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

Abstract

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.

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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, palladium ^2,3 complexes 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 M₁ (1 and 2), 5-HT₃ (3) and NK₁-receptors ^5,6 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

Fig. 1 Quinuclidine lead structures.

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 interest ¹¹ since some of these compounds exhibit high activity against chloroquine-resistant parasites.¹² Further examples of dimeric Cinchona alkaloid derivatives are chiral symmetrical pentamethinium cyanine dyes with hexahydroquininyl and -quinidinyl end groups (6).¹³

Fig. 2 Dimerized Cinchona alkaloids.

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 applications 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 (19).¹⁶ Iodinated alkynes were easily transformed into corresponding (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 14via hydrazide reduction.¹⁸

Scheme 1 Synthesis of precursors for quinine and quinidine cross-coupling. Reagents and conditions: i, 1. Br₂, CHCl₃–CCl₄, 0 °C, 2 h, 2. Et₃N, CHCl₃, rt, 2 h, 3. KOH, aliquat 336^®, THF, 6–20 h, rt or 70 °C; ii, AcCl, Et₃N, DCM, 0 °C→rt, 16 h; iii, I₂, morpholine, toluene, 55 °C, 10 h, 91–97%; iv, TsNHNH₂, NaOAc, THF, H₂O, 55 °C, 4–6 h, 56–65%.

Scheme 2 Synthesis of precursors for quincorine and quincoridine cross-coupling. Reagents and conditions: i, 1. Br₂, CHCl₃–CCl₄, 0 °C, 2 h, 2. Et₃N, CHCl₃, rt, 2 h, 3. KOH, aliquat 336^®, THF, 6–20 h, rt or 70 °C; ii, 1. 2,4,6-triisopropylbenzenesulfonyl hydrazide, Et₂O, rt, 16 h, 2. n-BuLi, TMEDA, hexane, −78 °C→0 °C, 1 h; 3. Bu₃SnCl, 0 °C→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 °C→rt, 3 h.

Usually, the Sonogashira coupling is carried out in the presence of catalytic amounts of a Pd(II)-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 studies ²⁰ 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%).

Table 1 Optimization of Sonogashira coupling of 10,11-didehydroquinidine and -quinine with phenyl halides

Entry	Alkyne	Ph-X (eq.)	Solvent, base ^a	Time/h	Yield (%)
a Typically, reactions were carried out at rt. b Temperature: 60 °C.
1	21a	Ph-I (1.0)	THF, Et2NH	6	60
2	21a	Ph-I (1.5)	THF, ^iPr2NH	6	66
3	21a	Ph-I (1.5)	—, Et3N	16 ^b	51
4	21a	Ph-I (1.5)	THF, Et3N	6	73
5	21a	Ph-I (1.5)	THF, Et3N	14	80
6	21a	Ph-I (1.5)	Et2O, Et3N	14	68
7	21a	Ph-I (1.5)	Dioxan, Et3N	14	63
8	21a	Ph-I (1.5)	DMF, Et3N	14	65
9	21a	Ph-I (1.5)	THF, —	72	44
10	21a	Ph-Br (1.5)	THF, Et3N	6	53
11	21a	Ph-Br (1.5)	THF, Et3N	20	71
12	21b	Ph-I (1.5)	THF, Et3N	14	94
13	22a	Ph-I (1.5)	THF, Et3N	16	70
14	22b	Ph-I (1.5)	THF, Et3N	16	86

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Scheme 3 Optimized Sonogashira coupling of 10,11-didehydroquinidine 9a,b, and -quinine 10a,b. Reagents and conditions: i, (Ph₃P)₂PdCl₂ (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 precursors 9b and 10b gave higher yields of up to 94% (Schemes 1 and 4, Tables 1 and 2). Reaction with less reactive bromobenzene 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 solvents 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 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

Table 2 Sonogashira coupling of 10,11-didehydroquinidine with aryl and vinyl halides

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.

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 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).

Table 3 Sonogashira coupling of 10,11-didehydroquincorine 18a–c and -quincoridine 20a,b with various aryl and vinyl halides

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.

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.

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.

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 heteroaromatic 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-didehydroquinine 10a,b underwent self-coupling in the presence of (Ph₃P)₂PdCl₂, CuI, I₂ (0.5 eq.) and Et₃N to give the corresponding diynes 28a,b and 29a,b exclusively (yields from 71 to 95%). The resulting products exhibit strongly enhanced basicity compared with parent quinine and quinidine (Scheme 7).

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.

Homocoupling of simple 10,11-didehydroquincorine 18a and 10,11-didehydroquincoridines 20a,b afforded the corresponding diynes (64–85%) without by-products. Moreover, further spacers could be introduced giving enediyne 32 and quincoridine-based diyne 33 with a benzene spacer. Interestingly, enediyne 32 underwent a Bergman cycloaromatization at moderately elevated temperature (60–70 °C) in CHCl₃ (86% yield), although the enediyne moiety was not incorporated into a strained medium sized ring (Scheme 8).

Scheme 8 Pd-mediated dimerization of 10,11-didehydroquincorine and 10,11-didehydroquincoridine. Reagents and conditions: i, (Ph₃P)₂PdCl₂ (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 °C, 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 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 conditions 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).

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 medicinal chemistry, supramolecular chemistry ²⁸ and asymmetric synthesis. As we have shown 10,11-didehydro Cinchona alkaloids represent a significantly new class of semi-natural Cinchona alkaloids ¹⁶ 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 = 5–10° from X-ray crystal studies).¹⁶ The additional functionality of the Cinchona alkaloid is tolerated by palladium-mediated cross-coupling without protection.

Experimental

General

Infrared spectra were recorded on a Perkin-Elmer 1710 infrared spectrometer. ¹H NMR and ¹³C NMR spectra were recorded on Bruker AVS 400 and Bruker AVM 500 spectrometers in deuterated chloroform unless otherwise stated, with tetramethylsilane 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 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 14 ¹⁸ (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 −78 °C 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 °C, 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 chromatography (EtOAc–MeOH 6∶1) to afford vinylstannane 15 (80%, 152 mg, 0.36 mmol); ν_max(CHCl₃)/cm⁻¹ 3304, 2960, 2929, 2872, 1564, 1463, 1419, 1379, 1362, 1342, 1292, 1230, 1150, 1082, 1050, 1007, 939 and 878; δ_H(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); δ_C(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), −9.02 (CH₂, SnBu₃), −9.13 (CH₂, SnBu₃) and −9.22 (CH₂, SnBu₃); m/z (MAT, 70 °C) (EI) 429.2054 (M⁺, C₂₀H₃₉N₁O₁¹²⁰Sn requires 429.2054), 313 (M⁺ − 2 Bu, 15%), 292 (7), 269 (100), 239 (10), 213 (20), 195 (1), 177 (27), 155 (23) and 121 (12).

(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 °C) and treated with CHI₃ (490 mg, 1.24 mmol, 2 eq.). After 10 min TBDMS-protected C10-aldehyde 16 ²⁹ (176 mg, 0.62 mmol, 1 eq.) was added at 0 °C 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 combined organic layer was dried (MgSO₄), filtered and concentrated 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); ν_max(CHCl₃)/cm⁻¹ 2956, 2932, 2900, 2860, 1672, 1604, 1460, 1408, 1388, 1256, 1228, 1172, 1132, 1092, 1064, 1004 and 948; δ_H(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); δ_C(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(C H₃)₃), 23.91 (CH₂, C-8), 22.19 (CH₂, C-3), 18.22 (C, SiC(CH₃)₃), −5.14 (CH₃, SiC H₃) and −5.37 (CH₃, SiC H₃); m/z (FAB) (EI) 408 (M⁺ + H, 100%), 394 (10), 282 (9), 221 (8), 207 (12), 147 (23) and 133 (19).

General procedure for the Sonogashira coupling of aryl and vinyl halides with terminal alkynes

(Ph₃P)₂PdCl₂ (0.05 eq.) and CuI (0.1 eq.) were dissolved in Et₃N and absolute THF (1∶1 mixture, 10 ml mmol⁻¹ 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 purified by column chromatography (EtOAc–MeOH) to yield the desired internal alkyne.

(3S,4S,8R,9S )-11-Phenyl-10,11-didehydro-6′-methoxycinchonan-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); ν_max(CHCl₃)/cm⁻¹ 3064, 2944, 2876, 2836, 2224, 1620, 1592, 1508, 1472, 1432, 1388, 1364, 1320, 1256, 1228, 1172, 1092, 1032, 996 and 828; δ_H(400 MHz; CDCl₃) 8.55 (d, 1 H, J 4.6, H-2′), 7.93 (d, 1 H, J 9.1, H-8′), 7.47–7.42 (m, 3 H, H-3′, 2 Ar-H), 7.33–7.28 (m, 3 H, Ar-H), 7.27 (d, 1 H, J 2.6, H-5′), 7.24 (dd, 1 H, J 9.2 and 2.6, H-7′), 5.67 (d, 1 H, J 5.4, H-9), 3.80 (s, 3 H, H-11′), 3.54–3.49 (ddd, 1 H, J 13.6, 7.0 and 2.0, H-2_endo), 3.20–3.14 (m, 1 H, H-8), 3.11–3.05 (dd, 1 H, J 13.3 and 8.5, H-2_exo), 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); δ_C(100 MHz; CDCl₃) 157.61 (C, C-6′), 147.62 (C, C-10′), 147.45 (CH, C-2′), 144.02 (C, C-4′), 131.63 (CH, Ar-H), 131.28 (CH, C-8′), 128.28 (CH, Ar-H), 127.77 (CH, Ar-H), 126.81 (C, C-9′), 123.69 (C, Ar-C), 121.52 (CH, C-7′), 118.74 (CH, C-3′), 101.39 (CH, C-5′), 92.68 (C, C-11), 81.70 (C, C-10), 71.41 (CH, C-9), 60.04 (CH, C-8), 55.64 (CH₃, C-11′), 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 °C) (EI) 398.1999 (M⁺, 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,8S,9R)-11-Phenyl-10,11-didehydro-6′-methoxycinchonan-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); ν_max(CHCl₃)/cm⁻¹ 2952, 1622, 1592, 1509, 1491, 1473, 1432, 1265, 1241, 1230, 1083, 1031, 909 and 857; δ_H(400 MHz; CDCl₃) 8.50 (d, 1 H, J 4.6, H-2′), 7.86 (d, 1 H, J 10.0, H-8′), 7.51 (d, 1 H, J 4.5, H-3′), 7.21–7.10 (m, 5 H, H-7′, H-5′, 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-11′), 3.76–3.68 (m, 1 H, H-8), 3.52–3.45 (m, 1 H, H-6_endo), 3.24 (dd, 1 H, J 13.3 and 10.0, H-2_exo), 3.05–2.98 (m, 1 H, H-2_endo), 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); δ_C(100 MHz; CDCl₃) 157.79 (C, C-6′), 147.26 (CH, C-2′), 143.87 (C, C-10′, C-4′), 131.30 (CH, Ar-H), 131.02 (CH, C-8′), 128.12 (CH, Ar-H), 127.92 (CH, Ar-H), 127.76 (C, C-9′), 123.03 (C, Ar-C), 121.61 (CH, C-7′), 118.63 (CH, C-3′), 101.18 (CH, C-5′), 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-11′), 42.90 (CH₂, C-6), 28.11 (CH, C-3), 27.22 (CH, C-4), 25.40 (CH₂, C-5) and 21.59 (CH₂, C-7); m/z (MAT, 180 °C) (EI) 398.1994 (M⁺, C₂₆H₂₆N₂O₂ requires 398.1994), 381 (3%), 341 (8), 326 (5), 283 (13) and 210 (100).

(3S,4S,8S,9R)-9-Acetoxy-11-phenyl-10,11-didehydro-6′-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); ν_max(CHCl₃)/cm⁻¹ 2952, 2868, 1744, 1620, 1508, 1472, 1432, 1372, 1232, 1084, 1032 and 852; δ_H(400 MHz; CDCl₃) 8.80 (d, 1 H, J 4.6, H-2′), 8.07 (d, 1 H, J 9.2, H-8′), 7.50 (d, 1 H, J 2.8, H-5′), 7.44 (d, 1 H, J 4.6, H-3′), 7.42 (dd, 1 H, J 9.3 and 2.6, H-7′), 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-11′), 3.76–3.69 (m, 1 H, H-8), 3.23 (dd, 1 H, J 13.6 and 10.0, H-2_exo), 3.19–3.12 (m, 1 H, H-6), 2.93–2.91 (m, 1 H, H-2_endo), 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); δ_C(100 MHz; CDCl₃) 170.14 (C, C-12), 157.89 (C, C-6′), 147.48 (CH, C-2′), 144.82 (C, C-4′), 143.46 (C, C-10′), 131.81 (CH, C-8′), 131.50 (CH, C-Ar), 128.24 (CH, Ar-H), 127.75 (CH, Ar-H), 127.04 (C, C-9′), 123.57 (C, Ar-C), 121.82 (CH, C-7′), 119.19 (CH, C-3′), 101.53 (CH, C-5′), 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-11′), 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 °C) (EI) 440.2105 (M⁺, 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-(3″-Quinolyl)-10,11-didehydro-6′-methoxycinchonan-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); ν_max(CHCl₃)/cm⁻¹ 3340, 3068, 2948, 2876, 2220, 1620, 1592, 1508, 1488, 1472, 1432, 1388, 1360, 1340, 1320, 1256, 1240, 1172, 1092, 1032, 908 and 828; δ_H(400 MHz; CDCl₃) 8.69 (d, 1 H, J 1.9, H-2″), 8.55 (d, 1 H, J 4.6, H-2′), 8.12 (d, 1 H, J 1.9, H-4″), 8.06 (d, 1 H, J 8.5, H-8″), 7.97 (d, 1 H, J 9.3, H-8′), 7.69 (d, 1 H, J 8.0, H-5″), 7.66 (ddd, 1 H, J 8.4, 6.9 and 1.5, H-7″), 7.57 (d, 1 H, J 4.5, H-3′), 7.51–7.48 (ddd, 1 H, J 8.0, 6.9 and 1.1, H-6″), 7.34 (d, 1 H, J 2.6, H-5′), 7.27 (dd, 1 H, J 9.2, 2.6, H-7′), 5.68 (d, 1 H, J 5.4, H-9), 3.80 (s, 3 H, H-11′), 3.61–3.54 (m, 1 H, H-2_endo), 3.25–3.19 (m, 1 H, H-8), 3.14–3.07 (dd, 1 H, J 13.4 and 10.4, H-2_exo), 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); δ_C(100 MHz; CDCl₃) 157.58 (C, C-6′), 152.30 (CH, C-6″), 147.99 (C, C-10′), 147.50 (CH, C-2′), 146.30 (C, C-10″), 144.17 (C, C-4′), 138.15 (CH, C-2″), 131.37 (CH, C-8′), 129.85 (CH, C-8″), 128.99 (CH, C-7″), 127.43 (CH, C-5″), 127.27 (C, C-9″), 127.23 (CH, C-4″), 126.96 (C, C-9′), 121.43 (CH, C-7′), 118.97 (CH, C-3′), 117.90 (C, C-3″), 101.70 (CH, C-5′), 96.57 (C, C-11), 78.80 (C, C-10), 71.71 (CH, C-9), 60.08 (CH, C-8), 55.59 (CH₃, C-11′), 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 °C) (EI) 449.2108 (M⁺, 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,8R,9S )-9-Acetoxy-11-(3″-quinolyl)-10,11-didehydro-6′-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, 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); ν_max(CHCl₃)/cm⁻¹ 2952, 2876, 2224, 1744, 1620, 1592, 1508, 1472, 1456, 1432, 1372, 1320, 1300, 1264, 1232, 1136, 1092, 1032 and 908; δ_H(400 MHz; CDCl₃) 9.03 (d, 1 H, J 2.0, H-2″), 8.81 (d, 1 H, J 4.4, H-2′), 8.37 (d, 1 H, J 1.9, H-4″), 8.16 (d, 1 H, J 8.4, H-8″), 8.08 (d, 1 H, J 9.2, H-8′), 7.85 (d, 1 H, J 8.1, H-5″), 7.83 (ddd, 1 H, J 8.4, 7.0 and 1.5, H-7″), 7.63–7.56 (ddd, 1 H, J 8.1, 7.0 and 1.1, H-6″), 7.55 (d, 1 H, J 2.6, H-5′), 7.45 (d, 1 H, J 4.6, H-3′), 7.41 (dd, 1 H, J 9.2 and 2.7, H-7′), 6.78 (d, 1 H, J 7.2, H-9), 3.89 (s, 3 H, H-11′), 3.47–3.41 (m, 1 H, H-8), 3.29–3.23 (m, 1 H, H-2_endo), 3.19–3.12 (dd, 1 H, J 13.8 and 8.5, H-2_exo), 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); δ_C(100 MHz; CDCl₃) 169.91 (C, C-12), 157.99 (C, C-6′), 152.43 (CH, C-6″), 147.49 (CH, C-2′), 146.64 (C, C-10″), 144.71 (C, C-10′), 143.56 (C, C-4′), 138.29 (CH, C-2″), 131.77 (CH, C-8′), 129.90 (CH, C-8″), 129.34 (CH, C-7″), 127.52 (CH, C-5″), 127.36 (C, C-9″), 127.28 (CH, C-4″), 127.03 (C, C-9′), 121.91 (CH, C-7′), 118.87 (CH, C-3′), 117.82 (C, C-3″), 101.43 (CH, C-5′), 96.38 (C, C-11), 79.18 (C, C-10), 73.45 (CH, C-9), 58.94 (CH, C-8), 55.52 (CH₃, C-11′), 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 °C) (EI) 491.2197 (M⁺, 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).

(3S,4S,8R,9S )-10,11-Didehydro-11-(2-naphthyl)-6′-methoxycinchonan-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); ν_max(CHCl₃)/cm⁻¹ 3412, 3084, 2948, 2876, 1620, 1592, 1508, 1472, 1432, 1388, 1364, 1320, 1240, 1188, 1104, 1032, 844 and 832; δ_H(400 MHz; CDCl₃) 8.46 (d, 1 H, J 4.6, H-2′), 7.90–7.82 (m, 3 H, H-8′, 2 naphthyl-H), 7.41 (d, 1 H, J 4.5, H-3′), 7.33–7.20 (m, 5 H, H-5′, H-7′, 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-11′), 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); δ_C(100 MHz; CDCl₃) 157.82 (C, C-6′), 147.69 (C, C-10′), 147.37 (CH, C-2′), 143.81 (C, C-4′), 133.44 (C, C-13), 133.28 (C, C-18), 131.17 (CH, C-8′), 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-9′), 121.69 (CH, C-7′), 118.98 (CH, C-3′), 101.26 (CH, C-5′), 96.42 (C, C-11), 80.09 (C, C-10), 69.98 (CH, C-9), 59.82 (CH, C-8), 55.87 (CH₃, C-11′), 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 °C) (EI) 448.2151 (M⁺, 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-(4-ethoxycarbonylphenyl)-6′-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); ν_max(CHCl₃)/cm⁻¹ 3076, 2944, 2876, 2220, 1740, 1712, 1620, 1604, 1508, 1472, 1432, 1368, 1276, 1228, 1176, 1108, 1068, 1028, 856 and 824; δ_H(400 MHz; CDCl₃) 8.77 (d, 1 H, J 4.5, H-2′), 8.07 (d, 2 H, J 8.4, H-14, H-16), 8.06 (d, 1 H, J 9.2, H-8′), 7.61 (d, 2 H, J 8.6, H-13, H-17), 7.52 (d, 1 H, J 2.6, H-5′), 7.42 (d, 1 H, J 4.6, H-3′), 7.40 (dd, 1 H, J 9.2 and 2.6, H-7′), 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-11′), 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-2_exo), 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); δ_C(100 MHz; CDCl₃) 169.90 (C, C-19), 166.14 (C, C-18), 157.97 (C, C-6′), 148.19 (C, C-15), 147.39 (CH, C-2′), 144.62 (C, C-10′), 143.59 (C, C-4′), 131.75 (CH, C-8′), 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-9′), 121.96 (CH, C-7′), 118.76 (CH, C-3′), 101.35 (CH, C-5′), 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-11′), 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 °C) (EI) 512.2335 (M⁺, 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-formylphenyl)-6′-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-bromobenzaldehyde (149 mg, 0.80 mmol, 1.5 eq.) to afford p-benzaldehyde-substituted alkyne 21g (83%, 208 mg, 0.44 mmol); ν_max(CHCl₃)/cm⁻¹ 2948, 2876, 2836, 2220, 1744, 1700, 1620, 1600, 1508, 1472, 1456, 1432, 1372, 1304, 1232, 1164, 1092, 1068, 1032 and 832; δ_H(400 MHz; CDCl₃) 10.05 (s, 1 H, H-18), 8.79 (d, 1 H, J 4.4, H-2′), 8.07 (d, 1 H, J 9.2, H-8′), 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-5′), 7.43 (d, 1 H, J 4.6, H-3′), 7.41 (dd, 1 H, J 9.4 and 2.7, H-7′), 6.73 (d, 1 H, J 7.3, H-9), 3.90 (s, 3 H, H-11′), 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-2_endo), 3.15–3.09 (dd, 1 H, J 14.0 and 10.4, H-2_exo), 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); δ_C(100 MHz; CDCl₃) 191.42 (CH, C-18), 169.92 (C, C-19), 157.94 (C, C-6′), 147.48 (CH, C-2′), 144.80 (C, C-10′), 143.49 (C, C-4′), 135.21 (C, C-15), 132.23 (2 CH, C-14, C-16), 131.83 (CH, C-8′), 130.12 (C, C-12), 129.59 (2 CH, C-13, C-17), 127.02 (C, C-9′), 121.86 (CH, C-7′), 118.89 (CH, C-3′), 101.44 (CH, C-5′), 97.44 (C, C-11), 81.28 (C, C-10), 73.49 (CH, C-9), 58.97 (CH, C-8), 55.49 (CH₃, C-11′), 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 °C) (EI) 468.2050 (M⁺, 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 )-9-Acetoxy-10,11-didehydro-11-(thiazolin-2-yl)-6′-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); ν_max(CHCl₃)/cm⁻¹ 2948, 2876, 2220, 1744, 1620, 1592, 1508, 1476, 1456, 1432, 1372, 1320, 1304, 1232, 1136, 1088, 1056, 1032 and 844; δ_H(400 MHz; CDCl₃) 8.79 (d, 1 H, J 4.6, H-2′), 8.08 (d, 1 H, J 9.0, H-8′), 7.86 (d, 1 H, J 3.3, H-13), 7.44–7.40 (m, 3 H, H-5′, H-3′, H-7′), 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-11′), 3.38–3.27 (m, 2 H, H-8, H-2), 3.21–3.15 (dd, 1 H, J 14.0 and 10.2, H-2_exo), 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); δ_C(100 MHz; CDCl₃) 169.85 (C, C-15), 157.99 (C, C-6′), 149.09 (C, C-12), 147.48 (CH, C-2′), 144.67 (C, C-10′), 143.69 (C, C-4′), 143.29 (CH, C-13), 131.85 (CH, C-8′), 126.76 (C, C-9′), 121.92 (CH, C-7′), 120.14 (CH, C-14), 118.32 (CH, C-3′), 101.25 (CH, C-5′), 98.31 (C, C-11), 75.07 (C, C-10), 73.91 (CH, C-9), 58.91 (CH, C-8), 55.66 (CH₃, C-11′), 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 °C) (EI) 447.1602 (M⁺, 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).

(3S,4S,8R,9S )-9-Acetoxy-10,11-didehydro-11-(2-thienyl)-6′-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); ν_max(CHCl₃)/cm⁻¹ 2956, 2876, 2224, 1744, 1620, 1592, 1508, 1472, 1456, 1432, 1372, 1300, 1236, 1136, 1092, 1028, 988, 844 and 828; δ_H(400 MHz; CDCl₃) 8.79 (d, 1 H, J 4.6, H-2′), 8.07 (d, 1 H, J 9.0, H-8′), 7.51 (d, 1 H, J 2.6, H-5′), 7.43–7.39 (m, 2 H, H-3′, H-7′), 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-11′), 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); δ_C(100 MHz; CDCl₃) 169.88 (C, C-16), 158.01 (C, C-6′), 147.42 (CH, C-2′), 144.38 (C, C-10′), 143.73 (C, C-4′), 131.77 (CH, C-8′), 131.43 (CH, C-15), 128.59 (C, C-12), 126.96 (C, C-9′), 126.29 (CH, C-13), 122.01 (CH, C-7′), 120.14 (CH, C-14), 118.53 (CH, C-3′), 101.29 (CH, C-5′), 96.71 (C, C-11), 74.87 (C, C-10), 73.79 (CH, C-9), 59.01 (CH, C-8), 55.57 (CH₃, C-11′), 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 °C) (EI) 446.1186 (M⁺, 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-11-(6,6,7-trimethyl-2,3,3a,3b,4,7,7a,8a-octahydrofuro[2,3-b]benzofuryl)-10,11-didehydro-6′-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); ν_max(CHCl₃)/cm⁻¹ 2960, 2940, 2884, 1744, 1620, 1592, 1508, 1472, 1456, 1368, 1304, 1228, 1136, 1108, 1084, 1040, 996, 940 and 852; δ_H(400 MHz; CDCl₃) 8.82 (d, 1 H, J 4.6, H-2′), 8.13 (d, 1 H, J 9.2, H-8′), 7.49 (d, 1 H, J 2.6, H-5′), 7.44–7.40 (dd, 1 H, J 9.2 and 2.6, H-7′), 7.39 (d, 1 H, J 4.6, H-3′), 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-11′), 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); δ_C(100 MHz; CDCl₃) 169.76 (C, C-24), 158.21 (C, C-6′), 147.89 (CH, C-2′), 147.40 (C, C-10′), 144.59 (C, C-4′), 132.17 (C, C-13), 131.71 (CH, C-8′), 126.89 (C, C-9′), 122.09 (CH, C-7′), 118.53 (CH, C-3′), 112.11 (C, C-12), 109.66 (CH, C-20), 101.45 (CH, C-5′), 98.02 (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-11′), 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 °C) (EI) 570.3127 (M⁺, 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-hydroxyphenyl)-6′-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); ν_max(CHCl₃)/cm⁻¹ 3420, 2940, 2876, 1744, 1620, 1592, 1508, 1472, 1456, 1368, 1304, 1236, 1136, 1084, 1064, 1028, 984, 916 and 844; δ_H(400 MHz; CDCl₃) 8.75 (d, 1 H, J 4.6, H-2′), 8.04 (d, 1 H, J 9.2, H-8′), 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-5′), 7.40–7.37 (dd, 1 H, J 9.2 and 2.6, H-7′), 7.36 (d, 1 H, J 4.7, H-3′), 6.57 (d, 1 H, J 6.8, H-9), 3.97 (s, 3 H, H-11′), 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); δ_C(100 MHz; CDCl₃) 169.93 (C, C-18), 166.34 (C, C-15), 157.93 (C, C-6′), 147.37 (CH, C-2′), 144.63 (C, C-10′), 143.85 (C, C-4′), 131.69 (CH, C-8′), 131.55 (CH, C-14, C-16), 129.48 (C, C-12), 128.19 (CH, C-13, C-17), 126.99 (C, C-9′), 121.88 (CH, C-7′), 118.51 (CH, C-3′), 101.39 (CH, C-5′), 96.13 (C, C-11), 81.97 (C, C-10), 73.59 (CH, C-9), 59.03 (CH, C-8), 55.62 (CH₃, C-11′), 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 °C) (EI) 456 (M⁺, 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-(3-hydroxyphenyl)-6′-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); ν_max(CHCl₃)/cm⁻¹ 3368, 2960, 2932, 2872, 1720, 1620, 1596, 1508, 1464, 1408, 1376, 1292, 1232, 1132, 1072, 1036, 992, 960 and 852; δ_H(400 MHz; CDCl₃) 8.79 (d, 1 H, J 4.6, H-2′), 8.25 (d, 1 H, J 9.2, H-8′), 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-3′), 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-7′), 7.26–7.18 (m, 2 H, H-5′, H-16), 6.52 (d, 1 H, J 6.4, H-9), 4.08 (s, 3 H, H-11′), 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); δ_C(100 MHz; CDCl₃) 169.79 (C, C-18), 166.90 (C, C-14), 157.22 (C, C-6′), 147.18 (CH, C-2′), 144.87 (C, C-10′), 143.91 (C, C-4′), 131.67 (CH, C-8′), 131.48 (CH, C-13), 131.39 (CH, C-15), 129.54 (C, C-12), 128.58 (CH, C-17), 126.93 (C, C-9′), 124.03 (CH, C-16), 121.38 (CH, C-7′), 117.85 (CH, C-3′), 101.66 (CH, C-5′), 95.62 (C, C-11), 81.32 (C, C-10), 73.02 (CH, C-9), 58.32 (CH, C-8), 55.19 (CH₃, C-11′), 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 (M⁺ + H, 17%), 413 (15), 391 (36), 279 (7), 167 (19), 149 (100) and 113 (21).

(3S,4S,8R,9S )-9-Acetoxy-11-(4-iodophenyl)-10,11-didehydro-6′-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-diiodobenzene (743 mg, 2.25 mmol, 1.5 eq.) to yield p-iodophenyl-substituted alkyne 21m (82%, 680 mg, 1.20 mmol); ν_max(CHCl₃)/cm⁻¹ 2944, 2876, 2224, 1744, 1624, 1592, 1508, 1484, 1456, 1432, 1372, 1300, 1232, 1172, 1136, 1092, 1032, 1004, 844 and 824; δ_H(400 MHz; CDCl₃) 8.79 (d, 1 H, J 4.6, H-2′), 8.07 (d, 1 H, J 9.2, H-8′), 7.73 (d, 2 H, J 8.6, H-14, H-16), 7.52 (d, 1 H, J 2.6, H-5′), 7.43–7.38 (m, 2 H, H-3′, H-7′), 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-11′), 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); δ_C(100 MHz; CDCl₃) 169.89 (C, C-18), 157.91 (C, C-6′), 147.44 (CH, C-2′), 144.77 (C, C-4′), 143.54 (C, C-10′), 137.47 (CH, C-14, C-16), 133.23 (CH, C-13, C-17), 131.78 (CH, C-8′), 126.99 (C, C-9′), 123.23 (C, C-12), 121.89 (CH, C-7′), 118.82 (CH, C-3′), 101.36 (CH, C-5′), 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-11′), 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 (M⁺ + H, 100%), 507 (6), 413 (17), 391 (29), 336 (15), 307 (7) and 279 (12).

(3S,4S,8R,9S )-9-Acetoxy-11-(2-aminophenyl)-10,11-didehydro-6′-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); ν_max(CHCl₃)/cm⁻¹ 3452 2960, 2868, 2836, 2216, 1740, 1620, 1572, 1508, 1472, 1432, 1368, 1304, 1236, 1144, 1084, 1032, 904 and 844; δ_H(400 MHz; CDCl₃) 8.79 (d, 1 H, J 4.6, H-2′), 8.09 (d, 1 H, J 9.2, H-8′), 7.50 (d, 1 H, J 2.7, H-5′), 7.42 (d, 1 H, J 4.6, H-3′), 7.40 (dd, 1 H, J 9.2 and 2.6, H-7′), 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-11′), 3.72–3.67 (m, 1 H, H-8), 3.28–3.21 (dd, 1 H, J 13.6 and 9.9, H-2_endo), 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); δ_C(100 MHz; CDCl₃) 170.17 (C, C-18), 157.94 (C, C-6′), 147.58 (C, C-13), 147.45 (CH, C-2′), 144.75 (C, C-10′), 143.49 (C, C-4′), 132.14 (CH, C-14), 132.04 (CH, C-15), 131.77 (CH, C-8′), 129.13 (C, C-12), 127.04 (C, C-9′), 121.84 (CH, C-7′), 119.26 (CH, C-3′), 117.89 (CH, C-16), 114.24 (CH, C-17), 101.61 (CH, C-5′), 98.60 (C, C-11), 81.27 (C, C-10), 73.79 (CH, C-9), 58.66 (CH, C-8), 55.64 (CH₃, C-11′), 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 °C) (EI) 455.2199 (M⁺, 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).

(3S,4S,8R,9S )-9-Acetoxy-3-benzofuryl-6′-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); ν_max(CHCl₃)/cm⁻¹ 3032, 2936, 2872, 2220, 1744, 1620, 1508, 1472, 1452, 1372, 1300, 1228, 1132, 1088, 1068, 1028, 988 and 844; δ_H(400 MHz; CDCl₃) 8.84 (d, 1 H, J 4.6, H-2′), 8.18 (d, 1 H, J 8.9, H-8′), 7.61 (d, 1 H, J 2.4, H-5′), 7.54–7.47 (m, 1 H, H-3′), 7.45–7.37 (m, 3 H, H-7′, 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-11′), 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); δ_C(100 MHz; CDCl₃) 170.30 (C, C-18), 160.35 (C, C-17), 158.01 (C, C-6′), 147.63 (CH, C-2′), 144.83 (C, C-10), 144.09 (C, C-10′), 143.65 (C, C-4′), 131.75 (CH, C-8′), 129.85 (C, C-12), 128.57 (C, C-9′), 123.58 (CH, C-15), 122.69 (CH, C-14), 121.97 (CH, C-7′), 120.49 (CH, C-13), 120.24 (CH, C-3′), 110.87 (CH, C-16), 102.20 (CH, C-11), 101.53 (CH, C-5′), 73.45 (CH, C-9), 59.15 (CH, C-8), 55.62 (CH₃, C-11′), 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 °C) (EI) 456.2050 (M⁺, 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).

(1S,2S,4S,5S )-2-Hydroxymethyl-5-phenylethynyl-1-azabicyclo[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); ν_max(CHCl₃)/cm⁻¹ 3380, 3054, 2955, 2868, 2224, 1599, 1489, 1454, 1412, 1378, 1338, 1265, 1230, 1099, 1069, 1021, 995 and 942; δ_H(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); δ_C(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 °C) (EI) 241.1468 (M⁺, C₁₆H₁₉N₁O₁ requires 241.1467), 210 (100%), 128 (27) and 85 (32).

(1S,2S,4S,5S )-2-tert-Butyldimethylsilanyloxymethyl-5-phenylethynyl-1-azabicyclo[2.2.2]octane 23b. 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 iodobenzene (110 mg, 0.54 mmol, 1.5 eq.) to yield phenyl-substituted alkyne 23b (84%, 107 mg, 0.30 mmol); ν_max(CHCl₃)/cm⁻¹ 3056, 2952, 2928, 2884, 2856, 1596, 1468, 1388, 1360, 1324, 1264, 1228, 1172, 1116, 1080, 1028, 940 and 836; δ_H(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-6_endo), 3.24–3.17 (m, 1 H, H-2), 3.16–3.09 (m, 1 H, H-6_exo), 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); δ_C(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(C H₃)₃), 25.72 (CH₂, C-8), 24.71 (CH₂, C-3), 18.39 (C, SiC(CH₃)₃), −5.23 (CH₃, SiC H₃) and −5.27 (CH₃, SiC H₃); m/z (MAT, 50 °C) (EI) 355.2333 (M⁺, C₂₂H₃₃N₁O₁Si 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).

(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); ν_max(CHCl₃)/cm⁻¹ 3424, 2955, 2868, 2222, 1595, 1519, 1490, 1454, 1410, 1344, 1308, 1285, 1230, 1193, 1175, 1108, 1019, 996, 942 and 855; δ_H(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); δ_C(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 °C) (EI) 286.1317 (M⁺, C₁₆H₁₈N₂O₃ requires 286.1317), 255 (100%), 228 (6), 209 (6), 181 (4), 152 (7), 126 (10), 102 (2), 87 (26) and 72 (12).

(1S,2S,4S,5S )-2-Hydroxymethyl-5-(4-ethoxycarbonylphenylethynyl)-1-azabicyclo[2.2.2]octane 23d. 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 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); ν_max(CHCl₃)/cm⁻¹ 3366, 2957, 2871, 2222, 1712, 1606, 1508, 1454, 1406, 1369, 1344, 1307, 1275, 1231, 1176, 1108, 1020, 996 and 858; δ_H(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); δ_C(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 °C) (EI) 313.1679 (M⁺, 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-Benzoyloxymethyl-5-(4-ethoxycarbonylphenylethynyl)-1-azabicyclo[2.2.2]octane 23e. 10,11-Didehydroquincorine 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); ν_max(CHCl₃)/cm⁻¹ 3060, 2944, 2868, 2220, 1712, 1604, 1508, 1452, 1404, 1368, 1276, 1176, 1108, 1068, 1048, 1024, 976 and 856; δ_H(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); δ_C(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, 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 °C) (EI) 417.1938 (M⁺, 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-(3′-quinolylethynyl)-1-azabicyclo[2.2.2]octane 23f. 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 3-bromoquinoline (67 μl, 0.54 mmol, 1.5 eq.) to yield quinolyl-substituted alkyne 23f (86%, 125 mg, 0.31 mmol); ν_max(CHCl₃)/cm⁻¹ 2940, 2928, 2856, 1596, 1468, 1388, 1344, 1320, 1256, 1188, 1116, 1084, 1028, 940 and 836; δ_H(400 MHz; CDCl₃) 8.86 (d, 1 H, J 2.2, H-2′), 8.17 (d, 1 H, J 2.1, H-4′), 8.08 (d, 1 H, J 8.4, H-8′), 7.76 (d, 1 H, J 8.0, H-5′), 7.71–7.66 (ddd, 1 H, J 8.3, 7.0 and 1.4, H-7′), 7.56–7.51 (ddd, 1 H, J 7.9, 7.2 and 1.1, H-6′), 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-6_endo), 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); δ_C(100 MHz; CDCl₃) 152.46 (CH, C-6′), 146.59 (C, C-10′), 138.01 (CH, C-2′), 129.67 (CH, C-8′), 129.36 (CH, C-7′), 127.39 (CH, C-5′), 127.34 (C, C-9′), 127.14 (CH, C-4′), 118.06 (C, C-3″), 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(C H₃)₃), 25.07 (CH₂, C-8), 22.68 (CH₂, C-3), 18.42 (C, SiC(CH₃)₃), −5.27 (CH₃, SiC H₃) and −5.34 (CH₃, SiC H₃); m/z (FAB) (EI) 407 (M⁺ + H, 8%), 355 (14), 325 (10), 281 (41), 221 (55), 207 (43) and 147 (100).

(1S,2S,4S,5S )-2-tert-Butyldimethylsilanyloxymethyl-5-(2-aminophenylethynyl)-1-azabicyclo[2.2.2]octane 23g. 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 (118 mg, 0.54 mmol, 1.5 eq.) to yield o-aminophenyl-substituted alkyne 23g (84%, 111 mg, 0.30 mmol); ν_max(CHCl₃)/cm⁻¹ 2940, 2928, 2856, 1612, 1492, 1456, 1388, 1360, 1304, 1256, 1228, 1116, 1084, 1028, 936, 836 and 808; δ_H(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-6_endo), 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); δ_C(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(C H₃)₃), 22.67 (CH₂, C-3), 18.39 (C, SiC(CH₃)₃), −5.30 (CH₃, SiC H₃) and −5.32 (CH₃, SiC H₃); m/z (FAB) (EI) 371 (M⁺ + H, 16), 313 (11), 240 (9), 201 (8), 189 (15) and 147 (100).

(1S,2S,4S,5S )-2-tert-Butyldimethylsilanyloxymethyl-5-benzofuryl-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, 0.28 mmol); ν_max(CHCl₃)/cm⁻¹ 2940, 2928, 2856, 1612, 1460, 1388, 1344, 1324, 1256, 1188, 1116, 1084, 1028, 1004, 936, 836 and 808; δ_H(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-6_endo), 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); δ_C(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(C H₃)₃), 25.01 (CH₂, C-3), 18.42 (C, SiC(CH₃)₃), −5.31 (CH₃, SiC H₃) and −5.33 (CH₃, SiC H₃); m/z (MAT) (EI) 372 (M⁺ + H, 44%), 341 (13), 281 (43), 221 (47), 207 (41), 184 (16) and 147 (100).

(1S,2R,4S,5S )-2-Hydroxymethyl-5-(phenylethynyl)-1-azabicyclo[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); ν_max(CHCl₃)/cm⁻¹ 3375, 3059, 2950, 2879, 2225, 1599, 1490, 1463, 1411, 1337, 1324, 1255, 1234, 1137, 1099, 1068, 1029, 1015 and 999; δ_H(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); δ_C(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 °C) (EI) 241.1467 (M⁺, 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-Hydroxymethyl-5-(3′-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-bromoquinoline (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%); ν_max(CHCl₃)/cm⁻¹ 3416, 3068, 2948, 2876, 2200, 1600, 1568, 1488, 1412, 1372, 1336, 1256, 1228, 1136, 1100, 1064, 1028, 1012 and 908; δ_H(400 MHz; CDCl₃) 8.87 (d, 1 H, J 2.0, H-2′), 8.18 (d, 1 H, J 2.0, H-4′), 8.09 (d, 1 H, J 8.4, H-8′), 7.78 (d, 1 H, J 8.3, H-5′), 7.74–7.68 (ddd, 1 H, J 8.4, 7.0 and 1.5, H-7′), 7.58–7.53 (ddd, 1 H, J 8.2, 7.0 and 1.3, H-6′), 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); δ_C(100 MHz; CDCl₃) 152.31 (CH, C-2′), 146.60 (C, C-10′), 138.16 (CH, C-8′), 133.61 (C, C-9′), 129.83 (CH, C-4′), 129.29 (CH, C-7′), 127.43 (CH, C-6′), 127.22 (CH, C-5′), 117.67 (C, C-3′), 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 °C) (EI) 292.1576 (M⁺, C₁₉H₂₀N₂O₁ requires 292.1576), 261 (6%), 237 (3), 224 (8), 207 (100), 175 (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); ν_max(CHCl₃)/cm⁻¹ 2952, 2880, 2856, 2220, 1712, 1604, 1508, 1464, 1404, 1368, 1344, 1276, 1176, 1108, 1052, 1020, 940, 856 and 836; δ_H(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); δ_C(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(C H₃)₃), 25.26 (CH₂, C-8), 25.09 (CH₂, C-3), 18.44 (C, SiC(CH₃)₃), 14.31 (CH₃, C-20), −5.23 (CH₃, SiC H₃) and −5.26 (CH₃, SiC H₃); m/z (FAB) (EI) 428 (M⁺ + H, 100), 370 (45), 355 (14), 281 (22), 267 (10), 221 (35) and 147 (53).

(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 (Ph₃P)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); ν_max(CHCl₃)/cm⁻¹ 2952, 2928, 2880, 2856, 2220, 1700, 1600, 1560, 1460, 1392, 1360, 1344, 1320, 1256, 1164, 1116, 1100, 1008 and 836; δ_H(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-6_endo), 3.18–3.15 (d, 1 H, J 13.1, H-6_exo), 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); δ_C(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(C H₃)₃), 25.94 (CH₂, C-8), 24.79 (CH₂, C-3), 18.39 (C, SiC(CH₃)₃), −5.33 (CH₃, SiC H₃) and −5.36 (CH₃, SiC H₃); m/z (MAT, 80 °C) (EI) 383.2279 (M⁺, 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-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); ν_max(CHCl₃)/cm⁻¹ 2952, 2932, 2880, 2856, 2220, 1592, 1452, 1388, 1360, 1344, 1288, 1256, 1156, 1116, 1096, 1052, 1024 and 836; δ_H(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, 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); δ_C(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(C H₃)₃), 25.02 (CH₂, C-8), 24.78 (CH₂, C-3), 18.44 (C, SiC(CH₃)₃), −5.29 (CH₃, SiC H₃) and −5.34 (CH₃, SiC H₃); m/z (MAT, 80 °C) (EI) 371 (M⁺, 6%), 356 (4), 328 (3), 314 (100), 301 (7), 290 (43), 278 (5), 226 (1), 129 (2), 115 (1) and 86 (3).

(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); ν_max(CHCl₃)/cm⁻¹ 2952, 2928, 2880, 2856, 2220, 1480, 1472, 1408, 1360, 1344, 1320, 1264, 1136, 1116, 1096, 1056, 1020, 936 and 836; δ_H(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); δ_C(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(C H₃)₃), 25.71 (CH₂, C-8), 25.16 (CH₂, C-3), 18.44 (C, SiC(CH₃)₃), −5.24 (CH₃, SiC H₃) and −5.27 (CH₃, SiC H₃); m/z (MAT, 50 °C) (EI) 362.1848 (M⁺, 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-thienylethynyl)-1-azabicyclo[2.2.2]octane 24g. 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-bromothiophene (52 μl, 0.54 mmol, 1.5 eq.) to yield thiophenyl-substituted alkyne 24g (80%, 104 mg, 0.29 mmol); ν_max(CHCl₃)/cm⁻¹ 2948, 2928, 2880, 2856, 2220, 1468, 1388, 1360, 1340, 1320, 1256, 1116, 1080, 1052, 1020, 936 and 908; δ_H(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); δ_C(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(C H₃)₃), 25.69 (CH₂, C-8), 25.16 (CH₂, C-3), 18.47 (C, SiC(CH₃)₃), −5.21 (CH₃, SiC H₃) and −5.23 (CH₃, SiC H₃); m/z (MAT, 80 °C) (EI) 361.1885 (M⁺, 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).

(1S,2R,4S,5S )-2-tert-Butyldimethylsilanyloxymethyl-5-(2-(E )-chlorovinylethynyl)-1-azabicyclo[2.2.2]octane 24h. 10,11-Didehydroquincoridine 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-dichloroethene (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); ν_max(CHCl₃)/cm⁻¹ 2936, 2880, 2856, 2210, 1468, 1380, 1360, 1320, 1256, 1228, 1176, 1116, 1092, 1052, 1024, 1004, 936, 916 and 836; δ_H(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); δ_C(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(C H₃)₃), 25.08 (CH₂, C-8), 24.25 (CH₂, C-3), 18.45 (C, SiC(CH₃)₃), −5.25 (CH₃, SiC H₃) and −5.29 (CH₃, SiC H₃); m/z (MAT) (EI) 339.1786 (M⁺, 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-(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); ν_max(CHCl₃)/cm⁻¹ 2948, 2880, 2856, 2208, 1464, 1388, 1360, 1324, 1256, 1116, 1084, 1052, 1020, 936, 912 and 836; δ_H(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); δ_C(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(C H₃)₃), 25.02 (CH₂, C-8), 24.36 (CH₂, C-3), 18.39 (C, SiC(CH₃)₃), −5.31 (CH₃, SiC H₃) and −5.34 (CH₃, SiC H₃); m/z (MAT) (EI) 339.1784 (M⁺, 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).

(3R,4S,8R,9S )-9-Acetoxy-11-(Z )-phenylethynyl-6′-methoxycinchonan 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); ν_max(CHCl₃)/cm⁻¹ 2940, 2876, 1744, 1664, 1620, 1592, 1508, 1472, 1456, 1372, 1356, 1304, 1236, 1176, 1120, 1084, 1068, 1028, 988 and 844; δ_H(400 MHz; CDCl₃) 8.81 (d, 1 H, J 4.6, H-2′), 8.12 (d, 1 H, J 9.2, H-8′), 7.74 (dd, 1 H, J 9.2 and 2.4, H-7′), 7.61 (m, 2 H, H-3′, H-5′), 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-11′), 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); δ_C(100 MHz; CDCl₃) 169.99 (C, C-20), 158.03 (C, C-6′), 145.99 (CH, C-2′), 144.02 (C, C-10′), 143.62 (C, C-4′), 132.14 (CH, C-15, C-19), 131.94 (CH, C-8′), 131.38 (CH, C-17), 129.21 (CH, C-10), 128.56 (CH, C-16, C-18), 128.24 (C, C-9′), 123.33 (C, C-14), 121.83 (CH, C-7′), 118.05 (CH, C-3′), 110.07 (CH, C-11), 101.59 (CH, C-5′), 93.96 (C, C-13), 86.26 (C, C-12), 73.58 (CH, C-9), 58.44 (CH, C-8), 55.68 (CH₃, C-11′), 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 (M⁺ + H, 28%), 429 (7), 401 (10), 355 (26), 341 (20), 325 (13), 295 (16), 281 (52), 221 (78), 207 (51) and 147 (100).

(3R,4S,8R,9S )-9-Acetoxy-11-(Z )-hept-1-ynyl-6′-methoxycinchonan 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); ν_max(CHCl₃)/cm⁻¹ 2936, 2872, 1744, 1664, 1620, 1592, 1508, 1472, 1456, 1432, 1372, 1304, 1236, 1172, 1112, 1084, 1068, 1032, 988 and 844; δ_H(400 MHz; CDCl₃) 8.84 (d, 1 H, J 4.4, H-2′), 8.16 (d, 1 H, J 9.2, H-8′), 7.43–7.37 (m, 3 H, H-7′, H-3′, H-5′), 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-11′), 3.77–3.68 (m, 1 H, H-8), 3.39–3.29 (m, 1 H, H-2_endo), 3.13–3.05 (dd, 1 H, J 15.6 and 12.7, H-2_exo), 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); δ_C(100 MHz; CDCl₃) 169.99 (C, C-19), 158.01 (C, C-6′), 147.67 (CH, C-2′), 144.09 (C, C-10′), 143.94 (C, C-4′), 131.77 (CH, C-8′), 128.75 (CH, C-10), 128.46 (C, C-9′), 121.96 (CH, C-7′), 118.55 (CH, C-3′), 110.48 (CH, C-11), 101.41 (CH, C-5′), 95.15 (C, C-13), 84.59 (C, C-12), 73.50 (CH, C-9), 58.85 (CH, C-8), 55.67 (CH₃, C-11′), 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 (M⁺ + H, 100%), 401 (29), 282 (21), 230 (83), 207 (30), 189 (35) and 147 (72).

(3R,4S,8R,9S )-9-Acetoxy-11-(Z )-(5-hydroxypent-1-ynyl)-6′-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); ν_max(CHCl₃)/cm⁻¹ 3624, 2940, 2876, 2212, 1744, 1664, 1620, 1592, 1508, 1472, 1456, 1432, 1372, 1228, 1172, 1136, 1032, 988 and 844; δ_H(400 MHz; CDCl₃) 8.75 (d, 1 H, J 4.6, H-2′), 8.06 (d, 1 H, J 9.0, H-8′), 7.42–7.40 (m, 1 H, H-7′), 7.39 (d, 1 H, J 2.7, H-5′), 7.38 (d, 1 H, J 4.6, H-3′), 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-11′), 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-2_endo), 2.92–2.78 (m, 3 H, H-2_exo, 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); δ_C(100 MHz; CDCl₃) 169.98 (C, C-17), 158.04 (C, C-6′), 147.27 (CH, C-2′), 144.55 (C, C-10′), 144.41 (CH, C-10), 143.76 (C, C-4′), 131.61 (CH, C-8′), 126.94 (C, C-9′), 122.01 (CH, C-7′), 118.46 (CH, C-3′), 110.31 (CH, C-11), 101.39 (CH, C-5′), 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-11′), 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 (M⁺ + H, 73%), 413 (12), 391 (23), 279 (8), 167 (19) and 149 (100).

(3R,4S,8S,9R)-9-Acetoxy-11-(Z )-hept-1-ynyl-6′-methoxycinchonan 26. (Z )-11-(2-Iodovinyl)quinine 12 (100 mg, 0.20 mmol, 1 eq.) was allowed to react according to the general 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); ν_max(CHCl₃)/cm⁻¹ 2936, 2869, 1743, 1622, 1593, 1510, 1474, 1434, 1372, 1265, 1238, 1086, 1031 and 850; δ_H(400 MHz; CDCl₃) 8.75 (d, 1 H, J 4.4, H-2′), 8.03 (d, 1 H, J 9.2, H-8′), 7.44 (d, 1 H, J 2.8, H-5′), 7.37 (dd, 1 H, J 9.3 and 2.6, H-7′), 7.36 (d, 1 H, J 4.6, H-3′), 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-11′), 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-2_exo), 3.16–3.08 (m, 1 H, H-6_endo), 2.91–2.83 (m, 1 H, H-2_endo), 2.74–2.66 (m, 1 H, H-6_exo), 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); δ_C(100 MHz; CDCl₃) 170.00 (C, C-19), 157.99 (C, C-6′), 147.47 (CH, C-2′), 145.24 (C, C-10′), 144.76 (C, C-4′), 131.92 (CH, C-8′), 130.95 (CH, C-10), 127.04 (C, C-9′), 121.83 (CH, C-7′), 118.78 (CH, C-3′), 110.18 (CH, C-11), 101.47 (CH, C-5′), 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-11′), 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 °C) (EI) 460.2726 (M⁺ + 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).

(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); ν_max(CHCl₃)/cm⁻¹ 3590, 2999, 2954, 2876, 2220, 1599, 1447, 1409, 1330, 1260, 1138, 1067 and 1024; δ_H(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); δ_C(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 °C) (EI) 239.1308 (M⁺, 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).

(3S,3″S,4S,4″S,8R,8″R,9S,9″S )-11,11″-Bi(10,11-didehydro-9-hydroxy-6′-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); ν_max(CHCl₃)/cm⁻¹ 3132, 2944, 2872, 1620, 1592, 1508, 1472, 1432, 1360, 1320, 1300, 1240, 1174, 1136, 1092, 1032, 1000, 932 and 832; δ_H(400 MHz; CDCl₃) 8.43 (d, 2 H, J 4.6, H-2′, H-2‴), 7.91 (d, 2 H, J 9.3, H-8′, H-8‴), 7.43 (d, 2 H, J 4.6, H-3′, H-3‴), 7.31 (dd, 2 H, J 9.3 and 2.6, H-7′, H-7‴), 7.18 (d, 2 H, J 2.6, H-5′, H-5‴), 5.68 (m, 2 H, H-9, H-9″), 3.89 (s, 6 H, H-11′, H-11‴), 3.69–3.61 (m, 2 H, H-8, H-8″), 3.19–3.12 (m, 2 H, H-2, H-2″), 2.91–2.84 (m, 2 H, H-2, H-2″), 2.75–2.51 (m, 4 H, H-6, H-6, H-6″, H-6″), 2.01–1.97 (m, 2 H, H-3, H-3″), 1.88–1.82 (m, 2 H, H-4, H-4″), 1.88–1.64 (m, 6 H, H-5, H-7, H-7, H-5″, H-7″, H-7″) and 1.41–1.33 (m, 2 H, H-5, H-5″); δ_C(100 MHz; CDCl₃) 157.77 (C, C-6′, C-6‴), 148.31 (C, C-10′, C-10‴), 147.43 (CH, C-2′, C-2‴), 143.73 (C, C-4′, C-4‴), 131.14 (CH, C-8′, C-8‴), 124.81 (C, C-9′, C-9‴), 121.36 (CH, C-7′, C-7‴), 119.07 (CH, C-3′, C-3‴), 101.32 (CH, C-5′, C-5‴), 81.28 (C, C-10, C-10″), 77.27 (CH, C-9, C-9″), 66.22 (C, C-11, C-11″), 60.39 (CH, C-8, C-8″), 55.95 (CH₃, C-11′, C-11‴), 49.76 (CH₂, C-2, C-2″), 49.33 (CH₂, C-6, C-6″), 29.69 (CH, C-3, C-3″), 28.79 (CH, C-4, C-4″), 24.91 (CH₂, C-7, C-7″) and 21.04 (CH₂, C-5, C-5″); m/z (FAB) (EI) 643 (M⁺ + H, 5%), 356 (10), 341 (11), 295 (9), 281 (41), 267 (19), 207 (48), 189 (28), 159 (29) and 147 (100).

(3S,3″S,4S,4″S,8R,8″R,9S,9″S )-11,11″-Bi(9-acetoxy-10,11-didehydro-6′-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); ν_max(CHCl₃)/cm⁻¹ 2948, 2876, 1744, 1620, 1592, 1508, 1472, 1456, 1432, 1372, 1320, 1300, 1228, 1136, 1092, 1032, 988 and 844; δ_H(400 MHz; CDCl₃) 8.81 (d, 2 H, J 4.4, H-2′, H-2‴), 8.11 (d, 2 H, J 9.4, H-8′, H-8‴), 7.48 (d, 2 H, J 2.7, H-5′, H-5‴), 7.43–7.40 (m, 4 H, H-3′, H-3‴, H-7′, H-7‴), 6.61 (d, 2 H, J 6.3, H-9, H-9″), 4.02 (s, 6 H, H-11′, H-11‴), 3.37–3.30 (m, 2 H, H-8, H-8″), 3.21–3.07 (m, 4 H, H-2, H-2, H-2″, H-2″), 2.89–2.80 (m, 2 H, H-6, H-6″), 2.75–2.64 (m, 4 H, H-6, H-6″, H-3, H-3″), 2.24 (s, 6 H, H-13, H-13″), 2.13–2.09 (m, 2 H, H-4, H-4″), 1.67–1.49 (m, 6 H, H-5, H-7, H-7, H-5″, H-7″, H-7″) and 1.38–1.27 (m, 2 H, H-5, H-5″); δ_C(100 MHz; CDCl₃) 169.84 (C, C-12, C-12″), 158.01 (C, C-6′, C-6‴), 147.53 (C, C-10′, C-10‴), 144.59 (CH, C-2′, C-2‴), 143.92 (C, C-4′, C-4‴), 131.81 (CH, C-8′, C-8‴), 126.89 (C, C-9′, C-9‴), 121.87 (CH, C-7′, C-7‴), 118.46 (CH, C-3′, C-3‴), 101.50 (CH, C-5′, C-5‴), 80.74 (C, C-10, C-10″), 73.92 (CH, C-9, C-9″), 66.39 (C, C-11, C-11″), 59.05 (CH, C-8, C-8″), 55.69 (CH₃, C-11′, C-11‴), 49.98 (CH₂, C-2, C-2″), 49.41 (CH₂, C-6, C-6″), 28.95 (CH, C-3, C-3″), 27.91 (CH, C-4, C-4″), 24.96 (CH₂, C-7, C-7″), 23.99 (CH₂, C-5, C-5″) and 21.12 (CH₃, C-13, C-13″); m/z (FAB) (EI) 727.1104 (M⁺, C₄₄H₄₆N₄O₆ requires 727.1118), 663 (9%), 496 (5), 391 (41), 279 (8) and 149 (86).

(3S,3″S,4S,4″S,8S,8″S,9R,9″R)-11,11″-Bi(9-acetoxy-10,11-didehydro-6′-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); ν_max(CHCl₃)/cm⁻¹ 2956, 2868, 1740, 1672, 1620, 1592, 1508, 1472, 1456, 1432, 1372, 1232, 1092, 1032, 996 and 848; δ_H(400 MHz; CDCl₃) 8.76 (d, 2 H, J 4.6, H-2′, H-2‴), 8.05 (d, 2 H, J 9.2, H-8′, H-8‴), 7.45 (d, 2 H, J 2.6, H-5′, H-5‴), 7.40–7.36 (m, 4 H, H-3′, H-3‴, H-7′, H-7‴), 6.49 (d, 2 H, J 7.5, H-9, H-9″), 3.95 (s, 6 H, H-11′, H-11‴), 3.59–3.52 (m, 2 H, H-8, H-8″), 3.14–3.04 (m, 4 H, H-2, H-6, H-2″, H-6″), 2.81–2.76 (m, 2 H, H-2, H-2″), 2.63–2.53 (m, 4 H, H-6, H-6″, H-3, H-3″), 2.14 (s, 6 H, H-13, H-13″), 2.13–2.06 (m, 2 H, H-7, H-7″), 2.04 (br s, 2 H, H-4, H-4″), 1.74–1.66 (m, 2 H, H-5, H-5″), 1.58–1.53 (m, 2 H, H-7″, H-7″) and 1.48–1.41 (m, 2 H, H-5, H-5″); δ_C(100 MHz; CDCl₃) 170.08 (C, C-12, C-12″), 157.95 (C, C-6′, C-6‴), 147.39 (C, C-2′, C-2‴), 144.65 (CH, C-4′, C-4‴), 143.48 (C, C-10′, C-10‴), 131.69 (CH, C-8′, C-8‴), 127.04 (C, C-9′, C-9‴), 121.90 (CH, C-7′, C-7‴), 119.06 (CH, C-3′, C-3‴), 101.46 (CH, C-5′, C-5‴), 81.15 (C, C-10, C-10″), 73.36 (CH, C-9, C-9″), 65.60 (C, C-11, C-11″), 58.62 (CH, C-8, C-8″), 57.12 (CH₂, C-2, C-2″), 55.63 (CH₃, C-11′, C-11‴), 41.80 (CH₂, C-6, C-6″), 28.25 (CH, C-3, C-3″), 26.98 (CH, C-4, C-4″), 25.96 (CH₂, C-7, C-7″), 24.68 (CH₂, C-5, C-5″) and 21.06 (CH₃, C-13, C-13″); m/z (FAB) (EI) 727 (M⁺, 100).

(1S,1′S,2S,2′S,4S,4′S,5S,5′S )-1,4-Bis(2-hydroxymethyl-1-azabicyclo[2.2.2]octan-5-yl)buta-1,3-diyne 30. 10,11-Didehydroquincorine 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 iodine (77 mg, 0.30 mmol, 0.5 eq.) to yield dimeric alkyne 30 (66%, 66 mg, 0.20 mmol); ν_max(CHCl₃)/cm⁻¹ 3456, 3000, 2944, 2868, 1480, 1452, 1412, 1376, 1344, 1324, 1260, 1236, 1132, 1100, 1020, 996 and 936; δ_H(400 MHz; CDCl₃) 3.52–3.44 (m, 4 H, H-9, H-9, H-9′, H-9′), 3.32–3.23 (m, 2 H, H-6, H-6′), 3.19–3.06 (m, 2 H, H-2, H-2′), 2.98–2.86 (m, 4 H, H-6, H-6′, H-7, H-7′), 2.68–2.53 (m, 4 H, H-7, H-7′, H-5, H-5′), 2.12–2.03 (m, 2 H, H-3, H-3′), 1.97–1.92 (m, 2 H, H-4, H-4′), 1.54–1.37 (m, 4 H, H-8, H-8, H-8′, H-8′) and 0.89–0.80 (m, 2 H, H-3, H-3′); δ_C(100 MHz; CDCl₃) 81.18 (C, C-10, C-10′), 65.68 (C, C-11, C-11′), 62.71 (CH₂, C-9, C-9′), 56.99 (CH, C-2, C-2′), 56.44 (CH₂, C-6, C-6′), 39.59 (CH₂, C-7, C-7′), 28.67 (CH, C-5, C-5′), 26.75 (CH, C-4, C-4′), 26.16 (CH₂, C-8, C-8′) and 24.98 (CH₂, C-3, C-3′); m/z (MAT, 170 °C) (EI) 328.2152 (M⁺, 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).

(1S,1′S,2R,2′R,4S,4′S,5S,5′S )-1,4-Bis(2-hydroxymethyl-1-azabicyclo[2.2.2]octan-5-yl)buta-1,3-diyne 31a. 10,11-Didehydroquincoridine 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); ν_max(CHCl₃)/cm⁻¹ 3412, 3000, 2948, 2876, 1452, 1412, 1376, 1320, 1296, 1252, 1236, 1188, 1136, 1100, 1060, 1028, 940 and 864; δ_H(400 MHz; CDCl₃) 5.36–5.21 (s, 2 H, OH, OH′), 3.75–3.67 (dd, 2 H, J 12.2 and 10.3, H-9, H-9′), 3.56–3.52 (dd, 2 H, J 12.1 and 4.5, H-9, H-9′), 3.13–2.86 (m, 10 H, H-6, H-6′, H-2, H-2′, H-6, H-6′, H-7, H-7′, H-7, H-7′), 2.72–2.65 (m, 2 H, H-5, H-5′), 2.06–1.99 (m, 2 H, H-4, H-4′), 1.75–1.57 (m, 6 H, H-3, H-3′, H-8, H-8′, H-8, H-8′) and 1.51–1.45 (m, 2 H, H-3, H-3′); δ_C(100 MHz; CDCl₃) 79.91 (C, C-10, C-10′), 66.43 (C, C-11, C-11′), 61.89 (CH₂, C-9, C-9′), 57.86 (CH, C-2, C-2′), 48.06 (CH₂, C-6, C-6′), 46.99 (CH₂, C-7, C-7′), 28.72 (CH, C-5, C-5′), 27.29 (CH, C-4, C-4′), 24.86 (CH₂, C-8, C-8′) and 24.07 (CH₂, C-3, C-3′); m/z (MAT, 170 °C) (EI) 328.2143 (M⁺, 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).

(1S,1′S,2R,2′R,4S,4′S,5S,5′S )-1,4-Bis(2-tert-butyldimethylsilanyloxymethyl-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); ν_max(CHCl₃)/cm⁻¹ 2948, 2880, 2856, 1468, 1388, 1360, 1320, 1300, 1256, 1148, 1116, 1080, 1052, 1020, 936 and 836; δ_H(400 MHz; CDCl₃) 3.77–3.67 (m, 4 H, H-9, H-9′, H-9, H-9′), 3.07–3.02 (m, 4 H, H-6, H-6′, H-2, H-2′), 2.99–2.92 (m, 2 H, H-6, H-6′), 2.89–2.74 (m, 4 H, H-7, H-7′, H-7, H-7′), 2.59–2.54 (m, 2 H, H-5, H-5′), 2.00–1.95 (m, 2 H, H-4, H-4′), 1.79–1.72 (m, 2 H, H-3, H-3′), 1.66–1.48 (m, 6 H, H-8, H-8, H-8′, H-8′, H-3, H-3′), 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); δ_C(100 MHz; CDCl₃) 80.63 (C, C-10, C-10′), 66.19 (C, C-11, C-11′), 65.22 (CH₂, C-9, C-9′), 57.30 (CH, C-2, C-2′), 49.18 (CH₂, C-6, C-6′), 48.82 (CH₂, C-7, C-7′), 29.02 (CH, C-5, C-5′), 27.82 (CH, C-4, C-4′), 26.03 (CH₃, SiC(C H₃)₃), 25.22 (CH₂, C-8, C-8′), 25.05 (CH₂, C-3, C-3′), 18.45 (C, SiC(CH₃)₃), −5.23 (CH₃, SiC H₃) and −5.27 (CH₃, SiC H₃); m/z (MAT, 150 °C) (EI) 556.3889 (M⁺, C₃₂H₅₆N₂O₂Si₂ 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).

(1′S,1″S,2′S,2″S,4′S,4″S,5′S,5″S )-(Z )-1,2-Bis(2-tert-butyldimethylsilanyloxymethyl-1-azabicyclo[2.2.2]octan-5-ylethynyl)ethene 32. 10,11-Didehydroquincorine 18b (200 mg, 0.72 mmol, 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); ν_max(CHCl₃)/cm⁻¹ 2928, 2856, 1468, 1320, 1264, 1116, 1084, 1028 and 836; δ_H(400 MHz; CDCl₃) 6.34 (d, 2 H, J_cis 7.4, H-12, H-13), 5.89 (dd, 2 H, J_trans 13.2 and 1.6, H-12, H-13), 3.69–3.65 (dd, 2 H, J 10.3 and 6.0, H-9′, H-9″), 3.63–3.59 (dd, 2 H, J 10.4 and 6.1, H-9′, H-9″), 3.24–3.17 (dd, 2 H, J 13.4 and 10.0, H-6_endo′, H-6_endo″), 3.07–2.87 (m, 4 H, H-2′, H-2″, H-6′, H-6″), 2.62–2.53 (m, 4 H, H-7′, H-7″, H-7′, H-7″), 2.32–2.27 (m, 2 H, H-5′, H-5″), 2.07–1.99 (m, 2 H, H-4′, H-4″), 1.96–1.91 (m, 2 H, H-3′, H-3″), 1.54–1.32 (m, 6 H, H-8′, H-8″, H-8′, H-8″, H-3′, H-3″), 0.89 (s, 18 H, SiC(CH₃)₃) and 0.06 (s, 12 H, SiCH₃); δ_C(100 MHz; CDCl₃) 112.41 (CH, C-12, C-13), 81.48 (C, C-10′, C-10″), 65.89 (C, C-11′, C-11″), 65.52 (CH₂, C-9′, C-9″), 57.92 (CH, C-2′, C-2″), 57.02 (CH₂, C-6′, C-6″), 41.70 (CH₂, C-7′, C-7″), 29.30 (CH, C-5′, C-5″), 27.64 (CH, C-4′, C-4″), 26.01 (CH₃, SiC(C H₃)₃), 25.08 (CH₂, C-8′, C-8″), 22.67 (CH₂, C-3′, C-3″), 18.41 (C, SiC(CH₃)₃), −5.32 (CH₃, SiC H₃) and −5.35 (CH₃, SiC H₃); m/z (FAB) (EI) 584 (M⁺ + 2 H, 2), 557 (100), 542 (8), 500 (37), 411 (5), 310 (6) and 282 (16).

(1′S,1″S,2′R,2″R,4′S,4″S,5′S,5″S )-1,4-Bis(2-hydroxymethyl-1-azabicyclo[2.2.2]octan-5-ylethynyl)benzene 33. 10,11-Didehydroquincoridine 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); ν_max(CHCl₃)/cm⁻¹ 3416, 3000, 2948, 2876, 2224, 1484, 1464, 1412, 1388, 1324, 1256, 1236, 1160, 1136, 1100, 1056, 1028, 1008, 944 and 820; δ_H(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, OH′), 3.73–3.56 (m, 4 H, H-9′, H-9″, H-9′, H-9″), 3.18–2.81 (m, 10 H, H-6′, H-6″, H-2′, H-2″, H-6′, H-6″, H-7′, H-7″, H-7′, H-7″), 2.69–2.61 (m, 2 H, H-5′, H-5″), 2.00–1.92 (m, 2 H, H-4′, H-4″), 1.79–1.52 (m, 6 H, H-3′, H-3″, H-8′, H-8″, H-8′, H-8″) and 1.46–1.33 (m, 2 H, H-3′, H-3″); δ_C(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-10′, C-10″), 81.08 (C, C-11′, C-11″), 61.91 (CH₂, C-9′, C-9″), 57.48 (CH, C-2′, C-2″), 48.35 (CH₂, C-6′, C-6″), 47.76 (CH₂, C-7′, C-7″), 29.11 (CH, C-5′, C-5″), 27.31 (CH, C-4′, C-4″), 24.16 (CH₂, C-8′, C-8″) and 22.57 (CH₂, C-3′, C-3″); m/z (FAB) (EI) 425 (M⁺ − 2 H + Na, 9%), 397 (18), 368 (100), 336 (14), 281 (15), 221 (20) and 147 (35).

(1′S,1″S,2′S,2″S,4′S,4″S,5′S,5″S )-1,2-Bis(2-tert-butyldimethylsilanyloxymethyl-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); ν_max(CHCl₃)/cm⁻¹ 2952, 2928, 2856, 1592, 1468, 1388, 1360, 1332, 1304, 1256, 1120, 1084, 1028, 1004, 936 and 836; δ_H(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-9′, H-9″, H-9′, H-9″), 3.31–3.25 (dd, 2 H, J 13.2 and 10.0, H-6_endo′, H-6_endo″), 3.12–2.90 (m, 4 H, H-2′, H-2″, H-6′, H-6″), 2.75–2.59 (m, 4 H, H-7′, H-7″, H-7′, H-7″), 2.40–2.36 (m, 2 H, H-5′, H-5″), 2.18–2.10 (m, 2 H, H-4′, H-4″), 2.03–1.95 (m, 2 H, H-3′, H-3″), 1.61–1.37 (m, 6 H, H-8′, H-8″, H-8′, H-8″, H-3′, H-3″), 0.92 (s, 18 H, SiC(CH₃)₃) and 0.09 (s, 12 H, SiCH₃); δ_C(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-9′, C-9″), 57.72 (CH, C-2′, C-2″), 57.09 (CH₂, C-6′, C-6″), 41.75 (CH₂, C-7′, C-7″), 28.88 (CH, C-5′, C-5″), 27.59 (CH, C-4′, C-4″), 26.02 (CH₃, SiC(C H₃)₃), 25.23 (CH₂, C-8′, C-8″), 22.70 (CH₂, C-3′, C-3″), 18.44 (C, SiC(CH₃)₃), −5.30 (CH₃, SiC H₃) and −5.32 (CH₃, SiC H₃); m/z (FAB) (EI) 586 (M⁺ + 2 H, 13), 578 (71), 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 α,β-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 compound (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]-6′-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); ν_max(CHCl₃)/cm⁻¹ 2944, 2876, 1744, 1668, 1620, 1588, 1508, 1472, 1456, 1432, 1360, 1296, 1236, 1176, 1136, 1084, 1028, 992 and 844; δ_H(400 MHz; CDCl₃) 8.73 (d, 1 H, J 4.5, H-2′), 8.02 (d, 1 H, J 9.9, H-8′), 7.41–7.35 (m, 3 H, H-7′, H-5′, H-12), 7.33 (d, 1 H, J 4.6, H-3′), 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-11′), 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); δ_C(100 MHz; CDCl₃) 198.45 (C, C-14), 169.93 (C, C-16), 157.97 (C, C-6′), 147.41 (CH, C-2′), 144.72 (C, C-10′), 143.66 (C, C-4′), 143.45 (CH, C-12), 137.88 (CH, C-13), 131.83 (CH, C-8′), 130.83 (CH, C-11), 127.54 (CH, C-10), 126.92 (C, C-9′), 121.81 (CH, C-7′), 118.53 (CH, C-3′), 101.43 (CH, C-5′), 73.42 (CH, C-9), 58.82 (CH, C-8), 55.68 (CH₃, C-11′), 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 °C) (EI) 434.2206 (M⁺, 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).

(3R,4S,8R,9S,10E )-11-(3-Oxopropylidene-6′-methoxycinchonan-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); ν_max(CHCl₃)/cm⁻¹ 3336, 2964, 2876, 1620, 1592, 1508, 1460, 1436, 1384, 1296, 1276, 1228, 1176, 1140, 1104, 1064, 1028, 992 and 872; δ_H(400 MHz; CDCl₃) 8.76 (d, 1 H, J 4.6, H-2′), 7.90 (d, 1 H, J 9.2, H-8′), 7.76 (d, 1 H, J 4.6, H-3′), 7.25–7.19 (m, 2 H, H-7′, H-5′), 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-11′), 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); δ_C(100 MHz; CDCl₃) 167.26 (C, C-14), 158.73 (C, C-6′), 147.23 (CH, C-2′), 144.93 (C, C-10′), 143.84 (C, C-4′), 143.31 (CH, C-12), 137.94 (CH, C-13), 131.30 (CH, C-8′), 130.93 (CH, C-11), 129.29 (CH, C-10), 125.66 (C, C-9′), 123.60 (CH, C-7′), 119.19 (CH, C-3′), 100.48 (CH, C-5′), 73.90 (CH, C-9), 60.16 (CH, C-8), 59.23 (CH₃, C-15), 58.58 (CH₃, C-11′), 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 °C) (EI) 408.3244 (M⁺, 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).

(3R,4S,8R,9S,11Z )-9-Acetoxy-11-(3-tert-butoxycarbonylpropylidene)-6′-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); ν_max(CHCl₃)/cm⁻¹ 2964, 2876, 1744, 1672, 1632, 1508, 1472, 1432, 1376, 1308, 1268, 1228, 1176, 1140, 1112, 1084, 1028, 992 and 872; δ_H(400 MHz; CDCl₃) 8.69 (d, 1 H, J 4.5, H-2′), 7.97 (d, 1 H, J 9.2, H-8′), 7.49 (dd, 1 H, J 15.2 and 11.6,H-12), 7.38–7.35 (m, 2 H, H-7′, H-5′), 7.32 (d, 1 H, J 4.5, H-3′), 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-11′), 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); δ_C(100 MHz; CDCl₃) 169.42 (C, C-19), 167.51 (C, C-14), 158.09 (C, C-6′), 147.34 (CH, C-2′), 144.84 (C, C-10′), 143.39 (C, C-4′), 143.02 (CH, C-12), 138.71 (CH, C-13), 131.82 (CH, C-8′), 127.78 (CH, C-11), 126.55 (C, C-9′), 122.76 (CH, C-10), 122.15 (CH, C-7′), 118.32 (CH, C-3′), 101.29 (CH, C-5′), 72.69 (CH, C-9), 70.61 (CH₂, C-15), 58.81 (CH, C-8), 55.61 (CH₃, C-11′), 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 (M⁺ + H, 17), 242 (100), 184 (8) and 142 (9).

(3R,4S,8R,9S,11Z )-9-Acetoxy-11-(3-oxopropylidene)-6′-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); ν_max(CHCl₃)/cm⁻¹ 3000, 2944, 2876, 1744, 1676, 1624, 1588, 1508, 1472, 1456, 1432, 1364, 1304, 1228, 1172, 1136, 1088, 1032, 988 and 844; δ_H(400 MHz; CDCl₃) 9.61 (d, 1 H, J 7.5, H-14), 8.70 (d, 1 H, J 4.6, H-2′), 7.98 (d, 1 H, J 9.2, H-8′), 7.40–7.30 (m, 4 H, H-7′, H-5′, H-12, H-3′), 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-11′), 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); δ_C(100 MHz; CDCl₃) 193.79 (CH, C-14), 169.88 (C, C-15), 157.91 (C, C-6′), 147.36 (CH, C-2′), 146.27 (CH, C-12), 144.95 (C, C-10′), 144.80 (C, C-4′), 143.59 (CH, C-13), 132.40 (CH, C-11), 131.77 (CH, C-8′), 127.41 (CH, C-10), 126.98 (C, C-9′), 121.85 (CH, C-7′), 118.31 (CH, C-3′), 101.42 (CH, C-5′), 73.31 (CH, C-9), 58.76 (CH, C-8), 55.53 (CH₃, C-11′), 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 °C) (EI) 420.2048 (M⁺, 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).

(3R,4S,8R,9S,11Z )-9-Acetoxy-11-(2-carbamoylethylidene)-6′-methoxycinchonan 35e. (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 acrylamide (70 mg, 0.99 mmol, 4.0 eq.) to afford (Z,E )-diene 35d (90%, 96 mg, 0.22 mmol); ν_max(CHCl₃)/cm⁻¹ 2940, 2876, 1744, 1676, 1624, 1592, 1508, 1472, 1456, 1432, 1372, 1304, 1228, 1156, 1120, 1084, 1032, 988 and 956; δ_H(400 MHz; CDCl₃) 8.72 (d, 1 H, J 4.5, H-2′), 8.01 (d, 1 H, J 9.9, H-8′), 7.51 (dd, 1 H, J 14.9 and 11.2, H-12), 7.36–7.32 (m, 3 H, H-7′, H-5′, H-3′), 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-11′), 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); δ_C(100 MHz; CDCl₃) 170.02 (C, C-14), 168.23 (C, C-15), 157.85 (C, C-6′), 147.35 (CH, C-2′), 144.59 (C, C-10′), 143.47 (C, C-4′), 141.62 (CH, C-12), 136.76 (CH, C-13), 132.05 (CH, C-11), 131.69 (CH, C-8′), 126.88 (C, C-9′), 123.93 (CH, C-10), 121.86 (CH, C-7′), 118.56 (CH, C-3′), 101.44 (CH, C-5′), 73.51 (CH, C-9), 58.84 (CH, C-8), 55.63 (CH₃, C-11′), 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 °C) (EI) 436.2224 (M⁺, 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).

(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); ν_max(CHCl₃)/cm⁻¹ 2960, 2936, 2876, 1672, 1632, 1468, 1408, 1384, 1360, 1316, 1256, 1232, 1112, 1092, 1064, 996 and 836; δ_H(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); δ_C(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(C H₃)₃), 24.69 (CH₂, C-8), 24.31 (CH₂, C-3), 22.15 (CH₃, C-15), 18.28 (C, SiC(CH₃)₃), −5.20 (CH₃, SiC H₃) and −5.38 (CH₃, SiC H₃); m/z (FAB) (EI) 350 (M⁺ + H, 23), 242 (100), 184 (10) and 142 (17).

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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Footnotes

† 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.

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