchona alkaloid chemistry continues to contribute to medi-
cinal chemistry, supramolecular chemistry28 and asymmetric
synthesis. As we have shown 10,11-didehydro Cinchona
alkaloids represent a significantly new class of semi-natural
Cinchona alkaloids16 showing enhanced basicity and polarity.
We have found that the C10–C11 triple bond facilitates
crystallization including that of simple didehydro-QCI (18a)
and didehydro-QCD (20a). These alkynes show also little
twisting and considerable eclipsing of the ethano bridge of the
azabicyclic cage (torsion angles Φ = 5–10Њ from X-ray crystal
studies).16 The additional functionality of the Cinchona alkaloid
is tolerated by palladium-mediated cross-coupling without
protection.
(1S,2S,4S,5R)-2-[(tert-Butyl)(dimethyl)silyloxymethyl]-5-[(E)-
2-iodovinyl]-1-azabicyclo[2.2.2]octane 17
CrCl2 (612 mg, 4.98 mmol, 8 eq.) was dissolved in absolute
THF, cooled (0 ЊC) and treated with CHI3 (490 mg, 1.24 mmol,
2 eq.). After 10 min TBDMS-protected C10-aldehyde 1629
(176 mg, 0.62 mmol, 1 eq.) was added at 0 ЊC and the resulting
reaction mixture was stirred for 3 h at rt. After filtration over
Celite sat. aq. NaHCO3, sat. aq. NaCl and H2O were added
and the aqueous layer was extracted with CHCl3. The com-
bined organic layer was dried (MgSO4), filtered and concen-
trated in vacuo. Purification of the crude product by column
chromatography (EtOAc–MeOH 20:1) furnished the desired
vinyl iodide 17 (66%, 167 mg, 0.41 mmol, E:Z ratio: 81:19);
νmax(CHCl3)/cmϪ1 2956, 2932, 2900, 2860, 1672, 1604, 1460,
1408, 1388, 1256, 1228, 1172, 1132, 1092, 1064, 1004 and 948;
δH(400 MHz; CDCl3) 6.61–6.53 (m, 1 H, H-10), 6.41–6.37 (d,
1 H, J 14.5, H-11), 3.85–3.72 (m, 2 H, H-9, H-9), 3.62–3.54
(m, 1 H, H-2), 3.43–3.34 (m, 1 H, H-6), 3.32–3.24 (m, 1 H, H-6),
3.18–3.10 (m, 1 H, H-7), 3.08–2.97 (m, 1 H, H-7), 2.49–2.45
(m, 1 H, H-5), 2.28–2.22 (m, 1 H, H-4), 2.17–2.11 (m, 1 H,
H-3), 2.10–1.93 (m, 1 H, H-8), 1.92–1.81 (m, 1 H, H-8), 1.80–
1.71 (m, 1 H, H-3), 0.88 (s, 9 H, SiC(CH3)3) and 0.13–0.08 (m,
6 H, SiCH3); δC(100 MHz; CDCl3) 144.42 (CH, C-10), 79.65
(CH, C-11), 62.29 (CH2, C-9), 58.79 (CH, C-2), 53.26 (CH2,
C-6), 43.81 (CH2, C-7), 31.49 (CH, C-5), 27.85 (CH, C-4), 25.97
(CH3, SiC(CH3)3), 23.91 (CH2, C-8), 22.19 (CH2, C-3), 18.22
(C, SiC(CH3)3), Ϫ5.14 (CH3, SiCH3) and Ϫ5.37 (CH3, SiCH3);
m/z (FAB) (EI) 408 (Mϩ ϩ H, 100%), 394 (10), 282 (9), 221 (8),
207 (12), 147 (23) and 133 (19).
Experimental
General
Infrared spectra were recorded on a Perkin-Elmer 1710 infrared
1
spectrometer. H NMR and 13C NMR spectra were recorded
on Bruker AVS 400 and Bruker AVM 500 spectrometers in
deuterated chloroform unless otherwise stated, with tetramethyl-
silane as internal standard. Mass spectra were recorded on a
Finnigan MAT 312 (70 eV) or a VG Autospec spectrometer.
Microanalyses were performed in the Department of Organic
Chemistry of the University of Hannover. Preparative column
chromatography was performed on J. T. Baker silica gel
(particle size 30–60 µm). Analytical TLC was carried out on
aluminium-backed 0.2 mm silica gel 60 F254 plates (E. Merck).
Ethyl acetate (EA) and methyl tert-butyl ether (MTBE) were
distilled before use. Methanol was dried over calcium hydride
and citric acid and distilled over magnesium before use. Silver
triflate was purchased from Aldrich, whereas silver benzoate
J. Chem. Soc., Perkin Trans. 1, 2001, 47–65
53

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General procedure for the Sonogashira coupling of aryl and vinyl
halides with terminal alkynes
and 21.59 (CH2, C-7); m/z (MAT, 180 ЊC) (EI) 398.1994 (Mϩ,
C26H26N2O2 requires 398.1994), 381 (3%), 341 (8), 326 (5),
283 (13) and 210 (100).
(Ph3P)2PdCl2 (0.05 eq.) and CuI (0.1 eq.) were dissolved in Et3N
and absolute THF (1:1 mixture, 10 ml mmolϪ1 alkaloid). The
reaction mixture was stirred for 15 min at rt under argon and
a solution of the corresponding aryl or vinyl halide (1.5 eq.)
in absolute THF was added. After stirring for 45 min at rt
a solution of the terminal alkyne in absolute THF was added
dropwise within 15 min. After having been stirred for 14–20 h at
rt, the resulting orange–brown reaction mixture was treated
with sat. aq. NaHCO3 and sat. aq. NaCl. The aqueous layer
was extracted several times with CH2Cl2 (up to 8×) and the
combined organic layer was dried (MgSO4) and concentrated
under reduced pressure. The resulting crude product was puri-
fied by column chromatography (EtOAc–MeOH) to yield the
desired internal alkyne.
(3S,4S,8S,9R)-9-Acetoxy-11-phenyl-10,11-didehydro-6Ј-
methoxycinchonan 22b. 10,11-Didehydroquinine 10b (130 mg,
0.35 mmol, 1 eq.) was allowed to react according to the general
procedure with (Ph3P)2PdCl2 (13 mg, 0.02 mmol, 0.05 eq.), CuI
(7 mg, 0.04 mmol, 0.1 eq.) and phenyl iodide (50 µl, 0.46 mmol,
1.3 eq.) to afford internal alkyne 22b (86%, 135 mg, 0.31 mmol);
νmax(CHCl3)/cmϪ1 2952, 2868, 1744, 1620, 1508, 1472, 1432,
1372, 1232, 1084, 1032 and 852; δH(400 MHz; CDCl3) 8.80 (d,
1 H, J 4.6, H-2Ј), 8.07 (d, 1 H, J 9.2, H-8Ј), 7.50 (d, 1 H, J 2.8,
H-5Ј), 7.44 (d, 1 H, J 4.6, H-3Ј), 7.42 (dd, 1 H, J 9.3 and 2.6,
H-7Ј), 7.36–7.29 (m, 5 H, Ar-H), 6.55 (d, 1 H, J 7.7, H-9), 3.95
(s, 3 H, H-11Ј), 3.76–3.69 (m, 1 H, H-8), 3.23 (dd, 1 H, J 13.6
and 10.0, H-2exo), 3.19–3.12 (m, 1 H, H-6), 2.93–2.91 (m, 1 H,
H-2endo), 2.78–2.67 (m, 2 H, H-6, H-3), 2.29–2.22 (m, 1 H, H-7),
2.19 (s, 3 H, H-13), 2.17 (br s, 1 H, H-4), 1.83–1.76 (m, 1 H,
H-5) and 1.64–1.51 (m, 2 H, H-7, H-5); δC(100 MHz; CDCl3)
170.14 (C, C-12), 157.89 (C, C-6Ј), 147.48 (CH, C-2Ј), 144.82
(C, C-4Ј), 143.46 (C, C-10Ј), 131.81 (CH, C-8Ј), 131.50 (CH,
C-Ar), 128.24 (CH, Ar-H), 127.75 (CH, Ar-H), 127.04 (C,
C-9Ј), 123.57 (C, Ar-C), 121.82 (CH, C-7Ј), 119.19 (CH, C-3Ј),
101.53 (CH, C-5Ј), 93.24 (C, C-11), 81.06 (C, C-10), 73.73
(CH, C-9), 58.54 (CH, C-8), 58.00 (CH2, C-2), 55.57 (CH3,
C-11Ј), 41.93 (CH2, C-6), 28.37 (CH, C-3), 27.06 (CH, C-4),
26.23 (CH2, C-5), 24.99 (CH2, C-7) and 21.10 (CH3, C-13);
m/z (MAT, 140 ЊC) (EI) 440.2105 (Mϩ, C28H28N2O3 requires
440.2099), 398 (2%), 381 (8), 330 (3), 280 (14), 277 (16), 231
(16), 210 (62), 204 (96), 189 (18), 167 (34), 149 (90) and 77 (100).
(3S,4S,8R,9S)-11-Phenyl-10,11-didehydro-6Ј-methoxy-
cinchonan-9-ol 21a. 10,11-Didehydroquinidine 9a (644 mg,
2.00 mmol, 1 eq.) was allowed to react according to the general
procedure with (Ph3P)2PdCl2 (70 mg, 0.10 mmol, 0.05 eq.),
CuI (95 mg, 0.20 mmol, 0.1 eq.) and phenyl iodide (0.33 ml,
3.00 mmol, 1.5 eq.) to afford internal alkyne 21a (80%, 637 mg,
1.60 mmol); νmax(CHCl3)/cmϪ1 3064, 2944, 2876, 2836, 2224,
1620, 1592, 1508, 1472, 1432, 1388, 1364, 1320, 1256, 1228,
1172, 1092, 1032, 996 and 828; δH(400 MHz; CDCl3) 8.55 (d,
1 H, J 4.6, H-2Ј), 7.93 (d, 1 H, J 9.1, H-8Ј), 7.47–7.42 (m, 3 H,
H-3Ј, 2 Ar-H), 7.33–7.28 (m, 3 H, Ar-H), 7.27 (d, 1 H, J 2.6,
H-5Ј), 7.24 (dd, 1 H, J 9.2 and 2.6, H-7Ј), 5.67 (d, 1 H, J 5.4,
H-9), 3.80 (s, 3 H, H-11Ј), 3.54–3.49 (ddd, 1 H, J 13.6, 7.0 and
2.0, H-2endo), 3.20–3.14 (m, 1 H, H-8), 3.11–3.05 (dd, 1 H, J 13.3
and 8.5, H-2exo), 2.91–2.83 (m, 1 H, H-6), 2.75–2.65 (m, 2 H,
H-6, H-3), 2.43–2.37 (m, 1 H, H-7), 2.09–2.05 (m, 1 H, H-4),
1.57–1.49 (m, 2 H, H-7, H-5) and 1.46–1.38 (m, 1 H, H-5);
δC(100 MHz; CDCl3) 157.61 (C, C-6Ј), 147.62 (C, C-10Ј),
147.45 (CH, C-2Ј), 144.02 (C, C-4Ј), 131.63 (CH, Ar-H), 131.28
(CH, C-8Ј), 128.28 (CH, Ar-H), 127.77 (CH, Ar-H), 126.81
(C, C-9Ј), 123.69 (C, Ar-C), 121.52 (CH, C-7Ј), 118.74 (CH,
C-3Ј), 101.39 (CH, C-5Ј), 92.68 (C, C-11), 81.70 (C, C-10),
71.41 (CH, C-9), 60.04 (CH, C-8), 55.64 (CH3, C-11Ј), 50.61
(CH2, C-2), 49.54 (CH2, C-6), 28.81 (CH, C-3), 28.12 (CH,
C-4), 25.03 (CH2, C-7) and 22.94 (CH2, C-5); m/z (MAT,
190 ЊC) (EI) 398.1999 (Mϩ, C26H26N2O2 requires 398.1994), 381
(3%), 369 (4), 341 (5), 326 (3), 312 (3), 283 (11), 262 (3), 240 (2),
226 (3), 210 (100), 200 (4), 189 (61), 172 (9), 155 (11), 128 (152),
115 (15), 91 (7) and 77 (9).
(3S,4S,8R,9S)-11-(3Љ-Quinolyl)-10,11-didehydro-6Ј-methoxy-
cinchonan-9-ol 21c. 10,11-Didehydroquinidine 9a (644 mg,
2.00 mmol, 1 eq.) was allowed to react according to the general
procedure with (Ph3P)2PdCl2 (70 mg, 0.10 mmol, 0.05 eq.),
CuI (95 mg, 0.20 mmol, 0.1 eq.) and 3-bromoquinoline (0.41
ml, 3.00 mmol, 1.5 eq.) to afford internal alkyne 21c (77%, 691
mg, 1.54 mmol); νmax(CHCl3)/cmϪ1 3340, 3068, 2948, 2876,
2220, 1620, 1592, 1508, 1488, 1472, 1432, 1388, 1360, 1340,
1320, 1256, 1240, 1172, 1092, 1032, 908 and 828; δH(400 MHz;
CDCl3) 8.69 (d, 1 H, J 1.9, H-2Љ), 8.55 (d, 1 H, J 4.6, H-2Ј), 8.12
(d, 1 H, J 1.9, H-4Љ), 8.06 (d, 1 H, J 8.5, H-8Љ), 7.97 (d, 1 H,
J 9.3, H-8Ј), 7.69 (d, 1 H, J 8.0, H-5Љ), 7.66 (ddd, 1 H, J 8.4,
6.9 and 1.5, H-7Љ), 7.57 (d, 1 H, J 4.5, H-3Ј), 7.51–7.48 (ddd,
1 H, J 8.0, 6.9 and 1.1, H-6Љ), 7.34 (d, 1 H, J 2.6, H-5Ј), 7.27 (dd,
1 H, J 9.2, 2.6, H-7Ј), 5.68 (d, 1 H, J 5.4, H-9), 3.80 (s, 3 H,
H-11Ј), 3.61–3.54 (m, 1 H, H-2endo), 3.25–3.19 (m, 1 H, H-8),
3.14–3.07 (dd, 1 H, J 13.4 and 10.4, H-2exo), 2.94–2.85 (m, 1 H,
H-6), 2.76–2.69 (m, 1 H, H-6), 2.46–2.40 (m, 1 H, H-3), 2.14–
2.09 (m, 1 H, H-4), 1.65–1.47 (m, 3 H, H-7, H-7, H-5) and 1.35–
1.26 (m, 1 H, H-5); δC(100 MHz; CDCl3) 157.58 (C, C-6Ј),
152.30 (CH, C-6Љ), 147.99 (C, C-10Ј), 147.50 (CH, C-2Ј), 146.30
(C, C-10Љ), 144.17 (C, C-4Ј), 138.15 (CH, C-2Љ), 131.37 (CH,
C-8Ј), 129.85 (CH, C-8Љ), 128.99 (CH, C-7Љ), 127.43 (CH, C-5Љ),
127.27 (C, C-9Љ), 127.23 (CH, C-4Љ), 126.96 (C, C-9Ј), 121.43
(CH, C-7Ј), 118.97 (CH, C-3Ј), 117.90 (C, C-3Љ), 101.70 (CH,
C-5Ј), 96.57 (C, C-11), 78.80 (C, C-10), 71.71 (CH, C-9), 60.08
(CH, C-8), 55.59 (CH3, C-11Ј), 50.44 (CH2, C-2), 49.54 (CH2,
C-6), 29.09 (CH, C-3), 28.19 (CH, C-4), 25.07 (CH2, C-7) and
23.31 (CH2, C-5); m/z (MAT, 180 ЊC) (EI) 449.2108 (Mϩ,
C29H27N3O2 requires 449.2103), 434 (7%), 421 (8), 392 (7), 378
(7), 363 (7), 283 (18), 261 (100), 249 (8), 233 (26), 220 (15), 206
(19), 189 (45), 179 (16), 167 (14), 158 (11), 128 (10), 117 (10), 91
(17) and 82 (10).
(3S,4S,8S,9R)-11-Phenyl-10,11-didehydro-6Ј-methoxy-
cinchonan-9-ol 22a. 10,11-Didehydroquinine 10a (200 mg,
0.62 mmol, 1 eq.) was allowed to react according to the general
procedure with (Ph3P)2PdCl2 (22 mg, 0.03 mmol, 0.05 eq.),
CuI (12 mg, 0.07 mmol, 0.1 eq.) and phenyl iodide (85 µl,
0.78 mmol, 1.3 eq.) to afford internal alkyne 22a (70%, 173 mg,
0.43 mmol); νmax(CHCl3)/cmϪ1 2952, 1622, 1592, 1509, 1491,
1473, 1432, 1265, 1241, 1230, 1083, 1031, 909 and 857;
δH(400 MHz; CDCl3) 8.50 (d, 1 H, J 4.6, H-2Ј), 7.86 (d, 1 H,
J 10.0, H-8Ј), 7.51 (d, 1 H, J 4.5, H-3Ј), 7.21–7.10 (m, 5 H, H-7Ј,
H-5Ј, Ar-H), 7.01–6.96 (m, 2 H, Ar-H), 5.67 (br s, 1 H, H-9),
3.77 (s, 3 H, H-11Ј), 3.76–3.68 (m, 1 H, H-8), 3.52–3.45 (m, 1 H,
H-6endo), 3.24 (dd, 1 H, J 13.3 and 10.0, H-2exo), 3.05–2.98 (m,
1 H, H-2endo), 2.77–2.66 (m, 2 H, H-6, H-3), 2.10 (m, 1 H, H-4),
1.91–1.69 (m, 3 H, H-7, H-7, H-5) and 1.54–1.45 (m, 1 H, H-5);
δC(100 MHz; CDCl3) 157.79 (C, C-6Ј), 147.26 (CH, C-2Ј),
143.87 (C, C-10Ј, C-4Ј), 131.30 (CH, Ar-H), 131.02 (CH, C-8Ј),
128.12 (CH, Ar-H), 127.92 (CH, Ar-H), 127.76 (C, C-9Ј),
123.03 (C, Ar-C), 121.61 (CH, C-7Ј), 118.63 (CH, C-3Ј), 101.18
(CH, C-5Ј), 92.16 (C, C-11), 81.49 (C, C-10), 70.58 (CH, C-9),
59.42 (CH, C-8), 57.82 (CH2, C-2), 55.83 (CH3, C-11Ј), 42.90
(CH2, C-6), 28.11 (CH, C-3), 27.22 (CH, C-4), 25.40 (CH2, C-5)
(3S,4S,8R,9S)-9-Acetoxy-11-(3Љ-quinolyl)-10,11-didehydro-
6Ј-methoxycinchonan 21d. 10,11-Didehydroquinidine 9b (130
mg, 0.36 mmol, 1 eq.) was allowed to react according to
the general procedure with (Ph3P)2PdCl2 (13 mg, 0.02 mmol,
54
J. Chem. Soc., Perkin Trans. 1, 2001, 47–65

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0.05 eq.), CuI (7 mg, 0.04 mmol, 0.1 eq.) and 3-bromoquinoline
(0.07 ml, 0.54 mmol, 1.5 eq.) to afford quininyl-substituted
alkyne 21d (94%, 165 mg, 0.34 mmol); νmax(CHCl3)/cmϪ1 2952,
2876, 2224, 1744, 1620, 1592, 1508, 1472, 1456, 1432, 1372,
1320, 1300, 1264, 1232, 1136, 1092, 1032 and 908; δH(400 MHz;
CDCl3) 9.03 (d, 1 H, J 2.0, H-2Љ), 8.81 (d, 1 H, J 4.4, H-2Ј), 8.37
(d, 1 H, J 1.9, H-4Љ), 8.16 (d, 1 H, J 8.4, H-8Љ), 8.08 (d, 1 H,
J 9.2, H-8Ј), 7.85 (d, 1 H, J 8.1, H-5Љ), 7.83 (ddd, 1 H, J 8.4, 7.0
and 1.5, H-7Љ), 7.63–7.56 (ddd, 1 H, J 8.1, 7.0 and 1.1, H-6Љ),
7.55 (d, 1 H, J 2.6, H-5Ј), 7.45 (d, 1 H, J 4.6, H-3Ј), 7.41 (dd,
1 H, J 9.2 and 2.7, H-7Ј), 6.78 (d, 1 H, J 7.2, H-9), 3.89 (s, 3 H,
H-11Ј), 3.47–3.41 (m, 1 H, H-8), 3.29–3.23 (m, 1 H, H-2endo),
3.19–3.12 (dd, 1 H, J 13.8 and 8.5, H-2exo), 2.92–2.74 (m, 2 H,
H-6, H-6), 2.33–2.27 (m, 1 H, H-3), 2.21–2.17 (m, 1 H, H-4),
2.16 (s, 3 H, H-13), 1.76–1.55 (m, 3 H, H-7, H-7, H-5) and 1.36–
1.25 (m, 1 H, H-5); δC(100 MHz; CDCl3) 169.91 (C, C-12),
157.99 (C, C-6Ј), 152.43 (CH, C-6Љ), 147.49 (CH, C-2Ј), 146.64
(C, C-10Љ), 144.71 (C, C-10Ј), 143.56 (C, C-4Ј), 138.29 (CH, C-
2Љ), 131.77 (CH, C-8Ј), 129.90 (CH, C-8Љ), 129.34 (CH, C-7Љ),
127.52 (CH, C-5Љ), 127.36 (C, C-9Љ), 127.28 (CH, C-4Љ), 127.03
(C, C-9Ј), 121.91 (CH, C-7Ј), 118.87 (CH, C-3Ј), 117.82 (C,
C-3Љ), 101.43 (CH, C-5Ј), 96.38 (C, C-11), 79.18 (C, C-10),
73.45 (CH, C-9), 58.94 (CH, C-8), 55.52 (CH3, C-11Ј), 50.39
(CH2, C-2), 49.49 (CH2, C-6), 29.09 (CH, C-3), 27.81 (CH,
C-4), 25.05 (CH2, C-7), 24.42 (CH2, C-5) and 21.14 (CH3,
C-13); m/z (MAT, 180 ЊC) (EI) 491.2197 (Mϩ, C31H29N3O3
requires 491.2195), 476 (9%), 448 (11), 432 (26), 421 (8), 402 (8),
392 (9), 375 (9), 325 (22), 284 (8), 261 (100), 245 (10), 233 (34),
220 (14), 204 (22), 189 (37), 179 (20), 166 (17), 154 (13), 128
(11), 117 (8), 94 (11) and 82 (10).
2 H, J 8.4, H-14, H-16), 8.06 (d, 1 H, J 9.2, H-8Ј), 7.61 (d, 2 H,
J 8.6, H-13, H-17), 7.52 (d, 1 H, J 2.6, H-5Ј), 7.42 (d, 1 H, J 4.6,
H-3Ј), 7.40 (dd, 1 H, J 9.2 and 2.6, H-7Ј), 6.73 (d, 1 H, J 7.0,
H-9), 4.44 (q, 2 H, J 7.1, H3C-H2C-O), 3.89 (s, 3 H, H-11Ј),
3.43–3.36 (m, 1 H, H-8), 3.24–3.18 (m, 1 H, H-2), 3.14–3.08
(dd, 1 H, J 13.8 and 10.1, H-2exo), 2.91–2.83 (m, 1 H, H-6),
2.81–2.72 (m, 1 H, H-6), 2.29–2.22 (m, 1 H, H-3), 2.14 (s, 3 H,
H-20), 2.15–2.10 (m, 1 H, H-4), 1.71–1.55 (m, 3 H, H-7, H-7,
H-5), 1.45–1.41 (t, 3 H, J 7.1, H3C-H2C-O) and 1.32–1.28 (m, 1
H, H-5); δC(100 MHz; CDCl3) 169.90 (C, C-19), 166.14 (C,
C-18), 157.97 (C, C-6Ј), 148.19 (C, C-15), 147.39 (CH, C-2Ј),
144.62 (C, C-10Ј), 143.59 (C, C-4Ј), 131.75 (CH, C-8Ј), 131.56
(2 CH, C-14, C-16), 129.52 (2 CH, C-13, C-17), 129.50 (C, C-
12), 128.38 (C, C-9Ј), 121.96 (CH, C-7Ј), 118.76 (CH, C-3Ј),
101.35 (CH, C-5Ј), 96.09 (C, C-11), 81.33 (C, C-10), 73.57 (CH,
C-9), 61.13 (CH2, H3C-H2C-O), 58.97 (CH, C-8), 55.52 (CH3,
C-11Ј), 50.42 (CH2, C-2), 49.50 (CH2, C-6), 29.05 (CH, C-3),
27.76 (CH, C-4), 25.08 (CH2, C-7), 24.38 (CH2, C-5), 21.09
(CH3, C-20) and 14.32 (CH3, H3C-H2C-O); m/z (MAT, 180 ЊC)
(EI) 512.2335 (Mϩ, C31H32N2O5 requires 512.2331), 497 (5%),
467 (10), 453 (30), 439 (6), 414 (9), 379 (4), 365 (18), 340 (4), 325
(22), 305 (8), 283 (100), 254 (19), 231 (34), 226 (8), 209 (9), 189
(44), 171 (18), 155 (18), 136 (14), 115 (10), 91 (7) and 77 (9).
(3S,4S,8R,9S)-9-Acetoxy-10,11-didehydro-11-(4-formyl-
phenyl)-6Ј-methoxycinchonan 21g. 10,11-Didehydroquinidine
9b (195 mg, 0.54 mmol, 1 eq.) was allowed to react according
to the general procedure with (Ph3P)2PdCl2 (19 mg, 0.03 mmol,
0.05 eq.), CuI (10 mg, 0.05 mmol, 0.1 eq.) and 4-bromo-
benzaldehyde (149 mg, 0.80 mmol, 1.5 eq.) to afford p-benz-
aldehyde-substituted alkyne 21g (83%, 208 mg, 0.44 mmol);
νmax(CHCl3)/cmϪ1 2948, 2876, 2836, 2220, 1744, 1700, 1620,
1600, 1508, 1472, 1456, 1432, 1372, 1304, 1232, 1164, 1092,
1068, 1032 and 832; δH(400 MHz; CDCl3) 10.05 (s, 1 H, H-18),
8.79 (d, 1 H, J 4.4, H-2Ј), 8.07 (d, 1 H, J 9.2, H-8Ј), 7.91 (d, 2 H,
J 8.4, H-14, H-16), 7.71 (d, 2 H, J 8.4, H-13, H-17), 7.53 (d, 1 H,
J 2.7, H-5Ј), 7.43 (d, 1 H, J 4.6, H-3Ј), 7.41 (dd, 1 H, J 9.4
and 2.7, H-7Ј), 6.73 (d, 1 H, J 7.3, H-9), 3.90 (s, 3 H, H-11Ј),
3.46–3.39 (m, 1 H, H-8), 3.24–3.19 (ddd, 1 H, J 14.0, 6.8
and 2.0, H-2endo), 3.15–3.09 (dd, 1 H, J 14.0 and 10.4, H-2exo),
2.91–2.72 (m, 3 H, H-6, H-6, H-3), 2.27–2.19 (m, 1 H, H-4),
2.15 (s, 3 H, H-20), 1.74–1.58 (m, 3 H, H-7, H-7, H-5) and 1.31–
1.27 (m, 1 H, H-5); δC(100 MHz; CDCl3) 191.42 (CH, C-18),
169.92 (C, C-19), 157.94 (C, C-6Ј), 147.48 (CH, C-2Ј), 144.80
(C, C-10Ј), 143.49 (C, C-4Ј), 135.21 (C, C-15), 132.23 (2 CH,
C-14, C-16), 131.83 (CH, C-8Ј), 130.12 (C, C-12), 129.59 (2
CH, C-13, C-17), 127.02 (C, C-9Ј), 121.86 (CH, C-7Ј), 118.89
(CH, C-3Ј), 101.44 (CH, C-5Ј), 97.44 (C, C-11), 81.28 (C,
C-10), 73.49 (CH, C-9), 58.97 (CH, C-8), 55.49 (CH3, C-11Ј),
50.30 (CH2, C-2), 49.46 (CH2, C-6), 29.11 (CH, C-3), 27.75
(CH, C-4), 25.06 (CH2, C-7), 24.55 (CH2, C-5) and 21.08 (CH3,
C-20); m/z (MAT, 190 ЊC) (EI) 468.2050 (Mϩ, C29H28N2O4
requires 468.2049), 453 (4%), 440 (2), 425 (8), 410 (26), 381 (3),
370 (4), 355 (2), 326 (26), 307 (2), 296 (4), 283 (3), 253 (7), 238
(100), 231 (21), 210 (9), 188 (44), 172 (14), 155 (19), 128 (11),
115 (14), 91 (7) and 77 (10).
(3S,4S,8R,9S)-10,11-Didehydro-11-(2-naphthyl)-6Ј-methoxy-
cinchonan-9-ol 21e. 10,11-Didehydroquinidine 9a (130 mg,
0.40 mmol, 1 eq.) was allowed to react according to the general
procedure with (Ph3P)2PdCl2 (14 mg, 0.02 mmol, 0.05 eq.), CuI
(8 mg, 0.04 mmol, 0.1 eq.) and 3-bromonaphthalene (125 mg,
0.61 mmol, 1.5 eq.) to afford naphthyl-substituted alkyne 21e
(67%, 121 mg, 0.27 mmol); νmax(CHCl3)/cmϪ1 3412, 3084, 2948,
2876, 1620, 1592, 1508, 1472, 1432, 1388, 1364, 1320, 1240,
1188, 1104, 1032, 844 and 832; δH(400 MHz; CDCl3) 8.46 (d,
1 H, J 4.6, H-2Ј), 7.90–7.82 (m, 3 H, H-8Ј, 2 naphthyl-H), 7.41
(d, 1 H, J 4.5, H-3Ј), 7.33–7.20 (m, 5 H, H-5Ј, H-7Ј, 3 naphthyl-
H), 6.80–6.59 (m, 2 H, naphthyl-H), 5.76 (s, 1 H, H-9), 3.84
(s, 3 H, H-11Ј), 3.68–3.63 (m, 1 H, H-8), 3.11–3.02 (m, 1 H,
H-2), 2.98–2.81 (m, 2 H, H-2, H-6), 2.73–2.59 (m, 1 H, H-6),
2.38–2.30 (m, 1 H, H-3), 1.98–1.92 (m, 1 H, H-4), 1.56–1.39 (m,
3 H, H-7, H-7, H-5) and 1.31–1.14 (m, 1 H, H-5); δC(100 MHz;
CDCl3) 157.82 (C, C-6Ј), 147.69 (C, C-10Ј), 147.37 (CH, C-2Ј),
143.81 (C, C-4Ј), 133.44 (C, C-13), 133.28 (C, C-18), 131.17
(CH, C-8Ј), 130.21 (CH, C-12), 130.09 (C, C-21), 128.69–126.88
(CH, C-14, C-15, C-16, C-17, C-19, C-20), 126.54 (C, C-9Ј),
121.69 (CH, C-7Ј), 118.98 (CH, C-3Ј), 101.26 (CH, C-5Ј),
96.42 (C, C-11), 80.09 (C, C-10), 69.98 (CH, C-9), 59.82 (CH,
C-8), 55.87 (CH3, C-11Ј), 49.29 (CH2, C-2), 46.63 (CH2, C-6),
29.98 (CH, C-3), 27.88 (CH, C-4), 24.34 (CH2, C-7) and 22.58
(CH2, C-5); m/z (MAT, 50 ЊC) (EI) 448.2151 (Mϩ, C30H28N2O2
requires 448.2151), 442 (6%), 426 (4), 411 (3), 399 (3), 373 (3),
355 (2), 321 (4), 284 (5), 267 (12), 254 (8), 239 (7), 202 (5), 189
(31), 173 (18), 160 (22), 129 (7), 116 (10), 99 (12) and 83 (100).
(3S,4S,8R,9S)-9-Acetoxy-10,11-didehydro-11-(thiazolin-2-
yl)-6Ј-methoxycinchonan 21h. 10,11-Didehydroquinidine 9b (130
mg, 0.36 mmol, 1 eq.) was allowed to react according to the
general procedure with (Ph3P)2PdCl2 (13 mg, 0.02 mmol, 0.05
eq.), CuI (7 mg, 0.04 mmol, 0.1 eq.) and 2-bromothiazole (48 µl,
0.54 mmol, 1.5 eq.) to yield thiazolinyl-substituted alkyne 21h
(90%, 144 mg, 0.32 mmol); νmax(CHCl3)/cmϪ1 2948, 2876, 2220,
1744, 1620, 1592, 1508, 1476, 1456, 1432, 1372, 1320, 1304,
1232, 1136, 1088, 1056, 1032 and 844; δH(400 MHz; CDCl3)
8.79 (d, 1 H, J 4.6, H-2Ј), 8.08 (d, 1 H, J 9.0, H-8Ј), 7.86 (d, 1 H,
J 3.3, H-13), 7.44–7.40 (m, 3 H, H-5Ј, H-3Ј, H-7Ј), 7.38 (d, 1 H,
J 3.3, H-14), 6.63 (d, 1 H, J 6.1, H-9), 3.98 (s, 3 H, H-11Ј), 3.38–
3.27 (m, 2 H, H-8, H-2), 3.21–3.15 (dd, 1 H, J 14.0 and 10.2,
(3S,4S,8R,9S)-9-Acetoxy-10,11-didehydro-11-(4-ethoxycarb-
onylphenyl)-6Ј-methoxycinchonan 21f. 10,11-Didehydroquinidine
9b (130 mg, 0.36 mmol, 1 eq.) was allowed to react according to
the general procedure with (Ph3P)2PdCl2 (13 mg, 0.02 mmol,
0.05 eq.), CuI (7 mg, 0.04 mmol, 0.1 eq.) and 4-iodobenzoate
(127 mg, 0.53 mmol, 1.5 eq.) to afford ethoxycarbonylphenyl-
substituted alkyne 21f (86%, 157 mg, 0.31 mmol); νmax(CHCl3)/
cmϪ1 3076, 2944, 2876, 2220, 1740, 1712, 1620, 1604, 1508,
1472, 1432, 1368, 1276, 1228, 1176, 1108, 1068, 1028, 856 and
824; δH(400 MHz; CDCl3) 8.77 (d, 1 H, J 4.5, H-2Ј), 8.07 (d,
J. Chem. Soc., Perkin Trans. 1, 2001, 47–65
55

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H-2exo), 2.90–2.73 (m, 2 H, H-6, H-6), 2.33–2.26 (m, 1 H, H-3),
2.22–2.18 (m, 1 H, H-4), 2.20 (s, 3 H, H-16), 1.64–1.56 (m, 3 H,
H-7, H-7, H-5) and 1.37–1.28 (m, 1 H, H-5); δC(100 MHz;
CDCl3) 169.85 (C, C-15), 157.99 (C, C-6Ј), 149.09 (C, C-12),
147.48 (CH, C-2Ј), 144.67 (C, C-10Ј), 143.69 (C, C-4Ј), 143.29
(CH, C-13), 131.85 (CH, C-8Ј), 126.76 (C, C-9Ј), 121.92 (CH,
C-7Ј), 120.14 (CH, C-14), 118.32 (CH, C-3Ј), 101.25 (CH,
C-5Ј), 98.31 (C, C-11), 75.07 (C, C-10), 73.91 (CH, C-9), 58.91
(CH, C-8), 55.66 (CH3, C-11Ј), 49.92 (CH2, C-2), 49.58 (CH2,
C-6), 29.11 (CH, C-3), 27.66 (CH, C-4), 24.92 (CH2, C-7), 23.77
(CH2, C-5) and 21.18 (CH3, C-16); m/z (MAT, 190 ЊC) (EI)
447.1602 (Mϩ, C25H25N3O3S requires 447.1606), 432 (2%), 404
(9), 388 (49), 372 (2), 348 (8), 325 (12), 297 (4), 265 (4), 253 (4),
231 (10), 217 (100), 202 (6), 188 (37), 172 (11), 162 (11), 132
(15), 117 (7), 104 (9) and 77 (9).
(C, C-11), 82.05 (C, C-10), 77.25 (CH, C-22), 71.74 (CH, C-9),
70.06 (CH2, C-18), 58.39 (CH, C-8), 58.14 (CH2, C-2), 53.60
(CH3, C-11Ј), 49.26 (CH2, C-6), 44.89 (CH, C-15), 39.33 (C,
C-14), 37.89 (CH, C-16), 28.27 (CH, C-3), 27.28 (CH, C-4),
26.53 (CH2, C-7), 25.81 (CH2, C-23), 24.19 (CH2, C-17), 23.27
(CH2, C-5), 21.16 (CH3, C-25), 16.37 (CH3, C-13-Me), 15.59
(CH3, C-14-Me) and 15.57 (CH3, C-14-Me); m/z (MAT, 220 ЊC)
(EI) 570.3127 (Mϩ, C35H42N2O5: requires 570.3134), 556 (9%),
528 (6), 512 (31), 340 (100), 325 (12), 312 (17), 298 (13), 285
(11), 251 (7), 231 (61), 211 (9), 189 (59), 172 (28), 160 (17), 136
(15), 121 (70), 105 (11) and 91 (28.95).
(3S,4S,8R,9S)-9-Acetoxy-10,11-didehydro-11-(4-hydroxy-
phenyl)-6Ј-methoxycinchonan 21k. 10,11-Didehydroquinidine
9b (130 mg, 0.36 mmol, 1 eq.) was allowed to react according to
the general procedure with (Ph3P)2PdCl2 (13 mg, 0.02 mmol,
0.05 eq.), CuI (7 mg, 0.04 mmol, 0.1 eq.) and 4-iodophenol (117
mg, 0.53 mmol, 1.5 eq.) to yield p-hydroxyphenyl-substituted
alkyne 21k (85%, 138 mg, 0.30 mmol); νmax(CHCl3)/cmϪ1 3420,
2940, 2876, 1744, 1620, 1592, 1508, 1472, 1456, 1368, 1304,
1236, 1136, 1084, 1064, 1028, 984, 916 and 844; δH(400 MHz;
CDCl3) 8.75 (d, 1 H, J 4.6, H-2Ј), 8.04 (d, 1 H, J 9.2, H-8Ј), 7.92
(d, 2 H, J 8.4, H-14, H-16), 7.59 (d, 2 H, J 8.4, H-13, H-17), 7.43
(d, 1 H, J 2.6, H-5Ј), 7.40–7.37 (dd, 1 H, J 9.2 and 2.6, H-7Ј),
7.36 (d, 1 H, J 4.7, H-3Ј), 6.57 (d, 1 H, J 6.8, H-9), 3.97 (s, 3 H,
H-11Ј), 3.32–3.26 (m, 1 H, H-8), 2.95–2.92 (d, 1 H, J 14.4, H-2),
2.93–2.69 (m, 3 H, H-2, H-6, H-6), 2.32–2.26 (m, 1 H, H-3),
2.15 (s, 3 H, H-19), 2.16–2.08 (m, 1 H, H-4), 1.94–1.78 (m, 2 H,
H-7, H-7) and 1.57–1.44 (m, 2 H, H-5, H-5); δC(100 MHz;
CDCl3) 169.93 (C, C-18), 166.34 (C, C-15), 157.93 (C, C-6Ј),
147.37 (CH, C-2Ј), 144.63 (C, C-10Ј), 143.85 (C, C-4Ј), 131.69
(CH, C-8Ј), 131.55 (CH, C-14, C-16), 129.48 (C, C-12), 128.19
(CH, C-13, C-17), 126.99 (C, C-9Ј), 121.88 (CH, C-7Ј), 118.51
(CH, C-3Ј), 101.39 (CH, C-5Ј), 96.13 (C, C-11), 81.97 (C, C-10),
73.59 (CH, C-9), 59.03 (CH, C-8), 55.62 (CH3, C-11Ј), 49.98
(CH2, C-2), 49.16 (CH2, C-6), 31.25 (CH, C-3), 27.87 (CH,
C-4), 26.35 (CH2, C-7), 23.28 (CH2, C-5) and 21.14 (CH3,
C-19); m/z (MAT, 200 ЊC) (EI) 456 (Mϩ, 7%), 455 (25), 397 (6),
369 (10), 355 (5), 325 (17), 313 (5), 297 (3), 279 (17), 258 (7), 231
(17), 226 (12), 197 (100), 183 (12), 168 (18), 143 (13), 123 (4),
105 (12) and 91 (16).
(3S,4S,8R,9S)-9-Acetoxy-10,11-didehydro-11-(2-thienyl)-6Ј-
methoxycinchonan 21i. 10,11-Didehydroquinidine 9b (130 mg,
0.36 mmol, 1 eq.) was allowed to react according to the general
procedure with (Ph3P)2PdCl2 (13 mg, 0.02 mmol, 0.05 eq.),
CuI (7 mg, 0.04 mmol, 0.1 eq.) and 2-bromothiophene (52 µl,
0.53 mmol, 1.5 eq.) to yield thiophenyl-substituted alkyne 21i
(88%, 140 mg, 0.31 mmol); νmax(CHCl3)/cmϪ1 2956, 2876, 2224,
1744, 1620, 1592, 1508, 1472, 1456, 1432, 1372, 1300, 1236,
1136, 1092, 1028, 988, 844 and 828; δH(400 MHz; CDCl3) 8.79
(d, 1 H, J 4.6, H-2Ј), 8.07 (d, 1 H, J 9.0, H-8Ј), 7.51 (d, 1 H,
J 2.6, H-5Ј), 7.43–7.39 (m, 2 H, H-3Ј, H-7Ј), 7.29–7.26 (m, 2 H,
H-13, H-15), 7.04 (dd, 1 H, J 5.3 and 3.7, H-14), 6.71 (d, 1 H,
J 6.4, H-9), 3.95 (s, 3 H, H-11Ј), 3.42–3.33 (m, 1 H, H-8), 3.26–
3.20 (m, 1 H, H-2), 3.07–2.99 (m, 1 H, H-2), 2.92–2.74 (m, 2 H,
H-6, H-6), 2.32–2.24 (m, 1 H, H-3), 2.16–2.11 (m, 1 H, H-4),
2.19 (s, 3 H, H-17), 1.67–1.54 (m, 3 H, H-7, H-7, H-5) and 1.37–
1.28 (m, 1 H, H-5); δC(100 MHz; CDCl3) 169.88 (C, C-16),
158.01 (C, C-6Ј), 147.42 (CH, C-2Ј), 144.38 (C, C-10Ј), 143.73
(C, C-4Ј), 131.77 (CH, C-8Ј), 131.43 (CH, C-15), 128.59 (C,
C-12), 126.96 (C, C-9Ј), 126.29 (CH, C-13), 122.01 (CH, C-7Ј),
120.14 (CH, C-14), 118.53 (CH, C-3Ј), 101.29 (CH, C-5Ј), 96.71
(C, C-11), 74.87 (C, C-10), 73.79 (CH, C-9), 59.01 (CH, C-8),
55.57 (CH3, C-11Ј), 50.49 (CH2, C-2), 49.59 (CH2, C-6), 29.24
(CH, C-3), 27.83 (CH, C-4), 25.11 (CH2, C-7), 24.13 (CH2, C-5)
and 21.14 (CH3, C-17); m/z (MAT, 140 ЊC) (EI) 446.1186 (Mϩ,
C26H26N2O3S requires 446.1188), 366 (10%), 324 (7), 306 (4),
278 (7), 262 (4), 231 (2), 216 (6), 201 (3), 183 (5), 167 (11), 149
(19), 136 (10), 115 (50), 101 (17), 86 (100) and 72 (37).
(3S,4S,8R,9S)-9-Acetoxy-10,11-didehydro-11-(3-hydroxy-
phenyl)-6Ј-methoxycinchonan 21l. 10,11-Didehydroquinidine 9b
(130 mg, 0.36 mmol, 1 eq.) was allowed to react according to
the general procedure with (Ph3P)2PdCl2 (13 mg, 0.02 mmol,
0.05 eq.), CuI (7 mg, 0.04 mmol, 0.1 eq.) and 3-iodophenol (117
mg, 0.53 mmol, 1.5 eq.) to yield m-hydroxyphenyl-substituted
alkyne 21l (82%, 134 mg, 0.30 mmol); νmax(CHCl3)/cmϪ1 3368,
2960, 2932, 2872, 1720, 1620, 1596, 1508, 1464, 1408, 1376,
1292, 1232, 1132, 1072, 1036, 992, 960 and 852; δH(400 MHz;
CDCl3) 8.79 (d, 1 H, J 4.6, H-2Ј), 8.25 (d, 1 H, J 9.2, H-8Ј), 8.16
(d, 1 H, J 1.6, H-13), 7.77 (dd, 1 H, J 5.7 and 3.3, H-15), 7.64 (d,
1 H, J 4.8, H-3Ј), 7.59 (dd, 1 H, J 5.8 and 3.4, H-17), 7.55–7.51
(dd, 1 H, J 9.2 and 2.6, H-7Ј), 7.26–7.18 (m, 2 H, H-5Ј, H-16),
6.52 (d, 1 H, J 6.4, H-9), 4.08 (s, 3 H, H-11Ј), 3.53–3.47 (m,
1 H, H-8), 3.34–3.27 (m, 1 H, H-2), 3.18–3.09 (m, 1 H, H-2),
2.92–2.74 (m, 2 H, H-6, H-6), 2.38–2.29 (m, 1 H, H-3), 2.24
(s, 3 H, H-19), 2.13–2.08 (m, 1 H, H-4), 1.76–1.68 (m, 3 H, H-7,
H-7, H-5) and 1.53–1.46 (m, 1 H, H-5); δC(100 MHz; CDCl3)
169.79 (C, C-18), 166.90 (C, C-14), 157.22 (C, C-6Ј), 147.18
(CH, C-2Ј), 144.87 (C, C-10Ј), 143.91 (C, C-4Ј), 131.67 (CH,
C-8Ј), 131.48 (CH, C-13), 131.39 (CH, C-15), 129.54 (C, C-12),
128.58 (CH, C-17), 126.93 (C, C-9Ј), 124.03 (CH, C-16), 121.38
(CH, C-7Ј), 117.85 (CH, C-3Ј), 101.66 (CH, C-5Ј), 95.62 (C,
C-11), 81.32 (C, C-10), 73.02 (CH, C-9), 58.32 (CH, C-8), 55.19
(CH3, C-11Ј), 49.77 (CH2, C-2), 48.51 (CH2, C-6), 29.74 (CH,
C-3), 28.29 (CH, C-4), 25.72 (CH2, C-7), 23.19 (CH2, C-5) and
22.31 (CH3, C-19); m/z (FAB) (EI) 457 (Mϩ ϩ H, 17%), 413
(15), 391 (36), 279 (7), 167 (19), 149 (100) and 113 (21).
(3S,4S,8R,9S)-9-Acetoxy-11-(6,6,7-trimethyl-
2,3,3a,3b,4,7,7a,8a-octahydrofuro[2,3-b]benzofuryl)-10,11-
didehydro-6Ј-methoxycinchonan 21j. 10,11-Didehydroquinidine
9b (73 mg, 0.20 mmol, 1 eq.) was allowed to react according to
the general procedure with (Ph3P)2PdCl2 (8 mg, 0.01 mmol, 0.05
eq.), CuI (4 mg, 0.02 mmol, 0.1 eq.) and the tricyclic vinyl
iodide (100 mg, 0.30 mmol, 1.5 eq.) to yield substituted alkyne
21j (94%, 107 mg, 0.19 mmol); νmax(CHCl3)/cmϪ1 2960, 2940,
2884, 1744, 1620, 1592, 1508, 1472, 1456, 1368, 1304, 1228,
1136, 1108, 1084, 1040, 996, 940 and 852; δH(400 MHz; CDCl3)
8.82 (d, 1 H, J 4.6, H-2Ј), 8.13 (d, 1 H, J 9.2, H-8Ј), 7.49 (d, 1 H,
J 2.6, H-5Ј), 7.44–7.40 (dd, 1 H, J 9.2 and 2.6, H-7Ј), 7.39 (d,
1 H, J 4.6, H-3Ј), 6.69 (d, 1 H, J 6.3, H-9), 5.73 (d, 1 H, J 4.8,
H-20), 4.18–4.13 (m, 1 H, H-22), 4.02 (s, 3 H, H-11Ј), 3.85–3.78
(m, 1 H, H-18), 3.69–3.61 (m, 1 H, H-18), 3.32–3.21 (m, 2 H,
H-8, H-2), 3.00–2.93 (m, 1 H, H-2), 2.90–2.74 (m, 2 H, H-6,
H-6), 2.62–2.54 (m, 1 H, H-3), 2.22 (s, 3 H, H-25), 2.15–2.02
(m, 3 H, H-4, H-15, H-16), 1.94–1.87 (m, 1 H, H-7), 1.85–1.67
(m, 2 H, H-7, H-5), 1.62–1.53 (m, 4 H, H-17, H-17, H-23, H-23),
1.32–1.28 (m, 1 H, H-5), 1.13 (s, 3 H, C-13-Me), 1.04 (s, 3 H,
C-14-Me) and 1.03 (s, 3 H, C-14-Me); δC(100 MHz; CDCl3)
169.76 (C, C-24), 158.21 (C, C-6Ј), 147.89 (CH, C-2Ј), 147.40
(C, C-10Ј), 144.59 (C, C-4Ј), 132.17 (C, C-13), 131.71 (CH,
C-8Ј), 126.89 (C, C-9Ј), 122.09 (CH, C-7Ј), 118.53 (CH, C-3Ј),
112.11 (C, C-12), 109.66 (CH, C-20), 101.45 (CH, C-5Ј), 98.02
56
J. Chem. Soc., Perkin Trans. 1, 2001, 47–65

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(3S,4S,8R,9S)-9-Acetoxy-11-(4-iodophenyl)-10,11-dide-
hydro-6Ј-methoxycinchonan 21m. 10,11-Didehydroquinidine 9b
(546 mg, 1.50 mmol, 1 eq.) was allowed to react according
to the general procedure with (Ph3P)2PdCl2 (53 mg, 0.08 mmol,
0.05 eq.), CuI (29 mg, 0.15 mmol, 0.1 eq.) and 1,4-diiodo-
benzene (743 mg, 2.25 mmol, 1.5 eq.) to yield p-iodophenyl-
1 H, J 8.9, H-8Ј), 7.61 (d, 1 H, J 2.4, H-5Ј), 7.54–7.47 (m, 1 H,
H-3Ј), 7.45–7.37 (m, 3 H, H-7Ј, H-13, H-16), 7.31–7.25 (m, 2 H,
H-14, H-15), 6.77 (d, 1 H, J 7.2, H-9), 6.59 (s, 1 H, H-11), 3.96
(s, 3 H, H-11Ј), 3.44–3.37 (m, 1 H, H-8), 3.27–3.10 (m, 2 H, H-2,
H-2), 2.98–2.84 (m, 2 H, H-6, H-6), 2.36–2.29 (m, 1 H, H-3),
2.24–2.20 (m, 1 H, H-4), 2.10 (s, 3 H, H-19), 2.07–1.98 (m, 1 H,
H-7) and 1.78–1.52 (m, 3 H, H-7, H-5, H-5); δC(100 MHz;
CDCl3) 170.30 (C, C-18), 160.35 (C, C-17), 158.01 (C, C-6Ј),
147.63 (CH, C-2Ј), 144.83 (C, C-10), 144.09 (C, C-10Ј), 143.65
(C, C-4Ј), 131.75 (CH, C-8Ј), 129.85 (C, C-12), 128.57 (C, C-9Ј),
123.58 (CH, C-15), 122.69 (CH, C-14), 121.97 (CH, C-7Ј),
120.49 (CH, C-13), 120.24 (CH, C-3Ј), 110.87 (CH, C-16),
102.20 (CH, C-11), 101.53 (CH, C-5Ј), 73.45 (CH, C-9), 59.15
(CH, C-8), 55.62 (CH3, C-11Ј), 49.89 (CH2, C-2), 47.57 (CH2,
C-6), 29.27 (CH, C-3), 27.88 (CH, C-4), 26.12 (CH2, C-7), 25.69
(CH2, C-5) and 21.12 (CH3, C-19); m/z (MAT, 200 ЊC) (EI)
456.2050 (Mϩ, C28H28N2O4 requires 456.2049), 441 (3%), 413
(3), 397 (9), 365 (4), 325 (5), 313 (2), 265 (2), 253 (6), 226 (100),
211 (7), 199 (22), 188 (51), 172 (22), 157 (29), 144 (82), 132 (23),
115 (6), 99 (7) and 86 (13).
substituted alkyne 21m (82%, 680 mg, 1.20 mmol); νmax
-
(CHCl3)/cmϪ1 2944, 2876, 2224, 1744, 1624, 1592, 1508, 1484,
1456, 1432, 1372, 1300, 1232, 1172, 1136, 1092, 1032, 1004, 844
and 824; δH(400 MHz; CDCl3) 8.79 (d, 1 H, J 4.6, H-2Ј), 8.07
(d, 1 H, J 9.2, H-8Ј), 7.73 (d, 2 H, J 8.6, H-14, H-16), 7.52 (d,
1 H, J 2.6, H-5Ј), 7.43–7.38 (m, 2 H, H-3Ј, H-7Ј), 7.28 (d, 2 H,
J 8.5, H-13, H-17), 6.73 (d, 1 H, J 7.3, H-9), 3.90 (s, 3 H, H-11Ј),
3.47–3.38 (m, 1 H, H-8), 3.22–3.07 (m, 2 H, H-2, H-2), 2.92–
2.84 (m, 1 H, H-6), 2.80–2.71 (m, 2 H, H-6, H-3), 2.27–2.20
(m, 1 H, H-4), 2.15 (s, 3 H, H-20), 1.72–1.53 (m, 3 H, H-7, H-7,
H-5) and 1.23–1.14 (m, 1 H, H-5); δC(100 MHz; CDCl3) 169.89
(C, C-18), 157.91 (C, C-6Ј), 147.44 (CH, C-2Ј), 144.77 (C, C-4Ј),
143.54 (C, C-10Ј), 137.47 (CH, C-14, C-16), 133.23 (CH, C-13,
C-17), 131.78 (CH, C-8Ј), 126.99 (C, C-9Ј), 123.23 (C, C-12),
121.89 (CH, C-7Ј), 118.82 (CH, C-3Ј), 101.36 (CH, C-5Ј), 94.37
(C, C-15), 93.48 (C, C-10), 80.92 (C, C-11), 73.52 (CH, C-9),
58.98 (CH, C-8), 55.49 (CH3, C-11Ј), 50.41 (CH2, C-2), 49.47
(CH2, C-6), 28.98 (CH, C-3), 27.71 (CH, C-4), 25.10 (CH2,
C-5), 24.48 (CH2, C-7) and 21.09 (CH3, C-20); m/z (FAB) (EI)
567 (Mϩ ϩ H, 100%), 507 (6), 413 (17), 391 (29), 336 (15), 307
(7) and 279 (12).
(1S,2S,4S,5S)-2-Hydroxymethyl-5-phenylethynyl-1-aza-
bicyclo[2.2.2]octane 23a. 10,11-Didehydroquincorine 18a (600
mg, 3.64 mmol, 1 eq.) was allowed to react according to the
general procedure with (Ph3P)2PdCl2 (128 mg, 0.18 mmol,
0.05 eq.), CuI (69 mg, 0.36 mmol, 0.1 eq.) and iodobenzene
(0.61 ml, 5.46 mmol, 1.5 eq.) to yield phenyl-substituted alkyne
23a (74%, 649 mg, 2.69 mmol); νmax(CHCl3)/cmϪ1 3380, 3054,
2955, 2868, 2224, 1599, 1489, 1454, 1412, 1378, 1338, 1265,
1230, 1099, 1069, 1021, 995 and 942; δH(400 MHz; CDCl3)
7.43–7.39 (m, 2 H, Ph-H), 7.32–7.27 (m, 3 H, Ph-H), 4.24 (s,
1 H, OH), 3.63–3.58 (m, 1 H, H-9), 3.54–3.47 (m, 1 H, H-9),
3.41–3.32 (m, 1 H, H-6), 3.20–3.07 (m, 2 H, H-2, H-6), 2.94–
2.79 (m, 2 H, H-7, H-7), 2.28–2.19 (m, 1 H, H-5), 2.13–2.08
(m, 1 H, H-4), 1.71–1.55 (m, 3 H, H-3, H-8, H-8) and 1.04–0.97
(m, 1 H, H-3); δC(100 MHz; CDCl3) 131.65 (CH, C-13, C-17),
128.28 (CH, C-14, C-16), 127.94 (CH, C-15), 123.34 (C, C-12),
91.99 (C, C-10), 81.71 (C, C-11), 62.18 (CH2, C-9), 57.64
(CH, C-2), 56.60 (CH2, C-6), 40.14 (CH2, C-7), 28.23 (CH,
C-5), 26.71 (CH, C-4), 25.51 (CH2, C-8) and 24.54 (CH2, C-3);
m/z (MAT, 70 ЊC) (EI) 241.1468 (Mϩ, C16H19N1O1 requires
241.1467), 210 (100%), 128 (27) and 85 (32).
(3S,4S,8R,9S)-9-Acetoxy-11-(2-aminophenyl)-10,11-dide-
hydro-6Ј-methoxycinchonan 21n. 10,11-Didehydroquinidine 9b
(130 mg, 0.36 mmol, 1 eq.) was allowed to react according to
the general procedure with (Ph3P)2PdCl2 (13 mg, 0.02 mmol,
0.05 eq.), CuI (7 mg, 0.04 mmol, 0.1 eq.) and 2-iodoaniline (117
mg, 0.53 mmol, 1.5 eq.) to yield 2-aminophenyl-substituted
alkyne 21n (92%, 150 mg, 0.33 mmol); νmax(CHCl3)/cmϪ1 3452
2960, 2868, 2836, 2216, 1740, 1620, 1572, 1508, 1472, 1432,
1368, 1304, 1236, 1144, 1084, 1032, 904 and 844; δH(400 MHz;
CDCl3) 8.79 (d, 1 H, J 4.6, H-2Ј), 8.09 (d, 1 H, J 9.2, H-8Ј), 7.50
(d, 1 H, J 2.7, H-5Ј), 7.42 (d, 1 H, J 4.6, H-3Ј), 7.40 (dd, 1 H,
J 9.2 and 2.6, H-7Ј), 7.19 (dd, 1 H, J 7.8 and 1.7, H-14), 7.14–
7.09 (m, 1 H, H-15), 6.71–6.66 (m, 2 H, H-16, H-17), 6.54 (d,
1 H, J 7.5, H-9), 4.08 (s, 2 H, NH2), 3.96 (s, 3 H, H-11Ј), 3.72–
3.67 (m, 1 H, H-8), 3.28–3.21 (dd, 1 H, J 13.6 and 9.9, H-2endo),
3.20–3.14 (m, 1 H, H-2), 2.97–2.89 (m, 1 H, H-6), 2.86–2.79 (m,
1 H, H-6), 2.74–2.66 (m, 1 H, H-3), 2.31–2.23 (m, 1 H, H-4),
2.18 (s, 3 H, H-19), 1.85–1.76 (m, 1 H, H-7), 1.67–1.53 (m, 2 H,
H-7, H-5) and 1.48–1.42 (m, 1 H, H-5); δC(100 MHz; CDCl3)
170.17 (C, C-18), 157.94 (C, C-6Ј), 147.58 (C, C-13), 147.45
(CH, C-2Ј), 144.75 (C, C-10Ј), 143.49 (C, C-4Ј), 132.14 (CH,
C-14), 132.04 (CH, C-15), 131.77 (CH, C-8Ј), 129.13 (C, C-12),
127.04 (C, C-9Ј), 121.84 (CH, C-7Ј), 119.26 (CH, C-3Ј), 117.89
(CH, C-16), 114.24 (CH, C-17), 101.61 (CH, C-5Ј), 98.60 (C, C-
11), 81.27 (C, C-10), 73.79 (CH, C-9), 58.66 (CH, C-8), 55.64
(CH3, C-11Ј), 50.32 (CH2, C-2), 48.91 (CH2, C-6), 28.62 (CH,
C-3), 27.15 (CH, C-4), 26.24 (CH2, C-7), 25.10 (CH2, C-5)
and 21.10 (CH3, C-19); m/z (MAT, 200 ЊC) (EI) 455.2199 (Mϩ,
C28H29N3O3 requires 455.2209), 396 (11%), 369 (5), 355 (6), 325
(9), 313 (8), 296 (5), 278 (4), 258 (7), 231 (17), 225 (56), 211 (6),
197 (100), 182 (19), 168 (30), 155 (10), 143 (42), 130 (21), 115
(15), 91 (16) and 77 (11).
(1S,2S,4S,5S)-2-tert-Butyldimethylsilanyloxymethyl-5-
phenylethynyl-1-azabicyclo[2.2.2]octane 23b. 10,11-Didehydro-
quincorine 18b (100 mg, 0.36 mmol, 1 eq.) was allowed to react
according to the general procedure with (Ph3P)2PdCl2 (13 mg,
0.02 mmol, 0.05 eq.), CuI (7 mg, 0.04 mmol, 0.1 eq.) and
iodobenzene (110 mg, 0.54 mmol, 1.5 eq.) to yield phenyl-
substituted alkyne 23b (84%, 107 mg, 0.30 mmol); νmax(CHCl3)/
cmϪ1 3056, 2952, 2928, 2884, 2856, 1596, 1468, 1388, 1360,
1324, 1264, 1228, 1172, 1116, 1080, 1028, 940 and 836; δH(400
MHz; CDCl3) 7.42–7.39 (m, 2 H, Ph-H), 7.31–7.28 (m, 3 H,
Ph-H), 3.84–3.80 (dd, 1 H, J 10.6 and 5.6, H-9), 3.78–3.73
(dd, J 10.5 and 5.8, H-9), 3.47–3.40 (dd, 1 H, J 12.9 and 10.4,
H-6endo), 3.24–3.17 (m, 1 H, H-2), 3.16–3.09 (m, 1 H, H-6exo),
2.87–2.76 (m, 2 H, H-7, H-7), 2.25–2.17 (m, 1 H, H-5), 2.12–
2.08 (m, 1 H, H-4), 1.70–1.62 (m, 1 H, H-3), 1.59–1.50 (m, 1 H,
H-8), 1.45–1.38 (m, 1 H, H-8), 1.32–1.26 (m, 1 H, H-3), 0.93
(s, 9 H, SiC(CH3)3), 0.11 (s, 3 H, SiCH3) and 0.10 (s, 3 H,
SiCH3); δC(100 MHz; CDCl3) 131.96 (CH, C-13, C-17), 128.45
(CH, C-14, C-16), 127.75 (CH, C-15), 123.61 (C, C-12), 92.79
(C, C-10), 81.33 (C, C-11), 65.28 (CH2, C-9), 57.51 (CH2, C-6),
57.45 (CH, C-2), 42.29 (CH2, C-7), 28.24 (CH, C-5), 27.20 (CH,
C-4), 25.84 (CH3, SiC(CH3)3), 25.72 (CH2, C-8), 24.71 (CH2,
C-3), 18.39 (C, SiC(CH3)3), Ϫ5.23 (CH3, SiCH3) and Ϫ5.27
(CH3, SiCH3); m/z (MAT, 50 ЊC) (EI) 355.2333 (Mϩ, C22H33-
N1O1Si requires 355.2331), 340 (8%), 299 (71), 280 (2), 270 (6),
240 (7), 222 (11), 210 (1000), 194 (3), 184 (40), 170 (10), 156
(26), 128 (15), 115 (11), 98 (6) and 75 (39.03).
(3S,4S,8R,9S)-9-Acetoxy-3-benzofuryl-6Ј-methoxycinchonan
21o. 10,11-Didehydroquinidine 9b (130 mg, 0.36 mmol, 1 eq.)
was allowed to react according to the general procedure with
(Ph3P)2PdCl2 (13 mg, 0.02 mmol, 0.05 eq.), CuI (7 mg,
0.04 mmol, 0.1 eq.) and 2-iodophenol (117 mg, 0.53 mmol,
1.5 eq.) to yield benzofuran 21o (78%, 127 mg, 0.28 mmol);
νmax(CHCl3)/cmϪ1 3032, 2936, 2872, 2220, 1744, 1620, 1508,
1472, 1452, 1372, 1300, 1228, 1132, 1088, 1068, 1028, 988 and
844; δH(400 MHz; CDCl3) 8.84 (d, 1 H, J 4.6, H-2Ј), 8.18 (d,
J. Chem. Soc., Perkin Trans. 1, 2001, 47–65
57

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(1S,2S,4S,5S)-2-Hydroxymethyl-5-(4-nitrophenylethynyl)-1-
azabicyclo[2.2.2]octane 23c. 10,11-Didehydroquincorine 18a
(600 mg, 3.64 mmol, 1 eq.) was allowed to react according to
the general procedure with (Ph3P)2PdCl2 (128 mg, 0.18 mmol,
0.05 eq.), CuI (69 mg, 0.36 mmol, 0.1 eq.) and p-nitrophenyl
iodide (1358 mg, 5.46 mmol, 1.5 eq.) to yield p-nitrophenyl-
substituted alkyne 23c (77%, 801 mg, 2.80 mmol); νmax(CHCl3)/
cmϪ1 3424, 2955, 2868, 2222, 1595, 1519, 1490, 1454, 1410,
1344, 1308, 1285, 1230, 1193, 1175, 1108, 1019, 996, 942 and
855; δH(400 MHz; CDCl3) 8.17–8.13 (d, 2 H, J 8.9, H-14, H-16),
7.56–7.51 (d, 2 H, J 9.0, H-13, H-17), 4.17 (s, 1 H, OH), 3.62–
3.57 (m, 1 H, H-9), 3.53–3.45 (m, 1 H, H-9), 3.37–3.29 (m, 1 H,
H-6), 3.19–3.08 (m, 2 H, H-2, H-6), 2.96–2.90 (m, 1 H, H-7),
2.85–2.76 (m, 1 H, H-7), 2.22–2.15 (m, 1 H, H-5), 2.13–2.08
(m, 1 H, H-4), 1.66–1.58 (m, 2 H, H-3, H-8), 1.46–1.41 (m, 1 H,
H-8) and 1.04–0.97 (m, 1 H, H-3); δC(100 MHz; CDCl3) 146.84
(C, C-15), 132.45 (CH, C-13, C-17), 130.48 (C, C-12), 123.55
(CH, C-14, C-16), 98.29 (C, C-10), 80.15 (C, C-11), 62.28 (CH2,
C-9), 57.55 (CH, C-2), 56.37 (CH2, C-6), 40.04 (CH2, C-7),
28.52 (CH, C-5), 26.63 (CH, C-4), 25.62 (CH2, C-8) and 24.69
(CH2, C-3); m/z (MAT, 130 ЊC) (EI) 286.1317 (Mϩ, C16H18N2O3
requires 286.1317), 255 (100%), 228 (6), 209 (6), 181 (4), 152 (7),
126 (10), 102 (2), 87 (26) and 72 (12).
C-16), 128.56 (CH, C-24, C-26), 128.30 (C, C-22), 127.84 (C,
C-15), 96.22 (C, C-10), 80.82 (C, C-11), 65.48 (CH2, C-9), 61.07
(CH2, C-19), 56.72 (CH2, C-6), 54.44 (CH, C-2), 40.39 (CH2,
C-7), 28.37 (CH, C-5), 26.93 (CH, C-4), 26.00 (CH2, C-8), 25.39
(CH2, C-3) and 14.31 (CH3, C-20); m/z (MAT, 120 ЊC) (EI)
417.1938 (Mϩ, C16H27N1O4 requires 417.1940), 367 (2%), 324
(4), 307 (2), 277 (100), 262 (2), 225 (4), 201 (19), 183 (15), 152
(9), 122 (15), 105 (26) and 77 (27).
(1S,2S,4S,5S)-2-tert-Butyldimethylsilanyloxymethyl-5-(3Ј-
quinolylethynyl)-1-azabicyclo[2.2.2]octane 23f. 10,11-Dide-
hydroquincorine 18b (100 mg, 0.36 mmol, 1 eq.) was allowed
to react according to the general procedure with (Ph3P)2PdCl2
(13 mg, 0.02 mmol, 0.05 eq.), CuI (7 mg, 0.04 mmol, 0.1 eq.)
and 3-bromoquinoline (67 µl, 0.54 mmol, 1.5 eq.) to yield
quinolyl-substituted alkyne 23f (86%, 125 mg, 0.31 mmol);
νmax(CHCl3)/cmϪ1 2940, 2928, 2856, 1596, 1468, 1388, 1344,
1320, 1256, 1188, 1116, 1084, 1028, 940 and 836; δH(400 MHz;
CDCl3) 8.86 (d, 1 H, J 2.2, H-2Ј), 8.17 (d, 1 H, J 2.1, H-4Ј), 8.08
(d, 1 H, J 8.4, H-8Ј), 7.76 (d, 1 H, J 8.0, H-5Ј), 7.71–7.66 (ddd,
1 H, J 8.3, 7.0 and 1.4, H-7Ј), 7.56–7.51 (ddd, 1 H, J 7.9, 7.2
and 1.1, H-6Ј), 3.70–3.66 (dd, 1 H, J 10.2 and 6.0, H-9), 3.64–
3.59 (dd, J 10.3 and 6.0, H-9), 3.24–3.18 (dd, 1 H, J 13.3 and
10.1, H-6endo), 3.11–2.89 (m, 3 H, H-2, H-6, H-7), 2.61–2.53 (m,
1 H, H-7), 2.34–2.30 (m, 1 H, H-5), 2.09–2.00 (m, 1 H, H-4),
1.96–1.92 (m, 1 H, H-3), 1.53–1.42 (m, 1 H, H-8), 1.32–1.21
(m, 2 H, H-8, H-3), 0.90 (s, 9 H, SiC(CH3)3) and 0.07 (s, 6 H,
SiCH3); δC(100 MHz; CDCl3) 152.46 (CH, C-6Ј), 146.59 (C,
C-10Ј), 138.01 (CH, C-2Ј), 129.67 (CH, C-8Ј), 129.36 (CH,
C-7Ј), 127.39 (CH, C-5Ј), 127.34 (C, C-9Ј), 127.14 (CH, C-4Ј),
118.06 (C, C-3Љ), 97.43 (C, C-10), 81.49 (C, C-11), 65.92 (CH2,
C-9), 57.86 (CH2, C-6), 57.13 (CH, C-2), 41.71 (CH2, C-7),
29.28 (CH, C-5), 27.61 (CH, C-4), 26.01 (CH3, SiC(CH3)3),
25.07 (CH2, C-8), 22.68 (CH2, C-3), 18.42 (C, SiC(CH3)3),
Ϫ5.27 (CH3, SiCH3) and Ϫ5.34 (CH3, SiCH3); m/z (FAB) (EI)
407 (Mϩ ϩ H, 8%), 355 (14), 325 (10), 281 (41), 221 (55), 207
(43) and 147 (100).
(1S,2S,4S,5S)-2-Hydroxymethyl-5-(4-ethoxycarbonylphenyl-
ethynyl)-1-azabicyclo[2.2.2]octane 23d. 10,11-Didehydroquin-
corine 18a (600 mg, 3.64 mmol, 1 eq.) was allowed to react
according to the general procedure with (Ph3P)2PdCl2 (128 mg,
0.18 mmol, 0.05 eq.), CuI (69 mg, 0.36 mmol, 0.1 eq.) and
4-ethoxycarbonylphenyl iodide (0.91 ml, 5.46 mmol, 1.5 eq.)
to yield 4-ethoxycarbonylphenyl-substituted alkyne 23d (71%,
808 mg, 2.58 mmol); νmax(CHCl3)/cmϪ1 3366, 2957, 2871, 2222,
1712, 1606, 1508, 1454, 1406, 1369, 1344, 1307, 1275, 1231,
1176, 1108, 1020, 996 and 858; δH(400 MHz; CDCl3) 7.98–7.96
(d, 2 H, J 8.6, H-14, H-16), 7.47–7.45 (d, 2 H, J 8.5, H-13,
H-17), 4.39 (q, 2 H, J 7.2, H-19), 4.35–4.28 (s, 1 H, OH), 3.68–
3.53 (m, 2 H, H-9, H-9), 3.48–3.38 (m, 1 H, H-6), 3.27–3.13 (m,
2 H, H-2, H-6), 3.04–2.97 (m, 1 H, H-7), 2.96–2.86 (m, 1 H,
H-7), 2.29–2.21 (m, 1 H, H-5), 2.17–2.12 (m, 1 H, H-4), 1.74–
1.63 (m, 3 H, H-3, H-8, H-8), 1.41–1.37 (t, 3 H, J 7.2, H-20)
and 1.11–1.04 (m, 1 H, H-3); δC(100 MHz; CDCl3) 166.07 (C,
C-18), 131.59 (CH, C-13, C-17), 129.73 (C, C-12), 129.43 (CH,
C-14, C-16), 127.83 (C, C-15), 94.73 (C, C-10), 81.41 (C, C-11),
61.99 (CH2, C-9), 61.13 (CH2, C-19), 57.91 (CH, C-2), 56.23
(CH2, C-6), 40.26 (CH2, C-7), 28.19 (CH, C-5), 26.64 (CH,
C-4), 25.33 (CH2, C-8), 24.39 (CH2, C-3) and 14.32 (CH3,
C-20); m/z (MAT, 110 ЊC) (EI) 313.1679 (Mϩ, C19H23N1O3
requires 313.1768), 283 (100%), 269 (7), 255 (6), 227 (2), 210 (2),
200 (6), 181 (2), 155 (4), 127 (3), 91 (1) and 72 (2).
(1S,2S,4S,5S)-2-tert-Butyldimethylsilanyloxymethyl-5-(2-
aminophenylethynyl)-1-azabicyclo[2.2.2]octane 23g. 10,11-Dide-
hydroquincorine 18b (100 mg, 0.36 mmol, 1 eq.) was allowed
to react according to the general procedure with (Ph3P)2PdCl2
(13 mg, 0.02 mmol, 0.05 eq.), CuI (7 mg, 0.04 mmol, 0.1 eq.)
and 2-iodoaniline (118 mg, 0.54 mmol, 1.5 eq.) to yield o-
aminophenyl-substituted alkyne 23g (84%, 111 mg, 0.30 mmol);
νmax(CHCl3)/cmϪ1 2940, 2928, 2856, 1612, 1492, 1456, 1388,
1360, 1304, 1256, 1228, 1116, 1084, 1028, 936, 836 and 808;
δH(400 MHz; CDCl3) 7.25 (dd, 1 H, J 7.5 and 1.5, H-17), 7.10–
7.05 (ddd, 1 H, J 8.9, 7.6 and 1.5, H-14), 6.69–6.63 (m, 2 H,
H-15, H-16), 4.23–4.10 (m, 2 H, NH2), 3.73–3.63 (m, 2 H, H-9,
H-9), 3.38–3.31 (dd, 1 H, J 13.2 and 10.0, H-6endo), 3.12–2.98
(m, 2 H, H-2, H-6), 2.81–2.57 (m, 2 H, H-7, H-7), 2.47–2.42 (m,
1 H, H-5), 2.18–2.10 (m, 1 H, H-3), 2.07–2.02 (m, 1 H, H-4),
1.59–1.46 (m, 1 H, H-8), 1.32–1.24 (m, 2 H, H-8, H-3), 0.91 (s,
9 H, SiC(CH3)3) and 0.07 (s, 6 H, SiCH3); δC(100 MHz; CDCl3)
147.62 (C, C-13), 132.12 (CH, C-14), 128.96 (CH, C-15), 117.83
(CH, C-17), 114.18 (CH, C-16), 108.62 (C, C-12), 98.96 (C,
C-10), 81.42 (C, C-11), 65.78 (CH2, C-9), 57.52 (CH2, C-6),
57.05 (CH, C-2), 41.84 (CH2, C-7), 29.55 (CH, C-5), 27.46 (CH,
C-4), 26.30 (CH2, C-8), 26.00 (CH3, SiC(CH3)3), 22.67 (CH2,
C-3), 18.39 (C, SiC(CH3)3), Ϫ5.30 (CH3, SiCH3) and Ϫ5.32
(CH3, SiCH3); m/z (FAB) (EI) 371 (Mϩ ϩ H, 16), 313 (11), 240
(9), 201 (8), 189 (15) and 147 (100).
(1S,2S,4S,5S)-2-Benzoyloxymethyl-5-(4-ethoxycarbonylphen-
ylethynyl)-1-azabicyclo[2.2.2]octane 23e. 10,11-Didehydroquin-
corine 18c (125 mg, 0.47 mmol, 1 eq.) was allowed to react
according to the general procedure with (Ph3P)2PdCl2 (16 mg,
0.03 mmol, 0.05 eq.), CuI (9 mg, 0.05 mmol, 0.1 eq.) and
ethyl 4-iodobenzoate (192 mg, 0.69 mmol, 1.5 eq.) to yield
4-ethoxycarbonylphenyl-substituted alkyne 23e (92%, 172 mg,
0.43 mmol); νmax(CHCl3)/cmϪ1 3060, 2944, 2868, 2220, 1712,
1604, 1508, 1452, 1404, 1368, 1276, 1176, 1108, 1068, 1048,
1024, 976 and 856; δH(400 MHz; CDCl3) 8.08–7.06 (d, 2 H,
J 7.5, H-23, H-27), 7.99–7.96 (d, 2 H, J 8.2, H-14, H-16), 7.54–
7.50 (m, 1 H, Ph-H), 7.48–7.45 (d, 2 H, J 8.2, H-13, H-17),
7.42–7.37 (m, 2 H, Ph-H), 4.53–4.46 (m, 1 H, H-9), 4.39 (q, 2 H,
J 7.1, H-19), 4.35–4.28 (m, 1 H, H-9), 3.52–3.42 (m, 1 H, H-6),
3.21–3.07 (m, 2 H, H-2, H-6), 2.88–2.76 (m, 2 H, H-7, H-7),
2.33–2.27 (m, 1 H, H-5), 2.14–2.08 (m, 1 H, H-4), 1.70–1.51 (m,
3 H, H-3, H-8, H-8), 1.41–1.36 (t, 3 H, J 7.1, H-20) and 1.26–
1.17 (m, 1 H, H-3); δC(100 MHz; CDCl3) 166.68 (C, C-21),
166.08 (C, C-18), 132.95 (CH, C-25), 131.52 (CH, C-13, C-17),
130.06 (C, C-12), 129.75 (CH, C-23, C-27), 129.39 (CH, C-14,
(1S,2S,4S,5S)-2-tert-Butyldimethylsilanyloxymethyl-5-benzo-
furyl-1-azabicyclo[2.2.2]octane 23h. 10,11-Didehydroquincorine
18b (100 mg, 0.36 mmol, 1 eq.) was allowed to react according
to the general procedure with (Ph3P)2PdCl2 (13 mg, 0.02 mmol,
0.05 eq.), CuI (7 mg, 0.04 mmol, 0.1 eq.) and 2-iodoaniline (119
mg, 0.54 mmol, 1.5 eq.) to yield benzofuran 23h (78%, 104 mg,
58
J. Chem. Soc., Perkin Trans. 1, 2001, 47–65

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0.28 mmol); νmax(CHCl3)/cmϪ1 2940, 2928, 2856, 1612, 1460,
1388, 1344, 1324, 1256, 1188, 1116, 1084, 1028, 1004, 936, 836
and 808; δH(400 MHz; CDCl3) 7.32–7.29 (dd, 1 H, J 7.7 and 1.6,
H-13), 7.23–7.18 (ddd, J 8.7, 7.1 and 1.6, H-14), 6.86–6.82 (m,
1 H, H-15), 6.81–6.79 (dd, 1 H, J 8.6 and 1.6, H-16), 6.51 (m, 1 H,
H-11), 3.73–3.61 (m, 2 H, H-9, H-9), 3.26–3.19 (dd, 1 H, J 13.4
and 10.0, H-6endo), 3.13–2.91 (m, 2 H, H-2, H-6), 2.81–2.57 (m,
2 H, H-7, H-7), 2.37–2.32 (m, 1 H, H-5), 2.09–2.01 (m, 1 H, H-3),
1.99–1.95 (m, 1 H, H-4), 1.68–1.61 (m, 1 H, H-8), 1.53–1.43
(m, 2 H, H-8, H-3), 0.91 (s, 9 H, SiC(CH3)3) and 0.07 (s, 6 H,
SiCH3); δC(100 MHz; CDCl3) 161.36 (C, C-17), 154.71 (C, C-
10), 129.44 (CH, C-13), 128.65 (C, C-12), 122.50 (CH, C-14),
120.38 (CH, C-15), 110.78 (CH, C-16), 101.75 (CH, C-11),
65.80 (CH2, C-9), 57.82 (CH2, C-6), 56.99 (CH, C-2), 41.67
(CH2, C-7), 35.77 (CH, C-5), 28.46 (CH, C-4), 27.07 (CH2,
C-8), 26.01 (CH3, SiC(CH3)3), 25.01 (CH2, C-3), 18.42 (C,
SiC(CH3)3), Ϫ5.31 (CH3, SiCH3) and Ϫ5.33 (CH3, SiCH3); m/z
(MAT) (EI) 372 (Mϩ ϩ H, 44%), 341 (13), 281 (43), 221 (47),
207 (41), 184 (16) and 147 (100).
(5), 166 (8), 149 (29), 128 (71), 105 (35), 101 (33), 86 (55) and
75 (78).
(1S,2R,4S,5S)-2-tert-Butyldimethylsilanyloxymethyl-5-(4-
ethoxycarbonylphenylethynyl)-1-azabicyclo[2.2.2]octane 24c.
10,11-Didehydroquincoridine 20b (100 mg, 0.36 mmol, 1 eq.)
was allowed to react according to the general procedure with
(Ph3P)2PdCl2 (13 mg, 0.02 mmol, 0.05 eq.), CuI (7 mg, 0.04
mmol, 0.1 eq.) and ethyl 4-iodobenzoate (148 mg, 0.54 mmol,
1.5 eq.) to yield 4-ethoxycarbonylphenyl-substituted alkyne 24c
(91%, 139 mg, 0.33 mmol); νmax(CHCl3)/cmϪ1 2952, 2880, 2856,
2220, 1712, 1604, 1508, 1464, 1404, 1368, 1344, 1276, 1176,
1108, 1052, 1020, 940, 856 and 836; δH(400 MHz; CDCl3)
7.97–7.95 (d, 2 H, J 8.4, H-14, H-16), 7.45–7.42 (d, 2 H, J 8.4,
H-13, H-17), 4.40–4.34 (q, 2 H, J 7.1, H-19, H-19), 3.79–3.76
(m, 2 H, H-9, H-9), 3.19–3.13 (m, 2 H, H-6, H-6), 3.05–2.83 (m,
3 H, H-2, H-7, H-7), 2.78–2.73 (m, 1 H, H-5), 2.09–2.05 (m,
1 H, H-4), 1.89–1.83 (m, 1 H, H-3), 1.71–1.58 (m, 3 H, H-8,
H-8, H-3), 1.41–1.37 (t, 3 H, J 7.1, H-20), 0.89 (s, 9 H,
SiC(CH3)3), 0.08 (s, 3 H, SiCH3) and 0.06 (s, 3 H, SiCH3);
δC(100 MHz; CDCl3) 166.12 (C, C-18), 135.74 (C, C-15), 131.49
(CH, C-14, C-16), 129.35 (CH, C-14, C-16), 128.44 (C, C-12),
96.03 (C, C-10), 81.15 (C, C-11), 65.21 (CH2, C-9), 61.05 (CH2,
C-19), 57.38 (CH, C-2), 49.69 (CH2, C-6), 49.02 (CH2, C-7),
29.08 (CH, C-5), 27.83 (CH, C-4), 26.00 (CH3, SiC(CH3)3),
25.26 (CH2, C-8), 25.09 (CH2, C-3), 18.44 (C, SiC(CH3)3), 14.31
(CH3, C-20), Ϫ5.23 (CH3, SiCH3) and Ϫ5.26 (CH3, SiCH3); m/z
(FAB) (EI) 428 (Mϩ ϩ H, 100), 370 (45), 355 (14), 281 (22), 267
(10), 221 (35) and 147 (53).
(1S,2R,4S,5S)-2-Hydroxymethyl-5-(phenylethynyl)-1-aza-
bicyclo[2.2.2]octane 24a. 10,11-Didehydroquincoridine 20a
(800 mg, 4.97 mmol, 1 eq.) was allowed to react according to
the general procedure with (Ph3P)2PdCl2 (174 mg, 0.25 mmol,
0.05 eq.), CuI (92 mg, 0.50 mmol, 0.1 eq.) and phenyl iodide
(1483 mg, 7.27 mmol, 1.5 eq.) to yield phenyl-substituted
alkyne 24a (65%, 759 mg, 3.15 mmol); νmax(CHCl3)/cmϪ1 3375,
3059, 2950, 2879, 2225, 1599, 1490, 1463, 1411, 1337, 1324,
1255, 1234, 1137, 1099, 1068, 1029, 1015 and 999; δH(400 MHz;
CDCl3) 7.42–7.39 (m, 2 H, Ph-H), 7.31–7.28 (m, 3 H, Ph-H),
4.62–4.45 (s, 1 H, OH), 3.83–3.63 (m, 2 H, H-9, H-9), 3.43–3.28
(m, 2 H, H-6, H-6), 3.26–3.07 (m, 3 H, H-2, H-7, H-7), 2.95–
2.89 (m, 1 H, H-5), 2.14–2.10 (m, 1 H, H-4), 1.87–1.68 (m, 3 H,
H-3, H-8, H-8) and 1.66–1.58 (m, 1 H, H-3); δC(100 MHz;
CDCl3) 131.67 (CH, C-15), 128.32 (CH, C-13, C-17), 128.07
(CH, C-14, C-16), 123.10 (C, C-12), 90.84 (C, C-10), 82.54
(C, C-11), 67.09 (CH2, C-9), 58.15 (CH, C-2), 48.36 (CH2, C-6),
47.91 (CH2, C-7), 28.31 (CH, C-5), 27.18 (CH, C-4), 24.49
(CH2, C-8) and 23.67 (CH2, C-3); m/z (MAT, 60 ЊC) (EI)
241.1467 (Mϩ, C16H19N1O1 requires 241.1467), 224 (3%), 210
(100), 194 (2), 182 (12), 167 (5), 154 (7), 141 (6), 128 (46), 115
(11), 102 (3) and 84 (14).
(1S,2R,4S,5S)-2-tert-Butyldimethylsilanyloxymethyl-5-(4-
formylphenylethynyl)-1-azabicyclo[2.2.2]octane 24d. 10,11-
Didehydroquincoridine 20b (100 mg, 0.36 mmol, 1 eq.) was
allowed to react according to the general procedure with (Ph3-
P)2PdCl2 (13 mg, 0.02 mmol, 0.05 eq.), CuI (7 mg, 0.04 mmol,
0.1 eq.) and 4-bromobenzaldehyde (100 mg, 0.54 mmol, 1.5 eq.)
to yield p-formylphenyl-substituted alkyne 24d (82%, 113 mg,
0.29 mmol); νmax(CHCl3)/cmϪ1 2952, 2928, 2880, 2856, 2220,
1700, 1600, 1560, 1460, 1392, 1360, 1344, 1320, 1256, 1164,
1116, 1100, 1008 and 836; δH(400 MHz; CDCl3) 10.01 (s, 1 H,
H-18), 7.84–7.81 (d, 2 H, J 8.5, H-14, H-16), 7.56–7.53 (d, 2 H,
J 8.2, H-13, H-17), 3.91–3.76 (m, 2 H, H-9, H-9), 3.31–3.28
(d, 1 H, J 13.2, H-6endo), 3.18–3.15 (d, 1 H, J 13.1, H-6exo), 3.12–
3.03 (m, 1 H, H-2), 2.99–2.82 (m, 2 H, H-7, H-7), 2.66–2.61 (m,
1 H, H-5), 2.17–2.13 (m, 1 H, H-4), 2.08–1.97 (m, 1 H, H-3),
1.78–1.57 (m, 3 H, H-8, H-8, H-3), 0.89 (s, 9 H, SiC(CH3)3),
0.09 (s, 3 H, SiCH3) and 0.07 (s, 3 H, SiCH3); δC(100 MHz;
CDCl3) 191.41 (C, C-18), 135.20 (C, C-15), 132.19 (CH, C-14,
C-16), 129.96 (C, C-12), 129.49 (CH, C-14, C-16), 96.82
(C, C-10), 81.34 (C, C-11), 64.59 (CH2, C-9), 57.20 (CH, C-2),
49.09 (CH2, C-6), 48.49 (CH2, C-7), 28.65 (CH, C-5), 27.79
(CH, C-4), 25.97 (CH3, SiC(CH3)3), 25.94 (CH2, C-8), 24.79
(CH2, C-3), 18.39 (C, SiC(CH3)3), Ϫ5.33 (CH3, SiCH3) and
Ϫ5.36 (CH3, SiCH3); m/z (MAT, 80 ЊC) (EI) 383.2279 (Mϩ,
C23H33N1O2Si requires 383.2281), 326 (3%), 280 (4), 264 (4),
238 (3), 222 (41), 202 (14), 184 (45), 156 (100), 135 (6), 110 (4),
83 (28) and 75 (64).
(1S,2R,4S,5S)-2-Hydroxymethyl-5-(3Ј-quinolylethynyl)-1-
azabicyclo[2.2.2]octane 24b. 10,11-Didehydroquincoridine 20a
(82 mg, 0.50 mmol, 1 eq.) was allowed to react according to
the general procedure with (Ph3P)2PdCl2 (35 mg, 0.05 mmol,
0.1 eq.), CuI (19 mg, 0.10 mmol, 0.2 eq.) and 3-bromo-
quinoline (90 µl, 0.75 mmol, 1.5 eq.) to yield quinolyl-
substituted alkyne 24b (62%, 90 mg, 0.31 mmol) (Found: C,
77.72; H, 7.36; N, 9.40. C19H20N2O1 requires C, 78.05; H, 6.89;
N, 9.58%); νmax(CHCl3)/cmϪ1 3416, 3068, 2948, 2876, 2200,
1600, 1568, 1488, 1412, 1372, 1336, 1256, 1228, 1136, 1100,
1064, 1028, 1012 and 908; δH(400 MHz; CDCl3) 8.87 (d, 1 H,
J 2.0, H-2Ј), 8.18 (d, 1 H, J 2.0, H-4Ј), 8.09 (d, 1 H, J 8.4,
H-8Ј), 7.78 (d, 1 H, J 8.3, H-5Ј), 7.74–7.68 (ddd, 1 H, J 8.4, 7.0
and 1.5, H-7Ј), 7.58–7.53 (ddd, 1 H, J 8.2, 7.0 and 1.3, H-6Ј),
4.12–3.95 (s, 1 H, OH), 3.77–3.71 (dd, 1 H, J 11.4 and 10.4,
H-9), 3.62–3.55 (dd, J 11.6 and 4.8, H-9), 3.17–3.05 (m, 3 H,
H-6, H-6, H-2), 2.99–2.91 (m, 1 H, H-7), 2.86–2.80 (m, 1 H,
H-7), 2.11–2.08 (m, 1 H, H-5), 1.76–1.70 (m, 1 H, H-4), 1.69–
1.54 (m, 3 H, H-3, H-8, H-8) and 1.33–1.23 (m, 1 H, H-3);
δC(100 MHz; CDCl3) 152.31 (CH, C-2Ј), 146.60 (C, C-10Ј),
138.16 (CH, C-8Ј), 133.61 (C, C-9Ј), 129.83 (CH, C-4Ј), 129.29
(CH, C-7Ј), 127.43 (CH, C-6Ј), 127.22 (CH, C-5Ј), 117.67 (C,
C-3Ј), 95.87 (C, C-10), 79.13 (CH, C-11), 62.10 (CH2, C-9),
57.43 (CH, C-2), 48.38 (CH2, C-6), 47.82 (CH2, C-7), 29.13
(CH, C-5), 27.45 (CH, C-4), 25.38 (CH2, C-8) and 23.34 (CH2,
C-3); m/z (MAT, 70 ЊC) (EI) 292.1576 (Mϩ, C19H20N2O1
requires 292.1576), 261 (6%), 237 (3), 224 (8), 207 (100), 175
(1S,2R,4S,5S)-2-tert-Butyldimethylsilanyloxymethyl-5-(3-
hydroxyphenylethynyl)-1-azabicyclo[2.2.2]octane 24e. 10,11-
Didehydroquincoridine 20b (100 mg, 0.36 mmol, 1 eq.) was
allowed to react according to the general procedure with
(Ph3P)2PdCl2 (13 mg, 0.02 mmol, 0.05 eq.), CuI (7 mg, 0.04
mmol, 0.1 eq.) and 3-iodophenol (119 mg, 0.54 mmol, 1.5 eq.)
to yield m-hydroxyphenyl-substituted alkyne 24e (89%, 118 mg,
0.32 mmol); νmax(CHCl3)/cmϪ1 2952, 2932, 2880, 2856, 2220,
1592, 1452, 1388, 1360, 1344, 1288, 1256, 1156, 1116, 1096,
1052, 1024 and 836; δH(400 MHz; CDCl3) 7.14–7.09 (m, 1 H,
H-16), 6.89 (m, 1 H, H-15), 6.82 (s, 1 H, H-13), 6.76 (m, 1 H,
H-17), 3.88–3.83 (dd, 1 H, J 10.5 and 6.9, H-9), 3.77–3.72 (dd,
J. Chem. Soc., Perkin Trans. 1, 2001, 47–65
59

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1 H, J 10.5 and 6.0, H-9), 3.26–3.18 (m, 2 H, H-6, H-6), 3.08–
2.99 (m, 2 H, H-2, H-7), 2.96–2.86 (m, 1 H, H-7), 2.82–2.76 (m,
1 H, H-5), 2.12–2.08 (m, 1 H, H-4), 1.88–1.80 (m, 1 H, H-3),
1.77–1.60 (m, 3 H, H-8, H-8, H-3), 0.87 (s, 9 H, SiC(CH3)3),
0.05 (s, 3 H, SiCH3) and 0.02 (s, 3 H, SiCH3); δC(100 MHz;
CDCl3) 157.00 (C, C-14), 129.30 (CH, C-15), 124.28 (C, C-12),
122.79 (CH, C-13), 118.99 (CH, C-16), 116.02 (CH, C-17),
91.27 (C, C-10), 82.12 (C, C-11), 64.31 (CH2, C-9), 57.66 (CH,
C-2), 49.44 (CH2, C-6), 48.49 (CH2, C-7), 28.80 (CH, C-5),
27.62 (CH, C-4), 26.05 (CH3, SiC(CH3)3), 25.02 (CH2, C-8),
24.78 (CH2, C-3), 18.44 (C, SiC(CH3)3), Ϫ5.29 (CH3, SiCH3)
and Ϫ5.34 (CH3, SiCH3); m/z (MAT, 80 ЊC) (EI) 371 (Mϩ, 6%),
356 (4), 328 (3), 314 (100), 301 (7), 290 (43), 278 (5), 226 (1), 129
(2), 115 (1) and 86 (3).
dehydroquincoridine 20b (100 mg, 0.36 mmol, 1 eq.) was
allowed to react with (Ph3P)2PdCl2 (13 mg, 0.02 mmol,
0.05 eq.), CuI (7 mg, 0.04 mmol, 0.1 eq.) and (E)-1,2-dichloro-
ethene (27 µl, 0.36 mmol, 1 eq.) in Pri2NH–THF (3:1) to yield
(E)-chlorovinyl-substituted alkyne 24h (78%, 95 mg, 0.28
mmol); νmax(CHCl3)/cmϪ1 2936, 2880, 2856, 2210, 1468, 1380,
1360, 1320, 1256, 1228, 1176, 1116, 1092, 1052, 1024, 1004, 936,
916 and 836; δH(400 MHz; CDCl3) 6.45 (dd, 1 H, J 13.6 and
0.8, H-13), 5.94 (dd, 1 H, J 13.6 and 2.2, H-12), 3.74–3.70 (dd,
1 H, J 10.2 and 6.0, H-9), 3.69–3.64 (dd, 1 H, J 10.3 and
6.8, H-9), 3.08–2.80 (m, 2 H, H-6, H-6), 2.69–2.65 (m, 1 H,
H-2), 2.61–2.51 (m, 2 H, H-7, H-7), 2.43–2.37 (m, 1 H, H-5),
1.94–1.90 (m, 1 H, H-4), 1.74–1.68 (m, 1 H, H-3), 1.63–1.50
(m, 3 H, H-8, H-8, H-3), 0.91 (s, 9 H, SiC(CH3)3), 0.08 (s,
3 H, SiCH3) and 0.07 (s, 3 H, SiCH3); δC(100 MHz; CDCl3)
129.02 (CH, C-13), 114.13 (CH, C-12), 95.96 (C, C-10), 77.39
(C, C-11), 65.34 (CH2, C-9), 57.23 (CH, C-2), 49.63 (CH2, C-6),
48.99 (CH2, C-7), 29.12 (CH, C-5), 27.75 (CH, C-4), 25.99
(CH3, SiC(CH3)3), 25.08 (CH2, C-8), 24.25 (CH2, C-3), 18.45
(C, SiC(CH3)3), Ϫ5.25 (CH3, SiCH3) and Ϫ5.29 (CH3, SiCH3);
m/z (MAT) (EI) 339.1786 (Mϩ, C18H30N1O1SiCl requires
339.1785), 324 (9%), 304 (11), 282 (100), 269 (1), 240 (18), 222
(4), 194 (22), 170 (8), 132 (7), 115 (8), 98 (32) and 73 (31).
(1S,2R,4S,5S)-2-tert-Butyldimethylsilanyloxymethyl-5-
(1,3-thiazolin-2-ylethynyl)-1-azabicyclo[2.2.2]octane 24f. 10,11-
Didehydroquincoridine 20b (100 mg, 0.36 mmol, 1 eq.) was
allowed to react according to the general procedure with
(Ph3P)2PdCl2 (13 mg, 0.02 mmol, 0.05 eq.), CuI (7 mg, 0.04
mmol, 0.1 eq.) and 2-bromothiazole (48 µl, 0.54 mmol, 1.5 eq.)
to yield thiazolinyl-substituted alkyne 24f (83%, 108 mg, 0.30
mmol); νmax(CHCl3)/cmϪ1 2952, 2928, 2880, 2856, 2220, 1480,
1472, 1408, 1360, 1344, 1320, 1264, 1136, 1116, 1096, 1056,
1020, 936 and 836; δH(400 MHz; CDCl3) 7.78 (d, 1 H, J 3.3,
H-14), 7.30 (d, 1 H, J 3.4, H-15), 3.79–3.70 (m, 2 H, H-9, H-9),
3.18–3.15 (m, 2 H, H-6, H-6), 3.05–2.96 (m, 1 H, H-2), 2.94–
2.82 (m, 2 H, H-7, H-7), 2.80–2.75 (m, 1 H, H-5), 2.13–2.09
(m, 1 H, H-4), 1.84–1.77 (m, 1 H, H-3), 1.70–1.56 (m, 3 H, H-8,
H-8, H-3), 0.89 (s, 9 H, SiC(CH3)3), 0.08 (s, 3 H, SiCH3) and
0.06 (s, 3 H, SiCH3); δC(100 MHz; CDCl3) 149.18 (C, C-12),
143.14 (CH, C-14), 119.96 (CH, C-15), 98.39 (C, C-10), 79.91
(C, C-11), 65.13 (CH2, C-9), 57.37 (CH, C-2), 49.00 (CH2, C-6),
48.92 (CH2, C-7), 29.19 (CH, C-5), 27.58 (CH, C-4), 26.04
(CH3, SiC(CH3)3), 25.71 (CH2, C-8), 25.16 (CH2, C-3), 18.44
(C, SiC(CH3)3), Ϫ5.24 (CH3, SiCH3) and Ϫ5.27 (CH3, SiCH3);
m/z (MAT, 50 ЊC) (EI) 362.1848 (Mϩ, C19H30N2O1S1Si requires
362.1848), 348 (3%), 321 (1), 305 (33), 280 (10), 264 (9), 240
(11), 222 (100), 195 (2), 184 (8), 156 (12), 134 (16), 110 (10), 91
(7), 82 (7) and 75 (42).
(1S,2R,4S,5S)-2-tert-Butyldimethylsilanyloxymethyl-5-(2-
(Z)-chlorovinylethynyl)-1-azabicyclo[2.2.2]octane 24i. 10,11-
Didehydroquincoridine 20b (165 mg, 0.59 mmol, 1 eq.) was
allowed to react with (Ph3P)2PdCl2 (21 mg, 0.03 mmol,
0.05 eq.), CuI (11 mg, 0.06 mmol, 0.1 eq.) and (Z)-1,2-
dichloroethene (86 mg, 0.89 mmol, 1.5 eq.) in piperidine–THF
(3:1) to yield (Z)-chlorovinyl-substituted alkyne 24i (83%, 166
mg, 0.49 mmol); νmax(CHCl3)/cmϪ1 2948, 2880, 2856, 2208,
1464, 1388, 1360, 1324, 1256, 1116, 1084, 1052, 1020, 936, 912
and 836; δH(400 MHz; CDCl3) 6.33 (dd, 1 H, J 7.4 and 0.5,
H-13), 5.94 (dd, 1 H, J 7.4 and 2.2, H-12), 3.77–3.72 (dd, 1 H,
J 10.2 and 6.2, H-9), 3.68–3.63 (dd, 1 H, J 10.3 and 7.1, H-9),
3.12–2.96 (m, 2 H, H-6, H-6), 2.94–2.76 (m, 3 H, H-2, H-7,
H-7), 2.68–2.63 (m, 1 H, H-5), 2.00–1.96 (m, 1 H, H-4), 1.79–
1.72 (m, 1 H, H-3), 1.63–1.49 (m, 3 H, H-8, H-8, H-3), 0.90 (s,
9 H, SiC(CH3)3), 0.08 (s, 3 H, SiCH3) and 0.07 (s, 3 H, SiCH3);
δC(100 MHz; CDCl3) 127.25 (CH, C-13), 112.31 (CH, C-12),
96.05 (C, C-10), 75.84 (C, C-11), 65.42 (CH2, C-9), 57.30 (CH,
C-2), 49.77 (CH2, C-6), 48.96 (CH2, C-7), 29.19 (CH, C-5),
27.82 (CH, C-4), 25.98 (CH3, SiC(CH3)3), 25.02 (CH2, C-8),
24.36 (CH2, C-3), 18.39 (C, SiC(CH3)3), Ϫ5.31 (CH3, SiCH3)
and Ϫ5.34 (CH3, SiCH3); m/z (MAT) (EI) 339.1784 (Mϩ,
C18H30NOSiCl requires 339.1785), 324 (9%), 304 (11), 282
(100), 261 (1), 249 (1), 240 (20), 194 (22), 170 (7), 131 (7), 116
(8), 98 (14) and 73 (30).
(1S,2R,4S,5S)-2-tert-Butyldimethylsilanyloxymethyl-5-
(2-thienylethynyl)-1-azabicyclo[2.2.2]octane 24g. 10,11-Dide-
hydroquincoridine 20b (100 mg, 0.36 mmol, 1 eq.) was allowed
to react according to the general procedure with (Ph3P)2PdCl2
(13 mg, 0.02 mmol, 0.05 eq.), CuI (7 mg, 0.04 mmol, 0.1 eq.)
and 2-bromothiophene (52 µl, 0.54 mmol, 1.5 eq.) to yield
thiophenyl-substituted alkyne 24g (80%, 104 mg, 0.29 mmol);
νmax(CHCl3)/cmϪ1 2948, 2928, 2880, 2856, 2220, 1468, 1388,
1360, 1340, 1320, 1256, 1116, 1080, 1052, 1020, 936 and 908;
δH(400 MHz; CDCl3) 7.21 (dd, 1 H, J 5.2 and 1.2, H-15), 7.14
(dd, 1 H, J 3.6 and 1.0, H-13), 6.97 (dd, 1 H, J 5.2 and 3.6,
H-14), 3.82–3.67 (m, 2 H, H-9, H-9), 3.15–3.09 (m, 1 H, H-6),
3.06–3.01 (m, 1 H, H-6), 2.98–2.72 (m, 3 H, H-2, H-7, H-7),
2.58–2.54 (m, 1 H, H-5), 1.99–1.95 (m, 1 H, H-4), 1.82–1.72 (m,
1 H, H-3), 1.69–1.49 (m, 3 H, H-8, H-8, H-3), 0.93 (s, 9 H,
SiC(CH3)3), 0.10 (s, 3 H, SiCH3) and 0.09 (s, 3 H, SiCH3);
δC(100 MHz; CDCl3) 131.13 (CH, C-15), 126.76 (CH, C-14),
126.06 (CH, C-13), 123.96 (C, C-12), 96.86 (C, C-10), 80.73 (C,
C-11), 65.37 (CH2, C-9), 57.37 (CH, C-2), 49.33 (CH2, C-6),
48.96 (CH2, C-7), 29.08 (CH, C-5), 27.81 (CH, C-4), 26.07
(CH3, SiC(CH3)3), 25.69 (CH2, C-8), 25.16 (CH2, C-3), 18.47
(C, SiC(CH3)3), Ϫ5.21 (CH3, SiCH3) and Ϫ5.23 (CH3, SiCH3);
m/z (MAT, 80 ЊC) (EI) 361.1885 (Mϩ, C20H31N1O1S1Si requires
361.1895), 346 (8%), 318 (3), 304 (100), 276 (2), 264 (4), 240 (9),
216 (58), 203 (3), 184 (9), 156 (16), 134 (21), 115 (91), 94 (9), 85
(49) and 73 (36).
(3R,4S,8R,9S)-9-Acetoxy-11-(Z)-phenylethynyl-6Ј-methoxy-
cinchonan 25a. (Z)-11-(2-Iodovinyl)quinidine 11b (92 mg, 0.19
mmol, 1 eq.) was allowed to react according to the general
procedure with (Ph3P)2PdCl2 (13 mg, 0.02 mmol, 0.1 eq.), CuI
(7 mg, 0.04 mmol, 0.2 eq.) and phenylacetylene (19 mg, 0.19
mmol, 1 eq.) to yield (Z)-enyne 25a (86%, 74 mg, 0.16 mmol);
νmax(CHCl3)/cmϪ1 2940, 2876, 1744, 1664, 1620, 1592, 1508,
1472, 1456, 1372, 1356, 1304, 1236, 1176, 1120, 1084, 1068,
1028, 988 and 844; δH(400 MHz; CDCl3) 8.81 (d, 1 H, J 4.6,
H-2Ј), 8.12 (d, 1 H, J 9.2, H-8Ј), 7.74 (dd, 1 H, J 9.2 and 2.4,
H-7Ј), 7.61 (m, 2 H, H-3Ј, H-5Ј), 7.54–7.43 (m, 2 H, Ph-H),
7.37–7.33 (m, 3 H, Ph-H), 6.64 (d, 1 H, J 6.8, H-9), 6.61–6.57
(dd, 1 H, J 9.7 and 8.6, H-10), 6.40–6.38 (d, 1 H, J 10.1, H-11),
3.99 (s, 3 H, H-11Ј), 3.78–3.69 (m, 1 H, H-8), 3.44–3.34 (m, 1 H,
H-2), 3.24–3.12 (m, 1 H, H-2), 3.08–2.96 (m, 2 H, H-6, H-6),
2.89–2.85 (m, 1 H, H-3), 2.21 (s, 3 H, H-21), 2.01–1.88 (m, 2 H,
H-4, H-7) and 1.74–1.57 (m, 3 H, H-7, H-5, H-5); δC(100 MHz;
CDCl3) 169.99 (C, C-20), 158.03 (C, C-6Ј), 145.99 (CH, C-2Ј),
144.02 (C, C-10Ј), 143.62 (C, C-4Ј), 132.14 (CH, C-15, C-19),
131.94 (CH, C-8Ј), 131.38 (CH, C-17), 129.21 (CH, C-10),
(1S,2R,4S,5S)-2-tert-Butyldimethylsilanyloxymethyl-5-(2-
(E)-chlorovinylethynyl)-1-azabicyclo[2.2.2]octane 24h. 10,11-Di-
60
J. Chem. Soc., Perkin Trans. 1, 2001, 47–65

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128.56 (CH, C-16, C-18), 128.24 (C, C-9Ј), 123.33 (C, C-14),
121.83 (CH, C-7Ј), 118.05 (CH, C-3Ј), 110.07 (CH, C-11),
101.59 (CH, C-5Ј), 93.96 (C, C-13), 86.26 (C, C-12), 73.58 (CH,
C-9), 58.44 (CH, C-8), 55.68 (CH3, C-11Ј), 49.70 (CH2, C-2),
47.23 (CH2, C-6), 29.69 (CH, C-3), 27.90 (CH, C-4), 26.24
(CH2, C-7), 25.31 (CH2, C-5) and 21.17 (CH3, C-21); m/z (FAB)
(EI) 467 (Mϩ ϩ H, 28%), 429 (7), 401 (10), 355 (26), 341 (20),
325 (13), 295 (16), 281 (52), 221 (78), 207 (51) and 147 (100).
procedure with (Ph3P)2PdCl2 (7 mg, 0.01 mmol, 0.05 eq.),
CuI (4 mg, 0.02 mmol, 0.1 eq.) and hept-1-yne (37 µl, 0.28
mmol, 1.4 eq.) to yield (Z)-enyne 26 (86%, 81 mg, 0.17 mmol);
νmax(CHCl3)/cmϪ1 2936, 2869, 1743, 1622, 1593, 1510, 1474,
1434, 1372, 1265, 1238, 1086, 1031 and 850; δH(400 MHz;
CDCl3) 8.75 (d, 1 H, J 4.4, H-2Ј), 8.03 (d, 1 H, J 9.2, H-8Ј), 7.44
(d, 1 H, J 2.8, H-5Ј), 7.37 (dd, 1 H, J 9.3 and 2.6, H-7Ј), 7.36 (d,
1 H, J 4.6, H-3Ј), 6.53 (d, 1 H, J 6.9, H-9), 5.85 (dd, 1 H, J 10.5
and 9.3, H-10), 5.44 (dd, 1 H, J 10.5 and 1.0, H-11), 3.97 (s, 3 H,
H-11Ј), 3.38 (ddd, 1 H, J 8.8, 7.7 and 7.6, H-8), 3.17 (dd, 1 H,
J 13.7 and 10.0, H-2exo), 3.16–3.08 (m, 1 H, H-6endo), 2.91–2.83
(m, 1 H, H-2endo), 2.74–2.66 (m, 1 H, H-6exo), 2.57–2.50 (m, 1 H,
H-3), 2.31 (m, 2 H, H-14, H-14), 2.13 (s, 3 H, H-20), 1.92 (m,
1 H, H-4), 1.89–1.81 (m, 1 H, H-7), 1.77–1.68 (m, 1 H, H-7),
1.65–1.49 (m, 4 H, 2 H-5, 2 H-15), 1.41–1.27 (m, 4 H, 2 H-16, 2
H-17) and 0.90 (t, 3 H, J 7.2, H-18); δC(100 MHz; CDCl3)
170.00 (C, C-19), 157.99 (C, C-6Ј), 147.47 (CH, C-2Ј), 145.24
(C, C-10Ј), 144.76 (C, C-4Ј), 131.92 (CH, C-8Ј), 130.95 (CH,
C-10), 127.04 (C, C-9Ј), 121.83 (CH, C-7Ј), 118.78 (CH, C-3Ј),
110.18 (CH, C-11), 101.47 (CH, C-5Ј), 95.28 (C, C-13), 77.19
(C, C-12), 73.64 (CH, C-9), 59.29 (CH, C-8), 57.70 (CH2, C-2),
55.71 (CH3, C-11Ј), 42.38 (CH2, C-6), 36.66 (CH, C-3), 31.05
(CH2, C-16), 28.44 (CH2, C-15), 27.52 (CH2, C-5), 27.05 (CH,
C-4), 24.48 (CH2, C-7), 22.20 (CH2, C-17), 21.10 (CH3, C-20),
19.49 (CH2, C-14) and 14.02 (CH3, C-18); m/z (MAT, 140 ЊC)
(EI) 460.2726 (Mϩ ϩ H, C29H36N2O3 requires 460.2725), 412
(4%), 367 (5), 308 (37), 294 (3), 277 (100), 230 (29), 201 (19),
183 (14), 152 (8) and 91 (35).
(3R,4S,8R,9S)-9-Acetoxy-11-(Z)-hept-1-ynyl-6Ј-methoxy-
cinchonan 25b. (Z)-11-(2-Iodovinyl)quinidine 11b (110 mg,
0.22 mmol, 1 eq.) was allowed to react according to the general
procedure with (Ph3P)2PdCl2 (8 mg, 0.01 mmol, 0.05 eq.), CuI
(4 mg, 0.02 mmol, 0.1 eq.) and hept-1-yne (38 µl, 0.29 mmol,
1.3 eq.) to yield (Z)-enyne 25b (82%, 84 mg, 0.18 mmol);
νmax(CHCl3)/cmϪ1 2936, 2872, 1744, 1664, 1620, 1592, 1508,
1472, 1456, 1432, 1372, 1304, 1236, 1172, 1112, 1084, 1068,
1032, 988 and 844; δH(400 MHz; CDCl3) 8.84 (d, 1 H, J 4.4,
H-2Ј), 8.16 (d, 1 H, J 9.2, H-8Ј), 7.43–7.37 (m, 3 H, H-7Ј, H-3Ј,
H-5Ј), 6.61 (d, 1 H, J 6.8, H-9), 6.17–6.13 (dd, 1 H, J 10.7 and
8.1, H-10), 5.61–5.57 (d, 1 H, J 10.8, H-11), 3.98 (s, 3 H, H-11Ј),
3.77–3.68 (m, 1 H, H-8), 3.39–3.29 (m, 1 H, H-2endo), 3.13–3.05
(dd, 1 H, J 15.6 and 12.7, H-2exo), 2.94–2.78 (m, 2 H, H-6, H-6),
2.38–2.34 (m, 1 H, H-3), 2.18 (s, 3 H, H-20), 1.92–1.85 (m, 3 H,
H-4, H-14, H-14), 1.64–1.53 (m, 4 H, 2 H-7, 2 H-15), 1.45–1.28
(m, 6 H, 2 H-5, 2 H-16, 2 H-17) and 0.98–0.90 (t, 3 H, J 7.1,
H-18); δC(100 MHz; CDCl3) 169.99 (C, C-19), 158.01 (C, C-6Ј),
147.67 (CH, C-2Ј), 144.09 (C, C-10Ј), 143.94 (C, C-4Ј), 131.77
(CH, C-8Ј), 128.75 (CH, C-10), 128.46 (C, C-9Ј), 121.96 (CH,
C-7Ј), 118.55 (CH, C-3Ј), 110.48 (CH, C-11), 101.41 (CH,
C-5Ј), 95.15 (C, C-13), 84.59 (C, C-12), 73.50 (CH, C-9), 58.85
(CH, C-8), 55.67 (CH3, C-11Ј), 49.88 (CH2, C-2), 49.74 (CH2,
C-6), 36.68 (CH, C-3), 31.07 (CH2, C-16), 28.45 (CH2, C-15),
27.72 (CH, C-4), 26.17 (CH2, C-7), 23.62 (CH2, C-5), 22.19
(CH2, C-17), 21.16 (CH3, C-20), 19.50 (CH2, C-14) and 14.01
(CH3, C-18); m/z (FAB) (EI) 461 (Mϩ ϩ H, 100%), 401 (29),
282 (21), 230 (83), 207 (30), 189 (35) and 147 (72).
(1S,2S,4S)-2-(Hydroxymethyl)-5-phenylethynyl-1-azabicyclo-
[2.2.2]oct-5-ene 27. Vinyltin precursor 15 (152 mg, 0.36 mmol,
1 eq.) was allowed to react according to the general procedure
with (Ph3P)2PdCl2 (13 mg, 0.02 mmol, 0.05 eq.), CuI (7 mg,
0.04 mmol, 0.1 eq.) and phenylacetylene (55 mg, 0.54 mmol,
1.5 eq.) to yield enyne 27 (69%, 59 mg, 0.25 mmol); νmax
-
(CHCl3)/cmϪ1 3590, 2999, 2954, 2876, 2220, 1599, 1447, 1409,
1330, 1260, 1138, 1067 and 1024; δH(400 MHz; CDCl3;
CD3OD) 7.41–7.37 (m, 2 H, Ar-H), 7.36–7.31 (m, 3 H, Ar-H),
6.68 (s, 1 H, H-6), 3.89–3.82 (m, 1 H, H-9), 3.76–3.69 (m, 1 H,
H-9), 3.64–3.56 (m, 1 H, H-7), 3.30–3.04 (m, 2 H, H-7, H-2),
2.39–2.24 (m, 2 H, H-4, H-3), 2.01–1.89 (m, 1 H, H-8) and
1.73–1.64 (m, 2 H, H-8, H-3); δC(100 MHz; CDCl3, CD3OD)
131.54 (CH, Ph), 131.17 (C, C-5), 128.96 (CH, C-6), 128.74
(CH, Ph), 121.82 (C, Ph), 90.05 (C, C-10), 83.97 (C, C-11),
62.14 (CH2, C-9), 58.41 (CH, C-2), 43.85 (CH2, C-7), 34.07
(CH, C-4), 21.39 (CH2, C-8) and 20.54 (CH2, C-3); m/z (MAT,
180 ЊC) (EI) 239.1308 (Mϩ, C16H17N1O1 requires 239.1310), 226
(100%), 208 (21), 198 (33), 180 (30), 171 (17), 155 (52), 140 (17),
127 (22), 113 (23) and 96 (36).
(3R,4S,8R,9S)-9-Acetoxy-11-(Z)-(5-hydroxypent-1-ynyl)-6Ј-
methoxycinchonan 25c. (Z)-11-(2-Iodovinyl)quinidine 11b (110
mg, 0.22 mmol, 1 eq.) was allowed to react according to the
general procedure with (Ph3P)2PdCl2 (8 mg, 0.01 mmol, 0.05
eq.), CuI (4 mg, 0.02 mmol, 0.1 eq.) and pent-4-yn-1-ol (20 µl,
0.22 mmol, 1 eq.) to yield (Z)-enyne 25c (78%, 78 mg, 0.17
mmol); νmax(CHCl3)/cmϪ1 3624, 2940, 2876, 2212, 1744, 1664,
1620, 1592, 1508, 1472, 1456, 1432, 1372, 1228, 1172, 1136,
1032, 988 and 844; δH(400 MHz; CDCl3) 8.75 (d, 1 H, J 4.6,
H-2Ј), 8.06 (d, 1 H, J 9.0, H-8Ј), 7.42–7.40 (m, 1 H, H-7Ј), 7.39
(d, 1 H, J 2.7, H-5Ј), 7.38 (d, 1 H, J 4.6, H-3Ј), 6.59 (d, 1 H,
J 6.4, H-9), 6.18–6.13 (dd, 1 H, J 10.6 and 8.4, H-10), 5.59–5.56
(d, 1 H, J 10.5, H-11), 3.99 (s, 3 H, H-11Ј), 3.79–3.71 (m, 2 H,
H-16, H-16), 3.35–3.28 (m, 1 H, H-8), 3.11–3.04 (dd, 1 H, J 12.7
and 9.7, H-2endo), 2.92–2.78 (m, 3 H, H-2exo, H-6, H-6), 2.55–
2.39 (m, 3 H, H-3, H-14, H-14), 2.18 (s, 3 H, H-18), 1.92–1.85
(m, 1 H, H-4), 1.84–1.76 (m, 2 H, H-15, H-15), 1.67–1.49 (m,
3 H, H-7, H-7, H-5) and 1.38–1.30 (m, 1 H, H-5); δC(100 MHz;
CDCl3) 169.98 (C, C-17), 158.04 (C, C-6Ј), 147.27 (CH, C-2Ј),
144.55 (C, C-10Ј), 144.41 (CH, C-10), 143.76 (C, C-4Ј), 131.61
(CH, C-8Ј), 126.94 (C, C-9Ј), 122.01 (CH, C-7Ј), 118.46 (CH,
C-3Ј), 110.31 (CH, C-11), 101.39 (CH, C-5Ј), 94.28 (C, C-13),
84.11 (C, C-12), 73.57 (CH, C-9), 61.37 (CH2, C-16), 58.76
(CH, C-8), 55.71 (CH3, C-11Ј), 49.79 (CH2, C-2), 49.64 (CH2,
C-6), 36.67 (CH, C-3), 31.54 (CH2, C-15), 27.72 (CH, C-4),
26.09 (CH2, C-7), 23.74 (CH2, C-5), 21.16 (CH3, C-18) and
16.15 (CH2, C-14); m/z (FAB) (EI) 449 (Mϩ ϩ H, 73%), 413
(12), 391 (23), 279 (8), 167 (19) and 149 (100).
(3S,3ЉS,4S,4ЉS,8R,8ЉR,9S,9ЉS)-11,11Љ-Bi(10,11-didehydro-9-
hydroxy-6Ј-methoxycinchonan) 28a. 10,11-Didehydroquinidine
9a (161 mg, 0.50 mmol, 1 eq.) was allowed to react according to
the general procedure with (Ph3P)2PdCl2 (18 mg, 0.025 mmol,
0.05 eq.), CuI (10 mg, 0.05 mmol, 0.1 eq.) and iodine (64 mg,
0.25 mmol, 0.5 eq.) to yield dimeric alkyne 28a (71%, 114 mg,
0.18 mmol); νmax(CHCl3)/cmϪ1 3132, 2944, 2872, 1620, 1592,
1508, 1472, 1432, 1360, 1320, 1300, 1240, 1174, 1136, 1092,
1032, 1000, 932 and 832; δH(400 MHz; CDCl3) 8.43 (d, 2 H,
J 4.6, H-2Ј, H-2ٞ), 7.91 (d, 2 H, J 9.3, H-8Ј, H-8ٞ), 7.43 (d, 2 H,
J 4.6, H-3Ј, H-3ٞ), 7.31 (dd, 2 H, J 9.3 and 2.6, H-7Ј, H-7ٞ),
7.18 (d, 2 H, J 2.6, H-5Ј, H-5ٞ), 5.68 (m, 2 H, H-9, H-9Љ), 3.89
(s, 6 H, H-11Ј, H-11ٞ), 3.69–3.61 (m, 2 H, H-8, H-8Љ), 3.19–3.12
(m, 2 H, H-2, H-2Љ), 2.91–2.84 (m, 2 H, H-2, H-2Љ), 2.75–2.51
(m, 4 H, H-6, H-6, H-6Љ, H-6Љ), 2.01–1.97 (m, 2 H, H-3, H-3Љ),
1.88–1.82 (m, 2 H, H-4, H-4Љ), 1.88–1.64 (m, 6 H, H-5, H-7, H-7,
H-5Љ, H-7Љ, H-7Љ) and 1.41–1.33 (m, 2 H, H-5, H-5Љ); δC(100
MHz; CDCl3) 157.77 (C, C-6Ј, C-6ٞ), 148.31 (C, C-10Ј, C-10ٞ),
147.43 (CH, C-2Ј, C-2ٞ), 143.73 (C, C-4Ј, C-4ٞ), 131.14 (CH,
C-8Ј, C-8ٞ), 124.81 (C, C-9Ј, C-9ٞ), 121.36 (CH, C-7Ј, C-7ٞ),
(3R,4S,8S,9R)-9-Acetoxy-11-(Z)-hept-1-ynyl-6Ј-methoxy-
cinchonan 26. (Z)-11-(2-Iodovinyl)quinine 12 (100 mg, 0.20
mmol, 1 eq.) was allowed to react according to the general
J. Chem. Soc., Perkin Trans. 1, 2001, 47–65
61

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119.07(CH,C-3Ј,C-3ٞ),101.32(CH,C-5Ј,C-5ٞ),81.28(C,C-10,
C-10Љ), 77.27 (CH, C-9, C-9Љ), 66.22 (C, C-11, C-11Љ), 60.39 (CH,
C-8, C-8Љ), 55.95 (CH3, C-11Ј, C-11ٞ), 49.76 (CH2, C-2, C-2Љ),
49.33 (CH2, C-6, C-6Љ), 29.69 (CH, C-3, C-3Љ), 28.79 (CH, C-4,
C-4Љ), 24.91 (CH2, C-7, C-7Љ) and 21.04 (CH2, C-5, C-5Љ); m/z
(FAB) (EI) 643 (Mϩ ϩ H, 5%), 356 (10), 341 (11), 295 (9), 281
(41), 267 (19), 207 (48), 189 (28), 159 (29) and 147 (100).
iodine (77 mg, 0.30 mmol, 0.5 eq.) to yield dimeric alkyne 30
(66%, 66 mg, 0.20 mmol); νmax(CHCl3)/cmϪ1 3456, 3000, 2944,
2868, 1480, 1452, 1412, 1376, 1344, 1324, 1260, 1236, 1132,
1100, 1020, 996 and 936; δH(400 MHz; CDCl3) 3.52–3.44 (m,
4 H, H-9, H-9, H-9Ј, H-9Ј), 3.32–3.23 (m, 2 H, H-6, H-6Ј), 3.19–
3.06 (m, 2 H, H-2, H-2Ј), 2.98–2.86 (m, 4 H, H-6, H-6Ј, H-7,
H-7Ј), 2.68–2.53 (m, 4 H, H-7, H-7Ј, H-5, H-5Ј), 2.12–2.03 (m,
2 H, H-3, H-3Ј), 1.97–1.92 (m, 2 H, H-4, H-4Ј), 1.54–1.37 (m,
4 H, H-8, H-8, H-8Ј, H-8Ј) and 0.89–0.80 (m, 2 H, H-3, H-3Ј);
δC(100 MHz; CDCl3) 81.18 (C, C-10, C-10Ј), 65.68 (C, C-11,
C-11Ј), 62.71 (CH2, C-9, C-9Ј), 56.99 (CH, C-2, C-2Ј), 56.44
(CH2, C-6, C-6Ј), 39.59 (CH2, C-7, C-7Ј), 28.67 (CH, C-5, C-5Ј),
26.75 (CH, C-4, C-4Ј), 26.16 (CH2, C-8, C-8Ј) and 24.98 (CH2,
C-3, C-3Ј); m/z (MAT, 170 ЊC) (EI) 328.2152 (Mϩ, C20H28N2O2
requires 328.2151), 311 (7%), 297 (91), 270 (40), 255 (11),
239 (49), 212 (42), 196 (14), 184 (34), 166 (17), 112 (37) and
86 (81).
(3S,3ЉS,4S,4ЉS,8R,8ЉR,9S,9ЉS)-11,11Љ-Bi(9-acetoxy-10,11-di-
dehydro-6Ј-methoxycinchonan) 28b. 10,11-Didehydroquinidine
9a (100 mg, 0.27 mmol, 1 eq.) was allowed to react according to
the general procedure with (Ph3P)2PdCl2 (10 mg, 0.02 mmol,
0.05 eq.), CuI (5 mg, 0.03 mmol, 0.1 eq.) and iodine (35 mg,
0.14 mmol, 0.5 eq.) to yield dimeric alkyne 28b (86%, 86 mg,
0.12 mmol); νmax(CHCl3)/cmϪ1 2948, 2876, 1744, 1620, 1592,
1508, 1472, 1456, 1432, 1372, 1320, 1300, 1228, 1136, 1092,
1032, 988 and 844; δH(400 MHz; CDCl3) 8.81 (d, 2 H, J 4.4, H-
2Ј, H-2ٞ), 8.11 (d, 2 H, J 9.4, H-8Ј, H-8ٞ), 7.48 (d, 2 H, J 2.7, H-
5Ј, H-5ٞ), 7.43–7.40 (m, 4 H, H-3Ј, H-3ٞ, H-7Ј, H-7ٞ), 6.61 (d, 2
H, J 6.3, H-9, H-9Љ), 4.02 (s, 6 H, H-11Ј, H-11ٞ), 3.37–3.30 (m, 2
H, H-8, H-8Љ), 3.21–3.07 (m, 4 H, H-2, H-2, H-2Љ, H-2Љ), 2.89–
2.80 (m, 2 H, H-6, H-6Љ), 2.75–2.64 (m, 4 H, H-6, H-6Љ, H-3, H-
3Љ), 2.24 (s, 6 H, H-13, H-13Љ), 2.13–2.09 (m, 2 H, H-4, H-4Љ),
1.67–1.49 (m, 6 H, H-5, H-7, H-7, H-5Љ, H-7Љ, H-7Љ) and 1.38–
1.27 (m, 2 H, H-5, H-5Љ); δC(100 MHz; CDCl3) 169.84 (C, C-12,
C-12Љ), 158.01 (C, C-6Ј, C-6ٞ), 147.53 (C, C-10Ј, C-10ٞ), 144.59
(CH, C-2Ј, C-2ٞ), 143.92 (C, C-4Ј, C-4ٞ), 131.81 (CH, C-8Ј, C-
8ٞ), 126.89 (C, C-9Ј, C-9ٞ), 121.87 (CH, C-7Ј, C-7ٞ), 118.46
(CH, C-3Ј, C-3ٞ), 101.50 (CH, C-5Ј, C-5ٞ), 80.74 (C, C-10, C-
10Љ), 73.92 (CH, C-9, C-9Љ), 66.39 (C, C-11, C-11Љ), 59.05 (CH,
C-8, C-8Љ), 55.69 (CH3, C-11Ј, C-11ٞ), 49.98 (CH2, C-2, C-2Љ),
49.41 (CH2, C-6, C-6Љ), 28.95 (CH, C-3, C-3Љ), 27.91 (CH, C-4,
C-4Љ), 24.96 (CH2, C-7, C-7Љ), 23.99 (CH2, C-5, C-5Љ) and 21.12
(CH3, C-13, C-13Љ); m/z (FAB) (EI) 727.1104 (Mϩ, C44H46N4O6
requires 727.1118), 663 (9%), 496 (5), 391 (41), 279 (8) and 149
(86).
(1S,1ЈS,2R,2ЈR,4S,4ЈS,5S,5ЈS)-1,4-Bis(2-hydroxymethyl-
1-azabicyclo[2.2.2]octan-5-yl)buta-1,3-diyne 31a. 10,11-Dide-
hydroquincoridine 20a (100 mg, 0.61 mmol, 1 eq.) was allowed
to react according to the general procedure with (Ph3P)2PdCl2
(21 mg, 0.03 mmol, 0.05 eq.), CuI (12 mg, 0.06 mmol, 0.1 eq.)
and iodine (77 mg, 0.30 mmol, 0.5 eq.) to yield dimeric alkyne
31a (64%, 64 mg, 0.19 mmol); νmax(CHCl3)/cmϪ1 3412, 3000,
2948, 2876, 1452, 1412, 1376, 1320, 1296, 1252, 1236, 1188,
1136, 1100, 1060, 1028, 940 and 864; δH(400 MHz; CDCl3)
5.36–5.21 (s, 2 H, OH, OHЈ), 3.75–3.67 (dd, 2 H, J 12.2 and
10.3, H-9, H-9Ј), 3.56–3.52 (dd, 2 H, J 12.1 and 4.5, H-9, H-9Ј),
3.13–2.86 (m, 10 H, H-6, H-6Ј, H-2, H-2Ј, H-6, H-6Ј, H-7, H-7Ј,
H-7, H-7Ј), 2.72–2.65 (m, 2 H, H-5, H-5Ј), 2.06–1.99 (m, 2 H,
H-4, H-4Ј), 1.75–1.57 (m, 6 H, H-3, H-3Ј, H-8, H-8Ј, H-8, H-8Ј)
and 1.51–1.45 (m, 2 H, H-3, H-3Ј); δC(100 MHz; CDCl3) 79.91
(C, C-10, C-10Ј), 66.43 (C, C-11, C-11Ј), 61.89 (CH2, C-9, C-9Ј),
57.86 (CH, C-2, C-2Ј), 48.06 (CH2, C-6, C-6Ј), 46.99 (CH2, C-7,
C-7Ј), 28.72 (CH, C-5, C-5Ј), 27.29 (CH, C-4, C-4Ј), 24.86
(CH2, C-8, C-8Ј) and 24.07 (CH2, C-3, C-3Ј); m/z (MAT,
170 ЊC) (EI) 328.2143 (Mϩ, C20H28N2O2 requires 328.2151),
311 (7%), 298 (62), 270 (22), 256 (9), 239 (18), 212 (12), 202 (22),
184 (26), 170 (9), 149 (11), 126 (23), 112 (21) and 82 (21).
(3S,3ЉS,4S,4ЉS,8S,8ЉS,9R,9ЉR)-11,11Љ-Bi(9-acetoxy-10,11-di-
dehydro-6Ј-methoxycinchonan) 29b. 10,11-Didehydroquinine 10a
(180 mg, 0.49 mmol, 1 eq.) was allowed to react according to
the general procedure with (Ph3P)2PdCl2 (17 mg, 0.025 mmol,
0.05 eq.), CuI (10 mg, 0.05 mmol, 0.1 eq.) and iodine (62 mg,
0.25 mmol, 0.5 eq.) to yield dimeric alkyne 29b (95%, 171 mg,
0.47 mmol); νmax(CHCl3)/cmϪ1 2956, 2868, 1740, 1672, 1620,
1592, 1508, 1472, 1456, 1432, 1372, 1232, 1092, 1032, 996 and
848; δH(400 MHz; CDCl3) 8.76 (d, 2 H, J 4.6, H-2Ј, H-2ٞ), 8.05
(d, 2 H, J 9.2, H-8Ј, H-8ٞ), 7.45 (d, 2 H, J 2.6, H-5Ј, H-5ٞ),
7.40–7.36 (m, 4 H, H-3Ј, H-3ٞ, H-7Ј, H-7ٞ), 6.49 (d, 2 H, J 7.5,
H-9, H-9Љ), 3.95 (s, 6 H, H-11Ј, H-11ٞ), 3.59–3.52 (m, 2 H, H-8,
H-8Љ), 3.14–3.04 (m, 4 H, H-2, H-6, H-2Љ, H-6Љ), 2.81–2.76 (m,
2 H, H-2, H-2Љ), 2.63–2.53 (m, 4 H, H-6, H-6Љ, H-3, H-3Љ), 2.14
(s, 6 H, H-13, H-13Љ), 2.13–2.06 (m, 2 H, H-7, H-7Љ), 2.04 (br s,
2 H, H-4, H-4Љ), 1.74–1.66 (m, 2 H, H-5, H-5Љ), 1.58–1.53 (m,
2 H, H-7Љ, H-7Љ) and 1.48–1.41 (m, 2 H, H-5, H-5Љ); δC(100
MHz; CDCl3) 170.08 (C, C-12, C-12Љ), 157.95 (C, C-6Ј, C-6ٞ),
147.39 (C, C-2Ј, C-2ٞ), 144.65 (CH, C-4Ј, C-4ٞ), 143.48 (C,
C-10Ј, C-10ٞ), 131.69 (CH, C-8Ј, C-8ٞ), 127.04 (C, C-9Ј, C-9ٞ),
121.90 (CH, C-7Ј, C-7ٞ), 119.06 (CH, C-3Ј, C-3ٞ), 101.46 (CH,
C-5Ј, C-5ٞ), 81.15 (C, C-10, C-10Љ), 73.36 (CH, C-9, C-9Љ),
65.60 (C, C-11, C-11Љ), 58.62 (CH, C-8, C-8Љ), 57.12 (CH2, C-2,
C-2Љ), 55.63 (CH3, C-11Ј, C-11ٞ), 41.80 (CH2, C-6, C-6Љ), 28.25
(CH, C-3, C-3Љ), 26.98 (CH, C-4, C-4Љ), 25.96 (CH2, C-7, C-7Љ),
24.68 (CH2, C-5, C-5Љ) and 21.06 (CH3, C-13, C-13Љ); m/z (FAB)
(EI) 727 (Mϩ, 100).
(1S,1ЈS,2R,2ЈR,4S,4ЈS,5S,5ЈS)-1,4-Bis(2-tert-butyldimethyl-
silanyloxymethyl-1-azabicyclo[2.2.2]octan-5-yl)buta-1,3-diyne
31b. 10,11-Didehydroquincoridine 20b (200 mg, 0.72 mmol,
1 eq.) was allowed to react according to the general procedure
with (Ph3P)2PdCl2 (33 mg, 0.036 mmol, 0.05 eq.), CuI (14 mg,
0.07 mmol, 0.1 eq.) and iodine (182 mg, 0.31 mmol, 0.5 eq.)
to yield dimeric alkyne 31b (85%, 169 mg, 0.30 mmol);
νmax(CHCl3)/cmϪ1 2948, 2880, 2856, 1468, 1388, 1360, 1320,
1300, 1256, 1148, 1116, 1080, 1052, 1020, 936 and 836; δH(400
MHz; CDCl3) 3.77–3.67 (m, 4 H, H-9, H-9Ј, H-9, H-9Ј), 3.07–
3.02 (m, 4 H, H-6, H-6Ј, H-2, H-2Ј), 2.99–2.92 (m, 2 H, H-6,
H-6Ј), 2.89–2.74 (m, 4 H, H-7, H-7Ј, H-7, H-7Ј), 2.59–2.54 (m,
2 H, H-5, H-5Ј), 2.00–1.95 (m, 2 H, H-4, H-4Ј), 1.79–1.72 (m,
2 H, H-3, H-3Ј), 1.66–1.48 (m, 6 H, H-8, H-8, H-8Ј, H-8Ј, H-3,
H-3Ј), 0.93 (s, 9 H, SiC(CH3)3), 0.92 (s, 9 H, SiC(CH3)3), 0.10
(s, 6 H, SiCH3) and 0.09 (s, 6 H, SiCH3); δC(100 MHz; CDCl3)
80.63 (C, C-10, C-10Ј), 66.19 (C, C-11, C-11Ј), 65.22 (CH2, C-9,
C-9Ј), 57.30 (CH, C-2, C-2Ј), 49.18 (CH2, C-6, C-6Ј), 48.82 (CH2,
C-7, C-7Ј), 29.02 (CH, C-5, C-5Ј), 27.82 (CH, C-4, C-4Ј), 26.03
(CH3, SiC(CH3)3), 25.22 (CH2, C-8, C-8Ј), 25.05 (CH2, C-3,
C-3Ј), 18.45 (C, SiC(CH3)3), Ϫ5.23 (CH3, SiCH3) and Ϫ5.27
(CH3, SiCH3); m/z (MAT, 150 ЊC) (EI) 556.3889 (Mϩ, C32H56N2-
O2Si2 requires 556.3880), 541 (11%), 499 (100), 443 (3), 425 (3),
411 (21), 384 (20), 368 (7), 326 (72), 298 (2), 279 (9), 238 (26), 222
(85), 202 (53), 185 (37), 155 (17), 110 (14), 89 (8) and 73 (60).
(1S,1ЈS,2S,2ЈS,4S,4ЈS,5S,5ЈS)-1,4-Bis(2-hydroxymethyl-1-
azabicyclo[2.2.2]octan-5-yl)buta-1,3-diyne 30. 10,11-Didehydro-
quincorine 18a (100 mg, 0.61 mmol, 1 eq.) was allowed to react
according to the general procedure with (Ph3P)2PdCl2 (21 mg,
0.03 mmol, 0.05 eq.), CuI (12 mg, 0.06 mmol, 0.1 eq.) and
(1ЈS,1ЉS,2ЈS,2ЉS,4ЈS,4ЉS,5ЈS,5ЉS)-(Z)-1,2-Bis(2-tert-butyl-
dimethylsilanyloxymethyl-1-azabicyclo[2.2.2]octan-5-ylethynyl)-
ethene 32. 10,11-Didehydroquincorine 18b (200 mg, 0.72 mmol,
62
J. Chem. Soc., Perkin Trans. 1, 2001, 47–65

View Online
1 eq.) was allowed to react with (Ph3P)2PdCl2 (33 mg,
0.036 mmol, 0.05 eq.), CuI (14 mg, 0.072 mmol, 0.1 eq.) and
(Z)-1,2-dichloroethene (27 µl, 0.36 mmol, 0.5 eq.) in Pri2NH–
THF (3:1) to yield (Z)-enediyne 32 (79%, 144 mg, 0.25 mmol)
which partially isomerized to the corresponding (E)-isomer
upon storage (1 d) in CHCl3 at rt (E:Z = 18:32); νmax(CHCl3)/
cmϪ1 2928, 2856, 1468, 1320, 1264, 1116, 1084, 1028 and 836;
δH(400 MHz; CDCl3) 6.34 (d, 2 H, Jcis 7.4, H-12, H-13), 5.89
(dd, 2 H, Jtrans 13.2 and 1.6, H-12, H-13), 3.69–3.65 (dd, 2 H,
J 10.3 and 6.0, H-9Ј, H-9Љ), 3.63–3.59 (dd, 2 H, J 10.4 and 6.1,
H-9Ј, H-9Љ), 3.24–3.17 (dd, 2 H, J 13.4 and 10.0, H-6endoЈ,
H-6endoЉ), 3.07–2.87 (m, 4 H, H-2Ј, H-2Љ, H-6Ј, H-6Љ), 2.62–2.53
(m, 4 H, H-7Ј, H-7Љ, H-7Ј, H-7Љ), 2.32–2.27 (m, 2 H, H-5Ј,
H-5Љ), 2.07–1.99 (m, 2 H, H-4Ј, H-4Љ), 1.96–1.91 (m, 2 H, H-3Ј,
H-3Љ), 1.54–1.32 (m, 6 H, H-8Ј, H-8Љ, H-8Ј, H-8Љ, H-3Ј, H-3Љ),
0.89 (s, 18 H, SiC(CH3)3) and 0.06 (s, 12 H, SiCH3); δC(100
MHz; CDCl3) 112.41 (CH, C-12, C-13), 81.48 (C, C-10Ј,
C-10Љ), 65.89 (C, C-11Ј, C-11Љ), 65.52 (CH2, C-9Ј, C-9Љ), 57.92
(CH, C-2Ј, C-2Љ), 57.02 (CH2, C-6Ј, C-6Љ), 41.70 (CH2, C-7Ј,
C-7Љ), 29.30 (CH, C-5Ј, C-5Љ), 27.64 (CH, C-4Ј, C-4Љ), 26.01
(CH3, SiC(CH3)3), 25.08 (CH2, C-8Ј, C-8Љ), 22.67 (CH2, C-3Ј,
C-3Љ), 18.41 (C, SiC(CH3)3), Ϫ5.32 (CH3, SiCH3) and Ϫ5.35
(CH3, SiCH3); m/z (FAB) (EI) 584 (Mϩ ϩ 2 H, 2), 557 (100),
542 (8), 500 (37), 411 (5), 310 (6) and 282 (16).
552 (73), 519 (100), 437 (43), 397 (45), 355 (63), 341 (63) and 327
(85).
General procedure for the Heck reaction of Cinchona alkaloid
precursors with ꢀ,ꢁ-unsaturated carbonyl compounds
Pd(OAc)2 (0.05 eq.), K2CO3 (2.50 eq.) and TBAI (1.00 eq.) were
dissolved in absolute DMF under argon. The reaction mixture
was stirred for 15 min at rt, the α,β-unsaturated carbonyl com-
pound (4.00 eq.) was added and stirring was continued for 15
min, followed by dropwise addition of a solution of vinyl iodide
precursor (1.50 eq.) in absolute DMF. Subsequent to stirring
at rt for 12 h, the dark-red reaction mixture was treated with
sat. aq. NaHCO3 and sat. aq. NaCl. The aqueous layer was
thorougly extracted with CH2Cl2 and the combined organic
layer was dried (MgSO4) and concentrated under reduced
pressure. DMF was then removed at elevated temperature
under reduced pressure. The resulting crude product was
purified by column chromatography (EtOAc–MeOH 20:1) to
yield the desired coupling product.
(3R,4S,8R,9S,10Z)-9-Acetoxy-11-[(4E)-3-oxobutylidene]-6Ј-
methoxycinchonan 35a. (Z)-11-(2-Iodovinyl)quinidine 11b
(121 mg, 0.25 mmol, 1 eq.) was allowed to react according to
the general procedure with Pd(OAc)2 (3 mg, 0.01 mmol,
0.05 eq.), K2CO3 (85 mg, 0.62 mmol, 2.5 eq.), TBAI (91 mg,
0.25 mmol, 1 eq.) and methylvinyl ketone (82 µl, 0.99 mmol,
4.0 eq.) to afford (Z,E)-diene 35a (92%, 98 mg, 0.23 mmol);
νmax(CHCl3)/cmϪ1 2944, 2876, 1744, 1668, 1620, 1588, 1508,
1472, 1456, 1432, 1360, 1296, 1236, 1176, 1136, 1084, 1028, 992
and 844; δH(400 MHz; CDCl3) 8.73 (d, 1 H, J 4.5, H-2Ј), 8.02
(d, 1 H, J 9.9, H-8Ј), 7.41–7.35 (m, 3 H, H-7Ј, H-5Ј, H-12), 7.33
(d, 1 H, J 4.6, H-3Ј), 6.57 (d, 1 H, J 6.8, H-9), 6.24 (d, 1 H, J 9.2,
H-10), 6.23 (d, 1 H, J 15.3, H-13), 6.16 (m, 1 H, H-11), 3.93
(s, 3 H, H-11Ј), 3.35–3.30 (m, 2 H, H-8, H-2), 3.06–2.97 (m, 1 H,
H-2), 2.89–2.78 (m, 3 H, H-6, H-6, H-3), 2.28 (s, 3 H, H-15),
2.14 (s, 3 H, H-17), 1.94–1.88 (m, 1 H, H-4), 1.81–1.76 (m, 1 H,
H-7) and 1.71–1.42 (m, 3 H, H-7, H-5, H-5); δC(100 MHz;
CDCl3) 198.45 (C, C-14), 169.93 (C, C-16), 157.97 (C, C-6Ј),
147.41 (CH, C-2Ј), 144.72 (C, C-10Ј), 143.66 (C, C-4Ј), 143.45
(CH, C-12), 137.88 (CH, C-13), 131.83 (CH, C-8Ј), 130.83 (CH,
C-11), 127.54 (CH, C-10), 126.92 (C, C-9Ј), 121.81 (CH, C-7Ј),
118.53 (CH, C-3Ј), 101.43 (CH, C-5Ј), 73.42 (CH, C-9), 58.82
(CH, C-8), 55.68 (CH3, C-11Ј), 50.07 (CH2, C-2), 49.67 (CH2,
C-6), 34.88 (CH, C-3), 28.26 (CH, C-4), 25.91 (CH2, C-7), 23.13
(CH2, C-5), 21.17 (CH3, C-17) and 13.73 (CH3, C-15);
m/z (MAT, 140 ЊC) (EI) 434.2206 (Mϩ, C26H30N2O4 requires
434.2205), 391 (1%), 373 (1), 315 (1), 285 (2), 258 (8), 204 (6),
167 (4), 155 (7), 139 (5), 111 (6), 99 (37) and 83 (100).
(1ЈS,1ЉS,2ЈR,2ЉR,4ЈS,4ЉS,5ЈS,5ЉS)-1,4-Bis(2-hydroxymethyl-
1-azabicyclo[2.2.2]octan-5-ylethynyl)benzene 33. 10,11-Dide-
hydroquincoridine 20a (100 mg, 0.61 mmol, 1 eq.) was allowed
to react according to the general procedure with (Ph3P)2PdCl2
(21 mg, 0.03 mmol, 0.05 eq.), CuI (12 mg, 0.06 mmol, 0.1 eq.)
and 1,4–diiodobenzene (99 mg, 0.30 mmol, 0.5 eq.) to yield
dimeric alkyne 33 (64%, 64 mg, 0.19 mmol); νmax(CHCl3)/cmϪ1
3416, 3000, 2948, 2876, 2224, 1484, 1464, 1412, 1388, 1324,
1256, 1236, 1160, 1136, 1100, 1056, 1028, 1008, 944 and 820;
δH(400 MHz; CDCl3) 7.63 (d, 4 H, J 8.4, H-2, H-3, H-5,
H-6), 5.42–5.33 (s, 2 H, OH, OHЈ), 3.73–3.56 (m, 4 H, H-9Ј,
H-9Љ, H-9Ј, H-9Љ), 3.18–2.81 (m, 10 H, H-6Ј, H-6Љ, H-2Ј, H-2Љ,
H-6Ј, H-6Љ, H-7Ј, H-7Љ, H-7Ј, H-7Љ), 2.69–2.61 (m, 2 H, H-5Ј,
H-5Љ), 2.00–1.92 (m, 2 H, H-4Ј, H-4Љ), 1.79–1.52 (m, 6 H, H-3Ј,
H-3Љ, H-8Ј, H-8Љ, H-8Ј, H-8Љ) and 1.46–1.33 (m, 2 H, H-3Ј, H-
3Љ); δC(100 MHz; CDCl3) 133.17 (CH, C-2, C-3, C-5, C-6),
122.95 (C, C-1, C-4), 93.52 (C, C-10Ј, C-10Љ), 81.08 (C, C-11Ј,
C-11Љ), 61.91 (CH2, C-9Ј, C-9Љ), 57.48 (CH, C-2Ј, C-2Љ), 48.35
(CH2, C-6Ј, C-6Љ), 47.76 (CH2, C-7Ј, C-7Љ), 29.11 (CH, C-5Ј,
C-5Љ), 27.31 (CH, C-4Ј, C-4Љ), 24.16 (CH2, C-8Ј, C-8Љ) and
22.57 (CH2, C-3Ј, C-3Љ); m/z (FAB) (EI) 425 (Mϩ Ϫ 2 H ϩ Na,
9%), 397 (18), 368 (100), 336 (14), 281 (15), 221 (20) and 147
(35).
(1ЈS,1ЉS,2ЈS,2ЉS,4ЈS,4ЉS,5ЈS,5ЉS)-1,2-Bis(2-tert-butyldi-
methylsilanyloxymethyl-1-azabicyclo[2.2.2]octanyl)benzene 34.
Enediyne 32 (58 mg, 0.10 mmol) cycloaromatized upon
refluxing in CHCl3 for 4 h furnishing aromatic dimer 34 (86%,
50 mg, 0.09 mmol); νmax(CHCl3)/cmϪ1 2952, 2928, 2856, 1592,
1468, 1388, 1360, 1332, 1304, 1256, 1120, 1084, 1028, 1004, 936
and 836; δH(400 MHz; CDCl3) 7.71–7.65 (m, 2 H, H-3, H-6),
7.51–7.46 (m, 2 H, H-4, H-5), 3.73–3.62 (m, 4 H, H-9Ј, H-9Љ,
H-9Ј, H-9Љ), 3.31–3.25 (dd, 2 H, J 13.2 and 10.0, H-6endoЈ,
H-6endoЉ), 3.12–2.90 (m, 4 H, H-2Ј, H-2Љ, H-6Ј, H-6Љ), 2.75–2.59
(m, 4 H, H-7Ј, H-7Љ, H-7Ј, H-7Љ), 2.40–2.36 (m, 2 H, H-5Ј,
H-5Љ), 2.18–2.10 (m, 2 H, H-4Ј, H-4Љ), 2.03–1.95 (m, 2 H, H-3Ј,
H-3Љ), 1.61–1.37 (m, 6 H, H-8Ј, H-8Љ, H-8Ј, H-8Љ, H-3Ј, H-3Љ),
0.92 (s, 18 H, SiC(CH3)3) and 0.09 (s, 12 H, SiCH3); δC(100
MHz; CDCl3) 132.17 (CH, C-3, C-6), 128.58 (CH, C-4,
C-5), 127.25 (C, C-1, C-2), 65.86 (CH2, C-9Ј, C-9Љ), 57.72
(CH, C-2Ј, C-2Љ), 57.09 (CH2, C-6Ј, C-6Љ), 41.75 (CH2, C-7Ј,
C-7Љ), 28.88 (CH, C-5Ј, C-5Љ), 27.59 (CH, C-4Ј, C-4Љ), 26.02
(CH3, SiC(CH3)3), 25.23 (CH2, C-8Ј, C-8Љ), 22.70 (CH2, C-3Ј,
C-3Љ), 18.44 (C, SiC(CH3)3), Ϫ5.30 (CH3, SiCH3) and Ϫ5.32
(CH3, SiCH3); m/z (FAB) (EI) 586 (Mϩ ϩ 2 H, 13), 578 (71),
(3R,4S,8R,9S,10E)-11-(3-Oxopropylidene-6Ј-methoxy-
cinchonan-9-ol 35b. (Z)-11-(2-Iodovinyl)quinidine 11a (111 mg,
0.25 mmol, 1 eq.) was allowed to react according to the general
procedure with Pd(OAc)2 (3 mg, 0.01 mmol, 0.05 eq.), K2CO3
(85 mg, 0.62 mmol, 2.5 eq.), TBAI (91 mg, 0.25 mmol, 1 eq.)
and methyl acrylate (90 µl, 0.99 mmol, 4.0 eq.) to afford
(Z,E)-diene 35b (68%, 69 mg, 0.17 mmol); νmax(CHCl3)/cmϪ1
3336, 2964, 2876, 1620, 1592, 1508, 1460, 1436, 1384, 1296,
1276, 1228, 1176, 1140, 1104, 1064, 1028, 992 and 872; δH(400
MHz; CDCl3) 8.76 (d, 1 H, J 4.6, H-2Ј), 7.90 (d, 1 H, J 9.2,
H-8Ј), 7.76 (d, 1 H, J 4.6, H-3Ј), 7.25–7.19 (m, 2 H, H-7Ј, H-5Ј),
6.83 (s, 1 H, H-9), 6.37–6.30 (m, 2 H, H-11, H-12), 6.26 (d, 1 H,
J 9.2, H-10), 5.99 (d, 1 H, J 15.2, H-13), 3.87 (s, 3 H, H-11Ј),
3.76 (s, 3 H, H-15), 3.71–3.63 (m, 1 H, H-8), 3.56–3.42 (m, 2 H,
H-2, H-2), 3.31–3.18 (m, 2 H, H-6, H-6), 2.52–2.45 (m, 1 H,
H-3), 2.14–1.98 (m, 2 H, H-4, H-7), 1.73–1.65 (m, 1 H, H-7)
and 1.50–1.42 (m, 2 H, H-5, H-5); δC(100 MHz; CDCl3) 167.26
(C, C-14), 158.73 (C, C-6Ј), 147.23 (CH, C-2Ј), 144.93 (C,
C-10Ј), 143.84 (C, C-4Ј), 143.31 (CH, C-12), 137.94 (CH, C-13),
131.30 (CH, C-8Ј), 130.93 (CH, C-11), 129.29 (CH, C-10),
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125.66 (C, C-9Ј), 123.60 (CH, C-7Ј), 119.19 (CH, C-3Ј), 100.48
(CH, C-5Ј), 73.90 (CH, C-9), 60.16 (CH, C-8), 59.23 (CH3,
C-15), 58.58 (CH3, C-11Ј), 51.82 (CH2, C-2), 49.89 (CH2, C-6),
38.72 (CH, C-3), 28.92 (CH, C-4), 24.34 (CH2, C-7) and 23.74
(CH2, C-5); m/z (MAT, 140 ЊC) (EI) 408.3244 (Mϩ, C24H28N2O4
requires 408.3239), 377 (2%), 335 (8), 323 (5), 279 (15), 254 (2),
220 (14), 167 (32), 149 (100), 127 (19), 113 (11), 87 (13), 71 (21).
the general procedure with Pd(OAc)2 (3 mg, 0.01 mmol,
0.05 eq.), K2CO3 (85 mg, 0.62 mmol, 2.5 eq.), TBAI (91 mg,
0.25 mmol, 1 eq.) and acrylamide (70 mg, 0.99 mmol, 4.0 eq.)
to afford (Z,E)-diene 35d (90%, 96 mg, 0.22 mmol); νmax
-
(CHCl3)/cmϪ1 2940, 2876, 1744, 1676, 1624, 1592, 1508, 1472,
1456, 1432, 1372, 1304, 1228, 1156, 1120, 1084, 1032, 988 and
956; δH(400 MHz; CDCl3) 8.72 (d, 1 H, J 4.5, H-2Ј), 8.01 (d,
1 H, J 9.9, H-8Ј), 7.51 (dd, 1 H, J 14.9 and 11.2, H-12), 7.36–
7.32 (m, 3 H, H-7Ј, H-5Ј, H-3Ј), 6.53 (d, 1 H, J 6.7, H-9),
6.20–6.08 (m, 2 H, H-10, H-11), 5.99 (d, 1 H, J 14.8, H-13), 3.92
(s, 3 H, H-11Ј), 3.32–3.23 (m, 3 H, H-8, H-2, H-2), 3.00–2.71
(m, 3 H, H-6, H-6, H-3), 2.13 (s, 3 H, H-16), 1.91–1.85 (m, 1 H,
H-7), 1.76–1.72 (m, 1 H, H-4) and 1.67–1.38 (m, 3 H, H-7, H-5,
H-5); δC(100 MHz; CDCl3) 170.02 (C, C-14), 168.23 (C, C-15),
157.85 (C, C-6Ј), 147.35 (CH, C-2Ј), 144.59 (C, C-10Ј), 143.47
(C, C-4Ј), 141.62 (CH, C-12), 136.76 (CH, C-13), 132.05 (CH,
C-11), 131.69 (CH, C-8Ј), 126.88 (C, C-9Ј), 123.93 (CH, C-10),
121.86 (CH, C-7Ј), 118.56 (CH, C-3Ј), 101.44 (CH, C-5Ј), 73.51
(CH, C-9), 58.84 (CH, C-8), 55.63 (CH3, C-11Ј), 49.92 (CH2,
C-2), 49.35 (CH2, C-6), 34.53 (CH, C-3), 27.98 (CH, C-4),
25.31 (CH2, C-7), 24.09 (CH2, C-5) and 21.19 (CH3, C-16);
m/z (MAT, 70 ЊC) (EI) 436.2224 (Mϩ, C25H30N3O4 requires
436.2236), 420 (2%), 392 (2), 376 (11), 349 (1), 242 (2), 231 (2),
205 (100), 189 (17), 173 (10), 154 (10), 142 (25), 132 (8), 95 (4)
and 79 (8).
(3R,4S,8R,9S,11Z)-9-Acetoxy-11-(3-tert-butoxycarbonyl-
propylidene)-6Ј-methoxycinchonan 35c. (Z)-11-(2-Iodovinyl)-
quinidine 11b (121 mg, 0.25 mmol, 1 eq.) was allowed to react
according to the general procedure with Pd(OAc)2 (3 mg, 0.01
mmol, 0.05 eq.), K2CO3 (85 mg, 0.62 mmol, 2.5 eq.), TBAI
(91 mg, 0.25 mmol, 1 eq.) and isobutyl acrylate (0.14 ml, 0.99
mmol, 4.0 eq.) to afford (Z,E)-diene 35c (88%, 106 mg, 0.22
mmol); νmax(CHCl3)/cmϪ1 2964, 2876, 1744, 1672, 1632, 1508,
1472, 1432, 1376, 1308, 1268, 1228, 1176, 1140, 1112, 1084,
1028, 992 and 872; δH(400 MHz; CDCl3) 8.69 (d, 1 H, J 4.5, H-
2Ј), 7.97 (d, 1 H, J 9.2, H-8Ј), 7.49 (dd, 1 H, J 15.2 and 11.6,H-
12), 7.38–7.35 (m, 2 H, H-7Ј, H-5Ј), 7.32 (d, 1 H, J 4.5, H-3Ј),
6.74 (d, 1 H, J 6.6, H-9), 6.26 (dd, 1 H, J 11.6 and 9.2, H-11),
6.14 (d, 1 H, J 9.2, H-10), 5.95 (d, 1 H, J 15.2, H-13), 3.94 (s,
3 H, H-11Ј), 3.91 (d, 2 H, J 6.7, H-15), 3.69–3.61 (m, 1 H, H-8),
3.42–3.23 (m, 2 H, H-2, H-2), 2.99–2.82 (m, 3 H, H-6, H-6,
H-3), 2.14 (s, 3 H, H-20), 2.02–1.93 (m, 1 H, H-4), 1.83–1.79 (m,
1 H, H-7), 1.69–1.57 (m, 3 H, H-7, H-5, H-5), 1.45–1.37 (m, 1 H,
H-16) and 0.97–0.89 (m, 6 H, H-17, H-18); δC(100 MHz;
CDCl3) 169.42 (C, C-19), 167.51 (C, C-14), 158.09 (C, C-6Ј),
147.34 (CH, C-2Ј), 144.84 (C, C-10Ј), 143.39 (C, C-4Ј), 143.02
(CH, C-12), 138.71 (CH, C-13), 131.82 (CH, C-8Ј), 127.78 (CH,
C-11), 126.55 (C, C-9Ј), 122.76 (CH, C-10), 122.15 (CH, C-7Ј),
118.32 (CH, C-3Ј), 101.29 (CH, C-5Ј), 72.69 (CH, C-9), 70.61
(CH2, C-15), 58.81 (CH, C-8), 55.61 (CH3, C-11Ј), 49.82 (CH2,
C-2), 49.27 (CH2, C-6), 34.07 (CH, C-3), 27.78 (CH, C-4), 25.68
(CH2, C-7), 24.30 (CH2, C-5), 21.13 (CH3, C-20), 19.12 (CH,
C-16) and 13.76 (CH3, C-17, C-18); m/z (FAB) (EI) 493
(Mϩ ϩ H, 17), 242 (100), 184 (8) and 142 (9).
(1S,2S,4S,5R)-2-tert-Butylsilanyloxymethyl-5-[(1E,3E)-5-
oxohexa-1,3-dienyl]-1-azabicyclo[2.2.2]octane 36. (E)-11-(2-
Iodovinyl)quincorine 17 (68 mg, 0.17 mmol, 1 eq.) was allowed
to react according to the general procedure with Pd(OAc)2
(2 mg, 0.01 mmol, 0.05 eq.), K2CO3 (57 mg, 0.42 mmol, 2.5 eq.),
TBAI (62 mg, 0.17 mmol, 1 eq.) and methyl vinyl ketone
(47 mg, 0.67 mmol, 4.0 eq.) to afford (Z,E)-diene 36 (84%,
49 mg, 0.14 mmol); νmax(CHCl3)/cmϪ1 2960, 2936, 2876, 1672,
1632, 1468, 1408, 1384, 1360, 1316, 1256, 1232, 1112, 1092,
1064, 996 and 836; δH(400 MHz; CDCl3) 7.13–7.03 (dd, 1 H,
J 15.6 and 9.7, H-12), 6.32–6.20 (m, 2 H, H-10, H-11), 6.08–
6.03 (d, 1 H, J 15.7, H-13), 3.74–3.68 (m, 2 H, H-9, H-9), 3.65–
3.42 (m, 3 H, H-6, H-6, H-2), 3.20–2.95 (m, 2 H, H-7, H-7),
2.35–2.32 (m, 1 H, H-5), 2.22 (s, 3 H, H-15), 2.12–2.04 (m, 2 H,
H-4, H-3), 1.95–1.74 (m, 3 H, H-8, H-8, H-3), 0.89 (s, 9 H,
SiC(CH3)3), 0.07 (s, 3 H, SiCH3) and 0.05 (s, 3 H, SiCH3);
δC(100 MHz; CDCl3) 198.73 (C, C-14), 142.82 (CH, C-12),
130.62 (CH, C-13), 130.58 (CH, C-11), 130.42 (CH, C-10),
62.64 (CH2, C-9), 58.14 (CH, C-2), 54.01 (CH2, C-6), 42.79
(CH2, C-7), 27.60 (CH, C-5), 26.81 (CH, C-4), 25.97 (CH3,
SiC(CH3)3), 24.69 (CH2, C-8), 24.31 (CH2, C-3), 22.15 (CH3,
C-15), 18.28 (C, SiC(CH3)3), Ϫ5.20 (CH3, SiCH3) and Ϫ5.38
(CH3, SiCH3); m/z (FAB) (EI) 350 (Mϩ ϩ H, 23), 242 (100), 184
(10) and 142 (17).
(3R,4S,8R,9S,11Z)-9-Acetoxy-11-(3-oxopropylidene)-6Ј-
methoxycinchonan 35d. (Z)-11-(2-Iodovinyl)quinidine 11b
(121 mg, 0.25 mmol, 1 eq.) was allowed to react according
to the general procedure with Pd(OAc)2 (3 mg, 0.01 mmol,
0.05 eq.), K2CO3 (85 mg, 0.62 mmol, 2.5 eq.), TBAI (91 mg,
0.25 mmol, 1 eq.) and acrolein (66 µl, 0.99 mmol, 4.0 eq.)
to afford (Z,E)-diene 35d (81%, 84 mg, 0.20 mmol); νmax
-
(CHCl3)/cmϪ1 3000, 2944, 2876, 1744, 1676, 1624, 1588, 1508,
1472, 1456, 1432, 1364, 1304, 1228, 1172, 1136, 1088, 1032, 988
and 844; δH(400 MHz; CDCl3) 9.61 (d, 1 H, J 7.5, H-14), 8.70
(d, 1 H, J 4.6, H-2Ј), 7.98 (d, 1 H, J 9.2, H-8Ј), 7.40–7.30 (m,
4 H, H-7Ј, H-5Ј, H-12, H-3Ј), 6.55 (m, 1 H, H-9), 6.40–6.25
(m, 2 H, H-10, H-11), 6.20–6.10 (m, 1 H, H-13), 3.92 (s, 3 H,
H-11Ј), 3.38–3.24 (m, 3 H, H-8, H-2, H-2), 3.05–2.75 (m, 3 H,
H-6, H-6, H-3), 2.13 (s, 3 H, H-16), 1.96–1.85 (m, 1 H, H-4) and
1.71–1.35 (m, 4 H, H-7, H-7, H-5, H-5); δC(100 MHz; CDCl3)
193.79 (CH, C-14), 169.88 (C, C-15), 157.91 (C, C-6Ј), 147.36
(CH, C-2Ј), 146.27 (CH, C-12), 144.95 (C, C-10Ј), 144.80 (C,
C-4Ј), 143.59 (CH, C-13), 132.40 (CH, C-11), 131.77 (CH,
C-8Ј), 127.41 (CH, C-10), 126.98 (C, C-9Ј), 121.85 (CH, C-7Ј),
118.31 (CH, C-3Ј), 101.42 (CH, C-5Ј), 73.31 (CH, C-9), 58.76
(CH, C-8), 55.53 (CH3, C-11Ј), 49.89 (CH2, C-2), 49.42 (CH2,
C-6), 34.97 (CH, C-3), 28.08 (CH, C-4), 25.11 (CH2, C-7), 23.47
(CH2, C-5) and 21.13 (CH3, C-16); m/z (MAT, 90 ЊC) (EI)
420.2048 (Mϩ, C25H28N2O4 requires 420.2049), 392 (8%), 378
(10), 361 (14), 349 (2), 325 (16), 294 (2), 265 (6), 242 (100), 231
(32), 211 (28), 190 (31), 173 (11), 155 (10), 142 (60), 128 (24), 99
(41) and 91 (41).
Acknowledgements
We thank the Fonds der Chemischen Industrie (J. F.) and the
Friedrich Naumann Stiftung (W. M. B.) for PhD fellowships,
Degussa AG Hanau for a generous gift of palladium salts,
Buchler GmbH-Chininfabrik Braunschweig for a generous gift
of Cinchona alkaloids and Ulrike Eggert for her help.
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65