Synthesis of 10,11-didehydro- and 10,11-dihydro-Quincorine and of the Quincoridine analogs: functionalized and enantiopure 1-azabicyclo[2.2.2]-octanes with four stereogenic centers

Schrake, Olaf; Braje, Wilfried M.; Hoffmann, H. M. R.; Wartchow, Rudolf

doi:10.1016/s0957-4166(98)00364-4

Cited by 24 publications

(11 citation statements)

References 6 publications

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“…The title compound 1 is derived from quinidine [2] via quincoridine® (QCD) [1,3,4] and is to be compared to the (lS,2S,4S,5S)-diastereomer 2 which is derived from quinine [5] via quincorine® (QCI) [1,3,4], The transformation of QCD and QCI to compounds 1 and 2, respectively, can formally be described as the replacement of the vinyl group by the ethynyl group (see scheme 1 in [6]). Compound 1 is called 10,11-didehydroquincoridine and compound 2 10,11-didehydro-quincorine [6].…”

Section: Discussionmentioning

confidence: 99%

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Crystal structure of (1S,2R,4S,5S)-5-ethynyl-2-hydroxymethyl-1-azabicyclo[2.2.2]octane, (HC2)(HOCH2)C7H11N)

Wartchow¹,

Frackenpohl²,

Hoffmann³

2001

Zeitschrift Für Kristallographie - New Crystal Structures

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Source of materialQuincoridine® [1] (2.0 g, 12 mmol) was dissolved in dry CCI4 (15 ml). Bromine (1.1 ml, 21.5 mmol) was added at 273 Κ. The reaction mixture was stirred for lh. After removal of the solvent in vacuo the resulting yellow solid was dissolved in CHCI3 (25 ml). Et3N (3.1 ml, 24 mmol) was added and the mixture was then stirred for 4h at RT. After work-up (CHCI3 and saturated aqueous solution NaHC03) the vinylic bromide (0.2 g, 0.81 mmol) was dissolved in THF (10 ml), followed by addition of powdered KOH (116 mg, 2.0 mmol) and aliquat 336® (0.73 ml, 0.16 mmol). The reaction mixture was heated at reflux for 7 h. Work-up (CHCI3 and saturated aqueous solution NaHCOs) and column chromatography (ethyl acetate / methanol 6:1) furnished the title compound which crystallized after 5 h at 273 K. The compound melts at 317 Κ and sublimes readily. DiscussionThe title compound 1 is derived from quinidine [2] via quincoridine® (QCD) [1,3,4] and is to be compared to the (lS,2S,4S,5S)-diastereomer 2 which is derived from quinine [5] via quincorine® (QCI) [1,3,4], The transformation of QCD and QCI to compounds 1 and 2, respectively, can formally be described as the replacement of the vinyl group by the ethynyl group (see scheme 1 in [6]). Compound 1 is called 10,11-didehydroquincoridine and compound 2 10,11-didehydro-quincorine [6]. In view of the high synthetic flexibility of alkynes we expect that 1 and 2 will become valuable homochiral building blocks, e.g. in asymmetric synthesis and in medicinal chemistry, similar to QCD and QCI [3,4,7]. The terminal alkynes 1 and 2 have the advantage of being solids at room temperature, while QCD and QCI are liquids. The crystal structure of 2 has already been reported inThe X-ray analysis of 1 (this work) shows that its crystal packing has the higher point group symmetry (222 instead of 2) but the lower density by about 2 %. In the solid state the molecules of compound 1 are connected to helical chains by hydrogen bonds in a similar manner as found in compound 2 (see the figure in [8]) and in quinidine [2]. The chain direction in 1 is [100] and corresponds to the [010] direction in 2. Substituted quinuclidines are often twisted [9]. The dihedral angles C2-N1-C4-C3, C6-N1-C4-C5 and C7-N1-C4-C8 are 10.9°, 9.7° and 9.1°, respectively, with an average of 9.9° for molecule 1 and 3.7°, 6.7°

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Section: Discussionmentioning

confidence: 99%

“…Compound 1 is called 10,11-didehydroquincoridine and compound 2 10,11-didehydro-quincorine [6]. In view of the high synthetic flexibility of alkynes we expect that 1 and 2 will become valuable homochiral building blocks, e.g.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of (1S,2R,4S,5S)-5-ethynyl-2-hydroxymethyl-1-azabicyclo[2.2.2]octane, (HC2)(HOCH2)C7H11N)

Wartchow¹,

Frackenpohl²,

Hoffmann³

2001

Zeitschrift Für Kristallographie - New Crystal Structures

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“…The reactions of alkynes 1a,b 18 with azide components 2 and 3, respectively, conducted in H 2 O/n-BuOH (1:1, v/v) for 10 h at room temperature in the presence of low catalyst loading (1 mol% of CuSO 4 , 5 mol% of Na-ascorbate) (Method i.) afforded mixtures of diastereomers, which were separated (isolated yields: 23/51% for4a/4c; 21/39% for4b/4d; 23/48% for5a/5c; and 29/44% for 5b/5d) with significant dominance of the epimerized products stabilized by intramolecular hydrogen bridge between the hydroxyl group and the quinuclidene N1-atom.…”

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confidence: 99%

Synthesis, structure and in vitro cytostatic activity of ferrocene—Cinchona hybrids

Kocsis

Szabó

Bősze

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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Exploring copper(I)-and ruthenium(II)-catalyzed azide-alkyne cycloadditions and a Sonogashira protocol, novel cytostatic ferrocene-cinchona hybrids were synthetized displaying significant in vitro activity on HEPG-2 and HT-29 cells. Preliminary SAR studies disclosed that compounds incorporating linkers with 1,2,3-triazole and chalchone residues can be considered as promising lead structures. According to the best of our knowledge this is the first report on the incorporation of ferrocene nucleus in the reputed cinchona family via triazole and chalcone linkers with established pharmaceutical profile.

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“…In view of the high synthetic and therapeutic potential of 5-substituted quinuclidine derivatives we prepared (1 S,2/?,5fl,6fl)-2-methoxy-6-( 16-nitrophenylethynyl)-1 -azabicyclo[3.2.2]nonane and present its crystal structure. Small torsion angles Φι (N1-C7-C6-C5) = 6.3° and Φ 2 (Ν 1-C8-C9-C5) = 2.4° suggest reduced conformational strain of the l-azabicyclo[3.2.2]nonane moiety compared with related l-azabicyclo[2.2.2]octanes which are strongly twisted to minimize eclipsing and ring strain [ 1 ]. The bridgehead nitrogen in the title compound is more flattened, with an expansion of bond angles, than in quincorine derivatives [8].…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of (1S,2R,5R,6R)-2-methoxy-6-(16-nitrophenylethynyl)-1-azabicyclo[3.2.2]nonane, C17H20N2O3

Frackenpohl

Röper

Hoffmann

et al. 2000

Zeitschrift Für Kristallographie - New Crystal Structures

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C17H20N2O3, orthorhombic, P2\2\2\ (No. 19), a = 7.096(1) Ä, b= 11.671(1) k,c= 19.277(2) Ä, V= 1596.5 Ä 3 ,Z = 4, R gl (F) = 0.032, wRrefiF 2 ) = 0.040, T= 300 K.Source of material p-N02-Phenyl substituted 10,11-didehydroquincorine [1] was transformed into its corresponding C9-iodide via mesylation and Lil-mediated iodination. The resulting 2-iodomethyl-5-(16-nitrophenylethynyl)-l-azabicyclo[3.2.2]-nonane (500 mg, 1.26 mmol, 1 eq) was dissolved in abs. MeOH (6 ml). After being stirred for 5 min at room temperature under argon freshly prepared silver benzoate (318 mg, 1.39 mmol, 1.1 eq) was added. The reaction mixture was stirred for 16 h at 323 K, diluted with MeOH and filtered. The remaining precipitate was washed with MeOH, the combined solutions were concentrated in vacuo and the resulting solid was dissolved in CH2CI2. After addition of saturated aqueous NaHCOs, the aqueous layer was extracted with CH2CI2, and the combined organic layer dried (MgS04)

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Synthesis of 10,11-didehydro- and 10,11-dihydro-Quincorine and of the Quincoridine analogs: functionalized and enantiopure 1-azabicyclo[2.2.2]-octanes with four stereogenic centers

Cited by 24 publications

References 6 publications

Crystal structure of (1S,2R,4S,5S)-5-ethynyl-2-hydroxymethyl-1-azabicyclo[2.2.2]octane, (HC2)(HOCH2)C7H11N)

Crystal structure of (1S,2R,4S,5S)-5-ethynyl-2-hydroxymethyl-1-azabicyclo[2.2.2]octane, (HC2)(HOCH2)C7H11N)

Synthesis, structure and in vitro cytostatic activity of ferrocene—Cinchona hybrids

Crystal structure of (1S,2R,5R,6R)-2-methoxy-6-(16-nitrophenylethynyl)-1-azabicyclo[3.2.2]nonane, C17H20N2O3

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