Synthesis of Enantiopure 3-Quinuclidinone Analogues with Three Stereogenic Centers:  <i>(1S,2R,4S)-</i> and <i>(1S,2S,4S)</i>-2-(Hydroxymethyl)-1-azabicyclo[2.2.2]octan-5-one and Stereocontrol of Nucleophilic Addition to the Carbonyl Group

Frackenpohl, Jens; Hoffmann, H. M. R.

doi:10.1021/jo9919815

Cited by 17 publications

(22 citation statements)

References 28 publications

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“…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° …”

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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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%

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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“…In the course of our investigations on the synthesis of chiral quinuclidinone analogs the title compound has been prepared from Quincoridine® [4] in enantiopure form following an eight step pathway [5]. Because of their low molecular weight and their compact azabicyclic structure quincoridine-derivatives are of general interest [6,7].…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of (1S,2R,4S)-2-bromomethyl-1-azabicyclo[2.2.2]·octan-5-one, C8H12BrNO

Wartchow

Frackenpohl

Hoffmann

2000

Zeitschrift Für Kristallographie - New Crystal Structures

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C 8 Hi 2 BrNO, orthorhombic, P2\2\2] (No. 19), a = 7.002(1) Ä, b = 7.432(1) Ä, c = 16.762(2) Ä, V=872.3 Ä 3 ,Z = 4, R & (F) = 0.031, wR m (F 2 ) = 0.050, T= 300 K. Source of materialMethanesulfonyl chloride (0.39 ml, 5.0 mmol) was added to (lS,2Ä,4S)-2-hydroxymethyl-l-azabicyclo[2.2.2]octan-5-one (600 mg, 3.9 mmol) and Et3N (1.08 ml, 7.7 mmol) in absolute CH2CI2 (10 ml) at 273 K. The reaction mixture was stirred for 10 h at room temperature, diluted with CH2CI2 and extracted with saturated aqueous NaHC03. The organic layer was dried, the solvent evaporated and the crude product (83 %,748 mg,3.21 mmol) dissolved in abs. dioxan (5 ml). Powdered lithium bromide (838 mg, 9.64 mmol, 3.0 eq) was added and the mixture was refluxed for 24 h at 383 K. After addition of saturated aqueous NaHCC>3 the aqueous layer was extracted with CH2CI2, and the combined organic layer dried (MgSCU) and evaporated. Purification by chromatography (EtOAc / MeOH 20:1) furnished the desired brominated ketone which was recrystallized from MTBE / acetone. Experimental detailsCompleteness of Laue data set in class mmm 100%, but Friedel pairs kept separate in the refinement. The empirical absorption corerection was based on a function of the mean intensity of the imaging plate versus angle φ improving the Rint from 0.201 to 0.076. A spherical absorption correction with μ-r = 0.34 was applied too. The Flack parameter was found to be -0.01(2). DiscussionSubstituted quinuclidines possess interesting and diverse pharmacological activities as the quinuclidine nucleus has been found to be a good mimic for the quaternary nitrogen in acetylcholine [1], The synthetic methods most frequently used for the preparation of quinuclidine-based pharmaceutical lead structures have started from quinuclidin-3-one [2, 3]. In the course of our investigations on the synthesis of chiral quinuclidinone analogs the title compound has been prepared from Quincoridine® [4] in enantiopure form following an eight step pathway [5]. Because of their low molecular weight and their compact azabicyclic structure quincoridine-derivatives are of general interest [6,7]. Oxidative degradation of the vinylic side chain of quincoridine was carried out by double bond shift, 1,2-dihydroxylation and subsequent diol cleavage. O-Mesylation of resulting (15,2/f,4S)-2-hydroxymethyl-l-azabicyclo[2.2.2]octan-5-one followed by LiBr-promoted SN2 displacement furnished the desired γ-amino δ-bromo ketone of which we present the crystal structure. (15,2if,45)-2-Bromomethyl-l-azabicyclo[2.2.2]-octan-5-one contains a prochiral carbonyl group and three stereogenic centres including the chiral 5-configurated bridgehead nitrogen. The analysis of N,C-bond angles shows a less developed pyramidalization of the bridgehead nitrogen than in 10,11-didehydroquincorine and -quincoridine [8,9,10]. Table 1. Data collection and handling. Crystal: Wavelength: μ: Diffractometer, scan mode: 20max: N(hkl)measured, N(hkl)u"ique: Criterion for I 0 bs, N(hkljp;. N(param) rermed: Programs: colourless plate II (100), size 0.06...

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“…[38] Substituted chiral quinuclidin-3-ones have been prepared by oxidative degradation of the vinyl side chains of QCI and QCD, carried out by (i) double bond shift, and (ii) dihydroxylation and subsequent 1,2-diol cleavage (Scheme 17). [39] The transformation of QCI and QCD into their corresponding keto analogues has been optimized and Scheme 16. a) Synthesis and application of quinidine-derived oxaza-twistanes in the asymmetric BaylisϪHillman coupling; b) Grob fragmentation of bromo-dihydroquinine 21b; reagents and conditions: a) HBr (62%), 3 d, room temp., b) KOH (25%), NaHCO 3 ; c) 1. AgBF 4 , THF, 0°C Ǟ room temp., 4 h; 2.…”

Section: Cage Helicity and Further Consequences Nucleophilic Attack mentioning

confidence: 99%

“…Nonetheless, face selectivity has been established, and nucleophilic attack has been directed preferentially toward the supposedly more hindered endo-π-face of the carbonyl group, mainly giving the functionalized quinuclidinols anti-30 and anti-31 with natural configuration at C5 in diastereomeric excesses of up to 97% (Scheme 18). [39] Scheme 18. Synthesis of substituted 2-(hydroxymethyl)quinuclidin-5-ols; masochistic nucleophilic attack on quinuclidinone helix π-Face selectivity, especially in the QCD series, is unprecedented and strongly depends on the size of the remote Oprotecting group: it is highest with bulky O-protecting groups, involving 1,7-stereoinduction (the bulk of the trityl group is evident from the fact that the dimeric hexaphenylethane does not exist).…”

Section: Cage Helicity and Further Consequences Nucleophilic Attack mentioning

confidence: 99%

Recent Advances inCinchonaAlkaloid Chemistry

2004

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Quinine has been among the best known alkaloids for over 300 years, thanks to its antimalarial activity. In the last two decades, Cinchona alkaloids have emerged as powerful chiral auxiliaries, resulting in some well known landmark developments in asymmetric synthesis, but more recently these alkaloids themselves have been shown to undergo some remarkable transformations and skeletal shifts that are rapidly widening perspectives in the chemistry of Cinchona bases, embracing both basic and applied science. The alkaloids enter into a series of fundamental transformations that have given rise to the industrial manufacture of a host of new enantiopure materials showing promise for asymmetric syntheses and combinatorial chemistry. Stereochemical diversity, well developed conformational minima not encountered in conventional organic substrates, hydrophilic pockets and stereoelectronics contribute subtle mechanistic features and structural complexity. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

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Synthesis of Enantiopure 3-Quinuclidinone Analogues with Three Stereogenic Centers: (1S,2R,4S)- and (1S,2S,4S)-2-(Hydroxymethyl)-1-azabicyclo[2.2.2]octan-5-one and Stereocontrol of Nucleophilic Addition to the Carbonyl Group

Cited by 17 publications

References 28 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)

Crystal structure of (1S,2R,4S)-2-bromomethyl-1-azabicyclo[2.2.2]·octan-5-one, C8H12BrNO

Recent Advances inCinchonaAlkaloid Chemistry

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