Tetrahedron: Asymmetry 21 (2010) 2740–2745

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Tetrahedron: Asymmetry

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Clickable 9-azido-(9-deoxy)-Cinchona alkaloids: synthesis and conformation

Karol Kacprzak ⇑, Bła _zej GierczykDepartment of Chemistry, A. Mickiewicz University, ul. Grunwaldzka 6, 60-780 Poznan, Poland

a r t i c l e i n f o a b s t r a c t

Article history:Received 14 October 2010Accepted 26 October 2010Available online 20 November 2010

0957-4166/$ - see front matter � 2010 Elsevier Ltd. Adoi:10.1016/j.tetasy.2010.10.023

⇑ Corresponding author. Tel.: +48 61 8291367; fax:E-mail address: karol.kacprzak@gmail.com (K. Kac

The synthesis and conformational preferences of 9-azido-(9-deoxy)-Cinchona alkaloids constituting anovel class of Cinchona alkaloid derivatives of both natural and 9-epi configurations are described. Oneand two-step preparative syntheses of 9-azido-(9-deoxy)-Cinchona alkaloids have been developed, allow-ing for their easy access on a multigram scale. The stereochemical integrity of these azides has been con-firmed from their circular dichroism and specific rotation data. The conformations of the 9-azidoCinchona alkaloids, deduced from both 1H NMR and DFT calculations, show that this class of Cinchonaderivatives largely reflect the conformational preferences of the corresponding Cinchona bases; this strat-egy, therefore, offers a defined chiral and clickable scaffold.

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1. Introduction

The Cinchona alkaloids comprising quinine and quinidine as itsmain members are a unique family of natural products which havefound numerous applications as pharmaceuticals,1 ‘Privileged’ typeorganocatalysts,2 resolving agents3, and chiral selectors in enantio-selective analytical applications.4 In most of these applications,parent (unmodified) alkaloids or their simple derivatives includingesters, ethers, or quaternary ammonium salts have been employed.Most recently, however, many more complex Cinchona alkaloidsderivatives have been demonstrated to be very efficient bifunc-tional organocatalysts, for example, 9-epi-Cinchona thioureas5 orhighly discriminative chiral selectors for enantioselective chroma-tography.4,6 Less attention has been devoted to other 9-substitutedCinchona alkaloids, for example, amides,7 imides, and imines8 orsulfides.9

9-Azido-(9-deoxy)-Cinchona alkaloids seem to be an attractiveplatform for their further elaboration into more complex deriva-tives due to the high inherent reactivity of the azido group10

located in a crucial part of Cinchona moiety. One of the moststraightforward ways of their further functionalization is the syn-thesis of the corresponding 1,2,3-triazoles via click chemistry(Huisgen 1,3-dipolar cycloaddition).11 Feasibility studies in thisarea demonstrated by our group have confirmed the easy synthesisof such types of triazolo-Cinchona hybrids.12 Encouraged by theseresults, we expanded our strategy to produce more complex Cin-chona-triazole linked derivatives and, therefore, needed a reliablemethod for the multigram preparation of 9-azido Cinchona alka-loids in pure stereochemical form. These relatively simple deriva-tives have not been systematically described in the literature.

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+48 61 829 1505.przak).

Brunner has adopted a one-pot Mitsunobu inversion–reductionprotocol for the synthesis of 9-amino Cinchona alkaloids, withoutthe isolation of intermediate 9-azido derivatives (their formationin situ has been confirmed by IR spectroscopy).13 More recently,Hoffmann et al. have also generated in situ 9-azido-(9-deoxy)-Cin-chona alkaloids and 9-azido-(9-deoxy)-10,11-didehydro Cinchonaalkaloids by nucleophilic substitution of their corresponding 9-O-mesylates with NaN3 and used them without isolation for an intra-molecular cycloaddition/rearrangement cascade.14

The aim of this work was to develop a scalable synthesis of9-azido-(9-deoxy)quinine and quinidine of the both natural and9-epi configurations, as well as their systematic characterizationin terms of their stability and stereochemical integrity. Another is-sue to be addressed is to study the conformation of 9-azido-(9-deoxy)-Cinchona alkaloids by using a combined approachinvolving NMR and DFT calculations in order to identify thepreferred geometry, helping the construction of structurallydefined Cinchona derivatives thereof.

2. Results and discussion

2.1. Synthesis

The first attempt to synthesise 9-azido-(9-deoxy)-Cinchonaalkaloids involved the one-step Mitsunobu inversion of the parentquinidine QD, quinine QN, and their epimers—9-epiquinidine epi-QD and 9-epiquinine epi-QN with HN3, following the protocol pub-lished by Brunner et al.13 or by using diphenylphosphoryl azide(DPPA) as the azide source (Scheme 1). Although these inversionswere successful and gave almost complete consumption of alka-loids after 12 h of reaction, very laborious chromatographic purifi-cation of the desired azides QD-2 and epi-QD-2 was requiredresulting in a large consumption of solvents and moderate isolated

Table 1Electronic circular dichroism (ECD) characteristics of 9-azido-(9-deoxy)-Cinchonaalkaloidsa

Azide CD bands

a, De (nm) p, De (nm) b, De (nm) Other, De (nm) Confg.

QD-2 �0.6 (337) �2.8 (267) +10.8 (243) �8.1 (208) (8R,9S)+0.6 (302) +9.8 (238)b

+0.6 (296)epi-QD-2 +0.3 (335) �0.8 (263) �6.3 (239) +14.5 (214) (8R,9R)

�0.1 (325) +14.1 (200)b

QN-2 +0.4 (337) — +2.6 (244) +13.7 (212) (8S,9R)�1.7 (295) +2.5 (233) +14.2 (206)b

epi-QN-2 �0.2 (337) +1.0 (278) +2.9 (233) +1.2 (215)b (8S,9S)

a All measurements in acetonitrile, c 10�4 M.b Shoulder.

N

N

OMe

OH

N

N

OMe

OH

N

N

OMe

OMs

N

N

OMe

N3

N

N

OMe

OMs

N

N

OMe

N3

QD epi-QD

98

a b a

c cd d

QD-1

epi-QD-2

epi-QD-1

QD-2N

N

OMe

N

N

N

QD-3

e

Scheme 1. Reagents and conditions: (a) MsCl, TEA, THF, rt; (b) tartaric acid, H2O, reflux 3 h; (c) DIAD, PPh3, HN3 (or DPPA), THF, rt 12 h; (d) NaN3, DMF, 40–50 �C, 12–24 h.Similar sequence has also been completed using quinine (QN) with exception of quinine-derived triazoline.

K. Kacprzak, B. Gierczyk / Tetrahedron: Asymmetry 21 (2010) 2740–2745 2741

yields of 55–60%. Thus, we decided to use a two-step sequenceinvolving the O-mesylation of the alkaloids followed by nucleo-philic substitution of 9-O-mesylates with inorganic azides(Scheme 1). 9-O-Mesylates were obtained using an efficient meth-od developed by Hoffmann14,15 with isolated yields of >80%. Theazidation step was then completed by using sodium azide(1.5 equiv) in DMF at 40–50 �C for 24-48 h. This route has beenfound to be very efficient for the substitution of 9-O-mesylates ofnaturally configured alkaloids and the resulting epi-configured 9-azides epi-QD-2 and epi-QN-2 after simple chromatographic isola-tion were produced in high yield with high purity (75–95%, seeSection 4). Under these conditions, epi-configured azides were sta-ble and we did not observe the formation of the correspondingtriazolines formed by the intramolecular cycloaddition of the azideto vinyl group (see also Ref. 14). Similarly, the azidation of 9-O-me-syl-9-epiquinine also proceeded cleanly to give 60–65% of the de-sired azide QN-2. Unfortunately the azidation of an analogous,pseudoenantiomeric 9-O-mesyl-9-epiquinidine epi-QD-1 gave inaddition to the expected azide QD-2, also significant amounts(20–40%) of the corresponding triazoline QD-3, which was theintramolecular cycloaddition product of the azide and vinylgroup.16 This contrasting behavior between naturally and 9-epiconfigured quinidines has already been observed by Hoffmann14

who rationalized it by means of different structures of these twostereoisomeric compounds (vide infra). Attempts to minimize thisside reaction by the use of lithium azide or HN3 in toluene as nucle-ophiles at room temperature showed similar levels of theformation of triazoline QD-3. On the other hand, practically quan-titative conversion of a mixture of 9-O-mesyl-epi-quinidine/so-dium azide or isolated azide QD-2 leading to QD-3 has beenobserved by an increase of temperature. For example, heating 9-azidoquinidine (0.03 M) in DMSO-[2H]6 at 333 K resulted in over95% formation of the corresponding triazoline after 24 h as moni-tored by 1H NMR spectroscopy giving the calculated intramolecu-lar reaction rate for k = 4 � 10�5 s�1. In contrast, 9-azido-(9-deoxy)epiquinidine epi-QD-2 gave only ca. 5% of the correspondingtriazoline after 7 days of heating under similar conditions.

Having in hand a reliable synthetic protocol, we checked thestereochemical integrity of the produced 9-azido Cinchona alka-loids by comparison of their electronic circular dichroism spectra(CD) and specific rotation data. Circular dichroism spectra of theparent Cinchona alkaloids usually show three distinct band, whichhistorically have been designated after Clar as a, p and b bands, and

correspond to the 1Lb, 1La and 1Bb bands in the naphthalene chro-mophore.17 9-Azido-(9-deoxy)-Cinchona alkaloids in addition tothe naphthalene chromophore also contain an azido group whichitself constitutes a chromophore,18 thus the CD of this class ofderivatives may involve the sum of their individual counterparts.Generally, alkyl azides show two weak transitions in the ultravioletregion.19 The first one, located at ca. 216 nm, is associated with s-px?p* transition, whereas the second at the longer wavelength(ca. 287 nm) originates from the p?p* transition. The CD spectraof 9-azido-(9-deoxy)-Cinchona alkaloids are presented in Table 1and Figure 1. As evidenced from the data, the spectra of the azidesdiffer from each other in terms of position, sign, and magnitude ofthe Cotton effect, but the main pattern (e.g. occurrence of the threetypical bands) shows a high degree of similarity as compared to thenative Cinchona alkaloids. The contribution of the weak transitionsoriginating from the presence of the azide chromophore in the CDspectra is unfortunately not evident, as they occur in the region ofthe quinoline chromophore absorption. More importantly, CDcharacteristics allow easy identification of each individual azide.20

For example, in the QN-2/QD-2 pair (natural configuration at car-bon-9, but pseudoenantiomeric relation) the long-wavelength Cot-ton effects at ca. 330, 290, and 270 as well as the short wavelengthCotton effect centered at 210 nm show a nearly perfect mirror-im-age with similar magnitudes of the Cotton effect. This is not thecase for the Cotton effect at 240 nm which is positive for azideQN-2 and QD-2. Generally, the CD characteristics of naturally con-figured QN-2 and QD-2 largely reflect the CD spectra of the parent

nm200 220 240 260 280 300 320 340 360

Δε

-5

0

5

10

15

QN-2QD-2epi-QD-2epi-QN-2

Figure 1. CD spectra of 9-azido-(9-deoxy)-Cinchona alkaloids (in MeCN, c�10�4 mol/dm3).

N

N

H

O

H

H

N3

H

HH

N

N

H

O

H

H

H

HH

N3

N

N

O

HN3

H

H

H

H

H

N

N

OCH3

H

H

H

H

HN3

H

3'

9

3'

8b 7a 6a

5'

6a

5'

7a8b

9

QN-2 epi-QN-2

5'

3'

8a

9

7b

2a 5'

3'

8a

9 7b

11'

11b

QD-2 epi-QD-2

Figure 2. Structure, proton numbering, and observed NOE’s in 9-azido-(9-deoxy)-Cinchona alkaloids (see text for details).

2742 K. Kacprzak, B. Gierczyk / Tetrahedron: Asymmetry 21 (2010) 2740–2745

quinine and quinidine, both with respect to the Cotton effect se-quence and position. A less clear situation is observed for the 9-epi-configured azides epi-QD-2 and epi-QN-2 because they bothshow less intense bands (especially epi-QN-2) making the compar-ison and precise assignment of the bands more difficult. Neverthe-less, the long-wavelength region of the epimers again showsmirror-image characteristics indicating that the transitions local-ized in this part of spectrum are sensitive to the configuration atC-8/9 in alkaloid moiety. This is not the case for the short wave-length Cotton effect which is positive for both epimers but differssignificantly with respect to the magnitude and position. Unfortu-nately, the rather complex CD picture of azides studied does not al-low correlation of the observed spectra with the conformation ofthe particular azides (vide infra).

2.2. Conformation

The conformational behavior of Cinchona alkaloids and theirderivatives is principally determined by the rotation of the two sin-gle C8-C9 and C40-C9 bonds connecting the rigid quinoline ring andquinuclidine moiety. Generally, two distinct compact conforma-tions are denoted where the lone electron pair of the quinuclidinenitrogen points over the quinoline ring (closed conformation)whereas two more relaxed conformers with the quinuclidine nitro-gen oriented away from the quinoline ring are denoted as open (seeFig. 2).21 Several studies in this subject22 reveal that the alkaloidsof natural configuration at C9 adopted in the non-polar solventsanti-open conformation, in contrast to the polar solvents whichmay stabilize also syn-closed conformers. The 9-epimers of Cin-chona alkaloids and their derivatives usually prefer the openconformation as has been demonstrated for 9-epi-configuredamides7 and imides.23

The different reactivities of 9-azides toward intramolecularcycloaddition as well as conformationally dependent propertiesof Cinchona alkaloids in stereoselective synthesis or in chiral recog-nition2a led us to study in more detail the conformation of thesenew derivatives. For this purpose, 1H NMR and NOESY spectros-copy as well as molecular modeling was examined. Determinationof the coupling constant of the doublet of protons H9 and H8 is asensitive measure of the conformation of the Cinchona alkaloids.We have found that independent of the configuration at C9, largeJH9–H8 values varying from 10.5 to 11.5 Hz (CDCl3) indicate an antiarrangement of these protons and as a consequence a closed con-formation for naturally configured and open for 9-epi-configuredCinchona azides.

A more detailed insight into the conformation of the studied 9-azido derivatives of Cinchona alkaloids has been made by analysisof nuclear Overhauser effects between H-9, quinoline and quinucli-dine moiety hydrogens (Fig. 2). For 9-azido-(9-deoxy)quinine QN-2, strong NOE’s between H-6a and H-9, H-30, H-50 as well as H-9and H-7a were observed, indicating closed conformations. Detec-tion of H6a/H30 and H6a/H50 NOEs shows that both syn-closedand anti-closed conformers are present in the solution. On the otherhand, the presence of open conformers is easily confirmed by H-8band H-9 as well as H-7a and H-30 NOEs. Since the irradiation of H-7a does not enhance a H-50 signal, the anti-open conformer in CDCl3

could be excluded. Analysis of the H-50 and H-30 signal intensitiesafter H-6a irradiation demonstrates that among closed conforma-tions, syn-closed is preferred (the ratio of syn-closed to anti-closedis about 2:1). The calculated ratio of open to closed conformers isabout 1:1.

In the case of 9-azido-(9-deoxy)quinidine QD-2, strong NOEswere observed between H-9 and H-2a as well as H-9 and H-7b,indicating the predominance of the open conformers. The contribu-tion of closed conformation into the conformational equilibrium ofQD-2 in chloroform is rather small as evidenced by very weakenhancement of the quinoline hydrogen signal after H-2a irradia-tion. The calculated amount of closed conformer population is lessthan 10%, but both the (syn and anti) species are present (both H-2a/H-50 and H-2a/H-30 NOEs were detected). Strong H-7b/H-30

NOEs, the absence of H-7b/H-50 NOEs, as well as H-9/H-30(50) andH-8b/H-30(50) NOEs ratios indicate that the syn-open conformer ismore stable in solution.

Irradiation of the H-6a hydrogen of 9-azido-(9-deoxy)epiqui-nine epi-QN-2 does not enhance any quinoline proton signalswhich thus allows us to exclude the occurrence of this compoundin the closed conformation. On the other hand, the presence of anopen conformation is confirmed by strong H-7a/H-30(50) and H-6a/H-9 NOEs. As a result of an almost equal increase of H-30 andH-50 intensities after H-8 (or H-7a) irradiation, the populations of

Figure 3. Computed lowest-energy conformers of 9-azido-(9-deoxy)-Cinchonaalkaloids (B3LYP hybrid functional and a 6-31g(D,P) basis set).

K. Kacprzak, B. Gierczyk / Tetrahedron: Asymmetry 21 (2010) 2740–2745 2743

syn-open and anti-open conformers in CDCl3 could be deduced to besimilar. The pseudoenantiomeric 9-azido-(9-deoxy)epiquinidineepi-QD-2 shows very similar behavior. The absence of nuclearOverhauser effects between H-2a and quinoline protons supportsthe exclusive presence of open conformers. These were also con-firmed by the detection of NOEs between H-7b and H-30(50) or H-110 and H-11b, respectively. As in the case of epi-QN-2, both syn-open and anti-open conformers of epi-QD-2 exist in solution in sim-ilar amounts.

2.3. Molecular modeling

Molecular modeling studies were carried out for all diastereo-isomeric azides QN-2 and epi-QN-2, and QD-2 and epi-QD-2. Sys-tematic generation of the conformers has been performed byrotating all the torsional angles which contribute to the conforma-tion (see Fig. 3) using a molecular mechanics method (MM+). Foreach individual azide, ca. 100 distinct conformers have been gener-ated within 0–10 kcal energy range and fully optimized by usingthe DFT method with the B3LYP hybrid functional and a 6-31g(D,P) basis set. The lowest energy conformers of each azideare despited in Figure 3. As expected, the computational datastrongly support the conformational characteristic of 9-azido Cin-chona alkaloids deduced from the spectroscopic experimentsaforementioned. Moreover, it is worth noting that for the naturallyconfigured azides both closed and open conformations have beenidentified as those of lowest energy whereas the open conformersare the most stable for epimeric azides epi-QN-2 and epi-QD-2.In particular, the lowest energy conformation of QN-2 is syn-closedbut the energy difference between the anti-closed (0.61 kcal/mol)and anti-open conformation (1.19 kcal/mol) is relatively small(note that computations are preformed in vacuo). This has alsobeen observed for quinine derived azide QN-2 for which anti-openand syn-closed conformers are of lowest energy, differing by about0.8 kcal/mol. The epimeric azides epi-QN-2 and epi-QD-2 bothshow very similar conformational preferences, with the most sta-ble syn-open conformation for epi-QN-2 and anti-open for epi-QD-2. In this case, however, the gain in energy when comparedwith their nearest closed conformations is about 1.5–2.5 kcal/mol,thus precluding their presence under ambient conditions (in agree-ment with experimental data, no closed conformation has not beenfound by NMR).

3. Conclusion

Synthetically interesting, especially with regards to Huisgen1,3-dipolar cycloaddition (click chemistry), stereoisomeric 9-azi-do-(9-deoxy)-Cinchona alkaloids derived from both quinine andquinidine have been prepared and systematically characterized.These azides largely reproduce the conformational dynamics oftheir precursors (parent Cinchona alkaloids) thus offering a chiralscaffold of predictable structure for further elaboration.

4. Experimental

4.1. General

Quinine QN and quinidine QD were of commercial grade (BuchlerGmbH) usually accompanied by <10% of 10,11-dihydro alkaloids. 9-Epiquinine epi-QN, 9-epiquinidine (epi-QD) were prepared by theprocedure of Hoffmann.24 9-O-Mesyl Cinchona alkaloids were ob-tained by standard mesylation as described in reference.15 HN3 solu-tion in benzene or toluene (caution: toxic and volatile) was preparedaccording to the literature.25 All other reagents were purchasedfrom Aldrich and Fluka and used as received. Anhydrous THF wasdistilled over potassium/benzophenone, other solvents were

distilled. Preparative column chromatography was performed onan Argonaut system using prepacked silica gel cartridges or by con-ventional column chromatography on silica gel.

The NMR spectra were recorded at 295.0 ± 0.1 K on BrukerAvance DRX 600 spectrometer, operating at frequencies of600.055 MHz for 1H and 150.899 MHz for 13C equipped with a5 mm triple-resonance inverse probehead {1H/31P/BB} with aself-shielded z-gradient coil. Spectra were measured in freshlydistilled CDCl3, the sample concentrations were 10 mg per 600 llof solvent. Before NOE experiments, samples were flame-sealedafter deoxygenation by purging with pure nitrogen gas for10 min, and then degassing using ultrasonic bath and evacuation.

2744 K. Kacprzak, B. Gierczyk / Tetrahedron: Asymmetry 21 (2010) 2740–2745

All shifts were referenced to the internal tetramethylsilane. 1D gra-dient selected NOESY spectra were recorded using a standard se-quence from Bruker sequences library, mixing time (d8) was setto 0.300 s; 256–512 scans were collected.

Mass spectra were recorded on a AMD 604/402, IR spectra (KBrpellets) were recorded on a Brucker ITS 113v spectrometer. Opticalrotation was measured using Perkin–Elmer LS-30 spectropolarim-eter. Cache Worksystem Pro 5 (Fujitsu) and GAUSSIAN 4.0 (Gauss-ian)26 was used for the molecular modeling.

4.2. General procedure for the synthesis of 9-azido-(9-deoxy)-Cinchona alkaloids by the substitution of the corresponding 9-O-mesylates (Method A)

A stirred solution of 2.5 g of 9-O-mesylquinidine (6.2 mmol,1 equiv) in 12 ml of anhydrous DMF was treated with 0.6 g ofNaN3 (9.23 mmol, 1.5 equiv). The mixture was stirred on oil bathat 45–55 �C until all the mesylate was consumed (12–48 h, TLCmonitoring), after which filtration of salts, and evaporation ofDMF under reduced pressure (water bath 50 �C) took place. Thecrude azide was dissolved in a small portion of dichloromethaneand purified by liquid chromatography on silica gel using 5% meth-anol in dichloromethane. Yield: 1.63 g (75%) as yellowish, denseoil.

4.3. General procedure for the synthesis of 9-azido-(9-deoxy)-Cinchona alkaloids by Mitsunobu inversion (Method B)

The reaction is preformed under an inert atmosphere. To thestirred solution of 0.51 g of 9-epi-quinidine (1.57 mmol, 1 equiv)and 0.62 g of triphenylphosphine (2.36 mmol, 1.5 equiv) in 15 mlof anhydrous THF cooled on an ice-bath to 0 �C, 0.41 mL of DPPA(1.88 mmol, 1.2 equiv) was added by syringe (or alternatively3 ml of hydrazoic acid �4%, �3 mmol in benzene—caution: volatilepoison) followed by the slow addition of DIAD (0.45 ml, 1.2 equiv).The solution was left to stir overnight. Solvent was removed onrotatory evaporator (bath <30 �C) and the residue was purified bycolumn chromatography on silica gel using 5% MeOH in dichloro-methane as the solvent. Products in the forms of dense oils wereprepared with yields of 50–60%.

4.4. (8R,9R)-9-Azido-(9-deoxy)epiquinidine epi-QD-2

1H NMR (CDCl3): d 8.79 (d, 1H, J = 4.3 Hz, H-20), 8.07 (d, 1H,J = 9.1 Hz, H-80), 7.45 (br s, 1H, H-50), 7.42 (dd, 1H, J = 9.1, 4.3 Hz,H-70), 7.37 (d, 1H, J = 4.3 Hz, H-30), 5.87 (ddd, 1H, J = 17.2, 10.8,6.3 Hz, H-10), 5.11 (dt, 1H, J = 10.4, 1.7 Hz, H-11b), 5.10 (dt, 1H,J = 17.2, 1.7 Hz, H-11a), 5.08 (br, 1 H, H-9), 3.97 (s, 3H, H-110),3.26 (pseudoq, 1H, J = 9.3 Hz, H-8a), 3.15 (dd, 1H, J = 14.5, 10.4 Hz,H-2b), 3.07 (dd, 1H, J = 13.5, 2.4 Hz, H-6a), 3.01 (ddd, 1H, J = 13.5,9.6, 7.9 Hz, H-6b), 2.94 (dd, 1H, J = 14.5, 7.6, 2.1 Hz, H-2a), 2.32(m, 1H, H-3), 1.65 (m, 1H, H-4), 1.55 (m, 2H, H-5a,b), 1.13 (ddd,1H, J = 13.8, 8.8, 1.8 Hz, H-7b), 0.94 (m, 1H, H-7a). 13C NMR(CDCl3): 158.11 (C-60), 147.46 (C-20), 144.98 (C-40), 140.92 (C-90),140.34 (C-10), 132.09 (C-80), 127.54 (C-100), 122.08 (C-70), 120.71(br, C-30), 114.77 (C-11), 101.29 (C-50), 62.40 (br, C-9), 59.85 (br,C-8), 55.57 (C-110), 49.34 (C-6), 47.39 (C-2), 39.18 (C-3), 27.19(C-4), 26.41 (C-5), 25.14 (C-7); HRMS (EI) calcd for C20H23N5O349.1903, found 349.1894, IR (KBr) m (cm�1) 2938, 2100, 1675,1621, 1508, 1475, 1433, 1258, 1227, 1137, 1090, 1030, 852, 828;[a]D = +55.7 (c 1, CHCl3).

4.5. (8R,9S)-9-Azido-(9-deoxy)quinidine QD-2

Method B, yellowish oil, 300 mg (55%), 1H NMR (CDCl3): d 8.79(d, 1H, J = 4.4 Hz, H-20), 8.06 (d, 1H, J = 9.2 Hz, H-80), 7.40 (dd, 1H,

J = 9.2, 2.7 Hz, H-70), 7.39 (d, 1H, J = 4.4 Hz, H-30), 7.29 (d, 1H,J = 2.7 Hz, H-50), 6.03 (ddd, 1H, J = 17.3, 10.4, 7.1 Hz, H-10), 5.22(bd, 1H, J = 6.3 Hz, H-9), 5.13 (dt, 1H, J = 10.4, 1.4 Hz, H-11b), 5.10(dt, 1H, J = 17.3, 1.4 Hz, H-11a), 3.95 (s, 3H, H-110), 3.20 (pseudoq,1H, J = 8.4 Hz, H-8a), 2.95 (ddd, 1H, J = 14.3, 7.9, 2.2 Hz, H-2a),2.89 (dd, 1H, J = 14.3, 9.9 Hz, H-2b); 2.84 (m, 1H, H-6b), 2.75 (m,1H, H-6a), 2.26 (m, 1H, H-3), 1.87 (dd, 1H, J = 13.9, 9.7 Hz, H-7b),1.87 (m, 1H, H-4), 1.56 (m, 2H, H-5a,b), 1.52 (m, 1H, H-7a). 13CNMR (CDCl3): 158.11 (C-60), 147.58 (C-20), 144.93 (C-40), 142.15(C-90), 140.23 (C-10), 132.09 (C-80), 127.13 (C-100), 121.72 (C-70),119.39 (C-30), 114.83 (C-11), 101.16 (C-50), 65.10 (br, C-9), 58.58(C-8), 55.64 (C-110), 49.86 (C-6), 48.71 (C-2), 39.70 (C-3), 27.87(C-4), 26.33 (C-5), 24.19 (C-7); HRMS (EI) calcd for C20H23N5O349.1903, found 349.1899, IR (KBr) m (cm�1) 2940, 2102, 1620,1588, 1473, 1450, 1259, 1228, 1133, 1088, 1032, 850, 830;[a]D = +28.0 (c 1, CHCl3).

4.6. (8S,9S)-9-Azido-(9-deoxy)epiquinine epi-QN-2

Method A, yellowish oil, yield 2.53 g (95%), 1H NMR (CDCl3): d8.79 (d, 1H, J = 4.5 Hz, H-20), 8.09 (d, 1H, J = 9.1 Hz, H-80), 7.48 (br,1H, H-50), 7.43 (dd, 1H, J = 9.1, 2.6 Hz, H-70), 7.34 (d, 1H,J = 4.5 Hz, H-30), 5.76 (ddd, 1H, J = 17.4, 10.4, 7.4 Hz, H-10), 5.02(br, 1H, H-9), 5.01 (dt, 1H, J = 17.4, 1.4 Hz, H-11a), 4.98 (dt, 1H,J = 10.4, 1.4 Hz, H-11b), 3.97 (s, 3H, H-110), 3.38 (pseudoq, 1H,J = 9.6 Hz, H-8b), 3.22 (m, 1H, H-6a), 3.32 (dd, 1H, J = 14.0,10.7 Hz, H-2a); 2.91 (m, 1H, H-6b), 2.85 (ddd, 1H, J = 14.0, 4.4,2.5 Hz, H-2b), 2.30 (m, 1H, H-3), 1.67 (m, 1H, H-4), 1.59 (m, 2H,H-5a,b), 1.40 (m, 1H, H-7b), 0.78 (ddm, 1H, J = 13.9, 7.7 Hz, H-7a).13C NMR (CDCl3): 158.09 (C-60), 147.94 (C-20), 145.01 (C-40),141.32 (C-10), 140.36 (C-90), 132.08 (C-80), 127.55 (C-100), 121.82(C-70), 120.89 (br, C-30), 114.26 (C-11), 101.60 (C-50), 63.67 (br, C-9), 59.11 (C-8), 55.99 (C-2), 55.57 (C-110), 40.91 (C-6), 39.35 (C-3), 27.94 (C-5), 27.18 (C-4), 26.15 (C-7); HRMS (EI) calcd forC20H23N5O 349.1903, found 349.1903, IR (KBr) m (cm�1) 2942,2100, 1674, 1621, 1590, 1508, 1475, 1432, 1259, 1242, 1228,1134, 1083, 1032, 918, 853, 831, 755; [a]D = +77.5 (c 1, CHCl3).

4.7. (8S,9R)-9-Azido-(9-deoxy)quinine QN-2

Method B, yellowish oil, yield 50%, 1H NMR (CDCl3): d 8.79 (d,1H, J = 4.6 Hz, H-20), 8.07 (d, 1H, J = 8.6 Hz, H-80), 7.41 (dd, 1H,J = 8.6, 2.7 Hz, H-70), 7.39 (d, 1H, J = 4.6 Hz, H-30), 7.32 (d, 1H,J = 2.7 Hz, H-50), 5.82 (ddd, 1H, J = 17.5, 10.2, 7.5 Hz, H-10), 5.19(br d, 1H, J = 7.2 Hz, H-9), 5.01 (dt, 1H, J = 17.5, 1.4 Hz, H-11a),4.99 (dt, 1H, J = 10.2, 1.4 Hz, H-11b), 3.95 (s, 3H, H-110), 3.27 (pseu-doq, 1H, J = 7.4 Hz, H-8b), 3.12 (m, 1H, H-6a), 3.06 (dd, 1H, J = 13.5,9.9 Hz, H-2b); 2.64 (m, 2H, H-2a, H-6b), 2.27 (br m, 1H, H-3), 1.90(m, 1H, H-7b), 1.86 (m, 1H, H-4), 1.70 (m, 1H, H-5a), 1.57 (ddm, 1H,J = 13.6, 7.8 Hz, H-7a), 1.53 (m, 1H, H-5b). 13C NMR (CDCl3): 158.04(C-60), 147.48 (C-20), 144.83 (C-40), 141.82 (C-90), 141.50 (C-10),131.99 (C-80), 127.03 (C-100), 121.65 (C-70), 119.46 (C-30), 114.49(C-11), 101.04 (C-50), 65.28 (br, C-9), 58.41 (C-8), 56.48 (C-2),55.59 (C-110), 41.98 (C-6), 39.48 (C-3), 27.59 (C-5), 27.50 (C-4),24.93 (C-7).HRMS (EI) calcd for C20H23N5O 349.1903, found349.1893, IR (KBr) m (cm�1) 2941, 2103, 1724, 1621, 1590, 1508,1473, 1455, 1432, 1256, 1242, 1228, 1132, 1084, 1031, 989, 912,852, 832, 737; [a]D = �28.2 (c 1.1, CHCl3).

4.8. QD-3 (triazoline)

1H NMR (DMSO-d6): d 8.77 (d, 1H, J = 4.6 Hz, H-20), 8.02 (d, 1H,J = 9.2 Hz, H-80), 7.59 (d, 1H, J = 4.6 Hz, H-30), 7.47 (dd, 1H, J = 9.2,2.7 Hz, H-70), 7.27 (d, 1H, J = 2.7 Hz, H-50), 6.34 (s, 1H, H-9), 4.49(dd, 1H, J = 20.8, 13.5 Hz, H-11b), 4.48 (m, 1H, H-10), 4.11 (dd,1H, J = 20.8, 12.8 Hz, H-11a), 3.94 (s, 3H, H-110), 3.35 (d, 1H,

K. Kacprzak, B. Gierczyk / Tetrahedron: Asymmetry 21 (2010) 2740–2745 2745

J = 10.0 Hz, H-8a), 2.84 (dd, 1H, J = 13.0, 9.6 Hz, H-6b), 2.72 (m, 1H,H-6a), 2.67 (dd, 1H, J = 14.4, 7.9 Hz, H-2b); 2.32 (d, 1H, J = 14.4 Hz,H-2a), 2.00 (m, 1H, H-4), 1.95 (m, 1H, H-7b), 1.71 (m, 1H, H-3), 1.52(m, 1H, H-5b), 1.37 (m, 1H, H-5a), 1.18 (m, 1H, H-7a). 13C NMR(CDCl3): 157.57 (C-60), 147.80 (C-20), 146.07 (C-40), 143.80 (C-90),131.61 (C-80), 125.82 (C-100), 121.39 (C-70), 120.19 (C-30), 101.03(C-50), 72.47 (C-11), 62.88 (br, C-9), 58.52 (C-10), 55.63 (C-8),55.57 (C-110), 47.49 (C-6), 45.36 (C-5), 39.09 (C-3), 26.19 (C-4),23.59 (C-5), 22.74 (C-7); IR (KBr) m (cm�1) 1620, 1591, 1506,1497, 1470, 1434, 1426, 1302, 1232, 1136, 1049, 1024, 827, 712

Acknowledgments

Research support from European Commission (project click-funGrant No. 206943) is gratefully acknowledged. The authors are in-debted to Dr. Paweł Skowronek for their help in molecularmodeling.

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